HELVETICA CHIMICA A C T A
-
v-01. 59, FaSC. 7 (1976) - Nr. 262
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262. W - N M R . Spectroscopy of Naturally Occurring Substances. XLV. Iboga Alkaloidsl) by Ernest Wenkert2), David W. Cochran, Hugo E. Gottlieb and Edward W. Hagaman Department of Chemistry, Indiana University, Bloomington, Indiana 47401, U.S.A. and Raimundo Braz Filhoa), Francisco Jose de Abreu Matos and Maria Iracema Lacerda Machado Madruga Departamento de Quimica Org2nica e Inorghnica, Centro de Cihcias, TJniversidade Federal do CearA, 60.000 Fortaleza, Brazil (29. 111. 76)
Summary. The carbon shifts of the Iboga-type alkaloids catharanthine, voacanginc, coronaridine, ibogaine, dihydrocatharanthine and epiibogamine were recorded and correlated with the conformation of the natural bases. A 13C-NMR. analysis of heyneaninc determined its C(19) configuration and a similar study of cpihcyneanine proved its structure.
I n connection with problems of structure determination and synthesis of indole alkaloids of the Iboga type it became of importance t o apply 13C-NMR. spectroscopy thereto. As a consequence the following study of a select group of such natural products was undertaken and isoquinuclidine (l),its N-methyl derivative (2), some monosubstituted bicyclo[2.2.2joctanes (3) and two bicyclo[2.2.2]octenes (4) used as models. The carbon shifts of the first two models are depicted on formulas 1 4 ) and 2 and those of bicycles 3 5 ) and 46) listed in Table 1. .46.9
.57.2
&z4
4 2 . 5 M e N 25.5
8
&42 3 :
&; 2
2
3a, R b, R C, R d, R
Mc 3 e , R = CHO Et f , R = COzH = CHzOH g, R = COzEt = CH(OH)Me h,R = Ac =
=
4 R'
4a, R = C H O
R = H
4b R =H R = CHO
For part XLIV see [l]. Present address : Department of Chemistry, Rice University, Houston, Texas 77001, U. S.A. Present address : Dcpartamento de Quimica, Universidade Federal Rural do Rio de Janeiro, Brazil. The nitrogen perturbs appreciably the vicinal methylene shifts of isoquinuclidine (1) (cf. the 26.1 ppm methylene shift of bicyclo[2.2.2]octanc [Z]). The total of the y-effects on C(l) and C(3) is 7.7 ppm greater for the hydroxy group of 3c than the methyl group of 3b, relative to 3a. The comparable magnitude of the y-effect of the two groups as a result of fixed gauche, non-bonded interactions [3] [4] and thc shielding of ycarbons by hydroxy groups truns anti-periplanar to them within rigid six-membered rings [j]suggest that the excess shielding by the hydroxy group of 3c is an acyclic equivalent of the lattcr phcnomenon. This result indicates that caution must be cxerciscd in the assessment of shielding contributions to y carbon atoms from oxygen in all staggered, acyclic conformations. The introduction of a double bond into the strained bicyclo[2.2.2]octane skeleton leads to stronger deshielding of the allylic carbons and a decrease of the cndocyclic homoallyl effect relative to the shift differences of cyclohexenes and cyclohexanes [2] [6] (cf. also the 6b + 5a change).
28.0 37.9 34.1 24.8 26.1 i) 25.4’) 20.7 27.5’) 28.7 12.1
30.2 30.2 35.6 25.0 26.1’) 25.0‘) 20.3 27.4’) 21.0
24.51) 38.2 29.9 24.1‘) 25.8J) 25.23) 20.4 26.7’) 65.6
3Cd) 24.2 43.8 30.4 23.7 25.7’) 24.8’) 20.3 26.4’) 69.2 20.8
3dc) 25.8 43.8 30.6 24.0 25.6’) 24.1 i ) 20.6 27.1’) 71.2 21.8
3d’c) e) 25.2 49.2 24.7 23.5 26.0’) 25.0’) 21.6 25.0’) 204.1
3ef) 27.2 41.5 27.7 23.5 26.0’) 24.8’) 21.6 25.0’) 182.2
3f9)
399) 27.3 41.6 27.9 23.5 26.0’) 24.9i) 21.6 25.0i) 175.8”)
3hc) 26.3 49.5 25.9 23.4 25.9‘) 24.5’) 21.0 24.6’) 209.4 27.7 29.9 49.8 25.0’) 29.0 135.03) 133.0j) 20.5 24.5’) 203.3
4af)h) 30.4 50.5 26.4 29.0 24.8’) 24.5’) 130.3j) 135.5j) 202.9
4bf)h)
3 39.1 52.6 47.6 19.5 109.4 128.1 118.1 119.0 121.7 110.2 134.7 29.3 121.6 46.0 35.8 10.2 26.1 149.0 63.0
138.6 53.2 49.4 20.9 110.0 128.5 117.8 118.7 121.9 111.3 135.4 30.4 123.2 55.6 37.4 11.2 26.2 148.1 62.9 172.7 52.6
136.0 52.9 49.3 21.0 110.2 128.4 117.7 18.9 21.3 10.2 34.7 30.4 23.4 .55.0 38.0 10.5 25.9 148.5 61.5 173.6 52.0 137.3 53.0 51.5 22.0 109.7 128.7 100.4 153.6 111.4 10.9 30.5 27.2 31.9 .55.0 36.2 11.5 26.6 38.9 57.2 175.4 52.2
bad)
6b 136.5f) 53.1 51.5 22.2 110.3 128.8 318.3 119.0 121.8 110.3 1 35.6 f) 27.2 32.0 55.1 36.3 11.6 26.6 38.9 57.2 175.9 52.4
6c e) 143.0 54.1 49.8 20.5 108.8 129.8 100.4 153.7 110.9 110.5 129.8 26.3 31.9 41.2f) 34.0 11.8 27.7 41.8f) 57.3
f)
135.9 52.0 g) 50.99) 21.6 109.6 128.4 118.3 120.3 22.1 10.4 35.b 26.0 28.6 54.1 36.5 22.1 70.7 40.2 54.7 174.8 52.6
136.5f ) 52.19) 51.1 P) 21.3 110.7 129.5 119.3 119.3 123.2 111.4 136.3f) 26.7 22.9 56.8 36.8 20.2 72.3 39.5 59.7 175.7 52.8
f)
6e
6d
135.6 f ) 56.1 53.5 17.9 108.8 126.5 117.8 118.6 121.4 111.3 135,lf) 24.4 28.2 47.1 34.4 12.0 25.6 37.1 55.4 171.7 52.7
7ab)
141.9 54.5 49.3 20.0 109.7 129.3 117.5 118.8 120.6 110.2 134.2 26.1 31.4 33.7 34.7 11.9 28.2 41.6 57.0
7b
”) The 8 values are in ppm downfield from TMS; S(TMS) = G(CDC13)+76.9 ppm. ”) In d6-DMSO; G(TMS) = G(dG-DMS0) +39.5 ppm. c) B(OCH2) = 67.9 ppm. d, A4romaticS(0Me) = 55.7 ppm. e ) Aromatic 6(OMe) = 55.9 ppm. f ) P) Signals in any vertical column may bc reversed.
C=O OMc
(721 I ~ \ - - I
C(20)
C(8)
C(7)
C(2) C(3) C(5) C(6)
5bc)
5ab)
5a
‘Table 2. Carbon Shifts of Iboga Albaloids a)
”) The 6 valucs arc in ppm downfield from TMS; G(TMS) = S(CUC13)+76.9 ppm. ”) Ref. [7]. C ) Ref. [S]. d) Rcf. [9]. e) The minor isomer 3d from thc rcaction of 3e with methyllithium. f) Ref. [lo]. g) Ref. [ l l ; . 11) Carbon atoms numbered as in compounds 3 for sake of convenience. i ) j ) Signals within any vertical column may be reversed. ”) Ester S(Mlc) = 14.1 and S(CH2) = 59.9 ppni.
B-C
cr-c
CP) C(2) C(3) C(4) (75) C(6) C(7) C(8)
3bc)
3ab)
Table I . Carhoiz Shifts of 2-suhstitiited bicvcZo[Z.2.,7]octaizesa)
HELVETICA CHIMICAACTA- Vol. 59, Fasc. 7 (1976) - Xr. 262
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The chemical shifts of all indole carbon atoms of the Iboga alkaloids catharanthine (5a), coronaridine (6b ) , heyneanine (Gd), dihydrocatharanthine (7a), and epiibogamine (7b) as well as the alkaloid model 5 b fit those previously assigned to natural, a,@-disubstituted indole bases [la]. The 10-methoxy group of voacangine Y
5a, R = CO2Mc b, R = CHzOH
6a, K b, R
C02Mc, R‘ = R = H, Y = OMe C O ~ M CR , = R’ = Y = H C, R = R’ = R” = H,Y = OMe d, R = COzMe, R’ = Y = H,K” = OH e, R = C02Mc, R’ = O H , R = Y = H = =
7a, R = COzMe b,R=H
(6a) and ibogaine (6c) induces unequal shift perturbations on its ortho centers, causing the C(11) and C(12) shifts to become similar. However, in the coupled spectra C(11) reveals a doublet of doublets ( 1 J c ~and 3 J c ~ )and C(12) a doublet (~JcH) [11 1131. The great dissimilarity of the environment of the non-aromatic carbon atoms of catharanthine (5 a) allows their direct signal assignment except for the five methylenes. C(17) is recognizable by its shift change in the alcohol 5 b as well as b y the carbomethoxy-induced, strong non-equivalence of its hydrogens (doublet of doublets in sford spectra; same observation for 6a and 6b), while C(6) and C(19) are identified by their coupling characteristics and by shift comparison with coronaridine (6 b) and the models, leaving C(15) determined for 6a and 6b. The shift assignment for the aminomethylenes of all the Iboga bases is associated intimately with their conformation and will be discussed below. Comparison of the dS(C(20)) value for voacangine (6a) and ibogaine (6c) with the dS(C(7)) value for the 3 9 bicyclo[2.2.2]octane pair reveals the y-effect exerted by the carbomethoxy group to be weaker in the alkaloids than in the models. The preferred rotamer population of the ester function of the models, involving exposure of a y-hydrogen to the face of the n-cloud, leads to a strong y-effect [12j,whereas the change of the ester conformation in voacangine (6a) and coronaridine (6b) due to a hydrogen bond between the carbonyl oxygen and the indole nitrogen decreases the n-C(20) y-effect and forces the metlioxy group into a non-bonded &interaction with C(20). The 6 b + 6 d change, as the 3 b --f 3d model alteration, modifies the shifts of m l y carbon atoms within non-bonded interacting distance from the new hydroxy group. The C(20) inversion of ibogaine (6c) into epiibogamine (7b) merely shields C(16) and leaves the C(19) shift invariant as a consequence of the replacement of the y-effect exerted by Nb in 6 c [12] by one of equal magnitude by C(16) in 7b. The shift assignment of dihydrocatharanthine (7a) follows the same arguments as for its 20-epimer (vide s u j ~ a )while , the general shift pattern of 7a is in sharp contrast
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HELVETICA CIIIMICAACTA- Vol. 59, Fasc. 7 (1976)
~
S r . 262
with that of the other Iboga bases and suggests that diliydrocatliaranthine (7a) is conforinationally unique (vide ifzfva). The Iboga alkaloid skeleton possesses a limited amount of conformational flexibility, e.g. the isoquinuclidine appearing in two slightly staggered twist forms and the tetrahydroazepine assuming two different conformations. The seven-membered ring of form 8 places C(6) and C ( 3 ) into a noii-bonded interaction of tlie azabutanegauche type, leading to y-effects between them, whereas form 9 forces C(6) into an eclipsed azabutane interaction with C(21). Comparison of the aminomethylene shift of N-methylisoquinuclidine (2) with the shifts of tlie as 5-et unassigned aininomethylene groups of 5, 6 and 7 b shows that C ( 3 ) must feel a y-effect from C(6) in all these substances. The aminomethylene shifts can be designated readily €or the alkaloids, whose C(3) and C(5) resonances vary greatly from each other, on the basis of a ca. 5 ppm optimum shift for a methylene-methylene gauche interaction. These arguments support conformation 8 (without specifying an exact isoquinuclidine twist boat form) for catharanthine (5a), voacangine (6a), coronaridine (6b) and lieyneanine (6d).
8
9
Whereas the seven-membered ring chair form, incorporated in structure 8, might be expected to be the favored conformation for the Iboga alkaloid skeleton, the tetrahydroazepine boat form 9 permits greater conformational flexibility within the isoquinuclidine nucleus. The latter is needed in dihydrocatharantliine (7a) in which especially an eclipsed form of the isoquinuclidine moiety maximizes the energetically unfavorable, non-bonded interaction between the axial ethyl and carbomethoxy sidechains. The tetrahydroazepine ring inversion into an isoquinuclidine twist boat form of 9 is indicated by the extra shielding of C(6) of dil-i?.drocatliaranthine (7a) in which this center is exposed to a y-effect from C(21) within an eclipsed azabutane conformation 1141. The conformational change removes the y-effect between C ( 3 ) and C(6) as shown b y the aminomethylene resonances, C(3) now appearing a t a field position nearly identical with that of N-methylisoquiiluclidine (2), while adding a y-effect between C(6) and C(21). Its magnitude is low in view of the loss of an acyclic y-effect from C ( l 8 ) , which, as the strong shielding of C(15) in 7a shows, is oriented preponderantly toward C(15) in dihydrocatharantliine (7 a). The mild shielding of C(17) in 7 a vs. 6 b may be due in part to a y-effect from N, which in the tetrahydroazepine boat (9) is not involved in hydrogen bonding with the carbonietlioxy group. Thus conformation 10 represents dihydrocatharanthine (7a). The intermediacy of the shifts of C(3) and C(6) of ibogaine (6c) and epiibogamine (7b) suggests that these alkaloids may be a mixture of the conformations depicted in 8 and 9. The carbon shifts of all the alkaloids are listed in Table 2. The dramatic shift differences of many carbon centers in coronaridine (6b) and dihydrocatharanthine (7a) allow a ready recognition of the C(20) configuration of
HELVETICA CHIMICAACTA- Vol. 59, Fasc. 7 (1976) - Nr. 262
2441
10
the Iboga alkaloids. Thus the shift correspondence of heyneanine (6d) and coronaridine (6b) a t all sites removed from oxy-C(19) confirms the previously assigned exo configuration7) of the hydroxyethyl sidechain [15] [16]. The heretofore unknown C(19) configuration of heyneanine (6d)s) can be determined by comparison of the relevant carbon shifts of the alkaloid with those of coronaridine (6b) and models 3b, 3 d and 3d' (see Table 1).As the shift changes for C(1) and C(3) in the 3b --f 3d and 3 b --f 3 d' conversions demonstrate, both carbon atoms are shielded in both diastereomeric alcohols. Whereas the same phenomenon niiglit be expected for C(21) and C(15) of heyneanine (6d) with respect to coronaridine (bb), C(15) is shielded excessively and C(21) surprisingly is deshielded. This fact points to a hydrogen bond between Nb and the hydroxy substituent. The presence of the new ring places the oxygen into a gazlche-butane relationship with C(15), thereby accounting for part of the shielding of the latter, and removes it from any non-bonded interaction with C(21). The deshielding of the latter by 2.5 ppm niust imply the removal of the acyclic y-effect of the methyl group in coronaridine (6b),in analogy with the OS(C(1)) value of 2.2 ppni for the 3 b --f 3a change, thereby orienting the methyl function of hey-
11
12
neanine (6d) toward C,(15) and accounting for the remainder of the shielding of the latter. These arguments lead to the relative configuration for heyneanine depicted in 6d and conformation 11. Recently there was isolated an indole alkaloid [18] whose mass-spectral and 1H-NMR. analysis suggested it to be a heyneanine isomer [19] 8). I n view of the above data it seemed reasonable that a 13C-NMR. analysis of this new Peschiera affik (MUELL.ARG.)MIERS constituent, named epiheyneanine, would furnish its relative configuration. Tlie 13C-NMR. spectra of the natural base reveal a shift pattern nearly identical with that of heyneanine (6d) except for the C(15) and C(21) shifts (see Table 2). This behavior can be interpreted only on the basis of epiheyneanine being 7)
8)
The ex0 configuration on the isoquinuclidine nucleus is defined as a sidechain orientation toward thc aininomethylcne bridge. Thus, for examplc, in voacangine (6a) C(2) is exo and the ester function endo. Some timc after completion of this work the relative configuration of heyneanine and cpiheyneanine was reported in [17]. 157
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HELVETICA CHIMICA ACTA - Vol. 59, Fasc. 7 (1976) -- Xr. 262
19-isoheyneanine ( 6 e ) .The desliielding of C(15) by 5.7 ppm :Lnd shielding of C(2l) by 5.0 ppm corroborates this point and shows epilieyneanine (6e) to posse-.^ > b conformation 129). The financial support of this work by the U.S. Public Health Service and gifts of samples by Drs. David R. Battiste (Rice University) (1,2), n’.Nezrzs (Eli L l l y and Co.) (5a), N . Wmzg (Rice University) (5b),L . Dorfman (Ciba-Geigy Corp., Summit) (6a, 6b, 6 c . 7 a . 7b) and 13. S. Joshi (Ciba-Geigy Corp., Bombay) (6d) arc acknowledged graicfully.
Experimental Part The 13C-KMR. spectra were recorded on L-arian D1’-60 and XL-100-15 XMR. spectrometers operating at 15.1 and 25.2 MHz, respectively, in the Fozrriw transform mod(.. The shifts on formulas 1 and 2 arc in ppm downfield from TMS; 6(TMS) =-- B(CDC13) 76.9 ppm.
+
REFERENCES
[lj E . Wenkevt, H . E . Gottlieb, 0. R. Goltlieb, .13. 0 . cia S. Pcreivn B Jf. D . FoYii?iga, Phytocheniistry, in press. 121 J . B.Stotlzers, J . R.Sweirson & C. 2’. Tun, Canad. J. Chemistry 53, 5S1 (1975). r3] J . D . Roberts, F . J . Weigert, J . 1. K r o s c h w i t z & H . J . Ileich, J . A\nier.chcni. Soc. 92, 1338 (1970). [4] G. E . Maciel, H . C . Dovn, R. L . Gveene, U’. A . Kleschick, M . I?. Peterson J Y . & G . H.U.ahl, ,Jr. Org. magn. Res. G, 178 (1974). [j! E . L . Eliel, W . F . Bailey, L . D . Kopp, it. L. Willer, D . M . Graizt, R.Brrlvaiitl, I
-
v-01. 59, FaSC. 7 (1976) - Nr. 262
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262. W - N M R . Spectroscopy of Naturally Occurring Substances. XLV. Iboga Alkaloidsl) by Ernest Wenkert2), David W. Cochran, Hugo E. Gottlieb and Edward W. Hagaman Department of Chemistry, Indiana University, Bloomington, Indiana 47401, U.S.A. and Raimundo Braz Filhoa), Francisco Jose de Abreu Matos and Maria Iracema Lacerda Machado Madruga Departamento de Quimica Org2nica e Inorghnica, Centro de Cihcias, TJniversidade Federal do CearA, 60.000 Fortaleza, Brazil (29. 111. 76)
Summary. The carbon shifts of the Iboga-type alkaloids catharanthine, voacanginc, coronaridine, ibogaine, dihydrocatharanthine and epiibogamine were recorded and correlated with the conformation of the natural bases. A 13C-NMR. analysis of heyneaninc determined its C(19) configuration and a similar study of cpihcyneanine proved its structure.
I n connection with problems of structure determination and synthesis of indole alkaloids of the Iboga type it became of importance t o apply 13C-NMR. spectroscopy thereto. As a consequence the following study of a select group of such natural products was undertaken and isoquinuclidine (l),its N-methyl derivative (2), some monosubstituted bicyclo[2.2.2joctanes (3) and two bicyclo[2.2.2]octenes (4) used as models. The carbon shifts of the first two models are depicted on formulas 1 4 ) and 2 and those of bicycles 3 5 ) and 46) listed in Table 1. .46.9
.57.2
&z4
4 2 . 5 M e N 25.5
8
&42 3 :
&; 2
2
3a, R b, R C, R d, R
Mc 3 e , R = CHO Et f , R = COzH = CHzOH g, R = COzEt = CH(OH)Me h,R = Ac =
=
4 R'
4a, R = C H O
R = H
4b R =H R = CHO
For part XLIV see [l]. Present address : Department of Chemistry, Rice University, Houston, Texas 77001, U. S.A. Present address : Dcpartamento de Quimica, Universidade Federal Rural do Rio de Janeiro, Brazil. The nitrogen perturbs appreciably the vicinal methylene shifts of isoquinuclidine (1) (cf. the 26.1 ppm methylene shift of bicyclo[2.2.2]octanc [Z]). The total of the y-effects on C(l) and C(3) is 7.7 ppm greater for the hydroxy group of 3c than the methyl group of 3b, relative to 3a. The comparable magnitude of the y-effect of the two groups as a result of fixed gauche, non-bonded interactions [3] [4] and thc shielding of ycarbons by hydroxy groups truns anti-periplanar to them within rigid six-membered rings [j]suggest that the excess shielding by the hydroxy group of 3c is an acyclic equivalent of the lattcr phcnomenon. This result indicates that caution must be cxerciscd in the assessment of shielding contributions to y carbon atoms from oxygen in all staggered, acyclic conformations. The introduction of a double bond into the strained bicyclo[2.2.2]octane skeleton leads to stronger deshielding of the allylic carbons and a decrease of the cndocyclic homoallyl effect relative to the shift differences of cyclohexenes and cyclohexanes [2] [6] (cf. also the 6b + 5a change).
28.0 37.9 34.1 24.8 26.1 i) 25.4’) 20.7 27.5’) 28.7 12.1
30.2 30.2 35.6 25.0 26.1’) 25.0‘) 20.3 27.4’) 21.0
24.51) 38.2 29.9 24.1‘) 25.8J) 25.23) 20.4 26.7’) 65.6
3Cd) 24.2 43.8 30.4 23.7 25.7’) 24.8’) 20.3 26.4’) 69.2 20.8
3dc) 25.8 43.8 30.6 24.0 25.6’) 24.1 i ) 20.6 27.1’) 71.2 21.8
3d’c) e) 25.2 49.2 24.7 23.5 26.0’) 25.0’) 21.6 25.0’) 204.1
3ef) 27.2 41.5 27.7 23.5 26.0’) 24.8’) 21.6 25.0’) 182.2
3f9)
399) 27.3 41.6 27.9 23.5 26.0’) 24.9i) 21.6 25.0i) 175.8”)
3hc) 26.3 49.5 25.9 23.4 25.9‘) 24.5’) 21.0 24.6’) 209.4 27.7 29.9 49.8 25.0’) 29.0 135.03) 133.0j) 20.5 24.5’) 203.3
4af)h) 30.4 50.5 26.4 29.0 24.8’) 24.5’) 130.3j) 135.5j) 202.9
4bf)h)
3 39.1 52.6 47.6 19.5 109.4 128.1 118.1 119.0 121.7 110.2 134.7 29.3 121.6 46.0 35.8 10.2 26.1 149.0 63.0
138.6 53.2 49.4 20.9 110.0 128.5 117.8 118.7 121.9 111.3 135.4 30.4 123.2 55.6 37.4 11.2 26.2 148.1 62.9 172.7 52.6
136.0 52.9 49.3 21.0 110.2 128.4 117.7 18.9 21.3 10.2 34.7 30.4 23.4 .55.0 38.0 10.5 25.9 148.5 61.5 173.6 52.0 137.3 53.0 51.5 22.0 109.7 128.7 100.4 153.6 111.4 10.9 30.5 27.2 31.9 .55.0 36.2 11.5 26.6 38.9 57.2 175.4 52.2
bad)
6b 136.5f) 53.1 51.5 22.2 110.3 128.8 318.3 119.0 121.8 110.3 1 35.6 f) 27.2 32.0 55.1 36.3 11.6 26.6 38.9 57.2 175.9 52.4
6c e) 143.0 54.1 49.8 20.5 108.8 129.8 100.4 153.7 110.9 110.5 129.8 26.3 31.9 41.2f) 34.0 11.8 27.7 41.8f) 57.3
f)
135.9 52.0 g) 50.99) 21.6 109.6 128.4 118.3 120.3 22.1 10.4 35.b 26.0 28.6 54.1 36.5 22.1 70.7 40.2 54.7 174.8 52.6
136.5f ) 52.19) 51.1 P) 21.3 110.7 129.5 119.3 119.3 123.2 111.4 136.3f) 26.7 22.9 56.8 36.8 20.2 72.3 39.5 59.7 175.7 52.8
f)
6e
6d
135.6 f ) 56.1 53.5 17.9 108.8 126.5 117.8 118.6 121.4 111.3 135,lf) 24.4 28.2 47.1 34.4 12.0 25.6 37.1 55.4 171.7 52.7
7ab)
141.9 54.5 49.3 20.0 109.7 129.3 117.5 118.8 120.6 110.2 134.2 26.1 31.4 33.7 34.7 11.9 28.2 41.6 57.0
7b
”) The 8 values are in ppm downfield from TMS; S(TMS) = G(CDC13)+76.9 ppm. ”) In d6-DMSO; G(TMS) = G(dG-DMS0) +39.5 ppm. c) B(OCH2) = 67.9 ppm. d, A4romaticS(0Me) = 55.7 ppm. e ) Aromatic 6(OMe) = 55.9 ppm. f ) P) Signals in any vertical column may bc reversed.
C=O OMc
(721 I ~ \ - - I
C(20)
C(8)
C(7)
C(2) C(3) C(5) C(6)
5bc)
5ab)
5a
‘Table 2. Carbon Shifts of Iboga Albaloids a)
”) The 6 valucs arc in ppm downfield from TMS; G(TMS) = S(CUC13)+76.9 ppm. ”) Ref. [7]. C ) Ref. [S]. d) Rcf. [9]. e) The minor isomer 3d from thc rcaction of 3e with methyllithium. f) Ref. [lo]. g) Ref. [ l l ; . 11) Carbon atoms numbered as in compounds 3 for sake of convenience. i ) j ) Signals within any vertical column may be reversed. ”) Ester S(Mlc) = 14.1 and S(CH2) = 59.9 ppni.
B-C
cr-c
CP) C(2) C(3) C(4) (75) C(6) C(7) C(8)
3bc)
3ab)
Table I . Carhoiz Shifts of 2-suhstitiited bicvcZo[Z.2.,7]octaizesa)
HELVETICA CHIMICAACTA- Vol. 59, Fasc. 7 (1976) - Xr. 262
2439
The chemical shifts of all indole carbon atoms of the Iboga alkaloids catharanthine (5a), coronaridine (6b ) , heyneanine (Gd), dihydrocatharanthine (7a), and epiibogamine (7b) as well as the alkaloid model 5 b fit those previously assigned to natural, a,@-disubstituted indole bases [la]. The 10-methoxy group of voacangine Y
5a, R = CO2Mc b, R = CHzOH
6a, K b, R
C02Mc, R‘ = R = H, Y = OMe C O ~ M CR , = R’ = Y = H C, R = R’ = R” = H,Y = OMe d, R = COzMe, R’ = Y = H,K” = OH e, R = C02Mc, R’ = O H , R = Y = H = =
7a, R = COzMe b,R=H
(6a) and ibogaine (6c) induces unequal shift perturbations on its ortho centers, causing the C(11) and C(12) shifts to become similar. However, in the coupled spectra C(11) reveals a doublet of doublets ( 1 J c ~and 3 J c ~ )and C(12) a doublet (~JcH) [11 1131. The great dissimilarity of the environment of the non-aromatic carbon atoms of catharanthine (5 a) allows their direct signal assignment except for the five methylenes. C(17) is recognizable by its shift change in the alcohol 5 b as well as b y the carbomethoxy-induced, strong non-equivalence of its hydrogens (doublet of doublets in sford spectra; same observation for 6a and 6b), while C(6) and C(19) are identified by their coupling characteristics and by shift comparison with coronaridine (6 b) and the models, leaving C(15) determined for 6a and 6b. The shift assignment for the aminomethylenes of all the Iboga bases is associated intimately with their conformation and will be discussed below. Comparison of the dS(C(20)) value for voacangine (6a) and ibogaine (6c) with the dS(C(7)) value for the 3 9 bicyclo[2.2.2]octane pair reveals the y-effect exerted by the carbomethoxy group to be weaker in the alkaloids than in the models. The preferred rotamer population of the ester function of the models, involving exposure of a y-hydrogen to the face of the n-cloud, leads to a strong y-effect [12j,whereas the change of the ester conformation in voacangine (6a) and coronaridine (6b) due to a hydrogen bond between the carbonyl oxygen and the indole nitrogen decreases the n-C(20) y-effect and forces the metlioxy group into a non-bonded &interaction with C(20). The 6 b + 6 d change, as the 3 b --f 3d model alteration, modifies the shifts of m l y carbon atoms within non-bonded interacting distance from the new hydroxy group. The C(20) inversion of ibogaine (6c) into epiibogamine (7b) merely shields C(16) and leaves the C(19) shift invariant as a consequence of the replacement of the y-effect exerted by Nb in 6 c [12] by one of equal magnitude by C(16) in 7b. The shift assignment of dihydrocatharanthine (7a) follows the same arguments as for its 20-epimer (vide s u j ~ a )while , the general shift pattern of 7a is in sharp contrast
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~
S r . 262
with that of the other Iboga bases and suggests that diliydrocatliaranthine (7a) is conforinationally unique (vide ifzfva). The Iboga alkaloid skeleton possesses a limited amount of conformational flexibility, e.g. the isoquinuclidine appearing in two slightly staggered twist forms and the tetrahydroazepine assuming two different conformations. The seven-membered ring of form 8 places C(6) and C ( 3 ) into a noii-bonded interaction of tlie azabutanegauche type, leading to y-effects between them, whereas form 9 forces C(6) into an eclipsed azabutane interaction with C(21). Comparison of the aminomethylene shift of N-methylisoquinuclidine (2) with the shifts of tlie as 5-et unassigned aininomethylene groups of 5, 6 and 7 b shows that C ( 3 ) must feel a y-effect from C(6) in all these substances. The aminomethylene shifts can be designated readily €or the alkaloids, whose C(3) and C(5) resonances vary greatly from each other, on the basis of a ca. 5 ppm optimum shift for a methylene-methylene gauche interaction. These arguments support conformation 8 (without specifying an exact isoquinuclidine twist boat form) for catharanthine (5a), voacangine (6a), coronaridine (6b) and lieyneanine (6d).
8
9
Whereas the seven-membered ring chair form, incorporated in structure 8, might be expected to be the favored conformation for the Iboga alkaloid skeleton, the tetrahydroazepine boat form 9 permits greater conformational flexibility within the isoquinuclidine nucleus. The latter is needed in dihydrocatharantliine (7a) in which especially an eclipsed form of the isoquinuclidine moiety maximizes the energetically unfavorable, non-bonded interaction between the axial ethyl and carbomethoxy sidechains. The tetrahydroazepine ring inversion into an isoquinuclidine twist boat form of 9 is indicated by the extra shielding of C(6) of dil-i?.drocatliaranthine (7a) in which this center is exposed to a y-effect from C(21) within an eclipsed azabutane conformation 1141. The conformational change removes the y-effect between C ( 3 ) and C(6) as shown b y the aminomethylene resonances, C(3) now appearing a t a field position nearly identical with that of N-methylisoquiiluclidine (2), while adding a y-effect between C(6) and C(21). Its magnitude is low in view of the loss of an acyclic y-effect from C ( l 8 ) , which, as the strong shielding of C(15) in 7a shows, is oriented preponderantly toward C(15) in dihydrocatharantliine (7 a). The mild shielding of C(17) in 7 a vs. 6 b may be due in part to a y-effect from N, which in the tetrahydroazepine boat (9) is not involved in hydrogen bonding with the carbonietlioxy group. Thus conformation 10 represents dihydrocatharanthine (7a). The intermediacy of the shifts of C(3) and C(6) of ibogaine (6c) and epiibogamine (7b) suggests that these alkaloids may be a mixture of the conformations depicted in 8 and 9. The carbon shifts of all the alkaloids are listed in Table 2. The dramatic shift differences of many carbon centers in coronaridine (6b) and dihydrocatharanthine (7a) allow a ready recognition of the C(20) configuration of
HELVETICA CHIMICAACTA- Vol. 59, Fasc. 7 (1976) - Nr. 262
2441
10
the Iboga alkaloids. Thus the shift correspondence of heyneanine (6d) and coronaridine (6b) a t all sites removed from oxy-C(19) confirms the previously assigned exo configuration7) of the hydroxyethyl sidechain [15] [16]. The heretofore unknown C(19) configuration of heyneanine (6d)s) can be determined by comparison of the relevant carbon shifts of the alkaloid with those of coronaridine (6b) and models 3b, 3 d and 3d' (see Table 1).As the shift changes for C(1) and C(3) in the 3b --f 3d and 3 b --f 3 d' conversions demonstrate, both carbon atoms are shielded in both diastereomeric alcohols. Whereas the same phenomenon niiglit be expected for C(21) and C(15) of heyneanine (6d) with respect to coronaridine (bb), C(15) is shielded excessively and C(21) surprisingly is deshielded. This fact points to a hydrogen bond between Nb and the hydroxy substituent. The presence of the new ring places the oxygen into a gazlche-butane relationship with C(15), thereby accounting for part of the shielding of the latter, and removes it from any non-bonded interaction with C(21). The deshielding of the latter by 2.5 ppm niust imply the removal of the acyclic y-effect of the methyl group in coronaridine (6b),in analogy with the OS(C(1)) value of 2.2 ppni for the 3 b --f 3a change, thereby orienting the methyl function of hey-
11
12
neanine (6d) toward C,(15) and accounting for the remainder of the shielding of the latter. These arguments lead to the relative configuration for heyneanine depicted in 6d and conformation 11. Recently there was isolated an indole alkaloid [18] whose mass-spectral and 1H-NMR. analysis suggested it to be a heyneanine isomer [19] 8). I n view of the above data it seemed reasonable that a 13C-NMR. analysis of this new Peschiera affik (MUELL.ARG.)MIERS constituent, named epiheyneanine, would furnish its relative configuration. Tlie 13C-NMR. spectra of the natural base reveal a shift pattern nearly identical with that of heyneanine (6d) except for the C(15) and C(21) shifts (see Table 2). This behavior can be interpreted only on the basis of epiheyneanine being 7)
8)
The ex0 configuration on the isoquinuclidine nucleus is defined as a sidechain orientation toward thc aininomethylcne bridge. Thus, for examplc, in voacangine (6a) C(2) is exo and the ester function endo. Some timc after completion of this work the relative configuration of heyneanine and cpiheyneanine was reported in [17]. 157
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HELVETICA CHIMICA ACTA - Vol. 59, Fasc. 7 (1976) -- Xr. 262
19-isoheyneanine ( 6 e ) .The desliielding of C(15) by 5.7 ppm :Lnd shielding of C(2l) by 5.0 ppm corroborates this point and shows epilieyneanine (6e) to posse-.^ > b conformation 129). The financial support of this work by the U.S. Public Health Service and gifts of samples by Drs. David R. Battiste (Rice University) (1,2), n’.Nezrzs (Eli L l l y and Co.) (5a), N . Wmzg (Rice University) (5b),L . Dorfman (Ciba-Geigy Corp., Summit) (6a, 6b, 6 c . 7 a . 7b) and 13. S. Joshi (Ciba-Geigy Corp., Bombay) (6d) arc acknowledged graicfully.
Experimental Part The 13C-KMR. spectra were recorded on L-arian D1’-60 and XL-100-15 XMR. spectrometers operating at 15.1 and 25.2 MHz, respectively, in the Fozrriw transform mod(.. The shifts on formulas 1 and 2 arc in ppm downfield from TMS; 6(TMS) =-- B(CDC13) 76.9 ppm.
+
REFERENCES
[lj E . Wenkevt, H . E . Gottlieb, 0. R. Goltlieb, .13. 0 . cia S. Pcreivn B Jf. D . FoYii?iga, Phytocheniistry, in press. 121 J . B.Stotlzers, J . R.Sweirson & C. 2’. Tun, Canad. J. Chemistry 53, 5S1 (1975). r3] J . D . Roberts, F . J . Weigert, J . 1. K r o s c h w i t z & H . J . Ileich, J . A\nier.chcni. Soc. 92, 1338 (1970). [4] G. E . Maciel, H . C . Dovn, R. L . Gveene, U’. A . Kleschick, M . I?. Peterson J Y . & G . H.U.ahl, ,Jr. Org. magn. Res. G, 178 (1974). [j! E . L . Eliel, W . F . Bailey, L . D . Kopp, it. L. Willer, D . M . Graizt, R.Brrlvaiitl, I
