An efficient strategy for the construction of X-azatricyclo [m.n.0.0 a,b ]alkanes by intramolecular [3 +2] cycloaddition of nonstabilized cyclic azomethine ylides

Various new structural entities related to X -azatricyclo[m.n.0.0. a,b ]alkanes 15a-d are constructed employing the intramolecular [3+2]-dipolar cycloaddition of nonstabilized cyclic azomethine ylides. The ylides are generated by the sequential double desilylation of N -alkyl- α , α '- bis(trimethylsilyl)cyclic amines 14a-d using Ag(I)F as a one-electron oxidant. More rigid azatetracyclo compounds of type 23 , in which benzene ring is attached as a tether unit in the N - alkyl chain moiety, are also synthesized by the cyclization of 22 . These rigid azatricyclo compounds 15 and 23 possess structural resemblance to the rigid azatricyclo analogues 8-10 , which are reported to exhibit selective and high binding affinity at dopamine transporter (DAT).

2][23] We have also explored its application for the regio-and stereoselective construction of Xazabicyclo[m.2.1]alkane skeletons. 24Synthetic application of this strategy have also been demonstrated for the synthesis of biologically important alkaloids epibatidine 25 and epiboxidine. 26

Scheme 1
Our continuing interest and the desire to explore the versatility of such ylides in the construction of complex polycyclic fused pyrrolidine ring systems led us to consider the intramolecular cycloaddition variant.We envisaged the construction of Xazatricyclo[m.n.0.0 a,b ]alkanes 7, a new azatricyclic structural entities, by the intramolecular [3+2]-dipolar cycloaddition reaction of a nonstabilized cyclic azomethine ylide 6 (Scheme 2).The interest of constructing skeletons of type 7 was further enlightened by the recent disclosure of Smith et al. 27,28 that the rigid cocaine analogues (8-10) having azatricyclo ring systems show high binding affinity to the site of the monoamine transporters.The enhanced selectivity of these rigid tropane analogues for the monoamine transporter inhibitors is understood to be influenced by the fixed orientation of the nitrogen lone pair due to the tethered carbon bridge of the tropane moiety.

Scheme 2
In this article we delineate the full details 29

Scheme 4
The intramolecular [3 + 2]-dipolar cycloaddition reaction was first carried out with the key precursor 14a, by essentially following the experimental protocol as reported earlier. 26A solution of 14a (1.0 g, 2.82 mmol) in dry DCM was added slowly to a stirred suspension of vacuum dried Ag(I)F (0.89 g, 7.02 mmol) at room temperature.The color of the reaction mixture gradually turned dark brown and the reaction was completed within 46 h with the concomitant formation of silver mirror on the surface of the reaction flask.The reaction mixture was passed through a Celite pad and the residue was purified by silica gel column chromatography using chloroform / methanol (7:3) to afford a single product 15a in 61 % yield, characterized by 1 H NMR, 13 C NMR and mass spectral data (Scheme 5).
The generality of the cycloaddition reaction was established by constructing a number of Xazatricyclo[m.n.0.0 a,b ]alkanes 15b-d through the intramolecular cycloaddition reaction of substrates 14b-d as illustrated in Scheme 5.

Scheme 5
Detailed 1 H NMR decoupling and 1 H COSY experiments determined the stereochemistry of the cycloadducts.For illustration in the 1 H COSY of 15a, the H 6 at δ2.53 (m, 1H) couples with H 7 at δ 2.95 (d, J = 5.7 Hz), H 5endo at δ1.51-1.64(m) and H 5exo at δ1.65-1.78(m), but not with H1 at δ 3.05-3.17(m).This observation is in conformity with the 1 H NMR patterns of the 7azabicyclo[m.2.1]alkane skeletons 36,37 where no coupling is observed between bridgehead bowsprit and the adjacent endo-hydrogen due to the dihedral angle of 90 o between them.Therefore, H 6 is assigned with an endo-orientation.In contrast, H 7 coupled with H 6 and H 8 at δ 3.73 (t, J = 4.6 Hz) confirming the endo orientation of the carboethoxy moiety.The stereochemistry of other cycloadducts 15b-d was ascertained similarly and it is confirmed that in all the cycloadducts the carbethoxy moiety is endo-oriented.
Considering the reported 27 high binding affinity at the dopamine transporter of the azatricyclo analogue 10 (Fig. 1), we extended our effort towards the synthesis of a more rigid azatetracyclo compounds of type 23  In summary, we have successfully demonstrated the synthesis of a number of polycyclic Xazatricyclo[m.n.0.0 a,b ]alkanes by employing the intramolecular [3+2]-dipolar cycloaddition of nonstabilized cyclic azomethine ylides.We believe that these rigid polycyclic structures may be of interest in natural product synthesis and medicinal chemistry.Studies related to the biological activities of these products are in progress and will be reported appropriately.

Experimental Section
General Procedures.All the yields reported refer to isolated material but are not optimized.Temperatures above and below ambient temperature refer to bath temperature unless otherwise stated.Solvents and anhydrous liquid reagents were dried according to the established procedures by distillation under argon atmosphere from an appropriate drying agent.Chemicals and reagents were procured from Aldrich, U. S. A. and SD Fine Chemicals, India.Analytical TLC was performed using precoated silica gel plates (0.25 mm).Column chromatography was performed using Silica gel by standard chromatographic techniques.
IR spectra were recorded on a Perkin-Elmer infrared spectrometer model 599-B and model 1620 FT-IR.All nuclear magnetic resonance spectra were recorded on either Bruker AC-200, Bruker MSL-300 and Bruker DRX-500 instruments using CDCl 3 as solvent.All chemical shifts are reported in parts per million down field from TMS; coupling constants are given in Hertz.Mass (m/z, relative intensity) spectra were recorded at a voltage of 70 eV on Finnigan-Mat 1020B instrument.

Preparation of ethyl-6-[2,5-di(trimethylsilyl)tetrahydro-1H-1-pyrrolyl]-(E)-2-hexenoate (14a).
To a suspension of 11a (1.9 g, 8.83 mmol) and K 2 CO 3 (2.47 g, 17.9 mmol) in 30 mL of acetonitrile was added a solution of 13a (1.6 g, 5.97 mmol) in 10 mL of acetonitrile under argon atmosphere at rt.The resultant suspension was refluxed for 24-30 h.The reaction mixture was cooled, filtered, diluted with EtOAc, washed with water, brine and dried over Na 2 SO 4 .The organic layer was evaporated under vacuum and the brownish oily residue was purified over silica gel column chromatography using hexane/EtOAc (8:2) to give 1.38 g (65 %) of 14a as a of our effort and the success on the construction of various X-azatricyclo[m.n.0.0 a,b ]alkanes skeleton 7 through the strategy as shown in Scheme 2.