Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters

Abstract

An enantioselective, intermolecular dehydrogenative Heck arylation of trisubstituted alkenes to construct remote quaternary stereocenters has been developed. Using a new chiral pyridine oxazoline ligand, good to high enantioselectivity is achieved for various combinations of indole derivatives and trisubstituted alkenes. However, some combinations of substrates led to lower enantioselectivity, which provided the impetus to use structure enantioselectivity correlations to design a better performing ligand.

Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis

“…107 Under halide-free conditions using a palladium catalyst modified by pyridine oxazoline ligand XXXI , olefin carbopalladation is followed by β-hydride elimination and migration of the resulting double bond along the alkyl chain, ultimately terminating in aldehyde or ketone formation. This method was later extended to the use of indoles 108 and vinyl triflates 109 as coupling partners using pyridine oxazoline ligands XXXII and XXXIII , respectively. This method enables enantioselective formation of remote quaternary carbon stereocenters from highly tractable and accessible coupling partners.…”

Parametrization of Non-covalent Interactions for Transition State Interrogation Applied to Asymmetric Catalysis

“…3 This tactic has allowed us to evaluate a number of complex reactions, providing predictions for output improvement as well as mechanistic insight on the basis of the parameters required to develop a mathematical model. 3a,4 The parameters used include spectroscopic, 5 geometric, 6 atomic charge, 7 and detailed size descriptors. 8 However, a key limitation thus far has been the absence of suitable parameters to describe attractive NCIs.…”

Multidimensional Correlations in Asymmetric Catalysis through Parameterization of Uncatalyzed Transition States

“…The resultant mathematical model can be used to extrapolate better catalysts through virtual screening thus improving the reaction performance. [2] Additionally, analysis of the parameters included in the equation provides information about the reaction mechanism. [2b, 3] Historically, limited parameters were available to probe such mechanistic considerations including Hammett σ, [4] Tolman cone angle, [5] Charton [6] and Taft parameters, [7] yet in recent years modern physical organic descriptors have been reported, [8] which have ultimately led to the rationalization of reactions of enhanced complexity.…”

“…[2] Additionally, analysis of the parameters included in the equation provides information about the reaction mechanism. [2b, 3] Historically, limited parameters were available to probe such mechanistic considerations including Hammett σ, [4] Tolman cone angle, [5] Charton [6] and Taft parameters, [7] yet in recent years modern physical organic descriptors have been reported, [8] which have ultimately led to the rationalization of reactions of enhanced complexity. [3b, 9] Even with these advances and the ability to perform multi-variate analysis of intricate processes for predictive purposes, there have been a number of cases wherein the sophistication of the reaction does not lend itself to straight-forward analysis.…”