ABSTRACT
The cis-1,2-dihydrocatechol 3, which can be obtained in enantiomerically pure form by microbial dihydroxylation of bromobenzene, has been converted into the enantiomer, ent-1, of the cyclolysine-based marine natural product bengamide E (1).
Subject(s)
Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Animals , Anthelmintics/chemical synthesis , Antineoplastic Agents/pharmacology , Azepines/pharmacology , Catechols/chemistry , Cell Division/drug effects , Endothelium, Vascular/cytology , Humans , Inhibitory Concentration 50 , Porifera/chemistry , Stereoisomerism , Tumor Cells, Cultured , Umbilical VeinsABSTRACT
The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Epidermal Growth Factor/antagonists & inhibitors , Pyrans/pharmacology , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
The enantiomerically pure cis-1,2-dihydrocatechol 2, which is obtained by microbial oxidation of chlorobenzene, has been converted, via intermediate 3, into the natural product (+)-aspicilin (1).