Enzymatic Synthesis of Optically Active Tertiary Alcohols: Expanding the Biocatalysis Toolbox

Abstract

Enantiopure tertiary alcohols are very valuable building blocks for the synthesis of many different natural products and pharmaceuticals. As a consequence, several chemical and enzymatic strategies to afford such chiral structures have been described. Promising enzymatic approaches with agents such as epoxide hydrolases, dehalogenases and hydroxynitrile lyases have been reported, as well as dihydroxylation by microorganisms. Apart from those valuable options, the hydrolase-based kinetic resolution of tertiary alcohols has been known for the last three decades, as several wild-type enzymes have been reported to be able to accept these sterically hindered molecules. More recently, the existence of an amino acid motif within an enzyme's active site has been identified as highly relevant for the acceptance of such bulky structures. This discovery clearly facilitates the identification of novel biocatalysts for this application. Although several tertiary alcohols have been successfully resolved with wild-type biocatalysts, enantioselectivities have often been too low for synthetic purposes. These limitations have recently been overcome by accessing enzymes from the metagenome through directed evolution or by rational protein design. This minireview describes the state of the art in this area, highlighting aspects of basic academic research into the practical application of biocatalysts for the synthesis of optically active tertiary alcohols.

Catalytic asymmetric alkylation of ketones using organometallic reagents

“…In one case it was possible to carry out the reaction using 60 mol% of titanium tetraisopropoxide [29]. In another case it was reported that Ti(OiPr) 4 -free 1,2-addition to aromatic ketones is possible when a 3-fold excess of organozinc reagent is used [30].…”

“…Different strategies for the preparation of single enantiomers of chiral secondary alcohols comprise kinetic resolution, enantioselective desymmetrization, and asymmetric hydrogenation (both with enzymes and transition-metal catalysts). Recently, also the catalytic enantioselective conjugate addition of water has been reported [4][5][6]. Generating chiral tertiary alcohols is however particularly challenging [7].…”

Protein engineering for development of new hydrolytic biocatalysts

“…This class of hydrolases have been a subject of much interest due to their potential as biocatalysts in asymmetric synthesis of vicinal diols [27][28][29][30]. Recent progress in understanding the mechanisms that decide reaction outcome and catalytic efficiencies are now focusing more on 6 guiding protein engineering aiming to improve biocatalyst properties and performance.…”

Produktion von L‐Carnosin mittels rekombinanter Ganzzell‐Biokatalysatoren

“…Neuerdings konnte mit der Entdeckung von sog. GGG(A)X-Motiv-Enzymen eine Enzymklasse mit guten katalytischen Eigenschaften in der Umsetzung dieser schwierigen Substrate gefunden werden [1,2]. Enantiomerenreine pyridylaliphatische tertiäre Alkohole von 1 (s.…”