- Email: [email protected]
Synthesis of gem -difluorosaccharides
SYNTHESIS OF GEM-DIFLUOROSACCHARIDES R.A. Sharma, I. Kavai, Y .L. Fu%nd M. Bobek* Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263. ir. TJS& 17 Juzze 1977; received ir. m for >IlbliCati@n 11 k:l:Xt
(Received
The biological properties
of fluorinated saccharides
and nucleosides have, in recent years,
prompted the development of several useful methods for their synthesis considerable
l-3
. In contrast to the
interest directed towards the synthesis and chemistry of fluorosugars
fluorine atom becomes attached to carbon, the synthesis of e-diflurosugars investigated.
The first e-difluorosaccharide,
by hydrolysis.
Some B-difluoromethylene
in which a single
has not been extensively
2-deoxy-2, 2-difluoro-D-arabino-hexose4, --
been prepared by addition of fluoroxytrifluromethane
15’77)
has recently
to 3,4,6-tri-g-acetyl-2-fluoro-I&glucal,
followed
sugar derivatives have been prepared 596 by treatment of
sugar aldehydes and ketones with (difluoromethylene) triphenylphosphorane .
In connection with our efforts towards the synthesis of potential antitumor nucleosides, became apparent that a general procedure for the preparation of gem-difluorosaccharides considerable groups.
value.
it
would be of
We now wish to report such a method based on the fluorination of sugar carbonyl
Sugar aldehydes and ketones can readily be prepared by oxidation7 of the corresponding
alcohols. While aromatic and aliphatlc gem-difluorides corresponding
carbonyl derivatives,
sulfur trifluoride
10,ll
have been prepared by fluorination of the
8 using reagents such as, SF Se F4 * pyridineg, and dialkylamino4 ’
, an earlier attempt to replace the carbonyl oxygen in a sugar derivative,
anhydro-2,4-dideoxy-2,4-difluoro-P-D-rib0 We have found that diethylaminosuliiz
-hexopyranos-3-ulose,
by fluorination with PhSF3 failed=.
trifluoride 10,11,.15 IS a useful reagent for the replacement of the
carbonyl oxygen in sugars and glycosides
protected with the isopropylidene
groups.
appears to be general for sugar aldehydes and ketones in the pyranosyl form.
*
Present address:
1,6-
International Paper Company, Tuxedo Park, N.Y.
3433
10987
The reaction
The following experimental procedures
were found typical for fluorinating sugar sldehydes
and ketones m 6-Deoxy-6,6-difluoro-1,2:3,
4-d.i-O_isopropylidene-c+-galactopyranose
5-pyranose l3 Q, 8.16g,
Crude 1,2:3,4-di-0_isopropylidene-c~-D-galado-hexodi~do-l, = was dried by distilling 100 ml of dry toluene from its solution. and 10 ml (0.08 mol) of diethylsminosulfur
ttiuoride
(4J.
It was then dissolved in 150 ml of CH2C12
(DEST) was added under N2 to this solution.
reaction mixture was stirred at room temperature under nitrogen for 16 hrs. NaHC03 solution. dried (Na2SC4).
0.031 mol)
The
It was then washed with
The aqueous layer was extracted with CH2C12 and the combined organic solution was The crude product,
obtained by evaporating the solvent, was purified on a dry silica
gel column using benzene as eluent a Compound 4 was obtained as an oil (3.78 g, 46% yield) which solidified when kept at room temperature for a few days; m.p. Methyl 2-deoxy-2,2-difluoro-3,
48-50“.
4-O_isopropylidene-6-l_erythro-pentopyranoside
Methyl 3,4-~-isopropylidene-P_L-e@hro-pentuloso-pyranoside
($j.
(5, 1.95 g, 0.0097 mol),
which was prepared by the oxidation of methyl 3,44_-isopropylidene-/3---arabino-pyranoside Ac2C, was dried by distilling approximately
100 ml of dry toluene from its solution.
by DMSO-
It was then
dissolved in 100 ml of benzene and to this solution was added under N2 3 ml (0.024 mol) of DEST. reaction mixture was refluxed for 16 hrs under N2 , cooled,
The
and then washed with NaHC03 solution.
The aqueous layer was washed with CH Cl3 (50 ml) and the combined organic solution was dried (Na2SC4). Evaporation of this solution and purification of the residue on a dry silica gel column, using benzene as tl eluent, gave 0.54 g(25% yield) of syrupy 5. Satisfactory analytical data (C, H, F) were obtained for compounds 2,&,6 and S. were firther characterized these derivatives, characteristic
by mass and
19 F magnetic resonance spectroscopy.
In the mass spectra of
M+-15 peaks were obtained, resulting from the loss of one CH3 group, which is a
fe+re
for sugar derivatives containing an isooropylidene
group
14
.
The application of this method to the synthesis of other gem-difluorosaccharides difluoronucleosides
These compounds
is underway in our laboratory.
and to B
Table 1 - Some Physical and Chemical Characteristics
Product
Carbonyl Compound
of Newly Prepared m-Difluorosugar
Derivatives
Mass Spectrum (m/e)
19 F NMR Chemic: Shiftb @pm)
209(M+ - 15)
129.0c
46%
265(M+ - 15)
131.6(Fa)d 133.6(Fb)
25%
209(M+ - 15)
126 .2(Fa)e 146.1(Fb)
U(M+) 209(M+ - 15)
113. l(Fa)f 115.9(Fb)
Yielda
O=CH
s
F
Decomposition
a) Yields were not optimized, d) m, JFan
b) measured in CDC13 - CFC13wc value), c) q, JFH 10 Hz, J
298.2 Hz, JFaH 10 Hz, J
f) complex multiplets JFan
256.5 Hz
FH(4) 56 Hz
FaH(5) 57n3 Hz* JFbH 5.5 HZ, JFbH(5) 54.7 Hz, e) complex multi1
3436
Acknowledgments This investigation was supported in part by Grants CH-55A from the American Cancer Society, CA-13038 from the National Cancer Institute, USPHS, and RPMI Core Grant POlCA-16656.
We thank Ms. Onda Dodson Simmons for determining the NMR and Dr. Girish
Chheda for mass spectra. References 1.
A.B.
Foster and J.H. Westwood, -Rev. Pure A&
2.
J. Pode&-a and J. Pa&,
3.
M. J. Robins, M. MacCoss, E, 738 l(1976).
4.
J. Adamson, A.B.
5.
J.M.J.
Tronchet,
B. BaehIer, and A. Bonenfant, -Helv. Chim. Acta, 59, 941(1976).
6.
J.M.J.
Tronchet,
D. Schwarzenbach,
7.
J.G. Moffatt, in “Techniques and Applications in Organic Synthesis, Vol.& Augustine and D.J. Tucker), Marcel Dekker, New York, New York, 1971.
8.
W.A. Sheppard and C.M. Sharts, “Organic Fluorine Chemistry, New York, NY 1969.
9.
G.A. Olah, M. Nojima, and I. Kerekes, Markovskij,
Foster,
Chem. , 35, 147 (1968).
. Listy, 67, 785 (1973). S.R. Naik, and G. Ramani, 2. --Amer. Chem. Sot. and J,H. Westwood, Carbohvd. Res. ,g,
and F. Barbalat-Rey,
345 (1971).
Carbohvd. Res.,
46,9(1976). 1, (Ed. R.L.
” W.A. Benjamin,
J. Amer. Chem. Sot., 96, 925 (1974). _PP
10.
L.N.
V.E. Pashinnik, and A.V.
Kirsanov,
11.
W.J. Middleton, 2. m
12.
D. Stropova’, Thesis, Charles University, J. Pa&k, Chem. Lia, 67, 785 (1973).
13.
D. Horton, M. Nakadste, and J.M.J.
14.
D.C . DeJongh and K. Biemann, _---’ J. Amer.
15.
M. Sharma and W. Korytnyk, Tetrahedron Lett.,
Synthesis, 787 (1973).
Chem., 40, 574 (1975). Prague, Czechoslovakia,
Tronchet,
1971, J. Podegva and
Carbohyd. Res., x, 56 (1968).
Chem. Sot.
-’86 67(1964).
573 (1977).
(Received
The biological properties
of fluorinated saccharides
and nucleosides have, in recent years,
prompted the development of several useful methods for their synthesis considerable
l-3
. In contrast to the
interest directed towards the synthesis and chemistry of fluorosugars
fluorine atom becomes attached to carbon, the synthesis of e-diflurosugars investigated.
The first e-difluorosaccharide,
by hydrolysis.
Some B-difluoromethylene
in which a single
has not been extensively
2-deoxy-2, 2-difluoro-D-arabino-hexose4, --
been prepared by addition of fluoroxytrifluromethane
15’77)
has recently
to 3,4,6-tri-g-acetyl-2-fluoro-I&glucal,
followed
sugar derivatives have been prepared 596 by treatment of
sugar aldehydes and ketones with (difluoromethylene) triphenylphosphorane .
In connection with our efforts towards the synthesis of potential antitumor nucleosides, became apparent that a general procedure for the preparation of gem-difluorosaccharides considerable groups.
value.
it
would be of
We now wish to report such a method based on the fluorination of sugar carbonyl
Sugar aldehydes and ketones can readily be prepared by oxidation7 of the corresponding
alcohols. While aromatic and aliphatlc gem-difluorides corresponding
carbonyl derivatives,
sulfur trifluoride
10,ll
have been prepared by fluorination of the
8 using reagents such as, SF Se F4 * pyridineg, and dialkylamino4 ’
, an earlier attempt to replace the carbonyl oxygen in a sugar derivative,
anhydro-2,4-dideoxy-2,4-difluoro-P-D-rib0 We have found that diethylaminosuliiz
-hexopyranos-3-ulose,
by fluorination with PhSF3 failed=.
trifluoride 10,11,.15 IS a useful reagent for the replacement of the
carbonyl oxygen in sugars and glycosides
protected with the isopropylidene
groups.
appears to be general for sugar aldehydes and ketones in the pyranosyl form.
*
Present address:
1,6-
International Paper Company, Tuxedo Park, N.Y.
3433
10987
The reaction
The following experimental procedures
were found typical for fluorinating sugar sldehydes
and ketones m 6-Deoxy-6,6-difluoro-1,2:3,
4-d.i-O_isopropylidene-c+-galactopyranose
5-pyranose l3 Q, 8.16g,
Crude 1,2:3,4-di-0_isopropylidene-c~-D-galado-hexodi~do-l, = was dried by distilling 100 ml of dry toluene from its solution. and 10 ml (0.08 mol) of diethylsminosulfur
ttiuoride
(4J.
It was then dissolved in 150 ml of CH2C12
(DEST) was added under N2 to this solution.
reaction mixture was stirred at room temperature under nitrogen for 16 hrs. NaHC03 solution. dried (Na2SC4).
0.031 mol)
The
It was then washed with
The aqueous layer was extracted with CH2C12 and the combined organic solution was The crude product,
obtained by evaporating the solvent, was purified on a dry silica
gel column using benzene as eluent a Compound 4 was obtained as an oil (3.78 g, 46% yield) which solidified when kept at room temperature for a few days; m.p. Methyl 2-deoxy-2,2-difluoro-3,
48-50“.
4-O_isopropylidene-6-l_erythro-pentopyranoside
Methyl 3,4-~-isopropylidene-P_L-e@hro-pentuloso-pyranoside
($j.
(5, 1.95 g, 0.0097 mol),
which was prepared by the oxidation of methyl 3,44_-isopropylidene-/3---arabino-pyranoside Ac2C, was dried by distilling approximately
100 ml of dry toluene from its solution.
by DMSO-
It was then
dissolved in 100 ml of benzene and to this solution was added under N2 3 ml (0.024 mol) of DEST. reaction mixture was refluxed for 16 hrs under N2 , cooled,
The
and then washed with NaHC03 solution.
The aqueous layer was washed with CH Cl3 (50 ml) and the combined organic solution was dried (Na2SC4). Evaporation of this solution and purification of the residue on a dry silica gel column, using benzene as tl eluent, gave 0.54 g(25% yield) of syrupy 5. Satisfactory analytical data (C, H, F) were obtained for compounds 2,&,6 and S. were firther characterized these derivatives, characteristic
by mass and
19 F magnetic resonance spectroscopy.
In the mass spectra of
M+-15 peaks were obtained, resulting from the loss of one CH3 group, which is a
fe+re
for sugar derivatives containing an isooropylidene
group
14
.
The application of this method to the synthesis of other gem-difluorosaccharides difluoronucleosides
These compounds
is underway in our laboratory.
and to B
Table 1 - Some Physical and Chemical Characteristics
Product
Carbonyl Compound
of Newly Prepared m-Difluorosugar
Derivatives
Mass Spectrum (m/e)
19 F NMR Chemic: Shiftb @pm)
209(M+ - 15)
129.0c
46%
265(M+ - 15)
131.6(Fa)d 133.6(Fb)
25%
209(M+ - 15)
126 .2(Fa)e 146.1(Fb)
U(M+) 209(M+ - 15)
113. l(Fa)f 115.9(Fb)
Yielda
O=CH
s
F
Decomposition
a) Yields were not optimized, d) m, JFan
b) measured in CDC13 - CFC13wc value), c) q, JFH 10 Hz, J
298.2 Hz, JFaH 10 Hz, J
f) complex multiplets JFan
256.5 Hz
FH(4) 56 Hz
FaH(5) 57n3 Hz* JFbH 5.5 HZ, JFbH(5) 54.7 Hz, e) complex multi1
3436
Acknowledgments This investigation was supported in part by Grants CH-55A from the American Cancer Society, CA-13038 from the National Cancer Institute, USPHS, and RPMI Core Grant POlCA-16656.
We thank Ms. Onda Dodson Simmons for determining the NMR and Dr. Girish
Chheda for mass spectra. References 1.
A.B.
Foster and J.H. Westwood, -Rev. Pure A&
2.
J. Pode&-a and J. Pa&,
3.
M. J. Robins, M. MacCoss, E, 738 l(1976).
4.
J. Adamson, A.B.
5.
J.M.J.
Tronchet,
B. BaehIer, and A. Bonenfant, -Helv. Chim. Acta, 59, 941(1976).
6.
J.M.J.
Tronchet,
D. Schwarzenbach,
7.
J.G. Moffatt, in “Techniques and Applications in Organic Synthesis, Vol.& Augustine and D.J. Tucker), Marcel Dekker, New York, New York, 1971.
8.
W.A. Sheppard and C.M. Sharts, “Organic Fluorine Chemistry, New York, NY 1969.
9.
G.A. Olah, M. Nojima, and I. Kerekes, Markovskij,
Foster,
Chem. , 35, 147 (1968).
. Listy, 67, 785 (1973). S.R. Naik, and G. Ramani, 2. --Amer. Chem. Sot. and J,H. Westwood, Carbohvd. Res. ,g,
and F. Barbalat-Rey,
345 (1971).
Carbohvd. Res.,
46,9(1976). 1, (Ed. R.L.
” W.A. Benjamin,
J. Amer. Chem. Sot., 96, 925 (1974). _PP
10.
L.N.
V.E. Pashinnik, and A.V.
Kirsanov,
11.
W.J. Middleton, 2. m
12.
D. Stropova’, Thesis, Charles University, J. Pa&k, Chem. Lia, 67, 785 (1973).
13.
D. Horton, M. Nakadste, and J.M.J.
14.
D.C . DeJongh and K. Biemann, _---’ J. Amer.
15.
M. Sharma and W. Korytnyk, Tetrahedron Lett.,
Synthesis, 787 (1973).
Chem., 40, 574 (1975). Prague, Czechoslovakia,
Tronchet,
1971, J. Podegva and
Carbohyd. Res., x, 56 (1968).
Chem. Sot.
-’86 67(1964).
573 (1977).