A Synthesis of C(16),C(18)-Bis-epi-cytochalasin D via Reformatsky Cyclization

Article abstract of DOI:10.1021/jo000533q

Triene 5 has been prepared by the E-selective olefination of aldehyde 12 with the ylide 11. Several alternative syntheses of 12 were evaluated, and the successful route involved conversion of 22 into the vinyl ether 23 by Petasis olefination, followed by Claisen rearrangement. Diels-Alder cycloaddition of 5 with 4 gave the adduct 6 in 77% yield, and Reformatsky cyclization under dilution conditions afforded 10 (67%). After conversion to enol silane 32, oxidation with dimethyldioxirane produced 34. Conversion to a key intermediate 38 using electrophilic selenenylation and selenoxide rearrangement, followed by enolate alkylation and deprotection, gave 43. The X-ray crystal structure of 43 was determined to prove the stereochemistry.

Full text of DOI:10.1021/jo000533q

J . Org. Chem. 2000, 65, 6073-6081
6073
A Syn th esis of C(16),C(18)-Bis-epi-cytoch a la sin D via Refor m a tsk y
Cycliza tion
E. Vedejs*,† and S. M. Duncan
Chemistry Department, University of Wisconsin, Madison, Wisconsin 53706
edved@umich.edu
Received April 10, 2000
Triene 5 has been prepared by the E-selective olefination of aldehyde 12 with the ylide 11. Several
alternative syntheses of 12 were evaluated, and the successful route involved conversion of 22 into
the vinyl ether 23 by Petasis olefination, followed by Claisen rearrangement. Diels-Alder
cycloaddition of 5 with 4 gave the adduct 6 in 77% yield, and Reformatsky cyclization under dilution
conditions afforded 10 (67%). After conversion to enol silane 32, oxidation with dimethyldioxirane
produced 34. Conversion to a key intermediate 38 using electrophilic selenenylation and selenoxide
rearrangement, followed by enolate alkylation and deprotection, gave 43. The X-ray crystal structure
of 43 was determined to prove the stereochemistry.
Sch em e 1
The cytochalasins have attracted interest because of
their broad spectrum of biological effects,1 and several
total syntheses of macrocyclic lactone or carbocycle
members of this family have been completed.2-5 In
general, the synthetic approaches have relied on the
combination of two chiral, enantiomerically pure subunits
to solve the problem of remote stereocontrol. Cytochalasin
D (1) is representative of the carbocyclic series in this
regard (total synthesis: Thomas et al.),2 and it has been
among the most intensively studied of the cytochalasins
from the biological, as well as the synthetic perspectives.
Our own interest in this and related structures was based
in part on the possibility that remote stereocenters might
be introduced under the control of medium ring confor-
mational preferences such that only one of the subunits
would need to be chiral.6 The work outlined below details
this effort and describes a stereocontrolled synthesis of
C(16),C(18)-bis-epi-cytochalasin D using this strategy.
Prior efforts have devised ways to convert cyclohexene
intermediates of general structure 2 into the required
allylic alcohol 3. Disconnection of the chiral tetrahy-
droisoindolone subunit in 2 at C(4),C(5) and C(8),C(9)
then leads to a diene component and a chiral dienophile
for a well-precedented Diels-Alder synthesis.2-5 Further
disconnection at C(19),C(20) results in the pivotal struc-
† Current address: Department of Chemistry, University of Michi-
gan, Ann Arbor, MI 48109.
(1) Tannenbaum, S. W., Ed. Cytochalasins: Biochemical and Cell
Biological Aspects; North-Holland, Amsterdam, 1978. Kapadi, A. H.;
Dev, S. In Recent Advances in Cytochalasans; Pendse, G. S., Ed.;
Chapman-Hall: New York, 1986; Chapter 2.
(2) Merifield, E.; Thomas, E. J . J . Chem. Soc., Chem. Commun. 1990,
464. Thomas, E. J .; Watts, J . P. J . Chem. Soc., Chem. Commun. 1990,
467. Merifield, E.; Thomas, E. J . J . Chem. Soc., Perkin Trans. 1 1999,
3269.
(3) Stork, G.; Nakahara, Y.; Nakahara, Y.; Greenlee, W. J . J . Am.
Chem. Soc. 1978, 100, 7775. Stork, G.; Nakamura, E. J . Am. Chem.
Soc. 1983, 105, 5510.
(4) (a) Vedejs, E.; Reid, J . G.; Rodgers, J . D.; Wittenberger, S. J . J .
Am. Chem. Soc. 1990, 112, 4351. (b) Vedejs, E.; Wittenberger, S. J . J .
Am. Chem. Soc. 1990, 112, 4357.
(5) (a) Vedejs, E.; Gadwood, R. C. J . Org. Chem. 1978, 43, 376. (b)
Vedejs, E.; Campbell, J . B., J r.; Gadwood, R. C.; Rodgers, J . D.; Spear,
K. L.; Watanabe, Y. J . Org. Chem. 1982, 47, 1534.
(6) Vedejs, E.; Gapinski, D. M. J . Am. Chem. Soc. 1983, 105, 5058.
Vedejs, E.; Dent, W. H., III; Gapinski, D. M.; McClure, C. K. J . Am.
Chem. Soc. 1987, 109, 5437.
tures 4 and 5 as shown in Scheme 1. Structure 5
incorporates all but one of the carbons that is required
in the eventual target (missing the C(16) methyl group).
The C(18) methyl is present early in the synthesis and
is attached to an sp2-hybridized carbon. In principle, this
allows construction of the target using a single chiral
component 4 in the Diels-Alder step if stereocontrol at
C(16) and C(18) is possible later in the scheme by
10.1021/jo000533q CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/22/2000

6074 J . Org. Chem., Vol. 65, No. 19, 2000
Vedejs and Duncan
Sch em e 2
exploiting the conformational preferences of the 11-
membered ring.6,7 The Diels-Alder adduct 6 is preacti-
vated for Reformatsky cyclization, as in a model study
reported earlier where the simplified analogue 8 was
assembled from 7.8 Conversion of 6 to 9 and 10 would
afford a versatile ring environment having differentiated
functionality in place to selectively activate the C(16) and
C(18) positions. As already indicated, it was expected that
these sites would also be differentiated sterically because
of conformational preferences.
The enol ether functionality in 5 was chosen to
simultaneously mask the C(17) ketone and to place the
C(18) methyl group in an achiral environment. Logical
precursors of 5 were therefore identified as 11 and 12,
based on E-selective olefination chemistry,9 but a practi-
cal synthesis of the aldehyde 12 would prove to be one of
the most difficult obstacles in this project. The initial
approach to 12 assumed that 14 would be easy to convert
to the O-methylated derivative 15 in view of the extensive
literature on C- vs O-alkylation of stabilized enolates.10
No problems were encountered in the preparation of 14
by dianion alkylation of 13,11,12 but enolate methylation
of 14 under a variety of conditions afforded mixtures of
C- and O-alkylation products. This route was not pursued
further.13
In an alternative approach, 13 was treated with methyl
orthoformate/TsOH to give an enol ether 16. Conversion
of 16 to the dienolate with LDA followed by allylation
provided the C-allylation product 17 in excellent yield.
Thermal Cope rearrangement produced the isomer 18,
but oxidative cleavage to the desired aldehyde 12 did not
succeed despite much effort. In most attempts, the results
were too complex to interpret, but the ozonolysis of 18
with a deficiency of ozone gave ethyl pyruvate and methyl
4-pentenoate as well as unreacted starting material. The
products are derived from cleavage of the tetrasubsti-
tuted double bond. Evidently, the vinylogous carbonate
environment does not provide sufficient stabilization to
direct oxidants to the terminal double bond.
An alternative route was devised that would incorpo-
rate the terminal carbon of 12 at the correct aldehyde
oxidation state using Claisen rearrangement. A suitable
allyl vinyl ether might be obtained by vinylation of the
tertiary alcohol 20, a structure that corresponds to the
adduct of ethyl pyruvate and R-methoxyvinyllithium (19),
eq 1 (Scheme 2).14 The desired addition of 19 did take
place in THF at low temperature and the alcohol 20 was
obtained in 35% yield. Deprotonation of ethyl pyruvate
by 19 probably occurs as well, as evidenced by starting
material recovery, and by the formation of an enone
byproduct tentatively identified as 21 (5-10%). This
product probably is formed by the addition of 19 to the
enolate of ethyl pyruvate, as shown in eq 2 (Scheme 2).
Purification of 20 was initially hampered by similarities
in chromatographic properties and volatility compared
to 21. However, separation of 20 by chromatography was
accomplished easily if the crude reaction mixture was
first treated with NaBH4/EtOH to destroy 21.
The next step was to incorporate the vinyl ether
moiety. Attempts to perform vinyl exchange in this
system failed, so a two-step vinylation method was
explored on the basis of O-formylation followed by
olefination of the presumably more reactive formate
carbonyl group. When the alcohol 20 was deprotonated
with n-BuLi at 0 °C and treated with acetic formic
anhydride, the formate ester 22 was obtained in 60%
yield, but some of the acetate ester was also formed. The
selectivity problem was solved and the yield improved
by using the easily purified tert-butyl formic anhydride
in a similar reaction.15 Thus, 20 was reacted with n-BuLi
followed by tert-butyl formic anhydride at 0 °C to afford
22 in 80% yield. The subsequent olefination of 22 was
challenging, but good results were obtained with the
Petasis reagent (Cp2TiMe2)16 in refluxing THF to give the
vinyl ether 23 in 70% yield. The Claisen rearrangement
(7) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.
(8) (a) Vedejs, E.; Ahmad, S. Tetrahedron Lett. 1988, 29, 2291. (b)
Maruoka, K.; Hashimoto, S.; Kitagawa, Y.; Yamamoto, H.; Nozaki, H.
J . Am. Chem. Soc. 1977, 99, 7705.
(9) Vedejs, E.; Huang, W. F. J . Org. Chem. 1984, 49, 210.
(10) (a) Kurts, A. L.; Macias, A.; Beletskaya, I. P.; Reutov, O. A.
Tetrahedron 1971, 27, 4759-67. (b) Kurts, A. L.; Dem’yanov, P. I.;
Macias, A.; Beletskaya, I. P.; Reutov, O. A. Tetrahedron 1971, 27, 4769.
(c) Kurts, A. L.; Genkina, N. K.; Macias, A.; Beletskaya, I. P.; Reutov,
O. A. Tetrahedron 1971, 27, 4777.
(11) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082. (b)
Wolfe, J . F.; Harris, T. M.; Hauser, C. R. J . Org. Chem. 1964, 29, 3249.
(12) The alkylating agent was made in two steps from 2-chloroeth-
anol (80% yield) according to Moody’s procedure: Heslin, J . C.; Moody,
C. J . J . Chem. Soc., Perkin Trans. 1 1988, 1417.
(13) An O-silylated analogue of 15 could be prepared, but it proved
unsuitable for the intended synthesis because the corresponding
derivative of 5 (replace methoxy by tert-butyldimethylsiloxy) undergoes
facile silatropic rearrangement to an isomeric ketone enol silane under
a variety of conditions, including exposure to silica gel.
(14) (a) Soderquist, J . A.; Hsu, G. J . H. Organometallics 1982, 1,
830. (b) Baldwin, J . E.; Hoefle, G. A.; Lever, O. W., J r. J . Am. Chem.
Soc. 1974, 96, 7125.
(15) Vlietstra, E. J .; Zwikker, J . W.; Nolte, R. J . M.; Drenth, W.
Recl.: J . R. Neth. Chem. Soc. 1982, 101, 460.

Synthesis of C(16),C(18)-Bis-epi-cytochalasin D
J . Org. Chem., Vol. 65, No. 19, 2000 6075
pholine N-oxide (TPAP/NMO)17 and 4A molecular sieves
afforded the aldehyde 5 in 70% yield. Like its precursors,
5 was also sensitive to chromatography and storage.
Reaction of an excess of 5 with the N-acylpyrrolinone
dienophile 4 (generated in situ from selenide 28 and
m-CPBA)4 afforded the Diels-Alder adduct 6 in 77%
yield. The stereochemical assignment for the main prod-
uct 6 was guided by precedent from earlier work in the
cytochalasin series,4,5 and the detailed structure was
eventually confirmed by X-ray crystallography after
cyclization to the 11-membered ring. Regioisomeric Di-
els-Alder adducts were not detected, but an isomer 29
(resulting from the alternative exo transition state with
respect to the dienophile) crystallized from more polar
chromatography fractions, and the structure was solved
by X-ray crystallography.18 The strong regiochemical
preference in the Diels-Alder process is a consequence
of the directing effect of a trimethylsilylmethyl substitu-
ent in the triene environment according to prior work in
our laboratory.5
Sch em e 3
As reported in a model study, intramolecular Refor-
matsky reaction can be used for the macrocyclization of
chloromethyl ketones containing an aldehyde at C(19)
(cytochalasin numbering).8a The Diels-Alder adduct 6
has a similar substitution pattern compared to the model,
but the aldehyde is a vinylogous formate ester. This
difference did not cause complications, and the cyclization
could be carried out effectively by following a variation
of the original procedure. Best results were obtained with
activated Rieke zinc19a prepared by the reduction of ZnCl2
in THF with sodium naphthalide at room temperature,19b
and slow addition of a dilute solution of 6 over 5-6 h
(300 mg scale) to the suspension of finely divided zinc
metal at 0 °C. The initially formed cyclization product 9
proved to be unstable to acid and afforded the elimination
product 10 (structure proof by X-ray crystallography: see
Supporting Information). Traces of DCl in CDCl3 were
initially responsible for this elimination, but the more
reliable procedure was to stir the crude reaction mixture
with 10% H2SO4 and ether for several hours. The reaction
also gave a second product tentatively identified as 30b
based on a signal at δ 15.19 ppm for the enolic proton,
and the absence of methoxy and aldehyde signals. This
substance is derived from protonation of the zinc enolate
to give 30a followed by enol ether hydrolysis. Isolation
of 30a was possible from an experiment where the H2-
SO4 step was omitted. Due to the heterogeneous nature
of the Reformatsky cyclization, the yield of 10 was
variable and somewhat dependent on the scale. Reactions
performed with 200-300 mg of starting material 6
appeared to be in the optimum range and could be
controlled to produce 10 in 60-67% yield.
of 23 could be effected by refluxing in THF overnight or
by heating several hours in refluxing toluene. The mod-
erately stable aldehyde 12 was obtained in 77% yield,
provided that 23 had been purified prior to the thermal
rearrangement step to remove titanium contaminants.
With the elusive aldehyde 12 finally in hand, conver-
sion to the conjugated triene 5 could be performed using
a Wittig reaction and a reduction/oxidation sequence. The
Wittig reaction with the E-selective ylide 11 was carried
out as previously reported for a simpler aldehyde,8a and
the ester 25 (Scheme 3) was obtained in 83% yield as an
inseparable mixture of E/Z isomers (ca. 87:13) at the
C(8),C(9) and C(10),C(11) double bonds. Ester 25 was
sensitive to extended storage or to prolonged exposure
to silica gel and was used promptly in the next step to
prepare the triene aldehyde 5. This involved the reduc-
tion of 25 with DIBAL/CH2Cl2/-78 °C and reoxidation
of 26, but the reaction required careful control due to the
risk of conversion of 26 to an enone 27. Treatment of 26
with tetrapropylammonium perruthenate/N-methylmor-
It was now necessary to differentiate the two ketone
carbonyl groups in the 11-membered ring. Treatment of
10 with lithium hexamethyldisilazide gave a dienolate
that reacted with TBSOTf to form a single product 31.
The yield of this reaction was very sensitive to any excess
of the silyl triflate, so the experiment was performed as
a titration, with the silyl triflate added dropwise until
the yellow color of the enolate had disappeared. The
(17) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(18) The NMR signals of 29 slowly appeared if purified 6 was heated
to 85 °C for several hours.
(16) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392-
(19) (a) Rieke, R. D. Acc. Chem. Res. 1977, 10, 301. (b) Arnold, R.
T.; Kulenovic, S. T. Synth. Commun. 1977, 7, 223.
4.

6076 J . Org. Chem., Vol. 65, No. 19, 2000
Vedejs and Duncan
Sch em e 4
sideproduct was difficult on preparative scale, and could
only be done after conversion to the acetate 32. The low
overall yield (44%) reflects the separation problem, but
there are other complications, apparently due to compet-
ing cleavage of the N-benzoyl group according to NMR
integration. This would result in the lactam 33, but the
C(19),C(20) dihydro derivative of 33 would presumably
form as well, and the polar fractions could not be
separated or fully characterized. The 1,4-reduction could
be avoided using NaBH4/CeCl3‚7H2O in ethanol at room
temperature, but these conditions gave extensive cleav-
age of the N-benzoyl group.
We had expected that the conversion to 32 would
closely resemble a similar enone reduction in the cy-
tochalasin D synthesis of Thomas et al. and that the
stereochemistry of the major product could be safely
assigned by analogy.2 In view of the selectivity and yield
problems in the case of 32, and of several structural
differences compared to the Thomas enone,2 the possibil-
ity remained that the C(21) configuration may not be
correct. However, it was clear that a single diastereomer
had been isolated after chromatography, and that the
NMR characteristics of 32 were consistent with those
reported by Thomas et al. for a related allylic acetate.
The stereochemistry shown for 32 was therefore assumed
and was eventually confirmed.
The next step desired in the synthesis is the incorpora-
tion of the C(18) hydroxyl by oxidation of the silyl enol
ether to the ketol 35 (Scheme 4). Osmylation is one
attractive option for this conversion,20 but several at-
tempts failed to produce either diastereomer (34 or 35)
cleanly. Oxidation with m-CPBA was more promising.21
The procedure afforded diastereomer mixtures in pre-
liminary experiments using dichloromethane or chloro-
form as the solvent and the product ratio was in the
range of 1:3-4 when the reaction was performed in the
presence of sodium carbonate. A similar experiment was
then carried out using a solution of dimethyldioxirane
22,23
in acetone/chloroform. The optimum procedure was
to treat the enol silane 32 in CHCl3 at -78 °C with
dimethyldioxirane/acetone solution and to allow the
reaction mixture to warm to room temperature before
quenching with dimethyl sulfide to destroy excess oxi-
dant. The crude product was then treated with acetic acid
in aqueous THF to ensure conversion of the intermediate
epoxide to ketols. This provided a single isomeric ketol
(>20:1 diastereomer ratio) in 57% yield, corresponding
to the minor product of the m-CPBA oxidation.
According to the NMR spectrum, the dimethyldioxirane
product could be either the desired structure 35, or the
C(18) diastereomer 34. Some evidence bearing on the
issue was available from NOE studies,24 but the inter-
pretation was uncertain because of the conformational
mobility of the 11-membered ring, and because of the
uncertainty regarding the configuration at C(21). A
decision was therefore made to proceed with the single
isomer obtained from the relatively clean dimethyldiox-
irane oxidation in the hope that a crystalline intermedi-
ate would be encountered in subsequent steps that could
presence of a new E-disubstituted double bond in 31 was
deduced from the NMR spectrum, so the silylation must
have occurred at the C(17) enolate oxygen. Direct evi-
dence for the geometry of the resulting enol ether at
C(17),C(18) was not obtained, but the isomeric enol silane
(not shown) would have an E-double bond with respect
to the 11-membered ring to make a total of three
E-double bonds as well as a trans-ring fusion. Based on
ring strain considerations, the product shown (31) is the
more likely isomer.
With the C(21) and C(17) carbonyls differentiated, the
next step was the reduction of the C(21) carbonyl group
in ketone 31 (Scheme 4). The reduction was carried out
with NaBH4 in ethanol at 0 °C, and the expected changes
in the NMR spectrum were observed. However, the NMR
integrals for the olefinic region of the main product
fraction could not be fully reconciled with the expected
structure, and it became clear that the material was
contaminated with an alcohol derived from a competing
1,4-reduction of the starting enone. Separation of the
(20) McCormick, J . P.; Tomasik, Witold; J ohnson, Mark W. Tetra-
hedron Lett. 1981, 22, 607.
(21) Rubottom, G. M.; Marrero, R. J . Org. Chem. 1975, 40, 3783;
Rubottom, G. M.; Gruber, J . M. J . Org. Chem. 1978, 43, 1599.
(22) Adam, W.; Mu¨ller, M.; Prechtl, F. J . Org. Chem. 1994, 59, 2358.
(23) Adam, W.; Chan, Y.-Y.; Cremer, D.; Gauss, J .; Scheutzow, D.;
Schindler, M. J . Org. Chem. 1987, 52, 2800.

Synthesis of C(16),C(18)-Bis-epi-cytochalasin D
J . Org. Chem., Vol. 65, No. 19, 2000 6077
be used to establish the configuration at C(21) as well
as at C(18). In the event, suitable crystals were not
encountered until the last step in the intended synthesis
(structure 43). According to the X-ray structure of 43,
the dimethyldioxirane product is 34, the isomer that
would correspond to a C(18)-epi-cytochalasin D. The
X-ray evidence also confirmed that the correct C(21)
configuration had been formed in the troublesome boro-
hydride reduction, but neither the C(21) nor the C(18)
assignments were clear when our limited material had
to be committed to a sequence of seven additional
synthetic steps.
The precedented conversion from 34 to 38 was per-
formed with minimal purification of intermediates prior
to the last step so that the challenging enolate alkylation
of 38 could be evaluated. Excess LDA conditions did
produce enolates from 38, and treatment with iodometh-
ane gave a complex mixture of products. New methyl
doublets were seen in the NMR spectrum, but the C(21)
acetate methyl signal was greatly diminished, suggesting
that the enolization may have occurred at C(21) as well
as at the C(16) position adjacent to ketone carbonyl.
Support for competing C(21)-acetate enolization and
methylation was found in the NMR spectrum of the crude
product in the form of C-ethyl quartets near 3 ppm,
consistent with the presence of C(21) propionate esters
such as 40. Acetate enolization could not be avoided at
partial conversion, and other bases were not helpful. No
single isomer corresponding to the desired structure 39
could be isolated. Therefore, the mixture of alkylation
products was treated with methanolic potassium carbon-
ate to cleave the N-benzoyl blocking group as well as to
remove the undesired C(21)-propionate. This gave the
lactam alcohol 41 as a mixture of isomers that could not
be separated efficiently. The material was taken through
the last two steps (re-acylation at C(21); silyl protecting
group cleavage with HF/acetonitrile) that would lead to
the cytochalasin D substitution pattern. Chromato-
graphic purification then afforded a fraction consisting
of a 5:1 ratio of two substances that closely resembled
cytochalasin D (1) in TLC behavior, but neither was
identical to the natural product. When the route was
repeated with the remainder of material, the combined
final product fractions were successfully separated (10-
15% overall from 38). The major isomer crystallized from
acetone and was shown by X-ray crystallography to have
the structure 43, corresponding to C(16),C(18)-bis-epi-
cytochalasin D. By inference, the minor isomer is prob-
ably the epimeric alkylation product 44, but this sub-
stance was not obtained in sufficient quantity or purity
for characterization.
F igu r e 1. Dimethyldioxirane oxidation of 32.
of 32 have been resolved by the X-ray structure of 43.
The stereochemistry of the borohydride reduction is the
same as in the cytochalasin D synthesis of Thomas et
al., as had been expected.2 However, further work will
be needed to reach the goal of control over stereochem-
istry in the 11-membered ring at C(16) and C(18). The
C(18) configuration resulting from the dimethyldioxirane
oxidation of 32 is shown to be epimeric compared to that
of cytochalasin D. A plausible geometry for the preferred
pathway can be proposed as shown in Figure 1, with
bonding from above to set the new C-O bonds. This
would produce a labile epoxide 45 that is converted into
34 by treatment with acid. If the C(18) stereocenter
controls the final enolate alkylation at C(16), then it may
be possible to achieve the desired configuration at C(16)
in the enolate alkylation step using a precursor that has
the correct C(18) stereochemistry. Experiments designed
to test this proposition are under way and will be
reported in a later publication.
Exp er im en ta l Section
Gen er a l Meth od s. Dry solvents were obtained as follows:
Et2O and THF were distilled from sodium-benzophenone
ketyl; CH2Cl2 was distilled from P2O5; CH3CN was distilled
from P2O5, redistilled from K2CO3, and stored over 4 Å
molecular sieves; benzene was distilled from sodium-ben-
zophenone ketyl and stored over 4 Å molecular sieves. Methyl
triflate and tert-butyldimethylsilyl triflate were distilled and
stored under N2 and kept in the dark at -10 °C.
Eth yl 2-Meth yl-6-ter t-bu tyld im eth ylsiloxy-3-oxoh ex-
a n oa te 14. Under an inert atmosphere, a THF (90 mL)
solution of ethyl acetopropionate (Aldrich, 15 mL, 100 mmol)
was added dropwise to a suspension of NaH (Aldrich, 60%,
137 mmol) in THF (180 mL) at 0 °C. After being stirred for 30
min at 0 °C, the reaction was treated with n-BuLi (1.64 M in
hexanes, 68 mL, 111 mmol) and stirred for an additional 30
min. The dianion was treated with a THF (40 mL) solution of
2-tert-butyldimethylsiloxyethyl iodide (37 g, 129 mmol). After
the reaction was warmed to room temperature and stirred for
1 h, it was quenched with NH4Cl and extracted with ether.
The organic layer was treated with brine and MgSO4. After
removal of solvent (aspirator), the residue was purified by flash
chromatography on silica gel (15 × 5 cm), 1:9 ether/hexane
eluent (21.15 g, 70%): analytical TLC on silica gel, 1:4 ether/
hexane, Rf ) 0.39; HRMS for C15H30O4Si M + 1 303.1986,
error ) 0 ppm, base peak ) 171 amu; IR (CDCl3, cm-1) 1745,
1720, 1270; 300 MHz NMR (CDCl3, ppm) δ 4.15 (2H, q, J )
7.0 Hz), 3.57 (2H, t, J ) 6.2 Hz), 3.49 (1H, q, J ) 7.4 Hz),
2.7-2.5 (2H, m), 1.80-1.72 (2H, m), 1.3 (3H, d, J ) 7.4 Hz),
1.23 (3H, t, J ) 7.0 Hz), 0.85 (9H, s), 0.0 (6H, s).
Su m m a r y
The synthetic work described above has established an
effective Diels-Alder/Reformatsky cyclization strategy
for the synthesis of the key intermediate 10. Uncertain-
ties regarding the configuration of products obtained by
the reduction of 31 and the dimethyldioxirane oxidation
(24) Irradiation of the C(18) methyl group in 34 gave a strong NOE
enhancement of the C(20) vinylic hydrogen, while the corresponding
experiment with a sample enriched in 35 resulted in the enhancement
of the C(19) hydrogen signal. This evidence is consistent with an
extended conformation of the 11-membered ring where the C(18)
methyl is pseudoaxial in 34, but pseudoequatorial in 35, and could
have been interpreted to make the correct assignment of C(18)
configuration.

6078 J . Org. Chem., Vol. 65, No. 19, 2000
Vedejs and Duncan
C/O Alk yla tion of 14. Under an inert atmosphere, a
suspension of KH (Aldrich, 25% oil suspension washed twice
with ether, 118 mg, 0.73 mmol) in HMPA (1.0 mL) at room
temperature was stirred 45 min with the ketoester 14 (148
mg, 0.49 mmol) in HMPA (1.5 mL). The reaction mixture was
treated with MeOTf (Aldrich, 0.1 mL, 0.88 mmol) and stirred
for 30 min. The reaction was quenched with water (5 mL) and
diluted with ether. The organic layer was washed with brine
and treated with MgSO4. After removal of solvent (aspirator),
the residue was purified by flash chromatography on silica gel
(15 × 1.5 cm), 1:9 ether/hexane eluent, to afford the O-
alkylated isomer 15 (31 mg, 20%): analytical TLC on silica
gel, 3:1:1 hexane/ether/dichloromethane, Rf ) 0.64; molecular
ion calcd for C16H32O4Si 316.20691, found m/e ) 316.2080,
error ) 3 ppm, base peak ) 259 amu; IR (CCl4, cm-1) 1735,
1697, 1280; 300 MHz NMR (CDCl3, ppm) δ 4.13 (2H, q, J )
7.0 Hz), 3.71 (3H, s), 3.66 (2H, t, J ) 5.4 Hz), 2.82 (2H, dd,
J ) 7.7, 10.9 Hz), 1.78 (3H, s), 1.78-1.69 (2H, m), 1.27 (3H, t,
J ) 7.0 Hz), 0.88 (9H, s), 0.04 (6H, s); followed very closely by
the C-alkylated isomer, ethyl 2,2-dimethyl-6-tert-butyldimeth-
ylsiloxy-3-oxohexanoate (30 mg, 20%); analytical TLC on silica
gel, 3:1:1 hexane/ether/dichloromethane, Rf ) 0.62; HRMS
with Et2O, and the organic layer was dried with MgSO4. After
removal of solvent and ethyl pyruvate (aspirator), the residue
was purified in two batches by flash chromatography on silica
gel (20 × 5 cm), 1:4 EtOAc/hexane eluent, 20 mL fractions.
The fractions were analyzed by TLC (1:4 EtOAc/hexane, I2
detection). The nonpolar byproducts resulting from the de-
composition of the cross-condensation products eluted first
(Rf ) 0.5, 1:4 EtOAc/hexane) and were discarded. Fractions
containing the product (Rf ) 0.29) eluted next and were
combined. The fractions following the product (Rf ) 0.2-0.1)
contained minor products and were discarded. The solvent was
removed (aspirator) from the combined fractions to give 20 (10
g, 35%) as a colorless oil: analytical TLC on silica gel, 1:4
EtOAc/hexane, Rf ) 0.29; molecular ion calcd for C8H14O4
174.08914, found m/e ) 174.0888, error ) 2 ppm, base
peak ) 101 amu; IR (CDCl3, cm-1) 1733, 3547, 1249; 200 MHz
NMR (CDCl3, ppm) δ 4.39 (1H, d, J ) 3.0 Hz) 4.24 (2H, q, J )
7.1 Hz) 4.12 (1H, d, J ) 3.0 Hz) 3.57 (3H, s) 3.53 (1H, s) 1.56
(3H, s) 1.27 (3H, t, J ) 7.1 Hz).
F or m a te Ester 22. Under a nitrogen atmosphere, a THF
(90 mL) solution of the alcohol 20 (11.5 g, 66 mmol) at -78 °C
was treated with n-BuLi (Aldrich, 1.51 M, 47 mL, 71 mmol)
dropwise over a 25 min period. The resulting yellow solution
was stirred at -78 °C for 30 min, warmed to 0 °C, and stirred
for an additional 30 min. The tert-butyl formic anhydride15
(11.2 mL, 86 mmol) was added dropwise over a 15 min period.
The solution was stirred for 45 min at 0 °C, warmed to room
temperature, and stirred for an additional 4.5 h. The reaction
was quenched with water and diluted with ether. The organic
layer was washed with water and brine. The aqueous layers
were combined and washed with ether, and the ethereal layers
were combined and dried (MgSO4). After removal of solvent
(N2 stream), the residue was purified by flash chromatography
on silica gel (5 × 16 cm), 6:1:1 hexane/ether/dichloromethane
(300 mL), 5:1:1 hexane/ether/dichloromethane (250 mL), 4:1:1
hexane/ether/dichloromethane (300 mL) eluent, 20 mL frac-
tions. The fractions were analyzed by TLC (1:4 EtOAc/hexane,
I2 detection). The initial fractions contained the product
resulting from the addition of BuLi to the ester (Rf ) 0.5, 1:4
EtOAc/hexane) followed by the tert-butyl ester product (Rf )
0.45) derived from pivaloyl transfer and were discarded. The
fractions immediately following these contain the product
(Rf ) 0.4) and were combined. The fractions that eluted after
the product contained the starting alcohol 20 (Rf ) 0.29) and
a minor product that was not characterized. The solvent was
removed (aspirator) from the combined fractions to give 22
(10.7 g, 80%) as a colorless oil: analytical TLC on silica gel,
1:4 EtOAc/hexane, Rf ) 0.4; molecular ion calcd for C9H14O5
202.08404, found m/e ) 202.0850, error ) 5 ppm, base
peak ) 101 amu; IR (CDCl3, cm-1) 1737, 1756, 1631; 300 MHz
NMR (CDCl3, ppm) δ 8.06 (1H, s), 4.52 (1H, d, J ) 3.3 Hz),
4.25 (1H, q, J ) 7.2 Hz), 4.24 (1H, q, J ) 7.2 Hz), 4.21 (1H, d,
J ) 3.3 Hz), 3.60 (3H, s), 1.80 (3H, s), 1.27 (3H, t, J ) 7.2 Hz).
Allyl Vin yl Eth er 23. A THF solution of dimethylti-
tanocene16 (0.5 M, 3 mL) was added to the neat formate 22
(205 mg, 1.01 mmol) and heated under a nitrogen atmosphere
at 70 °C for 25 h. The dark red solution was filtered through
Celite (5 × 1.5 cm) with hexane as eluent. The solution was
concentrated and the filtration performed again. After removal
of solvent (aspirator), the residue was purified by plug filtra-
tion chromatography on silica gel (10 × 1.5 cm), 8:92 EtOAc/
hex eluent, 5 mL fractions. The fractions were analyzed by
TLC (1:4 EtOAc/hexane, I2 detection). The fractions corre-
sponding to the top spot on the TLC plate contained titanium
byproducts (Rf ) 0.6, 1:4 EtOAc/hexane) that are yellow and
were discarded. These fractions were followed closely by
fractions containing the product 23 (Rf ) 0.5), and those were
combined. The fractions directly after the product contained
the formate 22 (Rf ) 0.4) and those were followed by fractions
containing the impure alcohol 20 (Rf ) 0.29). The solvent was
removed (aspirator) from the combined fractions to provide 23
(140 mg, 70%): analytical TLC on silica gel, 1:4 EtOAc/hexane,
Rf ) 0.5; molecular ion calcd for C10H16O4 200.10470, found
m/e ) 200.1041, error ) 4 ppm, base peak ) 129 amu; IR
(CDCl3, cm-1) 1742, 1637, 1253; 200 MHz NMR (CDCl3, ppm)
δ 6.35 (1H, dd, J ) 13.6, 6.4 Hz), 4.59 (1H, dd, J ) 13.6, 1.3
C
16H32O4Si, M - 57, 259.1374, error ) 3 ppm, base peak )
185 amu; IR (CCl4, cm-1) 1739, 1716, 1257; 300 MHz NMR
(CDCl3, ppm) δ 4.15 (2H, q, J ) 7.0 Hz), 3.57 (2H, t, J ) 6.2
Hz), 2.52 (2H, t, J ) 7.0 Hz), 1.75 (2H, p, J ) 7.0 Hz), 1.33
(6H, s), 1.23 (3H, t, J ) 7.0 Hz), 0.86 (9H, s), 0.0 (6H, s).
Allyla tion of 16 to 17. Under an inert atmosphere, an LDA
solution in THF (1.0 M, 7.2 mL, 7.2 mmol) at -78 °C was
treated with 16 (1.1 g, 6.95 mmol) in THF (10 mL). After the
solution was stirred for 45 min at -78 °C, the anion was
treated with allyl bromide (0.8 mL, 9.25 mmol), allowed to
warm to room temperature, and stirred for 3 h. The reaction
was quenched with water and diluted with ether. The organic
layer was washed with brine and treated with MgSO4. After
solvent removal (aspirator), distillation of the product gave a
clear liquid: bp 60-63 °C, 1 mm, Vigreux column (1.31 g, 96%);
analytical TLC on silica gel, 1:4 EtOAc/hexane, Rf ) 0.50;
molecular ion calcd for C11H18O3 198.12555, found m/e )
198.1260, error ) 2 ppm, base peak ) 125 amu; IR (CCl4, cm-1
)
1738, 1650, 1246; 300 MHz NMR (CDCl3, ppm) δ 5.74-5.6 (1H,
m), 5.1-5.05 (1H, m), 5.04-5.02 (1H, m), 4.14 (1H, q, J ) 6.0
Hz), 4.15 (1H, q, J ) 6.0 Hz), 4.06 (2H, s), 3.53 (3H, s), 2.60-
2.45 (2H, m), 1.23 (3H, t, J ) 6.0 Hz), 1.29 (3H, s).
Cop e Rea r r a n gem en t to 18. In a sealed tube under
vacuum 17 (460 mg, 2.3 mmol) was heated at 210 °C for 34 h.
The reaction was subjected to flash chromatography (SiO2,
15 × 2 cm) 1:19 ether/hexane eluent (240 mg, 52%): analytical
TLC on silica gel, 3:1:1 hexane/ether/dichloromethane, Rf )
0.6; molecular ion calcd for C11H18O3 198.12555, found m/e )
198.1251, error ) 2 ppm, base peak ) 129 amu; IR (CCl4, cm-1
)
1735, 1720, 1620; 300 MHz NMR (CDCl3, ppm) δ 5.87 (0.95H,
ddt, J ) 16.8, 10.0, 6.6 Hz), 5.75-5.58 (0.05H, m), 5.11-5.04
(1H, m), 5.00 (1H, dd, J ) 10.0, 1.5 Hz), 4.16 (2H, q, J ) 7.2
Hz), 3.7 (2.85H, s), 3.53 (0.15H, s), 2.86 (1.9H, br t, J ) 7.8
Hz), 2.53 (0.1H, t, J ) 6.6 Hz), 2.37-2.23 (2H, m), 1.81 (3H,
s), 1.23 (0.15H, t, J ) 6.9 Hz), 1.28 (2.85H, t, J ) 7.2 Hz).
Eth yl 3-Meth oxy-2-m eth yl-2-h yd r oxybu t-3-en oa te (20).
The procedure of Soderquist14a was used as follows. Under a
nitrogen atmosphere, a THF (90 mL) solution of methyl vinyl
ether (Aldrich, 11 g, 190 mmol) at -78 °C was treated with
t-BuLi (Aldrich, 1.7 M, 110 mL, 187 mmol). The solution was
warmed to 0 °C over a 15 min period. The R-methoxyvinyl-
lithium (19) was cooled to -78 °C and added dropwise over a
90 min period via a cold cannula to a THF (90 mL) solution of
ethyl pyruvate (Aldrich, 18 mL, 164 mmol) at -78 °C. After
being stirred for 20 min at -78 °C, the dark red solution was
quenched with NH4Cl (satd, 50 mL). The reaction mixture was
poured into ether and water, and the organic layer was washed
with water and brine. After the aqueous layers were washed
with ether, the combined ether layers were treated with
MgSO4. After solvent removal, the crude oil was diluted with
EtOH (95%, 50 mL) and treated at room temperature with
NaBH4 (Aldrich, 400 mg, 10 mmol) to destroy 21. The reaction
was quenched after 20 min with water (5 mL) and extracted

Synthesis of C(16),C(18)-Bis-epi-cytochalasin D
J . Org. Chem., Vol. 65, No. 19, 2000 6079
Hz), 4.44 (1H, d, J ) 3.3 Hz), 4.26 (1H, d, J ) 3.3 Hz), 4.24
(2H, q, J ) 7.2 Hz), 4.14 (1H, dd, J ) 6.4, 1.3 Hz), 3.58 (3H,
s), 1.62 (3H, s), 1.28 (3H, t, J ) 7.2 Hz).
hexane, Rf ) 0.57; molecular ion calcd for C20H34O3Si 350.22769,
found m/e ) 350.2261, error ) 4 ppm; IR (CDCl3, cm-1) 1690,
1617, 1285; 300 MHz NMR (CDCl3, ppm) δ 6.55 (0.12H, d,
J ) 15.3 Hz), 6.28-5.97 (2.88H, m), 5.71 (1H, dt, J ) 15.3,
6.9 Hz), 5.47 (0.88H, q, J ) 6.9 Hz), 5.26 (0.12H, q, J ) 6.9
Hz), 4.18 (2H, q, J ) 6.9 Hz), 3.72 (3H, s), 2.91-2.85 (2H, m),
2.37-2.30 (2H, m), 1.83 (3H, s), 1.78-1.65 (5H, m), 1.30 (3H,
t, J ) 6.9), 0.03 (9H, s).
Cla isen Rea r r a n gem en t of 23 to 12. A toluene (40 mL)
solution of the allyl vinyl ether 23 (3.9 g, 19.5 mmol) was
refluxed for 2 h. After solvent removal (aspirator), the residue
was purified by flash chromatography on silica gel (10 × 3
cm), 1:4 EtOAc/hexane eluent, 15 mL fractions. Due to the
instability of the aldehyde toward silica gel the flow rate for
the chromatography was increased with gentle air pressure
to minimize the contact time. The fractions were analyzed by
TLC (1:4 EtOAc/hexane, UV detection). The fractions contain-
ing the desired (UV active) material eluted first and were
combined. The decomposition products corresponding to the
baseline material were never removed from the column. The
solvent was removed (aspirator) from the combined fractions
to give 12 (3 g, 77%) as a colorless oil: analytical TLC on silica
gel, 1:4 EtOAc/hexane, Rf ) 0.2; molecular ion calcd for
C10H16O4 200.10470, found m/e ) 200.1048, error ) 0 ppm,
base peak ) 125 amu; IR (CCl4, cm-1) 1699, 1728, 1622; 300
MHz NMR (CDCl3, ppm) δ 9.82 (1H, s), 4.15 (2H, q, J ) 7.0
Hz), 3.67 (3H, s), 3.06 (2H, t, J ) 7.9 Hz), 2.69 (2H, t, J ) 7.9
Hz), 1.81 (3H, s), 1.27 (3H, t, J ) 7.0 Hz).
Con ver sion of Ester 25 to Ald eh yd e 5. Under a nitrogen
atmosphere, DIBAL (Aldrich, 1.0 M, 25 mL) was slowly added
via cannula over a 30 min period to a CH2Cl2 solution (50 mL)
of the ester 25 (4.1 g, 11.3 mmol) at -78 °C. After the reaction
was stirred for 30 min at -78 °C, Na2SO4‚10 H2O (40 g) was
added portionwise to destroy the excess DIBAL, and the
mixture was stirred for 2 h as it warmed to room temperature.
The reaction mixture was filtered through Celite (5 × 4 cm)
and the solvent removed (aspirator). The crude oil was diluted
in dry CH3CN (30 mL), cooled to 0 °C, and treated with
4-methylmorpholine N-oxide (Aldrich, 2 g, 17 mmol), 4 Å
molecular sieves (6 g), and tetrapropylammonium perruthen-
ate(VII) (Aldrich, 0.2 g, 0.56 mmol). The reaction was warmed
to room temperature and stirred until consumption of starting
material was complete by TLC (1:4, EtOAc/hexane), ap-
proximately 30 min. The reaction was filtered, the solvent
removed (aspirator), and the residue was purified by flash
chromatography on silica gel (15 × 4 cm), 1:4 EtOAc/hexane
eluent, 15 mL fractions. Due to its instability toward silica
gel the air flow rate for the chromatography was increased to
minimize the contact time of the aldehyde with the silica. The
fractions were analyzed by TLC (1:4 EtOAc/hexane, UV
detection). The elimination product 27 (top spot) eluted first
(Rf ) 0.57, 1:4 EtOAc/hexane) and these fractions were
discarded. The fractions containing the product (Rf ) 0.19)
followed and were combined. The solvent was removed (aspi-
rator) from the combined fractions to give 5 (2.5 g, 70%) as an
inseparable mixture of E/Z isomers, with a 87:13 ratio at both
the C(8),C(9) and C(10),C(11) double bonds: analytical TLC
on silica gel, 1:4 EtOAc/hexane, Rf ) 0.19; molecular ion calcd
for C18H30O2Si 306.20148, found m/e ) 306.2002, error ) 4
ppm; IR (CCl4, cm-1) 1641, 1615,1248; 300 MHz NMR (CDCl3,
ppm) δ 9.84 (1H, s), 6.53 (0.13H, d, J ) 17.4 Hz), 6.15-5.91
(2.87H, m), 5.7-5.3 (1H, m), 5.45 (0.87H, q, J ) 7.1 Hz), 5.24
(0.13H, q, J ) 7.1 Hz), 3.82 (3H, s), 2.82-2.77 (2H, m), 2.37-
2.29 (2H, m), 1.74-1.57 (8H, m), -0.02 (9H, s).
Diels-Ald er Ad d u ct 6. A CH2Cl2 solution (10 mL) of the
selenide 284 (335 mg, 0.65 mmol) at -78 °C was treated with
a CH2Cl2 solution (5 mL) of m-CPBA (Aldrich 50-60%, 290
mg, 0.84 mmol). The reaction was stirred for 10 min at -78
°C, warmed to 0 °C by placing the reaction in an ice bath,
stirred for 5 min, and then quenched with Me2S (0.5 mL). The
reaction should be worked up quickly due to the hydrolytic
sensitivity of the R,â-unsaturated imide. The reaction was
diluted with CH2Cl2, washed with Na2CO3, brine, and treated
with MgSO4. The organic layer was filtered directly into a flask
containing the neat triene aldehyde 5 (300 mg, 0.94 mmol).
After removal of solvent (aspirator), the residue was purified
by flash chromatography on silica gel (10 × 2 cm), 1:4 EtOAc/
hexane eluent, 5 mL fractions. The fractions were analyzed
by TLC (7:3 ether/hexane, UV detection). The starting material
5 (top spot) eluted first (Rf ) 0.6, 7:3 ether/hexane) followed
by the desired Diels-Alder adduct 6 (Rf ) 0.4), and then a
zone (70 mg) containing relatively more of a minor isomer 29,
ca. 3:1 29:6 as well as unknown impurities. All similar
fractions were collected and the solvent was removed (aspira-
tor) to afford the starting triene aldehyde (90 mg) and the
product 6 as a white foam (300 mg, 77%): analytical TLC on
silica gel, 7:3 ether/hexane, Rf ) 0.40; HRMS for C38H46ClNO5-
Si M + 1 660.2912, error ) 0 ppm, base peak ) 660 amu; IR
(CCl4, cm-1) 1726, 1681, 1658; 300 MHz NMR (C6D6, ppm) δ
9.79 (1H, s), 7.74-7.70 (2H, m), 7.15-7.08 (8H, m), 5.91 (1H,
dd, J ) 15.3, 9.6 Hz), 5.24 (1H, t, J ) 2.7 Hz), 5.17 (1H, dt,
J ) 15.3, 6.6 Hz), 4.46-4.39 (1H, m), 4.43 (1H, d, J ) 16.8
Hz), 3.27 (1H, dd, J ) 13.5, 6.3 Hz), 3.2 (1H, d, J ) 16.8 Hz),
3.14-3.08 (1H, m), 2.94 (3H, s), 2.94-2.68 (1H, m), 2.71 (1H,
dd, J ) 13.5, 2.7 Hz), 2.40-2.33 (1H, m), 2.15-2.06 (2H, m),
Tr ien e Ester 25. Solutions and solvents used in the workup
procedure were deoxygenated (N2 bubbled in for 20 min) prior
to use. All transfers were done under a nitrogen atmosphere
via cannula into flame dried flask cooled under a stream of
nitrogen for 30 min at room temperature.
A THF solution (20 mL) of E,E-4-(trimethylsilylmethyl)hexa-
2,4-dien-1-ol (5)5b (6 g, 32.5 mmol) at -78 °C was treated with
n-BuLi (Aldrich, 1.05 M, ca. 30 mL) under nitrogen until the
endpoint was reached as indicated by 1,10-phenathroline. After
being stirred for 5 min, the alkoxide was treated with ClP-
(O)(OEt)2 (5.0 mL, 34.4 mmol), the cooling bath was removed,
and the reaction was stirred at room temperature for 4 h. The
dienyl phosphate solution was cooled to -78 °C and treated
dropwise with a freshly made solution of lithiodiphenylphos-
phide prepared by addition of n-BuLi (Aldrich, 1.05 M, 28 mL)
to a THF solution (20 mL) of freshly distilled diphenylphos-
phine (Aldrich, 5.0 mL, 28.7 mmol) at -78 °C (nitrogen
atmosphere). The reaction was diluted with ether (200 mL)
and quenched with Na2CO3 (100 mL). The ethereal layer was
removed and washed with brine, dried over K2CO3, transferred
to another flask and the solvent was removed using a N2
stream. The viscous residue of the air-sensitive phosphine was
dissolved in ether (75 mL) at room temperature and treated
with methyl iodide (Aldrich, 12 mL, 192 mmol) for 10 h. The
resulting suspension was filtered to provide the dienyl phos-
phonium salt 24 (10.9 g, 77%) as an off-white powder. The
phosphonium salt was moderately stable, but over extended
periods of time would slowly decompose and was used without
purification.
Under a nitrogen atmosphere a suspension of the phospho-
nium salt 248a (8 g, 16.7 mmol) in THF (50 mL) at -78 °C
was treated with KHMDS (Aldrich, 0.8 M, 21 mL, 16.8 mmol).
The solution was warmed to 0 °C over a 30 min period and
then cooled to -78 °C and a THF solution (50 mL) of the
aldehyde 12 (3 g, 15 mmol) was added dropwise. After the
addition was complete, the reaction was warmed to room
temperature and stirred for 1 h. The reaction was quenched
with Na2CO3 (saturated, 25 mL) and diluted with ether, and
the organic layer was washed with brine and dried (MgSO4).
After removal of solvent (aspirator), the residue was purified
by flash chromatography on silica gel (10 × 4 cm), 1:9 ether/
hexane eluent, 20 mL fractions. Due to instability of the triene
product toward silica gel the flow rate for the chromatography
was increased using gentle air pressure to minimize the
contact time with the silica. The fractions were analyzed by
TLC (1:4 EtOAc/hexane, UV detection). The initial fractions
(Rf ) 0.7, 1;4 EtOAc/hexane) contained hexamethyldisilazane
and were discarded. These fractions were followed by the
product (Rf ) 0.57). The solvent was removed (aspirator) from
the combined fractions to give triene ester 25 (4.52 g, 83%) as
an inseparable mixture of E/ Z isomers, with an estimated
ratio of 87:13 at both the C(8),C(9) and C(10),C(11) double
bonds (NMR assay): analytical TLC on silica gel, 1:4 EtOAc/

6080 J . Org. Chem., Vol. 65, No. 19, 2000
Vedejs and Duncan
1.92 (3H, s), 1.75-1.65 (2H, m), 1.37 (2H, s), 0.78 (3H, d, J )
6.9 Hz), -0.06 (9H, s).
dienolate was treated with tert-butyldimethyltrifluorosulfonate
(Aldrich, 0.04 mL, 0.17 mmol) and stirred for 15 min before
quenching with NaHCO3 (saturated, 20 mL). The reaction was
warmed to room temperature and poured into ether, washed
with brine, and dried with K2CO3. After removal of solvent
(aspirator), the residue was purified by flash chromatography
on silica gel (5 × 1.5 cm), 3:7 ether/hexane eluent, 2 mL
fractions. The initial fractions contained silicon byproducts and
hexmethyldisilazane (Rf ) 0.7, 3:1:1 hexane/ether/dichlo-
romethane) and were discarded. These fractions were followed
closely by the major spot (Rf ) 0.64), the silyl enol ether 31
(62 mg, 94%) as a yellow foam: analytical TLC on silica gel,
3:1:1 hexane/ether/dichloromethane, Rf ) 0.64; molecular ion
calcd for C43H57NO4Si2 707.38263, found m/e ) 707.3847,
error ) 3 ppm, base peak ) 105 amu; IR (CCl4, cm-1) 1638,
1728, 1682; 250 MHz (340 K) NMR (C6D6, ppm) δ 8.1 (1H, d,
J ) 16.5 Hz), 7.71 (2H, dd, J ) 6.3, 1.7 Hz), 7.62 (2H, d, J )
7.0 Hz), 7.25-7.00 (6H, m), 6.42 (1H, d, J ) 16.5 Hz), 5.99
(1H, dd, J ) 15.4, 10.3 Hz), 5.17-5.02 (2H, m), 4.65-4.60 (1H,
m), 3.63 (1H, dd, J ) 5.4, 0.7 Hz), 3.25 (1H, dd, J ) 12.4, 3.5
Hz), 3.09 (1H, dd, J ) 12.7, 10.5 Hz), 2.90-2.87 (1H, m), 2.57-
2.47 (1H, m), 2.17-1.97 (4H, m), 1.81 (3H, s), 1.42-1.25 (2H,
m), 0.97-0.86 (3H, m), 0.93 (9H, s), 0.05 (6H, s), -0.13 (9H,
s).
Red u ction of 31: Con ver sion to th e Aceta te 32. An
ethanolic solution (4 mL) of the dienone silyl enol ether 31
(39 mg, 0.055 mmol) at 0 °C was treated with NaBH4 (Aldrich,
82 mg, 2.15 mmol) and stirred for 10 min. The reaction was
quenched with water (1 mL), extracted with ether, and dried
(MgSO4), and the solvents were removed (aspirator). A CH2-
Cl2 solution (2 mL) of the crude alcohol was added to a mixture
of triethylamine (0.4 mL), acetic anhydride (0.4 mL), and
(dimethylamino)pyridine (Aldrich, 5 mg). After 1 h, the solu-
tion was quenched with NaHCO3 (5 mL) and extracted with
CH2Cl2, and the organic layer was dried (MgSO4). After
evaporation (aspirator), the residue was purified by flash
chromatography on silica gel (10 × 1.5 cm), 6:1:1 hexane/ether/
dichloromethane eluent, 2 mL fractions. The less polar frac-
tions (Rf ) 0.6, 3:1:1 hexane/ether/dichloromethane) were
assayed by NMR and were found deficient in the integral for
alkenyl protons (6.87 and 6.15 ppm), as expected for the C(19),
C(20) dihydro derivative of 32 (11 mg). Characteristic signals
for the less polar fraction were seen for H(13) (δ 6.29 ppm),
C(21) acetate (δ 1.93 ppm), and C(5) methyl (δ 0.86 ppm).
Careful separation of increasingly polar fractions afforded
material (18 mg, 44%) having the correct integral for the C(19),
C(20) hydrogens of 32 as a foam after solvent removal:
analytical TLC on silica gel, 3:1:1 hexane/ether/dichloromethane,
Rf ) 0.54; molecular ion calcd for C45H61NO5Si2 751.40881,
found m/e ) 751.4088, error ) 0 ppm, base peak ) 105 amu;
IR (neat, cm-1) 1747, 1679; 1282; 250 MHz (340 K) NMR (C6D6,
ppm) δ 7.74-7.70 (2H, m), 7.52-7.46 (2H, m), 7.27-7.07 (6H,
m), 6.87 (1H, d, J ) 15.5 Hz), 6.36 (1H, dd, J ) 15.4, 9.6 Hz),
6.15 (1H, d, J ) 7.0 Hz), 5.45-5.30 (3H, m), 4.80-4.60 (1H,
m), 3.50-3.44 (1H, m), 3.05-2.96 (1H, m), 2.78-2.69 (1H, m),
2.39-2.04 (4H, m), 1.88 (3H, s), 1.83 (3H, s), 1.40 (2H, br s),
1.35-1.20 (1H, m), 0.94 (9H, s), 0.95-0.85 (1H, m), 0.53 (3H,
d, J ) 7.3 Hz), 0.07 (3H, s), 0.06 (3H, s), -0.1 (9H, s).
Fractions enriched in the minor diastereomer 29 from
several experiments were combined and were stored in ether.
This gave colorless crystals, mp 106 °C dec, suitable for X-ray
crystallography, resulting in confirmation of the structure and
of the double bond geometry assigned to the Diels-Alder diene
component 5: analytical TLC on silica gel, 7:3 ether/hexane,
Rf ) 0.3; HRMS for C38H46ClNO5Si M + 1 660.2904; IR (CCl4,
cm-1) 1724, 1680, 1660; 300 MHz NMR (C6D6, ppm) δ 9.92
(1H, s), 7.8-7.7 (2H, m), 7.57 (2H, d, J ) 7.7 Hz),7.30-7.15
(6H, m), 5.23-5.00 (3H, m), 4.67 (1H, br d, J ) 12.8 Hz), 4.34
(2H, AB q, J ) 16.5 Hz), 3.51 (1H, br t, J ) 7.2 Hz), 3.36-
3.22 (2H, m), 3.10 (3H, s), 2.67 (1H, dd, J ) 13.4, 12.2 Hz),
2.36-2.24 (2H, m), 2.00 (3H, s), 1.87-1.71 (3H, m), 1.47 (1H,
d, J ) 14.6 Hz), 1.27 (1H, d, J ) 14.6 Hz), 0.86 (3H, d, J ) 8.0
Hz), -0.01 (9H, s).
Refor m a tsk y Cycliza tion : Dik eton e 10. Under a nitro-
gen atmosphere, a THF solution (15 mL) of anhydrous ZnCl2
(1.49 g, 10.93 mmol; fused under vacuum, 1 Torr) was added
to a freshly prepared THF solution (45 mL) of sodium naph-
thalide (Na0, 220 mg, 9.56 mmol; naphthalene, recrystallized
from Et2O, 1.4 g, 10.9 mmol) at 0 °C. The fine black suspension
was stirred for 45 min and then a THF solution (45 mL) of
the Diels-Alder adduct 6 (295 mg, 0.44 mmol) was added
slowly over 6 h. After stirring for 5 min at 0 °C, the reaction
was quenched with NH4Cl (25 mL) and stirred for 20 min at
room temperature. The reaction mixture was poured into
ether, washed with brine, and dried with MgSO4. After solvent
removal (aspirator), the residue was diluted with ether (30 mL)
and treated with 10% H2SO4 (5 mL) for two h at room
temperature. The reaction was quenched with Na2CO3, diluted
with ether, the organic layer was washed with brine, and dried
(MgSO4). After removal of solvent (aspirator), the residue was
purified by flash chromatography on silica gel (10 × 3 cm),
4:1:1 hexane/Et2O/dichloromethane eluent, 5 mL fractions. The
initial fractions contained naphthalene (Rf ) 0.9, 7:3 ether/
hexane) and were discarded. The ensuing fractions contained
the product 10 (Rf ) 0.5) and were combined. These fractions
were followed by the hydrolyzed reduction product 30b (Rf )
0.3) and a minor unknown byproduct (Rf ) 0.25). Solvent
removal (aspirator) from the combined major fractions afforded
10 as a white powder (177 mg, 67%). Recrystallization from
ether/hexane afforded X-ray quality crystals of 10: mp 142.5-
145 °C dec; analytical TLC on silica gel, 1:4 EtOAc/hexane,
Rf ) 0.29, molecular ion calcd for C37H43NO4Si, 593.29614,
found m/e ) 593.2991, error ) 5 ppm, base peak ) 105 amu;
IR (CCl4, cm-1) 1734, 1696, 1677; 300 MHz NMR (C6D6, ppm)
δ 7.78-7.75 (2H, m), 7.21-7.08 (8H, m), 6.12 (1H, t, J ) 7.0
Hz), 5.71 (1H, dd, J ) 15.6, 10.0 Hz), 5.25 (1H, s), 4.99 (1H,
ddd, J ) 15.6, 9.9, 5.4 Hz), 4.47-4.43 (1H, m), 3.35 (1H, dd,
J ) 13.8, 6.3 Hz), 3.16-3.11 (1H, m), 3.04 (1H, t, J ) 10.0
Hz), 2.94 (1H, dd, J ) 5.1, 3.3 Hz), 2.77-2.68 (2H, m), 2.56-
2.47 (2H, m), 2.34 (1H, ddd, J ) 9.3, 6.3, 3.0 Hz), 2.05-1.85
(2H, m), 1.93 (3H, s), 1.37 (2H, s), 0.88 (3H, d, J ) 7.2 Hz),
-0.05 (9H, s). The more polar fractions afforded 50 mg of
material tentatively assigned as 30b based on signals for an
enol proton (δ15.19 ppm), the absence of methoxy and aldehyde
signals, and a signal for the C(18) methyl group at δ 1.25 ppm.
In a separate experiment where the sulfuric acid treatment
was omitted, a third product 30a was isolated from the more
polar chromatography fractions in addition to 30b. Charac-
terization data for 30a : analytical TLC on silica gel, 1.67:1:1
Dim eth yld ioxir a n e Oxid a tion of 32: Isola tion of Ketol
34. A CHCl3 solution (Fisher, 12 mL) of silyl enol ether 32 (73
mg, 0.097 mmol) at -78 °C was treated with dimethyldioxirane
(0.05 M, 3.0 mL, 0.15 mmol), prepared according to a known
procedure,23 and stirred for 15 min. The reaction was warmed
to room temperature over a 20 min period and quenched with
dimethyl sulfide (Aldrich, 0.5 mL). After removal of solvent
(aspirator), the crude product was diluted with THF/HOAc/
water (8:8:1, 8 mL) and stirred at room temperature for 5 h.
The mixture was quenched with NaHCO3 (10 mL) and
extracted with ether. The ethereal layer was washed with
water, brine, and treated with MgSO4. After removal of solvent
(aspirator), the residue was purified by flash chromatography
on silica gel (10 × 1.5 cm), 4:1:1 ether/hexane eluent, 2 mL
fractions. The initial fractions (Rf ) 0.7, 2:1:1 hexane/ether/
dichloromethane) contained silicon byproducts and were dis-
carded. These fractions were followed much later by the major
fraction followed closely by two minor unidentified contami-
hexane/ether/dichloromethane, Rf ) 0.27; HRMS for C38H47
-
NO5Si; M + 1, 626.3297, error ) 1 ppm, base peak ) 320 amu;
IR (CCl4, cm-1) 1735, 1704, 1677; 300 MHz NMR (C6D6, ppm)
δ 9.81 (1H, s), 7.83-7.79 (2H, m), 7.16-7.07 (8H, m), 6.10 (1H,
dd, J ) 15.3, 9.3 Hz), 5.27 (1H, br s), 5.22 (1H, dt, J ) 15.3,
6.6 Hz), 4.51-4.46 (1H, m), 3.22-3.14 (1H, m), 3.13-3.05 (1H,
m), 2.93 (3H, s), 2.95-2.75 (2H, m), 2.37-2.25 (1H, m), 2.21-
2.12 (2H, m), 1.93 (3H, s), 1.83-1.73 (2H, m), 1.84 (3H, s), 1.36
(2H, br s), 0.75 (3H, d, J ) 7.2 Hz), -0.05 (9H, s).
Con ver sion of 10 in to th e Silyl Dien yl Eth er 31. A THF
solution (20 mL) of diketone 10 (55 mg, 0.093 mmol) at -78
°C was treated with lithium hexamethyldisilazane (0.1 M, 1
mL, 0.1 mmol) and stirred for 30 min at -78 °C. The resulting

Synthesis of C(16),C(18)-Bis-epi-cytochalasin D
J . Org. Chem., Vol. 65, No. 19, 2000 6081
nants (Rf ) 0.2-0.3; 6.5 mg total). Solvent removal (aspirator)
from the major fraction provided the R-ketol 34 (>20:1
diastereomer ratio, NMR assay; 36 mg, 57%) as a white
powder: analytical TLC on silica gel, 2:1:1 ether/hexane/
dichloromethane, Rf ) 0.4; molecular ion calcd for C39H47NO6-
Si 653.31726, found m/e ) 653.3172, error ) 9 ppm, base
peak ) 105 amu; IR (CCl4, cm-1) 3462, 1736, 1706; 300 MHz
NMR (C6D6, ppm) δ 7.70-7.60 (2H, m), 7.50-7.40 (2H, m),
7.30-7.05 (6H, m), 6.39 (1H, dd, J ) 15.6, 2.1 Hz), 6.06 (1H,
dd, J ) 2.4, 2.1 Hz), 6.04 (1H, dd, J ) 15.6, 10.2 Hz), 5.23-
5.19 (1H, m, J ) 1.0 Hz), 5.16 (1H, dd, J ) 15.6, 2.4 Hz), 5.09
(1H, ddd, J ) 15.6, 10.2, 4.8 Hz), 4.47-4.40 (1H, m), 4.06 (1H,
br s), 3.34-3.25 (2H, m), 2.84 (1H, dd, J ) 12.9, 9.6 Hz), 2.46
(1H, dd, J ) 5.1, 2.7 Hz), 2.41-2.25 (2H, m), 2.18-1.80 (3H,
m), 1.82 (3H, s), 1.30 (2H, br s), 1.25 (3H, s), 0.52 (3H, d, J )
7.5 Hz), -0.11 (9H, s).
expected for the product 40 (no acetate methyl signal; poorly
resolved C-ethyl signals for the propionyl group). The next
fraction (1.4 mg, Rf ) 0.65-0.60) contained 40 and a minor
sideproduct, and the rest of the material from the column
(Rf < 0.55) was combined in fraction three (3.9 mg). The
combined material from the first two fractions (7 mg) was
dissolved in MeOH/THF (5:1, 3 mL) and treated with K2CO3
(100 mg) for 7 h, the mixture diluted with CH2Cl2 (20 mL),
washed with water (5 mL) and brine (5 mL), and dried
(MgSO4). After solvent removal (aspirator), the residue was
purified by flash chromatography on silica gel (6 × 0.6 cm)
with hexane/ether/dichloromethane 1:1:1 eluent, 1 mL frac-
tions. The major spot contained 41 (4.3 mg, Rf ) 0.6, 1:1:1
hexane/ether/dichloromethane) after solvent removal (aspira-
tor). The material was used directly in the next reaction.
Diagnostic NMR signals: (300 MHz, CDCl3, ppm) δ 6.55 (H19
,
Con ver sion of Ketol 34 to Bis-TBS Eth er 38. Under an
inert atmosphere, a CH2Cl2 solution (3 mL) of allylsilane 34
(30 mg, 0.046 mmol, 30:1 mixture of diastereomers by HPLC)
dd), 5.66 (H13, dd), 5.42 (H12a, br s), 5.1 (H21, br s), 5.1-4.95
(H14, m), 4.9 (H12b, br s), 4.85 (H20, dd), 1.13 and 1.11 (C5 and
C16 methyls; overlapping doublets).
at -78 °C was treated with PhSeSe+MePh BF4 (0.2 M, 0.28
-
The fractions containing alcohol 41 (4.3 mg, 0.006 mmol)
in CH2Cl2 (2 mL) were treated with triethylamine (0.5 mL,
3.6 mmol), acetic anhydride (0.4 mL, 4.2 mmol), and a catalytic
amount of (dimethylamino)pyridine for 30 min (rt, nitrogen
atmosphere). The reaction was quenched with water, extracted
with CH2Cl2, dried (MgSO4), and solvents evaporated (aspira-
tor) to afford the crude acetate 42. The products were used
directly in the next step without purification.
mL solution in CH2Cl2, 0.056 mmol), prepared as previously
described.4b The reaction was stirred for 10 min at -78 °C,
warmed to 0 °C, stirred for 5 min, and then quenched with
NaHCO3 (saturated, 5 mL). After extraction with CH2Cl2
(3 × 20 mL) and solvent removal (aspirator), the residue was
filtered through a column of silica gel (10 × 0.5 cm) with
hexane eluent to remove a nonpolar fraction containing
PhSeMe and then ether to recover the crude selenide 36 (Rf )
0.6). A CH2Cl2 solution (5 mL) of the selenide at -78 °C was
treated with a, m-CPBA (Aldrich, 55%, 25 mg, 0.08 mmol)
dissolved in CH2Cl2 (2 mL). After being stirred for 30 min,
dimethyl sulfide (0.5 mL) was added, and the mixture was
warmed to room temperature, quenched with Na2CO3 (satu-
rated, 5 mL), extracted with CH2Cl2, and dried (MgSO4). After
solvent removal (aspirator), the residue was filtered through
a column of silica gel (10 × 0.5 cm), hexane eluent, to remove
nonpolar selenium byproducts and then EtOAc to recover the
crude diol 37. A CH2Cl2 solution (3 mL) of the diol at room
temperature was treated successively with 4 Å molecular
sieves (0.5 g), Et3N (0.5 mL), and TBSOTf (0.4 mL) and stirred
for 5 h. The reaction was quenched with NaHCO3 (saturated,
5 mL), extracted with CH2Cl2 (3 × 25 mL), and dried (MgSO4).
After removal of solvent (aspirator), the residue was purified
by flash chromatography on silica gel (15 × 1 cm), 3:1:1
hexane/ether eluent, 2 mL fractions. The initial fractions
contained silicon byproducts (Rf ) 0.7, 3:1:1 hexane/ether/
dichloromethane) and were discarded. These fractions were
followed closely by the major fraction. Solvent removal (aspira-
tor) afforded the bis-silyl ether 38 (19 mg, 50%, Rf ) 0.61) as
an oil: analytical TLC on silica gel, 3:1:1 ether/hexane/
An acetonitrile solution (2 mL) of the acetates 42 was
treated with 48% HF (0.1 mL) at 0 °C for 15 min and then
warmed to room temperature and stirred for 1 h. The reaction
was quenched with water and diluted with ethyl acetate, and
the organic layer was washed with NaHCO3. After drying
(MgSO4) and solvent removal (aspirator), the residue was
purified by flash chromatography on silica gel (5 × 0.6 cm).
The column was eluted with hexane/ether/dichloromethane
1:1:1 to remove a high Rf product and then the column was
flushed with ethyl acetate to remove the polar products. The
polar residue was dissolved in a minimal amount of acetone
and hexane was added until the solution became cloudy. This
solution was placed in the refrigerator (-10 °C) overnight. The
1
precipitate (ca. 2 mg) consisted of a 5:1 ratio of 43 to 44 by H
NMR assay. Major product 43: analytical TLC on silica gel,
5:3 acetone/hexane, Rf ) 0.53; molecular ion calcd for C30H37
-
NO6 507.26202, found m/e ) 507.2657, error ) 7 ppm; 300
MHz NMR (CDCl3, ppm) δ 7.36-7.24 (3H, m), 7.15-7.12 (2H,
m), 6.51 (1H, dd, J ) 15.9, 2.3 Hz), 5.76 (1H, dd, J ) 15.1, 8.9
Hz), 5.56 (1H, br s), 5.45 (1H, br s), 5.41-5.32 (1H, m), 5.16
(1H, br s), 4.82 (1H, dd, J ) 15.9, 2.3 Hz), 3.83 (1H, br d, J )
11.2 Hz), 3.53-3.42 (1H, m), 3.34-3.28 (1H, m), 2.94 (1H, dd,
J ) 14.0, 4.2 Hz), 2.85-2.74 (2H, m), 2.57 (1H, dd, J ) 14.4,
10.1 Hz), 2.20 (3H, s), 2.22-1.92 (3H, m), 1.47 (3H, s), 1.19
(3H, d, J ) 6.4 Hz), 1.11 (3H, d, J ) 6.6 Hz), 1.10 (3H, d, 6.6
Hz). The products from this reaction were combined with the
corresponding fractions from a second experiment and 43
(Rf ) 0.53, 5:1 EtOAc/hexane) and 44 (Rf ) 0.30) were
separated by flash chromatography (silica gel, 5 × 0.5 cm) 3:1
EtOAc/hexane eluent, 1 mL fractions. The latter isomer was
not obtained free of contaminants, but several of the NMR
shifts were resolved, including δ 6.19 (H19) 5.63 (H21), 5.07
(H20), 1.19 (C16 methyl) and 0.97 (C5 methyl). Slow evaporation
of acetone from 43 provided X-ray quality crystals. The crystal
structure confirms the stereochemical assignment of the C(16)
center incorporated in this sequence along with the C(21),
C(18), C(7) centers established in earlier experiments.
dichloromethane, Rf ) 0.61; molecular ion calcd for C48H67
-
NO7Si2 825.44556, found m/e ) 825.4456, error ) 7 ppm, base
peak ) 105 amu; IR (CCl4, cm-1) 1748, 1730, 1712; 300 MHz
NMR (C6D6, ppm) δ 7.68-7.63 (2H, m), 7.39 (2H, br d, J ) 6.9
Hz), 7.23-6.99 (6H, m), 6.35 (1H, dd, J ) 15.3, 1.8 Hz), 6.14
(1H, t, J ) 1.8 Hz), 6.02 (1H, dd, J ) 15.3, 9.6 Hz), 5.50 (1H,
dt, J ) 15.9, 6.6 Hz), 4.97 (1H, br s), 4.93 (1H, br s), 4.90 (1H,
dd, J ) 15.3, 1.8 Hz), 4.60-4.53 (1H, m), 3.94 (1H, d, J ) 8.1
Hz), 3.35-3.21 (1H, m), 3.17 (1H, dd, J ) 12.3, 2.5 Hz), 3.00
(1H, dd, J ) 9.3, 8.4 Hz), 2.80 (1H, dd, J ) 12.3, 11.1 Hz),
2.72-2.63 (1H, p, J ) 6.0 Hz), 2.49-2.36 (1H, m), 2.20-2.10
(1H, m), 1.95 (1H, dddd, J ) 15.9, 8.1, 5.4, 2.7 Hz).
Alk yla tion of 38: Isola tion of 16,18-Bis-epi-cytoch a la -
sin D (43). Under a nitrogen atmosphere, a THF solution (2
mL) of 38 (11 mg, 0.013 mmol) at -78 °C was treated with
freshly prepared LDA (0.11 M in THF/hexane, 0.58 mL, 0.06
mmol) for 1 h. The enolate was treated with methyl iodide
(filtered over alumina and stored over 4 Å molecular sieves
for 1 h prior to use, 1 mL, 16 mmol) for 10 min. The reaction
was quenched with water and extracted with ether. After
solvent removal (aspirator), the residue was purified by flash
chromatography on silica gel (8 × 0.6 cm) hexane/ether/
dichloromethane 4:1:1 eluent, 1 mL fractions and fractions
were analyzed by TLC (silica gel, 3:1:1 hexane/dichloromethane/
THF, UV detection). The first fraction (5.6 mg, Rf ) 0.65, 3:1:1
hexane/ether/dichloromethane) had NMR characteristics as
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (CA17918).
The authors also thank Dr. D. R. Powell for the X-ray
crystal structures.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
isolated intermediates; X-ray data tables for 43. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O000533Q