Efficient asymmetric synthesis of a functionalized Δ2-pyrazoline

Article abstract of DOI:10.1016/S0040-4039(00)01582-3

The first asymmetric synthesis of the (4S,5R)-5-carbomethoxy-4-hydroxy-Δ²-pyrazoline in four steps is described starting from the methyl 4,4-dimethoxy-3-oxobutanoate by sequential catalytic hydrogenation and electrophilic amination. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01582-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8795–8797
Efficient asymmetric synthesis of a functionalized
D2-pyrazoline
Olivia Poupardin,a Christine Greckb,* and Jean Pierre Geneta,*
aLaboratoire de Synthe`se Organique (UMR 7573), Ecole Nationale Supe´rieure de Chimie de Paris,
11 rue Pierre et Marie Curie, 75231 Paris Ce´dex 05, France
bLaboratoire SIRCOB (Upres 8086), Universite´ de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats Unis,
78035 Versailles Ce´dex, France
Received 28 June 2000; accepted 12 September 2000
Abstract
The first asymmetric synthesis of the (4S,5R)-5-carbomethoxy-4-hydroxy-D2-pyrazoline in four steps is
described starting from the methyl 4,4-dimethoxy-3-oxobutanoate by sequential catalytic hydrogenation
and electrophilic amination. © 2000 Elsevier Science Ltd. All rights reserved.
A large number of D2-pyrazolines have been described in the literature1 due to their synthetic
accessibility and important applications. D2-pyrazolines are also known for their biological
activity as anti-inflammatory compounds.2 Procedures to obtain these systems in enantiomeri-
cally pure form are of great interest. Thus, D2-pyrazolines could be used as chiral precursors in
the preparation of several heterocyclic derivatives and as building blocks for the asymmetric
synthesis of functionalized chiral acyclic synthons.3 Recently, two routes to enantiomerically
pure D2-pyrazolines were reported: the diastereoselective dipolar cycloaddition reaction of
Me3SiCHN2 to optically active enoates described by Carreira and co-workers4 and the reaction
of diazo compounds with alkenyl Fischer carbenes derived from chiral alcohols reported by
Barluenga and co-workers.5
In connection with our continued work on the asymmetric synthesis of a-amino b-hydroxy
acids and nitrogen heterocycles,6 we report here a concise and stereoselective synthesis of the
chiral functionalized (4S,5R)-5-carbomethoxy-4-hydroxy-D2-pyrazoline 1.
* Corresponding authors. Fax: (33) 1 39254452 (C.G.); (33) 1 44071062 (J.P.G.); e-mail: greck@chimie.uvsq.fr;
genet@ext.jussieu.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01582-3

8796
The key intermediate of our approach is the anti diastereomer of methyl 2-hydrazino-3-
hydroxy-4,4-dimethoxybutanoate 2. This compound is a chiral C4 synthon highly functionalized
by an hydrazino group and three oxygenated substitutions at different oxidation degrees: an
alcohol, an acetal and an ester group. Compound 2 was obtained by sequential catalytic
hydrogenation and electrophilic amination starting from the b-ketoester 3.
Compound
3
was prepared by
a
two carbon homologation of methyl 2,2-
dimethoxyethanoate7 using the Masamune procedure.8 Asymmetric hydrogenation of the b-
ketoester was first carried out in presence of (R)-Binap RuBr2 in methanol under classical
conditions, but secondary reactions were observed giving methyl-3,4-dihydroxybutanoate and
hydroxy-d-lactone as side products. The use of 1 mol% of [(R)-Binap RuCl2]–Et3N9 as catalyst
gave reproducible results: in methanol at 65°C and under atmospheric pressure,10 the (S)-b-
hydroxyester 4 was isolated in 83% yield and 90% enantiomeric excess (Scheme 1).
Scheme 1. (a) H2 (1 atm), [(R)-Binap RuCl2]2–Et3N (1%), MeOH, 65°C, 18 h (83%, ee=90%). (b) 1. MeZnBr (1.1
equiv.), THF, 30 min, 0°C; 2. LDA (2.2 equiv.), THF, 1 h, −78°C; 3. CbzNꢀNCbz (2 equiv.), THF, 30 min, −78°C
(66%, de>95%). (c) H2, Pd/C, MeOH, rt, 1 h (quant.). (d) TFA, rt, 2 h (70%)
Dibenzyl azodicarboxylate was used as the electrophilic reagent for the amination step giving
the hydrazino derivative protected as benzyl carbamates, which can be deprotected in presence
of an acetal function. The zinc enolate of 4 was aminated at −78°C to produce the anti
diastereomer 5 exclusively in 66% isolated yield.
The cyclization was performed after hydrogenolysis of the benzyl carbamates (H2, Pd/C), by
treatment of the crude product with trifluoroacetic acid at room temperature. Compound 1 was
purified by silica gel flash chromatography and isolated in 70% yield.11
In conclusion, we describe here the first asymmetric synthesis of the (4S,5R)-5-carbomethoxy-
4-hydroxy-D2-pyrazoline 1 in four steps starting from the achiral b-ketoester 3 in 38% overall
yield. Its enantiomer could be obtained easily using (S)-Binap as chiral ligand for the
hydrogenation step. Compound 1 is a new constituent of a novel class of a-amino acids:
azaprolines proposed recently by Carreira.4 These analogs should find important applications as
3-hydroxyproline surrogates. The highly functionalized intermediate 2 should be useful for the
preparation of various a-amino-b-hydroxy acids and peptidomimetics.
Acknowledgements
We thank Glaxo-Wellcome France for a grant to O.P.

8797
References
1. For a review, see: Elguero, J. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, 1984; Vol. 5, p. 167.
2. Frigola, J.; Colombo, A.; Pares, J.; Martinez, L.; Sagarra, R.; Roser, R. Eur. J. Med. Chem. 1989, 24, 435–445.
3. Whitlock, G. A.; Carreira, E. M. J. Org. Chem. 1997, 62, 7916–7917. Sasaki, H.; Carreira, E. M. Synthesis, 2000,
135–138.
4. Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379–8380.
5. Barluenga, J.; Fernandez-Mari, F.; Aguilar, E.; Viado, A. L.; Olano, B. Tetrahedron Lett. 1998, 39, 4887–4890.
Barluenga, J.; Fernandez-Mari, F.; Aguilar, E.; Viado, A. L.; Olano, B.; Garcia-Granda, S.; Moya-Rubiera, C.
Chem. Eur. J. 1999, 5, 883–896.
6. Greck, C.; Geneˆt, J. P. Synlett 1997, 741–748. Ferreira, F.; Greck, C.; Geneˆt, J. P. Bull. Soc. Chim. Fr. 1997, 134,
615–621. Poupardin, O.; Greck, C.; Geneˆt, J. P. Synlett 1998, 1279–1281.
7. We gratefully thank Clariant S.A. for the gift of methyl 2,2-dimethoxyethanoate.
8. Brooks, D. W.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1979, 18, 72–74.
9. Kawano, H.; Ikariya, T.; Ichii, Y.; Saburi, M.; Yoshikawa, S.; Uchida, Y.; Kumobayashi, J. Chem. Soc., Perkin
Trans. 1 1989, 1571–1575. For recent structure elucidation of this catalyst, see: Ohta, T.; Tonomura, Y.; Nozaki,
K.; Takaya, H.; Mashima, K. Organometallics 1996, 15, 1521–1523.
10. Ratovelomanana-Vidal, V.; Cano de Andrade, C.; Pfister, X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995,
36, 4801–4804. Review: Ratovelomanana-Vidal, V.; Geneˆt, J. P. J. Organomet. Chem. 1998, 567, 163–171.
11. [h]2D5=−181 (c 0.6, CHCl3).
.