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Synthesis of 2′-methylated pyrimidine C -nucleosides
Tetrahedron Letters Vol. 21, pp 1971 - 1974 OPergamon Press Ltd. 1980. Printed in Great Britain
SYNTHESIS
OF ‘2‘-METHYLATED
T. Department
Summary:
The title C-nucleosides
manner through the polybromo
Introduction to retard
of methyl
the enzymatic X’-methylated
by lowering
the chemical
normal
ribofuranosyl
have been prepared
in a direct
cyclocoupling
group to the C-2’ thereby
nucleosides activity
and R. Noyori Chikusa,
ketonelfuran
or C-3’
>I<
Nagoya
position
increasing
and stereocontrolled
of certain
the biological to mimic
of the 2’-hydroxylfunction3 only limited
464, Japan
approach.
might be expected
However,
skeleton.
-C-NUCLEOSIDES1
Nagoya University,
destruction,
In addition,
PYRIMIDINE
Sato, H. Kobayashi,
of Chemistry,
0043-40~9/8O/C~C2-1971~~~.00/O
nucleosides
activities
2’-deoxy
is known 2 markedly.
nucleosides
either
or by changing conformation 294 are present
of for
number of reports
the synthesis
of such analogues mainly because of difficulty in preparation of branched-chain 5 Described herein is the first, general synthesis of 2’-methylated sugar moieties.
pyrimidine coupling
C_-nucleosides, reaction
which is based on the efficiency 6 of polybromo ketones and furans.
The oxabicyclic
ketone I was obtained in 86% yield by the reductive
a,(Y,a’,Ly ‘-tetrabromoacetone 14 h), followed
of the [ 3 + 41 reductive
by removal
and 3-methylfuran of bromine
using Zn/Ag couple7
cyclo-
cyclocoupling
(3:1:2 ratio,
of
THF,
atoms from the 13 + 41 adduct (Zn/Cu couple,
20 “C,
CH3OH
with NH Cl, 20 “C, 1 h). The unsaturated ketone I was then converted specifically i3 1 mol % of 0s04, to the acetonide II in 78% yield (1 s8 equiv of -N-methylmorpholine-N-oxide, saturated
(CH3)2CO-H20-~-C4H,0H;g substantiated numbering; Villiger
then acetone-anhyd
by occurrence indicated
oxidation
of the NMR signal for the C-3’
as H in formula
with CF3C03H,
presence
group was effected
70 “C, 1 h) to afford the synthesis
of various
V and urea (7 equiv, removal
V in 63% yield. pyrimidine
1 M C2H50Na
of the isopropylideneblocking
hydrogen (pseudouridine 10 In the subsequent Baeyer-
of the methyl
of III as the major regioisomer 13 II, III12/IV = 67 :33). Then introduction
to the carbonyl
was
11) as a singlet at d 4.15.
substituent at C-2’ gave a bias 11 (52% yield or 84% yield based on
toward the production consumed
The LYconfiguration
CUSO~-_~-TSOH).
of a one-carbon
unit to III at position
with t_butoxybis(dimethylamino)methane This compound -C-nucleosides. in C2H50H,
serves For
reflux,
as a versatile
example,
DMF,
intermediate
base-catalyzed
25 “C, 60 min,
for
reaction
3 h), giving VI l4 (32%), followed
group (10% HCl in CH30H, 1971
(excess,
LY
by
96%) gave
of
a 0
0
4
0
0
R
0
0
2% II
0
0
0
Q
R
R
0
x
CHNW$2
0
0
0
0
0
0
0
0
2-K rv
III
1
,“”
b’ I
0
R”0
0
0
VI,
RI-R’
= C(CH3)2;
A
R” = H
IX
VT1 t R’ = R” = H VIII,
RI-R’
= C(CH3)2;
HO
X, XI, All
R” = SO
2
CII
RI-R’
+iJ 0
OR’
R'O
XII,
= C(CH3)2
XIII,
R’ = H
R substituents
3
HO
0 ti R’O
0
in the formulas
are
RI-R’
OR'
= C(CH3)2
R’ = H (HCl
CH3 group.
salt)
1971
5 -( 2 -methyl-P-ribofuranosyl)uracil chemistry
at the anomeric,
(2 ‘-methylpseudouridine)
C-l’
position
cycle-(=-nucleoside
IX; the mesylate
83%) was cyclized
by 1,5-diazabicyclo[
IX in 81% yield.
When UV spectrum
with that of the corresponding characteristic
bathochromic
reflux,
VIII derived
A_.
(CH3CN,
pyridine, 80 “C, 3 h)
2’0 “C, 14 h, 17 to form
E 3080) was compared a well-known,
of the resulting X (10% HCl in CH30H) provided 515 (XI) in 68% yield. Similarly, condensation of V
and subsequent
acid deblocking
under standard
conditions
led to 5-
(XIII) as HCl salt15’ lg in 61% yield.
Thus we could open a stereocontrolled, -C-nucleosides
from VI (CH3SO2C1,
VI to the
onto the la&one V by use of thiourea (7 equiv, 1 M C2H50Na
(2-methyl-fi-ribofuranosyl)isocytosine
pyrimidine
The p stereo-
by converting
of IX in CH30H ( Xmax 293 nm,
3 h) and deprotection
giving XII,
chemically
5.4.0]undec-5-ene
(2-methyl-p-ribofuranosyl)-2-thiouracil and guanidine,
15,16
open form VI ( Amax 265 run, E 7430), 18 shift was observed.
Elaboration of a heterocycle in C2H50H,
was established
(VII).
starting
from
general
way to a variety
of C-2’
alkylated
nonsugar materials.
This work was partially supported by the Yamada Science Foundation.
REFERENCES 1. C_Nucleoside
Synthesis.
10.
AND NOTES
Part 9: T. Sato and R. Noyori,
Bull. Chem.
Sot.
in
Jpn.,
press. 2. E. Walton, :,sot
S. R. Jenkins,
R. F. Nutt, M. Zimmermann,
_88_, 4524 (1966); S. R. Jenkins,
B. Arisen,
J. Am.
and F. W. Holly,
and E. Walton,
J. Org.
Chem.,
Chem.
E,
2490
(1968). 3.-H.
T.
Shigeura
and S. D. Sampson,
4. H. P. Albrecht
and J. G. Moffatt,
Nature,
215, 419 (1967).
Tetrahedron
Lett.,
1063 (1970); A.
Sprinzl, andD. A, Baker, -Tetrahedron Lett., 4233(1970); A. Jordaan, Tronchet, 5
J. Chem.
Helv. Chim,
Sot.,
Perkin Trans.
Acta,
Tetrahedron 6. R. Noyori,
11,
Lett., Ace.
159 (1972);
7. T. Sato and R. Noyori, 8. Mp 72.0-73.0
“C,
sugars,
Res.,
see H. Grisebach and R. Scbmid, Angew. Pure Appl.
Chem.,
Ho, Can. J. Chem.,
and
-’49
57,
381,
1169 (1977);
Chem.,
P.-T.
Ho,
384 (1979).
12, 61 (1979).
Bull. Chem.
Sot.
IR (CHC13) 1720 cm-l
and 1.50 (s, isopropylidene
G. de Villers,
1, 1608 (1977); J. M. J. Tronchet and J. F.
H. Paulsen,
1623 (1978); P.-T.
Chem.
A. J. Brink, 0.
M.
62, 689 (1979).
For synthesis of branched-chain Int. Ed. Engl.,
Rosenthal,
CH3),
2.2-2.9
Jpn., z, (C=O).
2745 (1978). l HNMR
(CDC13) S 1.41 (s,
(m, H5 and H5,),
4.15
(s,
H3,),
CH3),
4.45
1.41
(t-like,
1974
-J = 5.0
Hz,
Hl, and H4,).
9. V. VanRheenen, VanRheenen,
R.
C. Kelly,
D. Y. Cha,
10. R. Noyori,
T. Sato,
11. The presence experiment
and D. Y. Cha,
and W. M. Hartley,
and Y. Hayakawa,
of the methyl revealed
group
Tetrahedron
Lett.,
Org.
58,
J. Am.
retards
Synth.,
Chem.
Sot.,
the oxidation
that II (R = CH3) reacts
1973 (1976); 43 (1978).
100 2561 (1978). --.--.?
considerably.
four times
V.
slower
A competition
than the parent
ketone
(II, R = H). 12. Mp 132-133 and 1.48
‘C.
(s,
isopropylidene
17 .O Hz, H5b), Hl, and H4!),
3.38 4.34
13. Mp 129.5-130 (s,
16.0
H5b),
Hz,
Hl’and
H4,),
4.14
(s,
16. Mp 138-142
H1),
“C.
(s,
Hz, H5,a),
1’7.0 Hz, 3.58
2.24
(C=o).
‘H NMR (C,D,)
(dd, J = 3.0,
14.0Hz,
H5,a),
16.0 3.62(d,
Hz,
6 1.32
CH3),
1.28
(dd,
-J =4.2,
H5,b),
3.82
(s,
2.52
J=14.OHz,
(m,
CH3),
1.34
(dd, -J = 4.8, H5,b),
3.78(m,
HZ,). 6 1.12 (s,
3.52
Hz,
3.92
(d-like, (s,
2~4.0
H5,),
(dimethyl-%
OH),
4.68
H4,),
1.32 4.36
and 1.51
(s, iso-
(d, L=3.0
Hz,
mixtures.
sulfoxide)
(s, I$,), 7.60
-C4,
U. Reichman,
sulfoxide)
of ribose),
C. K. Chu,
and R. S. Tipson
6 0.99
(d, 5=5-O
13C NMR (dimethyl-g6 81.53(Cl,
1, L. B. Townsend
(m.
CH3),
H6).
here are racemic
H NMR
H3).
(s,
2.52
Hz, H5a),
sulfoxide)
81.31,
H5,),
(d, -J = 14.6
H NMR (dimethyl-%
(br,
(br,
77.99,
1978,
14.6
J=3.2,
7.34 1
17. K. A. Watanabe, Part
J = 3.3,
CH3),
described
4.00
10.99
1
H&
15. All compounds
73.57,
(dd, J = 3.2,
6 1.28
H3,).
3.38(dd,
CH3),
4.80
2.26
IR (CHC13) 1736 cm -l
“C.
propylidene
and H5,),
(s,
CH3),
isopropylidene
14. Mp 126-128
H3,),
(dd,
“C.
and 1.48
‘HNMR(C,D,)
IR (CHC13) 1731 cm -l (C=O).
(s,
CH3),
Hz,
H6),
6 20.95
112.13,
Ed.,
(m, 60.31
150.
“Nucleic
90,
Acid
Wiley-Interscience,
H3 ,, H4 11
(d, -J = 5.0 Hz+
10.78
(CH3),
138.92,
and J. J. Fox,
3.60
(C,,), 163.68.
Chemistry”,
New York,
N.Y.,
p. 273.
18. A. M. Michelson 19. Mp 222-225
and W. E. Cohn, Biochem., 1,490 (1962). 1 H NMR (dimethyl-% sulfoxide) 6 1.02 (s, CH3),
“C.
and ~~ ,), 4.70
(s,
d 20.84
(cH3),
60.20
Hl ,), 7.88
138.33,
152.50,
159.53.
HCI) 222 nm (E 5800), (Received
(C,,),
(s, 73.35,
H6).
8.48
78.28,
(br,
UV Xmax (CH30H) 264 (4250),
Xmax (O.lN
in Japan 24 February 1980)
NH2).
80.97,
81.64
3.62
(m,
l3 C NMR (dimethyl-% (Cl,-C4,
224 nm ( E 10700),
of ribose), 265 (6890),
NaOH) 233 nm (E 9010),
H3 ,, H4,, sulfoxide) 117.18, hmax (O.lN
280 (6750).
SYNTHESIS
OF ‘2‘-METHYLATED
T. Department
Summary:
The title C-nucleosides
manner through the polybromo
Introduction to retard
of methyl
the enzymatic X’-methylated
by lowering
the chemical
normal
ribofuranosyl
have been prepared
in a direct
cyclocoupling
group to the C-2’ thereby
nucleosides activity
and R. Noyori Chikusa,
ketonelfuran
or C-3’
>I<
Nagoya
position
increasing
and stereocontrolled
of certain
the biological to mimic
of the 2’-hydroxylfunction3 only limited
464, Japan
approach.
might be expected
However,
skeleton.
-C-NUCLEOSIDES1
Nagoya University,
destruction,
In addition,
PYRIMIDINE
Sato, H. Kobayashi,
of Chemistry,
0043-40~9/8O/C~C2-1971~~~.00/O
nucleosides
activities
2’-deoxy
is known 2 markedly.
nucleosides
either
or by changing conformation 294 are present
of for
number of reports
the synthesis
of such analogues mainly because of difficulty in preparation of branched-chain 5 Described herein is the first, general synthesis of 2’-methylated sugar moieties.
pyrimidine coupling
C_-nucleosides, reaction
which is based on the efficiency 6 of polybromo ketones and furans.
The oxabicyclic
ketone I was obtained in 86% yield by the reductive
a,(Y,a’,Ly ‘-tetrabromoacetone 14 h), followed
of the [ 3 + 41 reductive
by removal
and 3-methylfuran of bromine
using Zn/Ag couple7
cyclo-
cyclocoupling
(3:1:2 ratio,
of
THF,
atoms from the 13 + 41 adduct (Zn/Cu couple,
20 “C,
CH3OH
with NH Cl, 20 “C, 1 h). The unsaturated ketone I was then converted specifically i3 1 mol % of 0s04, to the acetonide II in 78% yield (1 s8 equiv of -N-methylmorpholine-N-oxide, saturated
(CH3)2CO-H20-~-C4H,0H;g substantiated numbering; Villiger
then acetone-anhyd
by occurrence indicated
oxidation
of the NMR signal for the C-3’
as H in formula
with CF3C03H,
presence
group was effected
70 “C, 1 h) to afford the synthesis
of various
V and urea (7 equiv, removal
V in 63% yield. pyrimidine
1 M C2H50Na
of the isopropylideneblocking
hydrogen (pseudouridine 10 In the subsequent Baeyer-
of the methyl
of III as the major regioisomer 13 II, III12/IV = 67 :33). Then introduction
to the carbonyl
was
11) as a singlet at d 4.15.
substituent at C-2’ gave a bias 11 (52% yield or 84% yield based on
toward the production consumed
The LYconfiguration
CUSO~-_~-TSOH).
of a one-carbon
unit to III at position
with t_butoxybis(dimethylamino)methane This compound -C-nucleosides. in C2H50H,
serves For
reflux,
as a versatile
example,
DMF,
intermediate
base-catalyzed
25 “C, 60 min,
for
reaction
3 h), giving VI l4 (32%), followed
group (10% HCl in CH30H, 1971
(excess,
LY
by
96%) gave
of
a 0
0
4
0
0
R
0
0
2% II
0
0
0
Q
R
R
0
x
CHNW$2
0
0
0
0
0
0
0
0
2-K rv
III
1
,“”
b’ I
0
R”0
0
0
VI,
RI-R’
= C(CH3)2;
A
R” = H
IX
VT1 t R’ = R” = H VIII,
RI-R’
= C(CH3)2;
HO
X, XI, All
R” = SO
2
CII
RI-R’
+iJ 0
OR’
R'O
XII,
= C(CH3)2
XIII,
R’ = H
R substituents
3
HO
0 ti R’O
0
in the formulas
are
RI-R’
OR'
= C(CH3)2
R’ = H (HCl
CH3 group.
salt)
1971
5 -( 2 -methyl-P-ribofuranosyl)uracil chemistry
at the anomeric,
(2 ‘-methylpseudouridine)
C-l’
position
cycle-(=-nucleoside
IX; the mesylate
83%) was cyclized
by 1,5-diazabicyclo[
IX in 81% yield.
When UV spectrum
with that of the corresponding characteristic
bathochromic
reflux,
VIII derived
A_.
(CH3CN,
pyridine, 80 “C, 3 h)
2’0 “C, 14 h, 17 to form
E 3080) was compared a well-known,
of the resulting X (10% HCl in CH30H) provided 515 (XI) in 68% yield. Similarly, condensation of V
and subsequent
acid deblocking
under standard
conditions
led to 5-
(XIII) as HCl salt15’ lg in 61% yield.
Thus we could open a stereocontrolled, -C-nucleosides
from VI (CH3SO2C1,
VI to the
onto the la&one V by use of thiourea (7 equiv, 1 M C2H50Na
(2-methyl-fi-ribofuranosyl)isocytosine
pyrimidine
The p stereo-
by converting
of IX in CH30H ( Xmax 293 nm,
3 h) and deprotection
giving XII,
chemically
5.4.0]undec-5-ene
(2-methyl-p-ribofuranosyl)-2-thiouracil and guanidine,
15,16
open form VI ( Amax 265 run, E 7430), 18 shift was observed.
Elaboration of a heterocycle in C2H50H,
was established
(VII).
starting
from
general
way to a variety
of C-2’
alkylated
nonsugar materials.
This work was partially supported by the Yamada Science Foundation.
REFERENCES 1. C_Nucleoside
Synthesis.
10.
AND NOTES
Part 9: T. Sato and R. Noyori,
Bull. Chem.
Sot.
in
Jpn.,
press. 2. E. Walton, :,sot
S. R. Jenkins,
R. F. Nutt, M. Zimmermann,
_88_, 4524 (1966); S. R. Jenkins,
B. Arisen,
J. Am.
and F. W. Holly,
and E. Walton,
J. Org.
Chem.,
Chem.
E,
2490
(1968). 3.-H.
T.
Shigeura
and S. D. Sampson,
4. H. P. Albrecht
and J. G. Moffatt,
Nature,
215, 419 (1967).
Tetrahedron
Lett.,
1063 (1970); A.
Sprinzl, andD. A, Baker, -Tetrahedron Lett., 4233(1970); A. Jordaan, Tronchet, 5
J. Chem.
Helv. Chim,
Sot.,
Perkin Trans.
Acta,
Tetrahedron 6. R. Noyori,
11,
Lett., Ace.
159 (1972);
7. T. Sato and R. Noyori, 8. Mp 72.0-73.0
“C,
sugars,
Res.,
see H. Grisebach and R. Scbmid, Angew. Pure Appl.
Chem.,
Ho, Can. J. Chem.,
and
-’49
57,
381,
1169 (1977);
Chem.,
P.-T.
Ho,
384 (1979).
12, 61 (1979).
Bull. Chem.
Sot.
IR (CHC13) 1720 cm-l
and 1.50 (s, isopropylidene
G. de Villers,
1, 1608 (1977); J. M. J. Tronchet and J. F.
H. Paulsen,
1623 (1978); P.-T.
Chem.
A. J. Brink, 0.
M.
62, 689 (1979).
For synthesis of branched-chain Int. Ed. Engl.,
Rosenthal,
CH3),
2.2-2.9
Jpn., z, (C=O).
2745 (1978). l HNMR
(CDC13) S 1.41 (s,
(m, H5 and H5,),
4.15
(s,
H3,),
CH3),
4.45
1.41
(t-like,
1974
-J = 5.0
Hz,
Hl, and H4,).
9. V. VanRheenen, VanRheenen,
R.
C. Kelly,
D. Y. Cha,
10. R. Noyori,
T. Sato,
11. The presence experiment
and D. Y. Cha,
and W. M. Hartley,
and Y. Hayakawa,
of the methyl revealed
group
Tetrahedron
Lett.,
Org.
58,
J. Am.
retards
Synth.,
Chem.
Sot.,
the oxidation
that II (R = CH3) reacts
1973 (1976); 43 (1978).
100 2561 (1978). --.--.?
considerably.
four times
V.
slower
A competition
than the parent
ketone
(II, R = H). 12. Mp 132-133 and 1.48
‘C.
(s,
isopropylidene
17 .O Hz, H5b), Hl, and H4!),
3.38 4.34
13. Mp 129.5-130 (s,
16.0
H5b),
Hz,
Hl’and
H4,),
4.14
(s,
16. Mp 138-142
H1),
“C.
(s,
Hz, H5,a),
1’7.0 Hz, 3.58
2.24
(C=o).
‘H NMR (C,D,)
(dd, J = 3.0,
14.0Hz,
H5,a),
16.0 3.62(d,
Hz,
6 1.32
CH3),
1.28
(dd,
-J =4.2,
H5,b),
3.82
(s,
2.52
J=14.OHz,
(m,
CH3),
1.34
(dd, -J = 4.8, H5,b),
3.78(m,
HZ,). 6 1.12 (s,
3.52
Hz,
3.92
(d-like, (s,
2~4.0
H5,),
(dimethyl-%
OH),
4.68
H4,),
1.32 4.36
and 1.51
(s, iso-
(d, L=3.0
Hz,
mixtures.
sulfoxide)
(s, I$,), 7.60
-C4,
U. Reichman,
sulfoxide)
of ribose),
C. K. Chu,
and R. S. Tipson
6 0.99
(d, 5=5-O
13C NMR (dimethyl-g6 81.53(Cl,
1, L. B. Townsend
(m.
CH3),
H6).
here are racemic
H NMR
H3).
(s,
2.52
Hz, H5a),
sulfoxide)
81.31,
H5,),
(d, -J = 14.6
H NMR (dimethyl-%
(br,
(br,
77.99,
1978,
14.6
J=3.2,
7.34 1
17. K. A. Watanabe, Part
J = 3.3,
CH3),
described
4.00
10.99
1
H&
15. All compounds
73.57,
(dd, J = 3.2,
6 1.28
H3,).
3.38(dd,
CH3),
4.80
2.26
IR (CHC13) 1736 cm -l
“C.
propylidene
and H5,),
(s,
CH3),
isopropylidene
14. Mp 126-128
H3,),
(dd,
“C.
and 1.48
‘HNMR(C,D,)
IR (CHC13) 1731 cm -l (C=O).
(s,
CH3),
Hz,
H6),
6 20.95
112.13,
Ed.,
(m, 60.31
150.
“Nucleic
90,
Acid
Wiley-Interscience,
H3 ,, H4 11
(d, -J = 5.0 Hz+
10.78
(CH3),
138.92,
and J. J. Fox,
3.60
(C,,), 163.68.
Chemistry”,
New York,
N.Y.,
p. 273.
18. A. M. Michelson 19. Mp 222-225
and W. E. Cohn, Biochem., 1,490 (1962). 1 H NMR (dimethyl-% sulfoxide) 6 1.02 (s, CH3),
“C.
and ~~ ,), 4.70
(s,
d 20.84
(cH3),
60.20
Hl ,), 7.88
138.33,
152.50,
159.53.
HCI) 222 nm (E 5800), (Received
(C,,),
(s, 73.35,
H6).
8.48
78.28,
(br,
UV Xmax (CH30H) 264 (4250),
Xmax (O.lN
in Japan 24 February 1980)
NH2).
80.97,
81.64
3.62
(m,
l3 C NMR (dimethyl-% (Cl,-C4,
224 nm ( E 10700),
of ribose), 265 (6890),
NaOH) 233 nm (E 9010),
H3 ,, H4,, sulfoxide) 117.18, hmax (O.lN
280 (6750).