A novel purine nucleoside synthesis: 9-β-D-arabinofuranosyl-adenine

Tetrahedron

L&tars

A NOVEL

lo.

PURINE

13,

pp

1188,

1185-

NUCLEOSIDE

SYNTHESIS R.

The

Salk

(Received

Instttute

111 U8A 10 Dsoember 1974;

communtcatton

syntheses

deals

of a wade range

antl-tumor

agents.

constderable

of the

uttllty.

for

received

cultures

modtftcatron

of preformed 6

nucleostdes

stmpltctty

dertvatlves. For

the syntheses

prepared

tn good

chosen m dry

DMF,

followed

whtch

solution,

maternal.

salts

Isolated

as

against

herpes

Thus compound

showed

proved

to be a rather

during

the tsolatton

the bromo-mercury

unstable

bromtde

Catalyttc

hydrogenatton

colorless

foam

38.95,

H,

m the

m 46%

UV

(H2C).

Amax

310

nrn (10.100).

281

(M-H20)

material

above

N,

stltca

column

and apparently accountmg

reactlon

lead

gel

IR7,,,

mamly product

ytelded

over

analysis

calculated

22.72,

S.

Found

C,

(KBr),

(16, 900)

3200

[u]“,:

gave

to 3450,

= -181°

39.05,

and 297 1635

nm

was

product gel

H,

4.68,

cm-l,

tn MeOH).

yreld. (IV)

Exclusion

of

product

followed

(V).

by tsolatton (VI)

as a

H20

22.46,

(pH 1) 240

The

(IV)

tn 30%

S-alkylated

MS,

of

decomposltton

yteld.

N,

was

freed

C10H13N504*1/2

(8, 600).

and 1580

(1% solutton

1185

for

a

solutton

Compound

extensive

10% Pd/C,

was

hydrtde

the drammo-pyrtmtdtnyl-thlonoxazolldlne

Elemental

(M-H2S).

nm.

Isolated

to the unwanted (IV)

stltca

and 327

the low

yteld.

10.40.

over

245

underwent

for

Thts

mtxture

Ln

by the

was

sodrum

bromtde

(II).

A)

or Its

whtch

and the condensatton

at 215.

vtruses

and Herbst’

reactton

chromatography

thereby

(PH 8 and 12) 245.5

and 265

methods,

in methanol

of the condensatton

over

4.58,

after

(I),

dertvattve

have

(ara -

etther

wtth arabmose

of mercurtc

The

(III).

may

adenme

(I) wtth

or

the syntheses

and vacmla

of Bromund

amount

method

for

synthestzed

of the thtonoxazoltdme

of an equivalent

UV absorption

procedure,

mercurtc

by chromatography

foam,

been

syntheses

of the procedure

and prectpttatton

a colorless

sunplex

has earlter

total

as antt-vtral

thts

route

9-(3-D-arabmofuranosyl

or by nucleoslde

Treatment

to contam

by extractton

Involved,

an efflclent

the arabtnofurano-thtonoxazolldlne

by the addttton

LS belteved

Interest

agent,

wtth 4-ammo-6-chloro-5-nltropyrtmtdme

tnorgantc

C,

(VIII),

25 Fkhruary1975)

to the stereospectflc

of posstble

It provtdes

&-A

by a modtftcatton

as the startmg

treated

was

of -ara-A

yield

5

publication

approach

of the operattons

antmals.

nucleostdes

Ilritain.

Studtes

in UK for

purme

In particular,

and m expertmental

Greet

92112

and novel

naturally occurrmg antt-vtral l-4 has shown stgnlftcant acttvtty

whtch

(VIII),

Btologtcal

Caltfornta

of the Important

cell

in

9-P-D-ARABINOFURANOSYL-ADENINE

a simple

of modtfled

In vtew

practtcal

wtth

Printed

Press.

Ranganathan

San Dtego, Thrs

Per-n

1975.

S, (15,

10. 07. 900)

and

m/e,

299

NMR

spectrum

(Mf). 1s

1186

III

No. 13

agreement

0.7,

with

alummum

In view

flcatlon. 85O,

When

(I).

228

(19.900)

and 297

Desulfurlzatlon 46%

acid Nickel

Raney needles

(pH 6.8)

259.5

and 1630 (0.25% (relative for

nm

cm -l,

following

(14, 900),

P]

the steps pounds,

(12, 800).

(M-H2S),

above,

yield

UV nm

paper

5b

by

m water).

but without

0. 05M

adenoslne

isolating

0.48,

has

or purifying

(I) could

t 13.4O 0. 52.

was

achieved

-ara-A

(pH 11. 5)

(0. 5%

either

m the presence by heatmg

(VIII)

(KBr),

(Sh. ),

900),

Rf (C)

(pH 2. 2) 257

was

nm

3475,

e-A9

obtained

3300,

3195

p]

‘:

t 9. 9O

Rf (D) 0.09,

buffer,

Rf

pH 6. 8, 3000

By essentially

com-

Into ara-adenosme -

(VIII)

of 39%.

modIfxatlons

by employmg

thlocyanlc

scope

of this

approach

efforts

are

currently

of the substltuents

acid for

adducts

of other

the synthesis

directed

towards

m the chloromtropyrlmtdme

this

It

sugars,

of other

should

promising

be possible

purme

nucleoslde

derivative to extend

and

the

analogs.

Our

goal.

Acknowledgements I wish E.

*

to thank

McLendon System

A.

950/O C2H50H

for

V

following

any of the intermediate

be converted

at

(14, 900),

showed

Rf (C) 0.80, borate

at

, MS, m/e

effxlently

R t 4.8.

heated

300

(23,

-1

[a] ‘:

Authentic

Rf(A)

nm

methanol

IR max

purl-

the thlonoxazolldme

cm

(VIII)

method X max

electrophoresls

condltlons

peak,

found

8-mercapto-ara- -

(12, 600),

1660

, or more

900),

chromatography

240

to -ara-A

(H20), (14,

5b, 8

from

Rf (B) 0.42,

By the latter

255-56O,

solution

identical

li

It was

at pH 6 was

and 305

m aqueous

of Ikahara

(0.25%

Paper

t

kB

peroxide

(VI)

to 3450,

0. 36, (VII)

hydrogen

the arabmofurano-thlonoxazolldlne

By suitable

167

259.5

(B) 0.98,

under

described

In an overall

3100

Rf(A)

(pH 11.6)

t lZ”

“::

In water).

-1.1,

Rf(C)

chromatographlc

of 47%

(23,400)

ammonia.

m. p.

yield

298

(KBr),

condltlons,

product

221

the procedure

In aqueous

to adenosme)

1. 5 hr

with

m 830/o yield,

solution

0.49,

be accompllshed

Into the known

(pH 2.2)

chromatography

by treatment

of hydrochloric 9o” with

Rf (B)

also

prior

(15, 950),

max 235

of 8-mercapto-ara-adenosme -

yield

as white

265

reduced

converted

In an overall

fRymix

(M-H20),

Paper

X

(Sh. ),

nm (17,700),

281

smoothly

needles

UV (H20).

(pH 6. 8) 220

m MeOH).

In about

could

(VI) without

of the crude

It was

2’ as white

Isolated

not observed,

solution

solution

of N

154O (foams),

m.p.

(IV)

(IV) to hydrolytic

It to the ammo-throne

an aqueous

3fl7 nm (22, 650),

Rf (A) 0.64,

of the mtro-throne

of the nltro-throne

to reduce

(VII),

chromatography”

amalgam.

m an atmosphere

adenoslne

reduction

of the mstablllty

to be of advantage

Mi

The

and Rf (D) 0.35.

employmg

Paper

the structure.

the NatIonal

able

techmcal

I-PrOH, 1N NH40Ac

NH40~, (7 3),

Institute

of Health

assistance ~~0

(7 1*2),

pH 7.5,

and Dr. System

System

D,

for L. B,

the award E.

Orgel

n-BuOH,

n-BuOH

of a grant for

helpful

5N AcOH

saturated

(CA

12960).

Mrs.

dlscusslons. (2 l),

with water.

System

C,

1187

No. 13

A

Hz0

/

Ro-Nickel

*

H20/NH40H OH

(nrr)

(Iart)

1188

No. 13

References

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Davis

M.

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Schabel.

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A commercial

sample

recrystallized

from

of ara-A methanol

purchased before

use.

from

Terra-Marme

Bloresearch

was