Syntheses of Polycyclic Natural Products Employing the Intramolecular Double Michael Reaction

The one-pot intramolecular double Michael reaction of compounds having two different α, β-unsaturated carbonyl groups to form polycyclic compounds can be carried out by three different methods: in the first the substrate is treated with lithium hexamethyldisilazide, in the second with chlorotrimethylsilane, triethylamine, and zinc chloride at an elevated temperature, and in the third with tert-butyldimethylsilyl trifluoromethanesulfonate and triethylamine. The reaction proceeds with complete regioselectivity and high stereoselectivity following a stepwise mechanism. Spiro-fused bicyclo[2.2.2]octane derivatives can be constructed with high stereoselectivity by the intromolecular double Michael reaction by using the first method. Enantiomerically pure atisine and the enantiomer of atisirene were synthesized stereoselectively by application of this methodology. The syntheses of steroids and angular triquinane-type sesquiterpenoids were possible with the second method. Heterocyclic compounds with a bridgehead nitrogen atom were obtained by the reaction of α, β-unsaturated amides following the second and third methods. The asymmetric synthesis of tylophorine with diastereofacial control was achieved by the intramolecular reaction according to the third method. The sulfur-mediated intramolecular double Michael reaction utilizing the third method produced trans-hydroindane derivatives. Furthermore, the intramolecular Michael-aldol reaction can be employed in synthesizing polycyclic systems with cyclobutane units by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine. The intermolecular double Michael reaction and related reactions will also be described.