Organic Letters
Letter
accompanied by substantial epimerization of the C(20)
stereocenter.6
While the DIBALH-based aza-aldol reaction proceeds
without any meaningful selectivity,7,8 Ghosh has shown that
the use of the chiral Lewis acid (S)-TRIP (Scheme 1) gives 1
with ca. 3:1 selectivity.10,11
As part of an ongoing program on the synthesis and SAR
investigations of analogs of 1, we were interested in the
biological activity of 13-desmethylene zampanolide (4) (see
Scheme 2). If similarly active as 1, 4 would represent a more
zampanolide (4) with an excellent dr of 13.3:1, which allowed
the isolation of 4 as single isomer in 74% yield.19 Lowering the
reaction temperature to 0 °C improved the diastereomeric
ratio further, but only low conversion was obtained, possibly
due to decomposition of the BINAL-amide complex. The
reaction of aldehyde 5 with the putative amide transfer reagent
derived from (R)-BINOL (i.e., ent-7) gave the C(20)R-epimer
of 4 as the major product in 61% isolated yield (the dr of the
crude product before chromatography was 4.6:1). In contrast,
Gosh and co-workers have reported that the (R)-TRIP-
catalyzed reaction between 2 and 3 gave a 1:1 mixture of
diastereomers at C(20).11
The above methodology was also successfully applied to the
synthesis of natural (−)-zampanolide (1) from (−)-dactylolide
(2) (Scheme 3); 1 was obtained in 81% yield, which makes
this process more efficient than the (S)-TRIP-catalyzed aza-
aldol reaction, which gave 1 in 51% yield.10,11
Scheme 2. Stereoselective Construction of the Hemiaminal
Moiety in 4
Scheme 3. Stereoselective Synthesis of (−)-Zampanolide
(1) from (−)-Dactylolide (2)
readily accessible template for SAR studies, at least within the
framework of our own global strategy toward the synthesis of
1.8 Neither the synthesis of 13-desmethylene zampanolide (4)
nor its biological activity has been reported; however, Taylor
and co-workers have described the synthesis of 17-desmethyl-
13-desmethylene zampanolide, which they found to be a 17- to
57-fold less potent cell growth inhibitor than 1 (for a 1.5:1
diastereomeric mixture at C(20); tested against three cancer
cell lines).16
Finally, we also prepared the enantiomer of 1, i.e. ent-1, via
aza-aldol reaction of ent-2 with the amide transfer reagent
formed from (R)-BINOL, LiAlH4, ethanol, and 3 (Scheme 4).
Scheme 4. Stereoselective Synthesis of (+)-Zampanolide
(ent-1)
Initial attempts at the synthesis of 4 involved the addition of
(Z,E)-sorbamide (3) to aldehyde 58,12 with 10 mol % (S)-
TRIP as a chiral Brønsted acid catalyst according to
Ghosh.10,11 The reaction proceeded with only moderate
selectivity and gave 4 as a ca. 2:1 mixture of isomers in 33%
yield after 16 h (with incomplete conversion).
Given the fact that we had planned to prepare a series of
analogs of 4 for SAR studies, this level of selectivity was rather
unsatisfactory and would lead to substantial losses of material
in the purification process.8 Trying to develop a solution to the
selectivity problem, we took inspiration from Noyori’s earlier
work on the development of the chiral carbonyl reducing
agents (S)- and (R)-BINAL-H (6 and ent-6, Scheme 2).17,18
The latter are generated from (S)- or (R)-BINOL, respectively,
LiAlH4, and ethanol. We hypothesized that the addition of
(Z,E)-sorbamide (3) to a solution of (S)-BINAL-H could lead
to the formation of the aluminum carboximidoate complex 7
(Scheme 2), which would then transfer the sorbamide moiety
to 2 in a stereoselective fashion; based on Noyori’s work on
the BINAL-H reduction of aldehydes,18 we predicted that the
putative amide transfer reagent 7, derived from (S)-BINOL,
would give the desired C(20) S isomer 4 (Scheme 2). In the
event, the addition of a solution of (Z,E)-sorbamide (3) in
THF to a freshly prepared solution of (S)-BINAL-H (6) in
THF at room temperature produced an almost clear solution
of what we assumed to be BINAL-amide 7. When this solution
was added immediately to a solution of aldehyde 5 in THF at
room temperature, full conversion of the latter was observed
after 15 min. The reaction produced 13-desmethylene
Aldehyde ent-2 was prepared from L-aspartic acid in 14 steps
and 7% overall yield according to the route that we had
developed previously for the synthesis of 2.8,12 The aza-aldol
reaction proceeded with a dr of >25:1 and delivered ent-1 in
74% yield as a single isomer.20
After having established the utility of our stereoslective
amide transfer method for the stereoselective installation of the
C(20) stereocenter in zampanolide-type structures, we briefly
investigated its applicability to other systems (Scheme 5).
Somewhat disappointingly, the reaction of the amide transfer
reagent obtained from (S)-BINOL and amide 3 with (S)-
citronellal (11) gave N-acyl hemiaminal 13 essentially without
selectivity; analogous results were obtained with benzamide
instead of 3. In contrast, reaction of (purported) 7 with
B
Org. Lett. XXXX, XXX, XXX−XXX
Brütsch, Tobias M.
