Desymmetric Michael reactions

SCHEME 5.61. Combination of electrophile-triggered dearomatization with desymmetric Michael reaction. 

SCHEME 5.62. Desymmetric Michael reaction of active methylene groups to cyclodieones. 

Most recently. You and co-workers [120] presented a desymmetrization of cyclodienones bearing active methylene groups via a cinchonine alkaloids urea-catalyzed asymmetric Michael reaction, affording polycyclic cyclohexenones in high yields and enantioselectivites (Scheme 5.62). 

A strategy for the desymmetrization of cyclohexadienones via asymmetric aza-Michael reaction using cinchonine-derived thiourea 52 was developed by You s group (Scheme 11.33) [113]. A series of highly enantioenriched bicyclic pyrrolidine and morpholine derivatives were obtained in excellent yields and enantioselectivities. 

SCHEME 11.33. Desymmetrization process via asymmetric intramolecular aza-Michael reaction. 

Desymmetrization of cyclohexadienones bearing a bisphenylsulfonyl methylene group (164) via asymmetric Michael reaction catalysed by the cinchonine-derived urea (166a) has been reported to afford cyclization products (165) with <91% eeP ... 

You and coworkers developed a desymmetrization protocol based on an intramolecular oxo-Michael reaction, using as catalyst the phosphoric acid derivative 121 [110]. Cyclohexadienones 120 were transformed into the corresponding bicyclic systems 122 with high yields and enantioselectivities. Remarkably, the 4-substituent in the cyclohexadienone has a great influence on the enantioselective outcome of the reaction. Bulkier substituents at the 4-position lead to lower reaction rates and enantioselectivities (Scheme 33.35). This desymmetrization reaction was used as a key reaction for the efficient synthesis of the natural products cleroindicins C,... 

Chen et al. have further applied the TFA salt of 9-amino-9-deoxyepiquinine lo as chiral organocatalyst to the desymmetrization of prochiral a,a-dicyanoalkenes from 4-substituted cyclohexanones via domino Michael-Michael addition reactions with a, 3-unsaturated ketones. These reactions exhibited high synthetic efficacy and bicyclic products 16 with two new C—C bonds, and four stereogenic centers... 

Recently, an oxidative dearomatization of substituted phenols followed by a desymmetrizing asymmetric intramolecular Michael addition catalyzed by the pro-linol derivative 27 has been described towards the synthesis of highly functionalized polycyclic molecules with excellent enantioselectivities [40]. As shown in Scheme 2.15, the reaction starts with an oxidation of the phenol moiety to the corresponding mera-cyclohexadienones employing PhlCOAc), mild oxidant that does not react with the aldehyde nor with the catalyst. In the presence of different nucleophiles such as, methanol, cyanide, or fluoride, intermediates 26 are formed, which suffer intramolecular Michael addition of the aldehyde moiety to afford the desired chiral products 28 with excellent diastereo- and enantioselectivities. 

The NHC-generated azolium enolate can also react in a Mannich [lid], Michael [108], or aldol fashion [86], such as in the desymmetrization of 1,3-diketones to access enantiomerically-enriched cyclopentenes following decarboxylation of the P-lactone product [109]. Scheldt and coworkers took advantage of this reaction in the total synthesis of bakkenolides 1, J, and S (Scheme 18.26) [110]. 

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