Catalyst Optimisation for Asymmetric Synthesis by Ligand Chirality Element Addition: A Perspective on Stereochemical Cooperativity

Abstract

The concept of matched and mismatched stereochemical pairings has been utilised extensively in organic synthesis, with the cooperativity resulting from the former enabling many reactions to proceed with high stereoselectivity. This approach was first developed to improve the diastereoselectivity of a reaction by matching the configuration of an enantiopure reagent or catalyst with the configuration of an enantiopure substrate. It has been extended to the asymmetric transformation of prochiral substrates controlled by reagents and catalysts containing two or more stereogenic centres. Matched and mismatched pairings may again be identified, with the former resulting in higher product enantioselectivity. This Minireview examines stereochemical pairings within catalysts generated from the combination of a metal with an enantiopure ligand; specifically examples in which the ligand diastereoisomers examined for cooperativity are formally the result of the addition of a chiral element to an existing enantiopure ligand. Comparison of all three ligands in each of the fifty-six examples examined reveals that, in the majority of cases, the added element of chirality increases and decreases the enantioselectivity with respect to the parent ligand. The iterative application of this effect offers a potentially powerful method for catalyst optimisation for use in asymmetric synthesis.

Application of a Ferrocene‐Based Palladacycle Precatalyst to Enantioselective Aryl‐Aryl Kumada Coupling

“…Addition of a chirality element to an existing chiral non‐racemic ligand often results in an increase in catalysis product e.e. for one of the two resulting diastereoisomers [21] . To this end, we tested the P ‐stereogenic PPFA derivatives ( R , S p , S phos )‐ 13 and ( R , S p , R phos )‐ 14 containing an ortho ‐tolyl group in place of one or other of the diastereotopic phosphorus phenyl substituents [22] .…”

Copper(I) Complexes of P‐Stereogenic Josiphos and Related Ligands

“…In addition to e.e. optimisation by varying the steric and electronic properties of the R ’ and R ’’ substituents, there is the possibility of creating an additional phosphorus‐based stereogenic centre, such that one of the two resulting diastereomeric ligands B may lead to higher enantioslectivity [7] . We chose to explore this aspect of ligand‐optimisation by first synthesising a series of readily isolated and air‐stable copper(I) chloride complexes C (Ar’≠Ar’’ and Ar’=Ar’’).…”

Nickel‐Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric‐Ligand‐Controlled Regiodivergence

“…[11] It is often necessary to study the effects of diastereomeric ligands on the reactivity and enantioselectivity when using multi-chiral ligands in catalytic asymmetric reactions. [12] However, the corresponding effects on regioselectivity have received much less attention. This is somewhat counterintuitive,asthe diastereomeric ligands have different configurations and thus induce different regioselectivities.We therefore envision that the use of diastereomeric ligands in metal-catalyzed reactions involving ar egioselective issue would provide an ovel strategy to achieve regiodivergent synthesis (Scheme 1b).…”