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

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• 作者：Sarah E. Lindahl ; Hyunsoo Park ; Maren Pink ; Jeffrey M. Zaleski
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：March 13, 2013
• 年：2013
• 卷：135
• 期：10
• 页码：3826-3833
• 全文大小：378K
• 年卷期：v.135,no.10(March 13, 2013)
• ISSN：1520-5126

文摘

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: 未 = 41 ppm, J_Pt鈥揚 = 3346 Hz) with concomitant loss of 1 equiv of uncyclized phosphine chelate (³¹P: 未 = 鈭?3 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 未 = 51 ppm in the ³¹P NMR (J_Pt鈥揚 = 3171 Hz) and 谓_C鈮 = 2169 cm^鈥? 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掳 dihedral angle) via a restricted alkyne-terminal starting point. While the energies are disparate, the common theme in both structures is the elongated Pt鈥揚 bond lengths (>2.4 脜), indicating that nucleophilic ligand substitution by I^{鈥?/sup> 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.}