General\nAlkene 1,2-<i>syn</i>-Cyano-Hydroxylation\nProcedure Via Electrochemical Activation of Isoxazoline Cycloadducts

Stereoselective alkene\n1,2-difunctionalization is a privileged\nstrategy to access three-dimensional C(sp<sup>3</sup>)-rich chiral\nmolecules from readily available “flat” carbon feedstocks.\nState-of-the-art approaches exploit chiral transition metal-catalysts\nto enable high levels of regio- and stereocontrol. However, this is\noften achieved at the expense of a limited alkene scope and reduced\ngenerality. 1,3-Dipolar cycloadditions are routinely used to form\nheterocycles from alkenes with high levels of regioselectivity and\nstereospecificity. Nevertheless, methods for the ring-opening of cycloadducts\nto reveal synthetically useful functionalities require the use of\nhazardous reagents or forcing reaction conditions; thus limiting their\nsynthetic applications. Herein, we describe the implementation of\na practical, general and selective electrosynthetic strategy for olefin\n1,2-<i>syn</i>-difunctionalization, which hinges on the\ndesign of novel reagents–consisting of a nitrile oxide 1,3-dipole\nprecursor, equipped with a sulfonyl-handle. These can selectively\ndifunctionalize alkenes via “click” 1,3-dipolar cycloadditions,\nand then facilitate the telescoped electrochemical single electron\ntransfer activation of the ensuing isoxazoline intermediate. Cathodic\nreduction of the cycloadduct triggers a radical fragmentation pathway\ndelivering sought-after stereodefined 1,2-<i>syn</i>-hydroxy\nnitrile derivatives. Our telescoped electrochemical procedure tolerates\na wide range of functionalities, andcruciallyenables\nthe difunctionalization of both electron-rich, electron-poor and unactivated\nolefins, with diverse degree of substitution; thus providing a robust,\ngeneral and selective metal-free alternative to current alkene difunctionalization\nstrategies. Capitalizing on these features, we employed our electrosynthetic\nmethod to enable the late-stage <i>syn</i>-hydroxy-cyanation\nof natural products and bioactive compounds, and streamline the <i>de novo</i> synthesis of pharmaceutical agents.