Synthesis and Structure Determination of (2S, 2′ S)-3-Phenyl-2-(pyrrolidin-2′-yl)-propionic Acid

Article abstract of DOI:10.1081/SCC-120026314

Aβ²,β³-homoproline derivative, (2S, 2′S)-3-phenyl-2-(pyrrolidin-2′-yl)propionic acid, was synthesized starting from L-proline. After preparation of the (4S, 4aS)-4-benzyl-4a,5,6,7-tetrahydro-pyrrolo-[1,2-c]pyrimidine-1,3-dione under

Full text of DOI:10.1081/SCC-120026314

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3913–3917, 2003
Synthesis and Structure Determination of
(2S, 20S)-3-Phenyl-2-(pyrrolidin-20-yl)-
propionic Acid
*
Jin Jing Yi, Zheng Ming Hua, and Tian Guan Rong
Department of Chemistry, Yan Bian University,
Yan Ji City, Ji Lin, China
ABSTRACT
Ab2,b3-homoproline derivative, (2S, 20S)-3-phenyl-2-(pyrrolidin-20-
yl)propionic acid, was synthesized starting from L-proline. After
preparation of the (4S, 4aS)-4-benzyl-4a,5,6,7-tetrahydro-pyrrolo-
[1,2-c]pyrimidine-1,3-dione under a mild condition, the absolute
configuration of target compound was assigned using 2D H-H
COSY and H-H NOESY technologies.
Key Words: Synthesis; b2,b3–Homoproline derivative; (2S, 20S)-3-
Phenyl-2-(pyrrolidin-20-yl)propionic acid; (4S, 4aS)-4-Benzyl-4a,-
5,6,7-tetrahydro-pyrrolo-[1,2-c]-pyrimidine-1,3-dione.
*Correspondence: Tian Guan Rong, Department of Chemistry, Yan Bian
University, Yan Ji City, Ji Lin, 133002, China.
3913
DOI: 10.1081/SCC-120026314
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3914
Yi, Hua, and Rong
b-Peptides have particular appeal for extending our understanding of
protein structure and stabilization into the realm of folded, nonbiological
polymers, because b-amino acids represent the smallest step away from
a-amino acids in ‘‘backbone space’’.[1] b-Amino acids, as the constructing
units of b-peptides, have been invoked a great deal of synthetic
interests.[2] Because proline, as the only proteinogenic amino acid with
a secondary amino group, imparts special conformations on peptide
backbone, its homologues, b2- and b3-homoprolines, have been synthe-
sized to research their effects on the secondary structure of b-peptides.[3]
Since C2, C3-disubstituted amino acids shown a different character
in b-peptide self-assembly,[1] it is very interesting to synthesize b2,
b3-homoproline homologues to explore their effects on b-peptide
backbone. Here we report the synthesis and structure determination of
(2S, 20S)-3-phenyl-2-(pyrrolidin-20-yl)propionic acid (compound 3), a b2,
b3-homoproline with highly substitution.
The target compound was synthesized starting from L-proline. After
protecting the imino group of L-proline with benzyloxycarbonyl group
(Cbz-), the precursor for benzylation was obtained through Arndt-Eistert
homologation of the corresponding diazo ketone according to the Lit.[4]
Benzylation using LHDMS occurred stereo-selectively and only one dia-
stereomer (compound 1) was obtained after silica gel column.[5]
Following the hydrolysis with lithium hydroxide and deprotection on
Pd-C, the target compound 3 was obtained.[6] (Sch. 1)
To determine the absolute configuration of compound 3, we
prepared a uracil derivative 4, (4S, 4aS)-4-benzyl-4a,5,6,7-tetrahydro-
pyrrolo[1,2-c]pyrimidine-1, 3-dione, under a mild condition to minimize
the possibilities of racemization.[7] The initial formation of ureide can be
anticipated according to the Lit.[8] And the subsequent formation of uracil
derivatives may result as a condensation of the imino group with the
ureide following by deamination. Compared to the formation of azabicy-
clo[3,2,0]heptan-7-one catalyzed by triethylamine (MeCN, 80ꢀC),[9]
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
(2S, 20S)-3-Phenyl-2-(pyrrolidin-20-yl)propionic Acid
3915
Scheme 2.
Figure 1.
our method provided not only a milder acidic condition to minimize the
possibilities of racemization but also a modest yield (63%). And it also
shown a possible synthetic approach to tetrahydropyrimidine, an impor-
tant species for research the radical reactions involving DNA bases.[10]
(Sch. 2)
The absolute configuration of compound 4 was assigned using 2D
H-H COSY and H-H NOESY technologies.[11] The abstract signals of
H-4, H-4a, and H-5 were determined according to the 2D H-H COSY
spectrum, and then the H-5a peak was differentiated according to the
NOE effects with H-4a shown in the 2D H-H NOSEY spectrum.
The other observed NOE effects between H-5b and H-4 indicated the
proximity of the two protons. These results support an anti-periplanar
configuration of compound 4. (Fig. 1) Therefore, the (2S, 20S) configu-
ration of compound 3 was determined.
In conclusion, we synthesized (2S, 20S)-3-phenyl-2-(pyrrolidin-20-
yl)propionic acid stereo-selectively. To determination the absolute
configuration, we developed a new mild method to prepare the
corresponding uracil derivatives. The (2S, 20S) configuration of target
compound 3 was confirmed by H-H NOESY.
ACKNOWLEDGMENTS
This work was supported by the grants from the National Natural
Science Foundation of China and the Science and Technology

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3916
Yi, Hua, and Rong
Committee of Ji Lin Province, China. We also thank Professor D. H.
Kim and his group of Postech in Korea for their great help in this
research.
REFERENCES
1. Cheng, R.P.; Gellman, S.H.; DeGrado, W.F. b-Peptides: from
structure to function. Chem. Rev. 2001, 101, 3219.
2. For reviews, see: Cole, D.C. Recent stereoselective synthetic
approaches to b-amino acids. Tetrahedron 1994, 50, 9517.
3. Abele, S.; Vogtli, K.; Seebach, D. Oligomers of b2- and of
¨
b3-Homoproline: what are the secondary sturctures of b-peptides
lacking H-bonds? Helv. Chim. Acta 1999, 82, 1539.
4. (a) Cassal, J.M.; Fuerst, A.; Meier, W.; Synthesis of the enantiomeric
2-pyrrolidineacetic acids. Helv. Chim. Acta 1976, 59, 1917; (b)
Balaspiri, L.; Penke, B.; Papp, G.; Dombi, G.; Kovacs, K.
Synthesis of a-L-homoproline and derivatives. Preparation of 7-a-
L-homoprolinebradykinin. Helv. Chim. Acta 1975, 58, 969; (c)
Buchschacher, P.; Cassal, J.M.; Fuerst, A.; Meier, W.;
Contribution to the asymmetric synthesis of bicyclic compounds
catalyzed by optically active amino acids. Synthesis of (S)-2-pyrroli-
dinepropionic acid and (R)-4-amino-5-phenylvaleric acid. Helv.
Chim. Acta 1977, 60, 2747.
5. Compound 1: oil; yield: 70%. [a]D20, ꢁ1.65 (c ¼ 0.5, CHCl3). IR
(cmꢁ1, CHCl3): 1731, 1699. HRMS, Cacld. for C22H25NO4:
367.1784. Found: 367.1784. Compound 2: white powder; m.p.
94–95ꢀC. [a]D20, ꢁ1.45 (c ¼ 0.5, CHCl3). IR (cmꢁ1, CHCl3): 3062,
3031, 2973, 2887, 1700. Anal. Calcd. for C21H23NO4: C, 71.37; H,
6.56; N, 3.96. Found: C, 71.19; H, 6.49; N, 4.05. For both two
compounds, the existence of rotator is observed in their NMR spectra.
6. Compound 3: white powder, m.p. 248–249ꢀC (Dec.). [a]D20, ꢁ7.8
(c ¼ 0.1, H2O). IR (cmꢁ1, KBr): 3028, 2973, 2936, 1639, 1594.
1H NMR (ꢀ, D2O, 400 MHz): 7.28–7.16 (m, 5H), 3.47–3.41 (m,
1H), 3.27–2.18 (m, 2H), 2.90–2.82 (m, 1H), 2.77–2.71 (m, 1H),
2.13–1.27 (m, 1H), 1.98–1.93 (m, 1H), 1.91–1.85 (m, 1H), 1.65–1.59
(m, 1H). 13C NMR (ꢀ, D2O, 400 MHz): 177.57, 137.58, 127.60,
125.57, 60.45, 50.57, 44.34, 34.97, 26.65, 22.05. Anal. Calcd. for
C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 70.87; H, 7.81;
N, 6.45.
7. Compound 4: oil, yield, 63 %. [a]D20, ꢁ3.0ꢀ (c ¼ 0.2, EtOAc). IR
1
(cmꢁ1, CHCl3): 1703, 1698, 1693. H NMR (ꢀ, CDCl3, 300 MHz):

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
(2S, 20S)-3-Phenyl-2-(pyrrolidin-20-yl)propionic Acid
3917
7.50 (br, 1H), 7.29–7.18 (m, 5H), 3.57–3.53 (m, 1H), 3.45–3.38 (m,
2H), 3.28–3.24 (dd, 1H, J ¼ 5.0, 14.5 Hz), 3.06–3.01 (dd, 1H, J ¼ 6.1,
14.5 Hz), 2.64–2.58 (m, 1H), 2.03–1.94 (m, 2H), 1.87–1.69 (m, 1H),
1.40–1.34 (m, 1H). 13C NMR (ꢀ, CDCl3, 400 MHz): 172.07, 150.55,
138.52, 129.68, 129.01, 127.21, 58.09, 48.49, 45.04, 33.12, 32.89,
23.65. HRMS, Cacld. for C14H16N2O2: 244.1212. Found: 244.1212.
8. (a) Semikolennykh, L.M.; Katsnel’son, M.G.; Del’nik, V.B.
(Phenylacetyl)urea. U. S. S. R. 432, 136, 1974; (b) Seres, J.;
Daroczi, K.; Seres, P.; Koszegi, B. 5- (Or 1, 5-Di-) Substituted uracil
derivatives. Ger. (East) DD 1985, 222, 591.
9. Gilchrist, T.L.; Lemos, A.; Ottaway, C.J. Azabicyclo[3. 2. 0]
heptan-7-ones (carbapenams) from Pyrrole. J. Chem. Soc. Perkin
Trans. 1 1997, 19, 3005.
10. Fenick, D.J.; Falvey, D.E. Free radical rearrangements in uracil
derivatives. J. Org. Chem. 1994, 59, 4791.
11. 2D H-H COSY (ꢀ, CDCl3, 500 MHz): 3.49–3.48 (m, H-4a);
2.65–2.57 (m, H-4); 2.08–1.98 (m, 1H, H-5); 1.28–1.23 (m, 1H, H-5).
2D H-H NOESY (ꢀ, CDCl3, 500 MHz): 2.08–1.98 (m, H-5a);
1.28–1.23 (m, H-5b). H-5a of 4 was differentiated from the two
protons of 5-position by the observed NOE effects with H-4a. The
other observed NOE effects between H-4 and H-5b supported the
(4S, 4aS) configuration of 4.
Received in Japan April 21, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.

Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.