Egenine: a possible intermediate in phthalideisoquinoline biogenesis

ECENINE:

A POSSIBLE Belkfs

INTEBXDIATF Tekrnt

GGrler.1

Department

of

Chemistry,

unfverafty

(+)-Egenine

frolated

from

(Fumerfrce~e).

l%e of

the

phthal

.re

known.

sented 1 fne

nes

poser

the ed

an

-ver

analyzed,

were

L.

the

carrfed

it by

loss

followa

of that

blne

that

unknown vcd

ln

w.s the

the

found

the

phthal

(2)

as

the

trftfum

tion, and

a11

its

Itned

exact

are

past

be

of

whfch

Involved

fact

isolation

had yfelded

fn this

that

the

only

very carried

the man-

ber-

berbfncs

fnter-

f8 under-

large

number in

and classlc~l

Tbfs

on the of

final

a berblne

the

classfcal

1on 2.

revealed

are

tvo

aromatfc

6 6.36

the

and

lrowcfc HZ. of

ly

fn

vith

ethanol

barfc.

to 1.6

been

6.78.

one-proton

of

at

reaponsfble

H-l

for at

doublet to

near

at

6 2.56. 6 6.00,

l

6 6.58 6 3.93

by comparison

at

at

adjacent doublet with

6 5.&i

of Jo

7.9

can

read{-

with

the

phthalfdefaoqufnolfn~~.3 doublet

In

around

lingleta

as

two additional

centered

egenfne

features

singlet

appearing

and

protons

of

amorphous

rummrrized

substftuentr

proton,

be amsigned

alka-

repeated

mg of

structural

N-methyl

A one-proton

other

Kiitahya.

rubjected

Obvlour

pattern

NMR spectra

Sfmav,

provfde

has

an

of

extracted

MHz FT tiWB rpectrum

exprerr

parts

C2DH,906N.

(2,.

The 200

lerfal

(Fumarfaceae)

The crude,

was to

deuterfochloroform

doublet

T%fs

fractfon

near were

two methylenedfoxy

phth-

tranaforma-

out

room

(+)-egenfne

transitory

amounts.

rtudiem

of

hemface-

of

Lofael.

collected

chromatography

fnvoll

g).

lofdal Only

was observed.

serler

muat be quite

fn small

fne

into

and struc-

convenfon

and powdered

vafllantff

temperature.

stepa

of

(+)-cgenfne

source.

home light

III the

at

of

alkaloid

tnvolved

The dried

labels

berblne

isolation

the

a phthalfdelsoqufnolfne

Anatoll*,

In the

the

fnto

(650

l

indication

type.

h’ha t rema ined

l

may throw

Fumarfa

for

no

sequence.

natural

l

western

in ouch

of

phthalfdefsoqufnolfne from

productr

center

l

ffrrt

When the

precursors

sequence of

of

of

step

label-

below.

label

the

Isolated

compound

to w-

fdefsoqulnol

indicated

Clearly,

must

by the

llkalofd

fed

the

fntegrtty.5

converslon

produced

that

In nature

llfdeiaoqufnolfne. medtates

doubly

~a*

radioactive

berbiner

the

In one

precursor

in the

elucidation

t81

repre-

Lofsel.

with

intermediates

(5).

a tetra-

(+)-bfcucul-

the

C-IL lsymntric

the

mafntafns

biogenetic

We now dercrlbe

phthalidefsoqufnolf-

(2)

“a,

fwedfate

vafllantff

(1,.

tural

classi-

B as

problem.

phth~lidetaoqufnolfncr ner

the

ring

(Papaveracere).

and

(-)-a-narcotfne

It

of

the

posses8

experiments.

llfted

mfnor

of

(-)-scoulerfne

were

l

than

alkaloid

interemtfng

sanfferum

curtafn

the

hemfacetal

In Fumarfa

25 naturally

by the

key --in vfvo berbfne

found

More

They all

The bfogenesfs

l#

(+)-bfcucullfne

phthalfdefsoqufnolfne

phthalldelsoqufnolfncs.

and an intact

typically 394 (1).

been

any

phthalldelsoqufnolfnes

rkeleton

has

fro-

llblofds.

type

first

the

one

occurrtng cal

in U.S.A. 20 Septembu 1982)

represent

quinolfne

cyclic

16802

.mong

tnes

*

University,

subgroups

fdeiroqufnol

important

mO6t

Shwmaa

State

Pennsylvania

may act

alkaloid

and Mwrfce

The Pennaylvanfa

source

(+)-Egenfne

lccomprnyfng

the

I

(4)

a natural

Gd~ler,~

Park,

(Rtctiued Abstract:

IN PHTHALIDEISCQUINOLINE BIOGENESIS

AlImust

repre-

578

B. GbtLER

et 01.

3

:Sr NMII

Me0

T

O

H

-

\

Ms

/

Me

9

1

h67s

6.36~

=I

““B NM0

H

l-4

-

\

/

s

1

lent

the

H-9

..me

11ner,

by

proton

which

in

could

be assigned

rhovn

in cxpresaion ‘Ihe electron

nine there (H the

doea 1s

not l

the

usually

Flnblly,

5.60.’

with

analogy

to

rhift

of

between

one-proton

6 5.h8

doublet

a hcmiacetal 6

as

impact

m/r

molecular 351

peak

la)+.

The bane

peak m/r

familiar

bentylic

cleavage

chemical lold

ton.

of

ege-

Instead,

of

phthalide-

rhowed

peak8

the

molecular

veight,

for

the

mass

mass using

an m/r

to a molecular

spectral

spectrum laobutane.

370

weight

colnporition

The scheme from

important

ionlratton

fng

reprereottng 190 results

Other

wa# obtained

rpectrum

rmaa rpectrum

Inca.

are

m/r

168.

To lrcertain

and

at 55.68

linkage

froqulnol 188 and

5.

show .

anull

chemical

known phthalideiroquino-

falls .

the

peak, of

369

of

l

the

l lka-

Thin correrpondcalculated

C20H,90bN.

below findinga.

lurmurlzer

aOme of

the

&nine:

Egenine

m’z

The any

IR spectrum

carbonyl Jt

290

of

egentne

is

two

the

ring

since

such

Js

rortng

absence

1 show the

It

tion

Jt

maxims

C-l,

such

+99”

thJt

it

(c

the of the

too

low

or

in

methylene

redal

in

ether

a

(1). egenine

borohydride

VJS

in

provided

(YS,

9ucceJsion

of

qulnoline sion

an Redal

mJy

Jnd fill

relJys

I” --

the

or

for

viva

= sodium

hy grJnt

the

This

CA-11050

in

-Jnd

sig-

in

1.

type in

(-)-cJpnoi-

(!).

lumn

of

stlica

form

JJ

cl”Jnt*

ethJ-

2.

dibJ1

3.

bined

in

supported

VJJ

KJtionsl

the

Cancer

Of HeJlth.

23-26

IdcnticJl

on Merck with

H (for

nol-Jrmnonium

tions

using

of in

(+)-

bJnd, the

JJ”W

l nvi-

290

“Ill (log

J berbine

upon hydride;

Merck

FrJcfrJc-

prepJrJtive

TLC

glJJs

plJtes

benzene-chloroform-

The purified

egenine by

TLC in

Jy.tc”l.

Jddttton dibJ1

to

further

(+)-Egcninc

phthJlidetJoto

w.J

of

com-

v/v).

(L0:30:15:10).

Rf 0.5L.

with

were

Combined

G JnJlytiCJl

system

of

chloroform-methJ-

(98:2:0.5

Gel

co-

eluted

J column

collected.

solvent

the

on using

J

chloro-

J”V,““tJ

chloroform

subjected

SilicJ

using

Fracrlons

hydroxide

were

on

i,KreJJfng

in

TLC)

3 mL were

the

then

chloroform.

refrJctionJted

(+)-•genine Jnd

and

mesh)

basic.

crude.

fractionated

(TO-230

gel

Jnd Gel

The

VJJ

5% methJnol

SilicJ

str”c-

PurificJtion:

Jnd

of

bis(2-methoxyethoxy)Jluminum

research

Institutes

frJCtiOn

ttons

possible

vhich

then

very

encountered

(5).

from

NJtiOnJl

sodium

gJp in

5 would

ExpertmentJl

methJno1

yet

ChJrJcterirJtion

is

to close

clJsslcJ1

(-)-corledine

Jcetone-mcthJnol

It

process

Other

Acknowledgment:

poJJes-

(-)-bicu-

when

N?4R. CD)

llmi-

in

of

involved

its

(+)-egentne

(-)-Jdlumine

Jnd

JlksloidJl

hands,

our

only

J JignificJnt

biogenesis.

v)

Isolation

(1).

LsolJtlon (4)

of

reduction

IR.

with

JtJgeJ

which.

we hJve

Jre

Institute.

supply

our

in

toluene.

proof

dine

of

of (1)

phthJlidetJoqufnolines pl~nr

one

oxidation

of

borohydride

obtJined

or

In

N-methylated

USDHHS.

cJrbony1

In

then

Enrymic

the

JIJO

C-l.

ChromJtogrJphtcJlly

UV,

(-)-bicuculllnediol

ege-

or

to

FlnJl

ethanol

J diol

spectrJl1y

egentne

IJctone

provided

JnJlOgJ.

oxidized

Is

(5)

LOiJel.

.t

(1)

or

chloride.

(+)-egenine

VJillJntii

litersture

reduction

sodium

2 is

and

r-1JCtone

suspected

chtrJlity

(+)-bicuculline

produce

to

C-13,

co-occurJ

exhi-

CHC13)

the

and

nifiCJntly

(l,,

VJS

the

temperJt”re

culltnediol

The

of

either

nol,

(5)

in

relJted

C-8

(+)-bicuculltne

Since

hemfJcetJlr.7

of

“sing

of

S

the

JlkJlold Jt

S confipurJ-

0.11, it

188

dr

generate

phthJltde-

the

351

ml2

JIJO

nm mir3

prerent.

phthalidetsoqutnolines

Jmount

ture

(c

extdnt

corresponding

Jion,

320

c1esstcJl

HeOH).

reduction

clJssicJl

Jnd

rorJtion.’

+2lL”

is

bearIt

(+)-bicuculltne

possesses

partial

however. ted

Jll

0.12,

A report

296

encompass Js

te-

phthJlideisoquinolirrs

specific

I AJi’

show

[>I;

that

with

berbines

J conj”gJted

near

which

shov

of

conjugation

known

B positive

nine

of type

extensive

is

not

subsrituents.

clJsJicJ1

tsoquinolines

hit

or

methylenedioxy

confirmed

does

579

intermediate

190

I‘V spectrum,

chJrJcteriJtic

CrJhydrobenzylisoqutnolines ing

l

l-l/?.

The

nm.

Ii20

14R

Jbsorption.

J nuxtmum

-

(4)

a possible

(5).

E L.11. of

A Max HeOH 212, 3.75,

3.71).

hydroxide

base:

= diisobutylalumlnum

no

233

sh.

chJnge

v mJx hydride.

CHCl

3