Amino acid derivatives Mannich reactions

Other cyclizations at phosphorus have been observed when certain phosphinates were used in the acid-catalyzed Mannich reaction. As observed previously with various phosphonous acid derivatives, reaction of aliphatic phosphinic acids with primary amines favored the formation of 2 1 adducts (73). Thus, glycine and other a-amino acids reacted under the typical conditions with excess formaldehyde and alkyl phosphonous acids to give the bis-phosphinylmethyl adducts 125. 

C-H activation a to nitrogen generates f3-amino acid derivatives (Figure 5). Therefore, the reaction can be considered to be a surrogate of the Mannich reaction. 

This protocol complements Akiyama s method which provides P-amino carbonyl compounds as i yn-diastereomers [14], It tolerated aromatic, heteroaromatic, and aliphatic aldehydes. Cyclic ketones, acetone, as well as acetophenone derivatives could be employed. The use of aromatic ketones as Mannich donors was up to that time unprecedented in asymmetric organocatalysis. Rueping et al. independently expanded the scope of the asymmetric Brpnsted acid-catalyzed Mannich reaction of acetophenone [45]. 

Cordova A (2004) The direct catalytic asymmetric cross-Mannich reaction a highly enantio-selective route to 3-amino alcohols and alpha-amino acid derivatives. Chem Eur J 10 (8) 1987-1997... 

Scheme 6.49 Typical Boc-protected 5-amino acid derivatives obtained from 48-catalyzed Mannich reactions of N-Boc-protected aldimines with silyl ketene acetal.

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-... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Very recently, the List group applied this proline-catalyzed Mannich reaction efficiently in multi-step syntheses of several a-amino acid derivatives, such as protected 1,2-amino alcohol derivatives and oxazolidin-2-ones [25],... 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Trost and coworkers recently reported that these dinuclear zinc complexes catalyze Mannich reactions with unmodified aromatic hydroxy ketones as donors with excellent enantioselectivity [18]. Mannich-type reactions between an N-para-meth-oxyphenyl (PMP)-protected a-ethyl glyoxalate and hydroxyacetophenone in the presence of a catalytic amount of catalyst 5a afford the desired N-PMP protected amino acid derivative in 76 % yield with a dr of 7 1 and 95 % ee (Eq.5). 

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]. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

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]. 

The (S)-proline-catalyzed Mannich-type reactions that afford enantiomerically enriched aminoaldehyde derivatives constitute efficient routes to access enantiomerically enriched a- and / -amino acid derivatives and /Mactams [71a,b] and enzyme inhibitors [79] (Scheme 2.17). The Mannich products obtained from the... 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Deaminodecarboxylation (Fig. 91) has been observed in Mannich bases 244 having the p-amino acid structure. The reaction, which may be accompanied by side reactions, " takes place regardless of the fact that the carboxy group is estcrified, and even in derivatives pos.sessing the formyl or the oxalyl group. " - ... 

Mannich reaction Carbonyl compounds Amino acid derivatives 233, 240, 241... 

This BINAP silver(I) complex was subsequently used by Lectka and coworkers as a catalyst for Mannich-type reactions [35]. Slow addition of silyl enol ether 49 to a solution of tosylated a-imino ester 80 under the influence of 10 mol % (i )-BINAP AgSbFg at -80 °C affords the corresponding amino acid derivative 81 in 95 % yield with 90 % ee (Sch. 20). They reported, however, that (R)-Tol-BINAP-CuC104-(CH3CN)2 was a more effective chiral Lewis acid for the reaction and gave the highest yield and ee at 0 °C. 

Oxazolidine 139 derived from (/ )-phenylglycinol has also been used in a one-pot, Lewis acid-catalyzed Mannich reaction with difluoroenoxysilane 138 derived from the corresponding phenylacylsilane to give a /3-amino ketone 140 in good yield and diastereoselectivity (Scheme 35) <2005EJ04304>. 

The examples outlined in this chapter show that carbohydrates are efficient stereodifferentiating auxiliaries, which offer possibilities for stereochemical discrimination in a wide variety of chemical reactions. Interesting chiral products are accessible, including chiral carbo- and heterocycles, a- and 3-amino acid derivatives, 3-lactams, branched carbonyl compounds and amines. Owing to the immense material published since the time of the earlier review articles on carbohydrates in asymmetric synthesis [9,10], the examples discussed in this chapter necessarily focused on the use of carbohydrates as auxiliaries covalently linked to and cleavable from the substrate. Given the scope of this chapter, a discussion of other interesting asymmetric reactions has not been permitted — for example, reactions in which carbohydrate-derived Lewis acids, such as cyclopentadienyl titanium carbohydrate complexes, exhibit stereocontrol in aldol reactions [180]. Similarly, processes in which in situ glycosylation induces reactivity and stereodifferentiation — for example, in Mannich reactions of imines [181] — have also been excluded from this discussion. 

Sheehan, S. M. Preline-catalyzed asymmetric Mannich reactions The highly enantioselective synthesis of amino acid derivatives and 1,2-amino alcohols. Chemtracts 2002, 15, 384-390. 

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

The landem aza-Cope/Mannich cyclization reaction has also been used in the synthesis of enantiomerically pure tx-amino acid derivatives, e.g., proline derivative 741l49. Thus, the rearrangement of intermediate 70, derived from 69 and glyoxal by acid treatment, produces a 1 1 mixture of 72 and the head-to-tail self-condensation product 73, which can be transformed to 72 by subsequent acid treatment. 

In the case of protein amino acid-derived alkaloids, the second obligatory intermedia are synthesized from the obligatory intermedia by chemical reactions. In the pelletierine synthesis pathway started with L-lysine, the second obligatory intermedia is A -piperidinium cation. It is formed by a Mannich... 

Not long after List published his three-component methodology, the group of Barbas reported a fairly similar procedure [3]. Besides L-proUne (1), a penicillamine derivative appeared to effectively catalyze the reaction. Later on, various ketone donors 7b, 7e-g were successfully subjected to the preformed iV-PMP-protected a-imino ethyl glyoxylate 10a as imine acceptor, thereby yielding y-oxo-a-amino acid derivatives lla-d as the products (Scheme 5.4). Analogous to the results of List, the reactions proceeded smoothly resulting in Mannich products with excellent yn-selectivity in complete enantiomerically pure form [4],... 

Thus far only procedures to acquire the i y/t-Mannich adducts have been described. Equally valuable and perhaps more appealing are protocols that broaden the versatility of the former methodology by providing the Mannich bases in a highly anti-selective manner. The preparation of a/tft-Mannich adducts was initially conducted by Barbas et al. by means of a direct (5)-2-methoxymethylpyrroMine (34, SMP) catalyzed asymmetric Mannich-type reaction [26]. A variety of unmodified aliphatic aldehydes 2 were treated with A-PMP-protected iminoglyoxylate 10a in DMSO to afford the P-formyl-functionalized amino acid derivatives 35a-f in moderate to good ee s and with a dr that increased with the bulkiness of the aldehyde (Scheme 5.19). 

The corresponding (3-formyl functionalized amino acid derivatives are obtained in high yields and stereoselectivity. The reaction is readily performed on a multigram scale, and the catalyst loading can be decreased to 10 mol%. The proline-catalyzed cross-Mannich-type reactions to other preformed imines is also possible [41]. In this context, reduction of the aldehyde moiety is usually required to increase the stability of the Mannich adducts, and the corresponding amino alcohols are isolated in high yields and with >99% ee in several cases (Scheme 4.8) [41, 42]. Thus, the transformation can be viewed as a regiospecific asymmetric synthesis of 3-amino-l-ols. It is noteworthy that proline is also able to catalyze the one-pot... 

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