A new access to alkyl-α-ketoglutaric acids, precursors of glutamic acid analogues by enzymatic transamination. Application to the synthesis of (2S,4R)-4-propyl-glutamic acid

Stereoselective Chemoenzymatic Synthesis of the Four Stereoisomers of l-2-(2-Carboxycyclobutyl)glycine and Pharmacological Characterization at Human Excitatory Amino Acid Transporter Subtypes 1, 2, and 3

“…Aminotransferases are very common enzymes with broad substrate spectra, and a variety of biologically active compounds have been prepared, including unnatural l - and d -α-amino acids − as well as β-amino acids or simple amines. − Most naturally occurring l -α-aminotransferases accept l -Glu as a preferred substrate. Among them, aspartate aminotransferase (AAT) has proven useful for the stereoselective preparation of Glu analogues from the corresponding 2-oxoglutaric acid (KG) derivatives. ,− AAT offers the opportunity to shift the transamination equilibrium through the use of aspartic acid or cysteine sulfinic acid (CSA) as the amino donor substrate: an unstable keto acid is produced in both cases, which is decomposed into pyruvate, which is not a substrate for the enzyme. AAT is active toward many 4-substituted KG analogues, and its enantiopreference allows the stereoselective syntheses of a variety of Glu analogues and especially l -2,4- syn -4-alkylglutamic acids (Scheme 1) …”

“…Among them, aspartate aminotransferase (AAT) has proven useful for the stereoselective preparation of Glu analogues from the corresponding 2-oxoglutaric acid (KG) derivatives. 5,[25][26][27][28] AAT offers the opportunity to shift the transamination equilibrium through the use of aspartic acid or cysteine sulfinic acid 29 (CSA) as the amino donor substrate: an unstable keto acid is produced in both cases, which is decomposed into pyruvate, which is not a substrate for the enzyme. AAT is active toward many 4-substituted KG analogues, and its enantiopreference allows the stereoselective syntheses of a variety of Glu analogues and especially L-2,4-syn-4-alkylglutamic acids (Scheme 1).…”

Synthesis of 2-oxoglutarate derivatives and their evaluation as cosubstrates and inhibitors of human aspartate/asparagine-β-hydroxylase

“…2b ) 27 to access key synthetic intermediates; the corresponding 2OG derivatives ( 6 ) were obtained after saponification. Other approaches rely on oxidation reactions using ozone 28 or sodium periodate 29 as oxidants to convert Michael acceptors ( 10 ) into 2OG derivatives ( Fig. 2c ).…”

“…The described syntheses are frequently associated with limited scalability, low overall chemical yields, and/or narrow substrate scopes due to harsh reaction conditions requiring, for example, the use of strong bases and acids, 25,30 high pressure, 27 or strong oxidants. 28 a – c ,29 …”

Preparative biotransformations

“…When a full equivalent of the sulfinic acid is used the glutamate derivative is produced as the (2S,4R)-and the (2S,4S)-diastereomers in the ratio 3 : 1 and in 68% yield. 333 Fusarium oxysporum lipase was shown to catalyse bromination of monochlorodimedone by using the catalyst in the presence of hexanoic acid, hydrogen peroxide and bromide ion. 334 Macrophomate synthase has been purified and used to convert various 2-pyrones 157 into the corresponding benzoates 158.…”