Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.     

Development of atom-economical catalytic asymmetric reactions under proton transfer conditions: construction of tetrasubstituted stereogenic centers and their application to therapeutics

The development of atom-economical catalytic asymmetric reactions based on two distinct sets of catalyst, a rare earth metal/amide-based ligand catalyst and a soft Lewis acid/hard Br?nsted base catalyst, is reviewed. These catalytic systems exhibit high catalytic activity and stereoselectivity by harnessing a cooperative catalysis through hydrogen bond/metal coordination and soft-soft interactions/hard-hard interactions, respectively. The effectiveness of these cooperative catalysts is clearly delineated by the high stereoselectivity in reactions with highly coordinative substrates, and the specific activation of otherwise low-reactive pronucleophiles under proton transfer conditions. The rare earth metal/amide-based ligand catalyst was successfully applied to catalytic asymmetric aminations, nitroaldol (Henry) reactions, Mannich-type reactions, and conjugate addition reactions, generating stereogenic tetrasubstituted centers. Catalytic asymmetric amination and anti-selective catalytic asymmetric nitroaldol reactions were successfully applied to the efficient enantioselective synthesis of therapeutic candidates, such as AS-3201 and the β(3)-adrenoreceptor agonist, showcasing the practical utility of the present protocols. The soft Lewis acid/hard Br?nsted base cooperative catalyst was specifically developed for the chemoselective activation of soft Lewis basic allylic cyanides and thioamides, which are otherwise low-reactive pronucleophiles. The cooperative action of the catalyst allowed for efficient catalytic generation of active carbon nucleophiles in situ, which were integrated into subsequent enantioselective additions to carbonyl-type electrophiles.     

A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction

The direct catalytic asymmetric aldol reaction offers efficient access to β‐hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α‐sulfanyl 7‐azaindolinylamide, thus affording both aromatic and aliphatic β‐hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Brønsted base.     

Enantioselective synthesis of a GPR40 agonist AMG 837 via catalytic asymmetric conjugate addition of terminal alkyne to α,β-unsaturated thioamide

A concise enantioselective synthetic route to a potent GPR40 agonist AMG 837 is described. The crucial catalytic asymmetric conjugate addition of terminal alkyne was promoted by a soft Lewis acid/hard Br?nsted base cooperative catalyst, allowing efficient construction of the requisite stereogenic center. The thioamide functional group is key to both activation in asymmetric alkynylation and facile transformation into carboxylic acid.     

Intermediate as catalyst: catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides

Catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides is promoted by a mesitylcopper/(R)-DTBM-Segphos precatalyst, affording γ-nitrothioamides in moderate to high syn-selectivity and excellent enantioselectivity. The intermediate Cu-thioamide enolate functions as a soft Lewis acid/hard Br?nsted base cooperative catalyst to drive the catalytic cycle efficiently under proton transfer conditions.     

Direct catalytic asymmetric aldol reaction of thioamides: a concise asymmetric synthesis of (R)-fluoxetine

A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH₃CN)₄]PF₆/Li(OC₆H₄-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft–soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.     

Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

Optically active vicinal diamines are versatile chiral building blocks in organic synthesis. A soft Lewis acid/hard Brønsted base cooperative catalyst allows for an efficient stereoselective coupling of N‐alkylidene‐α‐aminoacetonitrile and ketimines to access this class of compounds bearing consecutive tetra‐ and trisubstituted stereogenic centers. The strategic use of a soft Lewis basic thiophosphinoyl group for ketimines is the key to promoting the reaction, and aliphatic ketimines serve as suitable substrates with as little as 3 mol % catalyst loading.     

A new family of cinchona-derived amino phosphine precatalysts: application to the highly enantio- and diastereoselective silver-catalyzed isocyanoacetate aldol reaction

A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Br?nsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained.     

Rich chemistry of nitroso compounds

Nitrosobenzene or nitrosopyridine are found to be attractive electrophiles in catalytic enantioselective carbon-nitrogen and/or carbon-oxygen bond forming reactions. In the presence of designer Lewis or Br?nsted acid catalysts, catalytic enantioselective O- and N-nitroso aldol reaction or nitroso Diels-Alder reaction proceed smoothly. The scope and limitation of new catalytic processes are described.     

Lewis base activation of Lewis acids: development of a Lewis base catalyzed selenolactonization

The concept of Lewis base activation of Lewis acids has been applied to the selenolactonization reaction. Through the use of substoichiometric amounts of Lewis bases with "soft" donor atoms (S, Se, P) significant rate enhancements over the background reaction are seen. Preliminary mechanistic investigations have revealed the resting state of the catalyst as well as the significance of a weak Br?nsted acid promoter.     

Direct asymmetric aldol reaction of acetophenones with aromatic aldehydes catalyzed by chiral Al/Zn heterobimetallic compounds

Chiral Al/Zn heterobimetallic complexes are effective catalysts for the direct highly enantioselective aldol reaction of acetophenones with aromatic aldehydes. The Al site in the complex acts as a Lewis acid to activate aldehyde, whereas ethylzinc alkoxide plays a role of a Brønsted base to form a reactive zinc enolate with acetophenone. Distinct nature of two different metals contributes to the efficient direct asymmetric aldol reaction.     

Asymmetric Direct Aldol Reactions Catalyzed by a Simple Chiral Primary Diamine–Br⊘nsted Acid Catalyst in/on Water

Abstract

The direct asymmetric aldol reaction catalyzed by the simple and commercially available chiral primary diamines, (1S,2S)-1,2-diphenylethane-1,2-diamine and (1R,2R)-1,2-diphenylethane-1,2-diamine, is presented. The catalyst system is a primary amine with Br?nsted acid–catalyzed direct aldol reaction of p-nitrobenzaldehyde and cyclohexanone with high chemo- and stereoselectivity on water, which furnishes the corresponding β-hydroxyketone with up to 94% ee.     

Super Brønsted acid catalysis

Br?nsted acid catalysis has emerged as a new class of catalysis in modern organic synthesis. However, in order to make the utility of the Br?nsted acid catalysis as broad as the well-developed Lewis acid catalysis, it is desirable to develop Br?nsted acids demonstrating both high reactivities and selectivities. In this feature article, we will present our achievement in the design and development of strong Br?nsted acids and their application to organic reactions. Furthermore, we will describe the Tf(2)NH-catalyzed Mukaiyama aldol reaction of super silyl enol ethers. We also will highlight the differences in reactivity and chemo- and stereo-selectivity between Br?nsted and Lewis acid catalysis.     

新型Br?nsted酸性离子液体催化二氧化碳与环氧化合物偶联反应

设计合成了一系列由碳链长度可调节的Br?nsted酸中心阳离子及Lewis碱中心阴离子构成的酸性离子液体,,并应用于二氧化碳与环氧化合物的偶联反应合成环碳酸酯。考察了离子液体结构以及温度、压力和催化剂用量等参数的影响。结果表明,具有长碳链的离子液体表现出高催化活性及可重复使用性能。离子液体的酸性影响催化活性。     

Direct enolization chemistry of 7-azaindoline amides: A case study of bis(tetrahydrophosphole)-type ligands

7-Azaindoline amides are particularly useful in direct enolization chemistry due to their facilitated enolization in soft Lewis acid/Brønsted base cooperative catalysis. The Cu(I) complex of (R,R)-Ph-BPE, a bis(tetrahydrophosphole)-type chiral bisphosphine ligand, exhibits consistently high catalytic performance and stereoselectivity irrespective of the nature of the α-substituent of the amides. Unexpectedly, however, alkyl-substituted bis(tetrahydrophosphole)-type ligands have substantially inferior catalytic performance. Evaluation of the optimized structures of Cu(I)/amide and Cu(I)/enolate complexes provided clues to dissecting the diverted reaction outcomes.     

Recent progress in asymmetric two-center catalysis

Recent progress using two types of enantioselective two-center catalysts, Lewis acid-Br?nsted base and Lewis acid-Lewis base bifunctional complexes, is described. The first part of this review discusses improvements in the syn-selective direct catalytic enantioselective aldol reaction and 1,4-addition reaction of a 2-hydroxyacetophenone derivative using a Zn-linked-BINOL complex. In the second part, we describe the development of catalysts displaying Lewis acidity and Lewis basicity in a catalytic enantioselective cyanosilylation of aldehydes and the logical extension to a tetrasubstituted carbon synthesis through a Reissert-type reaction and a cyanosilylation of ketones.     

Fast and selective sugar conversion to alkyl lactate and lactic acid with bifunctional carbon-silica catalysts

A novel catalyst design for the conversion of mono- and disaccharides to lactic acid and its alkyl esters was developed. The design uses a mesoporous silica, here represented by MCM-41, which is filled with a polyaromatic to graphite-like carbon network. The particular structure of the carbon-silica composite allows the accommodation of a broad variety of catalytically active functions, useful to attain cascade reactions, in a readily tunable pore texture. The significance of a joint action of Lewis and weak Br?nsted acid sites was studied here to realize fast and selective sugar conversion. Lewis acidity is provided by grafting the silica component with Sn(IV), while weak Br?nsted acidity originates from oxygen-containing functional groups in the carbon part. The weak Br?nsted acid content was varied by changing the amount of carbon loading, the pyrolysis temperature, and the post-treatment procedure. As both catalytic functions can be tuned independently, their individual role and optimal balance can be searched for. It was thus demonstrated for the first time that the presence of weak Br?nsted acid sites is crucial in accelerating the rate-determining (dehydration) reaction, that is, the first step in the reaction network from triose to lactate. Composite catalysts with well-balanced Lewis/Br?nsted acidity are able to convert the trioses, glyceraldehyde and dihydroxyacetone, quantitatively into ethyl lactate in ethanol with an order of magnitude higher reaction rate when compared to the Sn grafted MCM-41 reference catalyst. Interestingly, the ability to tailor the pore architecture further allows the synthesis of a variety of amphiphilic alkyl lactates from trioses and long chain alcohols in moderate to high yields. Finally, direct lactate formation from hexoses, glucose and fructose, and disaccharides composed thereof, sucrose, was also attempted. For instance, conversion of sucrose with the bifunctional composite catalyst yields 45% methyl lactate in methanol at slightly elevated reaction temperature. The hybrid catalyst proved to be recyclable in various successive runs when used in alcohol solvent.     

Direct Catalytic Asymmetric Mannich‐type Reaction of α,β‐Unsaturated γ‐Butyrolactam with Ketimines

We report a direct catalytic asymmetric Mannich‐type addition of α,β‐unsaturated γ‐butyrolactam to α‐ethoxycarbonyl ketimines promoted by a soft Lewis acid/Brønsted base cooperative catalyst. A thiophosphinoyl group on the nitrogen of ketimines was crucial for both electrophilic activation and α‐addition of γ‐butyrolactams. The obtained aza‐Morita–Baylis–Hillman‐type products bear an α‐amino acid architecture with a tetra‐substituted stereogenic center.     

Catalysis of the Michael addition reaction by late transition metal complexes of BINOL-derived salens

Salen metal complexes incorporating two chiral BINOL moieties have been synthesized and characterized by X-ray crystallography. The X-ray structures show that this new class of Ni-BINOL-salen catalysts contains an unoccupied apical site for potential coordination of an electrophile and naphthoxides that are independent from the Lewis acid center. These characteristics allow independent alteration of the Lewis acidic and Br?nsted basic sites. These unique complexes have been shown to catalyze the Michael reaction of dibenzyl malonate and cyclohexenone with good selectivity (up to 90% ee) and moderate yield (up to 79% yield). These catalysts are also effective in the Michael reaction between other enones and malonates. Kinetic data show that the reaction is first order in the Ni*Cs-BINOL-salen catalyst. Further experiments probed the reactivity of the individual Lewis acid and Br?nsted base components of the catalyst and established that both moieties are essential for asymmetric catalysis. All told, the data support a bifunctional activation pathway in which the apical Ni site of the Ni*Cs-BINOL-salen activates the enone and the naphthoxide base activates the malonate.     

Direct catalytic asymmetric Mannich-type reactions of gamma-butenolides: effectiveness of Brønsted acid in chiral metal catalysis

Direct catalytic asymmetric Mannich-type reactions of gamma-butenolides are described. A chiral Lewis acid/amine base/Br?nsted acid combination was used to catalyze a gamma-addition of gamma-butenolides to N-diphenylphosphinoyl imines, affording the products in up to >99% yield, anti/syn = >97:3, and 84% ee. The use of a catalytic amount of TfOH in addition to La(OTf)3/Me-PyBox/TMEDA was important for improving yield and stereoselectivity.