Abstract
The chiral intermediate (1S,2R) [3-chloro-2-hydroxy-1-(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester 2a was prepared for the total synthesis of a human immunodeficiency virus protease inhibitor, BMS-186318. The stereoselective reduction of (1S) [3-chloro-2-oxo-1(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester 1 was carried out using microbial cultures, among which Streptomyces nodosus SC 13149 efficiently reduced 1 to 2a. A reaction yield of 80%, enantiomeric excess (e.e.) of 99.8%, and diastereomeric purity of 99% were obtained for chiral alcohol 2a. Chiral l-6-hydroxy norleucine 3, an intermediate in the synthesis of antihypertensive drug, was prepared by reductive amination of 2-keto-6-hydroxyhexanoic acid 4 using beef liver glutamate dehydrogenase. The cofactor NADH required for this reaction was regenerated using glucose dehydrogenase from Bacillus sp. A reaction yield of 80% and e.e. of 99.5% were obtained for l-6-hydroxynorleucine 3. To avoid the lengthy chemical synthesis of the ketoacid, a second route was developed in which racemic 6-hydroxynorleucine [readily available from hydrolysis of 5-(4-hydroxybutyl) hydantoin 5] was treated with d-amino acid oxidase from Trigonopsis variabilis to selectively convert the d-isomer of racemic 6-hydroxynorleucine to 2-keto-6-hydroxyhexanoic acid 4 and l-6-hydroxynorleucine 3. Subsequently, the 2-keto-6-hydroxyhexanoic acid 4 was converted to l-6-hydroxynorleucine by reductive amination using glutamate dehydrogenase. A reaction yield of 98% and an e.e. of 99.5% were obtained.
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References
Sih, C.J., and C.S. Chen, Microbial Asymmetric Catalysis: Enantioselective Reduction of Ketones, Angew. Chem. Int. Engl. 23:570–578 (1984).
Jones, J.B., Enzymes in Organic Synthesis, Tetrahedron 42:3351–3403 (1986).
Csuz, R., and B.I. Glanzer, Baker’s Yeast Mediated Transformations in Organic Chemistry, Chem. Rev. 91:49–97 (1991).
Crosby, J., Synthesis of Optically Active Compounds: A Large Scale Perspective, Tetrahedron 47:4789–4846 (1991).
Simon, H., J. Bader, H. Gunther, S. Neumann, and J. Thanos, Chiral Compounds Synthesized by Biocatalytic Reductions, Angew. Chem. Int. Engl. 24:539–553 (1985).
Stinson, S.C., Chiral Drugs, Chem. Eng. News (Sept. 28):46–79 (1992).
Santaneillo, E., P. Ferraboschi, P. Grisenti, and A. Manzocchi, The Biocatalytic Approach to the Preparation of Enantiomerically Pure Chiral Building Blocks, Chem. Rev. 92:1071–1140 (1992).
Margolin, A.L., Enzymes in the Synthesis of Chiral Drugs, Enzyme Microb. Technol. 15:266–280 (1993).
Wong, C.-H., and G.M. Whitesides, Enzymes in Synthetic Organic Chemistry, Tetrahedron Organic Chemistry Series, Elsevier Science Ltd., New York, 1994, Vol. 12.
Patel, R.N., Stereoselective Biotransformations in Synthesis of Some Pharmaceutical Intermediates, Adv. Appl. Microbiol. 43:91–140 (1997).
Patel, R.N., Use of Lipases in Stereoselective Catalysis and Preparation of Some Chiral Drug Intermediates, Recent Res. Devel. Oil Chem. 1:187–211 (1997).
Patel R.N., A. Banerjee, C.G. McNamee, D.B. Brzozowski, and L.J. Szarka, Preparation of Chiral Synthon for HIV Protease Inhibitor: Stereoselective Microbial Reduction of N-α-Protected Aminochloroketone, Tetrahedron: Asymmetry 8:2547–2552 (1997).
Hanson, R.L., M.D. Schwinden, A. Banerjee, D.B. Brzozowski, B.-C., Chen, B.P. Patel, C.G. McNamee, G.A. Kodersha, D.R. Kronenthal, L.J. Szarka, and R.N. Patel, Enzymatic Synthesis of l-6-Hydroxynorleucine, Bioorg. Med. Chem., in press.
Barrish, J.C., E. Gordon, M. Alam, P.-F. Lin, G.S. Bisacchi, P.T.W. Cheng, A.W. Fritz, J.A. Greytok, M.A. Hermsmeier, W.G. Humphreys, K.A. Lis, M.A. Marella, Z. Merchant, T. Mitt, R.A. Morrison, M.T. Obermeier, J. Pluscec, M. Skoog, W.A. Slusarchyk, S. Spergel, J.M. Stevenson, C.Q. Sun, J.E. Sundeen, P. Taunk, J.A. Tino, B.M. Warrack, R. Colono, and R. Zahler, Amino Diol HIV Protease Inhibitors. 1. Design, Synthesis, and Preliminary SAR, J. Med. Chem. 37:1758–1771 (1994).
Robl, J.A., C. Sun, J. Stevenson, D.E. Ryono, L.M. Simpkins, M.P. Cimarusti, T Dejneka, W.A. Slusarchyk, S. Chao, L. Stratton, R.N. Misra, M.S. Bednarz, M.M. Asaad, H.S. Cheung, B.E. Aboa-Offei, P.L. Smith, P.D. Mathers, M. Fox, T.R. Schaeffer, A.A. Seymour, and N.C. Trippodo, Dual Metalloprotease Inhibitors: Mercaptoacetyl Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting and Neutral Endopeptidase, J. Med. Chem. 40:1570–1577 (1997).
Robl, J.A., and M.P. Cimarusti, A Synthetic Route for the Generation of C-7 Substituted Azapinones, Tetrahedron Lett. 35:1393–1396 (1994).
Maurer, P.J., and M.J. Miller, Mycobactins: Synthesis of (−)-Cobactin from ε-Hydroxynorleucine, J. Org. Chem. 46:2835–2836 (1981).
Maurer, P.J., and M.J. Miller, Microbial Iron Chelators: Total Synthesis of Aerobactin and Its Constituent Amino Acid, N 6-Acetyl-N 6-hydroxylysine, J. Am. Chem. Soc. 104:3096–3101 (1982).
Maurer, P.J., and M.J. Miller, Total Synthesis of a Mycobactin: Mycobactin S2, Ibid.:240–245 (1983).
Culvenor, C.C.J., M.C. Foster, and M.P. Hegarty, A Total Synthesis of Indospicine, 6-Amidino-2-aminohexanoic Acid, Aust. J. Chem. 24:371–375 (1971).
Bodanszky, M., J. Martinez, G.P. Priestly, J.D. Gardner, and V. Mutt, Cholecytokinin (pancreozymin). 4. Synthesis and Properties of a Biologically Active Analogue of the C-Terminal Heptapeptide with ε-Hydroxynorleucine Sulfate Replacing Tyrosine Sulfate, J. Med. Chem. 21:1030–1037 (1978).
Bommarius, A.S., Hydrolysis and Formation of C-N Bonds, in Enzyme Catalysis in Organic Synthesis, edited by K. Drauz and H. Waldmann, VCH, Weinheim, 1995, Vol. II, pp. 633–641.
Galkin, A., L. Kulakova, T. Yoshimura, K. Soda, and N. Esaki, Synthesis of Optically Active Amino acids from α-Keto Acids with Escherichia coli Cells Expressing Heterologous Genes, Appl. Environ. Microbiol. 63:4651–4656 (1997).
Gaudry, R., The Synthesis of D,l-α-Amino-ε-hydroxycaproic Acid and a New Synthesis of D,l-Lysine, Can. J. Res. (B) 26:387–392 (1948).
Hanson, R.L., J. Singh, T.P. Kissick, R.N. Patel, L.J. Szarka, and R.H. Mueller, Synthesis of l-β-Hydroxyvaline from α-Keto-β-hydroxyisovalerate Using Leucine Dehydrogenase from Bacillus Species, Bioorg. Chem. 18:116–130 (1990).
Oshima, T., and K. Soda, Biotechnological Aspects of Amino Acid Dehydrogenases, Int. Ind. Biotechnol. 9:5–11 (1989).
Oshima, T., N. Nishida, S. Bakthavatsalam, K. Kataoka, H. Takada, T. Yoshimura, N. Esaki, and K. Soda, The Purification, Characterization, Cloning and Sequencing of the Gene for a Halostable and Thermostable Leucine Dehydrogenase from Thermoactinomyces intermedius, Eur. J. Biochem. 222:305–312 (1994).
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Patel, R.N. Biocatalytic synthesis of chiral intermediates for antiviral and antihypertensive drugs. J Amer Oil Chem Soc 76, 1275–1281 (1999). https://doi.org/10.1007/s11746-999-0139-7
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DOI: https://doi.org/10.1007/s11746-999-0139-7