Si-H Insertion Research Articles

Enantioselective α-Boryl Carbene Transformations.

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

Rh(II)-Catalyzed Si-H Insertion with Nosyl-hydrazone-Protected Aryl Donor Diazo Compounds.

Dirhodium(II,II) paddlewheel catalysts were evaluated in silyl-hydrogen insertion reactions of aryl diazo compounds generated from o-nosyl hydrazones. The high reactivity of aryl diazo compounds necessitates their in situ generation from sulfonyl-protected hydrazones. Herein, we describe our efforts to evaluate this transformation utilizing Rh(II) catalysts, including those with tethered, axially coordinating ligands. The heteroleptic catalyst, Rh2(OAc)3(2-OX), provided the highest yield of silanes when dioxane was the solvent.

Catalytic asymmetric silicon-carbon bond-forming transformations based on Si-H functionalization

In view of the exciting advancement on silicon-carbon bond-forming transformations achieved in the past decade, this review intends to show a unified illustration of the recent findings on enantioselective Si-H bond functionalization aided by asymmetric catalysis. Accordingly, this review describes the enantioselective silicon-carbon bond-forming Si-H bond functionalization, focusing on the reactivity and stereoselectivity in catalytic asymmetric hydrosilylation, carbene Si-H insertion, Si-H silylation, and Si-C bond-forming cross-coupling reactions that were achieved with high enantioselectivity in the presence of transition-metal catalyst systems. This review highlights recent and representative examples of the enantioselective Si-H bond functionalization, discusses the origins of silicon-involving stereoselectivities, and evaluates the substrate scopes and limitations in these catalytic asymmetric Si-H bond functionalization reactions due to the special reactivity of different hydrosilanes.

α-Aminocarbene-Mediated Si-H Insertion: Deoxygenative Silylation of Aromatic Amides with Silanes.

While metal carbene-mediated Si-H insertion reactions have become a powerful strategy to build new C-Si bonds, the utilization of α-aminocarbene intermediates generated from readily available precursors in the Si-H insertion reaction remains a longstanding challenge. Herein, we develop a practical and general strategy to synthesize α-aminosilanes through a deoxygenative cross-coupling of amides and silanes mediated by Sm/SmI2. Given the simplicity and versatility, this methodology represents a fascinating example for the effective utilization of inert amides as α-aminocarbene precursors in organic synthesis.

YfeX - A New Platform for Carbene Transferase Development with High Intrinsic Reactivity.

Carbene transfer biocatalysis has evolved from basic science to an area with vast potential for the development of new industrial processes. In this study, we show that YfeX, naturally a peroxidase, has great potential for the development of new carbene transferases, due to its high intrinsic reactivity, especially for the N-H insertion reaction of aromatic and aliphatic primary and secondary amines. YfeX shows high stability against organic solvents (methanol and DMSO), greatly improving turnover of hydrophobic substrates. Interestingly, in styrene cyclopropanation, WT YfeX naturally shows high enantioselectivity, generating the trans product with 87 % selectivity for the (R,R) enantiomer. WT YfeX also catalyzes the Si-H insertion efficiently. Steric effects in the active site were further explored using the R232A variant. Quantum Mechanics/Molecular Mechanics (QM/MM) calculations reveal details on the mechanism of Si-H insertion. YfeX, and potentially other peroxidases, are exciting new targets for the development of improved carbene transferases.

Biocatalytic Carbene Transfer Using Diazirines.

Biocatalytic carbene transfer from diazo compounds is a versatile strategy in asymmetric synthesis. However, the limited pool of stable diazo compounds constrains the variety of accessible products. To overcome this restriction, we have engineered variants of Aeropyrum pernix protoglobin (ApePgb) that use diazirines as carbene precursors. While the enhanced stability of diazirines relative to their diazo isomers enables access to a diverse array of carbenes, they have previously resisted catalytic activation. Our engineered ApePgb variants represent the first example of catalysts for selective carbene transfer from these species at room temperature. The structure of an ApePgb variant, determined by microcrystal electron diffraction (MicroED), reveals that evolution has enhanced access to the heme active site to facilitate this new-to-nature catalysis. Using readily prepared aryl diazirines as model substrates, we demonstrate the application of these highly stable carbene precursors in biocatalytic cyclopropanation, N-H insertion, and Si-H insertion reactions.

Novel Porous Rhodium Metal-Organic Aerogel for Efficient Removal of Organic Dyes and Catalysis of Si-H Insertion Reactions.

Metal–organic gels (MOGs) are attracting increasing attention for removal of organic dyes from aqueous solution and for catalysis of Si–H insertion reactions. Herein, we report that a reaction of porphyrin derivative 1 with Rh2(OAc)4 generates stable metal–organic gels and subsequent subcritical carbon dioxide drying affords metal–organic aerogels. Owing to their micro- and mesoporosity, the aerogels adsorbed dyes. Moreover, aerogel I catalyzed Si–H insertion reactions to give organosilicon compounds in high yields.

Enantioselective Si-H Insertion Reactions of Diarylcarbenes for the Synthesis of Silicon-Stereogenic Silanes.

We report the first example of enantioselective, intermolecular diarylcarbene insertion into Si-H bonds for the synthesis of silicon-stereogenic silanes. Dirhodium(II) carboxylates catalyze an Si-H insertion using carbenes derived from diazo compounds where selective formation of an enantioenriched silicon center is achieved using prochiral silanes. Fourteen prochiral silanes were evaluated with symmetrical and prochiral diazo reactants to produce a total of 25 novel silanes. Adding an ortho substituent on one phenyl ring of a prochiral diazo enhances enantioselectivity up to 95:5 er with yields up to 98%. Using in situ IR spectroscopy, the impact of the off-cycle azine formation is supported based on the structural dependence for relative rates of diazo decomposition. A catalytic cycle is proposed with Si-H insertion as the rate-determining step, supported by kinetic isotope experiments. Transformations of an enantioenriched silane derived from this method, including selective synthesis of a novel sila-indane, are demonstrated.

Metal-Free Insertion Reactions of Silanes with Aryldiazoacetates.

Si-H insertion reactions represent an important method for the efficient construction of new C-Si bonds, and typically, they are conducted in the presence of metal catalysts. In this report, we describe a photochemical approach that now allows the insertion of carbenes into the Si-H bond of silanes under metal-free reaction conditions (23 examples, up to 83% yield).

Asymmetric CuI-Catalyzed Insertion Reaction of 1-Aryl-2,2,2-trifluoro-1-diazoethanes into Si-H Bonds.

An asymmetric copper(I)-catalyzed Si-H insertion reaction of 1-aryl-2,2,2-trifluoro-1-diazoethanes in dimethyl carbonate as a green solvent alternative was developed. A C2-symmetric copper(I) diimine complex enabled the asymmetric insertion reaction to give enantioenriched (1-aryl-2,2,2-trifluoroethyl)silanes with excellent stereoselectivities (up to 98:2 er). Successful conversion of the silanes into the corresponding alcohols was performed with retention of stereochemistry. Mechanistic studies and DFT calculations support the proposed model for the observed stereoselectivities.

Mechanistic Investigation of Biocatalytic Heme Carbenoid Si-H Insertions.

Recent studies reported the development of biocatalytic heme carbenoid Si-H insertions for the selective formation of carbon-silicon bonds, but many mechanistic questions remain unaddressed. To this end, a DFT mechanistic investigation was performed which reveals an FeII-based concerted hydride transfer mechanism with early transition state feature. The results from these computational analyses are consistent with experimental data of radical trapping, kinetic isotope effects, and structure-reactivity data using engineered variants of hemoproteins. Detailed geometric and electronic profiles along the heme catalyzed Si-H insertion pathways were provided to help understand the origin of experimental reactivity trends. Quantitative relationships between reaction barriers and some properties such as charge transfer from substrate to heme carbene and Si-H bond length change from reactant to transition state were found. Results suggest catalyst modifications to facilitate the charge transfer from the silane substrate to the carbene, which was determined to be a major electronic driving force of this reaction, should enable the development of improved biocatalysts for Si-H carbene insertion reactions.

Machine learning-assisted directed protein evolution with combinatorial libraries

To reduce experimental effort associated with directed protein evolution and to explore the sequence space encoded by mutating multiple positions simultaneously, we incorporate machine learning into the directed evolution workflow. Combinatorial sequence space can be quite expensive to sample experimentally, but machine-learning models trained on tested variants provide a fast method for testing sequence space computationally. We validated this approach on a large published empirical fitness landscape for human GB1 binding protein, demonstrating that machine learning-guided directed evolution finds variants with higher fitness than those found by other directed evolution approaches. We then provide an example application in evolving an enzyme to produce each of the two possible product enantiomers (i.e., stereodivergence) of a new-to-nature carbene Si-H insertion reaction. The approach predicted libraries enriched in functional enzymes and fixed seven mutations in two rounds of evolution to identify variants for selective catalysis with 93% and 79% ee (enantiomeric excess). By greatly increasing throughput with in silico modeling, machine learning enhances the quality and diversity of sequence solutions for a protein engineering problem.

Donor Rhodium Carbenes by Retro-Buchner Reaction.

Rhodium carbenes are key intermediates in a range of cycloadditions and insertion reactions. Herein, we report the first generation of donor RhII carbenes by decarbenation of 7-substituted 1,3,5-cycloheptatrienes. This discovery unlocks an improved retro-Buchner-cyclopropanation sequence, a Si-H insertion reaction for a broad-scope synthesis of allylsilanes, and a new method for the vinylogation of aldehydes. The last strategy led to the development of an iterative synthesis of E-polyenes, and to the total synthesis of navenones B and C.

Chemoselective Cyclopropanation over Carbene Y-H Insertion Catalyzed by an Engineered Carbene Transferase.

Hemoproteins have recently emerged as promising biocatalysts for promoting a variety of carbene transfer reactions including cyclopropanation and Y-H insertion (Y = N, S, Si, B). For these and synthetic carbene transfer catalysts alike, achieving high chemoselectivity toward cyclopropanation in olefin substrates bearing unprotected Y-H groups has proven remarkably challenging due to competition from the more facile carbene Y-H insertion reaction. In this report, we describe the development of a novel artificial metalloenzyme based on an engineered myoglobin incorporating a serine-ligated Co-porphyrin cofactor that is capable of offering high selectivity toward olefin cyclopropanation over N-H and Si-H insertion. Intramolecular competition experiments revealed a distinct and dramatically altered chemoselectivity of the Mb(H64V,V68A,H93S)[Co(ppIX)] variant in carbene transfer reactions compared to myoglobin-based variants containing the native histidine-ligated heme cofactor or other metal/proximal ligand substitutions. These studies highlight the functional plasticity of myoglobin as a "carbene transferase" and illustrate how modulation of the cofactor environment within this metalloprotein scaffold represents a valuable strategy for accessing carbene transfer reactivity not exhibited by naturally occurring hemoproteins or transition metal catalysts.

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.

Carbene Transfer Reactions Catalysed by Dyes of the Metalloporphyrin Group.

Carbene transfer reactions are very important transformations in organic synthesis, allowing the generation of structurally challenging products by catalysed cyclopropanation, cyclopropenation, carbene C-H, N-H, O-H, S-H, and Si-H insertion, and olefination of carbonyl compounds. In particular, chiral and achiral metalloporphyrins have been successfully explored as biomimetic catalysts for these carbene transfer reactions under both homogeneous and heterogeneous conditions. In this work the use of synthetic metalloporphyrins (MPorph, M = Fe, Ru, Os, Co, Rh, Ir, Sn) as homogeneous or heterogeneous catalysts for carbene transfer reactions in the last years is reviewed, almost exclusively focused on the literature since the year 2010, except when reference to older publications was deemed to be crucial.

Evolving artificial metalloenzymes via random mutagenesis.

Random mutagenesis has the potential to optimize the efficiency and selectivity of protein catalysts without requiring detailed knowledge of protein structure; however, introducing synthetic metal cofactors complicates the expression and screening of enzyme libraries, and activity arising from free co-factor must be eliminated. Here we report an efficient platform to create and screen libraries of artificial metalloenzymes (ArMs) via random mutagenesis which we use to evolve highly selective dirhodium cyclopropanases. Error-prone PCR and combinatorial codon mutagenesis enabled multiplexed analysis of random mutations, including at sites distal to the putative ArM active site that are difficult to identify using targeted mutagenesis approaches. Variants that exhibited significantly improved selectivity for each of cyclopropane product enantiomers were identified, and higher activity than previously reported ArM cyclopropanases obtained via targeted mutagenesis was also observed. This improved selectivity carried over to other dirhodium catalyzed transformations, including N- H, S-H and Si-H insertion, demonstrating that ArMs evolved for one reaction can serve as starting points to evolve catalysts for others.

Engineering catalytic coordination space in a chemically stable Ir-porphyrin MOF with a confinement effect inverting conventional Si-H insertion chemoselectivity.

An iridium-porphyrin ligand, Ir(TCPP)Cl (TCPP = tetrakis(4-carboxyphenyl)porphyrin), has been utilized to react with HfCl4 to generate a stable Ir(iii)-porphyrin metal-organic framework of the formula [(Hf6(μ3-O)8(OH)2(H2O)10)2(Ir(TCPP)Cl)3]·solvents (Ir-PMOF-1(Hf)), which possesses two types of open cavities (1.9 × 1.9 × 1.9 and 3.0 × 3.0 × 3.0 nm3) crosslinked through orthogonal channels (1.9 × 1.9 nm2) in three directions. The smaller cavity is surrounded by four catalytic Ir(TCPP)Cl walls to form a confined coordination space as a molecular nanoreactor, while the larger one facilitates reactant/product feeding and release. Therefore, the porous Ir-PMOF-1(Hf) can act as a multi-channel crystalline molecular flask to promote the carbenoid insertion reaction into Si-H bonds, featuring high chemoselectivity towards primary silanes among primary, secondary and tertiary silanes under heterogeneous conditions that are inaccessible by conventional homogeneous catalysts.

Rhodium(II)-Alkynyl Carbenoids Insertion into Si-H bonds: An Entry to Propargylic Geminal Bis(silanes).

α-Alkynyl-α'-trimethylsilylhydrazones are used as novel Rh(II)-carbenoids precursors. These new carbenoids have shown very good reactivity in Si-H insertion reactions, leading to original propargylic geminal-bis(silanes) in a two-step sequential process.

Reactions of Persistent Carbenes with Hydrogen-Terminated Silicon Surfaces.

Surface passivation has enabled the development of silicon-based solar cells and microelectronics. However, a number of emerging applications require a paradigm shift from passivation to functionalization, wherein surface functionality is installed proximal to the silicon surface. To address this need, we report here the use of persistent aminocarbenes to functionalize hydrogen-terminated silicon surfaces via Si-H insertion reactions. Through the use of model compounds (H-Si(TMS)3 and H-Si(OTMS)3), nanoparticles (H-SiNPs), and planar Si(111) wafers (H-Si(111)), we demonstrate that among different classes of persistent carbenes, the more electrophilic and nucleophilic ones, in particular, a cyclic (alkyl)(amino)carbene (CAAC) and an acyclic diaminocarbene (ADAC), are able to undergo insertion into Si-H bonds at the silicon surface, forming persistent C-Si linkages and simultaneously installing amine or aminal functionality in proximity to the surface. The CAAC (6) is particularly notable for its clean insertion reactivity under mild conditions that produces monolayers with 21 ± 3% coverage of Si(111) atop sites, commensurate with the expected maximum of ∼20%. Atomic force and transmission electron microscopy, nuclear magnetic resonance, X-ray photoelectron, and infrared spectroscopy, and time-of-flight secondary ion mass spectrometry provided evidence for the surface Si-H insertion process. Furthermore, computational studies shed light on the reaction energetics and indicated that CAAC 6 should be particularly effective at binding to silicon dihydride, trihydride, and coupled monohyride motifs, as well as oxidized surface sites. Our results pave the way for the further development of persistent carbenes as universal ligands for silicon and potentially other nonmetallic substrates.