Vinylboronic Esters Research Articles

In‐Cell Generation of Anticancer Phenanthridine Through Bioorthogonal Cyclization in Antitumor Prodrug Development

AbstractPharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. Using phenanthridines as cytotoxic model compounds, we designed ring‐opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid inside living cells of KB cancer spheroids so as to circumvent drug action.

In-Cell Generation of Anticancer Phenanthridine Through Bioorthogonal Cyclization in Antitumor Prodrug Development.

Pharmacological inactivation of antitumor drugs toward healthy cells is a critical factor in prodrug development. Typically, pharmaceutical chemists graft temporary moieties to existing antitumor drugs to reduce their pharmacological activity. Here, we report a platform able to generate the cytotoxic agent by intramolecular cyclization. Using phenanthridines as cytotoxic model compounds, we designed ring-opened biaryl precursors that generated the phenanthridines through bioorthogonal irreversible imination. This reaction was triggered by reactive oxygen species, commonly overproduced in cancer cells, able to convert a vinyl boronate ester function into a ketone that subsequently reacted with a pendant aniline. An inactive precursor was shown to engender a cytotoxic phenanthridine against KB cancer cells. Moreover, the kinetic of cyclization of this prodrug was extremely rapid inside living cells of KB cancer spheroids so as to circumvent drug action.

Enantiomerically Enriched α-Borylzinc Reagents by Nickel-Catalyzed Carbozincation of Vinylboronic Esters.

In this paper is described a synthesis of enantiomerically enriched, configurationally stable organozinc reagents by catalytic enantioselective carbozincation of a vinylboronic ester. This process furnishes enantiomerically enriched α-borylzinc intermediates that are shown to undergo stereospecific reactions, producing enantioenriched secondary boronic ester products. The properties of the intermediate α-borylzinc reagent are probed and the synthetic utility of the products is demonstrated by application to the synthesis of (-)-aphanorphine and (-)-enterolactone.

Aluminum Amidinates: Insights into Alkyne Hydroboration.

The mechanism of the aluminum-mediated hydroboration of terminal alkynes was investigated using a series of novel aluminum amidinate hydride and alkyl complexes bearing symmetric and asymmetric ligands. The new aluminum complexes were fully characterized and found to facilitate the formation of the (E)-vinylboronate hydroboration product, with rates and orders of reaction linked to complex size and stability. Kinetic analysis and stoichiometric reactions were used to elucidate the mechanism, which we propose to proceed via the initial formation of an Al-borane adduct. Additionally, the most unstable complex was found to promote decomposition of the pinacolborane substrate to borane (BH3), which can then proceed to catalyze the reaction. This mechanism is in contrast to previously reported aluminum hydride-catalyzed hydroboration reactions, which are proposed to proceed via the initial formation of an aluminum acetylide, or by hydroalumination to form a vinylboronate ester as the first step in the catalytic cycle.

Construction of Complex Cyclobutane Building Blocks by Photosensitized [2 + 2] Cycloaddition of Vinyl Boronate Esters.

Cyclobutyl moieties in drug molecules are rare, and in general, they are minimally substituted and stereochemically simple. Methods to assemble structurally complex cyclobutane building blocks suitable for rapid diversification are thus highly desirable. We report herein a photosensitized [2 + 2] cycloaddition with vinyl boronate esters affording straightforward access to complex, densely functionalized cyclobutane scaffolds. Mechanistic studies suggest an activation mode involving energy transfer to the styrenyl alkene rather than the vinyl boronate ester.

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Nickel-catalyzed site- and stereoselective reductive alkylalkynylation of alkynes

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Catalyst Development in the Dehydrogenative Borylation of Alkenes for the Synthesis Vinylboronate Esters

AbstractCatalytic dehydrogenative borylation of alkenes provides an efficient and straightforward method for the preparation of synthetically useful vinylboronate esters. Here, we present a summary of developments and recent advances in this area, classified according to the various reactants and catalyst systems.1 Introduction2 Catalytic Dehydrogenative Borylation of Alkenes by Using Boranes3 Catalytic Dehydrogenative Borylation of Alkenes by Using Diboranes4 Zirconium-Catalyzed H 2 –Acceptorless Dehydrogenative Borylation of Alkenes with Boranes5 Conclusion and Outlook

Conjunctive Cross-Coupling of Vinyl Boronic Esters

Key words boronic esters - photoredox catalysis - conjunctive cross-coupling

Decarboxylative Conjunctive Cross‐coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

AbstractThe synthesis of complex alkyl boronic esters through conjunctive cross‐coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross‐coupling cascade of vinyl boronic esters. Excellent functional‐group tolerance is displayed, and application of a range of carboxylic acids, including secondary α‐amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross‐coupling was also applied to the synthesis of sedum alkaloids.

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis.

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.

The synthesis of brominated-boron-doped PAHs by alkyne 1,1-bromoboration: mechanistic and functionalisation studies.

The synthesis of a range of brominated-Bn-containing (n = 1, 2) polycyclic aromatic hydrocarbons (PAHs) is achieved simply by reacting BBr3 with appropriately substituted alkynes via a bromoboration/electrophilic C–H borylation sequence. The brominated-Bn-PAHs were isolated as either the borinic acids or B-mesityl-protected derivatives, with the latter having extremely deep LUMOs for the B2-doped PAHs (with one example having a reduction potential of E1/2 = −0.96 V versus Fc+/Fc, Fc = ferrocene). Mechanistic studies revealed the reaction sequence proceeds by initial alkyne 1,1-bromoboration. 1,1-Bromoboration also was applied to access a number of unprecedented 1-bromo-2,2-diaryl substituted vinylboronate esters directly from internal alkynes. Bromoboration/C–H borylation installs useful C–Br units onto the Bn-PAHs, which were utilised in Negishi coupling reactions, including for the installation of two triarylamine donor (D) groups onto a B2-PAH. The resultant D–A–D molecule has a low optical gap with an absorption onset at 750 nm and emission centered at 810 nm in the solid state.

Hydroboration of Alkenes and Alkynes Employing Earth‐Abundant Metal Catalysts

AbstractIron complexes [BIAN]Fe(I)(η6‐toluene) (M1) and [BIAN]FeCl2 (M2) (BIAN=bis(2,6‐diisopropylaniline)acenaphthene) were found to be viable catalysts for the regioselective hydroboration of alkynes and alkenes. The hydroboration of alkynes and alkenes in the presence of HBpin and an activator at 70 °C afforded linear vinyl and alkyl boronic esters, respectively. Selectivity up to 98% was observed for alkyl boronic esters and exclusive formation of trans product was observed for vinyl boronic esters.

A low temperature, vinylboronate ester-mediated, iterative cross-coupling approach to xanthomonadin polyenyl pigment analogues

Approaches to the polyene natural product xanthomonadin, an octaenyl electron-deficient bacterial photoprotective agent, and its debromo analogue, were developed. These involved the iterative cross-coupling of multiple C2-fragments, using a vinylboronate ester as a formal vinyl dianion equivalent. Vinyl iodide starting materials undergo Heck-Mizoroki cross-coupling at ambient temperatures, allowing further iododeboronation to derive the next vinyl iodide. This works in a highly effective manner to access systems of up to pentaene chain length. However, final assembly of polyenylboronates with such polyenyl iodides through their Suzuki-Miyaura cross-coupling was less successful, even at lower temperatures, reflecting the extreme sensitivity of such octaenylxanthomonadin analogues. Despite this, the mild cross-coupling conditions could be effectively applied to the assembly of a range of useful polyenyl building blocks, as well as a truncated pentaenyl-debromoxanthomonadin analogue.

H2‐Acceptorless Dehydrogenative Boration and Transfer Boration of Alkenes Enabled by Zirconium Catalyst

AbstractThe first example of an efficient and direct dehydrogenative boration of alkenes for vinyl boronate ester synthesis was achieved using a zirconium catalyst. Our methodology avoids using precious transition metals, additional hydrogen acceptors, high temperatures, and long reaction times, which were required to overcome the reducing ability of borane, to give alkyl boronate esters. Detailed mechanistic studies revealed a reversible reaction pathway and further suggested applying the zirconium complex as a “shuttle catalyst” for transfer boration, which thus sidesteps the use of relatively sensitive borane.

H2 -Acceptorless Dehydrogenative Boration and Transfer Boration of Alkenes Enabled by Zirconium Catalyst.

The first example of an efficient and direct dehydrogenative boration of alkenes for vinyl boronate ester synthesis was achieved using a zirconium catalyst. Our methodology avoids using precious transition metals, additional hydrogen acceptors, high temperatures, and long reaction times, which were required to overcome the reducing ability of borane, to give alkyl boronate esters. Detailed mechanistic studies revealed a reversible reaction pathway and further suggested applying the zirconium complex as a "shuttle catalyst" for transfer boration, which thus sidesteps the use of relatively sensitive borane.

Vinylidene Homologation of Boronic Esters and its Application to the Synthesis of the Proposed Structure of Machillene

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron-rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron-deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C-Si and C-B bond breaking transition states. This vinylidene homologation was used in a short six-step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

Vinylidene Homologation of Boronic Esters and its Application to the Synthesis of the Proposed Structure of Machillene

AbstractAlkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron‐rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron‐deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C−Si and C−B bond breaking transition states. This vinylidene homologation was used in a short six‐step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

Palladium-Catalyzed Methylation of Aryl, Heteroaryl, and Vinyl Boronate Esters.

A method for the direct methylation of aryl, heteroaryl, and vinyl boronate esters is reported, involving the reaction of iodomethane with aryl-, heteroaryl-, and vinylboronate esters catalyzed by palladium and PtBu2Me. This transformation occurs with a remarkably broad scope and is suitable for late-stage derivatization of biologically active compounds via the boronate esters. The unique capabilities of this method are demonstrated by combining carbon-boron bond-forming reactions with palladium-catalyzed methylation in a tandem transformation.

New avenues for C-B bond formation via radical intermediates.

This perspective gives an overview on recent findings in the emerging area of C-radical borylation using diborons as radical trapping reagents. Aryl, vinyl and alkyl boronic esters can be accessed via such an approach under mild conditions. These processes are complementary to established transition metal catalysed cross coupling reactions. Radical borylations can be conducted in the absence of a transition metal but some processes require transition metals as catalysts. It will be shown that various readily available C-radical precursors can be used to run these borylations. For a better understanding of the chemistry, mechanistic discussions are also presented and an outlook on this topic will be provided at the end of the article.