Elsevier

Tetrahedron: Asymmetry

Volume 16, Issue 7, 4 April 2005, Pages 1305-1307
Tetrahedron: Asymmetry

Synthesis of (−)-(5R,6S)-6-acetoxyhexadecan-5-olide by l-proline-catalyzed asymmetric aldol reactions

https://doi.org/10.1016/j.tetasy.2005.02.017Get rights and content

Abstract

The natural mosquito attractant pheromone, (−)-(5R,6S)-6-acetoxyhexadecan-5-olide 1, was synthesized from readily available aldehyde 3 and cyclopentanone 4 using l-proline catalyzed asymmetric aldol reactions as the key step.

Introduction

The mosquito is a vector for filarial diseases and malaria. (−)-(5R,6S)-6-Acetoxyhexadecan-5-olide 1, was first isolated by Laurence and Pickett in 1982 from the apical droplet of mosquito eggs.1 The substance attracts other gravid females of the same and some related mosquito species inducing them to oviposit in the same spot where the original eggs are found. (+)-Muricatacin 2, a simple active acetogenin derivative, was isolated from the seeds of Annona muricata, and shows cytotoxic activity on tumor cell lines (with A-549, lung carcinoma, ED50 = 23.3 μg/mL).2

Both 1 and 2 have chiral lactone units in the structure; functionalized γ- and δ-lactones have attracted substantial attention in recent years due to their synthetic importance as building blocks in natural products synthesis. Owing to their remarkable physiological activities, much effort has been expanded on the development of methods for their syntheses.3 Although a great number of synthetic routes to the title compound have been published, a short and efficient route is still needed to be explored. With our interest in l-proline-catalyzed asymmetric aldol reactions,4 we herein report a short and efficient approach to the synthesis of 1 using l-proline5 as the catalyst (Fig. 1).

Section snippets

Results and discussion

The synthesis started from the known aldehyde 3 and cyclopentanone 4 catalyzed by l-proline (Scheme 1). After purification by flash column chromatography on SiO2, diastereomers 5a and 5b were obtained in 80% yield in a ratio of 85:15. The enantiomeric purity of syn-5a was determined to be 96% ee by HPLC analysis with a chiral stationary phase column. Protection of the resulting hydroxyl group of the aldol 5a with Ac2O at room temperature by a standard method gives ester 7 in a virtually

Conclusion

In summary, we have achieved a versatile procedure for the synthesis of enantiomerically pure (−)-(5R,6S)-6-acetoxy-hexadecan-5-olide 1, in 57.8% overall yield starting from aldehyde 3 in three steps, using l-proline as catalyst. The synthetic route reported here makes available the chiral lactones that may be of interest for structure-activity studies of this group of compounds.

Experimental

Melting points were measured on a Kofler hot stage apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Varian Mercury 300 BB spectrometer and Bruker AM-400 spectrometer in CDCl3 solution using TMS as an internal reference. IR spectra were obtained using a FT-170SX spectrophotometer. Low resolution mass spectra were measured on a HP-5988 mass spectrometer and high resolution mass spectra (HRMS) were determined on a Bruker Daltonics APEX II 47e Fourier Transform spectrometer

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No 20272020 and 20072012).

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There are more references available in the full text version of this article.

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