An efficient synthesis of substituted prolines by the selective reduction and reductive cyanation of 2-pyrrolidones

Article abstract of DOI:10.1016/S0040-4039(02)00097-7

Substituted pyrrolidones undergo selective reduction using Cp₂ZrHCl (Schwartz's reagent) to form Δ¹-pyrrolines, which can be isolated or directly cyanated and hydrolyzed to the corresponding proline. Short syntheses of glutamic semialdehyde (ethyl ester), the marine metabolite (2S,5S)-pyrrolidine-2,5-dicarboxylic acid, and the conformationally constrained amino acid 5,5-dimethylproline, are reported.

Full text of DOI:10.1016/S0040-4039(02)00097-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1597–1598
An efficient synthesis of substituted prolines by the selective
reduction and reductive cyanation of 2-pyrrolidones
Qian Xia and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 13 December 2001; revised 7 January 2002; accepted 8 January 2002
Abstract—Substituted pyrrolidones undergo selective reduction using Cp2ZrHCl (Schwartz’s reagent) to form D1-pyrrolines, which
can be isolated or directly cyanated and hydrolyzed to the corresponding proline. Short syntheses of glutamic semialdehyde (ethyl
ester), the marine metabolite (2S,5S)-pyrrolidine-2,5-dicarboxylic acid, and the conformationally constrained amino acid 5,5-
dimethylproline, are reported. © 2002 Elsevier Science Ltd. All rights reserved.
New methods for controlling the geometry of peptide
bonds are of interest in connection with the design of
discrete protein1 or protein-like (i.e. foldamer)2 archi-
tectures. Because proline confers unusual conforma-
tional properties on peptides and proteins, often
resulting in biological and therapeutic utility, substi-
tuted analogs and congeners of this amino acid have
been synthesized and studied.3,4 Versatile strategies for
assembling functionalized proline derivatives are there-
fore desirable.
Strecker reaction. When applied to substituted 2-
pyrrolidones, e.g. 4, the procedure leads to pyrrolidine-
2-carboxylic acids, e.g. 7 by way of intermediates 5 and
6 (Scheme 1). Moreover, the hydrolytically unstable
2-pyrrolines 5 are in some cases biologically interesting
metabolic intermediates, and can be isolated and char-
acterized. The scope and limitations of the method are
reported herein.
Reduction of the known8
-(−)-pyroglutamic acid ethyl
L
ester 8 (Scheme 2) with Cp2ZrHCl (1.6 equiv., THF,
−20 to 20°C, 3 h) and nonaqueous work-up (dilution of
the reaction mixture with hexane and filtration) led to
9, which is of biological interest since the corresponding
Several years ago, our laboratory developed a proce-
dure for reducing secondary amides and lactams selec-
tively to imines using Cp2ZrHCl (Schwartz’s reagent).5
That methodology enables the conversion of amides to
amines under mild conditions, and has further been
extended to the transformation of tertiary amides to
aldehydes.6 Most recently, in an application to the total
synthesis of (−)-a-kainic acid 3, we demonstrated that
pyrrolidone 1 (Eq. (1)) could be reduced to 2, which
underwent smooth addition of cyanotrimethylsilane
(TMSCN) to afford 3 after hydrolysis.7
carboxylic acid,
intermediate in both
L
-glutamic acid semialdehyde,9 is a key
L
-proline10 and chlorophyll11
biosynthesis. Imine 9 could be isolated pure (47% after
flash chromatography), or reacted directly with
TMSCN (2.1. equiv.) to afford the readily separable
a-aminonitriles 10 (45% from 8) and 11 (9% from 8).
Acidic hydrolysis (6N HCl) of 10 gave (2S,5S)-pyrro-
lidine-2.5-dicarboxylic acid (−)-12 (91%), a constituent
(1)
We now report that this process of reductive cyanation,
in which a secondary amide group is transformed into
an a-amino acid, represents a useful extension of the
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00097-7

1598
Q. Xia, B. Ganem / Tetrahedron Letters 43 (2002) 1597–1598
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Scheme 2.
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Starting from the known16 dimethylpyrrolidone 13,
which is readily prepared from the inexpensive reac-
tants 2-nitropropane and methyl acrylate, reduction
using Cp2ZrHCl gave imine 14. Cyanation of 14 and
hydrolysis of the incipient nitrile 15 afforded racemic 16
(52% yield), which has previously been resolved to
obtain the pure L
-enantiomer.15,17
In summary, we have shown that the reduction of
2-pyrrolidones selectively to D1-pyrrolines can be gener-
ally and conveniently achieved using Cp2ZrHCl. More-
over, cyanation of such imines provides access to a
variety of differentially substituted proline analogs and
congeners that may be of interest as natural products,
biosynthetic intermediates, or as probes of macromolec-
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17. Representative procedure: A solution of 13 (3.1 g) in THF
(50 mL) was added dropwise to Cp2ZrHCl (1.3 equiv.,
9.7 g in THF (50 mL)) at −20°C. The mixture warmed
slowly to rt for 3 h, then TMSCN (1.1 equiv.) was added
with stirring for 1 h. Addition of 6N HCl (100 mL)
formed a suspension that was washed once with CH2Cl2
(50 mL), then heated at reflux for 12 h. After cooling and
washing with CH2Cl2 (50 mL), the aqueous layer was
concentrated. The residue was dissolved in H2O (10 mL),
and purified over Dowex (50Wx8-400 mesh), eluting with
1N NH4OH. The residue was dissolved in EtOH/Et2O
and filtered to remove impurities (three times). Recrystal-
lization (EtOH/Et2O) afforded 16: colorless crystals (2.1
g, 52%), mp 194–197°C, lit.14 mp 194–196°C. See supple-
mentary material for additional procedures (available
upon request).
Scheme 3.
Acknowledgements
We are grateful to the NIH (GM 35712) for generous
financial support. Qian Xia was the recipient of the S.
M. Tsang Fellowship at Cornell. We also thank Profes-
sor H. A. Scheraga and Dr. V. Cerovsky for helpful
discussions.