Applications of the Sulfinimine-Mediated Asymmetric Strecker Synthesis to the Synthesis of α-Alkyl α-Amino Acids

Abstract

Addition of Et(2)AlCN and i-PrOH to ketosulfinimines (N-sulfinyl imines) affords corresponding alpha-alkyl alpha-amino nitriles in moderate to good yields. The diastereoselectivity is largely dependent on the E/Z isomer ratio of the ketosulfinimine. Hydrolysis of the diastereomerically pure amino nitriles affords enantiopure alpha-alkyl alpha-amino acids in moderate to good yields.

Is the optical rotation sign/absolute configuration relationship still a problem? Examples taken from unnatural quaternary aminoacids

“…CONCLUSION We have unambiguously established the absolute configuration of (À)-(R)-a-methyl-a-(p-tolyl)glycine 1a and (þ)-(S)-a-methyl-a-(p-bromophenyl)glycine 1b by X-ray diffraction studies of derivatives. These results concur with previous ones 3,4,5,19 to suggest that the assumption that enzymes such as esterases or amidopeptidases react preferentially with L-a-methyl-a-arylglycines ester or amide derivatives (the L configuration being attributed by analogy to proteinogenic aminoacids, the methyl group replacing the hydrogen of tertiary aminoacids) led to the wrong configuration.…”

“…Several studies demonstrated a (þ)-(S) relationship using complete structural characterization via single crystal X-ray diffraction of a dipeptide, 3 correlation of optical rotation with (þ)-(S)-isovaline after chemical modification, 4 or assumption of the mechanism in the diastereoselective addition of ethylaluminium cyanoisopropylate on a chiral ketosulfinimine. 5 However, the assumption that the hydrolysis of the corresponding amide by an aminopeptidase follows the trend observed with proteinogenic aminoacids led some authors to assign the (S) configuration to (À)-a-methyl-a-phenylglycine. 6 This discrepancy led other authors to refer to either of those results, depending mostly on the preparative method used: a (þ)-(S) relationship was usually attributed to a-methyl-a-phenylglycine obtained by chemical synthesis, 7,8 whereas a (À)-(S) relationship was attributed to a-methyl-a-phenylglycine obtained via biocatalytical methods.…”

“…Diastereoselective addition of ethylaluminium cyanoisopropylate to a chiral ketosulfinimine, followed by hydrolysis, afforded the (þ)-a-methyl-a-(p-tolyl)glycine, 5 which was assigned (S) for chemical mechanistic reasons. 11 On the other hand, enzymatic hydrolysis of the 2-amino-2-(ptolyl)-propionic amide led to the (À)-a-methyl-a-(p-tolyl)-glycine, that was also assigned (S) for biochemical mechanistic reasons: 10 in the same paper, (À)-a-methyl(p-bro-mophenyl)glycine, obtained in a similar way, was also assigned the (S) configuration (Fig.…”

Applications of tert‐Butanesulfinamide in the Asymmetric Synthesis of Amines

“…The utility of tert-butanesulfinamide for the asymmetric synthesis of amines is clearly indicated by its extensive use by other researchers. For example, reports have appeared from Olah and Prakash on the highly efficient synthesis of α-trifluoromethylamines [17], Davis on the asymmetric synthesis of α-amino acids [18], Mabic on the asymmetric synthesis of 1,2-diamines [19], Barrow on the asymmetric synthesis of 1,2-amino alcohols [13], Silverman on novel applications to support-bound β-amino acids [20], and researchers at Astra Zeneca, Separacor, and Merck on the asymmetric synthesis of α-branched amines [21], α,α-dibranched amines [22], and β-amino acids [23] for drug discovery applications.…”

Enantioselective synthesis of non-proteinogenic 2-arylallyl-α-amino acids via Pd/In catalytic cascades

“…Previously, our group reported highly regio-and diastereo-selective Pd/In mediated cascade allylations of carbonyl compounds including a highly stereoselective allylation of chiral N-sulfinyl aldimines. [4][5][6][7][8][9][10] We now report further applications of the tert-butyl sulfinyl chiral auxilliary, which has been widely used in the synthesis of chiral amines including 1,2-amino alcohols and α-and β-amino acids, [11][12][13] to a new approach to unusual α-amino acids.…”