Systematic investigations to develop an efficient enantioselective synthetic method for alpha-alkyl-alanine by catalytic phase-transfer alkylation were performed. The alkylation of 2-naphthyl aldimine tert-butyl ester, 1E, with RbOH and O(9)-allyl-N-2',3',4'-trifluorobenzylhydrocinchonidinium bromide, 6, at -35 degrees C showed the highest enantioselectivities, up to 96% ee.
A select series of N(2)-substituted D,L-cycloserine derivatives were prepared and evaluated for inhibitory activity against purified alanine racemases (alr gene product) from Escherichia coli, Staphylococcus aureus, and Mycobacterium tuberculosis, as well as in a growth inhibition assay. N(2)-Modification led to loss of enzymatic inhibitory activity in most cases consistent with a recent proposal for cycloserine function. D-Cycloserine (1) is a bioactive microbial product from Streptomyces (S, garyphalus sive orchidaceus)1,2) that is clinically used as a second-line drug for the treatment of tuberculosis.3) The primary macromolecular target for 1 is alanine racemase, an essential prokaryotic enzyme that is necessary for the conversion of L-to D-alanine, which is required for cell wall synthesis.4) Structure-activity relationship (SAR) studies have documented that most 1 structural changes gave diminished in vitro cell-based antimicrobial activities compared with 1.1,2) These investigations provided information concerning the antibiotic properties of cycloserine analogues, but they did not determine whether these derivatives interacted with alanine racemase since most cell growth studies do not monitor substrate cellular uptake, efflux and metabolism. In this study, we take advantage of new methodologies for protein expression3,4) to examine the importance of the N(2)-structural site in cycloserine for bioactivity. This position has been largely overlooked in earlier investigations.1,2) The biochemical properties of eighteen N(2)-modified cycloserine derivatives were tested against
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