Enolate, asymmetric Mannich reaction

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Catalytic Asymmetric Mannich Reactions via Metal Enolates. 148... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

The catalytic asymmetric Mannich reaction of lithium enolates with imines was reported in 1997 using an external chiral ligand [36]. First, it was found that reactions of lithium enolates with imines were accelerated by addition of external chiral ligands. Then, it was revealed that reactions were in most cases accelerated in the presence of excess amounts of lithium amides. A small amount of a chiral source was then used in the asymmetric version [(Eq. (8)], and chiral ligands were optimized to achieve suitable catalytic turnover [37]. 

An asymmetric Mannich reaction was recently successfully achieved by means of different types of catalyst, metal- and organocatalysts [20, 21]. With the latter the reaction can be performed asymmetrically by use of L-proline and related compounds as chiral organocatalyst [22-35]. A key advantage of the proline-catalyzed route is that unmodified ketones are used as donors, which is synthetically highly attractive. In contrast, many other asymmetric catalytic methods require preformed enolate equivalents as nucleophile. 

M. C. Sharma, A. K. Garcia, J. M. Gonzalez, A. Landa, C. Linden, A. a-Oxymethyl ketone enolates for the asymmetric Mannich reaction. From acetylene and N-alkoxycarbonylimines to /J-amino acids. Angew. Chem. Int. Ed. 2000, 39, 1063-1065. 

TABLE 10.3. Asymmetric Mannich Reactions of Enol Ethers with Alkynyl Imines... 

The peptidic phosphine ligands that had been introduced by Hoveyda and co-workers271 for enantioselective copper-catalyzed Michael additions (see Section 9.12.2.2.1) were also employed successfully in silver-catalyzed asymmetric Mannich reactions.3 Thus, the aryl-substituted imines 372 reacted with various silyl enol ethers in the presence of stoichiometric amounts of isopropanol, as well as catalytic amounts of silver acetate and ligand 373 to... 

Asymmetric Mannich reactions.24 Our enolate alkylation methodology has been subsequently extended to include asymmetric Mannich reactions. The Mannich reaction can be viewed as an imino analogue of the aldol reaction and is a very common synthetic method for the preparation of P-aminoketones. 

Enders D, Oberborsch S (2002) Asymmetric Mannich reactions with a-silylated trimethylsilyl enol ethers and IV-alkoxycarbonyl Imines. Synlett 2002 471-473... 

The asymmetric Mannich reaction of an enolate and an imine furnishing valuable p amino carbonyls is a fundamental C C bond forming process in organic chemistry that has broad utility in organic synthesis particularly for P amino acid synthesis [1]. Extending the enolate component into a dienolate offers the opportunity for a bond forming event with an electrophile both at the a and the y positions of this ambident nucleophile (Scheme 5.1). 

The development of a catalytic asymmetric addition of enolates to imines (Mannich reaction) has only recently received attention and it was not until 1998 that there were reports of this process giving products in over 90% enantiomeric excess. Since then a large number of both metal-based catalysts and organocatalysts for the asymmetric Mannich reaction have been investigated. 

Josephosohn, N. S., Snapper, M. L., Hoveyda, A. H. (2004). Ag-catalyzed asymmetric Mannich reaction of enol ethers with aryl, alkyl, alkenyl, and alkynyl imines. Journal of the American Chemical Society, 126, 3734-3735. 

Catalytic enantioselective Mannich reactions - addition reactions of enolates to the imine double bond - were less developed than the corresponding aldol protocols. In view of the analogy between the carbonyl and the imine group, it is not very surprising that many catalysts that had proven their efficiency in aldol protocols were tried to be applied in the asymmetric Mannich reaction as well. However, there are some inherent features that make the Mannich reaction more difficult to... 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

A facile, asymmetric Mannich reaction between chiral AAphosphonyl imines (103) and a,p-unsaturated ketone (104)-derived enolates has been reported as an easy and efficient strategy for the synthesis of chiral p -amino-a,p-enones (105) (Scheme 32). The reaction tolerated a wide scope of imine substrates (103) affording products in good chemical yields (up to 96%) and high diastereoselectivities (up to 98 2 dr). ... 

An ammonium betaine of type (R)-16 could be considered as an intramolecular version of ammonium phenoxide. The potential of chiral ammonium betaine (R)-16 as Br0nsted base catalyst has been demonstrated in asymmetric Mannich reactions (Scheme 14.9) [6b, 32]. The basic phenoxide anion is responsible for abstraction of the active methine proton of a nucleophile 18 and thus gives the corresponding chiral ammonium enolate. Subsequent stereoselective bond formation with imine 17 afforded ammonium amide that can be rapidly protonated by the in situ formed phenolic hydrogen to regenerate the ammonium betaine (R)-16. 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Ferraris et al.108 demonstrated an asymmetric Mannich-type reaction using chiral late-transition metal phosphine complexes as the catalyst. As shown in Scheme 3-59, the enantioselective addition of enol silyl ether to a-imino esters proceeds at —80°C, providing the product with moderate yield but very high enantioselectivity (over 99%). 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

The aldol reaction of an enolate or enolate equivalent with an imine is referred to as the Mannich-type reaction. Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched p-amino acid derivatives, which are versatile chiral building blocks for the synthesis of nitrogen-containing biologically important compounds [23]. Despite the enormous progress made in asymmetric aldol reactions [24], the corresponding asymmet-... 

An asymmetric synthesis of a,(3-disubstituted (3-amino esters and (3-lactams has been reported [181]. Chiral (3-amino esters were prepared by a stereocon-trolled Mannich reaction with enolizable imines using an enolate derived from... 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of multi-point recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106... 

Diastereoselective enolate amination as an approach to a-aminoke-tones.42 We have demonstrated that the Mannich reaction is successful for the highly stereoselective introduction of P-aminoketone moieties (vide supra, Asymmetric Mannich Reactions24). The diastereofacially selective electrophilic amination of enolates is attractive as a complementary approach to the asymmetric... 

Cationic Pd complexes can be applied to the asymmetric aldol reaction. Shibasaki and coworkers reported that (/ )-BINAP PdCP, generated from a 1 1 mixture of (i )-BINAP PdCl2 and AgOTf in wet DMF, is an effective chiral catalyst for asymmetric aldol addition of silyl enol ethers to aldehydes [63]. For instance, treatment of trimethylsi-lyl enol ether of acetophenone 49 with benzaldehyde under the influence of 5 mol % of this catalyst affords the trimethylsilyl ether of aldol adduct 113 (87 % yield, 71 % ee) and desilylated product 114 (9 % yield, 73 % ee) as shown in Sch. 31. They later prepared chiral palladium diaquo complexes 115 and 116 from (7 )-BINAP PdCl2 and (i )-p-Tol-BINAP PdCl2, respectively, by reaction with 2 equiv. AgBF4 in wet acetone [64]. These complexes are tolerant of air and moisture, and afford similar reactivity and enantioselec-tivity in the aldol condensation of 49 and benzaldehyde. Sodeoka and coworkers have recently developed enantioselective Mannich-type reactions of silyl enol ethers with imi-nes catalyzed by binuclear -hydroxo palladium(II) complexes 117 and 118 derived from the diaquo complexes 115 and 116 [65]. These reactions are believed to proceed via a chiral palladium(fl) enolate. 

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