Cu-catalyzed 1,4-addition

Addition of TCS 14 to Cu-catalyzed 1,4-additions of Grignard reagents of Li alkyls to a/yS-unsaturated carbonyl compounds has recently been repeatedly reviewed [42-44 a] and is thus not treated here. 

The same catalyst system works well in hetero-allylic asymmetric alkylations (h-AAA Scheme 1-16). Substrates such as enol esters 163 provide entry to nonracemic esters of allylic alcohols. Remarkably, competing 1,2-addition and/or acyl transfer were not issues yields are good (80-99%). In these cases, catalyst loading can go as low as 0.8%, and ee s are mostly >95%. Additional chemoselectivity has been noted in the case of cinnamyl ester 163, where the desired Sn2 AAA takes place without competing Cu-catalyzed 1,4-addition to the enoate. This sets the stage for a subsequent metathesis (GH-2 = Grubbs-Hoveyda second-generation catalyst) en route to butenolide 164. 

Metal-catalyzed reactions have been of major importance in synthetic organic chemistry. Over the past decade, enantio- and diastereoselective metal-mediated domino catalysis has emerged as an effective tool to construct really highly complex molecules in one-pot processes [2, 4b,d]. Among them, enantioseletcive metal-catalyzed conjugate additions (in particular, Cu-catalyzed 1,4-addition to a,P-unsaturated carbonyl compounds) have been useful components of domino reactions [4d, 5]. The generated metal enolates 2 after the additions of nucleophiles readily react with a variety of electrophiles (Scheme 11.1). Enantioselectivity of 3 depends on the first addition of nucleophiles to the P-position of the unsaturated carbonyl compounds 1. 

Scheme 11.12 Cu-catalyzed 1,4-addition/N-nitroso aldol reaction of 54 [23],...

Scheme 12.74 Domino Cu-catalyzed 1,4-addition ofZn-organic reagents/Fe-catalyzed allylation of Zn enolates [159],...

Scheme 2-152. Enantioselective Cu-catalyzed 1,4-addition of organozinc reagents.

Chiral acyl oxazolidinones also proved effective as auxiliaries on the acceptor component in asymmetric conjugate additions (Equation 17) [100]. Hruby reported a Cu-catalyzed 1,4-addition to phenyl-substituted acceptor 99 that proceeds with high diastereofacial selectivity to furnish 101 in 98 2 dr and 91 % yield. In these studies, low diastereomeric ratios were observed for the corresponding benzyl-substituted oxazolidinones. 

The examples given in Tab. 7.1 illustrate the scope of the Cu(OTf)2/(S, R, H)-18-catalyzed 1,4-addition. With various R2Zn reagents, excellent yields and enantiose-lectivities are obtained for cyclic enones (except for cyclopentenone, vide infra) [6, 38, 80]. 

Although the presence of BINOL in the ligands so far discussed has shown itself to be particular effective, modification of the diol moiety provides new classes of ligands for this addition reaction. Alexakis, screening a number of chiral phosphites in the Cu(OTf)2-catalyzed 1,4-addition, showed that an ee of 40% could be obtained for the addition of Et2Zn to 2-cyclohexenone and of 65% for addition to chalcone, by using cyclic phosphites derived from diethyl tartrate [51]. 

In the case of benzoquinone monoacetals 61, the two substituents at the 4-position are equal, and side-selective addition Re versus Si face) creates a single stereocenter (Scheme 7.17(a)). In the (S, R, R)-18/Cu(OTf)2-catalyzed 1,4-addition, depending on the nature of the R2Zn reagent and the size of the acetal moiety, enantioselectivities ranging from 85-99% were found (Table 7.4). The highest ees are provided by a combination of a small acetal moiety and Me2Zn 99% ee was obtained with 4,4-dimethoxy-5-methyl-2-cyclohexenone, for example. 

Alexakis, employing various chiral trivalent phosphorus ligands, has recently described Cu(OTf)2-catalyzed 1,4-additions of Et2Zn to a number of nitroalkenes (Scheme 7.22) [77]. TADDOL-based phosphonite 82 gave the highest ees for ar-ylnitroalkenes (up to 86%), whereas phosphoramidite 18 is the ligand of choice for alkylnitroalkenes [ees of up to 94%). 

Hiyama and co-workers have reported that the Mizoroki-Heck-type reaction of aryl- and alkenylsilanols is efficiently promoted by a Pd(OAc)2/Cu(OAc)2/LiOAc system (Equation (9)).50 50a in contrast, a dicationic Pd(ll) complex prepared in situ from Pd(dba)2, a diphosphine (dppe or dppben), and Cu(BF4)2 catalyzes 1,4-addition of aryltrialkoxysilanes to a-enones and a-enals in aqueous media (Equation (10)).51 The Pd-catalyzed 1,4-addition of the arylsilanes can be achieved also by using excess amounts of TBAF 3H20, SbCl3, and acetic acid.52... 

Many other binaphthalene-derived phosphoramidites were used as chiral ligands in copper-catalyzed Michael additions as well. Whereas 2,2 -bis(diphenylphosphino)-l,T-binaphthalene (BINAP) gave unsatisfactory stereoselectivities in Cu(OTf)2-catalyzed 1,4-additions of diethylzinc to enones,226 BINOL oxazoline phosphites obtained by Pfaltz et al. turned out to be remarkably versatile and in some cases complementary to phosphorami-... 

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. ... 

The enantioselective 1,4-addition addition of organometaUic reagents to a,p-unsaturated carbonyl compounds, the so-called Michael reaction, provides a powerful method for the synthesis of optically active compounds by carbon-carbon bond formation [129]. Therefore, symmetrical and unsymmetrical MiniPHOS phosphines were used for in situ preparation of copper-catalysts, and employed in an optimization study on Cu(I)-catalyzed Michael reactions of di-ethylzinc to a, -unsaturated ketones (Scheme 31) [29,30]. In most cases, complete conversion and good enantioselectivity were obtained and no 1,2-addition product was detected, showing complete regioselectivity. Of interest, the enantioselectivity observed using Cu(I) directly in place of Cu(II) allowed enhanced enantioselectivity, implying that the chiral environment of the Cu(I) complex produced by in situ reduction of Cu(II) may be less selective than the one with preformed Cu(I). 

In a more recent publication the same research group described a Cu(OTF)2/(POEt)3-catalyzed two-component Michael/aldol protocol of 2-112 and ZnEt2 leading to annulated cyclopentanols [46]. They showed that the enolate formed in the 1,4-addition can be trapped not only by a keto moiety, but also by an ester (Dieckmann condensation) or a nitrile functionality present in the molecule. Thus, as depicted in Scheme 2.26, there is a broad product variety. Starting from 2-112, compounds of type 2-114, 2-115 and 2-116 can be obtained via the enolate 2-113. 

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