6990 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA J. Org. Chem. 1993,58, zyxwv 6990-6995 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML Enantiomerically Pure Dimethyl (25)-N-(9-Phenyl~uoren-9-yl)-3,4-didehydroglutamate as Chiral Educt. Chirospecific Synthesis of (+)-5- 0-Carbamoylpolyoxamic Acid and 3-Alkylglutamates zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONM Manuel M. Paz and F. Javier Sardina' Departamento de Qutmica Orgbnica, Unioersidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain Received June 14, 1993. We report here a short and efficient synthesis (four steps, 78% overall yield) of dimethyl zyx (2,594- (9-phenylfluoren-9-yl)-3,4-didehydroglutamate (1) in enantiomerically pure form from L-glutamic acid. The C-C double bond in 1 was introduced by selective selenenylation-oxidation of dimethyl N-(9-phenylfluoren-9-yl)glutamate. 1 did not undergo loss of enantiomeric purity when stored for several weeks at room temperature, thus demonstrating the ability of the 9-phenylfluoren-9-yl (Pf) group to protect the highly acidic chiral center of 1 from racemization. The a,&unsaturated carboxyl group of 1 was selectively reduced with DIBAL. Carbamoylation of the resulting alcohol, followed by OsO4-mediated hydroxylation of the double bond and deprotection afforded (+)-5-0-carbam- oylpolyoxamic acid, a component of the polyoxin family of antifungal antibiotics (>40 zyx % overall yield from glutamic acid). 1 underwent lithium dimethyl cuprate addition with complete retention of chiral integrity, albeit in a nonstereoselective fashion, to give 3-methylglutamateg and 3-methylpy- roglutamates. Introduction The need to maintain the integrity of preexisting chiral centers during a chirospecific synthesis is becoming more acute as higher enantiomeric purity standards have to be met due to efficiency reasons and biological and phar- maceutical activity considerations. In the particular case of a-amino acid-based chirospecific synthesis, this usually implies that care should be exercisedto avoid racemization of the base-sensitive chiral a-center.' Recently, Rapoport has introduced the 9-phenylfluoren-9-yl (Pf) group for both nitrogen and chiral center protection in amino acid chemistrye2 The stereoelectronichindrances posed by the Pf group to abstraction of the a-hydrogen in amino acid esters has led to the development of elegant and efficient stereoselective preparations of 3-substituted aspartates and 4-substituted glutamates by alkylation of the corre- sponding amino acid diester e n ~ l a t e s . ~ ~ ~ Even a-amino aldehydes2"td and ketones2b have been turned into chirally stable, useful synthetic intermediates when N-protected with the Pf group. Abstract published in Aduance ACS Abstracts, October 15, 1993. (1) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis. Construc- tion of Chiral Molecules Using Amino Acids; Wiley: New York, 1987. (2) (a) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. zyxwvut J. Org. Chem. 1990,55, 3068-3074. (b) Lubell, W. D.; Jamison, T. F.; Rapoport, H. J. Org. Chem. 1990,55,3511-3522. (c) Lubell, W.;Rapoport, H. J. Org. Chem. 1989,54,3824-3831. (d) Lubell, W. D.; Rapoport, H. J. Am. Chem. SOC. 1987,109,236-239. (e) Christie, B. D.; Rapoport, H. J. Org. Chem. 1988,50,1239-1246. (3) Molecular mechanics calculations indicate that in a N-Pf a-amino acid derivative, the bulkiness of the Pf group forces the C-1 carboxyl group to adopt a conformation in which the dihedral angle between the a-hydrogen and the carbonyl group is -0' or 180° , thus effectively diminishing the acidity of this hydrogen (unpublished results from these laboratories). (4) (a) Dener, J. M.; Zhang, L.-H.; Rapoport, H. J. Org. Chem. 1993, 58,1159-1166. (b) Dunn, P. J.; Hber, R.; Rapoport, H. J. Org. Chem. 1990,55,5017-5025. (c) Wolf, J.-P.; Rapoport, H. J. Org. Chem. 1989,54, 3164-3173. (d) Koskinen, A. M. P.; Rapoport, H. J. Org. Chem. 1989,54, 1859-1866. (5) For a hydroxylation reaction see: Sardina, F. J.; Paz, M. M.; Femhdez-Megfa, E.; de Boer, R. F.; Alvarez, M. P. Tetrahedron Lett. 1992,33,4637-4640. 0022-3263/93/1958-6990$04.00/0 1 Figure 1. We desired to test if the Pf group could impart protection to even more acidic (i.e. more prone to racemization) chiral centers, such as the one present in the didehydroglutamate 1, in which the chiral center is part of a vinylogous malonate system. Derivatives of 1 in which the C-1 carboxyl group had been reduced to the alcohol oxidation state and protected have been used for the chirospecific synthesis of a number of natural and pharmacologically interesting products.6J In many instances the C-1 group had to be oxidized back to the carboxylate in order to obtain the desired pr~ducts.~ This reduction-oxidation protocol (which avoids racem- ization during the synthesis by greatly reducing the acidity of the chiral center) lengthens the synthesis and in some cases leads to complications during the deprotection and oxidation steps. To avoid these problems we decided to undertake the synthesis of the unsaturated diester 1 and (6) (a) Ikota, N. Tetrahedron Lett. 1992,33,2553-2556. (b) Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 1991, 32, 5983-5986. (c) Somfai,P.; He, H. M.; Tanner, D. Tetrahedron Lett. 1991, 32,283-286. (d) Ikota, N. Heterocycles 1989,29,1469-1472. (e) Ikota, N.; Hanaki, A. Heterocycles 1988,27, 2535-2537. zyxw (0 Ikota, N.; Hanaki, A. Heterocycles 1987,26,2369-2370. (g)Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1987, 35, 2140-2143. (7) (a) Jako, I.; Uiber, P.; Mann, A.; Wermuth, C.4.; Bodanger, T.; Norberg, B.; Evrard, G.; Durant, F. J. Org. Chem. 1991,56,5729-5733. (b) Langlois, N.; Andriamialisoa, R. 2. Tetrahedron Lett. 1991,32,3057- 3058. (c) Hanessian, S.; Ratovelomanana, V. Synlett 1991,222-224. (d) Hanessian, S.;Ratovelomanana, V. Synlett 1990,501-503. (e) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1989,30,3803-3804. (0 Yanagida, M.; Hashimoto, K.; Ishida, M.; Shinozaki, H.; Shirahama, H. Tetrahedron Lett. 1989,30,3799-3802. (g) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979-2984. (h) Oppolzer, W.; Thirring, K. J. Am. Chem. SOC. 1982, 104,4978-4979. (i) Ohfune, Y.; Tomita, M. J. Am. Chem. SOC. 1982,104, 3511-3513. 0 1993 American Chemical Society