Formation of Macrocyclic Ethers by Free Radical Cyclization:  Effects of Chain Length, Substituents, and Solvents

Abstract

Free radical reduction by tributylstannane of omega-iodopolyoxaalkyl acrylates derived from tri-, tetra-, penta-, hexa-, and heptaethylene glycols gives mixtures of uncyclized reduction products and macrocyclic ethers formed by endo cyclization. The rate constants for cyclization of the intermediate radicals at 80 degrees C in benzene were determined under carefully defined conditions to be 15 x 10(4), 13 x 10(4), 5.1 x 10(4), 10 x 10(4) and 3.6 x 10(4) s(-) (1), for formation of the 12-, 15-, 18-, 21- and 24-membered rings, respectively. These values indicate that the presence of oxygen atoms in the chains increases the rate by a factor of 10-30 by comparison with the previously reported cyclization of alkenyl species. The rate constants at 80 degrees C in benzene and the endo/exo ratio for reductive cyclizations of the methacrylate, crotonate, cinnamate, maleate, and fumarate esters of 8-iodo-3,6-dioxaoctanol have been determined. The reduction of the 8-iodo-3,6-dioxaoctyl acrylate in solvents of varying polarity indicated that the cyclization rate has a relatively low solvent dependence.

Synthesis of Macrocyclic Ketones through Catalyst-Free Electrophilic Halogen-Mediated Semipinacol Rearrangement: Application to the Total Synthesis of (±)-Muscone

“…Over the past decades, chemists devoted significant effort toward the construction of these ketones. Ring-closing strategies including Dieckmann condensation, radical initiated ring closing reactions, ring-closing metathesis, and intramolecular cross-coupling reactions (e.g., Stille coupling, Sonogashira coupling, Heck coupling) have been widely applied to construct complicated macrocyclic ketone structures (Scheme , eq 1). However, these traditional methods generally require harsh reaction conditions (e.g., strong bases and/or high temperatures) and the use of expensive metal catalysts.…”

Scalable and Cost-Effective Synthesis of a Linker for Bioconjugation with a Peptide and a Monoclonal Antibody

“…14 Even though the desired product could be detected by mass spectrometry analysis, the reaction did not proceed to completion and some decomposition was observed in the presence of catalytic sodium hydride or Na metal and a large excess of acrylate. AcOH, 115 °C 20 NaOH and n-Bu 4 NBr in toluene, r.t., NaOH and n-Bu 4 NBr in MTBE, r.t.) but only the combination of sodium hydroxide and tetrabutylammonium bisulfate in dichloromethane at reflux gave the desired product albeit in very low yield (15%) after chromatography. When sodium hydride in tetrahydrofuran was employed, 21 the desired product was also detected by mass spectroscopy analysis but, due to the low conversion, it was not isolated.…”

Synthesis of heterocycles by radical cyclisation

“…The radical reactions yield mixtures of uncyclised reduction products and macrocyclic ethers formed by endo cyclisation. 168 In these cyclisations the nucleophilic βalkoxyethyl radicals were cyclised onto the β-position of α,βunsaturated esters. This general protocol has also been adapted for use with water as a solvent using triethylborane as the initiator.…”