Acyclic ketones Mannich reaction

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

The work on organocatalytic aldol condensation continues unabated. In a recent advance, Armando Cdrdova of Stockholm University has found Angew. Chem. Int. Ed. 2004,43, 6528) that (S)-proline also will catalyze the Mannich reaction with high enantiomeric excess. Acyclic ketones also participate efficiently. 

Enders D, Oberborsch S, Adam J (2000) a-Silyl controlled asymmetric Mannich reactions of acyclic ketones with imines. Synlett 2000 644—646... 

Use of 3-pyrrohdine carboxylic acids (7.139) and (7.140) as catalysts results in formation of the anft -Mannich adduct as the major product. This reversal in diastereoselectivity arises from reaction of the s-cis conformer of the enamine formed from (7.139) or (7.140), as depicted in Figure 7.6. Catalyst (7.139) provides high ees in the anfr-Mannich reaction of aliphatic cyclic and acyclic ketones such as pentan-3-one (7.141) while the methyl-substituted analogue (7.140) catalyses the anti-addition of a range of aliphatic aldehydes in 98 to >99%... 

The same authors have designed novel chiral pyrrolidine-based amino sulfonamides, which were applied to promote a n -Mannich reactions of A/-PMP-protected a-imino esters with aldehydes, giving comparable results to those obtained with the binaphthyl-based amino sulfonamide catalyst. However, these novel pyrrolidine-based amino sulfonamides were found to be capable of promoting a //-Mannich reactions between A/-PMP-protected a-imino esters and a range of cyclic as well as acyclic ketones with excellent yields, enan-tioselectivities combined with moderate to high diastereoselectivities of up to 90% de (Scheme 3.13). 

In the same context, a direct asymmetric iy -Mannich reaction was developed by Teo et al. on the basis of using a chiral siloxy-L-serine organocata-lyst. The three-component Mannich reaction between a cyclic or an acyclic ketone, an aldehyde and pura-anisidine performed in the presence of water via a two-phase system afforded the corresponding spra-Mannieh produets in good yields, high enantioselectivities of up to 92% ee and moderate diastereoselee-tivities (Scheme 3.15). 

A chiral primary amine-thiourea organocatalyst was successfully applied for the first time by Tsogoeva et al. to the asymmetric Mannich reaction of ketones with readily available and stable a-hydrazonoesters, which proceeded with good yields and high enantioselectivities of up to 99% ee (Scheme 3.17). Interestingly, whereas acyclic ketones gave a tf-Mannich products, an excess of syn diastereomers was observed with the cyclic ketones. In both cases, only low... 

P. J., The reaction of some nuclear substituted acyclic conjugated styryl ketones and related Mannich bases with cthancthiol. Can. J. Chem... 58,984, 1980. 

The appropriately substituted vinylogous amides can imdergo an intramolecular photocycloaddition-retro-Mannich-Mannich sequence. This sequence is analogous to the photocycloaddition-retro-aldol-aldol sequence shown in the formation of 19 from 15 (vide supra). Thus, irradiation of 110 leads to the formation of ketoimine 112, the product of photoaddition followed by rerra-Mannich fragmentation. Reaction of 112 with 1 equiv of trimethyloxonium tetrafluoroborate, followed by treatment of the resulting iminium ketone with aqueous hydrochloric acid, provides the photocycloaddition-re/ro-Mannich-Mannich product 113 in 50% yield from the acyclic photosubstrate 110. ... 

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