Triquinane scaffolds: Shape and geometry as a function of saturation and bridgehead groups

• Synthesis of triquinane and triquinylamine derivatives.
• Characterization of compounds by means of single crystal X-ray analysis.
• Geometry as a function of saturation and bridgehead groups are discussed.
• Photocyclization and cycloreversion reaction mechanisms are explored.

Polycyclic hydrocarbon compounds, also known as “cage compounds”, are of interest in drug discovery due to their versatility as scaffolds. Derivatives of both pentacycloundecane-dione and triquinane-dione have been the focus of numerous investigations as multifunctional neuroprotective drugs where these compounds were used as novel drug scaffolds with the ability to cross the blood brain barrier. Here we present the synthesis, characterization and single crystal X-ray analysis for two triquinane synthons; tricyclo[6.3.0.02,6]undecane-4,9-diene-3,11-dione (compound 5 crystallizes in the monoclinic system, unit cell parameters are: a = 6.5876 (12) Å, b = 10.4204 (19) Å, c = 12.074 (2) Å; V = 825.4 (3) Å3 and Z = 4) and tricyclo[6.3.0.02,6]undecane-3,11-dione (compound 6 crystallizes in monoclinic system, unit cell parameters are: a = 7.5992 (7) Å, b = 10.7294 (10) Å, c = 10.8664 (10) Å; V = 884.04 (14) Å3 and Z = 4); as well as a triquinane derivative, N-(3-methoxybenzyl)-3,11-azatricyclo[6.3.0.02,6]undecane (compound 11 crystallizes in triclinic system, unit cell parameters are: a = 7.6714 (7) Å, b = 9.0100 (9) Å, c = 11.2539 (11) Å; V = 745.78 (12) Å3 and Z = 2). The size and geometrical conformation of the triquinane scaffolds were compared to tetra and pentacycloundecanes, revealing that tricyclo[6.3.0.02,6]undecane-3,11-dione experiences strain relief resulting in greater flexibility, a more asymmetric molecular shape and larger surface area. However, with the introduction of the aza-bridge in N-(3-methoxybenzyl)-3,11-azatricyclo[6.3.0.02,6]undecane, much of the flexibility and asymmetry is lost again. We also discuss the rearrangement mechanism for the observed retro cycloaddition and reversion, and utilized density functional theory calculations to discuss the photocyclization mechanism of this unique [2 + 2] Diels–Alder system.

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