An efficient methodology for a solid phase synthesis of D-and L-cycloserine derivatives is described. Fmoc-D-cycloserine 4 and its L-enantiomer 5 prepared by a selective amine acylation of bis-silylated parent compounds are immobilized on Sasrin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The resulting Fmoc-cycloserine resins 7, 10, and U are deproteeted with piperidine in DMF or DCM to generate immobilized cyeloserine reagents with a primary amino group exposed for various synthetic transformations. An example of the parallel D-cycloserine library synthesis on a reaction plate is described. O 1998 Elsevier Science Ltd. All rights reserved.
Combinatorial chemistry has been well recognized as an important drug discovery tool. An ongoing trend is to integrate the combinatorial approach with fundamentals of medicinal chemistry and rational drug design. Popular synthetic targets include peptidomimetic scaffolds, mechanism-or structure-based pharmaeophoric structures, de novo designed scaffolds, and natural product derivatives. | While historical precedence provides an ample number of drug examples derived from natural products, the latter has received relatively little attention from combinatorial chemists, mainly because of the degree of synthetic complexity associated with such molecules. Several reported sudies include solid phase syntheses (SPS) of carbohydrates, 2 Rauvolfia alkaloid derivatives, 3 epothilones 4 and taxoids, 5 and prostaglandin 6 derivatives. Indeed, combinatorial chemistry of natural products often presents serious difficulties, such as accessibility of natural product building blocks, chemical selectivity in a mulitifunctional molecular environment, stability of intermediates and target products under immobilization and cleavage conditions, etc. In this communication, we wish to report the first SPS of D-and Lcycloserine derivatives developed as part of our combinatorial chemistry aided drug discovery program.
D-Cycloserine [(R)-4-aminoisoxazolidine-3-one] 1 is a natural product isolated from fermentation broths of Streptomyces orchidaceus, Streptomyces garyphalus, and Streptomyces lavendulus. 7 The compound has received attention mainly as a broad spectrum antibiotic, which inhibits the bacterial cell wall biosynthesis via