Cyclohexadienones desymmetrization

Cyclohexadienones 61 and 64 are readily available from monoprotected hydro-quinones or para-substituted phenols, respectively. Conjugate additions to these symmetrical dienones result in desymmetrization of the prochiral dienone moieties, providing access to multifunctional chiral synthons in two steps from the aromatic precursors (Scheme 7.17) [72]. 

Rovis and Liu have accomplished the desymmetrization of cyclohexadienones by using triazolinylidene carbene 75b (Scheme 15) [75, 76], Mnltiple hydrobenzo-furanones 103-106 were synthesized in good yields and excellent enantio- and diastereoselectivity. Generation of three co ntiguous stereocenters may be achieved in >99% ee and 80% yield. 

SCHEME 11 Enantioselective desymmetrization of malonate-tethered cyclohexadienones. 

One of our simplest attempts at overriding the inherent diastereoselectivity was inspired by our success with using Cinchona alkaloid-based phase-transfer catalysts to promote the enantioselective desymmetrization of achiral malonate-tethered cyclohexadienones (Scheme 27). When catalyst B was... 

A highly enantioselective intramolecular AHR of the cyclohexadienone 322 to give 324 with 96% ee in 100% conversion was carried out using the chiral phosphoamidite-type ligand (III-IO), which is monodentate. The stereogenic center was not created at the site of C—C bond formation, but instead the cyclohexadienone was desymmetrized. The use of Cy2MeN as a base gave the best result. It should be added that the carbopalladation product 323 has no jS-H syn to Pd, and hence the cyclized product 324 was formed by syn y3-H elimination after epimerization [132]. 

Scheme 6.9 The desymmetrization of cyclohexadienones by the 119a-catalyzed intramolecular Stetter reaction.

Jia and You recently reported an enantioselective desymmetrization of cyclohexadienones via a D-camphor-derived triazolium salt catalyzed... 

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. 

Cyclohexadieones. Since cyclohexadienones are highly useful synthetic intermediates for natural product synthesis and drug discovery efforts, the catalytic asymmetric desymmetrization of cyclohexadienones has received much attention and several success have been made in recent years. Hayashi et al. [109] developed the first oragnocatalytic asymmetric desymmetrization of cyclohexadieones. Screening different secondary amines revealed that cysteine-derived amine is the most effective organocatalyst, affording the bicyclo[4,3,0]nonene skeleton in... 

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. 

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 ... 

A new enantioselective Rh-catalyzed domino transformation of boronic acids with a cyclohexadienone-tethered alkyne gave access to fused heterocycles by desymmetrization of alkyne-tethered cyclohexadienones via the formation of two new C-C bonds and two new stereocenters with good enantioselectivities, syn-addition of the rhodium-aryl species onto the alkyne (130L1148). 

Jia M-Q, You S-L (2012) Desymmetrization of cyclohexadienones via D-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction. Chem Commun 6363-6365... 

An interesting variation on the intramolecular Stetter reaction was disclosed in 2006 by Rovis and coworkers [47]. Both O- and C-substituted cyclohexadienones could be desymmetrized using a chiral N-anisyl-triazoUum salt in high diastereo-and enantioselectivity (up to >99% ee) (Scheme 18.10). All-carbon quaternary and up to three contiguous stereocenters could be formed in this process, with the a-alkoxy group apparently not involved in redox events (see below). 

Scheme 18.10 Desymmetrization of cyclohexadienones, according to Rovis and coworkers. 18.2.2.2 Intermolecular Stetter Reactions...

You and coworkers developed a desymmetrization protocol based on an intramolecular oxo-Micliael 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,... 

Scheme 18.10 Desymmetrization of cyclohexadienones, according to Rovis and coworkers.

Another example of the use of thiourea catalysts in total synthesis was reported by You and coworkers, who obtained (-)-mesembrine by means of an organocata-lyzed aza-Michael addition process (Scheme 44.8) [86]. The crucial step in this route is based on a previous study of the desymmetrization of cyclohexadienones performed by the same research group [87]. On this occasion, the difficult task of controlling the sterically congested chiral arylated quaternary carbon center was... 

Scheme 44.8 Enantioselective synthesis of (-)-mesembrine via desymmetrization of cyclohexadienones.

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