SYNTHESIS OF NEW DRIMANE AND HOMODRIMANE LACTAMS BY BECKMANN REARRANGEMENT OF SOME KETOXIMES

Introduction Many drimane and homodrimane sesquiterpenoids, including those with nitrogen, exhibit various types of a biological activity: antifungal, antibacterial, antiviral, cytotoxic, antifeedant, etc. [1]. Therefore, the development of synthetic methods for these compounds is of a scientifi c and practical importance. In a search for new biologically active compounds and in continuation of our group’s investigations of obtaining nitrogen-containing sesquiterpenoids [2-5], in the present paper the synthesis of new drimane and homodrimane lactams by the Beckmann rearrangement of some ketoximes is described. Earlier Grant et al. reported the preparation of amides 1-4 by the Beckmann rearrangement of Zand Eisomers of oxime 5 obtained from 14,15-dinorlabd-8(17)-en-13-one 6 [6]. Then, Barrero et al. described a multi-step synthesis of amide 7 from (-)-sclareol [7]. Later, amides 8 and 9 were synthesized by the Beckmann rearrangement of oxime 10 of 11-dihomodriman-8α-ol-12-one 11 [8] (Figure 1).


Introduction
Many drimane and homodrimane sesquiterpenoids, including those with nitrogen, exhibit various types of a biological activity: antifungal, antibacterial, antiviral, cytotoxic, antifeedant, etc. [1].Therefore, the development of synthetic methods for these compounds is of a scientifi c and practical importance.
In a search for new biologically active compounds and in continuation of our group's investigations of obtaining nitrogen-containing sesquiterpenoids [2][3][4][5], in the present paper the synthesis of new drimane and homodrimane lactams by the Beckmann rearrangement of some ketoximes is described.
Earlier Grant et al. reported the preparation of amides 1-4 by the Beckmann rearrangement of Zand Eisomers of oxime 5 obtained from 14,15-dinorlabd-8(17)-en-13-one 6 [6].Then, Barrero et al. described a multi-step synthesis of amide 7 from (-)-sclareol [7].Later, amides 8 and 9 were synthesized by the Beckmann rearrangement of oxime 10 of 11-dihomodriman-8α-ol-12-one 11 [8] (Figure 1).The Beckmann rearrangement is known to occur stereospecifi cally as a result of anti-migration of the bulkier radical.Therefore, it has been expected that the major product of the Beckmann rearrangement of oxime 10 would be amide 7.However, in the case of oxime 10, amide 9 is obtained as a result of the migration of CH 3 -group and concomitant dehydration.

Results and discussion
Herein, the synthesis of new drimane and homodrimane lactams 17-21 by the Beckmann rearrangement of the corresponding oximes 22 and 23 is described.Oximes 22 and 23 have been obtained earlier [10] from the commercially available norambreinolide 24 according to the procedure [11].
The treatment of ketoxime 22 with thionyl chloride in anhydrous dioxane according to the literature procedure [9,12] resulted in a mixture of isomeric lactams 17 and 19.The Beckmann rearrangement of oxime 23 under these conditions gave a mixture of lactams 20 and 21 (Scheme 1).
The structures of all new compounds were confi rmed by the IR, 1 H, 13 C, 15 N-NMR spectral data and by elemental analysis.
The NMR data of compound 20 have been assigned (Figures 3, 4) on the base of their 1D ( 1 H, 13 C, DEPT-135 o ) and 2D homo-( 1 H/ 1 H COSY-45 o , 1 H/ 1 H NOESY) and heteronuclear ( 1 H/ 13 C HSQC, 1 H/ 15 N HMQC and 1 H/ 13 C HMBC, 1 H/ 15 N HMBC) correlation spectra.According to the NMR spectral data, compound 20 is a homodrimane lactam.An analysis of 1 H, 13 C, 1 H/ 1 H COSY and 1 H/ 13 C HSQC NMR spectra suggested the presence of three isolated spin systems: CH 2 CH 2 CH 2 (C-11 to C-9), CHCH 2 NH (C-7 to NH), and CHCH 3 (C-4 to C-13) (Figure 3).Key 1 H/ 13 C HMBC and 1 H/ 15 N HMBC correlations for lactam 20 are also depicted in Figure 3.The rearranged carbon framework of compound 20 becomes obvious at a detailed analysis of its 1 H/ 13 C HMBC spectrum.Thus, the observed correlations from H-12 to sp 2 hybridized carbon (C-5, δ C 169.9) are indicative for the  5 (12) localization, which was supported also by the correlations H-12/C-4 and H-12/C-6.A signal of a lactam nitrogen atom has been found at δ N 110 ppm in the 1 H/ 15 N HMQC spectrum, while its proton resonates at δ H 5.93 ppm as a broad triplet with J = 5.8 Hz.The position of lactam has been corroborated by both 1 H/ 15 N HMBC and 1 H/ 13 C HMBC spectra.Thus, the H-7/N-2 cross-peak in the 1 H/ 15 N HMBC spectrum, as well as H 3 -13/C 3 , H 3 -13/C 4 and H 3 -13/C 5 in the 1 H/ 13 C HMBC spectrum, prove the localization of a lactam function as depicted in Figure 3.The migration of a double bond  4 (5) in precursor 23 to  5 (12) , as a result of the reaction, has additionally generated two centres of isomerism: a geometrical centre at C-5/C-12 and an optical one at C-4.The NOESY correlations between H-12 and H 3 -16, as well as H-12 and H-11, demonstrate the trans nature of the isomer at  5 (12) .The NOESY correlation between H-4 and H-7 indicates that they are in the α-plane and determines the (R) relative confi guration at C-4 (Figure 4).

Conclusion
New drimane and homodrimane lactams, derivatives of octahydro-1H-benzo[d]azepine and octahydro-1Hbenzo[c]azepine, which are of a scientifi c and practical importance as compounds with a potential biological activity, were synthesized.

General experimental procedure
Melting points (m.p.) have been determined on a Boetius heating stage and were not corrected.The IR spectra have been recorded on a Perkin-Elmer Spectrum 100 FT-IR spectrometer.The NMR spectra have been recorded on a Bruker 400 Avance III spectrometer at 400.13 MHz for 1 H, 100.62 MHz for 13 C and 40.55 MHz for 15 N in CDCl 3 , with tetramethylsilane (TMS) as an internal standard.Proton chemical shifts (δ) are reported in parts per million (ppm) and are compared against the residual non-deuterated solvent peak (7.26 ppm for CHCl 3 of CDCl 3 ).Chemical shifts of carbon atoms (δ) are reported in ppm and are compared against the deuterated solvent peak (77.00 ppm for 13 C of CDCl 3 ) and relative to MeNO 2 in the 15 N NMR spectra.Coupling constants (J) are recorded in Hertz.Signals in the 1 H and 13 C NMR spectra have been assigned using the DEPT-135, 1 H/ 1 H COSY-45, 1 H/ 13 C HSQC, 1 H/ 13 C HMBC, and 1 H/ 1 H NOESY experiments whereas the 1 H/ 15 N HMBC experiments have been used for the assignment of the 15 N nuclei chemical shift.The course of reactions has been monitored by the TLC on Silufol plates with the detection by I 2 vapours.The column chromatography has been performed on Silica Gel (L 70-230 mesh Fluka).Chemicals have been