Enantioselective synthesis of strobamine and its analogues

(2 S ,5 S ,8 R )-Strobamine (+)- 1a was synthesized by adding cinnamoyl cyanide 6a to tropinone 3 lithium enolate generated by treatment of ( S , S' )-α,α-dimethyldibenzylamide with butyl lithium in the presence of lithium chloride to give (–)-chalcostrobamine (–)- 7a , which yielded a one-to-one mixture of (+)- 1a and its C-2 epimer (–)- 2a on treatment with 2N sulfuric acid. Compounds (+)- 1a and (–)- 2a could be separated by column chromatography. (–)-Strobamine (–)- 1a and (+)- 2a were synthesized by a similar set of reactions using the tropinone 3 lithium enolate generated with butyl lithium in the presence of ( R , R' )-α,α'-dimethyldibenzylamide and lithium chloride. (+)- and (–)- p -Methylstrobamine (+)- and (–)- 1b and (+)- and (–)- epi-p-methylstrobamine (+)- and (–)- 2b were synthesized by a similar procedure. The absolute configuration of (+)- epi-p-methylstrobamine (+)- 2b was determined by X-ray analysis to have the (2 S ,5 R ,8 S ) configuration.

The IC50 value of 265 nM for the inhibition of binding to the dopamine transporter for (+)-1a was not appreciably different from that of the racemate.

Conclusions
The enantioselective synthesis of the natural product (+)-strobamine (+)-1a and its p-methyl analogue has been achieved.The absolute configuration of strobamine has also been determined for the first time by NMR and X-ray spectroscopic analysis of the (+)-p-methyl analogue (+)-2b.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Bruker 300 Spectrometer using TMS as an internal standard.Optical rotations were measured with an Autopol IV automatic polarimeter.HPLC analyses were carried out on a Dynamax HPLC system.The optical purity was determined by chiral HPLC [Sumichiral OA-4900 (4.6 mm × 25 cm).Flash column chromatography was performed using EM Science silica gel 60 (particle size 40-63 μm).CMA80 is a mixture of 80% chloroform, 18% methanol, and 2% concentrated ammonium hydroxide.Elemental analyses were performed by Atlantic Microlab, Inc., Atlanta, GA.

General procedure for the synthesis of strobamine and analogs
A solution of n-BuLi (0.95 mL, 2.5 M, 23.7 mmol) in hexane was added dropwise to a solution of (R,R')-or (S,S')-α,α'-dimethyldibenzylamine•HCl (0.30 g, 1.2 mmol) in anhydrous THF (28 mL) at 0 °C.The resulting mixture was stirred at 0 °C for 1 h and cooled to -78 °C.A solution of tropanone 3 (0.14 g, 1.0 mmol) in THF (1 mL) was added dropwise.The resulting mixture was stirred at -78 °C for 3 h, then the corresponding cinnamoyl cyanide (1.3 mmol) in THF (4.0 mL) was added.The mixture was stirred at -78 °C for another 1 h, treated with a solution of silver nitrate (0.17 g, 1.0 mmol) in THF (0.5 mL), water (0.25 mL), and acetic acid (0.25 mL).After warming to room temperature, the solution was extracted with chloroform.Chloroform was removed under vacuum, and the residue was dissolved in aqueous 2N H2SO4 and heated at 50 °C for 24 h.After the solution cooled, it was adjusted to pH 11 with conc.ammonium hydroxide and extracted with ether.The organic layers were combined, dried (Na2SO4), and concentrated in vacuo.The residue was purified by flash chromatography (silica gel, EtOAc/Et3N 9:1) to afford (-)-1a-c and (+)-2a,b when (R,R)-5 was used, and (+)-1a,b and (-)-2a,b when (S,S)-4 was used as liquids.

X-Ray crystal structure determination of [(+)-epi-2b]
Single-crystal X-ray diffraction data on (+)-epi-methylstrobamine (+)-epi-2b was collected at 293 °K using CuKa radiation produced by a Bruker Micro-STAR rotating anode equipped with Helios optics and a Bruker Platinum-135 CCD area detector.Crystals were prepared for data by mounting on the end of a thin glass rod using an acrylic adhesive.Corrections were applied for Lorentz, polarization, and absorption effects.The crystal was orthorhombic in space group P21212 with unit cell dimensions a = 11.2517(6)Å, b = 21.5455(12)Å, c = 6.5032(4)Å.Data were 97.2% complete to 68.12º q (approximately 0.83 Å), with an average redundancy of 4.92.The structure was solved by direct methods and refined by full-matrix least squares on F2 values using the programs found in the SHELXTL suite (Bruker, SHELXTL v6.10, 2000, Bruker AXS Inc., Madison, WI).Parameters refined included atomic coordinates and anisotropic thermal parameters for all non-hydrogen atoms.Hydrogen atoms on carbons were included using a riding model (coordinate shifts of C applied to H atoms) with C-H distance set at 0.96 Å.The absolute configuration was evaluated using likelihood methods in PLATON. 6,7Based on the analysis of 1077 Bijvoet pairs (90% coverage), this analysis indicated that the absolute structure had been correctly assigned.The method calculated that the probability that the structure is inverted is smaller than 1 × 10-34.Atomic coordinates for compound (+)-epi-2b have been deposited with the Cambridge Crystallographic Data Centre (deposition number 776942).Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].