Cyclohexenones chiral

Scheme 2.33. Formation of highly substituted chiral cyclohexenone derivatives using a domino conjugate addition/Dieckmann condensation.

A structural requirement for the asymmetric Birch reduction-alkylation is that a substituent must be present at C(2) of the benzoyl moiety to desymmetrize the developing cyclohexa-1,4-diene ring (Scheme 4). However, for certain synthetic applications, it would be desirable to utilize benzoic acid itself. The chemistry of chiral benzamide 12 (X = SiMes) was investigated to provide access to non-racemic 4,4-disubstituted cyclohex-2-en-l-ones 33 (Scheme 8). 9 Alkylation of the enolate obtained from the Birch reduction of 12 (X = SiMes) gave cyclohexa-1,4-dienes 32a-d with diastereoselectivities greater than 100 1 These dienes were efficiently converted in three steps to the chiral cyclohexenones 33a-d. 

The Stork reaction between methylvinyl ketone and enamine (130) derived from (S)-proline derivatives (131) is of particular interest since chiral cyclohexenones can be obtained. These are useful in many natural product syntheses. Optical yields of 20-50% have been reported 147>. 

A more subtle transposition of a chiral cyclohexenone into the optical antipode is shown in equation (II).9... 

Chiral cyclohexenones have been frequently employed in intermolecular [2 + 2]-photocydoaddition reactions directed towards natural product synthesis. A further case in point is the reaction of cydohexenone 32 with trans-1,2-dichloroethylene... 

Tsutsumi, K., Nakano, H., Furutani, A., Endou, K., Merpuge, A., Shintani, T., Morimoto, T., and Kakiuchi, K. (2004) Novel enhancement of diastereoselectivity of [2 + 2] photocycloaddition of chiral cyclohexenones to ethylene by adding naphthalenes. Journal of Organic Chemistry, 69, 785-789. 

To reach chiral cyclohexenones, we have found that the bicyclic lactam 10, derived from 5-oxohexanoic acid and the commercially available amino diol, gave excellent results. A number of examples were obtained (Table I).8... 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

TL3145>. The chiral cyclohexenone ketal (176) reacts with McjAl followed by AcjO to give... 

The photorearrangement of chiral cyclohexadienones and cyclo-hexenones has been covered in other reviews and is not examined here [173]. However, it is now well established that the formation of lumiketones from rigid enones and dienones (226, 228, and 231), or from monocyclic, chiral cyclohexenones having C-4 as the only asymmetric center, occurs with more than 99% selectivity [174] (Scheme 36). 

An early example of an asymmetric domino Michael/Knoevenagel reaction was reported by Jorgensen et al. [167] in 2006, providing the synthesis of chiral cyclohexenones from the reaction of tert-butyl 3-oxobutyrate and a, 3-unsaturated aldehydes catalyzed by chiral diphenylprolinol silyl ether derivative. Soon after, the... 

Finally, the organocatalytic KR of 6-aryl-2,6-hexanediones was achieved very recently by Cheng et al. [306] via intramolecular aldol reactions. These reactions catalysed by chiral secondary amines cleanly afforded chiral cyclohexenones together with enantioenriched starting hexanediones with moderate-to-high enantioselectivities. 

One of the most popular acyclic dienes in the Diels-Alder reaction is Danishefsky s diene (91) and numerous research groups have developed chiral catalysts for the reaction of this diene with a variety of dienophiles. For example, Nishida reported that Yb(III)-BINAMIDE complexes catalyze the asymmetric reaction of Danishefsky s diene with electron-deficient alkenes. In one case, diene 91 reacts with dienophile 92 to selectively provide a functionalized cyclohexene that, on hydrolysis, affords the desired chiral cyclohexenone 93 in high yield and high... 

Shibasaki and coworkers have used the Noyori-type three-component reaction in the synthesis of the fused poly heterocycle garsubellin A 195 (Scheme 6.27) [56]. The chiral cyclohexenone 193 reacts with methylmagnesium bromide, followed by trapping of the enolate with isopropan-aldehyde. The key intermediate 194 is isolated in 61% yield and diastereomeric ratio of 4 1. 

Mori, K., Katoh, T., Suzuki, T., Noji, T., Yamanaka, M., Akiyama, T. (2009). Chiral phosphoric acid catalyzed desymmetrization of meso-l,3-diones asymmetric synthesis of chiral cyclohexenones. Angewandte Chemie International Edition, 48, 9652-9654. 

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

Scheme 3.17 Synthesis of chiral cyclohexenones via Michael-aldol-dehydration reaction.

The obtained products could serve as crucial synthons for complex molecule synthesis by derivatization of both carbonyl moieties. This behavior was highlighted in the remarkable syntheses of polyanthelin, dihydrojunenol, or biyouyanagin A. Notably, the treatment of the 1,4 adduct under basic conditions (KOH) affords directly the corresponding chiral cyclohexenone by aldol condensation-elimination (Scheme 11.17). 

Further investigations were run on the chiral cyclohexenone 23 showing that the formal 1,2-phenyl migration to 24 occurred without any loss of optical purity." A bridged intermediate was proposed to explain the selective formation of the endo-bicycHc derivative 24 to the exclusion of any exo-derivative... 

Very recently, Kotsuki and coworkers reported an enantioselective Robinson annulation reaction for the synthesis of cyclohexenone derivatives bearing a quaternary center. Chiral vicinal diamine-chiral Bronsted acid conjugate 168 was found to be the optimal catalyst. The reactions afforded chiral cyclohexenone with moderate yields and good enantioselectivity [75], It was proposed that simultaneous enamine activation of donor and iminium activation of acceptor were involved in the catalytic cycle (Scheme 5.47). 

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