Asymmetric Synthesis of 5‐Hexadecanolide.

Abstract

Optically pure S-5-hexadecanolide (1) has been easily prepared from readily available aldehyde 2 and cyclopentanone (3) using L-proline-catalyzed asymmetric aldol reactions as the key step.Keywords 5-hexadecanolide, Baeyer-Villiger oxidation, aldol reaction, L-proline Chiral lactones are functional compounds commonly present in a number of natural products that function as pheromones or medicinal compounds. S-5-Hexadecanolide (1), natural pheromone isolated from the mandibular glands of the oriental hornet Vespa orientalis, 1 contains chiral lactone units in the structure. Owing to its remarkable physiological activities, much effort has been expanded on the development of methods for its syntheses.2 With our interest in L-proline-catalyzed asymmetric aldol reactions, 3 we report herein a short and simple approach to the synthesis of 1 using L-proline as the catalyst.The synthesis commenced from the known aldehyde 2 and cyclopentanone (3) catalyzed by L-proline 4 (Scheme 1). After purification by flash column chromatography on SiO 2 , the syn aldol 4 along with its anti isomer 5 was obtained in 80% yield 5 in a ratio of 85∶ 15. The enantiomeric purity of 4 was determined to be 96% ee by HPLC analysis with a chiral stationary phase column.5b Baeyer-Villiger oxidation of the ketone 4 by m-CPBA in anhydrous CH 2 Cl 2 at room temperature gave the desired compound 6 in 82% yield. Alcohol 6 was deoxygenated using the Barton protocol (NaH/CS 2 /MeI, AIBN/Bu 3 SnH) 6 to give 1 in 54% yield. Synthetic 1 showed identical spectral data with those of natural product 1 reported, and the optical property of synthetic 1 { In summary, a versatile procedure has been achieved for the synthesis of enantiomerically pure S-5-hexadecanolide (1) in 35% overall yield starting from aldehyde 2 in three steps, using L-proline as catalyst. The synthetic route reported here makes the chiral lactone available that may be of interest for structure-activity studies of this group of compounds. ExperimentalMelting points were measured on a Kofler hot stage C NMR spectra were recorded on a Varian Mercury 300 BB spectrometer or Bruker AM-400 spectrometer in CDCl 3 solution using TMS as an internal reference. IR spectra were obtained using an FT-170SX spectrophotometer. Low resolution mass spectra were measured on an HP-5988 mass spectrometer and high resolution mass spectra (HRMS) were determined on a Bruker Daltonics APEXII47e Fourier transform spectrometer with ESI ionization method. Specific rotations were determined using sodium D line on a Perkin-Elmer 341 polarimeter at 20 ℃. The enantiomeric excess values were determined by chiral stationary phase column. All solvents were