J. Org. Chem. 1988,53, 5729-5731
5729
Base-Catalyzed Epimerization Behavior and Unusual Reactivity of N-Substituted Derivatives of 2,5-Dicarbalkoxypyrrolidine. Preparation of a Novel Mixed Carbamic Carbonic Anhydride by a 4-(Dimethy1amino)pyridine-CatalyzedAcylation D. S. Kemp* and Timothy P. Curran Department of Chemistry, Room 18-584, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received September 17, 1987 The equilibration of cis-trans isomers of 1-substituted 2,5-dicarbalkoxypyrrolidinederivatives (1 = CH2Ph, H, CN, C02R) results in nearly 1:l mixtwes, contrary to a literature report for l-benzyl-2,5-dicarbalkoxypyrrolidine. Apparent conversion to the trans isomer in ethanol solution is shown to result from more rapid hydrolysis of the cis ester function. The acylation of 2,5-dicarbethoxypyrrolidinewith di-tert-butyl dicarbonate and DMAP results in the expected 1-Bocurethane in the case of the cis isomer; the trans isomer is shown to form an unstable, novel carbamic carbonic anhydride.
In the course of syntheses of rigid analogues of amino acids that can serve as templates for peptide and protein secondary structure, we required N-urethane blocked derivatives of trans-2,5-dicarbethoxypyrrolidine(3a). The preparation of these species proved unexpectedly difficult, and several unusual reactions have been discovered during the development of practical syntheses. Recent interest' in the 2,5-dicarb&oxypyrrolidines as intermediates in the preparation of C2-symmetricchiral agents prompts us to report our findings.
a
R1 =Et
1 R2 = CH2Ph 3R2=H 6 R2 = CO2- t - BU 7 R2 = CN 9 R2 = COsCOn-t-Bu
b 2 4 6 8
R1 =Me R2 = CHZPh R2= H R2 = CO2-t-Bu R2 = CN
A natural precursor of 3a is the N-benzyl analogue la, which has been reported by Lowe and Ridley2to be readily prepared in 45% yield by epimerization (0.5 M sodium ethoxide in ethanol, 25 OC, 4 days) of the cis isomer 2a or a cis-trans mixture which is in turn available by reaction of benzylamine with diethyl mes0-2,5-dibromoadipate.~ Initially, in our hands this procedure resulted only in a nearly quantitative recovery of a 1:l mixture of the epimers l a and 2a. More careful study revealed that this outcome is observed only if anhydrous ethanol is used as solvent and precautions are taken to exclude moisture. Use of 95% ethanol gives the outcome reported by Lowe and Ridley (recovered diester is less than 2% cis), owing evidently to the selective hydrolysis of the cis isomer 2a under the reaction condition^.^ (1) (a) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Kabuki, T.; Yamaguchi, M., Tetrahedron Lett. 1984,25,857. (b) Ito, Y.; Kabuki, T.; Yamaguchi, M. Ibid. 1984,25,6015. (c)Enomoto, M.; Ito, Y.; Kabuki, T.; Yamaguchi, M. Zbid. 1985,26, 1343. (d) Ito, Y.; Katsuki, T.; Yamaguchi, M. Zbid. 1985,26,4643. (e) Kabuki, T.; Tamaguchi, M. Zbid. 1986, 26, 5807. (f) Tamaguchi, M.; Hasebe, K.; Tanaka, S.; Minami, T. Zbid. 1986,27,959. (9) Hanamoto, T.; Kabuki, T.; Tamaguchi, M. Zbid. 1986, 27,2463. (h) Ikegami, S.;Hayama, T.; Kabuki, T.; Yamaguchi,M. Zbid. 1986,27,3403. (i) Uchikawa, M.; Hanamoto,T.; Katsuki, T.; Yamaguchi, M. Zbid. 1986, 27, 4577. (j)Uchikawa, M.; Hanamoto, T.; Kabuki, T.; Yamaguchi, M. Zbid. 1987,28, 651. (2) Lowe, G.; Ridley, D. D. J. Chem. Soc., Perkin Tram. 1 1973,2024. (3) Guha, P. C.; Sankaran, D. K. Organic Syntheses; Wiley: New York, 1955; Collect. Vol. 111, p 623. (4) Similar results have been obtained by Dr. T. Kabuki (personal communication).
0022-3263/88/1953-5729$01.50/0
Table I. Equilibrium Ratios of Cis-Trans Isomers of 1-Substituted 2,5-Dicarbethoxypyrrolidines l-substitcis/ trans isomers uent eauilibration conditions" ratio" 52:48 M; 12 h, la, 2a CHzPh NaOEt-EtOH; 5 X 23 "C M; 12 h, 55:45 3a, 4a H NaOEt-EtOH; 9 X 23 OC 55:45 M; 12 h, 5a, 6a C02tBu NaOEt-EtOH; 6 X 23 "C 7a, 8a CN M; 2 h, 45:55b DBU-toluene;b 6 X 90 o c aEquimolar base and urethane were used. All equilibra were studied from both directions by starting with pure cis and pure trans isomers; identical final equilibrium ratios were observed in each of the four cases studied. Equilibra were determined by 'H NMR measurements of the mixture resulting from solvent removal and extractive workup; the overall recovery of material was
