Tropane Alkaloids G. Fodor and R. Dharanipragada Department of Chemistry West Virginia University Morganto wn WV 26506- 6045 USA Reviewing the literature published between July 1983 and June 1984 (Continuing the coverage of the literature in Natural Product Reports 1984 Vol. 1 p. 231) 1 Occurrence and Structure of New Alkaloids 2 Synthesis and Chemical Transformations 3 Pharmacology 3.1 Atropine 3.2 Cocaine 3.3 Scopolamine 3.4 Miscellaneous Alkaloids 4 Analytical Aspects 5 References 1 Occurrence and Structure of New Alkaloids Convoline (1) an alkaloid occurring in Convolvulus krauseanus has been isolated' and its structure determined as (the mesoid) 3a-veratroyloxy-N-hydroxynortropane.The i.r. spectrum showed hydroxyl absorption at 3245 cm-I and the absorption of an ester carbonyl group at 1705 cm-I.The IH n.m.r. spectrum was indicative of six methoxyl protons (6 3.89 p.p.m.) but there was no signal for an N-methyl group. The mass spectrum (M+ 307) was consistent with the molecular formula C,,H2,05N. Alkaline hydrolysis gave veratric acid and a product that was expected to be N-hydroxynortropan-3a-01;unfortunately this was not characterized except by a molecular peak of m/z 143 in the mass spectrum. Reduction of convoline with zinc gave convolvine (0-veratroylnortropine). On this basis convoline appears to be the first N-hydroxynortropanol ester to be found in Nature. Hyoscyamine and hyoscine were found2 to be the major alkaloids of species within the tribe Anthocercideae of the Solanaceae.2 Synthesis and Chemical Transformations Noratropine oxalate was prepared3 by oxidative N-demethyla- tion of atropine sulphate with aqueous potassium permangan- ate followed by treatment with oxalic acid. Non-glycolate esters of (+)-tropan-2a-o1 and (-)-tropan-2P-ol were pre-pared4 by known transesterification procedures. A series of N-a1 koxycarbonylal kyl-nortropane-3-spiro-5'-hydantoins (2) have been synthesized5 by treatment of the appropriate N-substi- tuted nortropinone with potassium cyanide and ammonium carbonate in aqueous ethanol. The crystal and molecular structures of (2f) were determined by X-ray diffraction. In the crystalline state the cyclohexane ring of (2f) adopts a deformed chair conformation with a flattening at C-3 (C-5').This deformation is due to the steric interaction between the ethylene bridge and the hydantoin group. The opposite puckering at N-8 and the axial position of the N-substituent make the formation of the intramolecular N(3')-H..-N(8) bond easy. Stereospecific reduction of nortropinone derivatives was achieved6 in the presence of a rhodium-phosphine catalyst. Arylphosphine ligands gave the a-isomer (nortropine) whereas complexes with trialkylphosphines as ligands gave the p-isomer (norpseudotropine). The difference in selectivity is due to the different structures of the intermediate complexes and the different co-ordination of the substrate. Derivatives of noratro- pine which have anticholinergic activity and their addition HO (2) a; R= H b; R=Me C; R= CH,Ph d ; R = CH*CH,CO,Et e; R= Pri (2)f ; R = [CH,],CO,Et 9; R= C,H,-p-CO,Et o+-f3=+H OC-CHCH20H II I 0 Ph (31 Me\ NpoF,[cH,I" NR 0 (4) salts with acids (which are useful as bronchodilators) have been prepared.Thus N-isopropylnoratropine in methanol was treated with peracetic acid at 0 "C and the mixture was stirred overnight with warming to give (3) which was subsequently converted into its hydrochloride salt. The tropan-30-01 aminoalkanoates (4; n = 1,2 or 4; R2N = morpholino Me2N Et2N pyrrolidino piperidino or pipera- zino) were prepared8 from tropine and pseudotropine by successive acylation by o-chloroalkanoyl chlorides and subse- quent amination by the corresponding dialkylamines.NATURAL PRODUCT REPORTS 1985 Br-NHR~ 0 (51 -Br R (11) a ; RR = 0 b; R=H (13) Z = alkylene or phenylene The antidepressant and anxiolytic benzamides (5; R1 = C,- alkoxy; R2 = H or alkanoyl; R3 = C1 or Br; RS = Me,C Me,CHCH, or cyclopropyl; n = 1 or 2) were ~repared.~ For examp!e 3P-amino-8-neopentyl-8-azabicy-clo[ 3.2. lloctane was treated with 4-acetamido-5-chloro-2-meth-oxybenzoic acid to give (5; R1 = OMe R2 = Ac R3 = C1 R4 = Me,C n = 1). Isopropylatropinium bromide (6) has been synthesized. Oa The configuration of the ring nitrogen is described according to a previous convention. lobThus Robinson condensation of succinic aldehyde acetonedicarboxylic acid and isopropyl- amine gave N-isopropylnortropan-3-one.Reduction of this compound with lithium aluminium hydride gave 3-epimeric alcohols which were separated by chromatography.Transes- terification of the purified tropan-3a-01 with methyl phenylace- tate and then formylation with methyl formate in the presence of sodium followed by reduction and subsequent quaterniza- tion with methyl bromide gave the desired compound (6). The norscopines (7; R1= C2-10alkyl R2 = H) which are useful as synthons for pharmaceuticals were prepared' from the corresponding esters. Thus treatment of (7b) with sodium borohydride in ethanol at 20°C gave (7a). The quaternary 0-(6,ll -dihydrodibenzo[b,e]thiepin-11-y1)-N-alkyl N-methylnorscopinium bromide (8; R = Me) which is useful as a bronchodilator was prepared' by treating scopine hydrochloride with 1 I-chloro-6,ll-dihydrodibenzo[b,e]thie-pine followed by methylation with methyl bromide.Bicyclic benzamides of the type (9) which are useful as antiemetics and as dopamine antagonists have been pre- pared. Thus 2-methoxybenzoic acid was sulphonated with chlorosulphonic acid followed by reaction with pyrrolidine to (7) a; R'= Pri,RZ= H Ph b; R'= Pr' ,R2= COCH(Ph)CH,OH (as hydrochloride) o=s=o I 0 I12) R = alkyl ,alkenyl ,aryl or heteroaryl give 2-methoxy-5-(pyrrolidinosulphonyl)benzoicacid which was treated with ethyl chloroacetate and 3P-amino-8-benzyl-8- azabicyclo[3.2. lloctane to give (9). Norscopine (10) was prepared' from norscopolamine hydrochloride by treating it with sodium borohydride in ethanol.Azabicyclo[3.3.l]nonylphthalimidines of the type (1 1b) which are usehi1 as dopamine antagonists and as antiemetics have been prepared. Thus reduction of the phthalimide (1 1a) with tin and hydrogen chloride in acetic acid gave (1 lb). Ester derivatives of scopolamine of the type (12) and (1 3) were prepared' from scopolamine hydrobromide and the corresponding carboxylic acids or diacids in the presence of 4- N-methylaminopyridine and NN'-dicyclohexylcarbodi-imide. The absolute configuration of ( -)-anisodinic acid which is the esterifying acid of anisodine (14) was determined" by chemical correlation with (-)-(R)-2-phenylpropane- 172-diol and ( -)-(R)-2-hydroxy-2-phenylpropionicacid. A biomimetic synthesis of the ladybug alkaloids (1 8) and (1 9) of the adaline series was accomplished' via intramolecular Mannich reaction of the intermediate imminium-enols (1 7) which were generated from the corresponding 2-cyanopiperi- dines (15) and (16) (Scheme 1).A short convenient synthesis of 2-tropanyl 2-granatanyl and 2-homotropanyl methyl ketones [(20) (21) and (22), respectively] has been developed,' via Mannich cyclization of the dioxo-aminobutyl ketal-acetals (23a)-(23c) (Scheme 2). The same research group has also accomplished20a the synthesis of (+)-anatoxin-a and (-)-anatoxin-a (24) of high optical purity directly from D-and L-glutamic acids. Initial formation of a carbon-carbon bond proceeding from the NATURAL PRODUCT REPORTS 985 -G.FODOR AND R. DHARANIPRAGADA Bn pyroglutamate via sulphide contraction and transfer of the I chirality of the amino-acid by catalytic hydrogenation were . .. crucial to the synthesis (Schemes 3 and 4).Sulphide contraction '1 " is a processZob by which enamino-esters could be made from thioamides. Fii Total syntheses of ( +_)-knightin01(25) and (+)-acetylknight-"BMX Bn 'u Iv vii (15) R = Me (16) R = n-C5Hll 1 R$j R 4 4v (18) R = Me (19) R = n-C5Hll (Bn = CH,Ph) Reagents i PhCH,Br; ii NaBH, MeOH; iii m-chloroperoxybenzoic acid CH,CI,; iv (CF3CO)I0 CH,CI, at -10 "C for 20 minutes KCN H+ at pH 4; v HI Pd/C 10% EtOH; vi LiNPr', THF at -2O"C RX; vii MeOH 1OM-HCI (10%). Scheme 1 k Q 0 0 0 (211 n 1 NHBn (23) a;y=2 z=1 b;y=z= 2 c; y = 3,z = 1 1 Reagents i MeOH H20 HCI at 55-6OoC for 21 hours.Scheme 2 inol (26),which are the alkaloids of Knightia strobilina and the synthesis of ( +)-2,3-dihydrodarlingine (27) which is the alkaloid of Bellendena rnontana have been achieved (Scheme 5).21 Analogous synthetic transformations have led to the synthesis of strobamine (29) via chalcostrobamine(28)(Scheme 6).22 The 3C spin-lattice relaxation times of tropine and pseudotropine have been measured,23 in CDC13 as a function of concentration; they showed these molecules to be intramole- cularly hydrogen-bonded over the whole concentration range. 3 Pharmacology 3.1 Atropine Atropine was foundZ4 to reduce the tremors that are induced by physostigmine.When it was administered to cats atropine causedZS the classical shift of the electrocorticogram from a high-frequency-low-voltage pattern to a low-frequency-high- voltage pattern. Amongst other studies investigations of the role of the sympathetic nervous system in atropine-induced tachycardia in conscious cats,26 of the effects of an electrical current on the activity of mitochondria1 monoamine oxidase and on the total protein content of the rat brain after atropine has been admini~tered,~~ and of the influenceZ8 of atropine on a-adrenoceptors in the female rabbit urethra have been described. 3.2 Cocaine Cocaine has received considerable An extensive review on the behavioural effects of cocaine in humans and in laboratory animals has appeared.29 Amongst other effects studies on the sodium-sensitive binding of cocaine30 to rat striated membrane the disadvantages of using cocaine as a neuronal blocking agent,3 the discriminative stimulus proper- ties of cocaine in the rhesus monkey,32 the effects33 of cocaine on responding (under a multiple schedule of presentation of food or nitrous oxide),33 the relationship between reinforcing and subjective effects in crab-eating monkeys,34 cortical dopaminergic involvement in cocaine reinfor~ement,~~ and the sex-dependent difference^^^ between left- and right-side rats on cocaine-induced rotation were studied.In addition studies on the effects37 of cocaine on rats under a mild water-deprivation schedule and the effects38 of cocaine on the electromechanical activity of the gastric antrum and duodenum of conscious dogs have been reported.Classical conditioning and the decay and extinction of cocaine-induced hyperactivity and ~tereotyping~~ have been studied. 3.3 Scopolamine Scopolamine is still the focus of investigation^.^^-^^ Amongst other studies the effects of scopolamine on respiration and on blood pressure in rabbits40 and on the spontaneous activity of neurons of the nucleus locus cer~leus,~' the effects of repeated administration of scopolamine on ambulatory activity in mice,42 and the effect of scopolamine on stimulus sensitivity and response bias in a visual vigilance task43 have been investigated. Other studies included an investigation of the central antimuscarinic cholinergic of scopolamine and an assessment of the chromosomal aberrations that are induced by scop~lamine.~~ NATURAL PRODUCT REPORTS 1985 B u' 0,C.I Bn Bu'0,C' Bn - r n t But 0,C" Bu'0,C'' Bn hii B nN n iv,v,iii,vb But0,C ,OkN A.,c02Me Bn ix-xiJ.H ( Bn = CH,Ph 1 A? xii,xiii Me3Si0LQ I-)-Anatoxin -a(2L) Reagents i BrCH2C0,Me; ii PPh3 Et3N at 20 "C; iii H2 Pt/C; iv LiBH4 Et,O; v Ph3h ",,-, LiNPrI2 DMSO; vi PrnOH H+; \I -vii POCl, at 95 "C; viii conc. HCI MeOH at 57 "C; ix H2 Pd/C; x di-t-butyl dicarbonate; xi Me3SiC1 KH Et,N; xii Pd(OAc), MeCN; xiii 1M-CF,CO,H. Scheme 3 o=s=o HoYph I ._ 1 n But02CAN Bn %o ... C0,Bn MeNpO -+ (+I -Anatoxin -a k,vi 0 Scheme 4 MtNwrH OAc 3.4 Miscellaneous Alkaloids Effects of intravenous administration of anisodamine on the (261 haemodynamics of unshocked and endotoxin-shocked dogs have been studied.46 Anisodamine was found4' to reduce acute Reagents i NaH THF Ph-C-CN; ii H2 PtO,; iii Ac,O BF,.Et myocardial infarction in rabbits. The anti-shock action of at r.t. ;-iv 10 equiv. Ac,O catalytic 4-dimethylaminopyridine,heat; anisodamine was studied in cats in a well-controlled model of haemorrhagic shoc k.48 The effects of 8-(2-fluoroethyl)-3a-0 hydroxy-laH,5aH-tropanium bromide benzilate (Ba598Br) '"N ;vi 1M-H2S04 at 50 "C for 3 hours. which is a new atropine derivative on the canine airway were v9NaH7 Me Me HH investigated.Inhalation of 0.01%of Ba598Br had an inhibitory effect against acetylcholine-evoked bronchoconstri~tion.~~ Scheme 5 NATURAL PRODUCT REPORTS 1985 -G. FODOR AND R. DHARANIPRAGADA 0 II Reagents i PhCH=CH-C-CN; ii 1M-H2S04 at 50 "C for 3 hours. Scheme 6 4 Analytical Aspects The development of a second-order derivative U.V. spectropho- tometric assay of atropine hyoscine and benztropine in formulations has been described.50 An oscillopolarographic titration method has been developed5 to determine hyoscine butyl bromide alone or in injections. Atropine sulphate and its preparations have been analysedS2 by the double-phase titration method. Mass spectra of (-)-cocaine and its semi- synthetic epimer pseudococaine were founds3 to be similar but significant differences in the abundance of ions of m/z 152 and 94 could be used to distinguish between the two epimers.5 References 1 S. F. Aripova E. G. Sharova U. A. Abdullaev and S. Yu. Yunusov Khim. Prir. Soedin. 1983 749 (Chem. Abstr. 1984 100 171 549). 2 W. C. Evans and K. P. A. Ramsey Phytochemistry 1983,22,2219. 3 M. J. Van der Meer and H. K. L. Hundt J. Pharm. Pharmacol. 1983 35 408.. 4 E. R. Atkinson D. McRitchie-Ficknor L. S. Harris S. Archer M. Acito J. Pearl and F. P. 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