Supplementary Online Information - Journal of Chemical Ecology

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1 Supplementary Online Information - Journal of Chemical Ecology SYNTHESIS AND FIELD TESTS OF POSSIBLE MINOR COMPONENTS OF THE SEX PHEROMONE OF Prionus californicus ELIN C. MAKI 1, JOSH RODSTEIN 2, JOCELYN G. MILLAR 2,3, KAREN S. BARBOUR 1, LAWRENCE M. HANKS 4 AND JAMES D. BARBOUR 1 * 1 Southwest Idaho Research & Extension Center, Parma, ID , USA 2 Department of Entomology, 3 Department of Chemistry, University of California, Riverside, CA 92521, USA 4 Department of Entomology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

2 General Procedures Tetrahydrofuran (THF) was dried and purified by distillation from sodium-benzophenone ketyl under argon. Solutions of crude products were dried over anhydrous Na2SO4 and concentrated by rotary evaporation under reduced pressure, unless specified otherwise. Crude products were purified by flash or vacuum flash chromatography on mesh silica gel (Fisher Scientific, Pittsburgh, PA, USA). 1 H- and 13 C-NMR spectra were recorded on a Varian INOVA-400 spectrometer (Palo Alto, CA, USA) (400 and MHz, respectively), as CDCl3 solutions. Integer resolution mass spectra were obtained with a Hewlett-Packard (HP) 6890 GC (Avondale, PA, USA) interfaced to an HP 5973 mass selective detector, in EI mode (70 ev) with helium as carrier gas. The GC was equipped with a DB5-MS column (25 m 0.20 mm ID 0.25µ film; J&W Scientific, Folsom, CA, USA). Diethyl 2-methyl-2-octylmalonate (3, Scheme 1) Sodium metal (2.87 g, 125 mmol, Mallinckrodt, Hazelwood, MO, USA) was cut into small pieces and added in portions to absolute ethanol (125 ml) under argon, keeping the reaction flask in a water bath to maintain the reaction at ~ room temperature. After the sodium had completely dissolved, diethyl methylmalonate 1 (20.4 ml, 120 mmol, Aldrich Chemical Co., Milwaukee, WI, USA) was added drop-wise and the mixture stirred for 1 h, followed by drop-wise addition of 1-bromooctane 2 (23.2 g, 120 mmol, Avocado Research Chemicals Ltd., Heysham, UK). The reaction was warmed to reflux and stirred overnight. Most of the ethanol was distilled off, and the resulting mixture diluted with water and extracted with Et2O (3 ). The combined organic phases were washed with dilute HCl and brine, dried, and concentrated. The residue was purified by Kugelrohr distillation (oven temp. ~110 C, 1.5 Torr), yielding diethyl 2-methyl-2-octylmalonate (3) contaminated with

3 ethyl octyl ether. This product was carried on to the next step without further purification. 2-Methyldecanoic acid (4) Diester 3 and KOH (336 g, 6 mol) were dissolved in water (480 ml) and the mixture refluxed overnight. After cooling, the mixture was acidified with sulfuric acid (6M). The aqueous layer was extracted with Et2O (4 ), and the combined organic extracts washed with brine, dried and concentrated to yield g of crude 2-methyldecanoic acid 4, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3 H), 1.18 (d, J = 7.2 Hz, 3 H), 1.27 (m, 12 H), 1.43 (m, 1 H), 1.69 (m, 1 H), 2.47 (sextet, J = 7.2 Hz, 1 H). 13 C NMR (101 MHz, CDCl3): δ 14.2, 17.0, 22.8, 27.3, 29.4, 29.6, 29.7, 32.0, 33.7, 39.4, MS: m/z (%):186 (3), 157 (1), 143 (11), 129 (13), 115 (2), 101 (4), 87 (38), 74 (100), 55 (15), 41 (29). The 1 H and 13 C NMR spectra were consistent with those described by Constantinou-Kokotou et al. (2004). 2-Methyldecanol (5, Scheme 1) Lithium aluminum hydride (2.66 g, 70 mmol) was added in two portions to a dry three-neck flask charged with Et2O (140 ml) cooled to 0 C under argon. Crude acid 4 (13.06 g, ~70 mmol,) was added drop-wise (foams with H2 production!). After the addition was complete, the mixture was refluxed overnight, then cooled to room temperature, and quenched by drop-wise sequential addition (foams and becomes viscous!) of water (2.8 ml), 20% aqueous NaOH (2 ml), and water (9.8 ml), while stirring vigorously. The resulting mixture was stirred 20 min to allow the salts to granulate, then filtered, rinsing the filter cake with ether. The resulting clear solution was concentrated and Kugelrohr distilled (~80 C at 8 mm Hg) to yield g of 2- methyldecanol 5 (94%). 1 H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3 H), 0.91

4 (d, J = 6.8 Hz, 3 H), 1.11 (m, 1 H), 1.27 (m, 12H), 1.37 (m, 1 H), 1.45 (O-H, 1H), 1.61 (m, 1H), 3.42 (dd, J = 6.4, 10.4 Hz, 1 H), 3.51 (dd, J = 6.0, 10.4 Hz, 1 H). 13 C (101 MHz, CDCl3): δ 14.3, 16.7, 22.8, 27.1, 29.5, 29.8, 30.1, 32.1, 33.3, 35.9, MS: m/z (%): 154 (3, M + -18), 140 (1), 126 (8), 111 (14), 97 (21), 85 (28), 69 (41), 57 (92), 43 (100). The 1 H and 13 C NMR spectra were consistent with those described previously (Shimamura et al. 2007). 1-Bromo-2-methyldecane (6, Scheme 1) Methanesulphonyl chloride (6.6 ml, 85 mmol) was added drop-wise to a chilled solution (~-10 C in an ice-salt bath) of alcohol 5 (11.34 g, 65 mmol) and triethylamine (13.7 ml, 99 mmol) in methylene chloride (160 ml). The resulting mixture was stirred for 1.5 h at ~ -10 C, and then filtered with suction. The filtrate was washed sequentially with 1 M HCl, saturated NaHCO3, and brine, then dried and concentrated. The crude mesylate was taken up in acetone (160 ml) and LiBr (17.1 g, 197 mmol) was added in three portions, allowing the mixture to cool between addition of each portion. The mixture was stirred overnight, then filtered with suction, and the filtrate concentrated, then taken up in pentane and washed with water and brine. After drying and concentration, the residue was purified by vacuum flash chromatography on silica gel, eluting with pentane, yielding 1-bromo-2-methyldecane 6 (13.84 g, 89% yield, 93% purity). 1 H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 1.28 (m, 13 H), 1.44 (m, 1 H), 1.79 (m, 1 H), 3.33 (dd, J = 6.4, 10 Hz, 1 H), 3.41 (dd, J = 4.8, 9.6 Hz, 1 H). 13 C NMR (101 MHz, CDCl3): δ 14.3, 19.0, 22.8, 27.0, 29.4, 29.7, 29.9, 32.0, 35.0, 35.4, MS: m/z (%): 165 (2), 163 (2), 151 (31), 149 (33), 121 (6), 113 (6), 99 (19), 85 (47), 71 (58), 57 (100), 41 (95). The 1 H and 13 C NMR spectra were consistent with those described previously (Francke et al. 2000).

5 3,5-Dimethyltridecanoic acid (7, Scheme 1) Bromide 6 (13.74 g, 58 mmol) was dissolved in 100 ml dry THF, and 15 ml of the mixture added to Mg turnings (4.24g, 175 mmol), followed by 1,2-dibromoethane (0.1 ml), and the slurry stirred. After the reaction started, as evidenced by warming and the characteristic grey color, the remainder of the solution of 6 was added drop-wise over ~2 h. The resulting solution of 2-methyldecyl magnesium bromide was then added by syringe to a slurry of CuI (0.75 g, 3.9 mmol) and dry THF (10 ml) cooled to 0 C under argon, followed by drop-wise addition of b- butyrolactone (6.0 g, 70 mmol) in dry THF (47 ml) over 60 min. The mixture was stirred at 0 C for 30 min, warmed to room temperature overnight, then quenched with 1 M HCl and extracted three times with ether. The combined ether extracts were back extracted twice with 1 M NaOH. The combined basic aqueous layers were acidified with 3M HCl, and extracted twice with ether. The combined ether layers were washed with brine, dried, and concentrated to give 3,5-dimethyltridecanoic acid (7.89 g, 55%) as a mixture of stereoisomers, of 92% chemical purity by GC. NMR (400 MHz, CDCl3): δ 0.86 (t, J = 6.4 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H), 0.95 and 0.97 (d, J = 6.8 Hz, 3 H), (m, 2H), 1.27 (m, 14 H), 1.47 (m, 1 H), 2.13 (m, 2 H), 2.34 (m, 1 H). 13 C NMR (101 MHz, CDCl3): δ 14.3, 19.5, 19.6, 20.2, 20.5, 22.9, 27.0, 27.2, 27.9, 29.5, 29.9, 30.1, 30.2, 32.1, 36.8, 37.9, 41.5, 42.5, 44.5, 44.8, 179.2, MS m/z (%): 242 (2), 206 (1), 185 (14), 157 (2), 129 (19), 111 (17), 101 (12), 87 (100), 69 (48), 57 (62), 41 (93). Diethyl 2-decyl-2-methylmalonate (9, Scheme 1) This compound was prepared in analogous fashion to compound 3 from 1-bromodecane (8), sodium ethoxide, and 1, yielding 9 in 75% isolated yield of 88% purity. 1 H NMR (400 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 3H), 1.25 (m, 22 H), 1.39 (s, 3 H), 1.84 (m, 2 H), 4.18 (q, J = 7.2 Hz, 4H). 13 C

6 NMR (101 MHz, CDCl3): δ 14.2, 14.3, 20.0, 22.8, 24.3, 29.5, 29.5, 29.7, 29.7, 30.0, 32.0, 35.6, 53.8, 61.2, MS m/z (%): 269 (2), 241 (4), 213 (1), 195 (3), 174 (100), 155 (2), 143 (4), 128 (42), 115 (18), 100 (11), 87 (21), 55 (31), 41 (51). The 1 H and 13 C NMR spectra were consistent with those described previously for 3 (Shimamura et al. 2007). 2-methyldodecanoic acid (10, Scheme 1) This compound was prepared in analogous fashion to 4, using 9 instead of 3, to afford the desired acid in 80% yield of 94% purity. 1 H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 6.8 Hz, 3H), 1.18 (d, J = 5.6 Hz, 3H), 1.27 (m, 16 H), 1.44 (m, 1 H), 1.69 (m, 1 H), 2.45 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 14.3, 17.0, 22.8, 27.3, 29.5, 29.6, 29.6, 29.8 (2), 32.1, 33.7, 39.5, MS m/z (%): 214 (3), 185 (1), 157 (5), 143 (5), 129 (6), 115 (3), 101 (4), 87 (37), 74 (100), 55 (21), 41 (38). The 1 H and 13 C NMR spectra were consistent with those described previously (Hirase et al. 2003). 2-Methyldodecanol (11, Scheme 1) This compound was prepared in analogous fashion to 5, using 10 instead of 4, to afford the desired alcohol in 95% yield with 94% purity. 1 H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 7.2 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 1.1 (m, 1 H), 1.27 (m, 16 H), 1.37 (m, 1 H), 1.43 (s, 1 H), 1.61 (m, 1H), 3.42 (dd, J = 6.8, 10.4 Hz, 1 H), 3.51 (dd, J = 5.6, 10.4 Hz, 1 H) 13 C NMR (101 MHz, CDCl3): δ 14.3, 16.7, 22.8, 27.1, 29.5, 29.8 (3), 30.1, 32.1, 33.3, 36.0, MS m/z (%): 182 (1, M + -18), 154 (5), 140 (5), 125 (8), 111 (19), 97 (27), 69 (40), 57 (100), 43 (97). The 1 H and 13 C NMR spectra were consistent with those described previously by Schlamp et al. ( 2005). 1-Bromo-2-methyldodecane (12, Scheme 1) This compound was prepared in analogous fashion to 6, using 11 instead of 5, to afford the desired alkyl bromide in 94% yield with 98% purity. 1 H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.4 Hz,

7 3 H), 1.27 (s, 17 H), 1.45 (m, 1H), 1.79 (m, 1H), 3.33 (dd, J = 6.0, 9.6 Hz, 1 H), 3.41 (dd, J = 4.8, 9.6 Hz, 1 H). 13 C NMR (101 MHz, CDCl3): δ 14.3, 19.0, 22.8, 27.0, 29.5, 29.8 (3), 29.9, 32.1, 35.0, 35.4, MS m/z (%): 183 (7), 165 (3), 163 (3), 151 (38), 149 (38). 127 (10), 113 (15), 99 (19), 85 (44) 71 (66), 57 (100), 41 (93). 3,5-Dimethylpentadecanoic acid (13, Scheme 1) This compound was prepared in analogous fashion to 7, using the Grignard reagent from 12 instead of 6, to afford the desired acid in 82% yield with 90% purity. 1 H NMR (400 MHz, CDCl3): δ 0.86 (t, J = 6.4 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.4, 6.0 Hz, 3 H), 0.97 (d, J = 6.4, 6.0 Hz, 3 H), (m, 2H), 1.27 (m, 16 H), 1.47 (m, 1 H), 2.12 (m, 2 H), 2.34 (m, 1 H). 13 C NMR (101 MHz, CDCl3): δ 14.3, 19.4, 19.5, 20.2, 20.5, 22.9, , 27.8, 29.5 (2), 29.8, 29.9 (2), 30.1, 30.2, 32.1 (2), 36.8, 37.9, 41.5, 42.5, 44.5, 44.7, 179.4, MS m/z (%): 270 (3), 255 (1), 213 (11), 185 (1), 167 (2), 141 (3), 129 (22), 111 (15), 101 (18), 97 (93), 69 (49), 57 (73), 43 (100). Methyl-3,5-dimethyldodecanoate (14, Scheme 1) Acetyl chloride (0.03 ml, 0.4 mmol) was added drop-wise to methanol (2 ml) in an ice bath, followed by the drop-wise addition of 3,5-dimethyldodecanoic acid (0.49 g, 2 mmol). The reaction was stirred overnight at room temperature with a calcium chloride drying tube. The mixture was then poured into water, and extracted with ether (4 ), and the combined organic extracts washed with brine, dried, and concentrated. The resulting methyl ester was purified by Kugelrohr distillation (oven temp. ~100 C, 0.3 Torr) to give 14 (0.37 g, 70%) of 100% purity. NMR (400 MHz, CDCl3): δ 0.86 (t, J = 6.4 Hz, 3H), 0.90 and 0.92 (d, J = 6.8 Hz, 3 H), 0.91 and 0.93 (d, J = 6.4 Hz, 3 H), 1.07 (m, 2 H), 1.27 (m, 12 H), 1.46 (br s, 1 H), 2.08 (m, 2 H), 2.30 (m, 1 H), 3.67 (s, 3 H). 13 C NMR (101 MHz, CDCl3): δ 174.0, 51.5,

8 44.9, 44.6, 42.7, 41.8, 37.9, 36.9, 32.1, 30.2, 30.1, 29.6, 28.1, 27.2, 27.0, 22.8, 20.6, 20.3, 19.6, 19.5, MS: m/z (%): 242 (2, M + ), 227 (1), 185 (5), 169 (4), 143 (8), 115 (7), 101 (56), 83 (14), 74 (100), 55 (24), 43 (36). References: CONSTANTINOU-KOKOTOU, V., MAGRIOTI, V., and VERGER, R Sterically hindered triacylglycerol analogues as potent inhibitors of human digestive lipases. Chemistry: A European Journal 10: FRANCKE, W., PLASS, E., ZIMMERMANN, N., TIETGEN, H., TOLASCH, T., FRANKE, S., SUBCHEV, M., TOSHOVA, T., PICKETT, J. A., WADHAMS, L. J., and WOODCOCK, C. M Major sex pheromone component of female herald moth Scoliopteryx libatrix is the novel branched alkene (6Z,13)-methylheneicosene. J. Chem. Ecol. 26: HIRASE, K., SAKAGUCHI, S., and ISHII, Y Addition of carboxyalkyl radicals to alkenes through a catalytic process, using a Mn(II)/Co(II)/O2 redox system. J. Org. Chem. 68: SCHLAMP, K. K., GRIES, R., KHASKIN, G., BROWN, K., KHASKIN, E., JUDD, G. J. R., and GRIES, G Pheromone components from body scales of female Anarsia lineatella induce contacts by conspecific males. J. Chem. Ecol. 31: SHIMAMURA, H., SUNAZUKA, T., IZUHARA, T., HIROSE, T., SHIOMI, K., and OMURA, S Total synthesis and biological evaluation of verticipyrone and analogues. Org. Lett. 9:65-67.

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