Michael retro

Surprisingly, the 7t-system geometry in a substrate has a notable influence in the enzymatic aminolysis of esters. The reaction of diethyl fumarate with different amines or ammonia in the presence of CALB led to the corresponding trans-amidoesters with good isolated yields, but in the absence of enzyme, a high percentage of the corresponding Michael adduct is obtained (Scheme 7.9). Enzymatic aminolysis of diethyl maleate led to the recovery of the same a, P-unsaturated amidoester, diethyl fumarate, and diethyl maleate. The explanation of these results can be rationalized via a previous Michael/retro-Michael type isomerization of diethyl maleate to fumarate, before the enzymatic reaction takes place. In conclusion, diethylmaleate is not an adequate substrate for this enzymatic aminolysis reaction [23]. 

Hydrogenolysis, Oxidation, Michael, Retro-Diels-Alder). 248... 

It was suggested that this reaction proceeds via the DKR-mediated Michael-retro-Michael-Michael-Michael cascade reaction pathway the initially formed Michael adduct undergoes a DKR process in the presence of catalyst 81b, where the deprotonation of the highly acidic proton of 109 by the quinuclidine base of the catalyst leads to a reversible and stereoselective retro-Michael-Michael-Michael process. This proposal was supported by the observation that the reaction of racemic 109 with nitrostyrene under identical conditions depicted in Scheme 9.36... 

A variety of a,a-dicyanoalkenes derived from aryl ketones have also been extensively explored under the same catalytic conditions, and in general the vinylogous Michael adducts were obtained due to the steric hindrance in the following enamine catalysis by primary amine lo [28]. Nevertheless, an interesting domino Michael-Michael-retro-Michael reaction was observed for a,a-dicyanoalkenes derived from acetophenone and propiophenone, giving a facile process to chiral 2-cyclohexen-l-one derivatives. It was noteworthy that a kinetic resolution was observed in the intramolecular Michael addition step (Scheme 10.22). 

Scheme 10.22 Vinylogous Michael addition and domino Michael-retro-Michael reaction.

Realistically, we did not have the option of incorporating a second thio substituent to enhance the acidity of the substrate. Rather, we expected the twin effects of the thioester s electronic influence and the resonance stabilization of the Michael/ retro-Michael tandem to enable the formation of the enolate under mildly basic conditions. The electronic effect of the thioester was supported by a calculation, indicating that the pKa of the a-proton of the thioester would lower (by 1.5 p/C, units) in comparison with 9 [30]. It was not clear if this would be enough to permit racemization under reaction conditions that would support sufficient enzyme activity but relatively little work would be required to test the hypothesis. 

For examples of Michael/retro-Michael equilibria with the capacity for racemization a) W.-C. Shieh, J.A. Carlson, J. Org. Chem. 1994, 59, 5463-5465 b)... 

As in the uncatalyzed reactions with enamines (vide supra), there is potentially more than one point where stereochemical differentiation can occur (Scheme 59). Selectivity can occur if the initial addition of the enol ether to the Lewis acid complex of the a,/J-unsaturated acceptor (step A) is the product-determining step. Reversion of the initial adduct 59.1 to the neutral starting acceptor and the silyl enol ether is possible, at least in some cases. If the Michael-retro-Michael manifold is rapid, then selectivity in the product generation would be determined by the relative rates of the decomposition of the diastereomers of the dipolar intermediate (59.1). For example, preferential loss of the silyl cation (or rm-butyl cation for tert-butyl esters step B) from one of the isomers could lead to selectivity in product construction. Alternatively, intramolecular transfer of the silyl cation from the donor to the acceptor (step D) could be preferred for one of the diastereomeric intermediates. If the Michael-retro-Michael addition pathway is rapid and an alternative mechanism (silyl transfer) is product-determining, then the stereochemistry of the adducts formed should show little dependence on the configuration of the starting materials employed, as is observed. 

In 2007, Chen, Deng, and co-workers [42] reported the first asymmetric domino reaction catalysed by primary amines. A primary amine derived from quinine catalyzed a Michael-Michael-retro-Michael cascade, where the two reagents (64 and 65) act alternatively and selectively as the Michael donor and acceptor under readily controllable conditions. The corresponding cyclohexenones 66 were obtained in good yields and excellent stereoselectivities (Scheme 10.20). However, an extra step was sometimes necessary in order to push the reaction and thus to obtain the cyclic products. In this case, the initial Michael adduct was treated with benzylamine and TEA to render the cycloadduct. 

ESI Monitoring Michael-Michael-retro Michael addition Wu et al. [294]... 

Scheme 2.34 Tandem Henry-Michael-retro-Heniy reaction catalysed by a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine.

Ten years later, Lubineau et al. reported the direct reaction of unprotected carbohydrates with acetylacetone in aqueous alkali media [11]. By application of this method, an access to different mixtures of furanoid and pyranoid structures of a- and P-configured C-glycosides [12] was obtained. The ratio of the products depends on the conditions of execution for this reaction and the carbohydrates deployed (Eq. 2, Scheme 2.1). This Knoevenagel/Michael/retro-Claisen-aldol cascade is carried out at high temperature (60-90°C) and is associated with the loss of a C2 fragment of the starting 1,3-dicarbonyl component (when used with acetylacetone). 

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