Asymmetric Mannich-type reaction

The development of enantioselective Mannich-type reactions is an important subject in synthetic organic chemistry, because fhese reactions provide optically active nitrogen-containing compounds which are very valuable in syntheses of biologically active products and their derivatives. Until recently, this subject had been solved by use of chiral auxiharies [215]. In recent years, catalytic asymmetric Mannich-type reactions using chiral Lewis acids have been studied extensively [216]. This section deals wifh chiral Lewis acid-promoted reactions. 

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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... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Another recent example is the asymmetric Mannich-type reaction of hydroxyketones using a ZnEt2-BINOL complex as a catalyst.429 The complex provided superior enantioselectivity and had a very high turnover number. 

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%). 

Kobayashi et al.51 have reported an asymmetric Mannich-type reaction using chiral zirconium catalysts of type 124 (see Section 3.7). This catalyst is also effective for asymmetric aza Diels-Alder reactions. Kobayashi s study showed that the ligand had a profound influence on the yields and enantiose-lectivities of the reaction, and NMI (1-methylimidazole) proved to be the best ligand.51 With an increase in the amount of catalyst, both the chemical yields and enantioselectivities of the product can be enhanced. Scheme 5-39 depicts such aza Diels-Alder reactions, and its table shows that good to excellent enantioselectivity can be obtained for most reactions. 

In addition, quite recently a direct catalytic asymmetric Mannich-type reaction has been achieved by the cooperative catalysis of ALB and La(0Tf)3-nH20. 

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-... 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Saito, S. Hatanaka, K. Yamamoto, H. Asymmetric Mannich-type reactions of aldimines with a chiral acetate. Org. Lett. 2000, 2, 1891-1894. 

Recently, direct catalytic asymmetric Mannich-type reactions were reported via C-H activation of carbonyl compounds. The transformations are catalyzed both by organometallic complexes and metal-free organic catalysts. 

The cooperative complex of ALB 2 and La(OTf)3.nH20 catalyze direct asymmetric Mannich-type reactions with good selectivity providing /3-amino aryl ketones in good yields and with 31-44 % ee. 

Most recently, Shibasaki et al. reported that the Et2Zn-linked-BINOL complex 3 is an excellent catalyst for the direct asymmetric Mannich-type reaction (Fig. 2)... 

Barbas and coworkers later demonstrated that other amino acid derivatives in addition to proline can catalyze the direct asymmetric Mannich-type reaction with good enantioselectivity (Fig. 6) [29]. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Another important means of mediation of metal-free catalytic enantioselective Mannich-type reactions is via electrophilic activation of the preformed imines by chiral Bronstedt acids [7, 8, 46], By using this strategy Terada and coworkers performed chiral phosphoric acid-catalyzed direct asymmetric Mannich-type reactions between Boc-protected imines and acetoacetone that furnished aryl /3-amino... 

Catalytic Asymmetric Mannich-Type Reaction under Solid/Liquid Phase Transfer Conditions [11] (p. 146)... 

Matsunaga S, Kumagai N, Harada S, Shibasaki M (2003) anti-Selective direct catalytic asymmetric Mannich-type reaction of hydroxyketone providing beta-amino alcohols. J Am Chem Soc 125 4712—4713 Mayer S, List B (2006) Asymmetric counteranion-directed catalysis. 

Trost BM, Terrell LR (2003) A direct catalytic asymmetric mannich-type reaction to syn-amino alcohols. J Am Chem Soc 125 338-339 Tsogoeva SB, Yalalov DA, Hateley MJ, Weckbecker C, Huthmacher K (2005) Eur J Org Chem 2005 4995... 

Asymmetric Mannich-type reactions, using a chiral imine as substrate and high loadings of indium(III) chloride as catalyst, proceed with moderate yield and good diastereoselectivity in [C4Ciim][BF4], see Scheme 9.9.[35] It is interesting to note that higher conversion with a reduced formation of the... 

The highly enantioselective and diastereoselective asymmetric Mannich-type reaction of N-phosphinoylimines (487) with hydroxyketone (488) was catalysed by (S,S) linked BINOL, affording N-phosphinylated aminoalcohols (489). The observed complementary anti-selectivity, in combination with the facile removal of diphenylphosphinoyl group make this reaction synthetically attractive (Figure 92). ... 

Cordova, A., Barbas, C. E. Direct organocatalytic asymmetric Mannich-type reactions in aqueous media one-pot Mannich-allylation reactions. Tetrahedron Lett. 2003,44,1923-1926. 

Sodeoka et al. have found fhat binuclear /z-hydroxo palladium complex 87 is an efficient catalyst of fhe asymmetric Mannich-type reaction of a-N-arylimino esters with SEE (Scheme 10.80) [226]. Mechanistic studies using NMR and electrospray ionization mass spectrometry suggest that a unique binuclear palladium-sandwiched enolate 88 is involved in fhe palladium-catalyzed reaction. 

Lectka et al. have reported that Tol-BI NAP-coordinated CUCIO4 catalyzes fhe addition of SEE to a-N-tosylimino esters wifh high enantioselectivity (Scheme 10.81) [227]. The use of a-substituted SEE gives anti adducts wifh high diastereoselectivity. The Tol-BINAP complex is superior to fhe corresponding BINAP complex in diastereo- and enantioselectivity. It has been proposed that this asymmetric Mannich-type reaction proceeds by a Lewis acid-catalyzed mechanism, not a transmetalation mechanism as reported by Sodeoka et al. 

Quite recently, chiral diamine ligands have been used by Kobayashi et al. for highly enantioselective Mannich-type reactions [228, 229]. The chiral complex prepared from chiral diamine 89a and Cu(OTf)2 effects highly enantioselective addition of silyl enolates to a-N-acyhmino esters (Scheme 10.82) [228]. The first example of catalytic asymmetric Mannich-type reaction in aqueous media has been achieved by the combined use of ZnF2, diamine 89b, and TfOH in the reaction of a-hydrazono esters [229]. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

This catalytic asymmetric Mannich-type reaction of silyl enol ethers with a-im-ino esters is notable because it proceeds under neutral conditions. 

Asymmetric Mannich-Type Reactions of SUyl Enol Ethers of Thiol Esters. . 100... 

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