Visible-Light-Mediated Deaminative Alkylation of Primary Amines with Silacarboxylic Acids via Isonitrile Formation.

The functionalization of the C-N bond of amines is a straightforward strategy for the construction of complex scaffolds or for the late-stage functionalization of pharmaceuticals. Herein, we describe a photoredox-catalyzed strategy for the deaminative alkylation of primary amine-derived isonitriles that provides unnatural amino acid derivatives under mild conditions. The use of silacarboxylic acids as silyl radical precursors enables the generation of carbon-centered radicals that allow the construction of Csp-Csp bonds via a Giese-type addition, avoiding the undesired hydrodeamination product.

Csp-Csp Coupling of Isonitriles and (Hetero)arenes through a Photoredox-Catalyzed Double Decyanation Process.

Herein, we demonstrate the ability of isonitriles to be used as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp-Csp bond formation. This protocol allows for the preparation of functionalized heteroarenes from readily available isonitriles through a decyanation process. The reaction is general for primary, secondary, and tertiary substrates, including amino acid derivatives and druglike molecules.

Trityl isocyanide as a general reagent for visible light mediated photoredox-catalyzed cyanations.

A photoredox catalytic strategy has been developed to enable the functionalization of a variety of commercially available, structurally different radical precursors by the use of a bench-stable isonitrile as an efficient cyanating reagent. Specifically, a radical-based reaction has provided a mild and convenient procedure for the cyanation of primary, secondary and tertiary radicals derived from widely accessible sp-hybridized carboxylic acids, alcohols and halides under visible light irradiation. The reaction tolerates a variety of functional groups and it represents a complementary method for the cyanation of structurally different scaffolds that show diverse native functionalities, expanding the scope of previously reported methodologies.

Base-Induced Sulfoxide-Sulfenate Rearrangement of 2-Sulfinyl Dienes for the Regio- and Stereoselective Synthesis of Enantioenriched Dienyl Diols.

The base-induced [2,3]-sigmatropic rearrangement of a series of enantiopure 2-sulfinyl dienes has been examined and optimized using a combination of NaH and PrOH. The reaction takes place by allylic deprotonation of the 2-sulfinyl diene to give a bis-allylic sulfoxide anion intermediate that after protonation undergoes sulfoxide-sulfenate rearrangement. Different substitution at the starting 2-sulfinyl dienes has allowed us to study the rearrangement finding that a terminal allylic alcohol is determinant to achieve complete regioselectivity and high enantioselectivities (90:10-95:5) with the sulfoxide as the only element of stereocontrol.

Enantioselective Suzuki cross-coupling of 1,2-diboryl cyclopropanes.

Herein, we describe the catalytic enantioselective cross-coupling of 1,2-bisboronic esters. Prior work on group specific cross coupling is limited to the use of geminal bis-boronates. This desymmetrization provides a novel approach to prepare enantioenriched cyclopropyl boronates with three contiguous stereocenters, that could be further derivatized through selective functionalization of the carbon-boron bond.

Diboron reagents in the deoxygenation of nitrones.

Bnep efficiently promotes the N-O cleavage of nitrones to form imines in very high yields a simple, efficient, sustainable, functional group tolerant and scalable protocol. The reaction occurs in the absence of additives through a concerted mechanism. We demonstrated that DMPO and TEMPO, typically used as radical traps, are also deoxygenated by diboron reagents, which demonstrates their limitation as mechanistic probes.

Coupling of thiols and aromatic halides promoted by diboron derived super electron donors.

We have proven that pyridine-boryl complexes can be used as superelectron donors to promote the coupling of thiols and aromatic halides through a S1 mechanism. The reaction is efficient for a broad substrate scope, tolerating heterocycles including pyridines, enolizable or reducible functional groups. The method has been applied to intermediates in drug synthesis as well as interesting functionalized polythioethers through a controlled and consecutive intramolecular electron transfer process.

Regioselective Monoborylation of Spirocyclobutenes.

We present a strategy for the synthesis of spirocyclic cyclobutanes with modulable exit vectors based on the regioselective monoborylation of spirocyclobutenes. Using an inexpensive copper salt and a commercially available bidentate phosphine, a broad variety of borylated spirocycles have been prepared with complete regiocontrol. The boryl moiety provides a synthetic handled for further functionalization, allowing access to a wide array of spirocyclic building blocks from a common intermediate.

Stereoselective Diboration of Spirocyclobutenes: A Platform for the Synthesis of Spirocycles with Orthogonal Exit Vectors.

The diastereo- and enantioselective diboration of spirocyclobutenes provides a platform for the rapid preparation of a wide variety of chiral spirocyclic building blocks. The chemoselective functionalization of the carbon-boron bond in the products, including a stereospecific sp -sp Suzuki-Miyaura cross-coupling reaction, provides a powerful tool to control the directionality and the nature of the exit vectors in the spirocyclic framework.

Copper, Boron and Vinyl Epoxides: from 1,4-Diols to Cyclopropylboronates.

Herein we describe the reactivity found between vinyl epoxides and catalytically generated copper-boryl complexes. By tuning the substituents of the alkene and/or the reaction conditions, 1,4-diols, allylic alcohols or cyclopropylboronates can be prepared. The stereochemical information of the vinyl epoxide is transferred to the products with high levels of stereocontrol.

Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the 132 GABAR Transmembrane Domain.

GABA receptors (GABARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs).

Stereospecific Synthesis of α-Hydroxy-Cyclopropylboronates from Allylic Epoxides.

Herein, we report a catalytic and stereospecific method for the preparation of enantioenriched α-hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared.

Copper-catalysed cross-coupling of alkyl Grignard reagents and propargylic ammonium salts: stereospecific synthesis of allenes.

Herein we describe a robust and practical method to prepare enantiomerically enriched trisubstituted allenes using alkyl Grignard reagents and bench stable propargylic ammonium salts. Excellent yields as well as regio- and stereoselectivities are observed. Our conditions provide a solution to the allene racemization, which has been a long-standing problem when using Grignard reagents.

Copper-Catalyzed Enantioselective Synthesis of β-Boron β-Amino Esters.

In this report, the enantioselective, copper-catalyzed borylation of β-amidoacrylates is disclosed. A broad variety of biologically important α-aminoboronates has been prepared with consistently high levels of enantiocontrol using an inexpensive copper catalyst and a commercially available chiral ligand. The method can be applied to the synthesis of novel boron-containing dipeptides and hemiboronates.

Stereoselective Traceless Borylation-Allenation of Propargylic Epoxides: Dual Role of the Copper Catalyst.

Chiral α-allenols are prepared with high diastereocontrol through an unprecedented and spontaneous β-oxygen elimination of an α-epoxy vinyl boronate. Stochiometric experiments and DFT calculations support a dual role of the copper catalyst, which orchestrates the hydroboration and the syn-elimination step.

Regio- and Stereospecific Copper-Catalyzed Substitution Reaction of Propargylic Ammonium Salts with Aryl Grignard Reagents.

We have developed a copper-catalyzed substitution reaction of propargylic ammonium salts with aryl Grignard reagents. The reaction is stereospecific and α-regioselective and proceeds with exceptional functional group tolerance. Conveniently, a stable, inexpensive, and commercially available copper salt is used and no added ligand is required.

Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors.

Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells.

Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach.

The first catalytic enantioselective synthesis of cyclobutylboronates, by using a chiral copper(I) complex, is reported. A broad variety of cyclobutanes have been prepared with consistently high levels of diastereo- and enantiocontrol. Moreover, this method constitutes the first report of an enantioselective desymmetrization of meso-cyclobutenes to prepare chiral cyclobutanes.

Copper-Catalyzed Borylative Aromatization of -Quinone Methides: Enantioselective Synthesis of Dibenzylic Boronates.

In this report, we establish that DM-Segphos copper(I) complexes are efficient catalysts for the enantioselective borylation of -quinone methides. This method provides straightforward access to chiral monobenzylic and dibenzylic boronic esters, with enantiomeric ratios up to 96:4, using a commercially available chiral phosphine. Standard manipulations of the C-B bond afford a variety of chiral diaryl derivatives.

Copper-catalyzed silylation of p-quinone methides: new entry to dibenzylic silanes.

An efficient and general copper(I)-catalyzed silylation of p-quinone-methides is described. Non-symmetric dibenzylic silanes are obtained in high yields under mild reaction conditions. These compounds can be used as bench-stable benzylic carbanion precursors.

Copper-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes: synthesis of cyclopropylboronates.

A novel Cu-catalyzed diastereo- and enantioselective desymmetrization of cyclopropenes to afford nonracemic cyclopropylboronates is described. Trapping the cyclopropylcopper intermediate with electrophilic amines allows for the synthesis of cyclopropylaminoboronic esters and demonstrates the potential of the approach for the synthesis of functionalized cyclopropanes.

Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH).