Macrocycle Formation by Catalytic Intramolecular Cyclopropanation. A New General Methodology for the Synthesis of Macrolides

• Published in: Journal of the American Chemical Society 1997-09, Vol.119 (38), p.8826-8837
• Main Authors: Doyle, Michael P, Peterson, Chad S, Protopopova, Marina N, Marnett, Alan B, Parker, Dann L, Ene, Doina G, Lynch, Vincent
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja971687z

Catalytic intramolecular cyclopropanation by diazoacetates onto a remote carbon−carbon double bond resulting in the formation of 9- to 20-membered ring lactones is reported. When competition exists between proximal allylic and remote olefinic cyclopropanation, macrocyclization is favored by catalysts of increasing electrophilicity:  Rh2(pfb)4 > Rh2(OAc)4, Cu(MeCN)4PF6 > Rh(cap)4, and Cu(acac)2. Terpene systems, cis-nerolidyl diazoacetate and related structures, malonic ester derivatives, and those with 1,2-benzenedimethanol, pentaerythritol, and cis-2-buten-1,4-diol linkers all undergo cyclopropanation onto the most remote carbon−carbon double bond in good yield. Generally, only one cyclopropane diastereoisomer is observed, but increasing ring size allows stereochemistries in macrocyclization reactions that resemble those of their intermolecular cyclopropanation counterparts. In one system (25) macrocyclic addition is accompanied by ylide formation/[2,3]-sigmatropic rearrangement resulting in the formation of a 10-membered ring lactone. Overall, few limits to macrocycle formation are evident, and the methodology appears to have general applicability.