Tetrahedron 63 (2007) 8939ndash8948

Nor-limonoid and homoisoanticopalane lactonesfrom methyl isoanticopalate

Pilar Basabea Sergio Delgadoa Isidro S Marcosa David Dieza Alberto Diegoa

Monica de Romana Francisca Sanzb and J G Uronesa

aDepartamento de Quımica Organica Facultad de Ciencias Quımicas Universidad de SalamancaPlaza de los Caıdos sn 37008 Salamanca Spain

bServicio General de Rayos X de la Universidad de Salamanca Plaza de los Caıdos sn 37008 Salamanca Spain

Received 27 March 2007 revised 30 May 2007 accepted 5 June 2007

Available online 9 June 2007

AbstractmdashA nor-limonoid with a g-hydroxybutenolide group was obtained starting from the known methyl isoanticopalate A new route forthe synthesis of several lactones with a homoisoanticopalane skeleton has been opened The stereochemistry of three intermediates wasestablished by X-ray determination 2007 Elsevier Ltd All rights reserved

1 Introduction

Marine sponges are a rich source of biologically active sec-ondary metabolites with novel chemical structure1 Severalsesterterpenolides isolated from marine sponges2 showanti-inflammatory activity as the most important biologicalactivity

Petrosaspongiolides M(1) N(2) P(3) Q(4) and R(5) iso-lated from Petrosaspongia nigra3 are a serie of novel sester-terpenes possessing a cheilanthane skeleton that have beentested for activity against a panel of PLA2 enzymes (Fig 1)

Recently four cheilanthane sestertepenoids 6ndash9 were iso-lated from the marine sponge Ircinia sp4 The four com-pounds inhibit MSK1 and MAPKAPK2 two proteinkinases involved in nitrogen and stress signal transduction(Fig 2)

0040ndash4020$ - see front matter 2007 Elsevier Ltd All rights reserveddoi101016jtet200706004

Studies towards the synthesis of cheilanthane sestertepe-noids have been carried out by superacidic low temperaturecyclization of 13Z17Z and 13Z17E-bicyclogeranylfarne-soic acid methyl esters5 to afford 14-epi-cheilanthane 10and a rearranged 14-epi-cheilanthane terpenoid 11 (Fig 3)

H

H

HO

O

HO

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O

O

O

HOH

H

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O

OH

O

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HO

O

HO

OH

6 7

8 9

Figure 2

H

H

H

OH

OAc

R

OO

HOH

H

H

OH

OH

R

OO

HOH

H

H

COOHH

OO

HO

1 R = H2 R = OAc

3 R = H4 R = OAc

5

Figure 1

Keywords Sesterterpenolides Petrosaspongiolides Methyl isoanticopalate Nor-limonoids Homoisoanticopalane lactones Corresponding author Fax +34 923 294574 e-mail pbbusales

8940 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

In our group methyl isoanticopalate 12 that can be obtainedfrom sclareol6 has been used for the synthesis of secospon-gianes7 hyrtiosal8 subersic acid9 and sesterterpenolides asluffolide10

In this paper we communicate the synthesis of a nor-limonoid 15 that can be considered as an analogue of

H

H

COOMe

H

COOMe

10

1

3 7

9

12

14

17

19

20 21

22 2324

25

11

1

3 7

911

1719

20 21

22

23

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25

16

Figure 3

H

H

H

OH

O

O

O

OH

H

H

H COOMe H

H

H

O

O

H

H

H

OH

O

15

12 13

14

Scheme 1 Retrosynthetic scheme for the synthesis of compound 15 frommethyl isoanticopalate 12

petrosaspongiolides and several lactones 13 14 25 and26 with a homoisoanticopalane skeleton which are usefulsynthons for the synthesis of biological active compounds

2 Results and discussion

In order to achieve these objectives we decided to obtain firstof all lactone 13 from methyl isoanticopalate

The final objective is the synthesis of the nor-limonoid 15 inorder to obtain this compound we designed the followingretrosynthetic scheme (Scheme 1) Compound 15 could pro-ceed form lactone 14 by addition of 3-furyllithium and ulte-rior synthesis of the hydroxybutenolide following Faulknermethodology11 Compound 14 could be obtained from 13by changing the lactone ring disposition and the last com-pound from methyl isoanticopalate 12

21 Synthesis of lactone 13

As first objective we decided to obtain lactone 13 as shownin Scheme 2 Epoxidation of methyl isoanticopalate 12 ledto compound 16 its structure being confirmed by X-raycrystallography12 (Fig 4) Reaction of 16 in Ruvedas condi-tions13 gave the allylic alcohol 17 that was protected as itsMOM derivative 18 Elongation of the side chain in one car-bon atom was done by reduction to alcohol 19 oxidation tothe aldehyde 20 and Wittig reaction with methoxymethyltri-phenyl phosphorane14 gave mixture of enol ethers 21 in anexcellent yield These compounds were hydrolyzed to alde-hyde 22 which on oxidation to acid and esterification withTMSCHN2 gave the methyl ester 23 When this compound

H

H

COOMe

OH

H

H

COOMe

O

H

H

COOMe

H

H

COOMe

OMOM

H

OMOM

OHH

H

H

CHO

OMOM

H

H

OMOM

OMe

H

H

CHO

OMOM

H

COOMe

OMOM

H

H

H

O

O

16 1712

12

14

a b

181920

21a21b 22

d

hi

23

c

e

j

13

H H H

HHH

H H H

H

f

g

Scheme 2 (a) m-CPBA DCM rt 12 h 71 (b) Al(iPrO)3 benzene 150 C 4 h 94 (c) DMM P2O5 CHCl3 0 C to rt 30 min 99 (d) DIBAL-H DCM78 C 30 min 90 (e) TPAP NMO DCM sieves 4 A rt 10 min 86 (f) (MeOCH2PPh3)+Cl NaHMDS THF 78 C 45 min 82 (g) p-TsOH ace-tone rt 7 h 99 (h) tBuOH2-methyl-2-butene 25 NaH2PO4NaClO2 rt 99 (i) TMSCH2N2 benzenehexane rt 83 and (j) 6 N dioxaneH2SO4 (131)90 C 14 h 93

8941P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

was treated with sulfuric acid in dioxane it produced the de-sired lactone 13 in excellent global yield Scheme 2

22 Transformation of lactone 13 to lactone 14

With an easy way to obtain lactone 13 the transformationinto lactone 14 was carried out as follows Reduction of lac-tone 13 with LAH in THF gave diol 24 which on TPAPoxidation15 led to the unsaturated lactone 25 in a verygood yield Hydrogenation of 25 gave lactone 26 that showsthe CD rings union as cis As the stereochemistry for theplanned sesterterpenolide 15 for that rings is trans was nec-essary to isomerize to the trans lactone 14 This was quanti-tatively achieved by treatment in basic conditions obtaininglactone 14 in nearly quantitative yield (Scheme 3)

The X-ray crystallography of 14 corroborates the structure16

showing the trans disposition of H-13 and H-14 (Fig 5)

Lactones 13 14 25 and 26 are homoisoanticopalanes syn-thons potentially useful for future transformations intobiological active compounds

23 Synthesis of 15

Once we obtained lactone 14 in adequate quantities wedecided to follow to the synthesis of the nor-limonoid 15Lactone 14 was reduced with DIBAL17 to the lactol 27

Figure 4 X-ray crystallography of compound 16

and as stated previously in the retrosynthetic scheme severalattempts to add a furan ring to this lactol were tried but wereunsuccessful so we decided to change this strategy Lactol27 was treated under Wittig conditions to give olefin 28This unexpected result could be understood by an 15hydride transfer in an intermediate u-hydroxyaldehyde(Scheme 4)

Compound 28 was oxidized to aldehyde 29 (Scheme 5) bytreatment with TPAP under the usual conditions in nearlyquantitative yield As can be observed this compound hasan aldehyde as required for the organometalic additionAddition of 3-furyllithium18 to this aldehyde gave stereose-lectively alcohol 3019 whose stereochemistry at C-17 willbe corroborated later on The dihydroxylation of 30 withOsO4NMO followed by treatment with NaIO4 of the result-ing diol 31 led to lactol 3220 TPAP oxidation of the lastcompound gave lactone 33 that shows a nor-limonoid struc-ture The X-ray diffraction studies21 of 33 confirm its struc-ture and the stereochemistry of compound 30 at C-17(Fig 6)

Finally compound 33 was transformed into the requiredg-hydroxybutenolide 15 (68 yield) following Faulknerrsquosmethodology11 This functionality is present in many com-pounds with antitumoral activity and SAR studies will bepublished in due course

Figure 5 X-ray crystallography of compound 14

O

OH

H

O

O

H

H

OH

OHH

H

OOH

H

H

OOH

H

H

D

A B

C

13 24 25

a b

2614

c

d

H H H

H H

Scheme 3 (a) LAH THF rt 2 h 88 (b) MnO2 DCM rt 2 h 86 (c) 10 H2PdC EtOH rt 4 h 98 and (d) K+tBuOtBuOH 70 C 30 min 99

8942 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OOH

H

H

O

OHH

H

H

OHH

H

H

14 27

a b

28

H H H15

15b1

35

1819

17

12

7

1620

10 15a

Scheme 4 (a) DIBAL-H DCM 78 C 30 min 99 and (b) Ph3PCH2Br NaHMDS tolueneTHF 20 to 80 C 1 h 56

OHH

H

H

CHOH

H

H

O

OH

H

H

H

O

OH

O

H

H

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O

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OH

OH

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H

28 29 30

323315

a b

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ef

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31a31b

H H H H

HHH

1

3 5

911

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13

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1720 21

2223

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2829

30

1

3 5

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12

13

15 16

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20 2122

23

19

2829

30

Scheme 5 (a) TPAP NMO DCM sieves 4 A rt 1 h 99 (b) 3-bromofurane n-BuLi THF78 C 30 min 58 (c) OsO4tBuOHNMO tBuOHTHFH2O(721) rt 46 h 58 (d) NaIO4 THFH2O (21) rt 10 min 65 (e) TPAP NMO DCM sieves 4 A rt 1 h 99 and (f) 1O2 hn Rose Bengal DIPEA DCM78 C 3 h 68

3 Conclusions

In conclusion starting form methyl isoanticopalate 12a new route to nor-limonoids is described Several lactoneswith a homoisoanticopalane skeleton have been obtainedthat are useful synthons for the synthesis of biological activecompounds

4 Experimental

41 General

Unless otherwise stated all chemicals were purchased withthe highest purity commercially available and were used

Figure 6 X-ray crystallography of compound 33

without further purification Melting points are uncorrected1H and 13C NMR spectra were recorded at 200400 and 5075 MHz respectively The spectra were performed in CDCl3and referenced with respect to the residual peak of CHCl3 atd 726 and d 770 ppm for 1H and 13C respectively Chem-ical shifts are reported in parts per million and couplingconstants (J) are given in hertz Optical rotations were deter-mined on a polarimetre in 1-dm cells Diethyl ether and THFwere distilled from sodium and dichloromethane was dis-tilled from calcium hydride under Ar atmosphere

411 Methyl 12a13a-epoxy-isoanticopal-15-oate 16 Toan ice-cooled solution of 12 (70 g 223 mmol) in dryCH2Cl2 (250 mL) was added m-CPBA (70 g 406 mmol)The reaction mixture was stirred at room temperature for1 h diluted with water and extracted with Et2O The organiclayer was washed successively with 10 aqueous solution ofNa2SO3 6 aqueous solution of NaHCO3 and water Evap-oration of the dried extract gave 16 (53 g 71) Compound16 [a]D

20 230 (c 085 CHCl3) mp (hexane) 155ndash157 CIR 1740 1450 1320 1200 1170 1110 1010 cm1 1HNMR (200 MHz CDCl3) d 367 (3H s COOMe) 305(1H br s H-12) 247 (1H s H-14) 129 (3H s Me-16)107 (3H s Me-17) 089 (3H s Me-18) 083 (3H s Me-19) 079 (3H s Me-20) 22ndash092 (14H m) 13C NMR(503 MHz CDCl3) d 1726 (C-15) 621 (C-12) 603 (C-14) 569 (C-13) 564 (C-5) 510 (COOMe) 503 (C-9)419 (C-3) 404 (C-7) 395 (C-1) 373 (C-10) 361 (C-8)335 (C-18) 331 (C-4) 218 (C-11) 217 (C-19) 224 (C-16) 184 (C-2 C-6) 158 (C-17) 151 (C-20) MS mz ()334 (36) [M]+ 319 (80) 301 (71) 205 (53) 191 (64) 177(91) 143 (73) 123 (68) 95 (75) 81 (100) 69 (80) HRMScalcd for C21H34O3 [M]+ 3342508 found 3342564

8943P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

412 Methyl 12a-hydroxy-isoanticopal-13(16)en-15-oate 17 To a solution of 16 (23 g 70 mmol) in toluene(50 mL) was added 398 mg (19 mmol) of Al(iPrO)3 andthe mixture was stirred at 150 C for 24 h diluted with waterand extracted with Et2O The organic layer was washed with10 aqueous solution of NaOH and brine Evaporation ofthe dried extract gave 17 (22 g 94) Compound 17[a]D

20 322 (c 082 CHCl3) mp (hexane) 156ndash158 CIR 3462 2930 1734 1653 1456 1387 1194 11631044 1007 912 cm1 1H NMR (200 MHz CDCl3) d 498(1H s HA-16) 478 (1H s HB-16) 432 (1H s H-12)358 (3H s COOMe) 329 (1H s H-14) 104 (3H s Me-17) 086 084 081 (9H s each Me-18 19 and 20) 188ndash087 (14H m) 13C NMR (503 MHz CDCl3) d 1722 (C-15) 1453 (C-13) 1130 (C-16) 729 (C-12) 576 (C-14)569 (C-5) 518 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 402 (C-10) 398 (C-1) 374 (C-8) 335 (C-18)334 (C-4) 294 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 163 (C-17) 144 (C-20) MS mz () 334 (12) [M]+316 (34) 288 (6) 205 (49) 40 (92) 10 (100)

413 Methyl 12a-methoxymethoxy-isoanticopal-13(16)en-15-oate 18 To a solution of aldehyde 17 (66 g198 mmol) in CHCl3 (118 mL) DMM (118 mL 133 mol)and P2O5 (297 g 021 mol) were added and the mixturewas stirred for 30 min Then ice was added The organicphase was separated and the aqueous phase was extractedwith Et2O The organic layer was washed with aqueous solu-tion of 10 NaHCO3 and water dried over Na2SO4 and con-centrated under reduced pressure to give 18 (69 g 99)Compound 18 [a]D

20 36 (c 089 CHCl3) mp (hexane)65ndash67 C IR 1738 1458 1389 1163 1034 918 cm1 1HNMR (200 MHz CDCl3) d 503 (1H s HA-16) 498 (1H sHB-16) 465 (1H d Jfrac1466 Hz OCH2OCH3) 452 (1H dJfrac1466 Hz OCH2OCH3) 419 (1H t Jfrac1429 H-12) 364 (3Hs COOMe) 335 (3H s OCH2OCH3) 316 (1H s H-14)104 (3H s Me-17) 085 083 and 080 (9H s each Me-18 19 and 20) 190ndash085 (14H m) 13C NMR (503 MHzCDCl3) d 1721 (C-15) 1417 (C-13) 1131 (C-16) 932(OCH2OCH3) 761 (C-12) 579 (C-14) 568 (C-5) 554(OCH2OCH3) 525 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 401 (C-10) 398 (C-1) 375 (C-8) 335 (C-18) 334(C-4) 282 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 162(C-17) 145 (C-20) MS mz () 378 (8) [M]+ 346 (24) 333(45) 316 (92) 191 (94) 137 (62) 69 (100) HRMS calcd forC23H38O4 [M]+ 3782779 found 3782780

414 12a-Methoxymethoxy-isoanticopal-13(16)en-15-ol19 To a solution of 18 (434 mg 11 mmol) in dry methylenechloride (27 mL) was added a solution of DIBAL-H in tolu-ene (16 M 168 mL 24 mmol) under argon at78 C Thesolution stirred for 30 min was quenched by addition ofMeOH (5 mL) and water (5 mL) and extracted with Et2O(3100 mL) The organic layer was washed with water(330 mL) and dried over Na2SO4 Evaporation of the sol-vent followed by chromatography on silica gel (hexaneEtOAc 91) yielded the alcohol 19 (362 mg 90) Com-pound 19 [a]D

20 +16 (c 11 CHCl3) IR 3428 1719 16491387 1209 1099 907 cm1 1H NMR (200 MHz CDCl3)d 509 (1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)415 (1H s H-12) 377 (2H m H-15) 332 (3H sOCH2OCH3) 085 (3H s Me-17) 082 076 and 068

(9H s each Me-18 19 and 20) 235ndash086 (15H m) 13CNMR (503 MHz CDCl3) d 1459 (C-13) 1110 (C-16)938 (OCH2OCH3) 779 (C-12) 586 (C-15) 565 (C-5)555 (OCH2OCH3) 541 (C-14) 528 (C-9) 421(C-3)406 (C-7) 399 (C-1) 395 (C-10) 375 (C-8) 335 (C-18) 334 (C-4) 287 (C-11) 192 (C-2) 187 (C-6) 162(C-17) 157 (C-20) MS mz () 350 (1) [M]+ 288 (11)191 (18) 115 (14) 99 (100) 85 (68) 83 (37) HRMS calcdfor C22H38O3 [M]+ 3502821 found 3502812

415 12a-Methoxymethoxy-isoanticopal-13(16)en-15-al20 To a mixture of 19 (362 mg 103 mmol) N-methylmor-pholine N-oxide (NMO) (262 mg 19 mmol) and molecularsieves (515 mg 500 mgmmol) in anhydrous CH2Cl2(104 mL) under argon at room temperature and TPAP(32 mg 01 mmol) were added The reaction mixture wasstirred for 1 h and then filtered through a short pad of silicagel and Celite eluting with EtOAc Evaporation of the sol-vent yielded the aldehyde 20 (309 mg 86) Compound20 [a]D

20 +230 (c 088 CHCl3) IR 2947 2731 17171669 1464 1387 1148 1096 1034 918 cm1 1H NMR(200 MHz CDCl3) d 984 (1H d Jfrac1438 Hz H-15) 509(1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)414 (1H s H-12) 330 (3H s OCH2OCH3) 279 (1H s H-14) 108 (3H s Me-17) 082 081 and 076 (33H s Me-18 19 and 20) 2ndash083 (14H m) 13C NMR (503 MHzCDCl3) d 2050 (C-15) 1428 (C-13) 1136 (C-16) 931(OCH2OCH3) 762 (C-12) 633 (C-14) 567 (C-5) 554(OCH2OCH3) 518 (C-9) 421 (C-3) 409 (C-7) 400 (C-10) 397 (C-1) 376 (C-8) 335 (C-18) 334 (C-4) 282(C-11) 216 (C-19) 187 (C-2) 186 (C-6) 164 (C-17) 163(C-20) MS mz () 348 (11) [M]+ 316 (25) 286 (35) 191(18) 115 (59) 57 (100) HRMS calcd for C22H36O3 [M]+3482664 found 3482667

416 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)15a(15)-dienil-15-methylether To a suspensionof methoxymethyltriphenylphosphonium chloride (MeOCH2PPh3Cl) (44 g 128 mmol) in THF (6 mL) at 78 Cunder an argon atmosphere a 10 M solution of NaHMDSin THF (113 mL 113 mmol) was added dropwise andthe solution stirred for 20 min A solution of the aldehyde20 (45 g 129 mmol) in THF (145 mL) was added drop-wise and the mixture stirred for 1 h It was allowed towarm to room temperature quenched with aqueous NH4Cland extracted with Et2O The organic layer was washedwith water and dried over Na2SO4 The residue obtainedafter removing the solvent was purified by column chroma-tography (hexaneEtOAc 91) to afford a mixture 21a21b(303 g 82) (73 ZE) Compound 21a21b IR 29321665 1460 1387 1269 1244 1206 1148 1115 10941036 cm1 1H NMR (200 MHz CDCl3) d isomer Z (major)596 (1H d Jfrac1466 Hz H-15) 487 (1H br s HA-16) 479(1H br s HB-16) 464 (1H d Jfrac1466 Hz OCH2OCH3)448 (1H d Jfrac1466 Hz OCH2OCH3) 432 (1H dd J1frac14102 and J2frac1466 Hz H-15a) 417 (1H s H-12) 351 (3Hs OMe) 334 (3H s OCH2OCH3) 324 (1H d Jfrac14102 HzH-14) 25ndash09 (14H m) 081 079 077 and 068 (43H sMe-17 18 19 and 20) isomer E (minor) 616 (1H dJfrac14126 Hz H-15) 491 (1H br s HA-16) 479 (1H br sHB-16) 472 (1H dd J1frac14126 and J2frac1424 Hz H-15a) 460(1H d Jfrac1466 Hz OCH2OCH3) 445 (1H d Jfrac1466 Hz

8944 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OCH2OCH3) 419 (1H s H-12) 354 (3H s OMe) 333 (3Hs OCH2OCH3) 332ndash328 (1H m H-14) 25ndash09 (14H m)081 079 077 and 069 (43H s Me-17 18 19 and 20) 13CNMR (503 MHz CDCl3) d 1486 (C-13) 1474 (C-15)1122 (C-16) 1036 (C-15a) 931 (OCH2OCH3) 767 (C-12) 596 (OMe) 567 (C-5) 553 (OCH2OCH3) 524 (C-9) 470 (C-14) 423 (C-3) 409 (C-7) 399 (C-1) 395(C-10) 375 (C-8) 336 (C-19) 335 (C-4) 284 (C-11)217 (C-18) 191 (C-2) 188 (C-6) 163 (C-17) 146 (C-20) MS mz () 376 (8) [M]+ 344 (36) 331 (37) 299(29) 191 (74) 179 (75) 71 (100) HRMS calcd forC24H40O3 [M]+ 3762977 found 3762968

417 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)en-15-al 22 To a solution of 21a21b (470 mg149 mmol) in acetone (247 mL) and water (3 mL) p-TsOH (360 mg 19 mmol) was added at room temperatureAfter being stirred for 7 h the reaction mixture was dilutedwith water and extracted with Et2O The extracts werewashed with 6 aqueous NaHCO3 solution and water Evap-oration of the solvent yielded the aldehyde 22 (449 mg99) Compound 22 [a]D

20 +35 (c 079 CHCl3) IR 17281647 1462 1387 1258 1208 1148 1096 1032 918733 cm1 1H NMR (200 MHz CDCl3) d 953 (1H tJfrac1422 H-15) 495 (1H s HA-16) 457 (1H s HB-16)455 (1H d Jfrac1466 Hz OCH2OCH3) 444 (1H dJfrac1466 Hz OCH2OCH3) 413 (1H s H-12) 331 (3H sOCH2OCH3) 268 (1H t Jfrac1474 Hz H-14) 237 (2H ddJ1frac1474 and J2frac1422 Hz H-15a) 198ndash105 (14H m) 082(3H s) 078 (6H s) 066 (3H s) 13C NMR (503 MHzCDCl3) d 2033 (C-15) 1467 (C-13) 1126 (C-16) 993(OCH2OCH3) 768 (C-12) 565 (C-5) 554 (OCH2OCH3)528 (C-9) 462 (C-14) 421 (C-15a) 409 (C-3) 399 (C-7) 395 (C-1) 394 (C-10) 375 (C-8) 335 (C-19) 334(C-4) 285 (C-11) 216 (C-18) 192 (C-2) 187 (C-6)162 (C-17) 150 (C-20) MS mz () 362 (12) [M]+ 300(28) 191 (78) 157 (32) 123 (35) 69 (100) HRMS calcdfor C23H38O3 [M]+ 3622821 found 3622816

418 Methyl 12a-methoxymethoxy-15a-homo-isoantico-pal-13(16)en-15-oate 23 To a solution of 22 (28 g816 mmol) in tBuOH (97 mmL) a solution of 25NaH2PO4NaClO2 in water was added at room temperatureThe reaction mixture was stirred for 12 h diluted with waterand 2 N HCl and extracted with Et2O The organic layer waswashed with water and dried over anhydrous Na2SO4 Afterfiltration the solvent was evaporated to give the acid(305 g) To a solution of the acid (15 g 405 mmol) in ben-zene and methanol TMSCHN2 was added under an argonatmosphere at 0 C After 10 min of vigorous stirring thesolvent was evaporated to give a residue which was purifiedby silica gel column chromatography (hexaneEtOAc 91) toyield 23 (13 g 83) Compound 23 [a]D

20 81 (c 068CHCl3) IR 1738 1651 1441 1387 1329 1157 10961032 918 cm1 1H NMR (200 MHz CDCl3) d 493 (1Hs HA-16) 470 (1H s HB-16) 459 (1H d Jfrac1466 HzOCH2OCH3) 445 (1H d Jfrac1466 Hz OCH2OCH3) 415(1H s H-12) 360 (3H s COOMe) 333 (3H sOCH2OCH3) 262 (1H dd JBXfrac14110 and JAXfrac1440 HzH-14) 243 (1H dd JABfrac14158 and JAXfrac1440 Hz HA-15a)230 (1H dd JABfrac14158 and JBXfrac14110 Hz HB-15a) 168ndash087 (14H m) 081 (3H s) 076 (2H s) 064 (3H s)13C NMR (503 MHz CDCl3) d 1741 (C-15) 1469

(C-13) 1114 (C-16) 928 (OCH2OCH3) 762 (C-12)564 (C-5) 553 (OCH2OCH3) 524 (C-9) 516 (COOMe)478 (C-14) 421 (C-3) 404 (C-7) 395 (C-1) 392 (C-8)374 (C-10) 335 (C-18) 334 (C-4) 304 (C-15a) 287(C-11) 216 (C-19) 192 (C-2) 188 (C-6) 162 (C-17)148 (C-20) MS mz () 392 (12) [M]+ 347 (35) 315(32) 191 (100) 123 (48) 69 (92) HRMS calcd forC24H40O4 [M]+ 3922927 found 3922934

419 15a-Homo-isoanticopal-12en-1516-olide 13 Toa solution of 23 (1 g 26 mmol) in dioxane (149 mL) wasadded a solution of 6 N H2SO4 (115 mL) at 85 C The solu-tion was stirred for 24 h quenched by addition of ice andbrine and extracted with EtOAc (3100 mL) The organiclayer was washed with water (330 mL) and dried overNa2SO4 Evaporation of the solvent followed by chromato-graphy on silica gel (CHCl3) yielded the lactone 13(781 mg 93) Compound 13 [a]D

20458 (c 053 CHCl3)IR 1748 1464 1387 1258 1036 1017 cm1 1H NMR(200 MHz CDCl3) d 570 (1H br s H-12) 465 (1H d Jfrac14132 Hz HA-16) 456 (1H d Jfrac14132 Hz HB-16) 280ndash222(3H m) 220ndash098 (14H m) 085 083 079 and 070 (43H s Me-17 18 19 and 20) 13C NMR (503 MHz CDCl3)d 1743 (C-15) 1294 (C-13) 709 (C-16) 1239 (C-12)566 (C-5) 545 (C-9) 476 (C-14) 420 (C-3) 399 (C-7)399 (C-1) 357 (C-8) 375 (C-10) 336 (C-18) 334 (C-4)300 (C-15a) 232 (C-11) 218 (C-19) 187 (C-2) 186 (C-6) 154 (C-17) 142 (C-20) EIMS mz () 316 (M+) (1)256 (2) 192 (3) 137 (4) 86 (100) 69 (26) HRMS calcdfor C21H32O2 [M]+ 3162402 found 3162432

4110 15a-Homo-isoanticopal-12-en-1516-diol 24 Toa solution of 13 (500 mg 16 mmol) in THF (40 mL) at0 C under an argon atmosphere LAH (200 mg) was addedThe mixture was stirred for 1 h It was allowed to warm toroom temperature quenched with aqueous EtOAc and driedover Na2SO4 Evaporation of the solvent yielded the com-pound 24 (449 mg 99) Compound 24 [a]D

20 +122 (c01 CHCl3) IR 3380 1458 1439 1387 1364 12091049 988 839 cm1 1H NMR (200 MHz CDCl3) d 571(1H br s H-12) 427 (1H d Jfrac14120 Hz HA-16) 387 (1Hd Jfrac14120 Hz HB-16) 386ndash379 (1H m HA-15) 371ndash361(1H m HB-15) 170ndash152 and 087ndash070 (2H m H-1)167ndash151 (2H m H-2) 143ndash129 118ndash103 (2H mH-3) 090ndash075 (1H m H-5) 148ndash136 (2H m H-6) 195ndash180 121ndash105 (2H m H-7) 128ndash113 (1H m H-9) 180ndash163 (2H m H-11) 212ndash200 (1H m H-14) 222ndash186(2H m H-15a) 089 (3H s Me-17) 086 (3H s Me-18)082 (3H s Me-19) 074 (3H s Me-20) 13C NMR(503 MHz CDCl3) d 1385 (C-13) 1268 (C-12) 665 (C-16) 645 (C-15) 565 (C-5) 550 (C-9) 493 (C-14) 421(C-3) 408 (C-7) 400 (C-1) 374 (C-8) 371 (C-10) 336(C-18) 333 (C-4) 283 (C-11) 230 (C-15a) 219 (C-19)189 (C-2) 187 (C-6) 156 (C-17) 145 (C-20) EIMS mz() 302 (M18+) (3) 257 (4) 192 (12) 107 (38) 85(100) HRMS calcd for C21H36O2 [Mndash18]+ 3022610found 3022620

4111 15a-Homo-isoanticopal-12-en-1615-olide 25 Toa solution of 24 (200 mg 062 mmol) in DCM (25 mL) atroom temperature under anhydrous atmosphere MnO2

(200 mg) was added The mixture was stirred for 1 h Afterfiltration the solvent was evaporated to yield the compound

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8941P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

was treated with sulfuric acid in dioxane it produced the de-sired lactone 13 in excellent global yield Scheme 2

22 Transformation of lactone 13 to lactone 14

With an easy way to obtain lactone 13 the transformationinto lactone 14 was carried out as follows Reduction of lac-tone 13 with LAH in THF gave diol 24 which on TPAPoxidation15 led to the unsaturated lactone 25 in a verygood yield Hydrogenation of 25 gave lactone 26 that showsthe CD rings union as cis As the stereochemistry for theplanned sesterterpenolide 15 for that rings is trans was nec-essary to isomerize to the trans lactone 14 This was quanti-tatively achieved by treatment in basic conditions obtaininglactone 14 in nearly quantitative yield (Scheme 3)

The X-ray crystallography of 14 corroborates the structure16

showing the trans disposition of H-13 and H-14 (Fig 5)

Lactones 13 14 25 and 26 are homoisoanticopalanes syn-thons potentially useful for future transformations intobiological active compounds

23 Synthesis of 15

Once we obtained lactone 14 in adequate quantities wedecided to follow to the synthesis of the nor-limonoid 15Lactone 14 was reduced with DIBAL17 to the lactol 27

Figure 4 X-ray crystallography of compound 16

and as stated previously in the retrosynthetic scheme severalattempts to add a furan ring to this lactol were tried but wereunsuccessful so we decided to change this strategy Lactol27 was treated under Wittig conditions to give olefin 28This unexpected result could be understood by an 15hydride transfer in an intermediate u-hydroxyaldehyde(Scheme 4)

Compound 28 was oxidized to aldehyde 29 (Scheme 5) bytreatment with TPAP under the usual conditions in nearlyquantitative yield As can be observed this compound hasan aldehyde as required for the organometalic additionAddition of 3-furyllithium18 to this aldehyde gave stereose-lectively alcohol 3019 whose stereochemistry at C-17 willbe corroborated later on The dihydroxylation of 30 withOsO4NMO followed by treatment with NaIO4 of the result-ing diol 31 led to lactol 3220 TPAP oxidation of the lastcompound gave lactone 33 that shows a nor-limonoid struc-ture The X-ray diffraction studies21 of 33 confirm its struc-ture and the stereochemistry of compound 30 at C-17(Fig 6)

Finally compound 33 was transformed into the requiredg-hydroxybutenolide 15 (68 yield) following Faulknerrsquosmethodology11 This functionality is present in many com-pounds with antitumoral activity and SAR studies will bepublished in due course

Figure 5 X-ray crystallography of compound 14

O

OH

H

O

O

H

H

OH

OHH

H

OOH

H

H

OOH

H

H

D

A B

C

13 24 25

a b

2614

c

d

H H H

H H

Scheme 3 (a) LAH THF rt 2 h 88 (b) MnO2 DCM rt 2 h 86 (c) 10 H2PdC EtOH rt 4 h 98 and (d) K+tBuOtBuOH 70 C 30 min 99

8942 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OOH

H

H

O

OHH

H

H

OHH

H

H

14 27

a b

28

H H H15

15b1

35

1819

17

12

7

1620

10 15a

Scheme 4 (a) DIBAL-H DCM 78 C 30 min 99 and (b) Ph3PCH2Br NaHMDS tolueneTHF 20 to 80 C 1 h 56

OHH

H

H

CHOH

H

H

O

OH

H

H

H

O

OH

O

H

H

H

O

O

O

H

H

H

O

O

O

OH

O

H

H

H

O

OH

OH

OH

H

H

H

28 29 30

323315

a b

d

ef

c

31a31b

H H H H

HHH

1

3 5

911

12

13

15

16a 16

1720 21

2223

19

2829

30

1

3 5

9

12

13

15 16

17

20 2122

23

19

2829

30

Scheme 5 (a) TPAP NMO DCM sieves 4 A rt 1 h 99 (b) 3-bromofurane n-BuLi THF78 C 30 min 58 (c) OsO4tBuOHNMO tBuOHTHFH2O(721) rt 46 h 58 (d) NaIO4 THFH2O (21) rt 10 min 65 (e) TPAP NMO DCM sieves 4 A rt 1 h 99 and (f) 1O2 hn Rose Bengal DIPEA DCM78 C 3 h 68

3 Conclusions

In conclusion starting form methyl isoanticopalate 12a new route to nor-limonoids is described Several lactoneswith a homoisoanticopalane skeleton have been obtainedthat are useful synthons for the synthesis of biological activecompounds

4 Experimental

41 General

Unless otherwise stated all chemicals were purchased withthe highest purity commercially available and were used

Figure 6 X-ray crystallography of compound 33

without further purification Melting points are uncorrected1H and 13C NMR spectra were recorded at 200400 and 5075 MHz respectively The spectra were performed in CDCl3and referenced with respect to the residual peak of CHCl3 atd 726 and d 770 ppm for 1H and 13C respectively Chem-ical shifts are reported in parts per million and couplingconstants (J) are given in hertz Optical rotations were deter-mined on a polarimetre in 1-dm cells Diethyl ether and THFwere distilled from sodium and dichloromethane was dis-tilled from calcium hydride under Ar atmosphere

411 Methyl 12a13a-epoxy-isoanticopal-15-oate 16 Toan ice-cooled solution of 12 (70 g 223 mmol) in dryCH2Cl2 (250 mL) was added m-CPBA (70 g 406 mmol)The reaction mixture was stirred at room temperature for1 h diluted with water and extracted with Et2O The organiclayer was washed successively with 10 aqueous solution ofNa2SO3 6 aqueous solution of NaHCO3 and water Evap-oration of the dried extract gave 16 (53 g 71) Compound16 [a]D

20 230 (c 085 CHCl3) mp (hexane) 155ndash157 CIR 1740 1450 1320 1200 1170 1110 1010 cm1 1HNMR (200 MHz CDCl3) d 367 (3H s COOMe) 305(1H br s H-12) 247 (1H s H-14) 129 (3H s Me-16)107 (3H s Me-17) 089 (3H s Me-18) 083 (3H s Me-19) 079 (3H s Me-20) 22ndash092 (14H m) 13C NMR(503 MHz CDCl3) d 1726 (C-15) 621 (C-12) 603 (C-14) 569 (C-13) 564 (C-5) 510 (COOMe) 503 (C-9)419 (C-3) 404 (C-7) 395 (C-1) 373 (C-10) 361 (C-8)335 (C-18) 331 (C-4) 218 (C-11) 217 (C-19) 224 (C-16) 184 (C-2 C-6) 158 (C-17) 151 (C-20) MS mz ()334 (36) [M]+ 319 (80) 301 (71) 205 (53) 191 (64) 177(91) 143 (73) 123 (68) 95 (75) 81 (100) 69 (80) HRMScalcd for C21H34O3 [M]+ 3342508 found 3342564

8943P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

412 Methyl 12a-hydroxy-isoanticopal-13(16)en-15-oate 17 To a solution of 16 (23 g 70 mmol) in toluene(50 mL) was added 398 mg (19 mmol) of Al(iPrO)3 andthe mixture was stirred at 150 C for 24 h diluted with waterand extracted with Et2O The organic layer was washed with10 aqueous solution of NaOH and brine Evaporation ofthe dried extract gave 17 (22 g 94) Compound 17[a]D

20 322 (c 082 CHCl3) mp (hexane) 156ndash158 CIR 3462 2930 1734 1653 1456 1387 1194 11631044 1007 912 cm1 1H NMR (200 MHz CDCl3) d 498(1H s HA-16) 478 (1H s HB-16) 432 (1H s H-12)358 (3H s COOMe) 329 (1H s H-14) 104 (3H s Me-17) 086 084 081 (9H s each Me-18 19 and 20) 188ndash087 (14H m) 13C NMR (503 MHz CDCl3) d 1722 (C-15) 1453 (C-13) 1130 (C-16) 729 (C-12) 576 (C-14)569 (C-5) 518 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 402 (C-10) 398 (C-1) 374 (C-8) 335 (C-18)334 (C-4) 294 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 163 (C-17) 144 (C-20) MS mz () 334 (12) [M]+316 (34) 288 (6) 205 (49) 40 (92) 10 (100)

413 Methyl 12a-methoxymethoxy-isoanticopal-13(16)en-15-oate 18 To a solution of aldehyde 17 (66 g198 mmol) in CHCl3 (118 mL) DMM (118 mL 133 mol)and P2O5 (297 g 021 mol) were added and the mixturewas stirred for 30 min Then ice was added The organicphase was separated and the aqueous phase was extractedwith Et2O The organic layer was washed with aqueous solu-tion of 10 NaHCO3 and water dried over Na2SO4 and con-centrated under reduced pressure to give 18 (69 g 99)Compound 18 [a]D

20 36 (c 089 CHCl3) mp (hexane)65ndash67 C IR 1738 1458 1389 1163 1034 918 cm1 1HNMR (200 MHz CDCl3) d 503 (1H s HA-16) 498 (1H sHB-16) 465 (1H d Jfrac1466 Hz OCH2OCH3) 452 (1H dJfrac1466 Hz OCH2OCH3) 419 (1H t Jfrac1429 H-12) 364 (3Hs COOMe) 335 (3H s OCH2OCH3) 316 (1H s H-14)104 (3H s Me-17) 085 083 and 080 (9H s each Me-18 19 and 20) 190ndash085 (14H m) 13C NMR (503 MHzCDCl3) d 1721 (C-15) 1417 (C-13) 1131 (C-16) 932(OCH2OCH3) 761 (C-12) 579 (C-14) 568 (C-5) 554(OCH2OCH3) 525 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 401 (C-10) 398 (C-1) 375 (C-8) 335 (C-18) 334(C-4) 282 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 162(C-17) 145 (C-20) MS mz () 378 (8) [M]+ 346 (24) 333(45) 316 (92) 191 (94) 137 (62) 69 (100) HRMS calcd forC23H38O4 [M]+ 3782779 found 3782780

414 12a-Methoxymethoxy-isoanticopal-13(16)en-15-ol19 To a solution of 18 (434 mg 11 mmol) in dry methylenechloride (27 mL) was added a solution of DIBAL-H in tolu-ene (16 M 168 mL 24 mmol) under argon at78 C Thesolution stirred for 30 min was quenched by addition ofMeOH (5 mL) and water (5 mL) and extracted with Et2O(3100 mL) The organic layer was washed with water(330 mL) and dried over Na2SO4 Evaporation of the sol-vent followed by chromatography on silica gel (hexaneEtOAc 91) yielded the alcohol 19 (362 mg 90) Com-pound 19 [a]D

20 +16 (c 11 CHCl3) IR 3428 1719 16491387 1209 1099 907 cm1 1H NMR (200 MHz CDCl3)d 509 (1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)415 (1H s H-12) 377 (2H m H-15) 332 (3H sOCH2OCH3) 085 (3H s Me-17) 082 076 and 068

(9H s each Me-18 19 and 20) 235ndash086 (15H m) 13CNMR (503 MHz CDCl3) d 1459 (C-13) 1110 (C-16)938 (OCH2OCH3) 779 (C-12) 586 (C-15) 565 (C-5)555 (OCH2OCH3) 541 (C-14) 528 (C-9) 421(C-3)406 (C-7) 399 (C-1) 395 (C-10) 375 (C-8) 335 (C-18) 334 (C-4) 287 (C-11) 192 (C-2) 187 (C-6) 162(C-17) 157 (C-20) MS mz () 350 (1) [M]+ 288 (11)191 (18) 115 (14) 99 (100) 85 (68) 83 (37) HRMS calcdfor C22H38O3 [M]+ 3502821 found 3502812

415 12a-Methoxymethoxy-isoanticopal-13(16)en-15-al20 To a mixture of 19 (362 mg 103 mmol) N-methylmor-pholine N-oxide (NMO) (262 mg 19 mmol) and molecularsieves (515 mg 500 mgmmol) in anhydrous CH2Cl2(104 mL) under argon at room temperature and TPAP(32 mg 01 mmol) were added The reaction mixture wasstirred for 1 h and then filtered through a short pad of silicagel and Celite eluting with EtOAc Evaporation of the sol-vent yielded the aldehyde 20 (309 mg 86) Compound20 [a]D

20 +230 (c 088 CHCl3) IR 2947 2731 17171669 1464 1387 1148 1096 1034 918 cm1 1H NMR(200 MHz CDCl3) d 984 (1H d Jfrac1438 Hz H-15) 509(1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)414 (1H s H-12) 330 (3H s OCH2OCH3) 279 (1H s H-14) 108 (3H s Me-17) 082 081 and 076 (33H s Me-18 19 and 20) 2ndash083 (14H m) 13C NMR (503 MHzCDCl3) d 2050 (C-15) 1428 (C-13) 1136 (C-16) 931(OCH2OCH3) 762 (C-12) 633 (C-14) 567 (C-5) 554(OCH2OCH3) 518 (C-9) 421 (C-3) 409 (C-7) 400 (C-10) 397 (C-1) 376 (C-8) 335 (C-18) 334 (C-4) 282(C-11) 216 (C-19) 187 (C-2) 186 (C-6) 164 (C-17) 163(C-20) MS mz () 348 (11) [M]+ 316 (25) 286 (35) 191(18) 115 (59) 57 (100) HRMS calcd for C22H36O3 [M]+3482664 found 3482667

416 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)15a(15)-dienil-15-methylether To a suspensionof methoxymethyltriphenylphosphonium chloride (MeOCH2PPh3Cl) (44 g 128 mmol) in THF (6 mL) at 78 Cunder an argon atmosphere a 10 M solution of NaHMDSin THF (113 mL 113 mmol) was added dropwise andthe solution stirred for 20 min A solution of the aldehyde20 (45 g 129 mmol) in THF (145 mL) was added drop-wise and the mixture stirred for 1 h It was allowed towarm to room temperature quenched with aqueous NH4Cland extracted with Et2O The organic layer was washedwith water and dried over Na2SO4 The residue obtainedafter removing the solvent was purified by column chroma-tography (hexaneEtOAc 91) to afford a mixture 21a21b(303 g 82) (73 ZE) Compound 21a21b IR 29321665 1460 1387 1269 1244 1206 1148 1115 10941036 cm1 1H NMR (200 MHz CDCl3) d isomer Z (major)596 (1H d Jfrac1466 Hz H-15) 487 (1H br s HA-16) 479(1H br s HB-16) 464 (1H d Jfrac1466 Hz OCH2OCH3)448 (1H d Jfrac1466 Hz OCH2OCH3) 432 (1H dd J1frac14102 and J2frac1466 Hz H-15a) 417 (1H s H-12) 351 (3Hs OMe) 334 (3H s OCH2OCH3) 324 (1H d Jfrac14102 HzH-14) 25ndash09 (14H m) 081 079 077 and 068 (43H sMe-17 18 19 and 20) isomer E (minor) 616 (1H dJfrac14126 Hz H-15) 491 (1H br s HA-16) 479 (1H br sHB-16) 472 (1H dd J1frac14126 and J2frac1424 Hz H-15a) 460(1H d Jfrac1466 Hz OCH2OCH3) 445 (1H d Jfrac1466 Hz

8944 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OCH2OCH3) 419 (1H s H-12) 354 (3H s OMe) 333 (3Hs OCH2OCH3) 332ndash328 (1H m H-14) 25ndash09 (14H m)081 079 077 and 069 (43H s Me-17 18 19 and 20) 13CNMR (503 MHz CDCl3) d 1486 (C-13) 1474 (C-15)1122 (C-16) 1036 (C-15a) 931 (OCH2OCH3) 767 (C-12) 596 (OMe) 567 (C-5) 553 (OCH2OCH3) 524 (C-9) 470 (C-14) 423 (C-3) 409 (C-7) 399 (C-1) 395(C-10) 375 (C-8) 336 (C-19) 335 (C-4) 284 (C-11)217 (C-18) 191 (C-2) 188 (C-6) 163 (C-17) 146 (C-20) MS mz () 376 (8) [M]+ 344 (36) 331 (37) 299(29) 191 (74) 179 (75) 71 (100) HRMS calcd forC24H40O3 [M]+ 3762977 found 3762968

417 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)en-15-al 22 To a solution of 21a21b (470 mg149 mmol) in acetone (247 mL) and water (3 mL) p-TsOH (360 mg 19 mmol) was added at room temperatureAfter being stirred for 7 h the reaction mixture was dilutedwith water and extracted with Et2O The extracts werewashed with 6 aqueous NaHCO3 solution and water Evap-oration of the solvent yielded the aldehyde 22 (449 mg99) Compound 22 [a]D

20 +35 (c 079 CHCl3) IR 17281647 1462 1387 1258 1208 1148 1096 1032 918733 cm1 1H NMR (200 MHz CDCl3) d 953 (1H tJfrac1422 H-15) 495 (1H s HA-16) 457 (1H s HB-16)455 (1H d Jfrac1466 Hz OCH2OCH3) 444 (1H dJfrac1466 Hz OCH2OCH3) 413 (1H s H-12) 331 (3H sOCH2OCH3) 268 (1H t Jfrac1474 Hz H-14) 237 (2H ddJ1frac1474 and J2frac1422 Hz H-15a) 198ndash105 (14H m) 082(3H s) 078 (6H s) 066 (3H s) 13C NMR (503 MHzCDCl3) d 2033 (C-15) 1467 (C-13) 1126 (C-16) 993(OCH2OCH3) 768 (C-12) 565 (C-5) 554 (OCH2OCH3)528 (C-9) 462 (C-14) 421 (C-15a) 409 (C-3) 399 (C-7) 395 (C-1) 394 (C-10) 375 (C-8) 335 (C-19) 334(C-4) 285 (C-11) 216 (C-18) 192 (C-2) 187 (C-6)162 (C-17) 150 (C-20) MS mz () 362 (12) [M]+ 300(28) 191 (78) 157 (32) 123 (35) 69 (100) HRMS calcdfor C23H38O3 [M]+ 3622821 found 3622816

418 Methyl 12a-methoxymethoxy-15a-homo-isoantico-pal-13(16)en-15-oate 23 To a solution of 22 (28 g816 mmol) in tBuOH (97 mmL) a solution of 25NaH2PO4NaClO2 in water was added at room temperatureThe reaction mixture was stirred for 12 h diluted with waterand 2 N HCl and extracted with Et2O The organic layer waswashed with water and dried over anhydrous Na2SO4 Afterfiltration the solvent was evaporated to give the acid(305 g) To a solution of the acid (15 g 405 mmol) in ben-zene and methanol TMSCHN2 was added under an argonatmosphere at 0 C After 10 min of vigorous stirring thesolvent was evaporated to give a residue which was purifiedby silica gel column chromatography (hexaneEtOAc 91) toyield 23 (13 g 83) Compound 23 [a]D

20 81 (c 068CHCl3) IR 1738 1651 1441 1387 1329 1157 10961032 918 cm1 1H NMR (200 MHz CDCl3) d 493 (1Hs HA-16) 470 (1H s HB-16) 459 (1H d Jfrac1466 HzOCH2OCH3) 445 (1H d Jfrac1466 Hz OCH2OCH3) 415(1H s H-12) 360 (3H s COOMe) 333 (3H sOCH2OCH3) 262 (1H dd JBXfrac14110 and JAXfrac1440 HzH-14) 243 (1H dd JABfrac14158 and JAXfrac1440 Hz HA-15a)230 (1H dd JABfrac14158 and JBXfrac14110 Hz HB-15a) 168ndash087 (14H m) 081 (3H s) 076 (2H s) 064 (3H s)13C NMR (503 MHz CDCl3) d 1741 (C-15) 1469

(C-13) 1114 (C-16) 928 (OCH2OCH3) 762 (C-12)564 (C-5) 553 (OCH2OCH3) 524 (C-9) 516 (COOMe)478 (C-14) 421 (C-3) 404 (C-7) 395 (C-1) 392 (C-8)374 (C-10) 335 (C-18) 334 (C-4) 304 (C-15a) 287(C-11) 216 (C-19) 192 (C-2) 188 (C-6) 162 (C-17)148 (C-20) MS mz () 392 (12) [M]+ 347 (35) 315(32) 191 (100) 123 (48) 69 (92) HRMS calcd forC24H40O4 [M]+ 3922927 found 3922934

419 15a-Homo-isoanticopal-12en-1516-olide 13 Toa solution of 23 (1 g 26 mmol) in dioxane (149 mL) wasadded a solution of 6 N H2SO4 (115 mL) at 85 C The solu-tion was stirred for 24 h quenched by addition of ice andbrine and extracted with EtOAc (3100 mL) The organiclayer was washed with water (330 mL) and dried overNa2SO4 Evaporation of the solvent followed by chromato-graphy on silica gel (CHCl3) yielded the lactone 13(781 mg 93) Compound 13 [a]D

20458 (c 053 CHCl3)IR 1748 1464 1387 1258 1036 1017 cm1 1H NMR(200 MHz CDCl3) d 570 (1H br s H-12) 465 (1H d Jfrac14132 Hz HA-16) 456 (1H d Jfrac14132 Hz HB-16) 280ndash222(3H m) 220ndash098 (14H m) 085 083 079 and 070 (43H s Me-17 18 19 and 20) 13C NMR (503 MHz CDCl3)d 1743 (C-15) 1294 (C-13) 709 (C-16) 1239 (C-12)566 (C-5) 545 (C-9) 476 (C-14) 420 (C-3) 399 (C-7)399 (C-1) 357 (C-8) 375 (C-10) 336 (C-18) 334 (C-4)300 (C-15a) 232 (C-11) 218 (C-19) 187 (C-2) 186 (C-6) 154 (C-17) 142 (C-20) EIMS mz () 316 (M+) (1)256 (2) 192 (3) 137 (4) 86 (100) 69 (26) HRMS calcdfor C21H32O2 [M]+ 3162402 found 3162432

4110 15a-Homo-isoanticopal-12-en-1516-diol 24 Toa solution of 13 (500 mg 16 mmol) in THF (40 mL) at0 C under an argon atmosphere LAH (200 mg) was addedThe mixture was stirred for 1 h It was allowed to warm toroom temperature quenched with aqueous EtOAc and driedover Na2SO4 Evaporation of the solvent yielded the com-pound 24 (449 mg 99) Compound 24 [a]D

20 +122 (c01 CHCl3) IR 3380 1458 1439 1387 1364 12091049 988 839 cm1 1H NMR (200 MHz CDCl3) d 571(1H br s H-12) 427 (1H d Jfrac14120 Hz HA-16) 387 (1Hd Jfrac14120 Hz HB-16) 386ndash379 (1H m HA-15) 371ndash361(1H m HB-15) 170ndash152 and 087ndash070 (2H m H-1)167ndash151 (2H m H-2) 143ndash129 118ndash103 (2H mH-3) 090ndash075 (1H m H-5) 148ndash136 (2H m H-6) 195ndash180 121ndash105 (2H m H-7) 128ndash113 (1H m H-9) 180ndash163 (2H m H-11) 212ndash200 (1H m H-14) 222ndash186(2H m H-15a) 089 (3H s Me-17) 086 (3H s Me-18)082 (3H s Me-19) 074 (3H s Me-20) 13C NMR(503 MHz CDCl3) d 1385 (C-13) 1268 (C-12) 665 (C-16) 645 (C-15) 565 (C-5) 550 (C-9) 493 (C-14) 421(C-3) 408 (C-7) 400 (C-1) 374 (C-8) 371 (C-10) 336(C-18) 333 (C-4) 283 (C-11) 230 (C-15a) 219 (C-19)189 (C-2) 187 (C-6) 156 (C-17) 145 (C-20) EIMS mz() 302 (M18+) (3) 257 (4) 192 (12) 107 (38) 85(100) HRMS calcd for C21H36O2 [Mndash18]+ 3022610found 3022620

4111 15a-Homo-isoanticopal-12-en-1615-olide 25 Toa solution of 24 (200 mg 062 mmol) in DCM (25 mL) atroom temperature under anhydrous atmosphere MnO2

(200 mg) was added The mixture was stirred for 1 h Afterfiltration the solvent was evaporated to yield the compound

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8942 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OOH

H

H

O

OHH

H

H

OHH

H

H

14 27

a b

28

H H H15

15b1

35

1819

17

12

7

1620

10 15a

Scheme 4 (a) DIBAL-H DCM 78 C 30 min 99 and (b) Ph3PCH2Br NaHMDS tolueneTHF 20 to 80 C 1 h 56

OHH

H

H

CHOH

H

H

O

OH

H

H

H

O

OH

O

H

H

H

O

O

O

H

H

H

O

O

O

OH

O

H

H

H

O

OH

OH

OH

H

H

H

28 29 30

323315

a b

d

ef

c

31a31b

H H H H

HHH

1

3 5

911

12

13

15

16a 16

1720 21

2223

19

2829

30

1

3 5

9

12

13

15 16

17

20 2122

23

19

2829

30

Scheme 5 (a) TPAP NMO DCM sieves 4 A rt 1 h 99 (b) 3-bromofurane n-BuLi THF78 C 30 min 58 (c) OsO4tBuOHNMO tBuOHTHFH2O(721) rt 46 h 58 (d) NaIO4 THFH2O (21) rt 10 min 65 (e) TPAP NMO DCM sieves 4 A rt 1 h 99 and (f) 1O2 hn Rose Bengal DIPEA DCM78 C 3 h 68

3 Conclusions

In conclusion starting form methyl isoanticopalate 12a new route to nor-limonoids is described Several lactoneswith a homoisoanticopalane skeleton have been obtainedthat are useful synthons for the synthesis of biological activecompounds

4 Experimental

41 General

Unless otherwise stated all chemicals were purchased withthe highest purity commercially available and were used

Figure 6 X-ray crystallography of compound 33

without further purification Melting points are uncorrected1H and 13C NMR spectra were recorded at 200400 and 5075 MHz respectively The spectra were performed in CDCl3and referenced with respect to the residual peak of CHCl3 atd 726 and d 770 ppm for 1H and 13C respectively Chem-ical shifts are reported in parts per million and couplingconstants (J) are given in hertz Optical rotations were deter-mined on a polarimetre in 1-dm cells Diethyl ether and THFwere distilled from sodium and dichloromethane was dis-tilled from calcium hydride under Ar atmosphere

411 Methyl 12a13a-epoxy-isoanticopal-15-oate 16 Toan ice-cooled solution of 12 (70 g 223 mmol) in dryCH2Cl2 (250 mL) was added m-CPBA (70 g 406 mmol)The reaction mixture was stirred at room temperature for1 h diluted with water and extracted with Et2O The organiclayer was washed successively with 10 aqueous solution ofNa2SO3 6 aqueous solution of NaHCO3 and water Evap-oration of the dried extract gave 16 (53 g 71) Compound16 [a]D

20 230 (c 085 CHCl3) mp (hexane) 155ndash157 CIR 1740 1450 1320 1200 1170 1110 1010 cm1 1HNMR (200 MHz CDCl3) d 367 (3H s COOMe) 305(1H br s H-12) 247 (1H s H-14) 129 (3H s Me-16)107 (3H s Me-17) 089 (3H s Me-18) 083 (3H s Me-19) 079 (3H s Me-20) 22ndash092 (14H m) 13C NMR(503 MHz CDCl3) d 1726 (C-15) 621 (C-12) 603 (C-14) 569 (C-13) 564 (C-5) 510 (COOMe) 503 (C-9)419 (C-3) 404 (C-7) 395 (C-1) 373 (C-10) 361 (C-8)335 (C-18) 331 (C-4) 218 (C-11) 217 (C-19) 224 (C-16) 184 (C-2 C-6) 158 (C-17) 151 (C-20) MS mz ()334 (36) [M]+ 319 (80) 301 (71) 205 (53) 191 (64) 177(91) 143 (73) 123 (68) 95 (75) 81 (100) 69 (80) HRMScalcd for C21H34O3 [M]+ 3342508 found 3342564

8943P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

412 Methyl 12a-hydroxy-isoanticopal-13(16)en-15-oate 17 To a solution of 16 (23 g 70 mmol) in toluene(50 mL) was added 398 mg (19 mmol) of Al(iPrO)3 andthe mixture was stirred at 150 C for 24 h diluted with waterand extracted with Et2O The organic layer was washed with10 aqueous solution of NaOH and brine Evaporation ofthe dried extract gave 17 (22 g 94) Compound 17[a]D

20 322 (c 082 CHCl3) mp (hexane) 156ndash158 CIR 3462 2930 1734 1653 1456 1387 1194 11631044 1007 912 cm1 1H NMR (200 MHz CDCl3) d 498(1H s HA-16) 478 (1H s HB-16) 432 (1H s H-12)358 (3H s COOMe) 329 (1H s H-14) 104 (3H s Me-17) 086 084 081 (9H s each Me-18 19 and 20) 188ndash087 (14H m) 13C NMR (503 MHz CDCl3) d 1722 (C-15) 1453 (C-13) 1130 (C-16) 729 (C-12) 576 (C-14)569 (C-5) 518 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 402 (C-10) 398 (C-1) 374 (C-8) 335 (C-18)334 (C-4) 294 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 163 (C-17) 144 (C-20) MS mz () 334 (12) [M]+316 (34) 288 (6) 205 (49) 40 (92) 10 (100)

413 Methyl 12a-methoxymethoxy-isoanticopal-13(16)en-15-oate 18 To a solution of aldehyde 17 (66 g198 mmol) in CHCl3 (118 mL) DMM (118 mL 133 mol)and P2O5 (297 g 021 mol) were added and the mixturewas stirred for 30 min Then ice was added The organicphase was separated and the aqueous phase was extractedwith Et2O The organic layer was washed with aqueous solu-tion of 10 NaHCO3 and water dried over Na2SO4 and con-centrated under reduced pressure to give 18 (69 g 99)Compound 18 [a]D

20 36 (c 089 CHCl3) mp (hexane)65ndash67 C IR 1738 1458 1389 1163 1034 918 cm1 1HNMR (200 MHz CDCl3) d 503 (1H s HA-16) 498 (1H sHB-16) 465 (1H d Jfrac1466 Hz OCH2OCH3) 452 (1H dJfrac1466 Hz OCH2OCH3) 419 (1H t Jfrac1429 H-12) 364 (3Hs COOMe) 335 (3H s OCH2OCH3) 316 (1H s H-14)104 (3H s Me-17) 085 083 and 080 (9H s each Me-18 19 and 20) 190ndash085 (14H m) 13C NMR (503 MHzCDCl3) d 1721 (C-15) 1417 (C-13) 1131 (C-16) 932(OCH2OCH3) 761 (C-12) 579 (C-14) 568 (C-5) 554(OCH2OCH3) 525 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 401 (C-10) 398 (C-1) 375 (C-8) 335 (C-18) 334(C-4) 282 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 162(C-17) 145 (C-20) MS mz () 378 (8) [M]+ 346 (24) 333(45) 316 (92) 191 (94) 137 (62) 69 (100) HRMS calcd forC23H38O4 [M]+ 3782779 found 3782780

414 12a-Methoxymethoxy-isoanticopal-13(16)en-15-ol19 To a solution of 18 (434 mg 11 mmol) in dry methylenechloride (27 mL) was added a solution of DIBAL-H in tolu-ene (16 M 168 mL 24 mmol) under argon at78 C Thesolution stirred for 30 min was quenched by addition ofMeOH (5 mL) and water (5 mL) and extracted with Et2O(3100 mL) The organic layer was washed with water(330 mL) and dried over Na2SO4 Evaporation of the sol-vent followed by chromatography on silica gel (hexaneEtOAc 91) yielded the alcohol 19 (362 mg 90) Com-pound 19 [a]D

20 +16 (c 11 CHCl3) IR 3428 1719 16491387 1209 1099 907 cm1 1H NMR (200 MHz CDCl3)d 509 (1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)415 (1H s H-12) 377 (2H m H-15) 332 (3H sOCH2OCH3) 085 (3H s Me-17) 082 076 and 068

(9H s each Me-18 19 and 20) 235ndash086 (15H m) 13CNMR (503 MHz CDCl3) d 1459 (C-13) 1110 (C-16)938 (OCH2OCH3) 779 (C-12) 586 (C-15) 565 (C-5)555 (OCH2OCH3) 541 (C-14) 528 (C-9) 421(C-3)406 (C-7) 399 (C-1) 395 (C-10) 375 (C-8) 335 (C-18) 334 (C-4) 287 (C-11) 192 (C-2) 187 (C-6) 162(C-17) 157 (C-20) MS mz () 350 (1) [M]+ 288 (11)191 (18) 115 (14) 99 (100) 85 (68) 83 (37) HRMS calcdfor C22H38O3 [M]+ 3502821 found 3502812

415 12a-Methoxymethoxy-isoanticopal-13(16)en-15-al20 To a mixture of 19 (362 mg 103 mmol) N-methylmor-pholine N-oxide (NMO) (262 mg 19 mmol) and molecularsieves (515 mg 500 mgmmol) in anhydrous CH2Cl2(104 mL) under argon at room temperature and TPAP(32 mg 01 mmol) were added The reaction mixture wasstirred for 1 h and then filtered through a short pad of silicagel and Celite eluting with EtOAc Evaporation of the sol-vent yielded the aldehyde 20 (309 mg 86) Compound20 [a]D

20 +230 (c 088 CHCl3) IR 2947 2731 17171669 1464 1387 1148 1096 1034 918 cm1 1H NMR(200 MHz CDCl3) d 984 (1H d Jfrac1438 Hz H-15) 509(1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)414 (1H s H-12) 330 (3H s OCH2OCH3) 279 (1H s H-14) 108 (3H s Me-17) 082 081 and 076 (33H s Me-18 19 and 20) 2ndash083 (14H m) 13C NMR (503 MHzCDCl3) d 2050 (C-15) 1428 (C-13) 1136 (C-16) 931(OCH2OCH3) 762 (C-12) 633 (C-14) 567 (C-5) 554(OCH2OCH3) 518 (C-9) 421 (C-3) 409 (C-7) 400 (C-10) 397 (C-1) 376 (C-8) 335 (C-18) 334 (C-4) 282(C-11) 216 (C-19) 187 (C-2) 186 (C-6) 164 (C-17) 163(C-20) MS mz () 348 (11) [M]+ 316 (25) 286 (35) 191(18) 115 (59) 57 (100) HRMS calcd for C22H36O3 [M]+3482664 found 3482667

416 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)15a(15)-dienil-15-methylether To a suspensionof methoxymethyltriphenylphosphonium chloride (MeOCH2PPh3Cl) (44 g 128 mmol) in THF (6 mL) at 78 Cunder an argon atmosphere a 10 M solution of NaHMDSin THF (113 mL 113 mmol) was added dropwise andthe solution stirred for 20 min A solution of the aldehyde20 (45 g 129 mmol) in THF (145 mL) was added drop-wise and the mixture stirred for 1 h It was allowed towarm to room temperature quenched with aqueous NH4Cland extracted with Et2O The organic layer was washedwith water and dried over Na2SO4 The residue obtainedafter removing the solvent was purified by column chroma-tography (hexaneEtOAc 91) to afford a mixture 21a21b(303 g 82) (73 ZE) Compound 21a21b IR 29321665 1460 1387 1269 1244 1206 1148 1115 10941036 cm1 1H NMR (200 MHz CDCl3) d isomer Z (major)596 (1H d Jfrac1466 Hz H-15) 487 (1H br s HA-16) 479(1H br s HB-16) 464 (1H d Jfrac1466 Hz OCH2OCH3)448 (1H d Jfrac1466 Hz OCH2OCH3) 432 (1H dd J1frac14102 and J2frac1466 Hz H-15a) 417 (1H s H-12) 351 (3Hs OMe) 334 (3H s OCH2OCH3) 324 (1H d Jfrac14102 HzH-14) 25ndash09 (14H m) 081 079 077 and 068 (43H sMe-17 18 19 and 20) isomer E (minor) 616 (1H dJfrac14126 Hz H-15) 491 (1H br s HA-16) 479 (1H br sHB-16) 472 (1H dd J1frac14126 and J2frac1424 Hz H-15a) 460(1H d Jfrac1466 Hz OCH2OCH3) 445 (1H d Jfrac1466 Hz

8944 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OCH2OCH3) 419 (1H s H-12) 354 (3H s OMe) 333 (3Hs OCH2OCH3) 332ndash328 (1H m H-14) 25ndash09 (14H m)081 079 077 and 069 (43H s Me-17 18 19 and 20) 13CNMR (503 MHz CDCl3) d 1486 (C-13) 1474 (C-15)1122 (C-16) 1036 (C-15a) 931 (OCH2OCH3) 767 (C-12) 596 (OMe) 567 (C-5) 553 (OCH2OCH3) 524 (C-9) 470 (C-14) 423 (C-3) 409 (C-7) 399 (C-1) 395(C-10) 375 (C-8) 336 (C-19) 335 (C-4) 284 (C-11)217 (C-18) 191 (C-2) 188 (C-6) 163 (C-17) 146 (C-20) MS mz () 376 (8) [M]+ 344 (36) 331 (37) 299(29) 191 (74) 179 (75) 71 (100) HRMS calcd forC24H40O3 [M]+ 3762977 found 3762968

417 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)en-15-al 22 To a solution of 21a21b (470 mg149 mmol) in acetone (247 mL) and water (3 mL) p-TsOH (360 mg 19 mmol) was added at room temperatureAfter being stirred for 7 h the reaction mixture was dilutedwith water and extracted with Et2O The extracts werewashed with 6 aqueous NaHCO3 solution and water Evap-oration of the solvent yielded the aldehyde 22 (449 mg99) Compound 22 [a]D

20 +35 (c 079 CHCl3) IR 17281647 1462 1387 1258 1208 1148 1096 1032 918733 cm1 1H NMR (200 MHz CDCl3) d 953 (1H tJfrac1422 H-15) 495 (1H s HA-16) 457 (1H s HB-16)455 (1H d Jfrac1466 Hz OCH2OCH3) 444 (1H dJfrac1466 Hz OCH2OCH3) 413 (1H s H-12) 331 (3H sOCH2OCH3) 268 (1H t Jfrac1474 Hz H-14) 237 (2H ddJ1frac1474 and J2frac1422 Hz H-15a) 198ndash105 (14H m) 082(3H s) 078 (6H s) 066 (3H s) 13C NMR (503 MHzCDCl3) d 2033 (C-15) 1467 (C-13) 1126 (C-16) 993(OCH2OCH3) 768 (C-12) 565 (C-5) 554 (OCH2OCH3)528 (C-9) 462 (C-14) 421 (C-15a) 409 (C-3) 399 (C-7) 395 (C-1) 394 (C-10) 375 (C-8) 335 (C-19) 334(C-4) 285 (C-11) 216 (C-18) 192 (C-2) 187 (C-6)162 (C-17) 150 (C-20) MS mz () 362 (12) [M]+ 300(28) 191 (78) 157 (32) 123 (35) 69 (100) HRMS calcdfor C23H38O3 [M]+ 3622821 found 3622816

418 Methyl 12a-methoxymethoxy-15a-homo-isoantico-pal-13(16)en-15-oate 23 To a solution of 22 (28 g816 mmol) in tBuOH (97 mmL) a solution of 25NaH2PO4NaClO2 in water was added at room temperatureThe reaction mixture was stirred for 12 h diluted with waterand 2 N HCl and extracted with Et2O The organic layer waswashed with water and dried over anhydrous Na2SO4 Afterfiltration the solvent was evaporated to give the acid(305 g) To a solution of the acid (15 g 405 mmol) in ben-zene and methanol TMSCHN2 was added under an argonatmosphere at 0 C After 10 min of vigorous stirring thesolvent was evaporated to give a residue which was purifiedby silica gel column chromatography (hexaneEtOAc 91) toyield 23 (13 g 83) Compound 23 [a]D

20 81 (c 068CHCl3) IR 1738 1651 1441 1387 1329 1157 10961032 918 cm1 1H NMR (200 MHz CDCl3) d 493 (1Hs HA-16) 470 (1H s HB-16) 459 (1H d Jfrac1466 HzOCH2OCH3) 445 (1H d Jfrac1466 Hz OCH2OCH3) 415(1H s H-12) 360 (3H s COOMe) 333 (3H sOCH2OCH3) 262 (1H dd JBXfrac14110 and JAXfrac1440 HzH-14) 243 (1H dd JABfrac14158 and JAXfrac1440 Hz HA-15a)230 (1H dd JABfrac14158 and JBXfrac14110 Hz HB-15a) 168ndash087 (14H m) 081 (3H s) 076 (2H s) 064 (3H s)13C NMR (503 MHz CDCl3) d 1741 (C-15) 1469

(C-13) 1114 (C-16) 928 (OCH2OCH3) 762 (C-12)564 (C-5) 553 (OCH2OCH3) 524 (C-9) 516 (COOMe)478 (C-14) 421 (C-3) 404 (C-7) 395 (C-1) 392 (C-8)374 (C-10) 335 (C-18) 334 (C-4) 304 (C-15a) 287(C-11) 216 (C-19) 192 (C-2) 188 (C-6) 162 (C-17)148 (C-20) MS mz () 392 (12) [M]+ 347 (35) 315(32) 191 (100) 123 (48) 69 (92) HRMS calcd forC24H40O4 [M]+ 3922927 found 3922934

419 15a-Homo-isoanticopal-12en-1516-olide 13 Toa solution of 23 (1 g 26 mmol) in dioxane (149 mL) wasadded a solution of 6 N H2SO4 (115 mL) at 85 C The solu-tion was stirred for 24 h quenched by addition of ice andbrine and extracted with EtOAc (3100 mL) The organiclayer was washed with water (330 mL) and dried overNa2SO4 Evaporation of the solvent followed by chromato-graphy on silica gel (CHCl3) yielded the lactone 13(781 mg 93) Compound 13 [a]D

20458 (c 053 CHCl3)IR 1748 1464 1387 1258 1036 1017 cm1 1H NMR(200 MHz CDCl3) d 570 (1H br s H-12) 465 (1H d Jfrac14132 Hz HA-16) 456 (1H d Jfrac14132 Hz HB-16) 280ndash222(3H m) 220ndash098 (14H m) 085 083 079 and 070 (43H s Me-17 18 19 and 20) 13C NMR (503 MHz CDCl3)d 1743 (C-15) 1294 (C-13) 709 (C-16) 1239 (C-12)566 (C-5) 545 (C-9) 476 (C-14) 420 (C-3) 399 (C-7)399 (C-1) 357 (C-8) 375 (C-10) 336 (C-18) 334 (C-4)300 (C-15a) 232 (C-11) 218 (C-19) 187 (C-2) 186 (C-6) 154 (C-17) 142 (C-20) EIMS mz () 316 (M+) (1)256 (2) 192 (3) 137 (4) 86 (100) 69 (26) HRMS calcdfor C21H32O2 [M]+ 3162402 found 3162432

4110 15a-Homo-isoanticopal-12-en-1516-diol 24 Toa solution of 13 (500 mg 16 mmol) in THF (40 mL) at0 C under an argon atmosphere LAH (200 mg) was addedThe mixture was stirred for 1 h It was allowed to warm toroom temperature quenched with aqueous EtOAc and driedover Na2SO4 Evaporation of the solvent yielded the com-pound 24 (449 mg 99) Compound 24 [a]D

20 +122 (c01 CHCl3) IR 3380 1458 1439 1387 1364 12091049 988 839 cm1 1H NMR (200 MHz CDCl3) d 571(1H br s H-12) 427 (1H d Jfrac14120 Hz HA-16) 387 (1Hd Jfrac14120 Hz HB-16) 386ndash379 (1H m HA-15) 371ndash361(1H m HB-15) 170ndash152 and 087ndash070 (2H m H-1)167ndash151 (2H m H-2) 143ndash129 118ndash103 (2H mH-3) 090ndash075 (1H m H-5) 148ndash136 (2H m H-6) 195ndash180 121ndash105 (2H m H-7) 128ndash113 (1H m H-9) 180ndash163 (2H m H-11) 212ndash200 (1H m H-14) 222ndash186(2H m H-15a) 089 (3H s Me-17) 086 (3H s Me-18)082 (3H s Me-19) 074 (3H s Me-20) 13C NMR(503 MHz CDCl3) d 1385 (C-13) 1268 (C-12) 665 (C-16) 645 (C-15) 565 (C-5) 550 (C-9) 493 (C-14) 421(C-3) 408 (C-7) 400 (C-1) 374 (C-8) 371 (C-10) 336(C-18) 333 (C-4) 283 (C-11) 230 (C-15a) 219 (C-19)189 (C-2) 187 (C-6) 156 (C-17) 145 (C-20) EIMS mz() 302 (M18+) (3) 257 (4) 192 (12) 107 (38) 85(100) HRMS calcd for C21H36O2 [Mndash18]+ 3022610found 3022620

4111 15a-Homo-isoanticopal-12-en-1615-olide 25 Toa solution of 24 (200 mg 062 mmol) in DCM (25 mL) atroom temperature under anhydrous atmosphere MnO2

(200 mg) was added The mixture was stirred for 1 h Afterfiltration the solvent was evaporated to yield the compound

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8943P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

412 Methyl 12a-hydroxy-isoanticopal-13(16)en-15-oate 17 To a solution of 16 (23 g 70 mmol) in toluene(50 mL) was added 398 mg (19 mmol) of Al(iPrO)3 andthe mixture was stirred at 150 C for 24 h diluted with waterand extracted with Et2O The organic layer was washed with10 aqueous solution of NaOH and brine Evaporation ofthe dried extract gave 17 (22 g 94) Compound 17[a]D

20 322 (c 082 CHCl3) mp (hexane) 156ndash158 CIR 3462 2930 1734 1653 1456 1387 1194 11631044 1007 912 cm1 1H NMR (200 MHz CDCl3) d 498(1H s HA-16) 478 (1H s HB-16) 432 (1H s H-12)358 (3H s COOMe) 329 (1H s H-14) 104 (3H s Me-17) 086 084 081 (9H s each Me-18 19 and 20) 188ndash087 (14H m) 13C NMR (503 MHz CDCl3) d 1722 (C-15) 1453 (C-13) 1130 (C-16) 729 (C-12) 576 (C-14)569 (C-5) 518 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 402 (C-10) 398 (C-1) 374 (C-8) 335 (C-18)334 (C-4) 294 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 163 (C-17) 144 (C-20) MS mz () 334 (12) [M]+316 (34) 288 (6) 205 (49) 40 (92) 10 (100)

413 Methyl 12a-methoxymethoxy-isoanticopal-13(16)en-15-oate 18 To a solution of aldehyde 17 (66 g198 mmol) in CHCl3 (118 mL) DMM (118 mL 133 mol)and P2O5 (297 g 021 mol) were added and the mixturewas stirred for 30 min Then ice was added The organicphase was separated and the aqueous phase was extractedwith Et2O The organic layer was washed with aqueous solu-tion of 10 NaHCO3 and water dried over Na2SO4 and con-centrated under reduced pressure to give 18 (69 g 99)Compound 18 [a]D

20 36 (c 089 CHCl3) mp (hexane)65ndash67 C IR 1738 1458 1389 1163 1034 918 cm1 1HNMR (200 MHz CDCl3) d 503 (1H s HA-16) 498 (1H sHB-16) 465 (1H d Jfrac1466 Hz OCH2OCH3) 452 (1H dJfrac1466 Hz OCH2OCH3) 419 (1H t Jfrac1429 H-12) 364 (3Hs COOMe) 335 (3H s OCH2OCH3) 316 (1H s H-14)104 (3H s Me-17) 085 083 and 080 (9H s each Me-18 19 and 20) 190ndash085 (14H m) 13C NMR (503 MHzCDCl3) d 1721 (C-15) 1417 (C-13) 1131 (C-16) 932(OCH2OCH3) 761 (C-12) 579 (C-14) 568 (C-5) 554(OCH2OCH3) 525 (C-9) 511 (COOMe) 422 (C-3) 404(C-7) 401 (C-10) 398 (C-1) 375 (C-8) 335 (C-18) 334(C-4) 282 (C-11) 216 (C-19) 189 (C-2) 186 (C-6) 162(C-17) 145 (C-20) MS mz () 378 (8) [M]+ 346 (24) 333(45) 316 (92) 191 (94) 137 (62) 69 (100) HRMS calcd forC23H38O4 [M]+ 3782779 found 3782780

414 12a-Methoxymethoxy-isoanticopal-13(16)en-15-ol19 To a solution of 18 (434 mg 11 mmol) in dry methylenechloride (27 mL) was added a solution of DIBAL-H in tolu-ene (16 M 168 mL 24 mmol) under argon at78 C Thesolution stirred for 30 min was quenched by addition ofMeOH (5 mL) and water (5 mL) and extracted with Et2O(3100 mL) The organic layer was washed with water(330 mL) and dried over Na2SO4 Evaporation of the sol-vent followed by chromatography on silica gel (hexaneEtOAc 91) yielded the alcohol 19 (362 mg 90) Com-pound 19 [a]D

20 +16 (c 11 CHCl3) IR 3428 1719 16491387 1209 1099 907 cm1 1H NMR (200 MHz CDCl3)d 509 (1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)415 (1H s H-12) 377 (2H m H-15) 332 (3H sOCH2OCH3) 085 (3H s Me-17) 082 076 and 068

(9H s each Me-18 19 and 20) 235ndash086 (15H m) 13CNMR (503 MHz CDCl3) d 1459 (C-13) 1110 (C-16)938 (OCH2OCH3) 779 (C-12) 586 (C-15) 565 (C-5)555 (OCH2OCH3) 541 (C-14) 528 (C-9) 421(C-3)406 (C-7) 399 (C-1) 395 (C-10) 375 (C-8) 335 (C-18) 334 (C-4) 287 (C-11) 192 (C-2) 187 (C-6) 162(C-17) 157 (C-20) MS mz () 350 (1) [M]+ 288 (11)191 (18) 115 (14) 99 (100) 85 (68) 83 (37) HRMS calcdfor C22H38O3 [M]+ 3502821 found 3502812

415 12a-Methoxymethoxy-isoanticopal-13(16)en-15-al20 To a mixture of 19 (362 mg 103 mmol) N-methylmor-pholine N-oxide (NMO) (262 mg 19 mmol) and molecularsieves (515 mg 500 mgmmol) in anhydrous CH2Cl2(104 mL) under argon at room temperature and TPAP(32 mg 01 mmol) were added The reaction mixture wasstirred for 1 h and then filtered through a short pad of silicagel and Celite eluting with EtOAc Evaporation of the sol-vent yielded the aldehyde 20 (309 mg 86) Compound20 [a]D

20 +230 (c 088 CHCl3) IR 2947 2731 17171669 1464 1387 1148 1096 1034 918 cm1 1H NMR(200 MHz CDCl3) d 984 (1H d Jfrac1438 Hz H-15) 509(1H s HA-16) 484 (1H s HB-16) 461 (1H d Jfrac1466 Hz OCH2OCH3) 451 (1H d Jfrac1466 Hz OCH2OCH3)414 (1H s H-12) 330 (3H s OCH2OCH3) 279 (1H s H-14) 108 (3H s Me-17) 082 081 and 076 (33H s Me-18 19 and 20) 2ndash083 (14H m) 13C NMR (503 MHzCDCl3) d 2050 (C-15) 1428 (C-13) 1136 (C-16) 931(OCH2OCH3) 762 (C-12) 633 (C-14) 567 (C-5) 554(OCH2OCH3) 518 (C-9) 421 (C-3) 409 (C-7) 400 (C-10) 397 (C-1) 376 (C-8) 335 (C-18) 334 (C-4) 282(C-11) 216 (C-19) 187 (C-2) 186 (C-6) 164 (C-17) 163(C-20) MS mz () 348 (11) [M]+ 316 (25) 286 (35) 191(18) 115 (59) 57 (100) HRMS calcd for C22H36O3 [M]+3482664 found 3482667

416 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)15a(15)-dienil-15-methylether To a suspensionof methoxymethyltriphenylphosphonium chloride (MeOCH2PPh3Cl) (44 g 128 mmol) in THF (6 mL) at 78 Cunder an argon atmosphere a 10 M solution of NaHMDSin THF (113 mL 113 mmol) was added dropwise andthe solution stirred for 20 min A solution of the aldehyde20 (45 g 129 mmol) in THF (145 mL) was added drop-wise and the mixture stirred for 1 h It was allowed towarm to room temperature quenched with aqueous NH4Cland extracted with Et2O The organic layer was washedwith water and dried over Na2SO4 The residue obtainedafter removing the solvent was purified by column chroma-tography (hexaneEtOAc 91) to afford a mixture 21a21b(303 g 82) (73 ZE) Compound 21a21b IR 29321665 1460 1387 1269 1244 1206 1148 1115 10941036 cm1 1H NMR (200 MHz CDCl3) d isomer Z (major)596 (1H d Jfrac1466 Hz H-15) 487 (1H br s HA-16) 479(1H br s HB-16) 464 (1H d Jfrac1466 Hz OCH2OCH3)448 (1H d Jfrac1466 Hz OCH2OCH3) 432 (1H dd J1frac14102 and J2frac1466 Hz H-15a) 417 (1H s H-12) 351 (3Hs OMe) 334 (3H s OCH2OCH3) 324 (1H d Jfrac14102 HzH-14) 25ndash09 (14H m) 081 079 077 and 068 (43H sMe-17 18 19 and 20) isomer E (minor) 616 (1H dJfrac14126 Hz H-15) 491 (1H br s HA-16) 479 (1H br sHB-16) 472 (1H dd J1frac14126 and J2frac1424 Hz H-15a) 460(1H d Jfrac1466 Hz OCH2OCH3) 445 (1H d Jfrac1466 Hz

8944 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OCH2OCH3) 419 (1H s H-12) 354 (3H s OMe) 333 (3Hs OCH2OCH3) 332ndash328 (1H m H-14) 25ndash09 (14H m)081 079 077 and 069 (43H s Me-17 18 19 and 20) 13CNMR (503 MHz CDCl3) d 1486 (C-13) 1474 (C-15)1122 (C-16) 1036 (C-15a) 931 (OCH2OCH3) 767 (C-12) 596 (OMe) 567 (C-5) 553 (OCH2OCH3) 524 (C-9) 470 (C-14) 423 (C-3) 409 (C-7) 399 (C-1) 395(C-10) 375 (C-8) 336 (C-19) 335 (C-4) 284 (C-11)217 (C-18) 191 (C-2) 188 (C-6) 163 (C-17) 146 (C-20) MS mz () 376 (8) [M]+ 344 (36) 331 (37) 299(29) 191 (74) 179 (75) 71 (100) HRMS calcd forC24H40O3 [M]+ 3762977 found 3762968

417 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)en-15-al 22 To a solution of 21a21b (470 mg149 mmol) in acetone (247 mL) and water (3 mL) p-TsOH (360 mg 19 mmol) was added at room temperatureAfter being stirred for 7 h the reaction mixture was dilutedwith water and extracted with Et2O The extracts werewashed with 6 aqueous NaHCO3 solution and water Evap-oration of the solvent yielded the aldehyde 22 (449 mg99) Compound 22 [a]D

20 +35 (c 079 CHCl3) IR 17281647 1462 1387 1258 1208 1148 1096 1032 918733 cm1 1H NMR (200 MHz CDCl3) d 953 (1H tJfrac1422 H-15) 495 (1H s HA-16) 457 (1H s HB-16)455 (1H d Jfrac1466 Hz OCH2OCH3) 444 (1H dJfrac1466 Hz OCH2OCH3) 413 (1H s H-12) 331 (3H sOCH2OCH3) 268 (1H t Jfrac1474 Hz H-14) 237 (2H ddJ1frac1474 and J2frac1422 Hz H-15a) 198ndash105 (14H m) 082(3H s) 078 (6H s) 066 (3H s) 13C NMR (503 MHzCDCl3) d 2033 (C-15) 1467 (C-13) 1126 (C-16) 993(OCH2OCH3) 768 (C-12) 565 (C-5) 554 (OCH2OCH3)528 (C-9) 462 (C-14) 421 (C-15a) 409 (C-3) 399 (C-7) 395 (C-1) 394 (C-10) 375 (C-8) 335 (C-19) 334(C-4) 285 (C-11) 216 (C-18) 192 (C-2) 187 (C-6)162 (C-17) 150 (C-20) MS mz () 362 (12) [M]+ 300(28) 191 (78) 157 (32) 123 (35) 69 (100) HRMS calcdfor C23H38O3 [M]+ 3622821 found 3622816

418 Methyl 12a-methoxymethoxy-15a-homo-isoantico-pal-13(16)en-15-oate 23 To a solution of 22 (28 g816 mmol) in tBuOH (97 mmL) a solution of 25NaH2PO4NaClO2 in water was added at room temperatureThe reaction mixture was stirred for 12 h diluted with waterand 2 N HCl and extracted with Et2O The organic layer waswashed with water and dried over anhydrous Na2SO4 Afterfiltration the solvent was evaporated to give the acid(305 g) To a solution of the acid (15 g 405 mmol) in ben-zene and methanol TMSCHN2 was added under an argonatmosphere at 0 C After 10 min of vigorous stirring thesolvent was evaporated to give a residue which was purifiedby silica gel column chromatography (hexaneEtOAc 91) toyield 23 (13 g 83) Compound 23 [a]D

20 81 (c 068CHCl3) IR 1738 1651 1441 1387 1329 1157 10961032 918 cm1 1H NMR (200 MHz CDCl3) d 493 (1Hs HA-16) 470 (1H s HB-16) 459 (1H d Jfrac1466 HzOCH2OCH3) 445 (1H d Jfrac1466 Hz OCH2OCH3) 415(1H s H-12) 360 (3H s COOMe) 333 (3H sOCH2OCH3) 262 (1H dd JBXfrac14110 and JAXfrac1440 HzH-14) 243 (1H dd JABfrac14158 and JAXfrac1440 Hz HA-15a)230 (1H dd JABfrac14158 and JBXfrac14110 Hz HB-15a) 168ndash087 (14H m) 081 (3H s) 076 (2H s) 064 (3H s)13C NMR (503 MHz CDCl3) d 1741 (C-15) 1469

(C-13) 1114 (C-16) 928 (OCH2OCH3) 762 (C-12)564 (C-5) 553 (OCH2OCH3) 524 (C-9) 516 (COOMe)478 (C-14) 421 (C-3) 404 (C-7) 395 (C-1) 392 (C-8)374 (C-10) 335 (C-18) 334 (C-4) 304 (C-15a) 287(C-11) 216 (C-19) 192 (C-2) 188 (C-6) 162 (C-17)148 (C-20) MS mz () 392 (12) [M]+ 347 (35) 315(32) 191 (100) 123 (48) 69 (92) HRMS calcd forC24H40O4 [M]+ 3922927 found 3922934

419 15a-Homo-isoanticopal-12en-1516-olide 13 Toa solution of 23 (1 g 26 mmol) in dioxane (149 mL) wasadded a solution of 6 N H2SO4 (115 mL) at 85 C The solu-tion was stirred for 24 h quenched by addition of ice andbrine and extracted with EtOAc (3100 mL) The organiclayer was washed with water (330 mL) and dried overNa2SO4 Evaporation of the solvent followed by chromato-graphy on silica gel (CHCl3) yielded the lactone 13(781 mg 93) Compound 13 [a]D

20458 (c 053 CHCl3)IR 1748 1464 1387 1258 1036 1017 cm1 1H NMR(200 MHz CDCl3) d 570 (1H br s H-12) 465 (1H d Jfrac14132 Hz HA-16) 456 (1H d Jfrac14132 Hz HB-16) 280ndash222(3H m) 220ndash098 (14H m) 085 083 079 and 070 (43H s Me-17 18 19 and 20) 13C NMR (503 MHz CDCl3)d 1743 (C-15) 1294 (C-13) 709 (C-16) 1239 (C-12)566 (C-5) 545 (C-9) 476 (C-14) 420 (C-3) 399 (C-7)399 (C-1) 357 (C-8) 375 (C-10) 336 (C-18) 334 (C-4)300 (C-15a) 232 (C-11) 218 (C-19) 187 (C-2) 186 (C-6) 154 (C-17) 142 (C-20) EIMS mz () 316 (M+) (1)256 (2) 192 (3) 137 (4) 86 (100) 69 (26) HRMS calcdfor C21H32O2 [M]+ 3162402 found 3162432

4110 15a-Homo-isoanticopal-12-en-1516-diol 24 Toa solution of 13 (500 mg 16 mmol) in THF (40 mL) at0 C under an argon atmosphere LAH (200 mg) was addedThe mixture was stirred for 1 h It was allowed to warm toroom temperature quenched with aqueous EtOAc and driedover Na2SO4 Evaporation of the solvent yielded the com-pound 24 (449 mg 99) Compound 24 [a]D

20 +122 (c01 CHCl3) IR 3380 1458 1439 1387 1364 12091049 988 839 cm1 1H NMR (200 MHz CDCl3) d 571(1H br s H-12) 427 (1H d Jfrac14120 Hz HA-16) 387 (1Hd Jfrac14120 Hz HB-16) 386ndash379 (1H m HA-15) 371ndash361(1H m HB-15) 170ndash152 and 087ndash070 (2H m H-1)167ndash151 (2H m H-2) 143ndash129 118ndash103 (2H mH-3) 090ndash075 (1H m H-5) 148ndash136 (2H m H-6) 195ndash180 121ndash105 (2H m H-7) 128ndash113 (1H m H-9) 180ndash163 (2H m H-11) 212ndash200 (1H m H-14) 222ndash186(2H m H-15a) 089 (3H s Me-17) 086 (3H s Me-18)082 (3H s Me-19) 074 (3H s Me-20) 13C NMR(503 MHz CDCl3) d 1385 (C-13) 1268 (C-12) 665 (C-16) 645 (C-15) 565 (C-5) 550 (C-9) 493 (C-14) 421(C-3) 408 (C-7) 400 (C-1) 374 (C-8) 371 (C-10) 336(C-18) 333 (C-4) 283 (C-11) 230 (C-15a) 219 (C-19)189 (C-2) 187 (C-6) 156 (C-17) 145 (C-20) EIMS mz() 302 (M18+) (3) 257 (4) 192 (12) 107 (38) 85(100) HRMS calcd for C21H36O2 [Mndash18]+ 3022610found 3022620

4111 15a-Homo-isoanticopal-12-en-1615-olide 25 Toa solution of 24 (200 mg 062 mmol) in DCM (25 mL) atroom temperature under anhydrous atmosphere MnO2

(200 mg) was added The mixture was stirred for 1 h Afterfiltration the solvent was evaporated to yield the compound

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8944 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

OCH2OCH3) 419 (1H s H-12) 354 (3H s OMe) 333 (3Hs OCH2OCH3) 332ndash328 (1H m H-14) 25ndash09 (14H m)081 079 077 and 069 (43H s Me-17 18 19 and 20) 13CNMR (503 MHz CDCl3) d 1486 (C-13) 1474 (C-15)1122 (C-16) 1036 (C-15a) 931 (OCH2OCH3) 767 (C-12) 596 (OMe) 567 (C-5) 553 (OCH2OCH3) 524 (C-9) 470 (C-14) 423 (C-3) 409 (C-7) 399 (C-1) 395(C-10) 375 (C-8) 336 (C-19) 335 (C-4) 284 (C-11)217 (C-18) 191 (C-2) 188 (C-6) 163 (C-17) 146 (C-20) MS mz () 376 (8) [M]+ 344 (36) 331 (37) 299(29) 191 (74) 179 (75) 71 (100) HRMS calcd forC24H40O3 [M]+ 3762977 found 3762968

417 12a-Methoxymethoxy-15a-homo-isoanticopal-13(16)en-15-al 22 To a solution of 21a21b (470 mg149 mmol) in acetone (247 mL) and water (3 mL) p-TsOH (360 mg 19 mmol) was added at room temperatureAfter being stirred for 7 h the reaction mixture was dilutedwith water and extracted with Et2O The extracts werewashed with 6 aqueous NaHCO3 solution and water Evap-oration of the solvent yielded the aldehyde 22 (449 mg99) Compound 22 [a]D

20 +35 (c 079 CHCl3) IR 17281647 1462 1387 1258 1208 1148 1096 1032 918733 cm1 1H NMR (200 MHz CDCl3) d 953 (1H tJfrac1422 H-15) 495 (1H s HA-16) 457 (1H s HB-16)455 (1H d Jfrac1466 Hz OCH2OCH3) 444 (1H dJfrac1466 Hz OCH2OCH3) 413 (1H s H-12) 331 (3H sOCH2OCH3) 268 (1H t Jfrac1474 Hz H-14) 237 (2H ddJ1frac1474 and J2frac1422 Hz H-15a) 198ndash105 (14H m) 082(3H s) 078 (6H s) 066 (3H s) 13C NMR (503 MHzCDCl3) d 2033 (C-15) 1467 (C-13) 1126 (C-16) 993(OCH2OCH3) 768 (C-12) 565 (C-5) 554 (OCH2OCH3)528 (C-9) 462 (C-14) 421 (C-15a) 409 (C-3) 399 (C-7) 395 (C-1) 394 (C-10) 375 (C-8) 335 (C-19) 334(C-4) 285 (C-11) 216 (C-18) 192 (C-2) 187 (C-6)162 (C-17) 150 (C-20) MS mz () 362 (12) [M]+ 300(28) 191 (78) 157 (32) 123 (35) 69 (100) HRMS calcdfor C23H38O3 [M]+ 3622821 found 3622816

418 Methyl 12a-methoxymethoxy-15a-homo-isoantico-pal-13(16)en-15-oate 23 To a solution of 22 (28 g816 mmol) in tBuOH (97 mmL) a solution of 25NaH2PO4NaClO2 in water was added at room temperatureThe reaction mixture was stirred for 12 h diluted with waterand 2 N HCl and extracted with Et2O The organic layer waswashed with water and dried over anhydrous Na2SO4 Afterfiltration the solvent was evaporated to give the acid(305 g) To a solution of the acid (15 g 405 mmol) in ben-zene and methanol TMSCHN2 was added under an argonatmosphere at 0 C After 10 min of vigorous stirring thesolvent was evaporated to give a residue which was purifiedby silica gel column chromatography (hexaneEtOAc 91) toyield 23 (13 g 83) Compound 23 [a]D

20 81 (c 068CHCl3) IR 1738 1651 1441 1387 1329 1157 10961032 918 cm1 1H NMR (200 MHz CDCl3) d 493 (1Hs HA-16) 470 (1H s HB-16) 459 (1H d Jfrac1466 HzOCH2OCH3) 445 (1H d Jfrac1466 Hz OCH2OCH3) 415(1H s H-12) 360 (3H s COOMe) 333 (3H sOCH2OCH3) 262 (1H dd JBXfrac14110 and JAXfrac1440 HzH-14) 243 (1H dd JABfrac14158 and JAXfrac1440 Hz HA-15a)230 (1H dd JABfrac14158 and JBXfrac14110 Hz HB-15a) 168ndash087 (14H m) 081 (3H s) 076 (2H s) 064 (3H s)13C NMR (503 MHz CDCl3) d 1741 (C-15) 1469

(C-13) 1114 (C-16) 928 (OCH2OCH3) 762 (C-12)564 (C-5) 553 (OCH2OCH3) 524 (C-9) 516 (COOMe)478 (C-14) 421 (C-3) 404 (C-7) 395 (C-1) 392 (C-8)374 (C-10) 335 (C-18) 334 (C-4) 304 (C-15a) 287(C-11) 216 (C-19) 192 (C-2) 188 (C-6) 162 (C-17)148 (C-20) MS mz () 392 (12) [M]+ 347 (35) 315(32) 191 (100) 123 (48) 69 (92) HRMS calcd forC24H40O4 [M]+ 3922927 found 3922934

419 15a-Homo-isoanticopal-12en-1516-olide 13 Toa solution of 23 (1 g 26 mmol) in dioxane (149 mL) wasadded a solution of 6 N H2SO4 (115 mL) at 85 C The solu-tion was stirred for 24 h quenched by addition of ice andbrine and extracted with EtOAc (3100 mL) The organiclayer was washed with water (330 mL) and dried overNa2SO4 Evaporation of the solvent followed by chromato-graphy on silica gel (CHCl3) yielded the lactone 13(781 mg 93) Compound 13 [a]D

20458 (c 053 CHCl3)IR 1748 1464 1387 1258 1036 1017 cm1 1H NMR(200 MHz CDCl3) d 570 (1H br s H-12) 465 (1H d Jfrac14132 Hz HA-16) 456 (1H d Jfrac14132 Hz HB-16) 280ndash222(3H m) 220ndash098 (14H m) 085 083 079 and 070 (43H s Me-17 18 19 and 20) 13C NMR (503 MHz CDCl3)d 1743 (C-15) 1294 (C-13) 709 (C-16) 1239 (C-12)566 (C-5) 545 (C-9) 476 (C-14) 420 (C-3) 399 (C-7)399 (C-1) 357 (C-8) 375 (C-10) 336 (C-18) 334 (C-4)300 (C-15a) 232 (C-11) 218 (C-19) 187 (C-2) 186 (C-6) 154 (C-17) 142 (C-20) EIMS mz () 316 (M+) (1)256 (2) 192 (3) 137 (4) 86 (100) 69 (26) HRMS calcdfor C21H32O2 [M]+ 3162402 found 3162432

4110 15a-Homo-isoanticopal-12-en-1516-diol 24 Toa solution of 13 (500 mg 16 mmol) in THF (40 mL) at0 C under an argon atmosphere LAH (200 mg) was addedThe mixture was stirred for 1 h It was allowed to warm toroom temperature quenched with aqueous EtOAc and driedover Na2SO4 Evaporation of the solvent yielded the com-pound 24 (449 mg 99) Compound 24 [a]D

20 +122 (c01 CHCl3) IR 3380 1458 1439 1387 1364 12091049 988 839 cm1 1H NMR (200 MHz CDCl3) d 571(1H br s H-12) 427 (1H d Jfrac14120 Hz HA-16) 387 (1Hd Jfrac14120 Hz HB-16) 386ndash379 (1H m HA-15) 371ndash361(1H m HB-15) 170ndash152 and 087ndash070 (2H m H-1)167ndash151 (2H m H-2) 143ndash129 118ndash103 (2H mH-3) 090ndash075 (1H m H-5) 148ndash136 (2H m H-6) 195ndash180 121ndash105 (2H m H-7) 128ndash113 (1H m H-9) 180ndash163 (2H m H-11) 212ndash200 (1H m H-14) 222ndash186(2H m H-15a) 089 (3H s Me-17) 086 (3H s Me-18)082 (3H s Me-19) 074 (3H s Me-20) 13C NMR(503 MHz CDCl3) d 1385 (C-13) 1268 (C-12) 665 (C-16) 645 (C-15) 565 (C-5) 550 (C-9) 493 (C-14) 421(C-3) 408 (C-7) 400 (C-1) 374 (C-8) 371 (C-10) 336(C-18) 333 (C-4) 283 (C-11) 230 (C-15a) 219 (C-19)189 (C-2) 187 (C-6) 156 (C-17) 145 (C-20) EIMS mz() 302 (M18+) (3) 257 (4) 192 (12) 107 (38) 85(100) HRMS calcd for C21H36O2 [Mndash18]+ 3022610found 3022620

4111 15a-Homo-isoanticopal-12-en-1615-olide 25 Toa solution of 24 (200 mg 062 mmol) in DCM (25 mL) atroom temperature under anhydrous atmosphere MnO2

(200 mg) was added The mixture was stirred for 1 h Afterfiltration the solvent was evaporated to yield the compound

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8945P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

25 (170 mg 86) Compound 25 [a]D20 +83 (c 064

CHCl3) IR 2959 1717 1643 1458 1389 1262 1088932 733 cm1 1H NMR (200 MHz CDCl3) d 730ndash725(1H m H-12) 441 (1H ddd J1frac1455 J2frac142 and J3frac1412 Hz HA-15) 420 (1H ddd J1frac1466 J2frac1455 and J3frac1412 Hz HB-15) 233ndash201 (3H m) 190ndash110 (14H m)090 087 083 and 075 (43H s Me-17 18 19 and 20)13C NMR (503 MHz CDCl3) d 1656 (C-16) 1430 (C-12) 1263 (C-13) 684 (C-15) 563 (C-5) 537 (C-9) 422(C-14) 417 (C-3) 401 (C-1) 395 (C-7) 370 (C-8) 348(C-10) 333 (C-18) 331 (C-4) 242 (C-15a) 226 (C-11)216 (C-19) 185 (C-2) 183 (C-6) 153 (C17) 141 (C-20) EIMS mz () 316 (M+) (18) 301 (11) 192 (100)177 (53) 125 (71) 69 (42)

4112 (13R)-15a-Homo-isoanticopal-1615-olide 26 Toa solution of 25 (274 mg 085 mmol) in EtOH (17 mL) atroom temperature under hydrogen atmosphere PdC 10(83 mg) was added The mixture was stirred for 1 h After fil-tration with Celite and silica the solvent was evaporate toyield the compound 26 (276 mg 98) Compound 26 [a]D

20

433 (c 055 CHCl3) IR 2947 2845 1734 1697 14581385 1248 1024 801 cm1 1H NMR (200 MHz CDCl3)d 430 (1H ddd J1frac14115 J2frac1466 and J3frac1413 Hz HA-15)412 (1H dt J1frac14115 and J2frac1474 Hz HB-15) 260 (1H tJfrac1466 Hz H-13) 204ndash193 (1H m HA-15a) 188ndash170(1H m HB-15a) 168ndash157 and 100ndash085 (2H m H-1)170ndash120 (2H m H-2) 144ndash125 and 120ndash100 (2H mH-3) 084ndash068 (1H m H-5) 170ndash120 (2H m H-6)177ndash165 and 080ndash068 (2H m H-7) 086ndash068 (1H mH-9) 170ndash120 (2H m H-11) 249ndash230 and 151ndash140(2H m H-12) 191ndash208 (1H m H-14) 084 (3H s Me-18) 081 (3H s Me-17) 080 (3H s Me-20) 078 (3HsMe-19) 13C NMR (503 MHz CDCl3) d 1765 (C-16)655 (C-15) 595 (C-5) 566 (C-9) 454 (C-14) 420 (C-3) 405 (C-1) 394 (C-7) 387(C-8) 373 (C-10) 363 (C-13) 333 (C-4) 332 (C-18) 252 (C-12) 222(C-15a)214 (C-19) 182 (C-2) 178 (C-6) 170 (C-11) 163 (C-17) 138 (C-20) EIMS mz () 318 (M+) (18) 217 (15)191 (50) 163 (99) 123 (100) 99 (72) 81 (45)

4113 (13S)-15a-Homo-isoanticopal-1615-olide 14 Toa solution of 26 (128 mg 040 mmol) in tBuOH (40 mL)at room temperature under anhydrous atmosphere 1 MtBuOK+ in THF (18 mL 18 mmol) was added The mix-ture was heating and stirring in reflux at 70 C for 30 minThen saturated water and 2 N HCl were added The organicphase was separated and the aqueous phase was extractedwith EtOAc Extracts were washed with water and driedEvaporation of the solvent yielded the lactone 14 (131 mg99) as a crystalline colourless solid Compound 14 [a]D

20

275 (c 036 CHCl3) mp 199ndash201 C IR 2932 28451728 1699 1439 1385 1177 cm1 1H NMR (200 MHzCDCl3) d 437ndash412 (2H m H-15) 245ndash220 (2H m HA-15a and H-13) 140ndash130 (1H m HB-15a) 179ndash168 and111ndash098 (2H m H-1) 174ndash130 (2H m H-2) 143ndash130and 118ndash103 (2H m H-3) 087ndash071 (1H m H-5) 174ndash130 (2H m H-6) 170ndash160 and 087ndash073 (2H m H-7)085ndash073 (1H m H-9) 074ndash130 (2H m H-11) 236ndash223 and 142ndash128 (2H m H-12) 140ndash120 (1H m H-14) 088 (3H s Me-20) 086 (3H s Me-18) 083 (3H sMe-17) 081 (3H s Me-19) 13C NMR (503 MHzCDCl3) d 1750 (C-16) 677 (C-15) 589 (C-5) 565 (C-9)

491 (C-14) 412 (C-3) 401 (C-1) 398 (C-7) 394 (C-13) 374 (C-8) 373 (C-10) 333 (C-4) 333 (C-18) 280(C-12) 225 (C-15a) 214 (C-19) 198 (C-2) 185 (C-6)183 (C-11) 162 (C-17) 142 (C-20) EIMS mz () 318(M+) (35) 191 (34) 123 (28) 94 (100) HRMS calcd forC21H34O2 [M]+ 3182559 found 3182560

4114 (13S)-15a-Homo-isoanticopal-1615-epoxy-16RS-ol 27 To a solution of 14 (137 mg 043 mmol) in dry meth-ylene chloride (6 mL) was added a solution of DIBAL-H intoluene (16 M 06 mL 09 mmol) under argon at 78 CThe solution was stirred for 30 min quenched by additionof MeOH (16 mL) and Na+ and K+ tartrate (3 mL) and ex-tracted with EtAcO The organic layer was washed with wa-ter and dried over Na2SO4 Evaporation of the solvent yieldedthe lactol 27 (16S16R 82) (136 mg 99) Compound 27IR 3366 2932 2845 1458 1385 1127 1074 976 cm11H NMR (200 MHz CDCl3) d 498 (1H d Jfrac142 HzH-16R) 422 (1H d Jfrac1462 Hz H-16S) 401 (1H dddJ1frac14114 J2frac1440 and J3frac1422 Hz HA-15 major) 395 (1Hddd J1frac14100 J2frac1490 and J3frac1436 Hz HA-15 minor) 361(1H dt J1frac14100 and J2frac1432 Hz HB-15 minor) 344 (1Hdt J1frac14114 and J2frac1428 Hz HB-15 major) 208ndash202 (1Hm H-13) 165ndash090 (19H m) 085 (6H s) 083 (3H s)079 (3H s) 13C NMR (503 MHz CDCl3) d 1009 (C-16)658 (C-15) 595 (C-5) 566 (C-9) 527 (C-14) 422 (C-13) 421 (C-3) 399 (C-1) 406 (C-7) 375 (C-8) 364 (C-10) 332 (C-4) 333 (C-18) 286 (C-15) 243 (C-15a)214 (C-19) 195 (C-11) 186 (C-2) 185 (C-6) 164 (C-17) 150 (C-20) EIMS mz () 320 (M+) (64) 287 (9)259 (10) 191 (100) 123 (35) 69 (38) HRMS calcd forC21H36O2 [M]+ 3202715 found 3202725

4115 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-ol 28 To a suspension of Ph3PCH2Br (15 g 425 mmol)in toluene (37 mL) at 20 C under an argon atmosphere06 M NaHMDS in toluene (74 mL 444 mmol) was addeddropwise and the solution stirred for 30 min A solution of thelactol 27 (136 mg 042 mmol) in benzene (4 mL) was addeddropwise and the mixture stirred for 1 h at 80 C It was al-lowed to warm to room temperature quenched with aqueousNH4Cl and extracted with Et2O The organic layer waswashed with water and dried over Na2SO4 The residue ob-tained after the solvent was removed was purified by columnchromatography (benzene) to afford 28 (76 mg 56) Com-pound 28 [a]D

20 +5 (c 01 CHCl3) IR 3401 2926 28511653 1559 1458 1387 1262 1101 1044 907 801 cm11H NMR (200 MHz CDCl3) d 587 (1H dddd J1frac14172J2frac14102 J3frac1484 and J4frac1450 Hz H-15b) 505 (1H dJfrac14172 Hz HA-15) 496 (1H d Jfrac14102 Hz HB-15) 361(1H dd J1frac14114 and J2frac1440 Hz HA-16) 355 (1H ddJ1frac14114 and J2frac1430 Hz HB-16) 229 (1H ddd J1frac14176J2frac1450 and J3frac1424 Hz HA-15a) 185ndash175 (1H m HB-15a) 174ndash159 and 087ndash070 (2H m H-1) 118ndash166 (2Hm H-2) 141ndash129 and 119ndash105 (2H m H-3) 090ndash075(1H m H-5) 118ndash166 (2H m H-6) 198ndash185 and 111ndash096 (2H m H-7) 089ndash075 (1H m H-9) 167ndash160 and130ndash123 (2H m H-11) 174ndash187 (2H m H-12) 141ndash129 (1H m H-13) 105ndash089 (1H m H-14) 088 (3H sMe-20) 086 (3H s Me-18) 083 (3H s Me-17) 081(3H s Me-19) 13C NMR (503 MHz CDCl3) d 1412 (C-15b) 1140 (C-15) 655 (C-16) 596 (C-5) 564 (C-9)522 (C-14) 420 (C-3) 417 (C-13) 407 (C-7) 399

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8946 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

(C-1) 383 (C-8) 375 (C-10) 333 (C-18) 332 (C-4) 323(C-15a) 309 (C-12) 214 (C-19) 201 (C-11) 186 (C-2)185 (C-6) 162 (C-17) 151 (C-20) EIMS mz () 318(M+) (20) 277 (10) 191 (100) 109 (30) 95 (43) 69 (62)HRMS calcd for C22H38O [M]+ 3182923 found 3182923

4116 (13S)-15a15b-Dihomo-isoanticopal-15b(15)en-16-al 29 To a mixture of 28 (59 mg 018 mmol) N-methyl-morpholine N-oxide (NMO) (38 mg 028 mmol) and mole-cular sieves (90 mg 500 mgmmol) in anhydrous DCM(2 mL) under argon and at room temperature and TPAP(53 mg 0015 mmol) were added The reaction mixturewas stirred for 1 h and then filtered through a short pad of sil-ica gel and Celite eluting with EtOAc Evaporation of thesolvent yielded the aldehyde 29 (61 mg 100) Compound29 [a]D

20 +70 (c 01 CHCl3) IR 2932 2851 1724 14581387 1262 1103 1028 914 802 cm1 1H NMR(400 MHz CDCl3) d 942 (1H d Jfrac1448 Hz H-16) 567(1H dddd J1frac14160 J2frac14100 J3frac1484 and J4frac1460 Hz H-15b) 497 (1H d Jfrac14100 Hz HA-15) 494 (1H d Jfrac1416 Hz HB-15) 238ndash220 (2H m H-15a) 174ndash160 and085ndash070 (2H m H-1) 175ndash127 (2H m H-2) 146ndash130 and 120ndash105 (2H m H-3) 094ndash078 (1H m H-5)175ndash127 (2H m H-6) 194ndash186 and 114ndash097 (2H mH-7) 097ndash072 (1H m H-9) 175ndash127 (2H m H-11)171ndash163 and 137ndash129 (2H m H-12) 235ndash226 (1Hm H-13) 145ndash131 (1H m H-14) 088 (3H s Me-20)086 (3H s Me-18) 083 (3H s Me-17) 081 (3H s Me-19) 13C NMR (100 MHz CDCl3) d 2053 (C-16) 1385(C-15b) 1166 (C-15) 592 (C-5) 564 (C-9) 536 (C-14)511 (C-13) 419 (C-3) 406 (C-7) 399 (C-1) 377 (C-8)375 (C-10) 332 (C-18) 331 (C-4) 331 (C-15a) 272(C-12) 214 (C-19) 190 (C-11) 186 (C-2) 184 (C-6)162 (C-17) 150 (C-20) EIMS mz () 316 (M+) (13)301 (17) 191 (100) 123 (38) 95 (49) 69 (68) HRMS calcdfor C22H36O [M]+ 3162766 found 3162746

4117 (13S17R)-16a-Homo-18-nor-16-seco-meliac-16a(16)en-17-ol 30 A solution of 3-bromofurane (69 mL0767 mmol) in THF (175 mL) was treated dropwise withn-BuLi (16 M in hexane 05 mL 077 mmol) at 78 CAfter the reaction mixture was stirred for 10 min at this tem-perature a solution of aldehyde 29 (606 mg 0192 mmol) indry THF (1 mL) was added and stirred for an additional30 min The reaction mixture was treated with saturatedNH4Cl aqueous solution warmed to room temperature andextracted with Et2O The organic layer was washed withbrine and water and dried over Na2SO4 The residue ob-tained after removal of the solvent was purified by chroma-tography (benzene) to yield the alcohol 30 (424 mg 58)Compound 30 [a]D

20 +166 (c 02 CHCl3) IR 3484 29302853 1636 1464 1387 1262 1161 1028 909 876 797723 cm1 1H NMR (400 MHz CDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H s H-22) 599 (1Hdddd J1frac14168 J2frac14101 J3frac1492 and J4frac1451 Hz H-16a)512 (1H d Jfrac14168 Hz HA-16) 506ndash495 (2H m HB-16and H-17) 245ndash235 and 128ndash125 (2H m H-15) 170ndash159 and 082ndash070 (2H m H-1) 160ndash154 and 140ndash137(2H m H-2) 140ndash130 and 118ndash106 (2H m H-3)094ndash078 (1H m H-5) 164ndash159 (2H m H-6) 200ndash190 and 116ndash104 (2H m H-7) 097ndash072 (1H m H-9)162ndash158 and 122ndash120 (2H m H-11) 150ndash145 (2Hm H-12) 130ndash120 (1H m H-13) 151ndash141 (1H m

H-14) 086 (3H s Me-28) 083 (3H s Me-19) 081 (3Hs Me-29) 080 (3H s Me-30) 13C NMR (100 MHzCDCl3) d 1428 (C-23) 1413 (C-16a) 1389 (C-21) 1285(C-20) 1143 (C-16) 1086 (C-22) 666 (C-17) 595 (C-5) 564 (C-9) 519 (C-14) 450 (C-13) 420 (C-3) 409(C-7) 399 (C-1) 385 (C-8) 375 (C-10) 333 (C-28)332 (C-4) 322 (C-15) 249 (C-12) 214 (C-29) 198 (C-11) 186 (C-2) 185 (C-6) 161 (C-30) 151 (C-19)EIMS mz () 384 (M+) (8) 297 (19) 269 (20) 243 (10)191 (18) 143 (100) HRMS calcd for C26H40O2 [M]+3843028 found 3843032

4118 (13S17R)-16a-Homo-18-nor-16-seco-meliaca-16aRS1617-triol 31a31b To a solution of 30 (137 mg043 mmol) in a mixture of tBuOHTHFH2O 721 (1 mL)was added NMO (58 mg 0043 mmol) and OsO4 in tBuOHunder an argon atmosphere The solution was stirred for 46 hThen was added Na2SO3 (03 mL) and was stirred for 30 minmore and extracted with EtAcO The organic layer waswashed with water 10 Na2S2O3 2 N HCl H2O and brineand dried over Na2SO4 The residue obtained after removal ofthe solvent was purified by chromatography (hexaneEtOAc73) to yield the isomeric triols 31a (50 mg 28) and 31b(100 mg 56) Compound 31a 1H NMR (400 MHzCDCl3) d 737 (1H s H-23) 736 (1H s H-21) 625 (1Hs H-22) 507 (1H s H-17) 378ndash367 (2H m H-16a andHA-16) 342 (1H dd J1frac14172 and J2frac1495 Hz HB-16)198ndash079 (20H m) 085 081 080 and 079 (3H s eachMe-19 28 29 and 30) Compound 31b 1H NMR (400 MHzCDCl3) d 738 (1H s H-23) 733 (1H s H-21) 626 (1H sH-22) 496 (1H s H-17) 394ndash391 (1H m H-16a) 365(1H dd J1frac14124 and J2frac1432 Hz HA-16) 355 (1H ddJ1frac14124 and J2frac1474 Hz HB-16) 198ndash079 (20H m) 085081 080 and 079 (43H s Me-19 28 29 and 30)

4119 (13S16RS)-Hydroxy-18-nor-limonoid 32 To a so-lution of 31a31b (30 mg 0072 mmol) in a mixture of THFH2O 21 (036 mL) was added slowly NaIO4 (29 mg0134 mmol) The solution was stirred for 10 min andEt2O (2 mL) was added The organic layer was washedwith 4 NaHCO3 H2O and brine and dried over Na2SO4The residue obtained after removal of the solvent was puri-fied by chromatography (benzeneEtAcO 91) to yield thelactol 32 (18 mg 65) Compound 32 IR 3394 29282866 1740 1458 1387 1262 1132 1032 874 797 cm11H NMR (200 MHz CDCl3) d 741 (1H s H-23) 739(1H s H-21) 640 (1H s H-22) 483 (1H d Jfrac1460 HzH-17) 498ndash493 (1H m H-16) 198ndash081 (20H m)088 085 083 and 080 (43H s Me-19 28 29 and 30)

4120 (13S)-18-Nor-limonoid 33 To a mixture of 32(18 mg 005 mmol) N-methylmorpholine N-oxide (NMO)(12 mg 0085 mmol) and molecular sieves (25 mg500 mgmmol) in anhydrous CH2Cl2 (05 mL) under argonand at room temperature and TPAP (2 mg 0005 mmol)were added The reaction mixture was stirred for 1 h andthen filtered through a short pad of silica gel and Celiteeluting with EtOAc Evaporation of the solvent yielded thelactone 33 (195 mg 98) Compound 33 [a]D

20 486 (c015 CHCl3) IR 2932 2864 1734 17171458 1387 12621194 1032 801 cm1 1H NMR (400 MHz CDCl3) d 742(1H s H-23) 729 (1H s H-21) 624 (1H s H-22) 532(1H d Jfrac1460 Hz H-17) 259 (1H dd J1frac14188 and

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8947P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

J2frac1476 Hz HA-15) 241 (1H dd J1frac14188 and J2frac1476 HzHB-15) 169ndash154 (2H m H-1) 162ndash125 (2H m H-2)142ndash128 and 115ndash101 (2H m H-3) 073ndash061 (1H mH-5) 162ndash125 (2H m H-6) 107ndash091 and 087ndash067(2H m H-7) 084ndash069 (1H m H-9) 162ndash125 (2H mH-11) 182ndash170 and 094ndash088 (2H m H-12) 143ndash128(1H m H-13) 152ndash138 (1H m H-14) 088 (3H s Me-19) 084 (3H s Me-30) 082 (3H s Me-28) 079 (3H sMe-29) 13C NMR (100 MHz CDCl3) d 1719 (C-16)1433 (C-23) 1402 (C-21) 1225 (C-20) 1095 (C-22)780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368 (C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15) 287 (C-12) 214(C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30)143 (C-19) EIMS mz ()384 (M+) (37) 317 (18) 287(51) 246 (100) 191 (40) 137 (45) HRMS calcd forC25H36O3 [M]+ 3842664 found 3842655

4121 (13S21RS)-21-Hydroxy-2321-olide-18-nor-20(22)en-limonoid 15 Rose Bengal (2 mg) was added toa solution of 33 (10 mg 0026 mmol) and DIPEA(005 mL 027 mmol) in dry DCM (32 mL) at room tem-perature Anhydrous oxygen was bubbled in for 10 minand after that the solution was placed under oxygen atmo-sphere at 78 C and irradiated with a 200 W lamp After6 h irradiation was stopped the pink solution was allowedto warm to room temperature and saturated aqueous oxalicacid (1 mL) was added After 30 min of vigorous stirring themixture was diluted with water and extracted with DCMThe combined organic extracts were washed with waterand dried over anhydrous Na2SO4 After filtration the sol-vent was evaporated to give a residue which was purifiedby silica gel column chromatography (benzeneEtOAc 82)to yield 15 (8 mg 68) [a]D

20 261 (c 028 CHCl3) IR3339 2924 2855 1738 1462 1053 cm1 1H NMR(200 MHz CDCl3) d 620 (1H s H-22) 598 (1H s H-21) 535 (1H d Jfrac1460 Hz H-17) 258 (1H dd J1frac14184and J2frac1470 Hz HA-15) 233 (1H dd J1frac14184 andJ2frac14106 Hz HB-15) 220ndash102 (18H m) 088 (3H s)084 (6H s) 080 (3H s) 13C NMR (503 MHz CDCl3)d 1719 (C-16) 1692 (C-23) 1641 (C-20) 1216 (C-22)982 (C-21) 780 (C-17) 591 (C-5) 564 (C-9) 439 (C-14) 419 (C-3) 398 (C-7) 397 (C-1) 374 (C-8) 368(C-10) 359 (C-13) 332 (C-4) 332 (C-28) 295 (C-15)287 (C-12) 214 (C-29) 195 (C-11) 185 (C-2) 181 (C-6) 164 (C-30) 143 (C-19) EIMS mz () 417 (M++1)(25) 307 (12) 154 (100) 107 (31) 84 (33) HRMS calcdfor C25H37O5 [MH]+ 4172641 found 4172635

Acknowledgements

Financial support for this work came from Spanish MEC(CTQ2005-04046) The authors also thank Dr A M Lith-gow for the NMR spectra and Dr Cesar Raposo for themass spectra SD and Mde R are grateful for a doctoral fel-lowship to Junta de Castilla y Leon

Supplementary data

Supplementary data associated with this article can be foundin the online version at doi101016jtet200706004

References and notes

1 Blunt J W Copp B R Munro H G Northcote P TPrinsep M R Nat Prod Rep 2004 21 1ndash49

2 (a) de Silva E D Scheuer P Tetrahedron Lett 1980 211611ndash1614 (b) de Freitas J C Blankmeier L A JacobsR S Experientia 1984 40 864ndash865 (c) Glaser K BJacobs R S Biochem Pharmacol 1986 35 449ndash453 (d)Glaser K B Jacobs R S Biochem Pharmacol 1987 362079ndash2086 (e) Jacobs R S Culver P Langdon ROrsquoBrien T White S Tetrahedron 1985 41 981ndash984 (f)Lombardo D Dennis E A J Biol Chem 1985 2607234ndash7240 (g) Deems R A Lombardo D Morgan D PMielich E D Dennis E A Biochim Biophys Acta 1987917 258ndash268 (h) Kernan M R Faulkner D J JacobsR S J Org Chem 1987 52 3081ndash3083 (i) Keyzers R ADavies-Coleman M T Chem Soc Rev 2005 34 355ndash365

3 Randazzo A Debitus C Minale L Garcıa Pastor PAlcazar M J Paya M Gomez Paloma L J Nat Prod1998 61 571ndash575

4 Buchanan M S Edser A King G Whitmore J QuinnR J J Nat Prod 2001 64 300ndash303

5 (a) Ungur N Kulcitki V Gavagnin M Castellucio F VladP F Cimino G Tetrahedron 2002 58 10159ndash10165 (b)Ungur N Kulcitki V Gavaguin M Castellucio FCimino G Synthesis 2006 2385ndash2391

6 (a) Urones J G Sexmero M J Lithgow A Basabe PEstrella A Gomez A Marcos I S Dıez D CarballaresS Broughton H B Nat Prod Lett 1995 6 285ndash290(b) Urones J G Marcos I S Basabe P Gomez AEstrella A Nat Prod Lett 1994 5 217ndash220

7 (a) Basabe P Gomez A Marcos I S Dıez-Martın DBroughton H B Urones J G Tetrahedron Lett 1999 406857ndash6860

8 (a) Basabe P Diego A Dıez D Marcos I S Urones J GSynlett 2000 1807ndash1809 (b) Basabe P Diego A Dıez DMarcos I S Mollinedo F Urones J G Synthesis 200211 1523ndash1529

9 Basabe P Diego A Delgado S Dıez D Marcos I SUrones J G Tetrahedron 2003 59 9173ndash9177

10 Basabe P Delgado S Marcos I S Dıez D Diego ARoman M de Urones J G J Org Chem 2005 70 9480ndash9485

11 Kernan M R Faulkner D J J Org Chem 1988 53 2773ndash2776

12 CCDC no 641497 (16) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

13 Mischne M P Gonzalez-Sierra M Ruveda E J Org Chem1984 49 2035ndash2039

14 Marcos I S Pedrero A B Sexmero M J Dıez D BasabeP Garcıa N Moro R F Broughton H B Mollinedo FUrones J G J Org Chem 2003 68 7496ndash7504

15 Ley S V Norman J Griffith W P Marsden S P Synthesis1994 2 639ndash666

16 CCDC no 641498 (14) contains the supplementary crystallo-graphic data for this paper This data can be obtained free ofcharge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)

8948 P Basabe et al Tetrahedron 63 (2007) 8939ndash8948

17 (a) Winterfeldt E Synthesis 1975 617ndash630 (b) Yoon N MGyoung Y S J Org Chem 1985 50 2443ndash2450

18 (a) Marcos I S Hernandez F A Sexmero M J Dıez DBasabe P Pedrero A B Garcıa N Urones J GTetrahedron 2003 59 685ndash694 (b) Zoretic P A Fang HRibeiro A A Dubay G J Org Chem 1998 63 1156ndash1161 (c) Magnuson S R Sep-Lorenzino L Rosen NDanishefsky S J J Am Chem Soc 1998 120 1615ndash1616

19 Numbering of 30 has been considered as a meliacane skeleton20 Numbering of 32 has been considered as a nor-limonoid

skeleton21 CCDC no 641496 (33) contains the supplementary crystallo-

graphic data for this paper This data can be obtained freeof charge via wwwccdccamacukcontsretrievinghtml (orfrom the CCDC 12 Union Road Cambridge CB2 1EZ UKfax +44 12223 336033 e-mail depositccdccamacuk)