Copper-Catalyzed Diastereoselective Borylative Allylation of Alkenyl Sulfones and Base-Controlled Synthesis of Skipped Dienes.

Divergent functionalization of α,ß-unsaturated sulfones under copper catalysis is reported. Diastereoselective borylative allylation of alkenyl sulfones was achieved with a copper catalyst, allyl phosphate, bis(pinacolato)diboron, and LiOMe. In this method, the addition of a copper-boryl complex to alkenyl sulfone and subsequent allylic substitution rendered boroallylated products in good yield with excellent syn-diastereoselectivity. In contrast, a stronger base (KOt-Bu) promoted the reaction further toward the formation of (E)-skipped dienes, through elimination of the sulfonyl and boryl groups.

Asymmetric Synthesis of ß-Aminoboronates via Copper-Catalyzed Reductive Coupling of Vinyl Boronates with Imines.

We report a copper-catalyzed asymmetric reductive coupling of vinyl boronates with imines, which directly access enantiomerically enriched ß-aminoalkylboronates. Stereoselective addition of the in situ generated chiral α-borylalkyl copper to N-phosphinoyl imines provided target products in good yields with high diastereo- and enantioselectivity. Vinyl boronate with methylated acenaphthoquinone as a boron ligand was essential to efficiently spawn asymmetric products, and organic transformations of the boron moiety, along with the easily removable N-protecting group, proved their synthetic utility.

Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

Copper-catalysed asymmetric reductive cross-coupling of prochiral alkenes.

Asymmetric construction of C(sp3)-C(sp3) bond with good stereocontrol of the two connecting carbon centres retaining all carbon or hydrogen substituents is a challenging target in transition metal catalysis. Transition metal-catalysed reductive coupling of unsaturated π-substrates is considered as a potent tool to expediently develop the molecular complexity with high atom efficiency. However, such an asymmetric and intermolecular process has yet to be developed fully. Herein, we report an efficient strategy to reductively couple two prochiral conjugate alkenes using a copper-catalysed tandem protocol in the presence of diboron. Notably, this transformation incorporates a wide range of terminal and internal enynes as coupling partners and facilitates highly diastereo- and enantioselective synthesis of organoboron derivatives with multiple adjacent stereocentres in a single operation.

Enantioselective Cyclopropanation/[1,5]-Hydrogen Shift to Access Rauhut-Currier Product.

A Michael addition initiated cyclopropanation/[1,5]-hydrogen shift has been developed for the enantioselective synthesis of Rauhut-Currier products. The reaction of α-alkyl diazoesters and in situ generated o-quinone methides proceeds in the presence of chiral oxazaborolidinium ion, providing Z-stereocontrolled Rauhut-Currier products in high yields (up to 96%) with excellent Z/E selectivities (>20:1) and enantioselectivities (up to >99% ee). The synthetic utility was illustrated by conversion of the product to 3,4-dihydrocoumarins with two adjacent chiral stereocenters.

Asymmetric Conjugate Addition of Chiral Secondary Borylalkyl Copper Species.

We report the diastereo- and enantioselective conjugate addition of chiral secondary borylalkyl copper species derived from borylalkenes in situ to α,ß-unsaturated diesters. In the presence of a chiral bisphosphine-ligated CuH catalyst, the conjugate addition provides a direct access to enantioenriched alkylboron compounds containing two contiguous carbon stereogenic centers in good yield with high diastereo- and enantioselectivity (up to >98:2 dr, >99:1 er) by assembling readily available starting alkenyl reagents in a single operation without using preformed organometallic reagents or chiral auxiliaries. The resulting products were used in various organic transformations. The utility of the synthetic approach was highlighted by the synthesis of (-)-phaseolinic acid.

Asymmetric Synthesis of 1,2-Dihydronaphthalene-1-ols via Copper-Catalyzed Intramolecular Reductive Cyclization.

We describe a copper-catalyzed intramolecular reductive cyclization of easily accessible benz-tethered 1,3-dienes containing a ketone moiety. This process provided biologically active 1,2-dihydronaphthalene-1-ol derivatives in good yields with excellent enantio- and diastereoselectivity. Mechanistic investigations using density functional theory revealed that (Z)- and (E)-allylcopper intermediates formed in situ from the diene and copper catalyst undergo isomerization and selective intramolecular allylation of the (E)-allylcopper form of the major product through a six-membered boatlike transition state. The resulting products were further transformed to fully saturated naphthalene-1-ols by reactions of the olefin moiety.

Four-Channel Monitoring System with Surface Acoustic Wave Sensors for Detection of Chemical Warfare Agents.

Recently, efforts have been made to adapt surface acoustic waves (SAWs) for use in chemical sensors for detection of chemical warfare agents (CWAs). In this study, a four-channel real-time CWA detection system was constructed using four 250-MHz SAW sensors. Each system consists of three different chemical sensors and one reference sensor. The reference sensor compensates for frequency variations according to humidity and temperature conditions. Signals from the SAW sensors can be checked on a PC-based graphical user interface without additional measuring equipment. To measure dimethyl methylphosphonate (DMMP), a simulant of sarin gas, polyhedral oligomeric silsesquioxane (POSS) and thiourea (TU)-based synthetic polymers were used as sensing materials. The reference sensor was not coated, whereas the three different chemical sensors were coated with POSS, TU-1, and TU-2. The maximum frequencies of POSS, TU-1, and TU-2 were shifted 15.86, 13.85, and 0.944 kHz, showing significant values. We also found a relatively good linear relation between the frequency shift and the concentration of DMMP. The three sensing materials selected-POSS, TU-1, and TU-2-responded significantly to DMMP and triethylphosphate in the selectivity tests. This response is due to the chemical bonding of the sensing materials with the phosphonate in the nerve-agent simulants. These results indicate that the four-channel SAW monitoring system described in this paper shows potential as a portable real-time monitoring system to detect a variety of toxic vapors simultaneously, without using complex measuring equipment. In addition, this approach has demonstrated potential for developing excellent portable sensors to detect different types of CWAs.

Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst.

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective SN2'-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper-DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.

Direct Stereoconvergent Allylation of Chiral Alkylcopper Nucleophiles with Racemic Allylic Phosphates.

Copper-catalyzed stereoconvergent allylation of chiral sp3 -hybridized carbon nucleophiles with a racemic mixture of acyclic secondary allylic phosphates is reported. In the presence of a copper-catalyst complexed with chiral BenzP* ligand, tandem coupling reaction of vinyl arenes, bis(pinacolato)diboron, and racemic allylic phosphates provided ß-chiral alkylboronates possessing (E)-alkenyl moiety through a direct stereoconvergent allylic coupling with concomitant generation of a C(sp3 )-stereogenic center. A range of vinyl (hetero)arenes and secondary allylic phosphates bearing 1°, 2°, 3° alkyl and phenyl α-substituents were suitable for the reaction, forming products with high enantioselectivities up to 95 % ee. Density functional theory calculations were conducted in detail to elucidate the origin of the observed regioselectivity of borylcupration and stereoconvergent (E)-olefin formation from racemic allylic phosphates.

Asymmetric Synthesis of 1-Benzazepine Derivatives via Copper-Catalyzed Intramolecular Reductive Cyclization.

An asymmetric construction of enantioenriched 2,3-substituted-1-benzazepine derivatives containing a cyclic tertiary amine moiety was developed by copper-catalyzed reductive intramolecular cyclization of (E)-dienyl arenes with a tethered ketimine. This protocol involves tandem chemo-, regio-, and enantioselective hydrocupration and asymmetric cyclization in the presence of a chiral bisphosphine-copper catalyst. Under mild conditions, a broad range of 1-benzazepine derivatives was obtained in good to high yields with high degrees of diastereoselectivity and enantioselectivity.

Copper-Catalyzed Asymmetric Reduction of ß,ß-Disubstituted Alkenylboramides.

A highly enantioselective copper-catalyzed reduction of ß,ß-disubstituted alkenylboron compounds was developed using hydrosilane. The copper hydride catalyst coordinated with chiral Josiphos ligand efficiently discriminated ß-geminal substituents to generate corresponding ß-chiral alkylboramides with excellent enantioselectivities up to 99% ee. The enantioselective reduction protocol provides a facile approach to ß-chiral alkylboron compounds with less sterically discriminating substituents and spans a wide substrate range including aryl-substituted borylalkenes with effective functional group tolerance.

Catalytic Asymmetric Conjugate Addition of a Borylalkyl Copper Complex for Chiral Organoboronate Synthesis.

We report the catalytic enantioselective conjugate addition of a borylalkyl copper nucleophile generated in situ from a 1,1-diborylmethane derivative to α,ß-unsaturated diesters. In the presence of a chiral N-heterocyclic carbene (NHC)-copper catalyst, this method facilitated the enantioselective incorporation of a CH2 Bpin moiety at the ß-position of the diesters to yield ß-chiral alkyl boronates in up to 86 % yield with high enantioselectivity. The alkylboron moiety in the resulting chiral diester products was converted into various functional groups by organic transformation of the C-B bond.

Asymmetric synthesis of α-chiral ß-hydroxy allenes: copper-catalyzed γ-selective borylative coupling of vinyl arenes and propargyl phosphates.

Copper-catalyzed enantioselective coupling of vinyl arenes with bis(pinacolato)diboron (B2pin2) and propargylic phosphates is presented. The protocol affords a facile route to enantioenriched α-branched allenes with a versatile pinacolboronate group at the ß-position with high enantioselectivity up to 98 : 2 er. In the presence of a copper catalyst complexed with a chiral bisphosphine ligand, catalytic assembly of α-chiral ß-hydroxy allenes was accomplished through highly selective γ-addition of a borylalkyl copper species to propargyl substrates, followed by oxidation. Catalyst-controlled divergent cyclization reactions of the resulting allenes led to concise syntheses of enantioenriched dihydropyran and dihydrofuran rings without any loss of chiral purity.

NHC-copper-thiophene-2-carboxylate complex for the hydroboration of terminal alkynes.

An air-stable N-heterocyclic carbene-copper thiophene-2-carboxylate (CuTC) complex has been prepared for the stereoselective hydroboration of terminal alkynes using pinacolborane (HBpin) or 1,8-naphthalenediaminatoborane (HBdan). The newly synthesized complex can be directly activated by hydroboranes without a cocatalyst such as a base, and exhibits high reactivity for the hydroboration of alkynes under mild conditions. A gram-scale hydroboration of terminal phenylacetylene demonstrated the applicability of the copper complex for the preparation of alkenyl boronates.

Asymmetric Synthesis of γ-Hydroxy Pinacolboronates through Copper-Catalyzed Enantioselective Hydroboration of α,ß-Unsaturated Aldehydes.

We report a copper-catalyzed enantioselective hydroboration of α,ß-unsaturated aldehydes with pinacolborane. α,ß-Unsaturated aldehydes were converted to the corresponding γ-pinacolboronate alcohols in good yields and enantioselectivities through consecutive hydroboration of the C═O and C═C bonds. This process provides simple access to the hydroborated product of allylic alcohols, and the resulting γ-pinacolboronate alcohols could be utilized in various transformations.

Copper(I)-Catalyzed Enantioselective 1,6-Borylation of α,ß,γ,δ-Unsaturated Phosphonates.

Copper(I)-catalyzed asymmetric 1,6-borylation of 1,3-dienylphosphonates was achieved using ( S, S)-Ph-BPE as a chiral ligand. Regio-, stereo-, and enantioselective borylation successfully proceeded to afford phosphonate-containing allylboronates, with high enantioselectivity up to 97% ee. Further applications of the resulting products generated a valuable phosphonate analogue of γ-butyrolactone.

Copper-Catalyzed Regioselective and Diastereoselective Synthesis of Borylated 1-Benzo[ b]azepines.

A practical regioselective and diastereoselective synthesis of functionalized 1-benzo[ b]azepines by copper-catalyzed intramolecular cyclization has been developed. The reaction involves borylcupration of a mixture of ( E/ Z)-1,3-dienes, followed by capture of the generated ( Z)-allylcopper species with an imine to produce 7-membered N-heterocycles as single diastereomers. The reaction is applicable to various ( E/ Z)-dienyl arenes with an imine moiety at the ortho-position, including aryl, alkyl, and heterocyclic aldimines, and ketimines, affording borylated 2,3- cis-substituted 1-benzo[ b]azepines in good yields.

Copper-Catalyzed Tandem Hydrocupration and Diastereo- and Enantioselective Borylalkyl Addition to Aldehydes.

We report the copper-catalyzed stereoselective addition of in situ generated chiral boron-α-alkyl intermediates to various aldehydes including α,ß-unsaturated aldehydes under mild conditions. This tandem and multicomponent method facilitated the synthesis of enantiomerically enriched 1,2-hydroxyboronates bearing contiguous stereocenters in good yield with high diastereo- and enantioselectivity up to a ratio greater than 98:2. In particular, α,ß-unsaturated aldehydes were successfully used as electrophiles in Cu-H catalysis through 1,2-addition without significant reduction. The resulting 1,2-hydroxyboronates were used in various transformations.

Detection of Dimethyl Methylphosphonate (DMMP) Using Polyhedral Oligomeric Silsesquioxane (POSS).

The detection and monitoring of colorless and odorless chemical warfare agents (CWAs) has become important due to the increasing threat of terrorist activities. To enhance the sensitivity and selectivity of CWAs a number of sensing materials have been developed, including the widely used polyvinylidene fluoride (PVDF). However, PVDF is limited by its low sensitivity and selectivity for many CWAs. In this study, polyhedral oligomeric silsesquioxane (POSS) was used as a sensing material for dimethyl methylphosphonate (DMMP) a simulant of sarin nerve gas. Sensitivity, selectivity, and reusability were investigated with an AT-cut 5 MHz quartz crystal microbalance. At room temperature, POSS exhibited a strong response for DMMP vapor at different concentrations from 20 ppm to 120 ppm leading to fast chemical adsorption and desorption. To investigate selectivity the volatile organic compounds (VOCs) ethanol, water, toluene, ACN, methanol, and n-hexane were tested at a fixed flow rate. Targeted VOCs showed lower responses than DMMP as measured with a quartz crystal microbalance (QCM) sensor, demonstrating the high selectivity of the method. POSS can be considered a potentially useful material for sensing nerve simulants.