of using L-proline as the template on which one can
stereoselectively build new amino acid residues leading
to the formation of peptides that can potentially be the
structural analogues of such inhibitors. We have used a
functional N-protecting group on L-proline 1 (Scheme 1)
and used it to resolve kinetically racemic aziridine ester
2 to give the optically enriched acyl aziridine peptide 3.
The aziridine peptide 3 can be stereoselectively opened3
with appropriate nucleophiles to give â-substituted phe-
nylalanine-derived dipeptides 4. The N-cinnamoyl group
in 4 can be functionalized via epoxidation to give 5, which
may be stereoselectively opened with amines to give a
â-phenylisoserine residue leading to the synthesis of
tripeptide derivatives 6 (Scheme 1). This paper describes
our results on the synthesis of L-proline-â-phenylisoserine
â-substituted phenylalanine containing tripeptides 6 as
structural analogues of HIV protease inhibitors using
N-cinnamoyl-L-proline as the template on which the new
amino acid residues are synthesized stereoselectively.
Ster eoselective Syn th esis of â-Su bstitu ted
P h en yla la n in e-â-p h en ylisoser in e-Der ived
Tr ip ep tid es Usin g N-Cin n a m oyl-L-p r olin e
a s Tem p la te: Syn th esis of Str u ctu r a l
An a logu es of HIV P r otea se In h ibitor s
Biswajit Saha, J yoti Prokash Nandy, Shalini Shukla,
Iffat Siddiqui, and J aved Iqbal*,†
Department of Chemistry, Indian Institute of Technology,
Kanpur 208 016, India
javediqbaldrf@hotmail.com
Received October 8, 2001
Abstr a ct: N-Cinnamoyl-L-proline can be used as a template
on which â-substituted phenylalanine and â-phenylisoserine
residues can be synthesized leading to tripeptide derivatives
as structural analogues of HIV protease inhibitors.
The racemic aziridine4 ethyl ester 2 was resolved
kinetically (Scheme 2) using N-cinnamoyl-L-proline 1
under the conditions of mixed anhydride coupling
(iBuOCOCl/ Et3N/-10 °C). The resulting acyl aziridine
peptide 3 was optically pure as evidenced from rotation,
1H NMR (∼9:1 mixture of rotamers), and HPLC. It is
important to mention here that the 1H NMR spectra of 3,
4, 9, and 11 showed the presence of the other rotamer
(∼10-15%) arising due to the cinnamoyl-pro tertiary
amide bond. The absolute stereochemistry of aziridine
in 3 was confirmed by reductive opening of the three-
membered ring with sodium cyanoborohydride in TsOH
to give the corresponding L-phenylalanine-L-proline dipep-
dide 8 (Scheme 3).
The unnatural amino acid derived peptides are cur-
rently being used as potential enzyme inhibitors mainly
because they are not susceptible to proteolytic cleavage
by endopeptidases. This has spurred hectic research
activity for the synthesis1 of non-natural amino acids, and
there are several methodologies reported for the synthe-
sis of peptides containing side chains derived from these
amino acids.
One of the efficient ways to synthesize peptides con-
taining non-natural amino acid residues is to use a
template that already has a natural amino acid, and the
stereogenic centers present on the latter can be used to
exert asymmetric induction during the formation of the
former. In connection with work on pyrrolidine-contain-
ing HIV protease inhibitors,2 we explore the possibility
The authentic dipeptide 8 was prepared by mixed
anhydride coupling of L-phenylalanine ethyl ester and
N-cinnamoyl-L-proline 1. The optical rotation and NMR
spectra of 8 prepared from 1 and 3, respectively, were
identical, thereby confirming the (S) configuration for the
stereogenic carbon R to the ester group in aziridine 3.
The absolute stereochemistry for the benzylic carbon of
the aziridine ring in 3 was ascertained by converting it
to the corresponding dehydrophenylalanine derived dipep-
tide 9 (Scheme 4) on treatment with Me3SiI-Et3N in
acetonitrile. The (E) geometry of the double bond clearly
suggested the R-configuration for the benzylic carbon of
aziridine present in 3. Further evidence for the aziridine
† Present Address: Director, Regional Research Laboratory, Trivan-
drum 695019, India.
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recent advances, also see: Edmonds, M. K.; Abell. A. D. J . Org. Chem.
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(3) (a) Kemp, J . E. G. In Comprehensive Organic Synthesis; Trost,
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(4) The racemic aziridine ester
2 was synthesised from ethyl
glycidate according to the following protocol:
10.1021/jo0109826 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002
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J . Org. Chem. 2002, 67, 7858-7860