The primary focus of our research group is to develop new synthetic methodologies that utilize the power of transition metal catalysis. Transition metal catalysis has transformed the field of synthetic organic chemistry by enabling new and highly efficient reactions with exceptional control over regio- and enantioselectivity. Most transition metal catalysis relies heavily on neutral electrophiles, but we envisioned that it could also be efficiently used with cationic electrophiles to solve significant, long-standing challenges in organic synthesis. In particular, few methods are available for enantioselective additions to cyclic ketoxocarbenium and ketiminium ions to form diaryl, tetrasubstituted stereocenters. Harnessing our success in developing a copper-catalyzed addition of terminal alkynes to oxocarbenium ions to deliver isochromans with tertiary stereocenters, we have now developed a highly enantioselective, copper(I)/PyBox-catalyzed addition of terminal alkynes to isochroman ketals to set diaryl-substituted quaternary stereocenters.The success of this transformation relies on identification of a Cu/PyBox catalyst capable of distinguishing two aryl substituents on the forming stereocenter, which differ predominantly in their freedom of rotation and by their relationship to the oxygen substituents (alkyl vs lone pair). This highly challenging transformation enables the efficient conversion of readily available, racemic ketals to high-value, enantioenriched isochroman products, presumably via prochiral oxocarbenium ion intermediates. Reaction optimization, scope of both the ketal and alkyne, and elaboration of products will be presented. We were also able to use this potent copper(I)/PyBox catalyst to develop an enantioselective, copper(I)-catalyzed alkynylation of ketiminium ion intermediates to deliver tetrahydroisoquinolines with tetrasubstituted stereocenters in high yields and enantioselectivities. Select substrate scope and elaboration of products in this method will also be presented. We are currently investigating how the chiral copper/Pybox catalyst imparts enantioselectivity in these reactions. Initial mechanistic experiments elucidating the structure of the active catalyst as a dicopper acetylide species and further reactions inspired by these methods will also be discussed.

Copper(I)–catalyzed enantioselective alkynylation of oxocarbenium and iminium ions to set diaryl tetrasubstituted stereocenters

254th National Meeting (2017)

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