1.Combinatorial solution-phase synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides.
Malavasic C1, Brulc B, Cebasek P, Dahmann G, Heine N, Bevk D, Groselj U, Meden A, Stanovnik B, Svete J. J Comb Chem. 2007 Mar-Apr;9(2):219-29.
Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.
2.Effects of long-term administration of (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3- phenylpropyl)amino]propionyl]-2-oxoimidazolidine-4-carboxylic acid hydrochloride (TA-6366), a new angiotensin I converting enzyme (ACE) inhibitor, from the pre-hypertensive stage on morphological change and mechanical property related to sodium ion permeability in aorta of spontaneously hypertensive rats (SHRs).
Kubo M1, Kobayashi K, Ishida R. J Pharmacobiodyn. 1992 Nov;15(11):657-65.
Effects of (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]- propionyl]-2-oxoimidazolidine-4-carboxylic acid hydrochloride (TA-6366) on morphological change and mechanical property related to sodium ion permeability in the aorta of spontaneously hypertensive rats (SHRs) were examined, as compared with those of enalapril and captopril. Ten-week oral administration of TA-6366 (1 and 5 mg/kg/d) from 4 weeks of age impeded aortic media-thickening together with a rise in blood pressure in SHRs. Concomitantly, aorta weights in both groups were markedly decreased. The higher dose of TA-6366 almost fully suppressed the accelerated tension development induced by K(+)-free medium and decreased total sodium ion content in the aorta. These vascular effects of TA-6366 was more prominent than those of enalapril and captopril at 5 mg/kg/d. The difference in potencies on the above vascular parameters between TA-6366 and these drugs seemed to be mainly related to the difference in their antihypertensive activities.
3.Oxazoline-oxazinone oxidative rearrangement. divergent syntheses of (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-Trifluoroleucine.
Pigza JA1, Quach T, Molinski TF. J Org Chem. 2009 Aug 7;74(15):5510-5. doi: 10.1021/jo900654y.
Stereoselective syntheses of the valuable fluorinated amino acids (2S,3S)-4,4,4-trifluorovaline and (2S,4S)-5,5,5-trifluoroleucine have been achieved starting from 4,4,4-trifluoro-3-methylbutanoic acid by using a conceptually simple transformation: conversion to a chiral oxazoline, SeO2-promoted oxidative rearrangement to the dihydro-2H-oxazinone, and face-selective hydrogenation of the C=N bond, followed by hydrogenolysis-hydrolysis. The transformation is limited by the tendency of the intermediate beta-trifluoromethyldihydrooxazinone to undergo imine-enamine isomerization. Both amino acids were obtained as configurationally pure hydrochloride salts identical in all respects with those in literature reports.
