ABSTRACT
The ring-opening addition of methyl 2,3-dimethoxy-6-iodobenzoate to oxabenzonorbornadienes followed by cyclization in the presence of NiBr2(dppe) and Zn metal powder in acetonitrile at 80 degrees C to give the corresponding benzocoumarin derivatives is described. This methodology was then applied to the synthesis of natural product arnottin I, first isolated from Xanthoxylum arnottianum Maxim, using protecting group chemistry. After deprotection and subsequent ring closure, arnottin I was obtained in 21% overall yield after six steps starting from catechol.
Subject(s)
Coumarins/chemical synthesis , Nickel/chemistry , Catalysis , Cyclization , Iodobenzoates/chemistry , Norbornanes/chemistryABSTRACT
An efficient method for the synthesis of 2-alkyl- and 2-aryl pyrrolidines, piperidines, and azepanes from lactams, in either racemic or enantiopure form, is presented. The lactam nitrogens are acylated with either Boc anhydride or trans-cumylcyclohexyl (TCC) chloroformate. Selective reduction of the lactam carbonyl to the carbinolamide is followed by treatment with benzotriazole. Substitution of the benzotriazole is accomplished by treatment with organometallics, yielding the 2-substituted heterocycles. With TCC, up to 90% diastereoselectivity is achieved. After diastereomer purification, reductive removal of the auxiliary affords enantiopure 2-substituted heterocycles. A mechanistic hypothesis is presented that details the conformational equilibria of the key step.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Lactams/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
A new series of [4-(2-phenylethenesulfonylmethyl)phenyl]quinazolin-4-yl-amines was prepared and tested for its in vitro cytotoxic activity against a panel of 12 human cancer cell lines. Compounds 9, 15, 24 and 31 showed good in vitro activity and were further tested for their in vivo efficacy in the HT-29 human colon adeno carcinoma xenograft model. Compound 9 exhibited promising activity in this model. Dose-response studies for this compound against HT-29 human colon adeno carcinoma xenografts at 100, 200 and 400mg/kg doses were performed.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Quinazolines/administration & dosage , Quinazolines/chemical synthesis , Administration, Oral , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , HT29 Cells , Humans , Mice , Mice, Nude , Xenograft Model Antitumor Assays/methods , Xenograft Model Antitumor Assays/statistics & numerical dataABSTRACT
Alkylation of O-silylated N-alkylmalonylhydroxamic acids provides a method for the synthesis of 2-substituted N-alkylmalonyl hydroxamic acids. The substituent at C-2 does not materially change the chemistry of the alpha-lactam intermediates produced from them. They can be converted to unsymmetric ureas and hydantoins in high yields. The addition of unsaturated substituents at C-2 is used to produce cyclic ureas containing medium rings via RCM reactions.
