- Email: [email protected]
A general, stereocontrolled entry to pyrimidine homo-C -nucleosides
Tetrahedron Letters lo. 38, Pp 3669 - 3672. @Per&am@ Press Ltd. 1979. Printed in Great Britain.
A GENERAL,
STEREOCONTROLLED
T. Sato, Department
Summary: ribose
of Chemistry,
A simple
synthesis
and B-position
homo -C-nucleosides,
displayed
TO PYRIMIDINE
K. Marunouchi,
Chikusa,
analogues
appendages
3 in which the ribofuranosyl
moiety
synthesis
that starts
lactone
III4 possessing
a rigid C-b-glycoside
and spa-hybridized
the
with the readily
us to prepare
carbon
here the first
of the
stereocontrolled
accessible
chiral
structure.
H N
H o
0 0 w HO
OOH HO-LO
0
Y N/Y
HO-b-O
HO
group between
I and II2 prompted
We present
unit.
bicyclic
Japan
is outlined.
by the homonucleotides
homo-C-nucleosides
Nagoya 464,
with a methylene
heteroc yclic nuclei 8~) linked via a methylene of pyrimidine
HOMO-C-NUCLEOSIDESl
and R. Noyori*
Nagoya University,
of nucleoside
of pyrimidine
The unique activities
ENTRY
OH II
AH I The lactone
III was treated with 0.2 M methanolic CH30Na at 9 “C for 45 min to give the 5 The hydroxyl group was protected by treating with trityl chloride in pyridine methyl ester IV. 5.8 which was then reduced with LiA1H4 (1.0 mol, THF, -20 “C, 1 h) to produce leading to V, the primary original formation. pyridine,
alcohol
@ configuration The alcohol 0 “C,
crown-6/CH3CN, containing to afford
VI (83% yield based on III).’ at the anomeric
C-l
VI was converted
KOH (120 “C,
15 h) (59% yield).
position
VII (1.3
were
throughout
SO
mild that the
the trans-
equiv p-CH3C6H4S02C1/
VIII (3 equiv KCN and 9.1 equiv dicyclohexano-18Hydrolysis
20 h) and the resulting
IX (74% yield). 8 Sequential
conditions
was retained
to the tosylate
15 h) and then to the cyanide 82 “C,
The reaction
treatment
3669
of VIII was conducted
carboxylic
in ethylene
acid was methylated
of the methyl
ester
glycol
by diazomethane
IX in THF with lithium
di-
3670
lo.
isopropylamide
(2 equiv,
the formylated
derivative
-78 “C,
as a lithium
iodide
(5 equiv) to give the (E)-enol -
reflux
in 1 M ethanolic
@ stereochemistry
C 2H50Na,
at the C-l’
methyls
30 min) and then methyl salt,
which was subjected
ether X.
(5 equiv,
uracil
is indicated
0 ‘C,
to methylation
When a 1:7 mixture
the 5-substituted
position
formate
38
4 h) led to
with methyl
of X and urea was heated at
XI was produced
by the NMR spectra.
in 35% yield.’
The
The isopropylidene
show two ‘H signals 10 range. The corresponding
ppm),
again consistent
removed
by exposure
at d 1.30 and 1.50, and A.d value, 0.20 ppm, is clearly in the @ 13 C NMR signals (CDC13) occur at 6 25.79 and 27.58 (As 1.79 3b,5 with the j3 structure. Finally, the protective groups of XI were
to 10% HCl in CH30H
(5 -(g-D -ribofuranosyl)methyluracil) In a like manner, X with thiourea
yield) was deprotected pseudouridine
homopseudouridine
(XII). l1
elaboration
in refluxing
at 20 “C for 40 min to provide
of a 2-thiouracil
ethanolic
by the standard
C2H50Na procedure
ring was effected
for 12 h.
(10% HCl/CH30H)
(5 -(g- D-ribofuranosyl)methyl-2-thiouracil)
facilely
Compound
to afford
(XIV). l2
by treatment
XIII thus obtained
of
(68%
homo-2-thio-
Condensation
of X with
COOCH3 TrO
0 NH3
k4+
III
IV,
R = H
X
VI, X=OH VII, X = 0S02C6H4CH3-E
V, R = C(C6H5)3
VIII, X = CN IX, X = COOCH3
Rb XI, R-R XII,
6R = C(CH3)2;
R = R’ = H
R’ = Tr
XIII, XIV,
Rt)
6R
R-R
= c!(cH~)~;
R=R’=H
R’ = Tr
XV, XVI,
R-R
= C(CH3)2;
R’ = Tr
R = R’ = H (HCl salt)
so.
38
3671
guanidine
(1 M C2H50Na/C2H50H,
HCl-CH30H
formed
78 “C!, 19 h), giving XV,
homopseudoisocytidine
followed
by treatment
with 10%
(5-@-D-ribofuranosyl)methylisocytosine)
(XVI) as
HCl salt. l3 Since a variety cyclocoupling principle
reaction
provides
containing
of bicyclic
Acknowledgment: Foundation
of polybromo
a general
branched
14 of type III are available using the [ 3 + 41 reductive 15 ketones and furans as the key step, this method in
la&ones
procedure
for the synthesis
and the Ministry
of Education,
supported
by grants from the Kurata Science
Japanese
Government
REFERENCES
hedron 2. A.
Synthesis.
Lett.,
Czech.
3. (a) W. J. Gensler,
R. Ito,
5. H. Ohrui, Byram,
No. 311709).
AND NOTES
Part VI: T. Sato,
Chem.
S. Chan,
III, J. Org.
4. (a) R. Noyori, Sato,
VII.
(Grant-in-Aid,
M. Watanabe,
and R. Noyori,
Tetra-
in press.
Holy’, Collect.
Secrist
homo-(=-nucleosides
sugar moieties.
This work was partially
1. C-Nucleoside
of pyrimidine
E,
G. H. Jones,
J. Am.
6. T. J. Cousineau
Sot.,
J. Am.
J. Am.
and R. Noyori,
J. G. Moffatt,
Chem.
81 (1970). Chem.
Sot.,
436 (1975);
9J,
(b) J. A
2925 (1978).
and Y. Hayakawa,
Y. Hayakawa,
a,
and D. B. Ball,
Chem.,
T. Sato,
Commun.,
E,
Chem.
Sot.,
Tetrahedron
Lett.,
M. L. Maddox,
2561 (1978);
loo,
(b) T.
1829 (1978).
A. T.
Christensen,
and S. K.
4602 (1975).
and J. A. Secrist
III, J. Carbohydr.,
Nucleosides,
Nucleotides,
3_, 185
(1976). 7. IR (CHC13) 3560 cm-l 1.95
(m,
4.2,
10.5
H2,),
4.60
(dd, J_= 3.5,
(m,
lO.OHz,
1732 cm-l
(C=O).
CH2CH2COOCH3), H5,a),
H5,),
6.3 Hz, H3,),
(m,
Ann.
“C!.
CH2-uracil),
(m,
H2,),
Tr).
N.Y.
Sci.,
(m,
H5 ,), 3.62
H1,),
4.42
d 1.33
and 1.54 (s,
E,
(dd, J=
(dd, J= 5.2,
6.2 Hz,
isopropylidene
5=4.1,
3.17
0CH3),
6.3Hz,
(dd, J = 5.0,
3.93(m,
H4,),
H3,),
7.3O(m,
6.2Hz, CH3),
CH3),
2.66 H2,),
(m,
4.12 Tr).
CH2-uracil),
4.62(dd,J_=3.5,
264 nm (E 6850).
177 (1975).
CH30B). (m,
3.68(s,
isopropylidene
4.44(dd,
CH3),
3.32
Tr).
H5b),
UVh max (CH30H)
Acad.
(m,
4.59(dd,J_=3.5,
6 1.30 and 1.50 (s, Hl,andH4,),
4.12
isopropylidene
10.5 Hz, H5,a),
J = 7.2 Hz, CI12CCOCH3),
lO.OHz,
[(Y] 2oD -8.2”(~0.14, 3.43
7.36
2.52 (t-like,
and 1.53 (s,
(dd, 2=4.8,
’ H NMR (CDCl,)
6.2Hz,
4.13(m, (m,
3.17
H4, and CH20H),
3.30(dd,J_=4.1,
7.30
Imbach,
11. Mp 184-186
OH),
6.2 Hz, H3,),
H1,), 4.36(dd,g=5.0, 1 9. Foam. H NMR.(CDC13)
10. J.-L.
(br, (m,
(m,
3.26(m,
’ H NMR (CDC13) 6 1.33
2.24
Hz, H5,b ), 3.83
8. IR(CHC13) 1.99
(OH).
CI-12CH20H),
’ H NMR (dimethyl
H1, and H4,),
3.74
(m,
sulfoxide-c&)
H2, and H3,),
6 2.36 3.1-4.9
MO. 38
3672
(br,
OH), 7.27
30.06
(m,
H6),
(CH2-uracil),
139.14,
151.23,
10.69
62.00
and 11.00
(br,
(C5 ,), 71.11,
74.33,
UV Xmax (CH30H)
164.60.
7080), Xmax (1 N NaOH) 285 nm ( E 7100). 1 H NMR (dimethyl sulfoxide-d+) d 2.41 (m, 12. and H4,),
3.76
(m,
13C NMR (dimethyl 80.14,
83.96
216 nm, 261,
Hz, and H3,),
4.03
sulfoxide-d+)
6 30.12
( br,
81.10,
84.09
OH), 7.31
(m,
139.08,
290 (sh),
Xmax (1N HCl) 216 nm, was so hygroscopic
277,
12.17
61.65
that optical
127.79,
H5,),
3.61
and 12.36
(m,
(br,
(C5 ,), 70.86,
174.42.
290 (sh),
6
X max (1 N HCl) 266 nm ( E
H6),
161.45,
of ribose),
3.42 (m,
(CH2-2-tbiouracil),
114.49,
sulfoxide-d+)
(Cl,-C4,
CH2-2-thiouracil),
of ribose),
This compound
13C NMR (dimethyl
265 nm (E 7130).
(Cl, -C4,
277,
288.
NH).
Hl,
NH).
74.15,
UV Amax (CH30H)
x max (1N NaOHI 222 nm,
extinction
(E value)
could not be
obtained. 13. Mp 185-188
[cu] 201) -49” (20.37,
“C.
CH2-isocytosine), (br,
3.44 (m,
OH), 7.59
isocytosine), 152.28,
(C,,),
(br,
71.00,
3.64
T. Sato, Ann.
in Japan
N.Y.
(m,
‘H NMR (dimethyl
Hl, and H4,),
74.23,
80.07,
84.39
and R. Noyori,
Acad.
Sci.,
15 June 1979)
m,
225 (1977);
~~~
6 2.47 (m, 3.8-5.0
6 29.85
(CH2-
113.82,
138.05,
(1N HCl) 223 nm
281 (9100).
Tetrahedron Act.
Hz, and H3,),
of ribose),
263 (7830),
A max (1N NaOH) 232 nm ( E 11300),
sulfoxide-d+)
sulfoxide-s)
(Cl,-C4,
224 nm ( E 11500),
M. Watanabe,
3.80 (m,
13C NMR (dimethyl
NH).
UV Xmax (CH30H)
264 (9420),
14. For example, 15. R. Noyori,
H6), 8.49
61.79
160.27.
(E 12300),
(Reoeived
(s,
H5,),
cH30H).
Chem.
Lett., Res.,
4403 (197 8). 12,
61 (1979).
A GENERAL,
STEREOCONTROLLED
T. Sato, Department
Summary: ribose
of Chemistry,
A simple
synthesis
and B-position
homo -C-nucleosides,
displayed
TO PYRIMIDINE
K. Marunouchi,
Chikusa,
analogues
appendages
3 in which the ribofuranosyl
moiety
synthesis
that starts
lactone
III4 possessing
a rigid C-b-glycoside
and spa-hybridized
the
with the readily
us to prepare
carbon
here the first
of the
stereocontrolled
accessible
chiral
structure.
H N
H o
0 0 w HO
OOH HO-LO
0
Y N/Y
HO-b-O
HO
group between
I and II2 prompted
We present
unit.
bicyclic
Japan
is outlined.
by the homonucleotides
homo-C-nucleosides
Nagoya 464,
with a methylene
heteroc yclic nuclei 8~) linked via a methylene of pyrimidine
HOMO-C-NUCLEOSIDESl
and R. Noyori*
Nagoya University,
of nucleoside
of pyrimidine
The unique activities
ENTRY
OH II
AH I The lactone
III was treated with 0.2 M methanolic CH30Na at 9 “C for 45 min to give the 5 The hydroxyl group was protected by treating with trityl chloride in pyridine methyl ester IV. 5.8 which was then reduced with LiA1H4 (1.0 mol, THF, -20 “C, 1 h) to produce leading to V, the primary original formation. pyridine,
alcohol
@ configuration The alcohol 0 “C,
crown-6/CH3CN, containing to afford
VI (83% yield based on III).’ at the anomeric
C-l
VI was converted
KOH (120 “C,
15 h) (59% yield).
position
VII (1.3
were
throughout
SO
mild that the
the trans-
equiv p-CH3C6H4S02C1/
VIII (3 equiv KCN and 9.1 equiv dicyclohexano-18Hydrolysis
20 h) and the resulting
IX (74% yield). 8 Sequential
conditions
was retained
to the tosylate
15 h) and then to the cyanide 82 “C,
The reaction
treatment
3669
of VIII was conducted
carboxylic
in ethylene
acid was methylated
of the methyl
ester
glycol
by diazomethane
IX in THF with lithium
di-
3670
lo.
isopropylamide
(2 equiv,
the formylated
derivative
-78 “C,
as a lithium
iodide
(5 equiv) to give the (E)-enol -
reflux
in 1 M ethanolic
@ stereochemistry
C 2H50Na,
at the C-l’
methyls
30 min) and then methyl salt,
which was subjected
ether X.
(5 equiv,
uracil
is indicated
0 ‘C,
to methylation
When a 1:7 mixture
the 5-substituted
position
formate
38
4 h) led to
with methyl
of X and urea was heated at
XI was produced
by the NMR spectra.
in 35% yield.’
The
The isopropylidene
show two ‘H signals 10 range. The corresponding
ppm),
again consistent
removed
by exposure
at d 1.30 and 1.50, and A.d value, 0.20 ppm, is clearly in the @ 13 C NMR signals (CDC13) occur at 6 25.79 and 27.58 (As 1.79 3b,5 with the j3 structure. Finally, the protective groups of XI were
to 10% HCl in CH30H
(5 -(g-D -ribofuranosyl)methyluracil) In a like manner, X with thiourea
yield) was deprotected pseudouridine
homopseudouridine
(XII). l1
elaboration
in refluxing
at 20 “C for 40 min to provide
of a 2-thiouracil
ethanolic
by the standard
C2H50Na procedure
ring was effected
for 12 h.
(10% HCl/CH30H)
(5 -(g- D-ribofuranosyl)methyl-2-thiouracil)
facilely
Compound
to afford
(XIV). l2
by treatment
XIII thus obtained
of
(68%
homo-2-thio-
Condensation
of X with
COOCH3 TrO
0 NH3
k4+
III
IV,
R = H
X
VI, X=OH VII, X = 0S02C6H4CH3-E
V, R = C(C6H5)3
VIII, X = CN IX, X = COOCH3
Rb XI, R-R XII,
6R = C(CH3)2;
R = R’ = H
R’ = Tr
XIII, XIV,
Rt)
6R
R-R
= c!(cH~)~;
R=R’=H
R’ = Tr
XV, XVI,
R-R
= C(CH3)2;
R’ = Tr
R = R’ = H (HCl salt)
so.
38
3671
guanidine
(1 M C2H50Na/C2H50H,
HCl-CH30H
formed
78 “C!, 19 h), giving XV,
homopseudoisocytidine
followed
by treatment
with 10%
(5-@-D-ribofuranosyl)methylisocytosine)
(XVI) as
HCl salt. l3 Since a variety cyclocoupling principle
reaction
provides
containing
of bicyclic
Acknowledgment: Foundation
of polybromo
a general
branched
14 of type III are available using the [ 3 + 41 reductive 15 ketones and furans as the key step, this method in
la&ones
procedure
for the synthesis
and the Ministry
of Education,
supported
by grants from the Kurata Science
Japanese
Government
REFERENCES
hedron 2. A.
Synthesis.
Lett.,
Czech.
3. (a) W. J. Gensler,
R. Ito,
5. H. Ohrui, Byram,
No. 311709).
AND NOTES
Part VI: T. Sato,
Chem.
S. Chan,
III, J. Org.
4. (a) R. Noyori, Sato,
VII.
(Grant-in-Aid,
M. Watanabe,
and R. Noyori,
Tetra-
in press.
Holy’, Collect.
Secrist
homo-(=-nucleosides
sugar moieties.
This work was partially
1. C-Nucleoside
of pyrimidine
E,
G. H. Jones,
J. Am.
6. T. J. Cousineau
Sot.,
J. Am.
J. Am.
and R. Noyori,
J. G. Moffatt,
Chem.
81 (1970). Chem.
Sot.,
436 (1975);
9J,
(b) J. A
2925 (1978).
and Y. Hayakawa,
Y. Hayakawa,
a,
and D. B. Ball,
Chem.,
T. Sato,
Commun.,
E,
Chem.
Sot.,
Tetrahedron
Lett.,
M. L. Maddox,
2561 (1978);
loo,
(b) T.
1829 (1978).
A. T.
Christensen,
and S. K.
4602 (1975).
and J. A. Secrist
III, J. Carbohydr.,
Nucleosides,
Nucleotides,
3_, 185
(1976). 7. IR (CHC13) 3560 cm-l 1.95
(m,
4.2,
10.5
H2,),
4.60
(dd, J_= 3.5,
(m,
lO.OHz,
1732 cm-l
(C=O).
CH2CH2COOCH3), H5,a),
H5,),
6.3 Hz, H3,),
(m,
Ann.
“C!.
CH2-uracil),
(m,
H2,),
Tr).
N.Y.
Sci.,
(m,
H5 ,), 3.62
H1,),
4.42
d 1.33
and 1.54 (s,
E,
(dd, J=
(dd, J= 5.2,
6.2 Hz,
isopropylidene
5=4.1,
3.17
0CH3),
6.3Hz,
(dd, J = 5.0,
3.93(m,
H4,),
H3,),
7.3O(m,
6.2Hz, CH3),
CH3),
2.66 H2,),
(m,
4.12 Tr).
CH2-uracil),
4.62(dd,J_=3.5,
264 nm (E 6850).
177 (1975).
CH30B). (m,
3.68(s,
isopropylidene
4.44(dd,
CH3),
3.32
Tr).
H5b),
UVh max (CH30H)
Acad.
(m,
4.59(dd,J_=3.5,
6 1.30 and 1.50 (s, Hl,andH4,),
4.12
isopropylidene
10.5 Hz, H5,a),
J = 7.2 Hz, CI12CCOCH3),
lO.OHz,
[(Y] 2oD -8.2”(~0.14, 3.43
7.36
2.52 (t-like,
and 1.53 (s,
(dd, 2=4.8,
’ H NMR (CDCl,)
6.2Hz,
4.13(m, (m,
3.17
H4, and CH20H),
3.30(dd,J_=4.1,
7.30
Imbach,
11. Mp 184-186
OH),
6.2 Hz, H3,),
H1,), 4.36(dd,g=5.0, 1 9. Foam. H NMR.(CDC13)
10. J.-L.
(br, (m,
(m,
3.26(m,
’ H NMR (CDC13) 6 1.33
2.24
Hz, H5,b ), 3.83
8. IR(CHC13) 1.99
(OH).
CI-12CH20H),
’ H NMR (dimethyl
H1, and H4,),
3.74
(m,
sulfoxide-c&)
H2, and H3,),
6 2.36 3.1-4.9
MO. 38
3672
(br,
OH), 7.27
30.06
(m,
H6),
(CH2-uracil),
139.14,
151.23,
10.69
62.00
and 11.00
(br,
(C5 ,), 71.11,
74.33,
UV Xmax (CH30H)
164.60.
7080), Xmax (1 N NaOH) 285 nm ( E 7100). 1 H NMR (dimethyl sulfoxide-d+) d 2.41 (m, 12. and H4,),
3.76
(m,
13C NMR (dimethyl 80.14,
83.96
216 nm, 261,
Hz, and H3,),
4.03
sulfoxide-d+)
6 30.12
( br,
81.10,
84.09
OH), 7.31
(m,
139.08,
290 (sh),
Xmax (1N HCl) 216 nm, was so hygroscopic
277,
12.17
61.65
that optical
127.79,
H5,),
3.61
and 12.36
(m,
(br,
(C5 ,), 70.86,
174.42.
290 (sh),
6
X max (1 N HCl) 266 nm ( E
H6),
161.45,
of ribose),
3.42 (m,
(CH2-2-tbiouracil),
114.49,
sulfoxide-d+)
(Cl,-C4,
CH2-2-thiouracil),
of ribose),
This compound
13C NMR (dimethyl
265 nm (E 7130).
(Cl, -C4,
277,
288.
NH).
Hl,
NH).
74.15,
UV Amax (CH30H)
x max (1N NaOHI 222 nm,
extinction
(E value)
could not be
obtained. 13. Mp 185-188
[cu] 201) -49” (20.37,
“C.
CH2-isocytosine), (br,
3.44 (m,
OH), 7.59
isocytosine), 152.28,
(C,,),
(br,
71.00,
3.64
T. Sato, Ann.
in Japan
N.Y.
(m,
‘H NMR (dimethyl
Hl, and H4,),
74.23,
80.07,
84.39
and R. Noyori,
Acad.
Sci.,
15 June 1979)
m,
225 (1977);
~~~
6 2.47 (m, 3.8-5.0
6 29.85
(CH2-
113.82,
138.05,
(1N HCl) 223 nm
281 (9100).
Tetrahedron Act.
Hz, and H3,),
of ribose),
263 (7830),
A max (1N NaOH) 232 nm ( E 11300),
sulfoxide-d+)
sulfoxide-s)
(Cl,-C4,
224 nm ( E 11500),
M. Watanabe,
3.80 (m,
13C NMR (dimethyl
NH).
UV Xmax (CH30H)
264 (9420),
14. For example, 15. R. Noyori,
H6), 8.49
61.79
160.27.
(E 12300),
(Reoeived
(s,
H5,),
cH30H).
Chem.
Lett., Res.,
4403 (197 8). 12,
61 (1979).