synthesis of dolabelide A because the C7-C11 and C19-C23
polypropionate/polyacetate motifs appeared ideally suited for
construction through successive hydrogenation reactions.
From a retrosynthetic point of view, dolabelide A can be
disconnected into two fragments, C1-C14 and C15-C30,
which would be assembled by esterification and ring-closing
metathesis, a strategy successfully adopted by Leighton5
(Scheme 1). Following our efforts toward the synthesis of
ynone and diastereoselective reduction of the ketone function.
Our first synthetic task, therefore, was to prepare a suitable
aldehyde fragment.
We chose compound 15 as a target, and this was easily
prepared in ten steps from δ-valerolactone 6 (Scheme 2).9
Scheme 2. Synthesis of Aldehyde 15
Scheme 1. Retrosynthetic Analysis of Dolabelide A
dolabelide A,4 we report herein the highly stereoselective
convergent synthesis of the C15-C30 subunit of this
compound, bearing all suitably protected hydroxyl groups.
In our retrosynthetic plan, three of the five stereocenters
of the target subunit would be created via ruthenium-
mediated asymmetric hydrogenation7 of ꢀ-keto esters using
the atropisomeric ligand SYNPHOS8 as the chiral diphos-
phine. The trisubstituted C24-C25 (E)-double bond would
be obtained through addition of alkyne 3 to aldehyde 2
followed by 1,4-addition of methyl cuprate to the resulting
Addition of lithio ethyl acetate to 6 resulted in the formation
of the cyclic hemiketal 7. This compound is in equilibrium
with the ꢀ-keto ester 7′ which is suitable for the ruthenium-
mediated asymmetric hydrogenation of the ketone function.
The reduction was carried out using the convenient procedure
developed in our laboratories for the in situ preparation of
chiral ruthenium-diphosphine complexes starting directly
from RuCl3.10 Thus, hydrogenation of 7/7′ using 0.5 mol %
of RuCl3 associated to (R)-SYNPHOS as a ligand provided
ꢀ-hydroxy ester 8 in high yield and with excellent enanti-
oselectivity (99% ee, measured by HPLC analysis). After
protection of the diol as TBDPS and PMB ethers using
standard conditions, subsequent chain extension with lithio
tert-butyl acetate11 delivered the ꢀ-keto ester 11 required for
(7) For reviews on Ru-catalyzed asymmetric hydrogenation, see: (a)
Ohkuma, T.; Kitamura, M.; Noyori, R. Asymmetric Hydrogenation. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; pp 1-110. (b) Kitamura, M.; Noyori, R. Hydrogenation and
Transfer Hydrogenation. In Ruthenium in Organic Synthesis; Murahashi,
S.-i., Ed.; Wiley-VCH: Weinheim, 2004; pp 3-52. (c) Genet, J.-P. Acc.
Chem. Res. 2003, 36, 908–918. For references to Noyori reductions with
BINAP-ruthenium complexes, see: (d) Kitamura, M.; Tokunaga, M.;
Ohkuma, T.; Noyori, R. Org. Synth., Coll. Vol. IX 1998, 589–596. (e)
Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856–5858.
(8) For the synthesis of SYNPHOS and comparison with BINAP in
asymmetric hydrogenation, see:(a) Duprat de Paule, S.; Jeulin, S.; Ra-
tovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Tetrahedron
Lett. 2003, 44, 823–826. (b) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-
Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Eur. J. Org. Chem. 2003,
1931–1941. (c) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.;
Genet, J.-P.; Champion, N.; Deschaux, G.; Dellis, P. Org. Process. Res.
DeV. 2003, 7, 399–406.
(9) (a) Duggan, A. J.; Adams, M. A.; Brynes, P. J.; Meinwald, J.
Tetrahedron Lett. 1978, 19, 4323–4326. (b) Loubinoux, B.; Sinnes, J. L.;
O’Sullivan, A. C. J. Chem. Soc., Perkin Trans. 1 1995, 521–525.
(10) Madec, J.; Pfister, X.; Phansavath, P.; Ratovelomanana-Vidal, V.;
Genet, J.-P. Tetrahedron 2001, 57, 2563–2568.
(11) Rathke, M. W.; Lindert, A. J. Am. Chem. Soc. 1971, 93, 2318–
2320.
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