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Amino Acids. 7.1A a Novel Synthetic Route to L-Proline

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Amino Acids. 7.1A a Novel Synthetic Route to L-Proline 3494 J. Org. Chem. 1986,51, 3494-3498 Amino Acids. 7.1a A Novel Synthetic Route to L-Proline Karlheinz Drauz,*lb Axel Kleemann, Jiirgen Martens, and Paul Scherberich Forschung Chemie Organisch, Degussa AG, 0-6450 Hanau, West Germany Franz Effenberger* Institut fur Organische Chemie der Universitat Stuttgart, 0-7000 Stuttgart 80, West Germany Received April 1, 1986 Reaction of LBoxoproline esters L-2with phosgene at 0 OC gives ~-5,~dichloro-l-(chlorocarbonyl)prolineesters L-6,which readily lose hydrogen chloride to form ~-5-chloro-l-(chloroarbonyl)-4,5-dehydroprolineesters L-7. Catalytic hydrogenation (Pd/C, 180 bar) of L-7yields L-1-(chlorocarbony1)prolineesters L-15and thence, upon hydrolysis, L-proline (~17).A "one-pot reaction" for the whole sequence is described, starting from easily accessible L-5-oxoproline esters and yielding L-proline in 78% overall yield and 99.7% optical purity. Scheme I L-Proline is gaining increasing importance as the central component in pharmaceutical products and agricultural chemicals; several of its derivatives are valuable chiral auxiliary reagents. Some highly active ACE inhibitors, for H H hydrogenotion instance, are derived from L-proline, e.g., CaptopriP and its cyclic analogue2b and Merck's Enalapril.2c Bicyclic hydantoins derived from L-proline are employed as fun- L-J gicide~.~Chiral diamines that can be prepared from either L-proline or L-hydroxyproline in high optical purity have been employed as chiral auxiliary reagents in asymmetric syntheses4 (e.g., (S)-2-(anilinomethyl)pyrrolidine, (2S,2'S)-2-(hydroxymethyl)-l-[(l-methylpyrrolidin-2'-yl)- methyllpyrrolidine, (2S,4S)-2-(anilinomethyl)-l-ethyl-C pyrrolidinone8bor pyrrolidine." A technically interesting hydr~xypyrrolidine,~and (S)- 1-amino-2-(methoxy- variation is the preparation of D,L-proline from acrolein methyl)pyrrolidine)! with HCN and ammonia.8d The disadvantage of all these Until today, L-proline is obtained almost exclusively processes lies in the necessity for a resolution of the from protein hydrolysates by ion-exchange chromatogra- racemate. phy. The broad spectrum of applications for L-proline and The obvious chiral precursors for a direct, enantiose- its derivatives, listed above, makes it doubtful whether the lective synthesis of L-proline are L-5-oxoproline (L-1) or its amounts obtained from protein hydrolysates will suffice easily accessible esters L-2 (see Scheme whence, by to meet the demand for this amino acid in the near future. selective hydrogenation of the carboxamidoI)9 function, the Many efforts are directed, toward making L-proline ac- corresponding L-proline derivatives L-3might be obtained cessible by either straightforward chemical synthesis or directly. Many efforts have been directed therefore toward fermentation processes. selective hydrogenation L-2 to L-3. In this paper, we report a high-yield preparation of op- All attempts at selective catalytic hydrogenation of L- tically pure L-proline, starting from easily accessible and 5-oxoproline (L-1)have failed completely, however.loa low-priced L-glutamic acid. Reaction of L-5-oxoprolineethyl ester with sodium/ethanol Several procedures have been reported for the synthesis gave L-proline in only 3.7% yield.lob Hydrogenation of of racemic D,L-proline,8a starting from, e.g., 2- L-2with diboranegbor LiAlH411affords almost exclusively L-prolinol. From y-methyl L-glutamate and Na13H4, L- proline is obtained in yield. High-pressure hydro- (1) (a) For part 6, see: Burkard, U.; Walther, 1.; Effenberger, F. Liebigs 34.5% Ann. Chem., in press. (b) Amino Acid Transformations. Part 1. genation of 5-thioxopyrrolidine-2-carboxylicacid with (2) (a) Ondetti, M. A.; Cushman, D. W. (Squibb, E. R., and Sons, Inc.) Raney nickel also affords less than 20% of proline.'^ Ger. Offen. 2703828 (Cl.C07D20)/16), 1977; US Appl. 657 792, 1976; Chem. Abstr. 1978,88 7376c. (b) Kim, D. H. J. Heterocycl. Chem.1980, Reaction of the 0-alkyl derivative, obtained from L-2with 17, 1647. (c) Patchett, A. A.; Harris, E.; Trietram, E. W.; Wyvratt, M. Meerwein's salt, with excess NaBH4 has been reported to J.; Wu, M. T.; Taub, D.; Peterson, E, R.; Ikeler, J.; ten Broeke, J.; yield of ~-3,'~but this result could not be reproduced Thorsett, W. 3.; Greenlee, W. J.; Lohr, N. S.; Payne, L. G.; Ondeyka, D. 76% L.; Hoffsommer, R. D.,; Joshua, H.; Ruyle, W. V.; Robinson, F. M.; Hirschmann, R.; Sweet, C. S.; Rothrock, J. W.; Aster, S. D.; Maycock, A. L.; E. H.; Gross, D. M.: Vassil, T. C.; Stone, C. A. Nature (London) (8) (a) Greenatein, J. P.; Winitz, M. Chemistry of the Amino Acids; 1980,288,Ulm, 280. Wiley: New York, 1961; Vol. 111, p 2178. (b) Harm, K.; Wieland, A. (3) Wakabayashi, 0.;Matautani, K.; Ota, H.; Naohara, T.; Watanabe, Chem. Ber. 1960,93, 1686. (c) Schmidt, U.; Poisel, H. Angew. Chem. H. (Mitaubishi Chemical Instustries Co, La.) Jauan Kokai 7783686 1977,89,824; Angew. Chem., Znt. Ed. Engl. 1977,16,777. (d) Draw, K.; (Cl.C07D471/04), 1977, Appl. 76/224, 1976; Chim. Abstr. 1978, 88, Kleemann, A.; Samson, M. Chem.-Ztg. 1984,108, 391. 22905t. (9) (a) Hardy, P. M. Synthesis 1978, 290. (b) Schmidt, U.; Scholm, (4) (a) Blechert, S. Nachr. Chem., Tech. Lab. 1979,12,768. (b) Draw, R. Synthesis 1978, 752. K.; Kleeman, A,; Martens, J. Angew. Chem. 1982,94,590, Angew. Chem., (10) (a) McCay, C. M.; Schmidt, C. L. A. J. Am. Chem. SOC.1926,48, Int. Ed. Engl. 1982, 21, 584. 1933. (b) Fischer. E.: Boehner, R. Ber. Dtsch. Chem. Ges. 1911,44,1332. (5) Mukaiyama, T. Tetrahedron 1981, 37, 4111. (11)Buyle, R.'C&m. 2nd. (London) 1966,380. (6) (a) Enders, H.; Eichenauer, H. Angew. Chem. 1976,88,579;Angew. (12) Tanaka, M.; Kishi, T.; Kinoshita, S. Nippon Nogei Kagaku Chem.,Znt. Ed. Engl. 1976,15,549. (b) Enders, D.; Kipphard6 H. Nachr. Kaishi 1960,34, 782; Chem. Abstr. l963,59,6509a. Chem., Tech. Lab. 1985,33, 882. (13) Kleeman, A,; Martens, J.; Draw, K. Chem.-Ztg. 1981, 105, 266. (7) Draw, K.; Effenberger, F.; Kleemann, A.; Martens, J.; Scherberich, (14) (a) Monteiro, H. J. Synthesis 1974, 137. (b) Enders, D.; Eiche- P. (Degussa A.-G.) Ger. Offen. DE 3 137 377 C2 (CL07D207/16), 1983, nauer, H.; Pieter, R. Chem. Ber. 1979,112,3703. (c) Chung, B. Y.; Lee, Appl., 1981; Chem. Abstr. 1983, 99,38808b. C. H.; Yang, C. M. Bull. Korean Chem. SOC.1986,6, 177. 0022-3263/86/1951-3494$01.50/0 0 1986 American Chemical Society Amino Acids J. Org. Chem., Vol. 51, No. 18, 1986 3495 Scheme I1 Scheme IV k-z. COCI, L-6 -COI,- HCI Scheme I11 I-p I-f COCI,,CH,CI,O°C 20°C Scheme V k-: CI - no,- co, - k-;? * RCOCI Ob-- R CHJ C2H5 by other a~th0rs.l~~In a very recent publication, Cbz- protected methyl L-glutamate was reduced with diborane to give L-proline in 16% total yield with respect to L- R CHI C6H) glutamic A synthesis of L-proline from L-norvaline has recently proline esters (S)-5 in good yield (Scheme 11). been reported;15 considering the poor accessibility of L- Apparently, under the reaction conditions employed, the norvaline, this is of little practical importance. From imide chlorides L-4, once formed, are immediately sca- electrochemical reductions of L-2, L-proline likewise is venged by still present educt ~2.The same result has been obtained only in moderate yields and with partial race- reported for the reaction of 2-pyrrolidone with Pc15.19 mization.16 With phosgene, on the other hand, the L-5-oxoproline One may state, thus, in summing up, that all methods esters L-2are indeed converted into the surprisingly stable, employed so far for selective hydrogenation of L-2to L-3 readily handled amide chlorides L-6. At slightly higher have given at best only poor to moderate yields of L-proline temperature, the compounds L-6b lose hydrogen chloride derivatives, due to simultaneous or even preferred hy- to form the a-chloro enamines L-7b (Scheme 111). From drogenation of the ester group. In view of the higher the reaction of ecaprolactam with phosgene, likewise only carbonyl reactivity of an alkoxycarbonyl relative to a an elimination product, comparable to L-7,has been iso- carboxamido function, this is to be expected. lated.20 It is necessary, therefore, if the &oxo group in L-2 is to There are two possible mechansms for formation of L-6. be hydrogenated while still preserving the 1-carboxylate (i) The NH group of L-2 is initially attacked by phosgene function, either to mask this function (by acetalization), to give intermediate L-8,the 5-OXO function of which is then or to activate the 5-oxo function, e.g., by sulf~ration'~or halogentaed via L-9 (path A, Scheme IV). (ii) After pri- alkylation,14* as detailed above. One well-established mary reaction of the carbonyl group, via L-10,L-4 then adds method for selective reduction of carboxylic acid deriva- phosgene to give L-6 (path B). tives in the presence of other carbonyl functions is hy- Carboxamides, as ambident nucleophiles, are known to drogenation of the respective imide chlorides with any of be attacked by electrophiles preferentially at the oxygen a variety of hydrogenating agents." center. Path B, which represents the mechanistic analogue Chlorination of L-5-OxoprolineEsters. Imide or for the reaction of L-2 with phosgene, receives further amide chlorides generally are prepared from the respective confirmation from the nature of the byproducts, isolated carboxamides with PCl,, POCl,, S0Cl2,C0Cl2, or (COC1)2 from these preparations. (S)-5,which is the main product as halogenating agents.'* We have treated the L-5-oxo- from the reaction of L-2 with POCl,, can also be detected proline esters L-2with POC1, in dichloromethane at room in small amounts in the crude product mixture from the temperature and obtained the N-pyrrolidino-~-5-oxo- phosgene reactions but not the substituted urea expected from reaction of L-8with L-2in the case of path A.
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