Study On The Intramolecular Desymmetrization Of The Meso α,α’-Diazido Alcohols With Aryldiazoacetates

Highly functionalized glycerol, a,a’-diamino alcohols, and their derivatives, are very important building blocks and conventional subunits of natural products, lead compounds and drugs in the pharmaceutical research. For examples, the a,a’-diamino alcohol is used as the HIV-1 protease inhibitor, and the streptomycin is applied clinically for treatment of tuberculosis. Both these important compounds contain the C3-fragments with continuous stereocenters. And the C3-fragments contain two different functional groups (amino group, hydroxyl group,) at each of the three carbons. Following our group’s research on the intramolecular interception of alkyl azides with diazo(aryl) acetates, herein we described the asymmetric intramolecular desymmetrization of meso α,α’-diazido alcohols with aryldiazoacetates for assembly of chiral C3-fragments with three continuous stereocenters by one step conversion.In the first part, a brief review on the asymmetric desymmetrization reactions has been addressed. The desymmetrization reactions cover several different organic transformations, and the background and status have been reviewed.In the second part, modification of the sustituents of the bisoxazoline ligand provided several Cu-complexes catalyst. Catalytic asymmetric intramolecular desymmetrization of the meso a,a’-diazido alcohols with aryldiazoacetates in the presence of the modified catalyst delivered cyclic a-imino-esters with three continuous stereocenters. The yield was up to 99% and the enantiomeric excess was up to 97%. A broad range of substrates was investigated under the optimal reaction conditions. The research on the electron effect of the aromatic ring revealed that both the substrates with electron withdrawing or donating groups could afforded the desired imino ester with satisfactory yield and enantioselectivity. Moreover, good yield and enantioselectivity could be observed with the substrates substituted with the alkyl groups or locked as the cyclopentane ring. Further, the asymmetric chiral pocket induction model of the Cu-complexes, first proposed for the N-H insertion reaction by Zhou and co-workers, was used to illustrate the stereocontrol of the desymmetrization process. The observed enantioselectivity could be clarified by the chiral pocket. Further, the impact of relative configuration of the hydroxyl group with the two azido groups was investigated by two substrates, which were produced by Mitsunobu inversions of the hydroxyl group. The cyclic a-imino-esters with three continuous stereocenters could be produced under the optimal reaction conditions. The comparability study revealed that these two substrates were not suitable for the asymmetric desymmetrization process. The experimental result also well supported the proposed chiral pocket induction model.