Recent trends in the stereoselective synthesis of (poly)-substituted 2-oxo acids by biocatalyzed aldol reaction

Abstract

Recently, an increased interest toward enzymatic carboligation was observed, as biocatalytic carbon–carbon bond formation is a common obstacle in retrosynthetic planning. The construction of extended 2-oxoacid frameworks by 2-oxoacid aldolases and enzymes acting as aldolases is a potent tool for synthetic chemists since a broad spectrum of downstream reactions through functional group interconversions gives access to a plethora of compound classes. In the search for selective biocatalysts, successful protein engineering efforts and high throughput screenings from biodiversity expand the structural diversity of nucleophile and electrophile substrates. Several successful examples with an emphasis on reactions catalyzed by class II aldolases and enzymes acting as class II aldolases are highlighted, including reactions in which both enantiomeric products and in selected cases even diastereomeric products are accessed.

Catalytic and structural insights into a stereospecific and thermostable Class II aldolase HpaI from Acinetobacter baumannii

“…Nonetheless, the molecular dockings were performed and showed that N -benzyloxycarbonyl ( N -Cbz)-substituted aldehydes are surrounded by hydrophobic residues Trp23, Phe174, and Leu216, similar to the aldehyde binding residues identified in Ab HpaI. These properties offer an opportunity for Ab HpaI to serve as a biocatalyst to catalyze formation of 4-hydroxy-2-ketoacid and 2-keto-3-deoxy-D-sugar acid precursors valuable for the synthesis of APIs ( 48 , 49 ).…”

Biocatalytic Transamination of Aldolase‐Derived 3‐Hydroxy Ketones

“…In accordance with literature. [13] [(S)-5-(Benzyloxy)-4-hydroxypentan-2-one] (3 b) 207 mg isolated yield (62%), 87% ee, colorless oil. Chiral HPLC t R (R) = 16.2 min; t R (S) = 19.5 min.…”

“…mg isolated yield (56%), 79% de, yellow liquid 1 H NMR (300 MHz, d 4 -MeOH): Major: δ 7.37-7.25 (m, 5H), 4.54 (s, 2H), 3.88 (ddd, J = 9.6, 5.5, 4.4 Hz, 1H), 3.41 (d, J = 5.4 Hz, 2H), 3.21 (q, J = 6.5 Hz, 1H), 1.62-1.53 (m, 2H), 1.17 (d, J = 6.5 Hz, 3H). J = 6.5 Hz, 3H) 13. C NMR (75 MHz, d 4 -MeOH): Major: δ 139.6, 129.4, 128.9, 128.7, 75.9, 74.4, 70.3, 41.8, 22.1.…”

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…Enzymes from the aldolase family catalyze aldol reactions, which intriguingly set up a chiral alcohol center with concomitant C–C bond formation. − Examples for processes include the formation of the side chains of statins or hydroxy-amino acids (section ). , In a similar fashion, thiamine diphosphate (ThDP)-dependent enzymes form acyloin-type compounds (section ).…”