# Methods for Enantioselective Spirocycle Synthesis and Radical Hydroamination of Trisubstituted Alkenes

> **NIH NIH K99** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2023 · $120,767

## Abstract

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 chemis...

## Key facts

- **NIH application ID:** 10785901
- **Project number:** 1K99GM152819-01
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Melissa Ramirez
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $120,767
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785901

## Citation

> US National Institutes of Health, RePORTER application 10785901, Methods for Enantioselective Spirocycle Synthesis and Radical Hydroamination of Trisubstituted Alkenes (1K99GM152819-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10785901. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*