Total synthesis of 3,3-difluorinated 1-deoxynojirimycin analogues

Article abstract of DOI:10.1016/j.tet.2009.11.069

Difluorination of 1-deoxynojirimycin at position C(3) creates a competitive inhibitor 15 of 10 times higher activity against an α-glucosidase than the parent compound. Its screening against a panel of human cell lines showed a low cytotoxicity therefore m

Full text of DOI:10.1016/j.tet.2009.11.069

Tetrahedron 66 (2010) 467–472
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of 3,3-difluorinated 1-deoxynojirimycin analogues
*
´
¨
Rene Csuk , Erik Prell, Claudia Korb, Ralph Kluge, Dieter Strohl
Martin-Luther-Universita¨t Halle-Wittenberg, Organische Chemie, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Difluorination of 1-deoxynojirimycin at position C(3) creates a competitive inhibitor 15 of 10 times
Received 15 October 2009
Received in revised form
16 November 2009
Accepted 16 November 2009
Available online 18 November 2009
higher activity against an
human cell lines showed a low cytotoxicity therefore making this compound an interesting candidate for
further clinical investigations.
a-glucosidase than the parent compound. Its screening against a panel of
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1-Deoxynojirimycin
Difluorination
a
a
-Glucosidase inhibitor
-Galactosidase inhibitor
1. Introduction
biological evaluation of a 3,3-difluorinated analogue appeared in-
teresting since we expected that this compound might be an in-
1-Deoxynojirimycin (DNM, I, Fig. 1) and its analogues
(cf. miglitol, II) have a long history1 in the in vitro investigation of
diabetes and as antiviral agents. To increase the activity of
biologically active organic compounds2 often their fluorinated
analogues have been prepared and several procedures are available3
to introduce a fluorine substituent into a molecule. Interestingly
enough, the number of reliable and generallyapplicable methods for
introducing a geminal difluoromethylene group3 is limited. During
our investigations on glucosidase inhibition we became interested
in the synthesis of certain geminal difluorinated 1-deoxynojirimycin
analogues.
hibitor for an a-glucosidase as well as for an a-galactosidase. We
reasoned that the strongly electron-withdrawing geminal
difluoromethylene group should affect the binding to the enzyme
by changing the pKa of the iminosugar; also, C(3)-OH in an imi-
nosugar seems critically for a good binding to the enzymes. Since
the cleavage of methyl glycosides affords rather harsh conditions
we decided to start our approach employing an allyl-glycoside
since the allyl protective group can be cleaved off readily7 under
mild conditions.
Thus, glucose (1) was allylated8 (Scheme 1) in water/allylic
alcohol at 50 ꢀC in the presence of the
and 63% of the corresponding allyl b-D
b
-glucosidase from almonds
-glucopyranoside (2)8,9 was
obtained. Its treatment with benzaldehyde dimethylacetal in the
Figure 1. Structure of 1-deoxynojirimycin (I) and of miglitol (II).
2. Results and discussion
Extensive review of the literature and patents revealed there are
only a few reports describing the synthesis of a 4,4-4,5 and a 6,6-
difluorinated 1-deoxynojirimycin6 analogue. The synthesis and
Scheme 1. (a)
b
-Glucosidase (almonds) (Ref. 8), allyl alcohol/water, 50 ꢀC, 63%;
(b) PhC(OMe)2, DMF, HBF4$Et2O, 50 ꢀC, 97%; (c) BnBr, NaOH, Bu4NHSO4, reflux, com-
* Corresponding author. Tel.: þ49 (0) 345 5525660; fax: þ49 (0) 345 5527030
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
bined yield 73%.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.069

468
R. Csuk et al. / Tetrahedron 66 (2010) 467–472
presence of HBF4$Et2O at 50 ꢀC10,11 for one day gave the 4,6-O-
benzylidene acetal 3 in an excellent yield of 97%. Compound 3 was
benzylated12 to afford a mixture of the monobenzylated com-
pounds 4 and 5. This mixture (4:5¼25:48%) was easily separated by
chromatography.
Compounds 15 and 16 were assayed for their inhibitory activi-
ties towards several commercially available glucosidases under
ideal enzymatic pH using the well established24 4-nitro-phenolate
test. The results of these assays are summarised in Table 1.
Table 1
Swern-oxidation13,14 of 5 (Scheme 2) applying DMSO and tri-
fluoroacetic anhydride gave 75% of the hex-3-ulo-pyranoside 6
whose reaction with DAST in anhyd dichloromethane15 gave 55% of
the 3,3-difluorinated pyranoside 7. Interestingly enough, difluori-
nation of 6 with DAST in refluxing benzene gave only 17% of 7 in-
variably accompanied by deterioration products. Compound 7 is
characterised in its 19F NMR spectrum by the presence of two sig-
Inhibitory activities (IC50, mM) of several compounds against glycosidases. The
values are the average from at least three independent experiments; variation was
5%; n.i.: no inhibition
Compound
a
-Glucosidase
b-Glucosidase a-Galactosidase b-Galactosidase
(baker’s yeast) (almonds)
(green coffee
beans)
(E. coli)
Miglitol
15
16
9.88
0.84
2.24
0.21
0.82
1.40
13.93
3.30
9.12
0.19
n.i.
8.90
nals at
d
¼ꢁ119.01 and ꢁ132.73 ppm. In the 13C NMR spectrum of 7
the signal for C(3) is found at
d
¼117.2 ppm; it shows a coupling by
the adjacent fluorine substituents of J¼250 and 255 Hz being typ-
3. Conclusions
Compound 15 is an excellent competitive inhibitor for the
ical for geminal difluorinated carbons.
a
-
glucosidase from baker’s yeast showing an approx. 10-fold in-
creased inhibition compared to standard miglitol. It is also
a stronger inhibitor than miglitol for the
coffee beans. Less inhibitory activity can be detected for the epi-
meric compound 16 although its inhibitory activity for the -glu-
a-galactosidase from green
a
cosidase from baker’s yeast is approx four times enhanced
compared to miglitol. For both compounds a reduced or no activity
at all is observed when tested with a
b-galactosidase (from
Escherichia coli). Their screening against a panel of human cell lines
showed a low cytotoxicity therefore making these compound in-
teresting candidates for further investigations.
4. Experimental
4.1. General
Melting points are uncorrected (Leica hot stage microscope),
optical rotations were obtained using a Perkin–Elmer 341 polar-
imeter (1 cm micro cell), NMR spectra were recorded using the
Varian spectrometers Gemini 200, Gemini 2000 or Unity 500
Scheme 2. (a) DMSO, (F3CO2)2O, DCM, ꢁ78 ꢀC, then Et3N, 75%; (b) DAST, DCM, 25 ꢀC,
55%; (c) TFA (30% in DCM), H2O, 25 ꢀC, 44%; (d) BnBr, NaH, 25 ꢀC, 71%; (e) PdCl2, MeOH,
25 ꢀC, 64%; (f) LiAlH4, THF, 25 ꢀC, 76%; (g) DMSO, (F3CO2)2O, DCM, ꢁ78 ꢀC, then Et3N,
57%.
(d given in ppm, J in Hz, internal Me4Si or internal CCl3F), IR spectra
The 4,6-O-benzylidene acetal of compound 7 was cleaved off
with trifluoroacetic acid in dichloromethane/water16 to afford 8
that was benzylated17–19 to yield 71% of 2,4,6-tri-O-benzylated
compound 9. Deallylation20,21 was performed with PdCl2 in MeOH
to yield 10 whose reduction with LiAlH4 in THF14 at room tem-
perature gave the diol 11 in 76% yield. Compound 11 was subject to
a double Swern-oxidation to yield the corresponding 5-ulose 12 as
a mixture of the dicarbonyl compound and its corresponding hy-
drates. This mixture (Scheme 3) was subjected to a reductive
amination14 to afford a mixture of 13 and 14. These compounds
were easily separated by chromatography and debenzylated22,23 to
afford the target compound 15 and its matching C(5)-epimer 16.
(film or KBr pellet) on a Perkin–Elmer FT-IR spectrometer Spectrum
1000, MS spectra were taken on a Intectra GmbH AMD 402 (elec-
tron impact, 70 eV) or on a Thermo Electron Finnigan LCQ (elec-
trospray, voltage 4.5 kV, sheath gas nitrogen) instrument; for
elemental analysis a Foss–Heraeus Vario EL instrument was used;
TLC was performed on silica gel (Merck 5554, detection by UV
absorption or by treatment with a solution of 10% sulfuric acid,
ammonium molybdate and cerium(IV) sulfate) followed by gentle
heating. The solvents were dried according to usual procedures.
4.2. Allyl (R)-4,6-O-benzylidene-b-D-gluco-pyranoside (3)
A
solution of allyl
b-
D-gluco-pyranoside (2) (10.00 g,
45.41 mmol) in benzaldehyde
dimethylacetal (50.0 ml,
334.05 mmol) was stirred at 50 ꢀC for 10 min, then HBF4$Et2O
(3.00 ml) was added and stirring was continued at 50 ꢀC for another
24 h. After neutralisation with triethylamine, the solvent was re-
moved in vacuo and the remaining residue subjected to chroma-
tography (silica gel, methanol/ethyl acetate¼10:90) to afford 3
(13.64 g, 97.4%) as colourless crystals; mp 146–147 ꢀC (lit.25 146–
148 ꢀC); [
a]
D ꢁ51.68 (c 0.45, CHCl3) [lit.25
[
a
]
D ꢁ57.6 (c 1.02, CHCl3)];
Rf (hexane/ethyl acetate¼50:50) 0.29; Rf (methanol/ethyl
acetate¼10:90) 0.84; IR (KBr):
1374m, 1267w, 1172m, 1087m, 1043m, 1004m cmꢁ1
(400 MHz, CDCl3):
n
¼3511s, 2925m, 1647w, 1453w,
;
1H NMR
d
¼7.49–7.48 (m, 2H, Ph), 7.37–7.33 (m, 3H, Ph),
3
3
3
3
0
0
00
0
0
0
0
0
00
Scheme 3. (a) BnNH2, MeOH, ꢁ78 ꢀC, then NaBH3CN, ꢁ78 ꢀC/25 ꢀC/50 ꢀC, com-
5.93 (dddd, 1H, J2 ,1 ¼5.4, J2 ,1 ¼6.4, J2 ,3 ¼10.4, J2 ,3 ¼17.0, H-2 ),
4
2
bined yield 40%; (b) Pd/C, H2, MeOH, 35 ꢀC, 87%; (c) Pd/C, H2, MeOH, 35 ꢀC, 81%.
5.52 (s, 1H, CH-benzylidene), 5.32 (dddd, 1H, J3 ,1 ¼1.2, J3 ,3 ¼1.2,
00
0
00
0

R. Csuk et al. / Tetrahedron 66 (2010) 467–472
469
4
2
3
4
4
3
3
2
00
0
00 00
00
0
0
0
0
00
00
00 0
J3 ,1 ¼1.2, J3 ,2 ¼17.0, H-3 ), 5.23 (dddd, 1H, J3 ,1 ¼1.2, J3 ,1 ¼1.4,
4.56 (d, 1H, J1,2¼7.7, H-1), 4.40 (dd, 1H, J1 ,2 ¼5.2, J1 ,1 ¼12.7, H-
3
3
3 2
0
100), 4.32 (dd, 1H, J6B,5¼0 4.9, J6B,6A¼10.5, H-6B), 4.14 (dd, 1H,
0
00
0
0
J3 ,3 ¼1.2, J3 ,2 ¼10.4, H-3 ), 4.44 (d, 1H, J1,2¼7.7, H-1), 4.37 (dddd,
1H, 4J1 ,3 ¼1.4, J1 ,3 ¼1.4, J1 ,2 ¼5.4, J1 ,1 ¼12.6, H-1 ), 4.33 (dd, 1H,
J1 ,2 ¼5.7, J1 ,1 ¼12.7, H-1 ), 3.82 (dd, 1H, J3,2¼9.1, J3,4¼9.1, H-3),
4
3
2
3
2
3
3
00
00 00
00
0
00
0
00
0
0
0
0 00
3
3
2
4
4
3.76 (dd, 1H, 3J6A,5¼10.2, 2J6A,6B¼10.5, H-6A), 3.53 (dd, 1H, 3J4,3¼9.1,
0
0
0
00
J6B,5¼4.9, J6B,6A¼10.4, H-6B), 4.14 (dddd, 1H, J1 ,3 ¼1.2, J1 ,3 ¼1.2,
2
3
3
3J4,5¼9.6, H-4), 3.41 (ddd, 1H, 3J5,6B¼4.9, 3J5,4¼9.6, 3J5,6A¼10.2, H-5),
0
0
0
0 00
J1 ,2 ¼6.4, J1 ,1 ¼12.6, H-1 ), 3.81 (dd, 1H, J2,1¼7.7, J2,3¼9.1, H-2),
3.78 (dd, 1H, 3J6A,5¼10.2, 2J6A,6B¼10.4, H-6A), 3.55 (dd, 1H, 3J4,3¼9.1,
3.37 (dd, 1H, J2,1¼7.7, J2,3¼9.1, H-2) ppm; 13C NMR (125 MHz,
3
3
3J4,5¼9.4, H-4), 3.52 (dd, 1H, 3J3,2¼9.1, 3J3,4¼9.1, H-3), 3.44 (ddd, 1H,
CDCl3):
d
¼138.3 (Car), 137.0 (Ph), 133.6 (C20), 129.2 (Car), 128.5 (Car),
3J5,6B¼4.9, J5,4¼10.2, J5,6A¼9.4, H-5) ppm; 13C NMR (125 MHz,
128.3 (Car), 128.2 (Car), 128.1 (Car), 128.0 (Car), 127.9 (Car), 126.3 (Car),
126.0 (Car), 117.7 (C30), 102.9 (C1), 101.8 (CH-benzylidene), 81.8 (C2),
80.4 (C4), 74.8 (CH2(OBn)), 73.2 (C3), 70.7 (C10), 68.7 (C6), 66.1 (C5)
ppm; MS (ESI-MeOH): m/z (%)¼399.1 ([MþH]þ, 7), 416.1
([MþNH4]þ, 8), 421.3 ([MþNa]þ, 9), 617.2 ([M3þK, H]2þ, 7), 818.9
([M2þNa]þ, 100); analysis for C23H26O6 (398.45): calcd: C, 69.33; H,
6.58; found: C, 69.19; H, 6.80.
3
3
CDCl3):
d
¼136.9 (Car), 133.4 (C20), 129.3 (Car), 128.3 (Car), 126.3 (Car),
118.3 (C30), 102.1 (C1), 101.9 (CH-benzylidene), 80.5 (C4), 74.5 (C3),
73.2 (C2), 70.6 (C10), 68.6 (C6), 66.4 (C5) ppm; MS (ESI-MeOH): m/z
(%)¼309.2 ([MþH]þ, 10), 331.3 ([MþNH4]þ, 18), 482.2 ([M3þK, H]2þ
,
4), 639.0 ([M2þNa]þ, 100); analysis for C16H20O6 (308.33): calcd: C,
62.33; H, 6.54; found: C, 62.09; H, 6.71.
4.3. Allyl 3-O-benzyl-(R)-4,6-O-benzylidene-
pyranoside (4) and allyl 2-O-benzyl-(R)-4,6-O-benzylidene-
-gluco-pyranoside (5)
b
-
D
-gluco-
4.4. Allyl 2-O-benzyl-(R)-4,6-O-benzylidene-b-D-ribo-hexo-
3-ulo-pyranoside (6)
b
-
D
To a mixture of dry DMSO (8.41 g, 107.64 mmol) and anhyd
dichloromethane (72.0 ml) at ꢁ78 ꢀC a solution of trifluoroacetic
anhydride (16.05 g, 76.41 mmol) in anhyd dichloromethane
(18.0 ml) was added dropwise under argon and the mixture was
stirred at this temperature for 45 min. Then a solution of 5 (14.67 g,
36.82 mmol) in dry dichloromethane (40.0 ml) was added drop-
wise, maintaining the temperature at ꢁ78 ꢀC during this addition.
The mixture was stirred for 2 h at ꢁ78 ꢀC, then a solution of Et3N
(13.0 ml, 93.27 mmol) in anhyd dichloromethane (30.0 ml) was
added dropwise and the mixture was allowed to warm to 25 ꢀC.
Dichloromethane (300 ml) and water (100 ml) were added, the
phases were separated and the organic phase was extracted with
water (4ꢂ100 ml). The combined organic phases were evaporated
under reduced pressure and the remaining residue was subjected
to chromatography (silica gel, hexane/ethyl acetate¼50:50) to af-
To a solution of 3 (8.44 g, 27.27 mmol) and tetrabutylammo-
nium hydrogen sulfate (1.63 g, 4.80 mmol) in dichloromethane
(315.0 ml) an aq sodium hydroxide solution (1.3 M, 31.6 ml) was
added and the mixture was heated to reflux. Benzylbromide
(4.91 ml, 41.06 mmol) was added dropwise under vigorous stirring.
After stirring under reflux for 96 h and cooling to 25 ꢀC, water
(80 ml) was added, the phases were separated and the aq phase
was extracted with dichloromethane (3ꢂ100 ml). The combined
organic phases were evaporated and the remaining residue was
subjected to chromatography (silica gel, hexane/ethyl
acetate¼85:15) to afford 4 (2.71 g, 25.0%) and 5 (5.22 g, 48.1%). Data
for 4: colourless crystals; mp 139–140 ꢀC (lit.26 140–141 ꢀC); [
a]
D
ꢁ18.96 (c 0.42; CHCl3) [lit.26
[
a
]
þ39.9 (c 1; CHCl3)]; Rf (hexane/
D
ethyl acetate¼5:3) 0.53; IR (KBr): ¼3364s, 3067m, 3034m, 2971m,
n
2931m, 2907m, 2860s, 1966w, 1735s, 1643m, 1586m, 1498m, 1452s,
1400m, 1367s, 1303m, 1283m, 1264m, 1209m, 1173s, 1093s, 1066s,
1030s, 1008s, 964s, 932s, 876m, 753s, 697s, 665m, 629m, 593m,
ford 6 (10.90 g, 74.7%) as colourless crystals; mp 125–127 ꢀC; [
ꢁ64.84 (c 0.49, CHCl3); Rf (hexane/ethyl acetate¼5:3) 0.73; IR
(KBr):
a]
D
n
¼3426m, 3066m, 3032m, 2882m, 1746s, 1645m, 1497m,
450m cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼7.48–7.46 (m, 2H, Ph),
1452m, 1401m, 1384m, 1370m, 1362m, 1327m, 1276m, 1251m,
1216m, 1176s, 1162m, 1148m, 1128s, 1093s, 1074s, 1043s, 1030s,
1011s, 979s, 936m, 753s, 729m, 696s, 668w, 654m, 630w, 569m
3
3
0
00
0
0
7.39–7.26 (m, 8H, Ph), 5.093 (dddd, 1H, J2 ,1 ¼6.4, J2 ,1 ¼5.3,
3
3
0
0
0
00
J2 ,3 ¼10.5, J2 ,3 ¼17.2, H-2 ), 5.56 (s, 1H, CH-benzylidene), 5.32
2
3
2
00
00
0
00
0
0
00
(dddd, 1H, J3 ,3 ¼1.4, J3 ,2 ¼17.2, H-3 ), 5.22 0(0dddd, 1H, J3 ,3 ¼1.4,
cmꢁ1
;
1H NMR (500 MHz, CDCl3):
d
¼7.49–7.47 (m, 2H, Ph), 7.41–
3
2
2
3
0
0
0
00
0
0
00
J3 ,2 ¼10.5, H-300), 4.95 (d, 1H, JH ,H ¼11.7, CH 2(OBn)), 4.79 (d, 1H,
7.39 (m, 2H, Ph), 7.36–7.26 (m, 6H, Ph), 5.93 (dddd, 1H, J2 ,1 ¼5.3,
3
3 3 3
0
00
0
0
0
0
0
0
00
JH ,H ¼11.7, CH 2(OBn)), 4.44 (d, 1H, J1,2¼7.6, H-1), 4.36 (dddd,
J2 ,1 ¼5.6, J2 ,3 ¼10.8, J2 ,3 ¼17.2, H-2 ), 5.52 (s, 1H, CH-benzyli-
3
2
3
4 2 4 3
1H, J1 ,2 ¼5.3, J1 ,1 ¼12.8, H-100), 4.33 (dd, 1H, J6B,5¼4.9,
dene), 5.36 (dddd, 1H, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.5, J3 ,2 ¼17.2,
00
0
00
0
00
0
00
0
00 00
00
0
2
2
4
4
2
3
J6B,6A¼10.5, H-6B), 4.14 (dddd, 1H, 3J1 ,2 ¼6.4, J1 ,1 ¼12.7, H-1 ), 3.79
H-300), 5.24 (dddd,1H, J3 ,1 ¼1.4, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,2 ¼10.8, H-
0
0
0
0
00
0
0
0
00
0
00
0
0
2
2
(dd, 1H, 3J6A,5¼10.1, 2J6A,6B¼10.5, H-6A), 3.67 (m, 2H, H-3, H-4), 3.58
30), 4.89 (d, 1H, JH ,H ¼11.9, CH 2(OBn)), 4.75 (d, 1H, JH ,H ¼11.9,
00
00
0
0
00
3
3
(dd, 1H, 3J2,1¼7.6, 3J2,3¼9.5, H-2), 3.43 (ddd, 1H, 3J5,6B¼4.9, 3J5,4¼9.1,
CH02(OBn)), 4.72 (d, 1H, J1,2¼7.4, H-1), 4.45 (dd, 1H, J6B,5¼4.9,
3J5,6A¼10.1, H-5) ppm; 13C NMR (125 MHz, CDCl3):
d¼138.3 (Car),
J6B,6A¼10.4, H-6B), 4.40 (dddd, 1H, 4J1 ,3 ¼1.5, J1 ,3 ¼1.4, J1 ,2 ¼5.3,
2
2
4
3
00 00
00
0
00
0
00
0
137.2 (Ph), 133.5 (C20), 129.0 (Car), 128.4 (Car), 128.2 (Car), 128.0 (Car),
127.8 (Car), 126.0 (Car), 118.2 (C30), 102.2 (C1), 101.3 (CH-benzyli-
dene), 81.4 (C3), 80.2 (C4), 74.6 (CH2(OBn)), 74.3 (C2), 70.5 (C10),
68.7 (C6), 66.4 (C5) ppm; MS (ESI-MeOH): m/z (%)¼399.2 ([MþH]þ,
18), 416.1 ([MþNH4]þ, 30), 421.3 ([MþNa]þ, 22), 433.9 ([M2þK,
HMeOH]2þ, 3), 617.2 ([M3þK, H]2þ, 16), 818.9 ([M2þNa]þ, 100);
analysis for C23H26O6 (398.45): calcd: C, 69.33; H, 6.58; found: C,
69.17; H, 6.71.
J1 ,1 ¼12.7, H-1 ), 4.24–4.18 (m, 2H, H-4, H-1 ), 4.00 (dd, 1H,
00
0
3J2,1¼7.4, 4J2,4¼1.5, H-2), 3.85 (dd, 1H, 3J6A,5¼9.9, 2J6A,6B¼10.4, H-6A),
3.57 (ddd, 1H, J5,6B¼4.9, J5,4¼9.9, J5,6A¼9.9, H-5) ppm; 13C NMR
3
3
3
(125 MHz, CDCl3):
d¼196.4 (C]O (3)), 137.1 (Car), 136.3 (Ph),
133.2 (C20),129.3 (Car),128.8 (Car),128.4 (Car), 128.3 (Car),128.3 (Car),
128.4 (Car), 128.2 (Car), 128.1 (Car), 128.0 (Car), 127.9 (Car), 127.3 (Car),
126.3 (Car), 126.1 (Car), 118.1 (C30), 104.1 (C1), 101.7 (CH-benzyli-
dene), 82.8 (C2), 81.8 (C4), 73.6 (CH2(OBn)), 71.0 (C10), 69.2 (C6),
66.5 (C5) ppm; MS (ESI-MeOH): m/z (%)¼397.0 ([MþH]þ, 6), 414.1
([MþNH4]þ, 14), 446.1 ([MþNH4, MeOH]þ, 34), 451.3 ([MþNa,
MeOH]þ, 38), 815.0 ([M2þNa]þ, 100), 846.9 ([M2þNa, MeOH]þ, 60),
878.9 ([M2þNa, (MeOH)2]þ, 52); analysis for C23H24O6 (396.43):
calcd: C, 69.43; H, 6.10; found: C, 69.31; H, 6.28.
Data for 5: colourless crystals; mp 124–125 ꢀC (lit.27 124 ꢀC);
[
a
]
ꢁ17.70 (c 0.93; CHCl3); Rf (hexane/ethyl acetate¼5:3) 0.63; IR
D
(KBr):
n
¼3477s, 3288s, 3063m, 3030m, 2978m, 2877s, 1736w,
1645m, 1497m, 1454s, 1400m, 1384s, 1366m, 1348m, 1306m,
1266m, 1216m, 1180s, 1099s, 1046s, 1028s, 986s, 934s, 911m, 877m,
761s, 750s, 734s, 697s, 658m, 601m, 568m, 512m, 461m cmꢁ1 1H
;
NMR (400 MHz, CDCl3):
d
0
¼7.47–7.45 (m, 2H, Ph), 7.37–7.26 (m, 8H,
4.5. Allyl 2-O-benzyl-(R)-4,6-O-benzylidene-3-deoxy-3,3-
difluoro-b-D-ribo-hexopyranoside (7)
3
3
3
3
00
0
0
0
0
0
00
Ph), 5.93 (dddd, 1H, J2 ,1 ¼5.2, J2 ,1 ¼5.7, J2 ,3 ¼10.8, J2 ,3 ¼17.3,
2
H-20), 5.50 (s,00 1H, CH-benzylidene), 5.34 (dd, 1H, J3 ,3 ¼1.5,
00
0
3
2
3
0
00
0
2
0
00
0
0
J3 ,2 ¼17.3, H-3 ), 5.020 2 (dd, 1H, J3 ,3 ¼1.5, J3 ,2 ¼10.8, H-3 ), 4.94 (d,
To a solution of 6 (300 mg, 0.72 mmol) in anhyd dichloro-
methane (6.0 ml), DAST (417 l, 3.03 mmol) was added dropwise
2
0
00
0
0
00
1H, JH ,H ¼12.0, CH 2(OBn)), 4.72 (d, 1H, JH ,H ¼12.0, CH 2(OBn)),
m

470
R. Csuk et al. / Tetrahedron 66 (2010) 467–472
3
3
3
2
4
00
under argon and the mixture was stirred at 25 ꢀC for 5 days.
Methanol (5.0 ml) was carefully added and the solvents were re-
moved under diminished pressure. The oily residue was dissolved
in dichloromethane (90 ml) and washed with water (50 ml). The aq
phase was extracted with dichloromethane (3ꢂ100 ml); the
organic phases were combined and the solvent was evaporated.
The remaining residue was subjected to chromatography (silica gel,
hexane/ethyl acetate¼5:3) to afford 7 (167 mg, 55.2%) as a white
JF ,2¼4.4, JF ,4¼4.3, JF ,F ¼243.5, F ), ꢁ133.69 (dddd, 1F, JF ,1¼1.4,
00
00
00
0
0
3
2
0
0
0
0
00
JF ,2¼17.9, JF ,4¼17.9, JF ,F ¼243.5, F ) ppm; MS (ESI-MeOH): m/z
(%)¼331.1 ([MþH]þ, 4), 348.3 ([MþNH4]þ, 52), 353.3 ([MþNa]þ,
100), 515.0 ([M3þK, H]2þ, 46), 672.0 ([M4þNa, H]2þ, 26), 682.8
([M2þNa]þ, 74); analysis for C16H20F2O5 (330.32): calcd: C, 58.18; H,
6.10; found: C, 57.94; H, 6.35.
4.7. Allyl 2,4,6-tri-O-benzyl-3-deoxy-3,3-difluoro-b-D-ribo-
hexopyranoside (9)
foam; [
0.67; IR (film):
745w, 698m cmꢁ1; 1H NMR (500 MHz, CDCl3):
a
]
ꢁ27.89 (c 0.39; CHCl3); Rf (hexane/ethyl acetate¼5:3)
D
n
¼2927m, 1736m, 1454m, 1384m, 1252m, 1093s,
d¼7.50–7.48 (m, 2H,
To an ice-cold solution of 8 (2.79 g, 8.45 mmol) in dry DMF
(40 ml), sodium hydride (80% in mineral oil, 1.01 g, 33.79 mmol)
was slowly added in several portions. Stirring at 0 ꢀC followed by
stirring at 25 ꢀC was continued for another hour, then benzyl-
bromide (3.03 ml, 25.34 mmol) was slowly added at 0 ꢀC. After
stirring at 25 ꢀC for another 4 h, methanol (30 ml) was carefully
added and the solvents were removed under diminished pressure.
The oily residue was dissolved in diethylether (200 ml), washed
with water and brine (100 ml each) and dried (MgSO4). The sol-
vents were evaporated and the remaining residue was subjected to
chromatography (silica gel, hexane/ethyl acetate¼85:15) to afford 9
3
3
0
00
0
0
Ph), 7.41–7.28 (m, 8H, Ph),0 5.93 (dddd, 1H, J2 ,1 ¼0.7, J2 ,1 ¼5.8,
3
3
0
0
0
00
J2 ,3 ¼10.5, J2 ,3 ¼17.2, H-2 ), 5.53 (s, 1H, CH-benzylidene), 5.35
4
2
4
3
00
00
0
00
0
00 00
00
0
(dddd, 1H, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.5, J3 ,2 ¼17.2, H-3 ), 5.24
(dddd, 1H, 4J3 ,1 ¼1.3, J3 ,1 ¼1.5, J3 ,3 ¼1.3, J3 ,2 ¼10.5, H-3 ), 4.89 (d,
4
2
3
0
0
0
0
00
0
00
0
0
2
2
00
0
00
0
0
00
1H, JH ,H ¼11.5, CH 2(OBn)), 4.86 (d, 1H, JH ,H ¼11.5, CH 2(OBn)),
4.70 (dd, 1H, 3J1,2¼7.8, 4J1,F ¼1.1, H-1), 4.42–4.37 (m, 2H, H-6B, H-1 0),
00
0
4
4
3
2
0
0
0
00
0
0
0 00
4.18 (dddd, 1H, J1 ,3 ¼1.3, J1 ,3 ¼1.5, J1 ,2 ¼5.8, J1 ,1 ¼12.7, H-1 ),
3.79–3.68 (m, 3H, H-4, H-5, H-6A), 3.55 (ddd,1H, 3J2,1¼7.8, 3J2,F ¼4.7,
00
3J2,F¼18.9, H-2) ppm; 13C NMR (125 MHz, CDCl3):
¼137.1 (Car),
d
136.4 (Ph), 133.3 (C20), 129.3 (Car), 128.4 (Car), 128.3 (Car), 128.3 (Car),
128.0 (Car), 128.0 (Car), 127.8 (Car), 126.2 (Car), 117.9 (C30), 117.2 (dd,
(3.08 g, 71.4%) as a colourless oil; [
(hexane/ethyl acetate¼85:15) 0.74; Rf (hexane/ethyl acetate¼5:3)
0.79; IR (film):
¼3356m, 3032m, 2921m, 1723m, 1497m, 1454m,
1404m, 1351m, 1239m, 1061s, 860w, 739m, 698m cmꢁ1 1H NMR
a
]
D
þ11.32 (c 0.38, CHCl3); Rf
1J3,F¼250.0, J3,F¼255.5, C3), 101.9 (CH-benzylidene), 101.6 (d,
1
3J1,F¼5.7, C1), 78.5 (dd, J2,F¼18.3, J2,F¼18.5, C2), 77.9 (dd,
n
2
2
2J4,F¼18.5, 2J4,F¼18.9, C4), 75.1 (CH2(OBn)), 71.0 (C10), 68.7 (C6), 64.3
;
(d, 3J5,F¼6.9, C5) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢁ119.01 (ddd,
(500 MHz, CDCl3):
d
¼7.40–7.23 (m, 15H, Ph),0 5.93 (dddd, 1H,
3
3
2
3
4
3
3
3
1F, JF ,2¼4.7, JF ,4¼4.7, JF ,F ¼243.6, F00), ꢁ132.73 (dddd, 1F,
J2 ,1 ¼5.1, J2 ,1 ¼6.1, J2 ,3 ¼10.5, J2 ,3 ¼17.3, H-2 ), 050 .32 (dddd, 1H,
00
00
00
0
0
00
0
0
0
4
0
0
3
00
4
3
2
2
2
0
0
0
0
0
00
00
0
00
0
00 00
2
00
0
JF ,1¼1.1, JF ,4¼17.8, JF ,2¼18.9, JF ,F ¼243.6, F ) ppm; MS (ESI-
J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.6, J3 ,2 ¼17.3, H-3 ), 5.19 (dddd,
MeOH): m/z (%)¼419.1 ([MþH]þ, 56), 436.1 ([MþNH4]þ, 52), 441.3
([MþNa]þ, 53), 647.1 ([M3þK, H]2þ, 18), 853.8 ([M2þNH4]þ, 35),
858.7 ([M2þNa]þ, 100); analysis for C23H24F2O5 (418.43): calcd: C,
66.02; H, 5.78; found: C, 65.86; H, 5.92.
1H, J3 ,1 ¼1.3, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,2 ¼10.5, H-3 0)0, 4.88 (d, 1H,
4
4
3
0
0
0
0
00
0
00
0
0
2
2
00
00
0
00
0
JH ,H ¼11.5, CH 2(OBn)), 4.84 (d, 1H, JH ,H ¼11.1, CH 2(OBn)), 4.82
2
2
(d, 1H, JH ,H ¼11.5, CH02(OBn)), 4.58 (d, 1H, JH ,H ¼12.2,
0
00
00
0
4
3
CH002(OBn)), 4.56 (dd, 1H, J1,F ¼1.5, J1,2¼7.9, H-1), 4.53 (d, 1H,
0
2
2
JH ,H ¼11.1, CH02(OBn)), 4.50 (d, 1H, JH ,H ¼12.2, CH02(OBn)),
0
00
0
00
4
4
3
2
00
00 00
00
0
00
0
00 0
4.6. Allyl 2-O-benzyl-3-deoxy-3,3-difluoro-
b
-D
-ribo-
4.39 (dddd, 1H, J1 ,3 ¼1.6, J1 ,3 ¼1.5, J1 ,2 ¼5.1, J1 ,1 ¼12.9, H-1 0),
4
4
3
2
0
0
0
00
0
0
0 00
hexopyranoside (8)
4.13 (dddd, 1H, J1 ,3 ¼1.3, J1 ,3 ¼1.4, J1 ,2 ¼6.1, J1 ,1 ¼12.9, H-1 ),
3 3 3
00
0
3.74 (ddd, 1H, J4,F ¼3.4, J4,5¼9.8, J4,F ¼19.3, H-4), 3.68–3.65 (m,
2H, H-6B, H-6A), 3.58 (m,1H, H-5), 3.49 (ddd,1H, 3J2,F ¼4.4, J2,1¼7.9,
3
00
To a solution of 7 (2.25 g, 5.68 mmol) in dichloromethane
(14.7 ml), water (0.3 ml) and a solution of trifluoroacetic acid in
dichloromethane (30%, 8.0 ml) were added at 25 ꢀC and stirring
was continued for another hour. Dichloromethane (60 ml) and
water (40 ml) were added, the phases were separated and the aq
phase was extracted with water (3ꢂ100 ml). The aq phase was
extracted with dichloromethane (3ꢂ100 ml) and the combined
organic layers were dried (MgSO4). The solvents were evaporated
under reduced pressure and the remaining residue was subjected
to chromatography (silica gel, hexane/ethyl acetate¼50:50) to af-
3
J2,F ¼20.0, H-2) ppm; 13C NMR (125 MHz, CDCl3):
d
¼137.9 (Ph),
0
137.4 (Ph), 137.2 (Ph), 133.7 (C20), 128.7 (Car), 128.5 (Car), 128.5 (Car),
128.4 (Car), 128.3 (Car), 128.2 (Car), 128.1 (Car), 128.0 (Car), 127.9 (Car),
127.8 (Car), 127.7 (Car), 127.6 (Car), 122.5 (dd, 1J3,F¼248.1, 1J3,F¼252.8,
3
2
C3), 117.4 (C30), 100.9 (d, J1,F¼10.2, C1), 78.1 (dd, J2,F¼18.2,
2J2,F¼18.7, C2), 74.9 (CH2(OBn)), 74.9 (CH2(OBn)), 74.8 (CH2(OBn)),
73.5 (C4), 72.9 (d, 3J5,F¼8.2, C5), 70.5 (C10), 68.1 (C6) ppm; 19F NMR
3
3
00
00
(188 MHz, CDCl3):
d
¼ꢁ112.16 (ddd, 1F, JF ,4¼3.4, JF ,2¼4.4,
1
4
JF ,F ¼246.6, F0 ), ꢁ130.80 (dddd, 1F, JF ,1¼1.5, 3JF ,4¼19.3, 3JF ,2¼20.0,
00
00
0
0
0
0
1
þ
0
00
ford 8 (830 mg, 44.3%) as a colourless oil; [
CHCl3); Rf (hexane/ethyl acetate¼5:3) 0.06; Rf (methanol/ethyl
acetate¼10:90) 0.75; IR (film): ¼3396s, 3033m, 2883m, 1677m,
1498m, 1455m, 1407m, 1351m, 1237s, 1070s, 930m, 854m, 745m,
699s, 552w cmꢁ1; 1H NMR (500 MHz, CDCl3):
a
]
ꢁ20.67 (c 0.53,
JF ,F ¼246.6, F ) ppm; MS (ESI-MeOH): m/z (%)¼528.3 ([MþNH4] ,
D
52), 533.3 ([MþNa]þ, 46), 565.1 ([MþNa, MeOH]þ, 24), 597.1
([MþNa, (MeOH)2]þ, 16), 631.0 ([MþNa, (MeOH)3]þ, 8), 1042.7
([M2þNa]þ, 100), 1074.7 ([M2þNa, MeOH]þ, 20), 1106.5 ([M2þNa,
(MeOH)3]þ, 10), 1140.7 ([M2þNa,(MeOH)4]þ, 3) analysis for
C30H32F2O5 (510.57): calcd: C, 70.57; H, 6.32; found: C, 70.41; H,
6.54.
n
d
¼7.33–7.22 (m, 5H,
3
3
3
3
0
00
0
0
0
0
0
00
Ph),0 5.86 (dddd, 1H, J2 ,1 ¼5.4, J2 ,1 ¼5.8, J2 ,3 ¼10.5, J2 ,3 ¼17.2,
4
2
4
3
00
0
00
0
00 00
00
0
H-2 ), 5.27 (dddd, 1H, J3 ,1 ¼1.3, J3 ,3 ¼1.5, J3 ,1 ¼1.6, J3 ,2 ¼17.2,
4
4
2
3
H-300), 5.16 (dddd, 1H, J3 ,1 ¼1.3, 00 J3 ,1 ¼1.4, J3 ,3 ¼1.5, J3 ,2 ¼10.5,
0
0
0
00
0
00
0
0
H-30), 4.81 (d, 1H, JH ,H ¼11.5, CH 2(OBn)), 4.76 (d, 1H, 2JH ,H ¼11.5,
4.8. 2,4,6-Tri-O-benzyl-3-deoxy-3,3-difluoro-
hexopyranose (10)
D
-ribo-
2
00
0
0
00
4
3
CH02(OBn)), 4.57 (dd, 1H, J1,F ¼1.4, J1,2¼7.9, H-1), 4.31 (dddd, 1H,
0
4
4
4
3
2
00
00 00
00
0
00
0
00 0
J1 ,3 ¼1.3, J1 ,3 ¼1.4, J1 ,2 ¼5.4, J1 ,1 ¼12.8, H0-1 ), 4.10 (dddd, 1H,
4
3
2
0
0
0
00
0
0
0 00
J1 ,3 ¼1.3, J1 ,3 ¼1.3, J1 ,2 ¼5.8, J1 ,1 ¼12.8, H-1 ), 3.86 (m, 1H, H-6B),
To a solution of 9 (2.84 g, 5.56 mmol) in methanol (30.0 ml),
PdCl2 (400 mg, 2.26 mmol) was slowly added under argon and
stirring was continued for another 24 h. The suspension was fil-
trated and the remaining residue was washed with methanol
(4ꢂ100 ml). The combined organic layers were dried (MgSO4) and
the solvents were evaporated under reduced pressure. The
remaining residue was subjected to chromatography (silica gel,
hexane/ethyl acetate¼5:3) to afford 10 (2.61 g, 99.7%) as a mixture
3.76 (dd, 1H, 3J6A,5¼4.0, 2J6A,6B¼12.0, H-6A), 3.73 (ddd, 1H, 3J4,F ¼4.3,
00
3
3
3
0
J4,5¼9.9, J4,F ¼17.9, H-4), 3.42 (m, 1H, H-5), 3.38 (ddd, 1H,
J2,F ¼4.4, J2,1¼7.9, J2,F ¼17.9, H-2) ppm; 13C NMR (125 MHz,
3
3
00
0
CDCl3):
d
¼137.2 (Ph), 133.4 (C20), 128.3 (Car), 128.2 (Car), 128.0 (Car),
1
1
119.5 (dd, J3,F¼245.3, J3,F¼253.1, C3), 117.8 (C30), 100.9 (d,
3J1,F¼10.1, C1), 77.8 (dd, J2,F¼19.0, J2,F¼18.1, C2), 74.9 (CH2(OBn)),
2
2
73.7 (d, 3J5,F¼6.5, C5), 70.9 (C10), 68.5 (dd, 2J4,F¼20.1, 2J4,F¼20.1, C4),
61.6 (C6) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢁ116.08 (ddd, 1F,
of equilibrating anomers; colourless crystals; mp 128–130 ꢀC; [
a]
D

R. Csuk et al. / Tetrahedron 66 (2010) 467–472
471
þ27.17 (c 0.43, CHCl3); Rf (hexane/ethyl acetate¼85:15) 0.08 and
0.04; Rf (hexane/ethyl acetate¼5:3) 0.51 and 0.41; IR (KBr):
(2.0 ml) was added dropwise under argon and the mixture was
stirred for 45 min at ꢁ78 ꢀC. A solution of 11 (660 mg,1.40 mmol) in
anhyd dichloromethane (11 ml) was added dropwise and stirring
was continued at ꢁ78 ꢀC for 2 h followed by a solution of Et3N
(2.9 ml, 20.94 mmol) in anhyd dichloromethane (11.0 ml). After
stirring at ꢁ78 ꢀC for 30 min and 1 h at 25 ꢀC, followed by usual aq
work-up, the remaining residue was subjected to chromatography
(silica gel, hexane/ethyl acetate¼5:3) to afford 12 (370 mg, 56.5%)
as a mixture of dicarbonyl compound and its corresponding hy-
n
¼3442m, 3031m, 2919m, 2864m, 1734w, 1497w, 1454m, 1405w,
1362m, 1265m, 1237m, 1187m, 1094s, 1073m, 1049m, 1029m,
1003m, 914w, 864w, 788w, 756m, 734m, 699m, 649w, 620w, 523w
cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼7.40–7.21 (m, 30H, Ph), 5.20
2
00
0
(m, 1H), 4.90–4.80 (m, 6H), 4.72 (d, 1H, JH ,H ¼12.1, CH2(OBn)),
4.57–4.51 (m, 4H), 4.47 (d, 1H, 2JH ,H ¼12.0, CH2(OBn)), 4.45 (d, 1H,
00
0
2
00
0
JH ,H ¼12.2, CH2(OBn)), 4.10 (ddd, 1H, J¼1.6, J¼3.3, J¼5.8), 3.81
(ddd, 1H, J¼4.5, J¼9.7, J¼19.4), 3.77–3.62 (m, 7H), 3.42 (ddd, J¼4.2,
drates; white foam; [
a
]
ꢁ13.22 (c 0.25, MeOH); Rf (hexane/ethyl
D
J¼7.7, J¼19.9) ppm; 13C NMR (125 MHz, CDCl3):
d¼137.6 (Ph), 137.3
acetate¼5:3) 0.35; IR (KBr): ¼3418s, 2919s, 1732s, 1583w, 1454m,
n
(Ph), 137.3 (Ph), 137.2 (Ph), 137.2 (Ph), 137.1 (Ph), 128.6 (Car), 128.4
(Car), 128.4 (Car), 128.4 (Car), 128.4 (Car), 128.3 (Car), 128.2 (Car), 128.1
(Car), 128.0 (Car), 128.0 (Car), 128.0 (Car), 128.0 (Car), 127.9 (Car), 127.9
(Car), 127.8 (Car), 121.4 (m, C3), 120.8 (m, C3), 95.6 (d, 3J1,F¼10.6, C1),
1384m, 1268s, 1097s, 738w, 712m cmꢁ1; MS (ESI-MeOH): m/z
(%)¼504.3 ([MþNH4, H2O]þ, 43), 509.5 ([MþNa, H2O]þ, 76), 518.3
([MþNH4, MeOH]þ, 58), 523.4 ([MþNa, MeOH]þ, 100), 567.3
([MþNH4, (MeOH)2, H2O]þ, 58), 599.4 ([MþNH4, (MeOH)3, H2O]þ,
30), 994.9 ([M2þNa, (H2O)2]þ, 58), 1008.9 ([M2þNH4, (H2O)2]þ, 44).
3
91.3 (d, J1,F¼8.5, C1), 78.9 (m), 75.1–74.0 (m, CH2(OBn)), 73.6
3
3
(CH2(OBn)), 73.0 (d, J5,F¼8.2, C5), 68.3 (d, J5,F¼7.2, C5), 68.2 (6),
67.7 (6) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢁ107.81 (d, 1F,
1
1
00
00
00
0
0
00
JF ,F ¼247.6, F ), ꢁ111.89 (d, 1F, JF ,F ¼247.1, F ), ꢁ125.74 (ddd, 1F,
4.11. N-Benzyl-2,4,6-tri-O-benzyl-1,3,5-trideoxy-3,3-difluoro-
1
0
0
0
00
0
0
JF ,H¼20.3, JF ,H¼20.3, JF ,F ¼247.6, F ), ꢁ130.83 (ddd, 1F, JF ,H¼19.4,
1,5-imino-D-ribo-hexitol (13) and N-benzyl-2,4,6-tri-O-benzyl-
1
0
0
0
00
JF ,H¼19.4, JF ,F ¼247.1, F ) ppm; MS (ESI-MeOH): m/z (%)¼488.3
([MþNH4]þ, 15), 493.3 ([MþNa]þ, 15), 725.5 ([M3þK, H]2þ, 3), 962.8
([M2þNa]þ, 100); source CID: m/z (%)¼488.5 ([MþNH4]þ, 2), 493.4
([MþNa]þ, 100), 962.7 ([M2þNa]þ, 2); analysis for C27H28F2O5ꢂ
(470.51): calcd: C, 68.92; H, 6.00; found: C, 68.77; H, 6.29.
1,3,5-trideoxy-3,3-difluoro-1,5-imino-
L
-lyxo-hexitol (14)
To a solution of 12 (370 mg, 0.79 mmol) in abs methanol
(7.0 ml), sodium sulfate (1.00 g) was added and the solution cooled
to ꢁ78 ꢀC. A solution of benzylamine (103
ml, 0.95 mmol) and acetic
acid (135 ml, 2.34 mmol) in abs methanol (7.0 ml) was added and
4.9. 2,4,6-Tri-O-benzyl-3-deoxy-3,3-difluoro-
hexitol (11)
D
-ribo-
the mixture was stirred for 2 h at this temperature. Sodium cya-
nobohydride (109 mg, 1.74 mmol) was added in small portions and
the suspension was stirred for another 2 h. The solution was
allowed to warm to 25 ꢀC and stirring was continued for additional
24 h followed by 48 h at 50 ꢀC. Methanol (30 ml) was added and the
suspension was filtered through a thin layer of silica gel. The sol-
vents were evaporated, the remaining residue was dissolved in
dichloromethane (50 ml) and was washed with saturated sodium
hydrogen carbonate solution and saturated sodium chloride solu-
tion (20 ml each). The organic layer was dried (Na2SO4), the sol-
vents were evaporated and the remaining residue was subjected to
chromatography (silica gel, hexane/ethyl acetate¼85:15) to afford
13 (100 mg, 23.3%) and 14 (70 mg,16.3%). Data for 13: colourless oil;
To an ice-cold solution of 10 (1.99 g, 4.23 mmol) in abs THF
(150.0 ml), lithium aluminium hydride (642 mg, 16.92 mmol) was
added in several portions and the suspension was stirred for 12 h at
25 ꢀC. Methanol (30 ml) was carefully added and stirring was
continued for another 30 min. The solvents were evaporated under
reduced pressure. The remaining residue was subjected to
chromatography (silica gel, hexane/ethyl acetate¼5:3) to afford
11 (1.52 g, 76.1%) as a colourless oil; [
a
]
þ5.28 (c 0.40, CHCl3);
D
3Rf (hexane/ethyl acetate¼5:3) 0.36; IR (film): ¼3453s, 3090m,
n
3065m, 3032m, 2926m, 1732m, 1644m, 1497m, 1454s, 1360s,
1211m, 1102s, 1028s, 912m, 822m, 738s, 699s, 605m cmꢁ1; 1H NMR
[
a
]
ꢁ33.47 (c 0.30, CHCl3); Rf (hexane/ethyl acetate¼85:15) 0.51;
D
(500 MHz, CDCl3):
d
¼7.37–7.22 (m, 15H, Ph), 4.78 (d, 1H,
Rf (hexane/ethyl acetate¼5:3) 0.86; IR (film): ¼3088m, 3063m,
n
2
2
00
00
00
0
00
0
JH ,H ¼11.3, CH 2(OBn)), 4.74 (d, 1H, JH ,H ¼11.0, CH 2(OBn)), 4.69
3030m, 2922m, 2872m, 2360w, 1953w, 1875w, 1812w, 1737w,
1604w, 1586w, 1496s, 1454s, 1368s, 1321m, 1238s, 1207m, 1070s,
1028s, 1002s, 909w, 853w, 736s, 698s, 607w, 464w cmꢁ1; 1H NMR
(d, 1H, 2JH ,H ¼11.3, CH 2(OBn)), 4.63 (d, 1H, JH ,H ¼11.0, CH 2(OBn)),
2
0
0
0
00
0
00
2
2
00
00
0
0
00
4.54 (d, 1H, JH ,H ¼11.8, CH 2(OBn)), 4.48 (d, 1H, JH ,H ¼11.8,
CH02(OBn)), 4.14–3.97 (m, 3H, H-2, H-4, H-5), 3.85 (dd, 1H,
(500 MHz, CDCl3):
d
¼7.30–7.12 (m, 20H, Ph), 4.68 (d, 1H,
2
3
2
2
2
3J1B,2¼2.0, J1B,1A¼11.5, H-1B), 3.78 (dd, 1H, J1A,2¼5.7, J1A,1B¼11.5,
JH ,H ¼11.9, CH 2(OBn)), 4.67 (d, 1H, JH ,H ¼11.9, CH 2(OBn)), 4.60
00
0
00
0
0
00
H-1A), 3.68–3.61 (m, 2H, H-6B, H-6A) ppm; 13C NMR (125 MHz,
(d, 1H, JH ,H ¼12.0, CH002(OBn)), 4.50 00 (d, 1H, JH ,H ¼11.9,
2
2
00
0
0
00
2
CH02(OBn)), 4.44 (d, 1H, JH ,H ¼12.0, CH 2(OBn)),00 4.40 (d, 1H,
00
0
CDCl3):
d
¼137.8 (Ph), 137.4 (Ph), 137.2 (Ph), 128.6 (Car), 128.5 (Car),
2
2
0
0
00
00
0
128.5 (Car), 128.4 (Car), 128.4 (Car), 128.2 (Car), 128.2 (Car), 128.1 (Car),
JH ,H ¼11.9, CH 2(OBn)), 3.91 (d, 1H, JH ,H ¼13.9, CH 2(NBn)), 3.85
128.1 (Car), 127.9 (Car), 127.9 (Car), 127.8 (Car), 122.7 (dd, 1J3,F¼253.4,
(dd, 1H, J6B,5¼4.07, J6B,6A¼10.8, H-6B), 3.70 (dd, 1H, J6A,5¼1.6,
2 2
3
2
3
1J3,F¼250.5, C3), 79.4 (dd, J4,F¼24.4, J4,F¼26.4, C4), 77.9 (dd,
J6A,6B¼10.8, H-6A), 3.67 (m, 1H, H-4), 3.61 (d, 1H, JH ,H ¼13.9,
3
3
0
00
3J2,F¼22.5, J2,F¼24.9, C2), 75.4 (CH2(OBn)), 74.2 (CH2(OBn)), 73.5
CH02(NBn)), 3.49 (dddd, 1H, J2,F ¼5.4, J2,1B¼5.2, J2,1A¼10.4,
3
3
3
3
00
4
4
4
(CH2(OBn)), 70.5 (C6), 69.7 (C5), 60.6 (dd, J1,F¼4.4, J1,F¼4.8, C1)
3J2,F¼19.5, H-2), 3.37 (m, 1H, H-5), 2.65 (ddd, 1H, J1B,F¼2.2,
ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢁ112.78 (ddd, 1F, JF ,4¼12.2,
3J1B,2¼5.2, 2J1B,1A¼11.7, H-1B), 2.57 (dd, 1H, J1A,2¼10.4, 2J1A,1B¼11.7,
3
3
00
3
3
JF ,2¼12.2, 1JF ,F ¼269.9, F ), ꢁ114.80 (ddd, 1F, JF ,4¼12.0, 3JF ,2¼12.0,
H-1A) ppm; 13C NMR (125 MHz, CDCl3):
d¼139.1 (Ph), 138.4 (Ph),
00
00
00
0
0
0
1
þ
0
0
00
JF ,F ¼269.9, F ) ppm; MS (ESI-MeOH): m/z (%)¼473.3 ([MþH] , 6),
137.7 (Ph), 137.5 (C(ar(ipso; NBn))), 128.8 (Car), 128.7 (Car), 128.4
(Car), 128.7 (Car), 128.3 (Car), 128.2 (Car), 128.0 (Car), 127.9 (Car), 127.8
(Car), 127.7 (Car), 127.7 (Car), 127.6 (Car), 127.5 (Car), 127.0 (Car), 121.1
(dd, 1J3,F¼251.5, 1J3,F¼251.0, C3), 75.8 (dd, 3J4,F¼18.7, 3J4,F¼18.7, C4),
490.3 ([MþNH4]þ, 28), 495.4 ([MþNa]þ, 36), 728.6 ([M3þK, H]2þ
,
7), 966.9 ([M2þNa]þ, 100); analysis for C27H30F2O5 (472.52): calcd:
C, 68.63; H, 6.40; found: C, 68.45; H, 6.63.
3
3
74.5 (dd, J2,F¼18.7, J2,F¼19.2, C2), 73.4 (CH2(OBn)), 73.4
4
4.10. 2,4,6-Tri-O-benzyl-3-deoxy-3,3-difluoro-
hexos-5-ulose (12)
D
-erythro-
(CH2(OBn)), 73.1 (CH2(OBn)), 66.8 (C6), 60.6 (d, J5,F¼6.3, C5), 58.9
(CH2(NBn)), 46.9 (C1) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢁ114.002
(d, 1F, 1JF ,F ¼245.6, F ), ꢁ130.10 (dd, 1F, JF ,H¼15.9, 1JF ,F ¼245.6, F )
ppm; MS (ESI-MeOH): m/z (%)¼544.3 ([MþH]þ, 100), 566.4
([MþNa]þ, 4); analysis for C34H35F2NO3 (543.64): calcd: C, 75.12; H,
6.49; N, 2.58; found: C, 75.01; H, 6.62; N, 2.41.
3
00
00
0
0
0
00
To a mixture of dry DMSO (1.23 g, 15.86 mmol) and anhyd
dichloromethane (11.0 ml) at ꢁ78 ꢀC a solution of trifluoroacetic
anhydride (2.29 ml, 11.26 mmol) in anhyd dichloromethane

472
R. Csuk et al. / Tetrahedron 66 (2010) 467–472
Data for 14: colourless oil; [
(hexane/ethyl acetate¼85:15) 0.43; Rf (hexane/ethyl acetate¼5:3)
0.84; IR (film):
¼3063m, 3031m, 2920m, 1738w, 1604w, 1496m,
a
]
þ5.00 (c 0.35 g, CHCl3); Rf
1455m, 1319m, 1242m, 1140m, 1010m, 944s, 912s, 850s, 705m,
604w, 540w, 491w cmꢁ1 1H NMR (500 MHz, CD3OD):
¼3.86–
3.75 (m, 3H, H-6B, H-6A, H-2), 3.68 (ddd, 1H, J4,F ¼4.1, J4,5¼10.5,
D
;
d
3
3
00
n
3
3
3
3
0
1454s, 1365m,1318m, 1241s, 1107s, 1028s,1004m, 844m, 737s, 698s
J4,F ¼21.1, H-4), 3.20 (ddd, 1H, J5,6B¼4.8, J5,4¼10.5, J5,6A¼4.53,
cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
¼7.36–7.18 (m, 20H, Ph), 4.89 (d,
H-5), 2.85 (ddd, 1H, J1B,F¼3.9, J1B,2¼3.4, J1B,1A¼11.3, H-1B), 2.78
3 2
4 3 2
2
2
1H, JH ,H ¼10.9, CH 2(OBn)), 4.74 (d, 1H, JH ,H ¼12.0, CH 2(OBn)),
(dd, 1H, J1A,2¼11.9, J1A,1B¼11.3, H-1A) ppm; 13C NMR (125 MHz,
00
00
00
0
00
0
2
2
1
1
0
0
00
0
00
4.57 (d, 1H, JH ,H ¼12.0, CH 2(OBn)), 4.51 (d, 1H, JH ,H ¼10.9,
CD3OD):
d
¼119.5 (dd, J3,F¼249.1, J3,F¼246.2, C3), 67.8–66.4 (m,
4
2
CH02(OBn)), 4.44 (d, 1H, JH ,H ¼12.1, CH 2(OBn)),00 4.38 (d, 1H,
C2, C4), 59.1 (C5), 59.0 (C6), 46.7 (d, J1,F¼6.3, C1) ppm; 19F NMR
00
00
0
2
2
1
0
00
0
00
00
0
00
0
JH ,H ¼12.1, CH 2(OBn)), 4.02 (d, 1H, JH ,H ¼13.6, CH 2(NBn)), 3.79
(188 MHz, CD3OD):
d
3
¼ꢁ121.98 (d, 1F, JF ,F ¼237.7, F ), ꢁ141.67
3
3
3
3
1
0
00
0
0
0
0
00
(ddd, 1H, J4,F ¼3.8, J4,5¼9.9, J4,F ¼19.9, H-4), 3.77 (dd, 1H,
(ddd, 1F, JF ,4¼21.1, JF ,2¼21.1, JF ,F ¼237.7, F ) ppm; MS (ESI-
MeOH): m/z (%)¼184.3 ([MþH]þ, 100), 194.9 ([M2þH, Na]2þ, 40);
analysis for C6H11F2NO3 (183.15): calcd: C, 39.35; H, 6.01; N, 7.65;
found: C, 39.28; H, 6.21; N, 7.59.
3J6B,5¼1.8, J6B,6A¼10.7, H-6B), 3.72 (dd, 1H, J6A,5¼3.3, J6A0 ,6B¼10.7,
2
3
2
3
2
00
H-6A), 3.63 (m, 1H, J2,F¼19.9, H-2), 3.33 (d, 1H, JH ,H ¼12.6,
CH02(NBn)), 2.88 (ddd, 1H, 4J1B,F¼3.58, 3J1B,2¼4.6, 2J1B,1A¼11.2, H-1B),
3
3
3
2.55 (ddd, 1H, J5,6B¼1.8, J5,4¼9.9, J5,6A¼3.3, H-5), 2.26 (dd, 1H,
3J1A,2¼1.2, J1A,1B¼11.2, H-1A) ppm; 13C NMR (125 MHz, CDCl3):
2
Acknowledgements
d
¼137.9 (Ph), 137.7 (Ph), 137.6 (Ph), 137.5 (Ph), 128.9 (Car), 128.4
(Car), 128.4 (Car), 128.3 (Car), 128.2 (Car), 127.9 (Car), 127.9 (Car), 127.8
The cell-toxicity experiments were performed by Mr. Stefan
Schwarz using cell lines kindly provided by Dr. Thomas Mu¨ller
(Dept. of Hematology/Oncology, Univ. Halle).
(Car), 127.1 (Car), 121.7 (dd, 1J3,F¼246.1, 1J3,F¼246.1, C3), 76.0 (m, C4),
3
3
75.4 (CH2(OBn)), 74.1 (dd, J2,F¼17.3, J2,F¼18.7, C2), 73.3
4
(CH2(OBn)), 73.3 (CH2(OBn)), 65.5 (C6), 62.7 (d, J5,F¼6.3, C5), 56.1
(CH2(NBn)), 52.3 (d, 4J1,F¼3.0, C1) 0p0 pm; 19F NMR (188 MHz, CDCl3):
1
3
References and notes
00
0
0
d
3
¼ꢁ113.95 (d, 1F, JF ,F ¼238.1, F ), ꢁ135.63 (ddd, 1F, JF ,4¼19.9,
1
0
0
0
00
JF ,2¼19.9, JF ,F ¼238.1, F ) ppm; MS (ESI-MeOH): m/z (%)¼544.3
([MþH]þ, 100), 566.3 ([MþNa]þ, 10); analysis for C34H35F2NO3
(543.64): calcd: C, 75.12; H, 6.49; N, 2.58; found: C, 74.98; H, 6.69;
N, 2.38.
1. Compain, P.; Martin, O. R. In IminosugarsdFrom Synthesis to Therapeutic Appli-
cations; Compain, P., Martin, O. R., Eds.; J. Wiley & Sons: Chichester, UK, 2007;
pp 1–6; Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Stu¨tz, A. E.,
Ed.; Wiley-VCH: New York, NY, 1999.
2. Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
J. Wiley & Sons: Chichester, UK, 2008.
4.12. 3,3-Difluoro-1,3-dideoxynojirimycin (15)
3. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
4. Wang, R.-W.; Qing, F.-L. Org. Lett. 2005, 7, 2189–2192.
5. Wang, R. W.; Qiu, X.-L.; Bols, M.; Ortega-Caballero, F.; Qing, F.-L. J. Med. Chem.
2006, 49, 2989–2997.
6. Szarek, M. A.; Wu, X.; Szarek, W. A. Carbohydr. Res. 1997, 299, 165–170.
7. Kocienski, P. J. Protecting Groups; G. Thieme: Stuttgart, 1994; Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; J. Wiley & Sons:
New York, NY, 1991.
8. Kishida, M.; Akita, H. Tetrahedron 2005, 61, 10559–10568.
9. Tanaka, H.; Kawai, K.; Fujiwara, K.; Murai, A. Tetrahedron 2002, 58,
10017–10031.
10. Dobhal, M. P.; Li, G.; Gryshuk, A.; Graham, A.; Bhatanager, A. K.; Khaja, S. J.;
Joshi, Y. C.; Sharma, M. C.; Oseroff, A.; Pandey, R. K. J. Org. Chem. 2004, 69,
6165–6172.
11. Bodenteich, M.; Griengl, H. Tetrahedron Lett. 1986, 27, 4291–4292.
12. Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.; Dahmen, J.; Noori,
G.; Stenvall, K. J. Org. Chem. 1988, 53, 5629–5647.
13. Hanessian, S.; Butterworth, R. F.; Nakagawa, T. Carbohydr. Res. 1973, 26,
261–263.
14. Matos, C. R. R.; Lopes, R. S. C.; Lopes, C. C. Synthesis 1999, 571–573.
15. Middleton, W. J. J. Org. Chem. 1975, 40, 574–578.
16. Murphy, P. V.; O’Brien, J. L.; Gorey-Feret, L. J.; Smith, A. B., III. Tetrahedron 2003,
59, 2259–2271.
A solution of 13 (170 mg, 0.31 mmol) in dry methanol (22.0 ml)
containing palladium on charcoal (10%; 120 mg) was hydrogenated
(35 ꢀC, 4.43 atm, 72 h). The solution was filtered through a Celite
pad and this pad was washed with methanol (2ꢂ30 ml). The
combined organic phases were dried (MgSO4), the solvent was
removed and the residue subjected to chromatography (silica gel,
methanol/ethyl acetate¼20:80) to afford 15 (50 mg, 87.3%) as
a white foam; [
acetate¼10:90) 0.10; Rf (methanol/ethyl acetate¼20:80) 0.32; IR
(film):
¼3257s, 2010w, 1822w, 1457s, 1363s, 1317s, 1274s, 1242s,
1110w, 1058m, 977s, 935s, 708w, 541w, 491w cmꢁ1 1H NMR
(500 MHz, CD3OD):
¼4.00 (m, 2H, H-2, H-4), 3.77 (m, 2H, H-6B, H-
a
]
þ3.71 (c 0.59, MeOH); Rf (methanol/ethyl
D
n
;
d
6A), 2.80 (m, 1H, H-1B), 3.15–3.10 (m, 2H, H-1A, H-5) ppm; 13C NMR
(125 MHz, CD3OD):
d
¼116.4 (dd, 1J3,F¼242.4, 1J3,F¼260.6, C3), 67.9–
4
4
66.7 (m, C2, C4), 59.5 (C6), 59.3 (d, J5,F¼5.7, C5), 47.1 (d, J1,F¼5.3,
C1) ppm; 19F NMR (188 MHz, CD3OD):
d¼ꢁ114.81 (d, 1F,
17. Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167, 305–311.
18. Betaneli, V. I.; Ott, A. Y.; Brukhanova, O. V.; Kochetkov, N. K. Carbohydr. Res.
1988, 179, 37–50.
19. Nelsen, S. F.; Teasley, M. F. J. Org. Chem. 1986, 51, 4319–4320.
20. Paulsen, H.; Heume, M.; Gyo¨rgydeak, Z.; Lebuhn, R. Carbohydr. Res. 1985, 144,
57–70.
1
1
00
0
00
0
0
00
JF ,F ¼261.0, F ), ꢁ119.80 (d, 1F, JF ,F ¼261.0, F ) ppm; MS (ESI-
MeOH): m/z (%)¼184.3 ([MþH]þ, 100), 194.9 ([M2þH, Na]2þ, 24);
analysis for C6H11F2NO3 (183.15): calcd: C, 39.35; H, 6.01; N, 7.65;
found: C, 39.21; H, 6.18; N, 7.48.
21. Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta, K.; Takahashi, S.; Koshino, H.;
Sahara, H.; Sakaguchi, K.; Sugawara, F. Tetrahedron Lett. 2000, 41, 4403–4407.
22. Bevan, T. H.; Martin, T.; Tiplady, J. M. J. Chem. Soc. 1957, 3086–3089.
23. Gilham, P. T.; Khorana, H. G. J. Am. Chem. Soc. 1959, 81, 4647–4650.
24. Conchie, J.; Gelman, A. C.; Levvy, G. A. Biochem. J. 1967, 103, 609–615.
25. Garneau, S.; Qiao, L.; Walker, S.; Vederas, J. C. Bioorg. Med. Chem. 2004, 12,
6473–6494.
26. Gent, P. A.; Gigg, R. Carbohydr. Res. 1976, 49, 325–333.
27. Sanders, W. J.; Manning, D. D.; Koeller, K. M.; Kiessling, L. L. Tetrahedron 1997,
53, 16391–16422.
4.13. 3,3-Difluoro-1,3-dideoxy-L-idonojirimycin (16)
Hydrogenation of 14 (110 mg, 0.20 mmol) in the presence of
palladium on charcoal (10%, 200 mg) as described above afforded
16 (30 mg, 81.0%) as a colourless oil; [
Rf (methanol/ethyl acetate¼10:90) 0.08; Rf (methanol/ethyl
acetate¼20:80) 0.23; IR (film): ¼3264m, 2019w, 1806w, 1570w,
a
]
þ13.19 (c 0.35, MeOH);
D
n