Michael Schwarm

Biocatalysis to amino acid-based chiral pharmaceuticals : examples and perspectives

Abstract The search for and development of new pharmaceutically active structures drives the need for new enantiomerically pure compounds (EPC). Many N-containing structures can be derived beneficially from either l - or d -amino acids [K. Drauz, Chimia 51 (1997) 310–314.]. The largest growth occurs in the area of unnatural amino acids. Two examples discussed from the Degussa portfolio concern (i) d -amino acids [A.S. Bommarius, M. Kottenhahn, H. Klenk, K. Drauz, NATO ASI Series C 381 (1992) 161–174.] as components of LHRH antagonists of which the Degussas Cetrorelix is a prime example as well as (ii) l - tert -leucine, occurring in a fast-growing number of pharmaceutical compounds under development [A.S. Bommarius, M. Schwarm, K. Stingl, M. Kottenhahn, K. Huthmacher, K. Drauz, Tetrahedron Asymmetry 6 (1995) 2851–2888.]. For d -amino acids, results of the hydantoinase/carbamoylase route will be presented while redox catalysis by way of reductive amination is a suitable process to l - tert -leucine. The number of biocatalytic applications is growing and an updated list is discussed. The presentation will also cover comparisons of biocatalysis with potentially competitive technologies such as enantioselective crystallization, chemical asymmetric synthesis, or chromatographic separation of racemates. Future trends relevant to the perspective for biocatalysis include the need for ever more complex chiral molecules as well as shortened development times in the pharmaceutical industry.

SYNTHESIS AND USE OF ENANTIOMERICALLY PURE TERT-LEUCINE

Abstract Owing to its bulky, inflexible and hydrophobic tert -butyl side chain, tert -leucine (Tle) finds increased use in templates or catalysts in asymmetric synthesis as well as in peptidic medicinal compounds. ( S )-Tle, available through a large-scale enzymatic reductive amination process, has been incorporated into a variety of anti-AIDS and -cancer compounds. With two new routes to ( R )-Tle coming available, the number of applications of both ( R )- and ( S )-Tle can be expected to increase considerably.

l-methionine related l-amino acids by acylase cleavage of their corresponding N-acetyl-dl-derivatives

Abstract Acylase I from Aspergillus oryzae is an even more useful enzyme than suggested so far. Besides standard amino acids such as l -Met, l -Val and l -Phe, a number of additional sulfur- and selenium-containing amino acids can be obtained at useful reaction rates and in very high enantiomeric purity by kinetic resolution of the respective N- acetyl- dl -amino acids.

Kinetics of Peptide Amidase and its Application for the Resolution of Racemates

The chemical synthesis of various N-protected amino acid amides was carried out. These compounds served as substrates to determine the V max and KM values for the deamidation catalyzed by the peptide amidase from Citrus sinensis and Stenotrophomonas maltophilia, respectively, and to investigate the influence of the side chain of the amino acid on the performance of the enzymatic hydrolysis. The enzymatic resolution of racemic N-acetyl amino acids amides yielded N-acetyl-L-amino acids in optical purity ≧ 99% at complete conversion.

O-Acetyl-L-homoserine: A versatile synthon for the synthesis of L-homoserine peptides and 3-amino-2-pyrrolidinones

Although L-homoserine is a naturally occurring amino acid with important biological properties, only few examples of homoseryl peptides are known, which have been mainly prepared by using either the benzyl [1,2] or the trityl [3,4] group for the O-protection. Furthermore, homoserine amides are potential precursors for the introduction of a ring, which can act as conformational constraints in peptides and peptidomimetics [5-7]. Herein, we report new methods for the preparation of homoserine amides and their conversion into