Stereoselective total synthesis of reveromycin B and C19-epi-reveromycin B

Article abstract of DOI:10.1002/1521-3765(20000602)6:11<1987::AID-CHEM1987>3.0.CO;2-U

Our studies toward the total synthesis of the reveromycin family of natural products are described herein. Our synthetic approach is efficient, stereocontrolled, and convergent and has resulted in the first synthesis of reveromycin B (4) and C19-epi-reveromycin B (55). Key steps of this successful strategy include: a modified Negishi coupling (construction of C7-C8 bond) and a Kishi-Nozaki reaction (construction of C19-C20 bond), which were employed in the attachment of the target side chains. The key building blocks for the total synthesis were thus defined as vinyl iodide 6, alkyne 7, and alkyne 8. Our synthesis illustrates the utility of the modified Negishi coupling for the construction of complex dienes, confirms the proposed stereochemistry of reveromycins and paves the way for the preparation of designed analogues for biological study.

Full text of DOI:10.1002/1521-3765(20000602)6:11<1987::AID-CHEM1987>3.0.CO;2-U

FULL PAPER
Stereoselective Total Synthesis of Reveromycin B and
C19-epi-Reveromycin B
Keith E. Drouet and Emmanuel A. Theodorakis*[a]
Abstract: Our studies toward the total
synthesis of the reveromycin family of
natural products are described herein.
Our synthetic approach is efficient,
stereocontrolled, and convergent and
has resulted in the first synthesis of
reveromycin B (4) and C19-epi-revero-
mycin B (55). Key steps of this success-
ful strategy include: a modified Negishi
coupling (construction of C7 ± C8 bond)
and a Kishi ± Nozaki reaction (construc-
tion of C19 ± C20 bond), which were
employed in the attachment of the
target side chains. The key building
blocks for the total synthesis were thus
defined as vinyl iodide 6, alkyne 7, and
alkyne 8. Our synthesis illustrates the
utility of the modified Negishi coupling
for the construction of complex dienes,
confirms the proposed stereochemistry
of reveromycins and paves the way for
the preparation of designed analogues
for biological study.
Keywords: natural products ´ rever-
omycin ´ synthetic methods ´ total
synthesis
synergistically these compounds can induce DNA synthesis
and cellular reproduction. Undoubtedly, two of the best
studied growth factors are the epidermal growth factor (EGF)
and the transforming growth factor a (TGF-a), which exert
their mode of action by binding to the extracellular part of the
epidermal growth factor receptor (EGFR).[3] This binding
induces conformational changes in the intracellular portion of
EGFR, drastically affecting its tyrosine phosphorylation
activities and thereby engaging the cell into the cell cycle.[4]
Interestingly, many transformed cells overexpress EGFR and
its ligands, an event known as autocrine secretion, which in
turn prompts these cells to undergo continuous mitosis. For
these reasons, the EGF receptor and its signal transduction
pathways are considered prime targets for the development of
new anticancer drugs.[5]
In an effort to discover new inhibitors of the EGF/TGF-a
pathway, Osada and co-workers in Japan have isolated a new
family of natural products constituted by reveromycin A (1),
C (2), D (3), and B (4) (Figure 1).[6] These compounds were
produced from the culture broth of an actinomycete strain of
the genus Streptomyces, which was collected in Gunma
Prefecture (Japan). Among all members of this family,
reveromycin A (1) was the most naturally abundant compo-
nent and consequently the one whose biological profile and
chemical structure were most thoroughly studied.[7]
Introduction
The reveromycins constitute a novel class of polyketide-type
terrestrial metabolites of microbial origin. These natural
products share common structural features comprised of an
identical C1 ± C24 backbone folded in such a way as to create
a [6,6]- or [5,6]spiroketal core, flanked by two highly
unsaturated side chains. The biological profile of these
compounds is equally intriguing and includes a potent
antiproliferative activity against certain human tumor cell
lines. It has been postulated that the antitumor activity of
these compounds stems from their interaction with the
epidermal growth factor receptor (EGFR), whose intracellu-
lar signaling is essential for cellular proliferation. The
combination of novel molecular architecture and interesting
biological profile renders the reveromycins as attractive
targets for chemical synthesis. Herein, we provide a detailed
and updated account of our synthetic studies toward rever-
omycins, which culminated in the first total synthesis of
reveromycin B (4) and C19-epi-reveromycin B (55).[1]
Background and biological relevance: Regulation of cellular
proliferation is controlled by a number of mitogens, including
a series of polypeptide growth factors.[2] Acting alone or
Biological studies revealed that reveromycins share a
potent antiproliferative profile against certain human tumor
cell lines at low micromolar concentrations.[7a] In addition,
reveromycin A (1) was found to inhibit protein synthesis
selectively in eukaryotic cells (IC50 ˆ 40 nm) and induced
morphological reversion of srcts-NRKcells at 1.8 mgmLÀ1
without any noticeable cytotoxicity. More recent in vivo
[a] Prof. Dr. E. A. Theodorakis, K. E. Drouet
University of California San Diego
Department of Chemistry & Biochemistry, Dept. 0358
9500 Gilman Drive, La Jolla, CA 92093-0358 (USA)
Fax : (‡1)858-822-0386
E-mail: etheodor@ucsd.edu
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author.
Chem. Eur. J. 2000, 6, No. 11
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K. E. Drouet and E. A. Theodorakis
FULL PAPER
Figure 1. Structures of the reveromycin family of antibiotics.
studies in mice demonstrated that 1 exhibits strong antitumor
activity against human ovarian carcinoma BG-1 cells, which
are known to secrete large amounts of TGF-a.[7b] The
observed antitumor effects of 1 were shown to be comparable
to that of cisplatin treatment. Interestingly, however, the
significant side effects that commonly result from cisplatin
treatment, such as severe loss of body weight, were not
observed with reveromycin A. The combination of the above
data led to the proposition that reveromycins repress cell
cycle progression at the G0-G1 checkpoint by interfering with
transduction pathways associated with the EGF receptor.[2f, 7]
Moreover, these studies revealed the potential of these
natural products as tools for analyzing EGFR mediated
cellular proliferation.[6, 7]
Following the interesting biological studies on reveromycin
A (1), its chemical structure and absolute configuration were
determined through a series of NMR experiments, degrada-
tion, and chemical correlation.[8, 9] These experiments un-
veiled a 1,7-dioxaspiro[5.5]undecane ([6,6]spiroketal) core
adorned with a hemisuccinate ester, two alkenyl carboxylic
acid side chains, and two alkyl groups. Of particular interest is
the trans-diaxial orientation of the C18 succinate and C19 side
chain which undoubtedly introduces strain on the spiroketal
ring. The extreme scarcity of natural material precluded the
independent structural elucidation of the other members of
the reveromycin family. Nonetheless, their structures were
reasonably deduced by spectroscopic comparison with that of
1 and revealed an identical C1 ± C24 framework.
Figure 2. Retrosynthetic analysis of reveromycin A (1) and B (4).
after succinylation of the C19 hydroxyl group and functional
group deprotection. Alternatively, the C19 alcohol of 5 could
be recruited in a trans-spiroketalization reaction, thereby
affording the [6,6]spiroketal ring system of 1 and ultimately
leading to the synthesis of reveromycin A.[10]
We also reasoned that the last step(s) of our synthesis
should address the removal of all protecting groups, including
deprotection of the C1 and C24 carboxylic acids and the C5
allylic alcohol. Since reveromycins are reported to be sensitive
to basic treatment (facile desuccinylation),[6a] these depro-
tections needed to be performed under relatively neutral
conditions and if possible in a single step. Consideration of the
above factors led us to employ silicon-based protecting groups
for both the carboxylic acids (TMSE: Me3SiCH2CH2-)[11] and
the C5 hydroxyl group (Figure 2).
Disassembly of compound 5 across the C7 ± C8 and C19 ±
C20 bonds revealed three key components: vinyl iodide 6,
alkyne 7, and alkyne 8 (Figure 2). In the synthetic direction, a
palladium(0) coupling method was expected to be utilized for
the union of intermediates 7 and 8. Application of a Kishi ±
Nozaki coupling could then be used for the attachment of
iodide 6 onto the main fragment. The latter coupling requires
the presence of an aldehyde functionality at the C19 center,
which was masked as an acetonide unit in compound 8.[12]
Further disconnection of alkyne 8 at the C15 carbon center
unveils aldehyde 9 and iodide 10 (or iodide 11) as putative
synthetic precursors.
Results and Discussion
The above disconnections considerably reduced the level of
complexity of the reveromycin framework and redefined our
strategy as a problem in acyclic asymmetric synthesis. Our
efforts toward the realization of this plan are described below.
Retrosynthetic analysis: Close inspection of the proposed
structures of reveromycin A (1) and B (4) indicated that their
otherwise identical structures are formed by a different
folding of the C1 ± C24 backbone. Notably, the C18 oxygen
atom that is succinylated in the structure of 1 participates in
the formation of the [5,6]spiroketal core of 4 allowing the C19
oxygen to be succinylated. This observation formed the basis
of our retrosynthetic analysis and defined alcohol 5 as a
common and potentially biosynthetically relevant synthetic
precursor of both reveromycin A and B (Figure 2). According
to this plan, compound 5 could give rise to reveromycin B (4)
Synthesis of core fragment 8: The synthesis of fragments 9, 10,
and 11 are shown in Schemes 1, 2 and 3, while the assembly of
the core fragment 8 is described in Scheme 4. Our synthetic
venture towards aldehyde 9 began with conversion of l-
ascorbic acid (12) to the known aldehyde 13 (Scheme 1). This
was accomplished in 67% overall yield using a procedure
reported in the literature.[13]
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1987±2001
occur via application of two enantioselective methods:
Endersꢁ SAMP hydrazone methodology[16] for alkylation a
to a carbonyl group and Brownꢁs homoallylboration.[17] To this
end, condensation of 19 with SAMP hydrazine[18] afforded the
corresponding hydrazone, which after deprotonation and
alkylation furnished compound 20 in 64% overall yield. The
enantiomeric excess of this addition was found to be greater
than 95% as determined by NMR studies. Ozonolysis of 20
produced the labile aldehyde that was immediately treated
with Brownꢁs (‡)-diisopinocampheylallylborane. Quenching
of this mixture with basic hydrogen peroxide gave rise to the
desired homoallyl alcohol 21 in 78% overall yield and
excellent enantioselectivity (ee > 95%). Protection of the
resulting C11 hydroxyl group as the corresponding p-methox-
ybenzyl (PMB) ether, followed by fluoride-induced desilyla-
tion of the C14 silyl ether revealed primary alcohol 22 (81%
yield over two steps). Alcohol 22 was converted to the desired
iodide 10 in 97% yield upon treatment with triphenylphos-
phine, imidazole, and iodine[19] (Scheme 2).
Scheme 1. Synthesis of C15 ± C20 fragment 9. a) 0.1 equiv Pd/C (10%),
H2, H2O, 24 h, 558C, 96%; b) 1.3 equiv Et2C(OEt)2, 0.1 equiv CSA, DMF,
48 h, 258C, 82%; c) 1.2 equiv KIO4, 2.0 equiv KHCO3, THF/H2O 1:1, 2 h,
ˆ
238C, 85%; d) 1.5 equiv H2C CHCH2CH2MgBr (2.0m in THF), THF, À78
to 258C, 1 h, 92% (5:1 ratio at C18); e) 2.0 equiv PCC ´ celite, CH2Cl2,
258C, 2 h, 93%; f) 1.5 equiv BuMgBr (2.0m in THF), THF, À788C, 1.5 h,
95% (4:1 ratio at C18); g) 1.3 equiv TBSOTf, 1.5 equiv 2,6-lutidine,
CH2Cl2, 258C, 24 h, 99%; h) O3, CH2Cl2, 20 min, À788C; 2.0 equiv Ph3P,
95%.
Our plan was to convert the carbonyl center of 13 to the
desired C18 tertiary alcohol of 9 using two sequential
organometallic additions, which were predicted to proceed
with good stereochemical control due to the chirality present
on the C19 center (a-carbon) of 13.[14] Recognizing that the
desired chirality of the adduct could be controlled simply by
altering the order of the carbanionic additions, we inves-
tigated the nature of the organometallic reagents simply on
the basis of overall yield. Our studies led us to use Grignard
reagents as the appropriate nucleophiles, since they gave
better results than the corresponding organolithium counter-
parts. As shown in Scheme 1, reaction of 4-butene magnesium
bromide with aldehyde 13 afforded alcohol 15 as a 5:1 mixture
of diastereomers at the C18 center in 92% overall yield. This
mixture was subsequently oxidized with PCC to the corre-
sponding ketone 16 (93% yield). Treatment of 16 with
butylmagnesium bromide afforded a 4:1 mixture of tertiary
alcohols in 95% combined yield. The major diastereomer of
this addition (alcohol 17) was chromatographically isolated in
76% yield and was transformed to the desired aldehyde 9
upon silylation and ozonolysis (17 ! 18 ! 9, 94% overall
yield). The stereochemical outcome of both Grignard addi-
tions was rationally explained through the intermediacy of a
five-membered chelate formed by the C19 oxygen and the
C18 carbonyl center (as shown for intermediate 14).[15] Based
on this chelation-controlled model, we expected that alde-
hyde 9 had the desired stereochemistry at the C18 center.
However, additional and unambiguous confirmation of this
structure remained at large until the entire fragment 8 was
built (compound 8 was structurally confirmed using the
transformations described in Scheme 5).
Scheme 2. Synthesis of iodide 10. a) 1.0 equiv SAMP (neat), 3.0 equiv 19,
808C, 2 h, 92%; b) 1.1 equiv iPr2NH, 1.1 equiv nBuLi (1.6n in hexanes),
THF, 08C, 6 h; 1.1 equiv nBuLi (1.6n in hexanes), À208C, 2 h; 2.0 equiv
TBSO(CH2)2I, À100 to À208C, 70%; c) O3, CH2Cl2, À788C, 1 h;
ˆ
d) 1.5 equiv (‡)-(ipc)2B-CH2CH CH2 (3m in Et2O), Et2O, À788C, 2 h;
8.0 equiv H2O2 (30%), 13 equiv NaOH (3n), À78 to 258C, 15 h, 78% (over
two steps); e) 1.2 equiv KH, 1.5 equiv PMBCl, Et2O, 0 8C, 6 h; f) 1.3 equiv
TBAF ´ THF (1m), THF, 258C, 1 h, 81% (over two steps); g) 2.4 equiv
imidazole, 1.2 equiv Ph3P, 1.2 equiv I2, 08C, 1 h, 97%.
Although the above sequence delivered the C8 ± C14
fragment of the reveromycin framework and was used in the
synthesis of the natural product[1] it suffered from the use of
two chiral auxiliaries. During our repeated efforts to produce
multigram amounts of advanced intermediates, we developed
an expeditious synthesis of fragment 11, during which only
one chiral auxiliary was employed (Scheme 3). Thus, reaction
of aldehyde 23 under Brownꢁs asymmetric crotylboration
protocol afforded alcohol 24 and introduced simultaneously
both C11 and C12 chiral centers (80% yield).[20, 9b] Our initial
attempts to benzylate the resulting C11 alcohol using p-
methoxybenzyl chloride and a base (such as NaH, or KH) met
with failure, since substantial amounts of by-products result-
ing from scrambling of the primary TBS group were observed.
To circumvent this problem we desilylated compound 24
(using TBAF ´ THF in 98% yield) and treated the resulting
diol 25 with p-methoxybenzyl dimethyl acetal under acid
catalysis. This protocol furnished benzylidene acetal 26 in
98% yield. Exposure of 26 to DIBAL-H at À788C, followed
by warming of the solution to 258C, resulted in a regioselec-
The synthesis of iodide 10 commenced with propionalde-
hyde (19) as illustrated in Scheme 2. Installation of the desired
stereochemistry at the C12 and C11 centers was expected to
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K. E. Drouet and E. A. Theodorakis
FULL PAPER
tive reductive cleavage of the acetal functionality and gave
rise exclusively to primary alcohol 27 (91% yield).[21] Silyla-
tion of 27, followed by hydroboration of the terminal olefin
afforded, after quenching with hydrogen peroxide, compound
29 (82% overall yield). Treatment of the latter substance with
triphenylphosphine, imidazole, and iodine produced the
requisite fragment 11 in 96% yield (Scheme 3).
followed by quenching of the carbanion with aldehyde 9
afforded a 1:1 mixture of diastereomeric alcohols at the C15
center, which upon Dess ± Martin oxidation[22] produced
ketone 30 (810% yield, over two steps). TBAF-induced
simultaneous desilylation of the C18 and C9 hydroxyl groups,
followed by reductive deprotection of the p-methoxybenzyl
ether, resulted in the formation of spiroketal 31 as the sole
product (87% overall yield). The C9 primary alcohol of 31
was then oxidized using Dess ± Martin periodinane and the
resulting aldehyde 32 was subjected to the modified Corey ±
Fuchs olefination procedure[23] to produce geminal dibromide
33. Treatment of 33 with butyllithium and iodomethane
afforded alkyne 8 (three steps, 85% starting from 30).[24]
Before engaging further into the total synthesis of the target
molecule, it was deemed necessary to confirm that spiroketal
fragment 8 had the desired stereochemistry. To accomplish
this objective, we sought to synthesize triacetate 34 and
contrast its data with the comparable fragment obtained by
degradation of the natural reveromycin A.[9a] Conversion of
compound 31 to triacetate 34 was achieved in 74% yield using
a sequence of steps that included: a) acetylation of the C9
hydroxyl group and b) CSA-induced deprotection of the
C19 ± C20 acetonide and acetylation of the resulting diol
(Scheme 5). As anticipated, compound 34 exhibited identical
Scheme 3. Synthesis of iodide 11. a) 1.5 equiv tBuOK, 1.6 equiv trans-2-
butene, 1.5 equiv nBuLi, THF, À458C, 10 min, then 1.6 equiv (À)-
ipc2BOMe (1m in THF), 2.0 equiv BF3 ´ Et2O, À788C, 1.0 equiv 23, 3 h,
then 3n NaOH, 30% H2O2, 258C, 18 h, 80%; b) 1.2 equiv TBAF ´ THF,
THF, 258C, 30 min, 98%; c) 1.2 equiv PMBCH(OMe)2, 0.1 equiv CSA,
CH2Cl2, 258C, 6 h, 98%; d) 1.5 equiv DIBAL-H (1m in CH2Cl2), CH2Cl2,
À78 to 258C, 2 h, 91%; e) 2.5 equiv imidazole, 1.3 equiv TBSCl, CH2Cl2,
258C, 1 h, 97%; f) 1.0 equiv BH3 ´ THF, À408C, 10 h, then 3n NaOH, 30%
H2O2, 258C, 30 min, 85%; g) 2.4 equiv imidazole, 1.2 equiv Ph3P, 1.2 equiv
I2, THF, 08C, 30 min, 96%.
Scheme 5. Structural verification of fragment 8. a) 1.5 equiv Ac2O,
3.0 equiv pyridine, CH2Cl2, 258C, 15 min; b) 0.1 equiv CSA, CH2Cl2/
MeOH 9:1, 258C, 3 h; c) 3.0 equiv Ac2O, 6.0 equiv Et3N, CH2Cl2, 08C, 3 h,
74% (over three steps).
The assembly of spiroketal fragment 8 by union of frag-
ments 9 and 11 is described in Scheme 4. Treatment of iodide
11 with 2 molar equivalents of tert-butyllithium at À788C,
spectroscopic and analytical data with the one derived from
degradation of the natural product. This observation con-
firmed unambiguously the previous prediction for the for-
mation of the C18 stereocenter and further secured the
stereochemical assignment for five out of the seven stereo-
centers of the reveromycin framework.
Synthesis of C1 ± C20 fragment 35: Having completed the
synthesis of the core fragment 8 of the reveromycin skeleton,
we set out to investigate methods for constructing the critical
C7 ± C8 bond. To achieve this goal, we envisioned to employ a
palladium(0) methodology and defined two different sets of
coupling conditions: a Stille coupling between vinyl iodide 36
and vinyl stannane 37 and/or a Negishi coupling between vinyl
zincate 38 and vinyl iodide 39 (Figure 3).[25] This plan offered
the advantage of convergence, since both compounds 36 and
38 were expected to be produced by simple functionalization
of fragment 8, while compounds 37 and 39 could be furnished
from fragment 40. In the retrosynthetic direction, the desired
stereochemistry at the C4 and C5 centers of 40 was foreseen
to be introduced by implementation of Evansꢁ aldol proto-
col.[26]
Scheme 4. Synthesis of C8 ± C20 fragment 8. a) 1.0 equiv 11, 2.1 equiv
tBuLi, À788C, Et2O, 0.5 h, then 1.4 equiv 9, 0.5 h, 86%; b) 1.2 equiv Dess ±
Martin periodinane, CH2Cl2, 25C, 1 h, 94%; c) 3.0 equiv TBAF ´ THF,
THF, 508C, 2 h; d) H2, 0.1 equiv Pd/C (10%), EtOH, 12 h, 258C, 80%
(over two steps); e) 1.5 equiv Dess ± Martin periodinane, CH2Cl2, 08C, 2 h,
94%; f) 5.0 equiv CBr4, 10 equiv HMPT, THF, À308C, 30 min, 95%;
g) 2.1 equiv nBuLi, THF, À78 to À208C, 20 min; 5.0 equiv MeI, THF, À78
to 08C, 2 h, 95%.
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1987±2001
the intermediate aldehyde, which without purification was
treated with ylide 45 to afford ester 40 in 91% combined yield.
Hydrostannylation of the terminal alkyne functionality of 40
under palladium(ii) catalysis was expected to furnish the
desired trans-vinyl stannane 37.[28] Interestingly, the regio-
chemistry of this reaction was found to be dependent on the
choice of solvents: An unseparable mixture of isomeric
stannanes was obtained when THF or dichloromethane were
employed as solvents, while in benzene this addition afforded
exclusively the desired trans-adduct 37 in 91% yield. The
putative Negishi coupling partner 39 was subsequently
obtained by treatment of stannane 37 with iodine in dichloro-
methane (90% yield).[29]
With compounds 37 and 39 in hand, we focused our
attention on the formation of the crucial C7 ± C8 bond
(Scheme 7). In our initial studies we examined the potential
Figure 3. Strategies for the synthesis of C1 ± C20 fragment 35.
The synthesis of coupling partners 37 and 39 is described in
Scheme 6 and commences with Evans coupling of aldehyde 41
with oxazolidinone 42. This reaction afforded the desired
Scheme 7. Synthesis of C1 ± C20 fragment 35. a) 1.0 equiv 8, 2.0 equiv
Cp2ZrHCl, benzene, 258C, 8 h; I2 ´ CCl4 (excess), 08C, 15 min, 53%;
b) 1.0 equiv 36, 1.0 equiv 37, 0.05 equiv [Pd(CH3CN)2Cl2], DMF/THF 1:1,
258C, 15 h, 52%; c) 1.0 equiv 8, 2.0 equiv Cp2ZrHCl, THF, 508C, 2 h;
3.0 equiv ZnCl2, THF, 5 min, 258C; d) 1.0 equiv 38, 1.1 equiv 39, 0.05 equiv
[Pd(PPh3)4], THF, 2 h, 258C, 84% over two steps.
Scheme 6. Synthesis of C1 ± C7 fragments 37 and 39. a) 1.0 equiv 42,
1.0 equiv Bu2BOTf, 1.2 equiv Et3N, then 1.2 equiv 41, CH2Cl2, À78 to 08C,
5 h, 80%; b) 9.0 equiv AlMe3, 9.0 equiv MeO-NHMe ´ HCl, THF, À30 to
08C, 2 h; c) 2.0 equiv TBAF ´ SiO2, THF, 258C, 3 h; d) 1.5 equiv TIPSOTf,
3.0 equiv 2,6-lutidine, CH2Cl2, 258C, 15 min, 81% (over three steps);
e) 2.5 equiv DIBAL-H (1.5m in toluene), THF À788C, 0.5 h; f) 2.5 equiv
of a Stille coupling between iodide 36 and stannane 37.[30]
Compound 36 was expected to be synthesized by hydro-
zirconation of alkyne 8 and trapping of the intermediate vinyl
zirconium species with iodine.[31] Unfortunately, this reaction
was not regioselective and generated a mixture of vinyl
iodides with a combined yield of 74%. The desired iodide 36
was produced in a 2.5:1 ratio, effectively reducing its overall
yield to 53%. Undeterred by the low yield of 36, we decided
to attempt the Stille coupling before optimizing the above
procedure. Nonetheless, coupling of 36 with stannane 37
under Stille conditions proved quite challenging.[32] Use of
[Pd(PPh3)4] as a catalyst afforded no coupled product, but
ˆ
Ph3P CH-CO2TMSE (45), CH2Cl2, 258C, 15 h, 91% (over two steps);
g) 0.02 equiv [Pd(PPh3)2Cl2], 1.5 equiv nBu3SnH, benzene, 58C, 10 min,
91%; h) I2, CH2Cl2, 08C, 5 min, 90%.
aldol product 43 in 80% yield as the sole diastereomer and
introduced the correct stereochemistry in the two remaining
chiral centers of the reveromycin backbone. Treatment of 43
under the Weinreb conditions (Me3Al and MeONHMe),[27]
followed by fluoride-induced desilylation of the C7 center and
silylation of the C5 propargylic alcohol furnished amide 44 in
81% overall yield. Exposure of 44 to DIBAL-H gave rise to
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K. E. Drouet and E. A. Theodorakis
FULL PAPER
only compounds derived from dimerization of stannane 37.
The best results were produced using [Pd(CH3CN)2Cl2] as a
catalyst and afforded the desired adduct 35, albeit in low yield
(52%).[30] The by-products of this reaction were identified as
compounds arising from protodestannylation or dimerization
of stannane 37. Addition of excess iPr2NEt (to buffer any
adventitious acid)[33] and of copper(i) iodide (to accelerate the
coupling)[34] proved ineffective. We briefly examined the
effect of temperature: Although higher temperatures in-
creased the rate of coupling process they did not increase the
overall yield of 35 and cleaner conversion was observed at
258C.
commercially available acetol 46 which upon exposure to
Wittig ylide 45 gave rise to ester 47 in 85% yield. PCC
oxidation of the allylic hydroxyl group of 47 yielded aldehyde
48, which upon treatment with CrCl2 and CHI3 produced
exclusively the trans-iodide 6 in 57% overall yield.[38]
The construction of the C1 ± C24 reveromycin framework is
described in Scheme 9. The required conversion of acetonide
35 to aldehyde 50 was achieved by initially transforming 35 to
The low and often irreproducible yields of the above
coupling were attributed to a combination of steric hindrance
of trisubstituted vinyl iodide 36 and reduced electrophilicity
due to the presence of the C8 methyl group. Both factors were
held accountable for the attenuation of the rate of oxidative
addition of 36 with palladium, opening the way for formation
of by-products.
In considering this limitation we decided to alter the
nucleophilic/electrophilic role of the above partners and
evaluate the Negishi coupling (Scheme 7).[35, 36] We were
particularly interested in studying a recent modification of
the Negishi method, as reported by Panek and Hu.[37] The
ªmodifiedº version of this coupling involves initial hydro-
zirconation of a methyl acetylene, followed by in situ trans-
metallation to the vinyl zincate (with ZnCl2) and coupling
with vinyl iodides using Pd0 to afford the conjugated dienes in
excellent yields. Much to our delight, this intricate reaction
was facile and reproducible! A typical procedure involved
treatment of alkyne 8 with two molar equivalents of Schwartz
reagent at 508C for two hours, followed by addition of 3 molar
equivalents of ZnCl2 (ca 1m in THF). The resulting mixture
was treated with iodide 39 and catalytic amounts of
[Pd(PPh3)4] to produce the desired all-trans coupled product
35 in 84% yield. The overall efficiency of the Negishi coupling
process was attributed to the good electrophilicity and steric
accessibility of vinyl iodide 39 (facile oxidative addition) and
good nucleophilicity of the vinyl zincate intermediate 38
(facile transmetallation). Moreover, the reported modifica-
tion by Panek and Hu made the above reaction easier to
perform. Our immediate success with the Negishi coupling led
us to abandon any attempts to improve upon the yield of the
Stille reaction.
Scheme 9. Synthesis of C1 ± C24 fragment 5. a) 3.0 equiv PPTS, MeOH,
3 h, 408C, 75%; b) 6.0 equiv NaIO4, THF/H2O 2:1, 2 h, 08C, 95%;
c) 4.0 equiv 6, 24 equiv CrCl2 (with 0.5% NiCl2), DMF, 258C, 3 h, 65%
(1.2:1 ratio at C19); d) 1.5 equiv Dess ± Martin periodinane, CH2Cl2, 2 h,
258C, 93%; e) 5.0 equiv CeCl3 ´ 7H2O, 5.0 equiv LiBH4 (2m in THF), THF/
MeOH 1:1, À78 to 258C, 3 h, 81%.
diol 49. Among the several deprotection methods attempted,
exposure of 28 to pyridinium p-toluenesulfonate (PPTS) in
methanol at 408C proved to be the best and resulted in the
formation of diol 49 in 75% yield. Compound 49 was then
oxidatively cleaved with NaIO4 to afford aldehyde 50 (95%
yield), thereby setting the stage for the crucial Kishi ± Nozaki
coupling.[39] This coupling was conducted in the presence of
CrCl2 and NiCl2 (co-catalyst) and afforded a separable
mixture of epimeric alcohols 5 and 51. The structure of these
alcohols was assigned on the basis of their NOE spectra
(Figure 4). The two diastereomeric adducts 5 and 51 were
Synthesis of C1 ± C24 fragment 5: Having completed the
synthesis of fragment 35 we set out to prepare vinyl iodide 6,
our identified partner of the Kishi ± Nozaki coupling
(Scheme 8). Compound 6 was synthesized starting from
Figure 4. NOE data of the C19 proton for 5 and 51.
obtained in a ratio of 1:1.2 and in 65% combined yield.
Inexplicably, about 10 ± 20% of starting aldehyde 50 remained
unreacted even after further addition of reagents (catalysts
and iodide 6) and was recovered and reused after each
Scheme 8. Synthesis of iodide 6. a) 1.0 equiv 46, 1.2 equiv 45, CH2Cl2,
258C, 24 h, 85%; b) 2.1 equiv PCC ´ celite, CH2Cl2, 258C, 2 h, 88%;
c) 8.0 equiv CrCl2, 2.5 equiv CHI3, THF, 0 to 258C, 0.5 h, 65%.
1992
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Chem. Eur. J. 2000, 6, No. 11

Reveromycin B
1987±2001
coupling round. Furthermore, attempts to improve on the
selectivity of this coupling by changing the temperature, the
solvent or the composition of the catalysts proved unsuccess-
ful. Nonetheless, it is particularly noteworthy that the
intermediate organochromium nucleophile reacts selectively
with a hindered neopentylic aldehyde, such as 50, in the
presence of other potent electrophilic centers.
In an attempt to increase the amount of desired adduct 5 we
oxidized the unwanted epimer 51 to ketone 52 (93% yield),
which upon Luche reduction[40] produced a 3:1 ratio of 5:51 in
81% combined yield (Scheme 9).
Figure 5. Attempted trans-spiroketalization strategy toward reveromycin
A (1).
Synthesis of reveromycin B (4) and its C19 epimer (55): The
last steps toward the synthesis of reveromycin B (4) are shown
in Scheme 10. As expected, treatment of 5 with excess succinic
to observe the formation of [6,6]spiroketal core of reveromy-
cin A under any circumstances.[42] It is conceivable that the
desired trans-spiroketalization could be achieved by a suitable
adjustment of protecting groups. Nonetheless, our failure to
execute the desired transformation could also be attributed to
the steric hindrance and energetic difference between the
[5,6]- and [6,6]spiroketal core, in which the C18 tertiary
hydroxyl group and C20 ± C24 side chain are axially oriented.
These results parallel similar studies by McRae and Rizzaca-
sa,[9b] who reported that an acid-catalyzed equilibration of the
[5,6]- to [6,6]spiroketal ring of reveromycins favors strongly
the [5,6]spiroketal ring of reveromycin B (4).
Conclusion
We have described herein a stereoselective total synthesis of
(À) reveromycin B (4) and C19-epi-reveromycin B (55).[43]
The successful synthetic route is highly efficient and con-
vergent (four-component assembly) with the longest sequence
numbering 21 steps (51 steps overall) and provides both
reveromycin B (3.1% overall yield) and C19-epi-reveromycin
B (2.8% overall yield). Highlights of our strategy include a
modified Negishi coupling and a Kishi ± Nozaki coupling,
which were used for the installation of the polyene containing
side chains of reveromycins. Moreover, a number of synthetic
transformations on the spiroketal framework of reveromycins
have been delineated and an improved synthesis of fragment 8
is presented herein. Our synthetic approach is amenable to
the construction of novel and potentially bioactive analogues.
Our synthesis also confirms the proposed stereochemistry of
reveromycins.[44]
Scheme 10. Completion of the synthesis of reveromycin B (4) and C19-epi
reveromycin B (55). a) 10 equiv succinic anhydride, 12 equiv DMAP, 258C,
3 h, 85% for 53, 88% for 54; b) 10 equiv TBAF ´ THF, THF, 2 h, 258C, 69%
for 4, 61% for 55.
anhydride and DMAP afforded the succinate ester 53 in 85%
yield. Much to our relief TBAF-induced a smooth removal of
all protecting groups[41] and gave rise to synthetic reveromycin
B (4) (59% yield, over two steps), which exhibited identical
spectroscopic and analytical data with the natural product.
Identical reaction conditions were also applied to alcohol 51
and produced C19 epi-reveromycin B (55) via ester 54 in 54%
overall yield (over two steps).
Attempted synthesis of reveromycin A (1): Having achieved
the synthesis of reveromycin B (4) we turned our attention to
the construction of reveromycin A (1). We envisioned that an
acid-catalyzed trans-spiroketalization reaction of 5 could
produce the requisite [6,6]spiroketal system of 1, as illustrated
in Figure 5. To this end, a series of reagents and conditions
were employed. PPTS had no effect, while prolonged treat-
ment with camphorsulfonic acid (CSA) in CHCl3 (or CDCl3)
gave rise to the formation of multiple by-products, presum-
ably arising from elimination of the C5 silyl ether. Similar
studies were performed with the entirely deprotected C1 ±
C24 reveromycin framework. Unfortunately, we were unable
Experimental Section
General techniques: All reagents were commercially obtained (Aldrich,
Acros) at highest commercial quality and used without further purification
except where noted. Air- and moisture-sensitive liquids and solutions were
transferred via syringe or stainless steel cannula. Organic solutions were
concentrated by rotary evaporation below 458C at about 20 mmHg. All
nonaqueous reactions were carried out using flame-dried glassware, under
an argon atmosphere in dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium/benzophenone; dichloromethane
(CH2Cl2) and toluene from calcium hydride; and benzene from potassium.
N,N-Diisopropylethylamine, diisopropylamine, pyridine, triethylamine,
Chem. Eur. J. 2000, 6, No. 11
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1993

K. E. Drouet and E. A. Theodorakis
FULL PAPER
and boron trifluoride etherate were distilled from calcium hydride prior to
use. Dimethyl sulfoxide and dimethylformamide were distilled from
calcium hydride under reduced pressure (20 mmHg) and stored over 4 Š
molecular sieves. Yields refer to chromatographically and spectroscopically
(1H NMR) homogeneous materials, unless otherwise stated. Reactions
were monitored by thin-layer chromatography carried out on 0.25 mm E.
Merck silica gel coated glass plates (60F-254) using UV light as visualizing
agent and 7% ethanolic phosphomolybdic acid, or p-anisaldehyde solution
and heat as developing agents. E. Merck silica gel (60, particle size 0.040 ±
0.063 mm) was used for flash chromatography. Preparative thin-layer
chromatography separations were carried out on 0.25 or 0.50 mm E. Merck
silica gel plates (60F-254). NMR spectra were recorded on a Varian 400
and/or 500 MHz instruments and calibrated using residual undeuterated
solvent as an internal reference. The following abbreviations were used to
explain the multiplicities: s ˆ singlet; d ˆ doublet, t ˆ triplet, q ˆ quartet,
m ˆ multiplet, brˆ broad. IR spectra were recorded on a Perkin ± Elmer
Model 781 spectrometer. Optical rotations were recorded on a Perkin ±
Elmer 241 polarimeter. High resolution mass spectra (HR-MS) were
recorded on a VG 7070 HS mass spectrometer under chemical ionization
(CI) conditions or on a VG ZAB-ZSE mass spectrometer under fast atom
bombardment (FAB) conditions. Melting points (m.p.) are uncorrected,
and were recorded on a Thomas Hoover Unimelt capillary melting point
apparatus.
780 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 5.84 ± 5.76 (m, 1H), 5.04 (dd,
1H, J ˆ 17.0, 1.5 Hz), 4.96 (d, 1H, J ˆ 10.0 Hz), 4.00 (t, 1H, J ˆ 6.5, 9.0 Hz),
3.92 (t, 1H, J ˆ 8.0 Hz), 3.83 (t, 1H, J ˆ 8.0 Hz), 2.15 ± 2.11 (m, 1H), 2.04 ±
1.98 (m, 1H), 1.89 (brs, 1H), 1.67 ± 1.48 (m, 6H), 1.47 ± 1.42 (m, 1H), 1.38 ±
1.26 (m, 5H), 0.94 ± 0.86 (m, 9H); 13C NMR (125 MHz, CDCl3): d ˆ 138.6,
114.6, 112.4, 79.9, 73.1, 64.8, 36.7, 33.3, 29.5, 29.1, 27.3, 25.7, 23.1, 14.0, 8.1,
‡
8.0; HR-MS: calcd for C16H30O3 [M‡Cs] 403.1247, found 403.1262.
Silyl ether 18: A solution of alcohol 17 (15.1 g, 55.8 mmol) in CH2Cl2
(60 mL) was treated at 258C with 2,6-lutidine (9.7 mL, 83.7 mmol),
followed by tert-butyldimethylsilyl trifluoromethanesulfonate (16.6 mL,
72.5 mmol). After stirring at 258C for 24 h, the mixture was diluted with
Et2O (100 mL), washed with aqueous saturated sodium chloride (2 Â
100 mL), dried (MgSO4), filtered, and concentrated. Flash chromatography
(0 ± 10% Et2O in hexanes) gave the silyl ether 18 (21.2 g, 55.2 mmol, 99%).
18: colorless liquid; Rf ˆ 0.4 (10% Et2O in hexanes); [a]2D5: À47.4 (c ˆ1.7,
CH2Cl2); IR (film): nÄmax ˆ 2956, 2853, 1462, 1252, 1083, 936, 773 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 5.88 ± 5.78 (m, 1H), 5.02 (d, 1H, J ˆ
17.0 Hz), 4.95 (d, 1H, J ˆ 10.0 Hz), 4.02 (dd, 1H, J ˆ 8.5, 2.0 Hz), 3.90 (t,
1H, J ˆ 7.0 Hz), 3.78 (t, 1H, J ˆ 7.0 Hz), 2.10 ± 2.00 (m, 2H), 1.70 ± 1.59 (m,
6H), 1.42 ± 1.40 (m, 6H), 0.91 ± 0.87 (m, 18H), 0.10 (s, 3H), 0.09 (s, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 139.2, 114.1, 112.7, 80.8, 77.6, 65.6, 37.0,
35.7, 29.2, 28.2, 28.1, 25.9, 23.3, 18.6, 13.9, 8.3, 8.2, À2.1, À2.2; HR-MS:
‡
calcd for C22H44O3Si [M À CH3CH2] 355.2668, found 355.2658.
Alcohol 15: A solution of aldehyde 13 (15.0 g, 94.9 mmol) in tetrahydro-
furan (200 mL) was cooled at À788C and treated with a 2m solution of
4-magnesium bromobutene (71.1 mL, 142.2 mmol, prepared by adding
magnesium turnings into a solution of 4-bromo-1-butene in tetrahydrofur-
an). After stirring at À788C for 15 min, the solution was allowed to warm
to 08C and stirred at this temperature for 1 h. The reaction mixture was
then cooled at À788C, quenched with aqueous saturated ammonium
chloride (50 mL) and allowed to warm to 258C. The mixture was then
diluted with Et2O (300 mL) and the organic layer was washed with aqueous
saturated sodium chloride (3 Â 200 mL), collected, dried (MgSO4), filtered,
and concentrated. The crude residue was purified by chromatography (0 ±
15% Et2O in hexanes) to afford alcohol 15 (18.7 g, 87.3 mmol, 92%) as a
mixture of diastereomers (5:1 ratio at C18). 15: colorless liquid; Rf ˆ 0.3
(30% Et2O in hexanes); [a]: À45.1 (c ˆ 1.0, CH2Cl2); IR (film): nÄmax ˆ 3464,
2972, 2935, 2879, 1642, 1463, 1082, 915 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 5.85 ± 5.80 (m, 1H), 5.07 (dd, 1H, J ˆ 17.5, 1.5 Hz), 4.98 (d, 1H, J ˆ
10.0 Hz), 4.01 ± 3.95 (m, 2H), 3.88 ± 3.82 (m, 2H), 2.28 ± 2.26 (m, 1H), 2.17 ±
2.14 (m, 1H), 1.98 (brs, 1H), 1.69 ± 1.60 (m, 4H), 1.55 ± 1.53 (m, 1H), 1.45 ±
1.43 (m, 1H), 0.93 ± 0.86 (m, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 138.1,
115.2, 112.8, 78.8, 70.2, 64.8, 31.7, 29.9, 29.4, 29.0, 8.1, 7.9; HR-MS: calcd for
Aldehyde 9: A solution of alkene 18 (12.0 g, 31.2 mmol) in CH2Cl2
(100 mL) was cooled at À788C and treated with ozone for 20 min. The
excess ozone was then removed under
a positive flow of argon,
triphenylphosphine (16.4 g, 62.5 mmol) was added and the reaction mixture
was allowed to warm to 258C over 1 h. The solution was concentrated and
subjected to flash chromatography (0 ± 10% Et2O in hexanes) to afford
aldehyde 6 (11.46 g, 29.69 mmol, 95%). 6: colorless liquid; Rf ˆ 0.60 (25%
Et2O in hexanes); [a]2D5: À3.1 (c ˆ1.1, CH2Cl2); IR (film): nÄmax ˆ 2956, 2858,
1728, 1462, 1252, 1082, 835, 774 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 9.80
(s, 1H), 4.05 (t, 1H, J ˆ 7.5 Hz), 3.92 (t, 1H, J ˆ 7.5 Hz) 3.75 (t, 1H, J ˆ
7.5 Hz), 2.62 ± 2.49 (m, 2H), 1.97 ± 1.91 (m, 1H), 1.76 ± 1.56 (m, 5H), 1.40 ±
1.22 (m, 6H), 0.92 ± 0.86 (m, 9H), 0.86 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 202.5, 113.2, 80.7, 77.2, 65.7, 38.7, 35.8,
29.1, 28.5, 27.9, 26.0, 25.9, 23.3, 18.5, 13.9, 8.3, 8.2, À2.2, À2.3; HR-MS:
‡
calcd for C21H42O4Si [M‡Cs] 519.1907, found 519.1929.
Hydrazone 20: A solution of diisopropylamine (10.7 g, 105.3 mmol) in
tetrahydrofuran (300 mL) at 08C was treated with n-butyllithium (66 mL,
105.4 mmol, 1.6m in hexane) added dropwise over a period of 0.5 h. The
mixture was stirred at 08C for 20 min and treated with a solution of the
SAMP hydrazone of propionaldehyde (19, 16.3 g, 95.8 mmol) in tetrahy-
drofuran (70 mL). The reaction was stirred at 08C for 6 h, then cooled to
À208C and treated again with n-butyllithium (66 mL, 105.4 mmol, 1.6m in
hexane). After stirring at À208C for 2 h, the reaction mixture was cooled to
À1108C (liquid nitrogen/pentane bath) and treated with a solution of
TBSOCH2CH2I (54.8 g, 191.6 mmol) in tetrahydrofuran (50 mL). The
mixture was allowed to warm slowly (over a period of 2 h) to À208C and
the reaction was quenched with aqueous saturated ammonium chloride
(200 mL). The reaction mixture was then warmed to 258C and the organic
layer was diluted with Et2O (500 mL), washed with aqueous saturated
sodium chloride (3 Â 200 mL), dried over MgSO4, filtered, and concen-
trated. Flash chromatography of the crude residue (0 ± 15% Et2O in
hexanes) afforded hydrazone 20 (22.0 g, 67.1 mmol, 70%). 20: colorless
liquid; Rf ˆ 0.55 (30% Et2O in hexanes); [a]2D5: À54.9 (c ˆ 1.0, CH2Cl2); IR
‡
C12H22O3 [M‡Cs] 347.0621, found 347.0640.
Ketone 16: A solution of alcohol 15 (11.0 g, 51.4 mmol) in CH2Cl2 (30 mL)
was transferred under argon to
a stirred suspension of pyridinium
chlorochromate (22.1 g, 102.6 mmol, preabsorbed on celite) in CH2Cl2
(120 mL). After stirring for 2 h at 258C, the mixture was diluted with
hexanes, filtered through a pad of celite, washed with Et2O (2 Â 50 mL),
concentrated and subjected to flash chromatography (0 ± 10% Et2O in
hexanes) to afford ketone 16 (10.3 g, 47.8 mmol, 93%). 16: colorless liquid;
Rf ˆ 0.45 (20% Et2O in hexanes); [a]2D5: À60.1 (c ˆ 1.8, CH2Cl2); IR (film):
nÄmax ˆ 2966, 2882, 1718, 1463, 1087, 916 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 5.82 ± 5.78 (m, 1H), 5.04 (dd, 1H, J ˆ 17.0, 1.5 Hz), 4.98 (d, 1H, J ˆ
10.5 Hz), 4.42 (t, 1H, J ˆ 8.0 Hz), 4.19 (t, 1H, J ˆ 8.0 Hz), 3.88 (dd, 1H, J ˆ
6.5, 7.5 Hz), 2.72 (t, 2H, J ˆ 7.5 Hz), 2.32 (q, 2H, J ˆ 8.0 Hz), 1.72 ± 1.61 (m,
4H), 0.94 ± 0.84 (m, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 209.8, 137.0,
115.4, 115.0, 80.6, 66.5, 37.7, 29.1, 28.4, 26.8, 8.0, 7.9; HR-MS: calcd for
(film): nÄmax ˆ 2962, 2925, 2857, 1473, 1264, 1097, 836, 778 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d ˆ 6.50 (d, 1H, J ˆ 6.0 Hz), 3.63 (m, 2H), 3.58 (dd, 1H,
J ˆ 9.0, 3.5 Hz), 3.49 ± 3.39 (m, 1H), 3.37 (s, 3H), 3.35 ± 3.32 (m, 1H), 2.66
(m, 1H), 2.40 (m, 1H), 1.92 ± 1.50 (m, 7H), 1.05 (d, 3H, J ˆ 7.0 Hz), 0.88 (s,
9H), 0.03 (s, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 143.6, 74.7, 63.5, 61.2,
59.1, 50.3, 38.2, 33.7, 26.4, 25.9, 22.0, 19.0, 18.2, À5.41, À5.43; HR-MS: calcd
‡
C12H20O3 [M‡Cs] 345.0464, found 345.0471.
Alcohol 17: A solution of ketone 16 (10.0 g, 47.1 mmol) in tetrahydrofuran
(150 mL) was cooled at À788C and treated with butylmagnesium chloride
(35.5 mL, 70.7 mmol, 2.0m in tetrahydrofuran). After stirring for 1.5 h at
À788C, the reaction mixture was treated with aqueous saturated ammo-
nium chloride (50 mL), then allowed to warm to 258C and diluted with
Et2O (200 mL). The organic layers were washed with aqueous saturated
ammonium chloride (2 Â 200 mL), collected, dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography (0 ± 10% Et2O in hexanes) to afford alcohol 17 (9.67 g,
35.8 mmol, 76%), easily separated from its C18 epimer (2.41 g, 8.9 mmol,
19%). 17: colorless liquid; Rf ˆ 0.45 (20% Et2O in hexanes); [a]2D5: ‡28.1
(c ˆ 1.25, CH2Cl2); IR (film): nÄmax ˆ 3483, 2960, 2923, 2861, 1094, 835,
‡
for C17H36N2O2Si [M‡Cs] 461.1599, found 461.1617.
Alcohol 21: A solution of hydrazone 20 (22.0 g, 67.1 mmol) in CH2Cl2
(250 mL) was cooled to À788C and treated with ozone until the starting
material was consumed (tlc tests, ca 1 h depending on the scale). The
mixture was then purged with oxygen (5 min) and argon (5 min), allowed to
warm to 258C and concentrated. The crude aldehyde was taken immedi-
ately to the next step. A solution of (‡)-methoxydiisopinocampheylborane
(31.8 g, 100.6 mmol) in Et2O (300 mL) was cooled to À788C and treated
with allylmagnesium bromide (33 mL, 100.6 mmol, 3m in Et2O). After
1994
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Chem. Eur. J. 2000, 6, No. 11

Reveromycin B
1987±2001
stirring for 0.5 h at À788C, the mixture was warmed to 258C and stirred for
1 h. The reaction mixture was then cooled to À788C and treated with a
solution of the crude aldehyde in Et2O (30 mL). After stirring for 2 h at
À788C, the reaction was treated with a solution of 30% hydrogen peroxide
(95 mL) and 3n sodium hydroxide (432 mL) added dropwise over a period
of 0.5 h. The mixture was then allowed to warm slowly to 258C and stirred
at this temperature for 15 h. The organic layer was diluted with Et2O
(300 mL), washed with water (3 Â 300 mL), dried over MgSO4, filtered,
concentrated, and purified by chromatography (0 ± 10% Et2O in hexanes)
to afford alcohol 21 (13.5 g, 52.3 mmol, 78% over two steps). 21: colorless
liquid; Rf ˆ 0.4 (20% Et2O in hexanes); [a]2D5: À11.0 (c ˆ 1.1, CH2Cl2); IR
18 h at 258C. The mixture was diluted with Et2O (300 mL) and water
(100 mL), and the organic layer was separated. After extraction with Et2O
(3 Â 200 mL), the organic layers were combined, dried (MgSO4), filtered,
and concentrated. The residue was subjected to flash chromatography (0 ±
10% Et2O in hexanes) to afford alcohol 24 (15.6 g, 63.7 mmol, 80%). 24:
colorless oil; Rf ˆ 0.60 (25% Et2O in hexanes); [a]2D5: À6.9 (c ˆ 1.1,
1
CH2Cl2); IR (film): nÄmax ˆ 3483, 2960, 1260, 1094, 835, 780 cmÀ1; H NMR
(500 MHz, CDCl3): d ˆ 5.86 ± 5.79 (m, 1H), 5.07 (dd, 2H, J ˆ 13.0, 1.5 Hz),
3.90 ± 3.86 (m, 1H), 3.82 ± 3.77 (m, 1H), 3.70 ± 3.66 (m, 1H), 3.13 (brs, 1H),
2.25 ± 2.20 (m, 1H), 1.64 ± 1.60 (m, 2H), 1.03 (d, 3H, J ˆ 7.0 Hz), 0.88 (s,
9H), 0.059 (s, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 140.8, 115.1, 75.0,
62.8, 43.9, 35.4, 25.9, 25.8, 18.1, 15.6, À5.6, À5.7; HR-MS: calcd for
(film): nÄmax ˆ 3485, 2960, 2924, 2861, 1090, 837, 780 cmÀ1
;
1H NMR
‡
(400 MHz, CDCl3): d ˆ 5.91 ± 5.82 (m, 1H), 5.13 ± 5.07 (m, 2H), 3.77 ±
3.71 (m, 1H), 3.67 ± 3.61 (m, 1H), 3.47 ± 3.43 (m, 1H), 2.66 (brs, 1H),
2.34 ± 2.28 (m, 1H), 2.24 ± 2.12 (m, 1H), 1.77 ± 1.51 (m, 3H), 0.94 (d, 3H, J ˆ
7.0 Hz), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3): d ˆ 135.5,
117.1, 74.6, 61.1, 39.0, 36.0, 35.3, 26.0, 18.4, 16.4, À5.2; HR-MS: calcd for
C13H28O2Si [M‡Cs] 377.0911, found 377.0918.
Diol 25: A solution of 1m TBAF ´ THF (70 mL, 70 mmol) was added to a
solution of alcohol 24 (14.3 g, 58.5 mmol) in THF (50 mL) at 258C. After
stirring for 30 min, the reaction mixture was quenched with aqueous
saturated ammonium chloride (50 mL) and diluted with Et2O (150 mL).
The organic layer was separated and the aqueous layer was extracted with
Et2O (3 Â 100 mL). The organic layers were combined, dried (MgSO4),
filtered, and concentrated. The residue was subjected to flash chromatog-
raphy (50 ± 75% Et2O in hexanes) to afford diol 25 (7.45 g, 57.3 mmol,
98%). 25: colorless oil; Rf ˆ 0.45 (70% Et2O in hexanes). [a]2D5: À2.6 (c ˆ
‡
C14H30O2Si [M‡H] 259.2093, found 259.2104.
Alcohol 22: A solution of alcohol 21 (11.9 g, 46.4 mmol) in Et2O (250 mL)
was cooled to 08C and treated with potassium hydride (2.2 g, 55.7 mmol,
washed with Et2O) followed by 4-methoxybenzyl chloride (10.9 g,
69.7 mmol). After stirring for 6 h, the reaction was cooled to À308C and
quenched with ice/water added cautiously. The mixture was then diluted
with Et2O (100 mL) and allowed to warm to 258C. The organic layer was
washed with aqueous saturated sodium chloride (3 Â 200 mL), collected,
dried (MgSO4), filtered through a short pad of silica, and concentrated. The
crude residue was dissolved in Et2O (50 mL) and treated with tert-
butylammonium fluoride (56 mL, 56 mmol, 1m in THF) for 0.5 h at 258C.
Aqueous saturated ammonium chloride (200 mL) was then added and the
organic layer was extracted with Et2O (3 Â 200 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
subjected to flash chromatography (40 ± 60% Et2O in hexanes) to afford
alcohol 22 (9.93 g, 37.6 mmol, 81% yield over two steps). 22: colorless
liquid; Rf ˆ 0.4 (70% Et2O in hexanes); [a]2D5: À11.3 (c ˆ 1.49, CH2Cl2); IR
1.2, CH2Cl2); IR (film): nÄmax ˆ 3354, 2966, 2879, 1426, 1051, 909 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 5.76 ± 5.69 (m, 1H), 5.12 (d, 1H, J ˆ
18.5 Hz), 5.12 (d, 1H, J ˆ 10.5 Hz), 3.85 ± 3.77 (m, 2H), 3.65 ± 3.61 (m,
1H), 2.76 (brs, 2H), 2.33 ± 2.19 (m, 1H), 1.72 ± 1.69 (m, 1H), 1.64 ± 1.61 (m,
1H), 1.01 (d, 3H, 7.0 Hz); 13C NMR (125 MHz, CDCl3): d ˆ 140.2, 116.5,
‡
74.9, 61.6, 44.5, 35.1, 15.8; HR-MS: calcd for C7H14O2 [M‡Cs] 263.0045,
found 263.0069.
Acetal 26: A solution of diol 25 (7.31 g, 56.3 mmol) in CH2Cl2 (60 mL) at
258C was treated with 4-methoxybenzaldehyde dimethylacetal (12.3 g,
67.6 mmol) and CSA (1.31 g, 5.63 mmol). After stirring for 6 h, the reaction
was quenched with Et3N (5 mL) and the mixture concentrated and purified
by chromatography (0 ± 10% Et2O in hexanes) to afford the p-methox-
ybenzylidene acetal 26 (13.7 g, 55.2 mmol, 98%). 26: colorless oil; Rf ˆ 0.55
(film): nÄmax ˆ 3408, 2934, 1612, 1513, 1247, 1060, 821 cmÀ1
;
1H NMR
(25% Et2O in hexanes); [a]2D5: À25.1 (c ˆ 1.2, CH2Cl2); IR (film): nÄmax
ˆ
(500 MHz, CDCl3): d ˆ 7.27 (d, 2H, J ˆ 8.5 Hz), 6.87 (d, 2H, J ˆ 8.5 Hz),
5.88 ± 5.80 (m, 1H), 5.12 (d, 1H, J ˆ 17.0 Hz), 5.07 (d, 1H, J ˆ 10.5 Hz), 4.55
(d, 1H, J ˆ 10.5 Hz), 4.41 (d, 1H, J ˆ 11.0 Hz), 3.80 (s, 3H), 3.78 ± 3.60 (m,
2H), 3.30 ± 3.28 (m, 1H), 2.35 (t, 2H, J ˆ 6.5 Hz), 1.90 ± 1.50 (m, 4H), 0.94
(d, 3H, J ˆ 7.0 Hz); 13C NMR (125 MHz, CDCl3): d ˆ 159.3, 135.3, 130.6,
129.5, 116.8, 113.8, 82.5, 71.4, 60.4, 55.2, 35.2, 35.0, 32.8, 15.8; HR-MS: calcd
3353, 2960, 1260, 1094, 835 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.43 (d,
2H, J ˆ 8.4 Hz), 6.90 (d, 2H, J ˆ 8.4 Hz), 5.92 (m, 1H), 5.46 (s, 1H), 5.1 ±
5.05 (m, 2H), 4.28 ± 4.24 (m, 1H), 3.96 ± 3.90 (m, 1H), 3.80 (s, 3H), 3.75 (m,
1H), 2.44 ± 2.30 (m, 1H), 1.89 ± 1.81 (m, 1H), 1.46 ± 1.41 (m, 1H), 1.10 (d,
3H, J ˆ 7.2 Hz); 13C NMR (125 MHz, CDCl3): d ˆ 159.5, 140.0, 131.3, 127.1,
114.7, 113.4, 100.9, 80.3, 67.0, 55.3, 42.5, 28.0, 15.2; HR-MS: calcd for
‡
for C16H24O3 [M‡H] 265.1804, found 265.1816.
‡
C15H20O3 [M‡Cs] 381.0464, found 381.0489.
Iodide 10: Imidazole (4.36 g, 64.12 mmol) followed by triphenylphosphine
(8.40 g, 32.06 mmol) was added to a solution of alcohol 22 (7.05 g,
26.66 mmol) in THF (120 mL) and the mixture was stirred at 08C for
10 min. The flask was then protected from the light with aluminum foil and
the mixture was treated with iodine (8.14 g, 32.06 mmol) introduced slowly
(over 5 min). After stirring at 0 to 258C for 30 min, the reaction mixture
was diluted with Et2O (200 mL) and washed with aqueous saturated
sodium thiosulfate (2 Â 100 mL) and aqueous saturated sodium bicarbon-
ate (2 Â 100 mL). The organic layer was dried (MgSO4), concentrated, and
subjected to flash chromatography (0 ± 10% Et2O in hexanes) to yield
iodide 10 (9.67 g, 25.85 mmol, 97%). 10: colorless liquid; Rf ˆ 0.7 (10%
Et2O in hexanes); [a]2D5: À7.8 (c ˆ 1.3, CH2Cl2); IR (film): nÄmax ˆ 2936, 2852,
Alcohol 27: A solution of acetal 26 (12.7 g, 51.2 mmol) in CH2Cl2 (100 mL)
was treated at À788C with DIBAL-H (77 mL of a 1m solution in CH2Cl2,
77 mmol). After stirring for 30 min, the mixture was allowed to warm to
258C and stirred for 1.5 h. The reaction was quenched with methanol
(10 mL), diluted with ethyl acetate (100 mL) and Rochelle salt (100 mL)
and stirred vigorously for 2 h. After extraction with ethyl acetate (3 Â
100 mL), the organic layers were combined, dried (MgSO4), filtered, and
concentrated. The residue was subjected to flash chromatography (10 ±
25% Et2O in hexanes) to afford alcohol 27 (11.6 g, 46.4 mmol, 91%). 27:
colorless oil; Rf ˆ 0.35 (65% Et2O in hexanes); [a]2D5: 93.8 (c ˆ 1.0, CH2Cl2);
IR (film): nÄmax ˆ 3409, 2966, 2873, 1617, 1513, 1254, 1051, 817 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 7.28 (d, 2H, J ˆ 8.0 Hz), 6.88 (d, 2H, J ˆ 8.0 Hz),
5.81 ± 5.73 (m, 1H), 5.08 ± 5.04 (m, 2H), 4.59 (d, 1H, J ˆ 11.5 Hz), 4.42 (d,
1H, J ˆ 11.0 Hz), 3.79 (s, 3H), 3.71 (t, 2H, J ˆ 5.5 Hz), 3.57 ± 3.55 (m, 1H),
2.63 ± 2.61 (m, 1H), 2.26 (brs, 1H), 1.71 ± 1.64 (m, 2H), 1.04 (d, 3H, J ˆ
6.5 Hz); 13C NMR (125 MHz, CDCl3): d ˆ 159.3, 140.6, 130.4, 129.5, 114.9,
113.9, 81.4, 71.2, 61.0, 55.2, 39.5, 32.1, 13.4; HR-MS: calcd for C15H22O3
1
1614, 1510, 1249, 1181, 1097, 1040, 825 cmÀ1; H NMR (500 MHz, CDCl3):
d ˆ 7.26 (d, 2H, J ˆ 8.0 Hz), 6.88 (d, 2H, J ˆ 8.0 Hz), 5.85 ± 5.80 (m, 1H),
5.11 (d, 1H, J ˆ 17 Hz), 5.07 (d, 1H, J ˆ 10 Hz), 4.50 (d, 1H, J ˆ 10 Hz),
4.43 (d, 1H, J ˆ 10 Hz), 3.80 (s, 3H), 3.31 ± 3.20 (m, 2H), 3.14 ± 3.1 (m, 1H),
2.3 ± 2.2 (m, 2H), 2.1 ± 2.0 (m, 1H), 1.9 ± 1.8 (m, 1H), 1.7 ± 1.6 (m, 1H), 0.90
(d, 3H, J ˆ 7.0 Hz); 13C NMR (125 MHz, CDCl3): d ˆ 159.2, 135.5, 130.8,
129.3, 116.9, 113.7, 81.7, 80.8, 71.2, 55.2, 36.7, 36.3, 35.2, 14.6; HR-MS: calcd
‡
[M‡Cs] 383.0612, found 383.0638.
‡
for C16H23IO2 [M‡Cs] 506.9797, found 506.9817.
Olefin 28: A solution of alcohol 27 (11.6 g, 46.4 mmol) in CH2Cl2 (100 mL)
was treated at 08C with imidazole (7.57 g, 111.3 mmol) and tert-butyldime-
thylsilylchloride (8.38 g, 55.6 mmol). After 1 h the reaction was diluted with
aqueous saturated sodium bicarbonate (50 mL) and the reaction mixture
was extracted with Et2O (3 Â 50 mL). The organic layer was dried
(MgSO4), filtered, concentrated, and purified by chromatography (0 ± 5%
Et2O in hexanes) to afford silyl ether 28 (16.4 g, 45.0 mmol, 97%). 28:
colorless oil; Rf ˆ 0.50 (10% Et2O in hexanes); [a]2D5: ‡27.8 (c ˆ 3.0,
Alcohol 24: A suspension of potassium tert-butoxide (13.4 g, 119.5 mmol)
and trans-2-butene (12 mL, 127.5 mmol) in THF (50 mL), was mechanically
stirred, cooled to À458C and treated with n-BuLi (48 mL, 119.5 mmol,
2.5m in hexanes) added over a period of 10 min. The mixture was cooled to
À788C and treated with a solution of (À)-methoxydiisopinocampheylbor-
ane (40.3 g, 127.5 mmol) in THF (125 mL). The reaction mixture was stirred
for 30 min and treated with BF3 ´ OEt2 (19.9 mL, 159.3 mmol) followed by
addition of aldehyde 23 (15.0 g, 79.7 mmol). After 3 h, the reaction was
quenched with 3n NaOH (270 mL) and 30% H2O2 (45 mL), and stirred for
CH2Cl2); IR (film): nÄmax ˆ 2957, 2925, 2857, 1614, 1520, 1249, 1097, 836 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.28 (d, 2H, J ˆ 8.0 Hz), 6.88 (d, 2H, J ˆ
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-1995 $ 17.50+.50/0
1995

K. E. Drouet and E. A. Theodorakis
FULL PAPER
8.0 Hz), 5.82 ± 5.79 (m, 1H), 5.06 (d, 1H, J ˆ 17.0 Hz), 5.06 (d, 1H, J ˆ
14.0 Hz), 4.52 (d, 1H, J ˆ 11.0 Hz), 4.44 (d, 1H, J ˆ 11.0 Hz), 3.80 (s, 3H),
3.69 (t, 2H, J ˆ 7.0 Hz), 3.52 ± 3.49 (m, 1H), 2.53 ± 2.50 (m, 1H), 1.67 ± 1.61
(m, 2H), 1.04 (d, 3H, J ˆ 6.5 Hz), 0.89 (s, 9H), 0.043 (s, 3H), 0.039 (s, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 159.1, 141.0, 131.2, 129.4, 114.6, 113.7,
79.0, 71.5, 59.9, 55.2, 40.3, 34.0, 25.9, 18.2, 14.5, À5.4, À5.5; HR-MS: calcd
Spiroketal 31: A solution of ketone 30 (2.9 g, 3.85 mmol) in THF (5 mL)
and tetra-n-butylammonium fluoride (11.6 mL of a 1.0m solution in THF,
11.6 mmol) was stirred at 508C for 2 h. The reaction mixture was diluted
with Et2O (100 mL) and washed with aqueous saturated ammonium
chloride (2 Â 50 mL) and brine (2 Â 50 mL). The organic layer was dried
and concentrated under reduced pressure. The crude lactol was redissolved
in ethanol (20 mL) and subjected to hydrogenation under 10% Pd/C
catalysis (0.29 g) at 258C for 12 h. The reaction mixture was filtered
through a short pad of celite, concentrated, and subjected to flash
chromatography to produce spiroketal 31 (1.18 g, 3.1 mmol, 80%). 31:
colorless liquid; Rf ˆ 0.2 (15% Et2O in hexanes); [a]2D5: ‡36.0 (c ˆ 1.0,
‡
for C21H36O3Si [M‡Cs] 497.1486, found 497.1501.
Alcohol 29: A solution of alkene 28 (10.27 g, 28.2 mmol) in THF (100 mL)
was cooled to À408C and treated with BH3 ´ THF (28 mL of 1m solution,
28 mmol). After stirring for 10 h, the reaction was cautiously quenched
with 3n NaOH (93 mL) and 30% H2O2 (15 mL) and allowed to warm to
258C. Following extraction with Et2O (3 Â 100 mL) the organic layer was
dried (MgSO4), filtered, concentrated, and purified by chromatography
(15 ± 30% Et2O in hexanes) to afford alcohol 29 (9.16 g, 24.0 mmol, 85%).
29: colorless oil; Rf ˆ 0.45 (66% Et2O in hexanes); [a]2D5: ‡29.0 (c ˆ 1.2,
CH2Cl2); IR (film): nÄmax ˆ 3403, 2966, 2929, 2861, 1611, 1519, 1248, 1094,
835 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.26 (d, 2H, J ˆ 8.0 Hz), 6.87 (d,
2H, J ˆ 8.0 Hz), 4.49 (d, 1H, J ˆ 11.5 Hz), 4.45 (d, 1H, J ˆ 11.5 Hz), 3.79 (s,
3H), 3.71 ± 3.67 (m, 3H), 3.61 ± 3.57 (m, 1H), 3.47 ± 3.45 (m, 1H), 2.12 ± 2.10
(m, 1H), 1.97 ± 1.95 (m, 1H), 1.71 ± 1.48 (m, 4H), 0.94 (d, 3H, J ˆ 7.0 Hz),
0.88 (s, 9H), 0.035 (s, 3H), 0.032 (s, 3H); 13C NMR (125 MHz, CDCl3): d ˆ
159.2, 130.8, 129.4, 113.8, 79.3, 71.5, 60.5, 59.8, 55.2, 35.5, 33.5, 32.4, 25.8,
CH2Cl2); IR (film): nÄmax ˆ 3458, 2947, 2879, 1463, 1383, 1082, 996 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 4.21 (t, 1H, J ˆ 7.5 Hz), 4.0 (t, 1H, J ˆ
7.5 Hz), 3.82 ± 3.65 (m, 4H), 2.88 (brs, 1H), 2.12 (m, 1H), 1.95 ± 1.79 (m,
4H), 1.71 ± 1.44 (m, 10H), 1.41 ± 1.24 (m, 6H), 0.91 ± 0.80 (m, 12H);
13C NMR (125 MHz, CDCl3): d ˆ 113.3, 106.1, 87.3, 80.6, 75.8, 66.2, 60.4,
38.3, 35.6, 35.1, 34.9, 34.6, 30.1, 29.3, 29.0, 28.9, 25.8, 23.2, 17.5, 14.0, 8.1, 7.9;
‡
HR-MS: calcd for C22H40O5 [M‡Cs] 517.1927, found 517.1941.
Aldehyde 32: A solution of alcohol 31 (1.18 g, 3.1 mmol) in CH2Cl2 (5 mL)
was treated with Dess ± Martin periodinane (1.9 g, 4.6 mmol) at 08C for 2 h.
The mixture was then quenched with aqueous saturated sodium bicarbon-
ate/sodium thiosulfate (1:1 2 Â 20 mL) and extracted with Et2O (3Â 20 mL).
The organic layer was dried (MgSO4), concentrated and purified by chro-
matography (0±25% Et2O in hexanes) to afford aldehyde 32 (1.1 g, 2.9 mmol,
94%). 32: colorless liquid; Rf ˆ 0.45 (30% Et2O in hexanes); [a]2D5: ‡19.8
‡
18.1, 15.0, À5.4, À5.5; HR-MS: calcd for C21H38O4Si [M‡Cs] 515.1592,
found 515.1610.
Iodide 11: A solution of alcohol 29 (4.78 g, 12.5 mmol), imidazole (2.04 g,
30.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol) in THF (50 mL)
was treated at 08C with iodine (3.81 g, 15.0 mmol). After stirring for
30 min, the reaction was quenched with aqueous saturated sodium
thiosulfate (50 mL) and aqueous saturated sodium bicarbonate (50 mL)
and diluted with Et2O (100 mL). The organic layer was separated, and the
aqueous layer extracted with Et2O (3 Â 100 mL). The organic layers were
combined, dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was subjected to flash chromatography (0 ± 5%
Et2O in hexanes) to afford iodide 11 (5.91 g, 12 mmol, 96%). 11: light
yellow oil; Rf ˆ 0.55 (10% Et2O in hexanes); [a]2D5: ‡16.1 (c ˆ 1.0, CH2Cl2);
IR (film): nÄmax ˆ 2957, 2936, 2863, 1614, 1515, 1254, 1092, 836 cmÀ1; 1H NMR
(500 MHz, CDCl3): d ˆ 7.27 (d, 2H, J ˆ 8.0 Hz), 6.88 (d, 2H, J ˆ 8.0 Hz),
4.50 (d, 1H, J ˆ 11.5 Hz), 4.42 (d, 1H, J ˆ 11.5 Hz), 3.80 (s, 3H), 3.69 ± 3.66
(m, 2H), 3.47 ± 3.45 (m, 1H), 3.28 ± 3.27 (m, 1H), 3.18 ± 3.15 (m, 1H), 1.98 ±
1.86 (m, 2H), 1.71 ± 1.55 (m, 3H), 0.91 (d, 3H, J ˆ 7.0 Hz), 0.88 (s, 9H),
0.035 (s, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 159.2, 131.1, 129.4, 113.8,
78.2, 71.3, 59.8, 55.2, 36.5, 36.0, 33.3, 25.9, 18.2, 13.9, 5.5, À5.4, À5.5; HR-
(c ˆ 1.2, CH2Cl2); IR (film): nÄmax ˆ 2962, 2925, 2878, 1731, 1465, 1087 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 9.82 (d, 1H, J ˆ 1.5 Hz), 4.14 (t, 1H, J ˆ
7.0 Hz), 3.97 (t, 1H, J ˆ 7.0 Hz), 3.95 ± 3.90 (m, 1H), 3.78 (t, 1H, J ˆ 7.0 Hz),
2.58 ± 2.54 (m, 1H), 2.40 ± 2.36 (m, 1H), 2.08 ± 2.03 (m, 1H), 1.95 ± 1.91 (m,
1H), 1.82 ± 1.55 (m, 11H), 1.42 ± 1.28 (m, 6H), 0.94 ± 0.83 (m, 12H);
13C NMR (125 MHz, CDCl3): d ˆ 203.0, 122.4, 113.0, 106.4, 80.8, 72.2, 66.1,
47.4, 38.2, 35.3, 34.8, 34.7, 30.6, 29.2, 28.9, 28.8, 25.8, 23.3, 17.4, 14.0, 8.3, 7.9;
‡
HR-MS: calcd for C22H38O5 [M‡Cs] 515.1772, found 515.1793.
Alkene 33: A solution of carbon tetrabromide (3.90 g, 11.7 mmol) in
tetrahydrofuran (25 mL) was cooled to À258C and treated with HMPT
(0.96 g, 5.85 mmol). After stirring for 15 min, a solution of aldehyde 32
(0.90 g, 2.35 mmol) in tetrahydrofuran (10 mL) was added dropwise and
the mixture was stirred for 15 min. The reaction was quenched with
aqueous saturated sodium bicarbonate (20 mL), the mixture was diluted
with water (50 mL), and the organic layer was extracted with Et2O (2 Â
100 mL), dried (MgSO4), filtered, and concentrated. The crude residue was
then subjected to flash chromatography to afford dibromide 33 (1.20 g,
2.23 mmol, 95%). 33: colorless liquid; Rf ˆ 0.65 (15% Et2O in hexanes);
[a]2D5: ‡18.3 (c ˆ 1.25, CH2Cl2); IR (film): nÄmax ˆ 2958, 2923, 2861, 1094, 835,
780 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 6.56 (t, 1H, J ˆ 7.0 Hz), 4.13 (t,
1H, J ˆ 7.0 Hz), 3.95 (t, 1H, J ˆ 8.0 Hz), 3.88 (t, 1H, J ˆ 7.0 Hz), 3.49 ± 3.46
(m, 1H), 2.38 ± 2.33 (m, 1H), 2.23 ± 2.17 (m, 1H), 2.02 ± 1.92 (m, 2H), 1.83 ±
1.72 (m, 2H), 1.79 ± 1.53 (m, 7H), 1.35 ± 1.20 (m, 8H), 0.94 ± 0.83 (m, 12H);
13C NMR (125 MHz, CDCl3): d ˆ 136.0, 125.6, 113.0, 106.5, 74.3, 65.9, 38.3,
36.8, 34.7, 34.6, 34.1, 30.3, 29.6, 29.1, 29.0, 28.6, 25.9, 23.3, 17.5, 14.0, 8.4, 7.9;
‡
MS: calcd for C21H37IO3Si [M‡Cs] 625.0609, found 625.0631.
Ketone 30: A solution of iodide 11 (3.1 g, 6.3 mmol) in Et2O (20 mL) at
À788C was treated with tert-butyllithium (7.8 mL of a 1.7m solution in
pentane, 13.2 mmol), added over a period of 10 min. After stirring at
À788C for 30 min, the mixture was treated with a solution of aldehyde 9
(3.4 g, 8.8 mmol) in Et2O (10 mL) added over a period of 10 min. After
stirring at À788C for 30 min, the reaction mixture was quenched with water
(100 mL) and extracted with Et2O (2 Â 100 mL). The organic layer was
dried (MgSO4), concentrated and purified by chromatography (10 ± 30%
Et2O in hexanes) to afford a diastereomeric mixture of alcohols at the C15
center (4.08 g, 5.4 mmol, 86%). A solution of the above mixture (4.08 g,
5.4 mmol) in CH2Cl2 (20 mL) was treated with Dess ± Martin periodinane
(2.8 g, 6.5 mmol) at 258C for 1 h. The mixture was then quenched with
aqueous saturated sodium bicarbonate/sodium thiosulfate (1:1, 2 Â 40 mL)
and extracted with Et2O (3 Â 50 mL). The organic layer was dried
(MgSO4), concentrated, and purified by chromatography (0 ± 15% Et2O
in hexanes) to afford ketone 23 (3.82 g, 5.1 mmol, 94%). 23: colorless
liquid; Rf ˆ 0.6 (30% Et2O in hexanes); [a]2D5: À12.9 (c ˆ 1.3, CH2Cl2); IR
(film): nÄmax ˆ 2956, 1714, 1618, 1512, 1460, 1082 cmÀ1; 1H NMR (400 MHz,
CDCl3): d ˆ 7.26 (d, 2H, J ˆ 8.0 Hz), 6.84 (d, 2H, J ˆ 8.0 Hz), 4.48 (d, 1H,
J ˆ 11.2 Hz), 4.38 (d, 1H, J ˆ 11.2 Hz), 4.05 (dd, 1H, J ˆ 6.4, 8.0 Hz), 3.91 (t,
1H, J ˆ 7.6 Hz), 3.80 (s, 3H), 3.75 (t, 1H, J ˆ 8 Hz), 3.69 (t, 1H, J ˆ 6.4 Hz),
3.45 ± 3.43 (m, 1H), 2.60 ± 2.40 (m, 4H), 1.71 ± 1.56 (m, 12H), 1.42 ± 1.27 (m,
6H), 0.91 ± 0.81 (m, 12H), 0.89 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s,
3H), 0.041 (s, 3H), 0.037 (s, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 210.5,
158.8, 130.9, 129.1, 113.6, 112.8, 80.7, 78.9, 71.2, 65.7, 59.9, 55.3, 41.0, 37.2,
36.0, 34.9, 33.2, 30.4, 29.3, 28.2, 27.0, 26.2, 26.1, 26.0, 25.8, 23.5, 18.8, 18.4,
14.5, 14.2, 8.6, 8.5, À1.8, À1.9, À5.0, À5.1; HR-MS: calcd for C42H78O7Si2
‡
HR-MS: calcd for C22H31NO4Si [M‡Cs] 534.1073, found 534.1099.
Alkyne 8: A solution of the dibromoalkene 33 (104 mg, 0.19 mmol) in THF
(3 mL) was cooled at À788C and treated with n-butyllithium (254 mL of a
1.6 m solution in hexanes, 0.40 mmol). Stirring was continued for 20 min at
À788C and for 20 min at À208C. The reaction mixture was then cooled at
À788C, treated with freshly distilled iodomethane (60 mL, 0.96 mmol) and
subsequently allowed to warm to 08C where it was stirred for a period of
1 h. The solution was then quenched with water (1 mL), diluted with Et2O
(30 mL) and washed with brine (2 Â 20 mL). The organic layer was dried
(MgSO4), filtered, concentrated, and purified by chromatography (0 ± 15%
Et2O in hexanes) to give alkyne 8 (72 mg, 18.4 mmol, 95%). 8: colorless
liquid; Rf ˆ 0.65 (15% Et2O in hexanes); [a]2D5: ‡2.14 (c ˆ 0.84, CH2Cl2);
IR (film): nÄmax ˆ 2957, 2931, 2878, 1463, 1087, 930 cmÀ1; 1H NMR (500 MHz,
CDCl3): d ˆ 4.25 (t, 1H, J ˆ 7.5 Hz), 3.98 ± 3.95 (m, 2H), 3.47 ± 3.42 (m, 1H),
2.41 ± 2.37 (m, 1H), 2.30 ± 2.28 (m, 1H), 2.05 ± 2.00 (m, 2H), 1.79 ± 1.42 (m,
14H), 1.34 ± 1.25 (m, 6H), 0.94 ± 0.82 (m, 12H); 13C NMR (125 MHz,
CDCl3): d ˆ 112.8, 106.7, 87.1, 81.0, 76.1, 74.4, 66.0, 38.3, 34.53, 34.5, 33.8,
31.6, 29.1, 29.0, 28.6, 25.9, 23.6, 23.3, 17.5, 14.0, 8.4, 7.9, 3.5; HR-MS: calcd
‡
for C24H40O4 [M] 393.3005, found 393.3017.
Triacetate 34: A solution of alcohol 31 (102 mg, 0.26 mmol) in CH2Cl2
(2 mL) was treated with pyridine (63 mL, 0.8 mmol) and acetic anhydride
‡
[M‡Cs] 883.4337, found 883.4360.
1996
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-1996 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Reveromycin B
1987±2001
(40 mL, 0.40 mmol) at 258C for 15 min. The reaction mixture was diluted
with Et2O (20 mL) and washed with ammonium chloride (2 Â 10 mL) and
brine (2 Â 10 mL). The organic layer was dried (MgSO4), concentrated, and
the residue purified by chromatography (0 ± 25% Et2O in hexanes). The
acetylated product was dissolved in CH2Cl2/MeOH 9:1 (6 mL) and treated
with CSA (26 mmol) at 258C for 3 h. The reaction was quenched with excess
triethylamine and the residue was filtered through a short pad of silica gel
and concentrated. The crude diol was redissolved in CH2Cl2 (2 mL) and
treated with triethylamine (160 mg, 1.6 mmol) and acetic anhydride (80 mL,
0.80 mmol) at 258C for 3 h. The reaction mixture was diluted with Et2O
(20 mL) and washed with ammonium chloride (2 Â 10 mL) and brine (2 Â
10 mL). The organic layer was dried (MgSO4), concentrated, and the
residue purified by chromatography (0 ± 25% Et2O in hexanes) to afford
triacetate 34 (86.8 mg, 0.19 mmol, 74% over three steps). 34: colorless
liquid; Rf ˆ 0.45 (30% Et2O in hexanes); [a]2D5: ‡37.5 (c ˆ 1.0, CHCl3); IR
(MgSO4), filtered, concentrated, and subjected to flash chromatography
(10 ± 20% Et2O in hexanes) to give amide 44 (938 mg, 3.38 mmol, 81%
yield over three steps). 44: colorless liquid; Rf ˆ 0.3 (30% Et2O in
hexanes); [a]2D5: ‡48.0 (c ˆ1.2, CH2Cl2); IR (film): nÄmax ˆ 2939, 2869,
1651, 1460, 1418, 1390, 1115, 1064, 994, 882 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d ˆ 4.63 (dd, 1H, J ˆ 7.5, 1.5 Hz), 3.70 (s, 3H), 3.16 (s, 3H), 3.16 (m,
1H), 2.36 (d, 1H, J ˆ 2.0 Hz), 1.22 (d, 3H, J ˆ 6.5 Hz), 1.14 ± 1.02 (m, 21H);
13C NMR (125 MHz, CDCl3): d ˆ 174.7, 97.2, 84.6, 73.0, 64.5, 61.4, 44.0, 17.9,
‡
13.9, 12.2; HR-MS: calcd for C17H33O3NSi [M‡Cs] 460.1282, found
460.1298.
Ester 40: A solution of amide 44 (1.55 g, 4.74 mmol) in THF (30 mL) was
cooled at À788C and treated with DIBAL-H (7.9 mL of a 1.5m solution in
toluene, 11.8 mmol). After stirring for 30 min at À788C, the reaction
mixture was quenched with methanol (3 mL), diluted with ethyl acetate
(50 mL), allowed to warm to 258C and stirred for 30 min with a saturated
solution of Rochelle salt (100 mL). The mixture was extracted with ethyl
acetate (3 Â 50 mL) and the organic layer was dried (MgSO4) and
concentrated to produce the crude aldehyde, that was used for the next
step without any purification. A solution of the above aldehyde in CH2Cl2
(film): nÄmax ˆ 2931, 2868, 1745, 1463, 1369, 1238, 1050, 1083, 993, 923 cmÀ1
;
1H NMR (400 MHz, CDCl3): d ˆ 5.19 (dd, 1H, J ˆ 9.0, 2.5 Hz), 4.52 (dd,
1H, J ˆ 12.0, 2.0 Hz), 4.34 ± 4.26 (m, 1H), 4.24 (dd, 1H, J ˆ 12.0, 8.5 Hz),
4.18 ± 4.13 (m, 1H), 3.49 (ddd, 1H, J ˆ 10.8, 8.0, 2.8 Hz), 2.07 (s, 3H), 2.04
(s, 3H), 2.03 (s, 3H), 1.96 ± 1.50 (m, 11H), 1.31 ± 1.25 (m, 6H), 0.91 (t, 3H,
J ˆ 7.0 Hz), 0.87 (d, 3H, J ˆ 6.5 Hz); 13C NMR (100 MHz, CDCl3): d ˆ
171.27, 171.25, 170.4, 107.0, 86.2, 73.6, 63.9, 61.7, 38.4, 34.5, 34.4, 34.2, 32.1,
31.3, 29.6, 29.0, 25.4, 23.1, 21.0, 20.9, 20.7, 17.6, 14.0; HR-MS: calcd for
ˆ
(10 mL) was treated with Ph3P CH-CO2TMSE (45) (5.07 g, 11.85 mmol)
for 15 h, at 258C. The reaction mixture was then concentrated and
subjected to flash chromatography (0 ± 5% Et2O in hexanes) to afford ester
40 (1.76 g, 4.31 mmol, 91%). 40: colorless liquid; Rf ˆ 0.65 (15% Et2O in
hexanes); [a]2D5: ‡10.6 (c ˆ0.5, CH2Cl2); IR (film): nÄmax ˆ 2946, 2863, 1719,
1466, 1253, 1175, 860, 836 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 7.07 (dd,
1H, J ˆ 16, 7.5 Hz), 5.86 (d, 1H, J ˆ 16.5 Hz), 4.46 (dd, 1H, J ˆ 5.0, 2.0 Hz);
4.22 (t, 2H, J ˆ 8.0 Hz), 2.60 (q, 1H, J ˆ 6.0 Hz), 2.40 (d, 1H, J ˆ 2.0 Hz),
1.14 (d, 3H, J ˆ 6.5 Hz), 1.07 ± 0.99 (m, 23H), 0.026 (s, 9H); 13C NMR
(125 MHz, CDCl3): d ˆ 166.8, 149.5, 122.3, 83.1, 73.9, 66.4, 62.3, 43.6, 17.92,
‡
C23H38O8 [M‡Cs] 575.1619, found 575.1632.
Oxazolidinone 43: A solution of imide 42 (1.15 g, 4.94 mmol) in CH2Cl2
(20 mL) was cooled to À788C, treated with triethylamine (0.56 mL,
5.41 mmol) and dibutylborontriflate (4.95 mL, 4.95 mmol, 1m in CH2Cl2).
The solution was stirred for 30 min at À788C and then allowed to warm to
08C over a period of 1 h. The mixture was recooled to À788C, treated with
aldehyde 41 (1.00 g, 5.94 mmol) in CH2Cl2 (5 mL), stirred at À788C for
30 min, and warmed to 08C over a 2 h period. The resulting mixture was
treated with a solution of sodium acetate (4.2 g) in MeOH (70 mL) into
which 30% H2O2 (5.6 mL) was added and stirred for 30 min from 0 to 258C.
The reaction mixture was diluted with water (150 mL), hexane (100 mL),
and separated. The organic layer was washed with brine (25 mL), dried
(MgSO4), concentrated, and subjected to flash chromatography (10 ± 30%
Et2O in hexanes) to afford 43 (1.58 g, 3.95 mmol, 80%). 43: colorless liquid;
Rf ˆ 0.45 (50% Et2O in hexanes); [a]2D5: 7.5 (c ˆ 1.0, CH2Cl2); IR (film):
‡
17.90, 17.1, 14.6, 12.1, À1.6; HR-MS: calcd for C22H42O3Si2 [M‡Cs]
543.1725, found 543.1739.
Vinyl stannane 37: A solution of ester 40 (726 mg, 1.86 mmol) in benzene
(10 mL) was treated at 58C with dichlorobistriphenylphosphinepalladiu-
m(ii) (26 mg, 0.037 mmol) and tri-n-butyltin hydride (750 mL, 2.8 mmol).
After stirring at 58C for 10 min, the reaction mixture was concentrated and
subjected to flash chromatography (0 ± 10% Et2O in hexanes) to afford
stannane 37 (1.14 g, 1.70 mmol, 91%). 37: colorless liquid; Rf ˆ 0.85 (10%
Et2O in hexanes); [a]2D5: ‡8.4 (c ˆ1.0, CH2Cl2); IR (film): nÄmax ˆ 2957, 2925,
nÄmax ˆ 3471, 2960, 2929, 2855, 1777, 1697, 1470, 1371, 1199 cmÀ1
;
1H NMR
2868, 1719, 1463, 1254, 1175, 867, 836 cmÀ1 1H NMR (500 MHz, CDCl3):
;
(500 MHz, CDCl3): d ˆ 7.42 ± 7.34 (m, 3H), 7.29 ± 7.27 (m, 2H), 5.66 (d, 1H,
J ˆ 9.0 Hz), 4.78 (t, 1H, J ˆ 8.5 Hz), 4.72 (d, 1H, J ˆ 6.0 Hz), 4.00 ± 3.94 (m,
1H), 3.01 ± 2.83 (m, 1H), 1.39 (d, 3H, J ˆ 9.0 Hz), 0.92 (s, 9H), 0.88 (d, 3H,
J ˆ 8.0 Hz), 0.01 (s, 6H); 13C NMR (125 MHz, CDCl3): d ˆ 174.7, 152.3,
132.8, 128.7, 128.6, 125.4, 104.3, 88.6, 79.0, 63.7, 54.8, 44.1, 26.1, 16.6, 14.5,
d ˆ 7.07 (dd, 1H, J ˆ 16, 7.5 Hz), 6.04 ± 6.0 (d, 1H, J ˆ 19.5 Hz), 5.85 (dd,
1H, J ˆ 19.0, 7.0 Hz), 5.76 (d, 1H, J ˆ 15.5 Hz), 4.20 (t, 2H, J ˆ 8.5 Hz),
4.12 ± 4.10 (m, 1H), 2.53 (q, 1H, J ˆ 6.5 Hz), 1.48 ± 1.42 (m, 4H), 1.30 ± 1.24
(m, 6H), 1.04 ± 1.02 (m, 26H), 0.87 (t, 9H, J ˆ 7.5 Hz), 0.88 ± 0.85 (m, 8H),
0.03 (s, 9H); 13C NMR (125 MHz, CDCl3): d ˆ 166.9, 151.1, 148.8, 130.0,
121.2, 80.6, 62.2, 43.3, 29.0, 21.2, 18.1, 18.0, 13.6, 12.3, 9.4, À1.6; HR-MS:
‡
12.2, À4.57, À4.59; HR-MS: calcd for C22H31NO4Si [M‡Cs] 534.1074,
‡
found 534.1099.
calcd for C34H70O3Si2Sn [M‡Cs] 835.2946, found 835.2959.
Vinyl iodide 39: A solution of vinyl stannane 37 (202 mg, 0.29 mmol) in
CH2Cl2 (3 mL) was cooled to 08C and titrated with a saturated solution of
iodine in CH2Cl2, until the iodine color persisted. The solution was then
stirred for 5 min and partitioned between a solution of CH2Cl2 (20 mL) and
aqueous saturated sodium thiosulfate (20 mL). The organic layer was
collected, dried (MgSO4), filtered, concentrated, and purified by chroma-
tography (0 ± 10% Et2O in hexanes) to afford compound 39 (140 mg,
0.26 mmol, 90%). 39: colorless liquid; Rf ˆ 0.65 (10% Et2O in hexanes);
[a]2D5: ‡39.6 (c ˆ1.0, CH2Cl2); IR (film): nÄmax ˆ 2951, 2863, 1719, 1651, 1463,
Amide 44: A suspension of N,O-dimethyl-hydroxylamine hydrochloride
(3.65 g, 37.4 mmol) in THF (6 mL) was cooled to À308C and treated with
AlMe3 (18.7 mL, 37.4 mmol, 2.0m in toluene) over a 5 min period. After the
addition was complete, the solution was warmed to 258C and stirred for
15 min. The clear solution was cooled to À108C, and treated with imide 43
(1.67 g, 4.16 mmol) in THF (15 mL) added dropwise. The resulting mixture
was warmed to 08C and stirred for 2 h. The reaction mixture was poured
onto a mixture containing Rochelle salt (100 mL), aqueous saturated
sodium bicarbonate (50 mL) and ethyl acetate (150 mL) at 08C and
alllowed to warm to 258C under vigorous stirring. After 20 min, the
resulting mixture was partitioned, the organic layer separated and the
aqueous layer was extracted with ethyl acetate (2 Â 150 mL). The organic
layers were collected, dried (MgSO4), filtered, and concentrated. The
residue was subjected to flash chromatography (15 ± 30% Et2O in hexanes)
to yield the corresponding Weinreb amide (1.07 g, 3.75 mmol, 90%) as a
sticky oil. Rf ˆ 0.35 (66% Et2O in hexanes). A solution of the Weinreb
amide (995 mg, 3.67 mmol) in THF (3 mL) was treated with TBAF ´ SiO2
(7.3 g, 7.34 mmol) at 258C for 3 h. The reaction mixture was filtered through
a short pad of silica, concentrated and taken on crude to the next step. A
solution of the crude alcohol and 2,6-lutidine (1.30 mL, 10.9 mmol) in
CH2Cl2 (5 mL) was treated at 258C with triisopropylsilyl trifluorometha-
nesulfonate (1.50 mL, 5.58 mmol). After 15 min, the mixture was quenched
with aqueous saturated sodium bicarbonate (10 mL) and diluted with
CH2Cl2 (20 mL). The layers were separated, and the organic layer was
washed with brine (2 Â 10 mL). The organic layers were combined, dried
1
1254, 1175, 862, 841 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.01 (dd, 1H,
J ˆ 16.0, 7.0 Hz), 6.46 (dd, 1H, J ˆ 14.5, 7.0 Hz), 6.26 (d, 1H, J ˆ 15.0 Hz),
5.80 (d, 1H, J ˆ 15.5 Hz), 4.23 (t, 2H, J ˆ 8.0 Hz), 4.17 (dd, 1H, J ˆ 5.0,
7.5 Hz), 2.53 (m, 1H), 1.04 ± 1.03 (m, 26H), 0.03 (s, 9H); 13C NMR
(125 MHz, CDCl3): d ˆ 166.7, 149.4, 146.3, 122.1, 78.9, 77.8, 62.4, 42.8, 18.0,
‡
17.9, 17.2, 14.3, 12.2, À1.6. HR-MS: calcd for C22H43O3Si2I [M‡Cs]
671.0849, found 671.0859.
Vinyl iodide 36: A solution of alkyne 8 (200 mg, 0.51 mmol) in THF (2 mL)
was introduced dropwise into a stirred solution of bis(cyclopentadienyl)-
zirconium chloride hydride (263 mg, 1.02 mmol) in THF (2 mL). The
mixture was protected from the light and allowed to stir at 258C for 8 h. The
solution was then cooled at 08C and treated with a saturated solution of
iodine in CCl4, added dropwise until the iodine color persisted. The
reaction mixture was then diluted with Et2O (20 mL) and washed with
saturated aqueous sodium thiosulfate (2 Â 20 mL). The organic layer was
dried (MgSO4), filtered through a short pad of celite and concentrated
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-1997 $ 17.50+.50/0
1997

K. E. Drouet and E. A. Theodorakis
FULL PAPER
under reduced pressure. Flash chromatography (0 ± 10% Et2O in hexanes)
gave iodide 5 (142 mg, 27.3 mmol, 53%) together with the C9 trans-iodide
(57 mg, 11 mmol, 21%), that was taken to the next step without any further
purification. 36: colorless liquid; Rf ˆ 0.6 (10% Et2O in hexanes); IR (film):
Iodide 6: A solution of aldehyde 48 (2.0 g, 9.33 mmol) in tetrahydrofuran
(60 mL) was cooled to 08C and treated with chromium(ii) chloride (9.17 g,
74.6 mmol) and iodoform (9.2 g, 23.3 mmol). After stirring for 0.5 h, the
mixture was diluted with hexanes (25 mL), filtered over celite, washed with
Et2O (2 Â 10 mL), concentrated under reduced pressure, and purified by
chromatography (0 ± 5% Et2O in hexanes) to yield vinyl iodide 6 (2.05 g,
6.06 mmol, 65%). 6: light yellow oil; Rf ˆ 0.4 (5% Et2O in hexanes); IR
nÄmax ˆ 2925, 2863, 1463, 1379, 1186, 1087, 930 cmÀ1
;
1H NMR (500 MHz,
CDCl3): d ˆ 6.25 (t, 1H, J ˆ 7.0 Hz), 4.05 (t, 1H, J ˆ 6.5 Hz), 3.90 (t, 1H, J ˆ
6.5 Hz), 3.62 (t, 1H, J ˆ 6.5 Hz), 3.46 ± 3.40 (m, 1H), 2.35 (s, 3H), 2.30 ± 2.20
(m, 2H), 2.05 ± 1.86 (m, 6H), 1.6 ± 1.4 (m, 9H), 1.31 ± 1.24 (m, 4H), 0.92 ±
0.81 (m, 12H); 13C NMR (125 MHz, CDCl3): d ˆ 138.2, 112.2, 106.5, 94.5,
85.6, 80.1, 74.7, 65.5, 45.8, 40.2, 38.6, 34.4, 34.1, 33.8, 32.3, 29.7, 29.0, 27.7, 26.9,
(film): nÄmax ˆ 2957, 1719, 1619, 1243, 1154, 1055, 951, 836 cmÀ1
;
1H NMR
(400 MHz, C6D6) d ˆ 6.75 (d, 1H, J ˆ 14.5 Hz), 6.28 (d, 1H, J ˆ 14.8 Hz),
5.57 (s, 1H), 4.21 ± 4.17 (m, 2H), 2.01 (s, 3H), 0.89 (t, 2H, J ˆ 8.5 Hz), À0.96
(s, 9H); 13C NMR (100 MHz, C6D6) d ˆ 166.1, 150.9, 148.2, 120.9, 85.0, 62.3,
‡
23.5, 17.6, 14.1, 8.3, 8.0; HR-MS: calcd for C24H41O4I [M À C2H5] 491.1658,
‡
found 491.1675.
17.9, 13.5, À1.0; HR-MS: calcd for C11H19IO2Si [M‡Cs] 470.9251, found
470.9270.
Ester 35: (by Stille coupling of 36 with 37): A solution of iodide 36 (150 mg,
0.29 mmol) and stannane 37 (136 mg, 0.20 mmol) in DMF/THF 1:1 (1 mL)
was added dropwise to a stirred solution of bis(acetonitrile)dichloropalla-
dium(ii) (2.5 mg, 9.6 mmol) in DMF/THF 1:1 (1 mL) at 258C. After stirring
for 15 h the reaction mixture was diluted with aqueous saturated sodium
bicarbonate (10 mL) and extracted with Et2O (3 Â 10 mL). The organic
layer was dried (MgSO4), filtered, concentrated, and purified by chroma-
tography (0 ± 10% Et2O in hexanes) to afford compound 35 (84 mg,
0.11 mmol, 52%).
Diol 49: A solution of ester 35 (100 mg, 0.124 mmol) in MeOH (5 mL) was
treated with pyridinium p-toluenesulfonate (94 mg, 0.374 mmol) at 408C.
After 3 h, the reaction mixture was quenched with Et3N (2 mL),
concentrated, and subjected to flash chromatography (10 ± 25% Et2O in
hexanes) to afford diol 49 (69 mg, 0.093 mmol, 75%). 49: colorless liquid;
Rf ˆ 0.3 (30% Et2O in hexanes); [a]2D5: ‡7.08 (c ˆ 0.8, CH2Cl2); IR (film):
nÄmax ˆ 3434, 2960, 2923, 2867, 1716, 1463, 1377, 1254, 1082, 860, 842 cmÀ1
;
1H NMR (500 MHz, C6D6) d ˆ 7.47 (dd, 1H, J ˆ 7.0, 15.5 Hz), 6.36 (d, 1H,
J ˆ 16.0 Hz), 6.08 (d, 1H, J ˆ 15.5 Hz), 5.88 (t, 1H, J ˆ 7.5 Hz), 5.65 (dd,
1H, J ˆ 7.5, 15.5 Hz), 4.28 ± 4.21 (m, 4H), 3.95 ± 3.93 (m, 1H), 3.78 ± 3.76 (m,
1H), 3.62 ± 3.55 (m, 1H), 2.55 ± 2.34 (m, 2H), 2.25 ± 2.20 (m, 1H), 1.98 ± 1.93
(m, 1H), 1.72 (s, 3H), 1.39 ± 1.26 (m, 16H), 1.13 ± 1.11 (m, 21H), 1.02 (d, 3H,
J ˆ 7.0 Hz), 0.91 ± 0.88 (m, 2H), 0.85 (t, 3H, J ˆ7.5 Hz), 0.64 (d, 3H, J ˆ
7.0 Hz), 0.096 (s, 9H); 13C NMR (125 MHz, C6D6) d ˆ 166.8, 151.1, 136.8,
134.8, 129.3, 128.3, 127.6, 122.1, 106.5, 90.1, 78.0, 77.0, 76.4, 63.6, 62.2, 44.3,
39.4, 36.4, 35.0, 34.4, 32.2, 29.2, 28.9, 25.7, 23.4, 18.3, 18.2, 17.5, 17.3, 14.8,
Ester 35: (by modified Negishi coupling of 8 with 39): A solution of alkyne
8 (99 mg, 0.25 mmol) and bis(cyclopentadienyl)zirconium-chloride-hydride
(131 mg, 0.51 mmol) in tetrahydrofuran (1 mL) was stirred at 508C under
argon for 2 h in the dark. The resulted yellow solution was allowed to cool
to 258C and treated with a freshly prepared solution of anhydrous zinc
chloride (104 mg, 0.76 mmol) in tetrahydrofuran (0.8 mL), added via
cannula. The reaction mixture was stirred for 5 min and subsequently
treated with a solution of vinyl iodide 39 (165 mg, 0.31 mmol) and
palladium tetrakistriphenylphosphine (15 mg, 0.012 mmol) in tetrahydro-
furan (2 mL). The reaction was stirred for 2 h, then diluted with water
(10 mL), and extracted with Et2O (3 Â 30 mL). The organic layer was dried
(MgSO4), filtered, concentrated, and purified by chromatography (0 ± 5%
Et2O in hexanes) to afford compound 35 (168 mg, 0.21 mmol, 84% over
‡
14.1, 12.6, À1.8; HR-MS: calcd for C41H76O7Si2 [M‡Cs] 869.4184, found
869.4199.
Aldehyde 50: A solution of the diol 49 (58.0 mg, 0.079 mmol) in THF
(2 mL) and H2O (1 mL) was cooled to 08C and treated with sodium
periodate (0.101 g, 0.474 mmol). After 10 min, the solution was warmed to
258C and stirred for 2 h. The reaction mixture was diluted with Et2O
(20 mL) and partitioned with aqueous saturated sodium bicarbonate
(5 mL). The organic layers were collected, washed with water (2 Â 5 mL),
dried (MgSO4), and concentrated. The crude residue was subjected to flash
chromatography (0 ± 5% Et2O in hexanes) to afford aldehyde 50 (52.9 mg,
0.075 mmol, 95%). 50: colorless liquid; Rf ˆ 0.4 (5% Et2O in hexanes);
[a]2D5: ‡40.3 (c ˆ0.65, CH2Cl2); IR (film): nÄmax ˆ 2962, 2863, 1719, 1651,
two steps). 35: colorless liquid; Rf ˆ 0.45 (10% Et2O in hexanes); [a]D25
:
‡12.1 (c ˆ 0.93, CH2Cl2); IR (film): nÄmax ˆ 2936, 2863, 1719, 1651, 1463,
1
1254, 1170, 1087 cmÀ1; H NMR (500 MHz, CDCl3): d ˆ 7.10 (dd, 1H, J ˆ
7.0, 16.0 Hz), 6.08 (d, 1H, J ˆ 16.0 Hz), 5.76 (d, 1H, J ˆ 16.0 Hz), 5.56 (t,
1H, J ˆ 7.5 Hz), 5.42 (dd, 1H, J ˆ 8.5, 15.5, Hz), 4.23 ± 4.14 (m, 4H), 3.93 ±
3.89 (m, 2H), 3.48 ± 3.44 (m, 1H), 2.56 ± 2.53 (m, 1H), 2.41 ± 2.37 (m, 1H),
2.26 ± 2.21 (m, 1H), 1.92 ± 1.89 (m, 1H), 1.81 ± 1.24 (m, 21H), 1.02-.98 (m,
21H), 0.93 ± 0.87 (m, 14H), 0.81 (d, 3H, J ˆ 6.5 Hz), 2.23 (s, 9H); 13C NMR
(125 MHz, CDCl3): d ˆ 167.0, 151.2, 136.4, 134.0, 129.3, 126.9, 121.3, 112.7,
106.5, 86.9, 81.0, 77.8, 77.2, 75.4, 65.9, 62.2, 43.9, 38.3, 34.7, 34.2, 32.1, 31.4,
29.2, 29.18, 28.8, 26.0, 23.3, 18.1, 18.0, 17.7, 17.1, 14.2, 14.1, 12.6, 12.3, 8.4, 7.9,
1
1463, 1249, 1175, 1066, 862, 841 cmÀ1; H NMR (500 MHz, C6D6) d ˆ 9.67
(s, 1H), 7.48 (dd, 1H, J ˆ 7.5, 16.5 Hz), 6.36 (d, 1H, J ˆ 15.5 Hz), 6.09 (d,
1H, J ˆ 15.5 Hz), 5.73 (t, 1H, J ˆ 6.5 Hz), 5.66 (dd, 1H, J ˆ7.5, 15.5 Hz),
4.31 (dd, 1H, J ˆ 4.0, 8.0 Hz), 4.27 ± 4.23 (m, 2H), 3.61 ± 3.57 (m, 1H),
2.57 ± 2.55 (m, 1H), 2.37 ± 2.32 (m, 1H), 2.14 ± 2.11 (m, 1H), 1.92 ± 1.80 (m,
1H), 1.67 (s, 3H), 1.95 ± 1.61 (m, 13H), 1.16 ± 1.12 (m, 21H), 1.04 (d, 3H,
J ˆ 6.5 Hz), 0.91 (t, 2H, J ˆ 8.0 Hz), 0.80 (t, 3H, J ˆ 7 Hz), 0.67 (d, 3H, J ˆ
6.5 Hz), À0.10 (s, 9H); 13C NMR (125 MHz, C6D6) d ˆ 203.4, 166.4, 150.9,
136.9, 134.3, 129.8, 127.5, 122.2, 107.2, 90.4, 78.2, 76.9, 62.0, 44.3, 38.1, 35.0,
34.5, 33.8, 31.9, 29.4, 29.3, 25.5, 23.2, 18.3, 18.2, 17.5, 17.3, 14.6, 13.9, 12.6,
‡
À1.6; HR-MS: calcd for C46H84O7Si2 [M‡Cs] 937.4810, found 937.4835.
ˆ
Allylic alcohol 47: Ph3P CHCO2CH2CH2TMS (35) (34.1 g, 81 mmol) was
added to a solution of 1-hydroxyacetone (46) (5.0 g, 67.6 mmol) in CH2Cl2
(100 mL), and the mixture was stirred at 258C for 24 h. The solvent was
then removed under reduced pressure and the residue subjected to flash
chromatography (15 ± 35% Et2O in hexanes) to afford 47 (12.4 g,
57.4 mmol, 85%). 47: colorless liquid; Rf ˆ 0.45 (60% Et2O in hexanes);
‡
12.5, À1.7; HR-MS: calcd for C40H72O5Si2 [M‡Cs] 821.3973, found
IR (film): nÄmax ˆ 3446, 2947, 2892, 1716, 1654, 1229, 1149, 1057, 848 cmÀ1
;
821.3992.
1H NMR (500 MHz, CDCl3): d ˆ 5.96 (s, 1H), 4.20 (t, 2H, J ˆ 8.0 Hz), 4.13
(s, 2H), 2.08 (s, 3H), 1.80 (brs, 1H), 1.00 (t, 2H, J ˆ 8.0 Hz), 0.12 (s, 9H);
13C NMR (125 MHz, CDCl3): d ˆ 167.1, 157.0, 114.0, 67.1, 61.9, 17.3, 15.5,
Coupling of 6 with 50: A solution of aldehyde 50 (64 mg, 93 mmol) and vinyl
iodide 6 (123 mg, 0.363 mmol) in dry DMF (3 mL) was treated under argon
with chromium(ii) chloride (274 mg, 2.2 mmol) and nickel(ii) chloride
(1.4 mg, 0.01 mmol). After stirring for 2 h at 258C, the reaction mixture was
diluted with water (10 mL) and extracted with Et2O (3 Â 10 mL). The
organic layers were combined, dried (MgSO4), filtered, concentrated, and
purified by chromatography (preparative silica gel plate, 15% Et2O in
hexanes) to yield a 1:1.2 mixture of diastereomeric alcohols 5 and 51
(combined amount: 55.2 mg, 60 mmol, 65%). The minor diastereomer 5
was shown to have the desired stereochemistry (S) at the C19 carbon center
(NOE studies). Major diastereomer 51: (R)-stereochemistry at C19,
30.1 mg, 32.7 mmol, 35%; colorless liquid; Rf ˆ 0.4 (15% Et2O in hexanes);
[a]2D5: À24.5 (c ˆ 0.4, CH2Cl2); IR (film): nÄmax ˆ 3843, 2953, 2867, 1722, 1463,
1260, 1162, 860, 842 cmÀ1; 1H NMR (500 MHz, C6D6) d ˆ 7.48 (dd, 1H, J ˆ
7.0, 16.0 Hz), 6.70 (d, 1H, J ˆ 16.0 Hz), 6.35 (d, 1H, J ˆ 15.5 Hz), 6.14 (dd,
1H, J ˆ 5.5, 15.5 Hz), 6.10 ± 6.04 (m, 2H), 5.89 (t, 2H, J ˆ 7.5 Hz), 5.64 (dd,
1H, J ˆ 7.5, 15.5 Hz), 4.46 (d, 1H, J ˆ 6.0 Hz), 4.27 ± 4.22 (m, 5H), 3.71 ±
3.67 (m, 1H), 3.61 (brs, 1H), 2.57 ± 2.44 (m, 1H), 2.47 (s, 3H), 2.42 ± 2.36
‡
À1.6; HR-MS: calcd for C10H20O3Si [M‡Cs] 349.0234, found 349.0251.
Aldehyde 48: A solution of alcohol 47 (4.1 g, 18.1 mmol) in CH2Cl2 (20 mL)
was added via cannula to a stirred suspension of pyridinium chlorochro-
mate absorbed on celite (8.2 g, 38.1 mmol) in CH2Cl2 (100 mL). After
stirring for 2 h at 258C, the mixture was diluted with hexanes (50 mL),
filtered through a pad of celite and washed with Et2O (2 Â 50 mL). The
solvents were removed under reduced pressure and the residue subjected
to flash chromatography (0 ± 10% Et2O in hexanes) to produce aldehyde 48
(3.41 g, 15.9 mmol, 88%). 48: colorless liquid; Rf ˆ 0.4 (25% Et2O in
hexanes); IR (film): nÄmax ˆ 2957, 2899, 1719, 1222, 1165, 1045, 846 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 9.58 (s, 1H), 6.46 (s, 1H), 4.28 (t, 2H, J ˆ
8.5 Hz), 4.13 (s, 2H), 2.17 (s, 3H), 1.80 (brs, 1H), 1.04 (t, 2H, J ˆ 8.5 Hz),
0.12 (s, 9H); 13C NMR (125 MHz, CDCl3): d ˆ 194.7, 165.8, 150.3, 135.8,
‡
63.3, 17.2, 10.6, À1.7; HR-MS: calcd for C10H18O3Si [M‡Cs] 347.0077,
found 347.0096.
1998
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-1998 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Reveromycin B
1987±2001
(m, 1H), 2.35 ± 2.21 (m, 1H), 2.06 ± 1.98 (m, 1H), 1.70 (s, 3H), 1.58 ± 1.20 (m,
15H), 1.13 ± 1.08 (m, 21H), 1.01 (d, 3H, J ˆ 7.0 Hz), 0.10 ± 0.92 (m, 4H), 0.88
(t, 3H, J ˆ 6.5 Hz), 0.65 (d, 3H, J ˆ 6.5 Hz), À0.08 (s, 18H); 13C NMR
(125 MHz, C6D6) d ˆ 166.9, 166.5, 151.8, 150.9, 136.8, 135.1, 135.0, 134.8,
128.9, 127.7, 122.2, 120.2, 107.2, 91.6, 78.1, 77.3, 76.5, 62.1, 62.6, 44.2, 39.4,
37.5, 35.1, 34.1, 32.0, 29.2, 27.9, 27.7, 25.7, 23.4, 18.3, 18.2, 17.5, 17.4, 17.3, 14.6,
154.3, 151.5, 137.3, 135.5, 133.8, 131.3, 130.8, 127.5, 120.9, 120.8, 107.6, 88.0,
79.3, 78.3, 78.2, 62.7, 61.6, 44.7, 39.1, 34.8, 34.6, 34.5, 32.1, 31.9, 30.0, 29.9,
29.5, 25.7, 23.4, 18.3, 17.8, 17.5, 17.3, 14.2, 13.6, 12.7, 12.4, À1.7; HR-MS:
‡
calcd for C55H96O11Si3 [M‡Cs] 1149.5315, found 1149.5342.
Reveromycin B (4): A solution of acid 53 (3.1 mg, 3 mmol) in THF (0.1 mL)
was treated with tetra-n-butylammonium fluoride (30 mL of a 1m solution
in THF, 30 mmol) at 258C for 2 h. The reaction mixture was then diluted
with aqueous saturated ammonium chloride (2 mL), the pH was adjusted to
3 with dilute HCl and the mixture was extracted with ethyl acetate (5 Â
5 mL). The organic layer was dried, concentrated, and purified by
chromatography purified by chromatography on a preparative silica gel
plate (10% MeOH in CH2Cl2) to yield reveromycin B (4) (1.4 mg, 2.1 mmol,
69%). 4: white solid, Rf ˆ 0.25 (15% methanol in CH2Cl2); [a]2D5: À61 (c ˆ
0.1, MeOH); IR (film): nÄmax ˆ 3427, 2960, 2923, 2861, 1740, 1568, 1414, 1377,
‡
14.1, 13.9, 12.6, À1.74, À1.75; HR-MS: calcd for C51H92O8Si3 [M‡Cs]
1049.5154, found 1049.5189. Minor diastereomer 5: (S)-stereochemistry at
C19; 25.1 mg, 27.3 mmol, 30%; colorless liquid; Rf ˆ 0.38 (15% Et2O in
hexanes); [a]2D5: À25.5 (c ˆ 0.4, CH2Cl2); IR (film): nÄmax ˆ 3843, 2953, 2867,
1
1722, 1463, 1260, 1162, 860, 842 cmÀ1; H NMR (400 MHz, C6D6) d ˆ 7.45
(dd, 1H, J ˆ 7.2, 15.6 Hz), 6.60 (d, 1H, J ˆ 16.0 Hz), 6.34 ± 6.25 (m, 2H),
6.08 ± 6.03 (m, 2H), 5.86 (t, 1H, J ˆ 7.0 Hz), 5.65 (dd, 1H, J ˆ 8.0, 16.0 Hz),
4.29 ± 4.25 (m, 4H), 4.19 ± 4.17 (m, 1H), 3.72 ± 3.69 (m, 1H), 3.62 ± 3.57 (m,
1H), 2.53 ± 2.50 (m, 1H), 2.47 (s, 3H), 2.42 ± 2.21 (m, 1H), 2.04 ± 1.99 (m,
1H), 1.72 (s, 3H), 1.60 ± 1.20 (m, 15H), 1.13 ± 1.08 (m, 21H), 1.02 (d, 3H,
J ˆ 7.2 Hz), 0.91 ± 0.88 (m, 4H), 0.87 (t, 3H, J ˆ 6.4 Hz), 0.66 (d, 3H, J ˆ
6.4 Hz), À0.07 (s, 18H); 13C NMR (125 MHz, C6D6) d ˆ 166.9, 166.4, 151.8,
150.9, 136.7, 135.3, 135.0, 134.9, 129.0, 127.6, 122.2, 120.2, 107.2, 90.8, 78.1,
77.9, 77.4, 62.0, 61.6, 44.2, 39.5, 34.8, 34.1, 32.1, 30.1, 30.0, 29.2, 26.1, 23.4,
18.3, 18.2, 17.5, 17.4, 17.3, 14.4, 14.1, 13.9, 12.7, À1.7; HR-MS: calcd for
1
1260, 1162 cmÀ1; H NMR (400 MHz, CD3OD) d ˆ 6.94 (dd, 1H, J ˆ 15.6,
7.6 Hz), 6.38 (d, 1H, J ˆ 15.6 Hz), 6.25 (d, 1H, J ˆ 16.0 Hz), 6.19 (dd, 1H,
J ˆ 4.4, 16.0 Hz), 5.80 (d, 1H, J ˆ 15.6 Hz), 5.78 (s, 1H), 5.75 (t, 1H, J ˆ
6.8 Hz), 5.55 (d, 1H, J ˆ 4.4 Hz), 5.50 (dd, 1H, J ˆ 15.6, 7.6 Hz), 4.11 (m,
1H), 3.39 (m, 1H), 2.65 ± 2.45 (m, 5H), 2.25 ± 2.15 (m, 5H), 2.01 ± 1.30 (m,
18H), 1.01 (d, 3H, J ˆ 6.4 Hz), 0.91 (t, 3H, J ˆ 7.2 Hz), 0.83 (d, 3H, J ˆ
7.2 Hz); 13C NMR (125 MHz, CD3OD) d ˆ 177.9, 173.4, 171.7, 171.1, 152.0,
151.3, 138.6, 136.3, 135.3, 132.0, 131.0, 127.5, 123.6, 122.7, 108.7, 88.9, 80.5,
78.7, 77.4, 44.2, 39.7, 35.9, 35.6, 35.4, 33.0, 32.9, 31.4, 30.8, 30.3, 26.7, 24.4,
‡
C51H92O8Si3 [M‡Cs] 1049.5154, found 1049.5172.
Ketone 52: A solution of alcohol 51 (14.1 mg, 15.3 mmol) in CH2Cl2
(0.3 mL) was treated at 258C with Dess ± Martin periodinane (9.9 mg,
23.1 mmol). After stirring for 2 h, the mixture was quenched with aqueous
saturated sodium bicarbonate/sodium thiosulfate (1:1 2 Â 10 mL) and
extracted with Et2O (3 Â 10 mL). The organic layer was dried (MgSO4),
concentrated and purified by chromatography (0 ± 15% Et2O in hexanes)
to afford ketone 52 (13.1 g, 14.3 mmol, 93%). 52: [a]2D5: À42.1 (c ˆ 1.07,
‡
18.3, 15.3, 14.7, 14.1, 12.9; HR-MS: calcd for C36H52O11 [M‡Na] 683.3407,
found 683.3388.
C19-epi-Reveromycin B (55): White solid, Rf ˆ 0.20 (15% methanol in
CH2Cl2); [a]2D5: À19 (c ˆ0.1, MeOH); IR (film): nÄmax ˆ 3429, 2959, 2928,
2861, 1740, 1566, 1410, 1377, 1260 cmÀ1; 1H NMR (400 MHz, CD3OD) d ˆ
6.85 (dd, 1H, J ˆ 15.6, 7.6 Hz), 6.41 (d, 1H, J ˆ 15.6 Hz), 6.30 (d, 1H, J ˆ
16.0 Hz), 6.15 (dd, 1H, J ˆ 5.2, 16.0 Hz), 5.89 (s, 1H), 5.85 (d, 1H, J ˆ
14.8 Hz), 5.76 (t, 1H, J ˆ 7.6 Hz), 5.56 (d, 1H, J ˆ 6.0 Hz), 5.53 (dd, 1H, J ˆ
15.2, 7.6 Hz), 4.11 (m, 1H), 3.55 (m, 1H), 2.65 ± 2.45 (m, 6H), 2.25 ± 2.15 (m,
4H), 2.01 ± 1.30 (m, 18H), 1.01 (d, 3H, J ˆ 6.4 Hz), 0.91 (t, 3H, J ˆ 7.2 Hz),
0.83 (d, 3H, J ˆ 7.2 Hz); 13C NMR (125 MHz, CD3OD) d ˆ 178.0, 173.9,
173.8, 172.1, 171.6, 153.2, 152.0, 138.4, 137.7, 136.9, 130.6, 130.5, 127.7, 123.3,
122.2, 108.6, 88.9, 80.4, 78.1, 77.3, 44.0, 39.7, 35.6, 35.4, 35.3, 32.8, 31.5, 30.9,
30.3, 26.6, 24.7, 20.7, 18.1, 15.4, 14.2, 12.8; HR-MS: calcd for C36H52O11
CH2Cl2); 2957, 2863, 1719, 1599, 1468, 1254, 1228, 1160, 867, 841 cmÀ1
;
1H NMR (400 MHz, C6D6) d ˆ 7.55 (dd, 1H, 7.5, 16.5 Hz), 7.51 (dd, 1H, J ˆ
15.5, 6.5 Hz), 7.26 (d, 1H, J ˆ 15.5 Hz), 6.38 (d, 1H, J ˆ 15.5 Hz), 6.18 (s,
1H), 6.13 (d, 1H, J ˆ 15.5 Hz), 5.72 (t, 1H, J ˆ 6.5 Hz), 5.67 (dd, 1H, J ˆ
15.5, 8.0 Hz), 4.36 (dd, 1H, J ˆ 8.0, 4.5 Hz), 4.26 ± 4.22 (m, 4H), 3.56 ± 3.50
(m, 1H), 2.86 ± 2.80 (m, 1H), 2.64 ± 2.60 (m, 1H), 2.42 (d, 3H, J ˆ1.0 Hz),
2.38 ± 2.33 (m, 1H), 2.13 ± 2.07 (m, 1H), 1.92 ± 1.88 (m, 1H), 1.65 (s, 3H),
1.62 ± 1.26 (m, 13H), 1.16 ± 1.10 (m, 21H), 0.94 ± 0.89 (m, 7H), 0.80 (t, 3H,
7.0 Hz), 0.68 (d, 3H, J ˆ 6.5 Hz), À0.08 (s, 9H), À0.09 (s, 9H); 13C NMR
(125 MHz, C6D6) d ˆ 200.8, 166.4, 166.2, 150.9, 149.8, 145.2, 137.2, 133.9,
129.4, 128.3, 127.7, 127.0, 126.7, 122.3, 107.1, 91.6, 78.3, 76.7, 62.2, 62.0, 53.1,
44.4, 38.4, 38.0, 34.3, 31.9, 30.2, 30.0, 29.4, 25.9, 23.2, 18.3, 18.2, 17.7, 17.4,
‡
[M‡Na] 683.3407, found 683.3395.
‡
14.6, 13.9, 13.6, 12.7, À1.7, À1.8; HR-MS: calcd for C51H90O8Si3 [M‡Cs]
Acknowledgement
1047.4999, found 1047.4970.
Financial support from the Cancer Research Coordinating Committee, the
UCSD Academic Senate, the American Cancer Society (IRG, RPG CDD-
9922901), the NSF (Shared Instrumentation Grant CHE-9709183) and the
Hellman Foundation (Faculty Research Fellowship to EAT) is gratefully
acknowledged. We thank Professor H. Osada (RIKEN Institute, Japan) for
providing us with the NMR data of natural reveromycin B and for
stimulating discussions. We kindly thank David M. Remick, Donald A.
Watson and Hung V. Tran for their contributions to this project. We also
thank Professor M. Goodman (UCSD, Department of Chemistry and
Biochemistry) for allowing us access to his polarimeter and IR instruments
and Professor D. John Faulkner (Scripps Institute of Oceanography) for
critical suggestions on the reported NOE assignments.
Luche reduction of ketone 52: A solution of ketone 52 (17.0 mg, 18.6 mmol)
and CeCl3 ´ 7H2O (35 mg, 93 mmol) in THF/MeOH 1:1 (1.0 mL total) was
cooled at À788C and treated with LiBH4 (46 mL, 93 mmol, 2m in THF).
After stirring for 30 min, the mixture was allowed to warm to 258C and
stirred for 3 h. The reaction mixture was diluted with aqueous saturated
ammonium chloride (5 mL) and extracted with Et2O (5 Â 5 mL). The
organic layers were combined, dried (MgSO4), filtered, and concentrated.
The residue was purified by chromatography (preparative silica gel plate,
15% Et2O in hexanes) to afford a 3:1 mixture of diastereomeric alcohols 5
and 51 (combined amount: 13.8 mg, 15 mmol, 81%).
Acid 53: Succinic anhydride (12 mg, 120 mmol) and N-dimethylaminopyr-
idine (17 mg, 144 mmol) were added to a solution of alcohol 5 (11 mg,
12 mmol) in CH2Cl2 (1 mL) and the reaction mixture was stirred 3 h at
258C. Upon completion of the reaction, the mixture was diluted with
aqueous saturated ammonium chloride (5 mL) and extracted with CH2Cl2
(5 Â 5 mL). The organic layers were combined, dried (MgSO4), filtered,
concentrated, and purified by chromatography on a preparative silica plate
(2% MeOH in ethyl acetate) to yield acid 53 (10.3 mg, 10 mmol, 85%). 53:
colorless solid; Rf ˆ 0.5 (10% methanol in CH2Cl2); [a]2D5: À19.7 (c ˆ 0.12,
CH2Cl2); IR (film): nÄmax ˆ 3409, 2960, 2923, 1716, 1648, 1470, 1248,
[1] For a preliminary communication on the synthesis of 4, see: K. E.
Drouet, E. A. Theodorakis, J. Am. Chem. Soc. 1999, 121, 456 ±
457.
[2] For recent reviews on this topic see: a) Growth Factors andReceptors :
A Practical Approach (Eds.: I. A. McCay, K. D. Brown), University
Press, New York, 1998; b) Growth Factors andSignal Transduction in
Development (Ed.: M. Nilsen-Hamilton), Wiley-Liss, NY, 1994;
c) Growth Factors, Peptides and Receptors (Ed.: T. W. Moody),
Plenum Press, New York, 1993; d) V. Sorrentino, Anticancer Res.
1989, 9, 1925 ± 1936; e) N. W. Merrall, R. Plevin, G. W. Gould, Cellular
Signalling 1993, 5, 667 ± 675; f) D. T. Hung, T. F. Jamison, S. L.
Schreiber, Chem. Biol. 1996, 3, 623 ± 639.
1156 cmÀ1
;
1H NMR (500 MHz, C6D6) d ˆ 7.60 (dd, 1H, J ˆ 6.5, 15.5 Hz),
6.78 (d, 1H, J ˆ 15.5 Hz), 6.70 (d, 1H, J ˆ 16.0 Hz), 6.41 (dd, 1H, J ˆ 4.5,
16.0 Hz), 6.26 (t, 1H, J ˆ 6.5 Hz), 6.19 (d, 1H, J ˆ 16.0 Hz), 6.17 (s, 1H),
5.91 (d, 1H, J ˆ 3.5 Hz), 5.80 (dd, 1H, J ˆ 16.0, 8.5 Hz), 4.60 ± 4.58 (m, 1H),
4.29 ± 4.18 (m, 4H), 3.60 ± 3.56 (m, 1H), 2.79 ± 2.55 (m, 5H), 2.40 (s, 3H),
2.38 ± 2.04 (m, 3H) 1.81 (s, 3H), 1.76 ± 1.58 (m, 6H), 1.39 ± 1.21 (m, 8H),
1.17 ± 1.02 (m, 22H), 0.95 ± 0.82 (m, 10H), 0.73 (d, 3H, J ˆ 7.0 Hz), À0.80 (s,
9H), À0.10 (s, 9H); 13C NMR (125 MHz, C6D6) d ˆ 171.5, 168.6, 167.0,
[3] a) D. J. R. Laurence, B. A. Gusterson, Tumor Biol. 1990, 11, 229 ± 261;
b) L. C. Groenen, E. C. Nice, A. W. Burgess, Growth Factors 1994, 11,
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-1999 $ 17.50+.50/0
1999

K. E. Drouet and E. A. Theodorakis
FULL PAPER
235 ± 257; c) M. Baron, D. G. Norman, T. S. Harvey, P. A. Handford,
M. Mayhew, A. G. D. Tse, G. G. Brownlee, I. D. Campbel, Protein Sci.
1992, 1, 81 ± 90.
[19] a) P. J. Garegg, B. Samuelson, J. Chem. Soc. Perkin Trans. I 1980,
2866 ± 2869; b) J. A. Marshall, D. G. Cleary, J. Org. Chem. 1986, 51,
858 ± 863.
[4] a) T. Yamuchi, K. Ueki, K. Tobe, H. Tamemoto, N. Sekine, M. Wada,
M. Honjo, M. Takahashi, T. Takahashi, H. Hirai, T. Tushima, Y.
Akanuma, T. Fujita, I. Komuro, Y. Yazaki, T. Kadawaki, Nature 1997,
390, 91 ± 96; b) B. Margolis, S. G. Rhee, S. Felder, M. Mervic, R. Lyall,
A. Levitzki, A. Ullrich, A. Zilberstein, J. Schlessinger, Cell 1989, 57,
1101 ± 1107.
[5] a) K. Yoshida, E. Kyo, T. Tsuda, T. Tsujino, M. Ito, M. Niimoto, E.
Tahara, Int. J. Cancer 1990, 45, 131 ± 135; b) M. E. Stearns, M. Stearns,
Cancer Metastasis Rev. 1993, 12, 39 ± 52; c) J. G. M. Klijn, P. M. J. J.
Berns, P. I. M. Schmitz, J. A. Foekens, Endocrine Rev. 1992, 13, 3 ± 17;
d) H. Modjtahedi, C. Dean, Int. J. Oncol. 1994, 4, 277 ± 296; e) M. B.
Sporn, A. B. Roberts, Nature 1985, 313, 745 ± 747; f) A. S. Goustin,
E. B. Leof, G. D. Shipley, H. L. Moses, Cancer Res. 1986, 46, 1015 ±
1029.
[6] a) H. Koshino, H. Takahashi, H. Osada, K. Isono, J. Antibiot. 1992, 45,
1420 ± 1427; b) H. Takahashi, H. Osada, H. Koshino, T. Kudo, S.
Amano, S. Shimizu, M. Yoshihama, K. Isono, J. Antibiot. 1992, 45,
1409 ± 1413; c) H. Osada, H. Koshino K. Isono, H. Takahashi, G.
Kawanishi, J. Antibiot. 1991, 44, 259 ± 261.
[7] a) H. Takahashi, H. Osada, H. Koshino, M. Sasaki, R. Onose, M.
Nakakoshi, M. Yoshihama, K. Isono, J. Antibiot. 1992, 45, 1414 ± 1419;
b) H. Takahashi, Y. Yamashita, H. Takaoka, J. Nakamura, M.
Yoshihama, H. Osada, Oncology Res. 1997, 9, 7 ± 11.
[20] H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 5919 ± 5923.
[21] a) A. B. Jones, M. Yamaguchi, A. Patten, S. J. Danishefsky, J. A.
Ragan, D. B. Smith, S. L. Schreiber, J. Org. Chem. 1989, 54, 19 ± 20;
b) M. Nakatsuka, J. A. Ragan, T. Sammakia, D. B. Smith, D. E.
Ueling, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 5583 ± 5601.
[22] a) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277 ± 7287;
b) R. E. Ireland, L. Liu, J. Org. Chem. 1993, 58, 2899.
[23] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769 ± 3772.
[24] J. M. Humphrey, J. B. Eggen, A. R. Chamberlin, J. Am. Chem. Soc.
1996, 118, 11759Ð11770.
[25] For selected reviews on palladium-catalyzed transformations see: a) J.
Tsuji, Palladium Reagents and Catalysts. Innovations in Organic
Synthesis, Wiley, New York, 1997; b) R. F. Heck, Palladium Reagents
in Organic Synthesis, Academic Press, New York, 1985; c) T. N.
Mitchell, Synthesis 1992, 803 ± 815; d) V. Farina, Pure Appl. Chem.
1996, 68, 73 ± 78; e) V. Farina, V. Krishnamurthy, W. J. Scott, Organic
Reactions, Vol. 50 (Ed.: L. A. Paquette), Wiley, New York, 1997,
pp. 1 ± 652.
[26] a) D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982,
104, 1737 ± 1739; b) D. A. Evans, A. S. Kim, J. Am. Chem. Soc. 1996,
118, 11323Ð11324.
[27] a) A. Basha, M. Lipton, S. M. Weinreb, Tetrahedron Lett. 1977, 4171 ±
4174; b) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815 ±
3818; c) D. L. Clark, C. H. Heathcock, J. Org. Chem. 1993, 58, 5878 ±
5879.
[8] M. Ubukata, H. Koshino, H. Osada, K. Isono, J. Chem. Soc. Chem.
Commun. 1994, 1877 ± 1878.
[9] a) T. Shimizu, R. Kobayashi, K. Osako, H. Osada, T. Nakata,
Tetrahedron Lett. 1996, 37, 6755 ± 6758; b) K. J. McRae, M. A.
Rizzacasa, J. Org. Chem. 1997, 62, 1196 ± 1197; c) K. D. Drouet, T.
Ling, H. V. Tran, E. A. Theodorakis, Org. Lett. 2000, 2, 207 ± 210.
[10] For a recent review on spiroketals see: F. Perron, K. F. Albizati, Chem.
Rev. 1989, 89, 1617 ± 1661.
[11] In our recently communicated synthesis of 4 we abbreviated the
Me3SiCH2CH2- group as SEM. Since SEM usually refers to Me3-
SiCH2CH2OCH2-, we are using TMSE as the abbreviation herein.
We thank Professor B. H. Lipshutz for bringing to our attention this
oversight.
[12] For selected references on the Kishi ± Nozaki (Nozaki ± Hiyama ±
Kishi) reaction see: a) A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996,
118, 2533 ± 2534; b) P. Cintas, Synthesis 1992, 248 ± 257; c) H. Jin, J.
Uenishi, W. J. Christ, Y. Kishi, J. Am. Chem. Soc. 1986, 108, 5644 ±
5646; d) P. Wipf, S. Lim, J. Chem. Soc. Chem. Commun. 1993, 1654 ±
1656; e) K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K. Utimoto,
H. Nozaki, J. Am. Chem. Soc. 1986, 108, 6048 ± 6050; f) Y. Kishi, Pure
Appl. Chem. 1992, 64, 343 ± 350; g) Y. Kishi, Pure Appl. Chem. 1989,
61, 313 ± 324; h) C. Chen, K. Tagami, Y. Kishi, J. Org. Chem. 1995, 60,
5386 ± 5387; i) A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118,
12349 ± 12357.
[13] a) G. C. Andrews, T. C. Crawford, B. E. Bacon, J. Org. Chem. 1981, 46,
2976 ± 2977; b) C. R. Schmid, D. A. Bradley, Synthesis 1992, 587 ± 590.
[14] For selected reviews on this topic see: a) J. Jurczak, S. Pikul, T. Bauer,
Tetrahedron 1986, 42, 447 ± 488; b) M. T. Reetz, Acc. Chem. Res. 1993,
26, 462 ± 468; c) M. T. Reetz, Angew. Chem. 1984, 96, 542 ± 558;
Angew. Chem. Int. Ed. Engl. 1984, 23, 556 ± 569.
[28] H. X. Zhang, F. Guibe, G. Balavoine, J. Org. Chem. 1990, 55, 1857 ±
1867.
[29] A. B. Smith III, G. R. Ott, J. Am. Chem. Soc. 1998, 120, 3935 ± 3948.
[30] a) J. K. Stille, B. L. Groh, J. Am. Chem. Soc. 1987, 109, 813 ± 817; b) C.
Mateo, D. J. Cardenas, C. Fernandez-Rivas, A. M. Echavarren, Chem.
Eur. J. 1996, 2, 1596 ± 1606; c) A. L. Casado, P. Espinet, J. Am. Chem.
Soc. 1998, 120, 8978 ± 8985.
[31] D. W. Hart, T. F. Blackburn, J. Schwartz, J. Am. Chem. Soc. 1975, 97,
679 ± 680
[32] For selected impressive examples on the use of Stille coupling in
natural products synthesis see: a) M. B. Andrus, S. D. Lepore, J. Am.
Chem. Soc. 1997, 119, 2327 ± 2328; b) A. B. Smith III, G. R. Ott, J. Am.
Chem. Soc. 1996, 118, 13095 ± 13096; c) D. A. Evans, J. S. Johnson,
J. Org. Chem. 1997, 62, 786 ± 787; d) A. B. Smith III, S. S.-Y. Chen, F. C.
Nelson, J. M. Reichert, B. A. Salvatore, J. Am. Chem. Soc. 1997, 119,
10935 ± 10946; e) K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio,
N. Minowa, P. Bertinato, J. Am. Chem. Soc. 1993, 115, 4419 ± 4420;
f) K. C. Nicolaou, N. Winssinger, J. Pastor, F. Murphy, Angew. Chem.
1998, 110, 2677 ± 2680; Angew. Chem. Int. Ed. 1998, 37, 2534 ± 2537;
g) T. M Kamenecka, S. J. Danishefsky, Angew. Chem. 1998, 110,
3164 ± 3166; Angew. Chem. Int. Ed. 1998, 37, 2993 ± 2995; h) T. M.
Kamenecka, S. J. Danishefsky, Angew. Chem. 1998, 110, 3166 ± 3168;
Angew. Chem. Int. Ed. 1998, 37, 2995 ± 2998.
[33] D. A. Evans, J. R. Gage, J. L. Leighton, J. Am. Chem. Soc. 1992, 114,
9434 ± 9453.
[34] a) L. S. Liebeskind, R. W. Fengl, J. Org. Chem. 1990, 55, 5359 ± 5364;
b) V. Farina, S. Kapadia, B. Krishnan, C. Wang, L. S. Liebeskind, J.
Org. Chem. 1994, 59, 5905 ± 5911.
[15] a) C. H. Heathcock, S. D. Young, J. P. Hagen, M. C. Pirrung, C. T.
White, D. vanDerveer, J. Org. Chem. 1980, 45, 3846 ± 3856; b) H.
Nagano, M. Ohno, Y. Miyamae, Y. Kuno, Bull. Chem. Soc. Jpn. 1992,
65, 2814 ± 2820; c) H. Nagano, M. Ohno, Y. Miyamae, Chem. Lett.
1990, 463 ± 466; d) W. C. Still, J. H. McDonald, Tetrahedron Lett. 1980,
21, 1031 ± 1034; e) W. C. Still, J. A. Schneider, Tetrahedron Lett. 1980,
21, 1035 ± 1038; f) H. Iida, N. Yamazaki, C. Kibayashi, J. Org. Chem.
1986, 51, 3769 ± 3771.
[16] a) D. Enders, J. Tiebes, N. De Kimpe, M. Keppens, C. Stevens, G.
Smagghe, O. Betz, J. Org. Chem. 1993, 58, 4881 ± 4884; b) D. Enders,
W. Gatzweiler, U. Jegelka, Synthesis 1991, 1137 ± 1141; c) D. Enders,
Asymmetric Synthesis 1984, 3, 275 ± 339.
[35] a) E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, B. I. Spiegel,
J. Am. Chem. Soc. 1978, 100, 2254 ± 2256; b) D. E. Van Horn, E.
Negishi, J. Am. Chem. Soc. 1978, 100, 2252 ± 2254.
[36] For selected recent synthetic applications of Negishi coupling see:
a) B. H. Lipshutz, C. Lindsey, J. Am. Chem. Soc. 1997, 119, 4555 ±
4556; b) A. Palmgren, A. Thorarensen, J. E. Backvall, J. Org. Chem.
1998, 63, 3764 ± 3768; c) G. Boche, M. Klein, Synthesis 1999, 1246 ±
1250; d) M. Jorgensen, M. Larsen, J. Org. Chem. 1997, 62, 4171 ± 4173.
[37] a) J. S. Panek, T. Hu, J. Org. Chem. 1997, 62, 4912 ± 4913; b) J. S.
Panek, T. Hu, J. Org. Chem. 1997, 62, 4914 ± 4915; c) J. S. Panek, T. Hu,
J. Org. Chem. 1997, 64, 3000 ± 3001.
[38] For alternative, yet more tedious, approaches to this type of
conjugated dienes see: a) A. R. de Lera, A. Torrado, B. Inglesias, S.
Lopez, Tetrahedron Lett. 1992, 33, 6205 ± 6208; b) J. P. Genet, A.
Linquist, E. Blart, V. Mouries, M. Savignac, M. Vaultier, Tetrahedron
Lett. 1995, 36, 1443 ± 1446.
[17] H. C. Brown, P. K. Jadhav, B. Singram, Mod. Synth. Meth. 1986, 4,
307 ± 356.
[18] SAMP hydrazine was prepared according to the literature procedure:
D. Enders, P. Fey, H. Kipphard, Org. Synth. 1987, 65, 173 ± 182.
2000
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-2000 $ 17.50+.50/0
Chem. Eur. J. 2000, 6, No. 11

Reveromycin B
1987±2001
[39] For recent impressive demonstrations of the application of the Kishi ±
Nozaki coupling to natural products synthesis see: a) J. A. McCauley,
K. Nagasawa, P. A. Lander, S. G. Mischke, M. A. Semones, Y. Kishi, J.
Am. Chem. Soc. 1998, 120, 7647 ± 7648; b) X.-T. Chen, S. K. Bhatta-
charya, B. Zhou, C. E. Gutteridge, T. R. R. Pettus, S. J. Danishefsky, J.
Am. Chem. Soc. 1999, 121, 6563 ± 6579; c) M. M. Victor, R. A. Pilli,
Tetrahedron Lett. 1998, 39, 4421 ± 4424.
[40] A. L. Gemal, J.-L. Luche, J. Am. Chem. Soc. 1981, 103, 5454 ± 5459.
[41] a) P. Sieber, Helv. Chim. Acta 1977, 60, 2711 ± 2716; b) B. H. Lipshutz,
T. A. Miller, Tetrahedron Lett. 1989, 30, 7149 ± 7152.
(indicative of a [6,6]spiroketal ring), while the C15 center of 4
resonates at about d ˆ 109 (indicative of a [5,6]spiroketal ring).
[43] A second independent synthesis of reveromycin B (4) has been
recently reported: T. Masuda, K. Osako, T. Shimizu, T. Nakata, Org.
Lett. 1999, 1, 941 ± 944.
[44] Since the submission of this manuscript a third total synthesis of
reveromycin B (4) has been reported: A. N. Cuzzupe, C. A. Hutton,
M. J. Lilly, R. K. Mann, M. A. Rizzacasa, S. C. Zammit, Org. Lett.
2000, 2, 191 ± 194.
[42] Formation of
a putative [6,6]spiroketal ring was monitored by
13C NMR. The C15 spiroketal center of 1 resonates at about d ˆ 95
Received: November 15, 1999 [F2142]
Chem. Eur. J. 2000, 6, No. 11
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0947-6539/00/0611-2001 $ 17.50+.50/0
2001