A general approach to stereospecific Pd-catalyzed cross-coupling reactions of benzylic stereocenters.

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.

Pd-Catalyzed Arylation of Secondary α-Alkoxytricyclohexylstannanes.

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.

The Stereochemical Course of Pd-Catalyzed Suzuki Reactions Using Primary Alkyltrifluoroborate Nucleophiles.

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.

Conformational Sensing by a Mammalian Olfactory Receptor.

To identify odors, the mammalian nose deploys hundreds of olfactory receptors (ORs) from the rhodopsin-like class of the G protein-coupled receptor superfamily. Odorants having multiple rotatable bonds present a problem for the stereochemical shape-based matching process assumed to govern the sense of smell through OR-odorant recognition. We conformationally restricted the carbon chain of the odorant octanal to ask whether an OR can respond differently to different odorant conformations. By using calcium imaging to monitor signal transduction in sensory neurons expressing the mouse aldehyde OR, Olfr2, we found that the spatial position of the C7 and C8 carbon atoms of octanal, in relation to its -CHO group, determines whether an aliphatic aldehyde functions as an agonist, partial agonist or antagonist. Our experiments provide evidence that an odorant can manipulate an OR through its intrinsic conformational repertoire, in unexpected analogy to the photon-controlled aldehyde manipulation observed in rhodopsin.

A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters.

A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling reactions has been developed as a general solution to the long-standing challenge of conducting stereospecific cross-coupling reactions at nitrogen-containing stereocenters. This method enables direct access to enantioenriched products that are difficult (or impossible) to obtain via alternative preparative methods. Selective and predictable transfer of a single secondary alkyl unit can be achieved under reaction conditions that exploit subtle electronic differences between activated and unactivated alkyl units. Through this approach, enantioenriched α-stannylated nitrogen-containing stereocenters undergo Pd-catalyzed arylation and acylation reactions with exceptionally high stereofidelity in all instances investigated. We demonstrate this process by using α-stannylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic) nucleophiles in stereospecific reactions. This process will facilitate rapid and reliable access to enantioenriched compounds possessing nitrogen-substituted stereocenters, which constitute ubiquitous structural motifs in biologically active compounds emerging from the drug-discovery process.

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

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.

Preparation of Enantioenriched Alkylcarbastannatranes via Nucleophilic Inversion of Alkyl Mesylates for Use in Stereospecific Cross-Coupling Reactions.

We report the preparation of enantioenriched secondary alkylcarbastannatranes via a stereoinvertive SN2 reaction of enantioenriched alkyl mesylates and carbastannatranyl anion equivalents. Using this process, enantioenriched secondary alcohols may be converted into highly enantioenriched alkylcarbastannatranes, which are useful in stereospecific cross-coupling reactions.

Enantiodivergent Pd-catalyzed C-C bond formation enabled through ligand parameterization.

Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Here we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.

Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane Reagents.

We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site-specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions.

Stereospecific Palladium-Catalyzed Acylation of Enantioenriched Alkylcarbastannatranes: A General Alternative to Asymmetric Enolate Reactions.

We report the development of a Pd-catalyzed process for the cross coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles. Reactions involving optically active alkylcarbastannatranes occur with exceptional stereofidelity and with net retention of absolute configuration. Because the stereochemistry of the resulting products is entirely reagent-controlled, this process may be viewed as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies. Additionally, we report a new method for the preparation of optically active alkylcarbastannatranes, which should facilitate their future use in stereospecific reactions.

Configurationally Stable, Enantioenriched Organometallic Nucleophiles in Stereospecific Pd-Catalyzed Cross-Coupling Reactions: An Alternative Approach to Asymmetric Synthesis.

Several research groups have recently developed methods to employ configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions. By establishing the absolute configuration of a chiral alkyltin or alkylboron nucleophile prior to its use in cross-coupling reactions, new stereogenic centers may be rapidly and reliably generated with preservation of the known initial stereochemistry. While this area of research is still in its infancy, such stereospecific cross-coupling reactions may emerge as simple, general methods to access diverse, optically active products from common enantioenriched organometallic building blocks. This minireview highlights recent progress towards the development of general, stereospecific Pd-catalyzed cross-coupling reactions using configurationally stable organometallic nucleophiles.

Stereospecific pd-catalyzed cross-coupling reactions of secondary alkylboron nucleophiles and aryl chlorides.

We report the development of a Pd-catalyzed process for the stereospecific cross-coupling of unactivated secondary alkylboron nucleophiles and aryl chlorides. This process tolerates the use of secondary alkylboronic acids and secondary alkyltrifluoroborates and occurs without significant isomerization of the alkyl nucelophile. Optically active secondary alkyltrifluoroborate reagents undergo cross-coupling reactions with stereospecific inversion of configuration using this method.

Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides.

The development of transition metal-catalysed cross-coupling reactions has greatly influenced the manner in which the synthesis of complex organic molecules is approached. A wide variety of methods are now available for the formation of C(sp(2))-C(sp(2)) bonds, and more recent work has focused on the use of C(sp(3)) electrophiles and nucleophiles. The use of secondary and tertiary alkyl nucleophiles in cross-coupling reactions remains a challenge because of the propensity of these alkyl groups to isomerize under the reaction conditions. Here, we report the development of a general Pd-catalysed process for the stereoretentive cross-coupling of secondary alkyl azastannatrane nucleophiles with aryl chlorides, bromides, iodides and triflates. Coupling partners with a wide range of electronic characteristics are well tolerated. The reaction occurs with minimal isomerization of the secondary alkyltin nucleophile, and with retention of absolute configuration. This process constitutes the first general method to use secondary alkyltin reagents in cross-coupling reactions.

Palladium-catalyzed borylation of primary alkyl bromides.

A mild Pd-catalyzed process for the borylation of alkyl bromides has been developed using bis(pinacolato)diboron as a boron source. This process accommodates the use of a wide range of functional groups on the alkyl bromide substrate. Primary bromides react with complete selectivity in the presence of a secondary bromide. The generality of this approach is demonstrated by its extension to the use of alkyl iodides and alkyl tosylates, as well as borylation reactions employing bis(neopentyl glycolato)diboron as the boron source.

The Use of Tertiary Alkylmagnesium Nucleophiles in Ni-Catalyzed Cross-Coupling Reactions.

Nickel-catalyzed cross-coupling reactions of unactivated tertiary alkyl nucleophiles and aryl bromides have been developed using N-heterocyclic carbene ligands. These processes are reviewed alongside earlier attempts to employ unactivated tertiary alkyl nucleophiles in cross-coupling reactions. Potential mechanisms for the transformations, and future challenges in this field are discussed.

Nickel-catalyzed Kumada cross-coupling reactions of tertiary alkylmagnesium halides and aryl bromides/triflates.

We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.

Nickel-catalyzed Negishi cross-coupling reactions of secondary alkylzinc halides and aryl iodides.

A general Ni-catalyzed process for the cross-coupling of secondary alkylzinc halides and aryl/heteroaryl iodides has been developed. This is the first process to overcome the isomerization and ß-hydride elimination problems that are associated with the use of secondary nucleophiles, and that have limited the analogous Pd-catalyzed systems. The impact of salt additives was also investigated. It was found that the presence of LiBF(4) dramatically improves both isomeric retention and yield for challenging substrates.

Selective monoarylation of acetate esters and aryl methyl ketones using aryl chlorides.

Simple, efficient procedures for the monoarylation of acetate esters and aryl methyl ketones using aryl chlorides are presented. Previously, no general method was available to ensure the highly selective monoarylation of these classes of substrates using aryl chlorides. Using palladium precatalysts recently reported by our group, these reactions are easily accomplished under mild conditions that tolerate a wide array of heterocyclic substrates.

Simple, Efficient Protocols for the Pd-Catalyzed Cross-Coupling Reaction of Aryl Chlorides and Dimethylamine.

Simple and efficient procedures for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine are described. At room temperature with a strong base, t-BuXPhos is employed as the supporting ligand; at 110 °C with a weak base, XPhos is employed as the supporting ligand. In each of these cases, commercially available solutions constitute the source of the dimethylamine, and recently disclosed precatalysts constitute the source of the ligand and Pd. This work further expands the utility of these precatalysts in reactions that benefit from an easily activated source of L(1)Pd(0).

A highly active catalyst for Pd-catalyzed amination reactions: cross-coupling reactions using aryl mesylates and the highly selective monoarylation of primary amines using aryl chlorides.

A catalyst system based on a new biarylmonophosphine ligand (BrettPhos) that shows excellent reactivity for C-N cross-coupling reactions is reported. This catalyst system enables the use of aryl mesylates as a coupling partner in C-N bond-forming reactions. Additionally, the use of BrettPhos permits the highly selective monoarylation of an array of primary aliphatic amines and anilines at low catalyst loadings and with fast reaction times, including the first monoarylation of methylamine. Lastly, oxidative addition complexes of BrettPhos are included, which provide insight into the origin of reactivity for this system.