Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2‑Oxoacid Derivatives to Aldehydes

• Published in: Journal of the American Chemical Society 2020-11, Vol.142 (46), p.19754-19762
• Main Authors: Marín-Valls, Roser, Hernández, Karel, Bolte, Michael, Parella, Teodor, Joglar, Jesús, Bujons, Jordi, Clapés, Pere
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Aldehydes - metabolism; Binding Sites; Biocatalysis; Catalytic Domain; Escherichia coli - enzymology; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - genetics; Escherichia coli Proteins - metabolism; Hydroxymethyl and Formyl Transferases - chemistry; Hydroxymethyl and Formyl Transferases - genetics; Hydroxymethyl and Formyl Transferases - metabolism; Keto Acids - chemistry; Keto Acids - metabolism; Mutagenesis, Site-Directed; Stereoisomerism; Substrate Specificity
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c09994

The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.