Cydic Enones

Excellent enantioselectivities (96% ee) for 2-cydohexenone were also obtained with the ligands 22, 23, and 29, introduced by the groups of Pfaltz [47], Reetz [48], and Alexakis [63], respectivdy. Ees in the range of 90-92% were found with ligands 24, 25, 30, and 35 [49, 55, 60]. 

I 7 Copper-catslyzed Enantiosshctiifs Cor pgat Addition Reactions of Ofganozmc Reagents 

Optically active cydopentanes are among the structural units most frequently encountered in natural products sudi as steroids terpenoids and prostaglandins. Not unexpectedly the development of a highly enantioselective catalytic 1 4-addition reactions to 2-cydopentenones has proven to he a diaRenging goal. In contrast with the hi enantiosdectivity observed in the copper-phosphoramidite-catalyzed 1 4- 

Besides the very low stereosdectivities, a major problem encountered with this substrate is the low chemical yield (due to subsequent reaction between the resulting zinc enolate and the starting material) and the hi volatility of the product. Using TADDOL-phosphoramidite 27 in a tandem lj4-addition-aldol condensation to cydopentenone we were only able to obtain an ee of 37%, but the enantiosele-ctLvity was raised to 62% in the presence of wet powdered molecular sieves (4 A) [52]. This beneficial effect of water and molecular sieves in some catalytic 1,4-additions has been observed in other cases recently [52, 59]. Important to note is that the yidds in the tandem version are dramatically increased, presumably due to in situ trapping of the reactive enolate (vide infra). Pfaltz et al. reported a 72% ee in the addition of Et Zn to 44 when using BINOL-oxazoline phosphite ligand 22 [47]. 

Aryl-substituted enones (dialcones in particular) have been used as model substrates in studies of catalytic lj4-additions with organozinc reagents. Fig. 7.7 summarizes typical enantioselectivities achieved with various chiral ligands. 

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The sequential double migratory insertion of CO into acydic and cydic diorganozircono-cene complexes through acylzirconocene and ketone—zirconocene species provides a convenient procedure for preparing acyclic and cyclic ketones (Scheme 5.6) [8], Thus, the bi-cydic enones from enynes can be obtained through CO insertion into zirconacyclopen-tenes followed by a subsequent rearrangement (Scheme 5.7). The scope and limitations of this procedure have been described in detail elsewhere [8d]. This procedure provides a complementary version of the well-known Pauson Khand reaction [9]. 

Although the highest enantiomeric excess of the products was 43% only, in principle this route is an interesting and promising means of produdng cydic enones with a chiral center by use of a readily available catalyst. 

Tbe poor diasterosdectivity at tbe -carbon of cydic enones arises from poor fadal sdectivity during cuprate addition. Acydic enones may also give poor diaster e os dectivity at the -carbon center because of E Z isomerization arising from an equilibrium between an enone-cuprate d-n complex and starting materials. Much work remains to be done in the devdopment of asymmetric variations in ot-aminoalkyIcuprate chemistry. 

The first example of a chiral carbanionic residual ligand has recently been reported [238]. Chiral mixed cuprates generated from alkyhithium reagents and cydic a-sulfonimidoyl carbanions transfer allcyl ligands [such as n-Bu, Me, (CH2)30CH(Me)0Et] to cydic enones with excellent enantiosdectivities (77-99% ee). 

Cydic systems usually adopt distinct preferred conformations, which frequently allow them to pass throu a single reactive conformation in the course of a chemical reaction this may result in the formation of a sin e product. In this contesl, addition of organocuprates to a number of chiral, cydic enone systems frequently occurs vtith high levels of stereoselectivity. Historically, this chemistry has had a major impact on the fidd of total synthesis of steroids and prosta andins [la, k]. In this chapter we would thus like to present an overview of the most general stereochemical trends underlying the addition of organocuprates to chiral cydic enones. 

The examples given in Tab. 7.1 illustrate the scope of the Cu(OTf)2/(S, Rj Ji)-18-catalyzed 1,4-addition. With various R Zn reagents, excellent yields and enantiose-lectivities are obtained for cydic enones (except for cydopentenone, vide infra) [6, 38, 80]. 

For the transfer of arj l and alkenyl groups to enones, Hayashi s procedure, employing the corresponding boronic adds and a rhodium-BINAP catalyst, is the method of choice at present [24, 25]. For the transfer of alkyl groups to cydic enones the use of dialkylzinc reagents in the presence of copper-phosphoramidite catalysts is superior. Although the first examples of hi ly enantiosdective 1,4-ad-ditions of R Zn reagents to nitroalkenes have been reported, similar catalytic methods for numerous other dasses of a, -unsaturated compounds still need to be devdoped. 

In the enantioselective oopper(I)-catalyzed conjugate addition of a cydic enone with a chiral ligand, the observed nonlinear effects indicate that Cu(I) aggregates partidpate in the reaction [78]. 

In 2008, Ye and coworkers also developed a new type of multifunctional cinch-onidine-based catalyst, such as 119 having an additional primary amine moiety, for the Michael addition of nitroalkane to cydic enones [32], In the presence of an acid cocatalyst, the primary amine moiety of 119 can act as a Lewis base to activate the Michael acceptor via iminium formation. The catalysts 119a and 119b (5 mol%) provided quite excellent enantioselectivity (up to 98% ee) for the Michael addition of nitroalkanes to cyclohexenone (Scheme 9.40). The observed retardation of the reaction rate and the opposite sense of enantioselectivity obtained with the catalyst 119b indicated the importance of the configuration of the cydohexane... 

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