Synthesis of the phorboxazoles—potent, architecturally novel ...

REVIEW ARTICLE

Synthesis of the phorboxazoles—potent, architecturallynovel marine natural products

Zachary Shultz1 and James W Leahy1,2,3

The phorboxazoles have attracted the attention of synthetic chemists around the globe due to their potent biological activity and

novel structure. A review of the recent synthetic efforts as well as new phorboxazole analogs is discussed.

The Journal of Antibiotics (2016) 69, 220–252; doi:10.1038/ja.2016.8; published online 9 March 2016

INTRODUCTION

In 1995, Searle and Molinski reported the isolation of a pair of novelnatural products from the Indian Ocean marine sponge Phorbas sp.collected off the Muiron Islands that demonstrated potent antifungaland cytostatic activity.1 The subsequent structural elucidation of thesetwo macrolides,2–4 phorboxazoles A (1, Figure 1) and B (2), hasinspired considerable attention and synthetic creativity over thesucceeding two decades that has resulted in 10 total syntheses as wellas a number of additional synthetic approaches, the discovery of newmembers of the phorboxazole family, the creation of biological probesand the generation of analogs to uncover hints about their bioactivity.Some of the highlights of these efforts are reviewed here.More recently, Capon et al.5 isolated both 1 and 2 from a Raspailia

sp. sponge collected along the Australian Northern Rottnest Shelfwhile searching for nematocidal agents. This second isolation fromsuch a taxonomically distinct source suggests a potential microbialbiosynthetic origin or at least contribution that has yet to beuncovered, leaving synthesis as the primary source for furtherconsideration of the natural products.It is not surprising that the distinctive structural features of the

phorboxazoles, which includes the presence of four unique pyran ringsand two oxazoles, attracted the interest of a number of syntheticgroups. In fact, the first synthetic approach to the molecule wasreported before the final structure elucidation was published!6 Seitzand Hoffmann have previously examined some of the earliestsyntheses of the phorboxazoles,7,8 and therefore we will primarilyfocus on the efforts that were not previously highlighted.With a target as structurally diverse as the phorboxazoles, there is an

array of potential approaches to be considered. However, the need toform a macrolide left a limited number of options for the cyclization.The most commonly exploited approach was to close the ring via anolefination of the α,β-unsaturated macrolactone—a strategy that hasproven to be quite effective in this regard. Notably, the Evans totalsynthesis9 and the Paterson synthetic approach10 utilized a Yamaguchi

macrolactonization as an alternative. The other common disconnec-tion was about the C16–C18 oxazole or the C19–C20 olefin to join thetwo macrolide fragments. As the two natural products differ onlyabout the stereochemical disposition of the hydroxyl substituent at theC13 position, the phorboxazoles serve as an excellent vehicle for thestudy of the various approaches to solve the synthetic challengesposed. In this review, we will first evaluate the completed syntheses of1 and 2, respectively, followed by the approaches of other groups inthis regard and the efforts reported to date on the discovery of othermembers of the phorboxazole family, biological probes and additionalanalogs.

DISCUSSION

Total synthesesEarliest syntheses. As the earlier reviews covered the first generationsyntheses of 1 by Forsyth and Smith as well as the syntheses of 1 byPattenden and Williams and the synthesis of 2 by Evans, we will onlypoint out a few of the salient highlights from these seminal works.Forsyth, who was the first to complete the synthesis of either naturalproduct (Figure 2),11 established the Michael cyclization to thepentasubstituted pyran and developed a biomimetic route to theoxazoles. He observed the same lack of diastereoselectivity in theformation of the C38 center observed by Molinski and Leahy,2

ascertained the viability of the hetero-Diels–Alder approach to thepyrans and established the feasibility of the Still–Gennari macrocycli-zation. Before 2006, Evans had achieved the only synthesis of 2,9

which featured a macrolactonization strategy of an acetylene to enablea selective reduction to the Z C2–C3 olefin (Figure 3). In addition,Evans’ lithiation of the oxazole methyl, optimization of the C19–C20Wittig and use of β-ketoesters enabled many of the efforts thatfollowed. Smith’s pioneering use of the Petasis–Ferrier rearrangementserves as a hallmark of his synthesis of 1 (Figure 4),12 and heimplemented a Stille protocol for introduction of the exocyclicoxazole, allowing it to serve as a linchpin for the two complex

1Department of Chemistry, University of South Florida, Tampa, FL, USA; 2Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL,USA and 3Florida Center of Excellence for Drug Discovery and Innovation, University of South Florida, Tampa, FL, USACorrespondence: Professor JW Leahy, Department of Chemistry, University of South Florida, 4202 E. Fowler Avenue, CHE 205, Tampa, FL 33620, USA.E-mail: [email protected] to Professor Amos B Smith, III - an outstanding chemist, mentor and friend.Received 11 December 2015; revised 14 January 2016; accepted 19 January 2016; published online 9 March 2016

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fragments. Pattenden was the first to use a carbohydrate startingmaterial (D-xylose) in his synthesis of 1,13 and his utilization of theJulia olefination for the introduction of the polyene side chain wasadopted by several subsequent synthetic approaches (Figure 5). Inaddition to using a Horner–Wadsworth–Emmons approach toC19–C20 and C27–C28, Williams was able to take advantage of his

in situ asymmetric transmetallation/allylation protocol in his synthesisof 1 (Figure 6).14

Recent synthesesSecond generation synthesis of 1 by Amos B Smith, III. In the yearssince those syntheses were completed, five additional total syntheses

N

O

O

R1R2

OO

O

ON

O

OMeO

HO

BrMeO

OH

2

5

9

11

1519

22

26

2831

33

37

40

46

R2

OO

O

N

O

O

N

OO

OH

O

BrO

HO

13

16

19

22

25 2

3

28

33

40

R1

Phorboxazole A (1, R1 = H, R2 = OH)Phorboxazole B (2, R1 = OH, R2 = H)

O

Figure 1 Structures of phorboxazoles A and B.

N

O

O

OO

O

O

HO

H3NCl

OTBDPS

OMeO

MeO

BrMeO

OH

OH

O

OTES

O

HO

H3NCl

OH

O

H2N

HO

O

O

OTBDPS

PMBO

OMe

I

HO OMe

O

OMe

OMeO

H

O

HO

OTBDPS

OO

PMBO

BrTESO

OTES

OH

MeO

O

N

O

Boc

1

Figure 2 Retrosynthetic analysis of Craig Fosyth’s first-generation total synthesis of phorboxazole A.

Synthesis of the phorboxazolesZ Shultz and JW Leahy

221

The Journal of Antibiotics

I

Br

MeO

O

N

O

O

TESO

MeO

TESO OTIPS

H

O

N

O

O

O

Bu3PMsO-

OTIPS

PhHN

O

O

OTIPS

OTMS

O

O

OMeBnO

H

OHOH O

TESO

H

O

NHPh

O

ON

O

Bn

N

O

N

O N

O

TIPSO

O

O

OBn

OO

2

Figure 3 Retrosynthetic analysis of Dave Evans’ total synthesis of phorboxazole B.

N

O

O

MeO

HO

MeO

OTIPS

OTf

TMSN

O

O

OODMB

OMe3Sn

OBPS

OTBS

O

MeO OTIPS

I

N

O

OTfO Br

MeO

TMS

SnBu3OBz

O

CHON

O

O

O

OBPS

OTBS

PBu3Cl

OCHO

BPSO

N

O

S

O

iPrN

O

PMBO

CHO

1

Figure 4 Retrosynthetic analysis of Amos Smith’s first-generation total synthesis of phorboxazole A.


222


have been reported. The first of these was a second generationapproach to 1 by Smith,15 who has shown an admirable commitmentto developing scalable syntheses of scarce natural products in order tofacilitate their biological investigation.16,17 His retrosynthesis, which isa bit more convergent than his first generation approach but usesmany of the same disconnections, is shown in Figure 7. Asymmetrichetero-Diels–Alder cyclization of 14 with Danishefsky’s diene (15)

gave 17 in 95% ee using Jacobsen’s catalyst (16) on a 470-g scale(Scheme 1). Michael addition of an acetate provided excellent transselectivity, which allowed for the completion of the initial pyran 18.An acetate aldol set the stage for the formation of acetal 21, whichthen underwent the Petasis–Ferrier rearrangement to bis-pyran 22.Once the ketone was reduced to the axial alcohol, the C3–C19fragment (9) was completed as expected. Smith also used 14 as his

O

MeO

BrMeO

OH OPMP

OHO

N

O

O

O

MsOOTIPS

TBSOO

HO

N

OP(O)(OMe)2

NO O

O

OPMB

OTIPS

I

O O

HOO

PMBO OH

HOCO2Me

S

N

SO

O

BrMeO

OPMB

O

MeO OH

MeO OMe

3

OHOH

OHC

OHOH

1

Figure 5 Retrosynthetic analysis of Gerald Pattenden’s total synthesis of phorboxazole A.

N

O

O

MeO

HO

OH

OPiv

H

O

(OEt)2PO O

OMOM

OPMP

OTES

N

O

O

O

MsOOTBDS

TIPSO

N

O

PMBOOH OTBS

OPiv

Bu3SnOPiv

OTBS

PivOOTBDPS

O O

H

O

N

O

OTBDPS

I

H

O

OPMB

OMOM

O N

O O

Ph

3

1

Figure 6 Retrosynthetic analysis of David Williams’ total synthesis of phorboxazole A.


223


N

O

O

OO

O

O

OTBS

I

N

O

O

MeO

MeO

MeO

OTIPS

SnMe3

TMS

CHO

ODMB

OI

HO

HO

O

OBPS

O

N

O

PMBOCHO

N

O

O

O

OTBSMsO

OBPS

OBPS

HO O

HO

CHOI

TMS

MeO

SnBu3

O

MeOOTIPS

O

I

54

6

7

8

9

10

1112

13

1

Figure 7 Retrosynthetic analysis of Amos Smith’s second generation total synthesis of phorboxazole A.

OMe

OTMS

O

O

OBPS

OTMS

SEt

O

O

OBPS

SEt

O

O

OBPS

H

O

N S

SOO

OBPS

HO O

HO

BPSOCHO a

(85%)

(17, 95% ee)

b

(95%)

c

(74% over 2 steps)

d

(90% over 2 steps)

(13, 10:1 dr)

e

(95% over 2 steps)

N

O

O

O

O

PMBO

OBPS

O

(21, 10:1 dr)

f

(66% over 2 steps)

N

O

O

O

PMBO

OBPS

O

g

(94% over 2 steps)

N

O

O

O

PMBO

OBPS

OTBS

h

(96% over 2 steps)

N

O

O

O

OTBSMsO

OBPS

(23, 9:1 dr)

14

15 18 19

2022

9 N O

O

CrCl

16

Scheme 1 (a) 16, 4 Å MS, Me2O, RT; (b) TFA, 0 °C; (c) (1) Cp2TiMe2, ethyl pivalate, THF, 55 °C; (2) HSiEt3, 10% Pd-C, CH2Cl2, RT; (d) (1) 20, Sn(OTf)2,N-ethylpiperidine, −55 to −78 °C; (2) LiOH, H2O2, THF, 0 °C; (e) (1) HMDS, CH2Cl2, RT; (2) 12, TMSOTf, −78 to −30 °C; (f) (1) Cp2TiMe2, ethylpivalate, THF, 53 °C; (2) Me2AICl, Cs2CO3, CH2Cl2, RT; (g) (1) K-selectride, THF, −78 °C; (2) TBSOTf, 2-6-lutidine, CH2Cl2, −78 °C; (h) DDQ, H2O,CH2Cl2, RT; (2) MsCl, DIPEA, CH2Cl2, 0 °C.


224


entry point to the pentasubstituted pyran. Evans aldol additionfollowed by acetalization with 10 led to dioxanone 25, which under-went the two-step Tebbe olefination/Petasis–Ferrier rearrangement

without incident (Scheme 2). α-Methylation and elaboration toaldehyde 8 yielded the Wittig coupling partner. The synthesis ofSmith’s final pyran was achieved using an intermediate from his first

BPSOCHO a

(90% over 2 steps)

ON

OO

Bn

OBPS

HO O

HO

b

(93% over 2 steps)

O

OI

O

OBPS

(25, 20:1 dr)

c

(78% over 2 steps)

OI

O

OBPSd

(50% over 3 steps)

OI

ODMB

OBPS

(27, 6.8:1 dr)

e

(89% over 2 steps)

OI

ODMB

CHO

14

24

11

26 8

Scheme 2 (a) (1) 24, Bu2BOTf, DIPEA; (2) LiOH, H2O2, 0 °C; (b) (1) HMDS, CH2Cl2; (2) 10, TMSOTf, TfOH, 2-6-DTBMP; (c) (1) Cp2TiMe2, THF, 55 °C,(2) Me2AICl, CH2Cl2, −78 °C; (d) (1) LiHMDS, Mel, HMPA, −78 °C; (2) NaBH4, EtOH, −10 °C; (3) KH, DMBCl, 15-c-5; (e) (1) TBAF, THF, RT; (2) SO3pyr, Et3N, DMSO, CH2Cl2, RT.

BPSO

OH

BPSOCHO

OMea

(80% over 2 steps)BPSO

OMeb

(93% over 2 steps)

c

(57% over 2 steps)

MeO

BPSOO

Od

(100% over 2 steps)

MeO

HO OO

O

MeOOTIPS

O

e

(63% over 3 steps)

f

(83% over 2 steps)

O

MeOOTIPS

O

I

TBSO

O

HOTMS

MeOg

(69% over 3 steps)

h

(71% over 2 steps)

TMS

MeO

SnBu3

O

MeOOTIPS

O

TMS

MeO

BrPh3PCH2 TMS(31, 5.5:1 E/Z)

i (99%)

O

MeOOTIPS

TMS

MeO

MeO

O

NX

j

(56% over 2 steps)

39, X = OTf

4, X = SnMe3

k

28 29

30

32 33 34

763635

37N

O

Br OTf

38

Scheme 3 (a) (1) DTBMP, MeOTf, 4 d; (2) O3, PPh3; (b) (1) 30, n-BuLi, THF; (2) K2CO3, MeOH; (c) (1) AD Mix β, 0 °C, 5 d; (2) Me2C(OMe)2, PPTS; (d)(1) t-BuLi, Mel; (2) TBAF; (e) (1) TEMPO, MeCN, pH 6.7 buffer, NaOCl, NaClO2; (2) FeCl3-6H2O; (3) TIPSCl, imidazole; (f) (1) Bu3SnH, PdCl2(PPh3)2; (2)l2; (g) (1) TMS-acetylene, t-BuLi, BF3-Et2O; (2) MeOTf, DTBMP; (3) HCl (cat.), MeOH; (h) (1) SO3, pyr, DMSO; (2) CrCl2, Bu3SnCHBr2, Lil, THF/DMF; (i)Pd2(dba)3—CHCl3, DMF, RT, 4 h, Ph2PO2NBu4; (j) (1) 38, iPrMgCl, −78 °C; (2) PTSA, MeOH; (k) Pd(PPh3)4, (Me3Sn)2, LiCl, Dioxane, 90 °C.


225


generation synthesis (which could also be prepared from aldehyde 14,meaning all of the fragments emanate from the same startingmaterial), and features an asymmetric Sharpless dihydroxylation toset the C37 and C38 stereocenters, a Stille coupling of 6 and 7 toinstall the diene and the introduction of the linchpin oxazole (Scheme3). With all of the intermediates in hand, Wittig coupling of 8 and 9proceeded with outstanding selectivity (Scheme 4). Macrocyclizationwas achieved using the Still–Gennari conditions to give the Z-olefinwith 2.5:1 selectivity. The two fragments were united via a Stillecoupling, and the peripheral vinyl bromide was installed followed byglobal deprotection to give 1.

Total synthesis of 1 by James White. In their synthetic approach to 1,the White group installed the elaborated polyene before introducingthe bis-pyran portion of the macrolide (Figure 8).18,19 Asymmetricallylation of tartrate-derived 52 leads to 53, which was oxidized andacetalized (Scheme 5). Protection of the secondary alcohol allows forthe Wittig homologation to 58, which facilitated the generation oflactone 60. Asymmetric crotylation of 62 installed the C25 and C26stereocenters with 92% ee (Scheme 6), which was further elaboratedvia a second asymmetric crotylation with good diastereocontrol. Apalladium-mediated alkoxycarbonylation then created the pentasub-stituted pyran 66, which was converted to 47 in anticipation ofcoupling to 46, which was achieved via deprotonation of the oxazolemethyl (Scheme 7). Formation of enal 68 and Julia olefinationprovided the C20–C46 fragment. It should be noted that the vinylbromide had to be installed after the introduction of the oxazole, as itpromoted elimination to the undesired terminal alkyne.White prepared the bis pyran from the asymmetric allylation of 14

(Scheme 8). Seyferth–Gilbert homologation to the alkyne precededbromoboration and extension to allylsilane 49. Asymmetric allylationof 74 proceeded with outstanding enantiocontrol (Scheme 9), whichwas extended to 77 via a second asymmetric allylboration. The cispyran was again formed via a carbonylative process, which was thencoupled with 49 to complete the C3–C19 fragments. The undesired

diastereomer at C9 was able to be converted to 45 using an oxidation/reduction protocol. The final assembly of 1 was achieved via the Wittigunion of the fragments, which selectively gave the trans product(Scheme 10). The trans-pyran was then closed and the macrolideformed via intramolecular Horner–Wadsworth–Emmons olefinationwith 4:1 selectivity. Global deprotection yielded 1.

Second generation syntheses of 1 by Craig Forsyth. Forsyth has alsorecently disclosed an extensive study that culminated in a second-generation synthesis of 1, expanding on his de novo oxazole approach(Figure 9).20,21 Hetero–Diels–Alder cyclization with Garner’s aldehyde(84) gave an excellent yield of exclusively 86, which is initially thetrans-pyran (Scheme 11). Manta has also reported the synthesis of 86using this methodology. Upon elaboration to aldehyde 88, this couldbe equilibrated to the desired cis product (89). A second hetero-Diels–Alder cyclization with diene 85 then provided bis-pyran 90.β-Ketoimide aldol addition to 91 and directed reduction gave thestereotetrad of the pentasubstituted pyran, which was extended toα,β-unsaturated ester 96 and closed via the Michael protocol(Scheme 12) to render primarily the trans-pyran. Equilibration via aretro-Michael/Michael process then afforded the desired stereochem-istry, and the ester was extended and saponified to 82.Forsyth’s approach to the exoxyclic pyran ultimately emanated from

D-xylose derived 100 (Scheme 13). Silylketene acetal addition gave44:1 selectivity for 102, which was converted to the aldehyde andextended to 106. Julia addition of the terminus gave 108, which couldbe ketalized and advanced to vinyl bromide 81.Forsyth explored an impressive array of approaches to optimize the

final formation of 1, including a ring closing metathesis thatdramatically improved the C2–C3 Z:E selectivity and a tandem denovo oxazole formation of both rings. The most direct synthesis isshown in Scheme 14. Ultimately, his second-generation synthesisachieves 1 in an overall yield of 6% with a longest linear sequence of19 steps from 84.

N

O

O

O

OTBSMsO

OBPS

a

(96% over 2 steps)

N

O

O

O

OTBS

OBPSODMB

O

I

N

O

O

O

OTBS

OOH

O

I

HO

OP(OCH2CF3)2

O

d (88% over 2 steps)

N

O

O

OO

O

O

OTBS

I

(40, 20:1 E/Z)

b

(81% over 2 steps)

N

O

O

OO

O

ON

O

O

MeO

MeO

MeO

OTIPS

TMS

OTBSe

(68%)

9 41

42c,

5

43

f

(33% over 4 steps)1

Scheme 4 (a) (1) PBu3, DMF, RT; (2) 8, DBU, DMF, RT; (b) (1) KOH, 18-c-6, THF, 4% H2O; (2) Dess–Martin, NaHCO3, CH2Cl2, 0 °C; (3) DDQ, pH 7buffer, CH2Cl2; (c) (1) EDCl-Mel, HOBT, 42, CH2Cl2; (d) K2CO3, 18-c-6, toluene, RT; (e) Pd2(dba)3, CHCl3, 4, AsPh3, DIPEA, Ph2PO2NBu4, DMF, RT; (f)(1) AgNO3, NBS, acetone; (2) PdCl2(PPh3)2, HSnBu3, THF (6:1, ext:int); (3) NBS, MeCN, 0 °C; (4) 6% HCl, THF, RT.


226


a

(79% over 2 steps)

O

TBSOO

O

OMe

TBSOO

O

b

(95%)

OMe

TBSOO

O O

c

(87%) O

OMe

OMeOH

HO

d

(56% over 3 steps)O

OMe

OMeOBPS

HO

e

(47%)O

OMe

SPhOBPS

HO

f

(91% over 2 steps)O

OMe

SPhOBPS

MeO2C

g

(90% over 2 steps)O

OMe

SPhOBPS

OTBSh

(75% over 2 steps)O

OMe

OOBPS

OTBS

52 53 54 55

56 57 58

59 60

Scheme 5 (a) H2C=CHCH2MgBr, (− )-(lpc)2BOMe, Et2O, −100 °C; (2) NaH, Mel, THF, heat; (b) O3, CH2Cl2, PPh3, −78 °C; (c) MeOH, PPTS (cat.); (d) (1)TBSCl, imidazole, DMF, −78 °C; (2) TBDPSOTf, 2,6-lutidine, CH2Cl2; (3) MeOH, PPTS (cat.); (e) PhSSiMe3, Znl2, EDC; (f) (1) (COCl)2, DMSO, Et3N; (2)Ph3P=C(CH3)CO2Me, toluene, heat; (g) (1) DIBAL-H, toluene, −78 °C; (2) TBSCl, DIPEA, CH2Cl2; (h) (1) AgNO3, 2,6-lutidine; (2) TPAP, NMO, CH2Cl2.

OPMB

ON

O

OTBS N

O

O

OHC

Cl

O

O

MeO

BrMeO

OH

O

OPMB

ON

O

O

MeO

MeO

BrMeO

OBPS

N

O

O

HO

ClOBPS

OTES

BPSO

OBPSSIMe3

OBPS

OTES

OTIPS

OHN

O

N

O

OH

ClOBPS

44 45

46 47

48

49 50

51

1

Figure 8 Retrosynthetic analysis of James White’s total synthesis of phorboxazole A.


227


N

O

H

O

N

O

O N

O

OPMB

N

O

O

OPMB

N

O

PMBO

OH

N

O

O

OTIPS

CO2Me

a

(93%)

b

(67%)

c

(98%)

d

(53%)

e

(77% over 2 steps)

(63, dr > 96:4, er> 96:4)

(65, 6:1 dr)

f

(86%)

N

O

HO

OTIPS

g

(83% over 4 steps) N

O

O

OPMB

OTBS

61 62 64

48

66 47

Scheme 6 (a) Ph3P=CC(CH3)CHO, benzene, heat, 20 h; (b) trans-CH3CH=CHCH3, t-BuOK, n-BuLi, THF, then (+)-(lpc)2BOMe, THF, −70 °C, 6 h; H2O2,NaHCO3, RT, 15 h; (2) NaH, THF, heat, 40 min, then PMBCl, n-Bu4NI, heat, 6 h, 89%; (c) (1) OsO4 (cat.), NMO, THF-H2O, RT, 10 h, 84%; (2) NalO4,H2O-THF, RT, 30 min, 98%; (d) trans-CH3CH=CHCH3, t-BuOK, n-BuLi, THF, then (− )-(lpc)2BOMe; HOCH2CH2NH2, MeOH, RT, 3 h, 53%; (e) (1) TIPSOTf,2,6-lutidine, CH2Cl2, RT, 2 h, 99%; (2) AICl3, EtSH, CH2Cl2, −20 to −4 °C, 3.5 h, 78%; (f) Pd(OAc)2 (3 eq.), CO, MeOH–MeCN, 70 h; (g) (1) LiAIH4,Et2O, 0 °C; (2) TBAF, THF, 0 °C; (3) TBSCl, DIPEA, DMAP, CH2Cl2, (4) NaH, PMBCl, TBAI, THF.

N

O

O

OPMB

OTBS

a

(96%)

N

O

O

OPMB

OTBS

O

MeO

MeOOBPS

OTBS

b

(71% over 3 steps)

c

(99%)

N

O

O

OPMB

OTBS

O

MeO

MeOOBPS

O

N

O

O

OPMB

OTBS

O

MeO

MeOOBPS

BrMeO

d

(87%over 2 steps)

N

O

O

OPMB

O

O

MeO

MeOOBPS

BrMeO

47 67 68

69 44

Scheme 7 (a) Et2NH, n-BuLi, THF, −78 °C then 60; (b) (1) MeOH, PTSA; (2) MnO2, CH2Cl2; (3) TBSCl, imidazole, CH2Cl2; (c) 3, NaHMDS, THF, −78 °C;(d) (1) MeOH, PTSA; (2) Dess–Martin.

a

(63% over 3 steps)BPSO O

TESO b

(90%)

OP(OMe)2

O

N2

BPSO

TESO

c

(83% over 3 steps) BPSO

TESO

Br

d

(75% over 2 steps) BPSO

TESOSiMe2

BPSOCHO

14 70

71

72

73 49

Scheme 8 (a) (1) H2C=CHCH2MgBr, (+)-(lpc)2BOMe, Et2O, −100 °C; (2) TESOTf, 2,6-lutidine, CH2Cl2; (3) O3, CH2Cl2-MeOH, PPh3, −78 °C; (b) 71,NaOMe, MeOH-THF; (c) (1) PPTS, MeOH; (2) B-Br-9-BBN, CH2Cl2; (3) TESOTf, 2,6-lutidine, CH2Cl2; (d) Me3SiCH2MgCl, NiCl2(dppp).


228


Total synthesis of 2 by Guo-Qiang Lin and Wei-Shan Zhou. Two totalsyntheses of 2 have also been achieved in the last decade. The first ofthese came from the labs of Lin and Zhou (Figure 10).22 Asymmetricallylation and Wacker oxidation of the protected product gave an 87%

ee of ketone 126 (Scheme 15). Aldol addition and oxidation led todiketone 128, which was closed to pyranone 129. Hydrogenationsimultaneously set the C13 and C15 stereocenters, leading to aldehyde122. Aldol addition of 123 (derived as the opposite antipode to 126,

N

O

ClO

H a

(84%)

N

O

ClOH

N

O

ClOTBS

Ob

(69% over 2 steps)(75, er > 20:1)

N

O

ClOH

OBPSc

(56% over 3 steps)(77, dr > 12:1)

d

(77% over 2 steps)

N

O

ClO

OBPS

CHO

f

(55-65%)

N

O

ClO

OBPS

OH

BPSO

OTES(45, 1:1 mixture at C9)

74 76

50

Scheme 9 (a) (+)-(lpc)2BOMe, CH2=CHCH2MgBr, Et2O, −100 °C; (b) (1) TBSOTf, 2,6-lutidine, CH2Cl2, RT; (2) OsO4(cat.), NalO4, H2O-THF; (c) (1)(+)-(lpc)2BOMe, CH2=CHCH2MgBr, Et2O, −100 °C; (2) TBDPSOTf, 2,6-lutidine, CH2Cl2, RT; (3) HCl (3N), THF–H2O; (d) (1) PdCl2(MeCN)2, (10 mol%), CO(1 atm), MeOH, p-benzoquinone; (2) DIBAL-H, CH2Cl2, −78 °C; (f) 49, SnCl4, CH2Cl2, −78 °C (inverted unwanted diastereomer by [O]/[H] process).

N

O

ClO

OBPS

OH

BPSO

OTES

a

(85%)

N

O

O

OBPS

OH

BPSO

OTESN

O

O

OPMB

O

MeO

MeOOBPS

BrMeO

N

O

O

OBPS

ON

O

O

OPMB

O

MeO

MeOOBPS

BrMeO

OBPS

c

(53% over 4 steps)

N

O

O

OBPS

ON

O

O

O

O

MeO

MeOOBPS

BrMeO

OP(OMe)2O

O

d (15% over 3 steps)(4:1 Z/E)

45

b

(83% over 3 steps)

78

79 80

1

Scheme 10 (a) Bu3P, DMF, DBU, then 44; (b) (1) MsCl, Et3N; (2) MeOH, PPTS, CH2Cl2; (3) Et3N, MeCN; (c) (1) DDQ, CH2Cl2;(2) (MeO)2P(O)CH2CO2H,DCC, Ch2Cl2; (3) NH4F (excess), MeOH, 50°C; (4) Dess–Martin, CH2Cl2; (d) K2CO3, 18-c-6, toluene, −78°C to RT; (2) TBAF, THF; HCl (6%), THF.


229


OTBS

OMeO

CO2HMeO

Br

MeO

O

OTESNBoc

O

CO2H

O

OBPS

HOH2N

O

OPMB

81 82 83

1

Figure 9 Retrosynthetic analysis of Craig Forsyth’s second-generation total synthesis of phorboxazole A.

OPMB

OTBS

O

O

OPMB

ONBoc

a

(93%)

b

(95%)

O

OH

OPMB

ONBoc

c

(91% over 3 steps)

O

OBPS

O

ONBoc

d

(91%)

O

OBPS

O

ONBoc

e

(60% over 3 steps)

O

OBPS

ONBoc

O

OPMB

O

OBPS

HOH2N

O

OPMB

f

(77%)

O

O NBoc

8485

86 87 88

89 90 83

Scheme 11 (a) ZnCl2, CH2Cl2, 0 °C, then TBAF; (b) K-selectride, THF, −78 °C; (c) (1) TBDPSCl, imidazole, DMAP, CH2Cl2; (2) DDQ, pH 7 buffer, CH2Cl2,t-BuOH; (3) (COCl)2, DMSO, iPr2NEt, CH2Cl2; (d) DBU, benzene, reflux; (e) (1) 85, ZnCl2, CH2Cl2, 0 °C; (2) TBAF; (3) Ph3PCH3Br, n-BuLi, THF, 0 °C; (f)AcCl, MeOH, 0 °C.

O

N O

O

BnO

O

NBocO

H

O

H a

(77%)

OOOH

ONBoc

H

Xc

OOHOH

ONBoc

H

Xcb

(99%)

c

(90%)

O

OHNBoc

O

OH

d

(82%)

OH

NBocO

OH O

OEte

(89% over 2 steps)

O

CO2Et

OTESNBoc

O

f

(95%)

O

CO2Et

OTESNBoc

O

g

(89% over 2 steps)

O

OTESNBoc

O

CO2Et

O

OTESNBoc

O

CO2H

h

(93% after recycling)

91 92 93 94 95

96 97 98

99 82

Scheme 12 (a) (c-hexyl)2BCl, Et3N, Et2O, 0 °C, then 91, −78 °C; (b) Me4NBH(OAc)3, HOAc, MeCN, −20 °C; (c) DBU, CH2Cl2, then DIBAL-H, −78 °C; (d)Ph3PCHCO2Et, benzene, reflux; (e) (1) KOtBu, THF, −50 °C; (2) TESCl. Et3N, DMAP, CH2Cl2; (f) KH, THF, methyl pivolate, 0 °C to RT; (g) (1) DIBAL-H,CH2Cl2, −78 °C; (2) Ph3PCHCO2Me, MeCN, 65 °C; (h) LiOH, THF, H2O (recycled deprotected alcohol: TESCl, Et3N, DMAP, then aq NH4Cl).


230


O

OOPMBO

O O

OTMS

a

(90%)

OH

OOPMBO

O

O

O

(102, 4.4:1 dr)

b

(77%)

OMe

OOPMBO

O

O

O

c

(89% over 2 steps)

OMe

OO

O

O

O

H

O d

(94%)

OMe

OO

O

O

O

H

O

PPh3H

O

e

(79%)

TMS OMeS

N

S

O

O

OMe

OO

O

O

O

TMS OMe

f

(85%)

OMe

OO

TMS OMe

MeO O

O

g

(70%)

TMS OMe

OHO

OMe

OMe

O

OMe

h

(86% over 2 steps)

OMe

OTBSO

OMe

OMe

O

OMe

i

(63% over 3 steps)

OMe

OTBSO

OMe

OH

O

OMeBr

100 101 (103, 5:1 dr)

104

105

106

107

108

109

110

111 81

Scheme 13 (a) 101, Ti(OiPr)2Cl2 (1.2 eq.), toluene; (b) Me3O+BF4−, proton sponge, CH2Cl2, 3 A sieves; (c) (1) DDQ, CH2Cl2; (2) SO3-Pyr, DMSO, iPr2NEt,CH2Cl2; (d) 105, toluene, 60 °C; (e) 107, NaHMDS, THF, −78 °C; (f) MeOH (16 eq.), toluene, reflux; (g) TsOH, MeOH; (h) (1) TBAF, THF, 0 °C; (2) TBSCl,imidazole, DMAP, CH2Cl2; (i) (1) Bu3SnH, Et3B, benzene; (2) NBS, MeCN; (2) Ba(OH)2, MeOH, H2O.

O

OTESNBoc

O

CO2H

a

(79% over 3 steps) O

OTESNBoc

O

O

OBPS

N

O

OPMB

O

O

ONBoc

O

O

OBPS

N

O

OPMB

O

b

(87% over 2 steps)

P(OCH2CF3)2

O

O

c

(100% over 2 steps)

O

ONBoc

O

O

OBPS

N

O

O

O

P(OCH2CF3)2

O

O

O

OBocHN

HO

O

OBPS

N

O

O

O(115, 4:1 Z/E)

d

(75% over 2 steps)

e

(85% over 2 steps)

O

OHN

O

OBPS

N

O

O

OHOO

OMeO

BrMeO

OTBSMeO

f

(71% over 2 steps)O

O

O

OH

O

O

OHO

MeOOH

MeO

N

O

O

N

Br

d

(59% over 2 steps)

82 112

113

114

116 117

1

Scheme 14 (a) (1) 83, EDCl-Mel, HOBt, CH2Cl2; (2) Dess–Martin, NaHCO3, t-BuOH, CH2Cl2; (3) (CCl2Br)2, PPh3, DIPEA, CH2Cl2, RT; (b) (1) TBAF, THF;(2) 42, EDCl-Mel, HOBt, CH2Cl2; (c) (1) DDQ, pH 7 buffer, t-BuOH, CH2Cl2; (2) Dess–Martin, NaHCO3, t-BuOH, CH2Cl2; (d) (1) K2CO3, toluene, 18-c-6,RT, 3 h; (2) PTSA, MeOH; (e) TFA, CH2Cl2, then pH 7.4 buffer; (2) 81, PyAOP, i-Pr2NEt, CH2Cl2; (f) (1) Dess–Martin, NaHCO3, t-BuOH, CH2Cl2; (2)(CCl2Br)2, PPh3, i-Pr2NEt, CH2Cl2; (g) TBAF, EtOAc, THF; (2) aq HCl, THF.


231


Scheme 16) gave a nearly 8:1 diastereomeric ratio of 132. Nystedolefination and cyclization resulted in bis-pyran 135, which was thenprepped for the Wittig coupling. Sequential asymmetric crotylation ofglyceraldehyde 136 using Roush’s tartrate-derived methodology pro-duced 140 (Scheme 17), which was closed to the cis pyran using anintramolecular oxymercuration cyclization with good stereocontrol.Once the resultant iodide was transformed into a protected silyl ether,removal of the acetonide and periodate cleavage yielded ketone 144,which was adorned with the oxazole to complete the C20–C32 piece.The exocyclic pyran was generated from the Sharpless asymmetric

dihydroxylation of enoate 147 (Scheme 18). Upon extension to theallylic acetate, the primary TBS ether was converted to the corre-sponding aldehyde and subjected to a titanium silylketene acetaladdition with 4:1 selectivity at C35. Deprotection allowed selectiveδ-lactone cyclization, which led to 154. Methyl deprotonation andketalization was used to prepare 155 (Scheme 19), which underwentJulia olefination with 3 to C20–C46 fragment 118. Although its use inthe synthesis of the phorboxazoles was well established by Pattenden,

Lin and Zhou prepared 3 via dihydroxylation of bis-allyl ether 157 andWipf’s hydrozirconation protocol (Scheme 20). The synthesis of 2 wascompleted via Wittig coupling of the C19-C20 olefin and Horner–Wadsworth–Emmons macrocyclization (Scheme 21).

Total synthesis of 2 by Steven Burke. The Burke synthesis of 2(Figure 11) is a beautiful illustration of the use of two-directionalsynthesis.23 Readily available diol 171 was ozonolyzed and convertedto achiral tetraol 170 (Scheme 22). Palladium-catalyzed desymmetri-zation with Trost’s DPPBA ligand gave the bis-pyran 174 in 98% ee.Selective asymmetric dihydroxylation of the equatorial vinyl groupcompleted the desymmetrization, which was able to be oxidized tocarboxylate 177 and cyclized under Mitsunobu conditions to lactone178, thus differentiating the two secondary alcohols. Upon reductiveopening of the lactone, the exocyclic alkene was installed using theTebbe reagent to generate 180. Removal of the acetonide and selectiveprimary protection allowed for the introduction of nitrogen withdiphenylphosphoryl azide. Burke was the first to utilize an asymmetric

ON

O

O

MeO

MeO

BrMeO

OTIPS

N

O

O

O

BPSO

MsO

O

OPMB

O

OMe

OTIPSOTBSO

ON

OOPMB

OBPS

OTBS

N

OTBSO

O

OTBS

H

O OPMB

OBPS

O

118

119

120

121

122

123

3

2

Figure 10 Retrosynthetic analysis of Gua-Lin Qiang and Wei-Shan Zhou’s total synthesis of phorboxazole B.

O OPMB OPMB

OTBS

N

O

H

O

TBSO

OPMB

OTBSO

OPMB

OTBSO

N

O

OH

TBSO

N

OTBSO

O

O

OPMB HON

OTBSO OH

H

OPMB

a

(68% over 2 steps)

b

(89%)

d

(87% over 2 steps)

e

(65%)

(125, 87% ee)

c

(90% over 2 steps)

f

(82% over 3 steps)

N

OTBSO

O

OTBS

H

O

124 126

127

128

129 130 122

Scheme 15 (a) (1) (− )-lpc2BAIIyl, Et2O, −78 °C; (2) TBSCl, imidazole, DMF; (b) PdCl2 (cat.), CuCl, O2, DMF/H2O, RT, 6 h; (c) (1) LDA, 127, THF, −78 °C;(2) Dess–Martin, CH2Cl2, RT; (d) (1) HF in CH3CN, RT, 12 h; (2) TBSCl, imidazole, DMF, RT; (e) H2, 10% Pd/C, EtOAc (saturated with 0.1N HCl), 8 h (f)(1) TBSCl, imidazole, DMF; (2) DDQ, CH2Cl2, H2O; (3) Dess–Martin, CH2Cl2, RT.


232


O OBPS OBPS

OPMBa

(64% over 2 steps)

b

(86%)OBPS

OPMBOc

(68%)

O

OTBSO

N

OTBS

O

BPSO

O

OTBSO

N

OTBSHO

OOPMB

BPSO

(132, 7.8:1 dr)

O

OTBSO

N

OTBS

BzO

OPMB

BPSO

d

(66% over 2 steps)

O

OTBSO

N

OTBS

MsO

OH

BPSO

e

(67% over 3 steps)

f

(83%)

g

(73% over 2 steps)

O

OTBSO

N

OMs

O

BPSO

(131, 87% ee)

OZn Zn

Zn

Br Br

Nysted Reagent

14 123

133 134 135

119

Scheme 16 (a) (1) (+)-lpc2BAIIyl, Et2O, −78 °C; (2) PMBOC(=NH)CCl3, cyclohexane/CH2Cl2, BF3OEt2, 0 °C; (b) PdCl2 (cat.), CuCl, O2, DMF/H2O, RT, 6 h;(c) (1) LiHMDS, TMSCl, THF, −78 °C; (2) 122, TiCl4, −78 °C; (d) (1) BzCl, pyr, RT; (2) Nysted reagent, TiCl4, RT, 30 min; (e) (1) DIBAL-H, CH2Cl2, −78 °C; (2) MsCl, Et3N, CH2Cl2, 0 °C; (3) DDQ, CH2Cl2/H2O; (f) Et3N, MeCN, reflux; (g) (1) NH4F, MeOH, 50 °C; (2) DIPEA, MsCl.

OO

H

OO

O

OAc

OO

OAc

O OO

OH

OH

BO

O

R1

R3R2

R4

(-) 137: R1=R4=CO2iPr, R2=R3=H(+) 137: R1=R4=H, R2=R3=CO2iPr

OO

O

I

OH

b

(85%)

c

(70%)

a

(62% over 2 steps)

d

(86%)

(141, 5:1 dr)

OO

O

CN

OPMB

e

(64% over 2 steps) OO

O

OPMB

f

(72% over 2 steps)

OH

g

(53% over 4 steps)

O

OPMB

OBPS

O

h

(78% BORSM)

O

OPMB

OTBDPS

N

ON

O

PO(OMe)2

136 138 139 140

142 143

144145

121

Scheme 17 (a) (1) (− )-137, 4 Å MS, toluene, −78 °C, 7 h; (2) Ac2O, Et3N, DMAP (cat.), CH2Cl2, RT, overnight; (b) O3, MeOH, −78 °C; then PPh3, RT; (c)(+)-137, 4 Å MS, toluene, −78 °C, 6 h; (d) Hg(OAc)2, toluene, 0 °C, l2, 30 °C; (e) (1) PMBOC(=NH)CCl3, BF3OEt2, 0 °C; (2) NaCN, DMSO, 70 °C; (f) (1)DIBAL-H, CH2Cl2, 0 °C, then 1N HCl; (2) NaBH4, MeOH; (g) (1) TBDPSCl, Et3N, CH2Cl2; (2) HIO4, EtOAc; (3) MeLi, THF, −78 °C; (4) Dess–Martin,CH2Cl2, RT; (h) 145, LDA, THF, −78 °C.


233


hetero-Diels–Alder approach to the pentasubstituted pyran, installingfour of the centers in a single transformation in good yield andexcellent enantioselectivity (Scheme 23). Reduction of ketone 184 gavea solid that could be recrystallized to even higher enantiopurity, and

cyanation of the corresponding acetal afforded the axial nitrile, whichcould be methylated to ketone 187. Epimerization restored the desiredC26 equatorial orientation, and installation of the oxazole resulted inthe formation of the desired C20–C32 fragment.

OHHOa

(51% over 3 steps)OTBS

EtO2C b

(63% over 3 steps)OTBSHO

OPMB

OPMB

(148, 86% ee)

c

(84% over 2 steps)

OTBSOPMB

OPMBEtO2C

OTBSOPMB

PMBOd

(90% over 2 steps)AcO O

OPMB

PMBOe

(86% over 2 steps)AcO

OPMB

PMBOf

(74% over 2 steps)AcO

OMeCO2Et

(153, 4:1 dr)OTMS

OEt

g

(82% over 2 steps) HOOH

O

OMe

O

h

(59% over 2 steps) TBSOOTIPS

O

OMe

O

146 147

149 150 151

154

120

152

Scheme 18 (a) (1) NaH, TBSCl, THF, 0 °C; (2) PCC, CH2Cl2, RT; (3) Ph3P=CHCO2Et, benzene, reflux; (b) (1) AD-mix β, t-BuOH/H2O, RT; (2) PMBOC(=NH)CCl3, cyclohexane/CH2Cl2, BF3OEt2, 0 °C; (3) LiAIH4, Et2O, RT; (c) (1) (COCl)2, DMSO, CH2Cl2, −78 °C, then Et3N; (2) CH3CH(PPh3)CO2Et, CH2Cl2,reflux; (d) (1) DIBAL-H, CH2Cl2, −78 °C; (2) Ac2O, Et3N, CH2Cl2, RT; (e) (1) Bu4NF, THF, RT; (2) Dess–Martin, CH2Cl2; (f) (1) TiCl2(OiPr)2, toluene, −78 °C, then 152; (2) Me3OBF4, proton sponge, CH2Cl2, RT; (g) (1) K2CO3, EtOH; (2) 10% TFA, CH2Cl2, then Et3N; (h) (1) TBSCl, Et3N, CH2Cl2; (2) TIPSCl,AgNO3, pyr.

O

OPMB

OBPS

N

O

a

(50% over 2 steps)

O

OPMB

OBPS

N

O

O

MeO OTIPS

OH

MeOb

(73% over 2 steps)

O

OPMB

OBPS

N

O

O

MeO OTIPS

MeO

BrMeO

c

(71% over 2 steps)O

OPMBN

O

O

MeO OTIPS

MeO

BrMeO

O

121 155

156 118

Scheme 19 (a) (1) LiNEt2, THF, −78 °C, then 120; (2) PPTS, MeOH, 30 °C; (b) (1) Dess–Martin, CH2Cl2, pyr, RT; (2) 3, NaHMDS, THF, −78 °C; (c) (1)NH4F, MeOH, 50 °C; (2) Dess–Martin, CH2Cl2, pyr, RT.


234


The exocyclic pyran was also prepared using a hetero-Diels–Aldercyclization which, under europium catalysis, returned 191 as a singlediastereomer (Scheme 24). Hydrogenation set the C35 stereocenterand liberated the diol, which could be manipulated to selectivelyprotected 169. Lithiation of 121 and addition of 169 formed the C32–C33 bond (Scheme 25), and the peripheral triene moiety was realized

via the established Wittig/Julia methodology. Selective deprotection ofthe primary alcohol allowed the Wittig extension to α,β-unsaturatedacid 199, which was coupled to amine 168 to provide the oxazoleprecursor. Wipf cyclodehydration achieved the oxazole formation, andthe macrolide was closed via the Horner–Wadsworth–Emmonsolefination (Scheme 26). Desilylation completed the synthesis of 2.

TMSOH

OMeO

O

a, b

O

O

O

O

c

O

OOH

OH TMS

TMS

d

N

SHS

TMS

SS

NOMe

SS

NOMe

BrO

O

f, g

157 158 159

160

161

162 3

e

Scheme 20 (a) AD-mix-α, t-BuOH/H2O, RT, 87% ee, 66%; (b) (1) HBr, AcOH; (2) K2CO3, MeOH, 88%; (c) (1) TMSC2H, BuLi, BF3OEt2, THF, −78 °C; (2)Me3OBF4, proton sponge, CH2Cl2, RT, 70% for two steps; (d) CAN, CH3CN/H2O, RT, 91%; (e) 161, PPh3, DEAD, THF, 0 °C, 81%; (f) TBAF, THF, RT,99%; (g) (1) Cp2ZrHCl, THF; then NBS; (2) (NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, 56% for two steps.

O

OTBSO

N

OMs

O

TBDPSO

a


OPMB

N

O

O

MeOOTIPS

MeO

BrMeO

O

OTBSO

N

O

OH

O

OH

N

O

O

MeOOTIPS

MeO

BrMeO

O

OTBSO

N

O

O

b

(73% over 2 steps)

c


O

N

O

O

MeOOTIPS

MeO

BrMeO

O

OTBSO

N

O

O

d(51% over 2 steps)

(165, 5:1 Z/E)

119 163

164

2

Scheme 21 (a) (1) Bu3P, DMF, then 118, DBU, RT; (2) NH4F, MeOH, 50 °C; (b) (1) Dess–Martin, pyr, CH2Cl2, RT; (2) DDQ, CH2Cl2, pH 7 buffer; (c) (1)(EtO)2P(O)CH2CO2H, DCC, CH2Cl2; (2) K2CO3, 18-c-6, toluene, −20 °C; (d) TBAF, THF, RT; (2) 6% HCl, THF.


235


Additional synthetic approaches to the phorboxazolesPhorboxazole macrolide. Among the reported synthetic approachesto the phorboxazoles, only the Paterson group has published acompleted macrolide.10 The pentasubstituted pyran was assembledusing the anti-aldol addition of chiral ketone 204 to aldehyde 62,intramolecular Tishchenko reduction of the ketone and eventuallyMichael cyclization to the pyran (Scheme 27). The C5–C9 pyran wasprepared via the Michael allylation of enone 17 to set the requisitetrans-pyran with excellent diastereoselectivity (94% de) using allyltributylstannane (Scheme 28), and the subsequent aldehyde wasconverted into the corresponding acetylenic ester 211. Finally, theC9 side chain was deprotected and converted into siloxydiene 213 toset the stage for a second hetero-Diels–Alder cyclization. Following theWittig coupling of 214 to 209, this was achieved to provide a nearly1:1 mixture of diastereomeric pyrans 217 and 217a that provedresistant to improved diastereocontrol (Scheme 29). Reductionof ketone 218 followed by generation of the seco acid allowed forthe Yamaguchi macrolactonization developed by Evans and synthesisof 220.

The Hoffmann group recognized that the 8-oxabicyclo[3.2.1]octanering system mapped well onto the phorboxazole pyrans, and exploitedthat in their approach.24 Reduction of meso ketone 221 withL-Selectride and protection set the stage for the asymmetric hydro-boration of the olefin with diisopinocampheylborane to give 223 in96% ee (Scheme 30).25 Oxidation to the ketone and subsequentBaeyer–Villiger ring expansion provided 225, which underwentmethanolysis to provide pyran acetal 226. Allylation proceeded withexcellent trans selectivity (499% de), which set the stage for theelaboration to aldehyde 230. The C11 stereocenter was introduced viaasymmetric allylation, which allowed for the remaining elaboration ofC3–C13 fragment 233.Hoffmann’s approach to the pentasubstituted pyran started from

the racemic dimethylated bicycle 234 (Scheme 31).26 DIBAL reductionof the ketone and benzylation gave 235, which underwent asymmetrichydroboration to a mixture of 236 and 237. Both components ofthis mixture proved useful, as 236 was transformed into theC1–C7 portion of discodermolide while 237 was carried ontoward the phorboxazoles.27 Utilizing their PCC/Baeyer–Villiger

NH

O

OOPMB

O

ON

O

O

MeO

HO

BrMeO

OH OBPS

O O

O

OPMB

ON

O

O

MeO

HO

BrMeO

OH

TESO

O

O

OTES

OBPSH2N

O

O

MeO

OH

OMMTr OBPS

OPMB

ON

O

OAc

OH OH OH OH

OAc

166

167

168

169 121

170

3

2

Figure 11 Retrosynthetic analysis of Steve Burke’s total synthesis of phorboxazole B.


236


HO OHa

(42% over 2 steps)

OH OH OH OH b

(72%)

AcO OAc

OH OH OH OH

c

(75%)

O O

OHOH(174, 98% ee)

d

(68% over 2 steps)O

O

OAc

OAc

HO

HO e

(83% over 2 steps)O

O

OAc

OAc

O

O

HO

f

(91%)

O

O

OAc

OAc

O

O

OOH

g

(75% over 3 steps)

O

O

OBPS

O

O

OO

OAc OAc

h

(90% over 2 steps)

O

O

OH

OBPS

O

O

TESO

i

(72% over 2 steps)

O

O

OBPS

O

O

TESO

j

(70% over 3 steps)

O

O

OBPS

TESO

HO

TESO

O

O

OBPS

TESO

N3

TESO

k

(88%)

O

O

OBPS

TESO

H2N

TESO

l

(76%)

170171 172

173

175 176

177178 179

180 181 182 168

Scheme 22 (a) (1) O3, DMS, −78 °C to RT; (2) In, allyl bromide, H2O, RT, 24 h; (b) 173, Grubbs' second-generation, CH2Cl2:DMF (20:1), RT, 30 min; (c)Pd2dba-CHCl3 (2 mol%), (R,R),DPPBA (6 mol%), Et3N, CH2Cl2, 0 °C; (d) (1) Ac2O, DMAP, pyr, RT, 1 h; (2) AD-mix β, 0 °C, 3 h, (96% BORSM); (e) (1)2,2-DMP, PPTS (cat.), 1,2-DCE, 40 °C, 30 min; (2) disiamylborane, RT, 1.5 h, NaBO3, H2O, RT, 1.5 h; (f) RuCl3 (3 mol%), NalO4, 0 °C, 5 h; (g) (1) NaOH,MeOH, then Dowex CCR-3; (2) DIAD, PPh3, THF, 1 h; (3) TBDPSCl, Et3N, RT (h) (1) LiBH4, THF, 0 °C; (2) TESCl, 2,6-lutidine, CH2Cl2; (i) (1) Dess–Martin,CH2Cl2, RT, 4 h; (2) Cp2TiMe2, THF/toluene, 80 °C; (j) 1) PTSA, MeOH, 40 °C; (2) TESCl, imidazole, −78 °C; (k) DEAD, PPh3, N3-PO(OMe)2; (l) PPh3,H2O, THF, reflux.

O

OPMBMe Me

MeO

OBPS

O

OPMB

Me Me

NC

OBPS

O

OPMBMe Me

OBPS

O

Me

O

OPMBMe Me

OBPS

O

Me

MeO

MeOTES

Me

O

OBPS

O

O

Me Me

MeO

OBPSb

(81% over 2 steps)

c

(82%)

a

(77%)

d

(65%, 99% BORSM)

e

(77%)

f

(68%, 78% BORSM)

O

OPMB

Me

Me

OBPS

N

O

183

14

184 185

186 187

188 121

Scheme 23 (a) 16 (2 mol%), RT, 14 h, then HF/pyr/MeOH, −20 °C, 15 min; (b) (1) NaBH4, EtOH, −10 °C, 15 min (98.5% ee after recrystallization); (2)PMB-Cl, KH, RT, 2 h; (c) 0.5 eq. THM-OTf, TMS-CN, MeCN, 0 °C 2 h; (d) AIMe3 5% Ni(acac)2, 0 °C, 42 h; (e) KHMDS, LiCl, PhCH3, 55 °C 2 h, 91%; (f)145, LDA, THF, −78 °C to RT.


237


OTMSEtO

OMe

BnOOBn

O O

OMe

OBnOOBn

c

(71% over 2 steps)

a

(71%)

b

(85%) O

OMe

OHOOH

O

OMe

OMMTrOOBPS169

189190 191 192

Scheme 24 (a) [Eu(fod)3], CH2Cl2, 0 °C; (b) Pd-C, H2, EtOAc; (c) (1) MMTr-Cl, pyr, DMAP; (2) TBDPSCl, AgNO3, pyr, 50 °C.

d

(86%)

O

OPMB

Me

Me

OBPS

N

O

O

OPMB

Me

Me

OBPS

N

O

O

MeO

MeOOBPS

OH

a

(60% over 2 steps)

O

OPMB

Me

MeOBPS

N

O

O

MeO

MeOOBPS

b

(87% over 2 steps)

EtO2C

c

(87% over 2 steps)O

OPMB

Me

Me

OBPS

N

O

O

MeO

MeOOBPS

OHC

O

OPMB

Me

Me

OBPS

N

O

O

MeO

MeOOBPS

BrMeO

(197, 92:8 E/Z)

e

(81% over 2 steps)O

OPMB

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

f

(72% over 2 steps)

O

OPMB

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

OH

g


OPMB

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

O

O

OBPS

OH

NH

OH

EtO

OPPh3

121 193

194

195 196

198

199 200

Scheme 25 (a) (1) LiNEt2, 169, THF, −78 °C; (2) PPTS, MeOH; (b) (1) Dess–Martin, CH2Cl2; (2) 194, toluene, 80 °C; (c) (1) DIBAL-H, CH2Cl2, −78 °C;(2) Dess–Martin, CH2Cl2, 2,6-lutidine; (d) 3, NaHMDS, THF, −78 °C to RT; (e) (1) PTSA, MeOH, MeOH; (2) Dess–Martin, CH2Cl2; (f) (1) Ph3PCHCO2Et,toluene, 80 °C; (2) LiOH, THF/MeOH/H2O (4:1:1); (g) 168, EDC-Mel, HOBt, CH2Cl2.


238


protocol, Hoffmann synthesized 238, which was elaborated toacrylonitrile 241 and subjected to rhodium catalyzed oxazole cycliza-tion. Finally, LAH reduction simultaneously reduced the oxazole β-methoxy substituent and the ester to provide the C15–C26 fragment.Yadav initiated his synthetic approach to the macrolide portion

from vinyl furan 244, readily available from D-glucose (Scheme 32),28

which provided the C13 and C15 stereocenters of phorboxazole A.29 Itis notable that D-galactose would correspond to the phorboxazole B

stereochemistry. Upon opening the furan, the olefin was extended viaa hydroboration/oxidation/Wittig sequence, and Michael addition ofthe secondary alcohol of 249 formed cis-pyran 250. Asymmetricallylation followed by acylation with acryloyl chloride gave 252, whichwas closed with first-generation Grubbs catalyst to lactone 253.Reduction to the ethyl acetal and Lewis acid mediated allylationyielded expected trans-pyran 255, which represents the C2–C16portion of phorboxazole A.

ON

H

O O

OPMB a

f

ON

OH O

OPMB ON

O OTBS

OHb, c

hO

N

O OTBS

O

iPr

O

iPr

d, e O

OMe

ON

OH OTBS

OHO

N

O

OTBS

H

O

(94%, > % ds) (65% over 3 steps)

(91%)(86%) (81%, 80% ds)

62 204 205 206

207 208 209

Scheme 27 (a) (c-Hex)2BCl, Et3N, Et2O, 0 °C, 1 h; 62, −78 to −20 °C, 18 h; H2O2, MeOH, pH 7 buffer; (b) Sml2 (30 mol%), iPrCHO, THF, −20 °C; (c)(1) TBSCl, Imidazole, DMAP, DMF, 80 °C, 50 h; (2) DDQ, 20:1 CH2Cl2/H2O, 20 °C; (d) (COCl)2, DMSO, −78 °C, 10 min, −78°C, 1 h; Et3N, −78 to −40 °C, 40 min; (e) LiCl, DBU, (MeO)2P(O)CH2CO2Me, 4:1 CH3CN/CH2Cl2, 20 °C, 2.5 h; (f) DIBAL, CH2Cl2, −78 °C, 5 h; (h) SO3-pyr, Et3N, 2:1 CH2Cl2/DMSO,0 °C, 2 h.

O

OPMB

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

O

O

OBPS

OH

NH

OH

a

(71% over 2 steps)

O

OPMB

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

O

O

OBPS

N

O

b

(71% over 2 steps)O

O

Me

Me

N

O

O

MeO

MeOOBPS

BrMeO

O

O

O

OBPS

N

OO

P(OMe)2O

c

(93%)

(203, 3:1 Z/E)

O

O

N

O

O

MeOOBPS

MeO

BrMeO

O

OBPSO

N

O

O

200 201

202

d(61% over 2 steps)

2

Scheme 26 (a) (1) Dess–Martin, CH2Cl2; (2) 2,6-DBMP, PPh3, (CCl2Br)2, 0 °C, then DBU, MeCN, RT; (b) (1) DDQ, CH2Cl2, pH 7 buffer; (2) DIC, (MeO)2P(O)CH2CO2H, CH2Cl2; (c) K2CO3, 18-c-6, toluene, −40 °C to RT; (d) (1) TBAF, THF; (2) 0.72 N HCl, THF RT, 60 h.


239


O

O

BPSO

O

BPSO

a, b

H O

O

BPSO

c

Br

d

O

BPSO

MeO O

O

O

MeO O

H

e

O

MeO O

f, g

TESO

(86% over 5 steps) (98%, 2 steps) (86%)

(85% over 2 steps) (85% over 3 steps)

17 19 210

211 212 213

Scheme 28 (a) (1) H2C=CHCH2SnBu3, TMSOTf, CH2Cl2, −78 to −50 °C; (2) TBAF (1 M THF). AcOH (10:1, v/v), THF, 0 °C; (b) (1) OsO4 (4 mol%), NMO,t-BuOH-THF-H2O (4:4:1); (2) Ph3P=CH2, THF, −40 to −20 °C; (3) Pb(OAc)4, Na2CO3, CH2Cl2, 0 °C to RT; (c) (1) CBr4, Ph3P, CH2Cl2, −10 °C; (2)NaHMDS, THF, −98 °C; (d) (1) n-BuLi, THF, −78 °C, (2) MeOC(O)Cl, HMPA; (e) (1) HF. py, MeCN, 0 °C; (2) DMP, CH2Cl2; (f) MeC(O)CH2P(O)(OMe)2, Ba(OH)2·xH2O, THF; (g) TESOTf, Et3N, Et2O, 0 °C.

ON

O

OTBS

N

OCHO

b

cO

O

OMeO

OTES

O

NO

OTES

O

O

OMeO

O

O

N

ON

O

OTBS

e, fO

O

OHO

OBPS

O

N

ON

O

OH

O

O

OBPS

O

N

ON

O

O

O

(88%)

(36%, 55% BORSM)

(82% over 4 steps)

N

OBu3P

CO2tBu

a

ON

O

OTBS

N

OCO2

tBu

(91%, 89:11 E/Z)

214 215

ON

O

OTBS

d

(92%)

g

(92%)

216

217 218

219 220

217a

Scheme 29 (a) LiHMDS, DMF, 0 °C, 30 min, then 209, DMF, 0 °C, 1 h; (b) DIBAL-H, CH2Cl2, −78 °C; (c) 213, HDA cat. (10 mol%), 4 A molecular sieves;(d) TBAF-AcOH (1:2, mol/mol), THF, 0 °C; (e) LiAI(OtBu)3H, THF, −78 to −10 °C (2) BPSCl, imidazole, DMF; (f) conc. HCl (1%), MeOH; (2) LiOH . H2O,THF, H2O; (g) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, (2) DMAP, PhMe.


240


Yadav also prepared the pentasubstituted pyran from the8-oxabicyclo[3.2.1]octane ring system, starting from the asymmetrichydroboration of achiral dimethylated derivative 256 (Scheme 33).30

Ring opening of Baeyer–Villiger lactone 258 revealed pyran 259 which,

upon protection of the C20 Wittig precursor as a benzyl ether, wasoxidized to lactone 262. This allowed for the epimerization of the C25methyl using DBU with excellent selectivity and conversion. The C27side chain was then introduced via acetylenation, and hemiketal

O

O

O

HO OPMB

O

O OPMB

O

OPMBOO O

OPMB

MeOCO2Me

O

OH

CO2Me

O

OPMB

b ca d

e f

(85%)

(223, 96% ee)

(92%) (96%)

(91%) (85%)

(227, 96% de)

g

(97%) O

OTIPS

CO2Me

h

(88%) O

OTIPS

CH2OTBS

i

(100%) O

OTIPS

CH2OTBSCHO

221 222 224

225 226 228

229 230

j

(72%) O

OTIPS

CH2OTBS

k

(93%)

OH

(231, 92% de)

O

OTIPS

CH2OTBS

OTBS l

(98%)O

OTIPS

CH2OTBS

OTBSO

232 233

Scheme 30 (a) (1)24; (2) NaH, PMBCl, (n-Bu)4Nl, THF, reflux, 6 h; (b) (+)-lpc2BH, THF, −10 °C, 1 week; (c) PCC, DCM, RT, 5 h; (d) m-CPBA DCM, RT,overnight; (e) MeOH, conc. H2SO4 (cat.), RT, overnight; (f) allyltrimethylsilane, TMSOTf, MeCN, −20 °C to RT, 1 h; (g) TIPSCl, imidazole, DMF, RT, 16 h;(h) (1) DIBAL-H, −20 °C, THF, 2 h; (2) TBSCl, imidazole, DMF, RT, 16 h; (i) O3, DCM, −78 °C then PPh3 (j) (− )B-allyl-β-diisopinocampheyl-borane,toluene, −78 °C, 5 h then H2O2, NaOH; (k) TBSOTf, 2,6-lutidine, DCM, 0 °C, 30 min; (l) O3, DCM, −78 °C then PPh3.

O

O

Oa

(85%) OBn

b

(93%)

O

OBnHO

c

(82%)

O

O OBn

O

(237, > 95% ee)

d

(84%)

OMeO

OBn

CO2Me e

(71%)

OMeO

OBn

CHO f

(85%)

OMeO

OBn

CN

(241, 9:1 E/Z)

g

(61%)

OMeO

OBn

N

O

CO2Me

OMe h

(49%)

OMeO

OBn

N

O

CH2OH

(±) 234 (±) 235

239 240

242 243

O

OBnHO

236 238

Scheme 31 (a) (1) DIBAL-H, THF, −78 °C, 11 h; (2) NaH, THF, BnBr, reflux, 16 h; (b) (− )-(lpc)2BH, THF, −10 °C, 14 d, then NaOH, H2O2, 3 h; (c) (1)PCC/SiO2, DCM, RT, 15 h; (2) m-CPBA, NaHCO3, DCM, RT, 15 h; (d) H2SO4 (cat.), MeOH, 16 h; (e) (1) DIBAL-H, THF, 0 °C, 4 h; (2) PCC, DCM, RT, 15 h;(f) Ph3PCHCN, toluene, LiCl, RT, 20 h; (g) N2C(CO2Me)2, Rh2(OAc)4, CHCl3, 15 h, reflux; (h) LiAIH4, THF, −78 °C, 3 h.


241


reduction gave the elaborated pyran as a single isomer. Oxymercura-tion then gave ketone 265. The oxazole was introduced via a modifiedJulia olefination of 265 with sulfone 266 (Scheme 34), giving C20–C32fragment 267 as a 9:1 mixture of olefin isomers.The synthesis of the bis pyran was also achieved by the Rychnovsky

group using their expertise with the Prins reaction.31 Epoxide 268 wasopened with the lithium anion of 269 to give diol 270, which wassmoothly closed to the pyran and extended to trans thioester 273(Scheme 35). The C11 stereocenter was formed via reduction to thealdehyde and asymmetric allylation. Acylation of the C11 alcohol withoxazole 275 and conversion to the α-acetoxyether generated the Prinsprecursor, which proceeded as expected to the cis-pyran, representingthe C3–C19 portion of phorboxazole B. Rychnovsky showed that thePrins cyclization could also be achieved to install the C11 stereocenter,but the yields were diminished presumably due to the proximity of theoxazole nitrogen.The Prins reaction was also used by Rychnovsky to make the

pentasubstituted pyran as well.32 Asymmetric crotylation of aldehyde14 with 278 gave 279 in 98% ee (Scheme 36), setting the C22stereocenter. Acylation with protected lactic acid yielded 281, whichwas transformed into Prins precursor 282 in standard fashion. Thiscyclization proceeded as expected with catalytic BF3 etherate to set theremaining stereocenters of the pyran. Elaboration to ketone 284 wasfollowed by Horner Wadsworth Emmons olefination to afford theC20–C29 fragment as a 3.9:1 mixture of olefin isomers.The Clarke group also used the macrolide pyrans as a showcase for

their work on the asymmetric Maitland–Japp reaction. Toward thisend, diketene was able to be coupled to aldehyde 287 (setting the C11stereocenter) and oxazole aldehyde 61 in a one-pot transformation

using Ti(IV) and chiral ligand 295 to prepare pyranone 289 as amixture of C15 epimers in 73% ee (Scheme 37).33 The trans isomercould be converted to the desired cis isomer with Yb(OTf)3.Decarboxylation, reduction and protection thus gave pyran 290, whichwas converted to the aldehyde and subjected to a second Maitland–Japp reaction using Chan’s diene and Evans’ pybox ligand, whichestablished the trans pyran ring with excellent stereocontrol andcomplete enantiomeric enrichment. Once the exocyclic olefin at C7was introduced, the primary alcohol was liberated and activated fordisplacement with an acetylenic anion. Radical bromination of theoxazole methyl finally gave C1–C19 fragment 294 functionalized forfurther elaboration.Clarke’s initial efforts to utilize the Maitland–Japp reaction to

generate the pentasubstituted pyran resulted in a C23-epimericproduct, so he ultimately initiated his synthesis of the remainder ofthe macrolide fragment using the anti-aldol addition of 296 to 62(Scheme 38).34 Reductive removal of the chiral auxiliary followedsilylation of the C26 alcohol, which allowed for outstanding Felkin–Ahn control of the subsequent crotyl addition. Acrylate 300 was addedvia a metathesis reaction, which set the stage for the Michaelcyclization (13:1 selectivity) to the C20–C32 fragment.Taylor was able to demonstrate that his electrophile-induced ether

transfer methodology allowed access to the bis-pyran portion of 1(Scheme 39).35 Ether transfer of the BOM-protected analog of 28 withICl conferred the C5 stereocenter with exquisite control (20:1), andthe subsequent sulfone (303) could be cyclized and allylated to thetrans pyran nearly quantitatively. Following elaboration to aldehyde305, allylation gave a 1:1 mixture of C11 alcohols that could beseparated and completely converted into the desired 306 via

OOH

OH

OH

OH

HO

D-Glucose

aO

O

O b

(67% for 2 steps)

OH

OH OH

c

(73% for 2 steps)O

OBn O

OOBn O

HOd

(80%)

e

(72% for 2 steps)

OOBn O

EtO

O

f

(91%)HO

OBnHO

OEt

O

O OEt

O

MOMO

OBn

g

(74% for 2 steps) OMOMO

OBn

OH

h

(67% for 2 steps)

i

(93%) OMOMO

OBn

O O

j

(94%) OMOMO

OBn

O O

k

(86%) OMOMO

OBn

O OEt

l

(85%)

OMOMO

OBn

O

11

244 245 246

249248247

251252

255254253

(250, 20:1cis/trans)

Scheme 32 (a)27; (b) (1) 50% AcOH, H2SO4 (cat.), 2 h; (2) NaBH4, MeOH, 0 °C to RT, 1 h; (c) (1) PTSA (cat.), acetone, RT, 3 h; (2) NaH, BnBr, THF,reflux, 8 h; (d) BH3-DMS, NaOH, H2O2, THF, 8 h; (e) (1) IBX, THF, DMSO, RT, 2 h; (2) Ph3P=CHCO2Et, benzene, RT, 12 h; (f) CSA, MeOH, RT, 2 h; (g)(1) NaH, THF, −78 °C, 4 h; (2) iPr2NEt, MOMCl, CH2Cl2, 0 °C, 6 h. (h) (1) DIBAL-H, CH2Cl2, −78 °C, 1 h; (2) (+)-allyl diisopinocampheylborane, Et3N,H2O2, 1 h; (i) iPr2NEt, acryoyl chloride, CH2Cl2, 0 °C to RT, 4 h; (j) Grubb's 1st gen., Ti(iOPr)4, CH2Cl2, 60 °C, 6 h; (k) DIBAL-H, CH2Cl2, −78 °C, 30 minthen CSA, EtOH; (l) allyltrimethyl silane. TMSOTf, CH2Cl2, 0 °C, 1 h.


242


OBn

Oa

OBn

O

HOO

OBn

O

b O c

(85%) O

OBn

OMeMeO

O

O

OBn

OMeBnO

d

e

(55% for 2 steps) O

OBn

OBnO

f

(95%) O

OBn

OBnO

g

(90%)O

OBn

BnOOH

TMS

h

(85%) O

OBn

BnOTMS

i

(70%)O

OBn

OBn

O

(257, 96% ee)256 258 259

260 261 262 263

264 265

Scheme 33 (a) (− )-lpc2BH, THF, −23 °C, 24 h, NaOH (3N), 30% H2O2, RT, 6 h; (b) (1) PCC, CH2Cl2, RT, 3 h; (2) m-CPBA, NaHCO3, CH2Cl2, RT, 10 h;(c) H2SO4-MeOH, 0 °C to RT, 12 h; (d) (1) LiAIH4, THF, 0 °C to RT, 6 h; (2) BnBr, NaH, THF, RT, 12 h; (e) (1) AcOH-H2O (3:2), 55 °C, 15 h; (2) PCC,NaOAc, celite, RT, 3 h; (f) DBU, THF, RT, 12 h; (g) n-BuLi, TMS-acetylene, THF, −78 °C, 1.5 h; (h) Et3SiH, BF3-Et2O, MeCN/CH2Cl2 (1:1), −40 °C, 2 h;(i) HgO, H2SO4, acetone, 50 °C, 1 h.

N

O

CHOa

(80%) N

O

S N

S

OO

b

(70% BORSM)

O

OBn

OBn

N

O(267,9:1 E/Z)

61

266

Scheme 34 (a) (1) 161, PPh3, DEAD, THF, RT, 12 h; (2) oxone, THF-MeOH-H2O (2:1:1), 12 h; (b) NaHMDS, THF, −78 °C to RT, 4 h; 265.

BnO

TBSO Br

OH

OH

BnO

Oa b

BnO

O

OAc

c

t-BuS

OTMS

(50% from 268) (79%)

d

BnO

O

HOe

N

O CO2H

Cl BnO

O

O

OAc

ON

Cl

f

BnO

O

t-BuS

O

BnO

O

OAc

OON

Cl(72%) (78%) (56%)

268 269 270 271

272

273

274 276 277

275

Scheme 35 (a) (1) n-BuLi, BF3OEt2, THF, −94 °C; (2) TBAF, THF; (b) (1) IBX, DMSO; (2) Ac2O, DMAP, pyridine; (c) TMSOTf, 272, CH2Cl2, −78 °C; (d)(1) DIBAL-H; (2) (− )-lpc2B-allyl, Et2O, −100 °C; (3) NaOH, H2O2; (e) (1) 275, DCC, DMAP; (2) DIBAL-H; (3) Ac2O, DMAP, pyridine; (f) (1)TMSBr, CH2Cl2;(2) CsOAc, 18-c-6, benzene.


243


Mitsunobu inversion. Ether transfer again selectively introduces theC13 stereocenter of phorboxazole A, and cyclization leads to the C3–C17 fragment 308.Donaldson also explored the use of a hetero-Diels–Alder approach

to the phorboxazoles (Scheme 40).36 Allylation of acetal 309provided the trans pyran, and the resulting aldehyde was subjectedto asymmetric allylation to create the separable diasteromers 314 and315. The initial attempts to elaborate the second pyran via another

hetero-Diels–Alder reaction proved possible but ultimately not asproductive. Acryloylation of 314 followed by RCM gave the C3–C15fragment.The Panek group used their crotylsilane chemistry to approach the

phorboxazoles.37 Treatment of 317 (available in any isomeric form viaSharpless epoxidation) with aldehyde 318 gave cis-pyran 319 (Scheme41) as a single diastereomer. Epoxidation and reduction of the ester setthe stage for the selective methylation, which was achieved in excellent

OB O

MeMe

Cy

Cy c

OBPS

OHb

(279, 98% ee)CO2H

OBn

O

O

OBPS

OBn

O

OAcBnO

a

O

OAc

OBPS

BnO

d

OBPS

eO

OAc

OBPS

O

fO

OAc

OBPS

EtO2C

(70-91%)

(52%) (98%)

(285,73%, 3.9:1 E/Z)

(53% from 14)

278

280

281

282 283 284

Scheme 36 (a) 14, 0 °C 3 d; (b) DCC, CH2Cl2, 280, (c) (1) DIBAL-H, −78 °C, (2) Ac2O, pyr, DMAP; (d) 0.1 eq. BF3OEt2, HOAc, hexanes, 140 min, 0 °C;(e) (1) H2, Pd(OH)2/C; (2) Swern Ox.; (f) KHMDS, (EtO)2P(O)CH2CO2Et, THF, 25 °C.

OO

H

O

OBn

tBu

tBuOHN

Ph

OH

iPr

MeO

O O OH

BnO

a

OON

OBn

OMeO2C

(289, 73% ee)

b

288

OON

OBn

OTIPS

(78% over 3 steps)

OON

O

OTIPS

H

c

(100% over 2 steps)

d, e OON

OTIPS

O

OBn

O

f OON

OTIPS

O

OH

g OON

OTIPS

O

CONHPh

h OON

OTIPS

O

CON(Ph)Boc

(52% over 2 steps) (51% over 2 steps)

Br

(291, 99% ee)

(68%) (81%)

286 287

290

290 292

293 294295

(70%)

Scheme 37 (a) Ti(OiPr)4, 295, MeOH, CH2Cl2, −78 °C, then 61, TiCl4, −78 °C to RT; (b) (1) DMF, H2O, mw (300 W), 160 °C, 10 min; (2) NaBH4, MeOH,0 °C, (3) TIPSCl, imidazole, DMF, 50 °C; (c) (1) 10% Pd-C, H2, MeOH; (2) Dess–Martin, CH2Cl2; (d) ent-288, TiCl4, CH2Cl2, −20 °C to RT; (e) DMF, H2O,mw (300 W), 160 °C; (f) (1) 10% Pd-C, H2, MeOH (2) Ph3PCH3

+Br−, LDA, THF; (g) (1) Tf2O, pyr; (2) PhHNOCCCH, LDA, THF; (h) (1) Boc2O, pyr, DMAP,CH2Cl2; (2) LDA, NBS, THF, −100 to −78 °C.


244


yield to give the fully substituted pyran 322 that was subsequentlyelaborated to C19–C28 fragment 326. Panek also demonstrated aunique way of installing the exocyclic oxazole to a related fragment viaa Stille coupling to triflate 330 (Scheme 42).38 It is clear that thisstrategy was also the plan for introducing the other oxazole based onthe C19–C20 hydrostannylation.Chakraborty prepared the pentasubstituted pyran from aldehyde

332 starting with an asymmetric aldol addition (Scheme 43).39

Sharpless epoxidation installed the C22 stereocenter, but the radical-mediated ring opening gave a considerable amount of olefin 336 inaddition to the anticipated 337. The mixture could be completely con-

verted into the desired 337 via hydrogenation, which could be efficientlyconverted into alcohol 339. Upon oxidation to the aldehyde, acetylena-tion gave a mixture of diastereomeric propargyl alcohols, which couldbe closed to give 341 as well as the C26 epimer in a 2:1 ratio.Nagaiah synthesized the pyran from the proline-mediated aldol

addition of propionaldehyde to D-mannitol-derived glyceraldehyde136 (Scheme 44).40 Wittig elongation and reduction to the allylicalcohol provided the Sharpless epoxidation substrate, which wasopened to diol 346. Selective primary alcohol oxidation and anotherWittig elongation allowed for the Michael cyclization and generationof C20–C27 fragment 348.

Ph

O

O

O

N CHO a

O

N

OH

O

O Ph

NSO2MesBn

NSO2MesBn

(91%)

b

O

N

TBSO OH

(76% over 2 steps)

c

(80% over 2 steps)

O

N

TBSO OHd

S

O (68%)O

N

TBSO OH O

Sp-Tole

O

N

O

OH

COSp-Tol

(302, 13:1 dr)

62

296

297 298

299

300

301

Scheme 38 (a) 296, Et3N, (c-hex)2BOTf, CH2Cl2, −78 °C, 3 h, then 62; (b) (1) TBSOTf, 2,6-lutidine, CH2Cl2, 1 h; (2) DIBAL-H, CH2Cl2, 0 °C, 15 min; (c)Dess–Martin, CH2Cl2, 0 °C to RT, 1 h; (2) E-crotylboronic pinacol ester, hexane, 0 °C to RT, 17 h; (d) 301, Grubb's second generation (30 mol%), Cul(20 mol%), Et2O, reflux, 3 h; (e) TFA, CH2Cl2, H2O, RT.

OBPS

OH a

(46% over 3 steps) OBPS

OI

OBn

SO2Ph

b

(96% over 2 steps)

(303, >20:1 dr)

O

OBn

OBPS

c


OTBS

O OBPS

d

(81% over 2 steps)(after stereoinversion)

O

OTBS

OBPS

OH e

(45% over 3 steps)

O

OTBS

OBPS

OI

OBn

PhO2S

f

(41% over 3 steps)

O

OOTBS

BPSO

OBn

28 (304, >20:1 dr)

305 306

307 (308, >20:1 dr)

Scheme 39 (a) (1) BOMCl, DIPEA; (2) lCl, PhSH, Et3N; (3) TPAP, NMO; (b) (1) LiHMDS; (2) AICl3, AllylTMS; (c) (1) Li/NH3; (2) DDQ; (d) (3) TBSCl,imidazole; (4) O3, PPh3; (d) (1) allylMgBr; (49% of correct diastereomer) (2) DEAD, PPh3, p-NBA, K2CO3, MeOH (recycled 46% of unwanted diastereomer);(e) (1) BOMCl, DIPEA; (2) ICl, PhSH, Et3N; (3) (NH4)6Mo7O24-4H2O, H2O2; (f) (1) LiHMDS; (2) NaHMDS, allyl iodide, MeOH; (3) TMSOTf, Et3SiH.


245


Exocyclic fragments. In addition to completing the macrolide, Pater-son also completed the entire exocyclic portion of thephorboxazoles.10 Mukaiyama aldol addition of 101 to 349 usingEvans’ pybox catalyst installed the C37 stereocenter in 495% ee, andacid-catalyzed lactonization gave β-ketoester 351 (Scheme 45). Hydro-genation of the corresponding vinylogous carbonate simultaneously

installed the C35 center and liberated the primary alcohol, which wasoxidized to aldehyde 354. Meanwhile, the triene was formed fromasymmetric acetate aldol addition to aldehyde 357 (Scheme 46) in astraightforward manner. The Nozaki–Kishi addition of 362 to 354proceeded to give the fully elaborated C33–C46 fragment, though thereaction proceeded in disappointing yield and selectivity. The mixture

O

O

BPSO

a

(69%)

O

O

BPSO

OMe

b

(92%)

O

OH

BPSO

OMe

H H H

d

(73%)

O

OAc

BPSO

OMe

Hc

(92%)

O

OAc

BPSO

H

H

e

(89%)

O

OAc

BPSO

H

OHCH

O

OAc

BPSO

H

Hf

HO

O

OAc

BPSO

H

HHO

(42%) (41%)

(±) 17 (±) 309 (±) 311

(±) 312 (±) 313 315314

(±) 310

g

h

O

OAc

BPSO

H

HOO

O

OAc

BPSO

H

HOO

(52%)

(73%)

316317

Scheme 40 (a) Hg(OAc)2, MeOH, NaBH3CN, THF; (b) LiAI(OtBu)3, THF; (c) Ac2O, NaOAc, (d) TMS-allyl, TMSOTf, CH3CN; (e) O3, CH2Cl2, −78 °C, PPh3;(f) (− )-(lpc)2B-allyl, toluene, −78 °C, salt-free then NaBO3, toluene, H2O; (g) H2C=CHCOCl, Et3N, DMAP; (h) Grubb's cat. (0.2 eq.), Ti(iPrO)4.

CO2Me

OTES

SiMe2Ph O

TIPS

MeO2C

a

(60-70%)

O

TIPS

MeO2CO

b

(85%, dr = 13:1)

c

(92%)

O

TIPS

OH

OH

O

TIPS

OOH

OO

OHTIPS

Me-

O

TIPS

OH

OTf

eO

TIPS

OH

f

(80% for 3 steps)

TMS

d

(>90%)

O

TIPS

OH

TMS

g

(86%, dr = 8:1)

O

TIPSOTMS

h

(70% for 3 steps)

SnBu3

H

O

TIPS

317

318

319 320 321

322323324325326

Scheme 41 (a) TMSOTf (0.5 eq.), CH2Cl2, 20 °C; (b) m-CPBA, CCl4, RT; (c) LiAIH4, THF, 0 °C; (d) CH3MgBr/Cul, THF, 0 °C; (e) Tf2O, pyr, CH2Cl2, −15 °C; (f) (1) TMSOTf, 2,6-lutidine; (2) LDA, THF, TMS-acetylene, HMPA, −10 °C; (g) (1) Dess–Martin, CH2Cl2, RT; (2) LiAIH4, THF, 0 °C; (h) (1) TMSOTf, 2,6-lutidine; (2) NBS, AgNO3; (3)Bu3SnH, PdCl2(PPh3)2.


246


O

NO

Phb

(90%)

PhOTf

N

O

OOTBS

TBSO

a

(70%)

OOTBS

TBSO

c

(60%)

OOTBS

TBSO

N

OPh

Me3Sn

327 328

329 330

331

Scheme 42 (a) (Me3Sn)2CuCNLi2, THF, −78 °C; then Mel, DMPU, −78 °C to RT; (b) Tf2O, Et3N, THF, −78 °C; (c) Pd2(dba)3-CHCl3 (6 mol%), P(t-Bu)3(12 mol%), LiCl, NMP, 60 °C.

BnOCHO

N O

S

Bn

O

a

(53% over 3 steps)

BnO

OH

OBPSBnO

OH

OBPSb

(81%)

O

(335, 83% dr)

BnO

OH

OBPSc

OH

d

(65% over 2 steps)

BnO

OH

OBPS

OH

e

(56% over 2 steps) OH

OBPS

OO

f

(58% over 3 steps)

OTBSOO

g

(76% over 2 steps)

TMS

OH

g

(76% over 2 steps)

O

OTBS

OH

TMS

OTBS

OH

OO

O

OTBS

OH

TMS(37%) (21%)

332 333 334 336

337 338 339

340 341 342

Scheme 43 (a) (1) 333, TiCl4, DIPEA, CH2Cl2, −78 to 0 °C, 0.5 h then 332, −78 to 0 °C, 1 h; (2) NaBH4, EtOH, 0 °C, 15 min; (3) TBDPSCl, Et3N,DMAP, CH2Cl2, 0 °C to RT, 4 h; (b) Ti(Oi-Pr)4, (− )-DIPT, TBHP, CH2Cl2, 4 Å MS, −20 °C, 3 h; (c) Cp2TiCl2, Zn, ZnCl2, THF, −20 °C to RT, 12 h; (d) H2,10% Pd-C, CH3COONH4, MeOH, RT, 0.5 h; (e) (1) H2, Pd-C, MeOH, RT, 24 h; (2) 2,2-dimethoxypropane, CSA, CH2Cl2, 0 °C, 1 h; (f) (1) TBAF, THF, 0 °Cto RT, 4 h; (2) TBS-OTf, 2,6-lutidine, CH2Cl2, 0 °C, 0.5 h; (3) HF-pyr, THF, 0 °C to RT, 18 h; (g) SO3-pyr, Et3N, DMSO:CH2Cl2 (2:1.6), 0 °C, 0.5 h; (2)TMS-acetylene, n-BuLi, THF, −78 °C to RT, 1 h, then aldehyde, 0 °C, 15 min; (g) (1) MsCl, DMAP, pyridine, 0 °C, 0.5 h; (2) CSA, CH2Cl2, 0 °C to RT, 3 h.

O

HOO

a

OH

OO

H

O

(343, 90:10 syn/anti)

b

(76% over 2 steps)

OH

OO

COOEtOTBS

OO

OHc

(82% over 2 steps)

d

(53% over 2 steps)

TBSO

OO

OH

OH

e

(70% over 2 steps)

TBSO

OO

OH

OEt

O

f

O

CO2Et

OHOO

136 344 345

346 347 348

Scheme 44 (a) L-proline, EtCHO, DMF, 4 °C, 36 h; (b) Ph3P=CHCOOEt, benzene, 80 °C, 12 h; (c) (1) TBSOTf, 2-6,lutidine, CH2Cl2, 0 °C, 1 h; (2) DIBAL-H, CH2Cl2, −78 °C to RT, 4 h; (d) (1) (− )-DIPT, Ti(iPrO)4, TBHP, CH2Cl2, −20 °C, 10 h; (2) MeLi, Cul, Et2O, −20 °C, 6 h; (e) (1) TEMPO, BAIB, CH2Cl2,RT, 1 h; (2) Ph3P=CHCOOEt, benzene, 80 °C, 12 h; (f) TBAF, THF.


247


BnOO

H a, bO O

O

OHBnO(87% over 2 steps)

(350, ee >= 95%)

c

(99%) OBnO

O

O

d

(99%)

OBnO

O

OMe

e

(84%) OHO

O

OMe

f

(88%) OO

O

OMe

H

349 351

352 353 354

Scheme 45 (a) 101, [Cu((R,R)-Ph-pybox)]-(SbF6)2 (8 mol%), CH2Cl2, −98 °C to −78 °C; (b) PPTs, MeOH; (c) K2CO3, MeOH; (d) (MeO)2SO2, K2CO3,acetone; (e) H2, Pd-C, EtOAc; (f) Swern oxidation.

HO I a, b

(82% over 2 steps)IN

MeOO

IH

Oc

(95%)

I

OH

NS

O

d

(96%)

NS

O

O

O(359, R/S > 97:3)

I

OMeO

NMeOe

(72%)I

OMeOf

(94%)H I

OMeg, h

(99% over 2 steps)(7.5:1 E/Z)

Br

355 356 357

358

360 361 362

i

(29%)

OMeBr

O O

OMe

OH

(363, 1:3.4 dr)

j

(58%)

OMeBr

O O

OMe

O

364

Scheme 46 (a) MnO2, CH2Cl2; (b) MeON(Me)C(O)CH2,P(O)(OEt)2, LiCl, DBU, MeCN-CH2Cl2 (3:1); (c) DIBAL-H, THF, −78 °C; (d) (1) 358, Sn(OTf), N-ethylpiperidine, CH2Cl2, −40 °C, (2) 357, −98 to −78 °C; (e) (1) MeNHOMe.HCl, ImH, CH2Cl2; (2) Mel, Ag2O, Et2O, reflux; (f) DIBAL-H, THF, −78 °C; (g)nBu3SnCHI2, CrCl2, DMF; (h) NBS, MeCN, 0 °C; (i) NiCl2-CrCl2 (10:1), tBuC5H4N, THF; 354; (j) TPAP, 4 Å molecular sieves, CH2Cl2.

OTHPO OMPM

a

(71% for 3 steps)

OMe

OMPMHO

b

(86% for 2 steps)

OMe

OMPMCl

c

(78%)

OH

OH d

(86% for 2 steps)

OMe

OHO

O

OMe

OMPMCl

Cl

e

(79% for 2 steps)

OMeO

O

Cl

OH

OEt

O f

(80%)

OMeO

O

Cl

O

OEt

O g

(50%) O OEt

O

OMeHCl

OMe

OH

h

(63% for 3 steps) O OEt

O

OMeHHO

OMe

OMOM

i

(quant) O OEt

O

OMeHH

OMe

OMOM

O

(369, 94% de)

OMeBr S

O O

S

N j

(70%) O OEt

O

OMeH

OMe

OMOM

OMeBr

(377, 1:1 E/Z)

365 366 367 368

370 371

372 373 374 375

376

Scheme 47 (a) (1) n-BuLi, BF3Et2O, −78 °C; (2) NaH, Mel, THF; (3) PTSA, MeOH; (b) (1) LiAIH4, THF, reflux, 2 h; (2) PPh3, CCl4, reflux, 12 h; (c) AD-mixβ. 0 °C, 48 h; (d) (1) 2,2-DMP, PTSA, acetone; (2) DDQ, CH2Cl2-H2O (7:3); (e) (1) IBX; (2) LiHMDS; CH3COOEt, −78 °C; (f) PDC; (g) PPTS, MeOH, 36 h;(h) (1) MOMCl, DIPEA; (2) HCOONa, Nal, DMF, 80 °C, 3 d; (3) NaBH4, MeOH, 0 °C; (i) Dess–Martin Ox.; (j) 375, NaHMDS, THF, −78 °C.


248


BnO

O

CHOO PPh3

N

O

a

(80%, 99:1 dr)

BnO

OO O

N

O

b

(94%)

BnO

OO

N

OOHc

(92%)

BnO

OO

OEt

OOH

d

(65% over 4 steps)

HO

OO

OTBS

OMe OO

OH

OMe

f

(80% over 2 steps)

e

(57% over 2 steps)O

OOTBS

OMe

33

378 379 380 381 382

383 384

Scheme 48 (a) 379, toluene, 65 °C, 36 h, then H8-BINOL (5 mol%), Sm(O-i-Pr)3 (5 mol%), CMHP, THF/toluene 25 °C, 0.7 h; (b) PhSeSePh, NaBH4, EtOH/AcOH, 25 °C, 15 min; (c) EtSLi, EtOH, 25 °C, 40 min; (d) (1) CH3I, Ag2O, MS 3 Å, toluene, 45 °C, 36 h; (2) LiAIH4, EtO2, 25 °C for 30 min then reflux for40 min; (3) TBSCl imidazole, CH2Cl2, 25 °C, 50 min, (4) H2 (5 atm), Pd(OH)2, AcOEt/EtOH, NaHCO3, 25 °C, 18 h, (e) (1) PCC, AcONa, MS 3 Å, CH2Cl2,25 °C, 20 min then (CH3O)2P(O)C(N2)COCH3, K2CO3, CH3OH, 25 °C, 80 min.

OHHO

OH

OH

OH

OHO

O

OO

HOOH

a OO

OO

b

(58% over 3 steps) OBn

c

(62% over 3 steps)

D-Mannitol

OO

OBn

MeOO

O

d

(85%) OBn

H

OO

O

e

OBn

OH

S N

S O

Bn

N

O

S

S

Bn

f

(52% over 2 steps)

OO

OBn

OMeO

EtO

O

(62%)

gO OBn

OHOH

OMe

O

EtO

385 386

387 388

389

390

391 392

Scheme 49 (a)42; (b) (1) NalO4, CH2Cl2, 0 °C, 1 h; (2) NaBH4, MeOH; (3) NaH, THF, BnBr, 0 °C to RT, 12 h; (c) (1) 50% aq. AcOH, RT, overnight; (2)NalO4, CH2Cl2, NaHCO3, 0 °C to RT, 4 h; (3) Ph3P+CH2OMeCl−, t-BuOK, THF, −78 °C to RT, 4 h; (d) (AcO)2Hg; NaBH4, CO2, 0 °C, THF/H2O (1:4); (e)389, TiCl4, EtN(iPr)2, CH2Cl2, 0 to −78 °C, 1 h; (f) (1) Proton Sponge, Me3OBF4, CH2Cl2, 0 °C, 24 h; (2) EtOC(O)CH2COOK, MgCl2, imidazole, THF, RT,12 h; (g) PPTS, MeOH/CH2Cl2, 0 °C to RT, 3 h.

O O

MeO O

OS

O(+)menthyl

p-Tol a

(70%)

O OH

MeO O

SO

p-Tolb

(42-60%)

OH O

MeO O

SO

p-Tol

(396, dr > 98%)

c

(66% over 2 steps)

(S)

OH OH

N O

SO

p-Tol

OMe

(63% over 2 steps)

O O

O

SO

p-Tol (S)

(93%)

O

OH

Me

p-TolOSOMeH

(399, dr > 98%)(S)

(59%)O

OMe

Me

p-TolOSOMeH (49%)

OOHC

OMe

MeOMeH

393 394 395 397

398 400 401

Scheme 50 (a) NaH (2 eq.), t-BuLi (2 eq.), THF, 0 °C; (b) DIBAL-H, THF, −78 °C, 30 min; (c) (1) Me4NHB(OAc)3, HOAc, RT, 2 h; (2) HCl-N(OMe)Me,Me3Al, CH2Cl2, heat, 2 h; (d) (1) (MeO)2C(CH3)2, acetone, CSA, RT, 24 h; (2) MeMgBr, THF, 0 °C to RT, 1 h; (e) PPTS, MeOH, RT, 24 h; (f) NaH, Mel,THF, 0 °C, 10 h; (g) TFAA, 2,6-lutidine, CH3CN, RT, 10 min.


249


a

(54% over 3 steps)O

OMe

MeOCO2Me

402

O

OMe

MeO

403

N

O

CO2Meb

(78% over 2 steps)

404

c

(79% over 2 steps)

405

HO

OMe

N

O

OH

S

S

TBSO

OMe

N

O

OTBS

H

Od

(71% over 2 steps)

406

TBSO

OMe

N

O

OTBSOH

OH

EtO2C

Scheme 51 (a) (1) IBCF, N-methylmorpholine, L-serine methyl ester, CH2Cl2; (2) Burgess' reagent, THF; (3) CuBr2, HMTA, DBU, CH2Cl2; (b) (1) DIBAL-H,THF; (2) propane-1,3-dithiol, BF3OEt2; (c) (1) TBSOTf, 2,6-lutidine, CH2Cl2; (2) Hg(ClO4)2, CaCO3, MeCN/H2O; (d) (1) E-(EtO)2P(O)CH2CH=CHCO2Et, NaH,CH2Cl2 2) AD-Mix β, t-BuOH/H2O.

N

O

O

X

OO

O

O

R

N

Hemi-phorboxazole A (407, X = CH2, R = OH)408 X = O, R = H

N

O

O

X

OO

O

ON

O

O

MeO

HO

RMeO

OH

409 R =

410 R =

H, X = CH2, R = OH

Cl, X = CH2, R = OH

R

411 R = H, X = O, R = H

NNN

O

OO

O

ON

O

O

MeO

MeO

MeO

OH OH

412

N

O

O

OO

O

ON

O

O

MeO

RO

MeO

OH OH

O

O

X

413 R = H, X = OO

O

S

NHHN

O

414 R = Me, X =

OO

N

Figure 12 Examples of synthetic analogs of the phorboxazoles.


250


could be oxidized for potential controlled reduction, but those resultshave not been published.The Yadav group has also completed the entire exocyclic

fragment.41 Acetylenic opening of 366 with 365 set the C35 center,which was converted into allyl chloride 368 (Scheme 47). Sharplessdihydroxylation was then used to install the C37 and C38 stereo-centers, and the pyran was elaborated by formation of β-ketoester 372and ketalization to 373. Upon formation of aldehyde 375, Juliaolefination with 376 gave the full C31–C46 fragment as a 1:1 mixtureof olefin isomers.Shibasaki synthesized an intermediate from Smith’s phorboxazole

synthesis to demonstrate the utility of his catalytic asymmetricMichael additions to unsaturated acylpyrroles, installing the C35stereocenter with 499% control (Scheme 48) and efficiently generat-ing alkyne 33.42

Nagaiah was able to demonstrate that D-mannitol, which is theestablished synthetic precursor to glyceraldehyde 136, could also beused for the generation of the exocyclic pyran.40 Periodate cleavage ofdiol 385 allowed access to 386,43 which could be selectively convertedinto aldehyde 388 (Scheme 49). An asymmetric acetate aldol was thenused to install the C35 stereocenter, which was then extended toβ-ketoester 391 and cyclized to the C31–C39 fragment.Another approach to the exocyclic pyran from chiral sulfoxide 395

was reported from the Carreño and Solladié groups (Scheme 50).44

Reduction of this diketone proceeded with excellent diastereocontrolto set C37, which was then used to set C35 via a directed reduction.The terminal ester was converted into the methyl ketone, which couldthen be ketalized to 399. The sulfoxide could then be converted intoaldehyde 401 via the Pummerer reaction.Hoffmann also completed a synthesis of a ring-opened exocyclic

pyran that incorporated the exocyclic oxazole as well (Scheme 51).45

Addition of serine to 402 and aromatization gave 403, which could beconverted into aldehyde 405. Extended homologation via vinylogousHorner–Wadsworth–Emmons reaction and installation of the C37and C38 stereocenters completed the C28–C41 fragment.

Additional phorboxazoles and analogsIn 2009, Molinski reported the isolation of hemi-phorboxazole A(407, Figure 12),46 which contains the full macrolide but only a nitrileinstead of the exocyclic oxazole and hinting at its biosynthetic origin.Smith was able to confirm the structure of 407 via its synthesis froman advanced synthetic intermediate.47 This synthesis provided suffi-cient material to allow for the biological evaluation of 407, whichproved to be essentially inactive compared with 1. Interestingly,synthetic analog 408 showed much greater activity than the naturalproduct.The extensive synthetic efforts detailed above have also allowed for

the generation of phorboxazole analogs and tool compounds useful forunderstanding its mechanism of action. Both the Forsyth and Smithgroups prepared and evaluated alkyne analog 409,48,49 demonstratingthat it was nearly as active as 1 against several cancerous cell lines. Infact, changes to the terminus are reasonably well tolerated and evencould be used to make more active analogs such as vinyl chloride 410.Although modifications such as ketalization at the C33 position do notdestroy activity, the loss of either the macrolide or a significant portionof the exocyclic terminus dramatically reduces activity. Some purelysynthetic analogs such as acetal 411 are quite active, while the activityof others such as triazole 412 (formed through a copper catalyzed click1,3-dipolar cycloaddition) remain unreported.50

Forsyth has prepared some phorboxazole-based biological toolcompounds such as biotinylated analog 413 and fluorescent analog

414.51,52 The latter was shown to be taken up in HeLa cells and toinduce extranuclear cytokeratin intermediate filaments to associatewith cyclin-dependent kinase 4 (Cdk-4), a kinase that has beenexplored as a cancer target.53 The full mechanism of action of thephorboxazoles remains undetermined at this stage.

CONCLUSIONS

The novel structure and biological properties of the phorboxazoleshave clearly attracted the interest of the synthetic community. It hasbeen through these efforts that we have begun to understand some ofthe structural requirements for their impressive biological activity andgained a glimpse of their biochemical target. Given the impressivestrides that have been made in this regard, it is reasonable to think thatthere remain chapters of the phorboxazole story to be written.

CONFLICT OF INTERESTThe authors declare no conflict of interest.

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