Catalyst-Controlled Site-Selective Bond Activation

Abstract

One ultimate goal of synthetic chemistry is to install or manipulate any functional group at any position of a molecule. This Account discusses the potential and possible approaches to use catalysis to enable a reaction to occur at one of many C-H bonds or at one of several nearly identical functional groups.

Figure 1

Challenge of controlling site-selectivity for one functional group over other similar or more reactive functional groups, for one C–H bond over another, and for C–C bonds.

Figure 2

(A) Suzuki coupling in the synthesis of vancomycin showing the remarkable selectivity of the palladium catalyst for aryl bromide bonds over other potentially reactive bonds. (B) C–H borylation in the synthesis of doravirine showing the remarkable selectivity of the iridium catalyst for an aryl C–H bond over aryl halide bonds.

Figure 3

Several approaches to install functionality at specific C–H bonds. (A) General scheme for the combination of borylation of an aryl C–H bond and functionalization of the intermediate arylboronate. (B) Generic scheme for palladium-catalyzed directed functionalization of aryl C–H bonds under oxidative conditions. (C) Chemoenzymatic methods for fluorination of specific C–H bonds and different positions controlled by the site-selectivity of mutant P450 enzymes.

Figure 4

Depiction of an analysis by researchers at Merck of the potential to functionalize specific C–H bonds in two medicinally active compounds.

Figure 5

Use of a peptide catalyst to functionalize one of many alcohols of teicoplanin.

Figure 6

(A) Directed evolution of P450 enzymes leading to non-native site selectivity for hydroxylation of steroids. (B) Directed evolution of P450 analogs containing iridium in the porphyrin of the active site catalyze enantioselectively.