Efficient and stereoselective synthesis of novel cis-4-substituted proline analogues

Article abstract of DOI:10.1016/S0040-4039(02)02865-4

A series of novel cis-4-substituted proline analogues were designed and synthesized. Highly stereoselective alkylations at the γ-position of glutamic ester 2 were achieved, followed by reduction, mesylation, and cyclization to afford the title compounds 1 in good yields and high diastereoselectivity.

Full text of DOI:10.1016/S0040-4039(02)02865-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1413–1415
Efficient and stereoselective synthesis of novel cis-4-substituted
proline analogues
Junyi Zhang,a Wei Wang,b,* Chiyi Xionga and Victor J. Hrubya,*
aDepartment of Chemistry, University of Arizona, 1306 E. University Boulevard, Tucson, AZ 85721, USA
bGenomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
Received 29 October 2002; revised 18 December 2002; accepted 19 December 2002
Abstract—A series of novel cis-4-substituted proline analogues were designed and synthesized. Highly stereoselective alkylations
at the g-position of glutamic ester 2 were achieved, followed by reduction, mesylation, and cyclization to afford the title
compounds 1 in good yields and high diastereoselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
Proline is a unique amino acid with its rigid cyclic
system. It exerts great influence on both the structure
and function of peptides and proteins.1 Peptides and
proteins with a proline residue can influence important
secondary structures such as a b-turn and an a-helix.2
In addition, proline has been used as a rigid template to
design conformationally constrained amino acids for
the study of the interactions of peptide and protein
ligands with their receptors/acceptors.3–5 Such effects
on peptide conformations have created a great deal of
interests for the design of various substituted proline
analogues. In these proline compounds, 4-substitued
derivatives are particularly attractive since the C4 sub-
stituents can influence not only the conformation of the
pyrrolidine ring, but the rate of cis–trans isomerization
about the amide bond as well.4,6,7 In our ongoing
melanocyte stimulating hormones (MSH) project, the
substitution of histidine with proline in MT-II has
generated a potent and selective analogue with agonist
activity at the human MC5R.8 To further explore the
structure–activity relationship (SAR) of this ligand and
its receptors, we have designed novel 4-substituted
prolines.
and Goodman’s group have reported the synthesis of
cis- and trans-4-substituted proline analogues through
hydrogenation reactions from 4-trans-hydroxy pro-
line.3,4 Meanwhile we have developed asymmetric
hydrogenations/Suzuki-couplings for the preparation of
a number of novel x2 constrained amino acids.9 As an
alterative to these methods, herein we would like to
disclose an efficient and stereoselective approach to the
synthesis of cis-4-subsititued prolines. The synthetic
strategy for the preparation of the title compounds 1
employs stereoselective alkylation at the g-position of
glutamic ester 2, followed by selective reduction, mesyl-
ation, and cyclization to obtain cis-4-substituted pro-
lines 1 (Scheme 1).
The synthesis of cis-4-substituted proline analogues 1
started with commercially available (4S)-5-(tert-
butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic
acid (Scheme 2). The carboxylic acid was protected as a
t-butyl ester, which was orthogonal to the later v-
methyl ester 2. Thus, the methyl ester could be selec-
tively reduced without affecting the t-butyl ester. The
free v carboxyl functional group was converted into a
methyl ester 2 using dicyclohexylcarbodiimide (DCC)
as an activating agent with methanol in the presence of
Several methods for the synthesis of 4-substitued proli-
nes have appeared in the literature.3–5 Recently, our
Scheme 1. Strategy for the preparation of cis-4-substituted proline derivatives 1.
Keywords: proline; constrained amino acids; alkylation.
* Corresponding authors. Tel.:+1-(858)-332-4710; fax: +1-(858)-812-1942 (W.W.); Tel.: +1-(520)-621-6332; fax: +1-(520)-621-8407 (V.J.H.); e-mail:
wwang@gnf.org; hruby@u.arizona.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02865-4

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J. Zhang et al. / Tetrahedron Letters 44 (2003) 1413–1415
Scheme 2.
ester in 6 using DIBAL at −78°C did not give the
desired aldehyde 7. Even higher reaction temperatures
(room temperature to 70°C) did not work either. In all
cases, only starting materials were recovered. In con-
trast, our previous study with reduction of a similar
substrate without g-substituents under the same reac-
tion condition gave an aldehyde in excellent yield.10 The
presumed reason was steric hindrance in the g-substi-
tuted substrates 6.
a catalytic amount of dimethylaminopyridine (DMAP)
and triethylamine (TEA) in 76% yield (Scheme 2).10
The resulting compound 2 was used for the alkylations.
Alkylation at the C4 position of glutamates has been
reported in the literature.11,12 The studies indicated that
the stereoselectivity depended on the nature of the
N-substitutents13 and the esters.14,15 Recently, Hanes-
sian and co-workers achieved highly stereoselective
alkylations with Na-Boc or Cbz and the methyl
ester.11,12 The stereoselectivity was attributed to a
highly coordinated dianionic chair-like transition state.
However substrates with the bigger t-butyl ester, as in
our case, have not been studied. We believed that the
size of the ester groups would play an important role in
controlling the stereoselectivity of the alkylations based
on the proposed transition state. The large t-butyl ester
would further enhance the diastereoselectivity of the
alkylations by stabilization of the chair-like transition
state. As expected, only one single diastereomer (anti
Consequently we modified our synthetic strategy
(Scheme 2). We proposed the conversion of the methyl
ester 3 to an alcohol, which then was transformed into
a good leaving group for cyclization. The intramolecu-
lar nuclear substitution (cyclization) would provide the
target molecules. Reduction of the mono-Boc protected
methyl esters 3 with NaBH4 to give alcohols 4 were
achieved in good yields. Then the alcohols were con-
verted into mesylates 5 in high yields. The mesylated
intermediates were treated with NaH to give the cyclic
proline derivatives 1 in good yields. To test for racem-
ization during these conversions, we selectively depro-
tected the Boc group in 1a (due to rotamers) to 8,
which gave a ‘clean’ NMR (Scheme 4). One isomer was
observed by NMR indicating that no isomerization
occurred. With compound 3a as an example, an impor-
tant synthetic intermediate, the pyroglutamate ester 9,
which can be used as starting material in our dipeptide
b-turn mimetic synthesis,16 was obtained in three steps
(Scheme 4).
1
product) was obtained based upon H NMR analysis
(Scheme 2).
With the optically pure g-substituted alkyl glutamic
acid ester 3 in hand, initially we planed to selectively
reduce the methyl ester by diisobutylaluminumhydride
(DIBAL) at −78°C to an aldehyde, which subsequently
could undergo reductive amination to give the final
products 1. Based on our earlier study, the mono Boc
protected nitrogen interfered with the reduction.10
Therefore, a second Boc protecting group was intro-
duced by reaction of 3 with di-t-butyldicarbonate
[(Boc)2O] in the presence of a catalytic amount of
DMAP in acetonitrile after chromatography to give the
bis-Boc protected methyl ester 6 in over 80% yield
(Scheme 3).10 However, the reduction of the methyl
In conclusion, a series of novel cis-4-substituted proline
derivatives 1 were efficiently synthesized from readily
available starting materials. High stereoslective alkyla-
tions at the g-position of the glutamic ester 2 were
Scheme 3.

J. Zhang et al. / Tetrahedron Letters 44 (2003) 1413–1415
1415
prolines. See: (a) Tamaki, M.; Han, G.; Hruby, V. J. J.
Org. Chem. 2001, 66, 1038; (b) Tamaki, M.; Han, G.;
Hruby, V. J. J. Org. Chem. 2001, 66, 3593 and references
cited therein.
4. Recently, Goodman’s group reported the synthesis of cis-
and trans-trifluoro prolines. See: Del Valle, J. R.; Good-
man, M. Angew. Chem., Int. Ed. 2002, 41, 1600 and
references cited therein.
5. Bunuel, E.; Gil, A. M.; Diaz-de-Villegas, M. D.;
Cativiela, C. Tetrahedron 2001, 57, 6417.
6. Improta, R.; Benzi, C.; Barone, V. J. Am. Chem. Soc.
2001, 123, 12568.
7. Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber,
R.; Moroder, L. Angew. Chem., Int. Ed. 2001, 40, 923.
8. Grieco, P.; Lavecchia, A.; Cai, M.; Trivedi, D.; Wein-
berg, D.; MacNeil, T.; Van der Ploeg, L. H. T.; Hruby,
V. J. J. Med. Chem. 2002, 45, 5287.
Scheme 4.
9. We have synthesized x2 constrained amino acids using
asymmetric hydrogenations/Suzuki couplings. See: (a)
Wang, W.; Xiong, C. Y.; Yang, J. Q.; Hruby, V. J.
Tetrahedron Lett. 2001, 42, 7717; (b) Wang, W.; Zhang,
J.; Xiong, C.; Hruby, V. J. Tetrahedron Lett. 2002, 43,
2137; (c) Wang, W.; Xiong, C.; Zhang, J.; Hruby, V. J.
Tetrahedron 2002, 58, 3101; (d) Wang, W.; Cai, M.;
Xiong, C.; Zhang, J.; Tevil, D.; Hruby, V. J. Tetrahedron
2002, 58, 7365.
achieved. The resulting alkylation compounds were
transformed to the final products 1 through reduction/
mesylation/cyclization in high yields. The incorporation
of these unnatural amino acids into a-MSH peptides is
under investigation.
Acknowledgements
10. Wang, W.; Xiong, C.; Yang, J.; Hruby, V. J. Synthesis
2002, 94.
This work was supported by US Public Health Service
(DK 17420) and the National Institute of Drug Abuse
(DA 13449). We thank Professor Dominic V. McGrath
for the use of his group’s polarimeter. The opinions
expressed are those of the authors and not necessarily
those of the US Public Health Service.
11. Hanessian, S.; Schaum, R. Tetrahedron Lett. 1997, 38,
163.
12. Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39,
5887.
13. Gu, Z.-Q.; Hesson, D. P.; Pelletier, J. C.; Maccecchini,
M. L. J. Med. Chem. 1995, 38, 2518.
14. Koskinen, A. M. P.; Rapoport, H. J. Org. Chem. 1989,
54, 1859.
15. Baldwin, J. E.; North, M.; Flinn, A.; Moloney, M. G. J.
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3. Our group has synthesized 4-guanidino and 4-phenyl