Phosphoramidites conjugate addition

A variety of substrates has been used in this type of conjugate addition reaction with trialkyl phosphites, with assorted proton sources.361 384 Other types of trivalent phosphorus reagents without acidic (or conjugate base of acidic) sites have also been used successfully for this conjugate addition process, including triaryl phosphites (without dealkylation),369 phosphoramidites,385 389 phospho-nites,363 380 390 and phosphinites.360 380... 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

A remarkable number of chiral phosphorus ligands (phosphoramidites, phosphites, and phosphines with modular structures) have been introduced into the copper-catalyzed conjugate addition of R2Zn reagents, and high enantio-selectivities (>90%) are now possible for all three different classes of substrates 2-cyclohexenones and larger ring enones, 2-cyclopentenones, and acyclic enones. 

Feringa and co-workers applied chiral phosphoramidite ligand (S,R,R)-67 in the conjugate addition of dimethylzinc to acyclic unsaturated malonates 68 and obtained up to 98% ee (Scheme 22).71... 

The enantioselective conjugate addition of dialkylzinc to nitroalkenes using other phosphoramidite,79,79a 83a sulfonamide,84 and binaphthol-based thioether ligands65 has also been studied in the past few years. Particularly noteworthy are the efficient chiral monodentate phosphoramidite ligands (S,R,R)-29 and (A,A)-55 developed by Feringa et al. and Alexakis et al., respectively, for this reaction. (S,R,R)-29 provided excellent enantioselectivities (up to 98% ee) for acyclic nitroalkenes (Scheme 25).80 It also worked well for other nitroolefin substrates such as 3-nitrocoumarin 7068 and methyl 3-nitropropenoate 7185. 

Alexakis et al. showed that under optimized experimental conditions, the enantioselectivity of the Cu-catalyzed conjugate addition of dialkylzinc to cyclic nitroolefin was improved to 95% with both (A,A)-55 and (R,S,S)-29.79,79a Biphenol-based phosphoramidite ligand (S,S)-55 also provided acyclic nitroalkenes adducts with 95-96% ee.42... 

Ojima and co-workers found that chiral monodentate phosphoramidite (S,R,R)-35 was highly effective for the enantioselective conjugate addition of diethylzinc to acyclic nitroalkenes (up to 99% ee).86... 

In 1996, Feringa and co-workers (164) reported the use of binaphthol-derived phosphoramidite 232a as a ligand for the copper-catalyzed conjugate addition. Addition of 2 equiv of 232a to Cu(OTf)2 forms an effective catalyst for the selective... 

Meanwhile, copper salt catalyzed asymmetric conjugate addition of dialkylzincs has been developed. Alexakis and coworkers reported the catalytic addition of diethylzinc to cyclohexenone using copper salt111. Feringa and coworkers developed a marvelous phosphoramidite (49)112. In the presence of 49 and Cu(OTf)2, diethylzinc adds to cyclohexenone in >98% . Recently, asymmetric addition of diphenylzinc using 49 has been reported113. Nowadays, compounds 50114, 51115, 52116, 53117 and 54118 are known as highly enantioselective catalysts. 

A highly enantioselective synthesis of a-dehydroamino acids (186) with a stereogenic centre at the y -position has been developed, which employs a copper-catalysed asymmetric conjugate addition of diethylzinc to a,j3-unsaturated imines (185) with the TADDOL-derived phosphoramidite (187) as a chiral ligand.234... 

Huttenloch and co-workers prepared an entire library of phosphoramidite ligands on solid phase.50 However, these were only used for conjugate addition reactions. 

Once again, the zinc enolates generated in the conjugate addition can be trapped with various electrophiles besides protons. For example, reaction of the enolate 270 obtained by treating cyclohex-2-enone with dimethylzinc in the presence of Cu(OTf)2 and phosphoramidite 269 with trimethylsilyl triflate and diiodomethane provided the cyclopropanation product 271 with good diastereoselectivity and high enantiomeric excess and chemical yield... 

High levels of enantioselectivity (94-98% ee) and good chemical yield (72-95%) were observed in the catalytic conjugate addition of dialkylzinc reagents to numerous cyclic enones (eq 1) using a catalyst prepared in situ from Cu(OTf)2 and this chiral phosphoramidite ligand. Here the steric properties of the substrate and the reagent appear to be unimportant. 

Enantioselective copper phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to several 4,4-disubstituted cyclohexadienones is achieved with diastereomeric ratios ranging from 1/1 to 99/1 with 85% to 99% ee. When the two substituents are equal (eq 2), selective Re versus Si face-selective addition of the zinc reagent affords a single isomer. Sequential catalytic 1,4-addition to the prochiral dienones gave cis or trans bis-adducts with high enantio and diastereoselectivity. ... 

Membered cyclic phosphoramidites as ligands in catalytic asymmetric conjugate addition 00ACR346. 

Conjugate addition. A phosphoramidite ligand (1) is useful for chiral induction during reaction of organozinc reagents with enones and 4,4-disubstituted 1,5-cyclohexadienones in the presence of Cu(OTf)2. 

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