Spirolactam ruthenium complexes

Cyclohexadienyl ruthenium(II) complexes containing an azaspirocyclic ring system have been prepared from (η6-N-benzyl acetoacetamide)CpRu(II) precursors via sequential intramolecular nucleophilic addition and enolate trapping. The structural backbone of these spirocyclic ligands resembles that found in the spirostaphylotrichin and triticone families of naturally occurring fungal metabolites. Therefore, this spirocyclization protocol may be useful in the rational design of unnatural analogues possessing therapeutic value.; The spirocyclization reaction has been found to be applicable to N-benzyl acetoacetamide ligands possessing substituents that are strongly activating (methoxy) to mildly deactivating (chloro), in isolated yields ranging from 33% to 86%. Successful spirocyclization has also been accomplished with N-benzyl acetoacetamide ligands possessing an alkyl substituent at the benzylic carbon and with a more readily removable N-protecting group. However, arene ruthenium complexes prepared from ligands with a longer nucleophile-bearing side chain failed to undergo spirocyclization. Instead, these phenethyl acetoacetamide complexes participated in an intramolecular nucleophilic aromatic substitution (S_NAr) reaction yielding a benzazepine ring system. These results strongly suggest that the regioselectivity of aromatic addition in these reactions is not governed by remote electronic effects, but is a consequence of conformational restraints unique to the benzyl acetoacetamide side chain linking the nucleophilic center to the coordinated arene.; Two approaches to successfully remove the spirocyclic ligand from the metal center have been discovered leading to a host of metal-free spirocyclic and structurally-rearranged tetrahydroisoquinoline derivatives. The first approach is a Lewis acid mediated demetalation reaction that has intriguing properties, with BF₃ being the Lewis acid of choice. Although the reaction has limited scope (working best with the 4-methoxy substituted spirocyclic complex), the conditions of the reaction can be manipulated to deliver either a spirodien-4-one, spiromonoen-4-one, and/or a spiromonoepoxide product in good yield.; The second approach is oxidative demetalation and has been found to have a much broader scope, working best with methoxy- or chloro-substituted spirocyclic complexes. Although many oxidants can effect demetalation, the best results were achieved with CuCl₂. Exposure of methoxy- or chloro-substituted complexes to 2 equivalents of CuCl₂ yielded metal-free azaspirocylic compounds or isoquinoline derivatives (via rearrangement) in yields ranging from 22% to 99%. The type and position of substituents on the cyclohexadienyl ring system seem to dictate whether a structural rearrangement occurs concomitant with the loss of the metal center. For example, meta-methoxy groups and chloro substituents favor structural rearrangement, affording tetrahydroisoquinoline products. Methoxy groups in the ortho- or para-positions lead to spirodienone products, while complexes with both meta- and ortho- or para-methoxy groups provide a mixture of spirocyclic and rearranged products.; Subsequent manipulation of the demetalated products was met with limited success. Attempts at [2+4] cycloaddition using the fully-conjugated or cross-conjugated spirodienone metal-free products as either the diene or dienophile were unsuccessful. However, conjugate addition was successful with the cross-conjugated spirodien-4-one product. Epoxidation using alkaline H₂O₂ was also successful for both the spirodien-2-one and spirodien-4-one products, yielding a bis-epoxide in the latter case. (Abstract shortened by UMI.)...