Tetrahedron: Asymmetry 22 (2011) 487–492

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Tetrahedron: Asymmetry

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A concise and improved synthesis of (+)-eleutherin, (+)-allo-eleutherinand a formal synthesis of (+)-nocardione B

Rodney A. Fernandes ⇑, Vijay P. Chavan, Sandip V. MulayDepartment of Chemistry, Indian Institute of Technology Bombay, Powai 400076 Mumbai, Maharashtra, India

a r t i c l e i n f o

Article history:Received 20 January 2011Accepted 10 February 2011Available online 14 March 2011

0957-4166/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetasy.2011.02.011

⇑ Corresponding author. Fax: +91 22 25767152.E-mail address: rfernand@chem.iitb.ac.in (R.A. Fer

a b s t r a c t

A concise and improved stereoselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and the formalsynthesis of (+)-nocardione B is described. The synthesis is based on a Dötz benzannulation and animproved oxa-Pictet–Spengler cyclization as the key steps. The synthesis is achieved in six steps in over-all yields of 18% for eleutherin and 20% for allo-eleutherin.

� 2011 Elsevier Ltd. All rights reserved.

OOMe

O

O

OMe

O

OO

OOMe

O

O

(+)-eleutherin 1 (+)-allo-eleutherin ent-2

(+)-nocardione B 4

(-)-isoeleutherin 2

O OMe

O

O

OMe

O

OO

OH

O

OO

(-)-nocardione A 3 (-)-nocardione B ent-4

Figure 1. Eleutherins and related bioactive molecules.

1. Introduction

Pyranonaphthoquinone based compounds comprise a largeclass of natural products that show varied bioactivity such asanticancer, antibiotics, fungicides and anticoccidial agents.1a Theyhave also proposed to act as bioreductive alkylating agents.2 Thesecomprise such biologically important compounds such as eleuthe-rins, ventiloquinones, thysanones, aphid pigments, nanomycin A,deoxyfrenolicin, cardinalins, etc.1 Eleutherin 13 and the C-3 epimer,(�)-isoeleutherin 24 (Fig. 1) were isolated from the bulbs ofEleutherin bulbosa. Extracts of Eleutherin americana of which ele-utherin and isoeleutherin are the major constituents have beenused to treat the heart disease angina pectoris.5 Also, (+)-eleutherin1 is a reversible inhibitor of topoisomerase II, a target for antican-cer agents.6 (+)-Allo-eleutherin ent-2 (Fig. 1) can be producedwhen (+)-eleutherin is treated with phosphoric acid.4 Otani et al.isolated (�)-nocardione A 3 and (�)-nocardione B ent-4 from thefermentation broth of Nocardia sp. TP-A0248.7a Cancers of thehead, neck and breast are often associated with an elevated expres-sion of Cdc25B tyrosine phosphatase, which is the key enzyme insignal transduction of a large number of cellular processes.7b

Nocardiones show activity against Gram-positive bacteria andthe inhibition of enzyme cdc25B tyrosine phosphatase.7 These alsopossess moderate antifungal and cytotoxic activities.7a Althoughthere are a few synthetic strategies which have been developedto target these molecules, much of the work done is on racemicsynthesis.8 Furthermore, methods to target most of these mole-cules through a single strategy especially to build the differentlysubstituted naphthoquinone unit are less well described. Thereare two enantioselective syntheses9 of (+)-eleutherin 1. Donner’sapproach is based on a synthesis of (S)-mellein10 in several stepsfollowed by its conversion in a five-step sequence to eleutherin.9a

ll rights reserved.

nandes).

Brimble et al.9b employed the well-known Hauser–Kraus annula-tion11 in the synthesis of 1. Recently, a deoxyeleutherin synthesishas been reported by Waghmode et al. based on proline-catalyzedasymmetric a-aminoxylation of aldehydes and oxa-Pictet–Spenglercyclization.12 Nocardiones 3 and 4 were first synthesized by Moriet al.13 and their absolute configuration was also determined.Racemic syntheses of nocardiones are also known.14 A radicalcyclization strategy has also been used in the synthesis of (+)-nor-cardione A ent-3.15

As part of our research programme aimed at the enantioselec-tive synthesis of natural products,16 we developed an efficientstrategy to pyranonaphthoquinones based on Dötz benzannulationand oxa-Pictet–Spengler reactions.16c,16d,16j,17 Semmelhack et al.previously employed the Dötz benzannuation in the racemic syn-thesis of deoxyfrenolicin.18 A direct oxa-Pictet–Spengler reactionhas been used to obtain the trans-1,3-dimethyl pyran ring in thesynthesis of deoxyfrenolicin.19 In our preliminary communica-tion,16d we reported a short synthesis of (+)-1 and the first

488 R. A. Fernandes et al. / Tetrahedron: Asymmetry 22 (2011) 487–492

enantioselective synthesis of ent-2 based on Dötz benzannulationand oxa-Pictet–Spengler cyclization. We also reported the formalsynthesis of (+)-norcardione B.16d In our recent work on cardinalin3,17 we have found improved conditions for oxa-Pictet–Spenglerreaction to obtain the syn-1,3-dimethyl pyran ring with good dias-teroeselectivity. Similar reaction conditions were used in the syn-thesis of eleutherin. Herein, we report a full account and animproved synthesis of (+)-eleutherin 1, (+)-allo-eleutherin ent-2and the formal synthesis of (+)-norcardione B.

2. Results and discussion

The retrosynthetic plan to (+)-eleutherin, (+)-allo-eleutherinand (+)-nocardione B is illustrated in Scheme 1. All these com-pounds could be traced back to substituted naphthalene 8. (+)-Ele-utherin 1 and (+)-allo-eleutherin (ent-2) are C-1 diastereomers andcould be accessed from the common intermediate naphthalene 6through pyran ring formation via an oxa-Pictet–Spengler reac-tion.20 The substituted naphthalene 6 could be obtained from 8by methylation and silyl ether deprotection. The naphthalene 8could be obtained through Dötz benzannulation21 between o-methoxy phenyl chromium carbene complex 9 and alkyne 10.(+)-Nocardione B could be traced back to 7, which in turn couldbe obtained from naphthalene 8.

2.1. Synthesis of alkyne 10

The alkyne 10 required for the Dötz benzannulation was syn-thesized starting from (S)-ethyl-3-hydroxybutanoate 11 in threesteps as reported earlier (Scheme 2).16d,17 The relatively expensivecommercially available 11 was used initially.16d Later we prepared11 from ethyl acetoacetate in excellent yield and enantioselectivitythrough Noyori reduction.17a

EtO

OHO OTBDMSref. 17a

3 steps

11 10

Scheme 2. Synthesis of alkyne 10.

2.2. Synthesis of intermediate 6 and formal synthesis of (+)-nocardione B 4

The synthesis of intermediate 6 is shown in Scheme 3. TheFischer carbene complex 9 was synthesized from 2-bromoanisole

OOMe

O

O

OOMe

O

O

OMe

OMe

Cr(CO)5

1

ent-2

OMeOMe

OMe

O

5

9 10

+

OTBDMS

Scheme 1. Retrosynthetic an

12 following the literature procedure in 83% yield.22 The condensa-tion of carbene complex 9 with the alkyne 10 via a Dötz benzann-ulation21 reaction afforded the substituted naphthalene 8 in 69%yield. Removal of the TBDMS ether group gave 13 (91%). Theoxa-Pictet–Spengler reaction on alcohol 13 using acetaldehydedimethylacetal and the Lewis acid, BF3�OEt2 gave the seven-membered cyclic acetal 14 in 93% yield and no trace of desired pyr-an compound 15 was obtained. It is known in the literature8a,23

that the pyran ring formation on similar substrates with acetalde-hyde under acidic conditions gives a variable mixture of syn- andanti-1,3-dimethyl isomers depending on the reaction conditions.The formation of a cyclic acetal due to the free phenolic hydroxylgroup was different from pyran ring formation of similar hydroqui-none compounds when treated with acetaldehyde under acidicconditions.23 Compound 14 was confirmed by 1H NMR spectra,which includes a singlet at 6.56 ppm corresponding to the naph-thalene C-2 proton where pyranylation was supposed to occur.The formation of 14 was further confirmed by treating it with cer-ium(IV) ammonium nitrate (CAN) to produce quinone 17 in 83%yield. Further reduction of quinone 17 with sodium dithionate gavehydroquinone 7 which is a precursor in the Mori’s13 synthesis of(+)-nocardione B 4. This represented the formal synthesis of (+)-4(Scheme 3). Since phenolic hydroxyl group prevents the oxa-Pictet–Spengler reaction to give the desired pyran compound, itwas necessary to protect it before pyranylation. The phenolic hy-droxyl group in 8 was converted into methyl ether 16 in excellentyield (85%). The removal of the TBDMS ether gave the intermediatealcohol 6 in 95% yield.

2.3. Improved conditions for syn- or anti-1,3-dimethyl pyrancompounds in the oxa-Pictet–Spengler reaction: improvedsynthesis of (+)-eleutherin and (+)-allo-eleutherin

With the intermediate alcohol 6 in hand we attempted the oxa-Pictet–spengler reaction to install the pyran ring. Our initial exper-iments provided a mixture of syn- and anti-pyran products 5a and5b, respectively, with the latter being predominant (Table 1).24

Thus the reaction of 6 with acetaldehyde diemethylacetal in THF/ether (1:4) mixture for 14 h provided the mixture of 5a:5b in32:68 ratio (Table 1, entry 1). A shorter time reaction of 1 h gavea similar mixture (5a:5b = 36:64, entry 2). A slight improvementtowards equal amounts was observed with the reaction at 0 �C(5a:5b = 43:57, entry 3). In our preliminary work, this mixturewas efficiently separated and synthesis of (+)-eleutherin wascompleted.16d However, we were interested in improving the

OMe

O

OO

OMe

OH

OMe

OTBDMS

4

OH

OH

OMe

OH

OMe

OMe

OMe

OH

6

78

alysis for 1, ent-2 and 4.

Cr(CO)5

OMeOMe OMe

OH

OMe

OTBDMS10, THF

45 °C, 12 h

69%

OH

OMe

OH

OMe

OMeOMe

OO

OH

OH

OH

OMe

O

OMe

OH

OMe

O

OO

OMe

(+)-nocardione B 4

O

O

OH

OMe

TBAF, THFrt, 2 h, 91%

CAN, MeCN/H2O(1:1), rt, 1 h, 83%

Na2S2O4, TBAI

THF/H2O (4:3),

ref. 13

1315 14

17 7rt, 3 h, 80%

9 8

OMeBr

n-BuLi, THF, -78 oC, 5 minCr(CO)6, -78 oC to 0 oC, 3 h

then Me3OBF4, CH2Cl20 oC to rt, 3 h, 83%

(CH3O)2CHCH3BF3:Et2O

Et2O/THF (4:1)rt, 12 h

0% 93%

NaH, MeIDMF, 0 oCto rt, 2 h

OMe

OMe

OMe

OTBDMS

16

TBAF, THFrt, 2 h, 95%

OMe

OMe

OMe

OH

6

12

85%

Scheme 3. Synthesis of intermediate 6 and a formal synthesis of (+)-nocardione B 4.

R. A. Fernandes et al. / Tetrahedron: Asymmetry 22 (2011) 487–492 489

diastereoselectivity towards either diastereomer 5a or 5b. In ourrecent synthetic work on cardinalin 3,17 we observed that theuse of a protic acid, such as HCl, in the oxa-Pictet–Spengler reac-tion shifted the diastereoselectivity towards the syn-diastereomer.Similar reactions were attempted on compound 6. Thus, the oxa-Pictet–Spengler reaction using concd HCl at room temperatureshifted the ratio towards the syn-isomer (5a:5b = 60:40, entry 4)and at 0 �C (5a:5b = 65:35, entry 5). When HCl gas was bubbledthrough the reaction mixture, a further improvement wasobserved predominantly giving the syn-diastereomer 5a (5a:5b =70:30 at room temperature and 78:22 at 0 �C, entries 6 and 7,respectively). When an acetaldehyde solution in water was usedand HCl gas was bubbled, it still formed the syn-diastereomer asthe major product (5a:5b = 62:38, entry 8). The reaction at roomtemperature in CH2Cl2 solvent predominantly provided the anti-isomer (5a:5b = 21:79, entry 9). The formation of the diastereomermixtures indicates that an equilibrium exists between the syn- andanti-pyran products. In the Lewis acid mediated reactions theanti-pyran product probably arises from the formation of a Z-oxocarbenium ion and ring closure, while in the protonic catalysis,

Table 1Oxa-Pictet–Spengler reaction of 6

OH

OMe

OMe

OMe OMe

See Table 1

6

Entry Reaction conditions

1 (CH3O)2CHCH3 (2.0 equiv), BF3�OEt2 (3.0 equiv), THF/Et2

2 (CH3O)2CHCH3 (2.0 equiv), BF3�OEt2 (3.0 equiv), THF/Et2

3 (CH3O)2CHCH3 (2.0 equiv), BF3�OEt2 (3.0 equiv), THF/Et2

4 (CH3O)2CHCH3 (4.0 equiv), concd HCl, Et2O, rt, 15 h5 (CH3O)2CHCH3 (10.0 equiv), concd HCl, Et2O, 0 �C, 2.5 h6 (CH3O)2CHCH3 (10.0 equiv), HCl (g), Et2O, rt, 2.5 h7 (CH3O)2CHCH3 (10.0 equiv), HCl (g), Et2O, 0 �C, 2.5 h8 Acetaldehyde in water 35%, (10.0 equiv), HCl (g), 0 �C, 59 (CH3O)2CHCH3 (2.0 equiv), BF3�OEt2 (3.0 equiv), CH2Cl2,

it must be the E-oxocarbenium ion predominantly involved.19 Thediastereomer mixtures were separated and used in the synthesis ofeither eleutherin or allo-eleutherin as shown in Scheme 4. Thereaction mixture of entry 7, Table 1 was efficiently separated byflash silica gel column chromatography to give 5a in 66% and 5bin 18% yield. Similarly the reaction mixture of entry 9, Table 1was separated to give 5a in 16% and 5b in 70% yield. Compound5a upon oxidation with CAN provided (+)-eleutherin 1 in 86% yield,½a�25

D ¼ þ338 (c 0.25, CHCl3), natural (+)-eleutherin3a ½a�25D ¼ þ346

(c 1.01, CHCl3). Similarly the oxidation of 5b gave (+)-allo-eleuther-in in 89% yield, ½a�25

D ¼ þ65:6 (c 0.3, CHCl3), lit.4a ½a�25D ¼ þ45 (c

1.075, CHCl3). Compounds 1 and ent-2 were fully characterizedby spectroscopic and analytical data.

3. Conclusion

In conclusion, a concise and improved stereoselective synthesisof both (+)-eleutherin (18% overall yield) and (+)-allo-eleutherin(20% overall yield) has been achieved in six steps (for both). Thesynthetic strategy features an efficient combination of a Dötz

O

OMe

OMe

O

OMe

OMe

OMe

5a 5b

5a:5b Yield (%)

O (1:4), rt, 14 h 32:68 92O (1:4), rt, 1 h 36:64 84O (1:4), 0 �C, 2 h 43:57 78

60:40 6465:35 7370:30 8778:22 86

h 62:38 75rt, 10 h 21:79 90

O

OMe

OMe

OMe

O

OMe

OMe

OMe

5b

5a

(NH4)2Ce(NO3)6MeCN/H2O (1:1)

rt, 1 h, 86%

O

O

O

OMe

O

O

O

OMe(NH4)2Ce(NO3)6MeCN/H2O (1:1)

rt, 1 h, 89%

1

ent-2

Scheme 4. Synthesis of (+)-eleutherin and (+)-allo-eleutherin.

490 R. A. Fernandes et al. / Tetrahedron: Asymmetry 22 (2011) 487–492

benzannulation reaction with a chiral alkyne and the improvedoxa-Pictet–Spengler reaction as the key steps. The synthesis ofintermediate 7 involves the formal synthesis (+)-nocardione B4.13 We have also established the oxa-Pictet–Spengler reactionconditions for either syn- or anti-1,3-dimethyl pyran products.

4. Experimental

4.1. General Information

Flasks were oven or flame dried and cooled in a desiccator. Dryreactions were carried out under an atmosphere of Ar or N2. Sol-vents and reagents were purified by standard methods. Thin-layerchromatography was performed on EM 250 Kieselgel 60 F254 silicagel plates. The spots were visualized by staining with KMnO4 or byUV lamp. 1H NMR and 13C NMR were recorded on Varian MercuryPlus, AS400 spectrometer and the chemical shifts are based on TMSpeak at d = 0.00 pm for proton NMR and CDCl3 peak at d =77.00 ppm (t) in carbon NMR. IR spectra were obtained on PerkinElmer Spectrum One FT-IR spectrometer. Optical rotations weremeasured with Jasco DIP-370 digital polarimeter. HRMS wasrecorded using Micromass: Q-Tof micro (YA-105) spectrometer.

4.1.1. Methoxy (o-methoxyphenyl)methylene pentacarbonylchromium 9

To a solution of o-bromoanisole 12 (3.0 g, 16.04 mmol) in dryether (60 mL) at �78 �C under an argon atmosphere was addedn-BuLi (4.63 mL, 16.7 mmol, 3.6 M in hexane, 1.04 equiv). The reac-tion mixture was stirred for 5 min and then added to a suspensionof chromium hexacarbonyl (3.53 g, 16.04 mmol, 1.0 equiv) in dryether (20 mL) at �78 �C. The reaction mixture was stirred andbrought to 0 �C over 3 h and then concentrated. The residue wasdissolved in dry CH2Cl2 (60 mL), cooled to 0 �C and Me3OBF4

(3.55 g, 24.06 mmol, 1.5 equiv) was added in portions. The reactionmixture was stirred at 0 �C for 1 h and room temperature for 2 hand concentrated. The residue was purified by silica gel columnchromatography using petroleum ether/CH2Cl2 (9:1 to 4:1) as elu-ent to give 9 (4.61 g, 83%) as a brown-red oil which later solidified.Mp 70–71 �C, lit.22 71–74 �C. Spectroscopic and analytical datawere the same as reported.22

4.1.2. (2S)-2-(2-(tert-Butyldimethylsilyloxy)propyl-4,5-dimethoxynaphthalen-1-ol 8

To a freshly prepared chromium carbene complex 9 (3.0 g,8.76 mmol) in dry and degassed THF (30 mL) was added tert-butyldimethyl(pent-4-yn-2-yloxy)silane 10 (2.08 g, 10.5 mmol,1.2 equiv). The reaction mixture was stirred at 45 �C for 12 h. Itwas then cooled to room temperature and exposed to air and stirredfor a further 30 min. The reaction mixture was concentrated and the

residue purified by silica gel column chromatography using petro-leum ether/EtOAc (9:1 to 4:1) as eluent to give 8 (2.28 g, 69%) as apale yellow liquid which solidified on cooling. Mp 122–124 �C.½a�25

D ¼ �45:9 (c 0.5, CHCl3). IR (KBr) m = 3217, 2993, 2955, 2931,2900, 1624, 1602, 1586, 1509, 1464, 1389, 1381, 1329, 1304, 1263,1127, 1078, 1064, 984, 855, 840, 780, 757, 719 cm�1. 1H NMR(400 MHz, CDCl3/TMS): d = �0.04 (s, 3H), 0.06 (s, 3H), 0.91 (s, 9H),1.20 (d, J = 6.1 Hz, 3H), 2.86 (dd, J = 14.7, 7.0 Hz, 1H), 2.99 (dd,J = 14.4, 2.4 Hz, 1H), 3.98 (s, 3H), 4.05 (s, 3H), 4.30–4.32 (m, 1H),6.84 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.90 (d, J = 8.24 Hz,1H), 8.33 (s, 1H). 13C NMR (100 MHz, CDCl3): d = �4.8, �4.7, 18.0,22.8, 25.8 (3C), 41.9, 56.4, 58.0, 71.4, 106.1, 112.1, 115.4, 118.3,125.4, 129.0, 134.2, 145.4, 150.0, 156.7. HRMS (ESI-TOF): (m/z) calcdfor [C21H32O4Si+H] 377.2148, found 377.2152.

4.1.3. (2S)-2-(2-Hydroxypropyl)-4,5-dimethoxynaphthalen-1-ol13

To a solution of compound 8 (0.89 g, 2.36 mmol) in dry THF(30 mL) was added TBAF (2.83 mL, 2.83 mmol, 1 M in THF,1.2 equiv). The reaction mixture was stirred at room temperaturefor 2 h. It was then quenched with water (10 mL) and stirred for30 min. Next, THF was removed under reduced pressure and thesolution extracted with EtOAc (3 � 20 mL). The combined organiclayers were washed with brine, dried (Na2SO4) and concentrated.The residue was purified by silica gel column chromatographyusing petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 13(0.56 g, 91%) as a yellow solid. Mp 130–132 �C. ½a�25

D ¼ �95 (c 0.4,CHCl3). IR (KBr) m = 3461, 3363, 3157, 2967, 1627, 1603, 1509,1462, 1333, 1284, 1199, 1115, 1072, 1045, 977, 930, 894, 804,760, 667 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 1.31 (d,J = 6.4 Hz, 3H), 2.89–2.93 (m, 2H), 3.90 (s, 3H), 3.97 (s, 3H), 4.32–4.38 (m, 1H), 6.56 (s, 1H), 6.85 (d, J = 7.9 Hz, 1H), 7.37 (t,J = 7.9 Hz, 1H), 7.89 (dd, J = 7.6, 0.9 Hz, 1H). 13C NMR (100 MHz,CDCl3): d = 23.4, 40.6, 56.4, 57.9, 70.9, 106.3, 112.0, 115.3, 118.5,125.7 (2C), 129.1, 145.2, 150.1, 156.6. HRMS (ESI-TOF): (m/z) calcdfor [C15H18O4+H] 263.1283, found 263.1278.

4.1.4. (4S)-7,8-Dimethoxy-2,4-dimethyl-4,5-dihydronaphtho-[1,2-d] [1,3]dioxepine 14

To a solution of 13 (0.516 g, 1.96 mmol) in dry Et2O (8 mL) anddry THF (2 mL) under an N2 atmosphere were added acetaldehydedimethylacetal (0.38 mL, 3.58 mmol, 2.0 equiv) and BF3�Et2O(0.75 mL, 5.88 mmol, 3.0 equiv). The reaction mixture was stirredat room temperature for 12 h. It was then quenched with saturatedaqueous NaHCO3 (10 mL), and the solution extracted with EtOAc(3 � 20 mL). The combined organic layers were washed with brine,dried (Na2SO4) and concentrated. The residue was purified by silicagel column chromatography using petroleum ether/EtOAc (9:1 to4:1) as eluent to give 14 (0.527 g, 93%) as a yellow solid. Mp143–145 �C. ½a�25

D ¼ �71:5 (c 0.34, CHCl3). IR (KBr) m = 3138, 2968,2928, 1627, 1603, 1509, 1463, 1388, 1333, 1284, 1250, 1072,1045, 977, 927, 862, 842, 807, 761, 667 cm�1. 1H NMR (400 MHz,CDCl3/TMS): d = 1.41 (d, J = 6.28 Hz, 3H), 1.69 (d, J = 5.1 Hz, 3H),3.27–3.34 (m, 2H), 3.74–3.78 (m, 1H), 3.93 (s, 3H), 3.97 (s, 3H),4.84 (q, J = 5.1 Hz, 1H), 6.56 (s, 1H), 6.85 (d, J = 7.7 Hz, 1H), 7.38(t, J = 8.1 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H). 13C NMR (100 MHz,CDCl3): d = 22.4, 22.6, 44.2, 56.4, 57.1, 74.5, 103.4, 106.2, 109.2,114.7, 116.1, 126.5, 127.0, 131.3, 148.0, 152.7, 157.0. HRMS (ESI-TOF): (m/z) calcd for [C17H20O4+H] 289.144, found 289.1451.

4.1.5. (2S)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-dione 17

To a solution of compound 14 (0.20 g, 0.693 mmol) in MeCN/H2O (1:1, 10 mL) was added CAN (0.76 g, 1.38 mmol, 2.0 equiv).The resulting solution was stirred at room temperature for 1 h. Itwas then quenched with water (5 mL), and the solution extracted

R. A. Fernandes et al. / Tetrahedron: Asymmetry 22 (2011) 487–492 491

with EtOAc (3 � 30 mL). The combined organic layers were washedwith brine, dried (Na2SO4) and concentrated. The residue was puri-fied by silica gel column chromatography using petroleum ether/EtOAc (9:1 to 7:3) to afford 17 (0.142 g, 83%) as a yellow oil.½a�25

D ¼ þ65 (c 0.48, CHCl3). IR (CHCl3) m = 3450, 3022, 2928, 1709,1654, 1586, 1470, 1405, 1284, 1256, 1215, 1051, 977, 757,667 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 1.29 (d, J = 6.1 Hz,3H), 2.58 (ddd, J = 13.5, 7.9, 0.9 Hz, 1H), 2.75 (ddd, J = 14.0, 4.1,1.2 Hz, 1H), 4.0 (s, 3H), 4.02–4.12 (m, 1H), 6.79 (d, J = 0.9 Hz, 1H),7.29 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.74 (dd, J = 7.6,0.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 23.7, 39.1, 56.5, 66.8,118.0, 119.5, 119.9, 134.4, 134.7, 139.2, 145.6, 159.5, 184.3,186.1. HRMS (ESI-TOF): (m/z) calcd for [C14H14O4+H] 247.097,found 247.091.

4.1.6. (2S)-2-(2-Hydroxypropyl)-5-methoxynaphthalene-1,4-diol 7

To a solution of quinone 17 (0.15 g, 0.61 mmol) in THF/H2O (4:3,7 mL) was added Na2S2O4 (0.317 g, 1.82 mmol, 3.0 equiv) followedby TBAI (5 mol %). The reaction mixture was stirred at room tem-perature for 3 h. It was then quenched with water (5 mL) and thesolution extracted with EtOAc (3 � 20 mL). The combined organiclayers were washed with brine, dried (Na2SO4) and concentratedto give virtually pure 7 (0.121 g, 80%) as a brown thick oil.½a�25

D ¼ þ16 (c 0.50, CHCl3). IR (CHCl3) m = 3616, 3421, 3019, 2975,1713, 1654, 1612, 1518, 1465, 1411, 1217, 1072, 928, 767, 669,626 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 1.27 (d, J = 6.4 Hz,3H), 2.81 (dd, J = 14.6, 7.0 Hz, 1H), 2.92 (dd, J = 14.4, 2.4 Hz, 1H),4.03 (s, 3H), 4.13–4.31 (m, 1H), 6.56 (s, 1H), 6.75 (d, J = 7.9 Hz,1H), 7.29 (t, J = 7.6 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 8.90 (s, 1H).13C NMR (100 MHz, CDCl3): d = 23.1, 40.4, 56.0, 70.6, 104.0,113.0, 114.5, 116.4, 120.6, 124.9, 129.0, 143.4, 147.0, 156.0. HRMS(ESI-TOF): (m/z) calcd for [C14H16O4+H] 249.1127, found 249.1224.

4.1.7. (2S)-tert-Butyldimethyl-[1-(1,4,5-trimethoxynaphthalen-2-yl)propan-2-yloxy]silane 16

To a solution of naphthol 8 (0.57 g, 1.51 mmol) in dry DMF(20 mL) at 0 �C was added oil free NaH (0.109 g, 4.53 mmol,3.0 equiv) in portions over 5 min. The reaction mixture was stirredat room temperature for 20 min and then cooled to 0 �C and MeI(0.29 mL, 4.68 mmol, 3.1 equiv) was added. The reaction mixturewas stirred at room temperature for 2 h. It was then quenched withice cold water (5 mL) and the solution was extracted with EtOAc(3 � 20 mL). The combined organic layers were washed withwater, brine, dried (Na2SO4) and concentrated. The residue waspurified by silica gel column chromatography using petroleumether/EtOAc (9:1 to 4:1) to give 16 (0.502 g, 85%) as a colourlessoil. ½a�25

D ¼ þ16:4 (c 1.1, CHCl3). IR (CHCl3) m = 3013, 2956, 2932,2855, 1601, 1584, 1463, 1382, 1264, 1128, 1078, 1009, 872, 836,810, 757, 664 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 0.00 (s,3H), 0.11 (s, 3H), 0.99 (s, 9H), 1.35 (d, J = 6.1 Hz, 3H), 2.96 (dd,J = 13.2, 5.8 Hz, 1H), 3.08 (dd, J = 13.1, 7.3 Hz, 1H), 4.00 (s, 3H),4.09 (s, 3H), 4.13 (s, 3H), 4.33–4.39 (m, 1H), 6.85 (s, 1 H), 6.99 (d,J = 7.0 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.80 (dd, J = 8.4, 0.9 Hz,1H). 13C NMR (100 MHz, CDCl3): d = �4.9 (2C), 18.1, 23.9, 25.9(3C), 40.7, 56.4, 57.0, 61.6, 69.2, 106.0, 110.0, 114.8, 118.0, 126.4,128.2, 131.4, 147.8, 152.9, 157.4. HRMS (ESI-TOF): (m/z) calcd for[C22H34O4Si+H] 391.2305, found 391.2311.

4.1.8. (2S)-1-(1,4,5-Trimethoxynaphthalen-2-yl)propan-2-ol 6To a solution of compound 16 (0.5 g, 1.28 mmol) in dry THF

(20 mL) was added TBAF (1.53 mL, 1.53 mmol, 1.2 equiv). The reac-tion mixture was stirred at room temperature for 2 h. It was thenquenched with water (10 mL) and stirred for 30 min. Next, theTHF was removed under reduced pressure and the solution was ex-tracted with EtOAc (3 � 20 mL). The combined organic layers were

washed with brine, dried (Na2SO4) and concentrated. The residuewas purified by silica gel column chromatography using petroleumether/EtOAc (9:1 to 3:2) as eluent to give 6 (0.336 g, 95%) as a yel-low oil. ½a�25

D ¼ þ34:2 (c 0.38, CHCl3). IR (CHCl3) m = 3435, 3015,2933, 2841, 1619, 1601, 1584, 1509, 1463, 1451, 1264, 1216,1127, 1074, 1007, 933, 849, 810, 755, 667 cm�1. 1H NMR(400 MHz, CDCl3/TMS): d = 1.29 (d, J = 6.1 Hz, 3H), 1.65 (br s, 1H),2.92 (d, J = 6.1 Hz, 2H), 3.86 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H),4.13–4.2 (m, 1H), 6.65 (s, 1H), 6.86 (d, J = 7.0 Hz, 1H), 7.42 (t,J = 7.9 Hz, 1H), 7.64 (dd, J = 8.4, 0.9 Hz, 1H). 13C NMR (100 MHz,CDCl3): d = 23.3, 40.3, 56.5, 56.9, 61.6, 68.6, 106.3, 109.0, 114.7,117.8, 119.5, 126.8, 134.7, 147.6, 153.5, 157.4. HRMS (ESI-TOF):(m/z) calcd for [C16H20O4+H] 277.1440, found 277.1437.

4.1.9. (1R,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromene 5a and (1S,3S)-5,9,10-trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromene 5b [reaction asin entry 7, Table 1]

To a stirred solution of 6 (100 mg, 0.361 mmol) in dry ether(10 mL) was added (CH3O)2CHCH3 (0.325 g, 3.61 mmol, 10.0 equiv)and dry HCl gas was bubbled through the mixture at 0 �C for 1 h. Itwas then stirred at 0 �C for 1.5 h. The solvent was evaporated andthe residue was purified by silica gel column chromatographyusing petroleum ether/EtOAc (9:1 to 4:1) as eluent to give a mix-ture of 5a and 5b (94.1 mg, 86%) as a yellow oil (1H NMR of themixture indicated 5a:5b = 78:22). The mixture was separated byflash silica gel column chromatography using petroleum ether/EtOAc (9:1) to give 5a (72.2 mg, 66%) and 5b (19.7 mg, 18%). Datafor 5a: Pale yellow oil; ½a�25

D ¼ þ46:3 (c 0.8, CHCl3). IR (CHCl3)m = 2970, 2932, 2839, 1733, 1660, 1595, 1572, 1448, 1373, 1357,1338, 1263, 1132, 1069, 1013, 990, 972, 837, 763, 634 cm�1. 1HNMR (400 MHz, CDCl3/TMS): d = 1.41 (d, J = 6.1 Hz, 3H), 1.68 (d,J = 6.4 Hz, 3H), 2.58 (dd, J = 16.0, 10.9 Hz, 1H), 3.06 (dd, J = 16.0,1.8 Hz, 1H), 3.65–3.70 (m, 1H), 3.76 (s, 3H), 3.87 (s, 3H), 4.01 (s,3H), 5.25 (q, J = 6.4 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 7.36 (t,J = 7.9 Hz, 1H), 7.68 (d, J = 8.24 Hz, 1H). 13C NMR (100 MHz, CDCl3):d = 21.8, 23.1, 31.9, 56.0, 61.1, 61.5, 69.3, 71.2, 105.4, 114.5, 119.3,125.8, 126.0, 129.8, 130.3, 148.5, 149.1, 156.0. HRMS (ESI-TOF):(m/z) calcd for [C18H22O4+H] 303.1596, found 303.1591. Data for5b: Pale yellow oil. ½a�25

D ¼ þ37:5 (c 1.2, CHCl3). IR (CHCl3)m = 3022, 2934, 2835, 1715, 1654, 1594, 1497, 1462, 1374, 1262,1213, 1108, 1067, 1012, 988, 757, 669 cm�1. 1H NMR (400 MHz,CDCl3/TMS): d = 1.40 (d, J = 6.1 Hz, 3H), 1.64 (d, J = 6.7 Hz, 3H),2.61 (dd, J = 16.8, 10.9 Hz, 1H), 3.08 (dd, J = 16.8, 3.4 Hz, 1H), 3.81(s, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 4.15–4.20 (m, 1H), 5.34 (q,J = 6.7 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 7.38 (dd, J = 8.0, 7.6 Hz,1H), 7.66 (dd, J = 8.1, 1.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):d = 20.9, 22.3, 30.8, 56.2, 60.7, 62.0, 62.4, 69.0, 105.5, 114.6,119.3, 124.4, 125.8, 130.0, 130.1, 148.1, 149.1, 156.1. HRMS (ESI-TOF): (m/z) calcd for [C18H22O4+H] 303.1596, found 303.1589.

4.1.10. (1R,3S)-5,9,10-Trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromene (5a) and (1S,3S)-5,9,10-trimethoxy-1,3-dimethyl-3,4-dihydro-1H-benzo[g]isochromene 5b [reaction asin entry 9, Table 1]

To a solution of 6 (40 mg, 0.145 mmol) in CH2Cl2 (8 mL) wereadded (CH3O)2CHCH3 (26 mg, 0.29 mmol, 2.0 equiv) and BF3�Et2O(0.055 mL, 0.435 mmol, 3.0 equiv). The reaction mixture was stir-red at room temperature for 10 h. The solvent was evaporatedand the residue was purified by silica gel column chromatographyusing petroleum ether/EtOAc (9:1 to 4:1) as eluent to give a mix-ture of 5a and 5b (39.4 mg, 90%) as a colorless oil (1H NMR ofthe mixture indicated 5a:5b = 21:79). The mixture was separatedby flash silica gel column chromatography using petroleumether/EtOAc (9:1) to give 5a (7.0 mg, 16%) and 5b (30.6 mg, 70%).Data for 5a and 5b were the same as above.

492 R. A. Fernandes et al. / Tetrahedron: Asymmetry 22 (2011) 487–492

4.1.11. (+)-Eleutherin 1To a solution of compound 5a (34 mg, 0.112 mmol) in CH3CN/

H2O (1:1, 4 mL) was added CAN (0.123 g, 0.225 mmol, 2.0 equiv).The resulting solution was stirred at room temperature for 1 h.Water (5 mL) was added and CH3CN removed under reduced pres-sure. The solution was extracted with EtOAc (3 � 30 mL). The com-bined organic layers were washed with brine, dried (Na2SO4) andconcentrated. The residue was purified by silica gel column chro-matography using petroleum ether/EtOAc (9:1 to 7:3) to afford 1(26.3 mg, 86%) as a yellow solid. Mp 152–154 �C. ½a�25

D ¼ þ338 (c0.34, CHCl3), lit3a ½a�25

D ¼ þ346 (c 1.01, CHCl3). IR (CHCl3)m = 3016, 2917, 1709, 1654, 1369, 1215, 1064, 925, 845, 763,667 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 1.36 (d, J = 6.4 Hz,3H), 1.53 (d, J = 6.4 Hz, 3H), 2.20 (ddd, J = 18.3, 10.2, 2.7 Hz, 1H),2.75 (dd, J = 18.3, 2.7 Hz, 1H), 3.55–3.59 (m, 1H), 4.00 (s, 3H),4.82–4.90 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),7.72 (dd, J = 7.6, 0.9 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 20.7,21.2, 29.8, 56.4, 68.7, 70.2, 117.8, 119.0, 120.3, 134.0, 134.5,139.9, 148.7, 159.4, 183.79, 184.0. HRMS (ESI-TOF): (m/z) calcdfor [C16H16O4+H] 273.1127, found 273.1121.

4.1.12. (+)-Allo-eleutherin ent-2To a solution of compound 5b (30 mg, 0.099 mmol) in CH3CN/

H2O (1:1, 4 mL) was added CAN (0.108 g, 0.198 mmol, 2.0 equiv).The resulting solution was stirred at room temperature for 1 h.Water (5 mL) was added and CH3CN removed under reduced pres-sure. The solution was extracted with EtOAc (3 � 30 mL). The com-bined organic layers were washed with water, brine, dried(Na2SO4) and concentrated. The residue was purified by columnchromatography using petroleum ether/EtOAc (9:1 to 7:3) to af-ford ent-2 (24 mg 89%) as yellow needles. Mp 168–170 �C.½a�25

D ¼ þ65:6 (c 0.3, CHCl3). IR (CHCl3) m = 3016, 2923, 2852,1717, 1657, 1586, 1470, 1375, 1256, 1216, 1054, 927, 760,669 cm�1. 1H NMR (400 MHz, CDCl3/TMS): d = 1.36 (d, J = 6.1 Hz,3H), 1.55 (d, J = 6.7 Hz, 3H), 2.27 (ddd, J = 18.9, 10.2, 2.1 Hz, 1H),2.72 (dd, J = 19.1, 3.5 Hz, 1H), 3.98 (m, 1H), 4.01 (s, 3H), 5.03 (q,J = 6.7 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.1, 7.6 Hz,1H), 7.76 (dd, J = 7.6, 1 Hz, 1H). 13C NMR (100 MHz, CDCl3):d = 19.8, 21.6, 29.6, 56.5, 62.5, 67.5, 117.9, 119.2, 119.8, 134.2,134.8, 139.5, 148.1, 159.8, 182.8, 184.3. HRMS (ESI-TOF): (m/z)calcd for [C16H16O4+H] 273.1127, found 273.1122.

Acknowledgements

The authors are indebted to the Board of Research in NuclearSciences (BRNS), Government of India (Grant No. 2009/37/25/BRNS) for financial support. V.P.C. and S.V.M. are grateful to Coun-cil of Scientific and Industrial Research (CSIR), New Delhi forresearch fellowships.

References

1. (a) Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rep. 1999, 16, 267; (b)Brimble, M. A.; Nairn, M. R.; Prabaharan, H. Tetrahedron 2000, 56, 1937.

2. Moore, H. W.; Czerniak, R. Med. Res. Rev. 1981, 1, 249.

3. (a) Schmid, H.; Meijer, T. M.; Ebnöther, A. Helv. Chim. Acta 1950, 33, 595; (b)Schmid, H.; Ebnöther, A.; Meijer, T. M. Helv. Chim. Acta 1950, 33, 1751.

4. For isolation see: (a) Schmid, H.; Ebnöther, A. Helv. Chim. Acta 1951, 34, 561; Forconfiguration see: (b) Schmid, H.; Ebnöther, A. Helv. Chim. Acta 1951, 34, 1041.

5. (a) Chen, Z.; Huang, H.; Wang, C.; Li, Y.; Ding, J. Zhongcaoyao 1981, 12, 484; (b)Ding, J.; Huang, H. Zhongcaoyao 1982, 13, 499.

6. Krishnan, P.; Bastow, K. F. Biochem. Pharmacol. 2000, 60, 1367.7. (a) Otani, T.; Sugimoto, Y.; Aoyagi, Y.; Igarashi, Y.; Furumai, T.; Saito, N.;

Yamada, Y.; Asao, T.; Oki, T. J. Antiobiot. 2000, 53, 337; (b) Gasparotto, D.;Maestro, R.; Piccinin, S.; Vulosavljevic, T.; Barzan, L.; Sulfaro, S.; Boiocchi, M.Cancer Res. 1997, 57, 2366.

8. (a) Schmid, H.; Eisenhuth, W. Helv. Chim. Acta 1958, 41, 2021; (b) Webb, A. D.;Harris, T. M. Tetrahedron Lett. 1977, 24, 2069; (c) Naruta, Y.; Uno, H.;Maruyama, K. J. Chem. Soc., Chem. Commun. 1981, 1277; (d) Kometani, T.;Yoshii, E. J. Chem. Soc., Perkin Trans. 1 1981, 1191; (e) Kometani, T.; Yoshii, E. J.Chem. Soc., Perkin Trans. 1 1981, 1197; (f) Giles, R. G. F.; Green, I. R.; Hugo, V. I.;Mitchell, P. R. K. J. Chem. Soc., Chem. Commun. 1983, 51; (g) Giles, R. G. F.; Green,I. R.; Hugo, V. I.; Yorke, S. C.; Mitchell, P. R. K. J. Chem. Soc., Perkin Trans. 1 1984,2383; (h) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem. Commun.1986, 1568; (i) Uno, H. J. Org. Chem. 1986, 51, 350; (j) Kobayashi, K.; Uchida, M.;Uneda, T.; Tanmatsu, M.; Morikawa, O.; Konishi, H. Tetrahedron Lett. 1998, 39,7725.

9. (a) Tewierik, L. M.; Dimitriadis, C.; Donner, C. D.; Gill, M.; Willems, B. Org.Biomol. Chem. 2006, 4, 3311; (b) Gibson, J. S.; Andrey, O.; Brimble, M. A.Synthesis 2007, 2611.

10. Dimitriadis, C.; Gill, M.; Harte, M. F. Tetrahedron: Asymmetry 1997, 8, 2153.11. (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178; (b) Kraus, G. A.;

Sugimoto, H. Tetrahedron Lett. 1978, 2263.12. Sawant, R. T.; Jadhav, S. G.; Waghmode, S. B. Eur. J. Org. Chem. 2010, 4442.13. Tanada, Y.; Mori, K. Eur. J. Org. Chem. 2001, 4313.14. Yang, H.; Lu, W.; Bao, J. X.; Aisa, H. A.; Cai, J. C. Chin. Chem. Lett. 2001, 12, 883.15. (a) Clive, D. L. J.; Fletcher, S. P. Chem. Commun. 2003, 2464; (b) Clive, D. L. J.;

Fletcher, S. P.; Liu, D. J. Org. Chem. 2004, 69, 3282.16. (a) Fernandes, R. A. Eur. J. Org. Chem. 2007, 5064; (b) Fernandes, R. A.

Tetrahedron: Asymmetry 2008, 19, 15; (c) Fernandes, R. A.; Chavan, V. P.Tetrahedron Lett. 2008, 49, 3899; (d) Fernandes, R. A.; Chavan, V. P.; Ingle, A. B.Tetrahedron Lett. 2008, 49, 6341; (e) Fernandes, R. A.; Dhall, A.; Ingle, A. B.Tetrahedron Lett. 2009, 50, 5903; (f) Fernandes, R. A.; Chowdhury, A. K. J. Org.Chem. 2009, 74, 8826; (g) Fernandes, R. A.; Ingle, A. B. Tetrahedron Lett. 2009,50, 1122; (h) Fernandes, R. A.; Ingle, A. B.; Chavan, V. P. Tetrahedron: Asymmetry2009, 20, 2835; (i) Fernandes, R. A.; Ingle, A. B. Synlett 2010, 158; (j) Fernandes,R. A.; Chavan, V. P. Eur. J. Org. Chem. 2010, 4306; (k) Fernandes, R. A.; Ingle, A. B.Tetrahedron Lett. 2011, 52, 458; (l) Fernandes, R. A.; Chowdhury, A. K. Eur. J. Org.Chem. 2011, 1106.

17. (a) Fernandes, R. A.; Mulay, S. V. J. Org. Chem. 2010, 75, 7029; (b) Fernandes, R.A.; Mulay, S. V. Synlett 2010, 2667.

18. Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess, E.; Zask, A. J. Am.Chem. Soc. 1982, 104, 5850.

19. Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423.20. For examples of oxa-Pictet–Spengler reactions see: (a) Pyrek, J. S.;

Achmatowicz, O., Jr.; Zamojski, A. Tetrahedron 1977, 33, 673; (b) DeNinno, M.P.; Schoenleber, R.; Perner, R. J.; Lijewski, L.; Asin, K. E.; Britton, D. R.;MacKenzie, R.; Kebabian, J. W. J. Med. Chem. 1991, 34, 2561; (c) DeNinno, M. P.;Perner, R. J.; Morton, H. E.; DiDomenico, S., Jr. J. Org. Chem. 1992, 57, 7115; (d)Masquelin, T.; Hengartner, U.; Streith, J. Synthesis 1995, 780; (e) Masquelin, T.;Hengartner, U.; Streith, J. Helv. Chim. Acta 1997, 80, 43; (f) Giles, G. F.; Rickards,R. W.; Senanayake, B. S. J. Chem. Soc., Perkin Trans. 1 1998, 3949; (g) Contant, P.;Haess, M.; Riegl, J.; Scalone, M.; Visnick, M. Synthesis 1999, 821; (h) Bianchi, D.A.; Rua, F.; Kaufman, T. S. Tetrahedron Lett. 2004, 45, 411.

21. For examples of Dötz benzannulations see: (a) Dötz, K. H. Angew. Chem., Int. Ed.Engl. 1975, 14, 644; (b) Dötz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187.

22. Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. D.; Gilberton, S.R. Tetrahedron 1985, 45, 5813. Instead of methyl fluorosulfonate we used theMeerwein salt Me3OBF4 (see Section 4).

23. (a) Cameron, D. W.; Feutrill, G. I.; Pietersz, G. A. Aust. J. Chem. 1982, 35, 1481;(b) Pyrek, J., St; Achmatowicz, O., Jr.; Zamojski, A. Tetrahedron 1977, 33, 673; (c)Li, T.; Ellison, R. H. J. Am. Chem. Soc. 1978, 100, 6263; (d) Kometani, T.; Takeuchi,Y.; Yoshii, E. J. Org. Chem. 1983, 48, 2630; (e) Yoshii, E.; Kometani, T.; Nomura,K.; Takeuchi, Y.; Odake, S.; Nagata, Y. Chem. Pharm. Bull. 1984, 32, 4779; (f)Naruta, Y.; Uno, H.; Maruyama, K. Chem. Lett. 1982, 609.

24. The diastereomer ratio was determined by 1H NMR.