studies in opium alkaloids

Abstract

The thesis entitled "STUDIES IN OPIUM ALKALOIDS: (i) SYNTHETIC UTILITY OF AMINE QUATERNIZATION (ii) MICROBIAL TRANSFORMATIONS OF MORPHINE" consists of four chapters.

CHAPTER 1: CONVENIENT METHOD FOR REPLACEMENT OF TERTIARY N-METHYL BY OTHER ALKYL GROUPS In general, this chapter describes a simple method for replacing tertiary N-methyl by other alkyl groups in two simple steps: (i) Quaternization of the tertiary N-methyl compound with appropriate alkyl halide, and (ii) Preferential removal of the methyl group by benzenethiolate anion, a nucleophile (Scheme-1). This chapter has been divided into three parts: • Part I deals with the application of this method to some cyclic tertiary amines (model compounds). • Part II describes the successful application of this method to morphine alkaloids viz., morphine, codeine and thebaine. • Part III describes some of the limitations of this method encountered during the studies.

PART I: APPLICATION TO MODEL COMPOUNDS The replacement of N-methyl of 1-methylpiperidine, 4-methylmorpholine, 2-methyl-1,2,3,4-tetrahydroisoquinoline and tropine by n-propyl, n-butyl and isopropyl groups has been achieved in high yields by quaternization of the respective tertiary amine with appropriate alkyl halide and demethylation of the resulting quaternary salt with sodium benzenethiolate. It was established that demethylation is strongly favoured over the removal of n-propyl and n-butyl groups, whereas deisopropylation occurs to some extent. The N-methyl of 1-methylpiperidine has been replaced by 3-hydroxypropyl group, indicating that alkyl groups carrying hydroxyl function, a useful functional group for synthetic manipulations, can also be easily introduced by this method. The absence of Hofmann elimination in all these reactions shows that the experimental conditions are ideal for selective removal of N-methyl group from a quaternary salt by benzenethiolate anion through nucleophilic displacement.

PART II: APPLICATION TO MORPHINE ALKALOIDS N-Alkylnormorphines, N-alkylnorcodeines and N-alkylnorthebaines have been prepared from morphine, codeine and thebaine by quaternization of the respective alkaloid with appropriate alkyl halide and demethylation of the resulting quaternary compound with sodium benzenethiolate in butanone/acetonitrile. Unlike codeine and thebaine, morphine could not be quaternized with 2-iodopropane under similar conditions. Thebaine is quaternized more rapidly than morphine and codeine. The ease with which demethylation occurs in the case of quaternary compounds of morphine, codeine and thebaine when compared to those of model compounds may be due to release of strain by demethylation. The fact that the quaternary salts of thebaine, which are expected to be susceptible to aromatization of the nucleus by extrusion of the ethanamine chain, are smoothly demethylated to N-alkylnorthebaines in good yields indicates that demethylation, a bimolecular nucleophilic displacement, competes very successfully with elimination reaction. The mass spectral fragmentations of N-alkylnorcodeines and N-alkylnorthebaines are also discussed.

PART III: LIMITATIONS Epichlorohydrin, an epoxyalkyl halide, reacts with thebaine to give 2,3-epoxypropyl ether of thebaol instead of a quaternary salt. This reaction is quite analogous to the reaction of thebaine with acid chlorides or anhydrides producing esters of thebaol. A possible mechanism has been proposed. Benzenethiolate anion, being a nucleophile, can open up epoxide rings and replace easily leaving groups like halides by reaction. Deallylation of the quaternary salts competes well over demethylation with sodium benzenethiolate. It has been shown that sodium benzenethiolate does not effect O-demethylation under the experimental conditions standardized for N-demethylation of quaternary salts and effects O-demethylation to a minor extent (?10%) under severe experimental conditions (in DMF at 160°C). However, highly activated aromatic O-methyl groups by –I effect, as in the case of N-propylnornarcotine, can be easily removed by benzenethiolate anion. An attempt to replace N-methyl of narcotine by n-propyl group by quaternization with 1-iodopropane followed by treatment of the resulting quaternary salt with sodium benzenethiolate failed to yield N-propylnornarcotine. Instead, two other compounds were formed and identified as mono-O-demethylated and bis-O-demethylated derivatives.

CHAPTER 2: STEREOSELECTIVITY IN QUATERNIZATION OF THEBAINE High-resolution PMR (270 MHz) studies in detail on the quaternization of thebaine with n-propyl iodide and the comparatively bulkier isopropyl iodide have revealed that the major diastereomer is formed to the extent of ~90% of the mixture by axial attack of the alkyl halide. There was no significant change in the ratio of the diastereomers with solvent or with large excess of the alkyl halide used. The stereoselectivity in quaternization has been further proved by the technique of reverse quaternization. The minor product obtained in the case of ‘direct quaternization’ was the major product in the case of ‘reverse quaternization’, proving that the incoming alkyl group occupies axial position in the major diastereomer. The diastereomers were separated by column chromatography and the pure compounds were fully characterized by m.p., [?]D, PMR, IR, CD and microanalytical data. It has been reported in the quaternization of morphine and codeine that the alkyl halide approaches predominantly from the axial side. This approach of the alkyl halide can cause 1,3-steric interactions with the axial hydrogens on C-14 and C-15 in the case of morphine and codeine. Obviously, this 1,3-steric interaction will be minimized in the case of thebaine since H-14 is absent in this alkaloid. Therefore, thebaine is quaternized more rapidly than morphine and codeine under similar experimental conditions.

CHAPTER 3: CONVERSION OF NARCOTINE INTO A MACROLIDE Narcotine, which belongs to the phthalideisoquinoline group, is present in opium to a considerable extent (0.7–6.4%). This alkaloid is invariably obtained as a by-product when opium is processed for large-scale isolation of morphine. Though narcotine has a mild antitussive effect, reports have not indicated any extensive use in medicine. This chapter describes the conversion of narcotine into a 14-membered macrolide for the first time. This has been achieved by a simple three-step process using cheap reagents. Narcotine was quaternized With 3-bromopropanol, the resulting quaternary salt (8b) was treated with aqueous potassium hydroxide to give N-(3-hydroxypropyl) nornarceine (10b), which on lactonization with TsCl and TEA (triethylamine) in chloroform yielded the 14-membered macrolide (12). Attempts to lactonize 10b to 12 with cyanuric chloride or 2,4,6-trichloropyrimidine were unsuccessful and led to a complex mixture of unidentifiable products. Since many of the naturally occurring macrolides are biologically active, it is quite possible that the compound (12) may be biologically more active than the parent compound narcotine (8a). The reaction of cyanuric chloride with TEA has been utilized to convert TEA into diethylimine for the first time.

CHAPTER 4: MICROBIAL TRANSFORMATIONS OF MORPHINE Significant amount of information is available regarding the biosynthesis of morphine alkaloids in higher plants. But very little is known about their biodegradation in different living systems. Although transformations of morphine alkaloids using fungal systems have been attempted, there has been no report on the bacterial degradation of these compounds. We have been able to isolate a gram-positive bacterium which utilizes morphine as the sole source of carbon and energy. Fermentation of morphine (5a) by this strain resulted in the formation of codeine (5d), 14-hydroxymorphinone (13), 9,14-dihydroxymorphine N-oxide (14) and a conjugate of 14-hydroxydihydromorphinone (15). The 9,14-dihydroxymorphine N-oxide (14) is a new metabolite of morphine hitherto unknown. The finding of 14-hydroxylation of morphine as one of the reactions taking place during the bacterial transformations parallels results previously obtained with fungal systems. One of the peculiarities of the bacterial system is its ability to carry out N-oxidation in a stereospecific manner, producing only one diastereomer contrary to what has been observed in the case of higher plant systems.