ORGANIC
LETTERS
2007
Vol. 9, No. 21
4147-4150
Tandem Conjugate Addition−Elimination
for the Diastereoselective Synthesis of
4E-Alkenyl syn-1,3-Diols
Delphine Rotulo-Sims and Joe1lle Prunet*
Laboratoire de Synthe`se Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO,
F-91128 Palaiseau, France
Received July 11, 2007
ABSTRACT
We have developed a tandem conjugate addition
starting from vinyl sulfones. The sulfonyl group was then reduced with sodium amalgam to furnish the E-olefin as the major isomer. This
method was applied to the synthesis of a trisubstituted alkene modeling the C21 C25 fragment of Dolabelide C.
−elimination sequence for the diastereoselective synthesis of protected allylic syn-1,3-diols,
−
Dolabelide C (Figure 1) is a member of a family of four
macrolactones (Dolabelides A-D) isolated from the sea hare
described syntheses of Dolabelide fragments, and the total
synthesis of Dolabelide D has recently been reported by
Leighton and co-workers.4
The C21-C25 portion of this molecule encompasses a
syn-1,3-diol motif flanked by a trisubstituted olefin (Figure
1). We envisaged to install these functional groups by a
stereoselective intramolecular conjugate addition of a hemi-
acetal anion formed in situ from a δ-hydroxy vinyl sulfone
and benzaldehyde in the presence of base, followed by
elimination of a suitable leaving group (Scheme 1). The
resulting vinyl sulfone would then be reduced to the
corresponding olefin. Such a conjugate addition on simple
vinyl sulfones like 1a-c (eq 1) has already been reported
by us.5
Figure 1.
We first embarked on the synthesis of model substrates
of the C21-25 fragment lacking the methyl groups at C22
Dolabella auricularia (family Aplysiidae).1 It has been
shown to exhibit cytotoxic activity against HeLa-S3 cell
lines with an IC50 of 1.9 µg/mL. We2 and others3 have
(3) (a) C15-C24 and C25-C30: Desroy, N.; Le Roux, R.; Phansavath,
P.; Chiummiento, L.; Bonini, C.; Geneˆt, J.-P. Tetrahedron Lett. 2003, 44,
1763. C1-C13: Le Roux, R.; Desroy, N.; Phansavath, P.; Geneˆt, J.-P.
Synlett 2005, 429. (b) C15-C30: Schmidt, D. R.; Park, P. K.; Leighton, J.
L. Org. Lett. 2003, 5, 3535. (c) C1-C13: Keck, G. E.; McLaws, M. D.
Tetrahedron Lett. 2005, 46, 4911.
(4) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L. J. Am.
Chem. Soc. 2006, 128, 2796.
(5) Grimaud, L.; Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet, J.
Tetrahedron Lett. 2002, 43, 7477.
(1) Isolation of Dolabelides A and B: Ojika, M.; Nagoya, T.; Yamada,
K. Tetrahedron Lett. 1995, 36, 7491. Isolation of Dolabelides C and D:
Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada, K. J. Nat. Prod.
1997, 60, 155.
(2) C16-C24: Grimaud, L.; de Mesmay, R.; Prunet, J. Org. Lett. 2002,
4, 419. C1-C15: Vincent, A.; Prunet, J. Tetrahedron Lett. 2006, 47, 4075-
4077.
10.1021/ol701624y CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/19/2007