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C–H functionalization has recently received considerable attention because C–H functionalization during the late-stage transformation is a strong and useful tool for the modification of the bioactive compounds and the creation of new active molecules. Although a carbene transfer reaction can directly convert a C–H bond to the desired C–C bond in a stereoselective manner, its application in late-stage material transformation is limited. Here, we observed that the iridium–salen complex 6 exhibited efficient catalysis in asymmetric carbene C–H insertion reactions. Under optimized conditions, benzylic, allylic, and propargylic C–H bonds were converted to desired C–C bonds in an excellent stereoselective manner. Excellent regioselectivity was demonstrated in the reaction using not only simple substrate but also natural products, bearing multiple reaction sites. Moreover, based on the mechanistic studies, the iridium-catalyzed unique C–H insertion reaction involved rate-determining asynchronous concerted processes.

Iron-catalyzed asymmetric oxidative dearomatization of methylenebis(arenol)s, readily prepared from salicyl alcohol and naphthol derivatives under microwave irradiation, was developed using dioxygen in air as an oxidant. Various enantioenriched spirocyclic compounds were obtained with up to 89% chemical yield and 87% ee.

Nitrogen functional groups are found in many biologically active compounds and their stereochemistry has a profound effect on biological activity. Nitrene transfer reactions such as aziridination, C-H bond amination, and sulfimidation are useful methods for introducing nitrogen functional groups, and the enantiocontrol of the reactions has been extensively investigated. Although high enantioselectivity has been achieved, most of the reactions use (N-arylsulfonylimino)phenyliodinane, which co-produces iodobenzene, as a nitrene precursor and have a low atom economy. Azide compounds, which give nitrene species by releasing nitrogen, are ideal precursors but rather stable. Their decomposition needs UV irradiation, heating in the presence of a metal complex, or Lewis acid treatment. The examples of previous azide decomposition prompted us to examine Lewis acid and low-valent transition-metal complexes as catalysts for azide decomposition. Thus, we designed new ruthenium complexes that are composed of a low-valent Ru(II) ion, apical CO ligand, and an asymmetry-inducing salen ligand. With these ruthenium complexes and azides, we have achieved highly enantioselective nitrene transfer reactions under mild conditions. Recently, iridium-salen complexes were added to our toolbox.

The new Ru(CO)—salen complex RUCAL is used as an effective catalyst for asymmetric benzylic and allylic C—H bond amination using 2-(trimethylsilyl)ethanesulfonyl azide as the nitrene source.

Titanium(salalen) complex 1 was an effective catalyst for asymmetric epoxidation of enol esters. Although (E)-enol esters were reluctant to proceed, (Z)-enol esters underwent asymmetric epoxidation to give the epoxides in high yields with high enantioselectivity ranging from 86 to >99% ee in the presence of aqueous hydrogen peroxide as the stoichiometric oxidant. Complete enantioselectivity was observed in the reaction of (Z)-3,3-dimethylbut-1-en-1-yl 4-methoxybenzoate. The obtained epoxide was readily transformed into the corresponding 1,2-diol by reduction with lithium borohydride without erosion of the high enantiomeric excess.

Aluminum(salalen) complex 1 [salalen = half-reduced salen, salen = N,N'-ethylenebis(salicylideneiminato)] was found to be a highly efficient catalyst for asymmetric oxidation of cyclic dithioacetals in the presence of 30% hydrogen peroxide as an oxidant. In the reaction of a series of 2-substituted 1,3-dithianes bearing alkyl, alkenyl, alkynyl, and aryl groups as the substituent, the trans-monoxides were obtained in high yields with 19:1 → >20:1 dr (diastereomeric ratio) and 98-99% ee (enamtiomeric excess). The reaction of nonsubstituted 1,3-dithiane also proceeded in a highly enantioselective manner to give the monoxide with a small formation of the trans-1,3-dioxide, an overoxidation product. Five-membered 1,3-dithiolanes and seven-membered 1,3-dithiepanes also underwent oxidation to give monoxides with high diastereo- and enantioselectivity. It was found that the equilibrium between the two chairlike conformers of dithianes has relevance to the observed diastereoselectivity in the first oxidation process, and the dioxide formation in the oxidation of 1,3-dithiane and its stereochemistry also can be explained by the conformational equilibrium of the product monoxide.

Ru(NO)-salen complexes were found to catalyze asymmetric aerobic oxygen atom transfer reactions such as sulfide oxidation and epoxidation in the presence of water under visible light irradiation at room temperature. Oxidation of sulfides including alkyl aryl sulfides and 2-substituted 1,3-dithianes using complex 2 as the catalyst proceeded with moderate to high enantioselectivity of up to 98% ee, and epoxidation of conjugated olefins using complex 3 as the catalyst proceeded with good to high enantioselectivity of 76-92% ee. Unlike biological oxygen atom transfer reactions that need a proton and electron transfer system, this aerobic oxygen atom transfer reaction requires neither such a system nor a sacrificial reductant. Although the mechanism of this oxidation has not been completely clarified, some experimental results support the notion that an aqua ligand coordinated with the ruthenium ion serves as a proton transfer agent for the oxygen activation process, and it is recycled and used as the proton transfer mediator during the process. Thus, we have achieved catalytic asymmetric oxygen atom transfer reaction using molecular oxygen that can be carried out under ambient conditions.

Based on the analysis of the mechanism of aerobic oxidation of alcohols using Ru(NO)-salen catalyst, we designed a new complex, Ru(PPh3)(OH)-salen 3, which was proved to be an excellent catalyst for chemoselective aerobic oxidation of primary alcohols to the aldehydes in the presence of secondary alcohols under ambient and non-irradiated conditions. Complex 3 was also successfully applied to the oxidation of 1-phenyl-1,n-diols to the lactols or the n-hydroxy aldehyde. It is of note that selective oxidation of primary alcohols was achieved even in the presence of activated secondary alcohols.

The scope of asymmetric oxidation of sulfides using Fe(salan) complex as a catalyst and aqueous hydrogen peroxide as an oxidant in water was broadened by optimizing the reaction conditions with respect to reaction temperature, catalyst loading, and amount of water solvent. The oxidation proceeded with high enantioselectivity under the optimized conditions. The undesired over-oxidation of the resultant sulfoxides was significantly suppressed and the yields of sulfoxides were improved. Various functional groups were tolerant of the conditions.

Asymmetric oxidation catalysis with an aluminum-based complex was achieved by a combination of newly synthesized chiral aluminum(salalen) complexes (salalen = half-reduced salen = salan/salen-hybridized [ONNO]-type tetradentate ligand; salan = reduced salen, salen = N,N'-ethylenebis(salicylideneiminato)) derived from binol (1,1'-bi-2,2'-naphthol) with aqueous hydrogen peroxide as the oxidant. The combination was found to be efficient for asymmetric sulfur oxidation. Various sulfides were smoothly converted into the corresponding sulfoxides with high to excellent enantioselectivity. Thioacetals are also good substrates for the oxidation.

Ti(salan) complexes were found to be efficient catalysts for asymmetric epoxidation with aqueous hydrogen peroxide as the oxidant. In the presence of pH 7.4 phosphate buffer, the reaction of various conjugate olefins proceeded smoothly to afford the corresponding epoxides in high yield with high enantioselectivity, even on a multigram scale. Ti(salan) complexes could be prepared from Ti(OiPr)4 and the corresponding salan ligand and directly used without isolation and purification.

Chiral Ru(salen)(nitrosyl) complex 1 is a useful catalyst for asymmetric aerobic oxidation of alcohols under photo-irradiation. In this study, it was found that addition of β-hydroxy ketone or 1,3-diketone had a significant influence on its asymmetric catalysis. For example, the addition of 1,3-bis(p-bromophenyl)propane-1,3-dione 9 improved the relative reaction ratio in kinetic resolution of simple racemic secondary alcohols up to 30, while the addition gave an adverse effect on desymmetrization of an acyclic meso-1,3-diol. This additive effect was considered to be attributable to the chelate formation of the β-hydroxy ketone or 1,3-diketone with a Ru(salen) complex.

An optically active tripodal amine, (2 S,6 S)-2,6-bis( O-hydroxyphenyl)-1-(2-pyridylmethyl)piperidine, was proven to be a potent chiral catalyst (1-5 mol%) for methanolytic asymmetric desymmetrization of cyclic MESO-anhydrides to hemiesters. A good level of enantioselectivities (up to 81% ee) was achieved for various substrates, some of which were reported to be poor substrates for methanolysis using known chiral amines as catalysts.

A new optically active functionalized tertiary amine, (2R,6R)-2,6-bis(2-hydroxyphenyl)-1-(2-pyridylmethyl)piperidine {(R,R)-1}, was synthesized and its complexation behavior as a tripodal ligand was elucidated with titanium(IV) ion. Protonolysis of Ti(OPr-i)4 with (R,R)-1 and H2O in a stepwise manner led to the formation of C3-symmetric tris(μ-oxo)trititanium(IV,IV,IV) complex [Ti3L3(μ-O)3] {L = diphenolato anion of (R,R)-1} with unified chiralities induced at the metal center (A) and by the conformations of the N∧O chelate loops (λ) as well as the six-membered non-planner chair-like (Ti-μ-O)3 ring core as defined by X-ray crystallography. These stereochemical issues are principally regulated by the stereogenic centers on the ligand and a chair conformation of the piperidine skeleton, which settle an enantiotopos-differentiating cis(Ophenolato–Ophenolato) binding mode by unequivocally locating one Ophenolato in an axial position and the other Ophenolato in an equatorial plane.

Readily available α-diazo compounds have been shown to be efficient carbene precursors for asymmetric cyclopropanation using ruthenium(NO)-salen and cobalt-salen complexes, as catalysts. The stereoselectivity of the cyclopropanation depends on the metal ion, its valency, the structural and electronic nature of the salen ligand, and the apical ligand of the salen complex used. Both trans- and cis-selective asymmetric intermolecular cyclopropanation can be realized under mild conditions by using a suitable metallosalen complex. Furthermore, a wide range of alkenyl α-diazoacetates and the related alkenyl diazomethyl ketones undergo intramolecular cyclopropanation in a highly enantioselective manner by using various metallosalen complexes, easily prepared in a modular fashion, as catalyst.

A newly designed robust Ru(salen)(CO) complex 3 was found to catalyze asymmetric aziridination using azide compounds carrying p-nitrobenzenesulfonyl and 2-(trimethylsilyl)ethanesulfonyl (SES) groups, which are easily removable N-protecting groups under mild conditions, as a nitrene precursor in a highly enantioselective manner. In particular, the reactions with SES azide showed excellent enantioselectivity greater than 90% ee, except for one example.

Azide compounds that are readily available and easily manageable, are desirable nitrogen sources for nitrogen-atom-transfer reactions such as aziridination and sulfimidation, in terms of atom-effic...

N,N,N′,N′-Tetra-n-butyl-BINOL-3,3′-dicarboxamide 5d was found to promote phenyl transfer from ethylphenylzinc to both aromatic and aliphatic aldehydes with high enantioselectivity up to 96% ee in tert-butyl methyl ether.

The mechanism of aerobic oxidation of alcohols using (ON)Ru(salen) complex as catalyst under photo-irradiation was examined through studies of kinetics of the oxidation, kinetic isotope effect in the oxidation, and effect of the ligand structure on the chemoselectivity of the oxidation of primary and secondary alcohols. It was demonstrated that the aerobic oxidation includes an intramolecular hydrogen atom transfer process that is attributed to realization of efficient differentiation of primary and secondary alcohols in the oxidation.

Newly designed phosphino-phenol 1c was found to be an efficient chiral auxiliary for copper-mediated asymmetric conjugate addition of diethylzinc to acyclic enones. High enantioselectivity up to >99% ee was achieved in the reaction of acyclic α,β-enones.

Chemoselective aerobic oxidation of primary alcohols in the presence of activated secondary alcohols was effected under irradiation of visible light by using (nitrosyl)Ru(salen) complex 6 that possesses bulky 1-ethyl-1-methylpropyl groups at C3, C3′, C5 and C5′, as catalyst. For example, oxidation of n -decanol was >50 times faster than oxidation of 1-phenylethanol at 10 °C.

Palladium-catalyzed asymmetric tandem allylic substitution of (Z)-1,4-diacyloxy- and (Z)-1,4-bis(alkoxycarbonyloxy)-2-butene (2a–c ) using 2-(phosphinophenyl)pyridine 1 as chiral ligand provided optically active six-membered 2-vinyl-1,4-diheterocyclic compounds with good to high enantioselectivity. For example, the reactions with catechol, 2-(benzylamino)phenol, or 1,2-bis(benzylamino)ethane as a nucleophile gave 2-vinyl-1,4-benzodioxane (71% ee), 4-benzyl-2-vinyl-1,4-benzoxazine (86% ee), and 1,4-dibenzyl-2-vinylpiperazine (86% ee), respectively.

Pentagonal bipyramidal Hf(salen) complex 1 was found to serve as a catalyst for 1,4-addition reaction of thiol to N -(2-alkenoyl)-2-oxazolidinones.

Mukaiyama aldol reactions of silyl dienol ether and aldehydes proceeded with high enantioselectivity to give δ-hydroxy-β-keto ester derivatives by using chiral cationic Cr(salen) complex as catalyst in the presence of isopropyl alcohol and base (triethylamine or 2,6-dimethylpyridine).

Selective oxidation of alcohols to the corresponding carbonyl compounds is one of the most fundamental reactions in organic synthesis. Traditional methods for this transformation generally rely on stoichiometric amount of oxidants represented by Cr(VI) or DMSO reagents, though their synthetic utility is encumbered by unpleasant waste materials. From ecological and atom-economic viewpoints, catalytic aerobic oxidation is much more advantageous because molecular oxygen is ubiquitous and the byproduct is basically non-toxic water or hydrogen peroxide. On the other hand, phenol derivatives undergo oxidative coupling, forming CC or CO bond, through radical intermediates coupled with an electron-transfer process. Molecular oxygen is also well known to serve as electron acceptor in this reaction. Thus, a variety of transition metal complexes have so far been examined for aerobic oxidations of alcohols and phenols, and high catalytic activities have been achieved in some cases. However, stereo- and chemo-selective aerobic oxidations are still limited in number and are of current interest. Presented in this paper is our recent studies on catalytic aerobic oxidations with photoactivated nitrosyl ruthenium-salen complexes, including asymmetric oxidation of secondary alcohols to ketones (kinetic resolution), enantioselective oxidative coupling of 2-naphthols to binaphthols and oxygen-radical bicyclization of 2,2′-dihydroxystilbene, chemoselective oxidation of primary alcohols to aldehydes and diols to lactols, and asymmetric desymmetrization of meso-diols to lactols. © 2004 The Japan Chemical Journal Forum and John Wiley & Sons, Inc. Chem Rec 4: 96–109; 2004: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20001

An in situ generated Zn complex of salen ligand 4 was found to serve as an efficient catalyst for asymmetric addition reaction of an alkynylzinc reagent to various ketones. For example, addition of phenylacetylene to 3,3-dimethyl-2-butanone using the Zn complex as catalyst showed enantioselectivity as high as 91% ee.

Spectroscopic analysis of imidation of alkyl aryl sulfides with N -2,2,2-trichloro-1,1-dimethylethyloxycarbonyl azide 2 in the presence of (OC)Ru(salen) complex 1 strongly suggests that an addition compound of the azide 2 to 1 is the active species for the imidation, while the addition compound undergoes the undesired intramolecular CH insertion onto the salen ligand of the complex in the absence of sulfide, directly or via the corresponding nitrene–ruthenium species.

Intramolecular cyclopropanation of alkenyl α-diazoacetates and alkenyl diazomethyl ketones was examined by using optically active (ON + )Ru(II)(salen) and Co(II)(salen) complexes as catalysts. For the cyclization of 2-alkenyl α-diazoacetates, Co(II)(salen) complexes 9 and 10 were found to be superior catalysts to the corresponding (ON + )Ru(II)(salen) complexes 4 and 5 . On the other hand, (ON + )Ru(II)(salen) complex 2 was found to be the catalyst of choice for the cyclization of 3-alkenyl diazomethyl ketones, and complex 4 was found to be a good catalyst for the cyclization of ( E )-4-alkenyl diazomethyl ketones. The present study demonstrates that metallosalen complexes, especially optically active (ON + )Ru(II)(salen) and Co(II)(salen) complexes, can serve as efficient catalysts for the cyclization of alkenyl diazocarbonyl compounds, if a suitable salen ligand is used as the chiral auxiliary.

Newly introduced Pd-catalyzed asymmetric intramolecular allylic amination provides an easy access to pharmaceutically important 1-substituted tetrahydroisoquinolines. With this amination as the key step, (R)-carnegine wassynthesized in an enantioselective manner.

Chiral cationic palladium(II) 2-(phosphinophenyl)pyridine (1a) complex was found to be an effective catalyst for asymmetric Baeyer-Villiger oxidation of prochiral cyclobutanones. For example, good and excellent enantioselectivities (80% and >99% ees) were achieved in the reactions of 3-phenylcyclobutanone and a tricyclic cyclobutanone, respectively.

During studies of aziridination of α,β-unsaturated amides with diaziridine, we found that we could prepare both the cis- and trans-aziridinecarboxamides by choosing an appropriately substituted diaziridine. While 3-monosubstituted diaziridine 2 was suitable for the trans-selective aziridination, employment of 3,3-dialkyldiaziridine 1 resulted in the formation of cis-aziridine carboxamides, irrespective of the geometry of the substrate (Scheme 1 and Tables 1 and 2). To elucidate the unique nonstereospecificity and to expand these aziridinations to asymmetric ones, several optically active diaziridines were newly prepared. Aziridination with an optically active 3-monosubstituted diaziridine, 3-cyclohexyl-1-[(1R)-1-phenylethyl]diaziridine 16, proceeded smoothly with high trans-selectivity as well as excellent enantioselectivity (up to 98% ee; see Table 3). On the other hand, highly enantioselective cis-aziridination was achieved (>99% ee) with optically active 3,3-dimethyl-1-[(1R)-1-phenylethyl]diaziridine 15, though the yield was low (4%). This aziridination was considered to proceed stepwise by way of the enolate intermediate (Scheme 2). Careful inspection of the stereochemistry and its solvent-dependence suggested that the diastereoselection of the reaction was kinetically controlled: the 1,4-addition of N-lithiated diaziridine was a crucial step for determination of the stereochemical course of the aziridination (Figs. 2–4).

(R,R)-Zr(salen) complex was found to serve as an efficient catalyst for asymmetric Baeyer–Villiger oxidation of pro-chiral and racemic ketones using urea·hydrogen peroxide as the terminal oxidant: for example, high enantioselectivity of 87% ee was achieved in the Baeyer–Villiger reaction of 3-phenylcyclobutanone.

Aerobic oxidation of 1, n - and 1,ω-diols with (ON)Ru(salen) 1 as the catalyst was found to give the corresponding lactols in almost quantitative yields. Furthermore, in the oxidation of 2,2-dimethylalkane-1,ω-diols, less sterically hindered ω-alcohols were found to be preferentially oxidized when (ON)Ru(salen) 6 was used as the catalyst. n -Decanol was preferentially oxidized in the presence of 2,2-dimethylpropanol also by using 6 as the catalyst.

Asymmetric oxidation of 2-substituted 1,3-dithianes using a Ti(salen) and urea·hydrogen peroxide system in methanol was found to proceed with high enantioselectivity to give the corresponding mono-sulfoxides.

A new chiral oxa[7]heterohelicene 1b was synthesized by catalytic aerobic-oxidative tandem cyclization of the o-phenylene-linked bis(2-naphthol) derivative 3 with palladium acetate in dimethyl sulf...

Transition metal catalysis is a cornerstone of modern asymmetric synthesis. Recently, late transition metal complexes have attracted increasing attention because of their unique redox properties in aerobic oxidation catalysis. Among them, ruthenium, iridium and iron complexes have been found to serve as efficient catalysts for the asymmetric oxidation of aliphatic and aromatic hydroxy compounds using dioxygen in air as an oxidant, to afford optically active organic substances such as alcohols, esters, symmetric and non-symmetric 1,1′-biarenols, and cyclic α,β-unsaturated ketones. The use of dioxygen that is ubiquitous in air renders these oxidation reactions green and practical, because it is highly atom efficient and available without energy consumption for transport. In this chapter, enantioselective oxidative transformations, including kinetic resolution of secondary alcohols, desymmetrization of meso-diols, asymmetric coupling and dearomatization of aromatic hydroxy compounds, which use ruthenium, iridium and iron complexes as catalysts and air as oxidant, are described.

An efficient approach for the enantioselective formation of spirocyclic dihydrobenzofurans (III) from 1-methyl-2-naphthols (I) and phenol derivatives (II) via a new Fe-salan complex catalyzed [aerobic oxidative ortho-quinone methide formation followed by Michael addition and asymmetric dearomatization] is developed.

Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom-efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described.

Nitrogen functional groups are found in many biologically active compounds and their stereochemistry has a profound effect on biological activity. Nitrene transfer reactions such as aziridination, C-H bond amination, and sulfimidation are useful methods for introducing nitrogen functional groups, and the enantiocontrol of the reactions has been extensively investigated. Although high enantioselectivity has been achieved, most of the reactions use (N-arylsulfonylimino)phenyliodinane, which co-produces iodobenzene, as a nitrene precursor and have a low atom economy. Azide compounds, which give nitrene species by releasing nitrogen, are ideal precursors but rather stable. Their decomposition needs UV irradiation, heating in the presence of a metal complex, or Lewis acid treatment. The examples of previous azide decomposition prompted us to examine Lewis acid and low-valent transition-metal complexes as catalysts for azide decomposition. Thus, we designed new ruthenium complexes that are composed of a low-valent Ru(II) ion, apical CO ligand, and an asymmetry-inducing salen ligand. With these ruthenium complexes and azides, we have achieved highly enantioselective nitrene transfer reactions under mild conditions. Recently, iridium-salen complexes were added to our toolbox.

A tandem combination of ortho-quinone methide (o-QM) formation/Michael addition/asymmetric dearomatization, which is catalysed by an iron–salan complex in air with high enantioselectivity, provides an efficient method for spirocyclic (2H)-dihydrobenzofuran synthesis from 2-naphthols and phenols. The key to the success of the tandem synthesis is the development of aerobic oxidative o-QM formation.

Asymmetric sulfoxidation using di-μ-oxo Ti(salen) complex 2 as the catalyst was revealed to proceed through C 2 -symmetric Ti(salen) complex 6 and peroxo Ti(salen) complex 4 in sequence on the basis of MS and NMR studies of the complexes and the observation of positive non-linear effect.