Proline-catalyzed Mannich reaction

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... 

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],... 

Scheme 9.3. The first proline-catalyzed Mannich reaction.

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

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... 

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>. 

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. 

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) ... 

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

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

The Mannich reaction is a close relative of the aldol, whereby an imine replaces the aldehyde acceptor. Proline has been demonstrated to be an excellent catalyst of the Mannich reaction, inducing high enantiomeric excess, as shown in Table 6.13. ° " Pertinent to this discussion is that the stereochemical outcome of the proline-catalyzed Mannich reaction is opposite to that of the proline-catalyzed aldol reaction. 

List " suggested that the proline-catalyzed Mannich reaction proceeds in close analogy to the proline-catalyzed aldol reaction. As detailed in Scheme 6.10, the ketone and proline combine to form an enamine. The aldehyde reacts with a primary amine (usually an aniline derivative) giving an imine. The enamine and imine then combine to produce, after hydrolysis, the Mannich product. 

The lowest energy TS 72a does correspond with the experimentally observed major product, and the energy differences with the other TSs are consistent with the typically large ee found in experiment. These computations are consistent with List s mechanistic proposal for the proline-catalyzed Mannich reaction. Further confirmation was provided by a computational smdy of Reaction 6.28. 

The proline-catalyzed Mannich reaction has been applied also by List and co-workers (O Scheme 31) [160,161]. In their method enolizable aldehydes, ketones, and a primary amine are mixed together with a substoichiometric quantity of L- and D-proline to give the desired /3-aminocarbonyl compounds. When applied to hydroxyacetone the method furnishes 4-amino-4-deoxytetruloses. 

Miscellaneous reactions. The starting point of a practical route to P -amino acids is the proline-catalyzed Mannich reaction of aldehydes with a chiral iminium salt derived from A-benzyl-A-(a-phenethyl)amine. Condensation of aldehydes with A-Boc imines furnishes mainly i yn-adducts. "... 

FIGURE 2.8. The Houk transition state for intermolecular proline-catalyzed Mannich reactions. 

Nagata K, Nishimnra K, Yokoya M, Itoh T (2006) Enantioselective Syntheses of ent-Sedridine and (+)-Coniine via Proline-Catalyzed Mannich Reaction. Heterocycles 70 335... 

SCHEME 2.2 Plausible mechanism for the proline-catalyzed Mannich reaction. TABLE 2.1 Several proline-catalyzed multicomponent Mannich reactions... 

Comparably, Barbas HI et al. observed interesting results employing the quite similar ionic liquid 40 as solvent in a proline-catalyzed Mannich reaction (Scheme 2.11a, up to 95% ee) [32], whereas, Wang s group examined the properties of more complex ionic liquids as enamine activation catalysts (Scheme 2.1 lb). The best outcome in terms of yield (up to 99%) and stereoselectivities (91-99% ee) was observed performing the reaction in DMF at -20 °C and using 30 mol% of[EMlm][Pro] 41 [33]. 

Alternatively, natural (-)-lasubine II (220 ) was also accessible in 1.3% overall yield over 15 steps employing an L-proline-catalyzed Mannich reaction, Maruoka allylation, and aza-Michael addition as the key steps [154],... 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

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