Transition Mannich-type reactions

The assumed transition state for this reaction is shown in Scheme 5.5. The two bulky t-butoxy groups are expected to locate at the two apical positions. One of the 3,3 -phenyl groups would effectively shield one face of an imine, and consequently, a diene attacks from the opposite side. Judging from this model, similar selectivities were expected in the Mannich-type reactions of imines with silyl eno-lates. Actually, when ligand 10 was used in the reaction of imine la with S-ethyl-thio-l-trimethylsiloxyethene, the corresponding / -amino thioester was obtained in 84% ee (Scheme 5.6). As expected, the sense of the chiral induction in this case was the reverse of that observed when using catalyst 6 [12, 25]. 

Ferraris et al.108 demonstrated an asymmetric Mannich-type reaction using chiral late-transition metal phosphine complexes as the catalyst. As shown in Scheme 3-59, the enantioselective addition of enol silyl ether to a-imino esters proceeds at —80°C, providing the product with moderate yield but very high enantioselectivity (over 99%). 

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

Scheme 2.23 (a) Steric interactions in the possible transition state of 13-catalyzed Mannich-type reactions, (b) The proposed, most suitable transition state of the onh-selective Mannich-type reactions catalyzed by (/ )-3-pyrrolidinecarboxylic acid (18). 

Synthesis.—Mannich-type Reactions. The double Michael addition of amines to cyclohepta-2,6-dienone has been extended by the use of a series of optically active primary amines to the synthesis of chiral 8-azabicyclo-[3,2,l]octanes. Yields are typically ca. 70% circular dichroism studies show interesting effects. Perturbation of the n - rr transition must originate in the asymmetry of the nitrogen substituents which lie in the symmetry plane of the ring. The analysis of the tertiary amines is complicated by... 

Fig. 4.6 Transition state model for organocatalytic Mannich-type reactions...

On the basis of ESl-MS observation as well as positive nmilinear effects of this system, we assumed that p-oxo-p-aiyloxy-trimer complex is the most enantiose-lective active species (Fig. 3). Therefore, Sm50(0-/Pr)i3 with a well-ordered structure would have beneficial effects for the formation of desired trimer species. Postulated catalytic cycle of the reaction based on the initial rate kinetic studies and kinetic isotope effect studies is shown in Fig. 4. In this catalyst system, both Cu and Sm are essential. We assume that the cooperative dual activation of nitroalkanes and imines with Cu and Sm is important to realize the syn-selective catalytic asymmetric nitro-Mannich-type reaction. The Sm-aryloxide moiety in the catalyst would act as a Brpnsted base to generate Sm-nitronate. On the other hand, Cu(ll) would act as a Lewis acid to control the position of iV-Boc-imine. Among possible transition states, the sterically less hindered TS-1 would be more favorable. Thus, the stereoselective C-C bond formation via TS-1 followed by protonation with phenolic proton affords syn product and regenerates the catalyst. 

On the basis of observations from an X-ray crystallographic analysis of the 1 1 complex of 27b and 4-pyrroUdinopyridine, a transition-state model of the Mannich-type reaction was postulated (Scheme 7.47) [73b]. N-Boc imine would be activated by one of the two carboxyl adds in 27b and the steric hindrance of 3,3 -substituents and the binaphthyl moiety would restrict rotation of the O H-N hydrogen bond, thus regulating the conformational orientation of the imine. Then,... 

Distinct from the classical aminocatalysis, Tsogoeva and co-workers documented the first example of enol activation in the typical Mannich-type reaction catalyzed by primary amine-thiourea 63 (Scheme 5.48) [76], The isotope experiments exclude the involvement of a covalent enamine/iminium intermediate and theoretical calculation proves an enol type transition state in this reaction. 

A -Protected a-aminoalkyl-//-phosphinic acids (857) were found to be novel practical building blocks in three-component Mannich-type A -phosphonomethylation condensations with formaldehyde (858) and secondary amine/amino acids (859). This reaction led to multifunctional phosphinic pseudodipeptides (860), designed to act as extended transition state analogue inhibitors of selected cytosolic leucine and microsomal alanyl aminopeptidases (Scheme 215). ... 

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