'H-NMR SPECTRA OF NORDITERPENOID ATKALOIDS. A REVIEW' IV

57, NO. 11,pp. 1473-1483, N d 1 9 9 4. 1473. 'H-NMR SPECTRA OF NORDITERPENOID ATKALOIDS. A REVIEW'. JAMPANI BHOGI "UMAN and ALFRED KAZ*...
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Journal of Natural Products Vol. 57, NO.11,pp. 1473-1483, N d 1 9 9 4

1473

'H-NMR SPECTRA OF NORDITERPENOID ATKALOIDS. A REVIEW' JAMPANI

Natural Pr&s

BHOGI"UMAN and ALFREDKAZ*

Research Lahatmy Dr. A l H &k, Oberiuilerstr. 9, CH-4054 Basel, Swikeriand

ABSTRACT.-'RK 'H-nmr spectra of the diterpenoid moiety of 52 norditerpenoid alkaloids are dealt with in this review. The norditerpenoid alkaloids have been classified into six types. For each of these categories the average chemical shifts of the protons are represented in tables and discussed in the text. Dihedral angles, multiplicities, andJ values are tabulated.

Diterpenoid alkaloids occur in plants that grow throughout the Northern Hemisphere, species of the Ranunculaceae (Aconitum, Delphinium), Garryaceae (Gartya), Compositae (Inula rqyleuna), Saxifragaceae (Anopteras), and Rosaceae (Spiraeajaponica). Due to their high toxicity and varied pharmacological properties (2,3), they have attracted much interest. Two classes of diterpenoid alkaloids can be differentiated. One class includes the less toxic C,,-alkaloids. The second group comprises the highly toxic C,,-alkaloids, usually called norditerpenoid alkaloids, ofwhich their 'H-nmr data are the subject of this review. The norditerpenoid alkaloids display more oxygenation centers in the form of hydroxyl, 0-ester and methoxyl groups than do the C,,-type alkaloids. The alkaloids dealt with in this review have been classified into six types (I-VI) and are oxygenated at C-1, C-6 (except type V and compound 51),C-8 (except artifacts 12 and 13),C-14, C-16, and C-18. In types I-IV the 6-0-substituent is a-orientated, while in type VI p-orientation prevails. Depending on the position of the additional oxygen groups these six types can be distinguished as follows: Aconitine Type: Additional hydroxyl groups occur at C-3, C-13, and C-15. I. 11. Pseudaconitine Type: The additional hydroxyls are at C-13 and C-15 only. 111. Bikhaconitine Type: There is only one additional hydroxyl, which is at C-13. IV. Neoline Type: There is no additional oxygenation at C-3 (except falconerine [397),C-13, or C-15 (except 8-acetyl-1 Sa-hydroxyneoline 1407 and 15ahydroxy- 1-epi-neoline 1411). V. Isotalatizidine Type: There is no oxygenation at C-3, C-6, C-13, or C-15. VI. Lycoctonine Type: Oxygenation at C-7 is typical for this type. Oxygen substitution at C-6 is in most cases in the p- position. There is no oxygenation at C-3, C-13, or C-15. Although complete l3C-nrnr spectra of many norditerpenoid alkaloids have been reported, only a few complete 'H-nmr data compilations are available in the literature (4-6). The systematic studies in this laboratory on complete 'H-nmr spectra of norditerpenoid alkaloids (1, 7-12; S.J. Desai, unpublished results) has provided a 'Hnmr data bank of 46 compounds. The chemical shift assignments were based on onedimensional 'H-nmr spectra in conjunction with spin-spin decoupling experiments, two-dimensional 'H-'H COSY, and in some cases on confirmation with 'H-13C HETCOR. Furthermore, we have included in this review compounds 5 (13), 6 (14), 8 (15), 10(16), 42 (17), and 52 (IS), for which complete 'H-nmr data are available in the literature. Tables 1-7 show the average chemical shifts and shift ranges. They serve as the basis for the following discussion of the 'H-nmr spectra of compounds 1-52 . Table 8 summarizes the dihedral angles of the CH-bonds, the 'H multiplicities and the 'Communication No. 15 on Aconitum. For communication No. 14, see Hanuman and Katz (1).

Wol. 57, No. 11

Journal of Natural Products

1474

OH R7

'6

/

19

OMe

OHe Structures 1-32 No.

I.

Compound

R;

R,'

R,'

R,'

OMe OMe OMe OMe OMe OMe OMe OMe OMe OH OMe OMe

Et Et Et Et Et Et

OAc OH OH OMe OEt OEt OAc OMe OAc OAc OAc H

OBz OBz OH OH OB1 OBz OBz OBz OBz OB2 OBz OH

OH OH OH OH OH OH OH OH OH OH OH =O

N N

Me Me Me Et Et

OH OH OH OH OH OAc OH OH H H H OH

OMe

Et

OH

H

OH

=O

s

OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe

Et Et Et Et Et Et Et Et Et Et Et

OH OH OH OH OH OH OH OH OH OH OAc OAc OAc

OAc OH OH Olip. OAc Olip. OH OAc Olip. OH OAc OAc OH

OVr OVr OH OVr OAS OAS

H H H

O h

H H H H H H

N N N N N N N N N N

H

S

H H

N

OMe OMe OMe OMe OMe OMe

Et Et Et Et Et Et

H

OAc OH Olip. OH OAc OAc

OVr OVr OVr OH OBz OAS

H H H H H H

N N N N N N

R,'

R,

Sourceb

Aconitine rype

1 2 3

4 5 6 7 8

9 10 11 12 13 11.

14 15 16 17 18 19 20 21 22 23 24 25 26 111.

27 28

29 30 31 32

Aconitine Benroylaconine Aconine 8-O-Methylnconim 14-Benzoyl-8-O-ethylonine Polyschirtine A Mesaconitine Hokbusine A Hypaconitine 1-Demethylhyppconitine 3-hxyaconitine Desbenzoylpymonitine l~i-Desknzoylpyroaconitine

Me

s S N N N N N N N

s

Pseudaconitine type Pseudaconitine Ventroylpseudaconine Pseudaconine 8-Lippseudaconitine Yunaconitine 8-Lipoyunaconitine &Deacetylyunaconitim Indaconitine 8-Lipoindaconitine Ludaconitine 3-Acetylpseudaconitine 3-Acerylyunaconitine 3-Acetylventroylpseudaconine

Et Et

OBz OBz OBz OVr OAS OVr

H

S

Bikhaconitine rype Bikhaconitine Ventroylbikhaconine 8-Lipobikhaconitine Bikhaconine Chumaconitine Crassicauline A

H H H H H

'Me=methyl; Et=ethyl; Ac=acetyl; Vr=ventroyl; lip. =mixture of lipoyl fragments (palmitoyl, stearoyl, oleoyl, linoleyl, linolemyl); As=anisoyl. bN=natunl compound, S=semi-ryntheric compound.

calculated, as well as the observedJ values. Joshi and Pelletier (19) reviewed the work done on the basis of X-ray studies regarding the conformation of rings A-F. Rings A, B, and E of aconitine are in the chair form, and ring C is in the envelope form with C-

November 19947 Hanuman and Katz:

Norditerpenoid Alkaloid Nmr Data

1475

17

R.

19

R3 Structures 3346 No.

N. 33

34 35 36 37

38 39

40 41 42

V. 43

4.4 45

46

Compound

R,'

R;

R;

R,'

R,'

&'

R,

Sourceb

a-OH a-OH a-OH

H H H

H

OMe OH OH OAc

OH OH OH OH

OH OH OAc OAc

H H H H

N N N

a-OAc

OMe OMe OMe OMe

=O a-OMe a-OMe

OMe OMe OMe OMe OMe OMe

=O OMe OMe OMe OMe OMe

OH OAc OH OAc OH OH

OAc OVr OVr OH OH OAc

H H

S

B-OH a-OAc

H H OH H H H

OH OH H

N N N N N

OH OH OMe OMe

H H H H

OMe OH OMe OMe

H H H H

OH

OH OH OH OAc

H H H H

N N N N

Neoline type Neoline Senbusine A 14-0-Acetylsenbusine A 1,6,14-TriacetylsenbusineA 1,6-Dehydm-14-O-acetyIsenbusine A Falconericine Falconetine 8-Acetyl-1 5a-hydmxyneoline 1Sa-Hydroxy- 1+neoline 1,14-Diacetylneoline

a-OH

H

S

Isoralatizidine type Isotalatizidine Columbianine Talarisamine 14-0-Acetyltalatisamine

OH OH OH

'Me=methyl; Aczacetyl; Vr=ventroyl. b N = ~ r u r a lcompound, S=remi-synthetic compound.

14 at the flap. Ring D is in the boat form with the end at C-15 flattened, and ring F is in the half-chair form (20). RING A.-Depending on the oxygenation in ring A, two patterns of coupling systems can be observed. Compounds of types I and 11, which are oxygenated at C-1 and C-3, exhibit an ABXY system, whereas an A,B,X is noted in compounds of the 3-deoxy types 111-VI, and in compounds 9 and 11 of type I. The average chemical shift of X (H1P) of ABXY is 3.12 2 0.06 ppm and of Y (H-3P), 3.77 2 0.09 ppm. A (Ha-2)of ABXY resonates at 2.06+0.18 pprn and B (H,-2) at 2.36k0.04 ppm, both as multiplets. In compounds of type 11, acetylation of 3a-OH causes downfield shifts of AB (Ha,,-2)and Y (HP-3), which resonate at 2.3720.02 and 4.9020.01 ppm, respectively. These downfield shifts are due to an a-effect on the C-3 proton and an anisotropic effect of the acetyl carbonyl group on the C-2 methylene protons. In types 111-VI an A,B,X spin system is observed. In la-methoxy compounds, X (HP-1) of A,B,X appears at 3.0420.11, A, (H,-3) at 1.5920.20, and B, (H,-2) at 2.120.20 ppm. In la-hydroxy compoundsoftypesIV-VI, X(HP-1)resonatesat 3.6820.05,A2 (H2-2)at1.5950.13,

Wol. 57, No. 11

Journal of Natural Products

1476

Et

Structures 47-52 No. VI.

47

48 49 H,

51

52

Compound

R,'

R;

R;

R,'

R;

OH OMe OH OMe OH OH

OH OH OMe OMe OMe OMe

B-OMe B-OMe

OH OH OH OH OH OMe

OMe OMe OMe OMe OH OAc

Sourceb

Lycoctonine c y p Gigactonme Lycocronine 14-Methyldelphinifoline Dernethylenedelcorin Vimcenine Pubexenine

B-OH B-OH H u-OH

N N N N N N

'Me=methyl; Ac=acecyl % = m a d compound.

and B, (H,-3) at 1.7420.22 ppm, while in the 1P-hydroxy compound of type IV, X (HP-1) is noted at 3.90, A, (H,-2, H,-3) at 1.36, and B, (Hb-2, Hb-3)at 2.96/1.85 ppm, with a shift difference of 1.60 and 0.49 ppm between the A and B protons.

RINGB.-In compounds of types I-IV, oxygenation is observed at C-6a and C-8, in type Vat C-8, in type VI at C-6P (except 52: C-6a), C-7, and C-8. An ABXand AB,C spin system could be expected in types I-IV and V, respectively. However, due to the dihedral angle of ca. 110" between HP-6 and H-7 (8), an AX pattern is observed. In 8OH compounds, H-7 resonates at 1.97 2 0 . 1 1ppm, while in 8-OAc alkaloids it exhibits a downfield shift to 2.9020.12 pprn due to deshielding by the acetyl carbonyl. In &methoxy compounds of types I-IV, A (H-5) ofAX resonates at 2.0620.09 and X (HP6) at 4.0520.1 1 ppm. In the 6P-methoxy compounds of type VI, A (H-5) appears at 1.7820.09andX(HP-6)at 3.9220.07 ppm. In the6a-hydroxycompoundsoftypeIV, X (HP-6) resonates at 4.7420.03 ppm, and in 6a- and 6P-hydroxy compounds of type VI X(HP- and Ha-6)at 4.41 50.09ppm. This is adownfield shift of0.69 and 0.49ppm, respectively, compared with 6a- and 6P-methoxy compounds. The 6-deoxy compounds of type V display an A,BC pattern, while the 6-deoxy compound 51 of type VI shows an A,B system due to the tertiary hydroxyl substituent at C-7. The A, signal (HP-S/H,6) in both cases appears at 1.76+0.11/1.5620.06 ppm, whereas the B resonance (Hb6) of type VI appears at lower field (at 2.30 ppm) than B of type V, which resonates at 1.90?0.04 ppm. The C signal (Ha-7) of the A,BC system in type V appears as a multiplet at 2.10+0.02 ppm. RINGC.-The

oxygen substituents in ring C are located at either C-13 and C-14

November 19941 Hanuman and Katz: Norditerpenoid Alkaloid Nmr Data

1477

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November 19941 Hanuman and Katz:

1479

Norditetpenoid Alkaloid Nmr Data

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fvol. 57, No. 11

Journal of Natural Products

1480 TABLE 8.

Dihedral Angles, Multiplicities, andJ Values of Norditerwnoid Alkaloids.'

He-1/He-2................. H,- 1/H,-2 ................. Ha-1/H,-2 .................

Configuration

Angle

Position Chair 7'0 50" 180"

Boat 55" 60" 180"

Hp-1

Multiplicity

t

:xpected 1 Value

6.0 6.5

dd H,-l/H,-2

.................

He-2/H,-3 ................. H,-2/He-3 .................

50"

7.6

65"

50" 65"

70" 50"

H$-3

m

-

t

5.0

dd Y-2/H,-3 .................

165"

180' m

Ha-2/H,-3 ................. H-5/H,-6 .................. H-5/He-6 .................. H,-6/H-7 .................. H,-6/H-7 ..................

65"

50" 25'

Hp-5

d m

95" 110" 10"

Hf3-6

d dd m

H-9/Hn-10 ................

20"

H-9/Ha-14 ................

30"

H-l0/H,-12 .............. H- 1O/H,- 12 .............. He-12/H-13 .............. H,-12/H-13 .............. H,-14/H-13 ..............

0" 120"

H-13/Ha-16.............. H,-15/H-8 ................ H,-15/HC-8............... Ha-15/H,-16 .............

130" 40"

m HB-9

t

9.0 5.0 6.0 0.4 1.o 7.4 6.5 5.6

dd

He-15/H,-16 .............

6.0-8.8 5.8-7.5 7.5-11.0 8.2 4.0-6.0 8.0-13.0 -

4.2-7 .O -

6.0-8.0 5.0, 11.0 6.5-6.6 6.0 4.7-5.1

4.4 6.0

80"

40' 75'

Observed J Value

Hf3-14

1.8 6.0 2.5

4.0-6.0 -

t

9.6

d dd m d d dd

1.8

4.0 2.0-6.1 2.0-7.0 -

d m

4.0-16.0

80'

170"

50"

Hp-15

OHa- 15 H a - 16

m

He-17/H,-7 ............... Ha-18/Hb-18............. H2-19/Hb-19.............

90" 120" 120"

H a - 17 H-18 H-19

Ha-20/Hb-20.............

120"

H-20

br s ds d

1.0 4.4 4.4

dd t

4.4

dd m H-2 1

t

-

2.04.0

4.0-8.0 4.5-7.0 8.0-10.0 8.0-10.0 10.0-12.0 6.0-9.0 16.0 7.2 4.0-8.0 7.0-14.0 -

6.0-8.0

'Angles measured 2 5" on Dreiding models with a Buchi Torsiometer;J values expressed in Hz.

November 19941 Hanuman and Katz:

Norditerpenoid Alkaloid Nmr Data

1481

(types 1-111) or at C-14 only (types IV-VI). In the 13-hydroxy alkaloids (types I-111), an AX of H-9 and H-14 and an A,B system of H,-12 and H-10 are observed, whereas in types IV-VI we find the ABX system of H-13, H-9, and H-14, and the ABC system caused by H,-12 and H-10. In 8-OAc compounds of types 1-111, the A (H-9)of the AX system resonates at 2.9120.02 ppm, and in 8-OH compounds at 2.44k0.12 ppm. In 8-OAc, 14a-0-aryl ester compounds of types 1-111, X (HP-14) resonates at 4.8920.09 ppm, while in %OH, 14a-0-aryl ester compounds it appears at 5.0820.08 ppm, whereas in aconines (%OH, 14a-OH) the resonance is further upfield at 3.9650.05 ppm. In the 13-deoxy types IV-VI the A (H-9)ofABXappears at 2.332 0.19 pprn with the exception of the l4a-OMe alkaloids 47-50,where it appears at 3.1050.14 ppm. The B (H-13) signal ofABX in %OH, 14a-0-ester compounds appears at 2.64k0.12 ppm, whereas in aconines (%OH, 14a-OH), it resonates at 2.3020.05 ppm. The X (HP-14) of ABX appears in %OH, l4a-0-acetyl esters at 4.7820.04 ppm, in 8-OAc, as well as in %OH, 14a-0-aryl esters at 5.1020.06 ppm, and in aconines (%OH, 14a0 H ) a t higherfieldat4.1620.05 ppm. IntypesI-IIIA,(H-lO, Ha-12)ofA2Bresonates at 2.0320.13 ppmandB (Hb-12)appearsat2.6650.30ppm. Incontrast, in types IVVI the A (Ha-12) signal of ABC appears at 1.6920.28 ppm, B (H-10)at 1.8420.21 ppm, and c (Hb-12) at 2.2620.29 ppm.

RINGD.-The alkaloids of type I, as well as compounds 40 and 41 (type IV) are oxygenated at C-15 and C-16. They exhibit an XY (HP-15, Ha-16) spin system, in contrast toallothertypes whichdisplayanABX(H,-15, Ha-16). In 8-OAccompounds, the X (Ha-16) of XY resonates at 3.29k0.10 ppm, and in the semi-synthetic 15dehydro-l6P-epimer 13 it resonates at 3.88 ppm. The Y (HP-15) of XY resonates at 4.51 k0.06 pprn as a doublet of doublets due to coupling both with X (Ha-16) and H of 15a-OH. In 8-OAc, l4a-0-aryl ester compounds of types I1 and 111, A (H,-15) and B (Hb-15) of ABX resonate at 2.4520.05 and 3.0650.08 ppm, respectively, with X (Ha-l6)at 3.3750.05 ppm, whereas in %OH, 14a-O-arylestercompounds,A(Ha-15) resonates at 2.2850.06 ppm, B (Hb-15) at 2.57 20.04 ppm with adifference of 0.17 and 0.49ppm, andX(Ha-16)at 3.3720.05 ppm. In %OH, 14a-OAccompoundsoftypes IV and V, A (Ha-15), B (H,-15) and X (Ha-16), in turn, resonate at 2.0720.17, 2.37 2 0.1 3 and 3.20 k 0.17 ppm as multiplets, against shifts of 1.692 0.09,2.80 2 0.20, and 3.29k0.10 pprn displayed in %OH, 14a-OMe compounds of type VI. RINGE.-In ring E, C-17 and C-19 are bridged by a nitrogen atom resulting in relatively downfield resonances of H-17 and H,-19. In most of the norditerpenoid alkaloids, H-17 appears as a broad singlet without any splitting due to the bonding angle of 100' with the neighboring H-7. All la-methoxy compounds show this singlet at 3.02k0.22 ppm; in the la-hydroxy, 8-OH compounds 33-35 of type IV, it appears relativelyupfieldat 2.6020.07 ppm. In the 1-dehydrocompound 37,due to deshielding by the carbonyl group, a marked downfield shift to 3.34 ppm is observed. The Haand H, ofc-19 exhibit an AB spin system. In C-3 0-substituted compounds of types I and 11, A of H2-19resonates at 2.4220.15 ppm and B at 2.9220.16 ppm. The chemical shift differences of A and B are in the range of 0.4620.5 1ppm. The C-3 deoxy compounds of type I deviate from these values in a way which can not be analyzed until more compounds are available. In deoxyaconitine the shift difference of 0.78 pprn is particularly large. It results from a relatively low A of 2.13 ppm. In contrast, in hypaconitine the shift difference of 0.19 ppm results from a low value (2.55 ppm) of B. In compounds oftype 111, the chemical shift difference between Ha-and Hb-19in 8-OAc, 14a-0-arylesters is0.54ppm, in8-OH, 14a-O-arylesters0.3lppm,andin8-OH, 14aO H alkaloids, it is 0.14 ppm. The 3-0-substituted alkaloids (types I and 11)do not show

1482

Journal of Natural Products

Wol. 57, No. 11

these decreasing differences between Ha-and Hb-19.In types IV-VI, H,-19 resonates at 2.1420.16 ppm, and Hb-19at 2.5620.22 ppm.

N-ETHYLSIDE-CHArN.-In 15a-OH compounds of type I the methylene protons of the N-ethyl side-chain (H,,-20) display an AB system with a 0.2320.13 pprn shift difference [A (H,-20) resonates at 2.4620.09 pprn and B (Hb-20)at 2.6920.07 ppm), whereas in 15deoxy compounds the AB signals appear as multiplets. In compounds of types II-N, AB signals (Ha/Hb-20)appear as multiplets at 2.5220.07 pprn (except in the C-15-OH compounds 40 and 41 of type IV which show the same resonances as type I) and in type VI at 2.8920.05 ppm. This can be explained by considering a non-bonded electron interaction of 15a-OH and the nitrogen atom due to unfavored parallel disposition. As a result the non-bonded nitrogen electrons orient themselves close to the C-20 methylene protons, thus causing the shift difference. In all types the terminal methyl group appears as a triplet at 1.08?0.05 ppm. C-18 SIDE-CHAIN.-H,-~~displays an AB system. In 3a-OH compounds of type I and 11, as well as in compound 39 of type IV the shift difference of A (H,-l8) and B (Hb18)is 0.065 20.065 ppm, while in the 3a-OAc compounds, due to the anisotropic effect of the acetyl carbonyl, the difference is 0.9420.01 ppm. The 3deoxy alkaloids in types I, 111,and IV show differences of0.47 ?O. 13, in VofO. 1320.01, and inVI of0.22 50.07 ppm. The influence of the various substituents on these shift differences can not be evaluated. On examining Dreiding models of norditerpenoid alkaloids, W-conformation is noted among the following protons: 3P-H/19-Ha, la-OMe/3a-H or OH, 5-H/17-H7 14P-H/16P5-H/19-&, 8-OH/10-H79-H/13-OH, 9-H/1 5a-OH, 12aY-H/14a-OH, OMe, lbP-OMe/8-OH, H-16/13-OH,and 17-H/19-He.The long-range couplings set in bold type were observed in the ‘H-’H COSY nmr spectra of most of these alkaloids (8-12). In some cases they could not be read due to other, overlapping signals.

ESTERSUBSTITUENTS.-These present the well-known shifts and connectivities of veratroyl-, anisoyl-, benzoyl-, and acetyl- groups, and therefore are not dealt with in this review. LITERATURE CITED 1. 2. 3.

4.

J.B. Hanuman and A. Katz, Phytochemistry, 36, 1527 (1994). M.H. Benn and J.M. Jacyno, in: “Alkaloids: Chemical and Biological Perspectives.“ Ed. by S.W. Pelletier, John Wiley & Sons, Inc., New York, 1983, Vol. 1, pp. 153-194. K.M. Nadkarni, Id.Mat. Md., Popular Prakashan Prvt. Ltd., Bombay, 1991, Vol. 1, p. 24. S.W. Pelletier, N.V. Mody, B.S. Joshi, and L.C. Schramm, in: “Alkaloids:Chemical and Biological Perspectives.”Ed. by S.W. Pelletier, John Wiley & Sons, Inc., New York, 1984, Vol. 2, pp. 205-

460. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

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Received IG Febnrary 1994