Enantioselective Synthesis of Protected Isotetronic Acids

Abstract

Isotetronic acids are subunits of a number of natural products. They are of interest in agricultural and pharmaceutical research and are important synthetic intermediates. This paper describes the first highly diastereo-and enantioselective synthesis of isotetronic acids in 4 to 5 steps (de, ee b 98 %). Key steps in the reaction sequence are the diastereoselective aldol reaction of the 2-oxoesters 5 as their SAEP hydrazones (S)-6 with aldehydes, followed by base-promoted lactonization to the hydrazonolactones 8. Subsequent oxidative cleavage of the hydrazone moiety afforded the enantiomerically pure O-protected isotetronic acids (R)-/(S)-9.

C-4-Modified Isotetrones Prevent Biofilm Growth and Persister Cell Resuscitation in Mycobacterium smegmatis

“…Pyruvic acid acts as an excellent nucleophile to aldol reactions with carbonyl electrophiles and in biosynthesis, and the reaction is mediated by a type II aldolase enzyme. , Subsequent lactonization leads the resulting cross-aldol product to the isotetrone. Pyruvic acid as an important synthon is well-exploited in the chemical synthesis of many derivatives of isotetrone, with substitutions at C -3 to C -5 carbons. − Enantioselective synthesis led to a paradigm shift and syntheses of stereochemically pure butyrolactones are also achieved. − Recognizing the importance of deamination of amino acids to the corresponding substituted pyruvic acids, we undertook to synthesize isotetrones that possess variations of the substituent at C -4 carbon of the furanone scaffold.…”

“…Pyruvic acid as an important synthon is well-exploited in the chemical synthesis of many derivatives of isotetrone, with substitutions at C -3 to C -5 carbons. 38 − 40 Enantioselective synthesis led to a paradigm shift and syntheses of stereochemically pure butyrolactones are also achieved. 41 − 49 Recognizing the importance of deamination of amino acids to the corresponding substituted pyruvic acids, we undertook to synthesize isotetrones that possess variations of the substituent at C -4 carbon of the furanone scaffold.…”

Current Progress in the Acetate/Methyl Ketone Aldol Reaction

“…Enders and coworkers used a variation of the aldol with chiral amine base 20 to react 2-oxocarboxylic ester 21 with aldehydes in mannich fashion (Scheme 6) [21][22][23]. The product could be converted to the 4-hydroxy-2-oxocarboxylic ester through ozonolysis [23] or reacted further to give hydrazonolactones before removal of the hydrazone [21,22].…”

Approach to novel isotetronic acid derivatives: DBU-Et3N-mediated aldol/lactonization/O-protection sequence of 2-oxocarboxylic esters

“…1,2 This kind of compounds have been isolated from a variety of natural sources, 1,2 and their properties leading to use as flavoring agents, 3 perfumes 4 and anti-depressants 5 have been evaluated, and analgesic 6 and antifungal 7 activities have been documented.…”