Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer-Villiger Oxidation

Abstract

The structural analysis of a peptide-based catalyst for the Baeyer-Villiger oxidation (BVO) is reported. This unique structure is then analyzed in the context of its previously documented facility to control selectivity (both enantioselectivity and migratory aptitude) in catalytic reactions. The effects of additives on the solution conformation of the peptide are found to be dramatic, revealing substrate-specific interactions and a possible "induced fit" model. The experimental observation of dynamic behavior supports the notion that flexibility in stereoselective catalysts can be an advantageous feature.

Figure 1

(a) Generic Baeyer-Villiger oxidation reaction. (b) Baeyer-Villiger oxidation of substrate 2. The observed migratory aptitude is reversed when mCPBA is used in comparison to catalyst 1.

Figure 2

(a) Calculated structure of 1 showing parallel pyrollidine ring and proximal aspartic acid and lysine side chain structural features. (b) Zoomed-in section of 1 exhibiting γ-turn, a O_Lys to NH_Tyr(t-Bu) contact. (c) Zoomed-in section of 1 showing O_Lys to εNH_Lys hydrogen bond.

Figure 3

(a) Stacked spectra of mismatched substrate 6, peptide 1, and a 1:1 mixture of both. (b) Stacked spectra of lactone BVO-product 8, peptide 1 and a 1:1 mixture of both.

Figure 4

Overlay of calculated structures for 1. Green structure was calculated from NMR restraints from 1 alone, blue structure was calculated from restraints extracted from spectra of 1 and 6, and orange structure was calculated from spectra of 1 and product 8.

Figure 5

(a) Stacked 1D proton spectra of peptide 1 alone and a 1:1 mixture of ent-1 and 6. (b) Structural change in 1 upon exposure to matched substrate 6.

Figure 6

Proton Chemical Shift Analysis of Titrated Baeyer-Villiger Peptide. Histogram comparing the proton shifts of 1 and ent-1 in the presence of 6.