Sequential Staudinger ketene–imine cycloaddition, RCM approach to polycyclic macrocyclic bisazetidinones

Abstract

An efficient approach to novel macrocyclic azacrown ethers incorporating two azetidinone rings fused to the macrocycle through the 3,4-positions of the azetidinone rings and two macrocycles fused at 1,3,4positions of two azetidinone rings was achieved via sequential Staudinger ketene-imine cycloaddition of o-allyloxyphenoxyketene and bis-imines followed by RCM. The ketene-imine cycloaddition afforded the corresponding bis-o-allyloxyphenoxyazetidinones as the cis-cis diastereomers, exclusively obtained as a mixture of cis-syn-cis and cis-anti-cis diastereomers. RCM of the latter using Grubbs' II catalyst afforded good yields of the corresponding novel macrocyclic bisazetidinones. Two cis-anti-cis bisazetidinones were readily identified by 1 H NMR using Eu(hfc) 3 chiral shift reagent and the structure of two macrocycles was established by X-ray crystallography.

Three-Step Metal-Promoted Allene-Based Preparation of Bis(heterocyclic) Cyclophanes from Carbonyl Compounds

“…In addition to being the key structural motif in biologically relevant compounds such as antibiotics and enzyme inhibitors, the β-lactam moiety is a versatile building block in organic synthesis . Although the metathesis reaction is known to be a powerful tool for the preparation of macrocycles, in the field of β-lactam chemistry, only a few syntheses of macrocyclic β-lactams have been reported based on RCM . Initially, dienyl β-lactam 12a was selected as a model substrate for the RCM.…”

Variable-Sized bis(4-spiro-fused-β-lactam)-Based Unsaturated Macrocycles: Synthesis and Characterization

“…During our recent interest in the construction of new types of azacrown ethers, − a wide spectrum of macrocycles composed of two β-lactam sites, which are covalently linked with various organic and organometallic linkers through their 1,3-,1,4-, 3,4-, and 1,3,4-positions, have been achieved and reported in literature . However, examples of macrocycles incorporating bis-4-spiro-β-lactams moieties in their backbone core structures are still limited.…”

Sequential Diimination, Staudinger [2 + 2] Ketene–Imine Cycloaddition, and Ring-Closing Metathesis (RCM) Reactions: In Route to Bis(4-spiro-fused-β-lactams)-Based Macrocycles

“…In recent years, our research group and others have emerged this synthetic strategy in the synthesis of a collection of unsaturated azacrown ethers (Figure ). − The target macrocycles consist of two β-lactams units that are covalently linked through their 1,3-, 1,4-, 3,4-, and 1,3,4-positions with different organic/organometallic bridges such as alkyl, ferrocene, or variable length ethyelene glycolyl linkers. , All reported structures are composed of four diasteriomeric hydrogens, that is, two diastereomeric hydrogens per each β-Lactam unit, and to the best of our knowledge, there have been no reports describing the synthesis of bis-spiro-fused β-lactams-based azacrown ethers.…”