Assignments of1H and13C NMR resonances of some isoquinoline alkaloids

0031&9422/90 $3OL+OOO 0 1990PergamonPressplc

Phytochemlstry, Vol 29,No 10,pp 3331-3339, 1990 Prmtedm GreatBntam

ASSIGNMENTS

OF ‘H AND 13CNMR RESONANCES ISOQUINOLINE ALKALOIDS *

OF SOME

RICHARD H. A. M. JANSSEN, PETER WIJKENS, COR KRIJK,~ HUBERTUS W. A. BIESSELS,FRANCESCO MENICHINI$ HUBERT G. THEUNS

and

Orgamc Chemical Laboratory, State University of Utrecht, Transitormm 3, Padualaan 8, 3584 CH Utrecht, The Netherlands; t University of Amsterdam, Department of Orgamc Chemistry, Nwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands; $ Dipartlmento dl Chimlca, Umvers& della Calabna, 87030 Arcavacata dl Rende (CS), Italy (Recenzd 8 December 1989) Key Word Index-Alkaloids; ‘H and 13CNMR chemical shift assignments; lanthamde-induced chemical slufts; 13G1H shift correlated 2D NMR; laudanosme; laudanine, retlcuhne, 1,2,3,4-tetrahydro-6,7-dlmethoxyisoqumohne; hehamine, 0-methylcorypalhne, canadine; 1,2,3,4-tetrahydro-7,8-d~methoxy-2-methyl~soquinol~ne, anarcotme; j?-narcotine, narcotohne, hydrocotamme; alpmlgenine; tetrahydrothebaine, codeme.

Abstract-Aided by model compounds, lanthanide-induced chemical shifts (LIS) and 2D NMR, the assignment of ‘H and 13CNMR resonances of several isoquinoline alkaloids is discussed and demonstrated. The results obtained necessitate a reversal of many 13CNMR assignments reported in the literature. LIS constitutes a valuable tool in assigning NMR resonances and is complementary to other techniques used for this purpose. For b-narcotme it also provides information on the topology of the compound in solution. The spectra of several isoquinohne alkaloids having different structural skeletons are described.. These compounds may serve as model compounds in assigning resonances of related alkaloids

INTRODUCTION

Heliamine and 0-methylcorypalhne

In our earlier paper [l] some aspects of the use of lanthanide shift reagents in ‘H and 13CNMR were reported for some aromatic isoquinoline alkaloids. In the present study the uses of lanthanide-induced chemical shifts (LIS) and two-dimensional correlated NMR techniques are extended to other types of isoquinoline alkaloids. Properly applied these techniques can be very helpful in assigning NMR resonances and may even provide information on the stereochemistry of some alkaloids. RESULTS AND DISCUSSION

Lanthanide-induced

effects for some substttuted

benzenes

For 2-methoxy-6-methylphenol (1) the lanthanideinduced shifts are asymmetrically distnbuted over the aromatic nucleus (Table 1). The induced chemical shifts for 2-methoxy-4-methylphenol (2) are in agreement with those obtained for 2-methoxyphenol [2]. The 13CNMR data on 2-methoxy-5-methylphenol (3), 3,4-dimethoxytoluene (4) [l] and 2,3-dlmethoxytoluene (5) [l] are also mcluded in Table 1. The assignments of compounds l-3 were mainly based on examination of their ‘H-coupled ’ 3C NMR spectra.

*Part 2 in the series For Part 1 see ref. [l].

Hughes et al. [S] published 13CNMR chemical shift assignments of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (heliamine) (6) and 0-methylcorypalline 7. Studies of model compounds and incremental values of standard chemical shift theory indicated that these assignments could be partly erroneous. Therefore, these compounds were included m our study. Unequivocal assignments of 6 and 7 were attamed by recording “C-‘H shift correlated 2DNMR spectra [4] and the use of the APT (attached proton test) pulse sequence [S] in “CNMR. Unfortunately it was not possible to discriminate the methoxyl resonances in 13CNMR of 0-methylcorypalline (7). A strong preference for the assignments of the ‘HNMR methoxyl resonances (Table 2) is based on comparison of long-range couplings in 2D NMR observing C-6 and C-7. Both in heliamine and 0-methylcorypalline, Hughes et al. [3] are erroneous in the assignment of C-4a and C-8a. These results are in full agreement with Mata et al. [6]. Moreover, the assignments of the H-5 and H-8 resonances of 7 by Theuns et al. [7] also were erroneous. Laudanosine, laudanine and reticuline

Although 13CNMR data on laudanosine (8) were published some years ago [8-lo], this alkaloid was still considered to be an interesting substrate for testing the usefulness of LIS in assigning 13CNMR resonances. In the shift experiment on 8, both ortho-dimethoxy pairs were found to chelate with the shift reagent, unlike 3331

R H A M JANSSENet

3332

al

R4

1 2 3 4 5

R' OH OH OH Me Me

II 29 30 31

R1 OMe OMe OMe H OMe

R3 H H H OMe OMe

R' H Me H OMe H

RS H H Me H H

R' Rz R" H -OCH20OH OMe H OMe OMe H OMe OMe H

R4 H H OMe OH

R6 Me H H H H

R' 6 7 12 16

H Me Me H

36

Me

R3

R4

OMe OMe OMe OMe H OMe H OMe -OCH,O-

Rz

H H OMe OMe OMe

13 14 15

papaverme [ 11, but these pairs were not mfluenced to an equal extent, thus facilitating dtscrimination between the methoxyl resonances as well as the methoxyl bearmg carbon pairs. The latter were separated into a faster shiftmg pair (6147.0 and 146.1), with corresponding methoxyl resonances at 6.5527 and 55.47, and a slower shtftmg pan at 6 147 0 and 148 3, with methoxyl resonances at 655.51 and 55.62. In a similar ‘H NMR experiment a correspondmg result was obtained. The methoxyl resonances at 63 53 (7-OMe [ll, 121) and 3.77 were influenced to a larger extent than the ones at 63.73 and 3.78 C-5, C-5’, C-8 and C-2’ showed tdenttcal Induced shifts. Compartson of laudanosme with 3,4-dimethoxytoluene 4 and O-methylcorypalline 7 showed that C-2’ must be found at 6 112.8. In 2D NMR, the resonances at 6 110.8, 110.9 and 111.0 were found to be directly coupled (‘J) with H-5’ at 66.71, H-8 at 66 02 and H-5 at S6 50, respectively Carbon-4 was long-range coupled wtth H-2’ and H-6’ at 66.55 and 6 58, respectively, while C-3’ correspondmgly coupled with H-5’ at 66.71. The asstgnments so found indicate that m earlier work [8-lo] several resonances of 8 were wrongly assigned, and also demonstrate that tt IS possible to distmgutsh between methoxyl substituents m a compound havmg two orthodtmethoxy substttuents. By compartson of the r3CNMR and APT data for laudanine (9) with the models 3 and 7, and with the assignments for 8 most signals of 9 may be assigned, for example, C-6 of 9 is assigned at 6 146.9 by comparison with C-6 of 8 Notoriously difficult sets consist of signals

R' H H Me

8 9 10

R' Me Me H

R= Me H H

R' H Me H

found at nearly equal field and havmg the same signal multiplictties C-S/C-S/C-S, C-3’/C-4/C-7 and 4’OMe/6-OMe/7-OMe 2DNMR, opttmrzed for ‘Jcn, afforded the assignments for C-5, C-5’, C-S and 7-OMe, while 2D NMR, optimized for long-range Jcn [13], afforded the assignments for C-3’, C-4’ and C-7. The assignments for all ‘H and 13CNMR resonances of 9 were confirmed m 2D NMR, but the 13CNMR signals of 4’OMe and 6-OMe could not be distinguished by 2-D NMR, because then ‘H NMR resonances comcided Retlculine (10) was studied m a simiiar way. Usmg 2DNMR, opttmized for ‘Jcu and 3J,,, the assignments for the difficult sets C-5/C-5’/C-8 and C-3/C-4/C-6/C-7, respectively, could be assured These techmques, however, provtded no dtscrtmination of the 4’-OMe and 6OMe r3C NMR resonances, because their ‘H NMR resonances comctded. A partial assignment of the 13C NMR data of 10 was reported earlier by Shamma and Hmdenlang [ 141 Even some of the non-interchangeable asstgnments by these authors, however, prove to be erroneous Canadine

In the literature reports [3,9, 15-171 on the “CNMR chemical shaft assignments of canadme 11, the assignments of C-2 and C-3, C-la and C-4a, as well as C-8a and C-12a had to be considered Interchangeable For further clartfication of this aspect, canadme was mcluded m our study. In the shift experiment on 11 the aromattc rings A and D are readily dtstmgutshed The shaft reagent dts-

NMR of isoqumohne alkaloids

3333

plays no coordination with the methylenedioxy group and consequently the ring A carbons remain almost uninfluen~d. Yet, this experiment allowed tentative assignments of its resonances, in ‘I-I as well as 13C NMR. The ring D methoxyl oxygens, however, show strong coordinatton with the lanthanide shift reagent. In agreement with our observations on 5, the C-9 methoxyl group is influenced mostly, as well as the C-9 resonance Itself. Therefore, our results denmtely indicate at the necessity to reverse the literature asszgnments for the C-9 and C-10 carbons. The dist~bution of induced shafts over the ring D nucleus indicates that the effects extend to the C-8 carbon and that the C-8a and C-12a resonances are found at 6128.4 and 127.5, respectively (Table 4). The latter assignments were supported by the spectrum of 1,2,3,4tetrahydro-7,8-dim~thoxy-2-methylisoqulnoline (12) (Table 2). In the gated decoupled spectrum of the latter compound, the resonance at 6 126.3 showed more couplings than the one at 6128.0, m agreement with their assignments to carbons C-4a and C-8a, respecttvely. Also the C-8 resonance at S 144.3 was more complex than that of C-7 at 6149.3, m agreement with our revtsed asstgnments for 11. The di~ri~natlon of C-la and C-4a of canadine (considered interchangeable in ref. [3]) 1s based on the analysis of the tetrahydroprotoberbe~ne 13 skefeton by Takao et al. [15]. In that analysis, however, the chemical shift of C-9 1s given as 6 129.0, whereas the C- 1 resonance is found m the regton 6 125 6-126.2. Both these carbons are in comparabie situatrons as the C-8 carbon of 1,2,3,4-tetrahydroisoquxnollne. For the latter carbon a chemical shift of 6126.1 is known [3]. Takao et al. [15] were probably confused by the many coinciding resonances for the unsubstituted skeleton. Because of the arguments given, the C-9 carbon of tetrahydroproto~rberine 13 is found also at cu 6126, and this simdarly applies for the 13-methyl substituted derivatrves 14 and 15. Our results indicate that the C-7 and C-8 carbon resonances m 1,2,3,4-tetrahydro-7,8-dimethoxyisoqulnoline I6 ~emaireo~reine) are wrongly assigned [3,6] and that the C-4a and C-8a resonances in this compound are found at 6 128.0 and 129.9, respectively, not as described previously [6, 141. From these data tt is inferred that the spectra of many stmilarly substitute compounds are wrongfy assigned with respect to the orrho-methoxy groups bearing carbons. The C-9 and C-10 assignments of a- and /I-canadme methochlo~de I7 [18], tetrahydropalmatine 18 [9, 151, thalict~~avine 19 [15], mesothalictri~avine 20 [15], capaurine 21 f 15J, 0-a~tyIcapau~ne 22 [ 151, O-methyicapaurme 23 [16, 17, 193, corydaline 24 [15,20], mesocorydaline 25 [lS, 201, and ophiocarpine 26 [ZO] should be interchanged. Furthermore, the C-8, and C-12a assignments of compounds 18 and 21 should be interchanged also. Two tetrahydroprotoberberines, having C-9/C-10 methyIenedioxy substitution, tetrahydro~optis~ne 27 and tetrahydrocorysamine 28 [15] deserve further discussion. In agreement with the analysis of the tetrahydroprotoberberme skeleton discussed above, it is likely that for compound 27 within the pair C-9/C-10 the former carbon will be found at higher field, m accordance with orthodimethoxy substitution. Furthermore, comparison with 11 shows that the chemical shifts of C-2 and C-3 of 27 will be ca equal. Therefore, the C-2 and C-3 resonances should be assigned at 6 146.3 and 146.4 (an interchange-

R H A M

3334 Table 2 Identlficatlon of nucleus

13C NMR chenucal

JANSSEN

et

al

slnfts of compounds

6

6, 7. 12 and 36

7

12

36

‘H

l3C

6”

&

6”

6,

6,

&I

6,

H-l H-3 H-4

C-l c-3 c-4 C-4a c-5 C-6 c-7 C-8 C-8a 6-OMe 7-OMe

3 60 279 240

46 7 42 8 27 5 125 6 1114 1467 146.6 1086 1264 55 1 55 1

3 49 204 2 29

56 6 520 27 8 1248 110.8 146 7 1464 108.8 125 I 54 9” 550”

52 3 51 8 27.9 1263 1228 1100 149 3 1443 128 0

3 44 260 2 80

52.8 52 2 29 2 127 5 102 1 147 3 1334 1394 1195

H-5 H-6 H-7 H-8 6-OMe 7-OMe 8-OMe pOCH,ONMe NH

6.27

6 19 3 53 3 52

8-OMe -OCH,ONMe

Table 3

-

d&x

H-l H-3

C-l c-3

H-4

c-4

3.64 2.73 3 12 2 55 2 78 -

nd* nd nd nd nd

6 50 -

95

602 -

110

217 3 10 -

nd nd

6 55 -

nd

6.71 6 58 3 77 3 53 373 3 78 249

nd nd 152 169 129 124 29

H-5’ H-6’ 6-OMe 7-OMe 3’-OMc 4’-OMe NMe

450

C-4a C-5 C-6 c-7 C-8 C-8a C-la C-l’ c-2 C-3’ c-4 C-5’ C-6 6-OMe 7-OMe Y-OMe 4’-OMe NMe

_ 3 98 585 245

45 3 _-

slufts and Pr(fod),

induced

chemical

8 6”

H-2

243

‘H and 13C NMR chenucal

“C

H-la

_ 54.9

58 8 1001 45 8

awgnments

‘H

H-8

3 82” 3 81”

-

Identlficatlon of nucleus

H-5

649

631

590

3.30

“Interchangeable

6.57

* nd = not determmed tThese figures are not fully assured aInterchangeable assignments

because

slufts of compounds

&IO

9 6,

d&

646 468

30 3.5 -

254

30

1259 1110 147 0 146 1 1109 129 1 40.5

34 34 11 2 11.5 34 43 31

1323 1128 1483 147.1 1108 121 6 55.47 55 27 55 51 5562 42.5

35 34 8.9 84 34 24

of comcldmg

able pauj, whereas the C-9 and C-10 resonances wdl be found at 6 143.5 and 145.2, respectively. The effect on the C-9 chemical shift, exerted by 9,10+ubstitution, 1s much less pronounced for methylenedioxy substitution than for

9 21 lOl$ 76 71 33

(broadened)

6 1,

10 6,

3 64 2 74 309 2.57 2 74

643 45 6

.~

124.4 1107 1469 145 7 1108 1280 39 8

645

581 2 54 3.03 6 58

660 636 3 68 3 37 _ 3 68 240

242

1320 1161 145 5 145 4 1106 1206 55 48 54 8 55 2” 414

6” 3 65 2 75 3 15 2 55 2 80 _ 6 53

6 36 2 80 300

fit 64 5 46.8 25 1 125 3 1106 145 1 1434 1138 1305 409

671 657 3 83

1333 1157 145 3 145 0 1105 1209 55 9”

3 83 244

55 8” 424

6 75

signals m the LIS spectra

o&o-dimethoxy substitution. Thn difference will result from the different electron donatmg abilities of these substituents. For tetrahydrccorysamme 28 a stiar reasonmg applies C-9 will be found at highest field among

NMR of tsoqumolme alkalords

Table 4. ‘aCNMR

3335

chemrcal shaft assrgnments and lanthamde-mduced compound 11

Identificatton of nucleus

shtfts for

11

‘H

13C

6”

d&

6,

H-l

6.72

080

6.56

0.11

105 3 130.6 145.9’ 145 7’ 108.1 127 5

H-5

C-l C-la c-2 c-3 c-4 C-4a c-5

nd

nd

294

1.0

H-6

C-6

H-8 H-8

C-8

nd 4.25 3 52 -

nd 82 59 -

51.2 53.7

2.2 70

6.78 681

8.0 3.3

128.4 1449 1500 110.8 123.6 127.5 36.2 59.4 1005 59.9 55.6

14.8 57 8 51.4 13.9 6.2 5.9 3.5 2.9 0.4 404 29.7

H-4

H-11 H-12 H-13 H-13a -OCH,O9-OMe IO-OMe

C-8a c-9 c-10 c-11 c-12 C-12a c-13 C-13a -OCH,O9-OMe lo-OMe

nd nd

5 89 3.78 3 78

nd nd 015 172 11.1

d& 10 15 0.5 0.3 0.1 0.7

“Interchangeable assrgnments (strongly preferential).

the oxygen substituted carbons, and should be assigned at 6 143.2. Even in some publicattons in which 2DNMR techniques were used for signal identifications in 13C NMR, the C-9 and C-10 assignments of tetrahydroprotoberberines were found to be incorrect. Rothera et al. [21] gave incorrect assignments for C-9 and C-10 of caseanidine 29 though these carbons were correctly assigned in the 2D NMR spectrum depicted. Also Ruangrungsi et al. [22] erroneously interchanged the C-9 and C-10 resonances of O-methylthaicanine (30) and thaicanine (31), referring to Hughes and MacLean [23]. a-Narcotme, /?-narcotme, narcotoline and hydrocotarnine

The phthalideisoquinoline alkaloids a-narcotine (32), /I-narcotine (33) and narcotoline (34) possess an orthosubstituted methylenedioxy group and an ortho-dimethoxy group, the latter located next to a lactone group. In 32 [23] additton of the shift reagent resulted in largest i3C NMR shifts for the rings C and D carbons and the 4’and 5’-methoxyl carbons (Table 5). Of the latter, the one attached to C-4’ is most influenced in this experiment, followed by that at C-S, whereas the C-8 methoxyl group is not influenced much. In agreement with this observation, the respective methoxy bearing carbons are influenced. As expected a strong coordination is observed for the carbonyl function of the lactone group. Obviously, the bidentate shift reagent chelates with the 3’-carbonyl and the C-4’-methoxyl oxygen atoms, whereas the usual coordination with the pair C-4/C-5’ methoxyl oxygens is observed here to a lesser degree. These data also enable the assignments of the methoxyl resonances in the

‘H NMR (Table 5), for which a wrong preferential assignment was given previously [24]. The coordination with the mtrogen function of 32 was found to be weak but this is not true for 33. Comparison of induced shifts observed for the erythro compound 33 with those for the threo diastereomer 32, shows that their distributions over the skeletons are very different. In 33 the induced shift of C-3’ surpasses the one of C-4’. Also the C-l, C-3, C-l’ and N-methyl resonances show appreciable induced shifts. Therefore, a coordination of the shift reagent with the nitrogen functton and the T-oxygen atom 1s indicated in 33. Such chelation is possible only when these functional groups are stertcally in a favourable position, sufficiently near to each other to enable coordination of the shift reagent with the groups mentioned. Examination of Dreiding models shows for these groups in one conformation (Fig. 1) a non-bonded tnteratomic N-O distance of ca 0.28 nm, compattble with the chelation observed (the interatomic O-O distance for two aromatic methoxy groups in ortho-position is also 0.28 nm). The conformation of 33 so derived differs from the conformations proposed for the threo phthalideisoquinoline series. The N-methyl resonance of jI-narcotine is found at an unusually high field, when compared to the other compounds belonging to the same threo series. This effect is in agreement with the conformation derived, which indeed substantially differs from the one usual in the threo series. In fi-narcotine, the H-l and H-l’ hydrogens are not synclinal (staggered) as usual [25, 261, but anticlinal (eclipsed). This conclusion validates earlier ‘HNMR results [27]. A similar conformation was re-

R H A M JANSSENetal.

3336

RZO

R’

18 19 20 21 22 23 24 25 26 27 28

H H H OH OAc OMe H H H H H

R= R' R4 Me Me Me -CH,Me -CH2Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me -CH?Me -CH,--CH2-CH2--CH>-

R5 Me Me Me Me Me Me Me Me Me

R6 H H Me H H H Me H OH H H

R' H Me H H H H H (14-epr) Me (14-epr) H H Me

‘OMe

32 34

37 38

R= H R = CH1-C,H,

R = Me R= H

39

cently derived for noradlumme 35 from ‘HNMR experiments [28]. In the preferred conformation for 32 [29] (Fig. l), the correspondmg N-O distance amounts to ca 0.30-O 32 nm, which obviously is not suitable for coordination wtth the shift reagent. Accordingly, it is shown that LIS may contribute to the determination of the topology of such molecules m solution, and that LIS constitutes an efficient method for the determmation of the CL-or fi-conformation of these phthalideisoquinoline alkaloids, whereas it provides an unambiguous means for the assignment of methoxyl resonances, m *H as well as in 13CNMR

40

41 42

R= R=

Me H

The ‘H NMR assignment of the methoxyl resonances of 33 [30] was found to be erroneous (Table 5). Special attention is required for the assignments of the C-6’ and C-7’ hydrogens in compound 33. Their assignments at 66.93 and 7 13, respectively, are based on account of the data given by Smula et al. [3 11, and by comparison with the data on meconin [3], takmg mto account the effects due to substitution at the benzyhc carbon of the latter compound. The H-7’ resonance m 32 is found upfield due to an anisotropic effect of the aromatic rmg A in the preferred conformation [29] (Fig. 1). Comparison of 32 and 33 shows that for these compounds the chemical shifts of C-3 and C-4 are not at all diagnostic of the

NMR of lsoquinohne alkaloids

3331

Table 5 ‘H and 13CNMR chemical shifts and Pr(fod), mduced chemrcal shifts of compounds 32134 Identlficatlon of nucleus

32

‘H

‘V

&,t

H-l H-3

C-l c-3

H-4

c-4

4.40 23 26 19 2.3

-OCH,O-

C-4a C-5 C-6 C-l C-8 C-8a C-l’ C-3’ C-3’a c-4 c-5 C-6 C-7 C-7’a -OCH,O-

4’-OMe S-OMe 8-OMe NMe

4’-OMe S-OMe S-OMe NMe

H-5

H-l’

H-6’ H-7’

6.31

5.51 -

d& 3.7 nd nd nd nd 14 45 -

6.91 6.09

5.5 3.8

5.94 4.10 3.81 406 2.56

08 234 7.1 1.3 2.6

34*

33 6,

d6c

a,$

da,

6,

d&

60.7 49.8

5.0 3.0

4 16 nd

6.0 nd

60.9 494

102 8.3

218 1319 102 1 148 2 133 8 140.3 116.9 81.6 167.8 120.0 147 5 1520 118.1 117.5 141.0 100.5 -

2.7 2.8

nd -

-

-

264 131.2 102 3 148.0 133 5 139.8 118.0 82.9 168.4 119.5 147.7 1520 118.4 116.5 141.9 100.4

35

6 30 5.47

nd 15 6.6

62.0 56.6 59.2 46.1

14 1.1 1.5 2.2 4.3 5.2 30.4 19.0 348 16.7 55 4.9 9.7 0.9

6.93 7 13 5.81 5.82 4.07 3.86 3 93 2 10

34.1 91 16 3.6

3.2 3.2 0.8 0.7 11.8 3.8 12 43

62.2 561 590 449

3.1 1.8 1.1 1.4 2.2 44 9.1 23 1 13.6 21.9 11.3 4.9 43 1.7 08 20.3 5.8 1.5 10.2

6, 60.7 49.3 27.1 130.7 99.1 146.0 130.7 136.6 114.0 80.3 166.9 119.0 146.2 150.9 117.1 116.9 1398 99.6 59.5 55 5 45 3

*In chloroform-d-DMSO-d, (1: 1). tJ,,,,=3.9 Hz, J,..,.=8.7 Hz. $J,.,,= 1.97 Hz, Jo,,,,= 1.38 Hz; J,.,,. =8 16 Hz.

OMe

Me

/ Me 32 Fig. 1. Preferred conformation of

stereochemistry at C-l and C-l’ [3]. Here, LIS should be preferred for this purpose. Unfortunately, the phenolic counterpart of 32, narcotoline (34), has low solubility in chloroform-d, which prevented the performance of comparable LIS experiments. Its 13C NMR resonances in chloroform-d-DMSO-d, (1: 1) were assigned by comparison with those of 32. Both C-6 and C-4 were distinguished on account of their signal mtensities. The assignments of ring A carbons m these compounds being difficult, and various assignments for related systems being given in the literature [16, 17, 191, it was considered very useful to include in our study the

relative

a-

and j-narcotme

13C NMR assignments of hydrocotarnine (36) as a model compound, and to present the unambiguous assignment of 32. 13C-‘H shift correlated 2D NMR of 32 reyealed an unequivocal assignment of C-6 at S148.3 and C-8 at 6 140.3, respectively: C-6 showed long-range couplings with H-5 (66.31) and O-CH,-0 (65.94), whereas C-8 was long-range coupled with H-l (64.40) and OMe (64.06). C4’ (6147.5) and C-5’ (6152.0) showed long-range couplings with the ‘HNMR methoxyl signals at 64.10 and 3.87, respectively. The assignments of OMe-4’, OMe-5’ and OMe-8 at 662.0,56.6 and 59.2 were similarly assured. These data (Table 5) show that virtually all 13C NMR

3338

R H A M JANSSEN et al Table

6

‘H and “C NMR chemical shifts and Pr(fod), shifts of compound 39

Identllicatlon of nucleus

‘H

C-l

5 15

H-2

c-2

400

62 38

H-4 H-5

c-4 C-5 C-5a C-6 C-7 C-8 c-9 C-9a c-10 C-1Oa c-11 c-12 c-13 C-13a c-14 7-OMe 8-OMe 12-OMe 13-OMe NMe

nd nd

nd nd

H-10 H-11

H-14 7-OMe 8-OMe 12-OMe 13-OMe NMe “(preferential)

Table

7 Pr(fod),

Induced

Identlficatlon of carbon

d6,

6,

H-l

H-9

chemical and 41

chemxal

39 13C

H-6

Induced

6 64

119

7 24

128

7 23

18

6 87

11

6.37 3 86 3.86 3 86 3 94 2 32

97 21 6 21 6 04 51 2.0

Interchangeable

shifts of compounds

40

&

da,

62 8

84

615 55 8 310 1313 1130 !460A 146 9” 1082 1352 1243 1282 1134 1506 1448 1302 87 6 55 8 55 8 55 8 610 33 5

61 46 63 102 19 1 599 624 19 1 11 3 31 6X ‘8 59 160 12 6 165 46 7 46 7 23 117 33

assignments

40

asstgnment of all ‘H and r3C NMR resonances (Table 2). These results indicate that for compounds 37 and 38 [16, 17, 191 the assignments for C-l and C-3 should be interchanged

41

Alpwgenine C-l c-2 c-3 c-4 c-5 C-6 c-7 C-8 c-9 c-10 c-11 c-12 c-13 c-14 c-15 C-16 3-OMe 6-OMe NMe

asstgnments pubhcatron experrments

1192 1128 1420 146 2 91 2 66 3 1332 1280 58 7 202 1270 1309 42 8 406 356 46 2 56 1

107 174 45 2 57 3 38 8 57 7 244 124 78 79 128 218 189 133 95 66 27 5

42 9

57

118 1 1134 1415 1469 89 1 76 6 240 19 3 59 5 198 1266 1298 42 2 39 9 37 2 46 6 57 8 56 3 42.8

96 190 504 670 41 1 37 9 200 100 70 77 12 3 21 3 172 164 77 62 36 5 32 8 43

of the aromatic carbons of 32 m a recent [32] are erroneous. 2D NMR and APT on hydrocotarnme 36 enabled unambiguous

In the rhoeadme alkaloid, alpmtgenme (39) (Table 6 [33, 34]), chelatron of the shift reagent takes place at the C-7 and C-8 methoxyl groups, and to a lesser degree, at the C-14 hydroxyl and C-13 methoxyl groups, whereas the C-12 methoxyl group IS virtually uninfluenced and resembles an isolated methoxyl group m its induced shift behavtour This effect 1s due to the preferential coordination of the lanthamde shift reagent with the hydroxyl group. Therefore, this experiment enables the assrgnments for the methoxyl groups m ‘H and 13CNMR. Furthermore, rt is shown once more that the specific structure of the alkaloid, as well as the locatron and the nature of its functronal groups, govern the sates of chelatron.

Codeine and tetrahydrothehame As representatives of the group of morphman alkaloids, codeme (40) [35-371 and tetrahydrothebame (41) were mcluded in our study Chelation IS observed with the oxygen atoms at C-3 and C-4, and the C-6 hydroxyl and C-4 oxygen ether functions in 40 (Table 7) The latter coordmatton need not necessarrly be btdentate, coordmatron with the C-6 hydroxyl atom alone would explain the Induced shafts observed as well For 41, however, a similar

NMR of lsoqumohne alkaloids

coordinatton is observed, indicating that the C-5 oxygen chelation will be bidentate, the other site bemg the C-4 ether function. The shift experiment allowed the identification of methoxyl groups in “C NMR, and enabled the definitive assignments of C-10 and C-8, not only for 41, but also for dihydrocodeine 42 [36, 371. The C-10 resonance is found in 40 and 41 at 6 19.7-20.4. For this reason, the C-10 resonance of dlhydrocodeine 42 must be assigned at 619.7 [36], and may not be considered interchangeable with the C-8 resonance at 6 18.9. This con&sion validates the earlier results of ref. [37]. EXPERIMENTAL

‘H and 13CNMR spectra were recorded m 0.2 mol I-’ CDCl, solns, unless otherwlse noted Chemical slufts (6) in ppm were determined relative to the solvent signal and converted to the TMS scale. Lanthamde-induced sluft expenments were performed m CDCl, usmg Pf(fod),, as reported earher [Z]. The resulting Induced chemical shifts are expressed as normalized slueldmg gradients d6 (calcd Induced upfield shifts m ppm for eqmmolar complexes). Expenmental con&Ions were as reported earher [ 11. Pr(fod), induced effects m ‘H NMR of 2methoxyphenol 63.90 (2-OMe) d69 3 [38]; 65 59 (OH) da14,66.86 (H-3, H-4, H-5 and H-6) da3 1 For the Pr(fod), Induced effects observed m 13CNMR see ref [Z] Synthesu of canadme. Canadme was prepared by NaBH,-EtOH reduction of berberine chlonde Synthesis of hydrocotarmne A soln of cotarmne chloride (200 mg) in MeOH-H,O (5 2, 28 ml) was adJusted to pH 6-7 using 2 M HCl, and NaBH, (80 mg) was added portionwise The mrxt was stirred for 30 mm, H,O added, the MeOH removed in uacuo, aq Na,CO, added and CHCI, extn performed. The oily product obtained (130mg, 75%) was chromatographed over sihca gel, MeOH elution affording slowly sohdlfymg hydrocotarmne 36 (90 mg, 52%). Acknowledgements-The authors are Indebted to Mr D. SelJkens and Mr A. V. E. George (Organic Chemical Laboratory, State Umversity of Utrecht) for their contributions to this research, and to Dr P. Vnjhof (Dlosynth B V., Apeldoorn) for lus generous gifts of alkalcuds. REFERENCES

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