A Short and Efficient Enantioselective Synthesis of ( + ) and (-)-( Z )-7 , 15-hexadecadien-4-olide . The Sex Pheromone of the Yellowish Elongate Chafer , Heptophylla picea

Several classes of compounds such as pheromones, aromas and plant growth regulators exhibit a γbutyrolactone unity in their structures. Since the biological activity of such compounds often dependes on their absolut configuration, much work has been done to develop enantioselective routes to γ-butyrolactones. Recently we initiated a program aiming at the synthesis of enantiomericaly pure naturally occurring lactones using enzymes in a deracemization step. A versatile protocol introduced by us consists in the application of a methodology developed by Gutmam and coworkers, which transforms the commercially available 4-ketopimelic acid (1) into the chiral lactone (S)-(-)-2, which was transformed in our laboratory into both (S) and (R) isomers of jasmolactone 3, a compound with organoleptic properties, described as fruity, flowery, green, creamy, sweet and juicy (Scheme 1). This strategy is interesting since the common intermediate 2 can lead to both enantiomers of a naturaly occurring γ-butyrolactone. The female sex pheromone of the Yellowish Elongate Chafer (Heptophylla picea) (4) would be a good candidate to demonstrate the versatility of our methodology. Compound (R)-4 was prepared by Leal and coworkers in 14 steps starting from L-malic acid. Mori and Nakayama obtained (R)-4 and (S)-4 in respectively 95% and 94% e.e. through an enzymatic resolution of racemic 4 using different enzymes in more than one enzymatic step.


Introduction
Several classes of compounds such as pheromones, 1 aromas 2,3 and plant growth regulators 4 exhibit a γbutyrolactone unity in their structures.7][8] A versatile protocol introduced by us consists in the application of a methodology developed by Gutmam and coworkers, which transforms the commercially available 4-ketopimelic acid (1) into the chiral lactone (S)-(-)-2, which was transformed in our laboratory into both (S) 7 and (R) 8 isomers of jasmolactone 3, a compound with organoleptic properties, described as fruity, flowery, green, creamy, sweet and juicy 3 (Scheme 1).
This strategy is interesting since the common intermediate 2 can lead to both enantiomers of a naturaly occurring γ-butyrolactone.The female sex pheromone of the Yellowish Elongate Chafer (Heptophylla picea) (4) 9 would be a good candidate to demonstrate the versatility of our methodology.
Compound (R)-4 was prepared by Leal and coworkers in 14 steps starting from L-malic acid. 9,10Mori and Nakayama obtained (R)-4 and (S)-4 in respectively 95% and 94% e.e. through an enzymatic resolution of racemic 4 using different enzymes in more than one enzymatic step. 10,11
The synthesis of (S)-4 started with the reduction of 4ketopimelic benzyl ester as described previously (Scheme 3). 7,12The obtained alcohol 8 was submitted to enantioselective lactonization by PPL leading to (S)-2 in 92% e.e. 12 The (S) configuration of the lactone 2 was attributed by comparision of its specific rotation, [α] D 20 = -32,7 (c = 1.04;CH 2 Cl 2 ), with the literature value, [α] D 25 = -40,86 (c = 0.74; CH 2 Cl 2 ), 12 and its enantiomeric excess was determined by means of chiral HPLC. 7Transformation of the ester function of (S)-2 into an aldehyde was achieved by deprotection of the benzyl group followed by reduction with borane-methyl sulfide complex (BMS) and oxidation with pyridinium chlorochromate (PCC). 7,12Using this procedure, the integrity of the stereogenic center was preserved and (S)-5 was the product (Scheme 3).
The lactol 6 was prepared by reduction of (S)-2 with a slight excess of DIBAL-H in THF at -78 °C as previously reported 8 (Scheme 4).
The phosphonium salt 12, precursor of the Wittig reagent 7, was obtained starting from the commercially available 6-bromo-1-hexanol 9, which upon treatment with allylmagnesium bromide in THF in the presence of dilithium tetrachlorocuprate gave 8-nonenol 10 (Scheme 5).The bromide 11 was prepared by treating 10 with triphenylphosphine bromine complex in acetonitrile.The phosphonium salt 12 was prepared by refluxing triphenylphosphine and 11 in acetonitrile. 10e Wittig reagent 7 was obtained by treatment of the phosphonium bromide 12 with sodium hexamethyldisilazide in THF at -40 °C and then reacted with 5 or 6 to give (S)-4 and (R)-4, respectively, in 92% e.e. (Scheme 6).
For preparation of compound (R)-4, two equivalents of 7 were used.The first equivalent deprotonates the OH group opening the lactol ring and the second transforms the aldehyde into an olefine.The alkoxy oxygen at C 4 promotes a transesterification reaction of the benzyl ester group generating the lactone ring of (R)-4 (Scheme 7).Compounds (S)-4 and (R)-4 were obtained as Z/E mixtures (96 : 04), which were purified by column chromatography on silica gel impregnated with AgNO 3 to afford the desired products in pure form.The absolute configuration of both enantiomers was attributed by comparing the [α] D values of our products with those reported in the literature. 10Attempts to determine the enantiomeric excess of (S)-4 and (R)-4 by chiral gas chromatography were unsuccessful.In view of this failure compounds (S)-4 and (R)-4 were hydrogenated using Pd/ C as catalyst and the products were analysed by chiral GC using a β-cyclodextrine as a chiral phase on a capillary column.This analysis showed that both (S)-4 and (R)-4 were obtained with 92% e.e. (Figure 2).
In conclusion, (S) and (R)-(Z)-7,15-hexadecadien-4olide (4) were obtained in high enantiomeric excess in 4 and 3 steps respectively, starting from the easily prepared common intermediate (S)-2.With the completion of this synthesis we showed that (S)-2 is a versatile precursor of both enantiomers of naturally occurring γ-butyrolactones.

(S)-7,15-Hexadecadien-4-olide, [(S)-4]
To a solution of the dry phosphonium salt 12 (0.25 g, 0.53 mmol) in dry THF (4 mL) NaHDMS (0.58 mL, 0.58 mmol, 1 M THF solution) was added at -40 o C under Ar.After 10 min of stirring at the same temperature, the resulting orange solution was transferred via canula to a solution of the aldehyde 5 (0.071 g, 0.5 mmol) in dry THF (4 mL) at -78 o C under Ar.After stirring for 90 min at the same temperature, the reaction mixture was quenched with saturated NH 4 Cl solution.The organic layer was separated, and the aqueous layer was extracted with diethyl ether.The organic layer was washed with water and brine, dried with MgSO 4 and concentrated in vacuo.The crude product was purified by chromatography in silica gel impregnated with AgNO 3 eluting with pentane/diethyl ether    To a solution of the dry phosphonium salt 12 (0.568 g, 1.06 mmol) in dry THF (8 mL) NaHDMS (1.16 mL, 1.16 mmol, 1 mol L -1 THF solution) was added at -40 o C under Ar.After 10 min of stirring the same temperature, the resulting orange solution was transferred via canula to a solution of lactol 6 (0.125 g, 0.5 mmol) in dry THF (4 mL) at -78 o C under Ar.After stirring for 90 min at the same temperature, the reaction mixture was quenched with a saturated NH 4 Cl solution.The organic layer was separated and the aqueous layer was extracted with diethyl ether.The organic layer was washed with water and brine, dried with MgSO 4 and concentrated in vacuo.The crude product was purified by chromatoghraphy in silica gel impregnated with AgNO 3 eluting with pentane / diethyl ether (2 : 1) to give 0.067 g (55%) of the (R)-7,15-hexadecadien-4-olide, [(R)-4].The spectroscopic data agree with those of (S)-4.