# Insertion Into Unactivated/Deactivated C(sp3)-H Bonds Enabled by Oxidatively Generated, Highly Reactive a-Oxo Gold Carbenes: A Safe Non-Diazo yet More Potent Approach

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA BARBARA · 2020 · $279,721

## Abstract

Abstract
 Our group previously developed a facile access to versatile α-oxo gold carbenes via gold-catalyzed
intermolecular oxidation of readily available alkynes. Two salient features of this strategy are a) the avoidance of
hazardous and potentially explosive α-diazo carbonyl compounds and b) the exceptionally electrophilic nature of the carbene
center. Despite various synthetic methods developed by us and other researchers based on this approach, the
arguably most valuable transformation of metal carbenes, i.e., concerted insertion into unactivated C(sp3)-H
bonds and their enantioselective versions, have not been realized by our oxidative gold catalysis until a recent
preliminary study by us. Moreover, deactivated C(sp3)-H bonds have mostly not been succumbed to carbene
insertions. In this proposal, we aim to address these critical shortcomings and demonstrate that the advantages
of this approach over the mainstream Rh-diazo chemistry are much beyond the improvement of safety.
 Electron-withdrawing group-substituted α-oxo gold carbenes will be generated via gold-catalyzed
intermolecular oxidation of electron-deficient alkynes. These acceptor/acceptor-type carbenes are of exceptional
electrophilicity and, coupled with sufficient steric shielding, are capable of intramolecular insertions into
C(sp3)-H bonds, thereby affording highly efficient and streamlining access to a large array of these cyclic
ketones including various bicyclic and polycyclic ones. By adjusting the EWG, the gold catalyst, and the
reaction conditions, the reactivities of the gold carbene moiety can be substantially tuned to accommodate not
only unactivated C-H bonds but also deactivated ones. In contrast, the mainstream Rh-diazo approach is mostly
incapable of insertion into deactivated C-H bonds due to the generally lesser reactivity of the Rh carbene
counterparts. By the use of newly designed chiral NHC ligands, enantioselective C-H insertions by these highly
reactive gold carbenes would enable the synthesis of chiral cyclopentanones with high e.e., in contrast to the
moderate e.e. (≤80%) in the Rh-diazo approach, and asymmetric functionalization of deactivated C-H bonds.
 This strategy would also offer significant benefit in synthetic planning, as it enables a completely novel
entry into C-H insertion and presents unique solutions in terms of functional group compatibility and
protecting group strategies, as C-C triple bonds are distinctively different from carbonyl in tolerance of various
reaction conditions. Moreover, the rich chemistry of alkyne synthesis enables ready access to alkyne substrates
with well-controlled stereochemistries, the diazo carbonyl counterparts of which may require extraordinary
efforts. As such, our approach would open uncharted yet efficient access to valuable functional products, which
would otherwise be practically inaccessible or synthetically prohibitively inefficient via the diazo chemistry.
 The synthetic utility of this oxidative C-H ins...

## Key facts

- **NIH application ID:** 10001071
- **Project number:** 5R01GM123342-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA BARBARA
- **Principal Investigator:** Liming Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $279,721
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001071

## Citation

> US National Institutes of Health, RePORTER application 10001071, Insertion Into Unactivated/Deactivated C(sp3)-H Bonds Enabled by Oxidatively Generated, Highly Reactive a-Oxo Gold Carbenes: A Safe Non-Diazo yet More Potent Approach (5R01GM123342-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001071. Licensed CC0.

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