Abstract
The Minisci reaction is one of the most direct and versatile methods for forging new carbon–carbon bonds onto basic heteroarenes: a broad subset of compounds ubiquitous in medicinal chemistry. While many Minisci-type reactions result in new stereocenters, control of the absolute stereochemistry has proved challenging. An asymmetric variant was recently realized using chiral phosphoric acid catalysis, although in that study the substrates were limited to quinolines and pyridines. Mechanistic uncertainties and nonobvious enantioselectivity trends made the task of extending the reaction to important new substrate classes challenging and time-intensive. Herein, we describe an approach to address this problem through rigorous analysis of the reaction landscape guided by a carefully designed reaction data set and facilitated through multivariate linear regression (MLR) analysis. These techniques permitted the development of mechanistically informative correlations providing the basis to transfer enantioselectivity outcomes to new reaction components, ultimately predicting pyrimidines to be particularly amenable to the protocol. The predictions of enantioselectivity outcomes for these valuable, pharmaceutically relevant motifs were remarkably accurate in most cases and resulted in a comprehensive exploration of scope, significantly expanding the utility and versatility of this methodology. This successful outcome is a powerful demonstration of the benefits of utilizing MLR analysis as a predictive platform for effective and efficient reaction scope exploration across substrate classes.
Highlights
First developed into a general synthetic process by Minisci and co-workers in the late 1960s, the addition of nucleophilic radicals to electron-deficient heteroarenes has arguably become the leading method for direct carbon−carbon bond formation onto heteroaromatic scaffolds.[1]
Intrigued by the reduced levels of selectivity observed for certain substrate subsets in the initial exploration of reaction space, and driven by the importance of accessing varied chiral heteroarene building blocks, we initiated a study into the scope and limitations of the enantioselective Minisci protocol
These results suggest that the ability to effectively extrapolate to new reaction components results from a set of general transition state features that are fundamentally similar across the reaction range
Summary
First developed into a general synthetic process by Minisci and co-workers in the late 1960s, the addition of nucleophilic radicals to electron-deficient heteroarenes has arguably become the leading method for direct carbon−carbon bond formation onto heteroaromatic scaffolds.[1]. The prevalence of diverse heterocycles possessing additional heteroatoms in medicinal compounds led us to question the broader applicability of this enantioselective Minisci method.2b If the selectivity discriminants were consistent for a range of substrates, it may be possible to quantitatively transfer the insights gained from the correlations to the prediction of unique substrates not included in the training sets (Figure 1C) It is widely acknowledged by medicinal chemists that increasing the three-dimensionality of scaffolds in lead molecules enhances the odds of success as a drug candidate.[13] Three-dimensionality inevitably leads to stereoisomers, which often elicit distinct biological activity. Our model has identified pyrimidines and pyrazines to be amenable to the reaction conditions, successfully predicting protocol extension to the use of these valuable basic heteroarene motifs
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