α-Boryl Organometallic Reagents in Catalytic Asymmetric Synthesis

Abstract

Recent years have witnessed an increase in the popularity of α-boryl organometallic reagents as versatile nucleophiles in asymmetric synthesis. These compounds have been adopted in chemo- and stereoselective coupling reactions with a number of different electrophiles. The resulting enantioenriched boronic esters can be applied in stereospecific carbon-carbon or carbon-heteroatom bond construction reactions, enabling a two-step strategy for the construction of complex structures with high efficiency and functional group compatibility. Due to these reasons, tremendous effort has been devoted to the preparation of enantiomerically enriched α-boryl organometallic reagents and to the development of stereoselective reactions of related racemic or prochiral materials. In this review, we describe the enantio- or diastereoselective reactions that involve α-boryl organometallic reagents as starting materials or products and we showcase their synthetic utility.

Graphical Abstract

1. Introduction

α-Boryl organometallic reagents are potent and distinctive building blocks in asymmetric synthesis. Because the valance-deficient feature of tri-coordinated boron can stabilize the negative charge at an adjacent carbon atom,¹ α-boryl organometallic reagents often exhibit unusual reactivity compared to non-stabilized organometallic reagents. For example, geminal bis(boronates) are known to undergo deborylative alkylation of electrophiles in the absence of transition metal catalysts.² Of similar significance, the reaction products that arise from reaction of the geminal bimetallic moiety often possess considerable synthetic utility. For example, after reaction of the boron group, the silyl moiety of α-boryl silanes can serve as a masked hydroxy group. Alternatively, organoboronic esters are the products that arise from the reaction of many geminal α-boryl metallic reagents. For example, α-boryl zincs³ and zirconocenes⁴ can participate in coupling reactions with many electrophiles delivering chiral organoboron compounds as the product. Importantly, the resulting alkyl boronic esters are chemically stable, configurationally stable synthetic building blocks that can be used in many stereospecific reactions.

Even though α-metallated organoboronates have shown their importance in the synthesis of complex molecules since the 1990s,⁵ not until the last decade has substantial progress been made in the area related to asymmetric synthesis. Recent developments in asymmetric transition metal catalysis have driven the discovery of new routes for the synthesis of enantiomerically-enriched non-symmetric α-boryl and α-silyl organometallic reagents and in the enantio- and diastereoselective reactions of prochiral geminal bis(boronates). In this overview, we present advances in the use of α-boryl organometallic reagents in asymmetric synthesis, including the preparation and application of chiral metallated organoboronates based on B, Si, Zn, Zr and the enantioselective reactions involving achiral metallated organoboryl species.

2. Geminal bis(boronates)

Geminal bis(boronates) have attracted wide attention due to several unique features.⁶ First, the stability of these reagents in the presence of both air and moisture allows for simple dry-box free operation. Second, prochiral geminal bisboryl species can be readily prepared from commercially available precursors including methylene bis(boronates), geminal dibromides, alkynes,⁷ alkenes,⁸ ketones,⁹ diazo compounds,¹⁰ esters,¹¹ alkyl halides,¹², and allylic ethers.¹³ Although only a few synthetic methods have been described to provide enantioenriched gem-diboryl compounds, stereoselective reactions of prochiral geminal bis(boronates) have grown steadily in the past decade, which greatly broadens the synthetic applications of this type of reagent.

2.1. Synthesis of chiral geminal bis(boronates)

The first synthesis of enantiomerically enriched geminal bis(boronates) was reported by Hall and co-workers in 2011 (Scheme 1).¹⁴ With the combination of B₂(pin)₂ and a chiral copper catalyst, they accomplished an enantioselective boron conjugate addition to 3-boryl acrylate derivative 1, affording geminal diboryl carboxyl ester 2 in 99% enantiomeric excess. The subsequent chemo- and stereoselective Suzuki–Miyaura cross-coupling with sp² carbon electrophiles gave access to secondary boronates 3 with excellent levels of enantiomeric purity. X-ray analysis of the product 2 suggested possible coordination between the carbonyl oxygen and the boron on the pinacolato unit. During the cross-coupling, this interaction is expected to be stronger with trifluoroborate substrates due to the formation of the derived boronic acid intermediate in situ; such coordination facilitates the challenging transmetallation between palladium and alkyl boronates that occurs in the Suzuki–Miyaura reaction. Of note, the B(dan) (dan = 1,8-diaminonaphthalene) unit was proposed to stabilize the α-boryl Pd(II) intermediate, which suppresses potential unproductive β-hydride elimination pathway.

Scheme 1.

Copper Catalyzed Enantioselective Conjugate Borylation to Alkenyl Boronic Esters

Asymmetric hydroboration of alkenes is also a well-established method for the synthesis of chiral alkylboronates. Taking advantage of this approach, the Yun Group developed the copper catalyzed hydroboration of alkenyl B(dan) 4 resulting in 1,1-diboryl species 5 with excellent regio- and enantioselectivity (Scheme 2).¹⁵ The reaction was shown to proceed through Cu–H addition to the C–C double bond, with the resulting chiral α-boryl copper intermediate then undergoing σ-bond metathesis with pinacolborane to provide the gem-diboryl product 5. The regioselectivity of the Cu–H addition step was proposed to be controlled by the electron-deficient nature of the boron group. In spite of its decreased Lewis acidity, the B(dan) group reacted with improved regioselectivity relative to B(pin). This outcome is proposed to occur because the planarity of the B(dan) group allows it to more easily accommodate an adjacent bulky Cu–L moiety. In addition to reporting the catalytic reaction, the Yun Group also described a chemoselective homologation of the chiral bis(boronates) wherein the B(pin) unit was selectively converted with the retention of enantiomeric purity.

Scheme 2.

Copper Catalyzed Enantioselective Hydroboration to Alkenyl Boronic Esters to Synthesize Alkyl Bis(boronates)

As an alternative to the Yun hydroboration, Chirik and co-workers reported the asymmetric hydrogenation of 1,1-diboryl alkenes 6 to produce enantioenriched geminal diboryl compounds such as 7 (Scheme 3).¹⁶ This team identified the C₁-symmetric pyridine(diimine) (PDI) ligand on cobalt as an efficient and stereoselective catalyst for this transformation. Mechanistic studies revealed that sterically unencumbered boronate groups, such as B(dan) or B(cat), are essential to obtain the observed reactivity and enantioselectivity. Similar to Yun’s observation, deuterium-labeling experiments suggested that less encumbered boron ligands allow for higher α-selectivity during the migratory insertion step to form a boron-stabilized alkylcobalt intermediate. The chiral gem-bis(boronates) were converted to trifluoroborate salts 8, which were further applied in a stereoinvertive Suzuki–Miyaura cross-coupling reaction.

Scheme 3.

Enantioselective Hydrogenation to Alkenyl gem-Diboronates

More recently, the Masarwa Group established a diastereoselective desymmetrization strategy for the production of chiral geminal bis(boronates) 9.¹⁷ In this strategy, diastereotopic B(pin) groups were differentiated during a “trifluorination” process (Scheme 4). However, high diastereoselectivity was only achieved with cyclopropane derivatives (i.e. 10). The resulting gem-diboron salts 11 can be readily converted to different unsymmetrical gem-bis(boronates) 12 stereospecifically.

Scheme 4.

Desymmetrization of Alkyl gem-Diboronates through “Trifluorination” Process

Instead of generating chirality by using nonidentical boryl groups, another approach towards chiral gem-bis(boronates) is to construct a stereogenic center close to the prochiral gem-diboryl motif. Taking advantage of this neighboring stereogenic center, diastereoselective functionalization of one of the boryl groups can be realized. Following this strategy, in 2014, platinum-catalyzed enantioselective diboration of alkenyl boronic esters 13 (Scheme 5) was developed by the Morken Group for the preparation of enantioenriched 1,1,2-tris(boronates) 14.¹⁸ The tris(boronate) can be employed in subsequent substrate-controlled diastereoselective deborylative alkylation reactions, which afforded syn-diols 16 upon oxidation. In the deborylative alkylation step, hyperconjugation between the non-reacting carbon–boron σ-bond and an adjacent carbon–boron π bond was proposed to increase the nucleophilicity of the reactive intermediate and influence the stereochemical outcome of the reaction (Int-1). This reaction was applied as a key step in the stereoselective formal synthesis of exo-brevicomin.

Scheme 5.

Platinum Catalyzed Diboration of Alkenyl Boronic Esters to Access Non-racemic 1,1,2-Tris(boronates)

Enantioenriched boronic esters 18 were synthesized by Meek and co-workers in a one-pot three-component coupling reaction between lithiated methylenebis(Bpin), chiral epoxides 17, and allyl electrophiles (Scheme 6a).¹⁹ The chiral gem-diboronic esters Int-2 generated by the ring opening of epoxides, were not isolated but coupled with allyl electrophiles in situ in the presence of a copper catalyst. Different substitution patterns in the epoxide were well tolerated though trans-epoxides gave low conversion and selectivity. In order to reveal the source of high diastereoselectivity, mechanistic studies were conducted. Monitoring the reaction by ¹H NMR showed non-selective reaction to form both diastereomers of cyclic boron “ate” intermediate Int-3, which were then consumed at a similar rate by Cu-catalyzed reaction with the electrophile. This observation suggests that high diastereoselectivity obtained from the reaction arises either from diastereoconvergent transmetallation of the cyclic intermediates to the copper catalyst, or a dynamic kinetic resolution of the α-boryl copper intermediate. Various applications of products were shown including amination of the boronic ester for the formal synthesis of (+)-allo-sedamine, and alkene isomerization/allylboration to furnish compound 19 (Scheme 6b). The synthesis of 1,3-polyol motif 20 was accomplished by two consecutive sequences of epoxide opening/allylation (Scheme 6c).

Scheme 6.

Diastereoselective One-Pot Three-component Coupling of Lithiated Methylene BisB(pin), Epoxide and Allyl Bromide

By applying the same epoxide opening/transmetallation strategy to palladium catalysis, the reactivity was altered such that a dehydroboration reaction occurred and furnished alkenyl boronic esters 21 with high E-selectivity (Scheme 7).²⁰ A Pd-catalyzed β-hydride elimination was proposed to account for the formation of the double bond. To demonstrate the synthetic utility of products, a hydroxyl-directed Simmons-Smith reaction was employed to prepare cyclopropane 22 with high diastereoselectivity.

Scheme 7.

Diastereoselective Synthesis of Alkenyl Boronic Esters through Palladium Catalyzed Dehydroboration

In 2018, an Ir-catalyzed asymmetric allylic substitution reaction of metallated methylenebis(boronates) 24 (Scheme 8) was developed by the Cho Group. This process provides enantioenriched gem-diborylalkanes 25 with good yields and excellent enantioselectivity.²¹ The lithiated (diborylmethyl)lithium reagent 24 was prepared and isolated on an 8-gram scale, and a series of transformations of the product were executed including functionalizations of the alkene and the gem-diboron motif.

Scheme 8.

Iridium Catalyzed Asymmetric Allylic Substitution with Lithiated Methylene BisB(pin) to Access gem-Diboronates

Subsequent to Cho’s report, Ge and co-workers reported a chiral cobalt complex-catalyzed enantioselective diborylation of 1,1-disubstituted alkenes 26 to construct gem-bis(boronates) bearing a β-stereogenic center (Scheme 9).²² By using cyclooctene as a hydrogen acceptor, alkenes with a wide range of functional groups were successfully transformed into diboryl species 27. However, monoborylated alkanes were observed as a major byproduct in some cases. Of note, the reaction can be carried out on gram-scale while still occurring in good yield and selectivity. The synthetic utility of the diborylation was further demonstrated by the synthesis of (+)-ar-turmerone, which is a key intermediate towards the total synthesis of (+)-ar-himachalene²³ and (+)-bisacumol.²⁴

Scheme 9.

Cobalt Catalyzed Enantioselective Diborylation of 1,1-Disubstituted Alkenes

2.2. Achiral Geminal Bis(boronates) in Catalytic Asymmetric Synthesis.

The above-mentioned reactions enable the direct synthesis and applications of chiral nonracemic bis(boronates) for the construction of new stereogenic centers. However, in some cases tedious preparation of the starting material was necessary. Another option is to utilize easily accessible prochiral gem-diboryl alkanes in enantioselective transformations. The Morken Group²⁵ (Scheme 10a) and the Hall Group²⁶ (Scheme 10b) independently described the Suzuki-Miyaura reaction between achiral geminal bis(boronates) 28 with aryl halides in the presence of a palladium catalyst and TADDOL-derived phosphoramidite L4/L. This reaction furnishes optically enriched secondary benzylic boronic esters 29/30 with good levels of enantiomeric purity. Mechanistic studies suggest the transmetallation is the stereochemistry-determining step of the cross-coupling, and this step in the catalytic cycle occurs with inversion of the carbon center.

Scheme 10.

Pd-Catalyzed Enantioselective Suzuki Reaction with gem-Diboronates

Later, with a pre-complexed PdCl₂ and JosiPhos-derived chiral bidentate phosphine ligand, the Morken Group expanded the electrophile scope to alkenyl bromides (Scheme 11).²⁷ The resulting nonracemic disubstituted allylic boronates 31 can then be easily converted to enantioenriched secondary and tertiary alcohols, and can also be employed in stereospecific carbonyl allylations to construct stereogenic quaternary carbon centers.

Scheme 11.

Pd-Catalyzed Enantioselective Suzuki Reaction between geminal Bis(boronates) and Alkenyl Bromides

The success in asymmetric palladium catalysis inspired further exploration of the reactivity of 1,1-diboronates with other transition metals. For instance, activation of geminal bis(boronates) with copper catalysts can afford versatile chiral α-borylcopper intermediates which have been demonstrated to possess sufficient nucleophilicity to react with a broad range of electrophiles. Meek and co-workers took advantage of this strategy and developed a chiral copper complex catalyzed syn-selective 1,2-addition of 1,1-bisboryl ethane 32 to aryl or alkenyl aldehydes with good yield and selectivity.²⁸ However, low diastereoselectivity was observed for sterically unhindered cinnamaldehydes, which slightly favored the anti-product 34 (Scheme 12).

Scheme 12.

Copper Catalyzed Stereoselective 1,2-Addition of Alkyl Boronates to Aldehydes

Later in 2016, the Meek Group showed that the electrophile scope could include α-ketoesters 35 while retaining the same level of yield and selectivity (Scheme 13).²⁹ This reaction can tolerate a broader nucleophile scope and can be conducted on a gram scale. Synthetic utility was further demonstrated by a diastereoselective synthesis of highly substituted tetrahydropyran derivative 37. By adopting AgOAc as the catalyst, the Meek Group further broadened the synthetic utility of this approach to alternatively afford anti-β-hydroxyl boronates 38 – compounds that would otherwise be challenging to synthesize – with excellent diastereoselectivity (Scheme 14).³⁰ NMR experiments, as well as the observation of a homocoupling byproduct, suggested that α-boryl silver species Int-4 are reactive intermediates. To probe the synthetic utility, the 1,2-hydroxyboronate product was subjected to a stereospecific Aggarwal heteroarylation reaction furnishing the coupling product in good yield and selectivity.

Scheme 13.

Copper Catalyzed Stereoselective 1,2-Addition of Alkyl Boronates to Ketones

Scheme 14.

Preparation of trans-1,2-Hydroxyl Boronates by Silver Catalyzed Diastereoselective 1,2-Addition of Alkyl Boronates to Aldehydes

In addition to the 1,2-addition to carbonyls, coupling with aldimines and ketimines is another important reaction category enabled by copper catalysts. In 2016, the Cho Group reported the diastereoselective 1,2-addition of methylenebisB(pin) 23 to N-tert-butanesulfinyl aldimines 39.³¹ The resulting β-amino boronates can be converted in situ to chiral β-amino alcohols 40 (Scheme 15). Low diastereoselectivity was observed in the absence of the copper catalyst. Coordination of the sulfinyl oxygen atom with boron’s empty p-orbital was proposed to form a chair-like transition state, which accounts for the obtained diastereoselectivity. The same group also developed the copper-catalyzed enantioselective 1,2-addition to cyclic aldimines 41,³² which allows construction of products with adjacent stereogenic centers for a broad range of functionalized substrates (Scheme 16). The synthetic utility of this process was evaluated with the synthesis of chiral benzofuran derivative 43. While diastereoselectivity with acyclic aldimines was low, in 2019, the Cho Group found that by utilizing a N,N-dimethyl sulfamoyl protecting group, both reactivity and selectivity were improved.³³ A preparative scale experiment was also successfully conducted.

Scheme 15.

Copper Catalyzed Diastereoselective 1,2-Addition of CH₂[B(pin)]₂ to N-tert-Butanesulfinyl Aldimines to Access β-Amino Boronates

Scheme 16.

Copper Catalyzed Enantioselective 1,2-Addition of Alkyl gem-Diboronates to Cyclic Aldimines

Cho and co-workers also expanded the reactivity of imine additions to include more sterically hindered ketimines 44 (Scheme 17a) and α-iminoesters 46 (Scheme 17b).³⁴ The reaction of these substrates occurred with excellent yield and selectivity, and the presence of the attached ester group enabled transformation of the product into various heterocycles such as oxazolidinones and aziridines as depicted in Scheme 17.

Scheme 17.

Copper Catalyzed Enantioselective 1,2-Addition of Alkyl gem-Diboronates to Ketimines and α-Iminoesters

Another strategy for the synthesis of β-aminoalkylboronic esters was introduced by Hall and co-workers.³⁵ The stereospecific protodeborylation of β-sulfinimido gem-bis(boronates) 48. With the Ellman auxiliary present, the protodeborylation was was to provide syn-aminoalkylboronic esters 49 with excellent diastereoselectivity (Scheme 18). Both aryl and aliphatic imines generated from the corresponding aldehydes were well tolerated in this reaction. Mechanistic studies disclosed the important role that the sulfinyl N–H bond plays in obtaining high diastereoselectivity. The product of this intriguing process was applied to the formal synthesis of antitubercular agent 50.³⁶

Scheme 18.

Synthesis of β-Amino Boronates through Diastereoselective Protodeborylation of β-Sulfinimido gem-Bis(boronates)

In 2016, Hoveyda and co-workers described Cu-NHC catalyzed enantioselective allylic substitution (EAS) of methylenebisB(pin) 23 to allylic phosphates 51 (Scheme 19a).^37a The EAS reaction exhibited high S_N2’ selectivity to afford branched homoallylic boronates, which were converted enantiomerically enriched alcohols such as 52. The sulfonate motif installed on the ligand scaffold was crucial for obtaining the observed regioselectivity. It was proposed that the sulfonate participates in an alkali metal bridge (Int-5) with the Lewis basic phosphate unit, which results in a well-defined transition structure. A wide range of aryl and alkyl substituents can be tolerated and the application of this reaction was examined through the synthesis of natural product rhopaloic acid A (Scheme 19b).³⁸ The synthesis benefited from the formation of intermediate 53 containing both a boronic ester and a borane moiety, which allows for divergent functionalization with high efficiency.

Scheme 19.

Copper Catalyzed Enantioselective Allylic Substitution of Methylene Bis(boronates) to Allylic Phosphates

During the same year, Niu and co-workers provided an alternative method for allylation by employing well-established iridium-catalyzed asymmetric allylic substitution reaction. In this instance, reaction between methylenebisB(pin) 23 and allyl carbonates 54 (Scheme 20) was examined.³⁹ The addition of a silver salt is essential for the desired reactivity and selectivity. Although detailed mechanisms for the enhancement effect caused by silver salts remain unclear, control experiments showed that the Ag ion has a bigger contribution to the reaction efficiency and selectivity compared with the other counterions. A synthetic application was demonstrated by the synthesis of useful organic molecules such as bicyclic piperidines 56⁴⁰ and pyrrolidines 57.⁴¹

Scheme 20.

Iridium Catalyzed Asymmetric Allylic Substitution Reaction between Methylene Diboronates and Allyl Carbonates

Very recently, the Cho Group developed a copper-catalyzed enantiotopic-group-selective allylation reaction of gem-diborylalkanes 32.^37b This method afforded functionalized homoallylic boronates 58 in good yield and high stereoselectivity (Scheme 21). Density functional theory (DFT) based calculations suggested that a cyclic Lewis acid-base pair intermediate Int-5 was first formed between LiOtBu and tBuO–Cu, which served as a bridge during the process of C–B bond cleavage and Cu–B bond formation. Distortion-interaction analysis of the two transition states suggested that shorter distance between substrate and copper in the S-TS-1 over R-TS-1 is the key factor for the observed enantioselectivity. A stereoinvertive transmetalation between gem-diborylalkanes and copper catalysis was proposed based on the outcome of reactions with isotopically-chiral boronate substrates. Deuterium-labelling experiment utilizing a ²H-labeled allyl electrophile revealed that S_N2 and S_N2’ processes were both operative during the formation of 61.

Scheme 21.

Copper-Catalyzed Enantioselective Allylation of gem-Bis(boronates)

The deborylative conjugate addition of diboryl methane species was also reported. Yun and co-workers utilized a chiral Cu-NHC complex as the catalyst to accomplish high selective and efficient conjugate addition reaction with α, β-unsaturated diesters 62 (Scheme 22a).⁴² During this process, an alkyl copper intermediate can selectively add to the Re-face of the alkene. In the presence of an adjacent stereogenic center, matched and mismatched cases were observed. The synthetic utility was shown by stereospecific transformations of the product, including the synthesis of γ-lactones 64 and a formal synthesis of (S)-phenibut.⁴³ The Lee Group in 2021 demonstrated the reactivity with enone electrophiles 65 (Scheme 22b).⁴⁴ Li(acac) as an additive was found to prevent the ligand from degradation.

Scheme 22.

Copper Catalyzed Enantioselective Deborylative Conjugate Addition of Methylene Bis(boronates) to Alkenyl Malonates

Allylic gem-bis(boronates) show different reactivity compared with aliphatic analogues in that they can couple with aldehydes and imines without the activation by base. This unique feature originates from the ability of boron’s empty p-orbital to serve as a Lewis acid to activate the carbonyl or imino group and form a six-membered cyclic transition state. Stereoselective allylboration of aldehydes 68 and imines 70 by allylic gem-bis(boronates) 67 was reported by the Cho Group in 2017.⁴⁵ The reactions exhibit exclusive anti-selectivity and do not require any catalysts (Scheme 23). The authors proposed that reactions with aldehydes proceed through a chair-like transition state TS-2 and a half-chair like transition state TS-3 applies for reactions of imines, both of which account for the high observed diastereoselectivity, although we note that TS-3’ would also account for the outcome with imine substrates. The resulting alkenyl boronic esters can be engaged in cross-coupling or chlorination reactions. Moreover, γ-lactone 72 was synthesized by sequential oxidation reactions and a preliminary experiment showed that catalytic amounts of chiral phosphoric acid can induce enantioselectivity of this reaction. The crotylboration of Z-gem-bis(boronates) 73 to aldehydes was developed by the Chen Group wherein cis-product 74 was obtained with good yield and excellent diastereoselectivity (Scheme 24).⁴⁶ This reaction appears to proceed by six-membered ring transition state TS-4, which accounts for the diastereoselectivity. Of note, the Chen Group also developed a synthesis reagent 73 by a nickel catalyzed Z-selective alkene isomerization. Similar strategy has also been applied to the synthesis of E-γ’,δ-bis(boryl)-substituted syn-homoallylic alcohols.⁴⁷ In 2020, the Meek Group developed a copper-catalyzed allylboration of γ,γ-disubstituted allylbis(boronates) 75 to PMB-protected imines 76, which furnished enantiomerically enriched homoallylic amines bearing quaternary carbon centers with excellent yield and enantioenrichment (Scheme 25).⁴⁸ Of note, E- and Z-isomers of allylbisboryl nucleophiles 77 underwent stereospecific nucleophilic addition to afford diastereomeric products with high levels of selectivity, which enabled the formation of all four diastereoisomers of the product by altering the chirality of the ligand and the alkene configuration of the substrate. These results also suggested the existence of chiral allyl–copper intermediate Int-6 that was formed by enantioselective transmetallation. The synthetic utility of this process was highlighted by the synthesis of pyrrolidine derivatives 79.

Scheme 23.

Diastereoselective Allylboration of Allylic E-gem-Diboronates to Imines and Aldehydes

Scheme 24.

Diastereoselective Allylboration of Allylic Z-gem-Diboronates to Imines and Aldehydes

Scheme 25.

Copper Catalyzed Enantio- and Diastereoselective Allylboration of Allylic gem-Diboronates to PMB-protected Imines

More recently, Meek and co-workers further expanded the scope of the allylboration reaction to include carbonyl electrophiles (Scheme 26a).⁴⁹ Highly efficient, enantio- and diastereoselective allyl addition of γ,γ-disubstituted allyldiboron species 81 to sterically congested ketones 80 was catalyzed by chiral copper catalyst Cu-L11 to furnish tertiary alcohols 82 bearing a vicinal quaternary carbon center. Six-membered transition-state TS-5 is proposed to account for the high diastereoselectivity, which has previously been shown as challenging to obtain with ketone substrates.⁵⁰ In this model, in order to minimize the steric interaction between the bulky ligand and the ketone, the larger substituent on the ketone, R_L, is placed in the pseudo-equatorial position. This reaction exhibits broad substrate scope and the product can be further converted to highly substituted tetrahydrofuran 83 and γ-lactone 84. The authors also demonstrated that α, β-unsaturated ketones 85 are competent electrophiles for allylic gem-bis(boronates) (Scheme 26b) and these compounds engage in conjugate allyl addition reactions.⁵¹ In the presence of substoichiometric amount of CsF as an activator, a boron-stabilized allyl anion is formed and engages in the diastereoselective conjugate addition to enones 85 in high yield, regio- and diastereoselectivity. The reaction tolerates a broad range of ring sizes and functional groups on enone and allyl diboron. Acyclic enones are only active when less sterically congested mono-γ-substituted nucleophiles are employed. The stabilization of the second boryl group was demonstrated to be crucial for reactivity since the simple allylboron reagent 87 was not reactive under standard conditions. The synthetic utility is displayed by converting the 1,6-ketoalkenylboronate into carbocyclic scaffolds 88 and 89 through oxidation/cyclization sequences. The allyl addition of 81 to aldehydes was also achieved by the Meek Group with copper catalysis (Scheme 26c).⁵² Alkyl, alkenyl, and alkynyl aldehydes were all well tolerated and could be converted to the homoallylic alcohol products 91 in excellent yield, high enantioselectivity, and moderate diastereoselectivity. A high level of enantiomeric excess was retained after oxidation of the alcohol product to the corresponding ketone 92, which suggests the quaternary stereogenic center was constructed with high enantioselectivity during a stereoselective transmetallation step to form an α-boryl copper intermediate. These results suggest that the diastereoselectivity originated from the facial selectivity of the aldehyde addition reaction.

Scheme 26.

Allylboration of Ketones, Enones, and Aldehydes with Allylic gem-Diboronates

In the allylboration reactions discussed above, premade allylic gem-diboronates are utilized as the substrates. Murakami and co-workers provided a different approach by constructing an allylic diboryl species in situ through an alkene transposition reaction of 1,1-di(boryl)alk-3-enes 93⁵³ or 1,1-di(boryl)alk-1-enes 94⁵⁴ catalyzed by [{Pd(μ-Br)(PtBu₃)}₂] (Scheme 27). Importantly, the chiral phosphoric acid (R)-TRIP can catalyze the enantioselective allylboration reaction between allylboronates 96 and aldehydes to furnish δ-boryl-substituted anti homoallylic alcohols 97 containing Z-alkenes. In the Murakami process, the palladium catalyst works to not only isomerize substrates 93 or 94 to 96, but also to isomerization the geometry of the alkene in 97. As a result, only one stereoisomer of the homoallylic alcohol product 95 is delivered with high yield and selectivity. Later in 2017, the same group further expanded the usefulness of this strategy by synthesizing the product with Z-geometry.⁵⁵ A cationic ruthenium complex was found to be specifically effective for this process without alkene isomerization. After workup and purification, the boryl-substituted six-membered ring product 99 was obtained in excellent yield, enantioselectivity, and diastereoselectivity. Multiple times of transposition of the double bond could be achieved under standard reaction conditions as shown in Scheme 28) Suzuki-Miyaura cross coupling, bromination, and Chan-Lam coupling of the boryl substituted compounds were illustrated, which all afforded the desired products with good yield and retention of the Z/E geometry. Propionate-derived trisubstituted alkenes could be also synthesized with this strategy based on a recent report.⁵⁶

Scheme 27.

Palladium and Chiral Phosphoric Acid Relay-catalyzed Enantioselective Alkene Transposition/Allylboration/Alkene Isomerization Reaction

Scheme 28.

Ruthenium(II) and Chiral Phosphoric Acid Catalyzed Alkene Transportation/Allylboration of 1,1-Di(boryl)alk-3-enens

In 2020, the Chen Group synthesized α,α-disubstituted crotylboronates 100 and developed various stereoselective crotylboration reactions with these reagents.⁵⁷ The E-crotylboronate was synthesized by a ruthenium catalyzed alkene transposition (Scheme 29a) and the Z-crotylboronate was obtained through a methylation of the corresponding monosubstituted crotylboronate. In one direction, they found that crotylboration of E-100 using a chiral phosphoric acid catalyst, produces 101 in excellent yield, enantioselectivity and diastereoselectivity (Scheme 29b). Density functional theory (DFT) calculations suggested a longer distance H-bond and catalyst distortion that destabilizes the disfavored transition state, resulting in high enantioselectivity and E/Z selectivity. Moreover, a Z-selective crotylboration was developed with E-100 by using BF₃•Et₂O as the catalyst. They proposed that a more severe 1,3-syn-pentane interaction between Lewis acid catalyst and the pseudo-axial B(pin) moiety resulting in the Z-selectivity (TS-6). It is noteworthy that when Z-100 was used, Z-products could also be obtained with good yield and moderate selectivity.

Scheme 29.

Preparation of α,α-Disubstituted Crotylboronate Reagents and their Application in Asymmetric Crotylation

A unique functionalization of geminal bis(boronates) by a net intramolecular [2+2] cycloaddition was discovered by Morken and co-workers.⁵⁸ Without the addition of an electrophile, the boron-stabilized carbanion can form a four-membered boracycle 103 by cycloaddition with pendant carbon–carbon double bonds. The boracycle 103 can then be trapped with a broad range of electrophiles to generate tetrasubstituted cyclopentanes 104 diastereoselectively. Reversible formation of boracycle intermediate 103 was supported by ¹³C NMR and deuterium-labeling experiments. This method was applied to the total synthesis of aphanamal where trapping with Eschenmoser’s salt simplified the construction of the cyclopentane core. The resulting boronic ester 105 was then converted to methyl ketone 106 by modified Evans–Zweifel olefination. Subsequent oxidation and Cope elimination afforded alkenyl intermediate 107. Alkylation of 107 followed by olefin metathesis and allylic oxidation gave aphanamal with good overall yield (Scheme 30).

Scheme 30.

Intramolecular [2+2] Boron Alkylidene-Alkene Cycloaddition Reaction

Prochiral gem-bis(boronates) can also be converted to non-racemic chiral 1,2- and 1,3-bis(boronates) as reported by Aggarwal and co-workers (Scheme 31).⁵⁹ Chiral lithiated 2,4,6-triisopropylbenzoyl (TIB) esters 108 were generated by directed lithiation or lithium-tin exchange and were applied to stereospecific homologation reactions. 1,2-Diboron species 109 were obtained with synthetically useful yields and excellent enantiomeric purity. Sequential or one-pot double homologations were also accomplished to furnish 1,3-bis(boronates) 110/111 or 1,4-bis(boronates) 112 with high levels of diastereoselectivity. It is worth noting that 1,2-diboryl species can be differentiated by chemoselective protodeborylation or Pd-catalyzed cross-coupling reactions.

Scheme 31.

Stereoselective Homologation Reaction of Alkyl gem-Diboronates to Prepare Enantioenriched 1,2- or 1,3-Diboryl alkanes

The boron-Wittig reaction is another important class of transformation for gem-bis(boronates). Although the reactivity was initially utilized by Matteson solely for homologation of aldehydes by sequential boron-Wittig reaction and in situ oxidation,⁶⁰ in the absence of the oxidation step, this process was found to be an efficient method to synthesize stereodefined alkenyl boronic esters, which are stable and non-toxic cross-coupling partners in the Suzuki–Miyaura reaction.

Tetrasubstituted alkenyl boronates 115 were synthesized by the Shibata Group in 2010 (Scheme 32a).⁶¹ After deprotonation by amide bases, gem-bis(boronates) 113 can add to ketones 114 followed by B–O elimination to furnish tetrasubstituted alkenyl boronates with good yield and high levels of stereoselectivity. The synthetic utility of this boron-Wittig reaction was demonstrated by a two-step synthesis of a tamoxifen derivative 116, a compound that displays anticancer activity. Later, they applied the boron-Wittig reaction to geminal diboryl alkanes 117 bearing a silyl group to provide allyl silanes 118 with a fully substituted olefin (Scheme 32b). This process provides a simple route to allylsilanes that are useful reagents for stereoselective allylations with carbonyl species.

Scheme 32.

The boron-Wittig Reaction

In 2015, the Morken Group investigated the boron-Wittig reaction between (diborylalkyl)lithium and aldehydes or diiodomethane, which provides a route to 1,1-, 1,2-disubstituted (119/120) or 1,1,2-trisubstituted (121/122) alkenyl boronates with high yields and moderate to excellent stereoselectivity (Scheme 32c).⁶² In 2019, they further modified the reaction by employing triamines as additives and successfully applied (diborylmethyl)lithium to the reaction with ketone electrophiles to synthesize alkenyl boronic esters 123, which have a different substitution pattern (Scheme 32d).⁶³

By utilizing α-silyl substituted diborylmethane 124 in the boron-Wittig reaction with ketones, the Fernandez Group synthesized tetrasubstituted olefins represented by 125 (Scheme 32e).⁶⁴ The silyl and boryl substituents can be differentiated by selective iodination of alkenyl silane giving 127, which can undergo sequential stereoretentive Suzuki cross-coupling reactions to give fully substituted olefins 128.

3. α-Boryl Silanes

In the domain of α-boryl organometallics, the α-boryl silane is another unique member.⁶⁵ It possesses similar level of configurational stability compared with gem-bis(boronates). While the silyl group usually remains intact during transformations of the boron unit, the silyl moiety can subsequently be replaced by transformations such as oxidation, allylsilylation and cross-coupling, which significantly broadens the synthetic utility of this reagent.

The transition-metal-free preparation of chiral racemic 1,1-borylalkyl silanes has been extensively studied. In 2003, Shimizu and co-workers accomplished the silylborylation of heteroatom -substituted methanes to give racemic silylboronates.⁶⁶ The Wang^10a,67 and Ley⁶⁸ Groups developed the synthesis of alkyl or benzyl α-borylsilanes from diazo species. Racemic gem-borylallyl silanes were synthesized from allyl halides by a borylsilylation reaction⁶⁹ and lithiation-silylation of allylboranes.⁷⁰ Various strategies have also been investigated to obtain enantiomerically enriched α-boryl silanes, although early routes typically require a stoichiometric amount of chiral reagents.

In 1983, the Matteson Group accomplished the first synthesis of enantioenriched geminal silylboronates 131 by employing (+)-pinanediol derived organoboronates 129 in a homologation reaction with chlorosilyl methyllithium reagent 130 (Scheme 33).⁷¹ The enantiomeric enrichment was determined to be 73:27 after oxidation of the boron. Although the E/Z ratio of the substrate was not reported, crotylboryl silane 133 was shown to undergo crotylation with aldehydes with excellent diastereoselectivity.

Scheme 33.

Enantioselective Synthesis of Geminal Silylboronates by Homologation with Lithiated Chloromethylsilane

In 1988, the Soderquist Group utilized a different strategy that involved the hydroboration of alkenyl silanes 134 with optically pure (+)-isopinocamphenylborane ((+)-Ipc borane) (Scheme 34a).⁷² However, only moderate enantioenrichment was obtained (40% ee). Subsequently in 2013, Roush and Chen employed the same strategy by reacting (−)-(Ipc)₂BH with racemic allenylsilanes 136, followed by in situ crotylation to aldehydes. Using this approach, anti homoallylic alcohols 137 bearing an E-alkenyl silane were prepared with excellent enantiomeric excess (Scheme 34b).⁷³ A kinetic resolution of two enantiomers of allenylsilanes was found to be the stereochemistry-determining step. As might be expected, when enantiomerically pure allenes were submitted to the reaction, matched and mismatched cases were observed. When enantioenriched P-allene ((P)-138) was employed in the reaction, 80% yield and 95% ee product was obtained whereas corresponding M-allene ((M)-139) only provided product in 6% yield and 72% ee.

Scheme 34.

Synthesis and Utility of Allene-Derived Nonracemic Geminal Silylboronates.

In 2011, the Aggarwal Group reported the silaboration of chiral nonracemic lithiated carbamates 139, which were generated by enantioselective deprotonation, to provide gem-borylalkyl silanes 140 with excellent yield and selectivity.⁷⁴ The subsequent Zweifel olefination furnished versatile tertiary allylsilanes 141. It is worth noting that both E- and Z- olefins can be synthesized with high levels of diastereoselectivity from corresponding homologation reagents. A cascade synthesis sequence involving an enantioselective deprotonation, silylation, Matteson homologation, and Zweifel olefination was also developed as a general route for the synthesis of enantiomerically enriched quaternary allylsilanes 142 (Scheme 35a) Recently, Aggarwal applied the lithiation-silaboration strategy to the stereodivergent synthesis of stereotriads and stereopentads.⁷⁵ After a series of lithiation-homologation reactions, all eight stereoisomers of intermediate 143 were obtained with excellent diastereoselectivity. Further homologation-oxidation sequence provided tetraol 144 with high yield and full control of stereochemistry (Scheme 35b).

Scheme 35.

Silaboration of Lithiated Carbamates Provides Access to Enantiomerically Enriched gem-Silylboronates

A strategy for the synthesis of α-borylsilanes reported by Blakemore et al and co-workers. uses chiral bisoxazoline (BOX) ligand to achieve an enantioselective Matteson homologation reaction (Scheme 36).⁷⁶ The mechanism was suggested to be a dynamic kinetic resolution of lithiated α-silylcarbamates 145 by boronic esters. However, only moderate enantioenrichment (57% ee) was obtained despite the employment of a stoichiometric amount of chiral BOX ligand.

Scheme 36.

Enantioselective Homologation with a Bis(oxazoline)-based Ligand

In 2017, the Aggarwal Group developed a versatile chlorosilyl reagent 146 bearing a proline-derived chiral directing group for the synthesis of enantioenriched α-silylboronates 147 (Scheme 37).⁷⁷ Diastereoselective lithiation was achieved with the aid of the directing group to provide the enantiomerically enriched lithium reagent, which further reacted with organoboronic esters: after formation of an “ate” complex, 1,2-metalate rearrangement affords gem-silylboronates 146 with excellent yields and diastereoselectivity. The presence of the chiral directing group was necessary since the reaction with a previously developed (−)-sparteine-based system generated racemic product. The directing group can be readily removed by an Ir-catalyzed photoredox process. Utilizing the above-mentioned process in conjunction with sequential stereocontrolled homologation reactions enabled the programmed synthesis of polypropionate structures with precise control of each stereogenic center.

Scheme 37.

Assembly Line Synthesis of Polypropionates with Full Stereocontrol

Recent progress in transition metal catalysis has enabled catalytic approaches to gem-borylalkyl silanes. An early example of catalytic synthesis of achiral α-borylsilanes was developed by Suginome, who used iridium-catalyzed C–H borylation of tetraalkylsilanes⁷⁸ or ruthenium-catalyzed C–H silylation⁷⁹ of methyl boronic acid derivatives. A Pd-catalyzed cross-coupling of (diborylmethyl)silanes was also developed recently to prepare racemic α-borylsilanes.⁸⁰

The first catalytic approach to non-racemic α-boryl silanes was accomplished by the Yun Group in 2012. Through the copper-catalyzed chemoselective double borylation of silylacetylenes 149, α,β-diborylalkyl silanes 150 were prepared with syn selectivity.⁸¹ The mechanism was proposed to involve two consecutive borylation reactions where the regioselectivity of the first borylation was dictated by the steric effect of the silyl group, and the electronic activation provided by the boryl group determined the regioselectivity of the second borylation. When sterically encumbered XantPhos ligand was applied to the reaction, the reactivity was controlled such that the addition stops at the monoborylated stage due to steric congestion. In this case, only moderate enantioselectivity (68% ee) was observed when chiral ligands were applied to the system (Scheme 38).

Scheme 38.

Copper-catalyzed Chemo- and Enantioselective Double Borylation of Silylacetylenes

A highly enantioselective approach to gem-boryl silanes was accomplished by Hoveyda and co-workers in 2013 (Scheme 39).⁸² An elegant regio- and enantioselective copper-NHC complex catalyzed borylation of alkenyl silanes 151 was shown to afford geminal silylboronates 152. The stabilizing effect of the aryl substituent functioned in concert with the ligand scaffold to deliver the product with α-selectivity. For substrates bearing alkyl substituents, the reaction regioselectivity was inverted such that β-borylation occurred. For both classes of substrate, however, high levels of enantioselectivity were obtained. Synthetic application was demonstrated by the formal synthesis of natural product bruguierol A. In this case, the enantioenriched α-borylsilane was first subjected to Zweifel olefination followed by rhodium-catalyzed hydroformylation and in situ reduction to afford silyl carbinol 153. Then oxidation of the silyl group and a catalytic oxidation/lactonization sequence provided the lactone 154, which underwent methylation and Friedel–Crafts reaction to construct the tricyclic compounds 155. Further transformation of 155 to bruguierol A had been previously reported.⁸³

Scheme 39.

Regio- and Enantioselective Copper-NHC Catalyzed Protoboration of Alkenylsilanes

In 2017, Liu and co-workers reported a deoxygenative silylborylation/diborylation of aldehydes and ketones.⁹ Copper-NHC complex-catalyzed diborylation of aldehydes generated the α-hydroxy organoboronic ester intermediates 156. Subsequent treatment with silyl or boryl nucleophiles gave the gem-silylboronates or gem-bis(boronates) 157 with good yield (Scheme 40). Excellent enantioselectivity could be obtained in this reaction by employing chiral copper-DTBM Segphos complex as catalyst.

Scheme 40.

Deoxygenative Silylboration/Diboration of Aldehydes and Ketones

Among the above catalytic methods, high levels of enantioselectivity and yield was both obtained only when β-aryl substituted alkenyl boronic esters were employed. More recently, a general approach to enantioenriched gem-borylalkyl silanes was reported by the Morken Group through the Pt-catalyzed enantioselective hydrosilylation of readily accessible alkenyl boronates 158 (Scheme 41).⁸⁴ The reaction occurs with good yield and exhibits high enantioselectivity with broad functional group compatibility. Gram-scale and dry-box free reactions could be accomplished with low catalyst loading, while retaining high yields and selectivity. The synthetic utility was demonstrated by the synthesis of oxazolidinone 160 and a one-pot synthesis of α-silyl amines 161 by a hydroboration/hydrosilylation/amination sequence.

Scheme 41.

Preparation of Enantiomerically-enriched gem-Silylboronates by Pt-Catalyzed Hydrosilation

Enantioenriched benzylic silylboronates have also been prepared by the Cho Group using a Pd-catalyzed cross-coupling of (diborylmethyl)silanes 162 and aryl iodides.⁸⁵ The reaction can tolerate a number of functional groups including heterocycles and various silyl groups (Scheme 42).

Scheme 42.

Pd-Catalyzed Enantioselective Cross-Coupling of (Diboryl)methylsilanes and Aryl Iodides

The Chen Group synthesized the enantioenriched α-boryl silanes 164 by a palladium catalyzed diboration reaction of allenyl silanes, where the product was obtained with 60% ee (Scheme 43).⁸⁶ Conditions for chemoselective allylboration or allylsilation of product 165 were developed to afford the homoallylic alcohol 166 and 167, respectively.

Scheme 43.

Chemoselective Allyl Addition of α-borylsilanes to Aldehydes

In 2021, the Cho Group reported a kinetic resolution of α-silyl-substituted allylboronates rac-168 by chiral phosphoric acid catalyzed allylboration of aldehydes (Scheme 44).⁸⁷ Both homoallylic alcohols 169 and α-silylboronates R-168 were obtained in excellent enantiomeric enrichment. The transition state, where the silyl group occupied a pseudo-axial position, is favored to minimize steric repulsion between silyl and boryl moiety. Various transformations of the products were executed. For example, the silyl-substituted homoallylic alcohol could be applied to Hiyama cross-coupling. Additionally, enantioenriched α-silylboronates were used in allylboration and allylsilylation to afford homoallylic alcohols 170 and 171 with excellent diastereoselectivity.

Scheme 44.

Kinetic Resolution of α-Silyl-Substituted Allylboronic Esters

4. α-Boryl Zinc

Historically, achiral and racemic α-boryl zinc species have been synthesized by either zinc insertion to α-boryl halides^3e,3f or carbozincation to alkenyl boronates.⁸⁸ To the best of our knowledge, so far there is no known method for the preparation of enantioenriched α-boryl zinc compounds, but stereoselective transformations for this gem-bimetallic reagent have been developed, which increase its synthetic utility.

In 1990, Knochel and co-workers described the first synthesis of α-boryl zinc compounds 172 by a zinc insertion reaction^3f and demonstrated that the addition of CuCN•2LiCl furnishes nucleophilic α-boryl cuprate intermediates, which can add to a variety of electrophiles. It is noteworthy that the reaction of some β-branched Michael acceptors, including alkenyl malonates and benzylideneacetone, exhibited excellent diastereoselectivity. Miyaura and co-workers later discovered that the addition of α-borylzinc reagents to aldehydes occurs with useful levels of diastereoselectivity and furnishes anti-diols 174 after oxidation of the boronic ester (Scheme 45).⁸⁹

Scheme 45.

Synthesis of α-Boryl Zinc Reagents by Zinc Insertion

Carbonzincation of alkenyl boronic esters 176 with zincated hydrazone 175 was developed by the Nakamura Group.^88b This process affords isomerically-enriched β,γ-branched alkyl boronates 177 upon reaction with electrophiles (Scheme 46a). Both syn- and anti- diastereomers can be obtained by employing E or Z alkenyl boronates as starting material (Scheme 46b). Synthetic usefulness was demonstrated by the synthesis of 179. Hydrazone 178 obtained by carbozincation was hydrolyzed readily to the corresponding ketone with slightly erosion of stereochemistry. The ketone was further transformed to 1,4-diol 179 after hydrogenation of the alkene, reduction of carbonyl group, and oxidation of the boronic ester. A follow-up report from the same group further showcased the utility in asymmetric synthesis by starting with enantiomerically enriched hydrazone 178.^88c Of note, DFT calculations suggest that the reaction occurs by a highly ordered six-membered boat-like transition state TS-7, as the coordination of zinc and imine or hydrazone effectively lowered the activation energy and the steric repulsion between “dummy” tert-butyl ligand on zinc and bulky pinacol ligand on boron.

Scheme 46.

Access to α-Boryl Zinc Reagents by Addition of Metallated Hydrazones to Alkenyl Boronic Esters

5. α-Boryl Zirconocene

Racemic α-boryl zirconocenes can be readily accessed by hydrozirconation of alkenyl boronates with Schwartz’s reagent. This reaction occurs under mild conditions and has broad functional group compatibility. Srebnik and co-workers investigated the fundamental properties of the geminal dimetallic reagent including X-ray analysis, NMR studies, and reactivity such as halogenation, amination and copper-catalyzed nucleophilic substitution and addition reactions.^4a,4d–g,90

Enantioenriched α-boryl zirconocenes 182 were also synthesized by the Srebnik Group by a strategy involving diastereoselective hydrozirconation of chiral alkenyl boronic esters 181 with Schwartz’s reagent. Good yield and selectivity were achieved after quenching the resulting α-boryl zirconocenes with D₂O. Oxidation of the boronic ester furnished the enantiomerically enriched α-deuterated alcohols 183.⁹¹ Similar to the α-boryl zinc analog reported by Knochel, copper-catalyzed conjugate addition of α-boryl zirconocenes to cyclic unsaturated enones 184 was also investigated and found to favor the anti-product (Scheme 47).^4g

Scheme 47.

Synthesis of α-Boryl Zirconocenes by Diasereoselective Hydrozirconation.

A chemoselective cross-coupling reaction between α-boryl zirconocenes and aryl halides was described by the Qi Group (Scheme 48).⁹² The α-boryl zirconocenes 186 were generated by a boron-directed “chain walking” process of alkylzirconocenes, which were synthesized from hydrozirconation of internal alkene 185 with Schwartz’s reagent. A nickel–bipyridine complex, in conjunction with blue LEDs, was demonstrated to be an efficient catalyst system for the cross-coupling reaction between α-boryl zirconocenes 186 and aryl halides. The reaction exhibits good yield, chemoselectivity and functional group compatibility. Moreover, an enantioselective version was achieved by utilizing a chiral bis(oxazoline) ligand on nickel with moderate enantioselectivity (56% ee).

Scheme 48.

Chain-Walking Hydrozirconation Followed by Chemoselective Cross-Coupling of α-Boryl Zirconocenes

6. Conclusions

In this review, we have summarized the development and recent advances of reactions that employ gem-diboronates, α-boryl silane, zinc, and zirconocene reagents, especially their roles in asymmetric synthesis. gem-Diboronates have been employed in numerous carbon–carbon bond forming reactions including transition-metal-catalyzed cross-coupling, nucleophilic addition, allylic substitution, conjugate addition, allylboration, [2+2] cycloaddition, homologation and boron-Wittig reaction with high levels of enantio- and diastereoselectivity. These reactions provide valuable stereodefined intermediates towards the construction of more complex structures and natural products. Enantiomerically enriched α-boryl silanes are constructed by homologation, hydroboration, hydrosilylation, protoborylation, and deoxygenative silaboration strategies and proven to be highly efficient in the synthesis of polypropionate motifs. Despite the high reactivity of α-boryl zinc and zirconocene reagents and the ability of those reagents to undergo a broad array of diastereoselective transformations, enantioselective processes are still in their infancy. We hope this review can give the researchers insight in the reactivity of α-boryl organometallics and may inspire more development in the future.