Determination of absolute configuration of secondary alcohols using lipase‐catalyzed kinetic resolutions

Abstract

Lipases show high enantioselectivity toward a wide range of secondary alcohols. An empirical rule based on the relative sizes of the substituents predicts which enantiomer reacts faster. X-ray structures of lipases provide a molecular basis for this empirical rule: their alcohol-binding pocket contains large hydrophobic pocket open to solvent and another smaller pocket. This predictable enantiopreference of lipases allows the determination of the absolute configuration of secondary alcohols using lipase-catalyzed kinetic resolution. Researchers have used this relative method to determine the configuration of approximately 50 secondary alcohols either as the only method or in combination with other methods.

Lipase‐Catalyzed Kinetic Resolution of Novel Antifungal N‐Substituted Benzimidazole Derivatives

“…The comparison of the specific rotation values of other esters ( (À)-6a,c,d) and alcohols ((+)-5a,c,d) allowed us to state that all esters are R and alcohols S enantiomers. This is also in agreement with Kazlauskas rule, 39 according to which in lipase-catalyzed transesterification R enantiomer reacts faster.…”

Molecular Basis for the Enantio‐ and Diastereoselectivity of Burkholderia cepacia Lipase toward γ‐Butyrolactone Primary Alcohols

“…The enantioselectivity of lipase-catalyzed resolutions of secondary alcohols often increases when the difference in size of the substituents increases. [8] Primary alcohols are more flexible and when there is an oxygen at the stereocenter, the potential for hydrogen bonds depends on the rest of the structure. Thus, it is unlikely that simple, broadly applicable strategies could increase enantioselectivity toward primary alcohols with an oxygen at the stereocenter.…”

“…In the case of secondary alcohols, increasing the relative size difference of the substituents often increases the enantioselectivity. [8] One example of difficult-to-explain selectivity is the BCL-catalyzed hydrolysis of b-substituted-g-acetyl-A C H T U N G T R E N N U N G oxymethyl-g-butyrolactones. [12] Hydrolysis cleaves the acetate from the primary alcohol, but this substrate contains an oxygen at the stereocenter, so it belongs to the substrate type without an empirical rule to pre-These primary alcohols do not have an oxygen atom directly attached to the stereocenter, so the empirical rule for BCL applies to these substrates.…”

“…[1][2][3][4][5] Although an empirical rule based on relative sizes of substituents can predict the enantiopreference of most lipases toward secondary alcohols, [6][7][8] such rules are less successful and more limited for other substrates. For example, an empirical rule for primary alcohols works only for one lipase -Burkholderia cepacia lipase (BCL) -and only for primary alcohols without an oxygen at the stereocenter.…”

Enzymatic aerobic ring rearrangement of optically active furylcarbinols

“…wAlcohols 1c, 1b and 1g were prepared in optically active form by lipase-catalysed kinetic resolution. zAbsolute configuration established independently according to Prelog's rule (anti-Prelog-selective ADH) and Kazlauskas' rule in the acylative lipase-catalysed kinetic resolution 40 . See Supplementary Methods for full experimental details.…”