Bioinspired desaturation of alcohols enabled by photoredox proton-coupled electron transfer and cobalt dual catalysis

Long Huang,Magnus Rueping,Huifeng Yue,Tengfei Ji,Chen Zhu,Nursaya Zhumabay

doi:10.1038/s41467-022-28441-2

Abstract

In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins. The overall demethylation proceeds through two sequential monooxygenation reactions and a subsequent dehydroformylative saturation. To mimic the desaturation processes observed in nature, we have successfully integrated photoredox proton-coupled electron transfer (PCET) and cobaloxime chemistry for the acceptorless dehydrogenation of alcohols. The state-of-the-art remote and precise desaturation of ketones proceeds efficiently through the activation of cyclic alcohols using bond-dissociation free energy (BDFE) as thermodynamic driving force. The resulting transient alkoxyl radical allows C-C bond scission to generate the carbon-centered radical remote to the carbonyl moiety. This key intermediate is subsequently combined with cobaloxime photochemistry to furnish the alkene. Moreover, the mild protocol can be extended to desaturation of linear alcohols as well as aromatic hydrocarbons. Application to bioactive molecules and natural product derivatives is also presented.

Highlights

In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins
Visible light photoredox catalysis has emerged as a powerful technique in organic synthesis that relies upon energetic electron transfer processes to facilitate previously thermally inaccessible or kinetically inert transformations[6–10]
Subsequent multiple site proton-coupled electron transfer (PCET) reaction between the hydroxyl group and the radical cation in the presence of base would give the key alkoxyl radical species, which readily cleaves into a carbonyl moiety and a distal carbon-centered radical through β scission of the neighboring C–C bond

Summary

Introduction

In the biosynthesis sterols an enzyme-catalyzed demethylation is achieved via a stepwise oxidative transformation of alcohols to olefins. Visible light photoredox catalysis has emerged as a powerful technique in organic synthesis that relies upon energetic electron transfer processes to facilitate previously thermally inaccessible or kinetically inert transformations[6–10]. In this context, the activation of O–H bonds has found broad utility in a number of reactions for the construction of C–C 11–16, C–N 17–19, C–S 20, and C–X 21,22 bonds (Fig. 1b). Our group established a dual Nickel photoredox catalysis reaction to enable the remote cross coupling of tertiary alcohols[16] This catalytic manifold provides a general and facile access to carboncentered radicals remote to the carbonyl moiety via multiple site proton-coupled electron transfer (PCET)[34,35]. No change PC-II as photocatalyst PC-III as photocatalyst PC-IV as photocatalyst K3PO4 as base 2,6-lutidine as base Co(dmgH)(dmgH2)Cl2 as cobalt source Co(dmgH)2PyCl as cobalt source HFIP as solvent MeCN as solvent Toluene as solvent DCM as solvent No light or [Co] or collidine or PC-I

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Conclusion