A novel approach to the synthesis of cytotoxic C2-C3 unsaturated pyrrolo[2,1-c]benzodiazepines (PBDs) with conjugated acrylyl C2-substituents.
A concise synthesis of three novel C2-C3 unsaturated pyrrolo[2,1-c][1,4]benzodiazepine analogues (18-20) containing conjugated acrylyl C2-substituents is reported that utilises Heck coupling to install the C2-acrylyl side chains. These analogues possess significant cytotoxicity according to the NCI 60-cell line screen with 18 surpassing anthramycin (1) in potency.
Application of the Stille coupling reaction to the synthesis of C2-substituted endo-exo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs).
The Stille coupling reaction has been used to introduce novel vinyl, alkynyl and heterocyclic substituents to the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine dilactams. Sodium borohydride reduction followed by N10-SEM deprotection has provided five analogues (6b, 8a-d) that contain C2-endo/exo-unsaturation and novel C2-substituents. These analogues have significant multilog cytotoxicity profiles in the NCI 60-Cell Line screen, and provide new SAR data for the PBD family.
Highly enantio- and diastereoselective synthesis of β-methyl-γ-monofluoromethyl-substituted alcohols.
Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.