Asymmetric Michael Reaction of Aldehydes and Dicyanoalkenes Catalyzed by Diphenylprolinol Silyl Ether

Abstract

Asymmetric Michael reactions of aldehydes and dicyanoalkenes catalyzed by diphenylprolinol silyl ether give the corresponding Michael adducts in good yields with excellent enantioselectivities. The diastereoselectivity is dependent on the bulkiness of the Michael donor. The Michael adducts can be easily transformed into useful chiral compounds such as lactones, esters, and monocyanated derivatives.

Asymmetric Michael Reaction of Aldehydes and α‐Cyano α,β‐Unsaturated Esters Catalyzed by Diphenylprolinol Silyl Ether; a Facile Asymmetric Route to 3,4,5‐Trisubstituted Piperidines

“…The relative and absolute configurations of the nitrile 7 aa are known in the literature. [10] Thus, by comparing the optical data from our experimental result with the reported values, we were able to unambiguously establish the absolute configuration of the obtained Michael adduct. Solvent screening suggests that acetonitrile provides an appropriate medium for this reaction as it comparatively afforded the products with higher selectivities in spite of the moderate yield (entries 1-3).…”

“…[1] In this regard, organocatalytic asymmetric protocols have also emerged as a promising synthetic tool especially in the stereoselective design of chiral organic frameworks. [2][3][4] A prominent example is the extensive use of diphenylprolinol silyl ether 1, [5] which was independently developed by our group [6] and Jørgensen's group, [7] as a highly efficient organocatalyst for the asymmetric Michael reactions of nucleophilic aldehydes and electrophilic acceptors such as nitroalkenes, [6] vinyl sulfones, [8] βsubstituted α-nitroacrylates, [9] and dicyanoalkenes [10] (Scheme 1a). The catalytic process emanates from the initial condensation of an aldehyde with the organocatalyst 1, to generate a chiral enamine intermediate that stereoselectively adds to an olefinic electrophile, thereby furnishing the corresponding Michael adduct with high levels of enantio-and diastereo-control.…”

“…Previous reports of conjugate additions mediated by organocatalyst 1 have shown that the introduction of additives such as water or acids resulted in the enhancement of the yield and/or selectivity of the reaction. [6,9,10,15] Hence, we further investigated the reaction in the presence of p-nitrophenol, 2,4,6trichlorophenol, chloroacetic acid, and water (entries 4-7).…”

“…This pattern of substituent size-dependent diastereoselectivities was also disclosed in our previous report on the organocatalytic asymmetric Michael reaction of aldehydes and dicyano alkenes, and it was attributed to the relative orientation of both the Michael acceptor and the generated enamine in the transition state of the catalytic cycle. [10] Considering the functional endowment of the obtained Michael adducts 4, we embarked on a further transformation of the Michael adducts into trisubstituted piperidines 5 via a consecutive sequence of nitrile reduction and intramolecular reductive amination [16,17] [(Eq. (1-2)].…”