Ir-Catalyzed Regio- and Enantioselective Hydroalkynylation of Trisubstituted Alkene to Access All-Carbon Quaternary Stereocenters

Abstract

The stereoselective construction of all-carbon quaternary stereocenters, especially acyclic ones, represents an important challenge in organic synthesis. In particular, homopropargyl amides with a quaternary stereocenter β to a nitrogen atom are valuable synthetic intermediates, which could be transformed to diverse chiral structures through alkyne transformations. However, highly enantioselective synthetic methods for homopropargyl amides with a β quaternary stereocenter are extremely rare. We report here unprecedented substrate-directed, iridium-catalyzed enantioselective hydroalkynylations of trisubstituted alkenes to form an acyclic all-carbon quaternary stereocenter β to a nitrogen atom. The hydroalkynylation of enamide occurred with unconventional selectivity, favoring the more hindered reaction site. Homopropargyl amides with β-stereocenters were prepared in high regio- and enantioselectivities. Combined experimental and computational studies revealed the origin of the regio- and enantioselectivities.

Recent Advances in Transition-Metal-Catalyzed Asymmetric Functionalization of Enamides

“…In contrast, in the presence of electron-rich ligand L14, homopropargyl amides 95 with a  all-carbon quaternary center were obtained in both high yield and high enantioselectivity, albeit with a small amount of -alkynylation products (Scheme 20). 42 Computational studies indicated that the ligand is crucial for controlling the regioselectivity of the hydroalkynylation of ,-disubstituted enamides. The phosphoramidite ligand is less electron-donating than a bisphosphine ligand, so the electron density at the metal center is reduced, which is conducive to the reductive elimination of the iridium center, leading to the formation of the -hydroalkynylation product.…”

Acyclic Quaternary Carbon Stereocenters through Transition-Metal-Catalyzed Enantioselective Functionalization of Unsaturated Hydrocarbons

“…In this regard, Li and co-workers developed a substrate-directed regio-and enantioselective hydroalkynylation of trisubstituted alkenes (Scheme 28). 40 The catalytic C-C formation preferentially occurs at the more hindered position, generating acyclic quaternary carbon stereocenters  to an amide. Through a sequence of alkene hydroalkynylation and alkyne functionalization, diverse products containing quaternary carbon stereocenters were prepared.…”

Reaction mechanism study on reactions of phenylacetylenes with HSnEt3promoted by B(C6F5)3with and without DABCO

“…8 To date, density functional theory (DFT) calculations have been used to perform mechanistic studies on transition metal complex-catalyzed dehydrogenation reactions to obtain new C(sp)-C, C(sp)-B, and C(sp)-Sn bonds as coupling products. [9][10][11] Obviously, dehydrogenative couplings catalyzed by transition metals to synthesize new alkynes are more atomically efficient when compared with traditional methods, but transition metal catalysts are usually expensive and environmentally unfriendly. Therefore, scientists are diligently working to find new catalytic systems with low cost, eco-friendliness, and high selectivity.…”