Chlorocyclization of tryptamine derivatives has been developed with the use of a diphenyl diselenide–iodine cooperative catalyst. Various tryptamine derivatives can be smoothly converted to the corresponding C3a-chlorohexahydropyrrolo[2,3-b]indoles. Additionally, we demonstrate the formal total syntheses of (−)-psychotriasine and (−)-acetylardeemin by introducing nucleophiles to the C3a position of the products.

Highly enantioselective oxidative dearomatization of 2-naphthol derivatives was achieved for the first time by using conformationally flexible organoiodine catalysts derived from 2-aminoalcohol as a chiral source. Moreover, with the use of these catalysts, excellent enantioselectivities were also achieved for 1-naphthol derivatives, which had previously been obtained with only lower enantioselectivities. Furthermore, the product obtained from the present reaction could be transformed to a highly functionalized spirolactone in high yield and with excellent stereoselectivity.

A chiral magnesium potassium binaphthyldisulfonate cluster, as a chiral Brønsted acid catalyst, was shown to catalyze an enantioselective cycloaddition of styrenes with aldimines for the first time. The strong Brønsted acidity of the catalyst precursors, which might dissolve drying agents and take up the leached Mg2+ and K+, serendipitously led to good enantioselectivity. Mechanistic aspects were supported by X-ray and ESI-MS analysis of the catalyst and a kinetics study of the reaction. Useful transformations to optically active 1,3-amino alcohols on a gram scale were also demonstrated.

Boronic acid catalyst shuttle: In general, recovering homogeneous catalysts at the end of a chemical reaction is not easy. Easily recoverable homogeneous catalysts were developed for the dehydrative condensation reaction between carboxylic acids and amines to give amides: resin-bound boronates, and complexes between a boronic acid and DMAP or DMAP N-oxide. Soluble active boronic acids are released from these solids, and work as homogeneous catalysts during the reaction, and are recovered by decantation after the reaction completion. Their behavior resembles a space shuttle. More information can be found in the Communication by Kazuaki Ishihara et al. on page 1191 in Issue 9, 2017 (DOI: 10.1002/ajoc.201700194).

AbstractTwo novel boronic acid–base complexes were developed as reusable homogeneous catalysts for amide condensation. First, quaternary ammonium resin-bound boronates were shown to be effective catalysts that might release free boronic acids during reactions and could be regenerated afterwards. Next, a 1:1 mixture of 3,5-dinitro-4-tolueneboronic acid and 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO) or 4-(N,N,-dimethylamino)pyridine (DMAP) cooperatively promoted amide formation and precipitated as an acid–base solid complex after cooling. These inexpensive and reusable complexes may be useful in large-scale process chemistry.

Arylboronic acid and 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO) cooperatively catalyse the dehydrative condensation reaction between carboxylic acids and amines to give the corresponding amides under azeotropic reflux conditions. This cooperative use is much more effective than their individual use as catalysts, and chemoselectively promotes the amide condensation of (poly)conjugated carboxylic acids. The present method is practical and scalable, and has been applied to the synthesis of sitagliptin and a drug candidate.

Chiral phosphite–urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

Regioselective synthetic methods were developed for 1,4- and 1,6-conjugate additions of Grignard reagent-derived organozinc(II)ates to malonate-derived polyconjugated esters. By taking advantage of the tight ion-pair control of organozinc(II)ates, it was possible to switch between 1,4- and 1,6-conjugate additions by introducing a terminal ethoxy moiety in the conjugation.

BBr3–chiral phosphoric acid complexes are highly effective and practical Lewis acid-assisted Brønsted acid (LBA) catalysts for promoting the enantioselective Diels–Alder (DA) reaction of α-substituted acroleins and α-CF3 acrylate. In particular, the DA reaction of α-substituted acroleins with 1,2-dihydropyridines gave the corresponding optically active isoquinuclidines with high enantioselectivities. Moreover, transformations to the key intermediates of indole alkaloids, catharanthine and allocatharanthine, are demonstrated.

Highly practical synthetic methods were developed for the C- and N-selective Grignard addition reactions of N-4-MeOC6H4-protected α-aldimino esters in the presence or absence of zinc(II) chloride. Diastereoselective C-alkyl addition, tandem C-alkyl addition–N-alkylation, and some transformations to synthetically useful optically active azacycles were demonstrated.

The highly enantioselective cyano-alkoxycarbonylation of α-oxoesters with alkyl cyanoformates is promoted by a new chiral Brønsted acid–Lewis base cooperative organocatalyst. The present catalysis can be performed at room temperature under nitrogen or air.

We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide. The asymmetric environment created by intramolecular π–cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.

The first enantioselective Diels–Alder reaction of 1,2-dihydropyridines with α-acyloxyacroleins catalyzed by a chiral primary ammonium salt has been developed and it offers more efficient routes to key synthetic intermediates of alkaloids, for which the direct preparations were unavailable before. The asymmetric induction can be understood through the optimized geometry of an iminium salt aqua complex derived from the catalyst and the dienophile.

The Baeyer–Villiger (BV) oxidation of carbonyl compounds to the corresponding esters or lactones is one of the most important transformations. We recently introduced a highly efficient and selective LiB(C6F5)4- or Ca[B(C6F5)4]2-catalyzed BV oxidation of ketones with aqueous hydrogen peroxide to give the corresponding lactones in high yield. In this perspective article, we focus on our discovery and the development of BV oxidation reactions and cascade oxidative transformations through representative metal catalysts and organocatalysts.Keywords: Baeyer−Villiger oxidation; hydrogen peroxide; organocatalysis; tetraaryl borate salts; transition-metal catalysis

Nucleophilic phosphite–urea cooperative high-turnover catalysts have been designed for the highly selective bromocyclization of homogeranylarenes. The introduction of a urea moiety and bulky aryl groups in the catalyst inhibits decomposition of the catalyst and the generation of byproducts. Only 0.5 mol% of the catalyst successfully promotes the bromocyclization of 4-homogeranyltoluene to give the desired product in 96% yield.

Primary alkylboronic acids such as methylboronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of α-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.

A facile, atom-economical, and chemoselective esterification is crucial in modern organic synthesis, particularly in the areas of pharmaceutical, polymer, and material science. However, a truly practical catalytic transesterification of carboxylic esters with various alcohols has not yet been well established, since, with many conventional catalysts, the substrates are limited to 1°- and cyclic 2°-alcohols. In sharp contrast, if we take advantage of the high catalytic activities of La(Oi-Pr)3, La(OTf)3, and La(NO3)3 as ligand-free catalysts, ligand-assisted or additive-enhanced lanthanum(III) catalysts can be highly effective acid–base combined catalysts in transesterification. A highly active dinuclear La(III) catalyst, which is prepared in situ from lanthanum(III) isopropoxide and 2-(2-methoxyethoxy)ethanol, is effective for the practical transesterification of methyl carboxylates, ethyl acetate, weakly reactive dimethyl carbonate, and much less-reactive methyl carbamates with 1°-, 2°-, and 3°-alcohols. As the second generation, nearly neutral “lanthanum(III) nitrate alkoxide”, namely La(OR)m(NO3)3−m, has been developed. This catalyst is prepared in situ from inexpensive, stable, low-toxic lanthanum(III) nitrate hydrate and methyltrioctylphosphonium methyl carbonate, and is highly useful in the non-epimerized transesterification of α-substituted chiral carboxylic esters, even under azeotropic reflux conditions. In these practical La(III)-catalyzed transesterifications, colorless esters can be obtained in small- to large-scale synthesis without the need for inconvenient work-up or careful purification procedures.

Chiral phosphonium salts induce the kinetic resolution of racemic α-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (= kfast/kslow) values. Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization.

We developed a practical synthesis of optically pure 3,3′-diaryl-1,1′-binaphthyl-2,2′-disulfonic acids (i.e., (R)- or (S)-3,3′-Ar2-BINSAs) from the parent chiral sulfonimides via stepwise N–S bond cleavage of the sulfonimides and the resultant sulfonamides. This unusual synthesis, which provides arylsulfonic acids from arylsulfonamides, is valuable since common methods particularly give amines with the decomposition of sulfone groups during deprotection.

The potential of supramolecular catalysts to realize anomalous regio- and/or stereoselectivity in organic synthesis is highly attractive. To date, there have been a few examples of non-polymeric and non-covalent chiral supramolecular catalysts that induce practical enantioselectivity. In this regard, a metal–organic framework (MOF) may be one of the most important techniques for constructing conformationally rigid supramolecular catalysts. However, it is not easy to use the MOF technique to fine-tune a much more precise cage in catalysts for anomalous purposes. To establish high catalytic activity with anomalous regio- and/or stereoselectivity, in principle, an artificial cage should be conformationally flexible, like an active pocket in an enzyme with an induced-fit function. In this feature article, we focus on the anomalous endo/exo-selective Diels–Alder reaction, and overview the development of the successive catalysts including our recent highly active, conformationally flexible, and chiral supramolecular catalysts. The evolution from ‘ready-made’ single-molecule catalysts to ‘tailor-made’ supramolecular catalysts could offer not only high enantioselectivity but also high anomalous endo/exo-selectivities due to substrate-specific characteristics, as with enzymes.

A highly effective catalytic enantioselective direct aminal synthesis was developed. Chiral ammonium 1,1′-binaphthyl-2,2′-disulfonates, which were prepared in situ from (R)-BINSA and achiral amines, promoted the enantioselective addition of primary amides to aromatic aldimines.

In situ generated lanthanum(III) nitrate alkoxide is a highly active and nearly neutral transesterification catalyst, which can promote non-epimerized transesterification of α-substituted chiral carboxylic esters under reflux conditions.

A catalytic and enantioselective Diels–Alder reaction of α-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. α-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the first time. The Diels–Alder reaction affords chiral tertiary thiol precursors with up to 91% ee.

The rational design of small but highly functional artificial catalysts is very important for practical organic synthesis. Asymmetric Lewis acid catalyses with non-covalent secondary interactions have been developed for enantioselective reactions. This tutorial review describes the concept, design and examples of asymmetric Cu(II) catalyses for cycloaddition reactions based on intramolecular π–cation or n–cation interactions between the copper(II) cation and auxiliary Lewis basic sites of the chiral ligands.

Chiral Lewis base-assisted Brønsted acids (Chiral LBBAs) have been designed as new organocatalysts for biomimetic enantioselective cyclization. A salt of a chiral phosphonous acid diester with FSO3H catalyzes the enantioselective cyclization of 2-geranylphenols to give the desired trans-fused cyclized products with high diastereo- and enantioselectivities (up to 98:2 dr and 93% ee).

The transesterification of an equimolar mixture of carboxylic esters and primary (1°), secondary (2°), and tertiary (3°) alcohols in hydrocarbon solvents was promoted with high efficiency by a lanthanum(III) complex, which was prepared in situ from lanthanum(III) isopropoxide (1 mol %) and 2-(2-methoxyethoxy)ethanol (2 mol %). The present La(III) catalyst was highly effective for the chemoselective transesterification in the presence of competitive 1°- and 2°-amines. Remarkably, esters were obtained in good to excellent yields as colorless materials without an inconvenient workup procedure.

A practical transesterification of less reactive dimethyl carbonate and much less reactive methyl carbamates with primary (1°), secondary (2°), and tertiary (3°) alcohols was established with the use of a lanthanum(III) complex, which was prepared in situ from lanthanum(III) isopropoxide (3 mol %) and 2-(2-methoxyethoxy)ethanol (6 mol %). In particular, corresponding carbonates and carbamates obtained were of synthetic utility from the viewpoint of the selective protection and/or deprotection of 1°-, 2°-, and 3°-alcohols.

A highly practical, catalytic enantioselective alkyl and aryl addition to aldehydes and ketones with organozinc reagents, which were prepared in situ from commercially available Grignard reagents or arylboronic acids, was developed. A chiral phosphoramide ligand was essential for promoting the addition reactions in high yields with high enantioselectivities.

A chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular π−cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to β-lactams via reductive cleavage of the N−O bond using SmI2.

A highly practical, catalytic enantioselective 2°-alkyl addition to aldehydes and ketones was developed. Chiral phosphoramide ligand (1) with salt-free and solvent-free di(2°-alkyl)zinc reagents prepared from (2°-alkyl)MgCl was essential.

A highly enantioselective direct Mannich-type reaction of aldimines with dialkyl malonates was developed with the use of a Mg(II)-BINOLate salt, which was designed as a cooperative acid—base catalyst that can activate both aldimines and malonates. Optically active β-aminoesters and α-halo-β-aminoesters could be synthesized in high yields and with high enantioselectivities. This inexpensive and practical Mg(II)-BINOLate salt could be used in gram-scale catalysis.

Highly efficient alkylations and arylations of ketones with Grignard reagents (RMgBr and RMgI) have been developed using catalytic ZnCl2, Me3SiCH2MgCl, and LiCl. Tertiary alcohols were obtained in high yields with high chemoselectivities, while minimizing undesired side products produced by reduction and enolization.

A convenient synthesis of chiral 3,3′-disubstituted 1,1′-binaphthyl-2,2′-disulfonic acids (BINSA, 1) was developed. The key was directed ortho-lithiation of BINSA methyl ester 2 with n-BuLi and subsequent reaction with an electrophile. Electrophiles such as Br2, I2, Me3SiOTf, and i-PrOB(Pin) reacted smoothly with 3,3′-dilithiated BINSA methyl ester, and the corresponding 3,3′-dihalo-, 3,3′-bis(trimethylsilyl)-, and 3,3′-diboryl-BINSA derivatives were obtained in yields of 21–78%. This simple synthetic method is highly attractive since the ability to prepare 3,3′-disubstituted BINOLs in advance can be useful.(R)-Dimethyl 1,1′-binaphthalene-2,2′-disulfonateC22H18O6S2[α]D24=+80.8 (c 1.0, CHCl3)Source of chirality: (R)-BINSAAbsolute configuration: (R)(R)-Diethyl 1,1′-binaphthalene-2,2′-disulfonateC24H22O6S2[α]D24=+31.2 (c 1.0, CHCl3)Source of chirality: (R)-BINSAAbsolute configuration: (R)(R)-Dimethyl 3,3′-bis(trimethylsilyl)-1,1′-binaphthalene-2,2′-disulfonateC28H34O6S2Si2[α]D26=+77.7 (c 0.17, CHCl3)Source of chirality: (R)-BINSAAbsolute configuration: (R)Lithium (R)-3,3′-bis(trimethylsilyl)-1,1′-binaphthalene-2,2′-disulfonateC26H28Li2O6S2Si2[α]D28=+95.2 (c 0.29, MeOH)Source of chirality: (R)-BINSAAbsolute configuration: (R)(R)-Dimethyl 3,3′-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1′-binaphthalene-2,2′-disulfonateC34H40B2O10S2[α]D28=+96.9 (c 1.85, CHCl3).Source of chirality: (R)-BINSAAbsolute configuration: (R)(R)-3,3′-Diborono-1,1′-binaphthyl-2,2′-disulfonic acidC20H16B2O10S2[α]D28=+80.0 (c 1.0, MeOH).Source of chirality: (R)-BINSAAbsolute configuration: (R)

A highly diastereo- and enantioselective direct Mannich-type reaction of aldimines with 1,3-dicarbonyl compounds using Li(I) BINOLate salts as effective Lewis acid−Brønsted base catalysts has been developed. Li(I) BINOLate salts offered high catalytic activity toward 1,3-dicarbonyl compounds such as diketone, ketoester, ketothioester, ketoamide, and ketolactone. The reactions proceeded at −78 °C within 1−2 h in the presence of 1−10 mol % catalyst, which showed a catalytic activity (turnover frequency = 284 h−1) quite unlike those of other previous catalysts. Anti products were selectively obtained from acyclic ketoesters without epimerization at an α-3°-carbon center, and these are valuable since previous catalysts often gave syn/anti mixtures or the stereochemistry has not yet been determined.

The rational design of bis(oxazoline)-copper(II) catalysts based on postulated intramolecular secondary n-cation interaction for the highly enantioselective Diels−Alder reaction is presented. A theoretical calculation suggested that the n electrons of the 4,4′-sulfonamidomethyl groups successfully interact with the Cu(II) cation and that the counteranions with protons of sulfonamido groups. These secondary interactions might be essential for the high catalytic activity, the broad range of substrates, and the high level of induction of the enantioselectivity.

Over the past two decades there has been a dramatic increse in the use of hypervalent iodine compounds in synthetic organic chemistry due to their mild and selective oxidizing properties. Hypervalent iodine compounds catalyze various oxidation reactions such as the oxidation of alcohols, α-oxidation of ketones, oxidative spirocyclization of phenols, etc. Very recently, we found that 2-iodoxybenzensulfonic acid (IBS, 7a), which was generated from 2-iodobenzenesulfonic acidin situ, is an extremely active and mild catalyst for the highly chemoselective oxidation of various alcohols with powdered Oxone® to carbonyl compounds such as aldehydes, carboxylic acids, ketones and cycloalkenones under non-aqueous conditions. In this review, we focus on the design of hypervalent iodine catalysts and review the discovery and development of the oxidation of alcohols with the stoichiometric or catalytic use of hypervalent iodine compounds.

A 2-iodoxybenzenesulfonic acid (IBS)-catalyzed oxidative rearrangement of tertiary allylic alcohols to enones with powdered Oxone in the presence of potassium carbonate and tetrabutylammonium hydrogen sulfate has been developed.

A catalytic enantioselective Strecker reaction catalyzed by novel chiral lanthanum(III)−binaphthyl disulfonate complexes was developed. The key to promoting the reactions was a semistoichiometric amount of AcOH or i-PrCO2H, which takes advantage of HCN generation in situ. The corresponding cyanation products were obtained in high yields and with high enantioselectivities.

The hypervalent iodine-catalyzed oxylactonization of ketocarboxylic acids to ketolactones was achieved in the presence of iodobenzene (10 mol %), p-toluenesulfonic acid monohydrate (20 mol %) and meta-chloroperbenzoic acid as a stoichiometric co-oxidant.The hypervalent iodine-catalyzed oxylactonization of ketocarboxylic acids to ketolactones was achieved in the presence of iodobenzene (10 mol %), TsOH (20 mol %) and m-CPBA as stoichiometric co-oxidant.

Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(VI) oxide-catalyzed dehydrative cyclization, Sb(OEt)3-catalyzed ester–amide transformation, and WSCI and HOAt-promoted dehydrative amide formation.

We have designed a minimal artificial metalloenzyme that is prepared in situ from Cu(OTf)2 or Cu(NTf2)2 (1.0 equiv) and l-DOPA-derived monopeptide (1.1 equiv) based on the cation–π attractive interaction between copper(II) and the aromatic arm of the ligand, which is postulated on the basis of X-ray diffraction analysis and theoretical calculations. This catalyst (2–10 mol %) is highly effective for not only the enantioselective Diels–Alder reaction with α,β-unsaturated 1-acyl-3,5-dimethylpyrazoles but also the enantioselective Mukaiyama–Michael reaction with these compounds. Products bearing a 3,5-dimethylpyrazolyl auxiliary may be transformed into a range of carboxylic acid derivatives, such as the corresponding carboxylic acids, esters, amides, alcohols, aldehydes, ketones, and β-ketoesters, by known methods. The present results demonstrate that monopeptides are chirally economical and readily tunable ligands compared to bis(oxazoline)s, which have been reported to be notably useful ligands in various enantioselective reactions with bidentate electrophiles.

The ester condensation reaction is among the most fundamental organic transformations, and more environmentally benign alternative synthetic approaches to the ones currently used are in strong demand by the chemical industry1. Conventionally, the ester condensation reaction of carboxylic acids with alcohols is catalyzed by Brønsted acids such as HCl, H2SO4, p-toluenesulfonic acid and so on for acid-resistance substrates. For acid-sensitive substrates, weak Brønsted acids such as pyridinium p-toluenesulfonate should be used. However, these have lower catalytic activities and the reactants that can be used are rather limited. With regard to green chemistry, in particular with respect to atom economy and E-factor, several catalytic methods for the ester condensation reaction between equimolar amounts of carboxylic acids and alcohols have been developed2, 3, 4, 5, 6. Conventionally, in fact, esterifications are conducted with an excess of carboxylic acids or alcohols against its reaction counterpart in the presence of an acid catalyst, or with a stoichiometric dehydrating reagent or activated carboxylic acid derivative in the presence of a stoichiometric amount of base. The use of excess amounts of substrates is a wasteful practice in itself. Furthermore, the use of stoichiometric dehydrating reagents or activated carboxylic acid derivatives leads to the formation of significant amounts of undesired by-products. Purifying the crude products from (excess) substrates or from reaction by-products is a rather demanding task—also in financial terms—requiring additional apparati and additional amounts of materials, energy (e.g., for azeotropic reflux) and time. It is therefore evident why the direct catalytic condensation between equimolar amounts of carboxylic acids and alcohols that does not require the presence of dehydrating agents is, at least in principle, such an attractive synthetic goal. Among these 'green' catalytic condensations, metal-free organocatalytic methods are particularly desirable, especially for industrial processes. In 2000, Tanabe and co-workers2 reported that diphenylammonium triflate ([Ph2NH2]+[OTf]−, 1.0–10 mol%) efficiently catalyzed the ester condensation reaction at 80 °C without the need for removal of water. Unfortunately, however, as [Ph2NH2]+[OTf]− is the salt of a superacid (trifluoromethansulfonic acid (TfOH)) and a weak base (Ph2NH), it is a strong Brønsted acid, and as such is difficult to use in the reaction of sterically demanding and acid-sensitive alcohols.In the course of our continuing study on environmentally benign dehydration catalysts, we have developed N,N-dimesitylammonium pentafluorobenzenesulfonate (3) and N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate (4) as mild and selective ester condensation catalysts7, 8, 9. A scheme for the synthesis of ammonium catalysts 3 and 4 is shown in Figure 1. N,N-Dimesitylamine (1) is prepared from 2,4,6-trimethylaniline by palladium-catalyzed cross-coupling with 2,4,6-mesitylbromide10, 11. The reaction of 1 with an equimolar amount of pentafluorobenzenesulfonic acid (C6F5SO3H), which is prepared from pentafluorobenzenesulfonyl chloride by hydrolysis, gives ammonium salt 3. This catalyst 3 has been commercially available from Tokyo Chemical Industry Co., Ltd (TCI) since January 2007. Catalyst 4 can be prepared from 2,6-diisopropylaniline by an analogous procedure. It is, in particular, the synthesis of catalyst 4 that is detailed in the PROCEDURE section.C6F5SO3H (pKa(CD3CO2D) = 11.1, H0 = −3.98) is a weaker acid than TfOH (pKa(CD3CO2D) = −0.74, H0 = −14.00), concentrated H2SO4 (pKa(CD3CO2D) = 7.5, H0 = −11.93) and p-toluenesulfonic acid (pKa(CD3CO2D) = 8.5, H0 = −4.5). This means that 3 and 4 are milder acids than the corresponding ammonium triflates, sulfates and tosylates. Nevertheless, 3 and 4 have much higher catalytic activities than Tanabe catalyst ([Ph2NH2]+[OTf]−) (see data in Fig. 2), owing to the hydrophobic environment created around the ammonium protons in the catalyst12. Even though the ester condensation was performed under heating without the removal of water, the reaction proceeded well without any deceleration owing to the generated water.The X-ray single-crystal structures of 3 and [Ph2NH2]+[OTf]− are shown in Figure 3. The crystals obtained were dimeric cyclic ion pairs composed of two diarylammonium cations and two arenesulfonate anions. Interestingly, the dimeric cyclic ion pair of 3 was stabilized by two intermolecular π–π interactions as well as four hydrogen bondings, whereas there was no intermolecular π–π interaction in the ion pair of [Ph2NH2]+[OTf]−. It is conceivable that a 'hydrophobic wall' prevents polar water molecules from gaining access to the active site of the catalysts and thus inhibits the inactivation of the catalyst by water (Fig. 3). Furthermore, the steric bulkiness of the mesityl and pentafluorophenyl groups in the catalyst suppressed the dehydrative elimination of secondary alcohols to produce alkenes.When the ester condensation of 4-phenylbutyric acid with cyclododecanol (5; see Fig. 2) was conducted in the presence of Tanabe catalyst (5 mol%) in heptane under reflux conditions (bath temperature 115 °C), a significant amount of the undesired cyclododecene (7) was produced along with cyclododecyl 4-phenylbutyrate (6) (Fig. 2, graph a). The use of dimesitylammonium triflate ([Mes2NH2]+[OTf]−) showed higher catalytic activity than [Ph2NH2]+[OTf]− and reduced the production of 7 (Fig. 2, graph a). Furthermore, the ester condensation catalyzed by 3 (5 mol%) proceeded more rapidly, and the production of 7 decreased (Fig. 2, graph a). The use of less-polar solvents such as heptane is important. The catalytic activities of 3 and 4 increased in such less-polar solvents, to produce esters in high yields. One of the limitations of the present method is the need for less-polar solvents: it is difficult to perform ester condensation of hydrophilic substrates that cannot dissolve in less-polar solvents.Typically, the ester condensations of 1:1 mixtures of carboxylic acids and alcohols are carried out in the presence of 3 or 4 (1–5 mol%) in heptane by heating at 80 °C without the removal of water. Sterically demanding alcohols are condensed to produce the corresponding esters in high yields. For example, when the ester condensation of 4-phenylbutyric acid with 6-undecanol (1.0 equiv.) was performed in the presence of 4 (5 mol%) in heptane under heating conditions without the removal of water, the corresponding ester was obtained in 88% yield along with 5-undecene (3%) (Fig. 4). In Box 1, a detailed protocol for this reaction is reported. Esterification with 1,2-diols proceeded well to give the corresponding diesters in high yields, while Lewis acidic metal salts were not suitable for use with these diols owing to tight chelation with metal ions13. For example, the condensation between cis-1,2-cyclohexanediol and 4-phenylbutyric acid with 4 gave the corresponding diester in 90% yield, while no esterification product was obtained by heating a mixture of 1,2-butanediol and 1-adamantanecarboxylic acid in toluene in the presence of HfCl4·(THF)2. In addition, we have been able to recover and reuse the bulky diarylammonium pentafluorobenzenesulfonate catalyst immobilized on a polystyrene support without any loss of catalytic activity more than 10 times7, 8. On the contrary, a polystyrene-supported diarylammonium triflate could not be prepared, as the polymer support decomposed with superacidic TfOH.Ester condensation reactions with more reactive primary alcohols proceeded even at ambient temperature (22 °C) without solvents. Several carboxylic acids were esterified with 1.1 equiv. of methanol in good yield in the presence of 3 (1 mol%). For example, when condensation between 4-phenylbutyric acid and methanol (1.1 equiv.) was carried out in the presence of 3 (1 mol%) without the removal of water for 24 h, the corresponding ester was obtained in 95% yield (Fig. 5). This reaction can be carried out by the same protocol as that of the reaction in Figure 4 but without the use of solvent (heptane) and heating. 1-Octanol was also reactive, albeit slightly less reactive than methanol8. Octyl methoxyacetate was obtained in 74% yield under the same conditions described in Figure 5.Synthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)amine (2): Steps 1–7, 1 h; Step 8, 24–48 h; Step 9, 30 min; Step 10, 20 min; Steps 11–15, 2 h; Steps 16–18, 2 h; Steps 19 and 20; 1 hSynthesis of pentafluorobenzenesulfonic acid: Steps 22 and 23, 1 h; Step 24, ~12 h; Step 25, 30 min; Step 26, 30 min; Steps 27 and 28, ~14 hSynthesis of N-(2,6-diisopropylphenyl)-N-(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate (4): Steps 29 and 30, 1.5 h; Step 31, 30 min; Step 32, 30 min; Step 5, ~12 hTroubleshooting advice can be found in Table 1.Typical isolated yield, ~70–95%. 1H NMR (300 MHz, CDCl3) δ 7.10 (s, 3H), 6.76 (s, 2H), 4.68 (br s, 1H), 3.12 (septet, J = 6.9 Hz, 2H), 2.22 (s, 3H), 1.95 (s, 6H), 1.11 (d, J = 6.9 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ 143.3 (s, 1C), 140.4 (s, 1C), 139.1 (s, 1C), 130.0 (s, 2C), 129.0 (s, 1C), 126.3 (s, 2C), 124.2 (s, 2C), 123.2 (s, 2C), 27.9 (s, 2C), 23.4 (s, 4C), 20.4 (s, 1C), 19.3 (s, 2C); IR (KBr, cm−1) 1,484, 1,466, 1,442, 1,340, 1,270. HRMS (FAB) (m/z) [M + H+] calculated for C21H29N 295.2300, found 295.2308.N-(2,6-Diisopropylphenyl)-N-(2,4,6-mesityl)ammonium pentafluorobenzenesulfonate (4)Typical yield, >90%. 1H NMR (300 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.73 (s, 2H), 3.11 (septet, J = 6.8 Hz, 2H), 2.20 (s, 3H), 2.15 (s, 6H), 1.07 (d, J = 6.6 Hz, 12H); 13C NMR (125 MHz, CDCl3) δ 143.7 (t, J = 7.8 Hz, 2C), 143.3 (s, 1C), 142.0 (d, J = 255 Hz, 1C), 137.7 (s, 1C), 137.2 (d, J = 252 Hz, 2C), 134.1 (s, 1C), 132.3 (s, 1C), 131.4 (s, 2C), 130.9 (s, 2C), 129.2 (s, 2C), 125.0 (s, 2C), 118.7 (s, 1C), 28.6 (s, 2C), 23.5 (s, 4C), 20.3 (s, 1C), 19.1 (s, 2C); 19F NMR (282 MHz, CDCl3) δ −138.3 (dd, J = 6.2, 21.2 Hz, 2F), −153.0 (t, J = 21.2 Hz, 1F), −162.4 (dt, J = 6.2, 21.2 Hz, 2F). IR (KBr, cm−1) 1,489, 1,247, 1,227, 1,115.

A metal-free phosphazenium cation-catalyzed direct dehydrative condensation of phosphoric acid with alcohols has been developed for the environmentally benign synthesis of phosphoric acid monoesters.

Polycyclic bio-active natural products that contain halogen atoms have been isolated from a number of different marine organisms1. The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon–carbon double bond2, 3, 4 via a mechanism that is similar to a proton-induced olefin polycyclization5, 6, 7, 8. Enzymes such as haloperoxidases generate an electrophilic halonium ion (or its equivalent), which reacts with the terminal carbon–carbon double bond of the polyprenoid, enantioselectively inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids; although several brominated cyclic terpenoids have been synthesized via a diastereoselective halocyclization reaction that uses stoichiometric quantities of a brominating reagent9, 10, 11, 12, the enantioselective halocyclization of isoprenoids induced by a chiral promoter has not yet been reported. Here we report the enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds are able to promote the diastereoselective halocyclization reaction to give a halogenated cyclic product in excellent yields. Moreover, chiral phosphoramidites promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide to give iodinated cyclic products in up to 99% enantiomeric excess and diastereomeric excess. To the best of our knowledge, this is the first successful example of the enantioselective halopolycyclization of polyprenoids.

Asymmetric total syntheses of acid-sensitive (−)- and (+)-caparrapi oxides (1) and (+)-8-epicaparrapi oxide (2) from farnesol (10) are achieved using Sharpless–Katsuki epoxidation and Lewis acid-assisted chiral Brønsted acid (chiral LBA)-induced polyene cyclization as key steps. The relative configuration of (+)-dysifragin (4) is determined by a single-crystal X-ray diffraction and its total synthesis is accomplished by the diastereoselective epoxidation of (+)-1. Furthermore, (−)-1 can be directly synthesized from (S)-nerolidol (3) and (R)-LBA with 88% ds by reagent control, which overcame substrate control, while (−)-2 is obtained from (R)-3 and (R)-LBA with >99% ds by the double asymmetric induction.

Reverse micelle-type N,N-diarylammonium pyrosulfate (3–5 mol %) efficiently catalyzes the hydrolysis of esters (up to 100 mmol scale) under organic solvent-free conditions. The present method is successfully applied to the hydrolysis of various esters without the decomposition of the base-sensitive moieties and without any loss of optical purity for α-heterosubstituted carboxylic acids.

A highly practical, catalytic enantioselective alkyl and aryl addition to aldehydes and ketones with organozinc reagents, which were prepared in situ from commercially available Grignard reagents or arylboronic acids, was developed. A chiral phosphoramide ligand was essential for promoting the addition reactions in high yields with high enantioselectivities.

Chiral phosphite–urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

The first enantioselective Diels–Alder reaction of 1,2-dihydropyridines with α-acyloxyacroleins catalyzed by a chiral primary ammonium salt has been developed and it offers more efficient routes to key synthetic intermediates of alkaloids, for which the direct preparations were unavailable before. The asymmetric induction can be understood through the optimized geometry of an iminium salt aqua complex derived from the catalyst and the dienophile.

A highly effective catalytic enantioselective direct aminal synthesis was developed. Chiral ammonium 1,1′-binaphthyl-2,2′-disulfonates, which were prepared in situ from (R)-BINSA and achiral amines, promoted the enantioselective addition of primary amides to aromatic aldimines.

A facile, atom-economical, and chemoselective esterification is crucial in modern organic synthesis, particularly in the areas of pharmaceutical, polymer, and material science. However, a truly practical catalytic transesterification of carboxylic esters with various alcohols has not yet been well established, since, with many conventional catalysts, the substrates are limited to 1°- and cyclic 2°-alcohols. In sharp contrast, if we take advantage of the high catalytic activities of La(Oi-Pr)3, La(OTf)3, and La(NO3)3 as ligand-free catalysts, ligand-assisted or additive-enhanced lanthanum(III) catalysts can be highly effective acid–base combined catalysts in transesterification. A highly active dinuclear La(III) catalyst, which is prepared in situ from lanthanum(III) isopropoxide and 2-(2-methoxyethoxy)ethanol, is effective for the practical transesterification of methyl carboxylates, ethyl acetate, weakly reactive dimethyl carbonate, and much less-reactive methyl carbamates with 1°-, 2°-, and 3°-alcohols. As the second generation, nearly neutral “lanthanum(III) nitrate alkoxide”, namely La(OR)m(NO3)3−m, has been developed. This catalyst is prepared in situ from inexpensive, stable, low-toxic lanthanum(III) nitrate hydrate and methyltrioctylphosphonium methyl carbonate, and is highly useful in the non-epimerized transesterification of α-substituted chiral carboxylic esters, even under azeotropic reflux conditions. In these practical La(III)-catalyzed transesterifications, colorless esters can be obtained in small- to large-scale synthesis without the need for inconvenient work-up or careful purification procedures.

Highly efficient alkylations and arylations of ketones with Grignard reagents (RMgBr and RMgI) have been developed using catalytic ZnCl2, Me3SiCH2MgCl, and LiCl. Tertiary alcohols were obtained in high yields with high chemoselectivities, while minimizing undesired side products produced by reduction and enolization.

The potential of supramolecular catalysts to realize anomalous regio- and/or stereoselectivity in organic synthesis is highly attractive. To date, there have been a few examples of non-polymeric and non-covalent chiral supramolecular catalysts that induce practical enantioselectivity. In this regard, a metal–organic framework (MOF) may be one of the most important techniques for constructing conformationally rigid supramolecular catalysts. However, it is not easy to use the MOF technique to fine-tune a much more precise cage in catalysts for anomalous purposes. To establish high catalytic activity with anomalous regio- and/or stereoselectivity, in principle, an artificial cage should be conformationally flexible, like an active pocket in an enzyme with an induced-fit function. In this feature article, we focus on the anomalous endo/exo-selective Diels–Alder reaction, and overview the development of the successive catalysts including our recent highly active, conformationally flexible, and chiral supramolecular catalysts. The evolution from ‘ready-made’ single-molecule catalysts to ‘tailor-made’ supramolecular catalysts could offer not only high enantioselectivity but also high anomalous endo/exo-selectivities due to substrate-specific characteristics, as with enzymes.

In situ generated lanthanum(III) nitrate alkoxide is a highly active and nearly neutral transesterification catalyst, which can promote non-epimerized transesterification of α-substituted chiral carboxylic esters under reflux conditions.

A highly practical, catalytic enantioselective 2°-alkyl addition to aldehydes and ketones was developed. Chiral phosphoramide ligand (1) with salt-free and solvent-free di(2°-alkyl)zinc reagents prepared from (2°-alkyl)MgCl was essential.

Over the past two decades there has been a dramatic increse in the use of hypervalent iodine compounds in synthetic organic chemistry due to their mild and selective oxidizing properties. Hypervalent iodine compounds catalyze various oxidation reactions such as the oxidation of alcohols, α-oxidation of ketones, oxidative spirocyclization of phenols, etc. Very recently, we found that 2-iodoxybenzensulfonic acid (IBS, 7a), which was generated from 2-iodobenzenesulfonic acidin situ, is an extremely active and mild catalyst for the highly chemoselective oxidation of various alcohols with powdered Oxone® to carbonyl compounds such as aldehydes, carboxylic acids, ketones and cycloalkenones under non-aqueous conditions. In this review, we focus on the design of hypervalent iodine catalysts and review the discovery and development of the oxidation of alcohols with the stoichiometric or catalytic use of hypervalent iodine compounds.

Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(VI) oxide-catalyzed dehydrative cyclization, Sb(OEt)3-catalyzed ester–amide transformation, and WSCI and HOAt-promoted dehydrative amide formation.

Arylboronic acid and 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO) cooperatively catalyse the dehydrative condensation reaction between carboxylic acids and amines to give the corresponding amides under azeotropic reflux conditions. This cooperative use is much more effective than their individual use as catalysts, and chemoselectively promotes the amide condensation of (poly)conjugated carboxylic acids. The present method is practical and scalable, and has been applied to the synthesis of sitagliptin and a drug candidate.

Nucleophilic phosphite–urea cooperative high-turnover catalysts have been designed for the highly selective bromocyclization of homogeranylarenes. The introduction of a urea moiety and bulky aryl groups in the catalyst inhibits decomposition of the catalyst and the generation of byproducts. Only 0.5 mol% of the catalyst successfully promotes the bromocyclization of 4-homogeranyltoluene to give the desired product in 96% yield.

The rational design of small but highly functional artificial catalysts is very important for practical organic synthesis. Asymmetric Lewis acid catalyses with non-covalent secondary interactions have been developed for enantioselective reactions. This tutorial review describes the concept, design and examples of asymmetric Cu(II) catalyses for cycloaddition reactions based on intramolecular π–cation or n–cation interactions between the copper(II) cation and auxiliary Lewis basic sites of the chiral ligands.