迈克尔反应受体分子化学生物学研究

迈克尔受体是烯键或炔键与吸电子基团共轭相连形成的官能团,含有这样官能团的化学小分子能与亲核试剂发生迈克尔加成反应,因此称为迈克尔反应受体分子。迈克尔反应受体分子是一类重要的生理活性分子,它们直接或间接参与许多生命过程,同时也是细胞中许多信号转导途径的调节者,在化学生物学研究中起着重要的作用。本文对迈克尔反应受体分子化学生物学研究进展进行了综述。     

Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quaternary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of alkene geometry in the Michael acceptor.     

Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones: cocatalyst effects and evidence for an enamine intermediate

An enantioselective intermolecular Michael addition of aldehydes to enones catalyzed by imidazolidinones has been achieved. Chemoselectivity (Michael addition vs aldol) can be controlled through judicious choice of hydrogen-bond-donating cocatalysts. The optimal imidazolidinone/hydrogen-bond-donor pair affords Michael addition products in excess of 90% ee. Furthermore, we have isolated and characterized an enamine intermediate and demonstrated its efficacy as a nucleophile in the observed Michael addition reactions.     

Selective Michael Reaction Controlled by Supersilyl Protecting Group

Selective Michael reaction of organolithium reagents to supersilyl methacrylate is reported. The method was able to control a single and double Michael addition. The successful termination of the process using the supersilyl protecting group allows for the controlled, chemoselective, and diastereoselective Michael reaction.     

Amine-catalyzed Michael reactions of an aminoaldehyde derivative to nitroolefins

Catalytic enantioselective Michael addition reactions of α-amino functionalized aldehydes to nitroolefins have been developed. The Michael product was obtained in up to 98% ee, but the enantiomeric purity of the Michael product was decreased during isolation of the product.     

Tandem Michael addition of amines to maleic anhydride and 1,3-prototropic shift: experimental and theoretical results

Amines, namely diethylamine, diphenylamine, benzylamine, and pyrrolidine react with maleic anhydride to form Michael adducts. The Michael adducts formed with the first three amines undergo tandem 1,3-prototropic shift to give the final products. Computational calculations at the DFT (B3LYP/6-31+G*) level reveal that a reactant-complex formed between the initially formed Michael adduct and the respective amine plays a crucial role in the 1,3-prototropic shift. In the reaction of pyrrolidine with maleic anhydride, Michael addition is not followed by 1,3-prototropic shift. The theoretical studies of the latter reaction show that a reactant-complex is not formed in this case. Dimethyl maleate and dimethyl fumarate react with pyrrolidine to give the same Michael addition product.     

Ruthenium-catalyzed decarboxylative insertion of electrophiles

[reaction: see text]. A ruthenium complex, Cp*Ru(bipyridyl)Cl, has been developed as a catalyst for the first regioselective tandem Michael addition-allylic alkylation of activated Michael acceptors. The net transformation is the decarboxylative insertion of Michael acceptors into allyl beta-ketoesters.     

Sodium tetramethoxyborate: an efficient catalyst for Michael additions of stabilized carbon nucleophiles

Sodium tetramethoxyborate, easily prepared by reaction of inexpensive sodium borohydride with methanol, possesses a suitable combination of a Lewis base and a Lewis acid to catalyze Michael reactions at room temperature under practically neutral conditions. This reaction provides good to excellent yields of Michael addition products from a broad scope of Michael donor and Michael acceptor reagents.     

Promiscuous enzyme-catalyzed regioselective Michael addition of purine derivatives to α,β-unsaturated carbonyl compounds in organic solvent

Regioselective Michael addition of purine derivatives to α,β-unsaturated carbonyl compounds could be catalyzed by d-aminoacylase amano (DA) in DMSO. The influence of reaction conditions on the Michael addition, including solvent, temperature, and enzyme concentration was systematically investigated. Then we extended this methodology to six structurally diverse purine derivatives and a variety of α,β-unsaturated carbonyl compounds. 21 Michael adducts were selectively synthesized in moderate to high yields. It is the first report on enzyme-catalyzed Michael addition for the preparation of purine derivatives.     

α,β-Unsaturated γ-Oxo Carboxylic Acids in Heterocylic Synthesis II. Behavior of 4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic Acid Towards Carbon Nucleophiles under Michael Reaction Condition

4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic acid ( 1 ) was condensed with compounds containing active methylene groups under Michael reaction conditions to form the Michael adducts 2a-c , 3a-c , and 4a-b . The behavior of Michael adduct towards the action of hydrazine hydrate was investigated. The compounds were tested for biological properties.     

Relative rates of Michael reactions of 2'-(phenethyl)thiol with vinyl sulfones,vinyl sulfonate esters,and vinyl sulfonamides relevant to vinyl sulfonyl cysteine protease inhibitors

[reaction: see text] The relative rates of Michael additions of 2'-(phenethyl)thiol to representative vinyl sulfonyl Michael acceptors were measured. The dependence of the reactivity of the Michael acceptor on the nature of the sulfonyl R substituent was determined in order to evaluate the effect of these substituents on the inactivation kinetics of comparably substituted vinyl sulfonyl cysteine protease inhibitors. The rates of these Michael additions vary over 3 orders of magnitude, with phenyl vinyl sulfonate esters (R = OPh) being ca. 3000-fold more reactive than N-benzyl vinyl sulfonamides (R = NHBn).     

Synthesis of 9-substituted 1,8-dioxooctahydroxanthenes by using diethyl ethoxymethylenemalonate as a double Michael acceptor synthon

Tandem Michael addition/elimination/Michael addition/cyclization reactions of diethyl ethoxymethylenemalonate as a double Michael acceptor with cyclic ??-diketones furnished novel 9-substituted 1,8-dioxooctahydroxanthenes.     

Aza-Michael Addition of Isatin and Phthalimide to Symmetrical Fumaric Esters in Ionic Liquid Media

Highly efficient aza-Michael additions of isatin and phthalimide to symmetrical fumaric esters in ionic liquid media to produce the corresponding Michael adducts in excellent yields are described which were performed at 100 ℃ for 1—5 h. The results show that these aza-Michael additions are not effective with fumaric esters containing sterically hindered alkoxy groups.     

Three-component glycolate Michael reactions of enolates, silyl glyoxylates, and α,β-enones

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.     

Bifunctional 3,3'-Ph2-BINOL-Mg catalyzed direct asymmetric vinylogous Michael addition of α,β-unsaturated γ-butyrolactam

Bifunctional 3,3'-Ph(2)-BINOL-Mg catalyzed direct asymmetric vinylogous Michael addition of α,β-unsaturated γ-butyrolactam has been developed. The catalytic activity of this protocol was slightly affected by different types of Michael acceptors, such as a variety of enones as well as α,β-unsaturated N-acylpyrroles. The Michael products were obtained with high diastereoselectivities (up to 20:1) and excellent enantioselectivities (up to 98%).     

Asymmetric epoxidation, Michael addition, and triple cascade reaction using polymer-supported prolinol-based auxiliaries

The applicability of polymer-supported diphenylprolinol derivatives in directing either asymmetric epoxidation or Michael addition of suitable α,β-unsaturated substrates has been assessed. Epoxidation of cinnamaldehyde in the solid state give poorer yields and stereoselectivities than in the solution-phase systems. In contrast Michael additions of several aldehyde enolates to 2-nitro-1-arylalkenes gave results that approached or surpassed those in solution, and could be extended successfully to a three-component Michael/Michael/aldol cascade process. Comparisons of the results of pendant- versus crosslinked functionalized resins in these applications were revealing of the benefits and limitations of each, as were attempts to reuse the polymer-bound auxiliaries.     

Enantioselective Michael addition of aldehydes to nitroolefins catalyzed by pyrrolidine-HOBt

The oxytriazole catalyst “pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohexanone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins under similar reaction conditions. The results of this study indicate that, the oxytriazole catalyst “pyrrolidine-HOBt” is equally effective in promoting the Michael addition of aldehydes to nitroolefins on employing benzoic acid as an additive. The desired products, γ-nitrocarbonyl compounds were obtained in good yields and high enantioselectivities.     

Synthesis of nitro-substituted decalones by double Michael reaction,sequential Michael reaction,and by Diels-Alder reaction

4-Nitro-3-phenyl-decalones are obtained from 1-acetylcyclohexene by three different ways. Stereochemistry and reaction pathways are discussed, and, for the first time, an intermediate of a sequential Michael reaction is isolated.The Michael reaction is of great preparative value for the formation of CC bonds². We are especially interested in the stereochemistry of the double Michael reaction     

N-heterocyclic carbene catalyzed umpolung of Michael acceptors for intermolecular reactions

leahciM! The N-heterocyclic carbene catalyzed umpolung of Michael acceptors proceeds through the formation of a deoxy-Breslow intermediate (see scheme; EWG=electron-withdrawing group). This nucleophilic species can react with other Michael acceptors in an intermolecular fashion, thereby resulting in the formation of homo- or heterodimeric olefins. This "Michael umpolung" should become a valuable method for the formation of densely functionalized olefins.     

Antibody-catalyzed asymmetric intramolecular Michael addition of aldehydes and ketones to yield the disfavored cis-product

The development of new catalytic asymmetric reactions continues to be a major goal in organic chemistry. Here we report a novel antibody-catalyzed intramolecular Michael addition of aldehydes and ketones to enones. The reaction is enantioselective and diastereoselective with a high ee value and cis/trans ratio. This is the first example of asymmetric intramolecular Michael addition of ketones. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.