Is the ring conformation the most critical parameter in lipase-catalysed acylation of cycloalkanols?

Abstract

CAL-B catalysed the resolution of several five and six-membered cyclic -hydroxy esters efficiently with the exception of the cis-cyclohexanol ()-4. When employing molecular modelling techniques the conformation turned out to be the most important determinant for their reactivity towards O-acetylation. In all cases, the R enantiomers reacted faster than the S enantiomers since the reactive intermediates of the former can adopt more favourable ring conformations and thus experience less steric hindrance in the active site. Furthermore, the minimised structure for the main conformer of R-4 showed that the axial hydrogens in the 3 and 5-positions with respect to the hydroxyl group prevent the enzymatic reaction.

Molecular modeling of the lipase-catalyzed hydrolysis of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue

“…We have used the protocol that has been successfully applied to rationalize the selectivity of the enzyme-aided hydrolysis of esters [26][27][28][29][30][31][32][33][34][35][36]. The enantioselectivity of the hydrolysis stems from the difference in the potential energy between the substrates and the corresponding transition state.…”

From Salts to Ionic Liquids by Systematic Structural Modifications: A Rational Approach Towards the Efficient Modular Synthesis of Enantiopure Imidazolium Salts

“…As expected, the cis compounds were less reactive than the trans-derivatives in lipase-catalyzed reactions, especially in the case of the sixmembered cycles. [18] Cyclopentanol (AE )-cis-3 a showed an excellent enantioselectivity towards formation of the acetate (R,S)-4 a, although a lower reaction rate was observed in comparison with the corresponding trans derivative. This meant that higher temperatures were needed to reach 50 % conversion.…”

“…. [18] www.chemeurj.org no or only poor enantioselectivity for acylation of the racemic alcohol was achieved. Similarly low activities and enantioselectivities were observed with other biocatalysts [Candida rugosa lipase (CRL), Porcine pancreas lipase (PPL) or Candida antarctica lipase type A (CAL-A)] (entries 6-8, Table 2).…”

“…[b] c = ee S /( ee S + ee P ) in which the subscripts S and P stand for substrate and product, respectively. [c] E =ln[(1− c )×(1− ee S )]/ln[(1− c )×(1+ ee S )] 18. [d] THF as solvent.…”

Applying Lipase Catalysis to Access the Enantiomers of Dorzolamide Intermediates

“…Molecular modeling studies of CAL-B with the more thoroughly studied 2-substituted cyclohexanols give more support to the importance of conformation on reactivity. [15] On the basis of the above, the absolute configuration 4R,6S was elucidated for the ester products 6-8. With the enantiomers of rac-cis-4 the assigned configuration was in accord with those disclosed by a patent that gives the absolute configurations for the peaks in HPLC chromatograms, thus supporting our elucidation.…”