Data Science Enables the Development of a New Class of Chiral Phosphoric Acid Catalysts.

The widespread success of BINOL-chiral phosphoric acids (CPAs) has led to the development of several high molecular weight, sterically encumbered variants. Herein, we disclose an alternative, minimalistic chiral phosphoric acid backbone incorporating only a single instance of point chirality. Data science techniques were used to select a diverse training set of catalysts, which were benchmarked against the transfer hydrogenation of an 8-aminoquinoline. Using a univariate classification algorithm and multivariate linear regression, key catalyst features necessary for high levels of selectivity were deconvoluted, revealing a simple catalyst model capable of predicting selectivity for out-of-set catalysts. This workflow enabled extrapolation to a catalyst providing higher selectivity than both reported peptide-type and BINOL-type catalysts (up to 95:5 er). These techniques were then successfully applied towards two additional transforms. Taken together, these examples illustrate the power of combining rational design with data science (ab initio) to efficiently explore reactivity during catalyst development.

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines.

Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.