The total synthesis and biological assessment of trans-epothilone A

Article abstract of DOI:10.1002/1522-2675(200211)85:11<4086::AID-HLCA4086>3.0.CO;2-7

The total synthesis of (12S,13S)-trans-epothilone A (1a) was achieved based on two different convergent strategies. In a first-generation approach, construction of the C(11)-C(12) bond by Pd⁰-catalyzed Negishi-type coupling between the C(12)-to-C(15) trans-vinyl iodide 5 and the C(7)-to-C(11) alkyl iodide 4 preceded the (nonselective) formation of the C(6)-C(7) bond by aldol reaction between the C(7)-to-C(15) aldehyde 25 and the dianion derived from the C(1)-to-C(6) acid 3. The lack of selectivity in the aldol step was addressed in a second-generation approach, which involved construction of the C(6)-C(7) bond in a highly diastereoselective fashion through reaction between the acetonide-protected C(l)-to-C(6) diol 31 ('Schinzer's ketone') and the C(7)-to-C(11) aldehyde 30. As part of this strategy, the C(11)-C(12) bond was established subsequent to the critical aldol step and was based on B-alkyl Suzuki coupling between the C(1)-to-C(11) fragment 40 and C(12)-to-C(15) trans-vinyl iodide 5. Both approaches converged at the stage of the 3-O, 7-O-bis-TBS-protected seco acid 27, which was converted to trans-deoxyepothilone A (2) via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12)-C(13) bond could be achieved by epoxidation with Oxone in the presence of the catalyst 1,2:4,5-di-O-isopropylidene-L-erythro-2,3-hexodiuro-2,6-pyranose (42a), which provided a 8:1 mixture of 1a and its (12R,13R)-epoxide isomer 1b in 27% yield (54% based on recovered starting material). The absolute configuration of 1a was established by X-ray crystallography. Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two orders of magnitude lower than that of epothilone A or 1a.

Full text of DOI:10.1002/1522-2675(200211)85:11<4086::AID-HLCA4086>3.0.CO;2-7

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Helvetica Chimica Acta Vol. 85 (2002)
The Total Synthesis and Biological Assessment of trans-Epothilone A
by Karl-Heinz Altmann*a), Guido Boldb), Giorgio Caravattib), Donatienne Dennia), Andreas Flˆrsheimerb),
Alfred Schmidtc), Grety Rihsc), and Markus Wartmannb)
a) Corporate Research, Novartis Pharma AG
b) TA Oncology Research, Novartis Pharma AG
c) Central Technologies, Novartis Pharma AG
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
The total synthesis of (12S,13S)-trans-epothilone A (1a) was achieved based on two different convergent
strategies. In a first-generation approach, construction of the C(11)ÀC(12) bond by Pd0-catalyzed Negishi-type
coupling between the C(12)-to-C(15) trans-vinyl iodide 5 and the C(7)-to-C(11) alkyl iodide 4 preceded the
(nonselective) formation of the C(6)ÀC(7) bond by aldol reaction between the C(7)-to-C(15) aldehyde 25 and
the dianion derived from the C(1)-to-C(6) acid 3. The lack of selectivity in the aldol step was addressed in a
second-generation approach, which involved construction of the C(6)ÀC(7) bond in a highly diastereoselective
fashion through reaction between the acetonide-protected C(1)-to-C(6) diol 31 (−Schinzer×s ketone×) and the
C(7)-to-C(11) aldehyde 30. As part of this strategy, the C(11)ÀC(12) bond was established subsequent to the
critical aldol step and was based on B-alkyl Suzuki coupling between the C(1)-to-C(11) fragment 40 and C(12)-
to-C(15) trans-vinyl iodide 5. Both approaches converged at the stage of the 3-O, 7-O-bis-TBS-protected seco
acid 27, which was converted to trans-deoxyepothilone A (2) via Yamaguchi macrolactonization and subsequent
deprotection. Stereoselective epoxidation of the trans C(12)ÀC(13) bond could be achieved by epoxidation
¾
with Oxone in the presence of the catalyst 1,2:4,5-di- O-isopropylidene-l-erythro-2,3-hexodiuro-2,6-pyranose
(42a), which provided a 8 :1 mixture of 1a and its (12R,13R)-epoxide isomer 1b in 27% yield (54% based on
recovered starting material). The absolute configuration of 1a was established by X-ray crystallography.
Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and
to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two
orders of magnitude lower than that of epothilone A or 1a.
Introduction. Epothilones A and B (Fig. 1) are the main representatives of a family
of bacterial natural products that exhibit potent antiproliferative activity against a broad
range of human cancer cell lines. First isolated in 1993 by Reichenbach, Hˆfle, and co-
workers [1], these compounds were subsequently shown by Bollag et al. to be
microtubule depolymerization inhibitors [2] and, thus, to inhibit human cancer cell
¾
growth by the same mechanism of action as the renowned anticancer drug Taxol
(paclitaxel) [3]. At the time of this discovery, epothilones A and B, apart from paclitaxel
and its analogs, were the only compounds recognized in the literature to act as
microtubule-stabilizing agents1). However, in distinct contrast to paclitaxel, epothilones
were found to be equally effective in vitro against drug-sensitive and multidrug-resistant
cell lines [2][5 7], which immediately suggested that epothilone-derived anticancer
agents could eventually be useful for the treatment of drug-resistant tumors.
1
)
Several other natural products have recently been recognized to be microtubule depolymerization
inhibitors. For a review, cf. [4].

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4087
Fig. 1. Structures of epothilones A and B and of their deoxy variants. Deoxyepothilones A and B are also known
as epothilones C and D, respectively.
This very attractive in vitro profile, in combination with the knowledge that
epothilones (and related analogs) are well within the realm of modern total synthesis
techniques, presumably even on a scale sufficiently large to support clinical trials, has
turned these compounds into important lead structures for anticancer drug discovery.
More than 20 total syntheses of epothilones A and B have been published since their
absolute configuration was disclosed in 1996 (for recent reviews, cf. [8 11]); at the
same time, several hundred analogs have been prepared and their biological activities
investigated, which has led to a remarkably comprehensive understanding of the
structure-activity relationships (SAR) for epothilone-derived structures in a short
period of time (for recent reviews, cf. [6][8][9][12]).
As part of their early SAR work, Nicolaou and co-workers reported in 1997 the
intriguing observation that one of the two possible trans-epoxide isomers of epothilone
A is virtually equipotent with natural epothilone A [13]. These trans-epoxides were
obtained by nonselective epoxidation of trans-deoxyepothilone A (the C(12)ˆC(13)
trans isomer of deoxyepothilone A, cf. Fig. 1), which, in turn, had been produced as a
consequence of nonselective CˆC formation between C(12) and C(13), rather than
being the result of a directed synthetic effort. trans-Deoxyepothilone A had also been
described by Danishefsky and co-workers [14], who were the first to characterize the
biological activity of this analog in vitro [14a]. However, neither the stereoselective
synthesis of trans-deoxyepothilone A nor the stereo- and regioselective epoxidation of
trans-deoxyepothilones has been described in the literature so far, and, most
importantly, the absolute configuration of the epoxide moiety in the more active
isomer of trans-epothilones A had not been determined in Nicolaou×s work2).
To address this question, we have elaborated a stereoselective synthesis of trans-
epothilones A, and we have determined the epoxide configuration in the more active
isomer by X-ray crystallography. In this paper, we provide full details of our synthetic
work, and we report additional data on the in vitro antiproliferative activity of trans-
epothilones A3). The results of our biological experiments clearly reconfirm the
conclusions previously derived by Nicolaou and co-workers and thus refute a more
recent notion that trans-epothilones would be biologically inactive [18].
2
)
Nicolaou has recently reported a series of highly potent cyclopropyl analogs of trans-epothilone A, with
the configuration of the C(12)ÀC(13) cyclopropyl moiety corresponding to that in the active trans-
epothilone A isomer as determined in this work [15].
Preliminary accounts of this work, including the disclosure of the absolute configuration of the active
trans-epothilone A isomer have been published [16][17].
3
)

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Results and Discussion. The general features of our initial approach to the
synthesis of C(12), C(13) trans analogs of epothilone A are summarized in Scheme 1.
This approach combined elements of the strategies previously developed by Schinzer
and co-workers [19] and Nicolaou and co-workers [20] for the synthesis of natural
epothilones and was conceived to be based on four key steps: i) Pd0-catalyzed coupling
of vinyl iodide 5 with the zincate derived from alkyl iodide 4, ii) aldol reaction of
aldehyde 25, which would be derived from the product of coupling between 4 and 5, and
the dianion of carboxylic acid 3, iii) macrolactonization of seco acid 27, and iv)
stereoselective epoxidation of trans-deoxyepothilone A (2), for which appropriate
methodology needed to be developed. Based on literature precedent [20], the aldol
reaction between 3 and 25 was expected to be essentially nonselective and to provide a
Scheme 1. retro-Synthetic Analysis for the Synthesis of trans-Epothilones A (1)

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4089
ca. 1:1 mixture of syn isomers at C(6) and C(7) ((6S,7R) and (6R,7S), resp.); however,
assuming that these isomers could then be separated by chromatographic means, this
approach appeared to provide the most-rapid access to trans-deoxyepothilone A (2),
thus allowing the investigation of the crucial epoxidation step 2! 1 and the development
of the necessary methodology for stereoselective epoxide formation at C(12), C(13).
The synthesis of carboxylic acid 3 is summarized in Scheme 2 and was based on
Oppolzer chemistry [21] to establish the chiral center at C(3). Thus, reaction of
aldehyde 6 with the boron enolate of acetylsultam 7 provided the desired aldol product
8 in 46% yield after purification by simple recrystallization (> 99% de). Protection of
the free OH group in 8 as TBS ether (TBS ˆ tBuMe2Si) gave crystalline 9, which was
then converted to 3 by treatment with LiOOH in THF/H2O in 76% yield.
Scheme 2
i) 1. 7, Et3B ¥ OTf, iPr2NEt, 08, 40 min; 2 . ‡ 6, À788, 2h; 46%. ii) TBS-OTf, À788, 1 h, À788 ! r.t., 16 h; 92%.
iii) LiOH, H2O2, THF/H2O 4 :1, r.t., 7 h; 76%.
The crystallinity of compounds 8 and 9 allowed straightforward scale-up of this
reaction sequence to produce multi-hundred-g quantities of 3. It should be noted that
this strategy for the synthesis of 3 was originally conceived by De Brabander et al. [2 2 ],
but these investigators erroneously reported that 3 would be obtained by means of
(2S)-N-acetylbornane-10,2-sultam (i.e., the enantiomer of 7, ent-7). We have repeated
De Brabander×s work, and, based on X-ray crystallographic analysis, we were able to
show that the aldol product obtained upon reaction of 6 with ent-7 is, in fact, the
enantiomer of 8 (ent-8) with the undesired (3R) configuration (ca. 9 :1 selectivity in
favor of ent-8; see structure of ent-9 in Fig. 2). Subsequent to this discovery, De
Brabander et al. published a corrigendum to their original paper [23], which
corroborated our own experimental findings but, in our view, does not adequately
clarify which compound is actually described in their original report. It should also be
noted in this context that the optical rotation reported for carboxylic acid 3 by Nicolaou
and co-workers ([a]D ˆ ‡16) [20] is of the wrong sign.

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Fig. 2. ORTEP Plot of ent-9 with 30% displacement ellipsoids
The preparation of alkyl iodide 4 has previously been described by Schinzer and co-
workers [19], except for a different approach to the synthesis of carboxylic acid 11 and
the use of a valine- rather than phenylalanine-derived Evans auxiliary in the crucial
methylation step [13 ! 14, Scheme 3). Our own synthesis of this building block is
closely related to Schinzer×s approach (Scheme 3). In the initial step, pentano-5-lactone
was converted to 5-(benzyloxy)pentanoic acid (11) by treatment with KOH and benzyl
alcohol [24]. Treatment of 11 with oxalyl chloride gave the corresponding acid chloride
12, which was reacted with the Li-salt of (4S)-4-benzyloxazolidin-2-one to provide
acyloxazolidinone 13. On a g-scale, acid chloride 12 could be purified by bulb-to-bulb
distillation (50% yield), whereas, on larger-scale, attempts to distill the compound
resulted in complete decomposition. Large-scale preparation of 13 was, thus, based on
the reaction of the anion of (4S)-4-benzyloxazolidin-2-one with crude 12 (obtained by
simple evaporation of the reaction mixture), which still provided 13 in a satisfactory
82% overall yield based on 11. The choice of (4S)-4-benzyloxazolidin-2-one rather than
(4S)-4-isopropyloxazolidin-2-one [19] as the chiral auxiliary in the ensuing methylation
step was primarily based on the lower price of the former, which, in the anticipated
subsequent scale-up of the synthesis of 4, would be of significant importance.
Methylation of the sodium enolate of 13 with MeI at À788 furnished a 11:1 mixture of
diastereoisomers (by reversed-phase HPLC) in favor of the desired 14 (91%). This
mixture proved to be inseparable by TLC in a broad variety of solvent systems (>20
mixtures were investigated); fortunately, however, the material could eventually be
purified by crystallization from AcOEt/hexane, which provided 14 in 46% yield and in
diastereoisomerically pure form (> 99.5%, as determined by HPLC on a chiral
stationary phase). The relative configuration of 14 and, thus, the absolute configuration
at the newly created chiral center were confirmed by X-ray crystallographic analysis
(Fig. 3).

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Scheme 3
i) KOH, benzyl chloride, toluene, reflux, 16 h; 50%. ii) (COCl)2, DMF (cat.), toluene, r.t., 2h, 50 60 8, 1.75 h;
95% (crude). iii) (4S)-4-Benzyloxazolidin-2-one, BuLi, THF, À808, 2h; 86%. iv) 1. NaHMDS (sodium salt of
hexamethyldisilazane), THF, À75 to À708, 2.5 h; 2. MeI, THF, À788, 2h; 46%. v) LiAlH4, 58, 20 min, r.t., 1 h;
72%. vi) TBS-Cl, 1H-imidazole, DMF, 408, 1 h; quant. vii) H2, 10% Pd/C, MeOH/cyclohexane, 16 h; 94%. viii)
Ms-Cl, Et3N, CH2Cl2, 08, 15 min; quant. ix) NaI, acetone, 508, 25 h; 85%.
Fig. 3. ORTEP Plot of 14 with 30% displacement ellipsoids
It is important to note that methylation of the (4S)-N-acyl-4-isopropyl oxazolidi-
none analogous to 13 as described by Schinzer and co-workers [19] likewise led to a ca.
11:1 mixture of diastereoisomers, which, in our hands, was again inseparable by silica-
gel chromatography in numerous solvent systems, including the one reported [19] to
provide the diastereoisomerically pure methylation product. Reduction of 14 with

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Helvetica Chimica Acta Vol. 85 (2002)
LiAlH4 provided alcohol 15 in 72% yield after distillation, which was converted to the
TBS ether 16 by treatment with TBS-Cl. Removal of the benzyl protecting group by
catalytic hydrogenation over 10% Pd/C in MeOH/cyclohexane gave the mono-
protected diol 17 in 94% yield. In contrast, attempted hydrogenation in MeOH led to
the free diol, due to concurrent loss of both the benzyl as well as the TBS protecting
groups. Alcohol 17 was then elaborated into the desired iodide 4 via the corresponding
mesylate 18 in 85% overall yield. As for building block 3, the chemistry outlined in
Scheme 3 allowed the synthesis of 4 on a multiple-hundred-g scale.
The synthesis of building block 5 is based on the known alcohol 19 [19] as an
advanced intermediate (Scheme 4). Swern oxidation of 19 provided aldehyde 20 in
85% yield, which was then converted into dibromo-olefin 21 via Corey-Fuchs reaction
[25]. Treatment of 21 with BuLi and subsequent quenching with H2O gave acetylene
22. Hydrozirconation of 22 with Schwartz×s reagent [26] followed by reaction with I2
then furnished the desired trans-vinyl iodide 5 with high stereoselectivity and in 31%
overall yield for the four-step sequence from 19.
Scheme 4
i) 1. (COCl)2, DMSO, CH2Cl2, À758, 10 min; 2 . ‡ 19, À708, 40 min; 3. Et3N, À608 ! r.t., 1 h; 85%. ii) CBr4,
Ph3P, CH2Cl2, r.t., 1 h; 80%. iii) BuLi, THF, À758, 1 h, r.t., 1 h; 60%. iv) 1. [ZrCl(Cp)2H], THF, r.t., 30 min; 2. I2,
r.t., 20 min; 77%.
The construction of the epothilone macrocycle from building blocks 3, 4, and 5 is
summarized in Scheme 5. The first step in this assembly process involved reductive
coupling between vinyl iodide 5 and the preformed zincate derived from 4 in the
presence of a Pd0 catalyst [19], which provided trans-olefin 23 in 69% yield. Treatment
of 23 with 1.1 equiv. of camphorsulfonic acid (CSA) in CH2Cl2/MeOH led to selective
TBS removal from the primary OH group (80%), and the resulting free alcohol 24
underwent smooth Swern oxidation to furnish aldehyde 25 in good yield (79%). Aldol
reaction of this aldehyde with the dianion generated from carboxylic acid 3 [20] gave a
mixture of products, which was directly treated with excess TBS-OTf; subsequent
treatment of the crude persilylated material with K2CO3 in MeOH gave the desired free
carboxylic acid 26 in 31% yield (based on 25) as a single diastereoisomer after
purification by FC. The configuration of the newly formed stereogenic centers at C(6)

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Scheme 5
i) 4, ZnÀCu, [Pd(Ph3P)4], benzene, 60 808; 69%. ii) CSA, CH2Cl2/MeOH; 80%. iii) (COCl)2/DMSO, CH2Cl2,
À788; 79%. iv) 1. 3, LDA (lithium diisopropylamide), À788; 2. TBS-OTf, lutidine; 3. K2CO3, MeOH, 31% (3
steps). v) Bu4NF, THF, 64%. vi) 2,4,6-Cl3C6H2C(O)Cl, Et3N, DMAP (N,N-dimethylpyridin-4-amine), THF/
toluene; 61%. vii) CF3COOH/CH2Cl2; 91%.
and C(7) was confirmed by X-ray crystallographic analysis at the stage of trans-
epothilone A (vide infra). No attempts were made to determine the ratio of
diastereoisomers formed in the aldol step, as the reaction was expected to be
essentially nonselective. As indicated above, the choice of carboxylic acid 4 as a partner
in the aldol reaction to establish the C(6)ÀC(7) bond was primarily driven by the
desire to obtain rapid access to trans-deoxyepothilone A (2) for subsequent
epoxidation studies, while less emphasis was placed at an early stage on the
stereoselectivity of each single step in the overall sequence to 1. Treatment of 26
with 6 equiv. of Bu4NF for 3.5 h rather surprisingly gave the desired mono-desilylated
product 27 only in 35% yield together with substantial quantities of doubly deprotected
material. The degree of selectivity in this reaction is thus significantly lower than
described in the literature for related substrates (cf., e.g., [20]). The yield of 27 could be
improved to 64% by reducing the initial excess of Bu4NF and careful reaction
monitoring, but the formation of over-deprotected products could be only partially
suppressed. Fortunately, these byproducts were not lost, but could be recycled into 27
by treatment with excess TBS-OTf followed by cleavage of the TBS ester with K2CO3
in MeOH (vide supra). Cyclization of seco acid 27 by the method of Yamaguchi et al.
[27] gave protected trans-deoxyepothilone A 28 in 61% yield. Deprotection of this
material with 90% CF3COOH/CH2Cl2 then furnished trans-deoxyepothilone A (2) in
excellent yield (91%).
As will be outlined below, 2 could be successfully converted to the two
diastereoisomeric trans-epothilone A isomers 1 in a stereoselective fashion. This

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 6. retro-Synthetic Analysis for a Second-Generation Approach to the Synthesis of trans-Deoxyepo-
thilone A (2)
finding has subsequently prompted us to investigate more selective routes to 2, to
establish a selective and efficient overall synthesis of 1. However, apart from offering
improved access to 1, such a second-generation approach was also desired to provide
straightforward access to analogs with modified heterocyclic side chains (attached to
C(15)), which represent a major focus of our analog program [28]. As illustrated in
Scheme 6, a conceivable strategy to achieve these objectives was to perform aldol-based
construction of the C(6)ÀC(7) bond prior to formation of the C(11)ÀC(12) bond,
which, in turn, would be achieved by a Suzuki-type coupling between vinyl iodide 5 and
a trialkylborane generated in situ from olefin 40 [29][30]. Although this particular
sequence of steps is not a priori a critical feature for the synthesis of trans-epothilone A
itself, this strategy offers significant advantages in the synthesis of side-chain-modified
analogs of 1, as it obviates the need to repeat the critical aldol step for every new
modification. Olefin 40 was planned to be derived from aldehyde 30 (to be obtained
from alcohol 15, Scheme 3) and Schinzer×s ethyl ketone 31 [31], which was thought to
be readily accessible from carboxylic acid 3. Aldol reactions of 31 with aldehydes
related to 30 had been previously reported to proceed with high diastereoselectivity in
favor of the desired (6R,7S) isomer [20][32]. The choice of an alternative coupling
method for the construction of the C(11)ÀC(12) bond was mainly based on
favorable prior experience with the alkyl Suzuki approach in the coupling of 40 with
vinyl iodides other than 5 [28]. In addition, in preliminary experiments, the attempted
coupling of the C(1)-to-C(11) w-alkyl iodide corresponding to 40 with a vinyl iodide
similar to 5 proceeded much less efficiently than that involving the C(7)-to-C(11)
fragment 4.
As illustrated in Scheme 7, the elaboration of carboxylic acid 3 into ketone 31 was
readily achieved by borane-mediated reduction of the carboxylate moiety and
subsequent acetalization of the resulting monoprotected diol 29 with 5%
CF3COOH/acetone in 52% yield. In contrast, treatment of 29 with CuSO4 in acetone
at reflux temperature gave only recovered starting material. This is contrary to the
behavior of the isomer of 29 incorporating a primary TBS ether and a free secondary

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Scheme 7
i) BH3 ¥ Me2S, B(OMe)3, 08, 2h, 15 8, 6 h; 56%). ii) CF3COOH, acetone, 358, 18 h; 93%. iii) 1. LDA (0.5 equiv.),
THF, À788, 80 min; 2. ‡ 30 (0.5 equiv.), À788, 75 min; 82%. iv) PPTS (pyridinium p-toluenesulfonate),
MeOH, r.t., 22 h; 81%. v) TBS-OTf, 2,6-lutidine, CH2Cl2, r.t.; 81%. vi) CSA, MeOH/CH2Cl2, 08, 1 h; 80%. vii)
t
(COCl)2, DMSO, Et3N, CH2Cl2, À788; 92%. viii) NaClO2, isobutene, NaH2PO4, THF, BuOH, H2O, r.t., 4 h;
93%. ix) DCC, DMAP, MeOH, CH2Cl2, À208 ! r.t., 4 h; 71%. x) H2, Pd/C, MeOH, r.t., 1 atm., 1 h; 74%. xi) 1.
2-NO2ÀC6H4ÀSeCN, Bu3P, r.t., 1 h; 2. NaHCO3, 30% H2O2 soln., r.t., 24 h; 93%.
OH group, which can be efficiently acetalized under those conditions [31]. The 7-step
synthesis of 31 from b-keto aldehyde 6 constitutes a significantly more efficient
approach to this valuable building block than previously reported strategies, and it has
allowed the preparation of multi-hundred-g quantities of material.
Aldol reaction of 31 (2equiv.) with aldehyde 30 proceeded with excellent
stereoselectivity, and, after purification by FC, the desired aldol product 32 was

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Helvetica Chimica Acta Vol. 85 (2002)
obtained in diastereoisomerically pure form in 82% yield. Cleavage of the acetonide
moiety in 32 gave free triol 33, which was further elaborated into its partially protected
analog 35 via persilylation ( ! 34) and subsequent selective cleavage of the primary
TBS ether with 1.03 equiv. of CSA in MeOH/CH2Cl2 in 65% overall yield. Swern
oxidation of 35 followed by NaClO2-mediated oxidation [20] of the resulting aldehyde
36 provided carboxylic acid 37, which was converted to methyl ester 38 by N,N-
dimethylpyridin-4-amine (DMAP)-catalyzed esterification with dicyclohexylcarbodii-
mide (DCC)/MeOH. Finally, removal of the benzyl protecting group gave primary
alcohol 39, which was then smoothly transformed into the desired terminal olefin 40 via
the corresponding 2-nitrophenyl selenocyanate and in situ oxidation and elimination in
93% yield [33]. Thus, 40 could be obtained in remarkable 22% overall yield for the 9-
step sequence from aldol product 32.
Alkyl-Suzuki coupling of 40 (via the in situ formed trialkylborane) with vinyl
iodide 5 proceeded smoothly and gave the desired trans-olefin in 63% yield
(Scheme 8). Saponification of the methyl ester in the coupling product 41 with
LiOH/iPrOH provided carboxylic acid 25, which was then elaborated into trans-
deoxyepothilone A (2) as outlined in Scheme 5.
Scheme 8
i) 1. Olefin 40, 9-BBN (9-borabicyclo[3.3.1]nonane), THF, r.t.; 2. Cs2CO3, [PdCl2(dppf)2], Ph3As, vinyl iodide 5,
DMF, À108 to r.t.; 63%. ii) LiOH (6 equiv.), iPrOH/H2O 4 :1, 508; 85%.
The most critical step in the synthesis of trans-epothilone A 1 proved to be the
stereo- and chemoselective epoxidation of the trans C(12)ˆC(13) bond. Epoxidation
of 2 with methyl(trifluoromethyl)dioxirane [35] has been reported by Nicolaou and co-
workers to produce diastereoisomeric trans-epothilones A in 35 and 45% isolated yield,
respectively, after separation by prep. TLC [34]. Unfortunately, we were not able to
reproduce these results, and, in our hands, the epoxidation of 2 with methyl(trifluoro-
methyl)dioxirane gave a 1:1 mixture of diastereoisomeric trans-epothilones 1a/1b (cf.
Scheme 1) in only 28% isolated yield. Rather than trying to improve the chemical yield
of this transformation and subsequently optimize the separation of the diastereoisom-
ers 1a and 1b, we decided to explore the possibility of stereoselective epoxidation of the
trans C(12)ˆC(13) bond. One of the most-sensible options available in this context
appeared to be the use of fructose-derived epoxidation catalysts 42a/42b, which have
¾
been demonstrated by Shi and co-workers to catalyze the Oxone -mediated
epoxidation of isolated trans CÀC bonds with significant stereoselectivities [36].

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Preliminary orientational experiments on an analytical scale indeed revealed that
42a and 42b each catalyzed the epoxidation of 2 with a ca. 9 :1 selectivity in favor of 1a
¾
and 1b, respectively4). On a preparative scale, epoxidation of 2 (1 mmol) with Oxone
in the presence of 30% catalyst 42a4) led to a 8 :1 mixture of diastereoisomeric epoxides
1a/1b in 27% isolated yield (54% based on recovered starting material) (Scheme 9).
Although the chemical yield of the epoxidation thus was not fully satisfactory, the
results that the desired isomer 1a4) was produced with almost 10 :1 selectivity
represented a significant improvement over the reaction with methyl(trifluorome-
thyl)dioxirane (which had been characterized by a complete lack of selectivity (vide
supra)). The preferential formation of 1a is particularly significant in view of our
finding that the isolation of pure 1a on a multi-mg scale was practical only by means of
prep. HPLC. Pure 1a was finally obtained in 11% yield (based on 2; 22% based on
Scheme 9
¾
i) Oxone , 42a (30 mol-%), Bu4N(HSO4) (cat.), K2CO3, MeCN/1,2-dimethoxyethane/0.05m Na2B4O7 ¥ 10 H2O
in 4 ¥ 10À4 m Na2EDTA 2 :1:2, r.t., 1 h; 27% (1a/1b 8 :1; 50% recovered starting material).
4
)
The absolute configuration of the epoxides produced in the presence of 42a/42b at this point could be only
inferred from the known stereochemical preferences of the Shi catalysts. However, based on biological
studies with material obtained from the methyl(trifluoromethyl)dioxirane-mediated epoxidation of 2 via
HPLC separation, it was clear that 42a would lead to the biologically more-active isomer (which was later
demonstrated to correspond to structure 1a).

4098
Helvetica Chimica Acta Vol. 85 (2002)
Fig. 4. ORTEP Plot of trans-epothilone A (1a) with 30% displacement ellipsoids
recovered starting material) after prep. HPLC purification in quantities, which were
sufficient for broad biological profiling in vitro and in vivo (in vivo data not included in
this paper). The relative and absolute configuration of (the biologically active) trans-
epothilone A isomer 1a was established by X-ray crystallography (Fig. 4) and is in line
with the reported stereochemical preferences for epoxidation catalyst 42a [36].
At the biological level, compounds 1a and 1b were both evaluated for their ability
to induce tubulin polymerization in vitro and to inhibit the growth of human cancer cell
lines derived from different types of human tumors. Induction of tubulin polymer-
ization in vitro is commonly used as a measure of the strength of the interactions of
microtubule-stabilizing agents with tubulin/microtubules; in general, the degree of
tubulin-polymerization induction by such compounds reflects their ability to protect
preformed microtubules against various types of depolymerizing stimuli [37]. As
illustrated by the data summarized in Table 1, 1a is a very potent inducer of tubulin
polymerization, whose activity at the level of tubulin interactions is at least comparable
with that of natural epothilone A. In contrast, 1b did not show any measurable
induction of tubulin polymerization under our experimental conditions, thus making
this compound a significantly less-potent polymerization inducer than even trans-
deoxyepothilone A (2) (Table 1). These data clearly indicate that the biological activity
of trans-epothilone A is associated with a (12S,13S) configuration (natural config-
uration at C13).
As expected, similar findings were made in cancer cell growth-inhibition experi-
ments, where the antiproliferative activity of 1a proved to be comparable with that of
epothilone A itself, whereas 1b is more than two orders of magnitude less active
(Table 2). trans-Epothilone A (1a) also retains the ability to inhibit the growth of
multidrug-resistant cancer cell lines with the same potency as epothilone A, thus

Helvetica Chimica Acta Vol. 85 (2002)
4099
Table 1. Induction of Tubulin Polymerization of Epothilone Analogs. Tubulin polymerization was determined
by a modified version of the centrifugation assay described in [38].
Tubulin polymerization [%]a)
EC50 [mm]b)
Epothilone A
Epothilone B
65
85
85
0
4.61
2.63
3.86
1a
1bc)
2
> 50
48
n.d.d)
a) Induction of polymerization of porcine brain microtubule protein by 2 mm of test compound relative to the
effect of 25 mm of epothilone B, which gave maximal polymerization (85% of protein input). b) Concentration
required to achieve half-maximal tubulin polymerization with purified bovine brain tubulin. c) 1b was obtained
by prep. HPLC purification from a 1 : 1 mixture 1a/1b obtained in an initial epoxidation experiment with
methyl(trifluoromethyl)dioxirane. The material used in these experiments was contaminated with ca. 5% of 1a.
d) Not determined.
indicating that the compound, like epothilones A and B [2][5 7], is a poor substrate
for the P-gp efflux pump (cf. Table 2, data for KB-8511 and MCF-7/MDR cell lines).
Overall, these findings reconfirm and extend the previous observation by Nicolaou and
co-workers that changing the geometry of the epoxide moiety in epothilone A from cis
to trans is very well tolerated (for one of the two trans epothilone A stereoisomers) and
does not affect in vitro biological potency. We have not made any serious attempts,
either experimental or computational, to rationalize the differences in activity between
1a and 1b (or the similar activities of 1a and epothilone A) at the conformational level.
However, it seems worth noting that significant deviations between the X-ray crystal
structures of epothilone A and 1a are observed only in the immediate vicinity of the
epoxide moiety, while the remainder of the macrocycle is largely superimposable
Table 2. Growth Inhibition of Human Carcinoma Cell Lines by Epothilones A and B, trans-Epothilones 1a and
1b, and Paclitaxela)
Cell line (tissue type)
IC50 [nm]
Epo A
Epo B
PXT
1.93 Æ 0.36
351 Æ 26
2.29 Æ 0.56
7169 Æ 709
1a
1b
KB-31 (epidermoid)
KB-8511 (epidermoid)b)
MCF-7 (breast)
2.01 Æ 0.43
1.67 Æ 0.17
2.04 Æ 0.30
32.5 Æ 1.97
2.13 Æ 0.88
3.40 Æ 0.13
3.13 Æ 0.76
4.65 Æ 0.620.63
0.17 Æ 0.06
0.19 Æ 0.04
0.23 Æ 0.04
3.83 Æ 0.70
0.18 Æ 0.05
0.27 Æ 0.024.31
0.50 Æ 0.17
Æ 0.10
1.01 Æ 0.24
523, 212d)
400, 182d)
n.d.e)
0.86 Æ 0.34
1.01 Æ 0.11
24.7 Æ 2.2
MCF-7/MDR (breast)c)
MDA-MB-231 (breast)
A549 (lung)
n.d.e)
2.00 Æ 0.48
0.88 Æ 0.40
1.63 Æ 0.23
1.74 Æ 0.92n.d.
2.15 Æ 0.23
n.d.e)
Æ 0.78
2.84 Æ 0.63
4.84 Æ 1.05
n.d.e)
e
HCT-116 (colon)
PC-3M (prostate)
)
n.d.e)
a) Cells were exposed to compounds for 3 5 days, allowing for at least two population doublings. Cell numbers
were estimated by quantification of protein content of fixed cells by methylene blue staining [39]. For further
experimental details, cf. [40]. Data are presented as mean Æ s.d. based on three independent experiments.
Epo A ˆ epothilone A; Epo B ˆ epothilone B; PXTˆ paclitaxel. b) Multidrug-resistant P-gp-overexpressing
subline of the parental KB-31 line. c) Multidrug-resistant variant of the MCF-7 cell line (multiple resistance
mechanisms). d) Values are from separate single experiments which were performed with two different batches
of material. As this material still contained small amounts of 1a, the true IC50 values for 1b are higher than those
listed. e) Not determined.

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Helvetica Chimica Acta Vol. 85 (2002)
between the two structures. This suggests that the overall conformational preferences
of the macrolactone ring do not significantly change as a function of epoxide geometry
(as long as the (S)-configuration at C(13) is maintained), thus resulting in equivalent
biological potency for the (12R,13S) cis and the (12S,13S) trans isomers.
Conclusions. We have developed highly efficient and scaleable syntheses for
epothilone fragments 3 (31), 4 (30), and 5, which were subsequently employed in the
total synthesis of trans-epothilones A 1. While our first-generation approach to 1
suffered from a lack of stereoselectivity in the construction of the C(6)ÀC(7) bond, we
have developed a second-generation strategy that allows the synthesis of trans-
deoxyepothilone A (2) with high efficiency and stereoselectivity. This approach
features the unsaturated C(1)-to-C(11) fragment 40 as a key intermediate, which can be
accessed from 31 and 30 in excellent yield and which is of significant utility also for the
preparation of epothilone analogs other than 1. The C(12)ˆC(13) bond in 2 could be
epoxidized with reasonable selectivity and in acceptable yield in the presence of
fructose-derived epoxidation catalysts 42. However, further improvments in the yield
and also the selectivity of the epoxidation step are still desirable, especially in view of
the fact that the separation of epoxide isomers 1a and 1b on a preparative scale proved
¾
to be exceedingly difficult. Nevertheless, the epoxidation of 2 with Oxone in the
presence of 42 proceeds with significantly higher selectivity than previously reported
for other epoxidation systems, and it has given access to sufficient quantities of material
of 1a for detailed biological testing. X-Ray crystallographic analysis of 1a (in
combination with that of intermediates ent-9 and 14) unambiguously established the
configuration of the epoxide moiety in the more potent isomer of trans-epothilones A
(1a) to be (12S,13S).
Experimental Part
General. Abbreviations: 9-BBN, 9-borabicyclo[3.3.1]nonane; DMF, N,N-dimethylformamide; FC, flash
chromatography; LDA, lithium diisopropylamide; Ms, methylsulfonyl; NaHDMS, sodium hexamethyldisila-
zide; PPTS, pyridinium p-toluenesulfonate; TBS, (tert-butyl)dimethylsilyl; TBS-OTf, TBS triflate. If not noted
otherwise, all starting materials were purchased from commercial suppliers and used without further
purification. Solvents were of reagent-grade purity and used as purchased without any additional distillation.
Pre-dried THF from Fluka was used in H2O-sensitive reactions. FC: Merck silica gel 60 (0.043 0.060 mm).
NMR Spectra: 200 MHz, Varian Gemini-200; 300 MHz, Varian Gemini-300; 400 MHz, Varian Mercury 400;
500 MHz, Bruker DRX-500; d in ppm J in Hz. Electrospray mass spectra: Fisons Instruments VG Platform II.
X-Ray Crystallography. Suitable crystals of compound 1a were obtained from an Et2O soln. by slow
evaporation of the solvent. A Nonius-CAD4 (1a) or a Philips PW1100 (ent-9 and 14) automatic diffractometer
were used for data collection with MoKa radiation and a graphite monochromator. The structures were solved
by direct methods (SHELXS). The parameters were refined by full-matrix least-squares calculations (SHELXL)
with anisotropic displacement parameters for all non-H-atoms. Subsequent difference Fourier maps showed 34
out of 49 H-atoms for 1a, 32of 45 for ent-9, and 24 out of 27 for 14. The positions of the remaining H-atoms
were calculated based on normal geometry. H-Atom parameters were idealized and not refined. For 1a, the
positions of the H-atoms of the two OH groups were taken from the difference map and kept fixed.
Crystallographic data for the individual structures have been deposited in the Cambridge Crystallographic
Data Centre as deposition Nos. CCDC-192930 (1a), CCDC-192932 (ent-9), and CCDC-192931 (14). Copies of
the data can be obtained, free of charge, on application to the CCDC, 12Union Road, Cambridge CB21EZ, UK
(fax: ‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
2,2-Dimethyl-3-oxopentanal (6). Procedure analogous to the one reported for 2,2-dimethyl-3-oxobutanal
by Inukai and Yoshizawa [41]: To a soln. of 17.5 ml (0.200 mol) of propanoyl chloride in 50 ml of tBuOMe was

Helvetica Chimica Acta Vol. 85 (2002)
4101
added dropwise at r.t. within 3 min a soln. of 28.2 g (0.200 mol) of 1-(morpholin-4-yl)isobutene [42] in 50 ml of
tBuOMe. The resulting suspension was heated to reflux for 16 h and then allowed to cool to r.t. After dilution
with 100 ml of Et2O, the temp. was further lowered to 08, and the precipitate was collected by filtration and then
dried in vacuo (32.3 g of white crystals). This material was redissolved in 50 ml of H2O and the pH adjusted to 5
by addition of sat. aq. NaHCO3 soln. Et2O was added, and the mixture was stirred at r.t. for 18 h. The aq. phase
was extracted with Et2O (3 Â 50 ml), the combined org. phase washed with H2O (1 Â 50 ml), dried (MgSO4),
and evaporated, and the residue purified by fractionated distillation: 14.03 g (55%) of 6. Colorless liquid. B.p.
62 64 8/20 Torr. 1H-NMR (200 MHz, CDCl3): 9.58 (s, 1 H); 2.45 (q, 2H); 1.30 ( s, 6 H); 1.00 (t, 3 H).
1-[(1S,5R)-10,10-Dimethyl-3,3-dioxido-3-thia-4-azatricyclo[5.2.1.01,5]dec-4-yl]-ethanone (ˆ(3aS,6R,7aR)-
1-Acetylhexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole 2,2-Dioxide; 7). To a soln. of 430.0 g
(2.0 mol) of (‡)-camphor-10,2-sultam (Avocado) in 16 l of THF was added 96.0 g (2.200 mol) of NaH (55%
dispersion in oil) in portions within 25 min. After stirring at r.t. for 15 h, 170.0 ml (2.400 mol) of AcCl was added
to the suspension (ice-cooling) within 30 min. After stirring at r.t. for additional 15 min, 400 ml of THF/H2O 4 :1
was added to the light yellow suspension within 10 min. The THF was then evaporated, and the soln. was diluted
with 3 l of H2O and extracted with AcOEt (3 Â 2l). The combined org. extract was washed with 2l of brine,
dried (Na2SO4), and concentrated to a volume of ca. 2l, which resulted in the formation of a suspension.
Addition of 3 l of hexanes and cooling to 0 58 for 1 h provided, after filtration and drying at 508, 481.0 g (93%)
of 7. Light yellow crystals. M.p. 133 135. [a]rD:t: ˆ À96.8 (c ˆ 0.995, AcOEt); À109.5 (c ˆ 1.015, CHCl3).
1H-NMR (200 MHz, CDCl3): 4.83 (m, 1 H); 3.45 (dd, 2H); 2.39 ( s, 3 H); 2.10 (m, 2H); 1.85 ( m, 3 H); 1.35
‡
(m, 2H); 1.13 ( s, 3 H); 0.95 (s, 3 H). MS: 275 ([M ‡ Na] ).
Alternatively, compound 7 was prepared in comparable yield and quality without NaH according to the
following procedure [43]: To a soln. of 50 g (0.232 mol) of (À)-camphor-10,2-sultam (Fluka) in 1 l of MeCN was
added 41.3 ml (0.580 mol) of AcCl under Ar, and the mixture was heated under reflux for 4 h. Then 64.1 g of
K2CO3 was added, and stirring at reflux temp. was continued for 2h. The suspension was then cooled to r.t., and
750 ml of H2O was added together with 250 ml of CH2Cl2. The aq. phase was extracted with CH2Cl2 (3 Â
800 ml), the combined org. phase washed with 500 ml of sat. NaCl soln., dried (MgSO4), and evaporated.
Recrystallization of the residue from hot EtOH gave 56.58 g (95%) of 7. White crystals.
(3S)-1-[(1S,5R)-10,10-Dimethyl-3,3-dioxido-3-thia-4-azatricyclo[5.2.1.01,5]dec-4-yl)-3-hydroxy-4,4,dimeth-
ylheptane-1,5-dione (8). Under Ar, 336 ml (2.32 mol) of triethylborane was slowly added to 2.7 l of hexane at r.t.
(ca. 25 min). To this soln. was added 187 ml (2.14 mol) of CF3SO3H under cooling. After rinsing the dropping
funnel with 180 ml of CH2Cl2, the mixture was slowly warmed to 408 until gas evolution had ceased (ca. 70 min).
It was then cooled, and a soln. of 459 g (1.78 mol) of 7 in 4 l of CH2Cl2 was added at 0 28 within 20 min followed
i
by a soln. of 382 ml (2.23 mol) of Pr2NEt (H¸nig×s base) in 1.5 l of CH2Cl2 (also at 0 28; ca. 2 0 min). The
mixture was then cooled to À758, and a soln. of 320 g (2.50 mol) of 6 in 300 ml of CH2Cl2 was added at the same
temp. within 35 min. After an additional 1.5 h at À70 to À758, the reaction was quenched by addition of 400 ml
of THF/H2O 3 :1 followed by 3.5 l of sat. NH4Cl soln. The soln. was then concentrated and diluted with 2l of
AcOEt and 2l of H 2O. The aq. phase was extracted with AcOEt (3 Â 2l) and the combined org. phase washed
with H2O (6 Â 1 l) and brine (1 Â 1 l). Drying (Na2SO4) and evaporation gave a semicrystalline yellow residue
which was twice recrystallized from AcOEt/hexane: 316 g (46%) of 8 as a single diastereoisomer. White
crystals. M.p. 121 1228. [a]rD:t: ˆ À110 (c ˆ 1.03, CHCl3). 1H-NMR (200 MHz, CDCl3): 4.30 (m, 1 H); 3.85
(m, 1 H); 3.45 (dd, 2H); 3.25 ( m, 1 H); 2.80 (m, 2H); 2.55 ( q, 2H); 2.10 ( m, 2H); 1.90 ( m, 3 H); 1.35 (m, 2 H);
‡
1.17 (s, 3 H); 1.15 (s, 3 H); 1.10 (s, 3 H); 1.02( t, 3 H); 0.97 (s, 3 H). MS: 386 ([M ‡ H] ).
(3S)-3-[(tert-Butyl)dimethylsilyl)oxy]-1-[(1S,5R)-10,10-dimethyl-3,3-dioxido-3-thia-4-azatricyclo[5.2.1.01,5]-
dec-4-yl]-4,4-dimethylheptane-1,5-dione (ˆ(3aS,6R,7aR)-1-{(3S)-3-{[(tert-Butoxy)dimethylsilyl]oxy}-4,4-
dimethyl-1,5-dioxoheptyl}-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole 2,2-Dioxide; 9). To a soln. of
409 g (1.06 mol) of 8 in 3 l of CH2Cl2 was added 185 ml (1.59 mol) of 2,6-lutidine (ˆ2,6-dimethylpyridine)
followed by a soln. of 292 ml of TBS-OTf (1.272 mol) in 200 ml of CH2Cl2 (both additions at ca. À758).
The mixture was stirred at À758 for 2.5 h and then allowed to warm to r.t. overnight. The mixture was
then extracted with H2O (3 Â 1 l), the combined aq. extract back-extracted with CH2Cl2 (2 Â 1 l), the combined
org. extract evaporated, and the residue recrystallized from EtOH/H2O: 485 g (92%) of 9. White crystals
M.p. 87 898. [a]rD:t: ˆ À68.7 (c ˆ 0.95, AcOEt). 1H-NMR (200 MHz, CDCl3): 4.75 (t, 1 H); 3.83 (m, 1 H);
3.45 (dd, 2H); 2.95 ( dd, 1 H); 2.65 (dd, 1 H); 2.50 (q, 2H); 2.10 ( m, 2H); 1.85 ( m, 3 H); 1.35 (m, 2H); 1.13 (2 s,
‡
6 H); 1.03 (s, 3 H); 0.97 (−m×, 6 H); 0.83 (s, 9 H); 0.06 (s, 3 H); 0.04 (s, 3 H). MS: 500 ([M ‡ H] ). Anal. calc.
for C25H45NO5SSi (499.79): C 60.08, H 9.08, N 2.80, S 6.42, Si 5.62; found: C 60.28, H 8.96, N 2.99, S 6.43,
Si 5.50.

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Helvetica Chimica Acta Vol. 85 (2002)
(3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4,4-dimethyl-5-oxoheptanoic Acid (3). To
a soln. of 10.0 g
(0.020 mol) of 9 in 100 ml of THF/H2O 4 :1 was added 0.772g (0.032mol) of LiOH, followed by 3.37 ml of
30% aq. H2O2 soln. After 7 h stirring at r.t., 3.78 g of Na2SO3 was added to the mixture, and the THF was
evaporated. To the remaining aq. suspension was added 50 ml of AcOEt, and the pH was adjusted to 6 by
addition of 1n HCl. The aq. phase was extracted with AcOEt (2Â), the combined org. phase evaporated, and
the residue suspended in 50 ml of hexane. After stirring at 08 for 1 h, the mixture was filtered, the filtrate
evaporated, and the residue purified by FC (CH2Cl2/MeOH 97:3 ! 95 :1): 4.58 g (76%) of 3. Oil.
1H-NMR (200 MHz, CDCl3): 4.45 (m, 1 H); 2.50 (m, 3 H); 2.30 (dd, 1 H); 1.12( s, 3 H); 1.05 (s, 3 H); 1.00
(t, 3 H); 0.85 (s, 9 H). MS (neg.): 301 ([M À H]À).
On larger scale, the crude material obtained from the hexane filtrate after trituration was used directly in
the next step.
5-(Benzyloxy)pentanoic Acid (11). To a mixture of 150 ml (1.65 mol) of pentano-5-lactone (10), 462g
(8.25 mol) of KOH, and 3.5 l of toluene was added 608 ml (5.29 mol) of benzyl chloride under N2, and the
mixture was heated under reflux for 16 h. After cooling to r.t., 3 l of H2O, was added, and the mixture was
stirred. The aq. phase was then washed with 2l of Et 2O, acidified by addition of conc. HCl soln., and extracted
with Et2O (3 Â 3 l). The combined acid extract was washed with brine (2.5 l) and evaporated and the oily residue
co-evaporated with toluene (2 Â 200 ml) and then dried in vacuo: 172g (50%) of crude 11. Oil. This material was
used directly in the next step without further purification. If desired, 11 can be purified by distillation (b.p. ca.
1308/0.0075 Torr). 1H-NMR (200 MHz, CDCl3): 7.30 (m, 5 H); 4.48 (s, 2H); 3.45 ( t, 2H); 2.35 ( t, 2H); 1.70
(m, 4 H).
5-(Benzyloxy)pentanoyl Chloride (12). To a soln. of 220 g (1.05 mol) of crude 11 in 1.1 l of toluene under
Ar was added 0.9 ml of DMF followed by dropwise addition of 130 ml (1.47 mol) of oxalyl chloride at r.t. within
1.5 h. After stirring at r.t. for additional 30 min, the mixture was heated to 50 608 for 1.75 h, after which period
the solvents and excess oxalyl chloride were evaporated at a bath temp. of 408. The light yellow oily residue thus
obtained (226 g, 95%) was >90% pure and used as such in the next step. Although feasible on small scale,
attempts to purify this acid chloride by vacuum distillation resulted in lower-quality material and in greatly
reduced yields. B.p. 120 1228/0.075 Torr. 1H-NMR (200 MHz, CDCl3): 7.30 (m, 5 H); 4.48 (s, 2H); 3.45 ( t, 2 H);
2.93 (t, 2H); 1.90 1.60 ( m, 4 H).
(4S)-4-Benzyl-3-[5-(benzyloxy)pentanoyl]oxazolidin-2-one (13). To a soln. of 544 g (3.07 mol) of (4S)-4-
benzyloxazolidin-2-one in 9 l of THF was added 1.75 l of 15% BuLi soln. in hexane (4.1 mol) under Ar at À808
within 2h. To this soln. was then added a soln. of 757 g (3.34 mol) of 12 in 2l of THF dropwise over 1.5 h at
À808, and the mixture was stirred at À808 for 30 min. After that time, the reaction mixture was allowed to warm
to À208, and 400 ml of THF/H2O 4 :1 was added, followed by 800 ml of sat. aq. NH4Cl soln. The THF was
evaporated at 408, the residue diluted with CH2Cl2/H2O (2000 ml/400 ml), the aq. phase extracted with CH2Cl2
(1 Â 2l), the combined org. phase washed with 1 n NaOH (1 Â 2l) and brine (2 Â 4 l), and evaporated, the
residue co-evaporated with toluene (2 Â 1 l), and the resulting light brown oil purified by CC (silica gel,
tBuOMe/hexanes 1:1): 821 g (73%) of 13 as an oil. Rechromatography of 196 g of impure material gave
additional 151 g (13%) of 13. 1H-NMR (200 MHz, CDCl3): 7.30 (m, 8 H); 7.2 0 (m, 2H); 4.65 ( m, 1 H); 4.50
(s, 2H); 4.15 ( d, 2H); 3.51 ( t, 2H); 3.28 ( dd, 1 H); 2.95 (m, 2H); 2.74 ( dd, 1 H); 1.90 1.60 (m, 4 H).
(4S)-4-Benzyl-3-[(2S)-5-(benzyloxy)-2-methylpentanoyl]oxazolidin-2-one (14). All non-aq. steps were
carried out under Ar. A soln. of 205 g (0.558 mol) of 13 in 800 ml of THF was added dropwise at À758 to 690 ml
of 1m NaHMDS in THF. After completion of the addition (ca. 2h), the soln. was stirred for an additional 30 min
at À708 after which time a soln. of 198 ml (3.18 mol) of MeI in 800 ml of THF was added dropwise at the same
temp. (ca. 45 min). The mixture was then stirred at À708 for 75 min, the cooling bath removed, and the mixture
allowed to warm to r.t. After addition of 300 ml of THF/H2O 1:1 followed by 250 ml of sat. NH4Cl soln., the aq.
phase was extracted with tBuOMe (3 Â 300 ml), the combined org. phase evaporated, and the residue purified
by CC (silica gel, tBuOMe/hexane 1:1): ca. 11:1 mixture of diastereoisomers. Two-fold recrystallization of this
material from AcOEt/hexane (ca. 1:10) gave 98.5 g (46%) of 14, which was diastereoisomerically pure. White
crystalline solid. M.p. 51.5 53.38. 1H-NMR (200 MHz, CDCl3): 7.30 (m, 8 H); 7.2 0 (m, 2H); 4.62( m, 1 H); 4.48
(s, 2H); 4.10 ( m, 2H); 3.75 ( m, 1 H); 3.45 (t, 2H); 3.25 ( dd, 1 H); 2.75 (dd, 1 H); 1.80 (m, 1 H); 1.70 1.45
(m, 3 H); 1.22 (d, 3 H).
(2S)-5-(Benzyloxy)-2-methylpentan-1-ol (15). To a soln. of 67.5 g (0.175 mol) of 14 in 700 ml of dry THF
was added 150 ml of 1m LiAlH4 in THF (0.150 mol) at 58 within 20 min. The mixture was stirred at r.t. for 1 h and
then quenched by addition of 17 ml of THF/H2O, 10 :7 followed by 6.5 ml of 4n NaOH and 15 ml of H2O. The
resulting precipitate was removed by filtration, the residue washed with 250 ml of THF, and the filtrate
evaporated. The residue of the evaporation was then redissolved in 250 ml of AcOEt and this soln. extracted

Helvetica Chimica Acta Vol. 85 (2002)
4103
with 200 ml each of H2O, 1n NaOH, H2O, 1n HCl, and H2O followed by 300 ml of brine. The solvent was
evaporated and the residue co-evaporated with toluene (3 Â 100 ml). Vacuum distillation of the residue at 1058/
0.69 mbar gave 26 g (72%) of 15. Colorless oil. [a]rD:t: ˆ À8.7 (c ˆ 1, MeOH). 1H-NMR (200 MHz, CDCl3): 7.35
7.25 ( m, 5 H); 4.50 (s, 2H); 3.45 ( m, 4 H); 1.80 1.40 (m, 3 H); 1.30 1.10 (m, 1 H); 0.95 (d, 3 H). MS: 209
‡
([M ‡ H] ).
{[(2S)-5-(Benzyloxy)-2-methylpentyl]oxy}(tert-butyl)dimethylsilane (16): To a soln. of 256 g (1.22 mol) of
15 and 216 g (3.17 mol) of 1H-imidazole in 1 l of DMF at r.t. was added 248 g (1.59 mol) of TBS-Cl in 3 portions,
and the mixture was then stirred at 408 for 1 h. After cooling to 108, 500 ml of ice-cold H2O was added and the
soln. poured onto 1 l of AcOEt. The aq. phase was extracted with AcOEt (3 Â 500 ml), the combined org. phase
washed with H2O (3 Â 1 l) and brine (1 Â 1.5 l) and evaporated, and the residue co-evaporated with toluene
(1Â) and then purified by FC (silica gel, AcOEt/hexanes 1:6). 395 g (quant.) of 16. Colorless oil. 1H-NMR
(200 MHz, CDCl3): 7.35 7.25 (m, 5 H); 4.49 (s, 2H); 3.50 3.30 ( m, 4 H); 1.75 1.35 (m, 4 H); 0.88 (d ‡ over-
‡
lapping s, 3 H ‡ 9 H); 0.02( s, 6 H). MS: 323 ([M ‡ H] ).
(4S)-5-{[(tert-Butyl)dimethylsilyl]oxy}-4-methylpentan-1-ol (17). Compound 16 (102g, 0.31 mol) was
hydrogenated in 1800 ml of EtOH/cyclohexane 2:1 over 10% Pd/C (10 g) at r.t. and atmospheric pressure for
16 h. After removal of the catalyst by filtration, the solvents were evaporated, and the residue was purified by
FC (silica gel, hexane/AcOEt 6 :1 ! 1 :1). 67.7 g (94%) of 17. Colorless oil. [a]rD:t: ˆ À3.4 (c ˆ 1, MeOH).
1H-NMR (200 MHz, CDCl3): 3.62( t, 2H); 3.40 ( m, 2H); 1.70 1.30 ( m, 4 H); 1.25 1.00 (m, 1 H); 0.88 (d ‡
‡
overlapping s, 3 H ‡ 9 H); 0.02( s, 6 H). MS: 233 ([M ‡ H] ). Anal. calc. for C12H28O2Si (233.442): C 62.01,
H 12.14, Si 12.08; found: C 61.8, H 12.0, Si 11.90.
(tert-Butyl)[(2S)-5-iodo-2-methylpentyloxy]dimethylsilane (4). Mesylation of 17: To a soln. of 25 g
(0.107 mol) of 17 in 200 ml of CH2Cl2 at 08 was added 22.4 ml (0.161 mol) of Et3N followed by dropwise addition
of 11.0 ml (0.14 mol) of MsCl. The resulting white suspension was stirred at 08 for 15 min and then carefully
diluted with 100 ml of tBuOMe and 100 ml of H2O. The org. layer was washed consecutively with 100 ml of 1n
HCl, 100 ml of sat. NaHCO3 soln., and 200 ml of brine. The brine extract was back-extracted with 50 ml of
CH2Cl2. The combined org. extract was evaporated and the residue co-evaporated with toluene (1Â) to provide
32g (quant.) of 18 as a light yellow oil, which was used in the next step without further purification. 1H-NMR
(200 MHz, CDCl3): 4.20 (t, 2H); 3.40 ( d, 2H); 3.00 ( s, 3 H); 1.85 1.40 (m, 4 H); 1.25 1.05 (m, 1 H); 0.88 (d ‡
‡
overlapping s, 3 H ‡ 9 H); 0.00 (s, 6 H). MS: 311 ([M ‡ H] ).
A mixture of 30 g (0.096 mol) of 18, 30 g (0.193 mol) of NaI, and 200 ml of dry acetone was stirred at 508
for 25 h. After cooling to 158, 70 ml of brine was added, insoluble material removed by filtration, and the filter-
cake washed with 200 ml of AcOEt. The org. layer in the filtrate was then separated, the solvents were
evaporated, and the residue was purified by FC (silica gel, hexanes/AcOEt 9 :1): 28.0 g (85%) of 4. Colorless oil.
[a]Dr:t: ˆ À8.2( c ˆ 1.034, MeOH). 1H-NMR (200 MHz, CDCl3): 3.40 (m, 2H); 3.15 ( t, 2H); 1.95 1.75 ( m, 2 H);
1.70 1.40 (m, 2H); 1.25 1.00 ( m, 1 H); 0.88 ‡ 0.85 (s ‡ overlapping d, 9 H ‡ 3 H); 0.02( s, 6 H). Anal. calc. for
C12H27IOSi (342.339): C 42.10, H 7.95, I 37.07, Si 8.20; found: C 42.45, H 8.29, I 37.13, Si 8.05.
(3S,4E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-methyl-5-(2-methylthiazol-4-yl)pent-4-enal (20). A soln. of
35.6 ml (0.414 mol) of oxalyl chloride in CH2Cl2 (600 ml) was treated at À708 under N2 with a soln. of 61.4 ml
(0.864 mol) of DMSO in 120 ml of CH2Cl2. After stirring at À758 for 10 min, a soln. of 117.9 g (0.36 mol) of
alcohol 19 [19][31] in 300 ml of CH2Cl2 was added within 20 min, and stirring was continued for additional
30 min. To the clear mixture, Et3N (250.9 ml, 1.8 mol) was then added within 15 min, such that the temp. was
kept below À608. After 5 min, the cooling bath was removed and the mixture allowed to warm to 08 within 1 h.
H2O (500 ml) was then added, the aq. phase extracted with CH2Cl2 (1 Â 200 ml and 1 Â 100 ml), the combined
org. phase washed with brine, dried (Na2SO4), and evaporated and the resulting crude aldehyde purified by FC
(hexanes, then hexanes/AcOEt 9 :1 ! 8 :2 ):20 (99.4 g, 85%). Slightly yellow oil. 1H-NMR (200 MHz, CDCl3):
9.78 (m, 1 H); 6.94 (s, 1 H); 6.55 (br. s, 1 H); 4.68 (dd, J ˆ 7.5, 3.5, 1 H); 2.65 2.8 (m, 4 H); 2 .49 (ddd, J ˆ 16, 4,
‡
1, 1 H); 2.03 (s, 3 H); 0.88 (s, 9 H); 0.03, 0.08 (2s, 6 H). MS: 326.3 ([M ‡ H] ).
4-{(1E,3S)-6,6-Dibromo-3-{[(tert-butyl)dimethylsilyl]oxy}-2-methylhexa-1,5-dienyl}-2-methylthiazole (21).
A soln. of 32.51 g (0.123 mol) of triphenylphosphine in 58 ml of CH2Cl2 was added within 20 min to an ice-
cooled soln. of 20.56 g (0.0620 mol) of tetrabromomethane in 150 ml of CH2Cl2 under N2. The dark orange soln.
was stirred for 10 min without cooling followed by addition of a soln. of 18.34 g (0.0563 mol) of 20 in 49 ml of
CH2Cl2 over 30 min. During the addition of 20, the temp. was kept between 18 and 238. The resulting suspension
was stirred for 1 h at r.t., cooled in an ice bath, and filtered. The solid filter cake was washed with CH2Cl2/hexane
1:1 (25 ml). The combined filtrates were stirred with H2O (100 ml), and the mixture was neutralized by the
addition of sat. aq. NaHCO3 soln. The org. phase was then dried (Na2SO4), and evaporated and the residue
purified by FC (hexane/AcOEt 8 :2): 21 (21.77 g, 80%). Yellow oil. 1H-NMR (400 MHz, CDCl3): 6.92( s, 1 H);

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Helvetica Chimica Acta Vol. 85 (2002)
6.51 (br. s, 1 H); 6.44 (t, 1 H); 4.24 (dd, 1 H); 2.70 (s, 3 H); 2.44 (m, 2H); 2.01 ( s, 3 H); 0.88 (s, 9 H); 0.03, 0.09
(2s, 6 H).
4-{(1E,3S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-2-methylhex-1-en-5-ynyl}-2-methylthiazole (22). Dibromo-
olefin 21 (24.05 g, 0.05 mol) was dissolved under N2 in 150 ml of dry THF and the soln. cooled to À758. Then
1.6m BuLi in hexanes (66 ml, 0.1056 mol) was added dropwise over 30 min, and the dark mixture was stirred for
1 h at À758 and then 1 h at r.t. H2O (100 ml) was added slowly to the mixture followed by Et2O (300 ml). The aq.
phase was extracted with Et2O (2 Â 100 ml), the combined org. phase washed with brine, dried (Na2SO4), and
evaporated, and the crude product purified by FC (hexanes, then hexanes/AcOEt 99 :1 ! 92:8): 9.62g (60%) of
22. Yellow oil. 1H-NMR (200 MHz, CDCl3): 0.03, 0.09 (2s, 6 H); 0.88 (s, 9 H); 1.95 (t, J ˆ 2, 1 H); 2.01 (s, 3 H);
2.44 (dd, J ˆ 7.5, 2, 2 H); 2.70 (s, 3 H); 4.29 (br. t, J ˆ 7.5, 1 H); 6.51 (br. s, 1 H); 6.94 (s, 1 H). MS: 322.3 ([M ‡
‡
H] ).
4-{(1E,3S,5E)-3-{[(tert-Butyl)dimethylsilyl]oxy}-6-iodo-2-methylhexa-1,5-dienyl}-2-methylthiazole (5). To
a suspension of 26.1 g (0.0961 mol) of chlorobis(cyclopentadienyl)hydrozirconium (Schwartz×s reagent) in dry
THF (200 ml) was added dropwise a soln. of 20.6 g (0.0641 mol) of 22 in dry THF (50 ml) at r.t. under N2. After
stirring at r.t. for 30 min, an almost clear soln. was obtained, which was treated with solid I2 (0.0961 mol) over a
period of 10 min. During the addition, the temp. was maintained at 20 258 with an ice-water bath. The dark
mixture was stirred for additional 10 min and then added dropwise to 400 ml of sat. aq. NaHCO3 soln. under
stirring. Hexanes/AcOEt 9 :1 (200 ml) was added and the mixture stirred for 5 min. The aq. phase was extracted
with hexanes/AcOEt 9 :1 (2 Â 150 ml), the combined org. phase washed with brine (200 ml), dried (Na2SO4),
and evaporated, and the resulting black oil purified by FC (toluene, then toluene/AcOEt 98 :2 ! 96 :4): 5
(22.3 g, 77%). Brownish oil. 1H-NMR (200 MHz, CDCl3): 6.91 (s, 1 H); 6.6 6.7 (m, 2H); 6.04 (br. d, J ˆ 15,
1 H); 4.13 (br. t, J ˆ 7.5, 1 H); 2.69 (s, 3 H); 2.42 2.35 (m, 2H); 1.98 (br. s, 3 H); 0.88 (s, 9 H); À0.01, 0.05 (2s,
‡
6 H). MS: 450.1 ([M ‡ H] ).
4-{(1E,3S,5E,10S)-3,11-Bis{[(tert-butyl)dimethylsilyl]oxy}-2,10-dimethylundeca-1,5-dienyl}-2-methylthia-
zole (23). To suspension of ZnÀCu couple (3.74 g, 0.057 mol) in dry benzene was added 0.27 ml (0.0032 mol) of
ethylene bromide under N2. The mixture was immersed in a preheated oil bath, refluxed for 30 s and cooled to
r.t. (ice-water bath) followed by addition of Me3SiCl (0.27 ml, 0.0022 mol) and stirring for 5 min. To this mixture
was added a soln. of 12.7 g (0.037 mol) of 4 and 5.9 ml (0.063 mol) of N,N-dimethylacetamide in 31.5 ml of
benzene within 5 min. The resulting mixture was heated to 608 for 2.5 h and then cooled to r.t. After addition of
0.16 ml (0.00069 mol) of TMS-OTf and 5.9 ml (0.063 mol) of N,N-dimethylacetamide, heating was continued for
1 h at 808. After cooling to r.t., 1.09 g (0.00095 mol) of tetrakis(triphenylphosphine)palladium was added, and
the mixture was stirred for 5 min. A soln. of 11.1 g (0.0247 mol) of 5 in 23 ml of benzene was then added
dropwise and the mixture heated to 608 for 30 min and cooled to r.t. After addition of sat. aq. NH4Cl soln.
t
(39 ml) and 150 ml of BuOMe, the resulting mixture was filtered through Hyflo, the aq. phase extracted with
tBuOMe (2 Â 50 ml), the combined org. phase washed with brine (50 ml), dried (Na2SO4), and evaporated, and
the crude product purified by FC (hexanes, then hexanes/AcOEt 99 :1 ! 96 :4): 9.16 g (69%) of 23. Slightly
1
yellow oil. H-NMR (200 MHz, CDCl3): 6.90 (s, 1 H); 6.43 (br. s, 1 H); 5.27 5.51 (m, 2H); 4.08 (br. t, J ˆ 7.5,
1 H); 2.69 (s, 3 H); 2.17 2.28 (m, 2H); 3.25 3.47 ( m, 2H); 1.88 2.0 ( m, 5 H); 1.15 1.4 (m, 4 H); 0.78 0.9
‡
(m, 2 2 H);À0.02, 0.00, 0.09 (3s, 12H). MS: 450.0 ([ M ‡ H] ).
(2S,6E,9S,10E)-9-{[(tert-Butyl)dimethylsilyl]oxy}-2,10-dimethyl-11-(2-methylthiazol-4-yl)undeca-6,10-di-
en-1-ol (24). To a soln. of 18.24 g (0.0339 mol) of 23 in 500 ml of MeOH/CH2Cl2 1:1 was added solid (‡)-
camphor-10-sulfonic acid (7.88 g, 0.0339 mol) at 08 under N2 in portions over 5 min. The mixture was then stirred
at 08 for 30 min and subsequently for 2h at r.t. After addition of sat. aq. NaHCO 3 soln. (31.1 ml), the solvents
were evaporated, and the residue was partitioned between H2O (50 ml) and CH2Cl2 (200 ml). The aq. phase was
further extracted with CH2Cl2 (2 Â 30 ml), the combined org. phase dried (Na2SO4) and evaporated, and the
crude product purified by FC (hexanes/AcOEt 91:9 ! 77:23): 11.53 g (80%) of 24. Slightly yellow oil. 1H-NMR
(300 MHz, CDCl3): 6.92( s, 1 H); 6.44 (br. s, 1 H); 5.26 5.48 (m, 2H); 4.10 (br. t, J ˆ 7.5, 1 H); 3.35 3.5
(m, 2H); 2.70 ( s, 3 H); 2.15 2.34 (m, 2H); 1.92 2.02( m, 5 H); 1.2 1.5 ( m, 4 H); 0.85 1.11 (m, 14 H); À0.01,
‡
0.06 (2s, 6 H). MS: 424.3 ([M ‡ H] ).
(2S,6E,9S,10E)-9-{[(tert-Butyl)dimethylsilyl]oxy}-2,10-dimethyl-11-(2-methylthiazol-4-yl)undeca-6,10-di-
enal (25). A soln. of 0.185 ml (0.00215 mol) of oxalyl chloride in 4.6 ml of CH2Cl2 was treated at À708 under N2
with a soln. of 0.334 ml (0.0047 mol) of DMSO in 1 ml of CH2Cl2. After stirring at À708 for 10 min, a soln. of
0.83 g (0.00196 mol) of 24 in 3 ml of CH2Cl2 was added within 10 min, and stirring was continued for 30 min. To
the clear mixture, 1.365 ml (0.00979 mol) of Et3N was added within 10 min such that the temp. was kept below
À608. The cooling bath was then removed, and the mixture was allowed to warm to r.t. within 1 h. H2O (6 ml)
was added, the aq. phase extracted with CH2Cl2 (1 Â 5 ml and 1 Â 3 ml), the combined org. phase dried

Helvetica Chimica Acta Vol. 85 (2002)
4105
(Na2SO4) and evaporated and the crude aldehyde purified by FC (hexanes, then hexanes/AcOEt 95 :5 !
80 :20): 0.656 g (79%) of 25. Slightly yellow oil. [a]2D1 ˆ ‡20.16 (c ˆ 2.465, CHCl3). 1H-NMR (200 MHz,
CDCl3): 9.55 (d, J ˆ 2, 1 H); 6.90 (s, 1 H); 6.43 (br. s, 1 H); 5.27 5.5 (m, 2H); 4.09 ( t, J ˆ 6.5, 1 H); 2.69
(s, 3 H); 2.13 2.38 (m, 3 H); 1.9 2.05 (m, 5 H); 1.6 1.75 (m, 1 H); 1.22 1.44 (m, 3 H); 1.03 (d, J ˆ 7.5, 3 H);
‡
0.87 (s, 9 H); À0.02, 0.03 (2s, 6 H). MS: 422.2 ([M ‡ H] ).
(5S)-5-{[(tert-Butyl)dimethylsilyl]oxy}-7-hydroxy-4,4-dimethylheptan-3-one (29). To a soln. of 78 g of
crude 3 in 300 ml of THF was aded dropwise 90 ml (0.800 mol) of trimethyl borate at 08 within 5 min followed by
50 ml (0.500 mol) of BH3 ¥ Me2S within 15 min. The mixture was then stirred at ice-bath temp. for 22 h, at which
point 200 g of crushed ice was added in portions, such that the temp. did not exceed ‡ 58. The resulting emulsion
was stirred at r.t. for 30 min. The solvents were then removed by evaporation (azeotropic removal of H2O with
toluene), and 2l of hexanes were added to the milky residue followed by 80 g of H 2O and 100 g of Na2SO4. After
stirring at r.t. for 1 h, the mixture was filtered and the filtrate evaporated. Purification of the residue by FC
(CH2Cl2, 2runs) gave 3.25 g (56%) of
29. Clear colorless oil. [a]rD:t: ˆ ‡31.1 (c ˆ 1.0, CHCl3). 1H-NMR
(200 MHz, CDCl3; 1:2equilibrium between the open-chain and the cyclic-hemiacetal form (major component),
the latter being a diastereoisomer mixture; thus some of the integrals do not amount to signals of 1.0): 6.03
(d, 0.65 H, exchangeable with D2O); 4.12, 4.00 3.82, 3.70 3.58 (dt, m, m, 3 H); 2 .15 (m, 0.65 H); 1.80 1.40
(m, 3.35 H); 1.12 0.89 (− m×, 19 H); 0.13 (d, 3.9 H); 0.08 (d, 2.1 H). MS: 271 ([M À OH] ).
‡
2-[(4S)-2,2-Dimethyl-1,3-dioxan-4-yl]-2-methylpentan-3-one (31). A soln. of 32.0 g (0.111 mol) of 29 in a
mixture of 440 ml of acetone and 25.7 ml of CF3COOH was stirred at r.t. for 18 h. After cooling to 28, Et3N
(61.3 ml) was added within 10 min followed by 750 ml of Et2O and 165 ml of H2O. The emulsion was stirred at
r.t. for 15 min, the Et2O soln. back-extracted with H2O (3 Â 100 ml), the combined aq. extract in turn back-
extracted with Et2O (3 Â 100 ml), the combined org. phase washed with brine (1 Â 80 ml), dried, and
evaporated, and the residue purified by FC (hexane/Et2O 6 :1 (‡0.1% of Et3N)): 22.0 g (93%) of 31. Colorless
oil, which solidified upon standing at À208. [a]rD:t: ˆ ‡13.0 (c ˆ 1.335, CHCl3) ([31]: ‡ 12.4 (c ˆ 1.0, CHCl3)).
1H-NMR (200 MHz, CDCl3): 4.01 (dd, 1 H); 3.91 (dd, 1 H); 3.82( m, 1 H); 2,50 (q, 2H); 1,60 ( m, 1 H); 1.40
‡
(s, 3 H); 1.30 (s ‡ overlapping m, 3 H ‡ 1 H); 1.11 (s, 3 H); 0.98 (t, 3 H). MS: 215 ([M ‡ H] ), 157 (100, [M À
‡
acetone] ).
(2S)-5-(Benzyloxy)-2-methylpentanal (30). To a soln. of 10.71 g (0.085 mol) of oxalyl chloride in 170 ml of
CH2Cl2 was added a soln. of 13.19 g of DMSO (0.209 mol) in 15 ml of CH2Cl2 at À788 within 15 min. The soln.
was stirred at À788 for 15 min, when a soln. of 8.79 g of 15 (0.043 mol) in 35 ml of CH2Cl2 was added dropwise
within 15 min. The mixture was stirred at À788 for 45 min and then 25.62 g (0.254 mol) of Et3N was added
dropwise at À788 within 15 min. The cooling bath was removed and the mixture allowed to warm to r.t.
(suspension). It was then recooled to À308, and 110 ml of sat. aq. NH4Cl soln. was added. Subsequently H2O was
added at r.t. until a clear biphasic soln. had formed. The org. phase was washed with 75 ml of 2% KHSO4 soln.,
75 ml of sat. aq. NaHCO3 soln., and 75 ml of brine, dried (MgSO4), and evaporated. The residue was purified by
1
FC (AcOEt/hexane 3 :7): 7.15 g (81%) of 30. Oil. H-NMR (300 MHz, CDCl3): 9.62( d, 1 H); 7.32( m, 5 H);
4.50 (s, 2H); 3.50 ( t, 2H); 2.35 ( m, 1 H); 1.82( m, 1 H); 1.65 (m, 2H); 1.60 ( m, 1 H); 1.11 (d, 3 H). MS: 207
‡
([M ‡ H] ).
(4R,5S,6S)-9-(Benzyloxy)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethylnonan-3-one
i
(32). To a soln. of 9.6 ml (0.068 mol) of Pr2NH in 100 ml of THF was added dropwise 42.46 ml of 1.6m BuLi
(0.068 mol) in hexane at À5 to À08 within 10 min. The yellow soln. was stirred at 08 for 30 min and then cooled
to À788, and a soln. of 14.83 g (0.069 mol) of 31 in 100 ml of THF was added dropwise at À788 within 20 min.
After one additional hour at À788, a soln. of 30 (7.15 g, 0.0347 mol) in 125 ml of THF was added dropwise over
15 min. The mixture was then stirred at À788 for 1 h, when 150 ml of sat. aq. NH4Cl soln. was added. The
mixture was then allowed to warm to r.t., and 600 ml of Et2O was added followed by H2O until a clear biphasic
soln. had formed. The aq. phase was extracted with Et2O (2 Â 600 ml), the combined org. phase dried (MgSO4)
and evaporated, and the residue purified by FC (hexane/AcOEt 3 :2, 3 runs): 11.94 g (82%) of 32 as a single
diastereoisomer (by NMR). 1H-NMR (CDCl3, 500 MHz): 7.35 (s, 2H); 7.33 ( s, 3 H); 7.2 8 (m, 1 H); 4.50
(s, 2H); 4.05 ( dd, 1 H); 3.97 (m, 1 H); 3.86 (m, 1 H); 3.48 (m, 3 H); 3.38 (d, 1 H); 3.28 (q, 1 H); 1.85 1.70
(m, 2H); 1.68 1.35 ( m, 3 H; overlapping with s at 1.56, 3 H); 1.40 (s, 3 H); 1.35 (m, 1 H, overlapping with s at
‡
1.34, 3 H); 1.08 (s, 3 H); 1.02( d, 3 H); 0.85 (d, 3 H). MS: 421.4 ([M ‡ H] ).
(3S,6R,7S,8S)-11-(Benzyloxy)-1,3,7-trihydroxy-4,4,6,8-tetramethylundecan-5-one (33). To a soln. of 11.96 g
(0.0284 mol) of 32 in 360 ml of MeOH was added 7.15 g (0.0284 mol) of PPTS, and the mixture was stirred at r.t.
for 24 h. The solvent was evaporated and the residue purified by FC (Et2O): 8.75 g (81%) of 33. 1H-NMR
(CDCl3, 300 MHz): 7.32( m, 5 H); 4.50 (s, 2H); 4.03 ( m, 1 H); 3.85 (m, 2H); 3.49 ( m, 2H); 3.42 3.23

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Helvetica Chimica Acta Vol. 85 (2002)
(m, 4 H); 1.78 (m, 2H); 1.65 1.50 ( m, 4 H); 1.2 0 (s, 3 H); 1.15 (s, 3 H); 1.07 (d, 3 H); 0.88 (d, 3 H). MS: 403.0
‡
([M ‡ Na] ).
(3S,6R,7S,8S)-11-(Benzyloxy)-1,3,7-tris-{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8-tetramethylundecan-5-one
(34). To a soln. of 8.75 g of 33 (0.023 mol) in 300 ml of CH2Cl2 was added 12.3 g (0.115 mol) of 2,6-lutidine
followed by dropwise addition of 24.3 g (0.0919 mol) of TBS-OTf at 0 58 over 10 min. The mixture was stirred
at r.t. for 20 h, concentrated to ca. 50% of its original volume, and then poured on a mixture of 800 ml of AcOEt
and 500 ml of sat. aq. NaHCO3 soln. The aq. soln. was extracted with 300 ml of AcOEt, the combined org.
extract successively washed with H2O, 5% KHSO4 soln. (2Â), brine (2Â), and H2O, dried (MgSO4), and
evaporated, and the residue purified by FC (3% hexane/Et2O): 13.81 g (81%) of 34. 1H-NMR (CDCl3,
500 MHz): 7.32( m, 4 H); 7.2 8 (m, 1 H); 4.50 (s, 2H); 3.89 ( dd, 1 H); 3.78 (dd, 1 H); 3.66 (m, 1 H); 3.58
(m, 1 H); 3.46 (t, 2H); 3.15 ( m, 1 H); 1.70 (m, 1 H); 1.57 (m, 1 H); 1.48 (m, 2H); 1.40 1.15 ( m, 3 H,
overlapping with s at 1.22, 3 H); 1.05 (d, 3 H); 1.02( s, 3 H); 0.94 (d, 3 H); 0.92 0.84 (− m×, 27 H); 0.11 0.01
‡
(several s, 18 H). MS: 723.0 ([M ‡ H] ).
(3S,6R,7S,8S)-11-(Benzyloxy-3,7-bis{[(tert-butyl)dimethylsilyl]oxy}-hydroxy-4,4,6,8-tetramethylundecan-
5-one (35). To a soln. of 12.8 g (0.0174 mol) of 34 in 700 ml of CH2Cl2/MeOH 1:1 at 08 was added 4.18 g
(0.0180 mol) of camphorsulfonic acid portionwise over 5 min. The mixture was stirred at 08 for 1 h, when 2.5 ml
(0.0179 mol) of Et3N was added. The bulk of the CH2Cl2 was then evaporated, and 300 ml of AcOEt was added
to the remaining soln. This was followed by removal of the bulk of MeOH by evaporation (no heating) and
subsequent addition of additional 200 ml of AcOEt. This soln. was extracted with 400 ml of sat. aq. NaHCO3
soln. and H2O (2Â), the combined aq. extract once back-extracted with 300 ml of CH2Cl2, the CH2Cl2 soln.
washed several times with H2O (each 100 ml), the combined org. extract dried (MgSO4) and evaporated, and
the residue purified by FC (hexane/Et2O 2:1): 8.66 g (80%) of 35. 1H-NMR ((D6)DMSO, 500 MHz): 7.30
(m, 5 H); 4.42( s, 2H); 4.38 ( t, 1 H); 3.79 (dd, 1 H); 3.68 (m, 1 H); 3.46 (m, 1 H); 3.39 (t, 2H); 3.35 ( m, 1 H);
3.17 (m, 1 H); 1.62( m, 1 H); 1.48 (m, 2H); 1.32( m, 3 H); 1.15 (s, 3 H; overlapping with m, 1 H); 0.98 (d, 3 H);
‡
0.97 (s, 3 H); 0.90 0.84 (−m×, 21 H); 0.07 (s, 3 H); 0.05 (s, 3 H); 0.04 (s, 6 H). MS: 631.3 ([M ‡ Na] ).
(3R,6R,7S,8S)-11-(Benzyloxy)-3,7-bis{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8-tetramethyl-5-oxoundecanal
(36). To a soln. of 1.5 ml (0.0177 mol) of oxalyl chloride in 45 ml of CH2Cl2 was added 2.7 ml (0.0380 mol) of
DMSO at À758 within 5 min. The soln. was stirred at À758 for 10 min, when a soln. of 9.25 g (0.0148 mol) of
alcohol 35 in 45 ml of CH2Cl2 was added dropwise within 20 min. The mixture was stirred at À758 for 30 min,
and then 12.0 ml (0.0884 mol) of Et3N was added dropwise at À758 within 10 min. The mixture was allowed to
warm to À108, followed by addition of 200 ml of H2O and 300 ml of CH2Cl2. The org. phase was washed with
brine (2 Â 300 ml), the combined aq. phase re-extracted with CH2Cl2 (1 Â 200 ml), the combined org. extract
dried (MgSO4) and evaporated and the residue purified by FC (hexane/Et2O 4 :1) 8.51 g (92%) of 36. 1H-NMR
(CDCl3, 300 MHz): 9.76 (d, 1 H); 7.30 (m, 5 H); 4.50 (overlapping s and m, 3 H); 3.79 (d, 1 H); 3.47 (t, 2 H);
3.12( m, 1 H); 2.50 (dd, 1 H); 2.40 (dd, 1 H); 1.72( m, 1 H); 1.60 1.10 (m, 4 H; overlapping with s at 1.22, 3 H);
1.08 (s, 3 H); 1.05 (d, 3 H); 0.93 (d, 3 H); 0.90 (s, 9 H); 0.88 (s, 9 H); 0.09 (s, 3 H); 0.06 (s, 6 H); 0.04 (s, 3 H).
‡
MS: 607.3 ([M ‡ H] ).
(3S,6R,7S,8S)-11-(Benzyloxy)-3,7-bis{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8-tetramethyl-5-oxoundecanoic
Acid (37). To a soln. of ca. 7 g (0.0875 mol) of isobutene in 40 ml of THF at 08 was added a soln. of 8.5 g
(0.0137 mol) of 36 in 70 ml of tBuOH dropwise within 15 min followed by the dropwise addition of 14 ml of H2O
at 08. Then 4.8 g of NaClO2 (80%) and 2.9 g of NaH2PO4 ¥ H2O were added, and the mixture was stirred at r.t. for
4 h. The mixture was evaporated, the residue distributed between H2O and CH2Cl2 (500 ml each), the pH of the
separated aq. phase adjusted to 4.5 with 1n HCl, and the aq. phase recombined with the CH2Cl2 extract. After
extraction, the aq. phase was extracted with CH2Cl2 (2 Â 250 ml), the combined org. phase washed with H2O
(400 ml), dried, and evaporated, and the residue purified by FC (hexane/acetone 1:1): 8.10 g (93%) of 37. Oil.
1H-NMR (CDCl3, 300 MHz): 7.30 (m, 5 H); 4.50 (s, 2H); 4.39 ( m, 1 H); 3.80 (d, 1 H); 3.45 (m, 2H); 3.15
(m, 1 H); 2.48 (dd, 1 H); 2.31 (dd, 1 H); 1.72( m, 1 H); 1.45 (m, 1 H); 1.35 1.15 (m, 3 H; overlapping with s at
1.21, 3 H); 1.10 (s, 3 H); 1.06 (d, 3 H); 0.92( d, 3 H); 0.90 (s, 9 H); 0.88 (s, 9 H); 0.10 (s, 3 H); 0.06 (s, 9 H). MS
‡
(neg.): 621.5 ([M À H] ).
(3S,6R,7S,8S)-11-(Benzyloxy)-3,7-bis{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8-tetramethyl-5-oxoundecanoic
Acid Methyl Ester (38). A soln. of 3.27 g (0.00513 mol) of 37 in 90 ml of CH2Cl2 was cooled to À208, and 1.2g
(0.00582mol) of dicyclohexylcarbodiimide, 3.5 ml (0.00865 mol) of MeOH, and 0.647 mg (0.00535 mol) of N,N-
dimethylpyridin-4-amine were added. The mixture was allowed to warm to r.t., and after 4.5 h, it was diluted
with 400 ml of CH2Cl2. This soln. was extracted with H2O (2 Â 200 ml), the combined aq. phase re-extracted
with CH2Cl2 (2Â), the combined org. phase dried (MgSO4) and evaporated, and the residue purified by FC
(hexane/Et2O 9 :1). 2.478 g (71%) of 38. 1H-NMR (CDCl3, 300 MHz): 7.30 (m, 5 H); 4.50 (s, 2H); 4.40

Helvetica Chimica Acta Vol. 85 (2002)
4107
(m, 1 H); 3.80 (d, 1 H); 3.67 (s, 3 H); 3.47 (m, 2H); 3.15 ( m, 1 H); 2.42 (dd, 1 H); 2 .2 8d(d, 1 H); 1.72( m, 1 H);
1.60 1.20 (m, 4 H); 1.2 0 (s, 3 H); 1.06 (s, 3 H); 1.05 (d, 3 H); 0.91 (d, 3 H); 0.89 (s, 9 H); 0.87 (s, 9 H); 0.09
‡
(s, 3 H); 0.05 (s, 6 H); 0.03 (s, 3 H). MS: 659.2([ M ‡ Na] ).
(3S,6R,7S,8S)-3,7-Bis{[(tert-butyl)dimethylsilyl]oxy}-11-hydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic
Acid Methyl Ester (39). Compound 38 (1.25 g, 0.00123 mol) was hydrogenated over 150 mg of 5% Pd/C in 50 ml
of MeOH at r.t. and 1 atm. After 4 h, the catalyst was removed by filtration, the filtrate evaporated, and the
residue purified by FC (hexane/Et2O 1:1): 0.935 g (74%) of 39. Oil. 1H-NMR (CDCl3, 300 MHz): 4.41
(m, 1 H); 3.80 (d, 1 H); 3.68 (s, 3 H); 3.64 (t, 2H); 3.17 ( m, 1 H); 2.43 (dd, 1 H); 2 .2 9d(d, 1 H); 1.65 (m, 1 H);
1.55 1.30 (m, 4 H); 1.22 (s, 3 H); 1.10 (s, 3 H); 1.07 (d, 3 H); 0.95 (d, 3 H); 0.91 (s, 9 H); 0.88 (s, 9 H); 0.10
‡
(s, 3 H); 0.07 (s, 6 H); 0.02( s, 3 H). MS: 569.3 ([M ‡ Na] ).
(3S,6R,7S,8S)-3,7-Bis{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8-tetramethyl-5-oxoundec-10-enoic Acid Methyl
Ester (40). To a soln. of 5.0 g (0.00891 mol) of 39 and 6.44 g (0.0284 mol) of 2-nitrophenyl selenocyanate in
50 ml of THF was added 7.13 ml (0.0288 mol) of tributyl phosphine dropwise within 15 min such that the temp.
did not exceed 358. The mixture was stirred at r.t. for 1 h, at which point 23 g of solid NaHCO3 was added,
followed by dropwise addition of 31.2ml of 30% aq. H 2O2 soln., again such that the temp. did not exceed 358.
After 16 h at r.t., 185 ml of 5% KHSO4 soln. was added to the mixture, which was then extracted with Et2O (2 Â
400 ml). The combined org. extract was washed with H2O (200 ml), dried (MgSO4), and evaporated.
Purification of the residue by FC (hexane/AcOEt 95 :5) gave 4.495 g (93%) of 40. Yellow oil. 1H-NMR (CDCl3,
300 MHz): 5.73 (m, 1 H); 5.02( d, 1 H); 4.98 (s, 1 H); 4.41 (m, 1 H); 3.81 (d, 1 H); 3.68 (s, 3 H); 3.17 (m, 1 H);
2.43 (dd, 1 H); 2 .2 9 d(d, 1 H); 2 .2 5 m( , 1 H); 1.85 (m, 1 H); 1.40 (m, 1 H); 1.2 6 (s, 3 H); 1.10 (s, 3 H); 1.08
(d, 3 H); 0.96 (overlapping d and s, 12H); 0.94 ( s, 9 H); 0.10 (s, 1 H); 0.08 (s, 6 H); 0.03 (s, 3 H). MS: 529.1
‡
([M ‡ H] ).
(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8,16-pentamethyl-17-(2-methyl-
thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid Methyl Ester (41). To a soln. of 2.00 g (0.00378 mol) of 40 in
35 ml of THF was added 8.32ml of 0.5 m 9-BBN in THF (Aldrich) under Ar, and the mixture was stirred at r.t.
for 4 h (soln. A). In a separate flask, 1.28 g (0.00284 mol) of 5 was added to a mixture of 1.85 g (0.00567 mol) of
Cs2CO3, 0.236 g (0.000756 mol) of Ph3As, 0.261 g (0.00378 mol) of [PdCl2(dppf)], dppf ˆ 1,1'-bis(diphenyl-
phosphino)ferrocene, and 0.612ml (0.034 mol) of H 2O in 23 ml of DMF (soln. B). Soln. B was cooled to À108
and then soln. A was added. The mixture was allowed to warm to r.t. and stirred at r.t. for 24 h, when 400 ml of
H2O was added, followed by 400 ml of AcOEt. The aq. soln. was back-extracted with AcOEt (2 Â 200 ml), the
combined org. extract dried (Na2SO4) and evaporated, and the residue purified by FC (toluene/AcOEt 100 :1):
1.534 g (63%) of 41. Oil. 1H-NMR (300 MHz, CDCl3): 6.90 (s, 1 H); 6.44 (s,1 H); 5.41 (m, 2H); 4.40 ( dd, 1 H);
4.08 (m, 1 H); 3.75 (dd, 1 H); 3.65 (s, 3 H); 3.13 (m, 1 H); 2.69 (s, 3 H); 2.44 2.16 (m, 4 H); 1.99 (s, 3 H); 1.95
(m, 2H); 1.30 ( m, 1 H); 1.2 3 (s, 3 H); 1.05 (s, 3 H); 1.03 (d, 3 H); 0.90 0.85 (3s, 27 H); 0.09 (s, 3 H); 0.05
(s, 9 H); 0.01 (s, 3 H); À0.01 (s, 3 H).
(3S,6R,7S,8S,12E,15S,16E)-3,7,15-Tris{[(tert-butyl)dimethylsilyl]oxy}-4,4,6,8,16-pentamethyl-17-(2-methyl-
thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid (26). Approach A: To a soln. of LDA in THF (prepared from
i
47.2ml of 1.6 m BuLi in hexane (0.0755 mol) and 10.67 g (0.0755 mol) of Pr2NH in 100 ml of dry THF) was
added a soln. of 9.14 g (0.03 mol) of 3 in 60 ml of dry THF at À708 under N2 dropwise within 15 min. After
completion of the addition, the mixture was stirred for 15 min at À708 and for 1 h at À358. After re-cooling to
À788, a soln. of 10.6 g (0.025 mol) of 25 in 57 ml of dry THF was added dropwise within 15 min, the mixture was
stirred at À788 for 1 h, warmed to À508, and then quenched by the slow addition of sat. aq. NH4Cl soln.
(118.5 ml). The resulting suspension was warmed to 08 and treated with AcOH (12ml) and AcOEt (250 ml).
After extensive shaking, the aq. phase was re-extracted with AcOEt (3 Â 50 ml) and the combined org. extract
dried (Na2SO4) and evaporated: crude aldol product.
This material was dissolved in 250 ml of CH2Cl2 under N2 and the soln. cooled in an ice bath. Then, 2,6-
lutidine (18,97 ml, 0.1634 mol) was added followed by 24.9 ml (0.108 mol) of TBS-OTf, which was added
dropwise over 10 min. The clear soln. was stirred at 08 for 2h and then treated with 10% citric acid (250 ml).
After efficient stirring, the aq. phase was separated and extracted with CH2Cl2 (2 Â 50 ml). The combined org.
extract was dried (Na2SO4) and evaporated to give the crude per-silylated hydroxy acid. This material was
dissolved in 250 ml of MeOH, K2CO3 (8.3 g, 0.06 mol) and H2O (8.2ml) were added, and the mixture was
stirred for 1 h at r.t. After this time, the suspension was filtered and the filtrate acidified to pH 4 by the addition
¾
of Dowex 50WX8 (100 200 mesh) and filtered again. The filtrate was evaporated and the residue redissolved
in 200 ml of AcOEt. This soln. was washed with sat. aq. NH4Cl soln., the aq. phase back-extracted with AcOEt
(3 Â 50 ml), and the combined org. phase dried (Na2SO4) and evaporated to give the crude product as a mixture
of two diastereoisomers. These could be separated by six consecutive FC runs (run 1: toluene/acetone 95 :5 !

4108
Helvetica Chimica Acta Vol. 85 (2002)
70 :30; run 2: toluene/AcOEt 95 :5 ! 70 :30; run 3: CH2Cl2/MeOH 95 :5 ! 70 :30; runs 4 6: hexanes/AcOEt
95 :5 ! 70 :30): 6.5 g (31%) of the desired diastereoisomer 26 as a slightly yellow oil.
i
Approach B: To a soln. of 1.396 g (0.00164 mol) of 41 in 45 ml of PrOH/H2O 4 :1 was added 0.240 g
(0.0102mol) of LiOH ¥ H 2O, and the mixture was heated to 608 for 18 h. The mixture was then diluted with H2O
(200 ml) and CH2Cl2 (400 ml) and acidified to pH 4 with 1n HCl. The aq. soln. was back-extracted with CH2Cl2,
the combined org. phase dried (Na2SO4) and evaporated, and the residue purified by FC (hexane/AcOEt 9 :1 !
8 :2): 1.1662 g (85%) of 26. [a]2D1 ˆ À8.37 (c ˆ 2.03, CHCl3). 1H-NMR (300 MHz, CDCl3): 6.93 (s, 1 H); 6.47
(br. s, 1 H); 5.3 5.5 (m, 2H); 4.35 4.4 ( m, 1 H); 4.09 (t, J ˆ 6.5, 1 H); 3.79 (d, J ˆ 7.5, 1 H); 3.1 3.25 (m, 1 H);
2.71 (s, 3 H); 2.56 (dd, J ˆ 16, 4.5, 1 H); 2.16 2.38 (m, 3 H); 1.87 2.01 (m, 5 H); 1.2 1 (s, 3 H); 1.14 (s, 3 H);
1.02 1.47 ( m, 17 H, including 1.07 (d, J ˆ 7, 3 H)); 0.75 0.93 (m, 30 H); 0.12( s, 3 H); 0.09 (s, 3 H); 0.05
‡
(s, 9 H); 0.01 (s, 3 H). MS: 837.9 ([M ‡ H] ).
(3S,6R,7S,8S,12E,15S,16E)-3,7-Bis{[(tert-butyl)dimethylsilyl]oxy}-15-hydroxy-4,4,6,8,16-pentamethyl-17-
(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid (27). To a soln. of acid 26 (1.10 g, 0.00131 mol) in
20 ml of THF was added 3.9 ml (0.0039 mol) of 1m Bu4NF in THF at r.t. The soln. was stirred at r.t. for 24 h, at
which point additional Bu4NF was added (0.001 mol). Stirring was continued for additional 16 h, and the
mixture was then diluted with 150 ml of H2O, 120 ml of sat. aq. NH4Cl soln., and 400 ml of AcOEt. The org.
phase was back-extracted with AcOEt (1 Â 200 ml), the combined org. phase washed with H2O (100 ml), dried
(MgSO4) and evaporated, and the resulting yellow oil purified by FC (CH2Cl2/MeOH 94 :6): 27 (0.604 g, 64%).
‡
Yellow resin. [a]2D1 ˆ À20.77 (c ˆ 1.55, CHCl3). MS: 723.9 ([M ‡ H] ). 1H-NMR (300 MHz, CDCl3): 6.94
(s, 1 H); 6.58 (br. s, 1 H); 5.57 (td, J ˆ 15, 7.5, 1 H); 5.41 (td, J ˆ 15, 7.5, 1 H); 4.35 4.42( m, 1 H); 4.13 4.19
(m, 1 H); 3.79 (d, J ˆ 7.5, 1 H); 3.08 3.2( m, 1 H); 2.73 (s, 3 H); 2.53 (dd, J ˆ 16, 4.5, 1 H); 2.22 2.45 (m, 3 H);
1.95 2.06 (m, 5 H); 1.14 (s, 3 H); 1.22 (s, 3 H); 1.02 1.5 ( m, 14 H, including 1.07 (d, J ˆ 7, 3 H)); 0.77 0.95
(m, 21 H); 0.11 (s, 3 H); 0.07, 0.08 (2s, 9 H).
(4S,7R,8S,9S,13E,16S)-4,8-Bis{[(tert-butyl)dimethylsilyl]oxy}-5,5,7,9-tetramethyl-16-[(1E)-1-methyl-2-(2-
methylthiazol-4-yl)ethenyl]oxacyclohexadec-13-ene-2,6-dione (28). To a soln. of 2.35 g (0.00324 mol) of 27 in
38 ml of dry THF was added 2.71 ml (0.0194 mol) of Et3N at 108 followed by dropwise addition of 2.54 ml
(0.01626 mol) of 2,4,6-trichlorobenzoyl chloride. After stirring at 108 for 20 min, the soln. was diluted with dry
toluene (360 ml), and the resulting thin suspension was added slowly (3.5 h) to a soln. of 3.965 g (0.03245 mol)
of DMAP in 1.62l of dry toluene at r.t. After completion of the addition, the mixture was stirred for 1 h and then
filtered, and the filtrate was concentrated. The partially crystalline residue was stirred in Et2O (250 ml), the
mixture filtered, the filtrate evaporated, and the yellow resin obtained purified by FC (CH2Cl2/AcOEt 99 :1 !
98 :2): 28 (1.4 g, 61%). Colorless resin. 1H-NMR (400 MHz, CDCl3): 6.95 (s, 1 H); 6.55 (s, 1 H); 5.43 (m, 2 H);
5.25 (dd, 1 H); 4.40 (m, 1 H); 3.92( m, 1 H); 3.07 (m, 1 H); 2.72 (s, 3 H); 2.72 2.40 (m, 4 H); 2.13 (s ‡ m, 4 H);
1.92( m, 1 H); 1.59 (m, 3 H); 1.40 (m, 2H); 1.17 ( s, 3 H); 1.15 (d, 3 H); including 1.08 (s, 3 H)); 0.95 (d, 3 H);
‡
0.89 (s, 3 H); 0.87 (s, 3 H); 0.11 (s, 3 H); 0.085 (s, 3 H); 0.075 (s, 3 H); 0.05 (s, 3 H). MS: 706.2([ M ‡ H] ).
(4S,7R,8S,9S,13E,16S)-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[(1E)-1-methyl-2-(2-methylthiazol-4-yl)eth-
enyl]oxacyclohexadec-13-ene-2,6-dione (ˆtrans-Deoxyepothilone A; 2). To an ice-cooled soln. of 1.4 g
(0.00198 mol) of 28 in 13 ml of CH2Cl2 was added slowly 3.23 ml of CF3COOH and the slightly yellow soln.
was stirred in the ice bath for 2.5 h. The solvent was then evaporated and the residue purified by FC (hexanes/
AcOEt 67:33 ! 50 :50). Fractions containing pure product were collectively redissolved in CH2Cl2 (30 ml), and
the soln. was washed with sat. NaHCO3 soln./H2O 1:1 and sat. NaCl soln./H2O 1:1, dried (Na2SO4), and
evaporated: 2 (0.864 g (91%). Colorless resin. [a]2D1 ˆ À56.08 (c ˆ 0.765, CHCl3). 1H-NMR (300 MHz, CDCl3):
6.98 (s, 1 H); 6.57 (br. s, 1 H); 5.3 5.57 (m, 3 H); 4.20 (dd, J ˆ 9, 2, 1 H); 3.7 3.77 (m, 1 H); 3.19 3.29
(m, 1 H); 2.72 (s, 3 H); 1.9 2.62 (m, ca. 10 H; including 2.08 (s, 3 H)); 1.30 (s, 3 H); 1.2 0 (d, J ˆ 7.5, 3 H); 1.09
‡
(s, 3 H); 0.8 1.75 (m, ca. 20 H; including 1.00 (d, J ˆ 7.5, 3 H)). MS: 478.0 ([M ‡ H] ).
trans-Epothilone A( ˆ (1S,3S,7S,10R,11S,12S,16S)-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[(1E)-1-meth-
yl-2-(2-methylthiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; 1a). To a soln. of 2 (0.477 g,
0.001 mol) in 15 ml of MeCN/1,2-dimethoxyethane 2 :1 was added 10 ml 0.05m Na2B4O7 ¥ 10H2O in 4 ¥ 10À4
m
Na2EDTA at r.t. followed by 15 mg of Bu4N(HSO4) and 1,2:4,5-di- O-isopropylidene-l-erythro-2,3-hexodiuro-
2,6-pyranose (42a, 0.0775 g, 0.0003 mol) [36b]. The well-stirred mixture was cooled to 0 58 and treated
¾
simultaneously, within 1 h, with small portions of Oxone and a soln. of K2CO3 (0.932g, 0.0067 mol) in H 2O
(6.5 ml). After stirring at 08 for 1 h, the mixture was extracted with AcOEt (4 Â 40 ml). The combined org.
extract was dried (Na2SO4) and evaporated to give a yellow resin (ca. 300 mg), which, according to HPLC, was
composed of roughly 50% of starting material and 50% of a mixture of the desired epoxide 1a and its epimer 1b
in a ratio of 8 :1. Unreacted starting material was removed by prep. TLC (silica gel, CH2Cl2/MeOH 9 :1)
providing 0.13 g (27%; 54% based on recovered starting material) of a 8 :1 mixture 1a/1b. Purification of this

Helvetica Chimica Acta Vol. 85 (2002)
4109
material by prep. HPLC (Prontosil 120-5-C18 AQ 5 mm (250 Â 2 0 mm;Bischoff); 20 ml/min of MeCN/H2O,
30 min at 28% MeCN, ! 30% MeCN in 40 min, 110 min at 30% MeCN, ! 100% MeCN in 110 min (no
addition of CF3COOH, 4 runs)) provided 57.6 mg (11%) of pure 1a. [a]2D1 ˆ À37.1 (c ˆ 0.275, CHCl3). ([40]:
1
[a]2D2 ˆ À23.3 (c ˆ 0.40, CHCl3)). H-NMR (500 MHz, (D6)DMSO)5): 7.34 (s, 1 arom. H); 6.50 (s, HÀC(17));
5.29 (d, J ˆ 11, HÀC(15)); 5.24 (d, J ˆ 5.8 Hz, OHÀC(3)); 4.53 (d, J ˆ 6.0, OHÀC(7)); 4.17 (m, HÀC(3)); 3.51
(br. t, J ˆ 8.0, HÀC(7)); 3.11 (m, HÀC(6)); 2.89 (m, HÀC(12)); 2.83 (m, HÀC(13)); 2.64 (s, MeÀC(20)); 2.43,
2.38 (2m, CH2)); 2.07 (s, MeÀC(16)); 2.03, 1.73 (2m, CH2(14)); 1.68 (m, 1 H, CH2); 1.56 (m, 1 H, CH2); 1.43
(m, 1 H, CH2); 1.32( m, 1 H, CH2); 1.21 (m, 1 H, CH); 1.04 (m, 2H, CH 2); 1.20 (s, MeÀC(4)); 1.10 (d, J ˆ 6.0,
‡
MeÀC(6)); 0.89 (s, MeÀC(4)); 0.87 (d, J ˆ 6.0, MeÀC(8)). MS: 494.1 ([M ‡ H] ).
The authors are indebted to M. Hattenberger, W. Heinzelmann, R. Kesselring, J. Kˆppler, H. Lerch, J.
Loretan, R. Reuter, and W. Vetterli for excellent technical assistance in the synthesis (W. H., R. K., H. L., W. V.)
and biological evaluation (M. H., J. K., J. L., R. R.) of the target compounds.
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[3] P. B. Schiff, J. Fant, S. B. Horwitz, Nature (London) 1979, 277, 665.
[4] K.-H. Altmann, Curr. Opin. Chem. Biol. 2001, 5, 42 .
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Received August 12, 2002