Paterson et al.
SCHEME 1. Retrosynthesis of Discodermolide (1) Based on C5-C6 and C16-C17 Aldol Disconnections
ceutical industry, the landmark synthesis of over 60 g of
discodermolide for Phase I clinical trials has been achieved
by Novartis chemists, following a hybrid Smith-Paterson
route, as reported recently by Mickel and co-workers.21,22
Despite these impressive efforts, there is still a pressing
demand for developing a more practical and efficient
synthesis of discodermolide, particularly one that can be
adapted to provide a manufacturing route. Herein, we
report full details of our improved second-generation total
synthesis,19d which has the potential to be scaled up to
provide significant quantities of discodermolide.
Results and Discussion
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Synthesis Plan. In 2000, we reported an initial total
synthesis of discodermolide, based on the novel applica-
tion of complex aldol reactions, that proceeded in 10.3%
yield over 23 steps in the longest linear sequence and 42
total steps.19a-c Following on from this work, we sought
further refinements to enable the large-scale synthesis
of discodermolide within industry.19d Our revised strategy
(Scheme 1) was designed to rely upon substrate-based
stereocontrol only, thereby eliminating the use of all
chiral reagents and auxiliaries, while reducing the total
number of synthetic operations required. To achieve these
specific goals, a novel aldol coupling was envisaged
between C1-C5 aldehyde 9 and C6-C24 methyl ketone 10,
relying on the possibility of exploiting remote 1,6-asym-
metric induction from the C10 stereocenter in 10. The
methyl ketone 10 would then arise from diol 11, an
advanced intermediate from our first-generation synthe-
sis (also used in the Novartis large-scale synthesis of
discodermolide21), which would arise from the aldol union
of Heathcock-type23 ester 12 and aldehyde 13. The second
goal of our campaign was to be achieved by recognition
of the common 1,2-anti-2,3-syn stereotriad in each of our
key fragments 9, 12, and 13, which could arise from the
1,3-diol 14. A related common precursor strategy was
utilized by Smith and co-workers, to great effect.16
Synthesis of the Common Building Block. The
synthesis of the common building block 14 needed to
address several criteria. In particular, a concise, efficient
and stereocontrolled preparation, amenable to large-scale
operation, was required. We chose to exploit the boron-
mediated aldol reaction of the versatile dipropionate
equivalent 15 and formaldehyde to configure the requi-
site 1,3-anti methyl groups in diol 14 (Scheme 2).24,25 The
ethyl ketone 15 was readily prepared in three steps (84%
(23) (a) Montgomery, S. H.; Pirrung, M. C.; Heathcock, C. H. Org.
Synth., Coll. Vol. 1990, 7, 190. (b) Heathcock, C. H.; Pirrung, M. C.;
Montgomery, S. H.; Lampe, J. Tetrahedron 1981, 37, 4087. (c)
Heathcock, C. H. Aldrichimica Acta 1990, 23, 99.
(22) Gunasekera, S. P.; Mickel, S. J.; Daeffler, R.; Niederer, D.;
Wright, A. E.; Linley, P.; Pitts, T. J. Nat. Prod. 2004, 67, 749.
152 J. Org. Chem., Vol. 70, No. 1, 2005