Formation of chiral quaternary carbon stereocenters using silylene transfer reactions: Enantioselective synthesis of (+)-5-epi-acetomycin

Article abstract of DOI:10.1021/ol063072p

(Chemical Equation Presented) Chiral quaternary carbon stereocenters can be established with high diastereoselectivity by a silylene transfer/lreland- Claisen rearrangement. The utility of this method was demonstrated by application to a synthesis of (+)-

Full text of DOI:10.1021/ol063072p

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1037-1040
Formation of Chiral Quaternary Carbon
Stereocenters Using Silylene Transfer
Reactions: Enantioselective Synthesis
of (+)-5-epi-Acetomycin
Stacie A. Calad and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92627-2025
kwoerpel@uci.edu
Received December 19, 2006
ABSTRACT
Chiral quaternary carbon stereocenters can be established with high diastereoselectivity by a silylene transfer/Ireland−Claisen rearrangement.
The utility of this method was demonstrated by application to a synthesis of (+)-5-epi-acetomycin.
The construction of chiral molecules with all-carbon qua-
ternary stereocenters remains a significant challenge in
organic synthesis.1 Steric repulsions develop upon bringing
four alkyl groups together, which limit the number of
transformations that can be used to form these sterically
congested products. Controlling the absolute stereochemistry
of asymmetric quaternary carbon centers presents an even
further challenge.
facial selectivity5 to provide silalactone products possessing
a quaternary carbon stereocenter (eq 1).
We recently reported a method for the diastereoselective
construction of quaternary carbon stereocenters (eq 1).2 This
method involves silylene transfer to an R,â-unsaturated ester,
providing a silyl ketene acetal with complete regio- and
stereoselectivity. When transfer to an R,â-unsaturated allylic
ester occurs, the resulting silyl ketene acetal can undergo a
stereospecific Ireland-Claisen rearrangement3,4 with high
In this paper, we describe silylene transfer/Ireland-Claisen
reactions of enantiomerically pure esters to control the
absolute configuration of compounds with quaternary carbon
stereocenters. The utility of this methodology was demon-
strated by the synthesis of (+)-5-epi-acetomycin.6
The formation of new stereocenters in the silylene transfer/
Ireland-Claisen rearrangement can be controlled by a
stereocenter at the allylic position of an R,â-unsaturated
allylic ester.7,8 Metal-catalyzed silylene transfer to ester 4
(1) For recent reviews, see: (a) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105-10146. (b) Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. 2004, 101, 5363-5367. (c) Trost, B. M.; Jiang, C. Synthesis
2006, 369-396.
(2) Calad, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 2046-
2047.
(3) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III J. Org. Chem. 1991,
56, 650-657.
(4) Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M.
C. Tetrahedron 2002, 58, 2905-2928.
(5) Gilbert, J. C.; Yin, J.; Fakhreddine, F. H.; Karpinski, M. L.
Tetrahedron 2004, 60, 51-60.
(6) Tadano, K.-i.; Ishihara, J.; Ogawa, S. Tetrahedron Lett. 1990, 31,
2609-2612.
(7) Ho¨ck, S.; Koch, F.; Borschberg, H.-J. Tetrahedron: Asymmetry 2004,
15, 1801-1808.
10.1021/ol063072p CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/17/2007

likely occurred by formation of a silacarbonyl ylide (5),
which then underwent a 6π electrocyclization to provide
oxasilacyclopentene 6 (Scheme 1). This intermediate contains
The key step in our initial synthetic plan involved a silyl-
ene transfer/Ireland-Claisen rearrangement with all of the
stereochemistry of the target controlled by the allylic stereo-
center (Scheme 2). Disconnection of (+)-5-epi-acetomycin
Scheme 1. Controlling Quaternary Carbon Stereochemistry
Scheme 2. Acetomycin Retrosynthesis
a tetrasubstituted silyl ketene acetal moiety embedded within
the ring. At ambient temperature, oxasilacyclopentene 6
underwent an Ireland-Claisen rearrangement to afford
silalactone 7 with high diastereoselectivity and the formation
of an all-carbon quaternary center. The stereochemistry of
the product can be explained by a chairlike transition state
in which the isopropyl substituent adopts an equatorial
position.9
We chose to highlight the synthetic utility of the silylene
transfer/Ireland-Claisen rearrangement in the enantioselec-
tive synthesis of (+)-5-epi-acetomycin (8). This compound
is an anologue of (-)-acetomycin because the two com-
pounds differ only in the configuration at the acetal stereo-
center. Acetomycin is an antibiotic that was isolated from
Streptomyces ramulosus by Prelog and co-workers in 1958.10
The structure and the relative and absolute configurations
were later determined by X-ray crystallography.11,12 In
addition to showing antibacterial properties, this compound
has also demonstrated in vitro antitumor activity.13-15 Several
syntheses of acetomycin and its analogues have been
undertaken.6,15-22
at the acetal center provides an aldehyde, which would be
formed by ozonolysis of keto acid 9. The acetyl group of keto
acid 9 could arise by oxidation of silalactone 10, which could
be obtained from silylene transfer/Ireland-Claisen rearrange-
ment of ester 11 through a chairlike transition state. Because
the Ireland-Claisen rearrangement of trans-allylic ester 1 pro-
vided compound 3, the cis-ester 11 should provide the oppo-
site stereochemistry at the new allylic center in silalactone
10.8b
The silylene transfer/Ireland-Claisen rearrangement of a
cis-substituted R,â-unsaturated allylic ester was slow and
occurred with low stereoselectivity. Treatment of ester 12,
formed in two steps from tiglic acid, under the silylene
transfer conditions afforded an inseparable mixture of
silalactones 14 and 15 (Scheme 3). Silalactone 15 resulted
Scheme 3. Lack of Reactivity and Diastereoselectivity
(8) For examples of chirality transfer from secondary allylic alcohols in
the Claisen rearrangement, see: (a) Hill, R. K.; Edwards, A. G. Tetrahedron
Lett. 1964, 5, 3239-3243. (b) Chan, K.-K.; Cohen, N.; De Noble, J. P.;
Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497-3505. (c)
Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452.
(9) Faulkner, D. J.; Petersen, M. R. Tetrahedron Lett. 1969, 3243-3246.
(10) Ettlinger, L.; Gaumann, E.; Hutter, R.; Keller-Schierlein, W.;
Kradolfer, F.; Neipp, L.; Prelog, V.; Zahner, H. HelV. Chim. Acta 1958,
41, 216-219.
(11) Uhr, H.; Zeeck, A.; Clegg, W.; Egert, E.; Fuhrer, H.; Peter, H. H.
J. Antibiot. 1985, 38, 1684-1690.
(12) Cano, F. H.; Foces-Foces, C.; Elguero, J. Acta Crystallogr., Sect.
C.: Cryst. Struct. Commun. 1988, C44, 919-921.
(13) Mamber, S. W.; Mitulski, J. D.; Hamelehle, K. L.; French, J. C.;
Hokanson, G. C.; Shillis, J. L.; Leopold, W. R.; Von Hoff, D. D.; Tunac,
J. B. J. Antibiot. 1987, 40, 73-76.
from hydrolysis of intermediate silyl ketene acetal 13 before
the Ireland-Claisen rearrangement occurred. Upon pro-
longed standing at ambient temperature, the yield of desired
(14) Mamber, S. W.; Mitulski, J. D.; Borondy, P. E.; Tunac, J. B. J.
Antibiot. 1987, 40, 77-80.
(15) Chen, D.; Sprules, T. J.; Lavalle´e, J.-F. Bioorg. Med. Chem. Lett.
1995, 5, 759-762.
(16) Uenishi, J.; Okadai, T.; Wakabayashi, S. Tetrahedron Lett. 1991,
32, 3381-3384.
(18) Ishihara, J.; Tomita, K.; Tadano, K.-i.; Ogawa, S. J. Org. Chem.
1992, 57, 3789-3798.
(19) Ziegler, F. E.; Kim, H. Tetrahedron Lett. 1993, 34, 7669-7672.
(20) Sprules, T. J.; Lavalle´e, J.-F. J. Org. Chem. 1995, 60, 5041-5047.
(17) Echavarren, A. M.; de Mendoza, J.; Prados, P.; Zapata, A.
Tetrahedron Lett. 1991, 32, 6421-6424.
1038
Org. Lett., Vol. 9, No. 6, 2007

product 14 did not increase. The low reactivity observed for
substrate 12 is likely the result of increased steric congestion
and developing 1,3-diaxial interactions in the transition state
for rearrangement.
Scheme 5. Chiral Induction and Chirality Transfer
An additional stereochemical problem emerged with the
initial synthetic plan. Attempts to control the stereoselectivity
of the 6π electrocyclic reaction failed. Treatment of ester
16 to the silylene transfer/Ireland-Claisen rearrangement
conditions provided silalactone 17 with low diastereoselec-
tivity (eq 2).
Silylene transfer to chiral ester 4 followed by an Ireland-
Claisen rearrangement established two stereocenters, includ-
ing the quaternary carbon center, with high diastereoselec-
tivity (Scheme 5). Treatment of ester 4 with Cu(OTf)2 and
silacyclopropane 2 provided an oxasilacyclopentene, which
underwent an Ireland-Claisen rearrangement in 97% yield
with no apparent erosion of enantiomeric purity.29 Copper
salts proved to be optimal catalysts for this transformation
because problems with product inhibition were seen upon
scale-up of the silver-catalyzed reaction.
The synthetic plan was revised so that the acetyl moiety
of keto acid 9 could result from the carbonyl group of
silalactone 7 and the carboxylic acid moiety of acid 9 could
be revealed by a carbon-silicon bond oxidation of silalactone
7 (Scheme 4).23-25 Silalactone 7 could be obtained by silylene
transfer to chiral ester 4, as was demonstrated in Scheme 1.
The conversion of silalactone 7 to alcohol 19 was achieved
by nucleophilic additions to both the silicon atom and the
carbonyl group. Phenylmagnesium bromide did not add to
silalactone 7, but addition of allylmagnesium chloride yielded
a carboxylic acid (Scheme 5). Reduction of this carboxylic
acid with LiAlH4 afforded alcohol 19.
Scheme 4. Redesigned Acetomycin Retrosynthesis
Diol 21 was constructed in three high-yielding steps from
alcohol 19. Oxidation followed by addition of MeLi provided
alcohol 20 (Scheme 6). Oxidation of the carbon-silicon bond
Scheme 6. Synthesis of (+)-5-epi-Acetomycin
The initial stereocenter of ester 4 was established with
complete enantioselectivity. Addition of isopropylmagnesium
chloride to crotonaldehyde followed by kinetic resolution
provided a single enantiomer of 18 (Scheme 5).26-28 Esteri-
fication with methacryloyl chloride provided R,â-unsaturated
allylic ester 4 in 70% yield and >99% ee.
(21) Kinderman, S. S.; Feringa, B. L. Tetrahedron: Asymmetry 1998,
9, 1215-1222.
(22) Uenishi, J.; Kawatsura, M.; Ikeda, D.; Muraoka, N. Eur. J. Org.
Chem. 2003, 3909-3912.
(23) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4249-4252.
(24) Fleming, I.; Winter, S. B. D. Tetrahedron Lett. 1993, 34, 7287-
7290.
(25) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-
of alcohol 20 with cumene hydroperoxide and potassium
hydride in the presence of a fluoride source afforded diol
21 in 98% yield.23-25
6046.
(26) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(27) McKee, B. H.; Kalantar, T. H.; Sharpless, K. B. J. Org. Chem. 1991,
56, 6966-6968.
(28) Brown, J. M.; Leppard, S. J.; Oakes, J.; Thornthwaite, D. Chirality
2000, 12, 496-504.
(29) An analysis of the chirality transfer is provided in the Supporting
Information.
Org. Lett., Vol. 9, No. 6, 2007
1039

The synthesis of (+)-5-epi-acetomycin was completed in
three steps from diol 21. Stepwise oxidation of diol 21 to a
1,3-dicarbonyl compound, followed by further oxidation of
the aldehyde group to the acid, provided an intermediate
â-keto acid.30 This intermediate was prone to decarboxylation
at room temperature,17 so it was handled quickly at cooler
temperatures (0 to -78 °C). Immediate ozonolysis of the
carbon-carbon double bond,6,16 followed by in situ acetyl-
ation,17 provided (+)-5-epi-acetomycin in 41% yield.
In conclusion, the silylene transfer/Ireland-Claisen rear-
rangement of chiral R,â-unsaturated allylic esters affords
silalactone products containing chiral quaternary stereo-
centers. These reactions occur with chirality transfer and with
high diastereoselectivity. Application of this methodology
to the synthesis of (+)-5-epi-acetomycin has been ac-
complished in ten steps and 23% overall yield from the
known chiral allylic alcohol 17.
Acknowledgment. This research was supported by the
National Institute of General Medical Sciences of the
National Institutes of Health (GM-54909). S.A.C. thanks the
National Institutes of Health for a predoctoral fellowship.
K.A.W. thanks Amgen and Lilly for awards to support
research. We thank Dr. Phil Dennison (UCI) for assistance
with NMR spectroscopy and Dr. John Greaves and Ms.
Shirin Sorooshian (UCI) for mass spectrometry.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(30) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091-2096.
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