Zirconium-Catalyzed Asymmetric Carboalumination of Unactivated Terminal Alkenes. Academic Article uri icon


  • Carbometalation of alkenes with stereocontrol offers an important opportunity for asymmetric C-C bond formation. However, the scope of catalytic stereoselective carbometalation of alkenes had until recently been limited to electronically biased alkenes or those with the presence of directing groups or other auxiliary functionalities to overcome the challenge associated with regio- and stereoselectivity. Catalytic asymmetric carbometalation of unactivated alkenes on the other hand remained as a formidable challenge. To address this long-standing problem, we sought to develop Zr-catalyzed asymmetric carboalumination of alkenes (namely, ZACA reaction) encouraged by our discovery of Zr-catalyzed alkyne carboalumination in 1978. Zr-catalyzed methylalumination of alkynes (ZMA) shows high regioselectivity and nearly perfect stereoselectivity. Its mechanistic studies have revealed that the ZMA reaction involves acyclic carbometalation with "superacidic" bimetallic reagents generated by interaction between two Lewis acids, i.e., alkylalanes and 16-electron zirconocene derivatives through dynamic polarization and ate complexation, affectionately termed as the "two-is-better-than-one" principle. With the encouraging results of Zr-catalyzed carboalumination of alkynes in hand, we sought to develop its alkene version for discovering a catalytic asymmetric C-C bond-forming reaction by using alkylalanes and suitable chiral zirconocene derivatives, which would generate "superacidic" bimetallic species to promote the desired carbometalation of alkenes. However, this proved to be quite challenging. Three major competing side reactions occur, i.e., (i) -H transfer hydrometalation, (ii) bimetallic cyclic carbometalation, and (iii) Ziegler-Natta polymerization. The ZACA reaction was finally discovered by employing Erker's (-)-(NMI)2ZrCl2 as the catalyst and chlorinated hydrocarbon as solvent to suppress the undesired side reactions mentioned above. The ZACA reaction has evolved as a powerful tool for the efficient preparation of a wide range of chiral natural products through the following methodological developments: (1) three mutually complementary protocols for methyl-branched chiral alkanols; (2) water, MAO, and IBAO as promoters to accelerate otherwise sluggish carboaluminations; (3) one-step homologation synthesis of deoxypropionates based on one-pot ZACA-Pd-catalyzed vinylation tandem process; (4) ZACA-lipase-catalyzed acetylation-transition-metal-catalyzed cross-coupling processes for preparing various virtually enantiopure chiral alcohols; (5) the chemoselective ZMA and ZACA reactions as well as alkyne elementometalation-Pd-catalyzed cross-coupling for constructing a variety of chiral compounds containing regio- and stereodefined substituted alkenes; (6) the ZACA reaction of dienes to generate chiral organocyclic compounds including those with all-carbon quaternary stereocenters.

published proceedings

  • Acc Chem Res

altmetric score

  • 16.85

author list (cited authors)

  • Xu, S., & Negishi, E.

citation count

  • 46

complete list of authors

  • Xu, Shiqing||Negishi, Ei-Ichi

publication date

  • January 2016