Copper phosphoramidite

Pineschi and Feringa reported that chiral copper phosphoramidite catalysts mediate a regiodivergent kinetic resolution (RKR) of cyclic unsaturated epoxides with dialkylzinc reagents, in which epoxide enantiomers are selectively transformed into different regioisomers (allylic and homoallylic alcohols) [90]. The method was also applied to both s-cis and s-trans cyclic allylic epoxides (Schemes 7.45 and 7.46,... 

Optically active cyclopentanes are among the structural units most frequently encountered in natural products such as steroids, terpenoids, and prostaglandins. Not unexpectedly, the development of a highly enantioselective catalytic 1,4-addition reactions to 2-cyclopentenones has proven to be a challenging goal. In contrast with the high enantioselectivity observed in the copper-phosphoramidite-catalyzed 1,4-... 

When an alkyl and an alkoxy moiety are present at the 4-position of the dienone (Scheme 7.17(b)), desymmetrization during the 1,4-addition produces two stereocenters in a single step. The chiral copper-phosphoramidite catalyst derived from... 

Feringa and coworkers have developed a copper phosphoramidite catalyst system that accesses the diastereomeric anti products in the alkylative ring opening... 

An illustration of the use of -methyl-substituted thioesters in the synthesis of natural products is present in the total synthesis of a /3-D-mannosyl phosphomycoketide from Mycobacterium tuberculosis (Figure 5). Addition of MeMgBr to ethyl 6-benzyloxy-2-hexene thioate catalyzed by Cu/Josiphos (92% yield, 93% ee) furnished one of the building blocks. The other four methyl groups were introduced using copper/phosphoramidite-catalyzed dimethylzinc addition. 

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. ... 

Asymmetric allylation of cinnamyl halides, alkylation of alkynyl epoxides, and 1,4-addition of nitro olefins" are also successfully demonstrated by combination of an organozinc reagent and a chiral copper phosphoramidite. 

Kinetic Resolution and Desynnnetrization. A variety of substituted 2-cyclohexenones are obtained in enantiomerically pure form employing chiral copper phosphoramidite catalyst for kinetic resolution (eq 5) (> 99% ee at 52% conversion, selectivity S > 200). The enantioselective desymmetrization of methylidene epoxycycloalkanes is also reported. ... 

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. 

The copper-catalysed conjugate addition process is not limited to the use of Grignard reagents and dialkylzincs. Some success has been achieved using trimethylaluminium as nucleophile and up to 97% ee has been obtained in the addition to 2-cyclohexenones using copper-phosphoramidite catalysts. ... 

Screening different reaction parameters in the asymmetric ring opening of compound 89a with -BuLi, it was found that the use of a copper/phosphoramidite (R,R,R)-L7 complex, together with a Lewis acid (BF3-OEt2) at 80°C, allowed for the exclusive formation of the anti diastereoisomer with excellent... 

Fananas-Mastral M, Perez M, Bos PH, Rudolph A, Harutyimyan SR, Feringa BL (2012) Enantioselective synthesis of tertiary and quaternary stereogenic centers copper/ phosphoramidite-catalyzed allylic alkylation with organolithiiun reagents. Angew Chem Int... 

Bertozzi F, Pineschi M, Macchia F, Arnold LA, Minnaard AJ, Ftainga BL (2002) Copper phosphoramidite catalyzed enantioselective ling-opening of oxabicyclic alkenes remarkable reversal of stereocontrol. Org Lett 4 2703-2705... 

Scheme 2 Copper-phosphoramidite-catalysed ECA to P-substituted cyclohexenones by Alexakis [35]...

Scheme 5 Copper-phosphoramidite-catalysed EC A to p-aryl cyclohexenones by Alexakis [38]...

Scheme 7 Copper-phosphoramidite-catalysed ECA to oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylates by AlexaMs [39]...

Scheme 11 Copper-phosphoramidite-catalysed ECA of alkenyl aliuninium reagents (prepared via zirconium-catalysed hydroalumination) to p-substituted cyclohexenones by Woodward [45]...

The synthetic utility of copper-phosphoramidite-catalysed conjugate additions as a means for generating quaternary stereocentres using organoaluminium reagents has been demonstrated with the synthesis of several key intermediates in natural product syntheses, as represented in Scheme 12 [36, 46]. 

Scheme 61 Copper-phosphoramidite-catalysed ECA of organozinc reagents to Meldrum s acids dtaivatives by Fillirai [93-96]...

Minnaard, Feringa, et al. described asymmetric additions to in situ formed Ai-formyl imines 66, the resulting amines 65 being easily deprotected under mild conditions (Scheme 12b) [107]. This is the copper/phosphoramidite-catalyzed... 

Chiral alcohol (15,2/ )-52 (90-94% ee) was obtained as a major product by the chiral copper phosphoramidite-cata-lyzed alkylative ring opening of oxabenzonorbornadiene with diethylzinc. The esterification of alcohol (lS,2/ )-52 with (-)-CSDP acid yielded ester (15, 2/ )-(—)-53, which was recrystallized giving single crystals suitable for X-ray crystallography. The AC of (—)-53 was unambiguously determined based on the known AC of the CSDP acid moiety. 

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