Synthetic efforts towards the marine polyketide peloruside A

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C. R. Chimie 11 (2008) 1369e1381http://france.elsevier.com/direct/CRAS2C/

Account / Revue

Synthetic efforts towards the marine polyketide peloruside A

Richard E. Taylor*, Zhiming Zhao, Sebastian Wunsch

Department of Chemistry and Biochemistry and the Walther Cancer Center, 251 Nieuwland Science Hall,

University of Notre Dame, Notre Dame, IN 46556 5670, USA

Received 10 December 2007; accepted after revision 19 May 2008

Available online 22 July 2008

Abstract

Peloruside A is a highly oxygenated marine polyketide isolated from specimens of Mycale hentscheli collected from the PelorusSound on the north coast of the south island of New Zealand. Due to its potent cytotoxicity and performance in initial preclinicalstudies, peloruside A appears to have significant chemotherapeutic potential. Isolation alone is unlikely to provide sufficient quan-tities of peloruside A for early clinical development. This manuscript will review the current state of synthetic efforts towards theproduction of peloruside A up to April 2008. To cite this article: Richard E. Taylor et al., C. R. Chimie 11 (2008).� 2008 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Keywords: Peloruside A; Marine; Polyketide; Synthesis; Tubulin

1. Introduction

It is now well-recognized that natural products havedirectly or indirectly contributed to the discovery anddevelopment of as much as 75% of our current treat-ments for cancer and infectious diseases [1]. In addi-tion, Lipitor, a single example of the statin class ofantilipidemic drugs was not only the top-selling drugin U.S. Markets, but it was also derived from a naturalproduct, compactin. Despite this impressive track re-cord, natural products are no longer an in-house dis-covery vehicle for major pharmaceutical companies.One rationale for this could be an apparent desire tofind lead compounds for more diverse indications.However, pharmaceutical companies have themselvesarticulated a strong belief that ‘‘promising leads

* Corresponding author.

E-mail address: [email protected] (R.E. Taylor).

1631-0748/$ - see front matter � 2008 Academie des sciences. Published

doi:10.1016/j.crci.2008.05.010

come faster and more frequently out of combinatorialchemistry and synthetic techniques’’ [2]. Unfortunately,the importance of chemical diversity in the discoveryof new therapeutic agents cannot be underestimatedand natural products have been shown to fill a signifi-cantly greater percentage of chemical diversity spacethan synthetic libraries [3].

Material supply issues can significantly hamperrapid therapeutic development of natural product leadcompounds. The development of Taxol� is an excellentexample [4]. However, despite large investments offunds in search of a synthetic solution, total synthesisefforts resulted in little more than an academic exer-cise. This is in stark contrast to recent efforts in theevaluation of the sponge-derived polyketide discoder-molide. When it became clear that isolation of naturalmaterial was not an adequate source of material,Novartis produced 50 g of synthetic discodermolide[5]. The structural differences between Taxol� and

by Elsevier Masson SAS. All rights reserved.

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http://france.elsevier.com/direct/CRAS2C

O

OH

OMe

OHO

O

OMe

H

OH

(+)-peloruside A 1

23

7911

1315

MeO

19

HOOH

Fig. 1. Structure of peloruside A.

1370 R.E. Taylor et al. / C. R. Chimie 11 (2008) 1369e1381

discodermolide were the key determinant of the resultof each effort. Methods for the production of syntheticfragments related to polyketides, such as discodermo-lide, have evolved to the point where even the mostcomplex of these structures can be prepared on a scalenecessary for full biological evaluation. Moreover, ad-vancement in the characterization and genetic engi-neering of polyketide synthase gene clusters canprovide an alternative, manufacturing scale source ofmaterial through heterologous expression or analoguesthrough precursor-directed and combinatorial biosyn-thesis [6e8].

Peloruside A is an excellent example of a marinederived polyketide with significant therapeutic poten-tial. It was isolated from a marine sponge, Mycale hent-scheli, found off the coast of New Zealand [9].Peloruside A showed potent cytotoxicity (18 nM)against P388 murine leukemia cell line. In contrast tomany stereochemically rich polyketides, peloruside A1 is highly oxygenated with limited sites of methylsubstitution, Fig. 1. While solution NMR studies pro-vided the relative stereochemistry of the compound’s10 stereogenic centers, the absolute stereochemistry re-mained unknown until a recent total synthesis of theent-peloruside A by the De Brabander group at theUTSW Medical Center [10]. The first total synthesisof the naturally occurring enantiomer appeared shortlyafter [11].

In 2002, Miller and coworkers reported a studywhich established peloruside A as a potent cytotoxicagent with paclitaxel-like microtubule-stabilizing

O

OMOM

OMe

OHTBSO

O

OMe

H

OTES

HO

23

7911

1315

MeO

19

HO

MeO1. LiOH, THF2. PPh3, DIA

3. 4N HCl, TH

2

Scheme 1. De Brabander macrolact

activity [12]. Recently, it has been reported that peloru-side A appears not to bind to the Taxol�-binding siteon b-tubulin [13]. In fact, laulimalide was able to dis-place peloruside A and thus these compounds appear tohave similar binding properties. In fact, synergistic ef-fects have been observed with taxoid site drugs includ-ing Taxol�, epothilone, discodermolide, eleuthorobin,and others [14]. Transfer-NOE experiments in the pres-ence of microtubules have provided insight into thebound-conformation of peloruside A and dockingexperiments identified a potential binding site on a-tubulin [15]. However, recent experimental efforts us-ing hydrogenedeuterium exchange mass spectrometrysupported an alternative binding site [16]. Based on thesignificant in vivo activity, Reata Pharmaceuticals hasinitiated advanced preclinical development [17].

Page and coworkers have investigated the environ-mental influences contributing to the metabolite pro-duction of Mycale hentscheli [18]. Their effortsconcluded that an aquaculture program designed toharvest compounds such as peloruside A must care-fully control a number of biological factors which trig-ger metabolite production. Thus, prior to theidentification and characterization of the gene clusterresponsible for peloruside A production, total synthesismay play an important role in meeting the materialsupply requirements of early clinical evaluation. Thisreview will cover synthetic efforts towards the synthe-sis of peloruside A with an emphasis on overall syn-thetic strategy. De Brabander’s [10] and Taylor’s [11]efforts have been previously included in a detailed re-view of recent total syntheses of marine natural prod-ucts and will only be summarized herein [19].

2. Total synthesis

Late-stage macrolactonization is a common elementin the synthetic strategies towards naturally occurringmacrolides. Both total synthesis efforts successfullyexploited this process through cyclization of highlyfunctionalized seco-acids thus taking full advantage

O

OH

OMe

OHO

O

OMe

H

OH

HO

ent-(-)-peloruside A 3

MeO

HO

/H2OD, THF; 69%

F; 65%

23

7911

1315

19

onization to ent-peloruside A.

p-TsOH, PhMe, 92%

3. MeI, KOtBu4. TESOTf; 75%

4

6

5

OMOM

OMe

TESO

O

23

7

5 BnO

O

911

OMOM

OMe

O

O

23

7

1. LDA, THF; 4

2. DMP, 81%

BnO

TESO

911

7

OMOM

OMe

O

O

H

23

7BnO 911

8

OMOM

OMe

O

OMe

H

23

7BnO 911

OTES

MeO

1. NaBH4, CeCl32. m-CPBA, MeOH; 72%

Scheme 2. De Brabander’s synthetic sequence for the preparation of the C1eC11 fragment.

1371R.E. Taylor et al. / C. R. Chimie 11 (2008) 1369e1381

of conformational preorganization. In the DeBrabander lab, after saponification of C1-methyl ester2, exposure of allylic alcohol to classic Mitsunobuconditions [20] followed by acidic deprotection ofthe C2-methoxymethyl, C8- and C19-silyl ethers pro-vided ent-peloruside A 3 through a clean inversion pro-cess, Scheme 1 [10]. Interestingly, related cyclizationsof the diastereomers resulting from epimeric pairs atC13 and C15, uncovered mechanistic differences in-cluding an ionization pathway due to the allylic natureof the C15-activated intermediate [21]. These issuesoffer additional support for the influence of stereo-chemistry and conformation on the efficiency of biomi-metic lactonizations [22].

2. Me3OB

1. Et2BOT

9

87%, 2

O

MOMO

OMe

O

OMe

H

OTES

23

7911

13 MeO

MeO

OTBSO

CH315

19

O

10

BH3•DMS; 94%12:1 dr

OTBSO

15

MeO

19M

N BO

Ph Ph

CH3

H

5

OH

Scheme 3. De Brabander’s completion of the seco-acid with

The generation of the C5eC9-pyran representeda critical milestone of the De Brabander’s route to pe-loruside A, Scheme 2. Fragment coupling between theenolate of methyl ketone 5 and aldehyde 4 followed byoxidation provided b-diketone 6 in excellent yield forthe two steps. Cyclization to 4-pyrone 7 proceeded un-der the acidic conditions necessary for deprotection ofthe C5-OTES group. A stereoselective Luche reduction[23] at low temperature provided the C7-allylic alco-hol, which directed a selective epoxidation of theenol ether. In situ methanolysis of the intermediate gly-cal epoxide provided the methyl pyranoside in highyield as a single diastereomer. Selective methylationof the presumably less sterically encumbered equatorial

F4; 85%

f, DIPEA:1 dr

11

O

MOMO

OMe

OTBSO

O

OMe

H

OTES

HO

23

7911

1315

MeO

19

HO

MeO

2

O

MOMO

OMe

H

O

OMe

H

OTES

HO

23

7911

13HO

eO

5

5

a late-stage fragment coupling and ketone reduction.

O

OMOM

OMe

OHTIPSO

O

O

H

23

7911

1315

MeO

19

O

OMOM

OMe

OTIPSO

O

O

H

MeO

Xc

2. ; DMAP; 51%

1. LiOH, THF/H2O

12 13

1. NaBH4, CeCl32. m-CPBA; 52%

3. Me3O+BF4-

4. 4N HCl; 43%

O

OH

OMe

OHO

O

OMe

H

OH

(+)-peloruside A 1

MeO

HO

5

23

7911

1315

19

5

23

7911

1315

19

5

MOMO MOMO

OH

Xc = O N

O

Bn

Cl

ClCl

OCl

TCBCl

Scheme 4. Taylor’s macrolactonization and completion of peloruside A.


alcohol completed the structural features of the peloru-side pyran system and provided key intermediate 8 aftersilylation.

De Brabander and coworkers completed the carbonskeleton of peloruside A by a fragment coupling betweenthe C1eC13 and C14eC19 structural units, Scheme 3. Analdol reaction between the enolboronate derived frommethyl ketone 10 and aldehyde 9, while efficient, unfortu-nately proceeded with limited diastereoselectivity. Thetwo C13-isomers were readily separable and taken on in-dependently to the macrolactonization. Selective methylether formation was accompanied by acetal hydrolysisand isolation of C15-ketone 11. Reduction of the carbonyldid not require a specific stereochemical outcome as theconcomitant cyclization could be accomplished with in-version or retention of stereochemistry depending on thechoice of reaction conditions. However, stereoselective

1. allylMgBr; 70%, 1:1 dr2. BOC-ON

O

15

19

14

3. NIS; 84%

1113

15

19 3 2BF •OEt ; 91%8:1 dr

H3CCH3

OTMS

9CH3

16

O

TIPSO

TIPS

TIPSO

MeO

OTBS

Scheme 5. Taylor’s stereoselective r

reduction of C15 was ultimately accomplished by a re-agent-controlled method [24]. Exposure of ketone 11to (S)- or (R)-B-Me-CBS-oxazaborolidine and BH3$DMSprovided the diastereomeric allylic alcohols including 2in 80e94% yield with high diastereoselectivity.

Jin and Taylor [11] utilized an activated ester interme-diate, a Yamaguchi macrolactonization [25], to effectcyclization after saponification of a C1-oxazolidine 12,Scheme 4. The chiral auxiliary, necessary for the selec-tive generation of the C2,C3-vicinal stereogenic centers,was carried through several steps as a masked carboxylicacid. Completion of the total synthesis was accom-plished through functionalization of the 4-pyrone oflactone 13. Interestingly, epoxidation of the intermediateglycal resulted in selective deprotection of the C11-methoxymethyl group. The authors proposed that theMOM-group participated in the fragmentation of the

O

15

19

O

O

I 3. dithiane, BuLi; (CH3)2SO2; 85%4. MeI, H2O; 90%

1. K2CO3, MeOH2. TBSCl; 79%

13

15

19

15

17

OH

CH3

O

11 9

O

TIPSO

MeO

OTBS

oute to the C9eC17 fragment.

O

OH

OMe

OHO

O

OMe

H

OH

HO

ent-peloruside A 3

23

7911

1315

MeO

19

HO

18TIPSO

15

OPMB

O O

98

O

O

OTBS

PMP

32PMBO

TBSO

OMe

O

18

19

20

Fig. 2. Paterson’s ‘‘Di-aldehyde Linchpin’’ strategy.


glycal epoxide via anchimeric assistance. Hydrolysis ofthe intermediate carbonium ion then provided themethyl pyranoside and a C11-hydroxyl group. Comple-tion of the total synthesis was accomplished by deprotec-tion of the C2- and C19-ethers.

The Taylor group’s approach to the C9eC17 frag-ment was a linear strategy from aldehyde 14 as shownin Scheme 5. Allylation with Brown’s allylborane re-agents [26] resulted in the formation of the expectedhomoallylic alcohol with high diastereoselectivity. Un-fortunately, reaction by-products resulting from thechiral reagent hampered isolation on a large scale. Itwas then found that an unselective allylation followedby separation and interconversion of the undesired iso-mer provided high yields of the desired intermediate ina more practical fashion. The C15 stereogenic centerwas then utilized for the generation of the C13-stereo-genic center through a BarletteSmith iodo-carboxylationsequence to provide carbonate 15 [27]. Transesterifica-tion with methanol provided the intermediate epoxyalco-hol which after single carbon homologation withdithiane, methyl ether formation, and hydrolysis pro-vided aldehyde 16. The C11-stereogenic center, as alco-hol 17, was produced by an 1,3-anti-selectiveMukaiyama aldol reaction [28]. In preparation for the

OOBz

1. c-Hex2BCl, Me2NEt,HCHO; 82%2. TIPSCl TIPSO

TIPSO O 1. (-)-Ipc2BCl, Me2CO,

3. NaBH44. K2CO3, MeOH5. Pb(OAc)4; 88%21

22

ent-142. PMBTCA, TfOH, Et2

15

19

19

Scheme 6. Paterson’s route to

macrolactonization, the complete carbon skeleton of pe-loruside A was produced through 4-pyrone formation ina manner related to the De Brabander’s route. However,the production of this intermediate through a more con-vergent route resulted in an overall shorter synthetic se-quence of 29 steps.

3. Towards the synthesis of peloruside A

Several additional research labs have communicatedpreliminary results describing their synthetic efforts to-wards a total synthesis of this interesting marine poly-ketide. Paterson has presented a triply convergentstrategy through sequential aldol reaction via methylketones 18 and 20 with structural unit 19 serving as la-tent ‘‘dialdehyde’’ linchpin, Fig. 2 [29]. The stereose-lectivity of each fragment coupling would rely on theestablished preference for 1,5-anti-stereochemical rela-tionships as previously demonstrated by Paterson [30].

A sequential pair of stereoselective aldol reactions,shown in Scheme 6, provided access to methyl ketone18. The C18 stereogenic center was created in highyield by the condensation of formaldehyde with boronenolate of chiral ketone 21 derived from lactate. The Z-trisubstituted olefin was generated through a StilleGennari

O

1. (CF3CH2O)2P(O)CHMeCO2Me; 94%2. DIBAL

Et3N; 65% TIPSO OPMB

O18

3. DMP, CH2Cl2; 94%

O15

19

13

the C12eC19 fragment.

TIPSO OPMB

O

18

23

OPMBO

c-Hex2BCl, Et3N,Et2O, -78°C; 88% TIPSO OPMB

O

OH OPMB

SmI2, EtCHO, THF; 88%

TIPSO OPMB

HO

O

24

25

OPMB

O

15

19

1311

15

19

1311

15

19

13

Scheme 7. A 1,5-anti-aldol and EvanseTishchenko reduction.


olefination [31] and a reductioneoxidation sequenceprovided aldehyde ent-14. The C15 stereogenic centerwas then produced by an aldol reaction with acetone.Utilization of a chiral boron enolate [32] allowed theproduction of the desired C15-diastereomer with goodstereoselectivity. Finally, generation of the PMB etherproduced ketone 18.

With methyl ketone 18 in hand, Paterson exploredthe first aldol fragment coupling utilizing a modellinchpin, aldehyde 23 (Scheme 7). The c-Hex2B-eno-late of 18 was generated in the usual fashion. Couplingwith aldehyde 23 provided C11,C15-anti-aldol adduct24 in excellent yield and selectivity. Generation ofthe desired C11-configuration was supported byMosher ester analysis [33]. The C11-alcohol wasthen exploited for stereoselective reduction of theC13-ketone through an EvanseTishchenko reduction[34] with SmI2 and propionaldehyde to provide theC9eC19 fragment 25.

In early 2004, Zhou and Liu reported a highly con-vergent synthesis of the C1eC16 backbone of peloru-side A [35]. The key fragment coupling for the creationof the C10eC11 bond was an aldol reaction betweena highly substituted enolate derived from ketone 27and aldehyde 26 Fig. 3. Both fragments were generatedin highly stereoselective manners exploiting iterativeuse of Brown chiral allylation technology [26].

peloruside A 1

O

OH

OMe19

OHO

O

OMe

H

OH

HO

9

15

MeO

HO13

117

5

32

Fig. 3. Zhou’s stereoselective aldol strateg

Once both fragments were available, Zhou and Liuexplored a variety of aldol coupling conditions. Unfor-tunately, the highly substituted nature of the necessaryenolate derived from ketone 27 hindered clean reactiv-ity. No reactivity was observed under Mukaiyama aldolconditions, initiated by Lewis acids such as BF3$OEt2or TiCl4. Moreover, generation of intermediate tita-nium or boron enolates also met with disappointment.Fortunately, however, some modest reactivity was ob-served with a lithium enolate generated at low temper-atures with lithium diisopropyl amide (LDA). Asshown in Scheme 8, condensation of the lithiumenolate of ketone 26 and aldehyde 27 generated theC1eC16 backbone of peloruside A with fair stereose-lectivity for the desired configuration at C11.

Roush and Owen have proposed a highly conver-gent strategy for the preparation of the carbon skeletonof peloruside A [36] which utilizes two applications ofthe double allylboration reaction previously developedin their lab [37]. The bis-nucleophile 31 serves asa linchpin between terminal fragments 14 and 30 anddialdehyde equivalent 29, Fig. 4. With this bold strat-egy, essentially all of the chirality associated withthis highly oxygenated natural product would be con-trolled by the chiral allylborane reagent.

Successful demonstration of this concept is pre-sented in the preparation of the C3eC11 fragment 35,

OBz

MeO

O

O

26

OMOM

PMBO

OMe

OMe

MOMO

O

27

O1513

117

5

32

9

y for generating the C10eC11 bond.

26

OMOM

PMBO

OMe

OMe

MOMO

O

27

OBz

MeO

HO O

OMOMOMe

OMe

MOMOO

OPMBO

28

LDA, THF, -78°C;OBz

O

MeO

O

O+

60% based on recovered 27;

3:1 dr

1513 15

1311 9

7

5

32

97

5

32

Scheme 8. Key fragment coupling in Zhou’s synthetic route to the C1eC16 segment.


as detailed in Scheme 9. Sequential exposure of the bis-nucleophile 31 to aldehydes 29 and 30 resulted in theisolation of diol 33 in 36% yield as a single diastereo-mer and geometric isomer. The diastereoselectivity ob-served in the product supports selective formation ofthe intermediate 8,9-anti-boronate 32 and a highly or-ganized cyclic transition state. The enantioselectivityobserved in the product 33 and thus intermediate 32,as determined by Mosher analysis, was >95%. Com-pletion of the C3eC11 fragment then required genera-tion of the C7,C8-anti-vicinal diol unit. After selectivesilyl protection of the homoallylic C5-alcohol 33 [38],the E-olefin was epoxidized from the a-face with highfacial selectivity presumably directed by the allylicalcohol [39]. Further protection of C9 as a p-methoxy-benzyl ether was followed by Zn(II)-mediated epoxidefragmentation and isolation of lactone 34. Subsequentmethylation and hydride reduction provided the C3eC11 fragment of peloruside A, 35.

From a complementary perspective, Pagenkopf andcoworkers have proposed the use of a C8eC12 ‘‘bis-enolate’’ linchpin 37 for generation of the carbon skel-eton of peloruside A, Fig. 5 [40]. The key fragmentcoupling step would require a glycolate anti-aldolwith aldehyde related to 38 and generate the C7,C8-vicinal diol unit.

Pagenkopf generated the C1eC7 fragment rapidlyand in a practical fashion, as aldehyde 40, through ma-nipulation of readily available triacetal glucal. Whilea variety of aldol conditions were explored for

peloruside A 1

O

OH

OMe

OHO

O

OMe

H

OH

HO

11

15

MeO

HO

TBSO

14

23

5

7

913

19 19

Fig. 4. Roush’s common linchpin strategy

generation of the C7eC8 bond, classic Mukaiyamaconditions proved the most effective. As shown inScheme 10, trimethylsilyl enol ether 39 underwentcoupling with aldehyde 40 promoted by BF3$OEt2.The desired 5,7-anti-7,8-anti-adduct 41 was generatedin stereochemical excess (3.5:1) in good overall yield.Unfortunately, exploration of alternative Lewis acidsfailed to improve upon this ratio. At this point, bothtermini underwent oxidative cleavage with ozoneand, after selective oxidation of the C1-aldehyde, theresulting carboxylic acid was protected as a methyl es-ter. Despite the modest stereoselectivity observed forthe initial fragment coupling, the relative ease in prep-aration of each fragment within this strategy supportsits potential to access useful quantities of peloruside A.

Hoye and Ryba have presented a creative bi-direc-tional approach to a C8-epimer of the C1eC9 regionof peloruside A via terminal group differentiation,Scheme 11 [41]. Ozonolytic cleavage of the terminalalkenes in 44 produced a pseudo-C2-symmetric dialde-hyde intermediate 45. Selective formation of lactone46 was presumably a result of kinetic oxidation of anequilibrating mixture of diastereomeric hemi-acetal in-termediates. A related investigation of competitive lac-tonization reactions of bis-methyl esters providedadditional insight into the controlling factors of thismechanistically interesting selectivity.

Ghosh and Kim have proposed a fragment couplingstrategy complementary to Zhou’s (Fig. 3). An aldolcoupling to form the C9eC10 bond would also

15

OBO

OO

t-BuO

O

O

OBn

30

29

3111 9

3

5

B(R*)2

using a double allylboration reagent.

O

t-BuO

O

O

OBn

29

31 O

t-BuO

OB(2-dIcr)2

36%, >95% ee

O

t-BuO

OH

BO O

OH OBn

32 33

OPMB

OH

OBn

TESO

OO

OPMB

OMe

OBn

TESO

OH

1. Me3OBF4; 89%

34 35

30

BO

O B(2-dIcr)211 9 11 9

8 11 9 5

5

3

78

11 9

HO

5

3

78

9

11

2. LiBH4; 91%3. KHMDS, PMB-Br; 94%4. ZnCl2, Et2O; 85%

1. TESCl; 86%2. m-CPBA

Scheme 9. Roush’s synthesis of the C3eC11 fragment.

peloruside A 1

O

OH

OMe

OHO

O

OMe

H

OH

HO

9

15

MeO

HO

HO

11

OH

OO O

OH

O

HO

O

HO

OMe

HO

36

37

38

9

15

13

1919

13 11

7

5

32

32

7

5

Fig. 5. Pagenkopf’s glycolate aldol strategy for generation of the C7eC8 bond.

OTMSOBn

BF3•OEt2; 66%O O

OBn

OBz

OMe

OH

Br

O

OMe

OBz

Br

O+

39 40

42 43

41

O

OBnOMe

OMe

BzOTBSO

1. O3, PPh32. NaClO2, NaH2PO4 O

OBnOMe

O OMe

BzOTBSO

O

MeO

3. TMSCHN2; 45%

98

7 53

2

7 53

2

7

5

32

8911

7

5

32

8911

1. Me3OBF4; 90%2. Zn/Cu, EtOH; 82%

3. TBSCl; 82%

Scheme 10. Pagenkopf’s glycolate aldol coupling and generation of the C1eC12 fragment.


necessitate a highly substituted enolate of a C11 ketoneand an a-oxygenated C9-aldehyde. In 2003 they pre-sented a synthetic route to the C1eC9 region of ent-peloruside A [42a]. The vicinal diol functionalityfound at C2,C3 and C7,C8 was each incorporated bya Sharpless asymmetric dihydroxylation reaction [43]

(Scheme 12). The route began with a,b-unsaturated es-ter 47 available via a three-step sequence from 1,3-propan-diol [44]. Asymmetric dihydroxylation withAD-mix-a proceeded in high yield and 90% ee. Func-tional group manipulation provided 48. After a two-step conversion to b,g-unsaturated ketone 50, hydride

OMe

OMe

HO

OMOM44

MOMO

8

5

OMe

3

OMe

O

OMOM46

MeO2C

MOMO

O

45

65%, 8:1 drO3, NaOH,

MeOHOMe

O

MOMO7

OH

O

OMe

MOMO

Scheme 11. Hoye’s kinetic lactonization to the C8-epimer of the C1eC9 fragment of peloruside A.


reduction in the presence of LiI provided 1,3-syn-prod-uct 51 in 87% yield. The stereoselectivity was rational-ized by a chelated transition state 50 and axial additionof hydride. Acylation and ring-closing metathesis [45]provided the d-lactone 52 which enabled the selectivegeneration of the Z-alkene at C7,C8. Saponificationof the lactone, protection of the secondary alcoholand esterification followed by dihydroxylation withAD-mix-b afforded the desired diol 53, in 72% yieldas a 91:9 mixture of diastereomers.

Later in 2003, Ghosh and Kim published their syn-thetic route to their C1eC19 fragment, ketone 57,Scheme 13 [42b] The C15-homoallylic alcohol wasprepared as previously presented. Homologation ofthe terminal alkene was accomplished by the genera-tion of an intermediate acrylate and ring-closing me-tathesis to provide the d-lactone 55. The C13-stereogenic center was generated by a two-stepsequence; stereoselective epoxidation and reductivering opening. Protection of the secondary hydroxyl as

TBDPSO

EtO2C

O

OO

BnO

1. (allyl)M

HO

OO

BnO

6 steps

47 48

axial attack

50 51

BnO2. CH2N2; 80%3. AD mix-β; 72%

1. NaOH; TBSCl

2. DMP; 8

O

O

OH

BnO

Li

H

H

5

5

3

33

Scheme 12. Ghosh’s asymmetric dihydroxylation appro

a t-butyldiphenylsilyl ether provided lactone 56. Thelactone was then converted to ketone 57 by standardmethods.

Shortly after Ghosh’s communications, Gurjar andcoworkers reported a related route to C1eC11 regionof peloruside A [46]. As shown in Scheme 14, dihy-droxylation of a,b-unsaturated lactone 59 stereoselec-tively generated the C7,C8-vicinal diol functionality.The lactone was formed in a fashion similar to Ghoshexploiting a ring-closing metathesis reaction. However,in contrast, this substrate underwent osmylation withhigh facial selectivity without the need for chiral li-gands. Moreover, the C2,C3-stereogenic centers wereprovided by a practical choice of starting material, D-glucose.

Finally, Roulland and Ermolenko reported an effi-cient synthetic route to methyl ketone 67 which repre-sents the C12eC19 region of peloruside A [47]. Asdetailed in Scheme 15, non-racemic, homoallylic alco-hol 64, prepared in one step from (S)-propylene oxide,

gBr; 74%O

OO

BnO

1. ; 62%O

OO

BnO

O

49

LiAlH4, LiI; 87%

52

TBSO

OO

MeO2C

OHOH

53

8%

2. ; 90%

5

5

5

3

3

3

78

Cl

O

RuPh

ClCl

PCy3

PCy3

ach to the C1eC9 fragment of ent-peloruside A.

1. CH2=CHCOCl, Et3N; 77%2. Cl2(PCy3)2Ru=CHPh; 83%

1. H2O2, 6N NaOH; 74%2. NaBH4, PhSeSePh, AcOH, i-PrOH; 100%OHBnO

1315

19

OBnO

1315

19O

OBnO13

15

19O

OTBDPS

3. TBDPSCl; 100%

1. AlMe3, HN(OMe)MeáHCl; 93%2. MEMCl; 92%

3. i-PrMgCl; 61%

OMEMBnO

15

19

TBDPSO

O13

11

54 55

56 57

Scheme 13. Ghosh’s synthesis of the C10eC19 fragment of ent-peloruside A.


underwent diastereoselective epoxidation catalyzed byVO(acac)2. After protection of the secondary alcoholas a PMB ether, the epoxide was converted to the iso-meric allylic alcohol in high yield. Acylation with cro-tonyl chloride provided the b,g-unsaturated ester 66,which after deprotonation with LDA, underwent a-al-kylation with ethyl iodide to provide a mixture ofdiastereomers (18R:18S, 2:3). Ring-closing metathesisconditions provided exclusively the 18R-lactone 68and unreacted 18S-67. Lactone 68 was isolated in36% yield which is 95% based on the starting material,18R-67. Moreover, the authors demonstrated that un-reacted ester 18S-64 can be epimerized with LDA,AcOH and recycled into the sequence. Lithium alumi-num hydride reduction of lactone 68 produced an

O

OO

O

MeO

Zn, allyl bromide;

OH

OO

O

MeO

95%, 9:1 dr

57 58

1. OsO4, NMO

OO

O

MeO O

OEt

O

O

2. PTSA, DMP; 66%

60

1. NaH, CS2, MeI O

OMe

EtOOBn

OBn

OO

62

2. Bu3SnH, AIBN; 55%

2 5 33 2 5

3 57

8

2

87

53

2

Scheme 14. Gurjar’s chiral pool approach to

intermediate diol, which was selectively protected toprovide 69. Manipulation of protecting groups fol-lowed by oxidation of C13 provided the C12eC19fragment as methyl ketone 70. The overall sequenceis fairly efficient and highlighted by a useful, dia-stereo-differentiating RCM reaction.

4. Addendum

During the review of this manuscript a third totalsynthesis of peloruside A was reported by Ghosh andcoworkers, Fig. 6 [48]. Their second generation ap-proach relied on a complex aldol fragment couplingto generate the C10eC11 bond that had previously

OO

O

MeO O

O

59

O

OHOMe

EtOOBn

OBn

OO

7 steps

61

TBSO

OMe

OBnOBn

OBn

BnO

MeO2CO

63

13 steps

1. ; 76%

2. ; 72%

Cl

O

RuPh

Cl

Cl

PCy3

NN MesMes

3

3 5

87

5

2

2

23

87

5

the C1eC11 fragment of peloruside A.

HO

1. cat. VO(acac)2, t-BuO2H2. NaH, PMBCl

PMBO

OH

85%PMBO

O

O

LDA, EtI; 78%

PMBO

O18

O

PMBO

O

O

PMBO

OH

OTIPS

O

OMPM-3

OTIPS

3. i-Pr2NMgBr; 82%

64 65 66

67 68

36%; 95% basedon (18R)-67

1. NaH, 3-MPMCl; 100%2. DDQ; 89%

3. TPAP, NMO; 96%

69 70

18

1818

15

1515

15

15

Cl

O

1. LiAlH4; 92%

2. TIPSCl; 100%

RuPh

ClCl

PCy3

NN MesMes

Scheme 15. Ermolenko’s ring-closing metathesis approach to the C12eC19 fragment.


been investigated by Zhou, Fig. 3. This report includedoptimized routes to aldehyde fragment 71 and ketone72. Moreover, the successful approach contained sev-eral findings that significantly complement previouslypresented efforts.

As discussed above, Zhou and coworkers had previ-ously explored an aldol coupling strategy to form theC10eC11 bond. Due to the sterically hindered enolateintermediate, derived from ketone 27, Scheme 8, it isnot surprising that optimized conditions only providedmoderate yields and stereoselectivity. In contrast, Ghoshcreatively generated the necessary lithium enolate, notthrough typical LDA deprotonation, but through a conju-gate reduction of enone 72 with L-selectride, Scheme 16.Reaction of this enolate with aldehyde 71 at�78 �C pro-vided the aldol adduct in 92% yield with 4:1 diastereose-lectivity for the desired stereoisomer 73. Afterdeprotection of the TES and PMB ethers, the C1-primary

(+)-peloruside A 1

O

OH

OMe19

OHO

O

OMe

H

OH

HO

9

15

MeO

HO13

117

5

32

BnO

Fig. 6. Ghosh’s aldol fragment coupling strat

alcohol was oxidized to the carboxylic acid in two steps.Yamaguchi lactonization then provided the macrocycliclactone 74 in 64% yield. A unique aspect of this route isthe fact that the dihydropyran unit was not establishedprior to lactonization due to the protected C5-alcohol.One would assume that the conformation of 74 is quitedifferent from the natural system. However, it is not clearif the presence of the C7,C8-dioxolane provided someentropic advantage. Completion of the total synthesis re-quired sequential protecting group removal steps. Mildacid simultaneously deprotected the C5-TBS ether andthe isopropylidene resulting in an equilibrium mixtureof dihydropyran and open hydroxyeketone isomers. De-spite this complication, selective methyl ether formationat C7 proceeded well. Hydrogenolysis of the benzylgroup followed by aqueous acid removal of the C2-me-thoxymethyl group provided synthetic peloruside A,identical to reported data for natural material.

OTES

MeO

71

O

TBSO

O

OMePMBO

MOMO

O

72

O1513

11

7

5

32

9

egy for generating the C10eC11 bond.

O

TBSO

O

OMePMBO

MOMO

O

72

7

5

32

9

L-selectride; 71OTES

MeO

73

OH1513

11

BnO

O

TBSO

O

OMePMBO

MOMO

O7

5

32

992%, 4:1 dr

1. DDQ, H2O2. DDQ; 70%3. TPAP, NMO

4. NaClO2; 52%5. TCBCl, DIPEA; DMAP; 64%

O

MeO

74

OH1513

11

BnO

O

TBSO

O

OMeO

MOMO

O7

5

32

9

1. 1M HCl, THF2. Me3O+BF4

-; 73%

3. Pd/C, HCO2H4. 4M HCl, THF; 50%

(+)-peloruside A 1

Scheme 16. Fragment coupling and end game in the Ghosh’s synthesis of peloruside A.


5. Summary and prospective

The previous presentation represents a snapshot ofthe synthetic progress made towards peloruside A asof April 2008. While only three groups have completedtotal syntheses to this challenging polyketide target,several additional groups have made significant prog-ress. Moreover, these efforts have shown remarkablediversity in synthetic strategy and in the developmentof broadly applicable new tactics. At this point, it isnot clear whether any of these individual approachescan provide reliable quantities of material requiredfor preclinical and, if necessary, early clinical develop-ment. However, potential success may reside with a cre-ative combination of a subset of these efforts.

As has been true with other compilations of naturalproduct synthetic efforts, it is clear that chemists can pre-pare any naturally occurring compound. Unfortunately,we have yet to routinely demonstrate an ability to pre-pare compounds of this complexity at a practical levelnecessary for fully exploiting their chemotherapeuticpotential. Thus, synthetic chemistry is far from a maturefield when one carefully considers the ever-evolvingneeds of society and the resulting practical constraints.

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Documents

Synthetic efforts towards the marine polyketide peloruside A