Synthesis of pyrrolidin-1-yl analogues of pyrimidine dideoxynucleosides

0040-4039/91 $3 00 + Pergamor. Press plc

Tetrahedron Letters. Vol32, No 31, pp 3863-3866.1991 Prmtcd in Great Britain

Synthesis of Pyrrolidin- l-y1 Analogues of Pyrimidine Dideoxynucleosides Michael R. Harnden and Richard L. Jarvest* SnuthKIine Beecham Pharmaceutxals, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey KT18 SXQ.

Abstrucct: The synthesis IS described of the fmt members of a new class of nucleoside analogues m winch the tetrahydrofuran ring is replaced by a pyrrohdine nng hnked to the base through an N-N bond the pyrrolidinyl analogues of 2’,3’-hdeoxycyttdme (lo), unclme (S), and thymldme (9) were prepared via construction of the base on a 1-aminopynohdme (15).

A number of molecular causative

targets have been identified

in vmo I,2 by inhibition

uracil) block HIV replication to their respective

triphosphate

Of these compounds

esters.

hydrolase)

catalysis

didcoxynucleoslde

and

2’,3’-unsaturated

guanme

alternative

isomers

Following

our interest

as having

79 are inactive. in antiviral

in an N-~~~0-15

dideoxynucleoside HO

against

of

these

acyclonucleosides bond,16

however,

a pyrrolidine

here

analogues

the first

is attached members

to the base by a

of a new

Y=CH2

8 Base

= uracil

9 Base

= thymine

2 x=0 3 x=s

7 X = CH2,

Y=O

10

Base

senes

(8 - IO).

Y=CH2 Y = CH2

5 X = 0, 6 X = S,

68 or

have a carbon atom at the l’-posmon

X-Y 4 X = CHZ,

having a

‘BCH l89’)7

HO

1 X=CH2

rings

5 (Base = adenine, ‘iso-

ring linked to the base via the heteroatom

HO

drawbacks,

of tetrahydrothiopherres

in which the side-chain

we report

or

activity although the

3 (Base = cytosine,

examples

to have a

by other 5-membered

tetrahydrofuran

and an oxathiolane HIV, whilst

All these compounds,

analogues containing

some

4 (Base = adenine) has weak anti-HIV

‘dioxolane-T),6

conversion

(phosphorylase

(‘carbovir’) has potent acuvity. 4 Most recently

activity

or N-N

to overcome

ring has been replaced

an isomeric

thymine, or

are perceived

bond to acidic or enzymic

In an attempt

compound

2 (Base = thymtne,

all been reported

heteroatom

toxicity.

reverse

(1, Base = hypoxanthine)

of this class of compounds

in which the terahydrofuran

A carbocyclic

of HIV, the

after mtracellular

2’,3’-dldeoxyinosine

lability of the glycosidic

in the 2’- or 3’-position have been described:

ddA’),5 a dioxolane have

clinical

analogues

have been described. corresponding

including

to inhibit the replication

so far is the virally encoded

of the reverse transcnptase

appears to hold the most clinical promise. 3 Members number of disadvantages,

exploited

1 (Base = adenine, cytosine, guanine, hypoxanthine,

The 2’,3’-dideoxynucleosides

transcnptase.

heteroatom

for strategies

agent of AIDS, and of these the most successfully

= cytosine

of

3864

HO

11 .. .

tBuMe”=)~

OR

OCH,Ph

RO 11 12

R=H R = tBuMe2Si

3 i

13

R=H

14

R = MeSO

3

iii

1 iv

tBuMe2SiO N-NHCONH2

1v

tBuMe2SiO N-NH2

Yl

Y/

RO

18 R = tBuMe2Si

17 R = tBuMe2Si 8R=H

9R=H

3

vii

X

I 0

xi

AcO

RO

20 R = AC xii 1 lOR=H

19

Reagents EtOH,

and conditions:

i. NWHF

v. Me$hNCO/CH2C12;

KOt-Bu/t-BuOH/A 1,2,4mazole/C5HgN

then tBuMe2SEl;

II. H2/l’d-C/EtOH;

vi. (MeO)2CHCH2COOMe/NaH/DMSO/A;

then HCl/MeOH/A; then NH$MeOH.

III. McS02CW33NKH2CL2; vii 80% AcOWA,

ix. @0)2CHCHMeCOOEt/KOr-Buh-BuOH/A; xii. NH$MeOH.

IV NH2NH2/H20/

vm. (Me0)2CHCH2COOMe/

x. Ac~O/CSH~N:

XI. ClC&Ol’OC12/

3865

The synthetic construction treatment

route adopted for the preparation

of the pyrimidine

ring on a protected

with sodium hydride followed

yield.

Catalytic

hydogenolysis

methanesulphonyl

afforded

overnight.

diol

nucleoside

analogues

chloride

but by changing

the base/solvent

13 in quantitative

yield.

Both 14 and 15 were obtained

Reachon

8 in 73% yield.18

The optimum

although

lsocyanate

react with the alternative Condensation

13 with

hydride

base for the heterocyclic

in ethanolic

in anhydrous

sodium ethoxide

m dimethylsulphoxide,

heatmg with methanolic

to the double bond.

uracil synthon, methyl propiolate,

in

the use of t-

The urea 16 did not

under any of these conditions.

of 16 with ethyl 3,3-diethoxy-2-methylpropionate

with 80% acetic acid afforded the thymine nucleoside

analogue

t-butoxide

However,

HCl gave 8 directly m 36% yield

was not

the uracil 17 was

ring closure appeared to be potassmm

elimination

hydrate

sold (45% yield).

of 17 with 80% acetic acid at 7oOC afforded the dideoxyuridine

this did not result in complete

butoxide followed by extended

of

as liquids and neither were

Reaction of 15 with ttlmethylsilyl

to sodium

by

to afford the silyl ether 12 in 81%

14 (92% yield) and this was treated with bydrazine

reaction of 16 with methyl 3,3dimethoxypropionate

obtained in 19% yield. Deprotection

relies on the

The &ol 1117 was monoprotected

followed by aqueous work-up afforded the urea 16 as a stable crystalline

Attempted

t-butanol,

the

15 in 71% yield.

stable to storage at room temperature dichloromethane

successful

by t-butykhmethylsilyl

chloride gave the brs-sulphonate

to afford the 1-arnmopyrrolidine

of the py-rrolidinyl

1-ammopyrrolidine.

afforded

analogue 9. 19 Attempted

18 which on deprotection

formation

of the 5-ethyluracil

derivative by a similar reaction was unsuccessful. To obtain the cytosine pyridme,

derivative,

the uracil 8 was protected

giving the acetate 19 m 72% yteld.

1,2,4-triazole methanolic

followed

Complete

pyrrolidine

nucleosides

assignment

20 in 51% yield.

phosphorodichlondate Deprotection

all showed a distinctive

ring as the hydroxymethyl

of the 6-H signal;

characteristic

10 prepared m this way are racemic; synthesis of enantiomers The anhvlral activity of these compounds Acknowledgements:

at 27OMHz.

We thank Mr. P.J. Brown

Irradiation

thus, although

of the

the pyrrolidme

at the pyrrolidinyl

of the natural nucleosldes,

will be reported in a subsequent

will be disclosed

The

on the same side of

group but the two S-H signals were not separated.

an nOe enhancement

is in the anti-6 conformation

and

of 20 with

pattern for the lH n.m.r. signals of the pyrrolidine

exist as a mixture of a and p forms due to inversion

presumably proportion

m

analogue 10 in 9 1% yield.20

4’-H signal at 1.5 ppm and the 2’-H signal at 3.0 ppm are due to the hydrogens

the pyrrolidine nucleosides

cytosine

with acetic anhydride

was made on the basis of COSY and nOe experiments

3.0 ppm signal of 10 produced significant

Treatment of 19 with 4-chlorophenyl

gave the protected

ammonia afforded the dideoxycytidme

The pyrrohdinyl moiety.

by ammonia

by reaction

nitrogen,

Compounds

a 8 -

publication.

elsewhere.

and Miss S.E. Stratford

for the COSY and nOe.

determinations. References 1. 2.

and Notes

Mitsuya, H. and Broder, S. Proc. Natl. Acad. Sci USA, 1986,83,1911. Chu, C.K,;

Schinazi,

R.F.; Arnold,

Biochem. Pharmacol., 1988,37,3543.

B.H.; Cannon,

D.L.; Doboszewsh,

B.; Bhadti,

V.B.;

Gu, Z.

3846

3.

Yarchoan,

R.; Mitsuya, H.; Thomas, R.V.; Pluda, J.M.; Hartman,

Allam, J.-P.; Johns, D.G.; Broder, S. Science, 1989,245, 4.

Vince, R.; Hua, M.; Brownell, Weislow,

S ; Lee, F.; Shannon,

J.; Daluge,

O.S.; Kiser, R.; Canonico,

W.M.; Lavelle,

P.G.; Schulz, R.H.; Narayanan,

R.H.; Boyd, M.R. Biochem. Biophys. Res. Commun., 1988,156, 5.

N.R.; Pemo, C.-F., Marczyk,

KS.;

412. O.C.; Qualls, J;

V.L.; Mayo, 3 G.; Shoemaker,

1046.

Huryn, D.M.; Sluboski, B.C.; Tam, S.Y.; Todaro, L.J.; Weigele, M. Tetrahedron Left., 1989,30,

6.

Norbeck, D.W.; Spanton, S.; Broder, S.; Mitsuya, H. Tetrahedron Len, 1989,30,

7.

(a) Belleau, B.; Dixit, D.; Nguyen-Ba,

8.

Jones, M.F.; Noble, S.A.; Robertson,

9.

Bamford, M.J.; Humber, D.C.; Storer, R. Tetrahedron Len., 1991,32,271.

6259.

6263.

N.; Kraus, J.L. Abstr. Papers, Vh Int. Conf. on AIDS, Montreal,

1989. (b) Eur. Pat. No. 337713A (to IAF Bmchem. Int. Inc.). CA.; Storer, R. Tetrahedron Lett., 1991,32,247.

10.

Hamden,

R.L.; Parkin, A.; Wyatt, P.G. Tetrahedron Lert., 29, 1988,701.

11.

Hamden,

M.R. and Jarvest, R.L. .I. Chem. Sot. Perkrn Trans. 1,1989,2207.

12.

Hamden,

M.R.; Wyatt, P.G.; Boyd, M.R.; Sutton, D. J. Med Chem., 1990,33,

13.

Harnden, M.R.; Jennings,

L.J.; Parkin, A. J. Chem. Sot. Perkin Trans 1, 1990,2175.

14.

Hart&n,

L.J.; McKie, C.M.D.; Parkm, A. Synthesis, 1990,893.

15.

Bailey, S.; Hamden,

16.

Harnden M.R. and Jarvest, R.L. Tetrahedron Lett., 1988,29,

17.

Rastetter W.H. and Phillion, D.P. J. Org. Chem, 1981,46,

18.

Analytical data for 8: m.p. 143-146OC; &nut (H20) 265

M.R.; Jennings,

1680, and 162Ocm-l;

187.

M.R.; Jarvest, R.L., Parkin, A.; Boyd, M.R.J. Med. Chem., 1991,34,

6H [(CD3)2SO]

t, J 5.1Hz, D20 exchangeable, (lH, s, D20 exchangeable,

5995.

3204. (E

9,070)nm;

1.53 (lH, m, 4-H),

7.4Hz, 3-H), 3.02 (lH, dd, J 6.7 8r 8.4Hz, 2-H),

57.

vmax (KBr) 3470, 3050, 1695,

1.87 (lH, m, 4-H),

2.33 (lH,

3.2-3.4 (5H, m, 2-H, 2x 5’-H and CH20),

septet, J 4.62 ( lH,

OH), 5.43 ( lH, d, J 8.OHz, 5-H), 7.61 (lH,d, J 8OHz., 6-H), and 11.27 3-H)

(Found: C, 51.09; H, 6.24; N, 19.61%.

CgHl3N303

requires

C,

51.18; H, 6.20; N, 19 89%). 19.

Analytical

data for 9: m.p. 125-127OC

1685cm-l;

6H [(CD3)2SO]

septet,J7.4Hz, 4.62 ( lH, exchangeable,

1.53 (lH, m, 4-H),

3’-H), 3.01 (lH, dd, J6.7 t, J 5.2Hz,

&rmx (H20)

D20

270 (E 9,38O)nm, vmax (KBr) 3470, 1700, and

1.72 (3H, s, CH3),

& 8.lHz, 2-H),

exchangeable,

1.87 (lH, m, 4-H).

2.32 (lH,

3.2-3.4 (5H, m, 2-H, 2 x 5’-H and CH20),

OH), 7.53 (lH,

3-H) (Found: C, 53.09; H, 6.69; N, 18.61%.

s, 6-H),

Cl0Hl5N303

and 11.25 (lH,

s,

D20

requires C, 53.32; H, 6.71;

N, 18.66%). 20.

Analytical

data for 10: m.p. 200-203oC;

1635, 1520, 1490, and 147Ocm-l;

hmax (H20) 272 (E 8,23O)nm, vmx (KBr) 3340, 3190, 1655,

6H [(CD3)2SO]

1.53 (lH, m, 4-H),

1.86 (lH, m, 4-H), 2.32 (lH,

septet, J 7.2Hz, 3’-H), 3.04 (lH, dd, J 6.9 & 8.OHz, 2’-H), 3.2-3.4 (5H, m, 2-H, 2 x 5’-H and CH20), 4.58 ( lH, t, J 5.2Hz, D20 exchangeable, D20 exchangeable, CgHl4N402

OH), 5.54 ( lH, d, J 7.4Hz, 5-H), 7.02, 7.07 (2H, 2x br s,

NH2), and 7.51 (lH, d, J 7.2Hz, 6-H)

requires C, 51.42; H, 6.71; N, 26.65%).

(Recetved in UK 16 April 1991)

(Found:

C, 51.48; H, 6.71; N, 26.76%.