The present microreview summarizes our progress over the last few years in defining regioselective reductive cross-coupling reactions of unsymmetrical alkynes with terminal- and internal alkynes, aldehydes, and imines. We begin with a brief historical perspective of metal-mediated reductive dimerization reactions of aromatic alkynes and discuss the challenges associated with “crossed” versions of this mode of reactivity. Next, a collection of available methods that allow for regioselective reductive cross-coupling of internal alkynes with terminal and internal alkynes, aldehydes, and imines is summarized. After an examination of the requirements for regioselectivity in these cases, the logic behind our design of alkoxide-directed titanium-mediated reductive cross-coupling reactions is presented. A nomenclature is introduced to delineate the presumed mechanistic origin of regioselection associated with each reaction design, and a presentation of alkoxide-directed regioselective reductive cross-coupling reactions of alkynes follows. Throughout, principal issues related to reactivity and selectivity are discussed to assess scope and limitations of available methods and to describe the broad challenges that exist for defining complex fragment union reactions based on reductive cross-coupling chemistry.

Ti‐ght union: A highly regio‐ and stereoselective bimolecular coupling reaction is described for the union of substituted, unactivated olefins and internal alkynes (see scheme). The titanium‐mediated coupling reaction proceeds with CC bond formation occurring distal to a pendent hydroxy group.

A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2+2+2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne–alkyne coupling, followed by metal-centered [4+2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.

This perspective surveys the history of- and recent advances in- metallacycle-mediated coupling chemistry of substituted alkenes. While the reaction of preformed metal–π complexes with ethylene was reported nearly 30 years ago, the generalization of this mode of bimolecular C–C bond formation to the regio- and stereoselective union of complex substrates has only recently begun to emerge. This perspective discusses early observations in this area, the challenges associated with controlling such processes, the evolution of a general strategy to overcome these challenges, and a summary of highly regio- and stereoselective convergent coupling reactions that are currently available by metallacycle-mediated cross-coupling with substituted alkenes.

Using a modular approach: A concise synthesis of callystatin A has been developed. The modular pathway provides access to the highly unsaturated skeleton of the leptomycin natural products by using a complex titanium‐mediated reductive alkyne–alkyne cross‐coupling reaction as the key transformation (see scheme; TBS=tert‐butyldimethylsilyl).