Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This invention relates to 3'-deoxyribonucleosides and
derivatives thereof. More particularly, it relates to a process
for the conversion of ribonucleosi~es to 3'-deoxyribonucleosides
and their protected derivatives.
One example of a known 3'-deoxyribonucleoside which has
known and proven utility is the pharmaceutical compound
cordycepin which is 3'-deoxyadenosine of formula:
~L
~o~,/ ~I
~1 0~1
However, known synthetic methods for producing such compounds
containing the 3'-deoxyribose ring are complicated, involving a
substantial number of chemical synthetic steps required to be
conducted sequentially.
The chemical conversion of ribonucleosides to
3'-deoxynucleosides has not been easy to accomplish. Procedures
usually involve halogenation of the carbohydrate ring followed
by replacement of halogen with hydrogen. Alternatively, the
desulfurization of thioanhydronucleosides leads to
deoxynucleosides. 3'-deoxynucleosides such as cordycepin are of
considerable interest for their biological activity, but there
is a need for a general procedure for the conversion of
ribonucleosides into protected 3'-deoxynucleosides, both for
preparation of cordycepin and known compounds and for
preparation of novel compounds for investigation.
According to the present invention~ there is provided a
process for preparing a 3'-deoxynucleoside, which comprises:
reacting a 2',5'-diprotected ribonucleoside having a
3'-hydroxyl group with a thiocarbonyl compound so as to replace
the hydrogen atom of the 3'-hydroxyl with a substituted
thiocarbonyl group;
removing the substituted thiocarbonyl group from the
3'-position of the 2',5'-diprotected,
3'-(substituted-thiocarbonyl) ribonucleoside so prepared by
chemical reduction, to form therefrom a 2',5'-diprotected,
3'-deoxyribonucleoside;
and optionally deprotecting one or both of the 2' and
5'-positions.
2',5'-Diprotected ribonucleosides and their processes
of preparation are known. They are described, for example, in
"Tetrahedron Letters" 4775-4778 (1981), and in "Canadian Journal
of Chemistry" 60, 1106-1113 (1982~, both articles by G.H.
Hakimelahi, Z.A. Proba and K.K. Ogilvie. By means of such
processes, one may obtain compounds of general formula
~0~
( I )
~ o.5i 1
in which B represents a purine or pyrimidine group, e.g. uracil
or adenine, R represents a traditional nucleoside blocking group
such as dimethoxytrityl, and Sil represents a silyl or loweralkyl-
-- 3
sllyl group such as t.butyldimethylsilyl. In the present
invention, such products are reacted and reduced at their
3'-position, to proauce 3'-deoxynucleoside derivatives, which
may then be deprotected.
A suitable reagent to react at the 3'-hydroxyl is
phenyl chlorothionocarbonate, which reacts readily with the
2',5'-protected derivatives of formula I, thus:
Ro~ ~o~c.c~
~o ~.S;) ~ o o,s;l
When the base B is N-protected, however, the yield of clesired
product is low~ The resultant product II may then be reduced,
to replacQ the oxy-thiocarbonyl group with hydrogen, thus
producing a 3'-deoxynucleotide. Suitable reducing agents are
tri(n-butyl)tin monohydride in 2,2'-azobis
(2-methylpropionitrile), thus:
k~ (n l3~)3 S~, ~ > ~>~
~O-C-O ~,Sil (~
The silyl protecting group at position 2' is compound III can be
removed by known methods, e.g. reaction with tetrabutylammonium
fluoride (T~AF~. When B représents an N-protec~ed base group,
j - 4 -
e.g. N-benzoyl protected purines and pyrimidines, the
N-protecting groups are substantially unaffected by TBAF.
An alternative reagent to phenyl chlorothionocarbonate
is (thiocarbonyl) diimidazole. This reacts with compounds of
formula I as follows:
Ro o ~ o c~ ~
M - C~
Uo O,S;l 1~ . C - O O,S;~
(1 ~ s
where IM represents imidazole. Compound IV can be reduced
similarly to compound II, e.g. with (n-Bu)3SnH and 2,2'-azobis
(2-methylpropionitrile) to give a compound of formula III
above. This reaction proceeds well with both N-protected and
N-unprotected nucleosides, although in the case of N-benzoyl-
adenosine and N-benzoylguanosine derivatives, the reaction is
relatively slow.
The end products, of formula V:
R~< \,~1 (V )
o~
can be used directly in nucleotide synthesis. They can be
69
completely deprotected by standard procedures, to give 3'-
deoxynucleosides, such as cordycepin, of pharmacological
interest.
The invention is further described in the following
specific examples:
Example l:
1 m.mole of a protected nucleoside of formula I above,
in which R represented dimethoxytrityl DMT and B represented
uracil, was dissolved in 20ml acetonitrile and 6m.mole
4 (dimethylamino)pyridine, and 5m.mole phenyl
chlorothionocarbonate added. After stirring at room temperature
for six hours the solution was diluted with 40ml ethyl acetate.
The organic layer was washed three times with water, dried over
magnesium sulphate, and evaporated to leave the crude product.
The product was purified by silica gel chromatography. Similar
procedures were adopted and pursued with other starting
materials of formula I, but in which B represented adenine,
N-benzoyladenine, N-benzoylcytosine and N-benzoylguanine.
Results are shown in table I below.
Example 2:
1.1 m.mole of protected nucleoside was dissolved in
lOml dimethyl formamide (DMF) and 3 m.mole (thiocarbonyl)
~iimidazole was added. After stirring at room temperature for
times ranging from 1-85 hours, depending on the starting
material the solution was diluted with lOOml ethyl acetate and
50ml water. The organic layer was separated and was shecl with
water (3 x 50 ml), ~ried over MgSO4 and evaporated at reduced
pressure, the residue was purified by silica gel chromatography.
Reactions were generally over in 4 h except when the
starting material was N-ben~oyladenosine and N-benzoylguanine
derivatives ~hich required 85 h and 70 h respeccively. During
this long reaction period, isomerization of the silyl groups
occurred and mixtures of the 2'- and 3'-derivatives were
obtained. These mixtures were only resolved after reduction and
desilylation~ at which point they were readily separated.
The various starting materials, products, and the
results obtalned, according to Examples 1 and 2 are given in the
following Table 1. The compounds so obtained correspond to
general formuLa IV given above.
TABL~ I
Expt.No. Com~ound of Compound OL Reaction Yielcl Melting
formula II formula IV Time (~)Point
PrepareclPrepared (h) (C)
B R B R
1 Uracil DMT 6 6076-78
2 Uracil D~lT 4 5096-78
3 Adenine DMT 6 60 80-83
4 Adenine DMT 4 56 103-105
. . _
N-benzoyl DMT 85 4051-60
adenine
6 N-benzoyl DMT 4 5288-91
cYtosine
.. , . . . _ _ _ . ...
7 N-benzoyl MMT 70 50 42-49
quanine
. .
DMT represents ~imethoxytrityl, ~T represents monomethoxytrityl.
In each compound the silyl group Si is t-butyldimethylsilyl. In
Experiments 5 and 7 mixtures of 2'- and 3'- isomers were
obtained.
~e~
Compounds prepared according to the previous examples
and listed in Table I were reduced, and the 3'-deoxyderivatives
isolated.
In each case, a mixture of 6 m.mole of the compound, lg
of 2,2'-azobis ~2-methylpropionitrile) and 27 m.mole
(n-Bu)3SnH were heated at reflux in toluene for 3-4 hours.
Solvents were removed and products isolated by silica yel
chromatography. In some cases, the product so obtained, of
general formula III was subsequently de-silylated with
tetrabutylammonium fluoride (TBAF) to obtain product of formula
V. The results are given in Table II below.
TABLE II
Expt.No. Compound of Compound of Reaction Yield Melting
formula III formula V Time (~) Point
PreparedPrepared (hours) 1C)
B R B R
.
8 Uracil DMT 3 55 78-80
9 Uracil DMT 1 95 100-102
. . . _
10 Adenine DMT 4 42 69-72
.
11 Adenine DMT 1 93 123-126
12 N-benzoyl ~iT 4 35 35-45
adenine
13 N-benzoyl MMT 1 50111-112
adenine
. . _ _ . _
14 N benzoyl DMT 4 40 96-98
_ cytosine
N-benzoyl DMT 1 90119-122
cYtosine
-
16 N-benzoyl MMT 4 4135-42
a~uanine
17 N-benzoyl MMT 1 40140-141
auanine
In experiments 12 and 16, mixtures of 2'- and 3'- isomers were
obtained. The isomers were readily separable by TLC after
desilylation.
_ g
