Enantio- and diastereoselective, stereospecific mannich-type reactions in water

Catalytic asymmetric Mannich-type reactions in water proceeded in high yields and selectivities using a combination of ZnF2 and a chiral diamine that has the methoxy groups on the aromatic rings. In these reactions, either syn- or anti-Mannich adducts were stereospecifically obtained from (E)- or (Z)-silicon enolate, in contrast with most asymmetric Mannich-type reactions.     

The catalytic asymmetric Mannich-type reactions in aqueous media

The catalytic, diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF(2), a chiral diamine ligand, and trifluoromethanesulfonic acid.     

Remarkably stable chiral zirconium complexes for asymmetric Mannich-type reactions

Isolable, air-stable, storable, and highly selective chiral zirconium catalysts for asymmetric Mannich-type reactions have been developed. The reactions of imines with silicon enolates proceeded smoothly using 1-10 mol % of the powdered zirconium catalyst to afford the corresponding adducts in high yields with high stereoselectivities. The catalyst could be recovered and reused without significant loss of activity. On the other hand, zirconium single crystals for X-ray analysis were obtained, and the crystals also showed high performance in the asymmetric Mannich-type reactions. Although NMR analyses of these zirconium catalysts showed different structures in dichloromethane, the formation of the same key intermediate from the different catalysts was indicated.     

Lewis acid-catalyzed asymmetric hydroxymethylation of silicon enolates in aqueous media

Asymmetric hydroxymethylation of silicon enolates with formaldehyde in aqueous media has been achieved using praseodymium triflate and a chiral crown ether. Formaldehyde aqueous solution can be directly used for the reactions, and a water/THF mixture was found to be the best solvent system. This is the first example of catalytic asymmetric hydroxymethylation of silicon enolates.     

Catalytic asymmetric hydroxymethylation of silicon enolates using an aqueous solution of formaldehyde with a chiral scandium complex

Catalytic asymmetric hydroxymethylation of silicon enolates has been achieved. In this reaction, an aqueous solution of formaldehyde can be used to realize an easy and safe procedure, and high enantioselectivities have been obtained. This is the first example of catalytic asymmetric reactions in aqueous media with a chiral scandium complex.     

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.     

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.     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

An air-stable chiral Hf-based catalyst for asymmetric Mannich-type reactions

A new class of isolable, air-stable, storable, and Hf-based catalyst has been developed. In the presence of 10 mol % of the powdered Hf catalyst, the asymmetric Mannich-type reactions of imines with silicon enolates derived from esters proceeded smoothly to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. Hafnium single crystals for X-ray analysis were obtained, and the crystals also showed high performance in the asymmetric Mannich-type reactions.     

Palladium-catalyzed arylation of trimethylsilyl enolates of esters and imides. High functional group tolerance and stereoselective synthesis of alpha-aryl carboxylic acid derivatives

A general procedure for the palladium-catalyzed arylation of trimethylsilyl enolates of esters and imides is reported. In the presence of ZnF2 or Zn(O-t-Bu)2 as an additive, the trimethylsilyl enolates of esters, including those bearing alpha-alkoxy derivatives, underwent arylation in high yield with high functional group tolerance. This arylation chemistry was extended to ester derivatives bearing chiral auxiliaries to form new tertiary stereocenters. The arylation of imides bearing the Evans auxiliary proceeded with selectivities up to 90% de. Further, the arylation of the ketal developed by Ley provided alpha-aryl glycolates with excellent diastereoselectivities (90 to >98% de). This reaction provides a convenient route to the synthesis of enantiopure alpha-aryl-alpha-hydroxy esters. Reactions conducted with Zn(O-t-Bu)2 as an additive occurred at room temperature to give enhanced diastereoselectivities with both chiral reagents. Mechanistic studies showed that the reaction conditions are neutral enough that the observed diastereomeric ratios reflect kinetic selectivities.     

Asymmetric synthesis of α,β-diamino acid derivatives with an aziridine-, azetidine- and γ-lactone-skeleton via Mannich-type additions across α-chloro-N-sulfinylimines

The efficient asymmetric synthesis of new chiral γ-chloro-α,β-diamino acid derivatives via highly diastereoselective Mannich-type reactions of N-(diphenylmethylene) glycine esters across a chiral α-chloro-N-p-toluenesulfinylimine was developed. The influence of the base, LDA or LiHMDS, used for the formation of the glycine enolates, was of great importance for the anti-/syn-diastereoselectivity of the Mannich-type reaction. The γ-chloro-α,β-diamino acid derivatives proved to be excellent building blocks for ring closure towards optically pure anti- and syn-β,γ-aziridino-α-amino esters, and subsequent ring transformation into trans-3-aminoazetidine-2-carboxylic acid derivatives and α,β-diamino-γ-butyrolactones.     

Chiral zirconium catalysts using multidentate BINOL derivatives for catalytic enantioselective Mannich-type reactions; ligand optimization and approaches to elucidation of the catalyst structure

Catalytic enantioselective Mannich-type reactions of silicon enolates with aldimines were investigated using chiral zirconium catalysts prepared from Zr(O(t)Bu)(4), N-methylimidazole, and newly designed multidentate BINOL derivatives. These new multidentate BINOL ligands were designed on the basis of an assumed transition state structure of a chiral zirconium catalyst derived from two molecules of (R)-6,6'-Br(2)-BINOL. Not only tetradentate BINOL 4 but also tridentate BINOL derivatives were found to be effective, and high enantioselectivities were attained. In a structural study of the most effective zirconium complex prepared from tridentate ligand 6e, several NMR experiments and DFT calculations were carried out. Consequently, the structure of an active catalyst and plausible mechanism of asymmetric induction were elucidated.     

Catalytic,asymmetric Mannich-type reactions of N-acylimino esters: reactivity,diastereo- and enantioselectivity,and application to synthesis of N-acylated amino acid derivatives

In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N-acylimino esters reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made. In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total yield was 82.9%.     

Development of catalytic asymmetric reactions via chiral palladium enolates

This article describes the generation of chiral palladium enolates and their application to several kinds of catalytic asymmetric reactions. Two methods to generate chiral enolates were developed using novel cationic palladium complexes 1 and 2 . In these processes, water or a hydroxo ligand on palladium metal plays an important role as a nucleophile to promote the transmetallation or as a Brønsted base to abstract an acidic α‐proton of the carbonyl group. These enolates showed sufficient reactivity with various electrophiles. Using a chiral Pd enolate as a key intermediate, highly enantioselective reactions such as catalytic aldol reactions, Mannich‐type reactions, Michael reactions, and fluorination reactions were developed. The unique structures of the palladium enolate complexes were elucidated and reaction mechanisms are proposed. © 2004 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 4: 231–242; 2004: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20017     

水相不对称转移氢化*

手性醇和胺是重要的精细化学品,不对称转移氢化是获得这类手性化合物有效、实用的途径之一。在众多的催化剂中,Noyori等发展的手性二胺与过渡金属钌TsDPEN-Ru（TsDPEN = 1,2-二苯基乙二胺）络合物是最有效的催化剂。近年来,随着化学家对绿色化学的日益重视,水作为绿色溶剂被广泛地用作为不对称催化转移氢化的反应介质,具有很高的反应活性、对映选择性和化学选择性。本文综述近年来应用未经修饰和修饰的手性二胺配体与过渡金属钌[(cymene)RuCl₂]₂、铑[(Cp*)RhCl₂]₂和铱[(Cp*)IrCl_2]2的络合物催化的水相中酮、亚胺和活化烯烃的不对称转移氢化的研究进展。     

Recent advances in chiral phosphine-silver(I) complex-catalyzed asymmetric reactions

Since the first report of silver(I)-catalyzed asymmetric aldol-type reaction of activated isocyanides with aldehydes using a chiral ferrocenylphosphine as a chiral phosphine ligand has been appeared in 1990, various chiral phosphine-silver(I) catalysts have been utilized in asymmetric transformations. This feature articles describes recent examples of chiral phosphine-silver(I) complex-catalyzed asymmetric reactions such as allylation, aldol reaction, Mannich-type reaction, hetero-Diels-Alder reaction, 1,3-dipolar cycloaddition and nitroso aldol reaction.     

Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric Mannich reaction of N-protected aminoacetaldehydes: formal synthesis of (-)-agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.     

Allylation Reactions of Aldehydes with Allylboronates in Aqueous Media: Unique Reactivity and Selectivity that are Only Observed in the Presence of Water

Zn(OH)₂‐catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the α‐addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B‐to‐Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates ( 6a , 6b , 6c , 6d ) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2‐dimethyl‐1,3‐propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)₂ and achiral ligand 4d in aqueous media to afford the corresponding syn‐adducts in high yields with high diastereoselectivities. In all cases, the α‐addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9 . Based on the X‐ray structure of the Zn‐ 9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated.     

Catalytic Generation of C1 Ammonium Enolates from Halides and CO for Asymmetric Cascade Reactions

A general strategy for the design of asymmetric cascade reactions using readily available halides and carbon monoxide (CO) as substrates is developed. The key is the catalytic generation of C1‐ammonium enolates for the subsequent asymmetric cascade reactions through the combination of palladium‐catalyzed carbonylation and chiral Lewis base catalysis. Utilizing this strategy, we have established asymmetric formal [1+1+4] and [1+1+2] reactions to afford chiral dihydropyridones and β‐lactams with high yields and high enantio‐ and diastereoselectivities.     

Highly diastereoselective mannich-type reactions of chiral N-acylhydrazones

The Lewis acid-mediated addition of silyl enolates to easily accessible homochiral N-acylhydrazones derived from 3-amino-2-oxazolidinones proceeded in yields up to 71% and diastereomeric ratios of 99:1. In most cases, optimal reaction conditions entailed the simple use of ZnCl(2) in acetonitrile at room temperature. Hydrazones derived from phenyl-, isopropyl-, and benzyl-substituted 2-oxazolidinones were examined in the reaction in terms of yield and diastereoselectivity. The facile SmI(2)-mediated N-N bond cleavage of the formed hydrazines was demonstrated yielding a beta-amino acid derivative. Hence, the overall reaction sequence constitutes an efficient asymmetric Mannich-type reaction. The sense of diastereoselectivity was explained by a preferential attack on the less shielded Si face of the chiral hydrazones and confirmed by means of X-ray crystallography.