Chiral phosphoramidite ligand

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. 

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. 

Scheme 7.9. Copper-catalyzed 1,4-addition to cyclohexenone and chalcone, with phosphoramidites as chiral ligands.

The moderate ees obtained with the copper arenethiolate ligands discussed above prompted a search for new chiral ligands for use in asymmetric allylic substitution reactions. The binaphthol-derived phosphoramidite ligand 32, used successfully by Feringa et al. in copper-catalyzed 1,4-addition reactions [37], was accordingly tested in the reaction between 21 and n-BuMgl. 

Figu re 9.4 Chiral ligands other than phosphoramidites that have been used in Ir-catalyzed allylic substitutions. 

Some monophosphines are also revealed to work as reasonably effective ligands. Imamoto and Tsuruta prepared and applied P-chirogenic monophosphines 38 to the allylic alkylation (up to 96% ee) (Equation (7)). Nelson and Hilfiker found that monophosphines 39 bearing a tricarbonyl(arene)chromium moiety work as effective chiral ligands (up to 92% ee) (Equation (7)). " Some monophosphines 40-42 bearing a binaphthyl moiety and some mono-dentate phosphoramidites 43-45 work as quite effective chiral ligands (Equation (7)). Several other monophosphines 46-48 applied to the asymmetric allylic alkylation are summarized in Scheme 5 39,39a-39h... 

The copper-catalyzed enantioselective Michael addition of organometallic reagents to enones was the first successful application of phosphoramidite chiral ligands in catalysis [4, 43]. Since this early report, substantial enhancement of the enantioselectivity and/or of the substrate scope has been achieved through an untiring effort to optimize the ligand structure [5a, 44]. 

Feringa, B.L. (2004) Catechol-based phosphoramidites A new class of chiral ligands for rhodium-catalyzed asymmeti ic hydrogenations. Org. Lett.. 6. 1433-1436. 

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... 

Recently, Reek et al. published the synthesis of a 9H,9 H- [4,4 ]bicarbazole-3,3r-diol (BICOL)-based chiral monodentate phosphoramidite ligand, which was functionalized with two different third-generation carbosilane dendritic wedges (Fig. 26) [57]. As reference reaction in the catalytic study, the rhodium-catalyzed asymmetric hydrogenation of Z-methyl-a-acetamido-cinnamate was chosen. Using a ligand-to-rhodium ratio of 2.2 led to enantio-selectivities which were comparable to the results obtained using the parent BINOL-derived monodentate phosphoramidite MonoPhos. 

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-... 

It is evident from the previous examples that most copper catalysts have been applied only to simple, unsubstituted Michael acceptors so far. Only very recently, chiral, substituted cyclohex-2-enones were used as substrates for copper-catalyzed enantioselective 1,4-additions with phosphoramidites as the chiral ligand. Thus, highly enantioselective kinetic resolutions of several 4- or 5-substituted cyclohex-2-enones were reported by Feringa and co-workers.236,236a In contrast to these Michael acceptors, the corresponding 6-substituted cyclohex-2-enones possess a stereogenic center which can be... 

Finally, when aziridines bear a 2-alkenyl substituent, they can engage in an SN2 reaction with dialkylzinc reagents using copper catalysts. Enantioselectivity can also be induced by including a chiral ligand, such as the binaphthyl phosphoramidite 174. For example, the aziridinyl cyclohexane 175 provided exclusively the trans-, 4 adduct with 83% ee upon treatment with dimethylzinc in the presence of copper(II) triflate and ligand 174 <03TL8559>. 

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