Mark R. Biscoe

We report enantiodivergent Pd‐catalyzed cross‐coupling reactions between enantioenriched alkylcarbastannatrane nucleophiles and aryl electrophiles in which the stereochemical course of the reaction is dictated by the inclusion or omission of a Cu(I) additive. Using a new electron‐deficient biarylphosphine ligand (MaPhos), a previously unknown stereoinvertive pathway for the transmetalation of unactivated and benzylic secondary alkylstannanes to Pd has been uncovered. When a Cu(I) salt is included in the reaction, the stereochemical course of the reaction changes from stereoinvertive to stereoretentive. Thus, both enantiomers of the cross‐coupling product can be accessed in high enantiopurity using a single achiral ligand. Mechanistic investigations suggest that net‐stereoretentive alkyl transfer, in the presence of Cu(I), results from consecutive stereoretentive transmetalations from tin to copper and copper to palladium. In contrast, direct alkyl transmetalation from tin to palladium proceeds primarily via a stereoinvertive pathway that is facilitated by the presence of electron‐deficient ligands. Both experiment and DFT computations agree that ligand electronic properties play an important role in dictating the stereochemical course of direct (copper‐free) alkyl transmetalation from tin to palladium. DFT results additionally reveal the governing structural features and interactions that promote the stereoinvertive transmetalation pathway in the copper‐free reaction using MaPhos.

We report enantiodivergent Pd‐catalyzed cross‐coupling reactions between enantioenriched alkylcarbastannatrane nucleophiles and aryl electrophiles in which the stereochemical course of the reaction is dictated by the inclusion or omission of a Cu(I) additive. Using a new electron‐deficient biarylphosphine ligand (MaPhos), a previously unknown stereoinvertive pathway for the transmetalation of unactivated and benzylic secondary alkylstannanes to Pd has been uncovered. When a Cu(I) salt is included in the reaction, the stereochemical course of the reaction changes from stereoinvertive to stereoretentive. Thus, both enantiomers of the cross‐coupling product can be accessed in high enantiopurity using a single achiral ligand. Mechanistic investigations suggest that net‐stereoretentive alkyl transfer, in the presence of Cu(I), results from consecutive stereoretentive transmetalations from tin to copper and copper to palladium. In contrast, direct alkyl transmetalation from tin to palladium proceeds primarily via a stereoinvertive pathway that is facilitated by the presence of electron‐deficient ligands. Both experiment and DFT computations agree that ligand electronic properties play an important role in dictating the stereochemical course of direct (copper‐free) alkyl transmetalation from tin to palladium. DFT results additionally reveal the governing structural features and interactions that promote the stereoinvertive transmetalation pathway in the copper‐free reaction using MaPhos.

Atropisomerism is a stereochemical phenomenon that results from high configurational stability of chiral axes and is an important structural element in many functional molecules. Thus, understanding how different structural features can influence the stability of chiral axes can be an important consideration for molecular design. Recent studies have demonstrated that certain tropone-based chiral axes are significantly more stable than those of related benzenoids, likely a result of their relatively smaller external bond angles. The following manuscript explores this phenomenon through computational and experimental studies on a simple, class 3 atropisomeric α-naphthyl-substituted tropone (ΔG^‡ ∼ 32 kcal/mol). Conditions were established for an atropselective Suzuki cross-coupling that enabled its asymmetric synthesis, and the absolute configuration of the compound was determined using vibrational circular dichroism. Based on computational modeling, we found that the α-naphthyl-substituted tropone has a lower rotational energy barrier than the phenol analog, which appears to arise from the puckering ability of the tropone. Despite the lower rotational energy barrier, the α-naphthyl-substituted tropone still displays high configurational stability. Thus, this new atropisomeric scaffold has the potential for incorporation into drug design and should support the development of new classes of ligands and catalysts for use in asymmetric synthesis.

Atropisomerism is a stereochemical phenomenon that results from high configurational stability of chiral axes and is an important structural element in many functional molecules. Thus, understanding how different structural features can influence the stability of chiral axes can be an important consideration for molecular design. Recent studies have demonstrated that certain tropone-based chiral axes are significantly more stable than those of related benzenoids, likely a result of their relatively smaller external bond angles. The following manuscript explores this phenomenon through computational and experimental studies on a simple, class 3 atropisomeric alpha-naphthyl-substituted tropone (G‡ ~ 32 kcal/mol). Conditions were established for an atropselective Suzuki cross-coupling that enabled its asymmetric synthesis, and the absolute configuration of the compound was determined using vibrational circular dichroism. Based on computational modeling, we found that the alpha-naphthyl-substituted tropone has a lower rotational energy barrier than the phenol analog, which appears to arise from the puckering ability of the tropone. Despite the lower rotational energy barrier, the alpha-naphthyl-substituted tropone still displays high configurational stability. Thus, this new atropisomeric scaffold has the potential for incorporation into drug design and should support the development of new classes of ligands and catalysts for use in asymmetric synthesis.

We report an enantiodivergent Pd-catalyzed cross-coupling reaction between unactivated enantioenriched alkylcarbastannatrane nucleophiles and aryl electrophiles in which the stereochemical course of the reaction is dictated by the inclusion or omission of a Cu(I) co-transmetalating agent. Use of a new electron-deficient biarylphosphine ligand (MaPhos) is required to promote the previously unreported stereoinvertive transmetalation pathway for unactivated secondary alkylstannanes. When a Cu(I) salt is included as a co-transmetalating agent, the stereochemical course of the reaction changes from stereoinvertive to stereoretentive. Thus, both enantiomers of the cross-coupling product can be accessed in high enantiopurity using a single achiral ligand. Mechanistic investigations suggest that net-stereoretentive alkyl transfer, in the presence of Cu(I), results from consecutive stereoretentive transmetalations from tin to copper and copper to palladium. In contrast, direct alkyl transmetalation from tin to palladium proceeds primarily via a stereoinvertive pathway that is facilitated by the presence of electron-deficient ligands.

We have developed a general process for the formation of enantioenriched benzylic stereocenters via stereospecific Pd-catalyzed cross-coupling reactions of enantioenriched benzylic tricyclohexyltin nucleophiles. This process proceeds with excellent stereospecificity for a remarkably broad scope of electrophilic coupling partners including aryl and heteroaryl halides and triflates, acid chlorides, thioesters, chloroformates, and carbamoyl chlorides. Thus, enantioenriched 1,1-diarylalkanes as well as formal products of asymmetric enolate arylation are readily accessed using this approach. We additionally provide the first demonstration of a Sn-selective cross-coupling reaction using a vicinal alkylborylstannane nucleophile. In these reactions, the presence of cyclohexyl spectator ligands on tin is essential to ensure selective transfer of the secondary benzylic unit from tin to palladium.

We have developed a general process for the formation of α-arylethers via the Pd-catalyzed arylation of secondary α-alkoxytricyclohexylstannanes. Incorporation of cyclohexyl spectator ligands into the alkylstannane and the use of the electron-deficient ligand JackiePhos (1) are critical for achieving selective alkyl transfer in this process. This system circumvents the need for a coordinating/directing oxygen-protecting group to promote selective alkyl transfer and enables α-tetrahydropyran, α-tetrahydrofuran, and open-chain secondary α-alkoxy groups to be employed efficiently in Pd-catalyzed Stille reactions with a broad range of aryl electrophiles. These findings suggest that selective transmetalation of a single marginally activated secondary alkyl unit from Sn to Pd should be broadly achievable provided that unactivated secondary alkyl ligands comprise the other three groups of the tetraalkylstannane.

Using deuterium-labeled stereochemical probes, we show that primary alkyltrifluoroborate nucleophiles undergo transmetalation to palladium exclusively via a stereoretentive pathway and that the resulting stereospecificity is broadly independent of electronic and steric effects. This stands in stark contrast to the stereochemical course of transmetalation for secondary alkyltrifluoroborates, which varies between net stereoretention and net stereoinversion depending upon the electronic properties of the supporting phosphine ligand, the electronic properties of the aryl electrophile, and the steric properties of the alkylboron nucleophile. In this study, we additionally show that the stereochemical course of transmetalation for secondary alkylboron reagents can be under reagent steric control, while no such steric control exists for analogous primary alkylboron nucleophiles. The combined study reveals fundamental mechanistic differences between transmetalations of primary and secondary alkylboron reagents in Pd-catalyzed Suzuki reactions.

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(sp³)–C(sp²) 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.