be obtained using L-Selectride. Reductive cleavage to 11
followed by protecting group manipulation and elimina-
tion via the nitroselenoxide afforded silyl ether-olefin 12
(Scheme 1).
The parallel studies next examined osmylation of olefins
6 and 12, respectively. The Purdue group employed double
stereoselection via catalytic asymmetric dihydroxylation of
6, which delivered a pair of spiroketals in ∼6:1 selectivity
both bearing the 25S configuration.7,11 In comparison, stoi-
chiometric osmylation of 12 gave a 1:2 mixture favoring the
unnatural 25R stereochemistry.8
Application of the Suarez reaction to the C-23,26-dipro-
tected diol mixture 13 generated a 28/72 mixture of the two
5/5 ring spiroketals 14/15 in 83% yield. In stark contrast,
similar treatment of the C-26 protected substrate 7 generated
a single diastereomeric spiroketal 8, which was shown to
have the desired 22-natural stereochemistry (Scheme 2).
Figure 1.
oxidation reactions to introduce common features found in
both cephalostatin hemispheres (Figure 1).
Our revised approach to the North 1 and South 7 segments
is based upon the Suarez cyclization we employed for the
synthesis and structure correction of Ritterazine M.7 A related
model study has recently appeared from the Suarez group.8
We have found that it is essential to define the “gestalt”
effects of the entire steroid upon chemistry occurring at a
supposedly remote site. In this light, comparison of the
Suarez study8 with our current investigation is particularly
instructive.
Scheme 2
Our study began with compound 4,9 having C12 and
C14-15 in the required oxidation state. Reductive cleavage
of the spiroketal gave alcohol 5, which was converted to
olefin 6 through the intermediate iodide (Scheme 1).
These and other experiments (Vide infra) proVe that a
C14-15 olefin is required to achieVe stereospecific asym-
metric dihydroxylation at C25,26.
The new Purdue synthesis begins with our improved
transformation of hecogenin acetate 16 to â-hydroxyketone
17 in a one-pot 94% yield.9 Dimethyldioxirane has been
effectively used for the oxidation of tertiary C-H bonds in
steroids,12 and application of this reagent to spiroketal 17
smoothly provides diol 18 in 82% yield (15.7 g).14 Initial
experiments to effect bis-dehydration of 18 were quite
unrewarding. For example, treatment of hemiketal 18 with
2.1 equiv of BF3‚OEt2 in CH2Cl2 from -10 to +25 °C for
18 h gave dienone 19 in 27% yield. Attempts to intercept
Scheme 1
(11) Originally this mixture was misassigned as a mixture of stereoiso-
mers at C25,7 but the minor isomer is actually the C22â spiroketal and can
be equilibrated quantitatively to the natural C22R configuration under acidic
conditions (Lee, S. M. Unpublished results).
(12) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
124. Iida, T.; Yamaguchi, T.; Nakamori, R.; Hikosaka, M.; Mano, N.; Goto,
J.; Nambara, T. J. Chem. Soc., Perkin Trans. 1 2001, 2229. Bovicelli, P.;
Lupattelli, P.; Fiorini, V.; Mincione, E. Tetrahedron Lett. 1993, 34, 6103.
Dixon, J. T.; Holzapfel, C. W.; van Heerden, F. R. Synth. Commun. 1993,
23, 135. Bovicelli, P.; Lupattelli, P.; Fiorini, V.; Mincione, E. Tetrahedron
Lett. 1993, 34, 6103. Bovicelli, P.; Lupattelli, P.; Fracassi, D.; Mincione,
E. Tetrahedron Lett. 1994, 35, 935.
(13) Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.; Clarke,
T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.;
Sheppard, R. N.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1989, 45,
7161. Ley, S. V.; Anderson, J. C.; Blaney, W. M.; Jones, P. S.; Lidert, Z.;
Morgan, E. D.; Robinson, N. G.; Santafianos, D.; Simmonds, M. S. J.;
Toogood, P. L. Tetrahedron 1989, 45, 5175. Bernsmann, H.; Hungerhoff,
B.; Fechner, R.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett. 2000, 41, 1721.
(14) X-ray structural information relating to compounds 18, 20, and 26
can be obtained from the Cambridge Crystallographic Data Centre.
The Suarez group started with compound 10 having C12
and C14 in the fully reduced state. This material was con-
verted to the C23 ketone via the nitroimine.10 Similar to pre-
vious cases, reduction of the spiroketal C-23 ketone was
highly selective (5:95) for the (unnatural) equatorial alco-
hol, although a 63:37 ratio favoring the axial alcohol could
(7) Lee, S. M.; Fuchs, P. L. Org. Lett. 2002, 4, 317. Lee, S. M.; LaCour,
T. G.; Lantrip, D.; Fuchs, P. L. Org. Lett. 2002, 4, 313.
(8) Betancor, C.; Freire, R.; Perez-Martin, I.; Prange, T.; Suarez, E. Org.
Lett. 2002, 4, 1295.
(9) LaCour, T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.; Fuchs, P. L. J.
Am. Chem. Soc. 1998, 120, 692.
(10) Barton, D. H. R.; Sammes, P. G.; Taylor, M. V.; Werstiuk, E. J.
Chem. Soc. 1970, 1977. Gonzalez, A. G.; Freire, R.; Garcia-Estrada, M.
G.; Salazar, J. A.; Suarez, E. Anal. Quim. 1971, 67, 903. Gonzalez, A. G.;
Freire, R.; Garcia-Estrada, M. G.; Salazar, J. A.; Suarez, E. Tetrahedron
1972, 28, 1289.
2248
Org. Lett., Vol. 5, No. 13, 2003