Thermodynamics and isomerism of products and intermediates of a one-pot superbase-promoted assembly of tetracyclic frontalin derivatives: A quantum chemical study

Tetracyclic frontalin derivatives are used as precursors of drugs for the therapy and prevention of HIV infections and cancer, as well as antibiotics with a wide spectrum of antibacterial action. A recently proposed method of the preparation of tetracyclic frontalin derivatives from two cycloaliphatic ketone molecules and two acetylene molecules in a superbasic catalytic system KOH/DMSO has opened up an elegant and direct approach to the design of these classes of biologically active compounds. In this work, we carried out a quantum-chemical study of isomerism and thermodynamic stability of intermediates and product of the reaction underlying the aforementioned approach. Particular attention was paid to the issues of diastereomerism and violation of diastereoselectivity of the reaction when replacing alkylaromatic or dialkyl ketones by cycloaliphatic ketones in the reactions with acetylene. Based on the results we propose a possible reason for the experimentally observed formation of a mixture of diastereomers of 14,16-dioxatetracyclohexadecane in the cascade assembly of two cyclohexanone molecules and two acetylene molecules. It is shown that the observed ratio of the 14,16-dioxatetracyclohexadecane diastereomers correlates with the equilibrium ratio of cascade assembly intermediates, the semiketal anion diastereomers. (C) 2020 Elsevier B.V. All rights reserved.