General access to furan-substituted <i>gem</i> -difluoroalkenes enabled by PFTB-promoted cross-coupling of ene-yne-ketones and difluorocarbene

Replacement of a carbonyl group with fluorinated bioisostere (<i>e.g.</i>, CF₂[double bond, length as m-dash]C) has been adopted as a key tactical strategy in drug design and development, which typically improves potency and modulates lipophilicity while maintaining biological activity. Consequently, new <i>gem</i>-difluoroalkenation reactions have undoubtedly accelerated this shift, and conceptually innovative practices would be of great benefit to medicinal chemists. Here we describe an expeditous protocol for the direct assembly of furan-substituted <i>gem</i>-difluoroalkenes <i>via</i> PFTB-promoted cross-coupling of ene-yne-ketones and difluorocarbene. In this multi-step tandem reaction process, the furan ring and the <i>gem</i>-difluorovinyl group are constructed simultaneously in an efficient manner. These products can serve as bioisosteres of the α-carbonyl furan core, which is an important scaffold present in natural products and drug candidates. The broad generality and practicality of this method for late-stage modification of bioactive molecules, gram-scale synthesis and versatile derivatisation of products has been described. Biological activity evaluation showed that the <i>gem</i>-difluoroalkene skeleton exhibited dramatic antitumor activity.