Chapter 8 The Tropane Alkaloids

-CHAPTER

8-

THE TROPANE ALKALOIDS G . FODOR Department of Chemistry West Virginia University Morgantown. West Virginia

. .

I Introduction ..................................................... I1 Isolation and Structural Elucidation ................................ A . Brugine ...................................................... B . Apohyoscine .................................................. C Littorine ..................................................... D . Genus Datura. Section Brugmansia Alkaloids ...................... E . New Erythroxylon Alkaloid ..................................... F. Butropine and Valtropine ...................................... G . (+) 9.Aza.l.methylbicyclo[3.3.l]nonan. 3.one ...................... H Confirmation of Azetidinium Salt Structure for a Product from Cocaine I11. Stereochemistry . . . . . . . . . . . . . . . . . . . .......................... A . Confirmation of Relative Configurati y X-ray Crystallography ... B . Configuration of Quaternary Tropanium Salts ..................... C. N-Diastereomeric Tropane Hydrohalides .......................... D . Conformation of Tropanols and Halogenotropanes .................. E Conformational Analysis of Allococaine and Allopseudococaine . . . . . . . F Chirality of Tropinone Oxime ................................... G Chirality of the Disulfide Bridge in Brugine ....................... H . Configuration and Racemization of ~-(+)-BP-Tropanol. . . . . . . . . . . . . . I . Solvation Diastereomers of Cocaine .............................. IV Syntheses ............................................. A . From Cyclopropanones and Pyrroles ............................. B . From Pyrrolidines ............................................. C . Novel Applications of the Robinson Route ......................... D . From2. 6.Cycloheptadienone .................................... E . LabeledCompounds ........................................... F. Tropanyl Ethers, Carboxylic Acids. and Other Derivatives .......... V . ReactionsofTropanes ............................................. A . Photochemistry and Radiolysis .................................. B Hydrolysis. Solvolysis. and Fragmentation ........................ C. Enzymatic Epimerization ...................................... D . Miscellaneous Reactions ........................................ VI . Biosynthesis ..................................................... A . Hyoscyamine .................................................. B . Teloidine and Meteloidine ....................................... C Scopolamine .................................................. VII . Structure-Activity Relationships ................................... V I I I Metabolism of Tropane Alkaloids in the Animal Body . . . . . . . . . . . . . . . . . . I X . Addendum-13C NMR Spectroscopy of Tropanes ...................... References .......................................................

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. . .

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.

.

.

352 352 352 353 353 354 355 355 355 356 357 357 359 365 365 366 367 368 368 369 369 369 370 371 372 373 375 379 379 380 382 382 383 383 384 386 386 389 391 391

352

Cl. FODOR

I. Introduction Five years ago, when this field had been reviewed for the third time

( I ) , most of the structural problems seemed to be solved. Indeed, just

a few new alkaloids of tropane skeletons have since been detected, but the number of papers dealing with syntheses, stereochemistry, biogenesis, physiology, pharmacology, and metabolism published during this last period amounts to several hundreds. Therefore, the reviewer felt compelled t o summarize some of the major developments while quoting a considerable number of specialized observations.

11. Isolation and Structural Elucidation

A. BRUGINE This rather unusual tropeine was isolated (2) from stem bark of Bruguiera sexangula Lour., a tropical mangrove of New Guinea that contains 0.08% alkaloids. The major alkaloid is an optically active ( [a)”$-24” in chloroform) glassy material that darkens and polymerizes when heated. Also, formation of hydrogen sulfide was proven by the~ mass S Z spectrum pyrolysis. I t s empirical formula was C ~ Z H ~ ~ N; O showed molecular ion 273 with isotopic peaks a t M 1 and M 2 and 43% of the base peak a t mle 124 ; this corresponds, according t o previous work ( 3 )with tropeines, to the 3-tropanium radical ion (tropeine minus OR). Carbonyl absorption in the I R a t 1720 cm-1 indicated an ester. Also, hydrolysis gave 3a-tropanol (identified by its mixed melting point, I R , and NMR spectra) in addition to a carboxylic acid accompanied by polymeric material. This acid could, however, be purified by column chromatography on silicic acid and was identical with racemic synthetic ( 4 ) cyclic disulfide of 2,4-dimercaptobutyric acid, i.e., 1,2-dithiolane-3carboxylic acid. Thus, structure I has been assigned t o brugine, con-

+

+

0

I

0 I1

8.

T H E TROPANE ALKALOIDS

353

firmed by desulfurization with Raney nickel t o n-butyryl tropan-3a-01 (11).The NMR spectra have contributed to elucidate this constitution, for five protons of the acylating acid moiety appeared as three multiplets, with chemical shifts and splitting patterns that closely resembled the corresponding signals of 1,2-dithiolane-3-carboxylic acid, and no protons were exchanged with deuterium oxide. No data on the absolute configuration of the a-carbon in the disulfide acid were reported. See, however, Section 111, G.*

B. APOHYOSCINE Apohyoscine, 6,7,B-epoxy-3a-atropoyloxytropane (111))has been isolated ( 5 ) from the aerial part of Datura meteloides DC. together with hyoscine, norhyoscine, hyoscyamine, meteloidine, and norhyoscyamine. This olefinic tropeine was identified with the product of dehydration of hyoscine ( 6 ) . H3C,

II

0 I11

C. LITTORINE The major alkaloid of Australian Anthocercis Zittorea Labill is a hitherto unknown tropeine (7')) beside traces of partly racemized hyoscyamine and of meteloidine, while A . viscosa R. Br. and A . fasciculata F. Muell. are hyoscyamine-bearing plants. The name littorine was given to the optically active base (mp 96°C; [a]=-12.7") in ethanol) of molecular formula C17H23N03; it readily forms a picrate and a methiodide. It is an isomer of hyoscyamine (8-(-)-3a-tropoyloxytropane) and has a closely related structure. The IR data pointed to the presence of hydroxyl and ester-carbonyl groups and to a monosubstituted benzene ring, confirmed by TJV-spectral data. The molecular ion M+ 289 (14% of base peak) appeared a t m/e 290 after deuteration. Other characteristic peaks were m/e 272 (M-OH),m/e 124, indicative of 3-tropanium ion ( 2 , 3 ) , 82, 83, 94, and 96, all diagnostic ( 3 )for tropine derivatives, and mle 91, +C7H7, revealing no further details of the esterifying acid. The NMR

* The unusual structure of 2,3(2,3-tropeno)-5-methyl-y-pyrone was assigned to bellendine, based upon X-ray crystal analysis ( 1 9 2 ) .

354

G . FODOR

spectrum of littorine showed 18 protons in very similar environment to those of hyoscyamine, such as 6 7.28 and 6 7.26 (s, 5 , phenyl); 6 5.01

and S 5.03 ( t , 1 , H-3 equatorial ( 8 , 9 ) ) , S 2.20 ( s , 3, NCH3), 6 3.68 (s, 1 , disappeared upon deuteration, OH), and a complex multiplet for 8 protons 6 1.18-2.12; and 6 1.33-2.16 (H-2, 4, 6, 7 attached to tropane

skeleton). However, in hyoscyamine the remaining five protons gave rise to a broad signal a t 6 2.97 (s, 2 , H-1,5) and a complex ABC pattern a t 3.60-4.41 ppm (3, CHz-0 and tropic acid M-H).I n littorine these five protons appeared a t 6 4.37 (q, l),and an eight-line signal 6 2.73-3.33 (octuplet, 4) comprised the AB portion of an ABX system and a broad singlet a t 6 2.97, JAB= 13.8 cps, J,, = 7.9 cps, and J,, = 4.8 cps. The ABX system was assigned to the CsH.&Hz-C(OH)H-CO group, assuming nonequivalence of benzylic protons adjacent to the asymmetric center.

I/

0

IV

Alkaline hydrolysis gave 3~-tropanoland an acid, identified as (+)-2-hydroxy-3-phenylpropionicacid, the levorotatory form thereof being established (10) as S. Hence, littorine is R-(-)-3~-(2-hydroxy-3phenylpropiony1oxy)tropane (IV).Surprisingly, the racemate of IV was synthesized sixty years ago and found to be a powerful mydriatic (11).

D. GENUSDatura, SECTION BRUCMANSIA ALKALOIDS 6P-Tigloyloxytropane-3~-01 (V) has been identified as a minor component of the alkaloidal mixture of Datura cornigera Hook. leaves, and the presence of 3cc-tigloyloxytropan-6~-01 was suggested (12).I t s acetyl derivative (VI) and 0-acetylated tropanol, 3~-acetoxytropane,were isolated (13) from D.sanguinea R. & P. These are the first acetylated tropeines to be isolated. Since V and VI were hydrolyzed to (+)-tropane3~,6P-diol the (-) form of which proved to be the 3s : 6s enantiomer ( I ) their absolute configurations are likewise determined. The tiglic acid ester of 3cc-tropanol (VII) was detected in the roots of

8.

355

THE TROPANE ALKALOIDS

m

H3KN

H3C C ''

0

II

0

0

0 ,

VI

V

II

H3C,

C

,c=c

II

,CH3 \H

0

H

0 VII

Physalis alkekengi L. var. Franchettii and identified by the products of hydrolysis (14).

E. NEWERYTHROXYLON ALKALOID This year a new unsaturated tropeine from Erythroxylum ellipticum R. Br was described as tropine 3,4,5-trimethoxycinnamate(15).Structure determination in this case was accomplished by a combination of spectroscopy with hydrolytic cleavage into 3a-tropanol and 3,4,5trimethoxycinnamic acid. Tropinone was found for the first time (16) in Nicandra roots. AND VALTROPINE F . BUTROPINE

Semirational names have been given to the known Duboisia alkaloids (17) poroidine, i.e., isobutyryl tropine became butropine and a-methylbutryl tropine isoporoidine is now valtropine (18).

G. (+)

9 - A Z A -~-METHYLBIcYcLO [3,3,1]NONAN-3-ONE

A new homotropane (granatane) base, CgH15NO (mp 30°C), isolated (19)as a major alkaloid from Euphorbia atoto Forst., is of primary interest because it bears a C-1 methyl group not found before in this

356

G . FODOR

class of natural products; this has biogenetic significance. The new alkaloid is optically active ( [ a ] , ,+6", in methanol ; IR,1605 cm-1, ketone carbonyl, 3400 em-1, NH).It also forms an N-acetyl derivative (NMR, 6 1.17 (s, 1,-C-CH3) and 6 3.50-3.83 (broad, s, 1, H-5)),which confirmed the assignment of a 1-methyl norgranatan-3-one (VIII)to this compound together with mass spectral data analogous t o tropinone. Despite its

VIII

formal resemblance t o the tropane group, VIII is biogenetically closer to pinidine and the Lobelia alkaloids. It may arise from 3,5,9-triketodecanoic acid, itself formed by the acetate route, by condensation with ammonia rather than from an amino acid, i.e., 2-methyl lysine.

H. CONFIRMATIONOF AZETIDINIUMSALTSTRUCTURE FOR PRODUCT FROM COCAINE

A

As it has been pointed out in Volume I X , pp. 272-274, of this series ( I ) ,the product of internal condensation of 2~-chloromethyl-3~-tropanol

showed chromatographic properties and an I R spectrum in agreement with those of a strained azetidinium salt ( I X ) rather than the hydrochloride of a tropanooxethane (X) which we had assumed earlier (20). Detailed NMR study combined with mass spectral evidence now have corroborated ( 2 1 )the structure of 8-methyl-8-azoniabicyclo[2,2,1,129*]nonane chloride (IX). While X should eliminate HC1 in the mass

c1-

IX

5H'L

X

spectrometer, giving m / e 153, the actual molecular ion was found as m l, e 154, in harmony with I X . Furthermore, double irradiation of H-2/H-3, H-2/H-1, etc., combined with deuteration allowed unequivocal assignment to all protons. Most significant was the nonequivalence of H-1 and

8. THE TROPANE ALKALOIDS

357

H-5 (6 5.15 and 6 4.25); although the latter was overlapped by C(g)-CH2, ring closure of ecgoninol-9-d2 into the d2 salt revealed this proton. I n the N-methylated oxethane (X), on the contrary, H-1 and H-5 appear very closely a t 6 4.6, as expected. The NMR study seems t o support the alternate ring opening a t C-1 and C-9 of the azetidinium salt, as suggested recently ( I ) ,thus eliminating part of the confusion about ecgoninols that we have mentioned in Volume VI (22). 111. Stereochemistry

A. CONFIRMATION OF RELATIVE CONFIGURATIONSBY X-RAY CRYSTALLOGRAPHY The relative configurations of cocaine and pseudococaine have been determined by chemical methods ( 2 3 ) ,as reviewed in Volume V I of this

XI

(24)

358

G . FODOR

series ( 2 2 ) .Molecular dimensions, bond lengths, and bond angles are now available for cocaine hydrochloride (XI) ( 2 4 ) ,confirming the correctness of previous configurational assignments. Similarly, pseudotropine as a free base was subject to combined X-ray crystallographic and NMR studies, showing (25) that 3P-hydroxyl and N-methyl groups are both equatorial (XII)with definite intermolecular hydrogen bonding between 0 - 3 and N, axial. Tnterplanar angles indicated sizable deviations from

XI1 (25)

the classic chair form of the piperidine ring, in agreement with previous dipole-moment and NMR studies (9). These will be discussed in more detail in Sections 111, B and C.

8.

359

THE TROPANE ALKALOIDS

The three-dimensional structure of hyoscine hydrobromide ( X I I I )was investigated by X-ray crystallography (26),supporting previous assignments on the basis of the up-to-date interpretation of converting scopine to oscine and by the configurational correlation of scopolamine with 3~~,6P-tropandiol ( I , 22). The N-methyl group, however, in XI11 is axial, unlike that in the tropine hydrobromide and in the cocaine hydrochloride crystal." The configuration of ring nitrogen in pseudotropine ethobromide (27) and in N-carboxymethyl pseudotropinium bromide (28)will be discussed below.

B. CONFIGURATION OF QUATERNARY TROPANIUM SALTS The configuration of a number of quaternary ammonium salts of this series has been determined earlier by chemical methods, for example, lactone salt formation ( I , 22) of tropane N-acetic acids with an adjacent

XIVa

XIVb

hydroxyl and, in the case of N-ethylnortropine methobromide (XIVa), by X-ray crystallography (29).All these structural data, achieved with tropane alkamines like 3cr- and 3/3-tropanols,ecgoninol, 3a,6PP-tropandiol, and scopolamine, had indicated preferential attack of certain alkylating groups, e.g., ethoxycarbonylmethyl from the equatorial side. This concept became the object of increasing criticism by McKenna a.nd his associates in a number of papers ( 3 0 )and lectures, pointing to the much higher probability of an axial attack. This author cast doubt as to whether the quaternary tropanium salts that have been investigated (29, 31) were indeed major or rather minor products. Therefore, a more quantitative reinvestigation of previous work was imperative. Product analysis of quaternization with methyl-& iodide (31d) in the series of tropane bases listed above has shown SO-SO% selectivity, except for 2P-hydroxymethyl-3~-tropanol (62%). Assuming that the equatorial methyl should resonate in lower field than the axial one, two consistent sets have been established-those with hydroxyl or

* The absolute configuration of the tropic acid residue in hyoscine N-oxide was confirmed by anomalous scattering of X-rays (Bob) as being S( 1).

360

G . FODOR

XIVb

epoxide function(s) (XV) in the five-membered ring, indicating equatorial quaternization, versus the axial course in tropane and the 3-tropanols (XVI). Furthermore, 0-bromoacetyl pseudotropine gave, upon what was believed (32, 33) to be “internal” quaternization, a lactone salt (XVII)that was later proven by osmometry to be a polymer.

XVI; R = H R=OH

@ > : :R

CHI

BrOH

XVII

XVIIIa; XVIIIb; XVIIIC; XVIIId;

R=H R = Na R = CZH5 R = CH3

8.

361

THE TROPANE ALKALOIDS

Hydrolysis of the latter led to a pseudotropine N-acetic acid, also obtained in 90% yield on “direct” quaternization and hydrolysis. This seemed to prove axial quaternization. However, recent X-ray data of the sodium salt of the same acid showed an equatorial CH2COO- on nitrogen (XVIIIb); hence equatorial quaternization was proven and the structure of the lactone was rejected (28). Furthermore, the product of Br-

XIX

CH3

XXI

XIVb

“direct )’ethylation of pseudotropine, formed in 90% yield, was subject to X-ray analysis ( 2 7 ) and had the N-ethyl group in equatorial position (XIX).With four reference compounds (XIVa,b; XVIIIb; and X I X ) of structures established by X-ray, and the lactone salt of N-carboxymethyl-3a,6P-tropandiol (XX), unequivocal correlation of the major products of N-ethylation and alkoxycarbonylmethylation was feasible. Formula tables indicate the main lines of these chemical correlations. I n addition, product analysis by NMR spectra showed high (85-95%) selectivity in the great majority of cases. Tropine ethobromide (XIVb)was converted (28)into the same tropane ethobromide (XXI), as pseudotropine ethobromide (XIX), of known crystal structure. The N-stereoisomer was also previously shown by

XXIIb; R = CzHs

XIVb

362

G . FODOR

X-ray crystallography (29) to be XIVa. Tropine ethobromide was, by means of X-ray, directly proven ( 3 4 ) to be XIVb. N-Ethoxycarbonylmethyl tropinium bromide was converted into the N,-ethyl derivative XIVb, thus proving that it was XXIIb. Furthermore, the configuration of the methyl ester XXIIa was double-checked by conversion via XXIIIa into the same tropane-N-acetic acid (XXIV) as the one that was obtained from the pseudo-tropine N-acetic ester XVIIIc. The

I

XXIIIa SOClz DMF

i

XXIIa

XXIIIb SOClZ

CH3

XVIIId

8. THE TROPANE ALKALOIDS

363

sodium salt of this acid, acid XVIIIb, was recently investigated (28) by X-ray crystallography. A third proof was achieved when the lactone (XX) of unequivocal structure had been deoxygenated, via XXV and XXVI, to the same tropane-N-acetic acid XXIV as the 3a- and 3ptropanol derivatives. Therefore, final conclusions could be reached : (a)Quaternization of tropane, of 3-tropanone) and of the different tropanols and epoxides with methyl bromoacetate and ethyl bromide is preferentially equatorial. ( b ) Quaternization of tropine with methyl bromoacetate, 2-chloroethyl bromide, and 2-hydroxyethyl bromide likewise is selectively equatorial. (c) Catalytic decarboxylation of tropine and 3~~,6,Ll-tropandiol (equatorial) N-acetic acids-d XXII-d4 and XX-dS gave the same deuteromethyl tropanium salts XXVII and XXVIII as direct deuteromethylation with methyl-ds bromide of the alkamines.

XXII - d4 XX- d 5

XXII-d9 and XXVII; R = H XX-dS and XXVIII; R =OH

I n consequence, the axial N-methyl group in tropanium salts is more deshielded (35,36) than the equatorial one-unless there is a stronger deshielding upon the latter to emerge, for instance, by a neighboring hydroxyl or epoxide function (37, 38). This work has displayed final evidence in favor of equatorial preference of quaternization throughout the tropane series. It also disclaimed the former suppositions (30)that assignments were previously made on the basis of minor products of quaternization. Concerning the best explanation of this phenomenon, one should reiterate the concept outlined in Volume I X of this series (p. 289)) that is, application of the CurtinHammett principle for the transition state in tropane quaternizations.

364

G . FODOR

We now know that the angles a t C-2 and C-4 in the piperidine moiety, e.g., in pseudotropine (as),correspond to 141", whereas the angles a t C-1 and C-5 in the pyrrolidine ring measure 137", thereby forming a flattened six-membered ring and angularly deformed five-membered ring in the tropane molecule. A recent proton NMR contact shift study by Ohashi et al. (186) of some tropanes indicated a strongly flattened piperidine ring thus confirming previous statements (25, 29). Diaxial interaction by the 2,4/3-hydrogens is greater due to this flattened (25, 29) six-membered ring for the axial attack a t the nitrogen than compression by 6,7-hydrogens on the equatorial side. Angular deformation (9,25,29) of the five-membered ring helps to diminish this compression;

XXIX

therefore, the transition state described by XXIX has the lowest energy. Moreover, a bulkier group a t C-2 results in a decrease of reaction rates(39a) consistent with observed facts. Furthermore, the group already covalently bound to nitrogen can accommodate more easily to 2,4diaxial compression than can the incoming group which, in the transition state, is a charge-separated solvated species. This also explains the decrease in rates of N-methylation of amines having a bulkier group on nitrogen ( 3 0 ) .However, this does not mean what was supposed recently (39b),that quaternary tropanium salts with axial bulky groups both at the nitrogen and a t C-2 are incapable of existence. Recent product analysis (28b) by NMR of the quaternization with methyl bromoacetate of ecgoninol and diacetyl ecgoninol took place with high yields in boiling acetonitrile; the ratio of the N-epimers was 70:30 in favor of the equatorial isomer. This reflects the fact that in this case both transition states have higher energy but the difference between them is smaller in the case of an axial bulky group than otherwise. Piperidines can overcome such effects more easily than tropanes due t o possible swinging over into another conformation. Oxidation of tropine, scopolamine, and oscine with HzOz showed preferential formation of the axial amine oxide ( 3 7 ) ,assignments being based on shielding effects. Other authors report different results (40a). X-Ray work with scopolamine amine oxide hydrobromide now shows (40b) that the oxygen is equatorial.

8.

365

THE TROPANE ALKALOIDS

HYDROHALIDES C. N-DIASTEREOMERIC TROPANE The most intriguing new result in the field of nitrogen stereochemistry was the isolation by Lyle and Ellefson ( 4 1 ) of two N-diastereomeric hydrobromides of 3-phenyltropane ( X X X and X X X I ) .* These only differ

xxx

XXXI

in the relative positions of Me and H on the ring nitrogen, but this difference is reflected by I R and NMR spectra and X-ray powder patterns. The isomers are interconvertible by heating to 50°C in D20, as has been shown by NMR spectroscopy. The isomer with a high-field methyl signal was assigned to the axial AT-methyltropanium salt. This interpretation is a t variance with Closs ( 3 5 ) , Bottini’s ( 3 6 ) , and our recent concept (28).Furthermore Supple (188)found equatorial preference in both the direct quaternization of 3-phenyl-2-tropene and in the reverse quaternization of 3-phenyl-2-tropene. D. CONFORMATIONOF TROPANOLS AND HALOGEN~TROPANES Previous dipole-moment and NMR studies with 3a- and 3P-cyanotropanes (9) have indicated flattening of the six-membered ring in the tropane skeleton in case of the 3a-derivative; this is also true for 3a-tropanol. The reason for this appeared to be nonbonded interaction with the 6,7-placed a-hydrogens. However, an X-ray study of pseudotropine (25) that has no such a-snbstituent revealed similar flattening and, a t the same time, flattening of the five-membered ring. This situation prevails even in solution, for the 60 Mc NMR spectrum of pseudotropine gave a multiplet a t 6 3.88, t o be ascribed (9) to the C-3 proton. Coupling constants H-2/H-3, J 1 = 10.2 cps and J 2 = 6.6 cps, were found; the former being in good agreement with J calculated for a dihedral angle of 160°, again proving distortion of interplanar angle c1,2,4,5/C2,3,4 (25). Conformations of 3a-tropanol and of its products of displacement, i.e., 3P-chloro- and 3P-bromotropanes were subject to investigation ( 4 2 ) by

* Optically active derivatives were obtained from tropinone and optically active benzylidene-methyl-phenyl-n-propyl phosphorane by H. J. Bestmann and J. Lienert [Angew.Chem. 81, 751 (1969)l.These belong in the same class of geometrical enantiomers as Lyle’s compound. Their N-diastereomeric hydrohalides have also been prepared.

366

C . FODOR

NMR spectra. However, analysis of H-3/H-2 coupling constants and of the half-width of the H-1, 5 signal were merely used to prove that displacement had occurred by inversion and that the piperidine ring was in the chair form. These measurements (9, 42) have now been extended ( 4 3 ) to 3a-chloro- and 3a-bromotropanes by measuring coupling constants and dipole moments. Angular distortions were postulated similar to those reported by the Dutch authors ( 2 5 ) .Unfortunately, the 9 : 1 ratio of N-Me signals found with the hydrohalide was taken also as the ratio of N-Me conformers in the free base, an inference that can hardly be justified. A recent important contribution ( 4 4 ) t o conformational analysis of tropanes by NMR spectra has used 2P-bromo-3-tropanols and 2/3,3adibromotropane. Comparison of chemical shifts of H-6,7 protons in 3a- a,nd 3P-tropanol clearly revealed an anisotropic shift of 0.2-0.5 ppm caused by axial hydroxyl. Another deshielding by 0.5 ppm due to the 2P-bromine atom on H-4 in compounds X X X I I and X X X I I I was present, but was absent in compounds with no 2P-placed bromine atom. The ABX system comprising H-4P and H-5 was investigated after decoupling a t H-3, indicating J values as expected for axial-equatorial and vicinal diequatorial couplings. However, most values, except for X X X I I I deviated from those calculated for classic chair formation,

XXXII; Y = O H

XXXIII

Y=Br

alluding to a flattened chair form whenever a bulky 3a-substituent was present. Magnetic nonequivalence of H-6 and H-7, caused by the adjacent 3a-tropoyloxy groups, was reported for hyoscine ( 4 5 ) .Scopine, lacking such a group, indeed shows a singlet for these protons and a coupling pattern that fits well with the calculated (37)spectrum.

E. CONFORMATIONALANALYSIS OF ALLOCOCAINE AND ALLOPSEUDOCOCAINE Both relative (22-24) and absolute configurations (46) of cocaine and pseudococaine were known, while the steric structure of the two

8.

367

THE TROPANE ALKALOIDS

other epimers caused much confusion (Volume VI, p. 157; Vol. IX, p. 274). Conformational analyses of all four epimers were recently published ( 4 7 ); studies were made on chemical shifts and vicinal coupling constants, in particular J 2 , 3 , J 3 , 4 axial, and J 3 , 4 equatorial values. Spin decoupling was also used. Alloecgonine and allopseudoecgonine esters were obtained from 2-methoxycarbonyl-3-tropanone according to Findlay, but they were named ( 4 7 ) as suggested by Bainova et al. (as),a t variance with Findlay (49).Ecgonine and pseudoecgonine esters gave J2,3=5.4 and J 2 , 3 = 10.0 cps respectively, as expected for equatorial-axial and diaxial couplings. Similar values (6.0 and 10.4 cps) were recorded for cocaine and pseudococaine. Allococaine and alloecgonine showed very low J 2 , 3 values, pointing to equatorial-equatorial coupling, while allopseudococaine and COOR'

H (a)R ~ R~ = =H (b) R'= CH3; R2=COC,jH5

OR2 XXXIV

OR2

xxxv

allopseudoecgonine gave J 2 , 3 = 5 cps, corresponding t o the axialequatorial position of these protons. All these data, because of the known configurations (23) of cocaine and pseudococaine, pointed to their conformations and to configurations XXXIVa and XXXIVb for alloecgonine and allococaine, respectively, and XXXVa and XXXVb for the benzoyl esters allopseudoecgonine and allopseudococaine, respectively. The somewhat low J 2 , 3 values for pseudoecgonine and pseudococaine indicate an azimuthal value of about 160' for H-2/H-3, and hence flattening of the six-membered ring therein, although these compounds do not have a bulky group a t C-3. The product of benzoylation of 2-methoxycarbonyltropinone has been proven by NMR spectra to be the enol ester (50b).

F. CHIRALITY OF TROPINONE OXIME Tropinone oxime (XXXVI) has no high element of symmetry. Therefore it can be resolved (51)into enantiomers XXXVIa and XXXVIb. This type of molecular symmetry was predicted by Shriner et al. (52) and was later designated (53) by Lyle and Lyle geometrical enantiomerism, when they succeeded in resolving cis-2,6-diphenyl- 1 -methyl-4piperidone oxime. The resolution of tropinone oxime was achieved with

368

G . FODOR

I"'

HO

L XXXVIa

OH

mN'cH XXXVIb

(+)lo-camphorsulfonic acid (mp 108°C; [a],, -21.65"). Optical activity was destroyed by Beckmann rearrangement to 9-methyl-3,9-diazabicyclo[4,2,l]nonan-4-one.

G. CHIRALITY OF

THE

DISULFIDEBRIDGEIN BRUGINE

Disulfides have two enantiomeric conformations of maximum free energy with a dihedral angle close to 90 or 270". However, these are not separable unless one of the groups (or both) attached to the bridge bears additional asymmetry-as it is with glyotoxin and dithiolan carboxylic acid of brugine (I)( 2 ) .The evidence for this chirality was brought about by a circular dichroism (CD) study (54). The lowest energy band (320 mp) is diagnostic both in wavelengths and intensity of the disulfide chromophor in a saturated five-membered ring associated with a positive CD band a t 325 mp. Similarly to glyotoxin, the sign of the lowest frequency CD band is associated with known positive sense. I n the case of brugine this is right-handed. No enantiomeric conformation is revealed by the CD spectrum, although the tropine moiety is unable to impose any restraint on the molecule. The 277 mp band rather points to some sort of interaction between the esterified carboxyl group and the S-S system.

H.

CONFIGURATION AND

RACEMIZATION O F L(+)-2P-TROPANOL

~(+)-2P-Tropanyldiphenylborinate was prepared from Archer's 2Ptropanol(55) and diphenylborinic acid, while no such complex could be obtained from the 2cc-isomer (56).This serves as complementary evidence for the configurations of these epimers. This "complex') is in fact a boroxazolidine (XXXVII), as was pointed out by Zimmerman (57)) since it resists hydrolysis. This organoboron tropane compound was prepared for use in neutron-capture brain therapy ; it proved a powerful antiseptic and mydriatic (58).The parent I,(+)-amino alcohol raceniizes very quickly when treated with acetic anhydride a t 20°C in the presence

8.

369

THE TROPANE ALKALOIDS

XXXVII

XXXVIII

of perchloric acid (58), probably via the symmetrical tropanium ion XXXVIII.

I. SOLVATION DIASTEREOMERS OF COCAINE The phenomenon of compound +A forming diastereoisomers by solvation with -B and +B has been studied (59) by NMR spectroscopy. This was later investigated (60)with (-)-cocaine and (+)-and (-)-phenylmethylcarbinol in C S 2 or CC14 using 100 Mc NMR spectra. The difference between chemical shifts of the (-)/(+) and (-)/(-) pair increases at -40°C to 50 cps, as contrasted with 2.5 cps observed in other cases (59).

IV. Syntheses

A. FROM CYCLOPROPANONES AND PYRROLES A new entry into the tropane series has been achieved by treatment (61) of 2,2-dimethylcyclopropanone(XXXIX) with purified N-methyl

I

XLI

CH3

U

XLII

370

G. FODOR

pyrrole to give 2,2-dimethyl-6-tropen-3-one (XL) in 50% yield. This was characterized by NMR data: 6 0.87 (s, 3H) and 6 1.23 (s, 3H); 6 2.24 (s, 3H, N-Me); and 6 5.97-6.25 (m, 2H, vinylic). Hydrogenation During vapor-phase chromatography gave 2,2-dimethyl-3-tropanone. breakdown to (alkyl-pyrry1)-alkyl ketones XLI and XLII takes place. Generalization of this fascinating route is still expected.*

B. FROM PYRROLIDINES One of Willstatter’s tropinone syntheses (62)has been reinvestigated (63). “Succinyldiacetic ester” had been reported to give with methyl--+ ROOC-CH O C H - C O O ,

ROOC-CH2-~C-C~C-CH2-COOR

I

J ROOC-CH2

G-CH2-COOR

I

CH3 XLIV I 25%

ROOC-CH2 e C H 2 - C O O R

I

CH3 XLV

60%

ROOC-CH O ~ H Z - C O O R

I

CH3 XLVI

amine N-methylpyrrole 2’5-diaceticester (XLIV).Hydrogenation of the latter, followed by Dieckmann condensation, afforded 2-ethoxycarbonyltropinone. However, it was now demonstrated that only heating converts the pyrrolidine with two exocyclic double bonds, XLIII to XLIV. Partially hydrogenated species such as N-methyl-A3-pyrroline 2,5diacetic ester (XLV) were obtained in 25% yield besides the exocyclic olefine XLVI. Compound XLIII was known (22) as an intermediate of Raphael’s acetylenic route that leads to tropanes.

* 1,3-Dipolar addition of dienophiles, such as acrylonitrile, methyl methacrylate to 1-methyl-3-oxido pyridinium provides a new elegant route to 6-substituted-2-0x0-3tropenes (189).

8.

371

THE TROPANE ALKALOIDS

Another approach (64)that resulted in the synthesis of the 3a-phenyltropane derivative (type XLIX) converted cis-2,5-dicarbethoxy pyrrolidine (XLVII) to an N-tosyl pyrrolidine and the 2,5-dichloromethyl pyrrolidine (XLVIII) by ultimate condensation with benzyl cyanide. E t O O C ~ C O O E t N

I

1. TsCl 2. Red

ClHzC

CHzCl

3. SOClZ

H XLVII

V

I

Ph

XLIX

This route might not be limited to obtaining nonnatural tropane derivatives, for benzyl cyanide could be replaced by any other active methylene compound. OF C. NOVELAPPLICATIONS

THE

ROBINSON ROUTE

I n addition to previous scarce descriptions (22) of using ammonia instead of a primary amine, a more extensive work on the condensation of succinic aldehyde and 3-ketoglutaric acid has been published (50a); this leads to nortropinone. Unfortunately, the yield of nortropinone (L) was not high and was based on the amount of a precipitated derivative. R

L

LI

Oxidation of tropinone ethylenecycloketal with potassium ferricyanide seems to give competitive yields (65).However, separation from large amounts of inorganic salts seems not to be challenging. Cyanogen bromide degradation of tropinone into N-cyanonortropinone ( 6 6 ) ,

372

G. FODOR

followed by hydration (in glacial acetic acid with molar amounts of sulfuric acid a t O O C ) into the urea and subsequent hydrolysis with 2N hydrochloric acid gave nortropinone (L) in 75% overall yield ( 2 8 ) . Use of a-amino acids, e.g., glycine, alanine, etc., instead of primary amines led to isolation of 3-oxo-8-nortropaneaceticacids (LI) in about 34-35% yield. Reducing these afforded the nortropine-N-acetic acids (67). BE-Hydroxytropinone and 6a-methoxytropinone were isolated quite recently by S6ti (187) as by-products from the Robinson condensation of malic dialdehyde.

D.

FROM

2,6-cYCLOHEPTADIENONE

A facile synthesis of the ketones tropinone, 3-granatanone (pseudopelletierine), and their N-substituted derivatives (including quaternary salts) has been elaborated by Bottini and GB1 (68). For example,

ooRNH2

LII

R R R

=

=

=

CH, CaHs PhCHz

LIII

2,6-cycloheptadienone (LII) and methanolic methylamine gave 95% conversion of the ketone into tropinone (LIII), which was followed by scanning in the NMR spectrum of the vinyl region. The same reaction occurred with ethylamine and benzylamine, leading to N-ethyl- and N-benzylnortropinones, respectively. I n view of the easy access of a,a'-unsaturated cyclanones (69),this new route seems to be the most competitive to the Robinson synthesis. There was an earlier intention to explore this direction (70).Furthermore, a mixture of cycloheptadienones, obtained from tropinone methiodide, was reconverted into tropinone (71);also, anhydroecgonine was obtained from cycloheptatriene carboxylic acid ( 7 2 ) .Thus, this Michael addition, or retro-Hofmann reaction, is now open to more extensive preparative applications. Dialkylaminocycloheptenones, the presence of which was indicated (73) by polarography in the Hofmann elimination of tropinone methiodide with base, have now been assumed (27, 28, 7 4 ) t o be likely intermediates in the stereomutation of certain quaternary tropanium salts, e.g., LIV and LV, and the methylethyltropanium salts ( 2 7 ) .The

8.

373

THE TROPANE ALKALOIDS

synthesis of L I I I from L I I now strongly supports this view. Inversion around the nitrogen has been followed by NMR spectra that have indicated formation of a second N-methyl signal in t-butanol in the presence of Al-t-butoxide.

LIV

LV

The exchange of sulfur by methylamine in thiatropinone methiodide and inversely, replacement of nitrogen by sulfur in tropinone methiodide, may well proceed through similar pathways (71, 7 5 ) .

E. LABELED COMPOUNDS The increasing importance of biogenetic and metabolic studies with tropanes has put heavy emphasis on synthesizing both polytopically and specially labeled derivatives. Preparation of tropine-6,7T (LVIa and LVIb) has been achieved (76) by catalytic tritium addition t o 2,5-

LVIa

LVIb

dimethoxy-2,5-dihydrofuranand, following the Robinson route t o tropinone-6,7T, by subsequent reduction with hydrogen over Raney nickel.

374

G . FODOR

Synthesis of methyl-14C labeled tropine and atropine was carried out (77)from Nal4CN via methylarnine-l%, basically on the Robinson route but by an improved technique; methyl-14C tropinone was obtained in 70% overall yield and atropine-14C in 68% yield. Tropic acid l-14C (LVIII) was prepared from benzylmagnesium chloride followed by carbonation with 14C02 and addition of formaldehyde t o LVII. Double-labeled 14C atropine was thus obtained. A similar pathway from Nal4CN to atropine methyl-14C was described by others. H

H

I Ph-C-H

>-

I

I.

woa

2. IgMgC1

MgCl

I

Ph-C-14COzMgCl

I

MgCl LVII

cnzo

H

+

I I

Ph-C-14COzH CHzOH LVIII

Another pathway, leading t o microsynthesis of 1-14C-atropine, started with arabinose-59% (LIX) conversion into furan and application of the Clauson-Kaas route to succinic aldehyde and henceforth to 1- or 5-14C-tropinone (LX). Using arabinose-3,4-14C gives 6,7-14C-tropanes, thus showing the versatility of this method (78, 7 9 ) . HO-CH-CH-OH

I

HO-14CHz

I I

CH-C=O

I

OH H LIX

H3c'N LX

Atropine-2,3,4-14C, -2,4-14C, and -3-14C were obtained (80) from the correspondingly labeled citric acids via 3-ketoglutaric acid and a microcondensation and microesterification procedure. N-Methylation with the methyl-14C iodides of norscopolamine, norscopine, and noroscine was carried out ( 8 1 ) .N-Methyl-14C cocaine and ecgonine were prepared by similar methylation of the nor-bases (82). Also, methylation of benzoyl ecgonine with diazomethane-14C gives ester-methyl-14C cocaine, and benzoylation of ecgonine methyl ester with benzoyl chloride-a-14C to cocaine benzoyl-cc-14C are described in the same paper (82). Methyl-tritiated derivatives of (-)-cocaine, (+)pseudococaine, and (-)-hyoscine were obtained (83)from the nor-bases by methylation with CTH2I. Polytopic labeling using Wilzbach tritiation with tritium of atropine and norcocaine (84),of (-)-sccjpolamine (85)and of (-)-cocaine (86) were also described. Similar alkylation techniques were adapted well before ( 8 7 ) .

8. THE TROPANE

375

ALKALOIDS

F. TROPANYL ETHERS,CARBOXYLIC ACIDS,AND OTHER DERIVATIVES

The internal ether, “tropene oxide,” i.e., 3a,6a-oxidotropane (LXII) (22)had been formed (88)in an attempt to reduce, with lithium aluminum hydride, 3a-acetoxy-6-methanesulfonoxytropane (LXI). Similar conversion of scopolamine into oscine was well known (23b).

LXI

d

H O U

yo

NormalHCl

LXII

HO OH

LXIII

LXIV

LXV

6a-Tropanol (LXV) was synthesized (89) from 6P-hydroxy-3tropanone (LXIII) by hydrogenation of the carbonyl in normal hydrochloric acid over PtOs to LXIV, followed by oxidation into 6-tropanone and catalytic hydrogenation of the latter to LXV. The last step was stereospecific (99%) as shown by GLC. The 3a-benzhydryl ethers of tropine and of scopine were formerly prepared by arylalkylation with diphenyldiazomethane (90).Benzhydryl bromide was used (91) as reagent on N-2-hydroxyethylnortropine, affording 66% of the 3a-ester along with 33% N-2-benzhydryloxynortropine. No appreciable quaternization had occurred. 3-Chloro-, 3-bromo-, and 3P-mesyloxytropane have been converted (92) into the 3a- and 3P-pheny1, n-butyl, methyl, and thiophenyl ethers in moderate (21-48.5%) yields, with concomitant elimination and possibly fragmentation. Solvent effects upon the steric course of displacement were recorded. I n previous work (22) mention was made of a synthesis by Geissman et al. of 3-substituted tropanes of potential pharmacological interest. The full papers (93, 94) now give details of the synthesis of the 3a- and

376

G . FODOR

LXVII

LXVIa; R = H LXVIb; R = COCH3

LXVIIIa; R = CH3 LXVIIIb; R = H

LXIX

I

LXXa

I

LXXIa

I R

= H or

CH3

LXXb

I LXXIb

3P-hydroxymethyltropanes LXXIa and LXXIb via the 3-hydroxycarboxylic acid LXVI and LXVII LXX. The bridged quaternary ammonium salt (LXXIII) (93), prepared by internal quaternization of p-LXXII, is of particular interest. Anchimeric assistance by nitrogen to hydrolysis of the 3p-ester LXXb was established. A compound somewhat related to LXXIII, “ tropaquinuclidine,” i.e., 8-methyl-3,s-diazatricyclo [3,2,1,239*]decane (LXXVa) was obtained (95) from 3-azatropane (LXXIV) by chloroethylation and internal

377

8. THE TROPANE ALKALOIDS

LXXIIa

LXXIIb

LXXIII

cyclization. 3-Benzyl 8~-chloroethyl-3,8-diazabicyclo[3,2,l]octane was likewise cyclized into N-benzyltropaquinuclidine (LXXVb).

-

H3c'Ny--j4!, .H

LXXIV

1. HC1

2. Cl(CH&Br

LXXVa; R=CH3 LXXVb; R = CHzPh

Preparation of nortropane derivatives other than those mentioned in connection with Section 111,C include an improved Willstatter technique that was elaborated by Werner and his associates (96-98). Oxidation of (-)-cocaine, of (+)-pseudococaine, of 0-benzoyl-(+)-pseudoecgonin H /

LXXVI

LXXVII

propylester, of atropine, and of tropacocaine into the secondary amine bases with potassium permanganate in aqueous acetonitrile gave yields (96) ranging from 2347%. Norscopolamine (LXXVI) was obtained by a similar technique along with N-formylnorscopolamine and N-formylaposcopolamine (compare Volume IX, p. 27 1, oxidation of valeroidine).* A number of new scopine esters were also described. Several new norhyoscine derivatives were obtained by alkylating this secondary base (98).Also, an epoxide of the atropic residue of aposcopolamine was isolated.

* Ethyl chloroformate has been successfully used in demethylating acetyl tropine into nortropine and other tropanes (190, 191). N-Cyano tropinium and tropinonium bromides were trapped and analyzed ( 1 9 3 ) .

378

G . FODOR

Added i n proof Synthesis of +3,7P-dihydroxyatropine, i.e., teloidine 3a-tropic acid ester, was achieved (187) by condensation of (&) 0-benzyl tropic acid chloride and 6,7-benzalteloidine, followed by hydrogenolysis of the protecting groups. Biosynthetic assays should be carried out with that compound in order to determine whether hyoscine is formed from hyoscyamine and 6~-hydroxyhyoscyamine(128) via a trihydroxytropane tropic acid ester in the plant tissue. An oxime analog of atropine, phenylglyoxylic acid tropylester oxime (LXXVII), was synthesized (99). Synthesis of atropine (LXXIX) by hydroxymethylating phenylacetyl tropine (LXXVIII) with paraformaldehyde in DMSO was elaborated (100).

m

H3LN

CHZO ___f

0-C-CHzPh

LXXVIII

LXXX

II

0

DBIHO NaOEt

J33C\N

ma 0-C-C-Ph

II I

0 CHzOH

LXXIX

LXXXI

Homatropine, i.e., (i-)-mandelyl tropine (LXXX) was resolved (101) by camphor-P-sulfonic acid, the yields being 31 and 15%. Similarly, (-)- and (+)-hyoscyamine (yields 94 and 74%) were obtained from atropine. Comparable yields were obtained with L- and D-dibenzoyltartaric acid ( I ) . Synthesis of azoniaspironortropane derivatives (for example, LXXXI) was claimed (102) from nortropanols with 1,4 and 1,5 and higher a,w-dihalogeno compounds. A spiro-azetidine cycle wm not mentioned. 3-Tropanylphenylacrylateswere prepared (103)and listed for spasmolytic activity. Preparation of pure scopolamine butyl bromide was claimed (104)by ion exchange of scopolamine butiodide. A large number of 3-monocarbocyclic aryl-3-carboxytropanes were described (105),as well as an interesting new epoxide (LXXXII).

8.

379

THE TROPANE ALKALOIDS

N-substituted ketones of the nortropane series have been synthesized (106, 107), basically by the Robinson route, and checked extensively for pharmacological activity.

LXXXII

LXXXIII

Valeroidine, esterified with arylacetic acids, gave products (LXXXIII) (108) which are being screened for local anesthetic, hypotensive, and sedative properties. This is a n incomplete list ; further tropane derivatives are described in Sections V and VII.

V. Reactions of Tropanes

A. PHOTOCHEMISTRY AND RADIOLYSIS Photolysis (109) of tropinone in benzene solution saturated with oxygen, followed by chromatography over silica gel (methylene chloride), yields N-formyl nortropinone (LXXXIV) in 50 % yield. Compound 0

II

LXXXIV

LXXXIV was identified by I R (1680 and 1710 cm-I), NMR 6 8.26 (s, 1, CHO), mass spectra (M 153, m/e 125, 96, and 82), and others. The reaction does not occur in the absence of light; therefore it involved photochemically generated singlet oxygen, although its mechanism is not quite clear. Neither singlet oxygen alone (from HzOz), nor ground-state oxygen in the presence of benzoyl peroxide, converts N-Me into N-formyl. However, oxidation of tropanes with chromic oxide and permanganate (1,82, 83) has the same effect.

+

380

G . FODOR

The authors suppose that the carbonyl moiety is the sensitizer in photolysis and its triplet state is quenched by dissolved oxygen ; thus, singlet oxygen is generated adjacent t o the N-Me group. Atropine sulfate in aqueous solution is radiolytically decomposed up t o 21% when irradiated with X-rays from a 6Wo source. Tropine and tropic acid were identified, among other products, by polarography and thin-layer chromatography (110). B. HYDROLYSIS, SOLVOLYSIS, AND FRAGMENTATION Kinetics on the hydrolysis of tropine esters was studied (111)a t high and low pH, affording specific rate constants K1 and Kz, respectively.

LXXXV

Reaction 1 had activation energies of 7 . 1 , 11.3, 8.8, and 9.8 kcal/mole, for noratropine, tropine phenylacetate, phenoxyacetate, and p-nitrophenylacetate, and reaction 2 hadvalues of 6.9 , 5 . 4 , 7 . 9 ,and 11 kcal/mole. The hydrolysis rate constants usually follow the dissociation constants of the acids. Quaternary salts of atropine hydrolyze twice as fast as tertiary bases, due to inductive effects. This study was extended to homatropine derivatives. Hydrolysis of scopolamine to scopine (LXXXV) has been elaborated (112)using baryta that works 100times faster than Sorensen buffer (113). The behavior of 3P- and 3a-chlorotropanes under solvolytic conditions had already been subject to investigations (Volume I X , p. 291). Recently, a more profound study on solvolytic cleavage was carried out (114) with the hitherto unknown 3p- and 3a-chloronortropanes (LXXXVI and LXXXVII). Both the tertiary and secondary 3P-chlorotropanes underwent fragmentation to 2-allylpyrrolines (LXXXVIII), indicating a synchronous mechanism. Conditions for fragmentation, that is, antiperiplanar orientation, are present on lone nitrogen electrons with (equatorial) C-C1 bond and with the C-C bond to be broken. No such prerequisites prevail with 3a-chlorotropanes (LXXXVII), therefore, solvolysis in 80% alcohol gives a mixture of the 3a- and 3P-tropanols and ethers. I n aqueous dioxan ( 2 : l ) , 74% 3a-tropanol, 5% 3P-tropano1,

8.

381

THE TROPANE ALKALOIDS

and 20% 2-tropene had formed, according to GLC analysis. No fragmentation could be observed.

!WCl

R

H

LXXXVI

i

n

H

LXXXVII

R = H, CH3 O CI H & H = C H z

R LXXXVIII

Mass-spectral differentiation of stereoisomers can be performed with many amino alcohols, since the M-1 peak varies with configuration (115). However, in tropanes this peak is missing because neither the bridgehead ammonium ion XC nor the unsubstituted immonium ion LXXXIX is favorable.

On the other hand, fragmentation of alcohols to M-17 peak, e.g., in 3-tropanols, would not pass through the bridged ammonium ion XCI, since in view of the aforesaid (115),this step should be stereoselective ; thus, cleavage to XCII seems more likely.

-HO +

XCI XCII

382

C . FODOR

C. ENZYMATIC EPIMERIZATION Tropan-3a-01 was converted (116) into 3P-tropanol by synergism of Bac. alvei with an Enterococcus. A similar epimerization was known in the absence of enzymes to pass through the ketone oxidation-reduction mechanism (23c, 117, 118). However, on a tracer study, SP,T-tropine (XCIII) in the bacterial isomerization gave pseudotropine-3a,T-XCIV,

xcv thus proving that ( a ) no oxidation to tropinone was involved and ( b ) dehydration to 2-tropene (XCV), followed by hydration had taken place.

D. MISCELLANEOUS REACTIONS Trimethylsilylation of tropanols proved to be stereospecific, since only equatorial hydroxyls react (119). Racemization of hyoscyamine to atropine in aqueous solution was followed kinetically by polarimetry, and the rate constant was determined (120). Electrostatic factors were believed to account (121) for preferential equatorial hydrogen addition to tropinone over Pt, while the hydrochloride gave 57% pseudotropine ; this does not agree with previous

8.

THE TROPANE ALKALOIDS

383

data (22).Also, the claims (122)that sodium borohydride reduction leads t o preferential pseudotropine formation seems t o be a t variance with other investigators’ experience. Reaction of acetylene with tropinone proceeds normally (123)and was used in preparing 3-ethyltropan-3-01. Nitrosation of nortropane derivatives, e.g., N-nitroso-6/3-methoxytropane by “chemical” reduction, for example, LAH, gave rise to N-amino-6/3-methoxynortropane (XCVI) an intermediate for further syntheses (124).

XCVI

XCVII

Selective demethylation (125) with thiophenoxide ion in 2-butanone of several heterocyclic quaternary salts was announced ; tropine methochloride was demethylated (125). The Vitali reaction (a blue-violet coloration is obtained with a base upon the residue of evaporating atropine with nitric acid) has now been investigated (126).p-Nitroatropine nitrate ester is one of the products which, with base, gives a resonance-stabilized anion derived from

XCVII .

VI. Biosynthesis

A. HYOSCYAMINE It has again been confirmed (18,127)that hyoscyamine is the primary tropane alkaloid, while 6-hydroxyhyoscyamine seems t o be the intermediate in the juvenile plant (128) (Volume IX, p. 298). No doubt has arisen as to asymmetric incorporation into hyoscyamine of the cr-carbon of ornithine-al4C since the successful resolution and configurational proof of P-methyl tropidine (129, 130). However, putrescine a symmetrical compound, first claimed to be t,aken up by the plant when Datura seeds were pretreated with bromine water (131),proved soon thereafter to be incorporated under “normal ” conditions as well (127,132-134). A new precursor, succinic acid, appeared more recently on the scene. Labeled succinic acids 1,4-14C and 2,3-14C were incorporated into

384

G . FODOR

hyoscine and hyoscyamine in roots of D. innoxiu Mill. Therefore, succinic acid should give the whole pyrrolidine skeleton of tropanes, as suggested (135) in Schemes 1 and 2. Studies with labeled 1,3-14C- and 2-14C-acetone indicated its incorporation into the piperidine moiety a t C-2,3,4 of the tropane skeleton (136).

SCHEME1

CHz-COOH

I

CH2-COOH

2 H2

- 1

CH2-CHO CHz-CHO

I

+ 2 HzO

CHaNHz HOOC-CHz

\ ,c=o

IIOOC-CHz

SCHEME 2

B. TELOIDINE AND METELOIDINE Racemic ornithine-2-14C was fed to 3-month-old Duturu meteloides. Systematic degmdation of meteloidine (Scheme 3) proved that bridgehead carbons C-1 and C-5 became radioactive (137).It has been shown (138) that only the 6-amino nitrogen of ornithine gives the tropane nitrogen atom. Hygrine also may serve as a precursor for tropanols (138).

8.

THE TROPANE ALKALOIDS

*

H3C QCH3I

-

X

CH3COOH

385

X

CH3NHz+COz

CH3 SCHEME 3

It seems that atropine was the precursor of meteloidine; hence the assumption (128)of 6-hydroxyhyoscyamine and 6,7-dehydrohyoscyamine as intermediates in interconversions of tropane bases was corroborated. The tiglic acid moiety in meteloidine arises (139, 140) from isoleucine (Scheme 4). This was based on a tracer study with (+)-i~oleucine-2-1~C. H3C

H3C \

‘CH2

I

__f

H3C /CH\CH--NH2

I

H3C

H3C,

CHz

I

__f

/CH\

c=o I

I

,CH

__f

\

COOH

COOH

COOH Isoleucine

H3C

CHz

a-Keto-8-methylvaleric acid

H3C

C ‘’

H

II

H3C/C\COOH Tiglic acid SCHEME 4

a-Methylbutyric acid

386

G . FODOR

The whole label was discovered in the carboxyl carbon of the tiglic acid moiety of meteloidine. C. SCOPOLAMINE Previous statements (see Sections VI, A and B) apply by inference to scopolamine. A thesis (141) seems to confirm that 2-14C-ornithine is a precursor for scopolamine, although no decisive evidence was presented as to its formation prior to or simultaneously with that of hyoscyamine. Degradation of Solanaceae alkaloids in higher plants has been studied (142).Isolated leaves and central veins of Nicotiana rustica and Atropa belladonna showed no decreased alkaloid contents for 10 days, while addition of labeled atropine to a number of plants led to 60-70% degradation of alkaloids. This process involved hydrolysis, followed by decarboxylation of tropic acid. Investigation of root cultures of Datum innoxia showed a change in the habit of growth, but no change in hyoscyamine and hyoscine content when benzoin antioxime was added. This indicated that ascorbic acid oxidation was not involved (143)in alkaloid biosynthesis.

VII. Structure-Activity Relationships Up-to-date views have already been outlined in Volume I X of this series concerning manifold activities of both natural tropane bases as a function of structural elements. I n recent years molecular pharmacology has merely developed and served as a basis for drug design. This includes guidelines as to the modification of a structure given by nature. For reference, see Ariens (144). The chemical nature and mode of pharmacological actions of quaternary ammonium salts have previously be-n explained by Cavallito and Gray (145)in the same series. Another general survey on the contribution of medicinal chemistry to medicine is given by Cavallito (146).Finally, the ideas described in Volume I X on the special field of tropanes were reiterated and completed by Ntidor (147). Some details of this field are still worth reporting. Stereoisomeric forms of 2a- and 2P-acetoxytropanes (concerning racemization, see reference (8))have been converted into the methiodides and examined for pharmacological activity. Since the muscarinic properties of acetylcholine were associated with its transoid €orm, it was expected that XCVIII is more muscarinic, while XCIX which resembles the cisoid

8.

V

U XCIX

XCVIII

H3C

387

THE TROPANE ALKALOIDS

m

m CH3

\& /CH2

/k\C @ H z+

Tr = tropoyl

OTr

OTr

C

CI

form of acetyl choline, should act like nicotine. This has been supported by pharmacological assays ( 5 8 ) . Propionylatropine methyl nitrate (148)showed a greater potency than atropine. (~)-4-Biphenylylmethyl-3~-tropoyloxytropanium bromide, as compared with the 3P-ester, showed a remarkable importance of the a-configuration of the tropoyloxy group. However, no difference in order of magnitude of action between N-stereoisomers C and C I was found ( l a g ) , a t variance with previous suggestions (see Volume I X of this series). The UV spectra of C I of the corresponding bisxylylene derivative and of several 0-substituted derivatives have been described (150). A large group of C-3-substituted tropanes, with combinations of aryl, arylalkyl, carboxy, hydroxyl, and carbalkoxy groups were synthesized and screened (151).Most proved to be useful analgesics, and some have anticholinergic and ganglionic blocking activity. A similar blocking effect was ascribed to 0-alkyl- and acyl-N,-4-cyclohexylbenzyl tropinium bromides (CII) (152). Neuromuscular blocking action was claimed for N-hydroxyalkyl-3ahydroxytropanium salts (CIII) and their esters (153).Three of the four diastereoisomers (48) of cocaine have been subject to testing as local anesthetics (154).As expected, allococaine, a 3a-hydroxy derivative, had a weaker reaction than cocaine and pseudococaine. Adrenomimetic activity shows a sequence (-)-cocaine > allococaine > pseudococaine, which seems surprising in view of previous configuration-activity relatioiiships ( I , 22, 147). 3a-10,ll-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yloxytropane dihydrogen citrate (CIV) " deptropine," was synthesized and introduced as a new drug (155).

388

G . FODOR

CII

H H3C, + /

citrate-

“8 CIV

CIII

HC=C-H&\

Nw R1

/’

O-Tropyl

cv

N-Propargylnoratropine (CV) was reported as having (756), in addition to weaker central and cholinolytic activity than atropine, a fourfold increase in the analgesic-disorientating action of atropine. Atropine interacts with amino acids by forming a complex with UV maxima a t 290-295 mp. No such action was observed with acetylated amino acids, while guanidino and other basic groups enhance reactivity (757). This interaction does not affect the cholinolytic a.ctivity of atropine. This section of the review is incomplete. Many further pharmacological studies on tropanes have not been mentioned. Other papers dealt with structure versus toxicologic parameters (758) in esters of the tropanols. Cocaine has also been compared as an agent of reducing conditioned suppression (159). Structural changes and anticholinergic activity were compared in a-methyltropic esters (760) and other tropine esters (767). Interaction of aryl esters in the tropine and pseudotropine series with tissue chemoreceptors was established (762). New anticholinergic oximino esters and ethers, inter alia, of tropanols were described (763). The pharmacology of ethylbenzotropine (764)and of deptropine (765, 766) was investigated. Among quaternary tropanium salts, the pharmacology of N-ethyl (167)and N-alkylbenzyl (768) tropanium salts and bisscopolaminium xylylene dibromide (769)were subject t o research. Cocaine-T binding by the isolated guinea pig vas deferens was measured (770).

8.

389

THE TROPANE ALKALOIDS

VIII. Metabolism of Tropane Alkaloids in the Animal Body The transformations of tropane alkaloids in the mammalian organism have been an intriguing problem for many years. Elaboration of specific isotopic labeling of many tropanes, described in Section IV, A (77-86), enabled Werner’s group a t the Max Planck Institute in Frankfurt, Germany, to solve many open questions. Autoradiography, fluorometry, and many modern methods have enabled (171-174) that team to follow and chemically characterize metabolites of tropanes. Also, a number of new” enzymes have been found to explain certain reactions in vivo and to use these for synthetic or analytical purposes. ( 6

t -

Atropine-9‘-glucuronide

COz

+ Noratropine derivative

t-

Atropine

4’-Hydroxyatropine

--+

Tropine

+ Tropic acid

Derivative of 4’-hydroxyatropine

Glucuronic ester of 4‘-hydroxyatropine

SCHEME5 .

Application of these methods led to Schemes 5 and 6 for the metabolism (175-177) of hyoscyamine and hyoscine in mammalian organisms. The free tropic acid hydroxyl in hyoscyamine is converted in mice into glucuronate, followed by hydrolysis and/or degradation of the N-Me group. Alternatively, 4’-hydroxytropoyl tropine is formed and converted into its glucuronate (Scheme 5 ) .With hyoscine, glucuronation also takes place and, in addition, hydrolysis, dehydration, and N-demethylation were proved (Scheme 6). The most interesting facet was enzymatic reduction of the epoxide to 6-hydroxyhyoscyamine, an intermediate in theformation of hyoscine from hyoscyamine in the plant tissue ( 1 , 1 2 8 ) . Hydrolysis of (*)-hyoscyamine by enzymes showed definite stereospecificity ; the (+)-modification does not change. This allowed an enzymatic determination of the degree of racemization of (-)hyoscy-

390

G . PODOR (-)-Norscopolamine-g’glucuronide

T

-Norscopolamine

(-)-Scopolamine-9’glucuronide

I

c02

/

(-)-Scopolamine

SCHEME6

amine and (-)-hyoscine (178).Also, enzymatic asymmetric decomposition of (&)-atropinesulfate into (-)-hyoscyamine sulfate became feasible (177). This enzyme, (-)-hyoscyamine acylhydrolase (17 9 ) ,was purified, and its activity was followed by paper chromatography. Radiochemical techniques with atropine-9-14C, -8’-14C, and polytopically labeled -3H lent further support to Schemes 5 and 6 (180). Tropacocainesterase (181) from horse serum is a carboxylesterase similar t o the acylcholine acylhydrolases. It is extremely sensitive toward physostigmine. Nortropacocaine was hydrolyzed by an esterase in human brain ( 17 6 , 1 8 2 ) . (-)-Cocaine-3-acylhydrolasefrom rabbits allegedly attacks the methyl ester group first. Use of cocaines that were labeled alternately in the 2- and 3-positions with 1% has proved cleavage of the benzoic acid ester group first (183),while the methyl ester group was probably hydrolyzed in a nonenzymatic way. Using three differently labeled scopolamines-14C, i.e., 9-14C, 9-3H, and U-3H, in treating mice, rats, guinea pigs, and common marmoset, led to the following metabolites (184, 185): scopolamine-9’-glucuronide, (-)-norscopolamine-9‘-glucuronide,aposcopolamine, 6-hydroxy-(-)-hyoscyamine,and (-) -norscopolamine. This again corroborates previous statements on this metabolism depicted in Scheme 6. Atropine and cocaine are split by a hydrolase enzyme that abolishes mydriatic effect. Some animals lack this enzyme ; therefore they are 100-500 times more sensitive toward these alkaloids than others.

8.

T H E TROPANE ALKALOIDS

391

IX. Addendum-’ 3CNMR Spectroscopy of Tropanes Quite recently E. Wenkert (194)and his group a t Indiana University have elaborated the use of 13C NMR spectroscopy in the tropane field. N-Methyl-ethyl epimers and also N-methyl and deuteromethyl derivatives can clearly be distinguished and identified by this powerful novel technique details of which should be published soon. ACKNOWLEDGMENTS The author wishes to express his appreciation to Mrs. Motoko Yoshida for her help in collecting references, to Dr. J.-P. Fumeaux for drawing the formulas, and to Professor Carolyne MacGillavry for supplying the three-dimensional representation of XIVb, prior to publication.

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