7984
J . Org. Chem. 1996, 61, 7984-7985
Our strategy focused on the enantioselective construc-
tion of the quaternary center using an asymmetric Diels-
Alder reaction of the chiral dienophile 6, prepared from
the controller lactam 7 (ent-1 obtained from 1(S)-
camphor) and tris[(triisopropylsilyl)oxy] diene 8 (Scheme
1). Beginning with known aldehyde 9,9 two consecutive
Wittig reactions using (formylmethylene)triphenyl-
phosphorane and (1-acetylethylidene)triphenylphos-
phorane10 afforded 60% of the E,E dienone 10 ac-
companied by less than 5% of a mixture of Z isomers after
purification by chromatography. Hydrolysis of the ac-
etonide in 10 using wet acidic silica gel in CH2Cl2,
followed by silylation of the resulting keto diol with
TIPSOTf and triethylamine, provided the desired oxy-
genated triene 8 in >99% yield over two steps.
Owing to the acid lability of triene 8, the crucial Lewis
acid-catalyzed Diels-Alder reaction between 6 and 8
gave very poor yields of cycloadduct with a wide range
of Lewis acids.11 Recently, the TiCl4-SbPh3 complex had
been reported to be a superior Lewis acid promoter for
acid-sensitive substrates, apparently by minimizing the
presence of free TiCl4 in solution.12 When the TiCl4-
SbPh3 complex was employed for the cycloaddition of 6
and 8 in the presence of 1 equiv of (CH3)3Al as a proton
scavenger, decomposition of triene 8 was virtually elimi-
nated, affording a mixture of two diastereomeric cycload-
ducts 11 and 12 (11:1, endo/exo) in 89% yield with
complete diastereofacial selectivity within detection lim-
its.5,13 The absolute stereochemistry of the major dias-
tereomer 11 was determined by treatment of a mixture
of 11 and 12 with TBAF in THF at -78 °C and conversion
of the resulting diol with (CH3)2C(OCH3)2 and acid in
acetone to the nicely crystalline acetonide 13 whose
structure and absolute stereochemistry was confirmed by
single-crystal X-ray analysis.14
Tow a r d th e Develop m en t of a Gen er a l
Ch ir a l Au xilia r y. 5. High Dia ster eofa cia l
Selectivity in Cycloa d d ition s w ith Tr ien ol
Silyl Eth er s: An Ap p lica tion to a n
En a n tioselective Syn th esis of
(-)-Ca ssiosid e
Robert K. Boeckman, J r.* and Yugang Liu
Department of Chemistry, University of Rochester,
Rochester, New York 14627-0216
Received August 20, 1996
As part of a program directed at the development of
covalently bound and catalytic controllers for the dias-
tereofacially selective construction of carbon-carbon
bonds,1 we have developed a family of terpene-derived
bicyclic lactams 1-3 useful as chiral controller molecules
in a variety of applications.2,3 These controller molecules
have proven particularly valuable for the diastereofa-
cially selective construction of quaternary carbon centers
via [4 + 2] cycloaddition reactions, a significant short-
coming of a number of the most widely employed chiral
auxiliaries.1 Nevertheless, limitations in the scope of
cycloaddition methodology using 1-3 were still apparent.
Use of highly reactive oxygen-substituted dienes has not
been generally possible, although a few isolated cases
have been reported, owing principally to the sensitivity
of the dienes to the Lewis acids required to catalyze the
cycloaddition and to the lower diastereofacial selectivity
generally observed.2,4,5 We have addressed these prob-
lems by appropriate choice of protecting groups for the
dienes and modifications to the Lewis acids that mini-
mize the tendency toward destruction of the diene.
Having firmly established the absolute stereochemistry
of 11, reduction of the mixture of 11 and 12 with LiBH4
in THF gave rise to a mixture of the related alcohols and
recovered auxiliary 7 from which 14 was separated by
chromatography in 72% yield (Scheme 2). Conforma-
tional analysis of alcohol 14 suggested that the neopentyl
hydroxyl group was extremely hindered. Indeed, gly-
cosidation of 14 (and more advanced intermediates) failed
using a variety of commonly used glycosidation meth-
ods.15 The choice of the protecting group employed for
the glucose unit also proved to be crucial. The Kahne
We now report the successful use of suitably protected
oxygenated trienes in an application to the first synthesis
of the potent antiulcerogenic terpene glycoside (-)-
cassioside (4),6 isolated from the aqueous extract of the
Cinnamomi cortex and characterized by a J apanese
group in 1988.6 Owing to its biological activity and its
scarcity in nature, several syntheses of the aglycon (+)-
cassiol 5, which also exhibits very strong antiulcerogenic
properties, have appeared.7,8 These studies include a
conceptually related synthesis by Corey that appeared
as our effort was nearing completion.5
(5) Conceptually related studies toward (+)-cassiol were reported
during the course of our work: Corey, E. J .; Guzman-Perez, A.; Loh,
T.-P. J . Am. Chem. Soc. 1994, 116, 3611.
(6) Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yokoyama, K.;
Tanaka, S.; Fukui, H.; Tabata, M. Tetrahedron 1988, 44, 4703.
(7) (a) Takemoto, T.; Fukaya, C.; Yokoyama, K. Tetrahedron Lett.
1989, 30, 723. (b) Uno, T.; Watanabe, H.; Mori, K. Tetrahedron 1990,
46, 5563.
(8) Trost, B. M.; Li, Y. J . Am. Chem. Soc. 1996, 118, 6625.
(9) Bates, H. A.; Farina, J .; Tong, M. J . Org. Chem. 1986, 51, 2637.
(10) Fujiwara, K. Takahashi, H.; Ohta, M. Bull. Soc. Chem. J pn.
1962, 35, 2042.
(11) Among the Lewis acids tested, TiCl4 gave mainly diene decom-
position, Et2AlCl and Me2AlCl gave poor yields, and SnCl4 showed
insufficient reactivity.
(12) Suzuki, I.; Yamamoto, Y. J . Org. Chem. 1993, 58, 4783.
(13) This conclusion was based upon the observation that reduction
of the mixture of diastereomeric cycloadducts 11 and 12 (11:1) afforded
a similar mixture of diastereomeric alcohols (∼11:1) of which alcohol
14 was the major isomer. If adducts 11 and 12 were both endo arising
from facial selectivity in reaction with the diene, reduction would have
led to enantiomers of 14.
(14) Details of the single-crystal X-ray analysis of ketone 13 will be
published as part of a full account of this work.
(15) For reviews, see: (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993,
93, 1503. (b) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25,
212. (c) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(1) Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Seyden-
Penne, J ., Eds.; J ohn Wiley & Sons, Inc.: New York, 1995.
(2) (a) Boeckman, R. K., J r.; Connell, B. T. J . Am. Chem. Soc. 1995,
117, 12368. (b) Boeckman, R. K., J r.; J ohnson, A. T.; Musselman, R.
A. Tetrahedron Lett. 1994, 35, 8521. (c) Boeckman, R. K., J r.; Nelson,
S. G.; Gaul, M. D. J . Am. Chem. Soc. 1992, 114, 2258.
(3) Boeckman, R. K., J r.; Wrobleski, S. T. J . Org. Chem. 1996, 61,
submitted.
(4) Oppolzer, W.; Seletsky, B. M.; Bernardinelli, G. Tetrahedron Lett.
1994, 35, 3509.
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