Total synthesis of epothilones B and D: Stannane equivalents for β-keto ester dianions

Total Synthesis of Epothilones B and D: Stannane Equivalents for

ꢀ-Keto Ester Dianions

Gary E. Keck,* Robert L. Giles, Victor J. Cee,^†Carrie A. Wager,^‡Tao Yu,^§and

Matthew B. Kraft

Department of Chemistry, UniVersity of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah, 84112

keck@chemistry.utah.edu

ReceiVed October 8, 2008

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was

based on late-stage fragment assembly of two segments representing C₁-C₉and C₁₀-C₂₁of the structure.

The C₁-C₉fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-

methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-

dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane

equivalent of a ꢀ-keto ester dianion. An enantioselective addition of such a stannane equivalent for a

ꢀ-keto ester dianion was also used to fashion one version of the C₁₀-C₂₁subunit; however, the fragment

assembly (using bimolecular esteriﬁcation followed by ring-closing metathesis) with this subunit failed.

Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolacton-

ization to close the macrocycle. The C₁₀-C₂₁subunit needed for this approach was prepared in an efﬁcient

manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a

stereoselective SmI₂reduction of a ꢀ-hydroxy ketone and a critical opening of a valerolactone with aniline

which required extensive investigation.

Introduction

Epothilones A (1) and B (2, Figure 1) were ﬁrst isolated in

1987 by Ho¨ﬂe and Reichenbach from culture extracts of the

myxobacterium Sorangium cellulosum (Myxococcales), ﬁrst

found in soil samples taken from the river banks of the Zambesi

River in the Republic of South Africa. In his 1993 patent, Ho¨ﬂe

described the gross structure of the epothilones and reported a

very narrow antifungal spectrum against the fungus Mucor

hiemalis.¹Practical agricultural use of the epothilones as

fungicides and pesticides failed, as they were shown to be

phytotoxic. As a result, interest in the epothilones faded.

FIGURE 1. Epothilones A and B.

In 1995, Bollag and co-workers at Merck²independently

isolated epothilones A and B and found them to be highly

cytotoxic to a number of different tumor cell lines. These

compounds were then subjected to a ﬁltration-calorimetric

assay developed at Merck to detect microtubule-nucleating

activity as a screen to search for compounds that could stabilize

^†Present address: Amgen Inc., One Amgen Center Drive, Thousand Oaks,

CA 91320.

^‡Present address: Pﬁzer Inc., Eastern Point Road, Groton, CT 06340.

^§Present address: Schering-Plough Inc., 2015 Galloping Hill Road, Kenil-

worth, NJ 07033-3724.

(1) (a) Ho¨ﬂe, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF) DE-B

4138042, 1993; Chem. Abstr. 1993, 119, 180598. (b) Ho¨ﬂe, G.; Bedorf, N.;

Gerth, K.; Reichenbach, H. (GBF) DE-4138042, 1993; Chem. Abstr. 1993, 120,

528411.

(2) Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Leisch,

J.; Geotz, M.; Lazarides, E.; Woods, C. M. Cancer Res. 1995, 55, 2325–2333.

10.1021/jo802215v CCC: $40.75

Published on Web 11/08/2008

2008 American Chemical Society

J. Org. Chem. 2008, 73, 9675–9691 9675

Keck et al.

microtubules. At this time, Taxol,³a complex polyoxygenated

diterpene isolated by Wall and Wani⁴from the Paciﬁc Yew

tree Taxus breVifolia, was the only known example of a

compound that arrested cell growth and brought on apoptosis

by the stabilization of microtubules. The efﬁcacy and broad-

spectrum cytotoxicity of Taxol had generated enormous interest

in ﬁnding other microtubule-stabilizing compounds. Of the

thousands of compounds that were subjected to the Merck

microtubule-nucleating activity screen, only epothilones A and

B were found to induce the formation of microtubules.

epothilones A and B reported. Danishefsky¹⁴completed the ﬁrst

total synthesis of epothilones A and B in less than 6 months

after Ho¨ﬂe assigned the absolute conﬁguration. This was quickly

followed by syntheses from Nicolaou¹⁵and Schinzer.¹⁶In

comparison to Taxol, the relatively simple structuture of the

epothilones has made it quite amenable to the synthesis of

analogues, with over 100 reported to date. Given the relatively

small size of the epothilones, a more surprising aspect is that

the structure has allowed for such a large number of different

synthetic approaches.

Ring-Closing Metathesis Approach to Epothilone B. Our

original synthetic strategy chosen for epothilone B, 2, is shown

in Scheme 1. As with the majority of previously published

syntheses, we planned to make epothilone B by a well-

precedented diastereoselective epoxidation¹⁷of the C₁₂-C₁₃

oleﬁn of epothilone D (3), which would be accessed from the

macrolactone 4. To allow for a highly convergent synthesis,

we chose to divide the molecule into two fragments of similar

size by two sequential disconnections. The ﬁrst of these was

between two of the three contiguous C₉-C₁₁methylene groups,

to give 5, followed by disconnection of the ester linkage, giving

rise to a C₁-C₉fragment 6 and a C₁₀-C₂₁fragment 7.

The decision to close the macrolactone through a C₉-C₁₀

oleﬁn-forming reaction, in our case, ring-closing metathesis

(RCM), deserves mention. This approach requires selective

hydrogenation of the less sterically encumbered C₉-C₁₀disub-

stituted oleﬁn in the presence of two additional trisubstituted

oleﬁns. While there is precedent for this selective hydrogena-

tion,¹⁸a more obvious choice of an intermediate for RCM might

negate this requirement by having a saturated C₉-C₁₁segment

and have consummate diastereoselective oleﬁn formation at

C₁₂-C₁₃. Unfortunately, this strategy has been tried a number

of times, with both epothilone A and B intermediates, with

Further research showed that the cytotoxicity of the epothilones

resulted from the same microtubule stabilization properties

exhibited by Taxol, indicating that these compounds had the

potential to become only the second member in this powerful

class of anticancer drugs. Epothilones were shown to be

competitive inhibitors of [³H]Taxol binding, suggesting that

epothilones and Taxol have the same, or a largely overlapping,

binding site in the microtubule framework. In general, epothilones

A and B are potent antiproliferative compounds with IC₅₀values

in the subnanomolar to low nanomolar range. Remarkably,

epothilones A and B are active against a number of multidrug-

resistant cancer cell lines, which include Taxol-resistant cancer

cells.

Because microtubule assembly and disassembly require

extremely rapid dynamics, mitosis is acutely Vulnerable to

microtubule-targeted drugs. Microtubule-stabilizing agents, such

as Taxol and the epothilones, can suppress microtubule dynam-

ics and interrupt mitosis, leading to cell death. The success of

microtubule-stabilizing agents in the treatment of cancer have

led to microtubules being called, arguably, the best molecular

target for the development of anticancer treatments that have

been identiﬁed so far.⁵Since the discovery of Taxol and the

epothilones, other compounds with microtubule-stabilizing

properties have subsequently been identiﬁed through natural-

product screening including discodermolide,⁶sarcodictyin A,⁷

eleutherobin,⁸peloruside A,⁹and laulimalide.¹⁰

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While the gross molecular structures of epothilone A and B

were disclosed in Ho¨ﬂe’s original patent and subsequently

conﬁrmed by Bollag, the absolute and relative stereochemistry

were not elucidated by Ho¨ﬂe until 1996.¹¹Since then, the

epothilones have received unprecedented attention from the

synthetic community, with over 30 total syntheses^12,13of

(3) Taxol is a registered trademark of Bristol-Myers Squibb. The generic

name for Taxol is paclitaxel. Often, the name Taxol is used when referring to

the compound paclitaxel. No infringement on the Bristol-Myers Squibb trademark

is implied or intended by this usage.

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9676 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

SCHEME 1. Retrosynthetic Analysis of RCM Route to

Epothilone

SCHEME 2. Retrosynthetic Approach to Acid 6

SCHEME 3. Retrosynthetic Analysis of the C₁₀-C₂₁

Subunit

essentially no selectivity¹⁹(∼1:1 to 1.5:1) seen for the desired

C₁₂-C₁₃(Z)-oleﬁn geometry. While one might suspect that a

C₉-C₁₀RCM would yield the same poor oleﬁn diastereose-

lectivity, this residual stereochemical information will be lost

in the subsequent hydrogenation step which renders any

observed diastereoselectivity for the RCM step inconsequential.

The C₁-C₉carboxylic acid, 6, is the more stereochemically

complex coupling partner for the RCM precursor. It is a densely

functionalized fragment that contains the majority of the

stereocenters found in the natural product. A synthetic strategy

was envisioned (Scheme 2) wherein a single stereocenter, the

C₆-methyl stereocenter derived from commercially available,

enantiomerically pure methyl (2R)-3-hydroxy-2-methylpro-

panoate (12), would be the origin of all the remaining stereo-

centers in this subunit. Thus, 6 was envisioned to come from a

substrate-controlled crotylation reaction that would establish

both the C₇-hydroxyl and C₈-methyl stereocenters. The C₃-

hydroxyl stereocenter would then be set through a 1,3-syn

reduction of the corresponding δ-hydroxy ꢀ-keto ester 9. Finally,

the C₅-hydroxyl stereocenter would be derived from a diaste-

reoselective addition of a ꢀ-keto ester dianion synthon 11 to

the known aldehyde 10. We saw this “ꢀ-keto ester dianion”

addition as a unique opportunity to install the C₄-gem dimethyl

group of epothilone B through a stereoselective connective

fragment assembly. This is in contrast to the majority of previous

SCHEME 4. Potential Chan’s Diene Approach

(19) For examples, see: (a) May, S. A.; Grieco, P. A. Chem. Commun. 1998,

1597–1598. (b) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;

Roschangar, F.; Sarabia, F; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem.

Soc. 1997, 119, 7960–7973.

(20) For exceptions, see: (a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato,

P.; Su, D.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl.

1996, 35, 2801–2803. (b) Balog, A.; Bertinato, P.; Su, D. S.; Meng, D.; Sorensen,

E. J.; Danishefsky, S. J.; Zheng, Y. H.; Chou, T. C.; He, L.; Horwitz, S. B.

Tetrahedron Lett. 1997, 38, 4529–4532. (c) Liu, J.; Wong, C. H. Angew. Chem.,

Int. Ed. Engl. 2002, 41, 1404–1409.

syntheses of the epothilones that carry this gem-dimethyl

functional group in as a constituent of a simple precursor.²⁰In

an overall sense, this segment would be assembled in a very

convergent manner, by elaboration of aldehyde 10 at both ends.

While the C₁₀-C₂₁fragment 7 appears noticeably less

complex than the C₁-C₉fragment (Scheme 3), the (Z) C₁₂-C₁₃

trisubstituted oleﬁn presents a signiﬁcant synthetic challenge.

J. Org. Chem. Vol. 73, No. 24, 2008 9677

Keck et al.

SCHEME 5. Stannane Approach to δ-Hydroxy ꢀ-Keto

Esters

SCHEME 6. Prenyl Stannane Additions

Installation of this acyclic trialkyl-substituted oleﬁn through

either a Wittig or metathesis cross-coupling reaction inevitably

leads to either poor diastereoselectivity for the C₁₂-C₁₃oleﬁn

or low yield. We envisioned that the C₁₂-methyl of 7 could arise

from 13 by sequential reduction of the C₁₃-vinyltriﬂate followed

by the full reduction, and then deoxygenation, of the R-allyl

R,ꢀ-unsaturated ester. This method of indirectly forming the

trisubstituted oleﬁn from 13 would rely on the tendency of

enolates of ꢀ-keto esters to form chelates with their counterions

to selectively form the (Z)-enolate, as depicted in 14. The

requisite δ-hydroxy ꢀ-keto ester would be prepared via an

enantioselective addition of the ꢀ-keto ester dianion synthon

17 to the known aldehyde 18. It is worth noting here that while

the two subunits 6 and 7 appear to be quite different, a

δ-hydroxy ꢀ-keto ester is the starting point for the synthesis of

each fragment. Thus, an exploration of the use of ꢀ-keto ester

dianion equivalents was to be one focal point of this synthetic

plan.

SCHEME 7. Approach to Stannane 22

center could be accomplished in a stereocontrolled manner.²³

Model studies with the readily available prenyltri-n-butylstan-

nane 23 showed that Lewis acid promoted additions to chiral

R-methyl-ꢀ-alkoxyaldehydes 10 and 25 proceeded in excellent

yield and with high levels of diastereoselectivity (Scheme 6).

Moreover, the inﬂuence of protecting groups and Lewis acids

on reaction diastereoselectivity were found to be in accord with

the control elements previously described for additions of allyl-

and crotyltri-n-butylstannanes²⁴to these aldehydes and provided

access to either the chelation-controlled adduct 24 or the

complementary diastereomeric Felkin-Ahn adduct 26 with

essentially complete diastereofacial selectivity.

Results and Discussion

Approaches to δ-Hydroxy ꢀ-Keto Esters. In planning the

synthesis of 9, we took note that an effective method for making

δ-hydroxy ꢀ-keto esters from R-methyl ꢀ-alkoxy aldehydes such

as 10 might be through the use of the ꢀ-keto ester dianion

synthon, Chan’s diene 19.²¹

Although the dimethyl-disubstituted reagent 19 was unknown,

the parent compound (with each of the γ-methyls replaced with

a hydrogen) has been shown to undergo additions to aldehydes

with a high degree of diastereoselectivity.²²Initial investigations

of this connective approach to directly install the gem-dimethyl

group were frustrated by our inability to prepare the requisite

γ,γ-disubstituted Chan’s diene 19 from 20.

We were thus led to consider the use of an allylstannane

equivalent (Scheme 5) as a synthon for the dimethyl-substituted

Chan’s diene reagent 19. Hence, the desired δ-hydroxy ꢀ-keto

ester 9 could be envisioned to arise from oxidative cleavage of

the oleﬁn in 21, which in turn could arise from the Lewis acid

promoted addition of stannane 22 to aldehyde 10.

With conﬁdence established for high substrate-controlled

aldehyde facial selectivity in the critical stannane addition

reaction, the synthesis of the allylstannane 22 was then

undertaken. A 1,4-conjugate addition approach to 22 was

examined which consisted of a copper mediated addition of

tributylstannylmethyllithium 27 to allenic ester 28 followed by

protonation of the resulting enolate, as shown in Scheme 7. This

approach thus required access to the lithium reagent and the

allenic ester 28.

The requisite lithium reagent 27 is known²⁵and was derived

from a lithium-halogen exchange between n-BuLi and iodom-

ethyltributyltin 30. It was found that this known stannane 30

could be prepared from commercially available CH₂I₂and

Bu₃SnCl in >70 g batches using a modiﬁcation of the Seyferth

procedure.²⁶

Before embarking upon any attempted preparation of the very

highly substituted stannane 22, it seemed advisable to investigate

whether this approach to the introduction of the quaternary

For preparation of the allenic ester 28, we took a lead from

an Organic Synthesis preparation by Lang and Hansen.²⁷We

found that allenic ester 28 could be made in a single step on

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9678 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

SCHEME 8. Synthesis of Stannane 22

SCHEME 9. Synthesis of C₁-C₇Diol 34

SCHEME 10. SmI₂-Mediated Reduction of of ꢀ-Hydroxy

Ketone 9

multigram scale (Scheme 8) by the Wittig coupling of dimeth-

ylketene (derived from reaction of isobutyryl chloride with

triethylamine) and the commercially available phosphorane 32.

However, initial runs provided the desired allenic ester in low

yields of less than 20%. A simple change in the order of addition

of the reagents increased the yield to 68% on a >30 g scale

reaction.²⁸

With access to large quantities of iodide 30 and allenic ester

28 secured, the 1,4-conjugate addition was then optimized. This

coupling turned out to be more sensitive than we had originally

anticipated. The use of n-BuLi to effect the lithium-halogen

exchange with iodide 30 led to the formation of the desired

stannane 22; however, this cuprate addition gave highly variable

yields that ranged from ∼20% to >95% yield on up to a 2.5 g

scale. Reproducability and problems upon increasing the scale

of this reaction were found to be serious limitations in preparing

stannane reagent 22. It appeared that the difﬁculty was in the

initial lithium-halogen exchange. Switching from n-BuLi to the

more reactive t-BuLi (Scheme 8) gave much more consistent

results. Lithium-halogen exchange of iodide 30 using t-BuLi,

followed by formation of the (tri-n-butylstannyl)methyl cuprate

and addition into allenic ester 28 gave the desired stannane

reagent 22 in a fairly consistent 70% yield on ∼7 g scale.^29,30

This ꢀ,γ-unsaturated ester proved to be remarkably stable. Not

only could it be puriﬁed by silica gel chromatography, but it

could also be stored, as a neat reagent, for over a year at -20

°C without noticeable decomposition occurring, and without

detectable isomerization of the double bond to give a conjugated

system.

chelation-controlled adduct 21. While analytically pure alcohol

21 could be obtained by silica gel chromatography, it was prone

to undergo oleﬁn migration and lactonization. For preparative

purposes, it was best to carry it crude into the next step in the

sequence. Thus, ozonolysis gave δ-hydroxy ꢀ-keto ester 9 in

77% yield over the three steps.

At this point, our intent was to use this newly formed C₅-

hydroxyl stereocenter to direct the stereoselective reduction of

the C₃-ketone. Preliminary attempts to establish this C₃,C₅-syn

diol were, unfortunately, poorly selective. For example, while

Zn(BH₄)₂provided the desired C₃,C₅-syn diol 34, the ratio of

diastereomers was a disappointing 2:1.

Further investigation revealed similarly low levels of dias-

tereoselectivity for formation of the desired 1,3-syn diol

diastereomer through use of the usually powerful but rather

limited number of syn-selective hydride reducing agents. This

led us to consider whether the use of single-electron reducing

agents, such as SmI₂, might provide 1,3-diols stereoselectively

from ꢀ-hydroxy ketones. A number of features of this reagent

suggested that this might be the case. Unlike a number of other

single-electron reducing agents, including other low-valent

metals and metal complexes, SmI₂is remarkably stable in

alcohols and water.³¹This permits SmI₂reactions to include a

proton source during the reduction, thus allowing immediate

protonation of reactive anionic intermediates. Samarium(II) and

-(III) cations are also very oxophilic and can serve as potential

chelating Lewis acids.

Synthesis of the C₁-C₉Carboxylic Acid Fragment. The

synthesis toward the C₁-C₉fragment (Scheme 9) commenced

with the DIBAL half-reduction of R-methyl-ꢀ-benzyloxy ester

33 to the corresponding known aldehyde 10. This was followed

immediately by Lewis acid mediated addition of stannane 22,

using TiCl₄as the Lewis acid, to give the homoallylic alcohol

as a 10:1 mixture of diastereomers in favor of the desired

Treatment of ꢀ-hydroxy ketone 9 in THF, at room temper-

ature, with a solution of SmI₂(3 equiv) in THF and water (2

equiv) resulted in complete consumption of starting material

1

(28) It was assumed that this low yield resulted from the difﬁculty in

separating the desired, relatively volatile allenic ester from the large amount of

solid reaction byproducts, including triethylammonium chloride and triph-

enylphosphine oxide. We were surprised to ﬁnd that an aqueous workup resulted

in the formation of a new major byproduct, isobutyric acid. This led us to consider

that the ketene intermediate was surprisingly stable and perhaps preformation

of the ketene, before adding the Wittig reagent, might minimize some alternative

reaction pathways. This simple change in the order of addition of the reagents

increased the yield to 68% on a >30 g scale reaction.

(29) The limitation of scale here is of practical nature. We limited the reaction

scale to the use of a commercially available 100 mL Sure-Seal bottle of 1.7 M

solution of t-BuLi in pentanes, which was transferred directly from the bottle

into the reaction solution via cannula.

within 10 min. H and ¹³C NMR indicated the formation of

essentially a single diol diastereomer (dr >95:5), which was

isolated in 93% yield. The diol was converted to the acetonide

and the stereochemistry determined using the methods of

Rychnovsky and Evans.³²This revealed that the product of the

reaction was the unexpected C₃,C₅-anti diol 35. The stereo-

chemistry of this diol was further conﬁrmed by conversion of

(31) Hasegawa, E.; Curren, D. P. J. Org. Chem. 1993, 58, 5008–5010.

(32) (a) Rychnovsky, S. D.; Yang, G.; Powers, J. P. J. Org. Chem. 1993,

58, 5251–5255. (b) Rychnovsky, S. D.; Rodgers, B.; Yang, G. J. Org. Chem.

1993, 58, 3511–3515. (c) Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron

Lett. 1990, 31, 7099–7100. (d) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron

Lett. 1990, 31, 945–948.

(30) The major byproduct of the reaction, though not fully characterized,

gave an NMR spectrum that was consistent with the 1,4-addition of a tert-butyl

anion into the allenic ester, which shows that lithium-halogen exchange was not

fully complete even with the use of t-BuLi.

J. Org. Chem. Vol. 73, No. 24, 2008 9679

Keck et al.

SCHEME 11. Second-Generation C₁-C₉Retrosynthetic

Analysis

SCHEME 12. Synthesis of Aldehyde 39

reduction would ultimately require the δ-hydroxy ꢀ-keto ester

37, with opposite stereochemistry at C₅to that of our present

intermediate. We anticipated, based on previous work and the

earlier model studies with prenyltri-n-butylstannane additions,

that this diastereomer could be prepared from the Felkin-

controlled addition of stannane 22 to aldehyde 25, with the ꢀ-OH

now protected as a TBS ether rather than a benzyl ether. This

offered an additional potential advantage in that it seemed likely

that the requisite BF₃·OEt₂-mediated reaction needed to secure

the requisite stereoselectivity might be less prone to complica-

tions on scale up than would be the reaction using TiCl₄.

The synthesis of the new C₁-C₉fragment (Scheme 12)

commenced with the Lewis acid mediated addition of stannane

22 to the ꢀ-OTBS aldehyde 25. Using BF₃·OEt₂as the Lewis

acid did in fact give the desired Felkin controlled adduct 38,

with >95:5 diastereoselectivity. Initially, this alcohol was found

to be very susceptible to lactonization, with ratios of acyclic to

lactonized product varying from 10:1 to 1:6. It was subsequently

determined that lactonization was occurring primarily during

the quench and workup of the reaction mixture. By pouring the

cold (-78 °C) reaction mixture directly into an Erlenmeyer ﬂask

that contained a large excess of a vigorously stirring mixture

of CH₂Cl₂, pH 7 buffer, and water, essentially all lactonization

of the crude reaction product could be suppressed. On a 2.5 g

scale, this addition gave analytically pure alcohol 38 in 83%

yield and with >95:5 diastereoselectivity³⁵for the Felkin-Ahn

adduct. However, for practical reasons on larger scale, this

alcohol was consistently carried into the next reaction crude.

Following oxidative cleavage of the oleﬁn by ozonolysis, the

C₃stereocenter was established by reduction of the resulting

ꢀ-hydroxy ketone using the SmI₂electron-transfer reduction.

Under optimal conditions, reduction of the ꢀ-hydroxy ketone

37 using SmI₂in a solvent mixture of THF-MeOH gave diol

36 in 94% yield and with a 96:4 level of diastereoselectivity.

The next synthetic operation required liberation of the C₇-

hydroxyl group, which must be oxidized, while protecting those

at C₃and C₅, which must be retained. It was found that his

could be accomplished in a one-pot procedure. Thus, acid-

catalyzed methanolysis of the primary C₇-TBS ether using PPTS

in MeOH, at reﬂux, was followed by concentration and addition

of (5:1) dimethoxypropane/MeOH, which resulted in selective

formation of the internal acetonide.³⁶The unpuriﬁed mixture

was found to contain a small amount of terminal methoxyiso-

propyl (MIP) ketal, which was converted to the corresponding

ꢀ-hydroxy ketone 9 to the same anti-diol product 35 by

independent synthesis using Evans’ Me₄NBH(OAc)₃reduction

procedure,³³a method which is known to selectively produce

1,3-anti diols with high levels of diastereoselectivity.

While this SmI₂reduction did not furnish the desired 1,3-

syn diol necessary for use in the current synthetic strategy for

making epothilone B, it was, nevertheless, an excellent empirical

result.³⁴We thus considered the possibilty of incorporating this

new, highly selective, and especially convenient 1,3-anti diol

reduction into our synthesis of epothilone B.

Returning to the structure of epothilone B 2 (Scheme 11), it

can be seen that C₅is at the oxidation state of a ketone, which

we planned to generate by a late-stage oxidation of an existing

C₅-hydroxyl group. The absolute conﬁguration of the C₅-

hydroxyl group from either seven-carbon intermediate 34 or 35

is, therefore, inconsequential in terms of the natural product,

as this stereochemical information will be lost in the subsequent

oxidation. The critical function of the C₅-hydroxyl group

stereochemistry, rather, is to direct the reduction of a C₃-ketone

intermediate in order to establish the correct stereochemistry

for the C₃-hydroxyl group. In essence, there is an overall transfer

of oxidation states and chirality between functional groups on

C₃and C₅. From a retrosynthetic perspective, we are therefore

free to arbitrarily choose the absolute stereochemistry of the

C₅-hydroxyl group. Use of a synthetic plan using the 1,3-anti

1

(33) (a) Evans, D. A.; Chapman, T. K.; Carreira, E. M. J. Am. Chem. Soc.

1988, 110, 3560–3578. (b) Evans, D. A.; Chapman, T. K. Tetrahedron Lett.

1986, 27, 5939–5942.

(34) This reaction has been studied independently and a model for the

observed stereochemistry proposed. See: (a) Keck, G. E.; Wager, C. A.; Sell,

T.; Wager, T. T. J. Org. Chem. 1999, 64, 2172–2173. (b) Keck, G. E; Wager,

C. A. Org. Lett. 2000, 2, 2307–2309.

(35) Single diastereomer by 500 MHz H NMR.

(36) A number of times, this reaction gave yields of approximately 80%;

however, some yields were as low as 30% of the desired alcohol. On those

occasions where we experienced a low yield, all nonproduct-containing fractions

that were collected after the column chromatography were combined and

resubjected to the same reaction conditions, which allowed for further formation

of the desired alcohol.

9680 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

SCHEME 13. Synthesis of C₁-C₉Acid 43

SCHEME 14. Preparation of the C₁₀-C₂₁Alcohol 7

primary alcohol by redissolving the crude reaction material in

MeOH and immediately removing the MeOH under reduced

pressure. Swern oxidation of the primary alcohol then gave

aldehyde 39.

Coupling of aldehyde 39 and crotyl boronate 40³⁷(Scheme

13) proceeded in high yield and with good diastereoselectivity.

The major product was determined by X-ray crystallography

to be the desired C₆,C₇Felkin-Anh-controlled, C₇,C₈anti-aldol

isomer 41. The minor product 42 was conﬁrmed by Mosher

ester analysis and acetonide formation using a C₇-C₉1,3-diol

derivative to be the C₆,C₇anti-Felkin, C₇,C₈anti-aldol isomer.

This represents an optimum result which was obtained only after

extensive experimental investigation.

After conversion of the hydroxyl group of 41 to the TBS

ether, hydrolysis of the methyl ester gave carboxylic acid 43

(Scheme 13). The synthesis of this fragment was thus completed

in eight steps from the known aldehyde 25 in 40% overall yield.

Synthesis of the C₁₀-C₂₁Alcohol Fragment. While we were

developing our route to acid 43, we had also developed plans

to utilize a δ-hydroxy ꢀ-keto ester to fashion the requisite

trisubstituted oleﬁn in the C₁₀-C₂₁segment. Given the success

of the previous stannane addition approach to the formation of

δ-hydroxy ꢀ-keto esters in the synthesis of the C₁-C₉piece,

we sought to employ a similar strategy for this fragment. As

shown in Scheme 14, the known³⁸stannane 44 was coupled

with the known R,ꢀ-unsaturated aldehyde 18³⁹using our BITIP-

catalyzed asymmetric allylation reaction.⁴⁰Reaction using (S)-

BINOL and Ti(OiPr)₄afforded the (S)-homoallylic alcohol 45

in 72% yield and with excellent enantioselectivity (98:2 er).

After protection of the resulting alcohol as its TBS ether,

selective cleavage of the C₁₃oleﬁn was initially attempted using

ozone; however, these reaction conditions also caused cleavage

of the internal C₁₆-C₁₇trisubstituted oleﬁn. Use of a one-pot,

two-step oxidative cleavage procedure (dihydroxylation with

OsO₄/NMO followed by oxidative diol cleavage using NaIO₄)

was much more selective and afforded the corresponding ꢀ-keto

ester in 80% yield. Alkylation of the ꢀ-keto ester with allyl

iodide then gave 15 as a 1:1 mixture of diastereomers (and their

corresponding enol tautomers).

With the entire C₁₀-C₂₁carbon framework assembled, we now

turned to setting the (Z) geometry of the trisubstituted C₁₂-C₁₃

oleﬁn by trapping the sodium enolate of 15 as the vinyl triﬂate

using Comins’ reagent.⁴¹Vinyl triﬂate 13 was formed with 10:1

selectivity for the desired isomer and in 77% yield. The vinyl

triﬂate was then reduced under palladium-catalyzed tin hydride

reduction conditions⁴²to afford the requisite (Z)-oleﬁn (94%).

The R,ꢀ-unsaturated ester was then reduced using DIBAL to

give the allylic alcohol 46. This was deoxygenated in two steps

by conversion to the allylic chloride using the Corey-Kim

procedure⁴³followed by hydride reduction to give the requisite

C₁₂methyl substituent. Removal of the silyl ether was then

accomplished by acid-catalyzed hydrolysis to give alcohol 7.

Overall, the synthesis of this fragment was completed in 10

steps from the known aldehyde 18 and in 25% overall yield.

Fragment Coupling and Ring-Closing Metathesis. With

the C₁-C₉and C₁₀-C₂₁fragments in hand, carboxylic acid 43

and alcohol 7 were then subjected to DCC coupling, which gave

the desired ester 47 in 77% yield (Scheme 15). The resulting

diene was then exposed to RCM conditions using Grubb’s

second-generation ruthenium alkylidene catalyst 48. This yielded

a single compound, which unfortunately, turned out to be

compound 49, containing a seven-membered ring, rather than

the desired macrolactone.

(37) Hoffmann, R. W.; Zei, H. J. Org. Chem. 1981, 46, 1309–1314.

(38) While this stannane was noticeably less stable to silica gel chromatog-

raphy than the γ,γ-dimethyl-substituted stannane 22, it could be puriﬁed by quick

chromatography on a silica gel column which was slurry packed with 1% Et₃N/

EtOAc and then ﬂushed with hexanes prior to use.

(39) (a) Meng, D.; Sorensen, E. J.; Bertinato, P.; Danishefsky, S. J. J. Org.

Chem. 1996, 61, 7998–7999. (b) Shaﬁee, A.; Mazloumi, A.; Cohen, V. I.

J. Heterocycl. Chem. 1979, 16, 1563. (c) Shaﬁee, A.; Shahocini, S. J. Heterocycl.

Chem 1989, 26, 1627.

We suspected that the acetonide was the main cause of the

complete failure of 47 to form any of the macrolactone via

RCM. It is possible that the rigidity imposed by the acetonide

(41) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.

(42) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033–3340.

(43) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13, 4339–

4342.

(40) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,

115, 8467–8468. (b) Keck, G. E.; Yu, T. Org. Lett. 1999, 1, 289–291, and

references therein.

J. Org. Chem. Vol. 73, No. 24, 2008 9681

Keck et al.

SCHEME 15. Ester Coupling and Ring-Closing Metathesis

SCHEME 16. Other Epothilone RCM Results

did not allow the diene to readily adopt a conformation that

allowed the C₉and C₁₀oleﬁns to become sufﬁciently close to

undergo RCM. With the compound unable to undertake the

C₉-C₁₀metathesis, the C₁₀terminal oleﬁn is then left to undergo

RCM with the trisubstituted C₁₆-C₁₇oleﬁn. Other examples

of such RCM reactions in the context of epothilone synthesis

have been described (Scheme 16). Danishefsky ﬁrst performed

this reaction on a precursor that lacked the C₃,C₅acetonide

functionality encountered in our synthesis. When compound 50,

which has a C₃-TES ether and C₅ketone, was subjected to RCM,

the desired macrolactone 51 was formed in 38% yield as a single

trans isomer; however, the major product of the reaction was

the seven-membered ring 52, formed in 62% yield.⁴⁴To

circumvent this unwanted side product, Danishefsky synthesized

a new precursor, 53, which lacked the C₁₆-C₁₇trisubstituted

oleﬁn. This precludes formation of the seven membered ring.

In this case, RCM yielded the macrolactone 54 in 78% yield as

a single (E)-isomer. He then installed the thiazole ring in a

subsequent step. Sun and Sinha⁴⁵performed a RCM reaction

on the advanced epothilone precursor 55 containing the C₁₂-C₁₃

epoxide functionality and obtained the macrolactone 56 in 89%

yield as a 1:1 mixture of E/Z oleﬁn isomers.

From these reactions, it would appear that the presence of

the acetonide functionality is most likely the major cause for

the complete failure of our RCM precursor 47 to give the desired

macrolactone. Simple removal of the acetonide was not an

option due to formation of a six-membered ring lactone under

the reaction conditions (vide infra). We therefore decided to

abandon the RCM route and complete the synthesis by reversing

the order of the two operations of esteriﬁcation and formation

of the C₉-C₁₀alkene.

Macrolactonization Route to Epothilone B: Revised

Retrosynthetic Analysis of Epothilone B. The new retrosyn-

thetic analysis for epothilone B (2) is shown in Scheme 17.

We would now proceed by establishing the C₉-C₁₀oleﬁn before

closing the macrolactone. This macrolactonization strategy

would intercept a known late-stage intermediate 57.¹⁸The

C₉-C₁₀oleﬁn of intermediate 58 would result from a Wittig

coupling of aldehyde 59 and phosphonium salt 60. Such Wittig

reactions have been employed previously for fragment coupling

in the epothilone synthesis by White and co-workers.¹⁸As with

the previous RCM strategy, this disubstituted oleﬁn would later

be selectively reduced to form two of the three contiguous

methylene groups found in the natural product.

The requisite aldehyde was available trivially from our

previous C₁-C₉intermediate. Oxidative cleavage of the previ-

ously synthesized terminal oleﬁn 61 by the two-step procedure

of dihydroxylation with OsO₄/NMO followed by reaction with

NaIO₄gave aldehyde 59 in 89% yield. Therefore, the synthesis

of the new C₁-C₉fragment was completed in eight steps from

the known aldehyde 25 in 38% overall yield (Scheme 18.)

(44) (a) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Cho, Y. S.; Chou, T.-

C.; Dong, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 10913–10922.

(b) Rivkin, A.; Yoshimura, F.; Gabarda, A. E.; Chou, T.-C.; Dong, H.; Tong,

W. P.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 2899–2901.

(45) Sun, J.; Sinha, S. C. Angew. Chem., Int. Ed. Engl. 2002, 41, 1381–

1383.

9682 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

SCHEME 17. Revised Retrosynthetic Analysis of Epothilone

B

SCHEME 19. Retrosynthetic Approach to Phosphonium

Salt 60

SCHEME 20. Preparation of Phosphonium Salt 60

SCHEME 18. Preparation of Aldehyde 59

Synthesis of the C₁₀-C₂₁Phosphonium Salt Fragment.

Initially, we examined a synthetic route to this segment which

was based on minor modiﬁcations of the existing route. While

we were able to prepare the requisite phosphonium salt in this

manner (11 steps from the known aldehyde 18 in 14% overall

yield) the overall yield was poor and the sequence was much

longer than desirable. Thus, we attempted to design a more

efﬁcient route to phosphonium salt 60 (Scheme 19).

Based on our experience to date with this subunit, we believed

we could construct the desired C₁₀-C₂₁fragment 60 from the

key R,ꢀ-unsaturated ester intermediate 64. The C₁₂-C₁₃trisub-

stituted (Z)-oleﬁn geometry should be established with high

diastereoselectivity through reaction of aldehyde 66 with a

stabilized phosphorane. We decided to try to protect the C₁₀-

hydroxyl group by incorporating it into the lactone functionality

of phosphorane 65.

The synthesis (Scheme 20) of the C₁₀-C₂₁phosphonium salt

60 began with the CAA reaction of aldehyde 18 and allyltri-

n-butylstannane 67 to give the known CAA adduct 68. After

protection of the newly formed hydroxyl group as the corre-

sponding silyl ether, oxidative cleavage of the terminal oleﬁn

yielded aldehyde 66.⁴⁶Wittig coupling with the known phos-

phorane 65⁴⁷gave lactone 69 in quantitative yield and with

excellent (95:5) diastereoselectivity. This transformation not only

establishes the necessary geometry for the trisubstituted oleﬁn

but also incorporates the remaining carbon framework needed

(46) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.;

Vallberg, H.; Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974–

7991.

(47) Baldwin, J. E.; Moloney, M. G.; Parsons, A. F Tetrahedron 1992, 48,

9373–9384.

J. Org. Chem. Vol. 73, No. 24, 2008 9683

Keck et al.

SCHEME 21. Selective Allylic Chlorination

SCHEME 22. Synthesis of Lactone 74

for this C₁₀-C₂₁segment. Full reduction of the lactone using

DIBAL gave diol 63 nearly quantitatively (97%).

The successful utilization of this route depended upon an

efﬁcient differentiation of the two primary hydroxyl moieties

in diol 63. We were pleased to ﬁnd a single-pot procedure⁴⁸

that allowed for the conversion of diol 63 to the C₁₀-TBS-

protected allylic chloride 71 by the sequential, selective

chlorination of the allylic alcohol by reaction with the Corey-Kim

reagent, followed by protection of the remaining primary alcohol

as the corresponding TBS-silyl ether to give 71. The resulting

C₁₂-allylic chloride was then easily reduced with lithium

triethylborohydride (“Super-Hydride”) to give the trisubstituted

(Z)-oleﬁn 72. This was then smoothly converted to the C₁₀-C₂₁

phosphonium salt 60, which was obtained in 28% overall yield

from aldehyde 18.

SCHEME 23. Attempted Opening of Model Lactone

Substrate 75

One ﬁnal improvement remained. Although we were pleased

with the success of the one-pot conversion of 63 to 71, in

retrospect, it became clear that the TBS ether was being used

in only a single step, that being the Super-Hydride reduction of

the allylic chloride 71. Thus, we wondered if it might be possible

to conduct this operation on the free alcohol, and thus save the

steps of protection and deprotection. The concern here was

obviously the formation of a tetrahydrofuran by intramolecular

displacement of the allylic chloride by the boron alkoxide anion.

To determine the viability of leaving the primary alcohol

unprotected, allylic alcohol 63 was ﬁrst selectively chlorinated

(Scheme 21) by reaction with the Corey-Kim reagent to give

allylic chloride 70. The resulting chloro-alcohol was then

reduced, under carefully optimized conditions, with lithium

triethylborohydride (“Super-Hydride”) to the trisubstituted oleﬁn

62. It was found that this transpired without signiﬁcant formation

of the cyclic ether 73. Alcohol 62 was then converted to

phosphonium salt 60 as previously described. This optimization

thus provided the C₁₀-C₂₁fragment from the known aldehyde

18 in just nine steps and in a much improved 46% overall yield.

Wittig Coupling of the C₁-C₉and C₁₀-C₂₁Fragments.

Wittig coupling of aldehyde 59 and phosphonium salt 60,

Scheme 22, gave 58 in 87% yield. Differentiation of the C₃,C₅

diol was initiated by hydrolysis of the acetonide by exposure

to 2 N HCl in acetonitrile; this was accompanied by spontaneous

lactonization. The three free hydroxyl groups were then

protected as TBS silyl ethers to give lactone 74. Overall, this

two-step sequence served to differentiate the C₅-hydroxyl group,

which must be oxidized, from the other secondary alcohols. Our

plan was to open the lactone and effect the requisite oxidation,

ultimately giving the known carboxylic acid intermediate 57,

which would complete a formal synthesis of epothilones B and

D.¹⁸This sequence, however, proved to be much more difﬁcult

than had been anticipated.

Model Studies on the Lactone Opening. We chose to model

the lactone opening with the truncated lactone 75 (Scheme 23).

Simple hydrolysis of 75 with LiOH/H₂O was attempted ﬁrst.

Monitoring the course of the hydrolysis reaction by TLC showed

that after 2 h, all the starting material had been consumed with

formation of a very low R_fspot, which was assumed to be the

carboxylate 76. Upon mild workup, however, this unstable

intermediate reverted to the starting material to give lactone

75, in near quantitative yield, as the sole product of the reaction.

We also attempted to open this lactone reductively to give the

corresponding diol. After screening a number of hydride

reducing agents, only LiBH₄was found to give any signiﬁcant

formation of diol 78. Under these reduction conditions, the

(48) Hughes, R. C.; Dvorak, C. A.; Meyers, A. I. J. Org. Chem. 2001, 66,

5545–5551.

9684 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

SCHEME 24. Aniline Opening of Model Lactone 75

SCHEME 25. Attempted Opening of Lactone 74

SCHEME 26. Lactone Opening with Advanced Model 84

majority of the lactone starting material was converted to a 1:1

diastereomeric mixture of lactol 77, which was completely

unreactive to any further reduction.

In Evans’ synthesis of bryostatin 1,⁴⁹an identical lactonization

approach was used to differentiate between two secondary

hydroxyl groups in a 3,5-dihydroxy ester. In that case, the

lactone intermediate was opened using an aluminum amide

derivative of aniline (Me₃Al/C₆H₅NH₂·HCl). The resulting

amide could be subsequently converted to the carboxylic acid

in two steps by Boc activation of the amide followed by basic

hydrolysis.⁵⁰We were interested to see if our C₄-gem dimethyl

lactone could be converted to the carboxylic acid using the same

protocol. In the event, the conversion of the lactone model

compound to the desired aniline amide was sluggish and

proceeded in a low 46% yield (with 54% recovered starting

material), but the amide 80 proved to be stable to both workup

and silica gel chromatography.⁵¹

With the truncated aniline amide 80 in hand, we thought it

prudent to subject this model compound to the same oxidation

and hydrolysis conditions we planned to employ to make the

desired epothilone intermediate 57. Therefore, the secondary

alcohol 80 was oxidized (Scheme 24) using the Albright and

Goldman⁵²modiﬁcation of the Moffat conditions (Ac₂O,

DMSO, and Et₃N) to provide the desired ketone 81.⁵³The amide

was then activated for hydrolysis by Boc derivatization to give

82. Hydrolysis of this imide using lithium hydroperoxide gave

the desired carboxylic acid 83 in 71% yield over the three steps.

Thus, we felt that if some improvement in the conversion of

the lactone to amide could be realized, that a workable route to

convert the fully elaborated lactone 74 to the known intermediate

57 was in hand.

Even though we knew that using the aluminum aniline amide

conditions to open the lactone had proceeded in low yield for

the model compound, we still decided to try these conditions

on the real substrate. Surprisingly, the treatment of lactone 74

with the aluminum aniline amide, Scheme 25, returned only

starting material even after 3 days at room temperature.

The most logical difference between the model compound

75 and 74 is an increase in steric demand of the fully elaborated

lactone. A more sterically encumbered lactone, 84, was therefore

employed as a more realistic model for the requisite lactone

opening; indeed, this model represents fully half of the real

substrate (Scheme 26). Treatment of lactone 84 under the same

aluminum amide conditions that had proven unsuccessful for

the fully elaborated lactone 74, also gave none of the desired

amide 85. This was the expected result of this experiment which

was carried out on the basis of logical consistency.

Upon searching the literature on related reactions more

thoroughly, we found that Williams and co-workers at Merck

had reported observations very relevant to the present problem.

Speciﬁcally, they found that Weinreb amides could easily be

made in excellent yield from highly hindered esters using the

magnesium salt of the Weinreb amine, in cases where the more

standard aluminum-based reagent had failed to yield any amide

product.⁵⁴In a modiﬁcation of these Merck conditions, we

subjected the model lactone 84 to the magnesium anilide

prepared by the reaction of 2 equiv of i-PrMgCl with

C₆H₅NH₂·HCl. While these conditions yielded a moderate

amount of the desired aniline amide, the majority of the reaction

mixture was still unreacted starting material. Extending this

(49) (a) Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.; Charette, A. B.

J. Org. Chem. 1991, 56, 741–750. (b) Evans, D. A.; Carreira, E. M. Tetrahedron

Lett. 1990, 31, 4703–4706.

(50) Evans, D. A.; Carter, P. H.; Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.;

Kung, D. W. Tetrahedron Lett. 1997, 38, 4535–4538.

(51) No reversion of the amide 1.223 to lactone 1.218 was ever seen, even

after prolonged storage at-20 °C.

(52) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416–2423.

(53) This oxidation method has been shown to be highly effective for hindered

secondary alcohols, and we had previously found it effective for a secondary

alcohol vicinal to a gem-dimethyl group: Keck, G. E.; Yu, T.; McLaws, M. D.

J. Org. Chem. 2005, 70, 2543–2550.

(54) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,

U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461–5464.

J. Org. Chem. Vol. 73, No. 24, 2008 9685

Keck et al.

SCHEME 27. Completion of the Synthesis of Epothilone B

Following the precedent provided by Evans, the amide was

then activated for hydrolysis by Boc derivatization (Scheme 27).

Hydrolysis of the derived imide 87 was then affected using

lithium hydroperoxide to afford the known carboxylic acid 57.

For this transformation, we initially used the same hydrolysis

reaction conditions (LiOH, H₂O₂, THF, H₂O) that we had

previously used on the model compound 82 (see Scheme 24).

This had given an excellent yield (92%) of the desired carboxylic

acid 83. When applied to the Boc-protected amide 87, however,

the reaction produced low and variable yields of the carboxylic

acid 57. In addition, we observed for the ﬁrst time signiﬁcant

formation of a side product in which the BOC group had been

cleaved. Jacobi⁵⁵has made note of strong solvent effects for

the hydrolysis of similar compounds. When we applied new

mixed solvent hydrolysis conditions based on the Jacobi

observations (LiOH, H₂O₂, THF, DMF, H₂O), we saw an

increase in the yield of carboxylic acid 57 and a subsequent

reduction in the amount of BOC cleavage; however, the overall

yield of the reaction was still variable. After considerable

experimentation, we concluded that the problem we were

experiencing was due to adventitious decomposition of H₂O₂.

Use of rigorous precautions (complete avoidance of metal

needles and Teﬂon stirbars, and using glassware prewashed with

30% H₂O₂solution) gave much improved results. Despite these

precautions, occasionally no conversion of the Boc-protected

amide 87 to the carboxylic acid 57 was obtained. In such runs,

the reaction simply had to be worked up and started over.

With the synthesis of this carboxylic acid, we had completed

a formal synthesis of epothilones B and D.⁵⁶The completion

of the total synthesis of epothilones B and D began with the

selective removal of the secondary allylic TBS ether in 57 using

TBAF. The resulting hydroxy acid then underwent macrolac-

tonization under Yamaguchi conditions⁵⁷to give the desired

macrolactone in 65% yield. Global deprotection was ac-

complished using 2 N HCl in MeCN to give 88. The precedented

selective diimide reduction of the disubstituted oleﬁn using

triisopropylphenylsulfonylhydrazide⁵⁸then provided epothilone

D, 3. Finally, the known stereoselective epoxidation of epothilone

D using DMDO⁵⁹gave epothilone B (2) as an 8:1 mixture in

favor of the desired ꢀ-epoxide.⁶⁰

Summary

The total synthesis of epothilone B was completed in 20 steps

with an 8.9% total yield. This product became the genesis for

three new methodologies in our laboratories: the anti-selective

electron transfer reduction of ꢀ-hydroxy ketones using SmI₂,

the CAA addition of stannane 44, as a synthon for Chan’s diene,

(55) Jacobi, P. A.; Murphee, S.; Rupprecht, F.; Zheng, W. J. Org. Chem.

1996, 61, 2413–2427.

(56) (a) White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am.

Chem. Soc. 2001, 123, 5407–5413. (b) White, J. D.; Carter, R. G.; Sundermann,

K. F. J. Org. Chem. 1999, 64, 684–685.

(57) Inanaga, J.; Hirata, K.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc.

Jpn. 1979, 52, 1989–1993.

(58) (a) Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B. Tetrahedron

1996, 32, 2157–2162. (b) Ermolenko, M. S.; Potier, P. Tetrahedron Lett. 2002,

43, 2895–2898.

further, we then found that the lithium anilide, formed by the

reaction of two equivalents of n-BuLi with C₆H₅NH₂·HCl, gave

the desired amide 85 in near quantitative yield.

Completion of the Total Synthesis of Epothilones B

and D. Using the optimized lithium aniline amide conditions

with the real substrate, 74, we were pleased to ﬁnd that this

lactone was opened to give the aniline amide 86 in 94% yield,

Scheme 27. The secondary alcohol was then oxidized under

the modiﬁed Moffat conditions to provide the corresponding

ketone.

(59) Stachel, S. J.; Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6785–

6787.

(60) When we compared the ¹³C NMR spectra of our synthetic epothilone

B to other published spectra, it was found that there are several different reported

values for the carbon spectra of epothilone B. Our ¹³C NMR spectra data are in

excellent agreement with that of Avery.^13bFurther, we believe that our ¹³C NMR

spectra are correct as our ¹³C DEPT NMR spectra are consistent with the structure

of epothilone B.

9686 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

Sn satellites, 2H), 1.70 (s with Sn satellites, 3H), 1.65 (s with Sn

satellites, 3H), 1.56-1.40 (m, 6H), 1.36-1.22 (m, 6H), 1.22 (t, J

)6.8 Hz, 3H), 0.89 (t, J )7.3 Hz, 9H), 0.88-0.80 (m, 6H); 125

MHz ¹³C NMR (CDCl₃) δ 172.5, 125.2, 123.0, 60.5, 40.2, 29.3

(with Sn satellites), 27.6 (with Sn satellites), 21.1, 20.8, 17.0, 14.5,

13.9, 10.0 (with Sn satellites); DEPT 125 MHz ¹³C NMR (CDCl₃)

δ CH₃: 21.1, 20.8, 14.5, 13.9. CH₂: 60.5, 40.2, 29.3 (with Sn

satellites), 27.6 (with Sn satellites), 17.0, 10.0 (with Sn satellites)

ppm; IR (neat) 2854, 1736 cm^-1. Anal. Calcd for C₂₁H₄₂O₂Sn: C,

56.65; H, 9.51. Found: C, 56.92; H, 9.61.

and the substrate controlled additions of the highly substituted

stannane 22.

There are a number of elegant and practical total syntheses

of epothilone B published to date. The most notable differences

between these and the route described herein are in the formation

of the C₁-C₉fragment. The C₄gem-dimethyl group was

installed in this synthesis through a stereoselective connective

fragment assembly rather than as a constituent of a simple

precursor. This approach may well ﬁnd wider application as

the introduction of such quaternary centers is often difﬁcult.^61,62

In the C₁₀-C₂₁fragment, an efﬁcient approach was developed

that installed the C₁₂-C₁₃trisubsituted (Z)-oleﬁn with high

diastereoselectivity, and which culminated in the use of a

selective and efﬁcient diol differentiation protocol. Finally,

although the lactone opening sequence was very frustrating at

the time, eventually we found a solution to this problem which

should also prove to be of more general utility.

Ethyl (5S,6R)-5-Hydroxy-4,4,6-trimethyl-3-oxo-7-(1,1,2,2-tet-

ramethyl-1-silapropoxy)heptanoate. To a stirring solution of crude

aldehyde 25 (9.36 g, 46.2 mmol, 1.2 equiv) and CH₂Cl₂(430 mL)

in a 1 L round-bottom ﬂask under an atmosphere of nitrogen, at

-78 °C, was added a solution of stannane 22 (17.2 g, 38.5 mmol,

1.0 equiv) and CH₂Cl₂(20 mL) via cannula. An additional CH₂Cl₂

rinse (10 mL) was used to transfer the remaining aldehyde residue

into the reaction ﬂask. After 20 min at -78 °C, a 1.04 M solution

of BF₃·Et₂O (73.9 mL, 77.1 mmol, 2.0 equiv) in CH₂Cl₂was slowly

added via syringe pump (at a rate of 40 mL/h), down the side of

the ﬂask. After 2.5 h at -78 °C, the reaction was quenched (cold)

by pouring the reaction mixture directly into a 1.5 L Erlenmeyer

ﬂask that contained a vigorously stirring mixture of CH₂Cl₂(400

mL), pH 7 buffer (250 mL), and water (250 mL) and stirred for 30

min. The layers were separated, and the aqueous phase was

extracted with CH₂Cl₂(2 × 100 mL). The combined organic

extractions were dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated under reduced pressure to give ethyl 3-[(2S,3R)-2-

hydroxy-1,1,3-trimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)butyl]

but-3-enoate 38, which was used without further puriﬁcation.

Analytical data for oleﬁn 38: R_f0.32 (20% acetone/hexanes);

[R]²²_D) -19.2 (c ) 1.04, CH₂Cl₂); 300 MHz ¹H NMR (C₆D₆) δ

5.15 (s, 1H), 5.07 (s, H), 3.93 (q, J ) 7.1 Hz, 2H), 3.78 (dd, J )

3.4, 1.0 Hz, 1H), 3.52-3.42 (m, 2H), 3.12-3.11 (m, 2H), 2.69 (d,

J ) 3.4 Hz, 1H), 1.90-1.79 (m, 1H), 1.15 (s, 3H), 1.06 (s, 3H),

1.03 (d, J ) 6.8 Hz, 3H), 0.95 (s, 9H), 0.94 (t, J ) 7.1 Hz, 3H),

0.03 (s, 6H); 125 MHz ¹³C NMR (CDCl₃) δ 173.0, 148.2, 115.1,

75.7, 69.4, 60.8, 44.5, 38.4, 35.3, 25.9, 23.4, 23.3, 18.2, 14.2, 11.1,

-5.5, -5.5 ppm; IR (neat) 3516, 3096, 2956, 2930, 2885, 2858,

1738, 1635, 1472, 1257, 1177, 1093, 1036 cm^-1. Anal. Calcd for

C₁₉H₃₈O₄Si C, 63.64; H, 10.68. Found: C, 63.93; H, 10.71.

To a stirring mixture of the crude oleﬁn 38 and EtOAc (800

mL) in a 1 L round-bottom ﬂask, at -78 °C, was bubbled a steady

stream of ozone until the reaction solution turned light purple. The

solution was then purged with a steady stream of O₂until the purple

color subsided. To the -78 °C reaction solution was then added

Me₂S (15 mL), the bath removed, and the solution allowed to slowly

warm to rt over 30 min. The reaction mixture was diluted with pH

7 buffer solution (200 mL), and the layers were separated. The

aqueous phase was extracted with CH₂Cl₂(2 × 75 mL). The

combined organic extracts were dried over anhydrous Na₂SO₄,

ﬁltered, and then concentrated under reduced pressure. Puriﬁcation

of the material was accomplished by ﬂash column chromatography

on a 7 × 33 cm column, eluting with 10% acetone/hexanes. The

product-containing fractions were combined and then concentrated

under reduced pressure to give the desired ꢀ-hydroxy ketone (9.54

Experimental Section

4-Methyl-3-tributylstannanylmethylpent-3-enoic Acid Ethyl Es-

ter 22. To a stirring solution of iodomethyltributyltin 30 (20.8 g,

48.3 mmol, 2.3 equiv) and Et₂O (125 mL) in a 500 mL round-

bottom ﬂask under an atmosphere of argon, at -78 °C, was slowly

added a 1.7 M solution of t-BuLi (100 mL, 85.0 mmol, 4.0 equiv)

in pentane via cannula directly from a 100 mL commercially

available bottle. The resulting cloudy solution was allowed to stir

at -78 °C for 10 min. The reaction mixture was then warmed to

0 °C, at which point it became homogeneous and yellow.

In a separate 1 L three-necked, round-bottom ﬂask equipped with

a mechanical stirrer was added puriﬁed CuI (4.04 g, 21.2 mmol,

1.0 equiv). The ﬂask was sealed and purged with argon. The CuI

was covered in Et₂O (50 mL) and the resulting light gray slurry

cooled to -78 °C. To this stirring slurry was quickly added the

tri-n-butylstannyl)methyllithium solution via cannula. An additional

Et₂O rinse (10 mL) was used to transfer the remaining organolithium

residue into the reaction ﬂask. The resulting dark gray mixture was

allowed to warm to -15 °C and stirred for 30 min, at which time

the mixture became dark purple. The heterogeneous mixture was

cooled to -78 °C and a solution of allenic ester 28 (4.06 g, 28.9

mmol, 1.4 equiv) in Et₂O (5 mL) was added dropwise via cannula

to the reaction mixture. An additional Et₂O rinse (5 mL) was used

to transfer the remaining allenic ester residue into the reaction ﬂask.

The reaction mixture was stirred at -78 °C for 30 min and then

warmed to 0 °C. After 30 min at 0 °C, the reaction was quenched

by the dropwise addition of EtOH (20 mL) and the mixture was

then allowed to warm to rt. To this heterogeneous mixture was

added water (100 mL) and stirred for 10 min. The resulting

emulsion was ﬁltered through paper using a Buchner funnel and

the ﬁltrate collected and added to a separatory funnel containing

brine (250 mL). The layers were separated and the aqueous phase

was extracted with hexanes (2 × 100 mL). The organic extracts

were combined, dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated under reduced pressure. Puriﬁcation of the material

was accomplished by ﬂash column chromatography on a 7.5 × 33

cm column, eluting with 3% Et₂O/hexanes. The product-containing

fractions were combined and then concentrated under reduced

pressure to give stannane 22 (6.84 g, 72% yield) as a clear, colorless

oil: R_f0.38 (5% Et₂O/hexanes); 500 MHz ¹H NMR (CDCl₃) δ 4.09

(q, J ) 7.3 Hz, 2H), 2.92 (br s with Sn satellites, 2H), 1.77 (s with

g, 69% yield over three steps) as a clear, colorless oil: R_f0.54 (50%

1

Et₂O/hexanes); [R]²²) -19.4 (c ) 0.88, CH₂Cl₂); 500 MHz H

D

NMR (CDCl₃) δ 4.22-4.15 (m, 2H), 3.89 (s, 1H), 3.74 (d, J )

16.1 Hz, 1H), 3.67 (d, J ) 16.1 Hz, 1H), 3.66 (dd, J ) 9.5, 3.3

Hz, 1H), 3.58 (dd, J ) 9.9, 4.7 Hz, 1H), 3.09 (br s, 1H), 1.87-1.80

(m, 1H), 1.27 (t, J ) 7.1 Hz, 3H), 1.22 (s, 3H), 1.16 (s, 3H), 0.90

(s, 9H), 0.86 (d, J ) 9.3 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H); 125

MHz ¹³C NMR (CDCl₃) δ 209.1, 168.3, 79.0, 70.2, 61.3, 52.5,

46.8, 35.5, 26.1, 23.0, 21.0, 18.4, 14.3, 10.9, -5.3, -5.4; DEPT

125 MHz ¹³C NMR (CDCl₃) δ CH₃26.1, 23.0, 21.0, 14.3, 10.9,

-5.3, -5.3; CH₂70.2, 61.3, 46.8; CH₁79.1, 35.5 ppm (a very

minor set of signals resulting from the tautomeric form of the ꢀ-keto

(61) For other examples of the introduction of gem-dialkyl units using this

strategy, see: (a) Keck, G. E.; Welch, D. S.; Vivian, P. K. Org. Lett. 2006, 8,

3667–3670. (b) Keck, G. E.; Welch, D. S.; Poudel, Y. Tetrahedron. Lett. 2006,

47, 8267–8270.

(62) For the use of a chiral prenyl borane to introduce the epothilone gem-

dimethyl substituent, see: Ramachandran, P. V.; Chandra, J. S.; Prabhudas, B.;

Pratihar, D.; Reddy, M. V. R. Org. Biomol. Chem. 2005, 3, 3812–3824.

1

ester were also detected by both H and ¹³C NMR spectroscopy

J. Org. Chem. Vol. 73, No. 24, 2008 9687

Keck et al.

but are not reported here due to the complexity of the spectrum

and insufﬁcient signal-to-noise ratio); IR (neat) 3421, 1736, 1687

cm^-1. Anal. Calcd for C₁₈H₃₆O₅Si: C, 59.96; H, 10.06. Found: C,

59.76; H, 10.04.

Ethyl (3R,5R,6R)-3,5-Dihydroxy-4,4,6-trimethyl-7-(1,1,2,2-tet-

ramethyl-1-silapropoxy)heptanoate (36). To a suspension of Sm

metal (31.8 g, 211 mmol, 7.0 equiv) and THF (700 mL) in a 1 L

round-bottom ﬂask under an atmosphere of argon, at rt, was added

neat CH₂I₂(28.3 g, 8.5 mL, 106 mmol, 3.5 equiv) via syringe. The

mixture became yellow, then green, then dark blue over the course

of 1 h. The reaction mixture was allowed to stir for an additional

1 h, after which time a large amount of the suspended Sm still

remains.

were combined, dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated under reduced pressure. ¹H NMR analysis of the

unpuriﬁed reaction mixture indicates an 89:11 diastereoselectivity.

Puriﬁcation was accomplished by ﬂash column chromatography on

a 5 × 25 cm column, eluting with 1 L of 5%, 4 L of 10%, and 2

L of 20% EtOAc/hexanes. The product-containing fractions were

combined and then concentrated under reduced pressure to give

the major homoallylic alcohol isomer 41 (2.80 g, 80% yield) as a

light yellow, crystalline solid. Recrystallization of the major isomer

41 from 5% Et₂O/hexanes (slow evaporation) provided crystals

suitable for X-ray crystallography. Analytical data for the major

isomer 41: mp 46-50 °C; R_f0.33 (5% acetone/CH₂Cl₂); [R]²²

)

D

-14.9 (c ) 2.4, CH₂Cl₂); 500 MHz ¹H NMR (C₆D₆) δ 5.82 (ddd,

J ) 16.9, 10.5, 7.8 Hz, 1H), 5.02 (dd, J ) 9.6, 1.8 Hz, 1H), 5.00

(s, 1H), 4.14 (dd, J ) 11.2, 2.1 Hz, 1H), 3.62 (d, J ) 4.1 Hz, 1H),

3.38 (s, 3H), 3.34 (ddd, J ) 8.0, 2.6, 2.6 Hz, 1H), 2.41 (dd, J )

15.6, 11.0 Hz, 1H), 2.32-2.25 (m, 1H), 2.07 (dd, J ) 15.6, 2.3

Hz, 1H), 1.96 (d, J ) 2.3 Hz, 1H), 1.86-1.79 (m, 1H), 1.46 (s,

3H), 1.32 (s, 3H), 1.10 (d, J ) 6.9 Hz, 3H), 0.86 (d, J ) 6.9 Hz,

3H), 0.72 (s, 3H), 0.70 (s, 3H); 125 MHz ¹³C NMR (C₆D₆) δ 172.1,

142.3, 115.7, 101.9, 78.8, 78.5, 73.9, 51.5, 42.5, 40.4, 35.0, 34.9,

24.5, 24.1, 21.0, 20.4, 16.8, 8.8; DEPT 125 MHz ¹³C NMR (C₆D₆)

δ CH₃: 51.5, 24.5, 24.1, 21.0, 20.4, 16.8, 8.8. CH₂: 115.7, 35.0.

CH₁: 142.3, 78.7, 78.5, 73.9, 42.5, 34.9 ppm; IR (neat) 3535,

3076,2985, 2938, 2880, 1744, 1636, 1457, 1437, 1381, 1226, 1169,

1123, 1060, 1003 cm^-1. Anal. Calcd for C₁₈H₃₂O₅: C, 65.82; H,

9.82. Found: C, 65.79; H, 10.06.

To the heterogeneous SmI₂solution, cooled to -42 °C (CH₃CN/

CO₂), was added a precooled (0 °C) solution of the ꢀ-hydroxy

ketone (10.9 g, 30.2 mmol, 1.0 equiv), water (6.5 g, 6.5 mL, 362

mmol, 12 equiv), and THF (90 mL) via cannula. Two additional

THF rinses (5 mL each) were used to transfer the remaining

ꢀ-hydroxy ketone residue into the reaction ﬂask. The reaction

mixture was stirred for an additional 20 min at -42 °C and then

transferred to a -20 °C freezer where it was brieﬂy manually

agitated every 12 h. After 48 h at -20 °C, the reaction was

quenched (cold) by bubbling O₂through the solution until the

reaction mixture changed color from blue to yellow-green, and the

solution was then transferred (cold) directly into a 250 mL

Erlenmeyer ﬂask that contained a vigorously stirring mixture of

EtOAc (750 mL) and an aqueous pH 7 buffer solution (300 mL).

The resulting emulsion was stirred for 1 h and ﬁltered through paper

using a Buchner funnel, the precipitate washed with EtOAc, and

the ﬁltrate collected. The layers were separated, and the aqueous

phase was extracted with EtOAc (2 × 100 mL). The organic extracts

were combined and washed with saturated aqueous Na₂S₂O₃(200

mL) and brine (200 mL). The aqueous layer was back-extracted

with CH₂Cl₂(2 × 50 mL). The organic extracts were combined,

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated under

reduced pressure. HPLC analysis of the crude material showed a

diastereoselectivity of 96:4 anti/syn (Microsorb, 4% IPA/hexanes,

0.9 mL/min; t_Rminor: 5.915 min, t_Rmajor: 6.313 min.). Puriﬁcation

of the material was accomplished by ﬂash column chromatography

on a 5 × 33 cm column, eluting with 25% EtOAc/hexanes. The

product-containing fractions were combined and then concentrated

under reduced pressure to give diol 36 (10.3 g, 94% yield) as a

clear, colorless oil: R_f0.30 (30% EtOAc/hexanes); [R]²²_D) -32.1

Methyl 2-{6-[(1S,2R,3R)-1,3-Dimethyl-4-oxo-2-(1,1,2,2-tetra-

methyl-1-silapropoxy)butyl]-(4S,6S)-2,2,5,5-tetramethyl-1,3-dioxan-

4-yl}acetate (59). To a stirring solution of oleﬁn 61 (2.36 g, 5.33

mmol, 1.0 equiv), NMO (1.25 g, 10.7 mmol, 2.0 equiv) and 5:5:1

THF/t-BuOH/H₂O (55 mL) in a 250 mL round-bottom ﬂask, at rt,

was added a 0.16 M solution of OsO₄(3.4 mL, 0.533 mmol, 0.10

equiv) in THF via syringe. After 6 h at rt, NaIO₄(5.70 g, 26.7

mmol, 5.0 equiv) was added in one portion followed by H₂O (5

mL). After an additional 4 h at rt, the heterogeneous solution was

ﬁltered through a fritted funnel, the remaining solids were washed

with 50% EtOAc/hexanes (100 mL), and the ﬁltrate was collected.

The ﬁltrate was transferred directly into a 500 mL Erlenmeyer ﬂask

that contained a vigorously stirring mixture of 50% EtOAc/hexanes

(100 mL) and a saturated aqueous solution of Na₂S₂O₃(50 mL).

After being stirred at rt for 30 min, the layers were separated. The

organic phase was washed with water (25 mL) and brine (25 mL),

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated under

reduced pressure. Puriﬁcation was accomplished by Florisil column

chromatography on a 5 × 20 cm column, eluting with 10% EtOAc/

hexanes. The product-containing fractions were combined and then

concentrated under reduced pressure to give aldehyde 59 (2.10 g,

89% yield) as a clear, colorless oil: R_f0.22 (15% EtOAc/hexanes);

[R]²²_D) -68.1 (c ) 0.48, CH₂Cl₂); 500 MHz ¹H NMR (C₆D₆) δ

9.75 (d, J ) 2.1 Hz, 1H), 4.10 (dd, J ) 11.0, 2.1 Hz, 1H), 3.65

(dd, J ) 5.5, 4.7 Hz, 1H), 3.61 (d, J ) 1.3 Hz, 1H), 3.38 (s, 3H),

2.70-2.62 (m, 1H), 2.35 (dd, J ) 15.7, 11.0 Hz, 1H), 2.06 (dd, J

) 15.7, 2.1 Hz, 1H), 1.91-1.84 (m, 1H), 1.42 (s, 3H), 1.26 (s,

3H), 1.02 (d, J ) 7.2 Hz, 3H), 1.02 (d, J ) 7.2 Hz, 3H), 0.91 (s,

9H), 0.68 (s, 3H), 0.65 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H); 125

MHz ¹³C NMR (C₆D₆) δ 203.1, 172.1, 101.8, 78.7, 74.2, 73.6, 51.5,

50.1, 40.7, 38.8, 35.1, 26.6, 24.5, 24.4, 21.1, 21.1, 18.8, 13.5, 12.4,

-3.3, -3.9; DEPT 125 MHz ¹³C NMR (CDCl₃) δ CH₃51.5, 26.6,

24.6, 24.5 (21.1 × 2), 13.5, 12.4, -3.3, -3.9; CH₂35.2; CH₁203.0,

78.7, 74.3, 73.6, 50.2, 38.9 ppm; IR (neat) 2985, 2956, 2936, 2885,

2858, 2738, 1740, 1653, 1635, 1559, 1506, 1472, 1387, 1296, 1259,

1226, 1170, 1036, 1005 cm^-1; HRMS m/z (CI) calcd C₂₃H₄₅O₆Si

(M + H) 445.2985, obsd 445.3007.

1

(c ) 1.03, CH₂Cl₂); 500 MHz H NMR (CDCl₃) δ 4.19 (q, J )

7.2 Hz, 2H), 4.07 (ddd, J ) 7.2, 5.5, 4.3 Hz, 1H), 4.02 (br d, J )

3.9 Hz, 1H), 3.75 (d, J ) 3.4 Hz, 1H), 3.64 (dd, J ) 9.5, 4.2 Hz,

1H), 3.58 (dd, J ) 9.5, 5.1 Hz, 1H), 3.40 (d, J ) 3.4 Hz, 1H), 2.49

(d, J ) 7.3 Hz, 1H), 2.49 (d, J ) 5.9 Hz, 1H), 1.91-1.83 (m, 1H),

1.29 (t, J ) 7.3 Hz, 3H), 1.06 (d, J ) 7.3 Hz, 3H), 0.96 (s, 3H),

0.95 (s, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 125 MHz ¹³C NMR (CDCl₃)

δ 173.6, 80.1, 75.8, 70.5, 60.9, 40.7, 37.5, 35.4, 26.1, 22.1, 21.6,

18.4, 14.4, 11.7, -5.3, -5.3 ppm; DEPT 125 MHz ¹³C NMR

(CDCl₃) δ CH₃26.1, 22.2, 21.6, 14.4, 11.7, -5.3, -5.3; CH₂70.5,

60.9, 37.5; CH₁80.1, 75.8, 35.4 ppm; IR (neat) 3476, 2956, 2930,

2884, 2858, 1734, 1472, 1302, 1257, 1188, 1084, 1025 cm^-1. Anal.

Calcd for C₁₈H₃₈O₅Si: C, 59.63; H, 10.56. Found: C, 59.41; H,

10.47.

Methyl

2-[6-((2S,3S,1R)-2-Hydroxy-1,3-dimethylpent-4-

enyl)(4S,6S)-2,2,5,5-tetramethyl-1,3-dioxan-4-yl]acetate (41). To

crude aldehyde 39 (from Swern oxidation of the corresponding

alcohol, 2.85 g, 10.6 mmol) in a 25 mL round-bottom ﬂask, at rt,

was added neat crotyl boronate 40 (5.81 g, 31.9 mmol, 3.0 equiv)

via syringe. A magnetic stir bar was added to the ﬂask, and the

ﬂask was sealed and purged with argon. After being stirred for

24 h at rt, the reaction mixture was transferred directly into a 250

mL Erlenmeyer ﬂask that contained a vigorously stirring mixture

of CH₂Cl₂(50 mL) and water (25 mL). After the mixture was stirred

for 30 min, the layers were separated, and the aqueous phase was

extracted with CH₂Cl₂(2 × 25 mL). The combined organic extracts

3-[(4E)(3S)-4-Methyl-5-(2-methyl(1,3-thiazol-4-yl))-3-(1,1,2,2-tet-

ramethyl-1-silapropoxy)pent-4-enylidene]-4,5-dihydrofuran-2-

one (69). To a stirring solution of aldehyde 66 (5.87 g, 18.0 mmol,

1.0 equiv) and benzene (180 mL) in a 250 mL round-bottom ﬂask,

at rt, was added Wittig reagent 65 (7.49 g, 21.6 mmol, 1.2 equiv)

9688 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

in one portion. The ﬂask was ﬁtted with a reﬂux condenser and

nitrogen line and the reaction vessel purged with nitrogen. The

reaction mixture was heated at reﬂux (∼80 °C) for 1.5 h. The

solution was allowed to cool to rt, the stir bar extracted, and the

solvent removed under reduced pressure. To facilitate the removal

of triphenylphosphine oxide, the residue was dissolved in CH₂Cl₂

(100 mL) and silica gel (∼25 mL by volume) was added. The crude

heterogeneous slurry was concentrated under reduced pressure then

dried under high vacuum until the remaining material was a free-

ﬂowing powder. To a prepacked ﬂash silica gel column (5 × 15

cm), the above powder was added and topped with sand (5 × 1

cm). The column was eluted with 35% EtOAc/hexane and the crude

product-containing fractions were combined and then concentrated

under reduced pressure. The diastereoselectivity of the reaction was

determined to be 95:5 E/Z by 500 MHz ¹H NMR analysis.

Puriﬁcation of the material was accomplished by ﬂash column

chromatography on a 5 × 30 cm column, eluting with 10% acetone/

hexanes. The product-containing fractions were combined and then

concentrated under reduced pressure to give, as the major isomer,

(E)-R,ꢀ-unsaturated lactone 69 (6.65 g, 94% yield) as colorless,

ppm; IR (neat) 3331, 2928, 2856, 1659, 1507, 1471, 1443, 1388,

1361, 1341, 1254, 1188, 1071, 941, 837, 808, 777, 668 cm^-1. Anal.

Calcd for C₂₀H₃₅NO₃SSi: C, 60.41; H, 8.87; N, 3.52. Found: C,

60.31; H, 8.95; N, 3.42.

(3E,7E)(6S)-3-(Chloromethyl)-7-methyl-8-(2-methyl(1,3-thiazol-

4-yl))-6-(1,1,2,2-tetramethyl-1-silapropoxy)octa-3,7-dien-1-ol (70).

To a stirring heterogeneous mixture of NCS (1.21 g, 9.07 mmol,

2.5 equiv) and CH₂Cl₂(20 mL) in a 50 mL round-bottom ﬂask

under an atmosphere of nitrogen, at 0 °C, was added neat Me₂S

(620 mg, 730 µL, 9.98 mmol, 2.75 equiv) dropwise via syringe.

The white, milky solution was allowed to stir for 10 min at which

point a precooled solution (0 °C) of diol 63 (1.44 g, 3.63 mmol,

1.0 equiv) and CH₂Cl₂(2.5 mL) was added via cannula. An

additional CH₂Cl₂rinse (2.5 mL) was used to transfer the remaining

diol residue into the reaction ﬂask. After being stirred overnight at

0 °C, the reaction was quenched by the dropwise addition of a

solution of saturated aqueous NaHCO₃(2 mL). The reaction mixture

was warmed to rt and diluted with CH₂Cl₂(25 mL) and water (25

mL), and the layers were separated. The aqueous phase was

extracted with CH₂Cl₂(2 × 25 mL). The organic extracts were

combined, dried over anhydrous Na₂SO₄, ﬁltered, and then con-

centrated under reduced pressure. Puriﬁcation of the material was

accomplished by ﬂash column chromatography on a 3 × 15 cm

column, eluting with 35% EtOAc/hexanes. The product-containing

fractions were combined and then concentrated under reduced

pressure to give allylic chloride 70 (1.43 g, 95% yield) as a clear,

waxy solid: R_f0.25 (35% EtOAc/hexanes); [R]²²) +0.2 (c )

D

1

1.86, CHCl₃); 500 MHz H NMR (CDCl₃) δ 6.93 (s, 1H), 6.77

(dddd, J ) 10.4, 8.0, 2.8, 2.8 Hz, 1H), 6.49 (br s, 1H), 4.38-4.30

(m, 2H), 4.28 (dd, J ) 7.6, 5.2 Hz, 1H), 2.94-2.80 (m, 2H), 2.70

(s, 3H), 2.53-2.39 (m, 2H), 2.05 (d, J ) 0.9 Hz, 3H), 0.88 (s,

9H), 0.05 (s, 3H), 0.01 (s, 3H); 125 MHz ¹³C NMR (CDCl₃) δ

170.1, 164.8, 153.0, 141.2, 137.4, 127.1, 119.4, 116.0, 77.3, 65.5,

38.2, 25.9, 25.5, 19.4, 18.3, 14.2, -4.5, -4.9; DEPT 125 MHz

¹³C NMR (CDCl₃) δ CH₃25.9, 19.4, 14.2, -4.5, -4.9; CH₂66.5,

38.2, 25.5; CH₁137.4, 119.4, 116.0, 77.3 ppm; IR (neat) 3110,

2954, 2929, 2856, 1758, 1682, 1505, 1471, 1440, 1379, 1361, 1254,

1187, 1078, 1030, 949, 837, 811, 778, 756, 667 cm^-1; HRMS m/z

(CI) calcd C₂₀H₃₂NO₃SSi (M + H) 394.1872, obsd 394.1877.

colorless oil: R_f0.27 (35% EtOAc/hexanes); [R]²²) -7.4 (c )

D

1.12, CHCl₃); 500 MHz ¹H NMR (CDCl₃) δ 6.94 (s, 1H), 6.48 (br

s, 1H), 5.74 (dd, J ) 8.5, 6.2 Hz, 1H), 4.23 (dd, J ) 8.2, 4.1 Hz,

1H), 4.09 (s, 2H), 3.74 (t, J ) 5.0 Hz, 1H), 3.73 (t, J ) 6.4 Hz,

1H), 2.72 (s, 3H), 2.57 (ddd, J ) 14.2, 6.4, 6.4 Hz, 1H), 2.54 (ddd,

J ) 14.2, 6.4, 6.4 Hz, 1H), 2.44 (ddd, J ) 14.2, 5.7, 5.7 Hz, 1H),

2.35-2.32 (m, 1H) 2.30 (ddd, J ) 14.2, 5.0, 5.0 Hz, 1H), 2.02 (d,

J ) 1.4 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 125 MHz

¹³C NMR (CDCl₃) δ 164.8, 153.0, 142.0, 134.4, 131.1, 119.3, 115.7,

78.5, 61.1, 50.7, 35.8, 32.0, 26.0, 19.4, 18.5, 14.3, -4.4, -4.7 ppm;

DEPT 125 MHz ¹³C NMR (CDCl₃) δ CH₃26.0, 19.4, 14.3, -4.4,

-4.7; CH₂61.1, 50.7, 35.8, 32.0; CH₁131.1, 119.3, 115.7, 78.5

ppm; IR (neat) 3356, 2954, 2929, 2885, 2857, 1703, 1508, 1472,

1441, 1388, 1361, 1255, 1186, 1149, 1074, 945, 837, 807, 777,

690 cm^-1. Anal. Calcd for C₂₀H₃₄ClNO₂SSi: C, 57.73; H, 8.24; N,

3.37. Found: C, 57.70; H, 8.26; N, 3.41.

2-[(4E)(3S)-4-Methyl-5-(2-methyl(1,3-thiazol-4-yl))-3-(1,1,2,2-tet-

ramethyl-1-silapropoxy)pent-4-enylidene]butane-1,4-diol (63). To

a stirring solution of lactone 69 (3.62 g, 9.20 mmol, 1.0 equiv)

and THF (100 mL) in a 250 mL round-bottom ﬂask under an

atmosphere of nitrogen, at -78 °C, was added a 1.5 M solution of

DIBAL (15.3 mL, 23.0 mmol, 2.5 equiv) in toluene dropwise via

cannula from an oven-dried graduated cylinder, down the side of

the ﬂask. After 20 min at -78 °C, the reaction mixture was warmed

to -42 °C (CH₃CN/CO₂). After 20 min at -42 °C, the reaction

mixture was recooled to -78 °C and the reaction quenched by slow

dropwise addition of MeOH (10 mL). The reaction mixture was

allowed to stir at -78 °C for an additional 10 min and then

transferred (cold) directly into a 1.5 L Erlenmeyer ﬂask that

contained a vigorously stirring mixture of CH₂Cl₂(250 mL) and a

saturated aqueous solution of Rochelle’s salts (potassium sodium

tartrate) (250 mL). The resulting emulsion was stirred for 3 h, by

which time two layers formed. The mixture was ﬁltered through

paper using a Buchner funnel and the ﬁltrate collected. The layers

were separated and the aqueous phase extracted with CH₂Cl₂(3 ×

50 mL). The organic extracts were combined, dried over anhydrous

Na₂SO₄, ﬁltered, and then concentrated under reduced pressure.

Puriﬁcation of the material was accomplished by ﬂash column

chromatography on a 5 × 14 cm column, eluting with 90% EtOAc/

hexanes. The product-containing fractions were combined and then

concentrated under reduced pressure to give diol 63 (3.56 g, 97%

(6S)(3Z,7E)-3,7-Dimethyl-8-(2-methyl(1,3-thiazol-4-yl))-6-(1,1,2,2-

tetramethyl-1-silapropoxy)octa-3,7-dien-1-ol (62) from 70. To a

stirring solution of allylic chloride 70 (2.40 g, 5.79 mmol, 1.0 equiv)

and THF (60 mL) in a 250 mL round-bottom ﬂask under an

atmosphere of argon, at -78 °C, was slowly added a 1.0 M solution

of Super-Hydride (LiBHEt₃) (20 mL, 20.3 mmol, 3.5 equiv) in THF

via syringe pump (at a rate of 30 mL/min), down the side of the

ﬂask. After 30 min at -78 °C, the reaction mixture was warmed

to 0 °C. After 16 h at 0 °C, the reaction mixture was warmed to rt.

After 3 h at rt, the reaction was quenched by pouring the reaction

mixture directly into a 1 L Erlenmeyer ﬂask that contained a

vigorously stirring mixture of CH₂Cl₂(250 mL) and a solution of

saturated aqueous NH₄Cl (100 mL), the mixture was stirred for 10

min, the layers were separated, and the aqueous phase was extracted

with CH₂Cl₂(2 × 100 mL). The organic extracts were combined,

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated under

reduced pressure. Puriﬁcation of the material was accomplished

by ﬂash column chromatography on a 5 × 20 cm column, eluting

with 35% EtOAc/hexanes. The product-containing fractions were

combined and then concentrated under reduced pressure to give

alcohol 62 (2.16 g, 98% yield) as a clear, colorless oil: R_f0.48

yield) as a clear, colorless oil: R_f0.25 (90% EtOAc/hexanes); [R]²²

D

) -3.2 (c ) CHCl₃); 500 MHz ¹H NMR (CDCl₃) δ 6.92 (s, 1H),

6.44 (br s, 1H), 5.55 (dd, J ) 7.6, 7.1 Hz, 1H), 4.19 (dd, J ) 7.1,

5.7 Hz, 1H), 4.02 (s, 2H), 3.67 (ddd, J ) 16.1, 10.9, 5.7 Hz, 1H),

3.66 (ddd, J ) 16.1, 6.6, 5.2 Hz, 1H), 3.55 (br s, 2H), 2.69 (s, 3H),

2.47-2.34 (m, 3H), 2.28 (ddd, J ) 14.7, 6.2, 6.2 Hz, 1H), 1.97 (d,

J ) 1.4 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H); 125 MHz

¹³C NMR (CDCl₃) δ 164.9, 152.9, 142.4, 138.2, 127.1, 119.2, 115.4,

78.5, 68.3, 61.6, 35.3, 32.6, 26.0, 19.3, 18.4, 14.2, -4.5, -4.8;

DEPT 125 MHz ¹³C NMR (CDCl₃) δ CH₃26.0, 19.3, 14.2, -4.5,

-4.8; CH₂68.3, 61.6, 35.3, 32.6; CH₁127.1, 119.2, 115.4, 78.5

(50% EtOAc/hexanes); [R]²²) -18.5 (c ) 0.85, CH₂Cl₂); 500

D

MHz ¹H NMR (CDCl₃) δ 6.93 (s, 1H), 6.46 (s, 1H), 5.33 (dd, J )

7.3, 7.3 Hz, 1H), 4.17 (dd, J ) 8.8, 4.4 Hz, 1H), 3.67-3.64 (m,

2H), 2.70 (s, 3H), 2.53-2.41 (m, 2H), 2.29 (br s, 1H), 2.22-2.16

(m, 2H), 2.01, (s, 3H), 1.72 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H),

0.02 (s, 3H); 125 MHz ¹³C NMR (CDCl₃) δ 164.5, 153.1, 142.5,

J. Org. Chem. Vol. 73, No. 24, 2008 9689

Keck et al.

133.4, 125.1, 118.9, 115.2, 79.1, 60.6, 35.6, 35.4, 25.9, 23.8, 19.3,

18.4, 14.1, -4.7, -5.0; DEPT 125 MHz ¹³C NMR (CDCl₃) δ CH₃

26.0, 24.0, 19.4, 14.2, -4.4, -4.7; CH₂60.7, 35.8, 35.6; CH₁125.2,

119.0, 115.4, 79.2 ppm; IR (neat) 3368, 2953, 2927, 2884, 2856,

1653, 1539, 1472, 1255, 1185, 1073 cm^-1. Anal. Calcd for

C₂₀H₃₅NO₂SSi: C, 62.94; H, 9.24; N, 3.67. Found: C, 62.73; H,

9.04; N, 3.66.

remaining lactone residue into the reaction ﬂask. After 45 min at

-78 °C, the reaction mixture was warmed to -42 °C (CH₃CN/

CO₂). After 45 min at -42 °C, the reaction was quenched (cold)

by pouring the reaction mixture directly into a 250 mL Erlenmeyer

ﬂask that contained a vigorously stirring mixture of CH₂Cl₂(75

mL) and saturated aqueous NH₄Cl (50 mL) and stirred for 10 min.

The layers were separated, and the aqueous phase was extracted

with CH₂Cl₂(2 × 25 mL). The organic extracts were combined,

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated under

reduced pressure. Puriﬁcation of the material was accomplished

by ﬂash column chromatography on a 5 × 20 cm column eluting

with 10% EtOAc/hexanes. The product-containing fractions were

combined and then concentrated under reduced pressure to give

hydroxy amide 86 (1.52 g, 94% yield) as a clear, colorless oil: R_f

0.18 (10% EtOAc/hexanes); [R]²²_D) +3.3 (c ) 0.96, CHCl₃); 500

Methyl 2-{6-[(1S,2S,3S,10R)(4Z,7Z,11E)-2,10-Bis(1,1,2,2-tetra-

methyl-1-silapropoxy)-1,3,7,11-tetramethyl-12-(2-methyl(1,3-thia-

zol-4-yl))dodeca-4,7,11-trienyl](4S,6S)-2,2,5,5-tetramethyl-1,3-dioxan-

4-yl}acetate (58). To a stirring solution of phosphonium salt 60 (1.86

g, 2.47 mmol, 1.05 equiv) and THF (22 mL) in a 100 mL round-

bottom ﬂask under an atmosphere of argon, at -78 °C, was slowly

added a 2.49 M solution of n-BuLi (0.95 mL, 2.49 M in hexanes,

2.35 mmol, 1.0 equiv) in hexanes dropwise via syringe, dropwise

down the side of the ﬂask. After 2 min at -78 °C, to the deep

red-orange solution was slowly added a precooled (-78 °C) solution

of aldehyde 59 (1.05 g, 2.35 mmol, 1.0 equiv) and THF (2 mL)

via cannula. Two additional THF rinses (1 mL each) were used to

transfer the remaining aldehyde residue into the reaction ﬂask. After

30 min at -78 °C, the reaction mixture was warmed to rt, during

which time the yellow-red reaction mixture became heterogeneous.

After 30 min at rt, the reaction was quenched by pouring the

reaction mixture directly into a 250 mL Erlenmeyer ﬂask that

contained a vigorously stirring mixture of CH₂Cl₂(75 mL) and a

solution of saturated aqueous NH₄Cl (50 mL). The mixture was

stirred for 10 min, the layers were separated, and the aqueous phase

was extracted with CH₂Cl₂(2 × 25 mL). The organic extracts were

combined, dried over anhydrous Na₂SO₄, ﬁltered, and then con-

centrated under reduced pressure. Puriﬁcation of the material was

accomplished by ﬂash column chromatography on a 5 × 20 cm

column, eluting with 10% EtOAc/hexanes. The product-containing

fractions were combined and then concentrated under reduced

pressure to give the Wittig adduct 58 (1.66 g, 89% yield) as a clear,

colorless oil: R_f0.22 (10% EtOAc/hexanes); [R]²²_D) +13.2 (c )

1

MHz H NMR (CDCl₃) δ 8.06 (s, 1H), 7.50 (d, J ) 8.0 Hz, 2H),

7.30 (t, J ) 8.0 Hz, 2H), 7.09 (t, J ) 7.6 Hz, 1H), 6.95 (s, 1H),

6.93 (br s, 1H), 5.60 (dd, J ) 10.2, 10.2 Hz, 1H), 5.27 (ddd, J )

10.9, 8.5, 5.4 Hz, 1H), 5.20 (dd, J ) 6.9 Hz, 1H), 4.23 (dd, J )

6.9, 3.1 Hz, 1H), 4.09 (dd, J ) 6.4, 6.4 Hz, 1H), 3.68 (s, 1H), 3.54

(dd, J ) 4.7, 2.8 Hz, 1H), 3.35 (s, 1H), 2.86-2.62 (m, 4H), 2.70

(s, 3H), 2.48 (dd, J ) 15.4, 6.9 Hz, 1H), 2.34-2.22 (m, 2H), 2.00

(d, J ) 0.9 Hz, 3H), 1.86-1.78 (m, 1H), 1.68 (s, 3H), 1.03 (s,

3H), 1.01 (d, J ) 6.6 Hz, 3H), 0.96 (d, J ) 7.1 Hz, 3H), 0.92 (s,

9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.83 (s, 3H), 0.16 (s, 3H), 0.09 (s,

3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), -0.03 (s, 3H); 125

MHz ¹³C NMR (CDCl₃) δ 169.9, 164.7, 153.2, 143.0, 138.3, 135.8,

133.0, 129.2, 127.4, 124.3, 122.1, 119.9, 118.8, 115.3, 80.3, (2 ×

79.3), 75.4, 42.5, 41.9, 38.6, (2 × 35.8), 30.9, 26.4, 26.3, 26.0,

23.9, 23.4, 21.5, 19.7, 19.3, 18.6, (2 × 18.4), 14.1, 11.5, -3.5,

-3.5, -4.0, -4.5, -4.7, -4.8; DEPT 125 MHz ¹³C NMR (CDCl₃)

δ CH₃26.4, 26.3, 26.0, 23.9, 23.4, 21.5, 19.7, 19.3, 14.1, 11.5,

-3.5, -3.5, -4.0, -4.5, -4.7, -4.8; CH₂41.9, 35.8, 30.9; CH₁

133.0, 129.2, 127.4, 124.3, 122.1, 119.9, 118.8, 115.3, 80.3 (2 ×

79.3), 75.4, 38.6, 35.8 ppm; IR (neat) 2956, 2929, 2885, 2857, 1667,

1601, 1543, 1499, 1472, 1442, 1388, 1361, 1315, 1253, 1074, 1005,

939, 836, 811, 775, 754 cm^-1; HRMS m/z (CI) calcd for

C₅₁H₉₁N₂O₅SSi₃(M + H) 927.5956, obsd 927.5925.

7-[(1E)-1-Methyl-2-(2-methyl(1,3-thiazol-4-yl))vinyl]-

(3S,7S,14S,15S,16R)-3,15-bis(1,1,2,2-tetramethyl-1-silapropoxy)-

2,2,10,14,16-pentamethyl-6-oxacyclohexadeca-9,12-diene-1,5-di-

one. To a stirring solution of seco acid (132 mg, 0.179 mmol, 1.0

equiv), Et₃N (32 mg, 44 µL, 0.313 mmol, 1.75 equiv), and THF (4

mL) in a 25 mL round-bottom ﬂask under an atmosphere of argon,

at 0 °C, was added neat 2,4,6-trichlorobenzoyl chloride (50 mg,

35 µL, 0.206 mmol, 1.15 equiv). After 1 h at 0 °C, the resulting

mixed anhydride solution was warmed to rt and diluted with THF

(3 mL) and toluene (6 mL). To a stirring solution of DMAP (37

mg, 0.30 mmol, 1.7 equiv) and toluene (45 mL) in a 250 mL three-

necked, round-bottom ﬂask equipped with a reﬂux condenser, under

an atmosphere of argon, at 75 °C, was slowly added the mixed

anhydride solution via syringe pump (at a rate of 7.5 mL/h). An

additional 1:1 THF/toluene rinse (2 mL) was used to transfer the

remaining mixed anhydride residue into the reaction ﬂask. After

complete addition of the mixed anhydride solution, the reaction

mixture was stirred for an additional 1 h at 75 °C and then cooled

to rt. The reaction mixture was poured into a separatory funnel

that contained CH₂Cl₂(75 mL) and saturated aqueous NH₄Cl (50

mL), and the layers were separated. The aqueous phase was

extracted with CH₂Cl₂(2 × 75 mL) and EtOAc (50 mL). The

organic extracts were combined, dried over anhydrous Na₂SO₄,

ﬁltered, and then concentrated under reduced pressure. Puriﬁcation

of the material was accomplished by ﬂash column chromatography

on a 2.5 × 12 cm column, eluting with 10% EtOAc/hexanes. The

product-containing fractions were combined and then concentrated

under reduced pressure to give the desired macrolactone (84 mg,

65% yield) as a clear, colorless oil: R_f0.64 (20% EtOAc/hexanes);

[R]²²_D) -68.2 (c ) 0.96, CHCl₃); 500 MHz ¹H NMR (CDCl₃) δ

6.96 (s, 1H), 6.51 (br s, 1H), 5.66 (d, J ) 9.9, 9.9 Hz, 1H),

1

0.89, CHCl₃); 500 MHz H NMR (C₆D₆) δ 6.66 (br s, 1H), 6.58

(s, 1H), 5.76 (dd, J ) 10.4, 10.4 Hz, 1H), 5.46 (ddd, J ) 10.9, 7.1,

7.1 Hz, 1H), 5.38 (dd, J ) 7.3, 7.3 Hz, 1H), 4.22 (dd, J ) 6.9, 5.9

Hz, 1H), 4.17 (dd, J ) 11.1, 2.1 Hz, 1H), 3.58 (dd, J ) 6.7, 2.8

Hz, 1H), 3.46 (d, J ) 1.9 Hz, 1H), 3.38 (s, 3H), 3.06-2.88 (m,

2H), 2.88-2.80 (m, 1H), 2.58-2.50 (m, 1H), 2.48-2.40 (m, 1H),

2.40 (dd, J ) 15.6, 11.4 Hz, 1H), 2.28 (s, 3H), 2.27 (d, J ) 1.0

Hz, 3H), 2.08 (dd, J )15.4, 2.1 Hz, 1H), 1.94-1.87 (m, 1H), 1.76

(s, 3H), 1.50 (s, 3H), 1.36 (s, 3H), 1.17 (d, J ) 6.6 Hz, 3H), 1.17

(d, J ) 6.1 Hz, 3H), 1.04 (s, 9H), 1.02 (s, 9H), 0.76 (s, 3H), 0.74

(s, 3H), 0.17 (s, 3H), 0.14 (s, 6H), 0.10 (s, 3H) ppm; 125 MHz ¹³

C

NMR (C₆D₆) δ 172.1, 164.5, 154.5, 142.3, 136.1, 133.1, 128.7,

122.9, 119.7, 116.1, 101.7, 79.8, 79.1, 76.7, 73.8, 51.5, 40.7, 38.0,

37.5, 36.3, 35.1, 31.5, 26.9, 26.5, 24.6, 24.4, 24.3, 21.6, 21.5, 19.5,

19.3, 19.1, 18.9, 14.8, 12.2, -2.9, -3.2, -4.0, -4.4 ppm; DEPT

125 MHz ¹³C NMR (C₆D₆) δ CH₃51.5, 26.9, 26.5, 24.6, 24.4,

24.3, 21.6, 21.5, 19.5, 19.3, 14.8, 12.2, -2.9, -3.2, -4.0, -4.3;

CH₂36.3, 35.1, 31.5; CH₁133.3, 128.7, 122.9, 119.7, 116.1, 79.8,

79.1, 76.7, 73.8, 38.0, 37.5 ppm; IR (neat) 2956, 2930, 2898, 2856,

1748, 1700, 1653, 1506, 1472, 1457, 1436, 1387, 1362, 1296, 1255,

1227, 1177, 1060, 1005 cm^-1; HRMS m/z (CI) calcd for

C₄₃H₇₈NO₆SSi₂(M + H) 792.5088, obsd 792.5095.

((3S,5S,6S,7S,8S,15R)(9Z,12Z,16E)-5-Hydroxy-4,4,6,8,12,16-hex-

amethyl-17-(2-methyl(1,3-thiazol-4-yl))-N-phenyl-3,7,15-tris(1,1,2,2-

tetramethyl-1-silapropoxy)heptadeca-9,12,16-trienamide (86). To

a stirring suspension of PhNH₂·HCl (1.57 g, 12.1 mmol, 7 equiv)

and THF (10 mL) in a 100 mL round-bottom ﬂask under an

atmosphere of argon, at 0 °C, was added a 2.49 M solution of

n-BuLi (8.35 mL, 20.9 mmol, 12.0 equiv) in hexanes via syringe.

After 10 min at 0 °C, the gray, cloudy reaction mixture was cooled

to -78 °C. To the cold mixture was slowly added a precooled (-78

°C) solution of lactone 74 (1.45 g, 1.73 mmol, 1.0 equiv) and THF

(4 mL) dropwise via cannula, down the side of the ﬂask. Two

additional THF rinses (2 mL each) were used to transfer the

9690 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of Epothilones B and D

5.46-5.40 (m, 2H), 5.13 (dd, J ) 6.4, 6.4 Hz, 1H), 4.47 (dd, J )

8.3, 2.6 Hz, 1H), 3.77-3.74 (m, 1H), 3.20 (dd, J ) 15.8, 9.7 Hz,

1H), 3.04 (qd, J ) 7.1, 2.4 Hz, 1H), 2.73 (s, 3H), 2.72-2.52 (m,

3H), 2.58 (dd, J ) 14.9, 8.3 Hz, 1H), 2.44 (dd, J ) 15.1, 2.8 Hz,

1H), 2.41-2.36 (m, 1H), 2.10 (s, 3H), 1.75 (s, 3H), 1.15 (s, 3H),

1.12 (s, 3H), 1.08 (d, J ) 7.1 Hz, 3H), 1.01 (d, J ) 7.1 Hz, 3H),

0.94 (s, 9H), 0.88 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H), 0.09 (s, 3H),

0.07 (s, 3H); 125 MHz ¹³C NMR (CDCl₃) δ 216.0, 169.9, 164.9,

152.9, 137.8, 136.5, 130.8, 126.9, 121.1, 118.9, 116.6, 78.1, 76.5,

73.1, 54.0, 47.4, 41.2, 39.0, 31.1, 31.0, 26.4, 26.1, 24.5, 21.3, 20.5,

19.8, 19.5, 18.8, 18.3, 15.2, 14.7, -3.4, -3.5, -4.5, -4.6; DEPT

125 MHz ¹³C NMR (CDCl₃) δ CH₃26.4, 26.1, 24.5, 21.3, 20.5,

19.8, 19.5, 15.2, 14.7, -3.4, -3.5 (2 × -4.6); CH₂41.2, 31.1,

31.0; CH₁130.8, 126.9, 121.1, 118.9, 116.6, 77.9, 76.2, 72.9, 47.4,

39.0 ppm; IR (neat) 2956, 2930, 2886, 2857, 1738, 1709, 1471,

1253, 1089, 1049, 1022, 868, 837, 775, 758 cm^-1; LRMS m/z (CI)

calcd for C₃₉H₆₈NO₅SSi₃(M + H) 718.4, obsd 718.3.

7-[(1E)-1-Methyl-2-(2-methyl(1,3-thiazol-4-yl))vinyl]-

(3S,7S,14S,15S,16R)-3,15-dihydroxy-2,2,10,14,16-pentamethyl-6-ox-

acyclohexadec-9-ene-1,5-dione (Epothilone D, 3). To a stirring

solution of oleﬁn 4 (20.2 mg, 0.0413 mmol, 1.0 equiv), Et₃N (580

µL, 420 mg, 4.13 mmol, 100 equiv), and 1,2-dichloroethane (5 mL)

in a high-pressure vial, at rt, was added TrisNHNH₂(1.23 g, 4.13

mmol, 100 equiv) in one portion. The vial was sealed and placed

in a preheated oil bath (50 °C). After 6 h, an additional 100 equiv

each of Et₃N and TrisNHNH₂were added to the heterogeneous

reaction mixture. The vial was sealed and returned to the oil bath.

After an additional 6 h, another 100 equiv each of Et₃N and

TrisNHNH₂were added. The vial was sealed and returned to the

oil bath. After the reaction mixture stirred an additional 6 h at 50

°C, the reaction mixture was cooled to rt, diluted with EtOAc (25

mL), and ﬁltered through a pad of silica gel (3 × 3 cm) and Celite

(3 × 1 cm). The pad was rinsed with EtOAc (100 mL). The ﬁltrate

was collected and the solvent removed under reduced pressure.

Puriﬁcation of the material began by ﬂash column chromatography

on a 2.5 × 6 cm column, eluting with 100 mL each of 30% and

70% EtOAc/hexanes. The crude product-containing fractions were

combined and then concentrated under reduced pressure and

resubjected to ﬂash column chromatography on a 2.5 × 6 cm

column, eluting with 50% EtOAc/hexanes. The product-containing

fractions were combined and then concentrated under reduced

pressure to give epothilone D, 3 (14.3 mg, 70% yield) as a colorless

solid: R_f0.30 (50% EtOAc/hexanes); [R]²²) -70.6 (c ) 0.40,

D

1

CHCl₃); 500 MHz H NMR (CDCl₃) δ 6.96 (s, 1H), 6.59 (br s,

1H), 5.22 (dd, J ) 9.8, 1.5 Hz, 1H), 5.15 (dd, J ) 9.8, 4.9 Hz,

1H), 4.32-4.27 (m, 1H), 3.75-3.72 (m, 1H), 3.45 (d, J ) 5.4 Hz,

1H), 3.17 (qd, J ) 6.8, 2.4 Hz, 1H), 3.04 (s, 1H), 2.70 (s, 3H),

2.69-2.60 (m, 1H), 2.47 (dd, J ) 14.6, 11.2 Hz, 1H), 2.36-2.30

(m, 1H), 2.30 (dd, J ) 14.6, 2.4 Hz, 1H), 2.27-2.21 (m, 1H), 2.08

(d, J ) 1.0 Hz, 3H), 1.92-1.86 (m, 1H), 1.84-1.72 (m, 2H), 1.67

(s, 3H), 1.35 (s, 3H), 1.35-1.25 (m, 3H), 1.20 (d, J ) 6.8 Hz,

3H), 1.08 (s, 3H), 1.03 (d, J ) 7.3 Hz, 3H); 125 MHz ¹³C NMR

(CDCl₃) δ 220.9, 170.6, 165.3, 152.2, 139.5, 138.7, 121.1, 119.5,

115.8, 79.1, 74.3, 72.5, 53.8, 41.9, 39.8, 38.7, 32.8, 32.0, 31.8, 25.6,

(2 × 23.1), 19.3, 18.3, 16.1, 16.0, 13.6; DEPT 125 MHz ¹³C NMR

(CDCl₃) δ CH₃(2 × 23.1), 19.3, 18.3, 16.1, 16.0, 13.6; CH₂39.9,

32.8, 32.0, 31.8, 25.6; CH₁121.1, 119.5, 115.8, 79.1, 74.3, 72.5,

41.9, 38.7 ppm; IR (neat) 3445, 2966, 2935, 2878, 1734, 1686,

1465, 1457, 1449, 1377, 1304, 1294, 1252, 1187, 1145, 978, 732

cm^-1; LRMS m/z (CI) calcd C₂₇H₄₂NO₅S (M + H) 492.3, obsd

492.3.

Acknowledgment. Dedicated to the life and memory of our

friend Professor A. I. Meyers. Financial support of this research

by the National Institutes of Health, through Grant No.

GM28961, is gratefully acknowledged.

Supporting Information Available: Experimental proce-

dures and spectral and analytical data for compounds not given

1

in the Experimental Section and copies of H and ¹³C NMR

spectra. This material is available free of charge via the Internet

at http://pubs.acs.org.

JO802215V

J. Org. Chem. Vol. 73, No. 24, 2008 9691

Article Doi

Total synthesis of epothilones B and D: Stannane equivalents for β-keto ester dianions

DOI: 10.1021/jo802215v

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Article abstract of DOI:10.1021/jo802215v

Full text of DOI:10.1021/jo802215v

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