Our studies began with the optically active D ring diol 4,
which was prepared from epoxy sulfone 2 and triflate 3 in
six steps (Scheme 1).6 One-pot triflation and triethylsilylation5b
the tertiary alcohol 10 in good selectivity (dr 94:6) (Scheme
2).8 Removal of the PMB group of 10 with DDQ9 gave a
Scheme 2
Scheme 1
3:2 mixture of an allylic alcohol and the corresponding R,â-
unsaturated aldehyde. To avoid handling of the labile
aldehyde, the reaction mixture was further treated with
sodium borohydride in one pot, yielding the allylic alcohol
in 92% yield. The subsequent epoxidation with m-CPBA
gave â-epoxy alcohol 11 in high stereoselectivity (dr 96:
4),10 which was then subjected to SO3‚pyridine oxidation and
the Wittig reaction to afford vinyl epoxide 12 in 75% overall
yield. The vinyl epoxide underwent a smooth cyclization in
a 6-endo manner upon treatment with PPTS at 0 °C to afford
tetracyclic vinyl alcohol 13 in 74% yield.11
of diol 4 gave triflate 5 in 94% yield. The triflate was coupled
with the oxiranyl anion generated from the racemic trans-
R,â-epoxy sulfone 6 to afford a mixture of epoxy sulfones
7 composed of two diastereoisomers in 89% yield. Removal
of the triethylsilyl group followed by the reaction with
magnesium bromide gave a 1:1 mixture of diastereomeric
bromo ketones 8. Subjecting the mixture to cyclization with
DBU yielded tricyclic ketone 9 predominantly as one
diastereoisomer (dr 94:6) in good yield.7
Construction of the A ring is a challenging issue, because
its R-axial hydroxy group at C-6 and â-equatorial three-
carbon side chain at C-4 have to be installed stereoselectively.
The reported methods employed asymmetric allylation of an
aldehyde3a and reduction of a hydroxy epoxide4b to introduce
the C-6 hydroxy group and necessitated an additional
carbon-carbon bond-forming reaction and an intramolecular
hetero-Michael reaction to construct the A ring. We envi-
sioned that the hydroxy group and the side chain could be
constructed by the reaction of an epoxide derived from 13
with a 2-substituted lithiodithiane (Scheme 3).
This cyclization has the advantage that neither the stereo-
chemistry of bromo ketones 8, in turn, nor that of 7 is
relevant, because the initial cyclization products undergo
facile base-catalyzed equilibration to give the thermodynami-
cally more stable isomer 9 possessing an equatorial C-10
substituent.
Stereocontrolled installation of the C-11 â-axial methyl
group was accomplished with trimethylaluminum to provide
(4) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002,
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Am. Chem. Soc. 2002, 124, 14983-14992. (c) Kadota, I.; Takamura, H.;
Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2003,
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Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158-8159.
The homoallylic hydroxy-directed epoxidation12 of 13 with
13
tert-butyl hydroperoxide in the presence of VO(acac)2
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(10) Sharpless asymmetric epoxidation showed a lower diastereoselec-
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(11) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330-5334.
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