From an α‐Functionalized Silicon‐Stereogenic N,O‐Silane to a Monomeric and Tetracoordinate tBuLi Adduct with Lithium‐Centered Chirality

Donor‐functionalized silanes with stereogenic silicon centers are extremely rare. A convenient stereocontrolled route to a nitrogen‐oxygen‐functionalized silicon‐chiral compound with an additional aminomethyl function is presented. This silane was directly achieved in stereochemically pure form by a simple nucleophilic substitution reaction. Owing to the unique asymmetry of this silane and the presence of three donor functions, the first monomeric butyllithium compound with lithium‐centered chirality could be isolated; the configuration was assigned by X‐ray crystallography. This [silane? tBuLi] complex undergoes an unexpected deprotonation/stereospecific substitution sequence in toluene, leading to the development of a convenient one‐pot synthesis of a functionalized silicon‐chiral benzylsilane, which proceeds with inversion of configuration and complete preservation of the stereochemical integrity at silicon.     

Asymmetric Synthesis of Silicon‐Stereogenic Vinylhydrosilanes by Cobalt‐Catalyzed Regio‐ and Enantioselective Alkyne Hydrosilylation with Dihydrosilanes

The strategic carbon‐to‐silicon substitution at a stereogenic center can produce chiral silanes with significantly improved properties relative to their carbon congeners. We herein report an unprecedented cobalt‐catalyzed asymmetric hydrosilylation of unsymmetric alkynes with dihydrosilanes that furnishes silicon‐stereogenic vinylhydrosilanes with high regio‐ and enantioselectivity. The absolute configurations of the products were determined by chiroptical methods in combination with DFT calculations. The synthetic versatility of the vinylhydrosilanes as chiral building blocks was further demonstrated by asymmetric Si?H insertion and catalytic hydroboration reactions.     

Illuminating the Mechanism of the Borane‐Catalyzed Hydrosilylation of Imines with Both an Axially Chiral Borane and Silane

The reduction of C?O groups with silanes catalyzed by electron‐deficient boranes follows a counterintuitive mechanism in which the Si? H bond is activated by the boron Lewis acid prior to nucleophilic attack of the carbonyl oxygen atom at the silicon atom. The borohydride thus formed is the actual reductant. These steps were elucidated by using a silicon‐stereogenic silane, but applying the same technique to the related reduction of C?N groups was inconclusive due to racemization of the silicon atom. The present investigation now proves by the deliberate combination of our axially chiral borane catalyst and axially chiral silane reagents (in both enantiomeric forms) that the mechanisms of these hydrosilylations are essentially identical. Unmistakable stereochemical outcomes for the borane/silane pairs show that both participate in the enantioselectivity‐determining hydride‐transfer step. These experiments became possible after the discovery that our axially chiral C₆F₅‐substituted borane induces appreciable levels of enantioinduction in the imine hydrosilylation.     

Preparation of “Si‐Centered” Chiral Silanes by Direct α‐Lithiation of Methylsilanes

The direct α‐lithiation of methyl‐substituted silanes as an efficient method for the preparation and elaboration of Si‐chiral compounds is reported. Deprotonation of chiral oligosilanes occurs selectively and with high yields at the methyl group of the stereogenic silicon center, even in the presence of multiple methylsilyl or methylgermyl substituents. Computational studies have confirmed this preference as a consequence of pre‐coordination of the lithiating agent by the amino side‐arm and repulsion effects in the corresponding transition state. This complexation is also obvious from X‐ray structure analyses of the α‐lithiated silanes, which exhibit intriguing structure formation patterns differing in the type of aggregation and the amount of alkyllithium used. An alternative route to Si‐chiral compounds is also presented, which involves desymmetrization of dimethylsilanes mediated by a chiral side‐arm. Structure analyses and computational studies have shown that the diastereoselectivity of this α‐lithiation is influenced by the selectivity of the formation of the stereogenic nitrogen upon complexation of the alkyllithium.     

Stereoselective Alcohol Silylation by Dehydrogenative Si–O Coupling: Scope,Limitations, and Mechanism of the Cu–H‐Catalyzed Non‐Enzymatic Kinetic Resolution with Silicon‐Stereogenic Silanes

Ligand‐stabilized copper(I)–hydride catalyzes the dehydrogenative Si–O coupling of alcohols and silanes—a process that was found to proceed without racemization at the silicon atom if asymmetrically substituted. The present investigation starts from this pivotal observation since silicon‐stereogenic silanes are thereby suitable for the reagent‐controlled kinetic resolution of racemic alcohols, in which asymmetry at the silicon atom enables discrimination of enantiomeric alcohols. In this full account, we summarize our efforts to systematically examine this unusual strategy of diastereoselective alcohol silylation. Ligand (sufficient reactivity with moderately electron‐rich monophosphines), silane (reasonable diastereocontrol with cyclic silanes having a distinct substitution pattern) as well as substrate identification (chelating donor as a requirement) are introductorily described. With these basic data at hand, the substrate scope was defined employing enantiomerically enriched tert‐butyl‐substituted 1‐silatetraline and highly reactive 1‐silaindane. The synthetic part is complemented by the determination of the stereochemical course at the silicon atom in the Si–O coupling step followed by its quantum‐chemical analysis thus providing a solid mechanistic picture of this remarkable transformation.     

Lewis‐Base‐Mediated Diastereoselective Silylations of Alcohols: Synthesis of Silicon‐Stereogenic Dialkoxysilanes Controlled by Chiral Aryl BINMOLs

In the past years, stereoselective functionalizations of hydroxyl groups of alcohol substrates with chlorosilanes leading to silyl ether formation have evolved from a functional‐group protection to an enantioselective synthetic strategy. This work comprises a controlled desymmetrization of dichlorosilanes by using a family of structurally specific chiral diols, chiral 1,1′‐binaphthalene‐2‐α‐arylmethanol‐2′‐ol (Ar‐BINMOL). This process led to the facile construction of silicon‐stereogenic organosilicon compounds with high yields and good diastereoselectivities. In addition, the diasteroselective silylation of chiral diols might not only be of interest for the development of highly stereoselective nucleophilic silylation, but also shed light on the construction of novel chiral phosphine ligands bearing a silicon‐stereogenic center.     

Chirality Transfer from Silicon to Carbon

The exploitation of the asymmetry at silicon in stereoselective synthesis is an exceptionally challenging task. Initially, silicon‐stereogenic silanes have been utilized to elucidate the stereochemical course of substitution reactions at silicon. Apart from these mechanistic investigations, only a handful of synthetic applications with an asymmetrically substituted silicon as the stereochemical controller have been reported to date. In these transformations the chiral silicon functions as a chiral auxiliary. Conversely, a direct transfer of chirality from silicon to carbon during bond formation and cleavage at silicon has remained open until its recent realization in both inter‐ and intramolecular reactions. In this Concept, the pivotal considerations in relation to the nature of suitable silanes as well as mechanistic prerequisites for an efficient chirality transfer will be discussed.     

Enantioselective Construction of α‐Chiral Silanes by Nickel‐Catalyzed C(sp3)−C(sp3) Cross‐Coupling

An enantioselective C(sp³)?C(sp³) cross‐coupling of racemic α‐silylated alkyl iodides and alkylzinc reagents is reported. The reaction is catalyzed by NiCl₂/(S,S)‐Bn‐Pybox and yields α‐chiral silanes with high enantiocontrol. The catalyst system does not promote the cross‐coupling of the corresponding carbon analogue, corroborating the stabilizing effect of the silyl group on the alkyl radical intermediate (α‐silicon effect). Both coupling partners can be, but do not need to be, functionalized, and hence, even α‐chiral silanes with no functional group in direct proximity of the asymmetrically substituted carbon atom become accessible. This distinguishes the new method from established approaches for the synthesis of α‐chiral silanes.     

Palladium‐Catalyzed Desymmetrization of Silacyclobutanes with Alkynes to Silicon‐Stereogenic Silanes: A Density Functional Theory Study

The palladium‐catalyzed desymmetrization of silacyclobutanes using electron‐deficient alkynes proceeds with high enantioselectivity in the presence of a chiral P ligand; this provides a facile approach for the synthesis of novel silicon‐stereogenic silanes. In this work, we used hybrid density functional theory (DFT) to elucidate the mechanism of the palladium‐catalyzed desymmetrization of silacyclobutanes with dimethyl acetylenedicarboxylate. Full catalytic cycle including two different initiation modes that were proposed to be a possible initial step to the formation of the 1‐pallada‐2‐silacyclopentane/alkyne intermediate—the oxidative addition of the palladium complex to the silacyclobutane Si?C bond (cycle MA) or coordination of the Pd⁰ complex with the alkyne C≡C bond (cycle MB)—have been studied. It was found that the ring‐expansion reaction began with cycle MB is energetically more favorable. The formation of a seven‐membered metallocyclic Pd^II intermediate was found to be the rate‐determining step, whereas the enantioselectivity‐determining step, oxidative addition of silacyclobutane to the three‐membered metallocyclic Pd^II intermediate, was found to be quite sensitive to the steric repulsion between the chiral ligand and silacyclobutane.     

Asymmetric Synthesis of Silicon‐Stereogenic Silanes by Copper‐Catalyzed Desymmetrizing Protoboration of Vinylsilanes

The catalytic asymmetric creation of silanes with silicon stereocenters is a long‐sought but underdeveloped topic, and only a handful of examples have been reported. Moreover, the construction of chiral silanes containing (more than) two stereocenters is a more arduous task and remains unexploited. We herein report an unprecedented copper‐catalyzed desymmetrizing protoboration of divinyl‐substituted silanes with bis(pinacolato)diboron (B₂pin₂). This method enables the facile preparation of an array of enantiomerically enriched boronate‐substituted organosilanes bearing contiguous silicon and carbon stereocenters with exclusive regioselectivity and generally excellent diastereo‐ and enantioselectivity.     

Rhodium‐Catalyzed Asymmetric Synthesis of Silicon‐Stereogenic Dibenzosiloles by Enantioselective [2+2+2] Cycloaddition

A rhodium‐catalyzed asymmetric synthesis of silicon‐stereogenic dibenzosiloles has been developed through a [2+2+2] cycloaddition of silicon‐containing prochiral triynes with internal alkynes. High yields and enantioselectivities have been achieved by employing an axially chiral monophosphine ligand, and the present catalysis is also applicable to the asymmetric synthesis of a germanium‐stereogenic dibenzogermole. Preliminary studies on the optical properties of these compounds are also described.     

Asymmetric Conjugate Addition of Grignard Reagents to 3‐Silyl Unsaturated Esters for the Facile Preparation of Enantioenriched β‐Silylcarbonyl Compounds and Allylic Silanes

A highly enantioselective conjugate addition of Grignard reagents to 3‐silyl unsaturated esters to deliver synthetically useful chiral β‐silylcarbonyl compounds was developed. The synthetic value of this methodology was further illustrated by the synthesis of enantioenriched β‐hydroxyl esters and the facile access granted to various α‐chiral allylic silanes. A plethora of diastereoselective transformations of β‐silylenolates were also investigated and afforded manifold organosilanes that contained contiguous stereogenic centers with excellent enantioselectivity.     

Stereocontrolled synthesis of tertiary silanes via optically pure 1,3,2-oxazasilolidine derivatives

Optically pure 1,3,2-oxazasilolidine derivatives were synthesized from a chiral 1,2-amino alcohol. These heterocyclic compounds containing a stereogenic silicon atom produced tertiary silanes with excellent optical purity through successive reactions with Grignard reagents and diisobutylaluminum hydride. Stereochemical course of the reactions of the oxazasilolidine at the chiral silicon atom was elucidated based on the absolute configurations of the products and the substrate which were determined by chiral HPLC and X-ray crystallographic analyses.     

Rhodium‐Catalyzed Reaction of Silacyclobutanes with Unactivated Alkynes to Afford Silacyclohexenes

A Rh‐catalyzed reaction of silacyclobutanes (SCBs) with unactivated alkynes has been developed to form silacyclohexenes with high chemoselectivity. Good enantioselectivity at the stereogenic silicon center was achieved using a chiral phosphoramidite ligand. The resulting silacyclohexenes are useful scaffolds for synthesizing structurally attractive silacyclic compounds.     

Palladium‐Catalyzed Asymmetric Synthesis of Silicon‐Stereogenic 5,10‐Dihydrophenazasilines via Enantioselective 1,5‐Palladium Migration

A palladium‐catalyzed asymmetric synthesis of silicon‐stereogenic 5,10‐dihydrophenazasilines was developed that proceeds via an unprecedented enantioselective 1,5‐palladium migration. High enantioselectivity was achieved by employing 4,4′‐bis(trimethylsilyl) (R )‐Binap as the chiral ligand, and a series of mechanistic investigations were carried out to probe the catalytic cycle of this process.     

Desymmetrization‐Oriented Enantioselective Synthesis of Silicon‐Stereogenic Silanes by Palladium‐Catalyzed C−H Olefinations

A palladium‐catalyzed chelation‐assisted enantioselective C?H olefination of symmetrically diaryl‐substituted tetraorganosilicon derivatives was developed, enabling the generation of nitrogen‐containing silicon‐stereogenic tetraorganosilicon compounds with modest to good yields and good to excellent enantioselectivities (up to 95.5:4.5 e.r.). The Thorpe–Ingold effect exerted by the substituents on silicon was observed to have a profound influence on formation of olefinated products which were further converted into other relevant chiral organosilanes without the loss of enantiomeric purity, thus demonstrating the synthetic utility of the developed enantioselective olefination.     

Construction of a Chiral Silicon Center by Rhodium‐Catalyzed Enantioselective Intramolecular Hydrosilylation

Rhodium‐catalyzed enantioselective desymmetrizing intramolecular hydrosilylation of symmetrically disubstituted hydrosilanes is described. The original axially chiral phenanthroline ligand (S)‐BinThro (Binol‐derived phenanthroline) was found to work as an effective chiral catalyst for this transformation. A chiral silicon stereogenic center is one of the chiral motifs gaining much attention in asymmetric syntheses and the present protocol provides cyclic five‐membered organosilanes incorporating chiral silicon centers with high enantioselectivities (up to 91 % ee). The putative active Rh^I catalyst takes the form of an N,N,O‐tridentate coordination complex, as determined by several complementary experiments.     

Regio‐ and Enantioselective Cobalt‐Catalyzed Sequential Hydrosilylation/Hydrogenation of Terminal Alkynes

A highly regio‐ and enantioselective cobalt‐catalyzed sequential hydrosilylation/hydrogenation of alkynes was developed to afford chiral silanes. This one‐pot method is operationally simple and atom economic. It makes use of relatively simple and readily available starting materials, namely alkynes, silanes, and hydrogen gas, to construct more valuable chiral silanes. Primary mechanistic studies demonstrated that highly regioselective hydrosilylation of alkynes with silanes occurred as a first step, and the subsequent cobalt‐catalyzed asymmetric hydrogenation of the resulting vinylsilanes showed good enantioselectivity.     

Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond‐Forming Cross‐Coupling and Catalyst‐Controlled Atroposelective Cyclodehydration

Catalyst control over reactions that produce multiple stereoisomers is a challenge in synthesis. Control over reactions that involve stereogenic elements remote from one another is particularly uncommon. Additionally, catalytic reactions that address both stereogenic carbon centers and an element of axial chirality are also rare. Reported herein is a catalytic approach to each stereoisomer of a scaffold containing a stereogenic center remote from an axis of chirality. Newly developed peptidyl copper complexes catalyze an unprecedented remote desymmetrization involving enantioselective C?N bond‐forming cross‐coupling. Then, chiral phosphoric acid catalysts set an axis of chirality through an unprecedented atroposelective cyclodehydration to form a heterocycle with high diastereoselectivity. The application of chiral copper complexes and phosphoric acids provides access to each stereoisomer of a framework with two different elements of stereogenicity.     

Stereogenic‐Only‐at‐Metal Asymmetric Catalysts

Chirality is an essential feature of asymmetric catalysts. This review summarizes asymmetric catalysts that derive their chirality exclusively from stereogenic metal centers. Reported chiral‐at‐metal catalysts can be divided into two classes, namely, inert metal complexes, in which the metal fulfills a purely structural role, so catalysis is mediated entirely through the ligand sphere, and reactive metal complexes. The latter are particularly appealing because structural simplicity (only achiral ligands) is combined with the prospect of particularly effective asymmetric induction (direct contact of the substrate with the chiral metal center). Challenges and solutions for the design of such reactive stereogenic‐only‐at‐metal asymmetric catalysts are discussed.