Boron-mediated Transition-metal Catalyzed Selective Synthesis of Diverse Alkenes

Abstract

The stereoselective synthesis of alkenes has been one of the central objectives in organic chemistry. Significant advances in synthetic methodology have made mono-and disubstituted alkenes widely accessible from a variety of readily available precursors. However, increased steric hindrance in more highly substituted alkenes limits the effectiveness of these methods, and as a result, the efficient and selective synthesis of highly substituted alkenes remains a formidable challenge. Boron exhibits unique reactivity that enables highly chemo- and stereoselective transformations and facile access to diverse functional groups, making organoboron compounds versatile intermediates in organic synthesis. Herein, we reported three new boron-mediated transition-metal catalyzed reactions that highly regio- and stereoselectively afford diverse alkenes with valuable functionality.The first reaction, described in Chapter 1, is a method for the synthesis of allylic alcohols via a copper-catalyzed reductive coupling of terminal alkynes with α-chloro boronic esters, followed by in situ oxidation of the boronic ester to an alcohol. The reaction is highly E-selective and exhibits broad functional group tolerance. Mechanistic studies suggest that cross-coupling of the alkenyl copper intermediate with the α-chloro boronic ester proceeds via a stereospecific 1,2-metalate shift. With support from mechanistic insights, we established a robust synthesis of chiral allylic alcohols from terminal alkynes and readily accessible enantioenriched organoboron precursors. Following this development, Chapter 2 describes a highly regio- and diastereo-selective synthesis of trisubstituted alkenes via nickel-catalyzed hydroalkylation of alkynyl boronamides. In this transformation, boryl groups serve as versatile directing groups that can control the regioselectivity of the hydroalkylation and enables productively replacement via cross-coupling. Preliminary studies support the hydrometalation mechanism and the formation of alkyl radical intermediates. Finally, Chapter 3 described a regiodivergent and stereoselective synthesis of tetrasubstituted alkenes via palladium catalyzed direct trifunctionalization of terminal alkynes using organoboranes and allylic carbonates as coupling partners. Incorporation of the allylic electrophile can be accomplished with either branched and linear selectivity and with excellent diastereo- and enantioselectivity, allowing access to a range of highly complex 1,4-dienes. Experimental evidence supports that enantioselective allylic substitution proceeds through a dynamic kinetic resolution and inner-sphere reductive elimination pathway. Proposed mechanism involves alkynyl boron-ate formation followed by a palladium-promoted 1,2-metalate shift that controls the regio- and diastereoselectivity of the alkene formation. Notably, these three strategies exploit distinct properties of boron to achieve desired regio- and stereocontrol: the first and third employ stereoselective 1,2-metallate shift of tetracoordinated boron-ate complexes, whereas the second relies on intrinsic electronic bias between carbon and boron.