SYNTHESIS OF NEW NITROGEN-CONTAINING DRIMANE AND HOMODRIMANE SESQUITERPENOIDS FROM SCLAREOLIDE

The synthesis of new nitrogen-containing drimane and homodrimane sesquiterpenoids in cycle B is reported. A comparative study of the microwave (MW) assisted synthesis of drimenone versus classical conditions has been done. The drimanic and homodrimanic oximes were prepared on the base of ketones derived from commercially available sclareolide. The drimanic amine was obtained by reduction of corresponding oxime with LiAlH4. The structure of novel compounds was confi rmed using IR, 1H and 13C NMR analyses.


Introduction
Drimane and homodrimane sesquiterpenoids are classes of natural products with a broad spectrum of biological activities, including antifungal, antibacterial, antiviral, cytotoxic, antifeedant, and others [1].The presence of nitrogen in a molecule is usually accompanied either by the appearance of new activities or by intensifi cation of the original activity characteristic for the native terpenoids.
In scientifi c literature there are few examples about syntheses of cycle B functionalized drimanic and homodrimanic amines [2].Thus, the aim of this research is the synthesis of drimanic and homodrimanic compounds with nitrogen containing functional groups in cycle B.

Results and discussion
Herein we report the preparation of new nitrogen-containing drimane and homodrimane sesquiterpenoids in cycle B (Scheme 1).
In another case, ketoester 11 was treated with hydroxylamine hydrochloride in a mixture of ethanol:pyridine (1:1), giving ester oxime 15 described in [11], which was subsequently saponifi cated with KOH in methanol into the oxime 16 in 95% yield.
Oximes 15 and 16 were reduced with LiAlH 4 in anhydrous THF as in [8], giving two compounds: hydroxy oxime 17, in 55% and 60% yield and hydroxy ketone 18, in 10% and 12% yield.The structure of compound 17 was confi rmed by IR, 1 H, and 13 C NMR data.
Several attempts to reduce oximic functions from molecules of compounds 15 and 16 were unsuccessful, probably because of steric impediments which appear in the molecules of the mentioned homodrimanic oximes 15 and 16, but not in the molecules of drimanes.

Conclusion
Novel nitrogen-containing drimane and homodrimane sesquiterpenoids in cycle B were synthesized.They are of scientifi c interest as compounds with potential biological activity.

General experimental procedure
Melting points (m.p.) were taken on a Boetius hot stage apparatus.Optical rotations were determined on a Jasco DIP 370 polarimeter with a 1dm microcell, in CHCl 3 .IR spectra were obtained on Spectrum-100FT-IR spectrometer (Perkin-Elmer) with ATR technique.1 H and 13 C NMR spectra were recorded in CDCl 3 on Bruker Avance DRX 400 spectrometer.Chemical shifts are given in ppm in δ scale and referred to CHCl 3 (δ H at 7.26 ppm) and to CDCl 3 (δ C 77.00 ppm), respectively.Coupling constants (J) are reported in Hertz (Hz).The H, H-COSY, H, C-HSQC and H, C-HMBC experiments were recorded using standard pulse sequences, in the version with z-gradients, as delivered by Bruker Corporation.Carbon substitution degrees were established by the DEPT pulse sequence.
The microwave assisted (MW) transformations were carried out using a monomode reactor (800W, STAR SYSTEM-2, under a constant irradiation power, but at varying temperature.The best results were obtained when 30% of the full power of the magnetron was used. For analytical TLC, Merck silica gel plates 60G in 0.25 mm layers were used.The TLC plates were sprayed with conc.H 2 SO 4 and heated at 80°C.Column chromatography was carried out on Across silica gel (60-200 mesh) using petroleum ether (PE) (b.p. 40-60°C) and the gradient mixture of PE and EtOAc or the gradient mixture of methanol and CHCl 3 .
All solvents were purifi ed and dried by standard techniques before use.Solutions in organic solvents were dried over anhydrous Na 2 SO 4 , then fi ltered and evaporated under a reduced pressure.

General procedure of drimenone 12 preparation under microwave irradiation
Caution!It is hazardous to rapidly heat reactions under microwave irradiation.Therefore, caution should be exercised when conducting reactions of this type.
A solution of ketoester 11 (1g, 3.6 mmol) and potassium hydroxide (4.17g, 74.3 mmol) in ethanol (36 mL) was prepared as described in [10] and placed in the reaction vessel (quartz).The tube was then placed in the microwave cell and irradiated at 240 W for 1.5 h.Once the heating cycle was complete, the tube was cooled to ambient temperature and removed from the reactor.The 2/3 of the solvent volume were removed under a reduced pressure, then the residue was diluted with water (15 mL), extracted with Et 2 O (3 x 10 mL), and the organic layer was washed with water (2 x 20 mL) and dried.After the solvent removal, drim-8(9)-en-7-one 12 (0.776 mg, 98 %) was obtained, as white crystals m.p. 51-52°C.The spectral data of compound 12 are in accordance with those mentioned in [10].