title: Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis.
abstract: Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.
authors: Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.
authors: Miao
authors: M
authors: Yu
authors: Chenbo
authors: C
authors: Wang
authors: Andrew F
authors: AF
authors: Kyle
authors: Pavol
authors: P
authors: Jakubec
authors: Darren J
authors: DJ
authors: Dixon
authors: Richard R
authors: RR
authors: Schrock
authors: Amir H
authors: AH
authors: Hoveyda
mesh_terms: D000473:Alkanes / Q000737:chemistry; D000475:Alkenes / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D003500:Cyclization; D034261:Epothilones / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000473:Alkanes; D000475:Alkenes; D001688:Biological Products; D002243:Carbolines; D034261:Epothilones; C476640:nakadomarin A; C426624:epothilone C