Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

Abstract

Selectivity in the catalytic functionalization of complex molecules is a major challenge in chemical synthesis. The problem is magnified when there are several possible stereochemical outcomes and when similar functional groups occur repeatedly within the same molecule. Selective polyene oxidation provides an archetypical example of this challenge. Historically, enzymatic catalysis has provided the only precedents. Although non-enzymatic catalysts that meet some of these challenges became known, a comprehensive solution has remained elusive. Here, we describe low molecular weight peptide-based catalysts, discovered through a combinatorial synthesis and screening protocol, that exhibit site- and enantioselective oxidation of certain positions of various isoprenols. This diversity-based approach, which exhibits features reminiscent of the directed evolution of enzymes, delivers catalysts that compare favourably to the state-of-the-art for the asymmetric oxidation of these compounds. Moreover, the approach culminated in catalysts that exhibit alternative-site selectivity in comparison to oxidation catalysts previously described.

Figure 1. Precedent and goal of catalytic oxidation of farnesol

a, Catalytic cycle of aspartic acid-mediated epoxidations. b, Site-selectivity of m-CPBA and propionic acid. ^aDetermined by uncalibrated GC integrations (see Supplementary Information for details). ^b1.0 equiv. m-CPBA, Na₂HPO₄ (2.0 equiv.), DCM, H₂O. ^c10 mol% acid, HOBt (10 mol%), DMAP (10 mol%), 1.0 equiv. N,N′-diisopropylcarbodiimide (DIC), 2.0 equiv. H₂O₂. c, Precedents of the Sharpless epoxidation of 1. d, The goal of the present study.

Figure 2. Catalyst library design by split and pool synthesis via the one-bead-one-compound library method

a, Design of first directed library. b, Histogram of theoretical library composition.

Figure 3. Results and raw data for the site-selective oxidation of farnesol and geranylgeraniol with m-CPBA, 2,3-selective catalyst 9b and 6,7-selective catalyst 12d

a, Optimized oxidation conditions with 12d. Comparison of product ratios and GC spectra from crude reaction mixtures with m-CPBA, catalyst 9b, and catalyst 12d. Relevant area of GC spectra with, b, farnesol and, c, geranylgeraniol. ^aPeak has a shoulder that is integrated, overestimating the area. Conditions for m-CPBA reactions found in Fig. 1b; for reactions with catalyst 9b, in Table 2; for reactions with catalyst 12d, in a.