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

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.