# Biocatalytic C-H Activation for Enantioselective Carbon-Carbon Bond Formation

> **NIH NIH F32** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $65,310

## Abstract

PROJECT SUMMARY AND ABSTRACT
 Alcohols and amines are valuable pharmacophores found in countless pharmaceutical agents and bioactive
small molecules. Accordingly, expedient access to enantioenriched molecules bearing these pharmacophores
is of tremendous synthetic and medicinal interest. This is especially true for tertiary alcohols and carbinamines,
which are generally difficult products to access via modern asymmetric catalysis. One method for the synthesis
of chiral alcohols and amines is through carbenoid insertion into the α C-H bonds of these functional groups,
forging a carbon-carbon bond in the process; however, currently precious metal catalysts are limited in their
capacity to execute these transformations with efficient yields and enantioselectivities. As engineered
hemoproteins continue to perform increasingly difficult asymmetric reactions of carbenoids, it is evident that they
provide an attractive solution to this longstanding challenge.
 This proposal focuses on the development of such a protocol, which is unknown in natural systems and
represents a powerful extension of enzymatic iron-carbenoid chemistry. The specific aims are: (1) to evolve
existing hemoproteins to perform carbenoid insertions into the α C-H bonds of primary alcohols and carbinamines
to form enantioenriched small molecules via directed evolution; (2) to extend this protocol to secondary alcohols
and combine this reaction with alcohol racemization to furnish a dynamic kinetic resolution to access
enantioenriched tertiary alcohols. These aims will be initiated using the panoply of heme protein mutants
available in the Arnold Lab using directed evolution methods such as error-prone PCR and site-saturation
mutagenesis. Such a method provides a cogent solution to extant problems in C-H functionalization, further
information about enzymatic carbene transfer reactivity which can be applied to further synthetic problems, and
a green and sustainable route to valuable pharmacophores.

## Key facts

- **NIH application ID:** 9998968
- **Project number:** 5F32GM128247-03
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** David C. Miller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2018-09-17 → 2022-03-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998968

## Citation

> US National Institutes of Health, RePORTER application 9998968, Biocatalytic C-H Activation for Enantioselective Carbon-Carbon Bond Formation (5F32GM128247-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998968. Licensed CC0.

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