Templated assembly of medium cyclic ethers via exo-trig nucleophilic cyclization of cyclopropenes

Abstract

A novel method for the assembly of medium heterocycles via an intramolecular nucleophilic addition to cyclopropenes generated in situ from the corresponding bromocyclopropanes is described. The exo-trig nucleophilic cyclizations were shown to proceed very efficiently and in a highly diastereoselective fashion affording cis-fused bicyclic products possessing 7 to 10-membered medium rings; starting from a diastereomeric mixtures of bromocyclopropanes.

Directed nucleophilic addition of phenoxides to cyclopropenes

“…in the presence of a base. Two conditions were probed, which previously proved best for the base-assisted additions of alkoxides 8,9 and nitrogen-based nucleophiles. 14 The first set of conditions employed a suspension of finely powdered KOH (1.50 equiv.)…”

“…was obtained by hydrolysis of 1-(3-bromophenyl)-2-(trimethylsilyl)cycloprop-2-ene-1-carboxylate 9c (6.90 g, 21.2 mmol) using the protocol described for the synthesis of 1-(4-fluorophenyl)cycloprop-2-ene-1-carboxylic acid ( vide supra ). The titled compound was obtained as colorless crystalline solid, mp 88.4–89.7 °C, R f 0.33 (Hexanes/EtOAc 2:1).…”

“…7 We have previously reported a formal nucleophilic substitution of bromocyclopropanes operating via dehydrohalogenation/addition of O -based nucleophiles to cyclopropene intermediates, which can be carried out in both inter- 8 or intramolecular fashion. 9 Diastereoselectivity in these reactions is efficiently controlled by steric effects (Scheme 1, eq. 2), via a thermodynamically driven epimerization of one of the newly formed centers (eq.…”

Desymmetrization of Cyclopropenes via the Potassium-Templated Diastereoselective 7-exo-trig Cycloaddition of Tethered Amino Alcohols toward Enantiopure Cyclopropane-Fused Oxazepanones with Antimycobacterial Activity

“…We have recently communicated an efficient synthesis of medium cyclic ethers 6 via a formal nucleophilic cyclization of bromocyclopropanes 4 (Scheme 1, eq 2), 9a involving an in situ base-assisted generation of reactive cyclopropene 5 , which, once formed, is immediately trapped by a tethered alkoxide. Our computational studies suggested that the mechanism of this strain-release-driven reaction involves a transition state where the potassium ion is coordinated to both alkoxide and amide oxygens, as well as to the carbon atom bearing a partial negative charge (C-8) (TS1 in Scheme 6).…”

“…6,7 Both intermolecular (Scheme 1, eq 1) and intramolecular (Scheme 1, eq 2) addition of tethered nucleophiles, employing carbon- 8 or oxygen-based species, has been reported. 9,10 In all these studies achiral tethered nucleophilic entities were used for cyclizations affording racemic products. A diastereoselective 8- endo-trig cycloaddition using chiral cyclopropene precursor 8 has been demonstrated (Scheme 1, eq 3), 10 while a complementary approach involving intramolecular nucleophilic addition of tethered chiral alkoxides to prochiral cyclopropene moieties has not been fully explored.…”