A short and efficient enantioselective synthesis of (+) and (-)-(Z)-7,15-hexadecadien-4-olide: the sex pheromone of the yellowish elongate chafer, Heptophylla picea

ARTICLE

A short and efficient enantioselective synthesis of (+) and (-)-(Z)-7,15-hexadecadien-4-olide. The sex pheromone of the yellowish elongate chafer, Heptophylla picea

Giuliano C. Clososki; Luis C. Ricci; Carlos E. Costa; João V. Comasseto^*

Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, 05508-900 São Paulo - SP, Brazil

ABSTRACT

The (R) and the (S) enantiomers of the Z-7,15-hexadecadien-4-olide (4), the sex pheromone of Heptophylla picea, were synthesized. A known lipase-catalysed enantiolactonization in the key step afforded a common precursor for both enantiomers of the pheromone in 92% e.e.

Keywords: pheromone, Heptophylla picea, lipase

RESUMO

Os enantiômeros (R) e (S) da Z-7,15-hexadecadien-4-olida (4), o feromônio sexual da Heptophylla picea foram sintetizados. Na etapa chave foi utilizada uma enantiolactonização já conhecida, intermediada por uma lipase, levando a um precursor comum de ambos enantiômeros do feromônio em 92% de e.e.

Introduction

Several classes of compounds such as pheromones,¹ aromas^2,3 and plant growth regulators⁴ exhibit a g-butyrolactone 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 g-butyrolactones.⁵

Recently we initiated a program aiming at the synthesis of enantiomericaly pure naturally occurring lactones using enzymes in a deracemization step.^6-8 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 juicy³ (Scheme 1).

This strategy is interesting since the common intermediate 2 can lead to both enantiomers of a naturaly occurring g-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.^9,10 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.^10,11

Results and Discussion

Scheme 2 shows the retrosynthetic analysis for (R)- and (S)-(Z)-7-15-hexadecadien-4-olide (4) using our approach.

Compound (S)-2 would be transformed into aldehyde 5 or into lactol 6, which upon reaction with the Wittig reagent 7 would give (S)-4 and (R)-4.

The synthesis of (S)-4 started with the reduction of 4-ketopimelic benzyl ester as described previously (Scheme 3).^7,12 The 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, [a]_D²⁰ = -32,7 (c = 1.04; CH₂Cl₂), with the literature value, [a]_D²⁵ = -40,86 (c = 0.74; CH₂Cl₂),¹² and its enantiomeric excess was determined by means of chiral HPLC.⁷ Transformation 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).^7,12 Using 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 reported⁸ (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.¹⁰

The 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 C₄ 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 AgNO₃ to afford the desired products in pure form. The absolute configuration of both enantiomers was attributed by comparing the [a]^D values of our products with those reported in the literature.¹⁰ Attempts 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 b-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-4-olide (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 g-butyrolactones.

Experimental

General experimental procedures

The NMR spectra were recorded on Brucker DRX-500, Varian Inova (300 MHz) and Brucker AC-200 spectrometers using TMS (¹H NMR) and the central peak of the CDCl₃ signal (¹³C NMR) as internal reference. IR spectra were obtained with a FTIR Bomem MB100 grating infrared spectrophotometer. The GC analysis were performed on a Hewlett-Packard 5890(II) instrument with a capillary crosslinked 5% Ph-Me silicone column (25 m x 0.20 mm x 0.33 µm) and on a Shimadzu GC-17A instrument equipped with a Chirasil-DEX CD (Crompack) chiral phase capillary column (30 m x 0.25 mm x 0.25 µm). The mass spectra were performed on a Shimadzu GC-17A/QP5050A spectrometer. Optical rotations were measured on a Jasco, DIP 370 digital polarimeter. The enzymatic reactions were monitored in a Shimadzu LC10AD HPLC. 8-Nonen-1-ol (10) and 9-bromo-1-nonene (11) were prepared as described in the literature.¹⁰

Triphenyl-(8-noneyl)-phosphonium bromide, (12)

A solution of 9-bromo-1-nonene, (11) (0.97 g, 4.72 mmol) and triphenylphosphine (1.78 g, 6.80 mmol) in acetonitrile (12 mL) was refluxed for 24 h under Ar. The acetonitrile was concentrated in vacuo, and the excess of PPh₃ was removed by chromatography on silica gel eluting with ethyl acetate / methanol (80 : 20) to give 2.12g (96%) of the phosphonium salt 12 as a gum. ¹H NMR (CDCl₃, 200 MHz): d 1.25 (br. s, 6H), 1.63 (m, 4H), 1.92-1.95 (m, 2H), 3.71 (br. s, 2H), 4.86-5.0 (m, 2H), 5.73 (ddt, J 16.7 Hz, 10.1 Hz and 6.58 Hz, 1H), 7.60-7.90 (m, 15H); IR (KBr) n_max/cm^-1: 2932, 1431, 1104, 996, 733, 687, 521.

(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 ºC 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 ºC under Ar. After stirring for 90 min at the same temperature, the reaction mixture was quenched with saturated NH₄Cl 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 MgSO₄ and concentrated in vacuo. The crude product was purified by chromatography in silica gel impregnated with AgNO₃ eluting with pentane/diethyl ether (2 : 1) to give 0.074 g (60%) of the (S)-7,15-hexadecadien-4-olide [(S)-4]. ¹H NMR (CDCl₃, 500 MHz): d 1.21-1.4 (m, 8H), 1.5-1.7 (m, 1H), 1.75-1.91 (m, 2H), 2.00-2.08 (m, 4H), 2.16-2.22 (m, 2H), 2.33 (ddt, J 13.3 HZ, 6.8 HZ and 6.4 Hz, 1H), 2.53 (m, 2H), 4.50 (ddt, J 7.9 Hz, 6.7 Hz and 5.3 Hz, 1H), 4.9 (ddt, J 10.2 Hz, 3.3 Hz and 1.2 Hz, 1H), 4.98 (ddt, J 17.2 Hz, 13.6 Hz and 1.6 Hz, 1H), 5.35 (ddt, J 12.3 Hz, 7.2 Hz and 1.4 Hz, 1H), 5.45 (ddt, J 12.3 Hz, 7.2 Hz and 1.4 Hz, 1H), 5.8 (ddt, J 17.4 Hz, 10.3 Hz and 5.7 Hz, 1H); ¹³C NMR (CDCl₃, 50 MHz) d 23.4, 27.4, 28.2, 29.0, 29.1, 29.3, 29.4, 29.8, 34.0, 35.9, 80.6, 114.4, 127.9, 131.7, 139.4, 177.4; IR (KBr) n_max/cm^-1: 3104, 1775, 1667, 1452, 1362, 1177, 906; MS (m/z) (%rel): 41 (100), 55 (83.3), 67 (99.5), 79 (72.7), 93 (44.8), 107 (24.7), 121 (27.9), 135 (19), 150 (30.8), 166 (4), 177 (2.3), 190 (1.3), 207 (1.3); [a]_D²⁵: - 34.8 (c = 0.5, CHCl₃).

(R)-7,15-Hexadecadien-4-olide, [(R)-4]

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 ºC 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 ºC under Ar. After stirring for 90 min at the same temperature, the reaction mixture was quenched with a saturated NH₄Cl 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 MgSO₄ and concentrated in vacuo. The crude product was purified by chromatoghraphy in silica gel impregnated with AgNO₃ 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. [a]_D²⁵: + 35.1 (c = 0.5, CHCl₃).

Enantiomeric purity of (S)-4 and (R)-4

Compound (S)-4 and (R)-4 were hydrogenated to the corresponding 4-hexadecanolide by stirring in CH₃OH for 1 h under hydrogen atmosphere in the presence of catalytic amount of Pd/C. The solution was filtered through a short silica gel pad and directly injected in a gas chromatograph equipped with a Chirasil-DEX CD (Crompack) chiral phase capillary column. Separation of enantiomers was performed using the following gradient temperature program 145 ºC (130 min) to 155 ºC (30 min) at 1º C min^-1 gradient. Carrier gas pressure (H₂) was 60 kPa. The injector and detector temperatures were maintained at 220 ºC. The hydrogenated (S)-4 and (R)-4 were identified by their mass spectra. MS (m/z) (%rel): 28 (100), 29 (53), 41 (47), 43 (47), 55 (48), 57 (33), 69 (30), 83 (24), 85 (83) 254 (1).

Acknowledgements

The authors thank FAPESP, CNPq and CAPES for support.

References

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Received: March 31, 2004

Published on the web: October 1, 2004

Publication Dates

• Publication in this collection
  24 Jan 2005
• Date of issue
  Dec 2004

History

• Received
  31 Mar 2004
• Accepted
  01 Oct 2004