Iron‐ and Bismuth‐Catalyzed Asymmetric Mukaiyama Aldol Reactions in Aqueous Media

We have developed asymmetric Mukaiyama aldol reactions of silicon enolates with aldehydes catalyzed by chiral Fe^II and Bi^III complexes. Although previous reactions often required relatively harsh conditions, such as strictly anhydrous conditions, very low temperatures (?78 °C), etc., the reactions reported herein proceeded in the presence of water at 0 °C. To find appropriate chiral water‐compatible Lewis acids for the Mukaiyama aldol reaction, many Lewis acids were screened in combination with chiral bipyridine L1 , which had previously been found to be a suitable chiral ligand in aqueous media. Three types of chiral catalysts that consisted of a Fe^II or Bi^III metal salt, a chiral ligand ( L1 ), and an additive have been discovered and a wide variety of substrates (silicon enolates and aldehydes) reacted to afford the desired aldol products in high yields with high diastereo‐ and enantioselectivities through an appropriate selection of one of the three catalytic systems. Mechanistic studies elucidated the coordination environments around the Fe^II and Bi^III centers and the effect of additives on the chiral catalysis. Notably, both Brønsted acids and bases worked as efficient additives in the Fe^II‐catalyzed reactions. The assumed catalytic cycle and transition states indicated important roles of water in these efficient asymmetric Mukaiyama aldol reactions in aqueous media with the broadly applicable and versatile catalytic systems.     

Bifunctional transition metal-based molecular catalysts for asymmetric syntheses

The discovery and development of conceptually new chiral bifunctional transition metal-based catalysts for asymmetric reactions is described. The chiral bifunctional Ru catalyst was originally developed for asymmetric transfer hydrogenation of ketones and imines and is now successfully applicable to enantioselective C-C bond formation reaction with a wide scope and high practicability. The deprotonation of 1,3-dicarbonyl compounds with the chiral amido Ru complexes leading to the amine Ru complexes bearing C- or O-bonded enolates, followed by further reactions with electrophlies gives C-C bond formation products. The present bifunctional Ru catalyst offers a great opportunity to open up new fundamentals for stereoselective molecular transformation including enantioselective C-H and C-C as well as C-O, C-N bond formation.     

Lewis base catalyzed aldol additions of chiral trichlorosilyl enolates and silyl enol ethers

[structures: see text] The consequences of double diastereodifferentiation in chiral Lewis base catalyzed aldol additions using chiral enoxysilanes derived from lactate, 3-hydroxyisobutyrate, and 3-hydroxybutyrate have been investigated. Trichlorosilyl enolates derived from the chiral methyl and ethyl ketones were subjected to aldolization in the presence of phosphoramides, and the intrinsic selectivity of these enolates and the external stereoinduction from chiral catalyst were studied. In the reactions with the lactate derived enolate, the strong internal stereoinduction dominated the stereochemical outcome of the aldol addition. For the 3-hydroxyisobutyrate- and 3-hydroxybutyrate derived enolates, the catalyst-controlled diastereoselectivities were observed, and the resident stereogenic centers exerted marginal influence. The corresponding trimethylsilyl enol ethers were employed in SiCl4/bisphosphoramide catalyzed aldol additions, and the effect of double diastereodifferentiation was also investigated. The overall diastereoselection of the process was again controlled by the strong external influence of the catalyst.     

Enantioselective Trifluoromethylthiolating Lactonization Catalyzed by an Indane‐Based Chiral Sulfide

Enantioselective trifluoromethylthiolation, especially of alkenes, is a challenging task. In this work, we have developed an efficient approach for enantioselective trifluoromethylthiolating lactonization by designing an indane‐based bifunctional chiral sulfide catalyst and a shelf‐stable electrophilic SCF₃ reagent. The desired products were formed with diastereoselectivities of >99:1 and good to excellent enantioselectivities. The transformation represents the first enantioselective trifluoromethylthiolation of alkenes and the first enantioselective trifluoromethylthiolation that is enabled by a catalyst with a Lewis basic sulfur center.     

Application of the Lewis acid-Lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and beta3-adenergic receptor agonist

Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of beta(3)-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to beta-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.     

手性磷酸催化的有机催化不对称反应

手性磷酸是近年来发展起来的一类新型高效、高对映选择性的Brønsted酸类有机催化剂, 已成功应用于催化不对称Mannich反应、还原胺化反应、Pictet-Spengler反应、aza-Diels-Alder反应和aza-Ene反应等许多重要的有机合成反应. 手性磷酸催化剂分子内同时含有Lewis碱性位点和Brønsted酸性位点, 可同时活化亲电与亲核底物. 作为一种新型双功能有机催化剂, 手性磷酸具有较高的催化活性和对映选择性, 催化剂最低用量可达0.05 mol%. 对各类手性磷酸催化剂在有机催化不对称合成反应中的应用研究进展, 以及不对称诱导反应的机理、手性磷酸的分子结构及反应条件对其催化活性和不对称诱导活性的影响进行了评述.     

Chiral anion-mediated asymmetric ring opening of meso-aziridinium and episulfonium ions

Reactions proceeding through cationic intermediates that lack a Lewis or Br?nsted basic site present a challenge for traditional asymmetric catalysis based on chiral metals or organocatalysts. We present an enantioselective ring opening of tetrasubstituted meso-aziridinium ions with alcohol nucleophiles proceeding through a chiral ion pair with a binaphthol-phosphate anion. The reaction is initiated by silver-induced ring closure of beta-chloroamines using the Ag salt of the chiral anion as in situ generated catalyst. Use of insoluble Ag2CO3 as silver source is essential to obtain high enantioselectivity; we believe the chiral phosphate acts as a "chiral anion phase transfer catalyst" to bring silver ion into the organic phase. The chiral anion concept can also be extended to the related asymmetric opening of meso-episulfonium ions generated by protonation of trichloroacetimidates vicinal to sulfides.     

Complete stereocontrol in organocatalytic additions of β-ketosulfoxides to conjugated aldehydes

The use of β-ketosulfoxides as nucleophiles in reactions with α,β-unsaturated aldehydes catalyzed by proline derivatives allows complete control of configuration at the two chiral centers that are created during 1,4-addition reactions. The sulfinyl group can be used to create additional chiral centers in the resulting compounds and then removed while preserving the chirality of the carbon joined to the sulfur. The catalyst and the sulfinyl group are mainly responsible for the configurational control of the carbon atoms acting as electrophile and nucleophile, respectively, which allows the preparation of the four possible diastereoisomers in optically pure form. Theoretical calculations of the possible chiral nucleophilic species bearing diastereotopic faces allow us to postulate, for the first time, that enolates, instead of enols, are the active reagents in these reactions.     

Direct conversion of carbonyl compounds into organic halides: indium(III) hydroxide-catalyzed deoxygenative halogenation using chlorodimethylsilane

The reaction of carbonyls and chlorodimethylsilane was effectively catalyzed by indium(III) hydroxide and afforded the corresponding deoxygenative chlorination products, in which the carbonyl carbon accepted two nucleophiles (H and Cl) with releasing oxygen. Only In(OH)3 catalyzed the reaction, and typical Lewis acids such as TiCl4, AlCl3, and BF3.OEt2 showed no catalytic activity. The reaction mechanism of this deoxygenative chlorination includes initial hydrosilylation followed by chlorination. Other nucleophiles such as allyl or iodine were available for this methodology. The moderate Lewis acidity of indium catalyst enabled chemoselective reaction, and therefore ester, nitro, cyano, or halogen groups were not affected during the reaction course.     

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β‐Lactams with contiguous tetra‐ and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4‐exo‐trig cyclization of axially chiral enolates generated from readily available α‐amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β‐lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β‐lactam enolates thus formed through reversible intramolecular conjugate addition (4‐exo‐trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work‐up procedure) to give β‐lactams in up to 97 % ee.     

Bismuth triflate-chiral bipyridine complexes as water-compatible chiral Lewis acids

[reaction: see text] Catalytic asymmetric hydroxymethylation of silicon enolates with an aqueous formaldehyde solution has been developed using a chiral bismuth complex. This is the first example of highly enantioselective reactions using a chiral bismuth catalyst in aqueous media. In this paper, we have added Bi(OTf)(3)-1 complex as a "water-compatible Lewis acid". Bi(OTf)3 is unstable in the presence of water but is stabilized by the basic ligand.     

Palladium-catalyzed asymmetric allylic alkylation of ketone enolates

Palladium-catalyzed asymmetric allylic alkylation of nonstabilized ketone enolates to generate quaternary centers has been achieved in excellent yield and enantioselectivity. Optimized conditions consist of performing the reaction in the presence of two equivalents of LDA as base, one equivalent of trimethytin chloride as a Lewis acid, 1,2-dimethoxyethane as the solvent, and a catalytic amount of a chiral palladium complex formed from pi-allyl palladium chloride dimer 3 and cyclohexyldiamine derived chiral ligand 4. Linearly substituted, acyclic 1,3-dialkyl substituted, and unsubstituted allylic carbonates function well as electrophiles. A variety of alpha-tetralones, cyclohexanones, and cyclopentanones can be employed as nucleophiles. The absolute configuration generated is consistent with the current model in which steric factors control stereofacial differentiation. The quaternary substituted products available by this method are versatile substrates for further elaboration.     

Novel chiral hydrogen bond donor catalysts based on a 4,5-diaminoxanthene scaffold: application to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived catalyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleophiles, asymmetric conjugate addition to β-aryl nitroalkenes proceeded with good diastereoselectivity to provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with up to 95% ee.     

Dynamic chirality of (E)-5-cyclononen-1-one and its enolate

It has been found that (E)-5-cyclononen-1-one (2a) exhibits marginal planar chirality owing to an insufficient topological constraint, whereas the enolates 3 derived from 2a show robust planar chirality. Enantioenriched enolates are easily prepared by enzymatic hydrolysis, and they show an ability to serve as chiral nucleophiles.     

A chiral molecular recognition approach to the formation of optically active quaternary centres in aza-Henry reactions

An approach to asymmetric catalysis based on chiral molecular recognition by the combination of chiral Lewis acids and chiral organocatalysis for the formation of optically active quarternary centers in the aza-Henry reaction is presented; this procedure leads to products with up to 98% ee and a diastereomeric ratio of 14 : 1 in excellent yields with catalyst loadings of 5 mol%.     

Palladium‐Catalyzed Asymmetric Allylic Alkylation of Ketone Enolates

Palladium‐catalyzed asymmetric allylic alkylation of nonstabilized ketone enolates to generate quaternary centers has been achieved in excellent yield and enantioselectivity. Optimized conditions consist of performing the reaction in the presence of two equivalents of LDA as base, one equivalent of trimethytin chloride as a Lewis acid, 1,2‐dimethoxyethane as the solvent, and a catalytic amount of a chiral palladium complex formed from π‐allyl palladium chloride dimer 3 and cyclohexyldiamine derived chiral ligand 4 . Linearly substituted, acyclic 1,3‐dialkyl substituted, and unsubstituted allylic carbonates function well as electrophiles. A variety of α‐tetralones, cyclohexanones, and cyclopentanones can be employed as nucleophiles. The absolute configuration generated is consistent with the current model in which steric factors control stereofacial differentiation. The quaternary substituted products available by this method are versatile substrates for further elaboration.     

Generation and Reactivity of C(1)-Ammonium Enolates by Using Isothiourea Catalysis

C(1)-Ammonium enolates are powerful, catalytically generated synthetic intermediates applied in the enantioselective α-functionalisation of carboxylic acid derivatives. This minireview describes the recent developments in the generation and application of C(1)-ammonium enolates from various precursors (carboxylic acids, anhydrides, acyl imidazoles, aryl esters, α-diazoketones, alkyl halides) using isothiourea Lewis base organocatalysts. Their synthetic utility in intra- and intermolecular enantioselective C−C and C−X bond forming processes on reaction with various electrophiles will be showcased utilising two distinct catalyst turnover approaches.     

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.     

An Asymmetric, bifunctional catalytic approach to non-natural alpha-amino acid derivatives

A catalytic, asymmetric process for the synthesis of 1,4-benzoxazinones from o-benzoquinone imides and ketene enolates is reported. Addition of Lewis acids (Zn(OTf)2, In(OTf)3, and in particular Sc(OTf)3) creates a bifunctional catalytic system that dramatically increases the reaction rate and the yield of these non-natural amino acid precursors while preserving the remarkable enantioselectivity inherent to the reaction. Cocatalyst Sc(OTf)3 increases the yield by up to 42% while producing products in >99% ee.     

Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models

The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long‐standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar‐chiral ferrocene, a biomimetic asymmetric reduction has been realized using bench‐stable Lewis acids as transfer catalysts. A broad set of alkenes and imines could be reduced with up to 98 % yield and 98 % ee, likely enabled by enzyme‐like cooperative bifunctional activation. This reaction represents the first general biomimetic asymmetric reduction (BMAR) process enabled by chiral and regenerable NAD(P)H analogues. This concept demonstrates catalytic utility of a chiral coenzyme NAD(P)H in asymmetric catalysis.