Synthesis of (+/-)-5-epi-citreoviral and (+/-)-citreoviral and the kinetic resolution of an allylic silane by a [3 + 2] annulation.

Article abstract of DOI:10.1021/ol026343e

[reaction: see text] The [3 + 2] annulation reaction of allylsilane 1 with an alpha-keto ester provided the highly substituted tetrahydrofuran 2 as a single diastereomer in high yield. The synthesis of (+/-)-5-epi-citreoviral and (+/-)-citreoviral has bee

Full text of DOI:10.1021/ol026343e

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2945-2948
Synthesis of (±)-5-epi-Citreoviral and
(±)-Citreoviral and the Kinetic
Resolution of an Allylic Silane by a
[3 + 2] Annulation
Zhi-Hui Peng and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received June 11, 2002
ABSTRACT
The [3 + 2] annulation reaction of allylsilane 1 with an r-keto ester provided the highly substituted tetrahydrofuran 2 as a single diastereomer
in high yield. The synthesis of (±)-5-epi-citreoviral and (±)-citreoviral has been accomplished with this annulation reaction as the key step.
Using the pantolactone-derived r-keto ester, the allylsilane 1 has been resolved with high enantiomeric purity.
(+)-Citreoviral (1) and the related polyene R-pyrone myco-
toxins (-)-citreoviridin (2) and (+)-verrucosidin (3) were
isolated from a variety of Penicillium fungi (Figure 1).1 Other
biological activity and the complexity of the core tetra-
hydrofuran moiety possessing two tetrasubstituted carbon
atoms, these compounds have become attractive targets for
synthesis.4,5
The [3 + 2] annulation of allylic silanes is a highly
stereoselective reaction and a powerful method to prepare
functionalized five-membered carbocycles or heterocycles.6,7
This reaction seemed to be amenable to the synthesis of the
densely functionalized tetrahydrofuran ring in citreoviral and
related mycotoxins. Previously reported total syntheses of
(+)-citreoviral, (-)-citreoviridin, and (+)-verrucosidin uti-
lized epoxide 4 as the common advanced intermediate
(1) (a) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077-
3081. (b) Shizuri, Y.; Nishiyama, S.; Imai, D.; Yamamura, S.; Furukawa,
H.; Kawai, K.; Okada, N. Tetrahedron Lett. 1984, 25, 4771-4774. (c)
Burka, L. T.; Ganguli, M.; Wilson, B. J. J. Chem. Soc., Chem. Commun.
1983, 544-545.
(2) (a) Nishiyama, S.; Shizuri, Y.; Imai, D.; Yamamura, S.; Terada, Y.;
Niwa, M.; Kawai, K.; Furukawa, H. Tetrahedron Lett. 1985, 26, 3243-
3246. (b) Kruger, G. J.; Steyn, P. S.; Vleggaar, R.; Rabie, C. J. J. Chem.
Soc., Chem. Commun. 1979, 441-442. (c) Mulheirn, L. J.; Beechey, R.
B.; Leworthy, D. P.; Osselton, M. D. J. Chem. Soc., Chem. Commun. 1974,
874-876.
(3) (a) Boyer, P. D.; Chance, B.; Ernster, L.; Mitchell, P.; Racker, E.;
Slater, E. C. Annu. ReV. Biochem. 1977, 46, 955-1026. (b) Muller, J. L.
M.; Rosing, J.; Slater, E. C. Biochim. Biophys. Acta 1977, 462, 422-437.
(c) Gause, E. M.; Buck, M. A.; Douglas, M. G. J. Biol. Chem. 1981, 256,
557-559.
Figure 1.
structurally related natural products include citreoviridinol,2a
isocitreoviridinol,2a asteltoxin,2b and the aurovertins.2c These
compounds are known to be potent inhibitors of mitochon-
drial ATPase and oxidative phosphorylation.3 Because of this
10.1021/ol026343e CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/02/2002

(Scheme 1).4b,5 We envisioned that tetrahydrofuran 5, a
precursor to epoxide 4, could be accessed by the [3 + 2]
Scheme 2
Scheme 1
secondary â-silyl carbocation, a process that is likely to be
energetically unfavorable but not unprecedented.11,12 The
configuration of tetrahydrofuran 9, which is consistent with
the proposed mechanism for the [3 + 2] annulation,6a was
proven by X-ray crystallographic analysis of the reduction
product, diol 10.
Because a dimethylphenylsilyl group can be oxidized to
a hydroxyl group by the Tamao-Fleming protocol,13 the
tetrahydrofuran 9 has all the required functionality and
stereochemistry of citreoviral with the exception of an
incorrect configuration at C-5. Before solving this problem,
we decided to synthesize (()-5-epi-citreoviral to optimize
the remaining steps of the synthesis.
The oxidation of the dimethylphenylsilyl group was
problematic because of the steric hindrance and the sensitivity
of the reactant. After considerable experimentation, we found
that the oxidation could be achieved with the conditions
reported from our laboratory.14 Thus, treatment of the ether
11 with KH/t-BuOOH/TBAF in NMP gave the desired
alcohol 12 in 61% yield as well as 20% of the protodesily-
lation product 13 (Scheme 3). Substitution of cumene
annulation of the substituted allylic silane 6 with R-keto ester
7.8 This communication reports the synthesis of (()-
citreoviral and its C-5 epimer by this strategy and a highly
selective kinetic resolution to obtain the allylic silane 6 in
enantiomerically pure form. This compound could be applied
to the asymmetric synthesis of (+)-citreoviral, (-)-cit-
reoviridin, (+)-verrucosidin, and their unnatural enantiomers.
The annulation reaction of allylic silane 6 with R-keto ester
7 indeed provided rapid access to the core ring structure of
the targets. The allylic silane 6 was synthesized in one step
by the conjugate addition of dimethylphenylsilyl cuprate to
R,â-unsaturated aldehyde 8 followed by the in situ acetylation
of the enolate with acetic anhydride (Scheme 2).9 Treatment
of the allylic silane 6 with ethyl pyruvate in the presence of
SnCl4 at -78 °C gave the [3 + 2] annulation product 9 as
a single diastereomer in 85% yield.10 This process involves
a silyl migration from a tertiary â-silyl carbocation to a
(4) For the synthesis of citreoviral and citreoviridin in both racemic and
optically active form, see: (a) Hanaki, N.; Link, J. T.; MacMillan, D. W.
C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2,
223-226. (b) Whang, K.; Venkataraman, H.; Kim, Y. G.; Cha, J. K. J.
Org. Chem. 1991, 56, 7174-7177. (c) Begley, M. J.; Bowden, M. C.; Patel,
P.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1991, 1951-1958. (d)
Suh, H.; Wilcox, C. S. J. Am. Chem. Soc. 1988, 110, 470-481. (e) Williams,
D. R.; White, F. H. J. Org. Chem. 1987, 52, 5067-5079. (f) Bowden, M.
C.; Patel, P.; Pattenden, G. Tetrahedron Lett. 1985, 26, 4793-4796. (g)
Nishiyama, S.; Shizuri, Y.; Yamamura, S. Tetrahedron Lett. 1985, 26, 231-
234. (h) Hatakeyama, S.; Matsui, Y.; Suzuki, M.; Sakurai, K.; Takano, S.
Tetrahedron Lett. 1985, 26, 6485-6488. (i) Williams, D. R.; White, F. H.
Tetrahedron Lett. 1985, 26, 2529-2532.
Scheme 3
(5) For the synthesis of (+)-verrucosidin, see: (a) Hatakeyama, S.;
Sakurai, K.; Numata, H.; Ochi, N.; Takano, S. J. Am. Chem. Soc. 1988,
110, 5201-5203. (b) Whang, K.; Cooke, R. J.; Okay, G.; Cha, J. K. J. Am.
Chem. Soc. 1990, 112, 8985-8987.
(6) (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (b)
Kno¨lker, H.-J. J. Prakt. Chem. 1997, 339, 304-314.
(7) For the applications of [3 + 2] annulation of allylic silanes in natural
product synthesis, see, for example: (a) Peng, Z.-H.; Woerpel, K. A. Org.
Lett. 2001, 3, 675-678. (b) Roberson, C. W.; Woerpel, K. A. Org. Lett.
2000, 2, 621-623. (c) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3,
1949-1952.
hydroperoxide for tert-butyl hydroperoxide increased the
yield of the oxidation product to 85%.
(8) Akiyama, T.; Ishikawa, K.; Ozaki, S. Chem. Lett. 1994, 627-630.
(9) Isaka, M.; Williard, P. G.; Nakamura, E. Bull. Chem. Soc. Jpn. 1999,
72, 2115-2116.
(11) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1993, 58, 2345-2348.
(b) Radeitch, B.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 2430-2431.
(12) The reaction of allylic silane 26, the methyl analogue of 6, with
ethyl pyruvate gave tetrahydrofuran 27 in 90% yield as a single diastereomer:
(10) Raising the reaction temperature from -78 °C to room temperature
led to the Sakurai product 25 completely:
2946
Org. Lett., Vol. 4, No. 17, 2002

Further elaboration of the oxidation product 12 to (()-5-
epi-citreoviral is shown in Scheme 4. Because of the
(not shown) was isolated as the only byproduct (in 14%
yield). Reduction of the ester groups with LiBH4 gave the
corresponding diol in 87% yield. Selective formation of the
primary mesylate followed by LiAlH4 reduction revealed the
C-2 methyl group with concomitant removal of the TIPS
group to afford diol 19.
Scheme 4
With 19 in hand, we completed the synthesis of (()-
citreoviral by following a similar sequence as above (Scheme
6). Protection of diol 19 followed by oxidation of the C-Si
Scheme 6
difference in accessibility of the two benzyl ether groups of
12, the primary benzyl group could be removed selectively.
The resulting diol was treated with TPAP/NMO to afford
the bicyclic lactone 14.4a Reduction of the lactone with i-Bu2-
AlH afforded the lactol, which was submitted without
purification to the Wittig reaction to provide the R,â-
unsaturated ester 15 as exclusively the (E)-isomer. Depro-
tection of the secondary benzyl group with DDQ, reduction
of the ester with i-Bu2AlH, and oxidation of the resultant
allylic alcohol with MnO2 furnished (()-5-epi-citreoviral 16.
With a viable synthetic route in hand, we targeted epoxide
4 for the formal synthesis of (()-citreoviral (Scheme 1). A
comparison of the stereochemistry presented in epoxide 4
and the [3 + 2] annulation product 9 revealed the necessity
to invert the C-2 stereocenter of 9. This inversion could be
achieved by employing a â-functionalized R-keto ester as
electrophile in the annulation. The ester group in the resulting
tetrahydrofuran product 5 could then be reduced to the C-2
methyl group.
bond provided alcohol 20. The tertiary hydroxyl group was
then protected, and selective debenzylation gave the primary
alcohol 21. Oxidation of the alcohol followed by the Wittig
reaction afforded the R,â-unsaturated ester 22 as the (E)-
isomer only. Completion of the formal synthesis target,
epoxide 4, was achieved by the deprotection of the benzyl
ether, formation of the mesylate, and deprotection of the silyl
ether. Following literature procedures,4b we were able to
transform epoxide 4 to (()-citreoviral 1 in three steps.
For the enantioselective syntheses of citreoviral, cit-
reoviridin, and verrucosidin using the [3 + 2] annulation
strategy, we utilized the reaction of an allylic silane with a
chiral R-keto ester. Akiyama reported a highly stereoselective
[3 + 2] annulation of an allylic silane with the chiral R-keto
ester derived from L-quebrachitol. The tetrahydrofuran an-
nulation products were obtained with up to >98% ee after
removal of the chiral auxiliary.16 The chiral auxiliary they
used, however, was too expensive for our purpose. In
addition, three steps were needed to prepare the chiral R-keto
ester from the chiral auxiliary.
â-Triisopropylsilyloxy R-keto ester 17, prepared in three
steps from ethyl acrylate,15 was found to be the appropriate
electrophile (Scheme 5). The reaction of allylic silane 6 with
Scheme 5
The inexpensive alcohol (R)-(-)-pantolactone served as
an efficient chiral auxiliary for the kinetic resolution of a
racemic allylic silane (Scheme 7). Reaction of the racemic
silane 6 (2.0 equiv) with the chiral pyruvate 23, prepared in
one step from pantolactone, provided the [3 + 2] annulation
product 24 in 90% yield (based on 23) as a single diaste-
R-keto ester 17 afforded the [3 + 2] annulation product 18
in 83% yield as a single diastereomer. The Sakurai product
1
reomer by H NMR spectroscopic analysis.17 Reduction of
(13) (a) Tamao, K. AdVances in Silicon Chemistry; JAI: Greenwich, CT,
1996; Vol. 3, pp 1-62. (b) Fleming, I. Chemtracts-Org. Chem. 1996, 9,
1-64.
(15) See Supporting Information.
(16) Akiyama, T.; Yasusa, T.; Ishikawa, K.; Ozaki, S. Tetrahedron Lett.
1994, 35, 8401-8404.
(14) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-
6046.
Org. Lett., Vol. 4, No. 17, 2002
2947

both enantiomers of pantolactone are commercially available
and inexpensive, we could obtain both enantiomers of the
allylic silane 6 using this kinetic resolution. Thus, the
asymmetric syntheses of both enantiomers of citreoviral,
citreoviridin, and verrucosidin are possible using the synthetic
route reported above.
Scheme 7
In summary, we have achieved the synthesis of (()-5-
epi-citreoviral and (()-citreoviral using [3 + 2] annulation
reactions of allylic silanes, which also represented a formal
synthesis of citreoviridin and verrucosidin. The key annu-
lation process assembled the highly functionalized tetrahy-
drofuran core of these natural products in one step with high
diastereoselectivity. We also demonstrated that a highly
stereo- and enantioselective asymmetric annulation was
possible by the kinetic resolution of the racemic allylic silane
using an easily accessible chiral R-keto ester.
Acknowledgment. This research was supported by a
CAREER Award from the National Science Foundation
(CHE-9701622). K.A.W. thanks the American Cancer So-
ciety, AstraZeneca, Glaxo-Wellcome, the Camille and Henry
Dreyfus Foundation, Merck, and the Research Corporation
for awards to support research. Z.P. thanks Pharmacia for a
graduate fellowship in synthetic organic chemistry. We thank
Dr. John Greaves and Dr. John Mudd for mass spectrometric
data and Dr. Joseph Ziller for X-ray crystallographic
analyses.
24 with LiAlH4 afforded diol (-)-10 with an ee greater than
99%.18 We were also able to recover the unreacted allylic
silane 6 in 48% yield and with high enantiomeric purity.
Treatment of the recovered silane (-)-6 with ethyl pyruvate
followed by reduction afforded (+)-10 in >99% ee.18 Since
Supporting Information Available: Full experimental
and analytical data for all new compounds, X-ray data for
(()-10 and the enantiomer of the 5-ethyl analogue of 24,
and the chiral HPLC traces of (()-10, (-)-10, and (+)-10.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) An X-ray crystal structure of the enantiomer of the 5-ethyl analogue
of 24, which was derived from (S)-pantolactone, was obtained (see
Supporting Information). The relative and absolute stereochemistry of 24
was determined by comparison. Consequently, the stereochemistry of (-)-
10 and (+)-10 can be assigned, demonstrating the absolute configuration
of (-)-6 as well.
(18) The enantiomeric excess of (-)-10 and (+)-10 was determined by
HPLC analysis using a Chiracel OJ column, and the enantiomerically
enriched material was compared with racemic material.
OL026343E
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Org. Lett., Vol. 4, No. 17, 2002