Stereoselectivity in Pd-catalysed cross-coupling reactions of enantioenriched nucleophiles

Abstract

Advances in Pd-catalysed cross-coupling reactions have facilitated the development of stereospecific variants enabling the use of configurationally stable, enantioenriched, main-group organometallic nucleophiles to form C(sp ³)-C(sp ²) bonds. Such stereospecific cross-coupling reactions constitute a powerful synthetic approach to attaining precise 3D control of molecular structure, allowing new stereogenic centres to be readily introduced into molecular architectures. Examples of stereospecific, Pd-catalysed cross-coupling reactions have been reported for isolable enantioenriched alkylboron, alkyltin, alkylgermanium and alkylsilicon nucleophiles. In these reactions, a single, dominant stereospecific pathway of transmetallation to palladium is required to effect efficient chirality transfer to the cross-coupled product. However, the potential for competing stereoretentive and stereoinvertive pathways of transmetallation complicates the stereochemical transfer in these processes and impedes the rational development of new stereospecific cross-coupling variants. In this Review, we describe the use of enantioenriched organometallic nucleophiles in stereospecific, Pd-catalysed cross-coupling reactions. We focus on systems involving well-defined, isolable, enantioenriched nucleophiles in which a clear stereochemical course of transmetallation is followed. Specific modes of electronic activation that influence the reactivity of alkylmetal nucleophiles are described and presented in the context of their impact on the stereochemical course of cross-coupling reactions. We expect that this Review will serve as a valuable resource to assist in deconvoluting the many considerations that potentially impact the stereochemical outcome of Pd-catalysed cross-coupling reactions.

Fig. 1 |. Stereochemical considerations in the coupling of enantioenriched nucleophiles.

a | Catalytic cycle for Pd-catalysed cross-coupling reactions using configurationally stable enantioenriched nucleophiles. b | Potential transmetallation pathways. c | Inverse relationship between configurational stability and nucleophilicity for main-group organometallic nucleophiles. d | Relative rates of group transfer in Pd-catalysed coupling reactions and possible modes of activation.

Fig. 2 |. Use of unactivated, stereodefined organoboron nucleophiles in Pd-catalysed cross-coupling reactions.

a | Coupling of primary 9-BBN nucleophiles. Left: the Whitesides protocol using deuterium-labelled substrates to determine the stereochemical course of reaction by measuring vicinal proton–proton coupling constants. Centre and right: examples showing that coupling in these cases occurs with retention of stereochemistry^,. b | By contrast, coupling of secondary trifluoroborate nucleophiles was initially shown to occur through a stereoinvertive pathway and, later, that the preferred pathway was influenced by the electronic properties of the supporting phosphine ligand and the aryl electrophile^,. c | Burke’s coupling of N-2-benzyloxycyclopentyl-iminodiacetic acid (BIDA) boronates occurs with near-perfect stereoretention. d | Substrate steric effects can override previously determined patterns, as shown by Molander and Dreher. Part b is adapted with permission from reF., AAAS.

Fig. 3 |. Examples of electronically activated alkylboron nucleophiles in net-stereoretentive suzuki cross-coupling reactions^–.

The substrates feature a variety of α- and β-substituents and several different Pd catalysts have been used.

Fig. 4 |. Propargylic and allylic organoboron nucleophiles in couplings.

a | Couplings of propargylic and allylic boron nucleophiles often give isomerized products but generally occur with net retention of stereochemistry^–. b | Direct γ-transmetallation or an α-transmetallation followed by isomerization via a π-allyl intermediate both lead to the same isomerized product^,.

Fig. 5 |. Suzuki couplings of activated alkylboron nucleophiles that occur with net inversion of stereochemistry.

a | Examples of electronically activated organoboron nucleophiles in net-stereoinvertive Suzuki cross-coupling reactions^–. b | Mechanistic models for stereoinvertive transmetallation of alkylboron nucleophiles^–.

Fig. 6 |. Examples of the coupling of enantioenriched organostannanes in copper-promoted palladium-catalysed stille reactions.

With the exception of example 10, reactions occur with net retention of stereochemistry^–,.

Fig. 7 |. Copper-catalysed and copper-mediated cross-couplings of alkylstannanes.

a | Examples of copper-mediated and copper-catalysed Stille reactions — these reactions generally occur with net retention of stereochemistry^–. b | Mechanisms of transmetallation of C–Sn to form C–Cu in cross-coupling reactions with and without Pd. Note that, in the second case, there are two transmetallation steps that must both occur with retention in order to obtain the product.

Fig. 8 |. Pd-catalysed cross-coupling reactions of enantioenriched alkyltin, alkylgermanium and alkylsilicon nucleophiles.

a | Examples of copper-free Stille (alkyltin) cross-couplings — both retention and inversion of stereochemistry have been observed^,–. b | Examples of cross-couplings with organosilicon and organogermanium nucleophiles^–. c | γ-Transmetallation from silicon to palladium with allylic nucleophiles primarily occurs by a S_E′ mechanism and may occur with syn- or anti-stereoselectivity, depending on reaction conditions^–.