A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products

Citation
Rm. Borzilleri et al., A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products, J AM CHEM S, 122(37), 2000, pp. 8890-8897
Citations number
77
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis",Chemistry
Journal title
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
ISSN journal
0002-7863 → ACNP
Volume
122
Issue
37
Year of publication
2000
Pages
8890 - 8897
Database
ISI
SICI code
0002-7863(20000920)122:37<8890:ANAOAP>2.0.ZU;2-S
Abstract
Several lactam analogues of the epothilones were prepared using a concise s emisynthetic approach starting with the unprotected natural products. Highl ighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyz ed azidation reaction of a macrocyclic lactone. Subsequent reduction and ma crolactamization of the resulting azide acid intermediates provided the des ired macrolactams in satisfactory overall yields. The entire three-step seq uence was streamlined into a "one-pot" process for the epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An init ial total synthesis route to prepare the lactam analogue of epothilone C wa s completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.