Synthesis of benzyl (6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6- carboxylic ester, a new conformationally constrained peptidomimetic derivative

Article abstract of DOI:10.1016/S0040-4039(02)00574-9

We describe the synthesis of benzyl (6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6- carboxylic ester, a new conformationally constrained peptidomimetic derivative. This compound is prepared in seven steps from (S)-pyroglutamic acid as starting material.

Full text of DOI:10.1016/S0040-4039(02)00574-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3499–3501
Synthesis of benzyl
(
6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-
6
-carboxylic ester, a new conformationally constrained
peptidomimetic derivative
a,
b
b
b
b
Philippe Gloanec, * Yolande Herv e´ , Nathalie Br e´ mand, Jean-Pierre Lecouv e´ , Fabienne Br e´ ard
a
and Guillaume De Nanteuil
a
Institut de Recherches Servier, 11 rue des Moulineaux, 92150 Suresnes, France
b
Oril Industries, 13 rue Auguste Desgen e´ tais, 76210 Bolbec, France
Accepted 21 March 2002
Abstract—We describe the synthesis of benzyl (6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxylic
ester, a new conformationally constrained peptidomimetic derivative. This compound is prepared in seven steps from (S)-pyro-
glutamic acid as starting material. © 2002 Elsevier Science Ltd. All rights reserved.
The design of peptidomimetic derivatives is currently an
area of active investigation and has generated a consid-
erable amount of work in the synthesis of high affinity
In this paper, we report our preliminary results in the
design and synthesis of a novel peptidomimetic moiety,
benzyl
(6S)-1,3-dichloro-4-oxo-4,6,7,8-tetrahydro-
1
and selective new therapeutic agents. Conformation-
pyrrolo[1,2-a]pyrazine-6-carboxylic ester 11. Thus, the
proline-containing ring of the bicyclic lactam 1 was
combined with the insatured pattern of (3-amino-2-
oxopyridin-1(2H)-yl)acetic acid 2, to afford the novel
heterobicyclic ester 11 that could be used as a potential
dipeptide surrogate.
ally constrained dipeptides analogs are expected to
possess the same properties as their highly flexible
peptidic counterparts, with the added advantages of
increased metabolic stability and improved absorption
properties. This can be effectively realized by the sys-
tematic replacement of backbone amide bonds by con-
2
3
strained elements such as a cyclic or bicyclic lactam 1
As shown in Scheme 1, the benzyl (6S)-1,3-dichloro-
4
or heterocyclic isosteres 2 in order to reduce the con-
formational flexibility; (3-amino-2-oxopyridin-1(2H)-
4
-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-car-
5
boxylic ester 11 was prepared from (S)-pyroglutamic
acid in seven steps with a 22% overall yield.
yl)acetic acid 2 was used to mimic the alanylproline
sequence in the design of human leukocyte elastase
4
inhibitors, allowing the maintenance of the bioactive
The key intermediate in this synthesis was the aminoni-
interactions as the original peptidic substrate.
trile 8, obtained according to a modification of the
6
preparation described by Langlois. Commercially
available (S)-pyroglutamic acid was treated with thio-
nyl chloride in benzyl alcohol and a catalytic amount of
7
DMF under standard conditions to provide the benzyl
ester 4 in good yield (90%). Protection of the intermedi-
ate lactam 4 as a tert-butyloxy carbamate was per-
formed in dichloromethane in the presence of
dimethylaminopyridine to give 5 in quantitative yield
and without any racemization at the adjacent carbon
atom. Regioselective reduction of compound 5 with
DIBAL-H in THF at −78°C afforded a-hydroxy carba-
Keywords: peptidomimetic; pyroglutamic acid; 4-oxo-4,6,7,8-tetra-
hydro-pyrrolo[1,2-a]pyrazine.
*
Corresponding author. Tel.: 33.1.55.72.25.23; fax: 33.1.55.72.24.30;
e-mail: philippe.gloanec@fr.netgrs.com
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00574-9

3
500
P. Gloanec et al. / Tetrahedron Letters 43 (2002) 3499–3501
Scheme 1. Reagents and conditions: (i) PhCH OH, SOCl , DMF, rt, overnight, 90%; (ii) Boc O, DMAP, CH Cl , 0°C to rt,
2
2
2
2
2
overnight, 98%; (iii) DIBAL-H, THF, −78°C, 70%; (iv) MeOH, TsOH, 98%; (v) TMSCN, SnCl , CH Cl , −40°C, 60%; (vi) 4 M
4
2
2
HCl sol. in dioxane, AcOEt, 95%; (vii) oxalyl chloride, 1,2-dichlorobenzene, 65%.
mate 6 as a racemic mixture of diastereomers in 70%
yield. The a-methoxy derivative 7 was then obtained
quantitatively from 6 by treatment with a methanolic
solution of p-toluene sulfonic acid. Compound 7 was
further treated with trimethylsilylcyanide in the presence
of tin tetrachloride in dichloromethane at −40°C, leading
to the aminonitrile 8. The mixture of two diastereomers
was purified by silica gel chromatography (MERCK
silica gel 60 230–400 mesh, CH Cl /AcOEt, 95:5) and
and work is ongoing to evaluate 11 in other biological
active systems.
Acknowledgements
The authors are grateful to Sophie Cornet, Camille
Poindron, Dani e` le Heno for their expert technical assis-
tance and thank the Division of Analytical Chemistry for
their helpful assistance.
2
2
chlorohydrated with 1.1 equiv. of a 4 M HCl–dioxane
solution to provide the aminonitrile 9. Treatment of the
hydrochloride 9 with oxalyl chloride in 1,2-dichlorobenz-
8
ene at room temperature gave the intermediate benzyl
(
6S)-1-chloro -3 - hydroxy - 4- oxo - 4,6,7,8 - tetrahydro-
References
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oxalyl chloride gave the desired compound 11, which
was obtained after crystallisation in methanol without
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10
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P. Gloanec et al. / Tetrahedron Letters 43 (2002) 3499–3501
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0
9. Spectral data for 11: [h]
=−244 (c=1, CHCl ); ee=98%
D
3
determined using chiral HPLC (Chiracel OD, EtOH, 240
−
1
nm); mp 101–102°C; IR (Nujol): 1753 and 1671 cm ;
1
H NMR (300 MHz, CDCl
2.60 (m, 1H, CH), 3.15 (m, 2H, CH
CH), 5.22 (m, 2H, CH ), 7.35 (m, 5H, aromatic); elemental
analysis: calcd for C15 : C, 53.12; H, 3.57;
) l ppm 2.40 (m, 1H, CH),
3
), 5.20 (dd, 1H,
2
2
H
12Cl N O
2 2 3
N, 8.26; Cl, 20.91. Found: C, 53.24; H, 3.67; N, 8.22; Cl,
20.62.
10. De Nanteuil, G.; Gloanec, P.; Verbeuren, T.; Rupin, A.;
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4
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