Kiyooka et al.
steps involved in the synthesis of various types of
polypropionate frames. As a result, we were able to use
the aldol reaction strategy in the divergent construction
of a variety of polypropionate frames. This unique ap-
proach permits the introduction of all 13 stereocenters
of (+)-discodermolide by means of iterative Lewis acid-
mediated aldol reactions accompanied by a radical reduc-
tion with a high degree of stereoselection. The strategy
involved is described herein.
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. With respect to an acyclic
form related to (+)-discodermolide, our retrosynthetic
analysis dissected the target molecule at both sides of
C-14, thus generating segments A and B which contain
the necessary 13 stereogenic centers (Scheme 1). A two-
carbon unit at C-14 can be incorporated into segment B
as a (Z)-vinyl iodide by known methods,2e,f,10 prior to the
developed palladium(0)-cross-coupling reaction between
C-13 and C-14. Here segments A and B are the actual
targets. The fragments are similar, as depicted by the
squares in Scheme 1, which are bound in a series of
stereotriads.11 Smith effectively utilized a stereotriad as
(3) Segment syntheses: (a) Clark, D. L.; Heathcock, C. H. J . Org.
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Allison, B. D. Tetrahedron Lett. 1999, 40, 4461-4462. (i) Filla, S. A.;
Song, J . J .; Chen, L. R.; Masamune, S. Tetrahedron Lett. 1999, 40,
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F IGURE 1. Enantioselective or diastereoselective approach
to propionate units.
a precursor in the total synthesis of (+)-discodermolide.2f
If an easier synthetic access to the enantiopure equiva-
lents of the stereotriads were developed, it would directly
permit a systematic approach to the synthesis of a
natural product containing a variety of polypropionate
units. In practice, a series of chiral stereotriads could be
prepared from our chiral oxazaborolidinone-promoted
aldol reaction of racemic aldehydes.7 When the equivalent
segments, A and B, are simply derived from the corre-
sponding stereotriads, a versatile total synthesis of (+)-
discodermolide could be achieved. The C15-C21 segment
A could be prepared via two aldol reactions (providing
two syn-propionates) at the positions indicated by the two
slanted lines while the C1-C13 segment B, having eight
stereogenic centers, is shown by four slanted lines
indicating suitable positions for bond formation by four
sequential aldol reactions (providing one acetate, two
anti-propionates, and one syn-propionate). Thus, a quite
simple retrosynthetic route to (+)-discodermolide could
(8) A similar approach with selenides has been reported but it was
limited to the R-methyl-â-protected-oxy aldehydes, not bearing the
other substituent at the â position, which is essential for a model of
aldehydes toward the construction of polypropionate frameworks: (a)
Guindon, Y.; Houde, K.; Pre´vost, M.; Cardinal-David, B.; Landry, S.
R.; Daoust, B.; Bencheqroun, M.; Gue´rin, B. J . Am. Chem. Soc. 2001,
123, 8496-8501. (b) Guindon, Y.; Pre´vost, M.; Mochirian, P.; Gue´rin,
B. Org. Lett. 2002, 4, 1019-1022.
(9) Arjona, O.; Menchaca, R.; Plumet, J . J . Org. Chem. 2001, 66,
2400-2413.
(10) Arefolov, A.; Langille, N. F.; Panek, J . S. Org. Lett. 2001, 3,
3281-3264.
(11) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2055-
2070. (b) Arjona, O.; Menchaca, R.; Plumet, J . J . Org. Chem. 2001, 66,
2400-2413.
7968 J . Org. Chem., Vol. 68, No. 21, 2003