Remote Desymmetrization: Peptide versus Enzyme Catalysis

Key words

desymmetrization - peptide catalysis - enzyme mimic - acetylation

Significance

A catalytic protocol for the unprecedented remote asymmetric desymmetrization of bis(phenol) 1 via peptide-catalyzed monoacetylation has been developed. Since the desired site of functionalization is >5.7 Å from the ‘prochiral’ stereogenic center and the enantiotopic oxygen ­atoms are separated by a near-nanometer span, bis(phenol) 1 represents a particulary challenging substrate. After an examination of libraries of hexa­meric peptides 3, whose residue pattern was chosen as a mirror image of the alternating aromatic-aliphatic-aromatic nature of substrate 1, and followed by a truncation study of lead catalyst 4, tetramer 5 was identified as the best catalyst, delivering monoacetylated product 2 in 80% yield and with an er of 97.5:2.5.

Comment

Often enzymes are employed as chiral catalysts when facing a challenging problem for enantioselective catalysis. Due to their molecular complexity they are able to induce chirality over substantial distances. In the present example, however, the small tetramer 5 was superior to more than 450 enzymes screened in the asymmetric hydrolysis of the bis(acetate) of 1. In contrast to enzymatic catalysis, which leads to reasonable enantioselectivities only through secondary kinetic resolution of monoacetate 2, the selectivity in the peptide-catalyzed version is dominated by enantio­topic group discrimination. Potential for enantio­selective recognition, a property typically inherent in enzymes, was observed by ¹H NMR spectroscopy. Association of peptide catalyst 5 with bis(phenol) 1 caused the loss of degeneracy of the phenol ­moieties.