Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

Abstract

The catalytic addition of alkenes and amines (hydroamination) typically provides α-or β-amino stereocenters directly through C-N or C-H bond formation. Alternatively, desymmetrization reactions of symmetrical aminodialkenes or aminodialkynes provide access to stereogenic centers with the position controlled by the substrate's structure. In the present study of an enantioselective zirconium-catalyzed hydroamination, stereocenters resulting from C-N bond formation and desymmetrization of a prochiral quaternary center are independently controlled by the catalyst and reaction conditions. Using a single catalyst, the method provides selective access to either diastereomer of optically enriched five-, six-, and seven-membered cyclic amines from aminodialkenes and enantioselective synthesis of five-, six-, and seven-membered cyclic imines from aminodialkynes. Experiments on hydroamination of aminodialkenes testing the effects of the catalyst:substrate ratio, the absolute concentration of the catalyst, and the absolute initial concentration of the primary amine substrate show that the latter parameter strongly influences the stereoselectivity of the desymmetrization process, whereas the absolute configuration of the α-amino stereocenter generated by C-N bond formation is not affected by these parameters. Interestingly, isotopic substitution (H2NR vs D2NR) of the substrate enhances the stereoselectivity of the enantioselective and diastereoselective processes in aminodialkene cyclization and the peripheral stereocenter in aminodialkyne desymmetrization/cyclization. ABSTRACT: The catalytic addition of alkenes and amines (hydroamination) typically provides α-or β-amino stereocenters directly through C−N or C−H bond formation. Alternatively, desymmetrization reactions of symmetrical aminodialkenes or aminodialkynes provide access to stereogenic centers with the position controlled by the substrate's structure. In the present study of an enantioselective zirconium-catalyzed hydroamination, stereocenters resulting from C−N bond formation and desymmetrization of a prochiral quaternary center are independently controlled by the catalyst and reaction conditions. Using a single catalyst, the method provides selective access to either diastereomer of optically enriched five-, six-, and seven-membered cyclic amines from aminodialkenes and enantioselective synthesis of five-, six-, and seven-membered cyclic imines from aminodialkynes. Experiments on hydroamination of aminodialkenes testing the effects of the catalyst:substrate ratio, the absolute concentration of the catalyst, and the absolute initial concentration of the primary amine substrate show that the latter parameter strongly influences the stereoselectivity of the desymmetrization process, whereas the absolute configuration of the α-amino stereocenter generated by C−N bond formation is not affected by these parameters. Interestingly, isotopic substitution (H 2 NR vs D 2 NR) of the substrate enhances the stereoselectivity of the enantioselective and diastereoselecti...

β-SiH-Containing Tris(silazido) Rare-Earth Complexes as Homogeneous and Grafted Single-Site Catalyst Precursors for Hydroamination

“…For example, we recently reported that substrate concentration affected the cis:trans ratio in an enantioselective Zr-catalyzed monocyclization reaction of aminodialkenes and aminodialkynes to give optically active pyrrolidines. 45 In addition, Marks and co-workers showed in their seminal study that diastereoselectivity in Cp* 2 LaCH(SiMe 3 ) 2 -catalyzed hydroaminations of chiral aminoalkenes is also influenced by concentration. 46 Rare-earth compounds and a few zirconium catalysts give hydroamination/bicyclization products through a two-step process in which the second cyclization requires conditions more forcing than those in the first.…”

Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization

“…26 In the case of amino dialkenes ( 58a–58g ), two stereocenters are formed in the reaction, one through the desymmetrization of a quaternary center and the other through C–N bond formation. By varying reaction conditions the authors were able to achieve reasonable diastereocontrol.…”

Catalytic conversion reactions in nanoporous systems with concentration-dependent selectivity: Statistical mechanical modeling

“…The latter are neglected in MF treatments. The second phenomenon involves reactions with concentration-dependent selectivity, and specifically stereoselectivity where the product B can have distinct cis (B c ) and trans (B t ) forms [15]. Here, the selection of the B c or B t product is controlled by the concentration of the reactant, A.…”

“…However, here we first provide some brief comments for broader background and motivation regarding the type of systems falling into the above class and also on theoretical methodologies with the potential to provide a firstprinciples characterization of reaction kinetics. With regard to concentration-dependent selectivity, homogeneous catalytic desymmetrization of diallylamines to give diastereomers (using a Zr-centered catalyst) exhibits a quite strong variation with reactant concentration of cis to trans selectivity [15]. Specifically, the yield of trans relative to cis product increases with reactant concentration.…”

“…Specifically, the yield of trans relative to cis product increases with reactant concentration. These studies are part of a broader analysis of stereoselectivity in Zr catalyzed reactions [15,21]. To develop a heterogeneous version of this process, one might anticipate functionalizing the interior pore surfaces of MSN with an appropriate Zr-centered catalytic group.…”