Dataset Information

Modular, stereocontrolled C_β-H/C_α-C activation of alkyl carboxylic acids.

ABSTRACT: The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus, amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series.

SUBMITTER: Shang M

PROVIDER: S-EPMC6500144 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Modular, stereocontrolled C<sub>β</sub>-H/C<sub>α</sub>-C activation of alkyl carboxylic acids.

Shang Ming M Feu Karla S KS Vantourout Julien C JC Barton Lisa M LM Osswald Heather L HL Kato Nobutaka N Gagaring Kerstin K McNamara Case W CW Chen Gang G Hu Liang L Ni Shengyang S Fernández-Canelas Paula P Chen Miao M Merchant Rohan R RR Qin Tian T Schreiber Stuart L SL Melillo Bruno B Yu Jin-Quan JQ Baran Phil S PS

Proceedings of the National Academy of Sciences of the United States of America 20190417 18

The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vi ...[more]

PMID: 30996125

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Project description:In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp(3)-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp(2)-hybridized species, the development of methods for sp(3)-sp(3) bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp(3)-sp(3) bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp(3)-sp(3) coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp(3)-sp(3) bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Dataset Information

Modular, stereocontrolled C_β-H/C_α-C activation of alkyl carboxylic acids.

Publications

Modular, stereocontrolled C<sub>β</sub>-H/C<sub>α</sub>-C activation of alkyl carboxylic acids.

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Dataset Information

Modular, stereocontrolled Cβ-H/Cα-C activation of alkyl carboxylic acids.

Publications

Modular, stereocontrolled C<sub>β</sub>-H/C<sub>α</sub>-C activation of alkyl carboxylic acids.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Modular, stereocontrolled C_β-H/C_α-C activation of alkyl carboxylic acids.