Methods for Enantioselective Spirocycle Synthesis and Radical Hydroamination of Trisubstituted Alkenes
NIH
CALIFORNIA INSTITUTE OF TECHNOLOGY
Project Summary/Abstract  This proposal focuses on the synergy of experiments and computations in (1) understanding fundamental reactivity in organic and organometallic transformations and (2) enabling reaction design for the discovery of methods for enantioselective spirocycle synthesis and radical hydroamination of tri-substituted alkenes. Two distinct approaches to using aryl and alkyl nitriles for the synthesis of enantioenriched quaternary stereocenters and nitrogen-containing heterocycles, respectively, are proposed. The medicinal properties of molecules bearing quaternary centers have drawn particular attention, as a significant positive correlation exists between the number of stereogenic centers with clinical success. However, the construction of these structural motifs with a high degree of stereocontrol, especially in the synthesis of spiro centers, remains a significant challenge in organic synthesis. The goal of the proposed research is to access sterically congested, spirocyclic quaternary centers in a stereoselective manner by means of nickel-catalyzed acylation reactions of lactones (K99). Reaction optimization and substrate scope studies will first be performed to establish the desired reactivity with aryl nitriles. Upon validating the desired reactivity with aryl nitriles experimentally, computations will be performed to understand the reaction mechanism and help guide substrate scope expansion to alkyl nitriles.  Secondly, the chemical properties of aryl nitriles will be applied toward the synthesis of nitrogen-containing heterocycles (R00), which are considered critically important as more than half of the top 20 best-selling small molecule drugs and nearly 60% of all small molecule drugs possess them. Traditional approaches to C–N bond formation rely on transition-metal catalyzed transformations, such as Chan-Lam coupling, Buchwald–Hartwig amination, and Ullmann reaction. Given that most of these metal-catalyzed reactions require the use of high temperatures and pre-functionalized starting materials, the transition to radical-based C–N bond formation, which can use mild conditions and simpler starting materials, is highly desirable. My goal is to establish an independent research program focused on studying boryl radical chemistry for the generation of nitrogen-centered radicals and regiodivergent hydroamination of trisubstituted alkenes (R00). This project will involve 1) initial computations on key mechanistic steps to help identify NHC boranes that allow for regioselective formation of azepine and isoquinoline scaffolds and 2) experimental testing of computational predictions, reaction optimization, and substrate scope studies. Overall, computational analyses of reaction mechanism and the origins of stereo- or regioselectivity in the aforementioned transformations will provide a platform to expand the utility of Ni catalysis for enantioselective synthesis of spirocyclic scaffolds and the application of boryl radical chemistry for C–N bond formation. Project Narrative  The computational and synthetic development of methods for spirocycle synthesis and alkene hydroamination provide the opportunity to access a diverse array of medicinally privileged scaffolds and new chemical structures. The establishment of a Ni-catalyzed, intramolecular addition reaction of enolates to nitriles is anticipated to generate functionalized spirocyclic lactones, which are present in various natural products and bioactive molecules. Additionally, the discovery of a strategy for the hydroamination of trisubstituted alkenes using NHC borane chemistry will produce a variety of functionalized nitrogen-containing heterocycles.
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