Regioselectivity and nucleophilic control in the cyclopropane ring opening of duocarmycin SA derivatives under neutral and acid conditions: a quantum mechanical study in the gas phase and in solution.
We present a quantum mechanical investigation of the nucleophilic addition to the cyclopropane ring of a representative member of antitumor antibiotics related to CC-1065. We have analyzed, in particular, the regioselectivity of the reaction and its tuning by the nature of the etheroatom (O or N) in the nucleophile under both neutral and acidic conditions. Our results are in agreement with the experimental trends and suggest that, contrary to methanol, N-bases can be effective also under neutral conditions, irrespective of the additional steric constraints experienced in the biologically active substrate (DNA). The reliability of the computational protocol, rooted in the density functional theory coupled to a refined continuum solvent model, allows us to put forward reliable structure/reactivity relationships and to interpret the results in terms of reactivity indexes (hardness, electrophilic character).
Cimino
Paola
P
Dipartimento di Chimica, Università Federico II, Complesso Universitario Monte S.Angelo, via Cintia, I-80126 Napoli, Italy.
Gomez-Paloma
Luigi
L
Barone
Vincenzo
V
D003521:Cyclopropanes / Q000737:chemistry*; D000080890:Duocarmycins; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
D003521:Cyclopropanes; D000080890:Duocarmycins; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; C066098:duocarmycin SA