Platinum-catalyzed regio- and enantioselective diboration of unactivated alkenes with (pin)B-B(dan).

Asymmetric diboration of terminal alkenes is well established, and subsequent selective functionalization of the less hindered primary boronic ester is commonly achieved. Conversely, selective functionalization of the sterically less accessible secondary boronic ester remains challenging. An alternative way to control chemoselective functionalization of bis(boron) compounds is by engendering different Lewis acidity to the two boryl moieties, since reactivity would then be dictated by Lewis acidity instead of sterics. We report herein the regio- and enantioselective Pt-catalyzed diboration of unactivated alkenes with (pin)B-B(dan). A broad range of terminal and cyclic alkenes undergo diboration to furnish the differentiable 1,2-bis(boron) compounds with high levels of regio- and enantiocontrol, giving access to a wide variety of novel building blocks from a common intermediate. The reaction places the less Lewis acidic B(dan) group at the less hindered position and the resulting 1,2-bisboryl alkanes undergo selective transformations of the B(pin) group located at the more hindered position. The regioselectivity of diboration has been studied by DFT calculations and is believed to originate from the trans influence, which lowers the activation barrier for formation of the regioisomer that places the weaker electron donor [B(pin) vs B(dan)] opposite the strong electron donor (alkyl group) in the platinum complex.

Difluorinated thromboxane A2 reveals crosstalk between platelet activatory and inhibitory pathways by targeting both the TP and IP receptors.

BACKGROUND AND PURPOSE: Thromboxane A2 (TXA2) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA2 signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA2 analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function. EXPERIMENTAL APPROACH: Platelet functional and signalling responses were studied using aggregometry, Ca2+ mobilisation experiments and immunoblotting and compared with an analogue of the TXA2 precursor prostaglandin H2, U46619. Gαq/Gαs receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system. KEY RESULTS: BRET studies revealed that F-TXA2 and F2-TXA2 promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F2-TXA2 caused reversible aggregation in platelets, whereas F-TXA2 and U46619 induced sustained aggregation. Blocking the IP receptor switched F2-TXA2-mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F2-TXA2-mediated IP receptor activation. F2-TXA2 rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed. CONCLUSION AND IMPLICATIONS: F-TXA2 is a close analogue to TXA2 used as a selective tool for TP receptor platelet activation. In contrast, F2-TXA2 acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation.

Ruthenium-Catalyzed Dual Dehydrogenative Silylation of C(sp3)-H Bonds: Access to Diverse Silicon-Centered Spirocycles.

We report herein a pincer Ru-catalyzed dual intramolecular dehydrogenative silylation of primary C(sp3)-H bonds. The reaction features high efficiency, scalability, and good functional group tolerance, allowing a facile and atom-economical access to structurally diverse silicon-centered spirocycles, including unprecedented oxa-spirosilabiindanes and aza-spirosilabiindanes.

Consecutive ß,ß'-Selective C(sp3 )-H Silylation of Tertiary Amines with Dihydrosilanes Catalyzed by B(C6 F5 )3.

Tris(pentafluorophenyl)borane has been found to catalyze the two-fold C(sp3 )-H silylation of various trialkylamine derivatives with dihydrosilanes, furnishing the corresponding 4-silapiperidines in decent yields. The multi-step reaction cascade involves amine-to-enamine dehydrogenation at two alkyl residues and two electrophilic silylation reactions of those enamines, one inter- and one intramolecular.

Ruthenium-Catalyzed Hydrodefluorination with Silane as the Directing and Reducing Group.

We describe herein an efficient and selective Ru-catalyzed intramolecular HDF directed by a silyl group, which is readily installed, and removable and transformable following the HDF reaction. The hydrosilyl group in polyfluoroaryl silane acts not only as the directing group but also as the internal reductant, enabling precise control of the ortho-selectivity and avoiding overdefluorination. Mechanistic studies reveal a plausible catalytic cycle involving a Ru(IV)-aryne intermediate.

The Cyclohexa-2,5-dienyl Group as a Placeholder for Hydrogen: Organocatalytic Michael Addition of an Acetaldehyde Surrogate.

An aldehyde with a cyclohexa-2,5-dienyl group in the α-position is introduced as a storable surrogate of highly reactive acetaldehyde. The cyclohexa-2,5-dienyl unit is compatible with an enantioselective Michael addition to nitroalkenes promoted by a Hayashi-Jørgensen catalyst and can be removed by a boron Lewis acid mediated C-C bond cleavage. The robust two-step sequence does not require a large excess of the aldehyde component that is typically needed when directly using acetaldehyde.

Reductive Deamination with Hydrosilanes Catalyzed by B(C6 F5 )3.

The strong boron Lewis acid tris(pentafluorophenyl)borane B(C6 F5 )3 is known to catalyze the dehydrogenative coupling of certain amines and hydrosilanes at elevated temperatures. At higher temperature, the dehydrogenation pathway competes with cleavage of the C-N bond and defunctionalization is obtained. This can be turned into a useful methodology for the transition-metal-free reductive deamination of a broad range of amines as well as heterocumulenes such as an isocyanate and an isothiocyanate.

Defunctionalisation catalysed by boron Lewis acids.

Selective defunctionalisation of organic molecules to valuable intermediates is a fundamentally important transformation in organic synthesis. Despite the advances made in efficient and selective defunctionalisation using transition-metal catalysis, the cost, toxicity, and non-renewable properties limit its application in industrial manufacturing processes. In this regard, boron Lewis acid catalysis has emerged as a powerful tool for the cleavage of carbon-heteroatom bonds. The ground-breaking finding is that the strong boron Lewis acid B(C6F5)3 can activate Si-H bonds through η1 coordination, and this Lewis adduct is a key intermediate that enables various reduction processes. This system can be tuned by variation of the electronic and structural properties of the borane catalyst, and together with different hydride sources high chemoselectivity can be achieved. This Perspective provides a comprehensive summary of various defunctionalisation reactions such as deoxygenation, decarbonylation, desulfurisation, deamination, and dehalogenation, all of which catalysed by boron Lewis acids.

A BEt3-Base Catalyst for Amide Reduction with Silane.

Reported herein is the development of a simple but practical catalytic system for the selective reduction of amides with hydrosilane or hydrosiloxane. Low-cost and readily available triethylborane (1.0 M in THF), in combination with a catalytic amount of an alkali metal base, was found to catalyze the reduction of all three amide classes (tertiary, secondary, and primary amides) to form amines under mild conditions. In addition, the selective transformation of secondary amides to aldimines and primary amides to nitriles can also be achieved by using a proper combination of BEt3 and base. The scope of these BEt3-base-catalyzed amide hydrosilylation reactions has been explored in depth. Preliminary results of mechanistic studies suggest a modified Piers' silane Si-H···B activation mode wherein the hydride abstraction by BEt3 is promoted by the coordination of an alkoxide or hydroxide anion to the Si center.

Ruthenium-Catalyzed Site-Selective Intramolecular Silylation of Primary C-H Bonds for Synthesis of Sila-Heterocycles.

Incorporating the silicon element into bioactive organic molecules has received increasing attention in medicinal chemistry. Moreover, organosilanes are valuable synthetic intermediates for fine chemicals and materials. Transition metal-catalyzed C-H silylation has become an important strategy for C-Si bond formations. However, despite the great advances in aromatic C(sp2)-H bond silylations, catalytic methods for aliphatic C(sp3)-H bond silylations are relatively rare. Here we report a pincer ruthenium catalyst for intramolecular silylations of various primary C(sp3)-H bonds adjacent to heteroatoms (O, N, Si, Ge), including the first intramolecular silylations of C-H bonds α to O, N, and Ge. This method provides a general, synthetically efficient approach to novel classes of Si-containing five-membered [1,3]-sila-heterocycles, including oxasilolanes, azasilolanes, disila-heterocycles, and germasilolane. The trend in the reactivity of five classes of C(sp3)-H bonds toward the Ru-catalyzed silylation is elucidated. Mechanistic studies indicate that the rate-determining step is the C-H bond cleavage involving a ruthenium silyl complex as the key intermediate, while a η2-silene ruthenium hydride species is determined to be an off-cycle intermediate.

A Pincer Ruthenium Complex for Regioselective C-H Silylation of Heteroarenes.

A pincer Ru(II) catalyst for the highly efficient undirected silylation of O- and S-heteroarenes with (TMSO)2MeSiH and Et3SiH is described, producing heteroarylsilanes with exclusive C2-regioselectivity, good functional-group tolerance, and high turnover numbers (up to 1960). The synthetic utility of the silylated products is demonstrated by Pd-catalyzed Hiyama-Denmark cross-coupling under mild conditions. One-pot, two-step silylation and coupling procedures have been also developed.

A General and mild catalytic α-alkylation of unactivated esters using alcohols.

Catalytic α-alkylation of esters with primary alcohols is a desirable process because it uses low-toxicity agents and generates water as the by-product. Reported herein is a NCP pincer/Ir catalyst which is highly efficient for α-alkylation of a broad scope of unactivated esters under mild reaction conditions. For the first time, alcohols alkylate unactivated α-substituted acyclic esters, lactones, and even methyl and ethyl acetates. This method can be applied to the synthesis of carboxylic acid derivatives with diverse structures and functional groups, some of which would be impossible to access by conventional enolate alkylations with alkyl halides.