.alpha.,.alpha.-Difluoro-.beta.-aminodeoxystatine-containing renin-inhibitory peptides

Abstract

The preparations of sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates (7a and 7b) from sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(R)- and -3(S)-hydroxy-6-methylheptanoates (1a and 1b) are described. The key step involves the stereospecific intramolecular displacement via a Mitsunobu reaction for the conversion of a beta-hydroxy hydroxamate to a beta-lactam ring. Compounds 7a and 7b are useful as synthetic intermediates for the preparation of enzyme inhibitors that contain 3(S),4(S)- and 3(R),4(S)-diamino-2,2-difluoro-6-methylheptanoic acid inserts. Angiotensinogen analogues VII and VIII that contain these novel amino analogues of difluorostatine were shown to be inhibitors of the enzyme renin. The alpha,alpha-difluoro-beta-aminodeoxystatine-containing compounds were shown to be weaker inhibitors than the corresponding difluorostatine-containing congeners.

β‐Hydroxycarboxylic Acids from Simple Ketones by Carboxylation and Asymmetric Hydrogenation

“…To determine the solvent effect on the rate of decarboxylation, the decarboxylation of 2a in various deuterated solvents was monitored by 1 H NMR spectroscopy ( Figure 1). The decarboxylation follows first-order kinetics (the log plot is linear for over 2 half lives for DMSO and MeOH and for as long as was measured for the other solvents).…”

“…Potential products include b-hydroxycarboxylic acids, which have been shown to be valuable building blocks for pharmaceuticals such as b-amino acids, [1] b-lactams, [2] b-lactones, [3] and pheromones; [4] in addition, their use in anti-inflammatory products [5] is well-known. Currently, stereoselective methods for their synthesis are few and not ideal for industrial use.…”

Recent Developments in the Synthesis of Fluorine-Containingβ-Amino Acids andβ-Lactams

“…Reformatsky 反应制备 α,α'-二氟-β-羟基酸, 再通过分子 内 [24,25] 或分子间 [26] 的 Mitsunobu 反应将羟基转化为氨基 而得到. 例如 Nakayama 等 [10] 将 α,α'-二氟-β-羟基酰胺 以烷基氨为手性源的 Reformatsky 反应合成 β-氨基 酸的产率较低, 同时得到内酰胺类化合物, 主要原因是 采用了相对不活泼的金属锌作为反应试剂.…”

Direct Carboxylation of C(sp3)-H and C(sp2)-H Bonds with CO2 by Transition-Metal-Catalyzed and Base-Mediated Reactions

“…Moreover, chiral β-hydroxycarboxylic acids are important intermediates widely used as chiral precursors of anti-inflammatory products, [87] β-amino acids, [88] β-lactams, [89] β-lactones, [90] and pheromones [91].…”