Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp³)–C(sp³) Cross-Coupling via Radical Sorting

Abstract

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C­(sp 3)–C­(sp 3) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array of alkyl–alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C 1-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

Stereoretentive Post-Translational Protein Editing

“…Moreover, the functional utility that we demonstrate here now of an on-protein L-alanyl radical, without the need for additional stabilization, 14 opens the door to further radical processing methods including metal-relayed trapping and so-called 'sorting' 69 methods with further potential for editing of biological systems. It has also not escaped our attention that this strategy should readily enable complementary methods for the creation of epimeric series not only of L-residues but also D-residues in proteins and studies in this direction will be published in due course.…”

Radical Deoxyfunctionalisation Strategies**

“…Very recently, MacMillan and co‐workers reported the C sp 3 −C sp 3 coupling of fragments derived from alcohols and carboxylic acids [22] . The carboxylic acids are preactivated as iodonium dicarboxylates, while the alcohol gets activated by condensation with a N ‐heterocyclic carbene (NHC)‐derived reagent NHC‐1 (Scheme 11).…”

“…Very recently, MacMillan and co-workers reported the Csp 3 À Csp 3 coupling of fragments derived from alcohols and carboxylic acids. [22] The carboxylic acids are preactivated as iodonium dicarboxylates, while the alcohol gets activated by condensation with a N-heterocyclic carbene (NHC)-derived The authors rationalise this by comparing the higher stability of the latter to 24, as well as the stronger NiÀ C bond formed when 24 gets trapped by the Ni-catalyst. Overall, the reported NHCmediated deoxygenative coupling of aliphatic alcohols with activated carboxylic acids shows an impressive scope with more than 40 examples including formation of quaternary carbon centres, alcohol homologation and late-stage derivatisations with yields ranging from 34-80 %.…”

Photocatalytic Deoxygenative Alkylation of C(sp3)−H Bonds Using Sulfonylhydrazones

“…3 Historically, alkyl-alkyl couplings have been challenging to accomplish, but in recent years significant progress has been achieved using transition-metal catalysis, particularly by exploiting nickel-based complexes. [4][5][6][7][8][9][10][11][12][13][14][15][16] These methods rely on the availability of prefunctionalized electrophiles (e.g., alkyl halides) and nucleophilic coupling partners (i.e., organometallic reagents), and often require high catalyst loadings, which necessitate energyintensive purification strategies to remove any trace metal impurities. 15 Alternatively, an attractive option to enable C(sp 3 )-C(sp 3 ) bond formation would be to use easily accessible reagents in the absence of any transition metals, which would also facilitate applications that require higher regulatory scrutiny, such as the late-stage functionalization of medicinally relevant compounds.…”