Synthesis ofN(3),N‘(3)-Polymethylene-bis-hydantoins and Their Macrocyclic Derivatives

Abstract

An efficient and straightforward two-step approach toward N3,N'3-polymethylene-bis-hydantoins was developed. As a first step, a pyroglutamate is reacted with a diisocyanate to produce a bis-carbamoyllactam. The second step is a double-ring transformation by treatment of this bis-carbamoyllactam with KOtBu in ethanol. In this fashion N3,N'3-polymethylene-bis-hydantoins are produced in two quantitative steps and under very mild conditions. When properly derivatized, these compounds can be converted to their macrocyclic derivatives upon treatment with 5 mol % of second-generation Grubbs' catalyst. These macrocyclic derivatives are so far not described in the literature. It was proven that exclusively (E)-isomers are formed.

The Formation of trans‐Fused Macrocycles from N3,N3′‐Polymethylenebis(hydantoins) by Ring‐Closing Metathesis

“…The hydantoins 11 were synthesised by the previously described two-step protocol, [19] since the more straightforward one-step ring-closing ring-opening (Scheme 1) did not go to completion in THF and some side reactions resulting from the attack of the alkoxide anions on the isocyanates occurred. NaH was therefore added to a mixture of allyl pyroglutamate, synthesised by a Dean-Stark esterification reaction, and diisocyanate in dry ether (Scheme 2).…”

“…These products of the double ring-transformation can be converted into bicyclic hydantoin derivatives [18] and macrocycles. [19] In view of the promising results of earlier biotesting by chick heart invasion assay, [20] in which some bis(hydantoins) with hexa-and octamethylene spacers showed anti-invasive Scheme 1.…”

“…[24] For the macrocycles that we have previously synthesised it was shown that only the trans isomers were formed. [19] This was also evaluated for the 24-and 26-membered rings described below. As these ring structures are symmetrical entities, 3 J H,H coupling constants do not appear in the 1 H NMR spectra of these compounds, but can be recovered by using 1 H-and 13 C-correlated spectra obtained by inverse detection techniques.…”

One‐Pot Synthesis and Characterization of Some New Types of 5,5′‐Disubstituted Bis(imidazolidine‐2,4‐diones)

“…The bis‐hydantoin compounds, as potential bis‐drugs, are expected to be capable of double therapeutic behavior. Some pharmacological and therapeutic properties of bis‐hydantoins have been reported [1–9]. For example, recently there has been a growing concern about how to reduce or eliminate infections completely, especially those caused by antibiotic‐resistant bacterial strains.…”

Conformational Sampling of Macrocyclic Alkenes Using a Kennard−Stone-Based Algorithm

“…Compound 1 was synthesized by ring closing metathesis (RCM), and only the E isomer was observed experimentally. , Usually, RCM results in a mixture of E and Z isomers, , but in some cases, stereoselective formation of the E isomers has been reported . We can assume that a thermodynamic equilibrium was set.…”