Mannich activation modes

While I have focused on the developments of direct Mannich-type reactions when using aminocatalysis, there are several other important metal-free activation modes for achieving these types of transformations. In this context, an important way of accomplishing the metal-free catalytic enantioselective Mannich-type reaction is by use of chiral Brpnsted acids as catalysts [7, 8, 74]. Here, Uraguchi and Terada disclosed chiral-phosporic acid-catalyzed Mannich-type reactions using acetoacetone as nucleophile and Boc-protected imines as acceptors (Scheme 4.15) [74]. 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

Total syntheses of ( )-capaurine (194 R1 = R2 = R4 = R5 = Me, R3 = OH),209 ( )-isocorybulbine (195 R1 = Me, R2 = R3 = H, R4 = R5 = OMe),202 ( )-kikemanine (194 R1 = R2 = R4 = Me, R3 = R5 = H),210 and ( )-0-methylcaseadine (202)211 have been reported. In all cases, conventional routes involving Bischler-Napieralski cyclization to form benzylisoquinoline derivatives and subsequent insertion of the C(8)-carbon by reaction with formaldehyde were adopted. A further example of para-activation by an ethoxycarbonyl-amino-function for the Bischler-Napieralski reaction may be noted.211 In the synthesis of capaurine, the presence of the bromo-function in compound (203) forced the Mannich reaction with formaldehyde to produce the tetracyclic derivative (204) rather than the normally more favourable mode of cyclization para to the hydroxy-group. Debromination was effected at a later stage with zinc powder in 50 % acetic acid solution.209... 

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