Stereoselective Access to Gamma,Gamma-Dihalo-Beta-enols from Alkynes via Photobiocatalysis

Merging different catalytic strategies in one-pot is attracting considerable attention for the straightforward and sustainable synthesis of novel organic compounds. In particular, the exquisite selectivity displayed by enzymes and the possibility to couple biotransformations with metal-, photo and electrocatalytic processes opens new avenues for stereoselective synthesis. Herein, the preparation of chiral (hetero)aryl-3,3-halo-prop-2-en-1-ols has been described for the first time. To achieve this aim, a photochemical and biocatalytic one-pot sequence has been followed employing visible light irradiation and the action of stereoselective alcohol dehydrogenases (ADHs) for the transformation of commercial acetylenes into a series of optically active gamma,gamma-dihalo-beta-enols in aqueous medium. The one-pot two-step sequential approach consisted of the free-photocatalyst reaction between a series of terminal and internal alkynes with polyhalomethanes (CClBr3 or CBr4) leading to gem-dihaloenones, which were subsequently enzymatically reduced with ADHs. After optimisation of individual steps and finding conditions to perform both processes in one-pot, the use of complementary ADHs has allowed the synthesis of a novel family of optically active allylic alcohols with high stereodiscrimination, whose applicability has been demonstrated, for example, towards the synthesis of a chiral propargylic alcohol.