Amino Acid-Mediated Enantioselective Synthesis of a Bicyclic Ketocarbaldehyde: Theoretical and Experimental Insights into a Key Intermediate for Some Polycyclic Diterpene Synthesis

Abstract

A study on the amino acid-mediated intramolecular cyclization of diketoaldehyde 2 to form bicyclic ketocarbaldehyde 1, a potentially useful intermediate in the synthesis of some polycyclic diterpenes, is hereafter presented. This cyclization exhibits a peculiar enantio-selectivity if compared to similar intramolecular cyclizations due to its product being the (S)-enantiomer when using d-amino acids. Our findings reveal that the transformation proceeds through two irreversible steps: the cyclization and the subsequent dehydration process. The reaction enantiomeric excess (e.e.) was optimized by systematically varying the amino acids, solvents, and acids used. Aldol intermediates were successfully isolated. The structure of the most abundant one was confirmed by X-ray analysis, which supported the proposed reaction mechanism. NMR and MS were employed to monitor in real-time the formation and the evolution of these intermediates. This approach allowed us to detect the key species that contribute to the enantioselectivity and yield of the final product. Additionally, the transition state energies associated with the formation of the eight possible aldol intermediates were examined through computational studies, further elucidating the mechanistic pathway of this enantioselective cyclization.