This Account describes our recent studies on the chemical synthesis of cyclic, densely substituted molecules by means of a hybrid approach consisting of the synergistic interaction between computational and experimental chemistry. In addition, two related total syntheses of complex molecules (±)-Scopadulin and (-)-Exiguolide are presented as case studies in which computational chemistry can be used to detect and, eventually, avoid potential failures involving key transformations of advanced intermediates. 1 Introduction 2 Computational Treatment of Molecules 3 Computational Characterization of Reactants, Reaction Intermediates, Products and Transition Structures 4 Computational-Experimental Analysis of the Stereocontrol in Thermal Pericyclic Reactions 4.1 Concerted and Stepwise [3+2] Cycloadditions 4.2 Concerted and Stepwise [8+2] Cycloadditions 5 Total Synthesis of Complex Molecules; Two Case Studies 5.1 Total Synthesis of (±)-Scopadulin 5.2 Total Synthesis of (-)-Exiguolide 6 Conclusions and Outlook. © Georg Thieme Verlag KG Stuttgart · New York.

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