Enantioselective Copper(I)-Phosphoramidite Catalyzed Addition of Alkylzirconium Species to Acyclic Enones

Abstract

Catalytic asymmetric conjugate addition reactions of alkylzirconium species to acyclic enones are reported. The alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The reaction proceeds under mild and convenient conditions. A variety of functionalized nucleophiles can be used, and the method tolerates some variation in enone scope. The method uses a new chiral nonracemic phosphoramidite ligand in a complex with copper triflate.

Acyclic quaternary centers from asymmetric conjugate addition of alkylzirconium reagents to linear trisubstituted enones

“…17 Reaction using ligand A gave 3a with 46% yield, 45% ee using conditions optimized for cyclic quaternary centres, and we obtained 70% yield, 77% ee using conditions developed for acyclic tertiary centres (Table 1, entries 1 and 2). Using ligand D in the addition to 2a gave 80% yield and 84% ee (entry 3).…”

“…However, we were able to develop a method to construct acyclic tertiary centres with up to 91% ee. 17 …”

Recent Developments and Synthetic Applications of Nucleophilic Zirconocene Complexes from Schwartz's Reagent

“…Due to s ‐ cis/s ‐ trans conformational interconversion in acyclic α,β‐unsaturated enones, the enantioselectivity in ACAs related to these compounds is more challenging than in cyclic compounds. Thus, in order to access the desired enantioenriched ketone, the catalytic system must be able to differentiate the conformers or to produce the same enantiomer considering both isomers …”

“…The scope concerning various enones was also evaluated, allowing the use of different alkyl and aryl‐substituted enones, and the desired products attained in good to high yields (59–94 %) and with low to excellent enantiomeric excess (33–91 % ee ). Unfortunately, although the use of β‐substituted enones bearing ramified chains or aryl groups were tolerated, a decrease in the enantiomeric excess was observed …”

Catalytic Enantioselective Addition of Organozirconium Reagents to Aldehydes

“…Organozirconium reagents [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ] are relatively inert toward carbonyl compounds [ 49 ], but the use of catalysts or a stoichiometric mediator [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] enables the nucleophilic attack and subsequent carbon-carbon bond formation. Thus, in the presence of Ag(I), ZnBr 2 , or Me 2 Zn, organozirconium reagents can readily be added to aldehydes [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ], ketones [ 69 , 70 ], and also enones [ 71 , 72 , 73 , 74 ], epoxides [ 75 ], and isocyanates [ 76 ], although enantioselective protocols have been rare so far [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ,…”