Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis

Abstract

Chiral nitriles are valuable molecules in modern organic synthesis and drug discovery. Selectively differentiating the two nitrile groups of widely available malononitrile derivatives is a straightforward yet underdeveloped route to construct enantioenriched nitriles. Here we report an enantioselective nickel-catalyzed desymmetrization of malononitriles for the generation of nitrile-containing all-carbon quaternary stereocenters. This protocol involves a nickel-catalyzed addition of aryl boronic acids to alkynes, followed by a selective nitrile insertion, providing unprecedented access to enantioenriched 5−7-membered α-cyanocycloenones with a fully substituted olefin from a broad range of substrates. The synthetic utility of these nitrile products is demonstrated by gram-scale synthesis and conversion to several useful functional groups.

Precatalyst‐Enabled Selectivity: Enantioselective NiH‐Catalyzed anti‐Hydrometalative Cyclization of Alkynones to Endo‐ and Heterocyclic Allylic Alcohols

“…Additionally, the isomerization of the putative 1,2‐disubstituted cis ‐alkenylnickel species to the corresponding trans one requires overriding the steric repulsion between the nickel and the substituent on the neighboring carbon [13] . Indeed, such isomerization of 1,2‐disubstituted alkenylnickel has been rarely investigated, although strategies involving cis / trans isomerization of fully substituted alkenylnickel species formed via alkyne insertion into arylnickel species and sequential cyclization were successfully demonstrated by Liu, [14] Lam, [15] and our group [16] . Gratifyingly, a preliminary proof was obtained by the use of Ni(OTs) 2 ⋅6 H 2 O as the nickel precursor predominately resulting endocyclic product 2 a with 97:3 er (Scheme 1 c).…”

Nickel‐Catalyzed Arylative Cyclizations of Alkyne‐ and Allene‐Tethered Electrophiles using Arylboron Reagents

“…Only a few examples using other arylboron reagents such as aryl pinacolboronates, aryl trifluoroborates, or arylboroxines have been reported. [68,73] In nickel-catalyzed arylative cyclizations of alkyne-tethered electrophiles, two modes of cyclization are generally possible, which differ in both their regio-and stereochemical outcomes. [90] The first of these is anti-arylmetallative cyclization.…”

Ni-catalyzed enantioselective [2 + 2 + 2] cycloaddition of malononitriles with alkynes

“…Pioneering studies by the Louie group have demonstrated the capability of nickel catalysis in coupling diynes and nitriles to construct pyridines. [40][41][42][43][44][45][46] Inspired by their mechanistic studies 44 and in line with our interest in desymmetrization, 47,48 we envisaged that an intramolecular hetero-cyclometallation of an alkyne-tethered malononitrile 1 with a nickel complex could form an aza-nickelacyclopentadiene (int II), followed by an alkyne insertion (int III) and reductive elimination to deliver enantioenriched fully substituted pyridines (Scheme 1F). We anticipated that the formation of the rigid five-membered ring-fused int II could facilitate the discrimination of the two CN groups efficiently.…”