Unexpected formation of oxetanes from a geminal difluorinated δ-lactone

Article abstract of DOI:10.1016/j.tet.2009.12.010

A perbenzylated 3,3-difluorinated hexono-1,5-lactone was prepared in several steps. Reaction of this lactone with MeOH/p-TsOH followed by a treatment with ion-exchange resin led to the formation of an exocyclic oxetane derived vinylether. Similar reaction with ammonia gave the corresponding carboxamido substituted oxetane in good yields.

Full text of DOI:10.1016/j.tet.2009.12.010

Tetrahedron 66 (2010) 1313–1318
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unexpected formation of oxetanes from a geminal difluorinated d-lactone
*
´
Rene Csuk , Erik Prell
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:
A perbenzylated 3,3-difluorinated hexono-1,5-lactone was prepared in several steps. Reaction of this
lactone with MeOH/p-TsOH followed by a treatment with ion-exchange resin led to the formation of an
exocyclic oxetane derived vinylether. Similar reaction with ammonia gave the corresponding carbox-
amido substituted oxetane in good yields.
Received 10 November 2009
Received in revised form 30 November 2009
Accepted 2 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrate
Difluorination
Ring contraction
Oxetane
1. Introduction
that is, typical for a geminal difluoromethylene group. Cleavage of
the benzylidene acetal using 30% aq TFA8 afforded the diol 4 whose
Several (non-per)-fluorinated compounds have gained notable
economic importance in human life, among them 5-fluoro-uracil
benzylation9–11 yielded fully protected 5.
Treating 5 with PdCl2 in MeOH12,13 for one day led to an almost
quantitative deallylation and yielded 6 as a mixture of anomers.
These anomers could not be separated even by exhaustive chro-
matography because of fast anomerization. Nevertheless, the
anomeric mixture was oxidized applying Dess–Martin period-
(5-FU, anticancer), 2-deoxy-2-fluoro-D
-glucose (2-18FDG, di-
agnostic tool) or gemcitabine (antiviral and anticancer). In addition,
fluorinated carbohydrates are often used as probes of enzyme
specificity. Because of the importance and potency of fluorosugars
many applications in medicinal chemistry, pharmacology and bio-
chemistry have been reported during the last decades.1–3
inane14,15 to yield 73% isolated yield of the 3,3-difluoro-
D-ribono-
1,5-lactone 7. This lactone is characterized by the presence of
During our syntheses of difluorinated iminosugars4 we became
interested in the synthesis of gem-3,3-difluorinated carbohydrate
derived lactones as starting materials for the synthesis of the cor-
responding iminosugars. Following our previous approach,4 we
chose the allyl glycoside 1 as a starting material for our syntheses.
a signal at
d
¼166.5 ppm in the 13C NMR spectrum representative
for the lactone carbonyl group and two signals at
d
¼ꢀ111.46 and
0
d
¼ꢀ129.14 ppm (2JF,F ¼243.5 Hz) being representative for a gem-
difluoromethylene group.
An attempt to oxidize 6 by catal. amounts of tetra-n-propyl-
ammonium-perruthenate16 in the presence of NMMO and dry
molsieves (3 Å) failed. Under these conditions accompanying
2. Results and discussion
elimination of HF could not be avoided and the a,b-unsaturated
lactone 8 (Scheme 2) was formed in 84% yield. The presence of the
The benzylidene protected allyl glycoside 1 (Scheme 1) was
oxidized under Swern conditions5,6 to afford 75% of the uloside 2.
Compound 2 is characterized by the presence of a signal for the
double bond is indicated in the 13C NMR spectrum by the presence
of two sp2 hybridized carbons at
d
¼112.4 ppm (C-2, showing
newly created carbonyl group at
d
¼196.4 ppm in the 13C NMR
a
typical JC,F¼14.1 Hz) and at
d
¼156.1 ppm (C-3, showing
spectrum and a strong absorption signal in the IR at
n
¼1746 cmꢀ1
.
JC,F¼288.8 Hz) and only one fluorine substituent at ¼ꢀ116.12 ppm
d
in the 19F NMR spectrum.
Reaction of this 3-ulopyranoside 2 with DAST7 gave gem-difluori-
nated 3, that is, characterized in its 19F NMR spectrum by two
Lactone 8 was also obtained in 86% yield from the reaction of 7
with benzylamine in the presence of ion-exchange resin (IR 120Hþ)
under reflux. The reaction of 7 with benzylamine at 25 ꢁC provided
the aliphatic amide 9 in 78% isolated yield (Scheme 2). This ring
opening reaction leads to a dramatic change in the chemical shift of
2
0
signals at
d¼ꢀ119.01 and ꢀ132.73 ppm showing a JF,F ¼243.6 Hz,
* Corresponding author. Tel.: þ49 345 5525660; fax: þ49 345 5527030.
E-mail address: rene.csuk@chemie.uni-halle.de (R. Csuk).
one of the fluorine substituent (jDd F(in
j
¼12.01 ppm,
10), F(in 12)
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.010

1314
R. Csuk, E. Prell / Tetrahedron 66 (2010) 1313–1318
Scheme 1. (a) (F3CCO2)2O, DMSO, ꢀ78 ꢁC, 75%; (b) DAST, DCM, 25 ꢁC, 55%; (c) F3CCO2H, DCM, H2O, 25 ꢁC, 44%; (d) NaH, BnBr, DMF, 25 ꢁC, 71%; (e) PdCl2, MeOH, 25 ꢁC, 99%;
(f) periodinane, DCM, 25 ꢁC, 73%.
followed by a ring contraction with concomitant elimination of
a second molecule of HF. To corroborate our assumptions, isolated
10 was allowed to react with the ion-exchange resin and immedi-
ately compound 11 was formed. No intermediate, however, for this
transformation 10/11 could be detected. Therefore, lactone 7 was
allowed to react with 8 M ammonia and two compounds were
Scheme 2. (a) NMMO, perruthenate, 25 ꢁC, 84%; (b) BnNH2, toluene, 25 ꢁC, 78% (of 9);
(c) MeOH, p-TsOH, 25 ꢁC, 84% (of 10).
isolated from this reaction: open-chain 12 (25% isolated yield) and
the oxetane 13 (26% isolated yield). Treatment of 12 with ion-ex-
change resin led to the formation of 13, therefore making the
0
0
(in 12)
j
Dd F (in 10), F
j
¼4.15 ppm) but to a smaller difference between
postulated mechanism for the formation of oxetanes from six-ring
the chemical shifts of the fluorine substituents due to the formation
of an acyclic chain of higher flexibility in 9 compared with the
b,
b
0-difluoro substituted lactones probable.
This reaction parallels Fleet’s approach18 using
a-triflates of
0
0
strained system of 7 (jDd F,F (in 10)
j
¼17.68 vs jDd F,F
j
¼1.52 ppm).
(in 12)
g
-lactones to form oxetane rings in good yields provided that there
is a trans relationship between the C2 and C3 position. This
methodology has also been used19–21 to afford oxetane
-amino
A clean ring opening took place when 7 was allowed to react at
25 ꢁC with MeOH in the presence of cat. amounts of p-TsOH17 and
d
the methyl 3,3-difluoro-D-ribo-hexulosonate 10 was obtained in
acids with different configurations. The potential of this reaction for
the synthesis of building blocks for the formation of peptidimi-
metics22 and carbopeptoidic conformationally restricted foldamers
is now investigated in our laboratory.
84% yield. Reaction of 7 under the same conditions with MeOH/p-
TsOH at room temperature but followed by a work-up using the
ion-exchange resin IR-420 (OHꢀ form) led to an unexpected ring
contraction and a substituted exocyclic vinylether 11 (Scheme 3)
was formed. In the 19F NMR spectra of 11 no longer any fluorine
substituent could be detected. The 13C NMR spectrum showed the
presence of a methyl ester as indicated by chemical shifts at
3. Experimental
3.1. General
d
¼162.3 ppm (ester carbonyl) and ¼59.2 ppm (methyl group).
d
Melting points are uncorrected (Leica hot stage microscope),
optical rotations were obtained using a Perkin–Elmer 341 polari-
meter (1 cm micro cell, 20 ꢁC), NMR spectra were recorded using
the Varian spectrometers Gemini 200, Gemini 2000 or Unity 500
(d given in ppm, J in hertz, internal Me4Si or internal CCl3F), IR
spectra (film or KBr pellet) on a Perkin–Elmer FTIR spectrometer
Spectrum 1000, MS spectra were taken on a Intectra GmbH AMD
402 (electron impact, 70 eV) or on a Thermo Electron Finnigan LCQ
(electrospray, 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.
3.2. Allyl 2-O-benzyl-4,6-O-benzylidene-b-D-ribo-hex-3-ulo-
pyranoside (2)
Scheme 3. (a) MeOH, p-TsOH, then IRA-420 (OHꢀꢀ), 25 ꢁC, 66%; (b) MeOH, 8 M NH3,
25 ꢁC, 25% (of 12) and 26% (of 13); (c) IR-420 (OH ), 25 ꢁC, 88%.
As far as the formation of this oxetane is concerned, we rea-
soned that in a first step compound 7 is transformed to the acyclic
ester 10; ester 10 suffers under basic conditions an HF elimination
To a solution of dry DMSO (8.41 g, 107.64 mmol) in anhydr. DCM
(72.0 ml) at ꢀ78 ꢁC a solution of trifluoroacetic anhydride (16.05 g,
76.41 mmol) in anhydr. DCM (18.0 ml) was added dropwise and the

R. Csuk, E. Prell / Tetrahedron 66 (2010) 1313–1318
1315
3
2
mixture was stirred at this temperature for 45 min. Then a solution
of 1 (14.67 g, 36.82 mmol) in dry DCM (40.0 ml) was added drop-
wise, maintaining the temperature at ꢀ78 ꢁC during this addition.
The mixture was stirred for two hours at ꢀ78 ꢁC, then a solution of
Et3N (13.0 ml, 93.27 mmol) in anhydr. DCM (30.0 ml) was added
dropwise and the mixture was allowed to warm to 25 ꢁC. DCM
(300 ml) and water (100 ml) were added, organic and water phase
were separated and the water 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–EtOAc¼50:50) to afford 1
benzylidene), 101.6 (d, J1,F¼5.7 Hz, C1), 78.5 (dd, J2,F¼18.3,
2J2,F¼18.5 Hz, C2), 77.9 (dd, 2J4,F¼18.5, 2J4,F¼18.9 Hz, C4), 75.1 (CH2,
OBn), 71.0 (C10), 68.7 (C6), 64.3 (d, 3J5,F¼6.9 Hz, C5) ppm; 19F NMR
3
3
00
00
(188 MHz, CDCl3):
d
¼ꢀ119.01 (ddd, 1F, JF ,2¼4.7, JF ,4¼4.7,
2
4 3
JF ,F ¼243.6 Hz, F00), ꢀ132.73 (dddd, 1F, JF ,1¼1.1, JF ,4¼17.8,
00
0
0
0
JF ,2¼18.9, 2JF ,F ¼243.6 Hz, F ) ppm; MS (ESI–MeOH): m/z (%)¼419.1
2
0
0
0
00
([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 (418.44): calcd: C, 66.02; H, 5.78; found: C,
65.81; H, 5.81.
(10.90 g, 74.7%) as colourless crystals; mp 125–127 ꢁC; [
a
]
D ꢀ64.84
3.4. Allyl 2-O-benzyl-3-deoxy-3,3-difluoro-b-D-ribo-
(c 0.49, CHCl3); Rf (hexane–EtOAc¼5:3)¼0.73; IR (KBr):
n
¼3426m,
hexopyranoside (4)
3066m, 3032m, 2882m, 1746s, 1645m, 1497m, 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 cmꢀ1; NMR (500 MHz,
To a solution of 3 (2.25 g, 5.68 mmol) in DCM (14.7 ml), water
(0.3 ml) and a solution of trifluoroacetic acid in DCM (30%, 8.0 ml)
were added at 25 ꢁC and stirring was continued for another hour.
DCM (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 DCM (3ꢂ100 ml) and the com-
bined organic layers were dried (MgSO4). The solvents were
evaporated under reduced pressure and the remaining residue was
subjected to chromatography (silica gel, hexane–EtOAc¼50:50) to
CDCl3):
d
¼7.49–7.47 (m, 2H, Ph), 7.41–7.39 (m, 2H, Ph), 7.36–7.26
3 3 3
0
00
0
0
0
0
(m, 6H, Ph), 5.93 (dddd, 1H, J2 ,1 ¼5.3, J2 ,1 ¼5.6, J2 ,3 ¼10.8,
0
3
0
00
J2 ,3 ¼17.2 Hz, H-2 ), 5.52 (s, 1H, CH-benzylidene), 5.36 (dddd, 1H,
4
2
4
3
00
00
0
00
4
0
00 00
00
3
0
J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.5, J3 ,2 ¼17.2 Hz, H-3 ), 5.24 (dddd,
1H, 4J3 ,1 ¼1.4, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,2 ¼10.8 Hz, H-3 ), 4.809 (d, 1H,
2
0
0
0
0
00
0
00
0
0
2
2
00
00
0
0
00
JH ,H ¼11.9 Hz, CH 2, OBn), 4.75 (d, 1H, JH ,H ¼11.9 Hz, CH 2, OBn),
4.72 (d, 1H, 3J1,2¼7.4 Hz, H-1), 4.45 (dd, 1H, 3J6B,5¼4.9, 2J6B,6A¼10.4,
afford 4 (830 mg, 44.3%) as a colourless oil; [
a
]
ꢀ20.67 (c 0.53,
D
4
4
3
00 00
J1 ,3 ¼1.5,
00
0
00
0
H-6B), 4.40 (dddd, 1H,
J1 ,3 ¼1.4,
J1 ,2 ¼5.3,
CHCl3); Rf (methanol:EtOAc¼10:90)¼0.75; IR (film):
n
¼3396s,
2
00
0
00
0
J1 ,1 ¼12.7 Hz, H-1 ), 4.24–4.18 (m, 2H, H-4, H-1 ), 4.00 (dd, 1H,
3033m, 2883m, 1677m, 1498m, 1455m, 1407m, 1351m, 1237s,
3J2,1¼7.4, 4J2,4¼1.5 Hz, H-2), 3.85 (dd, 1H, 3J6A,5¼9.9, 2J6A,6B¼10.4 Hz,
1070s, 930m, 854m, 745m, 699s, 552w cmꢀ1
;
1H NMR (500 MHz,
3
3
3
H-6A), 3.57 (ddd, 1H, J5,6B¼4.9, 3J5,4¼9.9, J5,6A¼9.9 Hz, H-5) ppm;
CDCl3):
d
¼7.33–7.22 (m, 5H, Ph), 5.86 (dddd, 1H, J2 ,1 ¼5.4,
0
00
13C NMR (125 MHz, CDCl3):
d¼196.4 (C¼O, C3), 137.1 (Car), 136.3
J2 ,1 ¼5.8, J2 ,3 ¼10.5, J2 ,3 ¼17.2 Hz, H-20), 5.27 (dddd, 1H,
3
3
3
0
0
0
0
0
00
4
2
4
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-ben-
zylidene), 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, 69.68; H, 6.10; found: C, 69.52; H, 6.18.
J3 ,1 ¼1.3, J3 ,3 ¼1.5, J3 ,1 ¼1.6, J3 ,2 ¼17.2 Hz, H-3 ), 5.16 (dddd,
00
00
0
00
4
0
00 00
00
3
0
1H, 4J3 ,1 ¼1.3, J3 ,1 ¼1.4, J3 ,3 ¼1.5, J3 ,2 ¼10.5 Hz, H-3 ), 4.81 (d, 1H,
2
0
0
0
0
00
0
00
0
0
2
2
00
0
00
0
0
00
JH ,H ¼11.5 Hz, CH 2, OBn), 4.76 (d, 1H, JH ,H ¼11.5 Hz, CH 2, OBn),
4.57 (dd, 1H, 4J1,F ¼1.4, J1,2¼7.9 Hz, H-1), 4.31 (dddd, 1H, 4J1 ,3 ¼1.3,
3
0
00 00
4
4
3
2
J1 ,3 ¼1.4, J1 ,2 ¼5.4, J1 ,1 ¼12.8 Hz, H-100), 4.10 (dddd, 1H,
00
0
00
00
0
00 0
4
3
2
0
0
0
0
0
0
0 00
J1 ,3 ¼1.3, J1 ,3 ¼1.3, J1 ,2 ¼5.8, J1 ,1 ¼12.8 Hz, H-1 ), 3.86 (m, 1H, H-
3
2
6B), 3.76 (dd, 1H, J6A,5¼4.0, J6A,6B¼12.0 Hz, H-6A), 3.73 (ddd, 1H,
3
3
3
00
0
J4,F ¼4.3, J4,5¼9.9, J4,F ¼17.9 Hz, H-4), 3.42 (m, 1H, H-5), 3.38
(ddd, 1H, J2,F ¼4.4, J2,1¼7.9, J2,F ¼17.9 Hz, H-2) ppm; 13C NMR
3
3
3
00
0
(125 MHz, CDCl3):
d
¼137.2 (Ph), 133.4 (C20), 128.3 (Car), 128.2 (Car),
1
1
3.3. Allyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-3,3-
128.0 (Car), 119.5 (dd, J3,F¼245.3, J3,F¼253.1 Hz, C3), 117.8 (C30),
3
2
2
difluoro-
b-D
-ribo-hexopyranoside (3)
100.9 (d, J1,F¼10.1 Hz, C1), 77.8 (dd, J2,F¼19.0, J2,F¼18.1 Hz, C2),
3
74.9 (CH2, OBn), 73.7 (d, J5,F¼6.5 Hz, C5), 70.9 (C10), 68.5 (dd,
2
To a solution of 2 (300 mg, 0.72 mmol) in anhydr. DCM (6.0 ml),
DAST (417 l, 3.03 mmol) was added dropwise under argon and the
2J4,F¼20.1, J4,F¼20.1 Hz, C4), 61.6 (C6) ppm; 19F NMR (188 MHz,
3
3
2
00
4
00
00
0
m
CDCl3):
d
¼ꢀ116.08 (ddd, 1F, JF ,2¼4.4, JF ,4¼4.3, JF ,F ¼243.5 Hz,
3
3
mixture was stirred at 25 ꢁC for 5 days. MeOH (5.0 ml) was carefully
added and the solvents were removed under diminished pressure.
The oily residue was dissolved in DCM (90 ml) and washed with
water (50 ml). The aq phase was extracted with DCM (3ꢂ100 ml);
the organic phases were combined and the solvent was evaporated.
The remaining residue was subjected to chromatography (silica gel,
hexane–EtOAc¼5:3) to afford 3 (167 mg, 55.2%) as a white foam;
F00), ꢀ133.69 (dddd, 1F,
JF ,1¼1.4,
JF ,2¼17.9,
JF ,4¼17.9,
0
0
0
2
þ
0
0
00
JF ,F ¼243.5 Hz, F ) ppm; MS (ESI–MeOH): m/z (%)¼331.1 ([MþH] ,
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,
58.01; H, 6.23.
[
a
]
ꢀ27.89 (c 0.39; CHCl3); Rf (hexane–EtOAc¼5:3)¼0.67; IR
3.5. Allyl 2,4,6-tri-O-benzyl-3-deoxy-3,3-difluoro-b-D-ribo-
D
(film):
n
¼2927m, 1736m, 1454m, 1384m, 1252m, 1093s, 745w,
hexopyranoside (5)
698m cmꢀ1; NMR (500 MHz, CDCl3):
d
0
¼7.50–7.48 (m, 2H, Ph), 7.41–
3
3 3
00
0
0
0
0
7.28 (m, 8H, Ph), 5.93 (dddd, 1H, J2 ,1 ¼0.7, J2 ,1 ¼5.8, J2 ,3 ¼10.5,
To an ice-cold solution of 4 (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; benzyl bromide
(3.03 ml, 25.34 mmol) was slowly added at 0 ꢁC and after stirring
at 25 ꢁC for another 4 h, methanol (30 ml) was added and the
solvents were removed under diminished pressure. The oily resi-
due was dissolved in diethylether (200 ml), washed with water
and brine (100 ml each) and dried (MgSO4). The solvents were
evaporated and the remaining residue was subjected to chroma-
tography (silica gel, hexane–EtOAc¼85:15) to afford 5 (3.08 g,
3
0
0
00
J2 ,3 ¼17.2 Hz, H-2 ), 5.53 (s, 1H, CH-benzylidene), 5.35 (dddd, 1H,
4
2
4
3
00
00
0
00
0
00 00
00
3
0
J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.5, J3 ,2 ¼17.2 Hz, H-3 ), 5.24 (dddd,
1H, 4J3 ,1 ¼1.3, J3 ,1 ¼1.5, J3 ,3 ¼1.3, J3 ,2 ¼10.5 Hz, H-3 ), 4.809 (d, 1H,
4
2
0
0
0
0
00
0
00
0
0
2
2
00
00
0
0
00
JH ,H ¼11.5 Hz, CH 2, OBn), 4.86 (d, 1H, JH ,H ¼11.5 Hz, CH 2, OBn),
4.70 (dd, 1H, 3J1,2¼7.8, 4J1,F ¼1.1 Hz, H-1), 4.42–4.37 (m, 2H, H-6B, H-
0
4
4
3
2
100), 4.18 (dddd, 1H, J1 ,3 ¼1.3, J1 ,3 ¼1.5, J1 ,2 ¼5.8, J1 ,1 ¼12.7 Hz,
0
0
0
00
0
0
0 00
3
H-10), 3.79–3.68 (m, 3H, H-4, H-5, H-6A), 3.55 (ddd, 1H, J2,1¼7.8,
3
3
J2,F ¼4.7, J2,F¼18.9 Hz, H-2) ppm; 13C NMR (125 MHz, CDCl3):
00
d
¼137.1 (Car), 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, J3,F¼250.0, J3,F¼255.5 Hz, C3), 101.9 (CH-
1
1
71.4%) as a colourless oil; [
a
]
þ11.32 (c 0.38, CHCl3); Rf (hexane–
D

1316
R. Csuk, E. Prell / Tetrahedron 66 (2010) 1313–1318
EtOAc¼5:3)¼0.79; IR (film):
n
¼3356m, 3032m, 2921m, 1723m,
(%)¼488.5 ([MþNH4]þ, 2), 493.4 ([MþNa]þ, 100), 962.7
([M2þNa]þ, 2); analysis for C27H28F2O5 (470.51): calcd: C, 68.92; H,
6.00; found: C, 68.79; H, 6.11.
1497m, 1454m, 1404m, 1351m, 1239m, 1061s, 860w, 739m, 698m
cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
0
¼7.40–7.23 (m, 15H, Ph), 5.93
3
3
3
3
0
0
00
0
0
0
0
00
(dddd, 1H, J2 ,1 ¼5.1, J2 ,1 ¼6.1, J2 ,3 ¼10.5, J2 ,3 ¼17.3 Hz, H-2 ),
4
2
4
3
00
0
00
0
00 00
00
0
5.32 (dddd, 1H, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,1 ¼1.6, J3 ,2 ¼17.3 Hz, H-
3.7. 2,4,6-Tri-O-benzyl-3-deoxy-3,3-difluoro-D-ribo-hexono-
1,5-lactone (7)
4
4
2
3
300), 5.19 (dddd, 1H, J3 ,1 ¼1.3, J3 ,1 ¼1.5, J3 ,3 ¼1.5, J3 ,2 ¼10.5 Hz,
0
0
0
00
0
00
0
0
2
H-30), 4.88 (d, 10H0 , JH ,H ¼11.5 Hz, CH00
,
OBn), 4.84 0 (d, 1H,
00
0
2
2
JH ,H ¼11.1 Hz, CH 2, OBn), 4.82 (d, 1H, 2JH ,H ¼11.5 Hz, CH 2, OBn),
To a solution of 6 (2.70 g, 5.74 mmol) in abs. DCM (40.0 ml),
Dess–Martin periodinane (3.65 g, 8.61 mmol) was added in small
portions. After stirring at 25 ꢁC for 24 h, the solution was diluted
with DCM (60 ml) and was washed with satd sodium thiosulfate
(50 ml). The aq phase was extracted with DCM (3ꢂ100 ml), the
organic phases were combined, dried (Na2SO4), and the solvent was
evaporated under diminished pressure. The remaining residue was
subjected to chromatography (silica gel, hexane–EtOAc¼5:3) to
00
0
0
00
2
4
00
00
0
0
4.58 (d, 1H, JH ,H ¼12.2 Hz, CH 2, OBn), 4.56 (dd, 1H, J1,F ¼1.5,
3
2
0
0
00
J1,2¼7.9 Hz, H-1), 4.53 (d, 1H, JH ,H ¼11.1 Hz, CH 2, OBn), 4.50 (d,
2
4
1H, JH ,H ¼12.2 Hz, CH02, OBn), 4.39 (dddd, 1H, J1 ,3 ¼1.6,
0
00
00 00
4
4
3
3
2
J1 ,3 ¼1.5, J1 ,2 ¼5.1, J1 ,1 ¼12.9 Hz, H-100), 4.13 (dddd, 1H,
00
0
00
0
00
0
4
3
2
0
0
0
0
00
0
0
0 00
J1 ,3 ¼1.3, J1 ,3 ¼1.4, J1 ,2 ¼6.1, J1 ,1 ¼12.9 Hz, H-1 ), 3.74 (ddd, 1H,
J4,F ¼3.4, J4,5¼9.8, 3J4,F ¼19.3 Hz, H-4), 3.68–3.65 (m, 2H, H-6B, H-
3
00
0
3
3
00
6A), 3.58 (m, 1H, H-5), 3.49 (ddd, 1H, J2,F ¼4.4, J2,1¼7.9,
3
J2,F ¼20.0 Hz, H-2) ppm; 13C NMR (125 MHz, CDCl3):
d
¼137.9 (Ph),
afford 7 (1.96 g, 72.9%) as a white solid; mp 151–152 ꢁC; [
(c 0.71, CHCl3); Rf (hexane–EtOAc¼5:3) 0.70; IR (KBr):
a
n
]
D þ89.60
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
¼3065m,
3033m, 2873m, 1958w, 1770s, 1700m, 1604m, 1584m, 1497m,
1455s, 1364m, 1256s, 1211s, 1089s, 1029s, 913m, 884m, 803m, 741s,
1
(Car), 127.8 (Car), 127.7 (Car), 127.6 (Car), 122.5 (dd, J3,F¼248.1,
1J3,F¼252.8 Hz, C3), 117.4 (C30), 100.9 (d, 3J1,F¼10.2 Hz, C1), 78.1 (dd,
2J2,F¼18.2, 2J2,F¼18.7 Hz, C2), 74.9 (CH2, OBn), 74.9 (CH2, OBn), 74.8
(CH2, OBn), 73.5 (C4), 72.9 (d, 3J5,F¼8.2 Hz, C5), 70.5 (C10), 68.1 (C6)
699s, 635m, 601m, 561m, 468m cmꢀ1; 1H NMR (500 MHz, CDCl3):
2
00
00
0
d
¼7.42–7.22 (m, 15H, Ph), 5.04 (d, 1H, JH ,H ¼11.9 Hz, CH 2, OBn),
4.88 (d, 1H, 2JH ,H ¼11.1 Hz, CH 2, OBn), 4.87 (d, 1H, 2JH ,H ¼11.9 Hz,
00
00
0
0
00
ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢀ112.16 (ddd, 1 F, JF ,4¼3.4,
CH02, OBn), 4.54 (d, 1H, JH ,H ¼11.1 Hz, CH 2, OBn), 4.47 (d, 1H,
3
2
0
00
0
00
3
3
1
4
2
2
JF ,2¼4.4, JF ,F ¼246.6 Hz, F00), ꢀ130.80 (dddd, 1F, JF ,1¼1.5,
JH ,H ¼11.9 Hz, CH 2, OBn), 4.39 (d, 1H, JH ,H ¼11.9 Hz, CH 2, OBn),
00
0
00
00
0
0
00
0
0
00
3
1
JF ,4¼19.3, JF ,2¼20.0, JF ,F ¼246.6 Hz, F ) ppm; MS (ESI–MeOH):
4.33 (ddd,1H, 3J5,6B¼1.6, 3J5,4¼2.2, 3J5,6A¼9.3 Hz, H-5), 4.12 (ddd,1H,
0
0
0
0
00
m/z (%)¼528.3 ([MþNH4]þ, 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, 6.58.
J4,F ¼4.2, J4,5¼9.3, J4,F ¼22.8 Hz, H-4), 4.10 (dd, 1H, J2,F ¼4.2,
3
3
3
3
3
00
0
00
3
2
0
J2,F ¼21.9 Hz, H-2), 3.71 (dd, 1H, J6B,5¼1.6, J6B,6A¼11.2 Hz, H-6A),
3.63 (dd, 1H, J6A,5¼2.2, J6A,6B¼11.2 Hz, H-6A) ppm; 13C NMR
3
2
3
(125 MHz, CDCl3):
d
¼166.5 (d, J1,F¼9.7 Hz, C1), 137.2 (Ph), 136.5
(Ph), 136.0 (Ph), 128.5 (Car), 128.5 (Car), 128.4 (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), 128.1 (dd, 1J3,F¼252.5, 1J3,F¼251.4 Hz, C3), 77.4 (d, 3J5,F¼5.8 Hz,
C5), 75.2 (d, 4JCH2(OBn),F¼2.5 Hz, CH2, OBn), 74.4 (CH2, OBn), 74.2 (dd,
3.6. 2,4,6-Tri-O-benzyl-3-deoxy-3,3-difluoro-D-ribo-
hexopyranose (6)
3J4,F¼23.1, J4,F¼21.6 Hz, C4), 73.6 (CH2, OBn), 72.4 (dd, J2,F¼19.1,
3
1
1J2,F¼21.1 Hz, C2), 67.1 (C6) ppm; 19F NMR (188 MHz, CDCl3):
3
3
1
To a solution of 5 (2.84 g, 5.56 mmol) in MeOH (30.0 ml), PdCl2
(400 mg, 2.26 mmol) was slowly added. The suspension was stir-
red for 1 day, filtrated and the remaining residue was washed with
methanol (4ꢂ100 ml). The combined organic layers were dried
(MgSO4) and the solvents were evaporated under reduced pres-
sure. The remaining residue was subjected to chromatography
(silica gel, hexane–EtOAc¼5:3) to afford 6 (2.61 g, 99.7%) as
a mixture of equilibrating anomers as colourless crystals; mp 128–
d
¼ꢀ111.46 (ddd, 1F, JF ,4¼4.2, JF ,2¼4.2, JF ,F ¼243.5 Hz, F00),
00
00
00
0
3
3
1
0
0
0
0
00
ꢀ129.14 (ddd, 1F, JF ,4¼22.8, JF ,2¼21.9, JF ,F ¼243.5 Hz, F ) ppm;
MS (ESI–MeOH): m/z (%)¼958.8 ([M2þNa]þ, 100); source CID: m/z
(%)¼491.3 ([MþNa]þ, 100), 722.5 ([M3þK,H]2þ
, 10), 958.9
([M2þNa]þ, 20); analysis for C27H25FO5 (448.48): calcd: C, 72.31; H,
5.63; found: C, 72.29; H, 5.69.
3.8. 2,4,6-Tri-O-benzyl-2,3-dideoxy-3-fluoro-D-erythro-hex-2-
eno-1,5-lactone (8)
130 ꢁC; [
and 0.41; IR (KBr):
a
]
þ27.17 (c 0.43, CHCl3); Rf (hexane–EtOAc¼5:3) 0.51
D
n
¼3442m, 3031m, 2919m, 2864m, 1734w,
1497w, 1454m, 1405w, 1362m, 1265m, 1237m, 1187m, 1094s,
1073m, 1049m, 1029m, 1003m, 914w, 864w, 788w, 756m, 734m,
To a solution of 6 (100 mg, 2.13 mmol) in anhydr. DCM (2.0 ml)
powdered molsieve (100 mg) and 4-morpholine N-oxide (37 mg,
0.32 mmol) were added. After stirring at 25 ꢁC for ten minutes,
tetra-n-propylammonium tetra-oxoruthenate(VII) (TPAP) (4 mg,
0.01 mmol) was added and the solution was stirred at 25 ꢁC for two
hours. The solution was diluted with DCM (20 ml), washed with 5%
Na2SO3 in brine (10 ml), brine (10 ml), and satd. CuSO4 (15 ml) and
filtered through a thin layer of silica (2 cm). The silica was washed
with DCM (3ꢂ20 ml). The combined organic phases were dried
(Na2SO4) evaporated under reduced pressure and the remaining
residue was subjected to chromatography (silica gel, hexane–
699m, 649w, 620w, 523w cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
¼7.40–7.21 (m, 30H, Ph), 5.20 (m, 1H), 4.90–4.80 (m, 6H), 4.72 (d,
2
00
0
1H, JH ,H ¼12.1 Hz, CH2, OBn), 4.57–4.51 (m, 4H), 4.47 (d, 1H,
2
2
00
0
00
0
JH ,H ¼12.0 Hz, CH2, OBn), 4.45 (d, 1H, JH ,H ¼12.2 Hz, CH2, OBn),
4.10 (ddd, 1H, J¼1.6, J¼3.3, J¼5.8 Hz), 3.81 (ddd, 1H, J¼4.5, J¼9.7,
J¼19.4 Hz), 3.77–3.62 (m, 7H), 3.42 (ddd, J¼4.2, J¼7.7, J¼19.9 Hz)
ppm; 13C NMR (125 MHz, CDCl3):
d
¼137.6 (Ph), 137.3 (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 Hz,
EtOAc¼5:3) to afford 8 (80 mg, 83.9%) as a colourless oil; [
a]
D
þ81.29 (c 0.50, CHCl3); [ þ12.04 (c 0.15, MeOH); Rf (hexane–
a]
D
3
C1), 91.3 (d, J1,F¼8.5 Hz, C1), 78.9 (m), 75.1–74.0 (m, CH2, OBn),
EtOAc¼5:3)¼0.68; IR (film): ¼3452w, 3089m, 3064m, 3032m,
n
73.6 (CH2, OBn), 73.0 (d, 3J5,F¼8.2 Hz, C5), 68.3 (d, 3J5,F¼7.2 Hz, C5),
2870m, 1958w, 1739s, 1700s, 1604w, 1586w, 1497m, 1455s, 1382m,
1353m, 1272m, 1208s, 1171s, 1094s, 1028s, 914m, 807m, 744s, 699s,
68.2 (6), 67.7 (6) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢀ107.81 (d, 1
F, 1JF ,F ¼247.6 Hz, F ), ꢀ111.89 (d, 1 F, JF ,F ¼247.1 Hz, F ), ꢀ125.74
603m, 464m cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼7.38–7.19 (m,
1
00
00
00
0
0
00
1
0
(ddd, 1 F, JF ,H¼20.3, JF ,H¼20.3, JF ,F ¼247.6 Hz, F ), ꢀ130.83 (ddd,
15H, Ph), 5.08 (s, 2H, CH002(OBn), CH02, OBn), 4.61 (d, 1H,
0
0
00
0
1F, JF ,H¼19.4, JF ,H¼19.4, 1JF ,F ¼247.1 Hz, F ) ppm; MS (ESI–MeOH):
JH ,H ¼11.5 Hz, CH 2, OBn), 4.50 (m, 2H, CH00002(OBn), H-5), 4.45 (m,
2
0
00
0
0
0
00
00
0
m/z (%)¼488.3 ([MþNH4]þ, 15), 493.3 ([MþNa]þ, 15), 725.5
1H, H-4), 4.41 (d, 1H, JH ,H ¼11.9 Hz, CH 2, OBn), 4.37 (d, 1H,
2
00
0
([M3þK,H]2þ
,
3), 962.8 ([M2þNa]þ, 100); Source CID: m/z
JH ,H ¼11.9 Hz, CH 2, OBn), 3.50 (dd, 1H, J6B,5¼4.0, 2J6B,6A¼10.3 Hz,
2
3
0
0
00

R. Csuk, E. Prell / Tetrahedron 66 (2010) 1313–1318
1317
3
3
3
H-6B), 3.27 (dd, 1H, 3J6A,5¼6.3, 2J6A,6B¼10.3 Hz, H-6A) ppm; 13C NMR
OBn), 4.01 (ddd, 1H, J5,6B¼3.7, J5,4¼4.7, J5,6A¼6.9 Hz, H-5), 3.62–
(100 MHz, CDCl3):
d
¼161.1 (d, 3J1,F¼11.1, C1), 156.1 (d,
3.60 (m, 2H, H-6B, H-6A), 3.68 (s, 3H, COOCH3), ppm; 13C NMR
2J3,F¼288.8 Hz, C3), 137.1 (Ph), 137.6 (Ph), 136.0 (Ph), 128.6 (Car),
(125 MHz, CDCl3):
d
¼167.5 (C]O (COOCH3)), 137.7 (Ph), 137.4 (Ph),
128.5 (Car), 128.5 (Car), 128.4 (Car), 128.2 (Car), 128.0 (Car), 127.7 (Car),
136.2 (Ph), 129.0 (Car), 128.5 (Car), 128.5 (Car), 128.5 (Car), 128.5 (Car),
128.5 (Car), 128.4 (Car), 128.4 (Car), 128.3 (Car), 128.3 (Car), 128.2 (Car),
128.1 (Car), 128.0 (Car), 127.9 (Car), 127.9 (Car), 127.9 (Car), 127.8 (Car),
2
2
112.4 (d, J2,F¼14.1 Hz, C2), 77.9 (d, J4,F¼8.9 Hz, C4), 74.4 (d,
4JCH2(OBn),F¼3.4 Hz, CH2, OBn), 73.6 (CH2, OBn), 72.3 (CH2, OBn), 70.5
(d, J5,F¼21.1 Hz, C5), 68.2 (C6) ppm; 19F NMR (188 MHz, CDCl3):
127.7 (Car), 118.1 (dd, J3,F¼251.3, J3,F¼252.5 Hz, C3), 75.3 (CH2,
3
1
1
3 3
d
¼ꢀ116.12 (m, 1F); MS (ESI–MeOH): m/z (%)¼449.0 ([MþH]þ, 8),
OBn), 74.4 (CH2, OBn), 74.2 (dd, J4,F¼22.5, J4,F¼22.5 Hz, C4), 73.6
1 1
466.1 ([MþNH4]þ, 16), 471.2 ([MþNa]þ, 20), 692.1 ([M3þK,H]2þ, 2),
918.9 ([M2þNa]þ, 100); analysis for C27H25FO5 (468.49): calcd: C,
69.22; H, 5.59; found: C, 69.12; H, 5.74.
(CH2, OBn), 72.4 (dd, J2,F¼21.1, J2,F¼19.2 Hz, C2), 69.3 (C5), 67.1
(C6), 52.5 (COOCH3) ppm; 19F NMR (188 MHz, CDCl3):
d
3
¼ꢀ111.46
(d, 1F, 1JF ,F ¼243.9 Hz, F ), ꢀ129.14 (ddd, 1F, JF ,4¼20.3, JF ,2¼20.3,
3
00
00
0
0
0
1
þ
0
0
00
JF ,F ¼243.9 Hz, F ) ppm; MS (ESI–MeOH): m/z (%)¼501.1 ([MþH] ,
3.9. N-Benzyl 2,4,6-tri-O-benzyl-3-deoxy-3,3-difluoro-
D
-ribo-
6), 518.2 ([MþNH4]þ, 47), 523.3 ([MþNa]þ, 28), 769.9 ([M3þK,H]2þ
,
hexonamide (9)
3), 1022.7 ([M2þNa]þ, 100); analysis for C28H30F2O6 (500.53): calcd:
C, 67.19; H, 6.04; found: C, 67.00; H, 6.21.
To a solution of 7 (50 mg. 0.11 mmol) in abs toluene (1.0 ml),
benzylamine (20 l, 0.18 mmol) was added dropwise. After stirring
m
3.11. Methyl 2-benzyloxy-2-[(3R, 4R) 3-benzyloxy-4-
at 25 ꢁC for 12 h, the solution was diluted with toluene (9 ml) and
was washed with satd. Na2SO5 (5 ml). The aq phase was extracted
with toluene (3ꢂ10 ml), the combined organic phases were dried
(Na2SO4) and the solvent was evaporated under reduced pressure.
The remaining residue was subjected to chromatography (silica gel,
hexane–EtOAc¼5:3) to afford 9 (48 mg, 78.1%) as a colourless oil;
(benzyloxymethyl)]oxetan-2-ylidene acetate (11)
To a solution of 7 (650 mg, 1.39 mmol) in anhydr. MeOH
(20.0 ml) p-TsOH (300 mg) was added in small portions. After
stirring at 25 ꢁC for 24 h the solution was neutralized with
Amberlite IRA-420 (OHꢀ). The solution was filtered and dried
(Na2SO4). The solvent was evaporated under reduced pressure and
the remaining residue subjected to chromatography (silica gel,
hexane–EtOAc¼5:3) to afford 11 (420 mg, 65.7%) as a colourless oil;
[
a
]
D þ27.70 (c 0.44, CHCl3); Rf (hexane–EtOAc¼5:3)¼0.45; IR (film):
¼3415m, 3064m, 3031m, 2923m, 1679s, 1526s, 1497m, 1454s,
1361m, 1210s, 1174m, 110s, 1028s, 914m, 801m, 752s, 699s, 603m,
488m cmꢀ1 1H NMR (400 MHz, CDCl3):
n
;
d
¼7.37–7.20 (m, 20H, Ph),
[
n
a
]
D þ58.47 (c 0.33, CHCl3); Rf (hexane–EtOAc¼5:3)¼0.63; IR (film):
3
3
00
0
6.93 (dd, 1H, JNH,CH 2(NBn)¼5.8, JNH,CH 2(NBn)¼5.7 Hz, NH), 4.85 (d,
¼3434m, 3088m, 3064m, 3031s, 2952s, 2868s, 1957w, 1879w,
1H, 2JH,H¼11.0 Hz, CH2, OBn), 4.71–4.69 (m, 2H, CH2(OBn), CH2, OBn),
1719s, 1654s, 1606m, 1586m, 1497s, 1454s, 1383s, 1347s, 1241s,
4.56 (d,1H, 2JH,H¼11.3 Hz, CH2, OBn), 4.56 (d,1H, 2JH,H¼11.8 Hz, CH2, OBn),
1162s, 1069s, 1028s, 914m, 848m, 741s, 699s, 602m, 466m cmꢀ1; 1H
3
00
4.58–4.52 (m, 2H, CH2(OBn), H-2), 4.49 (dd, 1H, JCH 2(NBn),NH¼5.8,
NMR (500 MHz, CDCl32): ¼7.39–7.25 (m, 15H, Ph), 4.92 (s, 2H, CH2,
d
2
2
3
3
JH ,H ¼15.0 Hz, CH002(NBn)), 4.38 (dd, 1H, JCH 2(NBn),NH¼5.7,
OBn), 4.63 (d, 1H, JH ,H ¼11.5 Hz, CH00
,
OBn), 4.56 (d, 1H,
00
00
0
0
00
0
2
3
3
2
3
3
0
0
0
00
0
00
JH ,H ¼15.0 Hz, CH 2(NBn)), 4.27 (ddd, 1H, J4,F ¼10.6, J4,5¼5.5,
JH ,H ¼11.7 Hz, CH 2, OBn), 4.54 (ddd, 1H, J5,6B¼4.7, J5,4¼3.0,
3J5,6A¼7.0 Hz, H-5), 4.44 (s, 2H, CH2, OBn), 4.34 (d, 1H, 3J4,5¼3.0 Hz,
H-4), 3.89 (s, 3H, COOCH3), 3.57 (dd, 1H, 3J6B,5¼4.4, 2J6B,6A¼10.1 Hz,
H-6B), 3.33 (dd, 1H, 3J6A,5¼7.0, 2J6A,6B¼10.1 Hz, H-6A) ppm; 13C NMR
3
3
3
0
J4,F ¼15.4 Hz, H-4), 4.19 (ddd, 1H, J5,6B¼3.0, J5,4¼5.5, J5,6A¼6.6
Hz, H-5), 3.72 (dd, 1H, 3J6B,5¼3.0, 2J6B,6A¼9.8 Hz, H-6B), 3.67 (dd, 1H,
2
3J6A,5¼6.6, J6A,6B¼9.8 Hz, H-6A) ppm; 13C NMR (100 MHz, CDCl3):
d
¼166.3 (d, 3J1,F¼4.4 Hz, C1), 137.8 (Ph), 137.8 (Ph), 137.6 (Ph), 136.1 (Car),
(125 MHz, CDCl3):
d
¼162.3 (C]O (COOCH3)), 153.7 (C3), 137.3 (Ph),
128.7 (Car), 128.7 (Car), 128.5 (Car), 128.5 (Car), 128.4 (Car), 128.3 (Car),
128.2 (Car), 128.0 (Car), 127.8 (Car), 127.8 (Car), 127.6 (Car), 127.6
137.2 (Ph), 136.5 (Ph), 129.0 (Car), 129.0 (Car), 128.7 (Car), 128.7 (Car),
128.5 (Car), 128.5 (Car), 128.4 (Car), 128.4 (Car), 128.3 (Car), 128.2 (Car),
128.0 (Car), 127.7 (Car), 127.8 (Car), 127.7 (Car), 127.6 (Car), 126.1 (C2),
76.5 (C5), 74.5 (CH2, OBn), 73.4 (CH2, OBn), 71.9 (C4), 71.8 (CH2,
OBn), 68.4 (C6), 59.2 (COOCH3) ppm; MS (ESI–MeOH): m/z
(%)¼461.1 ([MþH]þ, 24), 483.1 ([MþNa]þ, 100); analysis for
C28H28O6 (460.52): calcd: C, 73.03; H, 6.13; found: C, 72.81; H, 6.17.
1
1
(Car), 121.3 (dd, J3,F¼254.8, J3,F¼253.0 Hz, C3), 78.7–78.1 (m, C2,
C4), 75.1 (CH2, OBn), 74.6 (CH2, OBn), 73.5 (CH2, OBn), 70.7 (C6),
69.5 (C5), 43.2 (CH2, NBn) ppm; 19F NMR (188 MHz, CDCl3):
3
3
1
00
00
00
00
0
d
¼ꢀ115.61 (ddd, 1F, JF ,4¼10.6, JF ,2¼11.0, JF ,F ¼259.6 Hz, F ),
ꢀ117.13 (ddd, 1F, 3JF ,4¼15.4, 3JF ,2¼12.1, 1JF ,F ¼259.6 Hz, F ) ppm; MS
(ESI–MeOH): m/z (%)¼576.3 ([MþH]þ, 40), 598.3 ([MþNa]þ, 32),
883.0 ([M3þK,H]2þ, 1), 1172.9 ([M2þNa]þ, 100); MS (ESI–MeOH):
m/z (%)¼574.3 ([MꢀH]ꢀ, 49), 620.3 ([MþHCO2]ꢀ, 100), 911.1
(cluster2ꢀ, 50); analysis for C34H35F2NO5 (575.65): calcd: C, 70.94;
H, 6.13; N, 2.43; found: C, 70.77; H, 6.28; N, 2.48.
0
0
0
0
00
3.12. (4R, 5R) 2,4,6-Tris(benzyloxy)-3-fluoro-5-hydroxy-hex-2-
enamide (12) and 2-benzyloxy-2-[(3R, 4R) 3-benzyloxy-4-
(benzyloxymethyl)oxetan-2-ylidene]-acetamide (13)
To a solution of 7 (200 mg, 0.43 mmol) in abs. MeOH (2.0 ml)
a solution of ammonia in abs methanol (8 M, 10.0 ml) was added.
After stirring at 25 ꢁC for 24 h, the solvents were evaporated under
diminished pressure and the remaining residue was subjected to
chromatography (silica gel, hexane–EtOAc¼50:50) to afford 12
(50 mg, 25.1%) and 13 (50 mg, mmol, 26.3%).
3.10. Methyl 2,4,6-tri-O-benzyl-3-deoxy-3,3-difluoro-D-ribo-
hexo-ulosonate (10)
To a solution of 7 (50 mg, 0.11 mmol) in anhydr. MeOH (1.0 ml)
p-TsOH (30 mg) was added in small portions. After stirring at 25 ꢁC
for 12 h, the solvents were evaporated under reduced pressure and
the remaining residue was subjected to chromatography (silica gel,
hexane–EtOAc¼5:3) to afford 10 (0.09 mmol, 84.2%) as a colourless
Data for 12: colourless oil; [
EtOAc¼50:50)¼0.30; IR (film):
1651s, 1586w, 1497w, 1454s, 1385m, 1245m, 1168m, 1072s, 1028m,
a
]
D þ0.15 (c 0.17, CHCl3); Rf (hexane–
n
¼3334m, 3032w, 2925w, 1694s,
oil; [
(film):
a
]
þ66.80 (c 0.35, CHCl3); Rf (hexane–EtOAc¼5:3)¼0.60; IR
¼3065m, 3032m, 2926s, 2871s, 1955w, 1770s, 1738s,
911w, 739m, 698s cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼7.39–7.25
D
n
(m, 15H, Ph), 5.41 (dd, 1H, 3J4,5¼8.8, 3J4,F¼28.050 Hz, H-4), 4.90 (s, 2H,
2
00
0
1604m, 1497m, 1455s, 1364m, 1258s, 1211s, 1091s, 1028s, 912m,
CH2, OBn), 4.55 (d, 1H, JH ,H ¼11.7 Hz, CH 2, OBn), 4.50 (d, 1H,
2
2
884m, 803m, 739s, 698s, 605m, 467m cmꢀ1
;
1H NMR (400 MHz,
JH ,H ¼11.5 Hz, CH 2, OBn), 4.48 (d, 1H, JH ,H ¼11.7 Hz, CH 2, OBn),
00
0
00
0
0
00
2
3
CDCl3):
d
¼7.35–7.19 (m, 15H, Ph), 4.750(0 d, 1H, 2JH ,H ¼11.5 Hz, CH
4.41 (d, 1H, JH ,H ¼11.5 Hz, CH 2, OBn), 3.96 (ddd, 1H, J5,6B¼2.9,
00
,
2
0
00
0
0
00
2
00
0
OBn), 4.74 (d, 1H, JH ,H ¼10.8 Hz, CH 2, OBn), 4.56–4.48 (m, 3H,
3J5,4¼8.8, 3J5,6A¼4.5 Hz, H-5), 3.68 (dd,1H, 3J6B,5¼2.9, 2J6B,6A¼9.7 Hz,
2
CH02(OBn), H-4, H-2), 4.44 (d,1H, JH ,H ¼11.5 Hz, CH 2, OBn), 4.11 (d,
H-6B), 3.63 (dd, 1H, 3J6A,5¼4.5, 2J6A,6B¼9.7 Hz, H-6A) ppm; 13C NMR
0
0
00
2
2
3
00
0
00
0
0
00
1H, JH ,H ¼14.2 Hz, CH 2, OBn), 4.09 (d, 1H, JH ,H ¼14.2 Hz, CH 2,
(125 MHz, CDCl3):
d¼165.7 (d, J1,F¼11.1 Hz, C1), 156.3 (d,

1318
R. Csuk, E. Prell / Tetrahedron 66 (2010) 1313–1318
2
1J3,F¼272.1 Hz, C3), 137.9 (d, J2,F¼29.2 Hz, C2), 136.1 (Ph), 136.0
References and notes
(Ph), 135.9 (Ph), 128.7 (Car), 128.7 (Car), 128.6 (Car), 128.4 (Car), 128.3
4
1. Compain, P.; Martin, O. R. In Iminosugars–From 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.
3. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
4. Prell, E.; Csuk, R. Bioorg. Med. Chem. Lett. 2009, 19, 5673–5674.
5. Hanessian, S.; Butterworth, R. F.; Nakagawa, T. Carbohydr. Res. 1973, 26,
261–263.
6. Matos, C. R. R.; Lopes, R. S. C.; Lopes, C. C. Synthesis 1999, 4, 571–573.
7. Middleton, W. J. J. Org. Chem. 1975, 40, 574–578.
8. Murphy, P. V.; O’Brien, J. L.; Gorey-Feret, L. J.; Smith, A. B., III. Tetrahedron 2003,
59, 2259–2271.
9. Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohydr. Res. 1987, 167,
305–311.
10. Betaneli, V. I.; Ott, A. Y.; Brukhanova, O. V.; Kochetkov, N. K. Carbohydr. Res.
1988, 179, 37–50.
11. Nelsen, S. F.; Teasley, M. F. J. Org. Chem. 1986, 51, 4319–4320.
12. Paulsen, H.; Heume, M.; Gyo¨rgydeak, Z.; Lebuhn, R. Carbohydr. Res. 1985, 144,
57–70.
13. Hanashima, S.; Mizushina, Y.; Yamazaki, T.; Ohta, K.; Takahashi, S.; Koshino, H.;
Sahara, H.; Sakaguchi, K.; Sugawara, F. Tetrahedron Lett. 2000, 41, 4403–4407.
14. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
15. Itoh, T.; Sakabe, K.; Kudo, K.; Ohara, H.; Takagi, Y.; Kihara, H.; Zagatti, P.; Renou,
M. J. Org. Chem. 1999, 64, 252–265.
16. Benhaddou, R.; Czernecki, S.; Farid, W.; Ville, G.; Xie, J.; Zegar, A. Carbohydr. Res.
1994, 260, 243–250.
17. Joseph, C. C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. Tetrahedron 2002,
58, 6907–6911.
18. Lopez-Ortega, B.; Jenkinson, S. F.; Claridge, T. D. W.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2008, 19, 976–983; Witty, D. R.; Fleet, G. W. J.; Vogt, K.; Wilson, F. X.;
Wang, Y.; Storer, R.; Myers, P. L.; Wallis, C. J. Tetrahedron Lett. 1990, 31, 4748–
4790; Chung, Y.-K.; Claridge, T. D. W.; Fleet, G. W. J.; Johnson, S. W.; Jones, J. H.;
Lumbard, K. W.; Stachulski, A. V. J. Peptide Sci. 2004, 10, 1–7.
19. Lucas, S. D.; Iding, H.; Alker, A.; Wessel, H. P.; Rauter, A. P. J. Carbohydr. Chem.
2006, 25, 187–196.
(Car), 128.0 (Car), 127.8 (Car), 127.6 (Car), 75.8 (d, JCH2(OBn),F¼7.4 Hz,
3
CH2, OBn), 74.1 (d, J4,F¼20.2 Hz, C4), 73.3 (CH2, OBn), 71.7 (CH2,
OBn), 70.5 (C6), 69.9 (C5) ppm; 19F NMR (188 MHz, CDCl3):
d
¼ꢀ125.17 (d, 3JF,4¼28.5 Hz) ppm; MS (ESI–MeOH): m/z (%)¼466.2
([MþH]þ, 16), 488.3 ([MþNa]þ, 70), 718.0 ([M3þK,H]2þ, 4), 952.9
([M2þNa]þ, 100); MS (ESI–MeOH): m/z (%)¼464.5 ([MꢀH]ꢀ, 100),
510.3 ([MþHCO2]ꢀ, 67); analysis for C27H28FNO5 (465.51): calcd: C,
69.66; H, 6.06; N, 3.01found: C, 69.57; H, 6.27; N, 3.08.
Data for 13: colourless oil; [
a
]
D ꢀ22.38 (c 0.32, CHCl3); Rf (hex-
ane–EtOAc¼50:50)¼0.71; IR (film):
n
¼3474m, 3345m, 3063w,
3031m, 2919m, 2869m, 1694s, 1633s, 1497m, 1454m, 1370m,
1296m, 1249m, 1212m, 1094s, 1028m, 916w, 744s, 699s, 605w,
646w cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
¼7.37–7.20 (m, 15H, Ph),
4.91 (d, 1H, 2JH ,H ¼11.3 Hz, CH 2, OBn), 4.86 0(0d, 1H, 2JH ,H ¼11.3 Hz,
00
00
0
0
00
2
CH02, OBn), 4.68 (d00 , 1H, JH ,H ¼11.8 Hz, CH 2, OBn), 4.64 (d, 1H,
00
0
2
3
00
0
JH ,H ¼11.5 Hz, CH 2, O0Bn), 4.58 (d, 1H, J4,5¼9.5 Hz, H-4), 4.55 (d,
2
2
0
0
00
0
00
1H, JH ,H ¼11.8 Hz, CH 2, OBn), 4.48 (d, 1H, JH ,H ¼11.5 Hz, CH 2,
3
3
3
OBn), 4.23 (ddd, 1H, J5,6B¼3.0, J5,4¼3.0, J5,6A¼9.5 Hz, H-5), 3.81
3
2
3
(dd, 1H, J6B,5¼3.0, J6B,6A¼11.3 Hz, H-6B), 3.74 (dd, 1H, J6A,5¼3.0,
2J6A,6B¼11.3 Hz, H-6A) ppm; 13C NMR (125 MHz, CDCl3):
¼162.4
d
(C]O (COONH2)), 147.7 (C2), 137.5 (Ph), 137.5 (Ph), 136.8 (Ph), 128.8
(Car), 128.7 (Car), 128.6 (Car), 128.5 (Car), 128.4 (Car), 128.3 (Car), 128.2
(Car), 128.0 (Car), 127.9 (Car), 117.5 (C3), 77.8 (C5), 73.8 (CH2, OBn),
73.7 (CH2, OBn), 73.6 (CH2, OBn), 70.2 (C4), 67.7 (C6) ppm; MS (ESI–
MeOH): m/z (%)¼446.2 ([MþH]þ, 20), 468.3 ([MþNa]þ, 100), 890.9
([M2þH]þ, 10), 912.9 ([M2þNa]þ, 58); analysis for C27H27NO5
(445.51): calcd: C, 72.79; H, 6.11; found: C, 72.62; H, 6.29.
20. Lucas, S. D.; Rauter, A. P.; Wessel, H. P. J. Carbohydr. Chem. 2008, 27, 172–187.
21. Lucas, S. D.; Rauter, A. P.; Schneider, J.; Wessel, H. P. J. Carbohydr. Chem. 2009, 28,
431–446.
22. Risseeuw, M. D. P.; Overhand, M.; Fleet, G. W. J.; Simone, M. I. Tetrahedron:
Asymmetry 2007, 18, 2001–2010.
Acknowledgements
We like to thank Dr. Dieter Stro¨hl for taking the NMR spectra and
Dr. Ralph Kluge for numerous ESI-spectra.