Elsevier

Tetrahedron

Volume 68, Issue 13, 1 April 2012, Pages 2827-2843
Tetrahedron

Concise synthesis of chiral 2(5H)-furanone derivatives possessing 1,2,3-triazole moiety via one-pot approach

https://doi.org/10.1016/j.tet.2012.01.092Get rights and content

Abstract

Combining three bioactive units, such as 2(5H)-furanone, 1,2,3-triazole, and amino acid together into one potential drug molecule with polyfunctional groups, a series of new chiral 2(5H)-furanone derivatives containing 1,2,3-triazole moiety have been designed and synthesized from (5S)-5-alkoxy-3,4-dibromo-2(5H)-furanones, amino acids, propargyl bromide, and organic azides via the sequential three steps, including asymmetric Michael addition–elimination, substitution, and click reaction. The latter two steps, substitution and click reaction could proceed smoothly in a one-pot process. Furthermore, the target products could be directly synthesized via a four-component one-pot approach.

Introduction

Molecules possessing 2(5H)-furanone moiety, a kind of α,β-unsaturated lactone substructure frequently found in natural products (Fig. 1), have received considerable interest due to their significant biological activities, such as antifungal, anti-bacterial, anti-inflammatory, and anti-tumor.1 At the same time, many 2(5H)-furanone compounds are important organic intermediates.2 These made the researches on 2(5H)-furanone chemistry become very intensive recently.3

Though more and more methods for 2(5H)-furanones with polyfunctional groups have been reported in the researches on 2(5H)-furanone, these synthetic methods can be divided into two categories according to different synthetic strategies. One is that introducing substituents first and then producing 2(5H)-furanone ring via cyclization.4, 5, 6, 7 The other is that taking simple furanones or other oxygen-containing five-membered cyclic compounds as starting materials and then introducing various substituents as required to synthesize a series of derivatives.8, 9 No matter which approach, the synthesis of 2(5H)-furanones with polyfunctional groups has been a challenge for a long time due to the instability of 2(5H)-furanone ring under certain conditions and the particularity of various functional groups.4, 5, 6, 7, 8, 9 Besides, the reported methods had some deficiencies, especially the starting materials were not easily available,4, 6 or the process was lengthy,7 or the catalysts were precious and not easily obtainable.5, 6, 9

As an important pharmacophore, 1,2,3-triazole nitrogen heterocycle plays an significant role in the anti-bacterial,10 anti-tumor,11 anti-inflammatory,12 anti-HIV,13 and anti-platelet aggregation.14 This makes many medicinal chemists and biochemists have increasing emphasis on the synthesis of 1,2,3-triazoles with polyfunctional groups.15 However, the studies on combination 1,2,3-triazole into 2(5H)-furanone compounds via different bioactive amino acids as building blocks16 have not been reported before. Herein, we tried to combine three bioactive units, such as 2(5H)-furanone, 1,2,3-triazole, and amino acid to design and synthesize potential bioactive chiral compounds 6 containing polyfunctional groups, e.g., butenolide ring, amino, ester, 1,2,3-triazole, and halogen (Scheme 1). Meanwhile, based on the mild, simple, economical three-step synthetic method, we further investigated their efficient syntheses via a multi-component one-pot approach.

Section snippets

Synthesis of target compounds by fractional-step method

Based on the synthesis of the intermediates N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acids 31(k), 3(t) and N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters 4,3u we investigated the fractional-step method in preparation the target compounds starting from propargyl esters 4. According to the most literature on click chemistry,15, 17, 18 all reactions in our experiments were carried out at room temperature. Choosing N-[(5S)-5-menthyl-oxy-2(5H)-furanonyl] 6-aminohexanoic acid 4af and

Conclusion

In summary, a series of novel chiral 2(5H)-furanone derivatives containing 1,2,3-triazole moiety with potential biological activity were designed and synthesized from available (5S)-5-alkoxy-3,4-dibromo-2(5H)-furanones, amino acids, propargyl bromide, and organic azides through an asymmetric Michael addition–elimination, substitution, and cycloaddition under mild conditions with economical catalysts. They also could be generated via a simple and efficient multi-component one-pot approach. Due

General

All the melting points were determined on an X-5 digital melting points apparatus and were uncorrected. Infrared spectra were recorded on a Bruker Vector 33 FT-IR instrument by liquid film method in the absorption range of 4000–400 cm−1. 1H and 13C NMR spectra were obtained in CDCl3 on a Varian DRX-400 MHz spectrometer and tetramethylsilane (TMS) was used as an internal standard. UV absorption peaks were measured by Shimazu UV-2550 ultraviolet absorption detector with dichloromethane as a

Acknowledgements

We thank the National Natural Foundation of China (No. 20772035), the Third Talents Special Funds of Guangdong Higher Education (No. Guangdong-Finance-Education[2011]431) and Guangdong Natural Science Foundation (No. S2011010001556) for financial support.

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