Mannich proline-catalyzed

The amine-catalyzed Mannich reaction has also been a subject of special reviews [243, 244]. In general, yields and enantioselectivities of proline-catalyzed Mannich reactions are very high. Initially, the reactions were restricted to imines bearing an aromatic A-substituent, such as the p-methoxyphenyl (PMP) group. This restriction considerably limited the usefulness of the protocol, because relatively... 

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-... 

It was reported that proline catalyzed the direct catalytic asymmetric Mannich reactions of hydroxyacetone, aldehydes, and aniline derivatives [(Eq. (10)] [40-44]. Not only aromatic aldehydes but also aliphatic aldehydes worked well in this reaction, and good to excellent enantioselectivity and moderate to excellent yields were observed. Mannich reactions of glyoxylate imines with aldehydes or ketones were also successfully performed [45,46]. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

Scheme 39 Proline-catalyzed Mannich reaction furnishing spiro-P-lactams...

Barbas et al. [113] have published the asymmetric synthesis of spiro-p-lactams 171 (Scheme 39) using proline-catalyzed Mannich reaction with branched aldehyde donors. The Mannich reactions of a,a-disubstituted aldehydes 168 with... 

List and coworkers discovered the first efficient catalytic asymmetric three-component Mannich reaction. In this proline-catalyzed Mannich reaction between ketones, aldehydes, and amines (typically p-anisidine, 6), Mannich products are formed in up to >99% ee and up to 96% yield (Scheme 9.3) [4],... 

An important feature of this reaction is that in contrast to most other catalytic asymmetric Mannich reactions, a-unbranched aldehydes are efficient electrophiles in the proline-catalyzed reaction. In addition, with hydroxy acetone as a donor, the corresponding syn-l, 2-aminoalcohols are furnished with high chemo-, regio-, diastereo-, and enantioselectivities. The produced ketones 14 can be further converted to 4-substituted 2-oxazolidinones 17 and /i-aminoalcohol derivatives 18 in a straightforward manner via Baeyer-Villiger oxidation (Scheme 9.4) [5]. 

The proline-catalyzed three-component Mannich reaction is proposed to proceed through the reaction of enamine a, formed by the reaction of the ketone with pro-... 

Scheme 9.3. The first proline-catalyzed Mannich reaction.

Scheme 9.6. Proline-catalyzed Mannich reaction under high pressure induced by water freezing.

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

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. 

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],... 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

Proline-catalyzed Mannich Reaction Process Development and Optimization... 

Despite their high synthetic potential, when L-proline-catalyzed reactions are evaluated, catalytic amounts in the range 20 to 35% and use of excess ketone (usually 20% v/v) represent reaction parameters to be optimized. Experimental studies addressing this issue have been conducted and impressive solutions were found by the List group [23], As a model reaction the Mannich synthesis using p-nitro-... 

The intramolecular cyclization of /3-carboethoxy-/ -amino acid 379, synthesized from L-proline-catalyzed Mannich reaction of aldehydes with an iminoester and subsequent oxidation, with sodium hydroxide yielded the cyclopentane-spirofused azetidin-2-one 380 (Scheme 56) <20040L2507>. 

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 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]. 

The mechanism of proline-catalyzed Mannich reactions is depicted in Scheme 5. The ketone or aldehyde donor reacts with proline to give an enamine. Next, the preformed or in-situ-generated imine reacts with the enamine to give, after hydrolysis, the enantiomerically enriched Mannich adduct the catalytic cycle can then be repeated. 

Scheme 5. The mechanism of proline-catalyzed direct asymmetric Mannich reactions.

The stereochemical outcome of L-proline catalyzed direct asymmetric Mannich reactions is explained by a Si-facial attack on the imine, which has a trans configuration, by the Si face of the enamine, which has a trans configuration (Fig. 7). 

Figure 7. (a) Transition-state of the proline-catalyzed direct asymmetric Mannich reaction, (b) Transition-state of the SMP-catalyzed direct asymmetric Mannich reaction. 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

Table 2.10 (S)-Proline-catalyzed Mannich-type reactions of aldehyde donors and /N/-PMP-protected glyoxylate imine [71 a,b].

Whereas the (S)-proline-catalyzed Mannich reactions afforded (2S,3S)-syn-isomers as the major products, (3R,5ft)-5-methyl-3-pyrrolidinecarboxylic acid (13) catalyzed the reactions and afforded (2S,3R)-anti-products in good yield with high, almost perfect, diastereo- and enantioselectivities (Table 2.12) [73]. The reaction rates of the 13-catalyzed Mannich reactions were approximately two- to threefold faster than the corresponding (S)-proline-catalyzed reactions that afford the syn-products. Thus, the reactions with only 0.01 or 0.02 equiv. of 13 afforded the desired products in reasonable yields within a few hours. 

Note that catalyst 13 was designed for anti-selective Mannich reactions based on the study of proline-catalyzed Mannich reactions. Four considerations are key for the diastereo- and enantioselectivities observed in the (S)-proline-catalyzed reactions (Scheme 2.15a) ... 

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... 

Scheme 2.17 Synthesis of important compounds through (S)-proline-catalyzed Mannich reactions /Mactam (top) [71 a,b] and serine protease inhibitor (bottom) [79].

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

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