Enantioselective Conjugate Addition to Enones

Several chiral catalysts for conjugate addition have been explored, including both protic and Lewis acids. 3,3 -hri-(4-Nitrophenyl)-BINOL-phosphoric acid gives 40-98% yields and 40-55% ee with p-aryl enones [243]. 

The group of Bandini and Umani-Ronchi investigated aluminum-salen complexes and found that enantioselectivity was promoted by amine bases, 2,6-lutidine being particularly effective. The optimized conditions gave 80-90% ee with several l-aryl-but-2-en-l-ones [245, 246]. 

Another chiral catalyst that was examined is an oxazaborolidinone derived from aZZo-threonine. The reaction proceeded in 80-95% yield and 80-95% ee. These conditions were apphcable to both 1- and 2-methyl indole, as well [247]. 

A series of a-hydroxy enones gave good results with a t-butyl BOX catalysts or its cyclopropyl analog [248]. 

Combinations of Z Zs-oxazolines with Cu(OTf)2 were also effective for enones having dimethyl phosphonate substituent groups [249]. 

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The use of vinyl epoxides as substrates in enantioselective copper-catalyzed reactions, on the other hand, has met with more success. An interesting chiral ligand effect on Cu(OTf)2-catalyzed reactions between cyclic vinyloxiranes and dialkylzinc reagents was noted by Feringa et al. [51]. The 2,2 -binaphthyl phosphorus amidite ligands 32 and 43 (Fig. 8.5), which have been successfully used in copper-catalyzed enantioselective conjugate additions to enones [37], allowed kinetic resolution of racemic cyclic vinyloxiranes (Scheme 8.26). 

Scheme 2.81 Organocatalytic enantioselective conjugate additions to enones catalyzed by bifhnc-tional thiourea 109...

Table 1 Enantioselective conjugate addition to acyclic enones...

In total, over the past six years, the chelating P,N-ligands have shown considerable promise in a variety of enantioselective processes, including transfer-hydrogenation and hydrosilylation of ketones, hydroboration of alkenes, conjugate addition to enones and Lewis-acid catalysed Diels-Alder reactions, in addition to those described above.128,341 It is anticipated that this list will continue to grow, and... 

Enantioselective addition (C H Zn with enones.1 In the presence of (1S,2R)-1 (1 equiv.), diethylzinc undergoes conjugate addition to enones to form (R)-P-ethyl ketones in 81-94% ee. Use of catalytic amounts of 1 decreases the enantioselectivity to 60-80% ee. 

Enantioselective Conjugate Addition to Prochiral Enones of Organometallic Reagents Modified with Ephedrine. Enantioselective conjugate addition to 2-cyclohexenone with chiral organo(alkoxo)cuprates [MCu(OR )R] has been studied. When the cuprate is prepared from the lithium alkoxide of ephedrine, Phenyllithium, and Cul, 3-phenylcyclo-hexanone with 50% ee is obtained. The enantioselectivity reaches 92% ee in enantioselective ethylation when a chiral diamino alcohol derived from ephedrine is employed (eq 13). ... 

A nickel-catalyzed carbozincation in which an allylzinc adds across the double bond of an unsaturated acetal has also been reported (Scheme 79). ] This procedme effectively provides a reverse-polarity approach to the functionalization of unsaturated carbonyl derivatives. Non-allylic Grignard reagents, however, add to cychc unsaturated acetals with the opposite regiochemistry. This latter procedure provides the basis for an enantioselective conjugate addition to cyclic enones (in 53% ee for the cyclopentenyl substrate and 85% ee for the cyclohexenyl homologue). ... 

The first Cu-catalyzed asymmetric borylative cyclization reaction between cyclohexadienone-containing 1,6-enynes and B2pin2 was established to afford an optically pure d5-hydrobenzo[l ]furan framework bearing alkenylboronate and enone substructures through a tandem process of selective P-borylation of the propargylic ether and subsequent enantioselective conjugate addition to cyclohexadienone (13JA11700). 

Scheme 3.52 Enantioselective conjugate addition to cyclic enones.

Conjugate Addition. Catalytic enantioselective conjugate addition of cyanotrimethylsilane to a,/3-unsaturated imides has been reported to afford 1,4-addition products in excellent yield and enantiomeric excess (eq 35). Under the catalysis of a chiral gadolinium complex, cyanotrimethylsilane can undergo facile conjugate addition to enones (eq 36) and a, 6-unsaturated... 

A short synthesis of (-f)-monomorine (1562) by Maruoka and coworkers used the chiral phase-transfer catalyst (R)-1672 to mediate an enantioselective conjugate addition between enone 1673 and the imine-protected glycine ester 1674 (Scheme 213). In a remarkable one-pot reaction, the intermediate adduct 1675 was then treated with Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate) in mildly acidic medium, which brought about deprotection of the acetal and imine as well as a double reductive amination in which the dihydropyridine acted as the hydrogen transfer agent. The resulting indolizidine ester (—)-1676 was... 

Stable precursors, such as boranes and silanes, were also shown to display good reactivity in NHC-Cu-catalyzed conjugated additions. The groups of Ohmiya and Sawamura reported the copper-catalyzed 1,4-addition of alkyl-boranes to enones, respectively in a racemic and enantioselective version. Organosilanes, te. RSiFj or RSi(OR )3, can also be used with NHC-Cu catalysts in conjugate addition to enones and allylic epoxides. ... 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

Ferrocen-l,l -diylbismetallacycles are conceptually attractive for the development of bimetal-catalyzed processes for one particular reason the distance between the reactive centers in a coordinated electrophile and a coordinated nucleophile is self-adjustable for specific tasks, because the activation energy for Cp ligand rotation is very low. In 2008, Peters and Jautze reported the application of the bis-palladacycle complex 56a to the enantioselective conjugate addition of a-cyanoacetates to enones (Fig. 31) [74—76] based on the idea that a soft bimetallic complex capable of simultaneously activating both Michael donor and acceptor would not only lead to superior catalytic activity, but also to an enhanced level of stereocontrol due to a highly organized transition state [77]. An a-cyanoacetate should be activated by enolization promoted by coordination of the nitrile moiety to one Pd(II)-center, while the enone should be activated as an electrophile by coordination of the olefinic double bond to the carbophilic Lewis acid [78],... 

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