The structure of barbeline, an unusual C19-diterpenoid alkaloid from delphinium barbeyi huth

Tetrahedron Letters,Vo1.29,No.ZO,pp Printed in Great Britain

2397-2400,1988

0040-4039/88 $3.00 + .OO Pergamon Press plc

THE STRUCTURE OF BARBELINE, AN UNUSUAL Clg-DITERPENOID ALKALOIO FROM DELPHINIUM BAR&WI HUTH Balawant

S.

Joshia,El-Sayeda A. El-Kashourya, Holtb,

aInstitute

for Natural Sciences,

John D. Olsenc

Products

Research

The University

bDepartment

of Chemistry,

cPoisonous

Plant Research

Oklahoma

Haridutt

and S. William

of Georgia,

Athens,

Laboratory,

Agricultural

of Agriculture,

Logan,

of Chemistry,

Georgia

30602,

Stillwater Research

Utah

Elizabeth

M.

Pelletiera*

and the Department

State University,

K. Desaia,

of Chemical

U.S.A.

Oklahoma

Western

84321,

School

74078,

Region,

U.S.A.

U.S. Department

U.S.A.

swmnary: From the ethanotic

extract of DsLphinium barber/i Huth, a novel Cl+iterpsnoid atkaloid barbelins (4) has been isolated and its structure determined by spectroscopic data and an X-ray crystal diffraction study. Barbsline is the only example of an alkaloid containing a C(l9)=N- aaomethine group among the 230 naturally oocurring Clg-diterpenoid alkaloids. Two other new alkaloids, 6-acetyldelpheline and 6-deoxydetpheline, a8 well as the known alkaloids brow&ins, delphatine and glaucenine have also been isolated from this plant. The

occurrence

tamine (D.

(2),

gZaucwn S.

novel

Watts)

obtained

(FAB-MS):

1650

been (4),

and

ethanolic

[a]g

+45.03"

extract

groups

in the molecule

ficant

absence

42.9,

lets: Five

94.1,

34.5,

to the acetate

signal

an adjacent

at double

I3C NMR

doublets:

40.8,

42.9 bond

here

the

30.6,

carbon

ppm

spectrum

of

24.1

m.p.

81.5,

265.5-267.5'C;

for

l-3

C25H35N08; C, 62.88;

(3H, 2,

methyl),

tert.

one

acetoxyl

is a new CIg-diterpenoid

showed

showed 80.4,

2.07

(3H, 2,

on D20

OAc),

alkaloid.2

-33.5

The signi-

that the nitrostudies.

57.5,

169.3,

49.6,

56.1,

81.5

90.8,

45.6,

55.5,

83.6,

38.1,

22.7

ppm)

can

be

atoms. 81.5,

and 21.4 ppm.

and 55.9 ppm can be readily

assigned

The medium

of -N = C than of an snide.4

The

five trip-

C(10) and C(ll),respectively.2

or N = C(I9).

methoxyl

24 lines due to 25 carbon

77.9, 62.6,

90.8, 83.6,

addition).

and three

suggested

six singlets:

quartets:

C(8),

2397

a

(pH

J = 6Hz, C(14)-PH), 4.96, 4.98 (each lH, 2,

at 169.3,

and C(7),

of

fraction

3190 (broad, OH), 1738 (ace-

of barbeline

and five

as in an amide3

1650 cm-l is more characteristic

isolation

IR (nujol)vmax

one methyl,

studies

81.7,

signals

(value

Huth

of an NH group was seen from the D20 exchange

by DEPT

carbonyl,

del-

barbeyi

the

(lH, brs, N = CH; not exchanged

presence

that barbeline

169.3,

delcosine,

alkaloidal

(6 2.4) or an N-Et group (triplet -61.1)

determined

of the quaternary

ascribed field

nine

report of

barbeyi,

D.

(lH,g,

7.44

the

We

liquors

(l),

Delphinium

H, 7.48; N, 2.83; Calc. for C25H35N08:

(CDC13): 6 1.21

The absence

decoupled

The multiplicities 55.9,

suggest

of an N-Me

gen is unsubstituted. proton-noise

and

of

(c, 0.31 CHC13);

IH NMR

considerations

mother

C, 63.10;

(each 3H, 2, OMe), 4.19

deltaline from

earlier.1

the

0-CH2-O),5.32 (lH, bri, C(6)-a-H), Biogenetic

delpheline,

lycoctonine,

reported from

(M+ + 1); Found:

(C = N)cm-I;

3.22, 3.34, 3.47

(3)

has

frown the

m/z 478

H, 7.39 N, 2.93%; tate),

anthranoyllycoctonine,

barbetine

alkaloid

8.5)

of

dictyocarpine

strength

to

C(4)

band

The overlapping

The downpossessing

in the IR at

signal

at 169.3

2398

ppm should be assigned to C(19).5

The broadened singlet at 6 7.44 is due to the

C(19)-Hof

the azomethine and shows a long range coupling with C(17)-H as in the case of anopterimine.6 One of the methoxyl group is located at C(1) as seen by the loss of 31 mass units (OMe) (m/z 446) from the molecular ion peak.7 The remaining signals for the methine, methylene and the methyl carbons closely resemble those for deltaline.8 structure (4) seemed likely for barbeline. line established structure 4.

On the basis of these data, the unique

An X-ray crystal diffraction study of barbe-

An ORTEP plot of the structure appears in figure 1.

CH,

1

R’ = AC;

2

R’ = H; R* = CH,

3

R’ = AC; R* - H

R2= CH1

4

Bar bellne

A crystal of 4, was mounted on a Syntex P3 automated diffractometer. Unit cell dimensions were determined by least squares refinement of the best angular positions for fifteen independent reflections (2 >15") during normal alignment procedures using molybdenum radiation (a = 0.71069&) and yielded: 2 = 16.767(a), 2 = 16.767, c = 15.747(8)A; a = p 120.0', and V = 3859(4)1(3. For Z = 6 the computed density was 1.233 g/cm3. was P6I.

Data, (1749 points) were collected at room temperature using a variable scan rate, a

6-20 scan mode and a scan width of 1.2' below Kq 45.0'.

= 90.0', Y=

The space group

and 1.2' above Ka2 to a maximum 28 value of

Backgrounds were measured at each side of the scan for a combined time equal to the

total scan time. The intensities of three standard reflections were remeasured after every 97 reflections and as the intensities of these reflections showed less than 6% variation, corrections for decomposition were deemed unnecessary. Data were corrected for Lorentz, polarization and background effects.

After removal of space-group forbidden and redundant data, ob-

served data, (1116 points) (I> 3.00 (I)) were used for solution and refinement. The structure was solved for carbon, nitrogen and oxygen positions using direct methods.9

Least

squares refinement10 converged with anisotropic thermal parameters. Hydrogen atom positions were calculated using appropriate geometry and a C-H distance of 0.97A.

Hydrogen positions

were included in the final refinement with isotropic thermal parameters but held invariant. A difference Fourier revealed no electron density of interpretable level. -were taken from Cromer and Mann .I1

Scattering factors

The final cycle of refinement-functionminimized x(\F,(-

2399

lFc1)2, led to final agreement factor, R = 7.0%; R = (C/(Fol-jFcll/ClFol) x 100.

Unit

weights were used until the final cycles of refinement when weights equal to l/O F were introduced.

R, = 9.6%.

The molecule was refined in the absolute configuration of other members

of the fanily.12 Barbeline is the only alkaloid containing a C(19)=N azomethine function among the 230 naturally occurring Clg-diterpenoid alkaloids. the HN<

type.

The likely biogenetic precursor would be of

But there are only three such alkaloids known (flavaconitine, hokbusine B,

and polyschistine C) and none of these is of the required lycoctonine type. convert the

closely related deltaline (1) to

(4) were

unsuccessful.

Our attempts to It

is

highly

unlikely, therefore, that barbeline is an artifact of isolation.

Figure 1.

An ORTEP plot of barbeline (4)

We have also isolated from the alkaloidal fractions two new alkaloids that have been identified

from

their

spectral

data2,13

as

B-aoetytdelphetine

and

6-deoxydetphstins

and the known alkaloids browniine, delphatine, and glaucenine.

Acknowledgent:

We thank Dr. A. K. Ganguly of Schering Corporation for providing the FAB-

mass spectrum of barbeline.

2400

REFERENCES ANDNOTES 1.

W.B.

Cook

Ferris,

and

J.

S.W.

Beath,

Harvey,

80, 497; J.A. 2.

O.A.

P.L.

Maddry,

Pelletier,

J.

Am. E.

Magat,

Ph.D. Thesis,

N.V.

Mody,

&em.

B.S.

Soo.,

Martin

and

University

Joshi

1952, O.W.

and L.C.

Boido,

V.

O.E.

Edwards,

K.L.

R.J.

Handa,

Schramm

Kolt

1411;

Mayo,

of Georgia,

J.

M.

Am.

Carmack,

Chum.

3.

P.

1958,

Sot.,

1985. in AZkaZoids: Chemicat cmd Bio-

togicat Perepectiuee, Ch. 5, Vol. 2, ed. S.W. Pelletier, 3.

74,

John Wiley,

and

K.K.

New York,

1984.

Purushothaman,

Can.

J.

Chem., 1984, 62, 778. 4.

D.H.

Williams

McGraw-Hill

5.

The

and

I.

C20-diterpenoid

displayed

N.K.

7.

M.S.

alkaloids

garryfoline

S.R.

J.A.

Johns,

azomethine

the N=CH signals

N.V. Mody and H.K. Desai, J.

Hart,

Chemistry, 3rd

Spectroscopic Method8 in Orgadc

Ed.,

1980.

in the I3C NMR spectra

Pelletier,

6.

Fleming,

Book Co., London,

and its acetate

at 170.4

(lindheimerine)

and 167.1,

respectively.

S.W.

Org. Chem., 1981, 46, 1840.

Lanberton,

H.

Suares

R.I.

and

Willing,

Austr. J. Chw.,

1976, 29, 1319. Yunusov,

Y.V.

Rashkes,

V.A.

Tel'nov

and

S.Y.

Yunusov,

Khti.

Prir.

So&in.,

1969, 515.

8.

I3C

NMR

data

of 4:

80.4

C-l,

24.1

C-7, 83.6 C-8, 49.6 C-9, 81.5 C-10,

81.2

C-16,

62.6

C-17,

22.7

C-18,

C-2,

40.8

C-3,

42.9

C-4,

45.6

C-5,

77.9

C-6,

55.9 C-11, 30.6 C-12, 38.1 C-13, 81.7 C-14, 169.3

C-19,

55.5

Cl OCH3, 94.1

90.8

34.5 C-15,

0CH20, 57.5

C-14 0CH3,

56.1 C-16 OCH3, 169.3 COCH3, 21.4 COC_H3. 9.

P. Main, "MULTAN

S.J. Fiske, 80-A

University

10. J.M.

System

Ed.,

The

12. Complete

of Maryland,

tables

Amorphous

(3H, 2,

5.41

(lH, c& J = 2 Hz, C(6)-a-H);

5,

78.6

OAc) , 3.25,

C-6,

C-14,

HCH2Cb,

91.9

33.9

55.3

C-7,

C-15,

C-l

3.33, 83.4

82.1

0CH3,

6 0.77

including

(3H, 2, C(4)-CH3),

3.42

C-9, C-17,

0-CH2-0,

57.7

112-115'C

C-3, 33.9 C-4, 49.4 C-5,

Report TR446 of the

1.01

C-14 M+

50.4 C-11,

C-18,

0CH3,

m/z

4.91

factors

56.9

(3H, 2, (each

56.2

433(2%),

28.1

C-19,

N-CH2-C&),

lH, 2.

402

C-12,

50.4

Cl6 0CH3,

3.26, 3.33, 3.43

5.00 (each lH, 2,

50.2

N-CH$H3,

13.8

NCH2C%,

(Received

in USA

1 February

OCH20),

38.8

N-CbCH3,

170.0 gCH3,

(M-OCH3)(100),

1988)

C-l

OCH3,

93.2

13.9 21.5

IH

NMR: 3.64

0CH20); 13C NMR: 83.1 C-l, 27.2 C-

32.6 C-6, 90.4 C-7, 81.7 C-8, 47.7 C-9, 38.3 C-10,

55.3

C-13,

(each 3H, 2, OCH3),

28.0 C-12, 43.7 C-13, 81.9 C-14, 37.5 C-15, 83.8 C-16, 61.3 C-17, 25.8 C-18,

OCH3.

and

Data Center.

27.0 C-2, 36.8 C-3, 33..9 C-4, 56.1 C-

C-10,

25.5

structure

Crystallographic

OCH3), 4.89,

40.0

1.05 (3H, 4, NCH2Cb),

2, 33.1

19,

(each 3H, f,

64.2

4.90,

and observed

(3H, 2, C(4)-CH3),

48.4

J = 4.5 Hz, C(14)-B-H),

C-11,

calculated

C-8,

(lH, t.

Structure",

Park, Maryland.

13C NMR: 83.5 C-l,

m.p.

and M.M. Woolfson,

of Crystal

A24, 321.

with the Cambridge

C-16,

93.5

6-Deoxydelpheline:

COcH3.

College

IH NMR: 6 0.83

2.05

81.7

J.P. DeClerg Solution

1980.

have been deposited

13. 6-Acetyldelpheline:

Automatic

Mann, Acta Cryet., (1968)

crystallographic parameters

for

XRAY System - Version of 1980, Techioa~

Computer Center, University 11. D.T. Cromer and 1.8. thermal

Programs

of York, York, England,

Stewart,

G. Germain,

S.E. Hull, L. Lessinger, of Computer

0CH20,

57.5

C-14

OCH3,

51.0

56.0 C-

56.0

C-16