Lactonization as a general route to ?-C(sp3)-H functionalization.

ABSTRACT: Functionalization of the ?-C-H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions1-5. Despite efforts for ?-C-H functionalization in carbon-carbon and carbon-heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope6-13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C-H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed ?-C(sp3)-H lactonization of aliphatic acids enabled by a mono-N-protected ?-amino acid ligand. The highly strained and reactive ?-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the ? position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(IV) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.

SUBMITTER: Zhuang Z 

PROVIDER: S-EPMC6994389 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature