MACROCYCLE FORMATION BY CATALYTIC INTRAMOLECULAR CYCLOPROPANATION - ANEW GENERAL METHODOLOGY FOR THE SYNTHESIS OF MACROLIDES

Catalytic intramolecular cyclopropanation by diazoacetates onto a remo te carbon-carbon double bond resulting in the formation of 9- to 20-me mbered ring lactones is reported, When competition exists between prox imal allylic and remote olefinic cyclopropanation, macrocyclization is favored by catalysts of increasing electrophilicity: Rh-2(pfb)(4) > R h-2(OAc)4, Cu(MeCN)(4)PF6 > Rh(cap)(4), and Cu(acac)(2). Terpene syste ms, cis-nerolidyl diazoacetate and related structures, malonic ester d erivatives, and those with 1,2-benzenedimethanol, pentaerythritol, and cis-2-buten-1,4-diol linkers all undergo cyclopropanation onto the mo st remote carbon-carbon double bond in good yield. Generally, only one cyclopropane diastereoisomer is observed, but increasing ring size al lows stereochemistries in macrocyclization reactions that resemble tho se of their intermolecular cyclopropanation counterparts. In one syste m (25) macrocyclic addition is accompanied by ylide formation/[2,3]-si gmatropic rearrangement resulting in the formation of a 10-membered ri ng lactone. Overall, few limits to macrocycle formation are evident, a nd the methodology appears to have general applicability.