- Email: [email protected]
The novel synthesis of a [6:5:6] linear isoguanosine type tricyclic nucleoside using carbonyl sulfide
Tetrahedron Letters Vol. 21, pp 1599 - 1602 @Pergamon Press Ltd. 1980. Prlnted m Great
Brltam
THE NOVEL SYNTHESIS OF A [6 5 61 LINEAR TRICYCLIC Fung-Lung
NUCLEOSIDE
Chung,
Robert
USING
ISOGUANOSINE
CARBONYL
A. Earl and Leroy
TYPE
SULFIDE B
Townsend*
Department of Medicinal Chemistry, College of Pharmacy, The University of Mlchlgan, Ann Arbor, Michigan, 48109 and Department of Medlclnal Chemistry and Department of Chemistry, The University of Utah, Salt Lake City, Utah, 84112
The novel one-step synthesis from an _o-aminonltrlle using
The significant in our laboratory,
antltumor
x,
of a fused pyrimidin-2-one-4-throne carbonyl sulfide is described.
observed 2y3 for certain
activity
derivative
tricyclic
nucleosides
prepared
4,5-diamino-8-(B-~-ribofuranosyl)pyrazolo[3',4'-5,4]pyrrolo[2,3-~]-
pyrimidme4
and 6-amino-4-methyl-8-(B-~ribofuranosyl)(4H,BH)pyrrolo[4,3,2-de]pyr~m~do[4,5-~]-
pyrldazlne'
prompted
have recently
us to continue
synthesized
[6 5 61 "lmear" we were unable
geometry
our research
efforts
a new class of trlcycllc with
to prepare,in
the rlbosyl
residing
(1) with _ fusion
ethyl
attempts
chloroformate,
of 1 with urea"
could be isolated.
followed
resulted
adenosine-lsoguanoslne
reactlon
or alkyl However,
5 directly
reaction
to convert
lmlno ether
group which
these attempts to be essentially
These
results
our earlier
amino group isoguanosine,
serves per
to deactivate
with
(5% yield based
resIstant
fIndIngs
group
se, has been accomplished'
imidazole-4-thiocarboxamide 6-thloxanthoszne
a cyano
from which group
located
dlethylcarbonate
more
derivatives attack
at the 5-positlon.
a
products
reactive
effectively
In a
were unproductive
by nucleophiles. a 4- and/or
The synthesis
6-
of
of 5-amino-l-(S-g-ribofuranosyl)-
in ethanollc
on the 2',3'-0-isopropylidene,
1599
Also,
no identifiable
that In this ring system,
by cyclization
approaches.
of 6-amlnotoyocamycln'
function
toward
However,
4,5-diamlno-9-(B-g-
of 1 into a more
should
We
has a
were unsuccessful.
to form the above
the cyano group was found confirmed
mixture
the 5-cyano
since
further
ammonia,
area.
ring.
the standard
by ring annulatlon6 with
the aglycon
analog
(2) using
by treatment
in a black
We then decided
form* such as an amidine ring-closing
to synthesize
In which
nucleoside
on the five membered
ribofuranosyl)pyrimldo[5,4-f]pyrrolo[2,3-d]pyrimldm-7-one Our inltlal
the trlcycllc
nucleosldes
moiety
this serles,the
m
sodium
ethoxlde
solution
5-ammo-4-cyanoimidazole
to give
1600
ribonucleoside) isoguanosine
The 6-thioxanthosxne was then methylated and treated with ammonia to afford
Attempts to use thx
procedure for the synthesis of 4-amino-V-(B-@lbofuranosyl)-
pyrimido[5,4-f]pyrrolo[2,3-6]pyrimidin-5-thlone-i-one from 6-aminothlosanglvamycin7 (2) only resulted In the isolation** of -1
/
R
-6
These unsuccessful attempts prompted us to subsequently initiate a novel approach for the synthesis of the desxred xoguanosxne nucleoslde analog 2
We now wash to report the successful
synthesis of 1 using a ring closure lnvolvlng an g-amlnonztrlle groupxng with the novel reagent carbonyl sulfide (1.5 ml) m
Treatment of 1 (500 mg, 1.63 mmoles) with a solution of carbonyl sulfide
methanollc-sodium hydroxide solution (300 mg, 7 5 mmoles in 18 ml of methanol) in
a sealed vessel at 180" for 7 hr furnlshed a yellow solid. The solld was dissolved -Lnwater and the pH of the solution adylustedto 5 by the slow addition of 2 N hydrochloric aced which resulted in the precxpltatlon of a solid (400 mg, 61% yield)
The elemental analysis of this solid
suggested an empirical formula corresponding to that of the trxyclic compound 2
Thxs product
1601
lacked
an absorption
band for a cyan0 group
uv spectrum
lndrcated
szgnlflcant
bathochromlc
_" end a h;ioH uv spectrum
that ring shift
closure
Although
we assumed
a posslblllty
that this product
that ring closure group)
which would
tanning
a seven-membered
ring.
However,
shown'2
to yield
sions
Methyl
dilute
ammonium
mg
Iodide
treatment provided
(10 mole
hydroxide
5-methylthlo
excess)
of 3 (300 mg) with ammonium
adenosine-isoguanoslne
(H-1') of 5 was observed
6 6.23
(compared
’
=
16,700)] 303
311
(E = 11,500),
was quite different
(c = 17,100),
Oxidatlve-hydrolysis vlded
287
a 56% yield
$H:""
which
of the knownI
In contrast
concentrated "linear"
ring closed
an -one derlvatlve
product
(6) - with
2.
an empirical
-8
UV)
for the dethiation
Therefore,
the nucleoside
product
of 2
i.e
at
a 64% yield
nucleoslde
chemical
at 6 2 18).
dethlatlon
was compared
Subsequent
and found to be
for the anomeric
the uv spectra $x1'
from the carbonyl
at
of -5
= 307
(F =
l2 analog -7 [Igx'
=
hF;;xll = 303 5 (E = 15,000)]. and 30% hydrogen
peroxide
pro-
4-amino-9-(B-g-ribofuranosyl)-
established
the "lmear"
of -3 using Raney
identical
in
as the desired
The signal
hydroxide
(4) which
conver-
at 130" for 14 hr
= 294 5 (E = 17,400),
nucleoside
con-
has been
to 6 5 10 for _7) and H-2' appeared
ammonzum
group
of the correspond-
establlshed
(DMSO-&)
303 (E = 18,500),
formula
;?, there was
(150 mg, 0.41 mmoles)
was observed
analog -7
-6 1s significantly
obtalned
of 2
to furnish
r~bofuranosyl)pyr~mido[5,4-f]pyrrolo[2,3-d]pyrlmidin-5-one12 (Pmr,
ring,
sulfide
of the adenoslne-guanosme
tricycllc
FInally,
carbonyl
to the pmr spectrum,
hEzoH
pyrim~do[5,4-f]pyrrolo[2,3-~]pyr~m~dm-5-7-d~one the orIgIna
In the
and the 4-amino
of the following
was subsequently
from the uv spectra
of 1. using
group
(1 5 ml of a 28% solution)
at 6 5 05 (compared
(E = L6,100),
nucleoside
type trlcycllc
of -1 with
singlet
hydroxide
the 5-cyano
to a solution
solution)
3-proton
(E = 13,900),
= 313
a
CH30H 1 (IMax of 292 nm for
to the pyrrole
trlcycllc
on the basis
The pmr spectrum
to 6 6 20 for 1)
(2) showed -
to a longer wavelength
a "triangular"
of the adenoslne-guanosine12
Proton
pH [4&X
was added
(71% yield)
analog 2
to the spectrum
yield
nucleoslde
2 (a sharp
material
the "linear"
the annulatlon
(15 ml of a 0.75%
derivative
nucleoside
similar
tricycllc
material7
is adjacent
had taken place between
than the 6-amino
a "linear"
group
the product
and the
than the 7-posltlon. was
(rather
since
this large shift
that the thione ring rather
occurred
to the starting
Furthermore,
is also indicative'l of the trlcyclic
had probably
in comparison
of 274 nm for -1)
the S-position
(region near 2200 cm-') III the lr spectrum
to the (8) _
different sulfide
nickel
nucleosfde However,
nature
of
has provided
4-ammo-9-(B-gthe spectral
data
from the data observedI ring closure
of -1 must
for
possess
1602
the structure 2 with the thione group located in the 5-positIon of the tricyclic ring rather than the isomerx structure with the throne group in the 7-posltlon We would like to propose that the mechanism of the ring-closing react-lonwith carbonyl sulfide is similar to that proposed13 for reactions of c-aminonitriles with carbon disulfide. The mechanism would involve
the initial formation of a monothlocarbamate salt, cycllzation to
a m-thlazlne derivative through nucleophxllc attack on the cyan0 group selectively, by sulfur ion, followed by a ring-openmg and a ring-reclosure sequence. This one-step synthesis of a fused pyrimldln-one-thione derivative should be of considerable utility and we are currently conducting experiments deslgned to test the general&y of this Interesting reaction
Acknowledgements. This lnvestlgation was supported by DR&D Research Contract NIH NCl-CM77142 from DCT, NCI, NIH, PHS REFERENCES 1.
Carbonyl sulfide was purchased from Matheson.
2.
Unpubhshed testing data from the Drug Research and Development Branch of the Division of Cancer Treatment, NCI, NIH
3.
L. W Roti Roti, J 40 (1978).
4.
R. L. Tolman and L. B
5.
K. H. Schram and L. B. Townsend, Tetrahedron Lett., 4757 (1971)
6.
E. C. Taylor and A. McKllIop, "The Chemistry of Cyclic Enaminonltriles and g-Aminonitriles," Interscience Publisher, New York, New York (1970)
7
K. H
a
F C. Schaefer m "The Chemistry of the Cyan0 Group," ed , 2 Publishers, 1970, Chapter 6.
9
A. Yamazaki, I. Kumashlro, T. Takenishi and M
L. Rot1 RotI, and L. B. Townsend, Proc. Amer
Schram and L. B
Assoc. Cancer Res., l9,
Townsend, Tetrahedron Lett., 4815 (1968).
Townsend, J. Chem
Sot., Perkin I, 1253 (1975). Rappoport, Interscience
Ikehara, Chem. Pharm. Bull., 16, 2172 (1968).
10. A possible mechanism for the conversion of the thiocarboxsmide group of 1 into a cyan0 group is as follows
r
E
R- -NH 2
->
11
A. G. Beaman, J. Am
12.
F. L. Chung, K. H Schram, R P publication in J. Med. Chem.
13.
E. C. Taylor, A. McKillop, and R
---+
R-CN
Chem. Sot., 76, 5633 (1954). Panzica, R
N
A
Earl, and L
B. Townsend, submltted for
Warrener, Tetrahedron, 2,
891 (1967)
14. Acceptable elemental analyses (C, H, N) have been obtained for all new compounds (Received m USA 10 December 1979)
Brltam
THE NOVEL SYNTHESIS OF A [6 5 61 LINEAR TRICYCLIC Fung-Lung
NUCLEOSIDE
Chung,
Robert
USING
ISOGUANOSINE
CARBONYL
A. Earl and Leroy
TYPE
SULFIDE B
Townsend*
Department of Medicinal Chemistry, College of Pharmacy, The University of Mlchlgan, Ann Arbor, Michigan, 48109 and Department of Medlclnal Chemistry and Department of Chemistry, The University of Utah, Salt Lake City, Utah, 84112
The novel one-step synthesis from an _o-aminonltrlle using
The significant in our laboratory,
antltumor
x,
of a fused pyrimidin-2-one-4-throne carbonyl sulfide is described.
observed 2y3 for certain
activity
derivative
tricyclic
nucleosides
prepared
4,5-diamino-8-(B-~-ribofuranosyl)pyrazolo[3',4'-5,4]pyrrolo[2,3-~]-
pyrimidme4
and 6-amino-4-methyl-8-(B-~ribofuranosyl)(4H,BH)pyrrolo[4,3,2-de]pyr~m~do[4,5-~]-
pyrldazlne'
prompted
have recently
us to continue
synthesized
[6 5 61 "lmear" we were unable
geometry
our research
efforts
a new class of trlcycllc with
to prepare,in
the rlbosyl
residing
(1) with _ fusion
ethyl
attempts
chloroformate,
of 1 with urea"
could be isolated.
followed
resulted
adenosine-lsoguanoslne
reactlon
or alkyl However,
5 directly
reaction
to convert
lmlno ether
group which
these attempts to be essentially
These
results
our earlier
amino group isoguanosine,
serves per
to deactivate
with
(5% yield based
resIstant
fIndIngs
group
se, has been accomplished'
imidazole-4-thiocarboxamide 6-thloxanthoszne
a cyano
from which group
located
dlethylcarbonate
more
derivatives attack
at the 5-positlon.
a
products
reactive
effectively
In a
were unproductive
by nucleophiles. a 4- and/or
The synthesis
6-
of
of 5-amino-l-(S-g-ribofuranosyl)-
in ethanollc
on the 2',3'-0-isopropylidene,
1599
Also,
no identifiable
that In this ring system,
by cyclization
approaches.
of 6-amlnotoyocamycln'
function
toward
However,
4,5-diamlno-9-(B-g-
of 1 into a more
should
We
has a
were unsuccessful.
to form the above
the cyano group was found confirmed
mixture
the 5-cyano
since
further
ammonia,
area.
ring.
the standard
by ring annulatlon6 with
the aglycon
analog
(2) using
by treatment
in a black
We then decided
form* such as an amidine ring-closing
to synthesize
In which
nucleoside
on the five membered
ribofuranosyl)pyrimldo[5,4-f]pyrrolo[2,3-d]pyrimldm-7-one Our inltlal
the trlcycllc
nucleosldes
moiety
this serles,the
m
sodium
ethoxlde
solution
5-ammo-4-cyanoimidazole
to give
1600
ribonucleoside) isoguanosine
The 6-thioxanthosxne was then methylated and treated with ammonia to afford
Attempts to use thx
procedure for the synthesis of 4-amino-V-(B-@lbofuranosyl)-
pyrimido[5,4-f]pyrrolo[2,3-6]pyrimidin-5-thlone-i-one from 6-aminothlosanglvamycin7 (2) only resulted In the isolation** of -1
/
R
-6
These unsuccessful attempts prompted us to subsequently initiate a novel approach for the synthesis of the desxred xoguanosxne nucleoslde analog 2
We now wash to report the successful
synthesis of 1 using a ring closure lnvolvlng an g-amlnonztrlle groupxng with the novel reagent carbonyl sulfide (1.5 ml) m
Treatment of 1 (500 mg, 1.63 mmoles) with a solution of carbonyl sulfide
methanollc-sodium hydroxide solution (300 mg, 7 5 mmoles in 18 ml of methanol) in
a sealed vessel at 180" for 7 hr furnlshed a yellow solid. The solld was dissolved -Lnwater and the pH of the solution adylustedto 5 by the slow addition of 2 N hydrochloric aced which resulted in the precxpltatlon of a solid (400 mg, 61% yield)
The elemental analysis of this solid
suggested an empirical formula corresponding to that of the trxyclic compound 2
Thxs product
1601
lacked
an absorption
band for a cyan0 group
uv spectrum
lndrcated
szgnlflcant
bathochromlc
_" end a h;ioH uv spectrum
that ring shift
closure
Although
we assumed
a posslblllty
that this product
that ring closure group)
which would
tanning
a seven-membered
ring.
However,
shown'2
to yield
sions
Methyl
dilute
ammonium
mg
Iodide
treatment provided
(10 mole
hydroxide
5-methylthlo
excess)
of 3 (300 mg) with ammonium
adenosine-isoguanoslne
(H-1') of 5 was observed
6 6.23
(compared
’
=
16,700)] 303
311
(E = 11,500),
was quite different
(c = 17,100),
Oxidatlve-hydrolysis vlded
287
a 56% yield
$H:""
which
of the knownI
In contrast
concentrated "linear"
ring closed
an -one derlvatlve
product
(6) - with
2.
an empirical
-8
UV)
for the dethiation
Therefore,
the nucleoside
product
of 2
i.e
at
a 64% yield
nucleoslde
chemical
at 6 2 18).
dethlatlon
was compared
Subsequent
and found to be
for the anomeric
the uv spectra $x1'
from the carbonyl
at
of -5
= 307
(F =
l2 analog -7 [Igx'
=
hF;;xll = 303 5 (E = 15,000)]. and 30% hydrogen
peroxide
pro-
4-amino-9-(B-g-ribofuranosyl)-
established
the "lmear"
of -3 using Raney
identical
in
as the desired
The signal
hydroxide
(4) which
conver-
at 130" for 14 hr
= 294 5 (E = 17,400),
nucleoside
con-
has been
to 6 5 10 for _7) and H-2' appeared
ammonzum
group
of the correspond-
establlshed
(DMSO-&)
303 (E = 18,500),
formula
;?, there was
(150 mg, 0.41 mmoles)
was observed
analog -7
-6 1s significantly
obtalned
of 2
to furnish
r~bofuranosyl)pyr~mido[5,4-f]pyrrolo[2,3-d]pyrlmidin-5-one12 (Pmr,
ring,
sulfide
of the adenoslne-guanosme
tricycllc
FInally,
carbonyl
to the pmr spectrum,
hEzoH
pyrim~do[5,4-f]pyrrolo[2,3-~]pyr~m~dm-5-7-d~one the orIgIna
In the
and the 4-amino
of the following
was subsequently
from the uv spectra
of 1. using
group
(1 5 ml of a 28% solution)
at 6 5 05 (compared
(E = L6,100),
nucleoside
type trlcycllc
of -1 with
singlet
hydroxide
the 5-cyano
to a solution
solution)
3-proton
(E = 13,900),
= 313
a
CH30H 1 (IMax of 292 nm for
to the pyrrole
trlcycllc
on the basis
The pmr spectrum
to 6 6 20 for 1)
(2) showed -
to a longer wavelength
a "triangular"
of the adenoslne-guanosine12
Proton
pH [4&X
was added
(71% yield)
analog 2
to the spectrum
yield
nucleoslde
2 (a sharp
material
the "linear"
the annulatlon
(15 ml of a 0.75%
derivative
nucleoside
similar
tricycllc
material7
is adjacent
had taken place between
than the 6-amino
a "linear"
group
the product
and the
than the 7-posltlon. was
(rather
since
this large shift
that the thione ring rather
occurred
to the starting
Furthermore,
is also indicative'l of the trlcyclic
had probably
in comparison
of 274 nm for -1)
the S-position
(region near 2200 cm-') III the lr spectrum
to the (8) _
different sulfide
nickel
nucleosfde However,
nature
of
has provided
4-ammo-9-(B-gthe spectral
data
from the data observedI ring closure
of -1 must
for
possess
1602
the structure 2 with the thione group located in the 5-positIon of the tricyclic ring rather than the isomerx structure with the throne group in the 7-posltlon We would like to propose that the mechanism of the ring-closing react-lonwith carbonyl sulfide is similar to that proposed13 for reactions of c-aminonitriles with carbon disulfide. The mechanism would involve
the initial formation of a monothlocarbamate salt, cycllzation to
a m-thlazlne derivative through nucleophxllc attack on the cyan0 group selectively, by sulfur ion, followed by a ring-openmg and a ring-reclosure sequence. This one-step synthesis of a fused pyrimldln-one-thione derivative should be of considerable utility and we are currently conducting experiments deslgned to test the general&y of this Interesting reaction
Acknowledgements. This lnvestlgation was supported by DR&D Research Contract NIH NCl-CM77142 from DCT, NCI, NIH, PHS REFERENCES 1.
Carbonyl sulfide was purchased from Matheson.
2.
Unpubhshed testing data from the Drug Research and Development Branch of the Division of Cancer Treatment, NCI, NIH
3.
L. W Roti Roti, J 40 (1978).
4.
R. L. Tolman and L. B
5.
K. H. Schram and L. B. Townsend, Tetrahedron Lett., 4757 (1971)
6.
E. C. Taylor and A. McKllIop, "The Chemistry of Cyclic Enaminonltriles and g-Aminonitriles," Interscience Publisher, New York, New York (1970)
7
K. H
a
F C. Schaefer m "The Chemistry of the Cyan0 Group," ed , 2 Publishers, 1970, Chapter 6.
9
A. Yamazaki, I. Kumashlro, T. Takenishi and M
L. Rot1 RotI, and L. B. Townsend, Proc. Amer
Schram and L. B
Assoc. Cancer Res., l9,
Townsend, Tetrahedron Lett., 4815 (1968).
Townsend, J. Chem
Sot., Perkin I, 1253 (1975). Rappoport, Interscience
Ikehara, Chem. Pharm. Bull., 16, 2172 (1968).
10. A possible mechanism for the conversion of the thiocarboxsmide group of 1 into a cyan0 group is as follows
r
E
R- -NH 2
->
11
A. G. Beaman, J. Am
12.
F. L. Chung, K. H Schram, R P publication in J. Med. Chem.
13.
E. C. Taylor, A. McKillop, and R
---+
R-CN
Chem. Sot., 76, 5633 (1954). Panzica, R
N
A
Earl, and L
B. Townsend, submltted for
Warrener, Tetrahedron, 2,
891 (1967)
14. Acceptable elemental analyses (C, H, N) have been obtained for all new compounds (Received m USA 10 December 1979)