title: Design and stereoselective preparation of a new class of chiral olefin metathesis catalysts and application to enantioselective synthesis of quebrachamine: catalyst development inspired by natural product synthesis.
abstract: A total synthesis of the Aspidosperma alkaloid quebrachamine in racemic form is first described. A key catalytic ring-closing metathesis of an achiral triene is used to establish the all-carbon quaternary stereogenic center and the tetracyclic structure of the natural product; the catalytic transformation proceeds with reasonable efficiency through the use of existing achiral Ru or Mo catalysts. Ru- or Mo-based chiral olefin metathesis catalysts have proven to be inefficient and entirely nonselective in cases where the desired product is observed. In the present study, the synthesis route thus serves as a platform for the discovery of new olefin metathesis catalysts that allow for efficient completion of an enantioselective synthesis of quebrachamine. Accordingly, on the basis of mechanistic principles, stereogenic-at-Mo complexes bearing only monodentate ligands have been designed. The new catalysts provide significantly higher levels of activity than observed with the previously reported Ru- or Mo-based complexes. Enantiomerically enriched chiral alkylidenes are generated through diastereoselective reactions involving achiral Mo-based bispyrrolides and enantiomerically pure silyl-protected binaphthols. Such chiral catalysts initiate the key enantioselective ring-closing metathesis step in the total synthesis of quebrachamine efficiently (1 mol % loading, 22 degrees C, 1 h, >98% conversion, 84% yield) and with high selectivity (98:2 er, 96% ee).
authors.affiliation: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Sattely
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Meek
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Malcolmson
authors.forename: Richard R
authors.initials: RR
authors.lastname: Schrock
authors.forename: Amir H
authors.initials: AH
authors.lastname: Hoveyda
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000475:Alkenes / Q000737:chemistry* / Q000145:classification; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D003503:Cyclobutanes / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D007854:Lead / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D013237:Stereoisomerism
chemical_list: D000438:Alcohols; D000475:Alkenes; D001688:Biological Products; D003503:Cyclobutanes; D006575:Heterocyclic Compounds, 3-Ring; D026121:Indole Alkaloids; D008024:Ligands; D007854:Lead; D002244:Carbon; C091897:quebrachamine; D009584:Nitrogen