One-pot synthesis of 1,3-bis(cytisinyl)propan-2-ol

Abstract

SHORT COMMUNICATIONS(-)-Cytisine {I, (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one} is an accessible alkaloid of the quinolizidine series. It attracts interest due to its broad spectrum of physiological activity (spasmolytic, cholinergic, analgesic) which originates from its high affinity for nicotine acetylcholine receptors (nAChRs) [1][2][3]. We found that introduction of a 2-hydroxyethyl fragment into cytisine molecule gives rise to high antiarrhythmic activity which was not found previously for cytisine derivatives; in addition, the toxicity of the resulting compound was lower than that of known antiarrhythmics [4,5].We succeeded in developing a new one-pot procedure for the synthesis of 1,3-bis(cytisinyl)propan-2-ol II from cytisine (I) and 1-chloro-2,3-epoxypropane. Compound II was synthesized previously in two steps with an overall yield of 34% [6]. By heating cytisine (I) with 1-chloro-2,3-epoxypropane at a molar ratio of 2 : 1 in MeOH-H 2 O (volume ratio 3 : 2) we obtained alcohol II in 80% yield with high selectivity. Compound II may be interesting not only as physiologically active substance but also as reagent for asymmetric syntheses. When methanol, acetone, or benzene was used as solvent, either a complex mixture of products was formed or no reaction occurred.The structure of compound II was confirmed by the 1 H and 13 C NMR spectra; signals were assigned using HH-COSY and CH-CORR techniques. In the 13 C NMR spectrum of II we observed two sets of signals from carbon atoms in the cytisine fragments. Exceptions were magnetically equivalent C 8 and C 8′ nuclei which resonated at δ C 25.73 ppm.(1R,5R,1′R,5′R)-3,3′-(2-Hydroxypropane-1,3-diyl) bis(1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido-[1,2-a][1,5]diazocin-8-one) (II). 1-Chloro-2,3-epoxypropane, 0.24 g (2.63 mmol), was added to 1.0 g (5.26 mmol) of cytisine in 20 ml of a mixture of methanol with water (volume ratio 3 : 2). The mixture was heated for 2 h under reflux, the solvent was removed under reduced pressure, 6 ml of water, 20 ml of chloroform, and ~1 ml of 20% aqueous sodium hydroxide were added to the residue (until pH 8-9), and the mixture was extracted with chloroform (3 × 25 ml). The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on silica gel using chloroform-methanol (9 : 1) as eluent. Yield 0.92 g (80%), colorless amorphous hygroscopic powder, R f 0.43 (CH 3 Cl-MeOH, 9 : 1), [α] D 20 = -230° (c = 0.175, CHCl 3 ). IR spectrum, ν, cm -1 : 3080-3600 (OH),