Takahiko Akiyama

Abstract The hydrosilylation of alkenes is one of the most important methods for the synthesis of organosilicon compounds. In addition to the platinum‐catalyzed hydrosilylation, silyl radical addition reactions are notable as economic reactions. An efficient and widely applicable silyl radical addition reaction was developed by using 2‐silylated dihydroquinazolinone derivatives under photocatalytic conditions. Electron‐deficient alkenes and styrene derivatives underwent hydrosilylation to give addition products in good to high yields. Mechanistic studies indicated that the photocatalyst functioned not as a photoredox catalyst but as an energy transfer catalyst. DFT calculations clarified that the triplet excited state of 2‐silylated dihydroquinazolinone derivatives released a silyl radical through the homolytic cleavage of a carbon‐silicon bond, and this was followed by the hydrogen atom transfer pathway, not the redox pathway.

Abstract A chiral calcium phosphate-catalyzed enantioselective Friedel–Crafts alkylation reaction of pyrroles and α-trifluoromethyl-β-nitrostyrenes has been developed. Pyrroles bearing an all-carbon quaternary center at 2-position were obtained with high to excellent enantioselectivity. Use of 4,7-dihydroindole as a nucleophile and subsequent oxidation resulted in the formation a 2-substituted indole derivative with excellent enantioselectivity. A 3,4-dihydropyrrolo[1,2-c]pyrimidine derivative was successfully synthesized by reduction followed by benzoylation of the product without loss of enantioselectivity. Application to a 1 mmol scale reaction was successfully achieved.

An enantioselective Friedel-Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.

Development of efficient chiral catalyst continues to be an important challenge in the fields of synthetic organic chemistry and medicinal chemistry. Although metal-based Lewis acid catalysts had been extensively studied for the activation of carbonyl group and imine, chiral Bronsted acid has emerged in the beginning of 21st century. We synthesized chiral phosphoric acid, derived from (R)-BINOL, and demonstrated its catalytic activity in the Mannich-type reaction as a chiral Bronsted acid in 2004. Chiral phosphoric acid functioned as bifunctional catalyst bearing both basic site and Bronsted acidic site. The 3,3'-substituents play an important role. Since then, chiral phosphoric acid catalysis has become a popular research area, and its utility has been remarkably expanded. In this article, we will describe the development of chiral phosphoric acid and recent progress of the chiral phosphoric acid catalysis from our research group, in particular following topics; 1) transfer hydrogenation reaction of ketimines by use of benzothiazoline as a hydrogen donor, and oxidative kinetic resolution of indolines, 2) Friedel-Crafts alkylation reaction of indoles, and 3) enantioselective synthesis of chiral biaryls by bromination and transfer hydrogenation. In addition, several tips for using chiral phosphoric acid are also described.

The catalytic defluorinative triallylation of alpha,alpha,alpha-trifluorotoluene derivatives via C-F bond activation has been achieved by the use of the NbCl5 catalyst and allyltrimethylsilane as a nucleophile. Several control experiments have suggested the importance of the conjugation between the fluorine atoms and the carbocation center in this reaction.

Reported herein is an enantiodivergent synthesis of chiral biaryls by a chiral phosphoric acid catalyzed asymmetric transfer hydrogenation reaction. Upon treatment of biaryl lactols with aromatic amines and a Hantzsch ester in the presence of chiral phosphoric acid, dynamic kinetic resolution (DKR) involving a reductive amination reaction proceeded smoothly to furnish both R and S isomers of chiral biaryls with excellent enantioselectivities by proper choice of hydroxyaniline derivative. This trend was observed in wide variety of substrates, and various chiral biphenyl and phenyl naphthyl adducts were synthesized with satisfactory enantioselectivities in enantiodivergent fashion. The enantiodivergent synthesis of synthetically challenging, chiral o-tetrasubstituted biaryls were also accomplished, and suggests high synthetic potential of the present method.

Oxidative C(sp(3))-H bond functionalization of the 1-position of tetrahydroisoquinoline (THIQ) derivatives was performed by using diethyl azodicarboxylate (DEAD) as the oxidant. A wide range of nucleophiles, including ketene silyl acetal, silyl enol ether, nitroalkane, dimethyl malonate, terminal alkyne, ketone, phosphonate, trimethylsilyl cyanide, and allylstannane gave very high yields without their excessive use. A mechanistic study revealed that the oxidative and basic nature of DEAD is responsible for its high efficiency.

A one-pot tandem approach for the synthesis of benzothiazoles from benzyl halides and o-aminobenzenethiol was described. Benzothiazoles were obtained in high chemical yields under mild conditions in DMSO in the absence of an additional oxidant. Both benzyl chlorides and bromides bearing a range of substituents proved to be suitable substrates.

Benzothiazoline proved to be an efficient reducing agent for the phosphoric acid-catalyzed enantioselective transfer hydrogenation reaction of imines. Corresponding amines were obtained with excellent enantioselectivities.

The montmorillonite K10-catalyzed aza Diels-Alder reaction of Danishefsky's diene with aldimines, generated in situ from aliphatic aldehydes and p-anisidine, proceeded smoothly in H2O or in aqueous CH3CN to afford 2-substituted 2,3-dihydro-4-pyridones in excellent yields.

On treatment of diallyldiisopropylsilane and alpha,beta-unsaturated ketones with BF3. OEt2, 1,4-addition of an allyl moiety and subsequent intramolecular allylation onto the beta-silyl carbocation intermediate furnished domino allylation products. Oxidative cleavage of the carbon-silicon bond furnished bis-homoallylic alcohols in good yields.

On treatment of allyl-t-butyldiphenylsilane with t-BuOK and 18-Crown-6 in DMSO at room temperature, isomerization of the olefinic double bond and subsequent substitution of phenyl group with hydroxy group took place smoothly to afford alkenylsilanol derivatives in good yields.

L-Quebrachitol (1L-(-)-2-O-methyl-chiro-inositol) is a naturally abundant chiral cyclitol obtained from the serum of the rubber tree. Although total syntheses of natural products starting from L-quebrachitol have been studied extensively, asymmetric reaction employing L-quebrachitol as chiral source had not been reported. Thus diastereoselective asymmetric reaction employing chiral cyclitol (2 and 3) as chiral auxiliaries were investigated. Reduction of α-keto ester (4) derived from 1L-3-O-t-butyldimethylsilyl-1,2:5,6-di-O-cyclohexylidene-chiro-inositol, which is readily available from L-quebrachitol, with K-Selectride in Et_2O underwent highly diastereoselectively and α-hydroxy ester with 2'S isomer was obtained in 96% de. On the other hand, addition of 18-Crown-6 completely reversed the diastereoselectivity and 2'R-isomer was obtained in 92%de. While addition of Grignard reagents to the α-keto ester (4) proceeded via re-face attack of the ketone to afford α-hydroxy ester with 2'S isomer in 96% de, those of alkyl lithium took place via si-face attack to afford 2'R isomer preferentially. SnCl4 promoted addition of allyl silane or sillyl enol ether to 4 also took place to afford single diastereomer exclusively. 1,3-Dipolar cycloaddition of an acryloyl ester (5) bearing 1L-3-O-t-butyldiphenylsilyl-1,2:5,6-di-O-cyclohexylidene-chiro-inositol with nitrile oxide furnished Δ^2-isoxazolines of high diastereomeric excess. It was found chiral cyclitols derived from L-quebrachitol are efficient chiral auxiliaries.

A combination system of AlCl3-N,N-dimethylaniline was found to cleave benzyl ethers readily to give parent alcohols in excellent yields. The system also cleaved allyl as well as methyl ethers. Numerous functional groups such as benzoyloxy, phenylthio, and olefinic double bond were not affected. Comparisons of AlCl3-N,N-dimethylaniline and AlCl3-anisole were described.

Racemic 1,2:5,6-di-O-cyclohexylidene- and 1,2:3,4-di-O-cyclohexylidene-myo-inositol were resolved by enzyme catalyzed esterification in organic solvent.

A naturally occurring optically active cyclitol, L-quebrachitol (1L-2-O-methyl-chiro-inositol), was stereoselectively transformed into myo-inositol derivatives via an oxidation-reduction process. The methyl ether was cleaved chemoselectively with AlCl3-NaI in the presence of a cis-cyclohexylidene moiety with D-myo-inositol 1-phosphate being efficiently obtained.

5'-O-Acryloyl-5-fluorouridine was prepared by use of p-methoxybenzyl (PMB) group as an N3-imide protecting group of 5-fluorouridine. PMB group was introduced chemoselectively by use of N,N-diisopropylethylamine or DBU as a base. A new deprotection method was developed by means of AlCl3-anisole system at room temperature.

Various kinds of 5'-O-unsaturated acyl 5-fluorouridines were synthesized to obtain 5-fluorouridine derivatives with low toxicity and high antitumor activity. Antitumor activity of the compounds against L-1210 leukemia in mice was examined, and the 5'-O-4-opentenoyl derivative showed the highest antitumor activity.

In the presence of a chiral diamine, the magnesium salt of tolyl sulfone reacts with acetone at the α-carbon to afford the corresponding β-hydroxy adduct in good optical purity.

α-Phenylthio-α,β-unsaturated ketones are prepared in fairly good yields on treatment of α-sulfinyl ketone with stannous triflate. α-Phenylthio-α,β-unsaturated cyanides are also prepared from α-sulfinyl cyanides according to the similar procedure.