Chiral CO2-synthons via catalytic asymmetric hetero-Diels-Alder reactions of ketomalonate and dienes

A catalytic enantioselective approach for the formation of chiral CO2-synthons is presented. The described methodology is based on the reaction of dienes with diethyl ketomalonate using C-2-symmetric bisoxazolines as the chiral ligands and copper(II) and zinc(II) as the Lewis acids. For cyclic dienes the reaction proceeds in good yield and with up to 93% ee for 1,3-cyclohexadiene, while for cyclopentadiene the reaction also proceeds well at low temperature, but increasing the temperature leads to a retro-Diels-Alder reaction. The reaction has been studied under different conditions and for various dienes, and it has been found that for activated dienes both the hetero-Diels-Alder and Mukaiyama aldol products are isolated. The compound formed by the enantioselective hetero-Diels-Alder reaction of 1,3-cyclohexadiene with ketomalonate has been converted to both the CO2-synthon formed in principle from the [2+4] cycloaddition reaction of CO2 and 1,3-cyclohexadiene, and attractive optically active 1,4-disubstituted cyclohexene diols. The absolute configuration of the hetero-Diels-Alder adduct has been assigned on the basis of the structure of (1S)-camphanic ester of a 1,4-disubstituted cyclohexene diol which gave suitable crystals for X-ray analysis. The reactions have also been analyzed from a theoretical point of view. First, the [2+4] cycloaddition reaction of CO2 with 1,3-cyclohexadiene has been investigated, and then the relative stability of the two major isomers of bidentate ketomalonate coordinated to a copper(II) or zinc(II) Lewis acid dication was investigated applying density functional theory calculations. Finally, the energetics of the [2+4] hetero-Diels-Alder addition mechanisms typical of the reaction with normal dienes catalyzed by C-2-symmetric bisoxazoline-zinc(II) complexes using semiempirical calculations are presented.