Isonitriles as Alkyl Radical Precursors in Visible Light Mediated Hydro- and Deuterodeamination Reactions.

Herein, we report the use of isonitriles as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Importantly, the method is general for Cα -primary, Cα -secondary and Cα -tertiary alkyl isonitriles. For most examples, high yields were obtained through direct visible-light irradiation of the isonitrile in the presence of a silyl radical precursor. Interestingly, in the presence of an organic photocatalyst (4CzIPN) a dramatic acceleration was observed. In-depth mechanistic studies using UV/Vis absorption, steady-state and time-resolved photoluminescence, and transient absorption spectroscopy suggest that the excited state of 4CzIPN can engage in a single-electron transfer with the isonitrile.

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 iPrOH. 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. Density functional theory (DFT) calculations provide an interpretation of these results.

Diboron reagents in the deoxygenation of nitrones.

B2nep2 efficiently promotes the N-O cleavage of nitrones to form imines in very high yields via 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.

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 sp3 -sp2 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 α1ß3γ2 GABAAR Transmembrane Domain.

GABAA receptors (GABAARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([3H]azietomidate) and mephobarbital [[3H]1-methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid ([3H]R-mTFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the α1ß3γ2 GABAAR transmembrane domain at ß +-α - (ß + sites) and α +-ß -/γ +-ß - (ß - sites) subunit interfaces. We now use competition photolabeling with [3H]azietomidate and [3H]R-mTFD-MPAB to identify para-substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to ß +, while derivatives with bulkier lipophilic substitutions [4-(tert-butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to ß - sites. Similar to R-mTFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the α +-ß - and γ +-ß - sites. However, we discovered four compounds that bind with different affinities to the two ß - interface sites. Two of these bind with higher affinity to one of the ß - sites than to the ß + sites. We deduce that 4-benzoyl-propofol binds with >100-fold higher affinity to the γ +-ß - site than to the α +-ß - or ß +-α - sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the α +-ß - site than to the ß + and γ +-ß - sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABAAR transmembrane domain, a property that may facilitate the development of subtype selective GABAAR 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. Functionalization of the carbon-boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediate.

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.

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 ß-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.

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 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.

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. Our results suggest that transmetallation, which is the enantiodetermining step, takes place with retention of stereochemistry at carbon.

Copper(I)-catalyzed formal carboboration of alkynes: synthesis of tri- and tetrasubstituted vinylboronates.

The first copper-catalyzed formal carboboration of alkynes, in which a C-B bond and a C-C bond are created in a single catalytic cycle, is presented. The reaction proceeds with high regioselectivity and syn-stereoselectivity to form tri- and tetrasubstituted vinylboronic esters from commercially available bis(pinacolato)diboron. A subsequent cross-coupling reaction gives access to highly substituted alkenes.

Expanding the scope of arylsulfonylacetylenes as alkynylating reagents and mechanistic insights in the formation of Csp2-Csp and Csp3-Csp bonds from organolithiums.

We describe the unexpected behavior of the arylsulfonylacetylenes, which suffer an "anti-Michael" addition of organolithiums producing their alkynylation under very mild conditions. The broad scope, excellent yields, and simplicity of the experimental procedure are the main features of this methodology. A rational explanation of all these results can be achieved by theoretical calculations, which suggest that the association of the organolithiums to the electrophile is a previous step of their intramolecular attack and is responsible for the unexpected "anti-Michael" reactions observed for substituted sulfonylacetylenes.

Arylsulfonylacetylenes as alkynylating reagents of Csp2-H bonds activated with lithium bases.

Chameleon: a new strategy for the synthesis of a wide variety of alkynyl derivatives by the reaction of substituted arylsulfonylacetylenes with organolithium species is described. The high yields, the simplicity of the experimental procedure, the broad scope of this reaction, and the formation of C(sp)-C(sp2) bonds without using transition metals are the main features of this methodology.

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 SRN1 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.

Sulfoxide-directed intramolecular [4 + 2] cycloadditions between 2-sulfinyl butadienes and unactivated alkynes.

Sulfinyl dienynes undergo thermal and catalyzed IMDA cycloadditions, often at room temperature, to produce cyclohexa-1,4-dienes with good yields and high selectivities. Additionally, the products preserve a synthetically useful vinyl sulfoxide functionality. The selective manipulation of the double bonds in the cycloadducts has also been examined in this work.

Asymmetric Claisen rearrangements on chiral vinyl sulfoxides.

Highly diastereoselective Claisen rearrangements of acyclic allyl vinyl ethers bearing a chiral sulfoxide at C-5 provide gamma-delta-unsaturated aldehydes or ketones with up to two consecutive asymmetric centers in the molecule whilst preserving a useful vinyl sulfoxide. The reactivity of related vinyl sulfides and sulfones has also been examined in this work.

Total synthesis of +-superstolide A.

A convergent and highly stereocontrolled synthesis of +-superstolide A (1) has been accomplished. Key steps of this synthesis include the intramolecular Suzuki reaction of 26 and the highly diastereoselective transannular Diels-Alder cyclization of macrocyclic octaene 3.