Michael reactions acceptors

The a, p-unsaturated diketone moiety in the curcuminoids is a Michael reaction acceptor, which belongs to the major class of phase II enzyme inducers... 

Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. 2001. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci USA 98 3404-3409. 

Dinkova-Kostova AT, Abeygunawardana C, Talalay P. 1998. Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors Correlation of potencies as phase 2 enzyme inducers and radical scavengers. J Med Chem 41 5287-5296. 

The conjugate system of the C-2 nitroalkenes should posses some interesting chemical reactivity and it should be an excellent Michael reaction acceptor with reactive nucleophiles. Moreover, the steric effect of the bulky 1,6-anhydro ring should be similar to that of levoglucosenone. As a consequence, nitroalkenes are excellent precursors for the stereoselective introduction of an additional sugar moiety at C-2 with subsequent additional functional group such as nitromethylene or its reduced/acetylated analog. Moreover, this unsaturated C-2 functionality additionally fixes the conformation of the system and most importantly sterically hinders the P-D-face of both enone molecules. 

The stereoselective, one-step synthesis of (l,4)-5-thiodisaccharides (7-2) is a classical example (Scheme 2) of exploiting the excellent functionality of levoglucosenone as Michael reaction acceptor. The methodology of functionalization of C-2 either via conventional and stereoselective reduction, or oximation and then stereoselective reduction of the oximino functionality is unique in providing both classes of 5-thio-disaccharides. Moreover, the C-2 amino functionalized nonhydrolyzable 5-thio-disaccharide, after deprotection of C-2 acetamido function represents a convenient molecular scaffold for the generation of diverse libraries of peptidomimetics as a selected class of glycoconjugates. 

Dibenzoylpropane (71) was inactive as an inducer probably due to its lack of an enone moiety. Dibenzoylmethane (69) was quite active with a CD value of 0.8 [iM the keto-enol tautomerization of the /3-diketone can provide the Michael reaction acceptor feature. The three natural curcuminoids showed similar CD values therefore, the methoxy group in the phenyl ring does not greatly affect the potency. However, the CD... 

Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, Kerns ML, Talalay P (2007) Induction of the phase 2 response in mouse and human skin by sutfinaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev 16 847—851 Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. 2001. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci USA 98(6) 3404-3409. 

Fluorme-containing Michael addition acceptors have been used as synthons, a portion of a molecule recognizably related to a simpler molecule, for the introduction of fluorine into the organic molecules Their reactions with enamines and ketones lead to a condensarion-cyclization process... 

The trifluorinated a, J-ethylenic ketone shown in equation 36 was prepared by two different methods and behaves like a Michael addition acceptor in reactions... 

Michael reactions take place by addition of a nucleophilic enolate ion donor to the /3 carbon of an a,(3-unsaturated carbonyl acceptor, according to the mechanism shown in Figure 23.7. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

What product would you obtain from a base-catalyzed Michael reaction of 2,4-pentanedione with each of the following a,/3-unsaturated acceptors ... 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The conjugate addition of a carbon nucleophile to an a./3-unsiituratcd acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (/3-keto esters or /3-diketones) and unhindered n,/3-unsaturated acceptors. Knamines, prepared by reaction of a ketone with a disu Instituted amine, are also good Michael donors. 

How might the following compounds be prepared using Michael reactions Show the nucleophilic donor and the electrophilic acceptor in each case. 

Michael reaction, 894-895 acceptors in, 895 donors in, 895 mechanism of. 894-895 Robinson annulation reactions and, 899-900... 

Feringa and coworkers have used the optical active furanone or pyranone as an acceptor for the diastereoselective Michael reactions (Eq. 4.133).193... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

Nitroglycals65 are excellent Michael-type acceptors,66 where O-, N-, S-, C- and P-nucleophiles can be used as donors.67 An application of this kind of reaction was reported by Schmidt et al. for a new synthesis of 2-deoxy-2-nitro-D-galactose nucleoside 86 and of /V-acetyl-D-galactosamine nucleoside 88, based on addition reactions to 3,4,6-tri-0-benzyl-2-nitro-D-galactal 85 (Scheme 28).68... 

FIGURE 8.12 Michael reaction of glutathione with acrolein and acrolein-like reactive metabolites of felbamate, terbinaflne, as well as the formation of a Michael acceptor metabolite of abacavir. 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

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