5738
J . Org. Chem. 1998, 63, 5738-5739
core heterocyclic system.7 A feature common to our syn-
thetic work is the stereospecific cyclization of the aziridine
of 3 onto the (E)-â-bromoacrylate to form the pyrrolidine ring
of target 2. Furthermore, the dehydroamino acid of 3 is
introduced from aldehyde 4 by Wadsworth-Horner-Em-
mons olefination. Thus, aldehyde 4 in suitably protected
form is the cornerstone intermediate in our synthetic plans.
Herein, we detail a synthetic approach to the core aziridino-
[1,2-a]pyrrolidine system 2 of the azinomycins that is based
on chelation-controlled addition of γ-alkoxycrotylstannane
6 to serine aldehyde 7 for the stereoselective introduction
of the differentiated C12/C13 syn-diol of intermediate 5, and
hence aldehyde 4.
Syn th esis of th e Aza bicyclic Cor e of th e
Azin om ycin s: In tr od u ction of Differ en tia ted
tr a n s-Diol by Cr otylsta n n a n e Ad d ition to
Ser in a l
Robert S. Coleman,*,†,‡ Thomas E. Richardson,† and
Andrew J . Carpenter§
Department of Chemistry and Comprehensive Cancer Center,
The Ohio State University, Columbus, Ohio 43210, and
Department of Chemistry and Biochemistry, University of South
Carolina, Columbia, South Carolina 29208
Received May 28, 1998
Azinomycins A (1a ) and B (1b) are antitumor agents
isolated from cultures of Streptomyces.1 These agents
contain a highly functionalized aziridino[1,2-a]pyrrolidine
ring system, which presents perhaps the most significant
synthetic challenge of these natural products. Synthetic
issues presented by this substructure include the tetrasub-
stituted (E)-dehydroamino acid double bond, of the selec-
tively acylated C12-C13 vic-diol, and of the electrophilic
aziridine ring system. Herein, we detail a short synthesis
of the aziridino[1,2-a]pyrrolidine substructure of the azino-
mycins that addresses these synthetic objectives.
Marshall and co-workers8 have demonstrated that γ-alkoxy
stannanes 6 (R1 ) SiMe2-t-Bu or CH2OCH3) undergo Lewis
acid-promoted addition to R-amino aldehydes 7 with high
syn stereoselectivity. In the context of the azinomycins, this
strategy would produce intermediate 5 with the emergent
C12 position unprotected (R2 ) H) and so would allow the
divergent introduction hydroxyl protecting groups at this
position. Stereoselection for the C11/C12 syn/C12/C13 syn
diastereomer 5 in the addition of 6 to 7 is a consequence of
a chelated aldehyde (C11/C12 bond) and the anti-SE′ transi-
tion state for crotylstannane addition (C12/C13 bond).9
In practice, when serine aldehyde (S)-910 was treated with
MgBr2‚OEt2 in CH2Cl2 at -20 °C followed by stannane (S)-
811 and warming to 25 °C, selectively protected diol 10 was
produced in near-quantitative yield with >10:1 selectivity
for the syn diastereomer.12 Performing the addition to (S)-9
with the racemic stannane rac-8 (2.5 equiv) effected useful
levels of kinetic resolution (>10:1 S/R) and obviated the need
for tedious and expensive preparation of enantiomerically
pure γ-alkoxy stannane (S)-8.
Azinomycins A and B exhibit potent in vitro cytotoxic
activity and significant in vivo antitumor activity,2 and the
electrophilic epoxide and aziridine rings suggest that the
azinomycins act by covalent cross-linking of DNA.3 The
azinomycins are attractive targets for synthetic efforts,4 but
with the exception of our work, there are no reports of
azabicyclic systems containing a differentiated C12/C13 diol
system, and no total synthesis of the natural products has
been reported.
A number of less than optimal features of our original
synthetic plan5,6 led us to devise alternative routes to the
† The Ohio State University.
‡ Comprehensive Cancer Center.
§ University of South Carolina.
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At this point, we selected an enzymatically removable
phenylacetate ester13 for C12 hydroxyl group protection. The
sterically crowded hydroxyl group of 10 was unreactive
(5) Coleman, R. S.; Carpenter, A. J . J . Org. Chem. 1992, 57, 5813.
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(7) Concurrent with the present work, we developed a complementary
synthesis of the core substructure 2 (R′ ) CH3): Coleman, R. S.; Kong, J .-
S. J . Am. Chem. Soc. 1998, 120, 3538.
(8) Marshall, J . A.; Seletsky, B.; Coan, P. S. J . Org. Chem. 1994, 59, 5139.
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(12) For the syn-selective addition of a vinylzinc reagent to R-amino
aldehydes in
a similar context, see: Coleman, R. S.; Carpenter, A. J .
Tetrahedron Lett. 1992, 33, 1697.
S0022-3263(98)01006-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998