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

Abstract

A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral β- and γ-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated.

Facile assembly of 1,5-diazocan-2-ones via cyclization of tethered sulfonamides to cyclopropenes

“…We have recently reported on the key role of potassium cations in the chelation-controlled cyclization of cyclopropenes 4 linked to nucleophilic alkoxide moieties. [27][28][29] This innovative approach allows for a highly efficient and diastereoselective assembly of cyclic ethers 5 with ring sizes 7 to 10 (Scheme 1). [27][28][29] These bicyclic structures produced new, highly selective anti- mycobacterial agents.…”

“…[27][28][29] This innovative approach allows for a highly efficient and diastereoselective assembly of cyclic ethers 5 with ring sizes 7 to 10 (Scheme 1). [27][28][29] These bicyclic structures produced new, highly selective anti- mycobacterial agents. 29 Closely related diazepinones and diazecanones 7 demonstrated antitumor activity.…”

“…[27][28][29] These bicyclic structures produced new, highly selective anti- mycobacterial agents. 29 Closely related diazepinones and diazecanones 7 demonstrated antitumor activity. These species could be accessed via the potassium-templated cyclization of cyclopropenes 6 with tethered carbamates (Scheme 1).…”

“…It should be pointed out, that a scope of substituents R 1 and R 2 as well as ring size in such bicyclic scaffolds was already previously investigated. 29,30 The current study is focused on evaluating the activating properties of different sulfonyl protecting groups. We also briey examined the use of these sulfonamides as chiral auxiliaries.…”

Cyclopropene-Templated Assembly of Medium Cycles via Ru-Catalyzed Ring-Closing Metathesis

“…Our research group has extensive experience in controlling the chemo- and stereoselective assembly of medium-sized rings by employing the metal-templated addition of oxygen- , or nitrogen-based nucleophiles to functionalized cyclopropenes. We showed that this approach allowed for the highly efficient cyclization of 7- to 10-membered rings. − We envisioned that a cyclopropene unit could also serve as a practical rigidified linchpin for a “click–click–cyclize” approach , to prepare medium-sized lactams via RCM. Herein we now disclose on the design and realization of this diversity-oriented synthetic strategy.…”