Kazunori Nagao

Anti-Selective Vicinal Silaboration and Diboration of Alkynoates through Phosphine Organocatalysis

Trialkylphosphine organocatalysts have enabled anti-selective vicinal silaboration and diboration of the C-C triple bond in alkynoates to produce β-boryl-α-silyl acrylates and α,β-diboryl acrylates, respectively. The anti stereoselectivity was complete and robust. A variety of functional groups were tolerated in the alkynoates. The two vicinally installed heteroatom substituents of the β-boryl-α-silyl acrylates and α,β-diboryl acrylates could be differentiated and transformed in a stepwise manner, allowing the synthesis of a diverse array of unsymmetrical tetrasubstituted alkenes.

Reversible 1,3-anti/syn-stereochemical courses in copper-catalyzed γ-selective allyl-alkyl coupling between chiral allylic phosphates and alkylboranes.

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.

Phosphine-Catalyzed Anti-Carboboration of Alkynoates with Alkyl-, Alkenyl-, and Arylboranes

We found that trialkylphosphine organocatalysts promoted unprecedented anti-carboboration of alkynoates with alkyl-, alkenyl-, or arylboranes to form β-boryl acrylates. The regioselectivity of the carboboration across the polar C-C triple bond exhibited inverse electronic demand, with the less electronegative B atom being delivered to the positively charged β carbon atom. The regioselectivity and the anti stereoselectivity were both complete and robust. In addition, the substrate scope was broad with excellent functional group compatibility.

Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

Lighting the way to drug labeling It is important during drug development to study how candidate compounds get absorbed and broken down biologically. One common technique for tracking a drugs fate is to label its molecular framework with heavier isotopes of hydrogen (either deuterium or tritium). Loh et al. developed a light-promoted protocol to install these labels on alkyl carbons adjacent to nitrogen. The technique relies on incorporation of the heavy isotope into a thiol from a convenient heavy water source through acid-base chemistry. Next, a photoredox catalyst strips a hydrogen atom equivalent from the carbon, and the thiol engages in radical chemistry to transfer the deuterium or tritium in its place. Science, this issue p. 1182 A light-promoted atom transfer protocol uses heavy water to isotopically label alkyl sites for drug metabolism studies. Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.

Synthesis of 1,1‐Diborylalkenes through a Brønsted Base Catalyzed Reaction between Terminal Alkynes and Bis(pinacolato)diboron

A method for the synthesis of 1,1-diborylalkenes through a Brønsted base catalyzed reaction between terminal alkynes and bis(pinacolato)diboron has been developed. The procedure allows direct synthesis of functionalized 1,1-diborylalkenes from various terminal alkynes including propiolates, propiolamides, and 2-ethynylazoles.

Copper(I)-Catalyzed Intramolecular Hydroalkoxylation of Unactivated Alkenes

A Cu(I)-Xantphos system catalyzed the intramolecular hydroalkoxylation of unactivated terminal alkenes, giving five- and six-membered ring ethers. This system is applicable to both primary and secondary alcohols. A reaction pathway involving the addition of the Cu-O bond across the C-C double bond is proposed. A chiral Cu(I) catalyst system based on the (R)-DTBM-SEGPHOS ligand promoted enantioselective reaction with moderate enantioselectivity.

Phosphine-Catalyzed Vicinal Acylcyanation of Alkynoates

Phosphine organocatalysis enabled vicinal acylcyanation of alkynoates with acyl cyanides to form acrylonitrile derivatives with a tetrasubstituted alkene moiety. The acyl and cyano groups were introduced at the α and β carbon atoms, respectively, of the C-C triple bond in the alkynoates with complete regioselectivity and high anti stereoselectivity. A variety of functional groups in the acyl cyanides and alkynoates were tolerated.

Synthesis of Trisubstituted Alkenylstannanes through Copper‐Catalyzed Three‐Component Coupling of Alkylboranes, Alkynoates, and Tributyltin Methoxide

A versatile route to trisubstituted alkenylstannanes is presented. The alkyl and Sn moieties were introduced at the β and α carbon atoms of alkynoates, respectively, in a formal syn addition mode with complete regioselectivity. A variety of functional groups were tolerated in the alkylboranes and alkynoates.

Phosphine-Catalyzed Anti-Hydroboration of Internal Alkynes

Trialkylphosphine organocatalysts have enabled regioselective anti-hydroboration of internal alkynes with pinacolborane reagents to provide ( E)-disubstituted alkenylboronate compounds. The alkenylboronate can be used for derivatizations, such as protodeborylation, Suzuki-Miyaura coupling, conjugate reduction, and Diels-Alder reactions.

Copper-Catalyzed γ-Selective and Stereospecific Allylic Cross-Coupling with Secondary Alkylboranes.

The scope of the copper-catalyzed coupling reactions between organoboron compounds and allylic phosphates is expanded significantly by employing triphenylphosphine as a ligand for copper, allowing the use of secondary alkylboron compounds. The reaction proceeds with complete γ-E-selectivity and preferential 1,3-syn stereoselectivity. The reaction of γ-silicon-substituted allylic phosphates affords enantioenriched α-stereogenic allylsilanes.