Addition of pentadienyl indium to hemiacetal 14 afforded
1,4-diene 15 as a 1:1 mixture of diastereomers in 96% yield.5
The primary alcohol was selectively protected as a silyl ether,
and the secondary alcohol was eliminated under either
Mitsunobu type conditions or with Martin’s sulfurane to give
triene 16 in yields of 90% and 99%, respectively. Material
closely related to alcohol 15 was also synthesized from
aldehyde 13 (R ) Bn) by a parallel diene addition. Fluoride-
induced removal of the primary silyl group in 16 released
alcohol 17, which was oxidized under Swern conditions to
give aldehyde 18. This compound was reacted directly with
vinylmagnesium bromide to generate allylic alcohol 19. A
second Swern oxidation formed ketone 20 in situ which
cyclized spontaneously (without isolation of this enone) at
room temperature (21 °C) to afford adduct 21 (R ) H, 78%).
The bridgehead methyl substituent (C-19) was introduced
by reacting aldehyde 18 with 2-propenylmagnesium bromide.
Oxidation of the resulting alcohol 19 (R ) Me) under Swern
conditions afforded ketone 20 (R ) Me). In the same manner
as above, the ketone was not isolated and cyclized after 1 h
at 0 °C to provide adduct 21 (R ) Me) in 76% yield.
This cis isopropylidene acetal system cyclized more readily
than a closely related trans isomer.6,7 Thus epimerization of
an acetal center improved the efficiency of the reaction but
led to the same stereochemical result.
cycloaddition. A variety of tetracyclic steroidal type systems
related to 22 were produced, with high stereocontrol in yields
of 83-92%, depending upon the cyclic dienophile selected
(box, Scheme 3). These dienophiles added from the most
accessible convex face of 21 in an endo orientation as
illustrated in Figure 2.
In a parallel fashion, benzoquinone added selectively to
21 (Scheme 4) from the top face to form the highly
Scheme 4. Cycloaddition to Nor-Triterpenoid 23
The endo transition state 23 is preferred, in which the tether
adopts a boatlike conformation to accommodate the adjacent
acetonide oxygen bond and neighboring ether in an equatorial
relationship. This orientation places the diene and dienophile
in close proximity for facile cyclization (Figure 2). The
oxygenated nor-triterpenoid 25 in 85% yield. A single-crystal
X-ray analysis of 25 confirmed the stereochemical assign-
ments illustrated. It is obvious that considerable functional
group manipulation of these ring systems is possible. In
addition, the six-membered rings in 25 bearing carbonyl
groups may be viewed as either the A or the D ring
component depending upon the synthetic objective. Further-
more, the ring fusion in these adducts may be adjusted at
several of the different bridgehead positions due to the
presence of the adjacent ketone or vinyl functionality.
In conclusion, we have developed a versatile tandem
Diels-Alder strategy, based on acetal and triene building
blocks, for the rapid assembly of highly oxygenated, nor-
methyl triterpenoid and steroid type skeletons in an enan-
tiospecific manner. Additional investigations are under
development and will be reported in due course.
Figure 2. Cycloaddition Transition States
significant nonbonded interactions, between the vinyl and
methoxymethyl substituents, evident in other transition states
such as 24, are thus avoided.
(6) Melekhov, A. G.; Legoupy, S.; Forgione, P.; Lee, M. L.; Fallis, A.
G. Abstracts of Papers, 218th National Meeting of the American Chemical
Society, New Orleans, LA, Aug 22-26, 1999; American Chemical
Society: Washington, DC, 1999; Abstract ORGN 546.
(7) Wong, T.; Wilson, P. D.; Woo, S.; Fallis, A. G. Tetrahedron Lett.
1997, 38, 7045.
The decalin diene 21 containing the A-B framework is
now suitably functionalized for a second (tandem11) [4 + 2]
(8) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R. Tetrahedron 1989,
45, 319.
(9) (a) Wu, W. L.; Wu, Y. L. J. Org. Chem. 1993, 58, 3586. (b) Wu, W.
L.; Wu, Y. L. Tetrahedron Lett. 1993, 21, 4665.
(3) (a) Siddall, J. B.; Horn, D. H. S.; Middleton, E. J. J. Chem. Soc.,
Chem. Commun. 1967, 899. (b) Siddall, J. B.; Marshall, J. P.; Bowers, A,;
Cross, A. D.; Edwards, J. A.; Fried, J. H. J. Am. Chem. Soc. 1966, 88, 397.
(c) Siddall, J. B.; Cross, J. A.; Fried, J. H. J. Am. Chem. Soc. 1966, 88,
862.
(4) (a) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464; (b) Can. J. Chem.
1999, 77, 159; (c) Pure Appl. Chem. 1997, 69, 495.
(5) (a) Woo, S.; Squires, N.; Fallis, A. G. Org. Lett. 1999, 1, 573-575.
(b) See also: Hirashita, T.; Inoue, S.; Yamamura, H.; Kawai, M.; Araki, S.
J. Organomet. Chem. 1997, 549, 305.
(10) Ballou, C. E. J. Am. Chem. Soc. 1957, 79, 165.
(11) (a) Winkler, J. D. Chem. ReV. 1996, 96, 167. (b) Spino, C.; Crawford,
J. Can. J. Chem. 1993, 71, 1094. (c) Spino, C.; Crawford, J.; Bishop, J. J.
Org. Chem. 1995, 60, 844. Tandem is sometimes defined rather loosely to
encompass all coupled reactions, but applied rigorously it involves two
sequential reactions in the same reaction vessel. This is possible in these
examples but purity is improved if a discrete workup intervenes.
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