cis- and trans-3-(3-indolyl)proline derivatives as conformationally restricted analogues of tryptophan

Article abstract of DOI:10.1055/s-1999-2708

A method for the diastereoselective generation of 3-indolyl-3-proline derivatives has been developed. The [3+2] cycloaddition reaction of 3- vinylindoles with dimethyl N-ethoxycarbonyl-N-methoxymethylaminomalonate in the presence of TiCl₄, afforded the title compounds after acid hydrolysis and decarboxylation reactions. These new amino acids may be viewed as conformationally restricted mimetics of tryptophan.

Full text of DOI:10.1055/s-1999-2708

786
LETTER
cis- and trans-3-(3-Indolyl)proline Derivatives as Conformationally Restricted
Analogues of Tryptophan
D. Damour,* J.-P. Pulicani, M. Vuilhorgne, S. Mignani
Rhône-Poulenc Rorer SA, Centre de Recherche de Vitry-Alfortville, 13 Quai Jules Guesde-BP 14, 94403, Vitry-sur-Seine Cedex France
Fax 33 (1) 55 71 80 63; E-mail: dominique.damour@rp-rorer.fr
Received 11 February 1999
Abstract: A method for the diastereoselective generation of 3-in-
dolyl-3-proline derivatives has been developed. The [3+2] cycload-
dition reaction of 3-vinylindoles with dimethyl N-ethoxycarbonyl-
N-methoxymethylaminomalonate in the presence of TiCl4, afforded
the title compounds after acid hydrolysis and decarboxylation reac-
tions. These new amino acids may be viewed as conformationally
restricted mimetics of tryptophan.
Key words: constrained amino acids, tryptophan analogue, 3-(3-
indolyl)prolines, cycloaddition, azomethine ylide
The incorporation of constrained a-amino acids into pep-
tides is an important approach to understand their bioac-
tive conformations.1 The use of proline as a template in
Figure 1. Conformationally constrained analogues of norleucine,
order to introduce conformational restrictions is well
known.2 In this vein, cis- and trans-3-substituted proline
analogues have been investigated, which retain the side
chain moieties of standard amino acids. Thus, 3-n-propyl-
proline 1, 3-phenylproline 2a,b and 3-carboxyproline de-
rivatives 3a-c have been prepared as constrained
analogues of norleucine (Nle), phenylalanine (Phe), ty-
rosine (Tyr), aspartic acid (Asp), glutamic acid (Glu) and
glutamine (Glut) respectively (Fig.1).3 To the best of our
knowledge, some tryptophan mimetics have been already
described, and five main modifications of tryptophan have
been synthesized through a cyclisation between: a) the
tryptophan a-carbon and the indole ring; 4a b) the amino
group and the indole ring;4b c) the carboxyl group and the
b-position;4c d) the a- and b-positions;4d e) b- and b-posi-
tions.4e None of these tryptophan mimetics have a proline
as template. In the present paper, we describe the synthe-
sis of novel cis- and trans-3-(3-indolyl)proline derivatives
4 (Fig.1).
phenylalanine, tyrosine, aspartic acid, glutamic acid and glutamine.
um bromide through a Wittig-olefination reaction under
standard reaction conditions affording pure 7 in 93%
yield. With 7 in hand, we turned our attention to the syn-
thesis of the pyrrolidine derivative 11 by regioselective
[3+2] cycloaddition reaction with the betaine 10 which
was generated in situ from 9 in the presence of TiCl4 and
TEA at reflux in 99% yield in a ~50g scale. The synthesis
of the malonate derivative 9 was achieved through an an-
odic oxidation of 8 7 in presence of methanol under the ex-
perimental conditions reported by Shono et al.5,8 in 65%
yield. We have found that the yield of the synthesis of 9
increases highly when the concentration of 8 is close to
0.8M in a mixture of methanol and acetic acid 98/2. Then,
tandem deesterification-decarboxylation reaction of 11
was performed using conc. HBr (47%) in acetic acid to
give 12 as a cis/trans epimeric mixture in a ~6/4 ratio (de-
termined by 1H-NMR, 300 MHz) in 97% yield. After es-
terification of 12 using a methanolic HCl solution (giving
13 with 63% yield) followed by N-Boc protection under
standard experimental conditions afforded 14 as a mixture
of the cis- and trans-3-(3-indolyl)proline methyl esters
As depicted in Scheme 1, the synthetic approach is based
on a [3+2] cycloaddition reaction of the 3-vinylindole de-
rivative 7 with azomethine ylide 10 which was generated
by acid treatment (Lewis acid) in the presence of the di-
methyl N-ethoxycarbonyl-N-methoxymethylaminoma-
lonate 9.5 Among the several methods examined with the
aim to construct 3-(3-indolyl)proline skeleton, the [3+2]
cycloaddition of 10 with the adequate olefinic dipolaro-
phile 7 has been chosen due to its high regioselectivity in
multigram scale preparation.
According to the procedure described by Pindur et al.,6
treatment of the commercially available indolyl-3-carbox-
aldehyde 5 with sulfonyl chloride gave 6 in 98% yield
which was then treated with triphenylmethylphosphoni-
1
(~7/3 ratio, determined by H-NMR, 300 MHz) in 72%
yield. Selective saponification of 14 using 0.5N NaOH al-
lowed separation into pure cis-3-(3-indolyl)proline meth-
yl ester 16 and trans-3-(3-indolyl)proline 15 in 66% and
29% yield respectively. Finally, the target compounds
were obtained by treatment with 3N NaOH affording pure
4 trans and 4 cis both in 99% yields.9
Synlett 1999, No. 6, 786–788 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
cis- and trans-3-(3-Indolyl)proline Derivatives as Conformationally Restricted Analogues of Tryptophan
787
N. J.; Gallagher, T. ; Tetrahedron Lett., 1990, 31, 39, 5653;
utilisation of trans-3-n-propyl-L-proline as a methionine
analogue, see : : Holladay, M. W.; Lin, C. W.; May, C. S.;
Garvey, D. S.; Witte, D. G.; Miller, T. R.; Wolfram, C. A. W.;
Nadzan, A. M.; J. Med. Chem., 1991, 34, 455 ; Sasaki, N. A. ;
Dockner, M. ; Chiaroni, A. ; Riche, C. ; Potier, P.; J. Org.
Chem., 1997, 62, 765.
b) For conformationally restricted proline analogues of
phenylalanine, see: Belokon, Y. N.; Bulychev, A. G.; Pavlov,
V. A.; Fedorova, E. B. ; Tsyryapkin, V. A.; Belikov, V. M.; J.
Chem. Soc. Perkin Trans 1, 1988, 2075; Sarges, R. ; Tretter, J.
R. J. Org. Chem. 1974, 39, 12, 1710 ; Chung, J. Y. L.;
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Holladay, M. W.; J. Org. Chem., 1990, 55, 270; Holladay, M.
W. ; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte, D. G.;
Miller, T. R.; Wolfram, C. A.; Nadzan, A. M.; J. Med. Chem.,
1991, 34, 457.
In conclusion, we describe herein a new approach for the
construction of original cis- and trans-3-(3-indolyl)pro-
line derivatives 4 cis and 4 trans that utilises the [3+2] cy-
cloaddition reaction of the 3-vinylindole derivative 7 with
azomethine ylide 10 as the key step. These two proline de-
rivatives are the first two conformationally constrained
tryptophan analogues. Preparation of a variety of 3-substi-
tuted proline derivatives may be envisioned using this
route.
Acknowledgement
We wish to thank G. Doerflinger, I. Gozzi, P. Hubert, R. Poulain, A.
Renaudon and J-C. Szmigel for technical assistance.
c) For conformationally restricted proline analogues of
tyrosine, see : Waid, P. P.; Flyn, G. A.; Huber, E. W.; Sabol,
J. S.; Tetrahedron Lett., 1996, 37, 24, 4091.
References and Notes
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Synlett 1999, No. 6, 786–788 ISSN 0936-5214 © Thieme Stuttgart · New York

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D. Damour et al.
LETTER
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Synthesis, 1987, 1099.
(9) All new compounds gave satisfactory analytical and
spectroscopic data (1H NMR, IR, MS and elemental analysis).
Representative data for the selected products obtained: 4
trans: pale yellow solid; m.p. 212 °C ; IR (KBr) 3410 and
3275 (indole), 1725 (CO acid), 1675 (CO carbamate), 740
(indole) cm-1; 1H NMR (DMSO-d6, 300 MHz, 393 K) d 7.6
(dd, J = 8 and 2, 1H, Hz, H5’), 7.35(dd, J = 8 and 2 Hz, 1H,
H8’), 7.15 (s, 1H, H2’), 6.95-7.15 (m, 2H, H6’ and H7’), 4.3
(d, J = 5 Hz, 1H, H2), 3.7 (m, 1H, H3), 3.40-3.65 (m, 2H, H5),
2.0-2.4 (two m, 2H, H4), 1.40 (s, 9H, t-Bu) ; MS (EI, 70ev)
330 (M+), 286, 274, 229; Anal. Calc. C18H22N2O4: C, 65.43;
H,6.71; N, 8.48; O, 19.37. Found : C, 65.1; H, 7.1; N, 8.2. 4
cis: white solid; m. p. 229 °C ; IR (KBr) 3350 (indole), 1725
(CO acide), 1635 (CO carbamate), 737 (indole) cm-1; 1H NMR
(DMSO-d6, 300 MHz, 393 K) d 7.6 (dd, J = 8 and 2, 1H, Hz,
H5’), 7.35 (dd, J = 8 and 2 Hz, 1H, H8’), 7.15 (s, 1H, H2’),
6.95-7.15 (m, 2H, H6’ and H7’), 4.5 (d, J = 8.5 Hz, 1H, H2),
4.0 (m, 1H, H3), 3.75 (m, 1H, H5), 3.50 (m, 1H, H5), 2.(0 (m,
1H, H4), 2.30 (m, 1H, H4), 1.40 (s, 9H, t-Bu) ; MS (EI, 70ev)
330 (M+), 286, 274, 229; Anal. Calc. C18H22N2O4: C, 65.43;
H,6.71; N, 8.48; O, 19.37. Found : C, 65.1; H, 6.7; N, 8.2; O,
19.3. NMR assignments were secured by 2D COSY
experiments while the relative stereochemistry was confirmed
by nOe experiments performed on compounds 4 trans and 4
cis: larger effects were observed between H2, H3 and H2’ for
the trans arrangement compared to the cis derivative.
(10) Silica gel 60 (0.063-0.2 mm), Merck.
(6) Pindur, U.; Pfeuffer, L.; Monatsh. Chem., 1989, 120, 157.
(7) Dimethyl-N-ethoxycarbonyl-N-methylaminomalonate 8 was
prepared in two steps in 67% overall yield by the action of N-
methylbenzylamine with diethylbromomalonate(EtOH, TEA,
reflux, 3h) followed by hydrogenation (EtOH, AcONH4,
Pd(C), 40°C, 1h).
Article Identifier:
1437-2096,E;1999,0,06,0786,0788,ftx,en;G07499ST.pdf
Synlett 1999, No. 6, 786–788 ISSN 0936-5214 © Thieme Stuttgart · New York