Diastereoselective radical hydroacylation of chiral alkylidenemalonates with aliphatic aldehydes is realized by the combination of a hypervalent iodine(III) reagent and UV-light irradiation. The reaction is initiated by the photolysis of hypervalent iodine(III) reagents under mild, metal-free conditions, and is the first example of diastereoselective addition of acyl radicals to olefins to afford chiral ketones in a highly stereoselective fashion. The obtained optically active ketones are useful chiral synthons, as exemplified by the short formal synthesis of (−)-methyleneolactocin.

Thiyl-radical-catalyzed cyclization reactions of N-tosyl vinylaziridines and alkenes were developed as a new synthetic method for the generation of substituted pyrrolidines. The key to making this process accessible to a broad range of substrates is the use of a sterically demanding thiyl radical, which prevents the undesired degradation of the catalyst.

Thiyl-radical-catalyzed cyclization reactions of N-tosyl vinylaziridines and alkenes were developed as a new synthetic method for the generation of substituted pyrrolidines. The key to making this process accessible to a broad range of substrates is the use of a sterically demanding thiyl radical, which prevents the undesired degradation of the catalyst.

A simple axially chiral amine catalyst promoted the regio-, diastereo-, and enantioselective conjugate addition of aldehydes to β-tosyl enones, which serve as ynone surrogates. The adducts were readily converted by treatment with L-selectride into less accessible enones with a γ stereogenic center. Such compounds cannot be prepared through the amine-catalyzed conjugate addition of aldehydes to ynones. The obtained enones underwent further conjugate addition of diorganozinc compounds in the presence of a copper catalyst.

The efficient construction of nitrogen-containing organic compounds is a major challenge in chemical synthesis. Imines are one of the most important classes of electrophiles for this transformation. However, both the available imines and applicable nucleophiles for them are quite limited given the existing preparative methods. Described herein are imine precursors which generate reactive imines with a wide variety of substituents under mild basic conditions. This approach enables the construction of various nitrogen-containing molecules which cannot be accessed by the traditional approach. The utility of the novel imine precursor was demonstrated in the asymmetric Mannich-type reaction under phase-transfer conditions.

Although phase-transfer-catalyzed asymmetric S_NAr reactions provide unique contribution to the catalytic asymmetric α-arylations of carbonyl compounds to produce biologically active α-aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron-withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S_NAr reactions of α-amino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron-donating substituents. The arylation was efficiently promoted by binaphthyl-modified chiral phase-transfer catalysts to give the corresponding α,α-disubstituted α-amino acids containing various aromatic substituents with high enantioselectivities.

A simple axially chiral amine catalyst promoted the regio-, diastereo-, and enantioselective conjugate addition of aldehydes to β-tosyl enones, which serve as ynone surrogates. The adducts were readily converted by treatment with L-selectride into less accessible enones with a γ stereogenic center. Such compounds cannot be prepared through the amine-catalyzed conjugate addition of aldehydes to ynones. The obtained enones underwent further conjugate addition of diorganozinc compounds in the presence of a copper catalyst.

The efficient construction of nitrogen-containing organic compounds is a major challenge in chemical synthesis. Imines are one of the most important classes of electrophiles for this transformation. However, both the available imines and applicable nucleophiles for them are quite limited given the existing preparative methods. Described herein are imine precursors which generate reactive imines with a wide variety of substituents under mild basic conditions. This approach enables the construction of various nitrogen-containing molecules which cannot be accessed by the traditional approach. The utility of the novel imine precursor was demonstrated in the asymmetric Mannich-type reaction under phase-transfer conditions.

The catalytic asymmetric Diels–Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl-substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels–Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3-alkyl quinone imine ketals from the inherently favored unsubstituted CC bond to the disfavored alkyl-substituted CC bond.

Although phase-transfer-catalyzed asymmetric S_NAr reactions provide unique contribution to the catalytic asymmetric α-arylations of carbonyl compounds to produce biologically active α-aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron-withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S_NAr reactions of α-amino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron-donating substituents. The arylation was efficiently promoted by binaphthyl-modified chiral phase-transfer catalysts to give the corresponding α,α-disubstituted α-amino acids containing various aromatic substituents with high enantioselectivities.

The catalytic asymmetric Diels–Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl-substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels–Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3-alkyl quinone imine ketals from the inherently favored unsubstituted CC bond to the disfavored alkyl-substituted CC bond.

A practical approach for the oxidation of unactivated C_sp3H bonds by an ortho-nitrophenyl-substituted hypervalent iodine(III) reagent is presented. The nitro group coordinates to the adjacent iodine center through dipolar interaction, which leads to a single substitution of the acetate ligand by tert-butyl hydroperoxide. As a result, a strong iodanyl radical is formed, which can activate the inert C_sp3H bonds in a highly efficient manner. The reagent is stable in the presence of moisture, and can be used for oxidation reactions on semipreparative scale.

Highly enantioselective α-arylation of α-amino acid derivatives via nucleophilic aromatic substitution (S_NAr) was achieved under phase-transfer conditions. Various kinds of α-amino acids and aryl triflates containing a nitro group can be tolerated in this reaction to give α,α-disubstituted α-amino acids in good to high enantioselectivity. This reaction demonstrates a valuable method for the catalytic asymmetric synthesis of α,α-disubstituted α-amino acids containing an aromatic substituent.

Although phase-transfer reactions catalyzed by using quaternary ammonium salts are generally believed to require base additives, we discovered that, even without any base additives, conjugate additions of 3-substituted oxindoles to nitroolefins proceeded smoothly in the presence of lipophilic quaternary ammonium bromide under water–organic biphasic conditions. The mechanism of this novel base-free neutral phase-transfer reaction system is investigated and the assumed catalytic cycle is presented together with interesting effects of water and lipophilicity of the phase-transfer catalyst. The base-free neutral phase-transfer reaction system can be applied to highly enantioselective conjugate addition and aldol reactions under the influence of chiral bifunctional ammonium bromides as key catalysts. The structure of the chiral ammonium enolate intermediate is discussed based on the single-crystal X-ray structures of relevant ammonium salts and the importance of bifunctional design of catalyst is clearly explained in the model of intermediate.

Direct acyl radical formation of linear aldehydes (RCH₂-CHO) and subsequent hydroacylation with electron-deficient olefins can be effected with various types of metal and nonmetal catalysts/reagents. In marked contrast, however, no successful reports on the use of branched aldehydes have been made thus far because of their strong tendency of generating alkyl radicals through the facile decarbonylation of acyl radicals. Here, use of a hypervalent iodine(III) catalyst under visible light photolysis allows a mild way of generating acyl radicals from various branched aldehydes, thereby giving the corresponding hydroacylated products almost exclusively. Another characteristic feature of this approach is the catalytic use of hypervalent iodine(III) reagent, which is a rare example on the generation of radicals in hypervalent iodine chemistry.

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all-carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S_NAr reaction of 3-aryloxindoles under phase-transfer conditions. The presence of a urea moiety in the chiral phase-transfer catalyst was important for obtaining high enantioselectivity in this reaction.

Direct acyl radical formation of linear aldehydes (RCH₂-CHO) and subsequent hydroacylation with electron-deficient olefins can be effected with various types of metal and nonmetal catalysts/reagents. In marked contrast, however, no successful reports on the use of branched aldehydes have been made thus far because of their strong tendency of generating alkyl radicals through the facile decarbonylation of acyl radicals. Here, use of a hypervalent iodine(III) catalyst under visible light photolysis allows a mild way of generating acyl radicals from various branched aldehydes, thereby giving the corresponding hydroacylated products almost exclusively. Another characteristic feature of this approach is the catalytic use of hypervalent iodine(III) reagent, which is a rare example on the generation of radicals in hypervalent iodine chemistry.

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all-carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S_NAr reaction of 3-aryloxindoles under phase-transfer conditions. The presence of a urea moiety in the chiral phase-transfer catalyst was important for obtaining high enantioselectivity in this reaction.

Phase-transfer catalysis has been recognized as a powerful method for establishing practical protocols for organic synthesis, because it offers several advantages, such as operational simplicity, mild reaction conditions, suitability for large-scale synthesis, and the environmentally benign nature of the reaction system. Since the pioneering studies on highly enantioselective alkylations promoted by chiral phase-transfer catalysts, this research field has served as an attractive area for the pursuit of “green” sustainable chemistry. A wide variety of asymmetric transformations catalyzed by chiral onium salts and crown ethers have been developed for the synthesis of valuable organic compounds in the past several decades, especially in recent years.

Die Phasentransferkatalyse bildet eine effiziente Grundlage zur Einführung praktischer Methoden in die organische Synthese, denn sie bietet mehrere Vorteile wie einfache Handhabung, milde Reaktionsbedingungen, die Eignung für großtechnische Synthesen und ein umweltfreundliches Reaktionssystem. Seit den wegweisenden Arbeiten zu hoch enantioselektiven Alkylierungen mit chiralen Phasentransferkatalysatoren ist dieses Forschungsgebiet im Hinblick auf eine umweltverträgliche, nachhaltige Chemie von Interesse, und in den vergangenen Jahrzehnten, vor allem in den letzten Jahren, wurden zahlreiche asymmetrische, durch chirale Oniumsalze und Kronenether katalysierte Umwandlungen für die Synthese wertvoller organischer Verbindungen entwickelt.

Catalytic asymmetric synthesis of axially chiral o-iodoanilides and o-tert-butylanilides as useful chiral building blocks was achieved by means of binaphthyl-modified chiral quaternary ammonium-salt-catalyzed N-alkylations under phase-transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N-allyl-o-iodoanilide was transformed to 3-methylindoline by means of radical cyclization with high chirality transfer from axial chirality to C-centered chirality. Furthermore, stereochemical information on axial chirality in o-tert-butylanilides could be used as a template to control the stereochemistry of subsequent transformations. The transition-state structure of the present phase-transfer reaction was discussed on the basis of the X-ray crystal structure of ammonium anilide, which was prepared from binaphthyl-modified chiral ammonium bromide and o-iodoanilide. The chiral tetraalkylammonium bromide as a phase-transfer catalyst recognized the steric difference between the ortho substituents on anilide to obtain high enantioselectivity. The size and structural effects of the ortho substituents on anilide were investigated, and a wide variety of axially chiral anilides that possess various functional groups could be synthesized with high enantioselectivities. This method is the only general way to access a variety of axially chiral anilides in a highly enantioselective fashion reported to date.

The catalytic enantio- and diastereoselective synthesis of trans-3-substituted proline derivatives has been accomplished by chiral phase-transfer-catalyzed asymmetric conjugate addition of N-(diphenylmethylene)glycine ester to α,β-unsaturated aldehydes. Various 3-substituted prolines that contain aromatic, heteroaromatic, and alkyl groups were synthesized efficiently with good to high enantioselectivity. This synthetic method can be applied to the efficient enantioselective synthesis of core structures of L-pyrrolysine and telaprevir, which are important biologically active compounds. The practicability of the method was demonstrated by a gram-scale synthesis of a core structure of telaprevir.

A highly efficient catalytic asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines has been achieved via asymmetric alkylation or Michael addition of 1-cyanotetrahydroisoquinolines using binaphthyl-modified N-spiro-type chiral phase-transfer catalysts.

The acid-catalyzed reaction of diazoacetates and aldimines (Brookhart–Templeton aziridination) is now recognized as a reliable method to provide enantiomerically enriched disubstituted aziridines, thus owing to the development of asymmetric catalysis. However, the extension of this method to prepare trisubstituted aziridines has not been explored to date, even for racemic products. In this context, and considering their synthetic importance and lack of alternative direct synthetic methods, we recently launched a program to realize this unmet challenge. Herein, we report a detailed study, which led to the establishment of a highly stereoselective synthesis for various trisubstituted aziridines, building on the use of N-α-diazoacyl camphorsultams as a key component.

The phase-transfer-catalyzed alkylation of α-alkynylcrotonates was developed as a means to provide 1,4-enynes deconjugated by an all-carbon quaternary center. Extension to the asymmetric version using the chiral phase-transfer catalyst (S)-3 provided the alkylated compounds with up to 87% ee.

Highly enantioselective phase-transfer-catalyzed alkylation of tert-butyl 2-benzoyloxy-3-oxobutanoate was realized by the use of an N-spiro chiral quaternary ammonium salt, as a complementary approach to the asymmetric hydroxylation of α-alkyl-β-keto esters. The synthetic utility of the alkylated compounds is highlighted by the diastereoselective reduction and alkylation of the remaining ketone moiety to give various enantiomerically enriched congested 2,3-dihydroxycarboxylic acid esters.

A series of chiral quaternary ammonium salts derived from commercially available (R)- or (S)-binaphthol have been designed as new C₂-symmetric chiral phase transfer catalysts. In order to realize the flexible design of these phase transfer catalysts, the combinatorial design approach has been developed. These chiral high-performance organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives including α-alkyl and α,α-dialkyl-α-amino acids in addition to alkaloids. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 254–259; 2010: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.201000019

A very efficient, chiral phase-transfer catalyst, (S)-2 Db, was prepared by taking advantage of the combinatorial approach from the readily available (S)-1,1′-binaphthyl-2,2′-dicarboxylic acid. This catalyst exhibited high catalytic performance (0.01–0.1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester relative to other chiral phase-transfer catalysts in current use. This has created a general and highly practical procedure for the enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids as well as α,α-dialkyl-α-amino acids. A similar simplified catalyst, (S)-2 Fb, is also applicable to the direct asymmetric aldol reaction between glycine Schiff base and aldehydes with moderate syn selectivity and high enantioselectivity.

Bis-titanium chiral Lewis acids that contain two oxygen-bridged titanium centers were successfully applied to the asymmetric 1,3-dipolar cycloaddition of nitrones and α,β-unsaturated aldehydes. The introduction of the diphenylmethyl group as the N substituent on the nitrones, with the aim of destabilizing the nitrone–Lewis acid complex, led to the drastic enhancement of not only the reactivity but also the enantioselectivity. By employing this approach, 1,3-dipolar cycloadditions of nitrones and the rather unreactive methacrolein were facilitated to give cycloadducts that bear one all-carbon quaternary center with unique regioselectivity and excellent stereoselectivity.