ja308190q_si_003.pdf (277.29 kB)
Download file

Utilizing Redox-Mediated Bergman Cyclization toward the Development of Dual-Action Metalloenediyne Therapeutics

Download (277.29 kB)
journal contribution
posted on 13.03.2013, 00:00 authored by Sarah E. Lindahl, Hyunsoo Park, Maren Pink, Jeffrey M. Zaleski
Reaction of 2 equiv of 1,2-bis­((diphenyl­phosphino)­ethynyl)­benzene (dppeb, 1) with Pt­(cod)­Cl2 followed by treatment with N2H4 yields the reduced Pt(0) metalloenediyne, Pt­(dppeb)2, 2. This complex is stable to both air oxidation and metal-mediated Bergman cyclization under ambient conditions due to the nearly idealized tetrahedral geometry. Reaction of 2 with 1 equiv of I2 in the presence of excess 1,4-cyclohexadiene (1,4-CHD) radical trap rapidly and near-quantitatively generates the cis-Bergman-cyclized, diiodo product 3 (31P: δ = 41 ppm, JPt–P = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (31P: δ = −33 ppm). In contrast, addition of 2 equiv of I2 in the absence of additional radical trap instantaneously forms a metastable Pt­(dppeb)22+ intermediate species, 4, that is characterized by δ = 51 ppm in the 31P NMR (JPt–P = 3171 Hz) and νCC = 2169 cm–1 in the Raman profile, indicating that it is an uncyclized, bis-ligated complex. Over 24 h, 4 undergoes ligand exchange to form a neutral, square planar complex that spontaneously Bergman cyclizes at ambient temperature to give the crystalline product Pt­(dppnap-I2)­I2 (dppnap-I2 = (1,4-diiodonaphthalene-2,3-diyl)­bis­(diphenylphosphine)), 5, in 52% isolated yield. Computational analysis of the oxidation reaction proposes two plausible flattened tetrahedral structures for intermediate 4: one where the phosphine core has migrated to a trans-spanning chelate geometry, and a second, higher energy structure (3.3 kcal/mol) with two cis-chelating phosphine ligands (41° dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt–P bond lengths (>2.4 Å), indicating that nucleophilic ligand substitution by I is on the reaction trajectory to the cyclized product 5. The efficiency of the redox-mediated Bergman cyclization reaction of this stable Pt(0) metalloenediyne prodrug and resulting cisplatin-like byproduct represents an intriguing new strategy for potential dual-threat metalloenediyne therapeutics.