Biocatalytic hydroxylation tertiary C-H bonds for synthesis of chiral tertiary alcohols by cytochrome P450

Abstract

In view of the importance and beneficial characteristics of enantioenriched tertiary alcohols in pharmaceutical chemistry, efficient and green strategies for their synthesis are highly sought after. Here, we report a simple synthesis of the elusive chiral tertiary alcohols. A cytochrome P450 monooxygenase called P450PL2 was developed to enable chiral tertiary alcohols by the benzylic CH bonds asymmetric hydroxylation of the racemic tertiary carbon substrates. This P450-catalyzed protocol provides various chiral tertiary alcohols with unexpectedly functional group tolerance and excellent enantioselectivities (up to >99 % ee). The method features mild reaction and employs molecular oxygen as an oxidant, avoids the use of pre-oxygen functionalized substrates. Preliminary molecular dynamics simulation studies were carried out to reveal the possible reasons for the exceptional selective hydroxylation of substrate during P450PL2 catalysis.