RESUMEN
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).
Asunto(s)
Antineoplásicos/síntesis química , Azepinas/síntesis química , Animales , Antihelmínticos/síntesis química , Antineoplásicos/farmacología , Azepinas/farmacología , Catecoles/química , División Celular/efectos de los fármacos , Endotelio Vascular/citología , Humanos , Concentración 50 Inhibidora , Poríferos/química , Estereoisomerismo , Células Tumorales Cultivadas , Venas UmbilicalesRESUMEN
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.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Piranos/síntesis química , Compuestos de Espiro/síntesis química , Antibióticos Antineoplásicos/farmacología , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Piranos/farmacología , Compuestos de Espiro/farmacología , EstereoisomerismoRESUMEN
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).