Tetrahedron Letters No.35, PP. 3095-3102, 1965. Pergaaon Prern Ltd. Printed in Great Britain.

A NEW CATALYST FOR TRE SYNTHESIS OF NUCLEOSIDES

(ORGANOPROSPHORUS coMpoum3, PART vI)

Takeshl Hashizume and Hajlme Iwamura

Department of Agricultural Chemistry,

Kyoto University, Kyoto, Japan

(Received 3 July 1965)

We wish to report that bls-(p-nftrophenyl) hydrogen

Phosphate and the methyl derivative act as effective catalysts

for the fusion method developed recently for the synthesis of (l-5)

purine nucleosldes. The method has involved heating fully O-

acetylated D-pentoses and hexoses with various purlnes in the (1) (2.3)

presence of catalysts like -toluenesulfonic acid, zinc chloride, 8) (5) (6)

concentrated sulfuric acid, sulfamic acid, and chloroacetic acid.

Recently, we Investigated the fusion of penta-o-acetyl-

B-D-glucopyranose(1) and two purlnes(I1 anTV;II) employing

bls-(p-nltrophenyl)hydrogen phosphate(VII1) and the related

compounds as catalysts.

Bis-(p-nitrophenyl) hydrogen phosphate was used after drying for thirty minutes at 100° under a pressure 1 mm. Hg.

3096 No.35

II. R: H

IV R. 2',3*,4' 6'-tktra-o- . . 9

scetyl-B-D-g$uco-

~yranosyl residue

VI. R: P-D-glucopyranosyl

residue

III. R:

V. R:

VII. R:

When theophylline(I1) was fused with

H

2',3',4',6'-tetra-o-

acetyl-+D-gluco-

pyranosyl residue

B-D-glucopyranosyl

residue

I In the presence of

VIII at 140e-1600 for one hour, N7-(2',3',4',6'-tetra-o-acetyl-

B-D-glucopyxanosyl)theophylline(IV) was obtained in 47$ yield.

m.p. 1459-1460.

H. Calcd, for C21H26011N4: C, 49.41; H, 5.13; N, 10.97.

Found: C, 49.38; H, 5.16; N, 10.95.

Removal of ,;he acetyl groups from IV In methanollc ammonia

afforded N7 -(!3-D-glucopyranosyl) theophylline(V1) in 75% yield.

Recrystallkation from aqueous methanol gave colorless needles.

m.p. 2660-2680.

m. Calcd. for C18H1807N4: C, 45.61: H, 5.30; N, 16.37

Found: C, 45.58: H, 5.29: N, 16.23

A>;. 275 ~P.(E 8800),[~1;~ -3.56O(c, 1.49, water).

( ,Reported: m.p. 267-2690,

[alA9

(8)272D!9)[a)D -2.33°(water)!9)

+39.09°(c,0.92,water)!10~)

No.33 3097

no formation of the glyconide link at pomition 7 of fi*oph~llin*

maa mprtd by the ultraviolet absorption 8pCCtrC of thC CCqCd

VI, N7-methyltheophylllne (caffeine, ASH 5 9 max .

A;zx5

273 w.1, “d&

methyltheophylline (lsocaffeine, 239 and 267 w. 1.

The anomerlc configuration was assigned as S- from the coupling

constant for the C I, proton of glucose ( FIG. I., Jl, 2,=8.7-8.8 3

c.p.s.)!12*13*he lnf rared spectra of the compound VI and N7-(a-

D-glucopyranosyl)theophylline synthesized according to the Fischer (9)

-Helferich procedure were su (147

erlmposable. Further, the optical

rotatory dispersion curve was negative plain as shown In FIC.11.

Similarly, the fusion of II with I employing bls-(p-nitro-

phenyl) methylphosphate Instead of VIII afforded IV in 31%

yield, whereas the desired product(W) eosld set be obtained *es

trls-(p-nitrophenyl) phosphate was used and unreacted theophylline

was recovered almost quantitatively.

For the comparison of the catalytic effects of these organo-

phosphorus compounds with that of previously known catalysts, p- (15,16,17)

toluenesulfonic acid and ethyl polyphosphate were used In similar

manner described above. Hut the yield of IV were 20% employing

p-toluenesulfonic acid and 31% when ethyl polyphosphate was used. (3)

Moreover, earlier paper reported a few percent yield in the

synthesis of IV using zinc chloride. Thus,it is apparent that

the catalytic effect of his-(p-nitrophenyl) hydrogen phosphate

is superior than known catalysts for fusion procedure. Considerab

activity of bis-(p-nitrophenyl) methylphosphate may be explained

by the demethylation durlng.the fusion.

le

3098 No.35

I

Eo x

0

-I

-6

,::,.I;:

w

160 400 460 600 680 606 6" 700

Optical rotatory dispersion curve

of VI.

No.35

In addition, the fusion of N1 -acetyl hypoxanthine* and

in the presence of VIII at 150 0-1600 for thirty minutes gave

N9-(2',3*,4(,6'-tetra-0-acetyl-B-D-glucopyranosyl)hypoxanthine

(V) in 13% yield after recrystallization from ethyl acetate.

m.p. 27@-277O.

&. Calcd. for C19H22010N4: C, 48.93: H, 4.75: N, 12.01.

Found: C, 48.92; H, 4.85: N, 12.01.

~~:~:EtoH2~~8~~.(13.300), [&9 -26.4O(c, 0.73, chloroform).

(Reported: m.p. 265-267.5O, [cz1z8 -19.2O(c, 3.06, chloroform).

Removal of the acetyl groups from V in methanolic ammonia gave

N9-(g-D-glucopyranosyl) hypoxanthine(VI1) in 78% yield.

m.p. 272°-2730(from 50% aqueous ethanol).

u. Calcd. for Cl1 14 6 4. 2 H 0 N H 0: C, 41.77; H, 5.10; N, 17.72.

Found: C, 41.70; H, 5.15; N, 17.64.

&$.248.5 mp.(E 12,600). ~:;:~~-~~~248.5 mu.( E 12,100),

h0'05N-NaoH253.5 mp.( tl3,700): (a." max. -38.4O(c, 2.11, N-NaOH).

The allocation of Cl, of glucose.te r>sition 0 of

hypoxanthine was based on the ultraviolet spectra of the compound

obtained, authentic N 9-(VII):*N7-(b-D-glucopyranosyl) hypoxanthine

(,0.05N-HC1254 m,, max.

0.05N-NaOH263 mp )*,,N9_ (19)

'*'max. . 3 , and N7-methyl-

hypoxanthine. The assignment of the P-COnfi@ratiOn at Cl, Of

This derivative was prepared in refluxing hypoxanthine with acetic anhydride and N,N-dimethylformamide. m.p.238*-2400. The position of the acetyl group linked was inferred from the infrared spectra. ** K+,ndly given to us by Mr. H. Yamazaki who prepared both N9-,and N -(B-D-glucopyranosyl) hypoxanthine by Davoll-Lowy method.

No.35

FIC.III. N.m.r.spectrum of VII measured in D20.

2

0

-2

-4

- -6 L X

0 -2

-10

-I2

-14

-IO

-10

-20

360 4qo 450 Mx, sao 6qo 650 700

w

FIG.IV. Optical rotatory dispersion

curve of VII.

the compound was based on the coupling constant, J1, 2, of the (20) ’

proton at C1, and the equation of Karplus. (FIC.III., J1, 2,s ,

8.7-8.8 c.P.s.). Moreover, upon admixture with an authentic

specimen, the compound showed no depression of melting point.

Further, the optical rotatory dispersion curve is shown In FIG.IV.

The o.r.d. curves were measured on a JASCO automatic recording

spectropolarimeter end the n.m.r. spectra were recorded on a

Varian A-60 spectrometer.

Work with other bases and sugars in this fusion procedure

using VIII Is In progress and an improved synthesis of nebularine,

a nucleoside antibiotics, will be reported independently.

We are grateful to Dr. T. Mitsui for performing the microanalyses

and Dr. T. Okuda for measuring the o.r.d. curves.

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