Enantioselective Synthesis of α-Quaternary Amino Acid Derivatives by Sequential Enzymatic Desymmetrization and Curtius Rearrangement of α,α-Disubstituted Malonate Diesters

Abstract

A convenient and versatile enantioselective synthesis of biologically important alpha-quaternary amino acid derivatives was based on the sequential double alkylation or arylation of dimethyl malonate, followed by desymmetrization with porcine liver esterase (PLE) and Curtius rearrangement. The PLE-mediated hydrolysis of the prochiral dialkylated malonate diesters produced the corresponding chiral half-esters in high yield and with enantiomeric excesses of 43% to >98%. Curtius rearrangement of the latter products, after trapping of the intermediate isocyanates with benzyl alcohol or amines, afforded the corresponding Cbz-protected amino esters or ureas. The absolute configurations of the major products in five examples were established by conversion to compounds with known specific rotations, or by X-ray crystallography of derivatives obtained with chiral amines of known configuration.

Stereodivergent synthesis of the LFA-1 antagonist BIRT-377 by porcine liver esterase desymmetrization and Curtius rearrangement

“…However, we later noted that the ee increased considerably to 80% when the 2-benzyl substituent was homologated to the corresponding 2-(2-phenethyl) group. 5 This suggested that the increased size of the phenethyl substituent resulted in tighter binding to the large hydrophobic pocket of PLE in the Jones model. 6b Similarly, we reasoned that the larger p-bromobenzyl substituent of 3, compared with benzyl, might provide enhanced binding to the enzyme and afford improved enantioselectivity.…”

Recent Advancements in the Synthesis of Half-Esters and Their Applications

“…Enzymes have been widely applied to the preparation of half-esters, especially for monohydrolysis of diesters (Scheme 6). Among the most frequently employed enzymes are esterases [15][16][17][18][19][20][21][22][23] and lipases 24 for the hydrolysis of esters. The enzyme catalysts have broad substrate specificities, activities, and enantioselectivities.…”

“…Ohno et al developed one of the most pioneering studies using half-esters obtained by the monohydrolysis of symmetric diesters mostly with pig liver esterase. They applied several half-esters, 53, 60, and 63 (Scheme 7) to the total synthesis of a wide range of natural products and pharmaceuticals such as nucleosides, 15 (-)-fortamine, 16 and carbapenems 17,18 including asparenomycin C, thienamycin, and carbetimycin A. Nagao et al reported the synthesis of (+)-carbacyclin, 19 More recently, Back et al 21 and Materson et al 22 performed the enantioselective synthesis of amino acid derivatives from the half-esters of malonic acid derivatives also obtained by pig liver esterase. Nakada However, distinguishing two identical ester groups has been a more challenging task.…”

Crystal structure, Hirshfeld surfaces and DFT computation of NLO active (2E)-2-(ethoxycarbonyl)-3-[(1-methoxy-1-oxo-3-phenylpropan-2-yl)amino] prop-2-enoic acid

“…Malonic acid half-esters, which falls under the class of geminal half-ester finds extensive applications as important intermediates in the synthesis of natural products such as virantmycin [24], amino acids [25], β-hydroxy esters or β-amino esters [26] and in the synthesis of tri carbonyl compounds [27]. The synthesis of functionalized malonic acid half-ester derivatives has been reported earlier by our group [28].…”