Concise asymmetric syntheses of ( S )-ethyl 4-methyloctanoate and its acid: aggregation pheromones of rhinoceros beetles of the genus Oryctes

A concise stereoselective approach to the asymmetric syntheses of ( S )-ethyl 4-methyloctanoate and its acid, main aggregation pheromones of the genus Oryctes and an important fragrance compounds, is described. The synthesis utilizes the organocatalyzed MacMillan’s cross aldol reaction as key step. The synthetic approach outlined permits synthesis of a variety of enantiopure branched methyl unsaturated and saturated fatty acids

1][22] More recently, Guerrero and co-worker reported the asymmetric synthesis of (R)and (S)-4-methyloctanoic acid (2) via chirality induction through Myers alkylation reaction as key step. 23erein, we are reporting a simple synthetic approach to the ethyl 4-methyloctanoate (1) and its acid 2 and further its application to the asymmetric syntheses (S)-ethyl 4-methyloctanoate (1a) and its acid 2a from monosilylated ethylene glycol as a starting material employing organocatalyzed MacMillan's cross aldol reaction and Wittig olefination as key steps.

Results and Discussion
Our retrosynthetic analysis to the synthesis of (S)-ethyl 4-methyloctanoate (1a) and its acid 2a is displayed in Scheme 1.The α,β-unsaturated ester derivative 6 was visualized as a synthetic intermediate from which ethyl 4-methyloctanoate (1) and its acid 2 could be synthesized via silyl ether deprotection, oxidative cleavage of diol, Wittig homologation and reduction following standard organic functional group transformations.The α,βunsaturated ester derivative 6 envisaged from readily available monosilylated ethylene glycol derivative 7 via organocatalyzed MacMillan's cross aldol reaction of aldehyde derived from 7 with propionaldehyde and Wittig homologation reaction.The (R)-and (S)-configuration of the target compounds ethyl 4-methyloctanoate (1) and its acid 2 can be manipulated by simply changing organocatalyst under MacMillan's cross aldol conditions.Scheme 1. Retrosynthetic approach to asymmetric syntheses of ethyl 4-methyloctanoate (1) and its corresponding ethyl ester 2.

Conclusions
In conclusion, we have developed a simple and flexible approach to the total syntheses of (S)-ethyl 4methyloctanoate (1a) and its acid 2a from readily available starting materials.The synthetic sequence demonstrates the application of organocatalyzed MacMillan's cross aldol reaction and Wittig olefination as the key steps.The synthetic approach described has significant potential for stereochemical variations and further extension to other stereoisomers and their analogues.

Ethyl (S)-4-methyloctanoate (1a).
To a stirred solution of NaIO4 (226 g, 1.06 mmol) in H2O:THF (1:1, 10 mL) was added a suspension of olefin diol 9 (100 mg, 0.53 mmol) in THF (3 mL) and stirred for 20 min at room temperature.To the reaction mixture EtOAc and water were added, the aqueous layer was extracted with EtOAc (3 x 15 mL).The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.The aldehyde intermediate obtained was used as such for next reaction without further purification.
To a suspension of propyltriphenylphosphonium bromide (264 mg, 0.69 mmol) in dry THF (5 mL) dropwise n-BuLi (2.5 M in hexane, 0.3 mL, 0.79 mmol) at -78 o C was added.The reaction mixture was warmed to rt over a period of 1 h before being cooled to -78 o C. To the obtained orange solution above crude aldehyde dissolved in THF (3 mL) was added and the reaction mixture was left to warm to rt over 2 h before the addition of H2O (10 mL).The resulting suspension was extracted with EtOAc (3 x 10 mL).The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford olefin intermediate 10 as a colorless liquid which was used for the next reaction.(S)-4-methyloctanoic acid (2a).A mixture of ethyl (S)-4-methyloctanoate (1a) (50 mg, 0.27 mmol), LiOH (34 mg, 0.81 mmol), THF (2 mL) and water (0.5 mL) was stirred at room temperature for 6 h.The organic solvent was removed under reduced pressure, and the residue obtained was then acidified to pH 5 with 1 N HCl, and the reaction mixture was extracted with EtOAc (3 x 10 mL).The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.Silica gel column chromatography (hexane /EtOAc 9:1) afforded the target compound (S)-4-methyloctanoic acid (2a) (39 mg, 92%) as a colorless liquid.
To a stirred solution of unsaturated ester 6a (1.4 g, 3.28 mmol) in dry THF (10 mL) TBAF (4.91 mL, 4.92 mmol) was added dropwise at room temperature.After stirring the reaction mixture at room temperature for 4 h, the reaction mixture was diluted with water and ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure.
To a solution of above olefin intermediate 10 in methanol (4 mL) catalytic amount of palladium on carbon (10%) was added and resulting reaction mixture was stirred under hydrogen atmosphere for 4 h at room temperature, at which point TLC indicated the completion of reaction.The reaction mixture was filtered through a pad of Celite, solvent was removed in vacuo and silica gel column chromatography (hexane/ EtOAc 9, 29.1, 22.9, 19.2, 14.2, 14.1.HRMS (ESI), m/z calcd for C11H22O2Na [M + Na] + 209.1512; found 209.1514.