Synthesis of a fluoro seco phenanthroindolizidine analogue

Journal of Fluorine Chemistry, 44 (1989) 15 5 - 159

155

Received:October 18,1988:accepted:February 26,1989

PRELIMINARY

Synthesis

NOTE

of a Fluoro

b.R. VENKATACHALAM,

Seco Phenanthroindolizidine

L.P.

BADHEKA

and N.B.

Analogue

MULCHANDANI

Bio-Organic Division Bhabha Atomic Research Centre Bombay-400 085 (India)

SUMMARY

Synthesis zidine(VIIIrhas

of a fluorine-substituted been

and homoveratric report

been

as building

bio-active

utiliiing

p-fluorobenzyldehyde

blocks.

This

of such a fluoro

is

analogue

alkaloids

constitute

of biologically

secondary

metabolites.

shown

to possess

active

antileukemic

antifungal

activities. hispidine

[31,

related

The

(X1

the

first

which

is

a

molecule.

Phenanthroindolizidine

bacterial,

and

acid

of the preparation

potentially

group

accomplished

seco phenanthroindoli-

antifeedant

have

These

[l], antiasthmatic

seco bases

171 have

an interesting

[21 , anti

[4] and antiamoebic

such as septicine isolated

also been

(IX)

from

[51

[61

natural

sources. Introduction substance

often

0022-I139/89/$3.50

of enhances

fluorine

in

its activity

a

biologically

or alters

the

active biological

0 Elsevier Sequoia/Printedin The Netherlands

156

profile

in the resultant

carried

out

synthesis

the

to the parent

gave

(II!

yields.

the

system.

UV

two

methoxyls

acid

(III)

the

spectrum

mass

of

was for

two methoxyls

the

immediatly

corresponding

good yields. peak

presence the

The mass at m/z

371.

of

chromophore. aliphatic

in

diazomethane

of

L-prolinol

group The protons

while

the

function.

in

protons

phosphorus (VI)

the of an

the

(7H,m)

which

was

(VII) in molecular

(VII) indicated

pyrrolidine

(V),

tribromide

the base

the UV spectrum

the

while

the stilbene

1 H NMR of this base of

The mass

In the'H NMR of

(VII) revealed of

furnish

The presence

to give

The IR spectrum

The

ion peak

de'rivative

bromo

of

protons.

ester

(6H,s) and aromatic (V) with

stilbene

the presence

gave

288.

group

at m/z 316

of an

its IR spectrum.

a

yield.

ion peak

at m/z

of

cyclised

satisfactory

to

The molecular

of

seco

of a carboxyl

aluminumhydride

spectrum

of the hydroxyl

stilbene

presence

with

(III)

the presence

The bromination

condensed

acid

(IV) in quantitative

located

we

homoveratric

(I) and

(III) confirmed

yields.

from

be further

for all the aromatic

lithium

(V) was

confirmed

observed.

yielded

ion

indicated

(IV) with

of

could

the presence

with

this,

derivative.

the molecular

(V) in moderate

signals were

(IV) showed

spectrum

alcohol

ester

of

containing

the presence

of

esterified

methyl

of

alcohol

which

indicated

and accounted

spectrum

Reduction

showed

spectrum

was

corresponding

IR

fluorine

the fluorostilbene

1H NMR spectrum

The

In view

of p-fluorobenzaldehyde

Its IP. spectrum

while

a

phenanthroindolizidine

Condensation acid

of

alkaloid

phenanthroindolizidine

[81.

derivativa

the

suggested showed ring

the as

157

F CHO I ,COOH

(ii) (i)

CH2

0

I COOR 0 C%O l&R -3

H3CO

=H

OCti3

OCH3

IJr,R=CH3

a

CH2 R’ H3CO

H3CO OCH3 Y,R’=OH

bCH3 xu

91 ,A’= Br.

OCH3

Reagents: (I) AcZO/EtgN;(II) CH2NZ; (Iii)LIA1H4;(Iv) PBr3; (v) L-Prolinol;

(VI)CH3S02C1: (vii)NeH. scheme

158

multiplets

in

methoxyls

and

basic

character

test

[91.

methane

seven of

product, layer

(VIII) at m/z

resembled exhibited

protons

were

the

sodium

hydride

from

that of hispidine the signals

(i'H,m) as expected Attempts

for methoxyls

cyclise

photolysis

and oxidative

oxyfluoride

and thallium

the corresponding

fluoro

with

derivative From

spectrum

Diels

the

was crude

of hydroxyl

by

of this seco

-Alder

a

base

cleavage

group

spectrum

in

of

(VIII)

of

NMR spectrum

(VIII)

of

(6H,s) and aromatic

(VIII) protons

(VIII)?

(VIII) by the known

coupling

Dragendorff

at m/z 353 and

The'H

for the structure to

mesyl

The UV

(Xl.

The

(VIII) was isolated

ion peak

its IR spectrum.

observed.

[lo].

The mass

The absence

two

for

(VII) was mesylated

seco derivative

the parent

signals

also

and the resultant

chromatography.

moiety.

The

by a positive

(M-69) due to the retro

the indolizidine evident

.

aminoalcohol

using

showed 284

region

(VII) was confirmed

cyclised

preparative

was

aromatic

sulphonylchloride

reaction

peak

up-field

The foregoing

immediately

base

the

using

trifluoroacetate

methods

reagents [ll]

phenanthroindolizidine

vanadium

like

failed

viz.,

to

yield

derivative.

la b

Gellert,E. and Rudzats,R., J.Med.Chem. 1 (19641, 361. Rao,K.V., Wilson,R.A. and Cummings,B., J.Pharm.Sci.a (1971),1725.

2

Gore,K.V., Rao,A.K. (igao), 144.

3

Ferenczy,L., Zsolt,J., Acta. Microbial. Acad.

4

Verma,G.S., Chadha,M.S.,

3c The presence was confirmed

19F NMR.

Ind.J.Med.Res.71

Haznagy,A., Toth,L. and Szendrei,K., Sci. Hung. 12 (1965/66), 337.

Ramakrishnan,V., Entmol. Exp. Appl.

of a fluorine by

and Guruswamy,M.N.,

40

Mulchandani,N.B. (1986). 99.

atom in all the synthetic

and

derivatives

159

5

Bhutani,K.K., 532.

6

Russel,J.H.,

7

Venkatachalam,S.R. (1982). 287.

8

Filler,R. and Kobayashi,Y. Fluorine Chemistry' Kodansha Amsterdam (1982).

9

Harborne,

J.B.,

and Hall,

London

Sharma,G.L.

Naturwiss.N and

and Ali, M., Planta

(1963),

(1987),

443.

Mulchandani,N.B.,

Naturwiss.

in 'Bio-Medicinal Tokyo and Elsevier

in 'Phytochemical

Med.

Methods'

69

Aspects of Biomedical,

p-188

Chapman

(1973).

10

Russe1,J.H.

and Hunzike,H.,

Tetrahedron

Lett.

(1969),

4035.

11

and Herbert, R-B., Jackson,F.B., Moody,C.J. and Cragg,J.E. Nicolson,I.T., J.Chem. Sot. Perkin Trans. 1 (19821, 2477.