Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties
Konstantin Ponomarev ∙ Evgeniy Suslov ∙ Alla Pavlova ∙ Oleg Ardashov ∙ Dina Korchagina ∙ Andrej Nefedov ∙ Tat’yana Tolstikova ∙ Konstantin Volcho ∙ Nariman Salakhutdinov
SUPPORTING INFORMATION
1. Procedures for the synthesis of aldehydes 6b, 6c, 6g, 6h and 6i
2. 1H and 13C NMR spectra of compounds 5a and 5f
(+)-Myrtenal (6b).
(+)-Myrtenal 6b was synthesized according to the procedure (Kiesgen de Richter et al., 1990). t-BuOOH was extracted from 70% aqueous solution of t-BuOOH (10 ml) with CH2Cl2 (13 ml). SeO2 (0.17 g, 1.55 mmol) and (+)-α-pinene (7) (2.9 g, 21.3 mmol, = 50.4 (c = neat)) were added under stirring to the solution of t-BuOOH in CH2Cl2 (11.6 ml). The reaction mixture was kept at 35 °C for two days, then cooled to room temperature, washed with 10% aqueous NaOH and H2O to pH ~ 7 and dried over Na2SO4, the drying agent was filtered off and washed with EtOAc, and then the solvents were removed. The residue was purified by column chromatography on SiO2. Yield of (+)-myrtenal 6b was 1.98 g (62%).
2-((1S,5R)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)acetaldehyde (6c).
Aldehyde 6c was synthesized as described (Firouzabadi and Sharifi 1992). Zn(ClCrO3)2·9H2O (4.5 g, 9.03 mmol) was added in four portions during 15 min to a stirred solution of (-)-nopol 8 (1 g, 6.02 mmol, = -37 (c = neat)) in CH2Cl2 (70 mL). The mixture was stirred for 2 h, then diluted with 60 ml CH2Cl2 and filtered through a glass filter with layer of SiO2. SiO2 was washed with CH2Cl2 (2 × 60 mL). The filtrates were combined, added to 4 g SiO2 and stirred for 30 min. SiO2 was filtered and the solvent was removed. As a result, we have obtained 6c in 44% yield (0.43 g). The spectral characteristics of compound 6c corresponded to those described in article (Burford et al., 1983).
2-((1R,3R)-3-Acetyl-2,2-dimethylcyclobutyl)acetaldehyde (6g).
Aldehyde 6g was synthesized as described (Barton and Fontana 1996). A solution of compound 10 (5.00 g 36.8 mmol, = -44 (c = neat)) in 50 ml of methanol was placed in a three-necked flask equipped with a thermometer, a mechanical stirrer and a bubbler. The reaction mixture was cooled to -70 °C with a cooling system of isopropanol - liquid nitrogen. A mixture of O2/O3 (O3= 28.2 mmol/h) was bubbled into the solution until a blue color appeared (after 120 min). The reaction mixture was purged with argon for 15 min. Me2S (5 ml, 67.7 mmol) was added at ~ -40 °C and the reaction mixture was allowed to stay at room temperature for 3 days. The solvent was distilled off. The residue was diluted 50 mL Et2O, washed with saturated NaHCO3 (2´25 mL) and NaCl (2´25 mL). The organic phase was dried over MgSO4, the drying agent was filtered off and the solvent was removed. As a result, we have obtained 6g in 46% yield (2.86 g). 1H NMR spectrum of compound 6g coincides with the literature data (Boltukhina et al., 2011).
R)-2-(2,2,3-Trimethylcyclopent-3-en-1-yl)acetaldehyde (6h) and (S)-2-(2,2,3-trimethylcyclopent-3-en-1-yl)acetaldehyde (6i).
Aldehydes 6h and 6i were synthesized from (-)- and (+)-α-pinene epoxides 11 and 12, respectively, based on the method described in (Lopez et al., 1994) with minor changes (we used benzene instead of CH2Cl2). Freshly dried ZnCl2 (0.5 g) was added to a solution of (-)-α-pinene epoxide 11 (synthesized from (-)-α-pinene = -44 (c = neat)) or (+)-α-pinene epoxide 12 (synthesized from (+)-α-pinene = 50.4 (c = neat)) (5.26 g, 34.55 mmol) in 33 mL of dry benzene. The reaction mixture was stirred for 2 h at room temperature. Then CH3COOH (2 mL) and H2O (2 mL) were added. The organic phase was dried over Na2SO4, the drying agent was filtered off and the solvent was removed. As a result, we have obtained 6h 3.14 g (60%) and 3.35 g (64%) 6i. The spectral characteristics of compounds 6h and 6i corresponded to those described in article (Lopez et al., 1994).