Mannich transition states

In the L-proline-catalyzed intermolecular Mannich reaction [9], the stereoselectivity is opposite that of the aldol reaction the si face of the imine is preferentially attacked, and the major Mannich adducts have a syn relative configuration. Computational investigations by Bahmanyar and Houk [26] show that the more stable trans-imine acceptor is placed so as to accommodate proton transfer to the nitrogen lone pair which is in a c/s relationship with the imine C-substituent this forces this substituent to occupy a more crowded pseudoaxial position (Figure 2.8). The anti-re Mannich transition state was calculated (in a model compound) to be 3 kcal/mol less stable than the anti-si one. It is worth noting that this model also accounts for the fact that, contrary to aldol reactions, best enantioselectivities are obtained when the C-imine substituent R is a relatively unhindered planar aryl group. 

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]. 

Scheme 23 Transition states in aldol and Mannich reactions...

Scheme 1.1.3 Postulated transition states for the asymmetric Mannich reaction.

The Mannich adducts are readily transformed to optically active a-amino-y-lac-tones via a one-pot diastereoselective reduction and lactonization sequence and the tosyl group exchanged for a Boc group via a two-step procedure. The cop-per(II) ion is crucial for the success of this reaction [21]. It has the properties necessary both to generate the enol species in situ and, in combination with the C2-symmetric ligand, coordinate it as well as the imine in a bidentate fashion. The reaction proceeds via a cyclohexane-like transition state with the R substituent of the enol in the less sterically crowded equatorial position, which is required to obtain the observed diastereoselectivity (Fig. 5). 

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

Scheme 2.15 The proposed, most suitable transition states of the (S)-proline- and 13-catalyzed Mannich reactions [73].

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

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). 

As with C-alkylation, the mechanism of amino group replacement can follow the elimination/addition or the nucleophilic replacement path. Both mechanisms are indeed mentioned in the literature and are cxrcasionally claimed to occur concurrently. The elimination/addition path is suggested in the reaction of p-aminoketones with uracils, and a four-centered transition state is proposed for the. same reaction with indole Mannich bases. ... 

Proposed transition states for the i-proiine-cataiyzed asymmetric Mannich and aidoi reactions... 

Scheme 5.6 Proposed transition states for the vinylogous Mannich reaction as origin for the enantio and diastereoselectivity [7],...

Propose a transition state for the direct vinylogous Mannich reaction with the bifunctional thiourea catalyst 51 reported by Chen and his group that accounts for the observed relative and absolute configurations of the products (Scheme 5.11). 

This asymmetric Mannich reaction could also proceed by an enamine pathway because nucleophilic addition of the in situ-generated enamine would be faster to an imine than to an aldehyde. As shown in the Fig. 12.59, the reaction starts with enamine 34 activation of the cyclohexanone by the proline anion and an electrostatic interaction with the imidazolium moiety of the catalyst In a second pre-equilibrium, the aldehyde and aniline produce an imine. Then enamine-activated 35 reacts with the imine to form 35 via transition state A. The last step is a dehydration reaction to afford the corresponding product. The catalyst is regenerated in the subsequent step. 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

Figure 7.5 Transition state of the L-proiine-cataiysed Mannich Reaction...

Figure 7.6 Transition state of the organocatalysed anf/-Mannich reaction...

While several metal-catalysed approaches to solve the task of generating fl tz-l,2-diols have been developed, this method remains remarkable, since it represents the first small molecule-catalysed, catalytic version of this transformation. The starting materials do not need activation or protection, and the reaction can be performed under standard conditions without further precautions. The selectivity of the reaction potentially results from a hydro Q acetone enamine-initiated transition state (5). More recently, Enders et al. applied a related method to the organocatalytic synthesis of sialic acid precursors (Scheme 5.6). Protected pyruvic aldehyde (6) was reacted with several aldehydes, forming the desired aldols (7) in moderate yields, but good selectivities (31-51%, 90-92% de, 73-99% ee). The conditions were optimised to limit detrimental side reaetions sueh as Mannich elimination or formation of the aeetal self-aldolisation produet. While generally easily applicable and robust, the method laeks effieiency in one key parameter, its reaction time. This limitation, combined with moderate yields unfortunately prevents a scale-up to or beyond the pilot plant. 

In contrast to aldol reactions, the major diastereoisomer formed in the Mannich reaction has syn configuration, because the orientation of the imine is opposite to that of the carbonyl in the transition state (figure C in Scheme 6.5). Carter et al. reported an organocatalysed domino Mannich-aza-Michael reaction for accessing nitrogen-containing [2.2.2]-bicyclic scaffolds promoted by 15e, in a highly enantioselective and diastereoselective manner (eqn. (3) in Scheme 6.5). 

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