7070
J . Org. Chem. 2000, 65, 7070-7074
New Ap p r oa ch to Ap h id icolin a n d Tota l Asym m etr ic Syn th esis of
Un n a tu r a l (11R)-(-)-8-Ep i-11-h yd r oxya p h id icolin by Ta n d em
Tr a n sa n n u la r Diels-Ald er /Ald ol Rea ction s
Guillaume Be´langer and Pierre Deslongchamps*,†
Laboratoire de synthe`se organique, De´partement de chimie, Institut de Pharmacologie, Universite´ de
Sherbrooke, Fleurimont, Que´bec, Canada J 1H 5N4
pierre.deslongchamps@courrier.usherb.ca
Received May 18, 2000
The 8-epiaphidicolane skeleton (3) was formed in one key reaction by highly diastereoselective
tandem transannular Diels-Alder (TADA)-aldol reactions from the trans-trans-cis trienic mac-
rocycle (4). The unnatural derivative (11R)-(-)-8-epi-11-hydroxyaphidicolin (2) was thus constructed,
and an original solution to the C16 functionalization problem of many aphidicolin (1) syntheses is
presented.
In tr od u ction
(+)-Aphidicolin (1, Figure 1) is a diterpenoic tetraol
isolated from Cephalosporium aphidicolia fungus. This
inhibitor of DNA polymerase R is known to act against
Herpes simplex type I virus, as well as to slow eucaryotic
cells proliferation. The latter property is quite interesting,
placing aphidicolin among potential agents for cancer
treatment. Its structure was elucidated by Hesp in 1972,
and many total syntheses have been published since
then. However, in most of them,4a-q functionalization at
the C16 position proved to be problematic with respect
to diastereoselectivity. This problem was first tackled by
A. B. Smith III4r,s in 1988, who successfully accomplished
F igu r e 1. (+)-Aphidicolin (1) and unnatural derivative (2).
the introduction of the hydroxymethyl moiety in a five-
step process.
Looking more closely at aphidicolan derivative 2, the
(11R)-hydroxyl could be of great utility for correct func-
tionalization at the C16 position by inducing facial
selectivity. Moreover, as we reported in a previous article,
a superimposition of the AM1 minimized structure of
aphidicolin and of its C8 epimer showed a good overlap
of the four hydroxyl functions. Knowing that aphidicolin
binding in the host cavity is due to these hydroxyls, the
overlap suggests a potential activity for the unnatural
C8 epimer. With these two arguments, we developed an
enantioselective total synthesis of (11R)-(-)-8-epi-11-
hydroxy-aphidicolin (2) as reported herein.6c
The strategy employed uses a tandem transannular
Diels-Alder (TADA)-aldol reaction as the key step,
performed on trans-trans-cis trienic macrocycle 4 (Scheme
1). The tetracycle 3 thus produced would lead to aphidi-
colin 1 or its derivative 2 by further elaboration. First,
macrocycle 4 could be obtained from Stille coupling
between vinylic iodide 5 and vinylic stannane 6, followed
by macrocyclization. Finally, iodide 5 could be generated
from our previously reported Weinreb amide 7.7 The
synthesis of tetracycle 3 has already been published by
Hall and Deslongchamps,5 but we significantly increased
the convergence and completed the synthesis from tet-
racyclic intermediate 3 to the end.
† Tel.: (819) 564-5300. Fax: (819) 820-6823.
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10.1021/jo0007635 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000