Fluorinated acyclo-C-nucleoside analogues from glycals in two steps

Article abstract of DOI:10.1016/j.carres.2006.01.011

A convenient two-step strategy is reported for the synthesis of fluorinated optically pure acyclo-C-nucleoside analogues starting from simple glycals. In the first step, benzyl- or p-methoxybenzyl-protected glycals are treated with trifluoroacetic anhydri

Full text of DOI:10.1016/j.carres.2006.01.011

Carbohydrate Research 341 (2006) 1758–1763
Note
Fluorinated acyclo-C-nucleoside analogues from glycals in two stepsI
Constantin Mamat, Martin Hein and Ralf Miethchen*
Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Straße 3a, D-18059 Rostock, Germany
Received 3 December 2005; received in revised form 31 December 2005; accepted 10 January 2006
Available online 26 January 2006
Dedicated to Professor Dr. Reint Eujen on the occasion of his 60th birthday
Abstract—A convenient two-step strategy is reported for the synthesis of fluorinated optically pure acyclo-C-nucleoside analogues
starting from simple glycals. In the first step, benzyl- or p-methoxybenzyl-protected glycals are treated with trifluoroacetic anhy-
dride, bromodifluoroacetyl chloride, trichloroacetyl chloride, and perfluorooctanoyl chloride, respectively, in the presence of
Et3N. This one-pot procedure yields 1,2-unsaturated sugars (1,5-anhydro-3,4,6-tri-O-benzyl (or p-methoxybenzyl) 2-deoxy-2-
perhalogenoacyl-D-arabino / lyxo-hex-1-enitols 4–9) acylated at C-2. In the second step, a selective ring transformation is induced
by treatment of the C-acylated glycals with bis-nucleophiles (hydrazine, phenylhydrazine, o-phenylenediamine, hydroxylamine). In
particular, 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trifluoroacetyl-D-arabino-hex-1-enitol (4) and 1,5-anhydro-2-deoxy-2-trifluoro-
acetyl-3,4,6-tri-O-(p-methoxybenzyl)-D-arabino-hex-1-enitol (8) were reacted with these nucleophiles generating the final C-nucleo-
side analogues of pyrazole (10, 11, and 12), diazepine (13), and isoxazole (15), respectively, containing a carbohydrate side chain
linked to the heterocyclic ring.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Carbohydrates; Heterocycles; Ring transformation; Trifluoromethylated C-nucleosides
Fluorinated analogues of natural substances are mainly
of interest in bioorganic chemistry,2–7 since single fluor-
ine atoms or trifluoromethyl groups introduced in place
of hydrogen atoms often increase the biological activity
of parent compounds. However, reviews on synthetic
strategies of trifluoromethyl substituted natural sub-
stance analogues3 and of trifluoromethyl substituted
heterocycles8 show that the pool of suitable fluorinated
building blocks, as well as of methods for their prepara-
tion, are quite limited, especially when trifluoromethyl
substituted heteroaromatics linked to a chiral moiety
are the target molecules. Due to the interest in trifluoro-
methyl-substituted heteroaromatics with a hydrophilic
lateral chain, we focused our efforts on a two-step stra-
tegy for the synthesis of such compounds starting from
1,2-unsaturated monosaccharide derivatives.
It is well known that the enol ether unit of glycals
allows electrophilic addition reactions9–12 including C-
acylations. Generally, acylations of enol ethers require
the use of carboxylic acid reagents with high electro-
philic potential.13–16 Activation of the reagents can be
made by Friedel–Crafts-type catalysts, however, poly-
merization often results even when mild Lewis acid
catalysts are used.13,15 In carbohydrate chemistry, 2-C-
formylations have been described by Ramesh and Bala-
subramanian17 under Vilsmeier–Haack conditions and
2-C-acetylations were realized by Priebe et al.12 using
acetic anhydride in the presence of Lewis acids.
When the reaction was carried out in the presence
of triethylamine, we found that, after the addition of
highly electrophilic carbonyl compounds (perhalogeno-
carboxylic acid anhydrides or chlorides), a selective
1,2-elimination to glycals follows. Thus (Scheme 1),
1,5-anhydro-3,4,6-tri-O-benzyl-D-arabino-hex-1-enitol
(1) and trifluoroacetic anhydride, bromodifluoroacetyl
chloride, trichloroacetyl chloride, or pentadecafluoro-
octanoyl chloride gave under these reaction conditions
q Organofluorine Compounds and Fluorinating Agents, Part 34; for
Part 33, see Ref. 1.
*
Corresponding author. Fax: +49 381 498 6412; e-mail: ralf.
miethchen@uni-rostock.de
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.01.011

C. Mamat et al. / Carbohydrate Research 341 (2006) 1758–1763
1759
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
i
ii
89%
79%
BnO
O
BnO
O
BnO
1
BrF2C
O
F3C
O
5
4
BnO
BnO
BnO
BnO
iii
iv
63%
52%
BnO
O
BnO
O
F3C(F2C)6
Cl3C
6
7
PMBO
R1
PMBO
R1
O
O
8: R1 = H
i
R2 = PMBO (92%)
9: R1 = PMBO
2: R1 = H, R2 = PMBO
3: R1 = PMBO, R2 = H
R2
R2
R2 = H (81%)
PMBO
PMBO
O
F3C
Scheme 1. Reagents and conditions: (i) (CF3CO)2O, Et3N, DMF, rt; (ii) BrF2C–C(O)Cl, Et3N, DMF, rt; (iii) Cl3C–C(O)Cl, Et3N, DMF, rt; (iv)
F3C(CF2)6C(O)Cl, pyridine, DMF, rt, PMB = p-methoxybenzyl.
the corresponding b-keto vinyl ether derivatives 4–7 in
yields of 52–89%. Moreover, the p-methoxybenzyl pro-
tected starting materials 2 and 3 were reacted with tri-
fluoroacetic anhydride in the presence of triethylamine
generating the C-trifluoroacetylated glycals 8 and 9,
respectively (yields 81% and 92%).
The addition–elimination sequence of such acylation
reactions was already investigated as two-step proce-
dure. At first, the 1:1 adduct from 3,4-dihydro-2H-
pyran and trichloroacetyl chloride was isolated at room
temperature. Subsequent thermal treatment of the
compound resulted in HCl elimination with re-forma-
tion of the double bond18 (see also Refs. 15 and 19).
C-Acylations of the glycals 1–3 in the presence of
triethylamine proceeded readily at room temperature
with subsequent elimination. However, reaction times
of 2–5 days were required for a completion of the
reaction.
a,b-Unsaturated carbonyl compounds are suitable
bis-electrophiles in syntheses of five- and six-membered
heterocycles.14,20–24 In particular, the 2-C-trihaloacetyl-
ated glycals 4–9 are potential precursors for syntheses
of halomethyl substituted heteroaromatics. Optically
pure acyclo-C-nucleoside analogues should be likewise
accessible from those using a method of ring transfor-
mation based on a strategy reported by Peseke and
co-workers.25,26 and Yadav et al.27 The authors synthe-
sized optically pure acyclo-C-nucleoside analogues by
treatment of 2-C-formyl glycals with different bis-nucleo-
philes. The reaction starts by attack of the correspond-
ing bis-nucleophile on the formyl group and proceeds
through intramolecular cyclization with simultaneous
opening of the pyranose ring set off by the second nucleo-
philic group. The heterocyclic ring so generated is linked
to a chiral side chain consisting of C4–C6 of the former
pyranose unit. This type of reaction was only applied to
formyl derivatives of unsaturated sugars so far. Because
of the interest in trifluoromethyl-substituted heteroaro-
matics, the applicability of the method on the carbonyl
active b-keto vinyl ethers 4 and 8 was studied (Schemes
2 and 3).
It is known that N-nucleophiles such as aliphatic
amines, aniline, and hydrazine react with fluorine
containing a,b-unsaturated carbonyl compounds.22
The condensation of 1,5-anhydro-3,4,6-tri-O-benzyl-2-
trifluoroacetyl-2-deoxy-D-arabino-hex-1-enitol (4) with
hydrazine and phenylhydrazine yields pyrazole deriva-
tives 10 and 11, respectively (Scheme 2). In the same
manner, the p-methoxybenzyl protected glucal 8 reacts
with hydrazine to give compound 12.
Because some benzodiazepines show biological
activity, for example, chlorodiazepine oxide is used as
tranquilizer28 and fluoroazepine as a soporific,29 the
strategy of ring transformation was also used to synthe-
size a trifluoromethyl substituted benzodiazepine deriva-
tive. 5-Trifluoromethyl-2,3-dihydro-1,4-diazepine has
previously been synthesized by Chu et al.21 from 4-eth-
oxy-1,1,1-trifluoro-3-buten-2-one and ethylene diamine
in good yield. However, the reaction with o-phenyl-
enediamine only produced benzimidazole derivatives as
elimination products. In our case no elimination was
observed when o-phenylenediamine reacts with the

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C. Mamat et al. / Carbohydrate Research 341 (2006) 1758–1763
OH
RO
RO
OR
OH
OR
RO
O
NH
i
ii
RO
OR
F3C
NR'
N
OR
F3C
RO
O
N
F3C
10: R = Bn, R' = H (84%)
11: R = Bn, R' = Ph (40%)
12: R = PMB, R' = H (61%)
4: R = Bn
8: R = PMB
13: R = Bn (44%)
Scheme 2. Reagents and conditions: (i) H2NNHR0, EtOH, 24 h, reflux; (ii) o-phenylenediamine, EtOH, 24 h, reflux.
OH
OBn
OH
OBn
ii
i
BnO
4
BnO
N
N
OBn
F3C
OBn
F3C
O
O
OH
15 (35%)
14
Scheme 3. Reagents and conditions: (i) Hydroxylamine, EtOH, 24 h, rt; (ii) (CF3CO)2O, pyridine, rt.
glucal 4 as shown in Scheme 2. Diazepine derivative 13
was isolated as a yellowish oil in 44% yield.
Intecta AMD 402 (EI with 70 eV or chemical ionization
with isobutane). Optical rotations were measured on a
polar LlP (IBZ Meßtechnik) instrument. Chromato-
graphic separations and TLC detections were carried
out with Merck Silica Gel 60 (63–200 lm) and Merck
Silica Gel 60 F254 sheets, respectively. TLCs were devel-
oped by 5% methanolic sulfuric acid and heating.
The reaction of 4 with hydroxylamine proceeds in pyr-
idine to give the hydroxyisoxazoline derivative 14, which
was not isolated in pure form but instead the crude
product was dehydrated to isoxazole 15 by treatment
with trifluoroacetic anhydride in pyridine (Scheme 3).
The structures of the new compounds are supported
by NMR spectra, micro- and GC–MS analyses. The
1,2-unsaturated monosaccharide derivatives 4–9 show
characteristic H-1 (7.70 to 8.38 ppm) and C-1 signals
(161.1–162.2 ppm). The 19F NMR-spectra of com-
pounds 4, 8, and 9 show singlets for the trifluoromethyl
group at about ꢀ70 ppm; the singlet of the difluoro-
methyl group of 5 is found at ꢀ55.1 ppm. The downfield
shift of the CF3-signal of compounds 10, 11, and 12
(ꢀ50 to ꢀ60 ppm) indicates that this group is linked
to an aromatic system.22 The corresponding signals for
diazepine derivative 13 (ꢀ66.9 ppm) and isoxazole 15
(ꢀ68.8 ppm) indicate that these CF3-groups are located
on an activated double bond.
1.2. 1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trifluoro-
acetyl-D-arabino-hex-1-enitol (4)
To a solution of 1.0 g (2.4 mmol) of 1,5-anhydro-3,4,6-
tri-O-benzyl-D-arabino-hex-1-enitol (1)30 in dry DMF
(5 mL) and dry Et3N (0.5 mL) trifluoroacetic anhydride
(0.9 mL, 4.8 mmol) was added (argon atmosphere) and
the solution was stirred for 4 days at rt (TLC control).
Then, an ice/ethyl acetate/Et3N-mixture (20/20/1 mL)
was added and the aqueous phase was extracted three
times with ethyl acetate. The organic layer was washed
with water and dried with MgSO4, the solvent was evap-
orated under reduced pressure and the residue was puri-
fied by column chromatography (silica gel; heptane/
ethyl acetate 10:1). Yield of 4: 1.1 g (89%). Rf 0.55
23
1. Experimental
1.1. General
(heptane/EtOAc 10:1); ½aꢁD +1.1 (c 2.0, CHCl3); 1H
NMR (250 MHz, CDCl3): d 3.63 (dd, 1H, 2J = 10.7,
3J5,6a = 4.9 Hz, H-6a,), 3.79 (dd, 1H, 2J = 10.7,
3
3J5,6b = 7.6 Hz, H-6b), 3.84 (t, 1H, J3,4 = 2.2 Hz,
3
3
Melting points were obtained using a Leitz polarizing
microscope (Laborlux 12 Pol) equipped with a hot stage
(Mettler FP 90) and are uncorrected. Microanalyses
were carried out with a C/H/N/S-analyser Thermoquest
H-3), 4.42 (dd, 1H, J4,5 = 2.4, J3,4 = 2.2 Hz, H-4),
4.47–4.65 (m, 6H, 3 · CH2Ph), 4.70–4.77 (ddd, 1H,
3
3
3J4,5 = 2.4, J5,6a = 4.9, J5,6b = 7.6 Hz, H-5), 7.20–7.36
(m, 15H, Ph), 7.86 (d, 1H, J = 1.5 Hz, H-1); 13C NMR
(75.5 MHz, CDCl3): d 66.3 (C-4), 68.3 (C-6), 70.9 (C-
3), 71.8, 73.1, 73.5 (3 · CH2Ph), 78.7 (C-5), 110.7 (C-
2), 116.8 (q, JC,F = 291.1 Hz, CF3), 127.9, 128.0, 128.1,
128.3, 128.6, 128.7 (Ph), 137.2, 137.7, 137.9 (Ph,
1
Flash EA 1112. H, 13C, and 19F NMR spectra were
recorded on Bruker instruments: AC 250, ARX 300
1
and AVANCE 500, internal standard TMS for H and
13C NMR spectra, CFCl3 for 19F NMR spectra. MS:

C. Mamat et al. / Carbohydrate Research 341 (2006) 1758–1763
1761
3 · quart. C) 161.7 (C-1), 179.4 (q, JC,F = 34.6 Hz,
C@O); 19F NMR (235 MHz, CDCl3): d ꢀ69.9 (CF3);
MS (FAB pos. NBA/NaCl): m/z (%) = 535 (33)
[M++Na]; 405 (34) [M+ꢀOBn]. Anal. Calcd for
C29H27F3O5 (512.52): C, 67.96; H, 5.31. Found: C,
67.83; H, 5.46.
described for compound 4. 254 mg (52%) of product 7
22
was isolated; Rf 0.60 (heptane/EtOAc 2:1); ½aꢁD ꢀ11.3
1
(c 1.4, CHCl3); H NMR (250 MHz, CDCl3): d 3.65
2
3
(dd, 1H, J = 10.7, J5,6 = 5.2 Hz, H-6a), 3.79 (dd, 1H,
3
2J = 10.7, J5,6 = 7.6 Hz, H-6b), 3.84 (t, 1H, 3J =
2.4 Hz, H-3), 4.42–4.54 (m, 6H, CH2Ph, H-4), 4.65
3
(d, 1H, CH2Ph), 4.68–4.76 (dd, 1H, J5,6a = 5.2,
1.3. 1,5-Anhydro-3,4,6-tri-O-benzyl-2-bromodifluoro-
acetyl-2-deoxy-D-arabino-hex-1-enitol (5)
3J5,6b = 7.6 Hz, H-5), 7.19–7.39 (m, 15H, Ph), 7.94 (s,
1H, H-1); 13C NMR (75.5 MHz, CDCl3): d 66.4 (C-4);
68.1 (C-6); 70.8 (C-3); 71.6, 73.0, 73.3 (CH2Ph); 78.5
(C-5); 113.1 (C-2); 127.7, 127.8, 128.0, 128.1, 128.4,
128.7 (Ph), 137.1, 137.5, 137.8 (Ph, quart. C) 162.2 (C-
1), 181.2 (C@O, JC,F = 25 Hz); 19F NMR (235 MHz,
CDCl3): d ꢀ80.5 (CF3); ꢀ112.0, ꢀ112.2 (CF2C@O);
ꢀ120.8, ꢀ121.0, ꢀ121.7, ꢀ122.4 (4 · CF2); ꢀ125.9
(CF2CF3); MS (FAB pos. NBA): m/z (%) = 705 (20)
[M+ꢀOBn]. Anal. Calcd for C35H27F15O5 (526.21): C,
51.74; H, 3.35. Found: C, 51.53; H, 3.19.
Glucal 1 (0.56 g, 1.3 mmol) was acylated with bromodi-
fluoroacetyl chloride (0.9 mL, 2.6 mmol) as described
for compound 4. 0.61 g (79%) of product 5 was isolated.
21
Rf 0.70 (heptane/EtOAc 1:1); ½aꢁD ꢀ19.3 (c 1.3, CHCl3);
1H NMR (250 MHz, CDCl3): d 3.63 (dd, 1H, 2J = 10.7,
3J5,6a = 4.9 Hz, H-6a), 3.80 (dd, 1H, 2J = 10.7,
3J5,6b = 7.9 Hz, H-6b), 3.84 (m, 1H, H-3), 4.42–4.46
(m, 1H, H-4), 4.47–4.66 (m, 6H, 3 · CH2Ph), 4.69–4.77
(m, 1H, H-5), 7.20–7.36 (m, 15H, Ph), 8.02 (s, 1H, H-
1); 13C NMR (75.5 MHz, CDCl3): d 66.4 (C-4), 68.1
(C-6), 70.9 (C-3), 71.6, 72.8, 73.3 (CH2Ph), 78.4 (C-5),
108.7 (C-2), 114.0 (t, J = 317.5 Hz, CF2Br), 127.7,
127.8, 127.9, 128.1, 128.3, 128.4, 128.6 (Ph), 137.1,
137.4, 137.7 (Ph, quart. C) 161.4 (C-1), 181.4 (t,
J = 25.8 Hz, C@O); 19F NMR (235 MHz, CDCl3): d
ꢀ55.1 (CF2); MS (EI, 70 eV): m/z (%) = 572 (0.1)
[M+]; 465 (20) [M+ꢀOBn]; 359 (15) [M+ꢀ2OBn]. Anal.
Calcd for C29H27BrF2O5 (573.43): C, 60.74; H, 4.75.
Found: C, 60.40; H, 4.71.
1.6. 1,5-Anhydro-2-deoxy-2-trifluoroacetyl-3,4,6-tri-O-
(p-methoxybenzyl)-D-arabino-hex-1-enitol (8)
1,5-Anhydro-3,4,6-tri-O-(p-methoxybenzyl)-D-arabino-
hex-1-enitol (2)32 (1.15 g, 2.33 mmol) was acylated
with trifluoroacetic anhydride (2.3 mL, 4.66 mmol) as
described for compound 4. 1.3 g (92%) of the syrupy
product 8 was isolated; Rf 0.66 (heptane/EtOAc 1:2);
21
½aꢁD ꢀ6.9 (c 1.8, CHCl3); 1H NMR (250 MHz, C6D6): d
2
3.28, 3.29, 3.30 (3s, 9H, OMe), 3.61 (dd, 1H, J = 10.7,
3J5,6a = 5.7 Hz, H-6a), 3.70 (dd, 1H, 2J = 10.4 Hz,
3
1.4. 1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-trichloro-
acetyl-D-arabino-hex-1-enitol (6)
3J5,6b = 7.3 Hz, H-6b), 3.81 (t, 1H, J3,4 = 2.1 Hz, H-3),
4.17 (dd, 2H, 2J = 11.9 Hz, CH2Ph), 4.21 (s, 2H,
2
CH2Ph), 4.55 (dd, 2H, J = 10.9 Hz, CH2Ph), 4.63 (t,
3
3
Glucal 1 (1.0 g, 2.4 mmol) was acylated with trichloro-
acetyl chloride (0.5 mL, 4.8 mmol) as described for com-
pound 4. 0.85 g (63%) of product 6 was isolated; Rf 0.70
1H, J4,5 = 2.1 Hz, H-4), 4.74 (ddd, 1H, J4,5 = 2.1,
3J5,6a = 5.7, J5,6b = 7.3 Hz, H-5), 6.70–6.83 (m, 6H,
3
Ph), 6.98–7.16 (m, 6H, Ph), 7.78 (d, 1H, J = 1.2 Hz, H-
1); 13C NMR (75.5 MHz, C6D6): d 54.8 (OMe), 66.6
(C-4), 68.1 (C-6), 70.7 (C-3), 71.2, 72.9, 73.1 (CH2Ph),
79.1 (C-5), 111.4 (C-2), 114.1, 114.3 (Ph), 121.4 (q,
JC,F = 292.3 Hz, CF3), 129.6, 129.8, 130.1, 130.3, 130.5
(Ph), 159.9, 160.0 (Ph, quart. C), 161.8 (C-1), 179.4 (q,
JC,F = 34.6 Hz, C@O); 19F NMR (235 MHz, C6D6):
d ꢀ68.6 (CF3). MS (EI, 70 eV): m/z (%) = 602 (1) [M+],
482 (12) [M+ꢀPMB], 362 (2) [M+ꢀ2PMB]. Anal. Calcd
for C32H33F3O8 (602.60): C, 63.78; H, 5.52. Found: C,
63.77; H, 5.55.
22
(heptane/EtOAc 1:1); ½aꢁD +4.5 (c 1.1, CHCl3); 1H
NMR (250 MHz, CDCl3): d 3.63 (dd, 1H, 2J = 10.7,
3J5,6a = 4.9 Hz, H-6a), 3.81 (dd, 1H, 2J = 10.7,
3J5,6b = 7.9 Hz, H-6b), 3.83 (m, 1H, H-3), 4.42–4.46
(m, 1H, H-4), 4.47–4.66 (m, 6H, CH2Ph), 4.69–4.77
(m, 1H, H-5), 7.20–7.36 (m, 15H, Ph), 8.38 (s, 1H,
H-1); 13C NMR (75.5 MHz, CDCl3): d 67.8 (C-4), 68.3
(C-6), 71.4 (C-3), 71.7, 73.0, 73.4 (CH2Ph), 78.1 (C-5),
106.3 (C-2), 127.8, 127.9, 128.0, 128.2, 128.5, 128.6,
128.7 (Ph), 137.4, 137.7, 138.1 (Ph, quart. C) 161.1 (C-
1), 180.8 (C@O), MS (EI, 70 eV): m/z (%) = 453 (5)
[M+ꢀPhCH2O]; 347 (14) [M+ꢀ2PhCH2O]. Anal. Calcd
for C29H27Cl3O5 (561.88): C, 61.99; H, 4.84. Found: C,
62.15; H, 5.04.
1.7. 1,5-Anhydro-2-deoxy-2-trifluoroacetyl-3,4,6-tri-O-
(p-methoxybenzyl)-D-lyxo-hex-1-enitol (9)
1,5-Anhydro-3,4,6-tri-O-(p-methoxybenzyl)-D-lyxo-hex-
1-enitol (3)32 (1 g, 2.4 mmol) was acylated with trifluoro-
acetic anhydride (0.9 mL, 4.8 mmol) as described for
compound 4. 0.82 g (81%) of the syrupy product 9 was
1.5. 1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-perfluoro-
octanoyl-D-arabino-hex-1-enitol (7)
23
Glucal 1 (250 mg, 0.6 mmol) was acylated with penta-
isolated. Rf 0.64 (heptane/EtOAc 1:1); ½aꢁD ꢀ43.1 (c
1
decafluoro-octanoyl chloride31 (519 mg, 1.2 mmol) as
0.3, CHCl3); H NMR (250 MHz, CDCl3): d 3.78–3.95

1762
C. Mamat et al. / Carbohydrate Research 341 (2006) 1758–1763
2
(m, 12H, H-4, H-6a, H-6b, 3 · MeO), 4.45 (dd, 2H,
2J = 11.6 Hz, CH2Ph), 4.52 (d, 1H, 2J = 11.6 Hz,
CH2Ph), 4.59–4.71 (m, 4H, H-3, CH2Ph), 4.74 (d, 1H,
2J = 10.4 Hz, CH2Ph), 6.82–6.92 (m, 6H, Ph), 7.19–
7.26 (m, 6H, Ph), 7.70 (d, 1H, JH,F = 1.2 Hz, H-1); 13C
NMR (75.5 MHz, CDCl3): d 55.4 (MeO), 66.2 (C-3),
68.1 (C-6), 71.6 (CH2Ph), 73.0 (C-4), 73.1, 74.5
(2 · CH2Ph), 78.5 (C-5), 112.2 (C-2), 113.7, 113.9,
114.1 (Ph), 116.7 (q, JC,F = 294.0 Hz, CF3), 129.3,
129.4, 129.7, 130.0, 130.8 (Ph), 161.5 (JC,F = 5.3 Hz,
C-1), 178.6 (q, JC,F = 35.2 Hz, C@O); 19F NMR
(235 MHz, CDCl3): d ꢀ70.1 (CF3); MS (CI-isobutane):
m/z (%) = 602 (1) [M+]; 482 (3) [M+ꢀPMBꢀH]; 360
(1) [M+ꢀ2PMB]. Anal. Calcd for C32H33F3O8
(602.60): C, 63.78; H, 5.52. Found: C, 63.21; H, 5.37.
CH2Ph), 4.52 (dd, 2H, J = 12.2 Hz, CH2Ph), 4.64 (d,
2
3
1H, J = 11.0 Hz, CH2Ph), 5.10 (d, 1H, JH,F = 1.8 Hz,
H-10), 7.10–7.53 (m, 20H, Ph), 7.97 (s, 1H, H-5); 13C
NMR (125 MHz, CDCl3): d 70.2 (C-30), 71.1 (C-40),
71.9 (CH2Ph), 72.1 (C-10), 73.6, 74.6 (CH2Ph), 81.0
(C-20), 120.5 (q, JC,F = 269.4 Hz, CF3), 123.0 (C-4),
126.1, 127.9, 128.0, 128.1, 128.4, 128.6, 128.7, 129.1,
129.5 (Ph), 137.4, 137.9, 138.5 (Ph, quart. C), 137.9
(q, JC,F = 34.0 Hz, C-3), 141.5 (C-5), 19F NMR
(235 MHz, CDCl3): d ꢀ54.4 (CF3); MS (CI-isobutane):
m/z (%) = 603 (14) [M++H], 495 (29) [M+ꢀOBn]. Anal.
Calcd for C35H33F3N2O4 (602.65): C, 69.76; H, 5.52; N,
4.65. Found: C, 69.39; H, 5.91; N, 4.41.
1.10. 4-[1,2,4-Tri-O-(p-methoxybenzyl)-D-arabino-
1,2,3,4-tetrahydroxybutyl]-1-phenyl-3-trifluoromethyl-
1H-pyrazole (12)
1.8. 4-(1,2,4-Tri-O-benzyl-D-arabino-1,2,3,4-tetra-
hydroxybutyl)-3-trifluoromethyl-1H-pyrazole (10)
Glucal 8 (251 mg, 0.4 mmol) was dissolved in 15 mL eth-
anol, and 1 mL of hydrazine hydrate (98%) was added.
The solution was heated for 24 h under reflux. After re-
moval of the solvent, the residue was purified by column
chromatography (heptane/EtOAc 2:1). Yield 156 mg
Glucal 4 (324 mg, 0.63 mmol) was dissolved in 15 mL
ethanol, and 1 mL of hydrazine hydrate (98%) was
added. The solution was heated for 24 h under reflux.
After removal of the solvent, the residue was purified
by column chromatography (heptane/EtOAc 2:1). Yield
22
(61%). Rf 0.29 (heptane/EtOAc 1:2); ½aꢁD ꢀ31.8 (c 0.9,
21
280 mg (84%). Rf 0.42 (heptane/EtOAc 1:1); ½aꢁD ꢀ12.6
CHCl3); mp 84.5–87.5 ꢁC (heptane); 1H NMR
(250 MHz, CDCl3): d 2.84 (br s, 1H, OH), 3.52–3.59
(m, 3H, H20, H-40a, H40b), 3.70, 3.77, 3.78 (s, 9H,
OMe), 4.96–4.06 (m, 1H, H-30), 4.10 (d, 1H, 2J =
1
(c 1.2, CHCl3); H NMR (250 MHz, C6D6): d 3.07 (s,
1H, OH), 3.05–3.68 (m, 2H, H-40a, H-40b), 3.84 (dd,
1H, J2 ;1 ¼ 2:7 Hz, H-20), 4.11–4.49 (m, 7H, 2J =
3
0
0
2
3
11.3 Hz, H-30, CH2Ph), 5.35 (d, 1H, J1 ;2 ¼ 2:7 Hz, H-
10), 7.05–7.35 (m, 15H, Ph), 7.50 (s, 1H, H-5 pyrazole);
13C NMR (125 MHz, C6D6): d 70.2 (C-30), 71.3 (C-40),
71.6 (CH2Ph), 72.6 (C-10), 73.3, 74.4 (CH2Ph), 81.9 (C-
20), 118.4 (C-4 pyrazole), 122.6 (q, JC,F = 268.9 Hz,
CF3), 127.4, 127.6, 127.7, 127.8, 127.9, 128.1, 128.3
(Ph), 131.1 (C-5 pyrazole), 138.0, 138.1, 138.2 (Ph, quart.
C), 139.8 (q, JC,F = 36.2 Hz, C-3 pyrazole); 19F NMR
(235 MHz, C6D6): d ꢀ57.7 (CF3); MS (FAB pos. NBA/
NaCl): m/z (%) = 549 (55) [M++Na+], 509 (10)
[M+ꢀOH], 457 (5) [M+ꢀCF3], 419 (62) [M+ꢀOBn].
Anal. Calcd for C29H29F3O4 (526.21): C, 66.15; H, 5.55;
N, 5.52. Found: C, 66.14; H, 5.80; N, 5.05.
11.0 Hz, CH2Ph), 4.25 (dd, 2H, J = 11.6 Hz, CH2Ph),
0
0
4.44 (dd, 2H, 2J = 11.6 Hz, CH2Ph), 4.48 (d, 1H,
2
3
0
0
J = 11.0 Hz, CH2Ph), 5.00 (d, 1H, J1 ;2 ¼ 2:4 Hz, H-
10), 6.68–7.28 (m, 12H, Ph), 7.79 (s, 1H, H-5); 13C
NMR (75.5 MHz, CDCl3): d 70.2 (C-30), 70.8 (C-40),
71.1 (CHPh), 71.4 (C-10), 73.1, 74.0 (CHPh), 81.7 (C-
20), 113.6, 113.9 (Ph), 118.3 (C-4), 121.9 (q,
JC,F = 268.8 Hz, CF3), 129.5, 129.6, 129.7, 129.9, 130.0
(Ph), 131.5 (C-5), 139.6 (q, JC,F = 36.4 Hz, C-3), 159.3,
159.4, 159.5 (Ph, quart. C), 19F NMR (235 MHz,
CDCl3): d ꢀ59.4 (CF3). MS (CI–isobutane): m/z
(%) = 616 (2) [M+], 494 (1) [M+ꢀPMB]. Anal. Calcd
for C32H35F3N2O7 (616.63): C, 62.33; H, 5.72; N, 4.54.
Found: C, 62.11; H, 5.80; N, 4.71.
1.9. 4-(1,2,4-Tri-O-benzyl-D-arabino-1,2,3,4-tetrahydr-
oxybutyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole (11)
1.11. 3-(1,2,4-Tri-O-benzyl-D-arabino-1,2,3,4-tetra-
hydroxybutyl)-4-trifluoromethyl-1H-benzo[b] [1,4]-
diazepine (13)
Glucal 4 (150 mg, 0.29 mmol) was dissolved in 15 mL
ethanol, and 0.3 mL of freshly distilled phenylhydrazine
was added. The solution was heated for 24 h under
reflux. After removal of the solvent, the remaining phen-
ylhydrazine was distilled off by bulb tube distillation at
70 ꢁC/10ꢀ1 Torr and the residue was purified by column
chromatography (heptane/EtOAc 10:1). Yield 70 mg
Glucal 4 (204 mg, 0.4 mmol) was dissolved in 15 mL eth-
anol, and 43 mg (0.4 mmol) of o-phenylenediamine were
added. The solution was stirred 24 h at rt. After removal
of the solvent, the residue was purified by column chro-
matography (heptane/EtOAc 5:1). Yield 104 mg (44%).
22
22
(40%); Rf 0.52 (heptane/EtOAc 1:1); ½aꢁD ꢀ44.6 (c 1.1,
Rf 0.51 (heptane/EtOAc 1:1); ½aꢁD +192.6 (c 1.0,
1
1
CHCl3); H NMR (250 MHz, CDCl3): d 3.61–3.68 (m,
CHCl3); H NMR (250 MHz, CDCl3): d 3.70 (dd, 2H,
3H, H-40a, H-40b, H-20), 4.09 (dt, 1H, H-30), 4.28 (d,
J3 ;4 ¼ 4:0 Hz, H-40a, H-40b), 3.75 (dd, 1H, J2 ;3
¼
3
3
0
0
0
0
2
2
3
3
7:6, J1 ;2 ¼ 2:1 Hz, H-20), 4.17 (m, 1H, J2 ;3 ¼ 7:6,
0
0
0
0
1H, J = 11.0 Hz, CH2Ph), 4.41 (dd, 2H, J = 11.6 Hz,

C. Mamat et al. / Carbohydrate Research 341 (2006) 1758–1763
1763
2
3
J3 ;4 ¼ 4:0 Hz, H-30), 4.34–4.58 (m, 2H, J = 11,3 Hz,
0
0
3. Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; John Wiley and Sons: New York, 1991.
4. Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Organo-
fluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993.
CH2Ph), 5.26 (d, 1H, J1 ;2 ¼ 2:1 Hz, H-10), 6.90–7.35
3
0
0
3
(m, 19H, Ph, H-6 to H-9), 8.03 (d, 1H, JN,2 = 13.4 Hz,
H-2), 9.05 (d, 1H, JN,2 = 13.4 Hz, NH); 13C NMR
3
(125 MHz, CDCl3): d 70.1 (C-30), 71.0 (C-40), 72.3,
73.7, 75.3 (CH2Ph), 76.8 (C-10), 82.2 (C-20), 104.4 (C-
3), 121.8 (q, J = 292.9 Hz, CF3), 117.5, 120.0, 126.0
(C6–C9), 128.0, 128.1, 128.2, 128.3, 128.5, 128.6, 128.7
(Ph), 137.0, 137.4, 137.9 (Ph, quart. C), 149.0 (C-2),
176.5 (q, JC,F = 31.7 Hz, C-4); 19F NMR (235 MHz,
CDCl3): d ꢀ66.9 (s, CF3); MS (ESI, +c): m/z
(%) = 603 (100) [M++H], 585 (48) [M+ꢀOH], 495 (50)
[M+ꢀOBn].
5. Resnati, G.; Soloshonok, V. A. Fluoroorganic Chemistry:
Synthetic Challenges and Biomedical Rewards; Pergamon
Press: Oxford, 1996.
6. Yamamoto, H. Organofluorine Compounds—Chemistry
and Applications; Springer: Berlin, 2000.
7. Special Issue: Fluoro Sugars, Miethchen, R.; Defaye, J.
(Eds.), Carbohydr. Res. 2000, 327, 1–218.
8. Burger, K.; Wucherpfennig, U.; Brunner, E. Adv. Hetero-
cycl. Chem. 1994, 60, 1–64.
9. Collins, P.; Ferrier, R. Monosaccharides: Their Chemistry
and their Roles in Natural Products; Wiley: Chichester,
1995; p 319.
1.12. 4-(1,2,4-Tri-O-benzyl-D-arabino-1,2,3,4-tetra-
hydroxybutyl)-5-trifluoromethyl-isoxazole (15)
10. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed.
1996, 35, 1380–1419.
11. Seeberger, P. H.; Haase, W. C. Chem. Rev. 2000, 100,
4349–4393.
Glucal 4 (313 mg, 0.61 mmol) was dissolved in 5 mL of
pyridine, and 0.5 mL of saturated hydroxylamine hydro-
chloride solution was added. The solution was stirred
for 2 days. After removal of the solvent the residue
was dissolved in 0.5 mL of pyridine and 0.5 mL of tri-
fluoroacetic anhydride. The solution was stirred over-
night. Then, a satd NaHCO3-solution was added and
the aqueous phase was extracted three times with ethyl
acetate. The organic layer was dried with MgSO4, the
solvent was evaporated under reduced pressure and
the residue was purified by column chromatography
(silica gel; heptane/ethyl acetate 10:1). Yield 108 mg
12. Priebe, W.; Grynkiewicz, G.; Nemati, N. Tetrahedron
Lett. 1992, 33, 7681–7684.
13. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo,
S. Chem. Lett. 1976, 499–502.
14. Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.;
Fischer, P. Synthesis 1991, 483–486.
15. Effenberger, F.; Maier, R.; Scho¨nwa¨lder, K.-H.; Ziegler,
T. Chem. Ber. 1982, 115, 2766–2782.
16. Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagawa, M.
Synthesis 1986, 1016–1917.
17. Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron
Lett. 1991, 32, 3875–3878.
18. Trost, B. M.; Balkovec, J. M.; Mao, M. K.-T. J. Am.
Chem. Soc. 1983, 105, 6755–6757.
19. Bailey, D. H.; Johnson, R. E.; Albertson, N. F. Org.
Synth. 1971, 51, 100–103.
20. Zanatta, N.; de Cortelini, M. F. M.; Carpes, M. J. S.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem.
1997, 34, 509–513.
21. Chu, Q.-L.; Wang, Y.; Zhu, S.-Z. Synth. Commun. 2000,
30, 677–687.
22. Song, L.-P.; Chu, Q.-L.; Zhu, S.-Z. J. Fluorine Chem.
2001, 107, 107–112.
23. Abdel-Fattah, A. A. A. Synthesis 2005, 245–249.
24. Jones, B. G.; Branch, S. K.; Thompson, A. S.; Threadgill,
M. D. J. Chem. Soc., Perkin Trans. 1 1996, 2685–
2691.
25. Montero, A.; Feist, H.; Michalik, M.; Quincoces, J.;
Peseke, K. Synthesis 2002, 664–668.
26. Bari, A.; Feist, H.; Michalik, D.; Michalik, M.; Peseke, K.
Synthesis 2004, 2863–2868.
27. Yadav, J. S.; Reddy, B. V. S.; Satheesh, G.; Naga
Lakshmi, P.; Kiran Kumar, S.; Kunwar, A. C. Tetra-
hedron Lett. 2004, 45, 8587–8590.
28. Cash, D. J.; Serfo¨zo¨, P.; Allan, A. M. J. Pharmacol. Exp.
Ther. 1997, 283, 704–711.
22
(34%). Rf 0.52 (heptane/EtOAc 1:1); ½aꢁD +11.3 (c 1.3,
1
2
CHCl3); H NMR (250 MHz, CDCl3): d 3.70 (dd, J =
2
11.0, J3 ;4 b ¼ 4:6 Hz, H-40b), 3.78 (dd, 1H, J = 11.0,
3
0
0
J3 ;4 a ¼ 5:5 Hz, H-40a), 3.94 (t, 1H, 3J = 4.9 Hz, H-
3
0
0
20), 4.19–4.24 (m, 1H, J1 ;2 ¼ 4:9 Hz, H-10), 4.51 (s,
3
0
0
3
3
0
0
0
0
2H, CH2Ph), 4.53–4.60 (m, 1H, J3 ;4 a ¼ 5:5, J3 ;4 b
¼
4:6 Hz, H-30), 4.61, 4.62 (2s, 2H, CH2Ph), 4.65 (d, 1H,
2J = 11.2 Hz, CH2Ph), 4.81 (d, 1H, 2J = 11.2 Hz,
CH2Ph), 7.20–7.40 (m, 16H, Ph, H-5); 13C NMR
(62 MHz, CDCl3): d 66.8 (C-40), 71.1 (C-20), 72.9 (C-
10), 73.1, 73.6, 73.7 (CH2Ph), 79.3 (C-30), 114.2 (C-4),
122.6 (q, JC,F = 276.6 Hz, CF3), 127.8, 128.0, 128.1,
128.4, 128.5, 128.6, 128.8 (Ph), 136.6, 137.0, 137.5 (Ph,
quart. C); 19F NMR (235 MHz, CDCl3): d ꢀ68.8
(CF3). MS (CI–isobutane): m/z (%) = 510 (29)
[M+ꢀOH], 418 (15) [M+ꢀBnOH]. Anal. Calcd for
C29H28F3NO5 (527.54): C, 66.03; H, 5.35; N, 2.66.
Found: C, 66.22; H, 4.60; N, 2.89.
29. Hunter, A. W. Pharm. J. 1974, 212, 88–90.
30. Blackburne, I. D.; Fredericks, P. M.; Guthrie, R. D. Aust.
J. Chem. 1976, 29, 381–391.
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