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

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.