Asymmetric Synthesis of Contact Sex Pheromone of Tetropium fuscum and Its Enantiomer

Tetropium fuscum is a harmful forest pest and attacks spruces. The contact sex pheromone of this pest, (S)-11-methyl-heptacosane, and its enantiomer were synthesized via Evans’ chiral auxiliaries. The key steps of this approach included acylation of carboxylic acid, diastereoselective methylation of oxazolidinone amide, and Wittig coupling of the aldehyde with chiral phosphonium salt. The synthetic pheromones would have potential utility in the control of this pest.

The strategy based on pheromones for controlling agricultural pests is one of the most promising, effective, and safe solutions [11,12]. The contact sex pheromone of Tetropium fuscum was identified as (S)-11-methyl-heptacosane ((S)-1) ( Figure 1) by Silk, meanwhile, (S)-1 and its enantiomer (R)-1 were synthesized from (S)-and (R)-citronellyl bromides [13]. To study future utilization of the contact sex pheromone [14], herein, we prepared the contact sex pheromone of Tetropium fuscum and its enantiomer using Evans' chiral auxiliaries. Our synthesis was easily performed and afforded the target pheromone with high enantiomeric purity.
The strategy based on pheromones for controlling agricultural pests is one of the most promising, effective, and safe solutions [11,12]. The contact sex pheromone of Tetro pium fuscum was identified as (S)-11-methyl-heptacosane ((S)-1) (Figure 1) by Silk, mean while, (S)-1 and its enantiomer (R)-1 were synthesized from (S)-and (R)-citronellyl bro mides [13]. To study future utilization of the contact sex pheromone [14], herein, we pre pared the contact sex pheromone of Tetropium fuscum and its enantiomer using Evans chiral auxiliaries. Our synthesis was easily performed and afforded the target pheromone with high enantiomeric purity.

Retrosynthetic Analysis
In view of retrosynthetic analysis of contact sex pheromone of (S)-1 (Scheme 1), the key step is to construct the chiral center. It was envisaged that Evans' chiral auxiliaries

Retrosynthetic Analysis
In view of retrosynthetic analysis of contact sex pheromone of (S)-1 (Scheme 1), the key step is to construct the chiral center. It was envisaged that Evans' chiral auxiliaries including acylation of dodecanoic acid (2) and diastereoselective methylation of oxazolidinone amide would introduce chiral methyl of amide (S,S)-5. The target pheromone (S)-1 could be synthesized via hydrogenation reduction of olefin (S)-10, which could be divided into two including acylation of dodecanoic acid (2) and diastereoselective methylation of dinone amide would introduce chiral methyl of amide (S,S)-5. The target pherom 1 could be synthesized via hydrogenation reduction of olefin (S)-10, which coul vided into two components, pentadecanal (9) and phosphonium salt in situ prep hydrocarbon bromide (S)-7 and triphenylphosphine. Furthermore, (S)-1-bromo-2dodecane ((S)-7) could be easily prepared from chiral alcohol (S)-6 through App tion. Scheme 1. Retrosynthetic analysis of contact sex pheromone (S)-1.

General Information
All reactions were performed in a Schlenk system under an argon atmosphere unless otherwise indicated. All commercial reagents were used directly, whereas solvents were purified following the standard strategies before use. Polarimetric measurements were taken on a Perkin-Elmer PE-341 polarimeter. Enantiomeric excesses were determined by an Agilent 1200 HPLC system with a Daicel Chiralcel OD-H column with the eluents of n-hexane and isopropanol. 1 H and 13 C NMR spectra were recorded on a Bruker DP-X500 MHz spectrometer. Chemical shifts were reported in ppm relative to tetramethylsilane for 1 H NMR and CDCl3 (77.16 ppm) for 13 C NMR. High resolution mass spectra were collected on Waters LCT Premier™ with an ESI mass spectrometer. Low-resolution mass spectra were obtained from an Exactive GC-MS (EI).

General Information
All reactions were performed in a Schlenk system under an argon atmosphere unless otherwise indicated. All commercial reagents were used directly, whereas solvents were purified following the standard strategies before use. Polarimetric measurements were taken on a Perkin-Elmer PE-341 polarimeter. Enantiomeric excesses were determined by an Agilent 1200 HPLC system with a Daicel Chiralcel OD-H column with the eluents of n-hexane and isopropanol. 1 H and 13 C NMR spectra were recorded on a Bruker DP-X500 MHz spectrometer. Chemical shifts were reported in ppm relative to tetramethylsilane for 1 H NMR and CDCl 3 (77.16 ppm) for 13 C NMR. High resolution mass spectra were collected on Waters LCT Premier™ with an ESI mass spectrometer. Low-resolution mass spectra were obtained from an Exactive GC-MS (EI).

Synthesis of (S)-4-Benzyl-3-dodecanoyloxazolidin-2-one ((S)-4) (CAS 198649-20-6)
The catalytic amount of DMF was added to a stirred solution of dodecanoic acid (2) (5.00 g, 24.97 mmol) in DCM (40 mL) at 0 • C. Oxalyl chloride (4.75 g, 37.43 mmol) was then added dropwise, and the reaction mixture was stirred for 1 h at 0 • C. After being warmed to room temperature and maintained for another 1 h, the solvent was removed under reduced pressure. The crude dodecanoyl chloride (3.49 g, 64% yield) was obtained as a slight yellow solid. NaH (0.99 g, 60% in mineral oil, 24.75 mmol) was added in portions to a stirred solution of (S)-4-benzyloxazolidin-2-one ((S)-3) (2.95 g, 16.64 mmol, >99% ee) in THF (20 mL) at 0 • C. The resulting mixture was warmed to room temperature and stirred for 2 h, followed by the addition of the crude dodecanoyl chloride. The reaction mixture was maintained for another 3 h at the same temperature, then quenched with saturated aqueous NH 4 Cl (10 mL). After the layers were separated, the aqueous phase was extracted with EtOAc (3 × 50 mL). The EtOAc extracts were combined with organic layer, washed with saturated aqueous NaCl (50 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/petroleum ether 2:8) to afford (S)-4-benzyl-3-dodecanoyloxazolidin-2-one ((S)-4) as a colorless oil (
n-BuLi (0.25 mL, 2.4 M in n-hexane, 0.60 mmol) was added dropwise to a stirred solution of phosphonium salt (0.24 g, 0.45 mmol) in dry THF (5 mL) at room temperature via syringe. After the reaction mixture was maintained for 2 h at the same temperature, it was cooled to −35 • C. n-Pentadecanal (9) (0.068 g, 0.30 mmol) in dry THF (3 mL) was then added. The reaction mixture was stirred for 5 h at −35 • C and quenched with saturated aqueous NH 4 Cl (5 mL). After the layers were separated, the aqueous phase was extracted with Et 2 O (3 × 5 mL). The ether extracts were combined with the organic layer, washed with saturated aqueous NaCl (20 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give the Z/E mixtures of (S)-11-methylheptacos-9-ene ((S)-10) (0.062 g, 53% yield, Z:E = 5.1:1, determined by 13