Stereochemistry enamine activation

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

CPCM) solvation, to study the mechanisms and stereochemistries of this important synthetic reaction. Interestingly, from these calculations, it was concluded that secondary enamine-mediated aldols have high activation energies if there is no proton source, and oxetane intermediates such as 1 can be formed (Equation 1) <2001JA11273>. 

The focus of this chapter is on the stereoselectivity of the conjugate addition of the Lewis acid and enamine Michael additions. Only donors that are formally enol equivalents are considered. Selectivity that results from preferential addition to one of the faces of an endocyclic enamine or enol ether as a result of the influence of a stereocenter in the ring is not emphasized. In general, the factors that control the stereochemistry in these instances are analogous to those active in the reactions of other electrophiles with such compounds. 

Stereochemistry, substituent effects and activation parameters of most ketene reactions are consistent with a one-step cycloaddition polar effects of substituents and solvents, as well as the isotope effect, often require, however, that a fair amount of charge separation (that is, unequal bond formation) characterises the transition state. It has been kinetically proved that cycloadditions of enamines to ketenes can also proceed through a dipolar intermediate this is so for the reaction between dimethylketene and N-isobutenylpyrrolidine . In the latter case, the rate coefficient for the formation of the intermediate strongly depends on solvent polarity itacetonuriie/ cyclohexane = 560. Use of the Same criteria used for ketenes (as far as experimental data allow it) in the case of the 1,2-cycloadditions of fluorinated olefins results, instead, in the conclusion that a two-step biradical mechanism is operating. Results for 1,2-cycloaddition of sulfonyl isocyanates to olefins, cases (g) and (h) in Table 17, give indications of dipolar intermediates during the course of these reactions. 

When optically active enamine derivatives are used as substrates, full control of absolute stereochemistry is feasible, and the process is appUcable to the synthesis of a known precursor of (+)-thienamycin in very high optical yieldf" (Scheme 20). 

A dual-activation way is invoked based on the similar widely accepted catalytic mode of activation for L-proline catalyst. In this context, the acidic tetrazole moiety activates the electrophilic imine by a hydrogen-bonding interaction, and the pyrrolidine moiety would activate the nucleophilic P-ketoester via formation of an enamine intermediate. The stereochemistry of the acidic tetrazole moiety seems to be crucial for the stereoselectivity in the final products. This... 

Mechanistically, the activation of the aldol donor substrates is achieved by stereospecific deprotonation along two different pathways (Fig. 2) [28] Class I aldolases bind their substrates covalently via imine/enamine formation to an active site lysine residue to initiate bond cleavage or formation (Fig. 2a) in contrast, class II aldolases utilize transition metal ions as a Lewis acid cofactor (usually Zn " ) which facilitates (Fig. 2b) deprotonation by a bidentate coordination of the donor to give the enediolate nucleophile [29]. Usually, the approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospecif-ically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzyme, in... 

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