Khyberine and the biogenesis of dimeric aporphine-benzylisqoquinoline alkaloids

Tetrakedron Letters Vol. 21, np 4573 - 4576 @Per_Tmon Press Lti. lgB0. Printed in Sre.ztBritain

KHYBERINE

AND THE BIOGENESIS

OF DIMERIC 1

S. Fazal Hussain, Department

M. Tariq

of Chemistry, University

APORPHINE-BENZYLISOQUINOLINE

Siddiqui

1

and Maurice

The Pennsylvania

Park,

State

ALKALOIDS

Shamma",

IJniversity,

16802

Pennsylvania

The new u~o2rrphine-benzyZisoquinoZine khyberine (4BI is present in Berberis caZZiobotr*ys Aitch. er Bienert in about one part per million. An effort is made to present a compzete scheme for the biogenesis of apnirOhine-benayZisoquinaZi.ne di.merswhich arise ,Cromthe condensation of two cocZaurine units.

Following

the original

isolation

the aporphine-benzylisoquinoline

of the proaporphine-benzylisoquinoline

pakistanine

(3.4) from Berberis -

2 eeael, we have carefully

screened

or northwestern

for their alkaloidal

recently

Pakistan,

yielded

importantly particular

three new alkaloids,

kalashine interest

side of the dienone present times

4

(El,

since

together

as

favored

involving

te\,.

Our efforts

Bienert

ex Aitch.

Frontier

Province

Ethanol

extraction

acid work-up

were

of the Khyber

tic on Merck

obtained

(*A,, pakistanine

a C-l hydroxylated

was also observed

that

whereas obtained

present

C-11 substituted

greenish-blue

under

aporphinoids

benzylisoquinolines. new alkaloid

denoting

Perusal

had to possess

study

to afford

of B. calliobotrys

near Chitral,

in the Northwest

six kilograms

of dried material.

gel plates

(%I,

pakistanlne

fluorescence

to

of one third of this fraction

as the known pakistanamine

(1).

and kalashine to detect

(3B). Near the a faint greenish spot,

5

than any of its congeners. (E),

under

and chitraline

long-wave

(g),

It

in which

length uv light;

such as kalashine pakistanamine

(33) as well as l-O-methylkalashine (z), 4 (1) in 3N HCl, exhibit a greenish-blue

The new phenolic

that it belonged

of the structural

structure

is not as

One half of this amount was subjected

more polar

(g),

system

only the dimer chitraline

of the alkaloids

it was possible

appreciably

the same conditions.

fluorescence,

chitraline

a purplish-blue

as a minor product by heating

fluorescence

(g),

however,

aporphinoid

silica

is about one hundred

side. yielding

which were characterized

1-O-methylpakistanine

C-11 is unsubstituted,

Pass,

(3B) is -

that dienone-phenol

side of the dienone

to the less hindered

a detailed

which

thus indicating

was less rewarding,

towards

of the thin layer chromatogram,

denoting

(g),

325 g of crude extracts.

by preparative

alkaloids

pakistanine

in northern

is the fact that kalashine

per million,

of the wet roots were collected

north

then yielded

l-0-methylpakistanine origin

therefore,

Seven kilograms

Noteworthy

to the more hindered

Schneider

of Pakistan,

followed

Several

(10 91.

companion

all collected

334 Kalashine is of (3A). rearrangement to the more hindered

pakistanine

that a dienone-phenol

aryl migration

turned,

the known

species,

(1) - and (Berberida-

Ahrendt

-B. orthobotrys Bienert ex Aitch. (%I, chitraline (4&),3 and very

of only five parts

aryl migration

of B. zabeliana

Berberis

contents.

in nature,

to the extent

the opposite

The study

with

is possible

less than its more abundant

additional

l-O-methylpakistanine

it demonstrates

system

in E& orthobotrys

rearrangement

several

pakistanamine

baluchistanica

48. -

scheme

Before

and polar aporphinoid

to the 'IB" series reproduced

below made

a

aporphine-

it evident

this fact could be ascertained,

4575

displayed

of dimeric

that the

however,

it was

necessary

to obtain

quaternary distinct

the alkaloid

protoberberinium tic operations

salts.

using

again by CHC13-HN(C2Hg)2

in pure form,

This was achieved

first CHC13-HN(C2Hg)2

(9O:lO).

mp 145-14'7o (CHC13-MeOH),

the living

plant.

material.

The mass spectrum

(M - l)+, denoting

402

(M - a), 296

272, 29&h

611 - c),

in question.

in the Table,

The absence

at C-7'.

•3.06~~~,

singlet

-54.0234,

silica

gel tic plate.

with CHC13-HN(C2Hg)Z

were present,

and which

nary protoberberinium demonstrates work-up

(g),

to khyberine were

salts.

superimposed

The detection

that the dienone-phenol

during

the isolation

A biogenetic

dilemma

question

bear a phenolic

rearranges

over to furnish precursor known

Compound

(A),

chitraline

on accompanying

itself

5 incorporates -

than a

f3.24308,

nm' of that for kalashine 4 configuration.

applied

directly

on a

of pakistan-

amounts

(3Bf. -

of this alkaloid

bisbenzylisoquinolines

and quater-

2A-4A and 38 under these conditions -is a natural process, and is not due to acid

Given

at this juncture.

that pakistanamine

it is tempting

at C-10,

to speculate

that pakistanamine

0-demethylation in mind,

(1) could very well be a bisbenzylisoquinoline

oxidative phenolic

from the dimerization

coupling functions

(1) is the

and that all of the aporphine-benzylisoquinolines

known,

(51, derived

intramolecular

rather

shows A&

(+&), and kalashine

due to the minute

at C-11,

process.

presents

function

of pakistanamine

Were

of structure

substitution

sh owed the presence

Sequential to 2A along with the less favored 2B. It must be borne 3A and e, as well as 3B and 4H. -

(+I-berbamunine

undergo

(9O:lO)

the aporphine

in favor

of alkaloids

rearrangement

only proaporphine-behzylisoquinoline

first

pakistanine

(4B) was blurred -

absolute

extracts

264sh,

to that for kalashine

of a phenol

reminiscent

the identical

ethanol

(M - _ a + H)+, 220sh,

for the other aporphi-

(48) in methanol -

strongly

403

around

evidence

of

of

48 and shows m/e -

ht-y

is very close

the presence

microcrystalline,

one part per million

structure

the data available

and

followed

this one milligram

peak near 68.0 denotes

a pattern

thus indicating

Development

with

conclusive

3.40 indicates

half of the crude

(&>, l-0-methylpakistanine

amine

The spot corresponding which

(g),

of the remaining

with

proton

of khyberine

and +36.0z14,

(3B) and l-0-methylkalashine Portions

together

near

to about out using

The uv spectrum,

3.80 and 3.70),

(FT) yielded

the cd spectrum

Finally,

+3.42216,

corresponding

and

separate

(85:15),

of colorless,

to 1,2,10,11-substitution

of a downfield

and the lack of a three-proton methoxyl

pointing

at 200 MHz

of three

Cf16H8ROgN2 and loss of a proton,

3.97, 4.02,

(g3,,4

The CDC13 nmr spectrum

4B and has been summarized noids

one milligram

192 (base, a), and 107 (5 - a).

and 304 nm (log E 4.53,

a succession

is in full agreement

formula

bisbenzylisoquinolines

then CHC13 -MeOH

work was then carried

of khyberine

the molecular

(2B) and l-0-methylkalashine nucleus.

was obtained,

All of the structural

through (90:10),

In this fashion,

khyberine,

593

free of accompanying

to the putative

of two coclaurine

however,

that a

such as the which

proaporphine-benzylisoquinoline

at C-l and C-7',

and its rapid

(1)

then takes

alkaloid units,

in

dienone-phenol

could 5. rearrange-

these could in turn furnish then lead to -4A and 4B. Through sequential O-methylation, Intermediate 5 could also suffer and -3B and then 2B on the other. It is, of course, always possible that the pakistanamine (1). 6 true biogenetic sequence will prove to be a complex interlacing of these two sequences.

ment would

2A on the one hand, -3A and then direct G-methylation to furnish

Acknowledgment: National

This research

Institutes

of Health,

was supported USPHS.

by grant

CA-11450

from the National

Cancer

Institute,

4575

l-O-Methylpakistanine B. calliobotrys -. orthobotrys

(2A)

l-O-Methylkalashine

Pakistanine (3A) B. baluchistazca E. calliobotrys ?& orthobotrys

Kalashine (3B) B. calliobotrys E. orthobotrys

a __.

Chitraline (4A) B. calliobotrys B. orthobotrys g -* zabeliana

(+)-Berbamunine

(2)

Khyberine

(48)

(2B)

4576

XMFtResonances

TABLE.

Methylimino Compound

(2A) 2.50 -

2.55

Pakistanine

(3A) 2.51 -

2.55

Chitraline

(4A) -

l-O-Methylkalashine (2B) -

2.50

2.51

2.45

2.55

3.72 3.67

c-2

c-6'

c-7'

H-8'

3.84

3.89

3.64

3.85

3.92

3.64

3.86

3.92

3.77

3.82

(3B) -

2.47

2.56

-

3.82

3.83

Khyberine

(48) -

2.41

2.55

-

3.83

3.83

Chemical

are on the fi scale.

shifts

respectively.

Chemical

for the H-11 singlets J2",3"

8.0 Hz I‘or compounds

Permanent

2.

M. Shamma,

3.

S.F. Hussain,

4.

S.F. Hussain

5.

The Rf values plates

address:

J.L. Moniot,

listing

see G. Guinaudeau, M. Shamma,

7.01d

6.96d

7.0&i

6.98d

6.816

6.57d

7.146

6.98d

6.88d

6.674

7.14d

7,OOd

6.89d

6.69d

6.72

6.37

6.54

6.57

6.75

3.42

5.85

6.52

6.52

3.40

5.85

6.53

6.56

6.16

6.51

6.56

assignments

for H-3 and H-5' are interchangeable.

8.13, and 8.12, for compounds

Peshawar,

(9O:lO)

2,

2,

and 2,

in the Table.

J~,s is

Pakistan.

and M. Ikram, J. Am. Chem. z,, --

E.,

95, 5742

in press.

using Merck

silica

(2A) 0.47, -

(3B1 0.18, chitraline -

gel F-254 preprepared

1-O-methylkalashine

(4A) 0.10, and khyberine alkaloids

glass

(2Bl 0.36, (4B) 0.07. -

and their nmr and uv spectra,

See also and A. Cave, -J. Natural Products, 42, 133 (1979). Alkaloids, Academic Press, New York (1972), pp. 205-206,

M. Lebceuf

and J.L. Moniot,

New York

(1979), p. 165.

(Received

in USA 28 July

(1973).

in press.

of aporphine-benzylisoquinoline

The Isoquinoline -

and M. Shamma

6.986

-

6.70

6.57

,

H-9

and Footnotes

l-0-Methylpakistanine

(3A) 0.27, kalashine -

For a complete

6.994

7.10d

6.61

6.57

Heterocycles,

Tetrahedron

in CHC13-HN(CzHgj2

7.lOd

6.57

6.11

S.Y. Yao, G.A. Miana

and M. Shamma,

-

6.11

8.7 Hz for each of the compounds

Laboratories,

L. Khan and M. Shamma,

are as follows:

pakistanine 6.

PCSIR

H-3"$"

H-8

are 68.11,

are about and J5.6" z, g, and 4B.

H_2"6"

H-5'

-

shift

Proton

H-3

-

References

1.

in CDC~~

Aromatic

Kalashine

All values

(FT)

Methoxyl

N-2' N-6 C-l ----p_------_____

l-O-Methylpakistanine

at 200 MHZ

1980)

Isoquinoline

Alkaloids

Research

1972-1977,

Plenum

Press,