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Transformation of Tobacco Alkaloids* by T Beitrage zur Tabakforschung International· Volume 9 ·No. 5 ·December 1978 Transformation of Tobacco Alkaloids* by T. Kisaki, S. Maeda, A. Koiwai, Y. Mikami, T. Sasaki and H. Matsushita Central Research Institute, The Japan Tobacco and Salt Public Corporation, Yokohama, Japan This is a review of the work on the transformation of We found another rearrangement reaction of the oxide. tobacco alkaloids which has been carried out at the Upon acyl halides' or anhydrides' being reacted with Japan Tobacco and Salt Public Corporation in the past nicotine-N' -oxide by triturating it with a glass roq in a ten years. glass flask, the oxide was spontaneously rearranged giv­ Figure 1 shows the transformation of N-methylpyrro­ ing an N-acylated butylamine derivative [IV]. When lidines and N-methylpiperidine oxides. Nicotine oxide [11] this reaction occurs under cooled conditions, then a near­ is easily formed from nicotine under natural conditions, theoretical yield of N' -acylated pseudooxynicotine can and it is stable at room temperature. Rayburn {1) has be obtained. When the N'-methylmyosmine [V] was shown that the oxide is rearranged to 2-methyl-6-(3'­ heated under vacuum, nicotyrine [VI], N-methylnico­ pyridyl)tetrahydro-1,2-oxazine [Ill] by heating. tinamide [VII], other pyridine compounds and a large • Presented at the 6th International Tobacco Scientific Congress (Coresta) held in Tokyo, Japan, in November 1976. Figure 1. Reaction of nlcotlne-N'-oxlde. o-9 + (0) ~ . I CHJ o-90CH3 11 ~v•. ~ N <(. CHJ i~ vacuum llMJ '~-~ C-NHCH3 lit CH3 V erN Vlt Reaction of N-methylpyrrolldlne and N-methylplperldlne oxide. 0 Q 11 I ~0 (R-C)20 CHJ -:,0 R-c 'X Q 0I ~0 I CH3 CH3 1: nicotine 11: nlcotlne-N'-oxlde IV: N-acyi-N-methyl-4-oxo-4-(3'-pyrldyl)butylamlne VI: nlcotyrlne Ill: 2-methyl-6-(3'-pyrldyl)tetrahydro-1;2-oxazlne V: N'-methylmyosmlne VII: N-methylnlcotlnamlde 308 amount of resin were obtained. This is very suggestive from N' -methylmyosmine. When a nicotine salt solution of natural nicotine degradation. Nicotine-N'-oxide [11] was heated at 200 °C under vacuum in an autoclave is formed during fermentation, but it is stable at room to determine the manner of initial pyrolytic degradation temperature. However, a nucleophilic attack on the oxide of nicotine, nornicotine was obtained as a major product [11] would probably occur during fermentation, so that together with metanicotine and dihydrometanicotine. In the formed unstable N' -methylmyosmine [V] would be all the detected degradation products, the C-N bonds of transformed to give various further transformed com­ the pyrrolidine ring moiety were cleaved (5, 6). pounds. This rearrangement reaction of the N'-oxide [11] In the tobacco plant, nicotine has been regarded as a could be used for the preparation of L\1-pyrrolines or secondary metabolite. However, dealkylation of nic­ L\1-piperideines (2, 3). N' -methylmyosmine is regarded otine commonly occurs in most wild species and some as a key compound in nicotine degradation. However, cultivars. We tried to establish a structural minimum there has been no information confirming the structure requirement of the dealkylation system of tobacco alka­ of so-called "N'-methylmyosmine". We obtained N'­ loids in tobacco plants, using a number of derivatives of methylmyosmine (b.p. 90-93 °C, 2 mmHg) by reflux­ tobacco alkaloids and leaves of the Cherry Red strain ing pseudooxynicotine with benzene and confirmed the of the Bright yellow variety of Nicotiana tabacum L., as structure of 1-methyl-2-(3'-pyridyl)-2-pyrroline by com­ Dawson (7) has worked using a limited number of to­ paring with 2-methyl-1-(2'-methyl-6'-cyclohexene-1'-yl)­ bacco alkaloid derivatives. Experimental leaves were pre­ pyrrolidine by means of lH-NMR (18). pared by grafting the tobacco scion on a tomato stock. Frankenburg and eo-workers (4) have demonstrated a The substrates were fed from the end of the petiole of number of degradation products of nicotine in cigar to­ the leaves and analyzed. The substrates in the feeding bacco. We conducted an experiment on nicotine aeration experiment were prepared by chemical synthesis or isola­ to determine the oxidation of nicotine by air at room tion from natural sources. As shown in Table 1, among temperature. A number of products were identified, as compounds analogous to nicotine, both R- and S-nic­ seen in Fig. 2. A large part of the products was nicotine­ otine (pKa 1 = 7.9, pKa 2 = 3.1), N'-methylanabasine, N' -oxide. N'-Methylmyosmine was first identified as a nicotine-N' -oxide (being reduced to nicotine) and 6- degradation product. Most compounds, except cotinine hydroxynicotine were demethylated. No nicotyrine and nicotine-N' -oxide, are supposedly derived from N'­ (pKa 1 = 4.9) and cotinine (pKa 1 = 4.5) resulted in the methylmyosmine. Nicotinic acid must be derived from demethylated compound. From these result~ it was in­ N-methylnicotinamide which has in turn been derived ferred that the methylated nitrogen atom is required to Figure 2. Air oxidation and low-temperature pyrolysis of nicotine. 0 N air a-?N~ CH3 I ~0N 11 CH3 N Ill o.-9CH3 30 °C, 4 weeks N I 0 er-9N IV CH3 o:-0N V o-flN VI oC-CH3 11 o-COOH NHCH3 NH3 N 0 N VII VIII 3days ll~H3 .. ) ~ c er9N IX a-?N X CH3 N VI ~ o-0 lN~ HN: N V XI CH3 1: cotlnlne IV: N"-methylmyosmlne VII: 3-pyrldylmethyl ketone 11: nlcotlne-N'-oxlde V: myosmlne VIII: nicotinic acid X: dlhydrometanlcotlne Ill: nlcotyrlne VI: 3-pyrldylpropyl ketone IX: nornlcotlne XI: metanlcotlne 309 Table 1. Demethylatlon of tobacco alkaloid analogues In tobacco leaves. Substrata Product Substrata Product (partially Py--CJ racemic) L-~ H none ~ ..N JJ '!~CH,, OL-Py--C:J (0-domlnant) I CH, o-q HO N CH, HOo-9 N Py-0 none N I none CH, L-Py-Oo none I CH, none OL-Py-0 Py-0 (0-domlnant) I H CH3 none L-Py-CJ L-Py--CJ Py--Q l"'llo I H none CH3 CH, (partially racemic) L-Py_()._ none none CH3 none o--7N CH, PyD 0 NH I none CH, none PyJf] H,c 1 I none CH, Py -,P,.N,..) o" I none CH, Dl-Py-r:J HO NH I none DL-Py-CJ CH, I none CO I Pyn .. CH, N-CH, I none Dl-Py-0 CH, none I CHO CH, CH, CH3 CH, Dl-Py ~ ) N ) (D-dominant) H N Py...J..... I H H CH, Py-Q H Py- CH2 CH, 'N""" I CH, Figure 3. Minimum requirement of the structure for de- Figure 5. Transformation of anabasine In Nlcotlana taba­ alkylation of nicotine analogues In tobacco leaves. cum. D-domlnant In R Ef> R' ~ 0 ()"' ~~- . N. tabacum L ,N: and H CH. N cPN o+N 'R" Anabasine Anabaseine R- or :1= R' R- or :1= R" further transformed in the plant. The metabolite was identified as anabaseine by isolation (12). The trans­ be ionized for demethylation under physiological con­ formation pathway of anabasine in tobacco leaves is ditions. The anionic site would be present in the de­ shown in Fig. 5. alkylation enzyme system. No alicyclic amine such as We have noticed the presence of a fairly large amount pyrrolidine or piperidine was necessarily required for the of an isatin-positive alkaloid (I-A) other than nornic­ dealkylation substrate. An appropriate distance (approx. otine in the Cherry Red strain of converter-type tobacco 4.16 A) between the nitrogen atom in the pyridine and (14), as shown in the paper chromatogram (Fig. 6). I-A the nitrogen atom to be dealkylated is required. The was isolated from Cherry Red leaves of Nicotiana taba­ dealkylation was not confined to methyl groups. Experi­ cum L., Bright yellow, by the sequential procedure of mentally, we could work out the structural minimum methanol extraction, cation exchange chromatography, requirement of the dealkylation system in tobacco leaves partition chromatography using tert-amylalcohol-acetate as shown in Fig. 3 (8). buffer and HPLC. I-A was isolated in a resinous form. Tobacco alkaloids are secondary products which have This was crystallized by treatment with chloroform and been regarded as metabolically inert substances except purified by recrystallization from chloroform and liquid their N-methyl group. The N-methyl group of nicotine chromatography [m.p. 66-68 °C (decomposition), is fairly well metabolized. L-Nicotine was demethylated [a]~ = -83.80° (c = 1.08 in H20)]. A high-pressure to give partially racemized L-nornicotine (9). We proved further transformation of nornicotine and anabasine in liquid chromatogram of the methanol extract of tobacco is shown in Fig. 7. Color test, hydrolysis, .and spectral tobacco leaves by feeding optically inactive ones and by data (lH- and lSC-NMR, MS, IR and UV}'sllggest that measuring the optical activity of recovered alkaloids. As seen in Table 2, the optically inactive alkaloids were transformed into optically active compounds. Nicotine Table 2. Transformation of nicotine and nornlcotlne In Nlcotlana tabacum L (Cherry Red) leaves. was predominantly demethylated in D-form, and nor­ nicotine was predominantly dehydrogenated to myos­ DL-nicotine feeding DL-nornicotlne feeding mine in L-form (10, 11, 12). The transformation path­ 4 4 way of nicotine in tobacco leaves is shown in Fig. 4. hours la1& weeks [al& Recently, myosmine was also confirmed as a metabolite in the leaves by Leete and his eo-workers (13). 0 0 0 0 Anabasine is a principal alkaloid in Nicotiana glauca L. 64 -4.57 2 +0.98 and also a common minor alkaloid in N icotiana tab a­ 112 -6.76 4 +2.62 cum L.
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