Synthesis of homochiral 2-C-trifluoromethyl D- and L-ribose via trifluoromethylation of pentopyranosid-2-uloses

Article abstract of DOI:10.1002/jhet.5570400221

Efficient syntheses of 2-C-trifluoromethyl D- and L-ribose and some O-glycosides via trifluoromethylation of D- and L-3,4-O-isopropylidene-β-erythro-pentopyranosid-2-ulose with Ruppert's reagent are described.

Full text of DOI:10.1002/jhet.5570400221

Synthesis of Homochiral 2-C-Trifluoromethyl D-and L-Ribose via
Trifluoromethylation of Pentopyranosid-2-uloses
Mar-Apr 2003
329
Uwe Eilitz, Christoph Böttcher, Lothar Hennig, and Klaus Burger*
Department of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig,
+
Alois Haas and Simone Gockel
Ruhr-Universität Bochum FNO 034, D-4478 Bochum
Joachim Sieler
Department of Inorganic Chemistry, University of Leipzig, Linnéstraße 3, D-04103 Leipzig, Germany
Received August 1 2002
th
Dedicated to Prof. Rüdiger Mews on the occasion of his 60 birthday.
Efficient syntheses of 2-C-trifluoromethyl D- and L-ribose and some O-glycosides via trifluoromethyl-
ation of D- and L-3,4-O-isopropylidene-β-erythro-pentopyranosid-2-ulose with Ruppert’s reagent are
described.
J. Heterocyclic Chem., 40, 329 (2002).
Introduction.
spectroscopy in vitro and in vivo. Therefore, the develop-
ment of new routes to homochiral trifluoromethyl and
perfluoroalkyl substituted carbohydrates, especially pen-
toses, is of current interest to bioorganic and medicinal
chemists [6,7].
Chemically modified carbohydrates, especially pen-
toses, are substructures of nucleosides, like AZT, ddC, ddI,
d4T, 3TC, exhibiting antiviral, anticancer and anti-HIV
activities [1]. Among the possible modifications of the car-
bohydrate ring (Figure 1), substitution reactions at C-2 are
highly attractive targets, since it has been demonstrated
that already the incorporation of a methyl group into C-2
position of a sugar moiety induces severe conformational
changes. Among other effects, rotation about the N-glyco-
sidic bond is restricted, resulting in an improved nuclease
resistance and consequently in an enhanced biological
activity [2].
Results and Discussion.
A report on the first synthesis of 2’-C-β-trifluoromethyl
pyrimidine ribonucleosides [8] prompts us to disclose our
results. Recently, we reported on a synthesis of 2-C-triflu-
oromethyl DL-ribose and DL-arabinose and of homochiral
2-C-trifluoromethyl D-ribose [9] starting from methyl
trifluoropyruvate. We now describe efficient methodology
for the stereoselective transfer of a trifluoromethyl group
to a carbonyl moiety in a late step of the synthesis, apply-
ing Ruppert’s reagent [10]. As substrates we used methyl
and benzyl D- and L-3,4-O-isopropylidene-β-erythro-
pentopyranosid-2-ulose (1,6), readily available on oxida-
tion from acetone protected D- and L-arabopyranosides
[11] with pyridinium dichromate (PDC) [12] or Dess-
Martin reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benzio-
doxol-3(1H)-on) [13]. From nmr experiments (APT, HET-
Figure 1. General strategies for carbohydrate modification.
1
1
COR, DEPT, H, H-COSY) β-configuration of O-glyco-
sides (1,6) was established.
When 1a was treated with trifluoromethyl trimethylsi-
lane [14] in the presence of a fluoride source [tetrabutyl-
ammonium fluoride (TBAF) or tetrabutylammonium
When a perfluoroalkyl group is attached to C-2 of a
carbohydrate, reactions at C-1 via cationic intermediates
are much more difficult to achieve [3]. Consequently,
glycosides derived from thus modified carbohydrates
should exhibit improved chemical and enzymatic stability.
Fluoroalkyl groups placed in strategic positions of bioac-
tive molecules may improve lipophilicity increasing in vivo
absorption, enhancing permeability through certain body
barriers [4,5]. Furthermore, they are suitable nmr probes for
difluorotriphenyl-stannate] 2a (R = CH ) was obtained as
3
→
colorless crystals, while in the case of 1b
2b (R = Bn)
even after column chromatography we were not able to
19
get a crystalline product. F nmr spectroscopy of crude 2
revealed that only one diastereomer was formed. Because
of the concave geometry of 1 the carbonyl group should
be attacked preferentially from the Si-site to give 2-C-tri-
19
monitoring transport and metabolism of drugs by F nmr

330
U. Eilitz, C. Böttcher, L. Hennig, K. Burger, A. Haas, S. Gockel and J. Sieler
Vol. 40
Scheme 1
Synthesis of 2-C-trifluoromethyl-D-ribose (5) and L-ribose (10).
Deblocking of the glycosidic OH function can be
achieved on heating compounds 3a,b under reflux with
diluted trifluoroacetic acid (v/v = 7:3) in excellent yields
(85-90%). A freshly prepared solution of the unprotected
fluoromethyl-3,4-O-isopropylidene-β-D-erythro-ribopy-
ranosides (2a,2b) and from the Re-site in the case of 6 to
give the enantiomers 7. Pentacoordinated silicium species
are the intermediates of the nucleophilic trifluoromethyla-
tion reaction [15]. They add to the carbonyl moiety to give
O-silylated tert-alcohols, which are deblocked on treat-
ment with diluted acid or tetrabutylammonium fluoride
(TBAF) [16].
Satisfactory yields were obtained only, when the catalyst
was dried prior to use. We found that tetrabutylammonium
difluorotriphenylstannate [14] is superior to TBAF hydrate
when methylene chloride is used as solvent.
The application of Ruppert’s reagent for trifluoromethy-
lation reactions in carbohydrate chemistry restricts the
arsenal of protection groups, since O-acyl groups are of no
use, because Ruppert’s reagent reacts readily with an ester
carbonyl moiety [17].
Deblocking of the acetonide protecting group to give the
homochiral O-glycosides 3a,b was achieved on treatment
with aqueous acetic acid (v/v = 3:2). On recrystallization
of 3a from tetrahydrofuran/hexane we obtained suitable
crystals to perform a X-ray structure analysis [18] to estab-
lish the pyranose structure and to elucidate the relative
configuration at C-2. Since the configuration at C-3 and C-
4 is known, the absolute configuration of C-2 can be deter-
mined unequivocally as 2-C-trifluoromethyl-β-D-ribopy-
ranoside 3a, C-(1) exhibiting R-configuration, as expected
for steric reasons.
compound in D -acetone after column chromatography
6
(eluent: ethyl acetate/methanol) and recrystallization
reveals that only a single compound is present. Based on
1
13
the H and C nmr data we ascribe this compound the
structure of a 2-C-trifluoromethyl-α-furanose 5. In water
solution mutarotation [19] can be observed: For a freshly
prepared solution of 5 in water (c = 0.33) an optical rota-
tion of [α] = -2.5° was recorded, which changed to [α] =
D
D
-17.0° after 24 hours.
Starting the above discussed reaction sequence from
3,4-O-isopropylidene-β-L-erythro-pentopyranosid-2-
ulose 6 [11] the corresponding compounds of the L-series
7 - 10 become readily avaiable. The spectroscopic data of
compounds 2 - 5 and 7 - 10 are identical, only the optical
rotation values are opposite. The optical rotation value of a
freshly prepared solution of 10 (c = 0.52, H O) changed
2
from [α] = + 1.0° to [α] = + 15.3° during 24 hours.
D
D
To study the fluorine effect we compared some physi-
cal data of compounds 2 - 5 and 7 - 10 with methyl sub-
stituted analogues 11 - 13. Surprisingly, we could not find
complete nmr data of 2-C-methylribopyranosides in the
literature. Therefore, we synthesized the protected ben-
zyl-2-C-methylribopyranoside derivative 11, which was
transformed into the benzyl-2-C-ribopyranoside 12 on

Mar-Apr 2003
Synthesis of Homochiral 2-C-Trifluoromethyl D-and L-Ribose
331
1
13
pK value of 12.4 is described for 2,2,2-trifluoroethanol
a
treatment with diluted acid. Relevant H and C nmr
data are summarized in Table 1.
[25] (C H OH: 15.9); a pK value of 13.86 (± 0.02)
mea-
2
5
a
Scheme 2
Table 1
Table 3
1
13
Relative Amounts of Tautomeric Forms for Differently Substituted Riboses
H and C NMR Data of 2-C-Trifluoromethyl- and 2-C-
*
**
at Equilibrium in D O at 40 °C, and Acetone-d at Room Temperature.
Methylribopyranosides (acetone-d )
2
6
6
ribose
2-C-H
2-C-CH
2-C-CF
α-furanose β-furanose α-pyranose β-pyranose
C-1 C-2 C-3 C-4 C-5 H-1 H-3 H-4 H-5a H-5b
*
6
35
65
69
18
22
21
17
20
28
2
56
15
12
14
[19,23]
[24]
3a 101.4 77.5 65.8 70.3 63.4 4.68 3.69 3.98 3.90 3.73
3b 99.7 76.5 64.7 70.4 63.8 4.23 4.10 4.10 4.01 3.79
12 102.0 72.6 73.8 66.8 63.9 4.56 3.69 4.02 3.75 3.55
**
3
**
3
**
2-C-C F
<1
3
7
Table 2
Mps and Optical Rotation Values of Methyl- and benzylribopyranosides
methyl-2-C-trifluoromethyl-β-
D-ribopyranoside (3a)
methyl-2-C-methyl-β-
D-ribofuranoside [20]
methyl-β-D-ribopyranoside
[21]
mp
180.5 - 182 °C
109 °C
80 - 81 °C
[α] - 130.9° (c = 1.1, acetone)
-82° (c = 0.5, EtOH) [21]
- 142.0° (c = 0.2, CHCl )
D
3
benzyl-2-C-trifluoromethyl-β-
D-ribopyranoside (3b)
benzyl-2-C-methyl-β-
D-ribopyranoside (12)
benzyl-β-D-ribo-
pyranoside [22]
mp
184.5 - 186 °C
109 - 110.5 °C
105 - 106 °C
[α] - 147° (c = 1, acetone)
- 120.0° (c = 1, acetone)
- 116° (c = 1.3, H O)
D
2
Remarkable are the significantly higher melting points of
the 2-C-trifluoromethyl substituted ribopyranosides 3a and
3b in comparison to the 2-C-methyl and 2-C-H analogues.
The relative amounts of tautomeric forms at equilibrium
very much depend upon the size of the substituents at C-2.
With increasing size of the substituents at C-2 the ratio of
α-furanose increases, where the anomeric OH group is
placed trans in respect to the bulky trifluoromethyl group.
In contrast, in the pyranose series β-pyranose dominates,
where the anomeric OH-function is cis positioned with
respect to the sterically demanding trifluoromethyl group,
occupying the favorable axial position (anomeric effect).
Alcohols with a trifluoromethyl group in β-position
sured for 2a [18] was found in the expected region. This
result explains convincingly the unsuccessful fluorodehy-
droxylation experiments of 2 with DAST [26].
We carried out a series of reactions of 2-C-trifluo-
romethyl O-glycosides with trimethylsilylbromide [27],
BCl [28] and NBS [29]. Substitution products at C-1 and
3
at C-2 were not obtained, as a consequence of the destabi-
lization of cationic and radical intermediates at C-1 as well
as at C-2 caused by the trifluoromethyl group [4].
In summary, we demonstrated that Ruppert’s reagent is
useful for CF -group transfer to carbonyl compounds.
3
However, the synthetic potential of the new 2-C-trifluo-
romethyl subsituted O-glycosides as glycosyl-donors
seems to be limited.
exhibit lower pK -values than unfluorinated analogues. A
a

332
U. Eilitz, C. Böttcher, L. Hennig, K. Burger, A. Haas, S. Gockel and J. Sieler
Vol. 40
Scheme 3
Tautomeric forms of 5 and 10 at equilibrium in acetone-d at room temperature.
6
EXPERIMENTAL
with 1.70 g (12 mmol = 2 ml) trifluoromethyl trimethylsilane. R
f
value: 0.71 (eluent: ethyl acetate); Yield: 1.05 g (39%) 2a
(method A), 1.75 g (64%) (method B), mp 95 - 96.5 °C, colorless
General.
crystals; [α] = - 137.5° (c = 1.76, CHCl ); pK -value: 13.86 ±
D
3
s
Microanalyses were carried out with a Heraeus CHN-O Rapid
apparatus. Melting points were determined on a Boetius appara-
tus. Mass spectra were obtained with a MASSLAB VG 12-250
instrument (EI, 70 eV). Ir spectra were measured with a Genesis
Series FTIR ATI Mattson spectrometer. Nmr spectra were
0.02 (v/v = 3:1, dioxane/water; pK = 16.74; ir (Nujol): 2940,
w
-1
1
2854, 1460, 1190 cm ; H nmr (CDCl ): δ 1.40 (s, 3H), 1.59 (s,
3
3H), 3.28 (s, 1H, C(2)-OH), 3.42 (s, 3H), 3.98 (dd, 1H, J = 13.3
Hz, J = 3.2 Hz), 4.08 (d, 1H, J = 13.3 Hz), 4.29 (dd, 1H, J = 6.4
13
Hz, J = 3.2 Hz), 4.49 (d, 1H, J = 6.4 Hz), 4.79 ppm (s, 1H);
C
1
13
recorded on Varian GEMINI 200 ( H 199.98; C 50.29 MHz);
nmr (CDCl ): δ 25.1, 26.4, 56.5, 58.2, 68.9 (q, J = 1.9 Hz), 70.3
3
1
13
GEMINI 2000 ( H 200.04; C 50.31 MHz) and GEMINI 300
(q, J = 26.6 Hz), 70.8, 98.9 (q, J = 1.9 Hz), 110.0, 124.9 ppm (q, J
1
13
( H 300.08; C 75.46 MHz) instruments. Chemical shifts are
reported in ppm relative to tetramethylsilane. For F nmr spec-
19
= 286.1 Hz); F nmr (CDCl ): δ 0.15 ppm (s, CF ); ms (EI) m/z
3
3
19
+
+
+
= 257 [M - CH ] (25), 241 [M - OCH ] (6), 215 [M - C H O]
3
3
3 5
tra, external trifluoroacetic acid is used as reference. Optical rota-
tions were measured with a Schmidt and Haensch POLARO-
TRONIC-D polarimeter. Thin-layer chromatography was
+
+
(23), 182 [M - CH OH, CH COCH ] (19), 154 [C H O ] (7),
3
3
3
7 6 4
+
+
+
142 [C H O ] (10), 137 [C H O ] (19), 100 [C H O ] (11),
6
6
4
7
5
3
5 8 2
+
+
+
85 [C H O ] (19), 59 [C H O] (58), 43 [C H ] (100).
4
5
2
3
7
3 7
performed on Merck (Darmstadt, Germany) Kieselgel 60F
254
Anal. Calcd. for C
H F O (272.23): C, 44.12; H, 5.55.
10 15 3 5
precoated plates. All solvents were dried by standard methods.
Reactions are carried out under dry argon.
Found: C, 44.25; H, 5.81.
(-)-Benzyl-3,4-O-Isopropylidene-2-C-trifluoromethyl-β-D-
ribopyranoside (2b).
Trifluoromethylation of 3,4-O-Isopropylidene-β-D-ribopyrano-
sides with Trifluoromethyl trimethylsilane (1 → 2).
Benzyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-D-ery-
thro-pentopyranosid-2-ulose (1b) 2.80 g (10.0 mmol) were
treated with 1.70 g (12 mmol = 2 ml) trifluoromethyl trimethylsi-
General Procedure.
Method A: 10.0 mmol pentopyranosid-2-ulose (1 or 6) were
dissolved in 20 ml dry THF and stirred under argon at 0 °C with
1.70 g (12 mmol = 2 ml) trifluoromethyl trimethylsilane, which
was added via syringe. The reaction was started on addition of
0.5 ml of a TBAF solution in dry THF. After stirring the reaction
mixture at 0 °C for 1 hour, the mixture was warmed up to room
temperature, and stirred for another 4 hours (reaction followed by
TLC). After evaporation of the solvent in vacuo, the residue was
dissolved in 20 ml of methylene chloride. The organic phase was
washed carefully with water (3 x 10 ml). Afterwards the organic
lane in 20 ml dry THF. R value: 0.70 (eluent: ethyl acetate);
f
Yield: 1.38 g (40%) 2b (method A), 2.25 g (65%) (method B),
colorless oil; [α] = -127.7° (c = 0.81, CHCl ); ir (Nujol) ν 2930,
D
3
-1
1
1459, 1380, 1189 cm ; H nmr (CDCl ): δ 1.36 (s, 3H), 1.60 (s,
3
3H), 3.36 (s, 1H, C(2)-OH), 4.05 (dd, 1H, J = 13.6, J = 3.2 Hz),
4.13 (dd, 1H, J = 13.6 Hz, J = 1.4 Hz), 4.30 (dd, 1H, J = 6.5 Hz, J
= 2.2 Hz), 4.51 (d, 1H, J = 11.6 Hz), 4.56 (d, 1H, J = 6.5 Hz), 4.74
13
(d, 1H, J = 11.6 Hz), 5.01 (s, 1H), 7.26 - 7.35 ppm (m, 5H);
C
nmr (CDCl ): δ 25.2, 26.5, 58.7, 69.0 (q, J = 1.9 Hz), 70.5 (q, J =
3
phase was dried with MgSO , then the solvent was distilled off
under reduced pressure. The residue was purified by column
chromatography (eluent: ethyl acetate).
26.4), 70.7, 70.8, 97.0 (q, J = 1.7 Hz), 110.1, 125.0 (q, J = 286.2
4
19
Hz), 128.4, 128.7, 129.0, 136.6 ppm; F nmr (CDCl ): δ 0.57
3
+
+
ppm (s, CF ); ms m/z = 348 [M] (< 1), 333 [M - CH ] (4), 257
3
3
+
+
+
Method B: Procedure see method A. However, dry methylene
chloride was used as solvent and tetrabutylammonium difluorot-
riphenylstannate as catalyst. After completion of the reaction
(reaction followed by TLC), the solvent was distilled off in
vacuo, the residue was redissolved in methanol and stirred 6
hours with 2.59 g (10.0 mmol) TBAF. After the reaction mixture
was evaporated to dryness, the residue was purified by column
chromatography (eluent: ethyl acetate).
[M - Bn] (5), 199 [M - Bn, - CH COCH ] (11), 153 [C H O ]
3
3
8 9 3
+
+
+
(5), 97 [C H O ] (32), 91 [C H ] (100), 59 [C H O] (17), 41
5
5
2
7
7
3 7
+
[C H ] (25).
3
5
Anal. Calcd. for C
H F O (348.33): C, 55.17; H, 5.50.
16 19 3 5
Found: C, 55.35; H, 5.39.
(+) Methyl-3,4-O-Isopropylidene-2-C-trifluoromethyl-β-L-
ribopyranoside (7a).
Methyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-L-ery-
thro-pentopyranosid-2-ulose (6a) 2.04 g (10.0 mmol) were
treated with 1.70 g (12 mmol = 2 ml) trifluoromethyl trimethylsi-
(-)-Methyl 3,4-O-Isopropylidene-2-C-trifluoromethyl-β-D-
ribopyranoside (2a).
Methyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-D-ery-
thro-ribopyranosid-2-ulose 1a 2.04 g (10.0 mmol) was treated
lane in 20 ml dry THF. R value: 0.71 (eluent: ethyl acetate);
Yield: 1.08 g (40%) 7a (method A), 1.89 g (70%) (method B), mp
f

Mar-Apr 2003
Synthesis of Homochiral 2-C-Trifluoromethyl D-and L-Ribose
333
+
+
+
95 - 96.5 °C, colorless crystals; [α] = + 139.1° ( c = 1.1,
142 [ C H F O ] (15), 128 [C H F O ] (16), 85 [C H O ]
D
4
5
3
2
3
3
3
2
4 5 2
-1
1
+
+
CHCl ); ir (KBr) ν 3510, 2998, 1387, 1192, 1161 cm ; H nmr
(26), 61 [C H O ] (100), 41 [C H ] (51).
3
2 5 2 3 5
(CDCl ): δ 1.34 (s, 3H), 1.53 (s, 3H), 3.25 (s, 1H, C(2)-OH), 3.36
Anal. Calcd. for C H F O (232.16): C, 36.22; H, 4.78.
3
7
11 3 5
(s, 3H), 3.94 (dd, 1H, J = 13.6 Hz, J = 3.2 Hz), 4.04 (dd, 1H, J =
Found: C, 36.53; H, 4.79.
13.6 Hz, J = 0.8 Hz), 4.23 (dd, 1H, J = 6.4 Hz, J = 3.2 Hz), 4.43
(-)-Benzyl-2-C-trifluoromethyl-β-D-ribopyranoside (3b).
13
(d, 1H, J = 6.4 Hz), 4.72 ppm (s, 1H); C nmr (CDCl ): δ 25.1,
3
26.4, 56.5, 58.2, 68.9 (q, J = 1.9 Hz), 70.3 (q, J = 26.3 Hz), 70.8,
Benzyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-D-
ribopyranoside (2b) 1.74 g (5.0 mmol) were deblocked on reac-
tion with aqueous acetic acid according to the general procedure.
Yield: 1.46 g (95%) 3b, mp 184.5 - 186 °C, colorless crystals;
19
98.9 (q, J = 1.9 Hz), 110.0, 124.0 ppm (q, J = 286.5 Hz);
F
+
NMR (CDCl ) δ 0.14 ppm (s, 3F); ms m/z = 272 [M] (< 1), 257
3
+
+
[M - CH ] (17), 182 [M - CH OH - CH COCH ] (13), 143
[C H O ] (7), 137 [C H O ] (22), 100 [C H O ] (9), 85
[C H O ] (29), 59 [C H O] (38), 42 [C H ] (100).
3
3
3
3
+
+
+
6
7
4
7
5
3
5
8
2
[α] = - 147° (c = 1, acetone); ir (KBr): ν 3341, 1268, 1206,
D
+
+
+
-1
1
4
5
2
3
7
3 6
1185, 1141 cm ; H nmr (acetone-d ): δ 3.79 (dd, 1H, J = 12.6
6
Anal. Calcd. for C
H F O (272.23): C, 44.12; H, 5.55.
10 15 3 5
Hz, J = 2.0 Hz), 4.01 (d, 1H, J = 12.6 Hz), 4.10 (m, 1H), 4.10 (dd,
1H, J = 9.2 Hz, J = 3.4 Hz), 4.23 (d, 1H, C(3)-OH, J = 9.2 Hz),
4.56 (d, 1H, J = 11.8 Hz), 4.77 (d, 1H, J = 11.8 Hz), 4.93 (s, 1H),
Found: C, 44.07; H, 5.43.
(+)-Benzyl-3,4-O-Isopropylidene-2-trifluoromethyl-β-L-ribopy-
ranoside (7b).
4.98 (d, 1H, C-(4)-OH, J = 4.8 Hz), 5.37 (s, 1H, C(2)-OH), 7.30 -
13
7.40 ppm (m, 5H); C nmr (acetone-d ): δ 63.8, 64.7, 69.9, 70.4,
6
Benzyl-3,4-O-isoproyplidene-β-L-erythro-pentopyranosid-2-
ulose (6b) 2.80 g (10.0 mmol) was trifluoromethylated according
76.5 (q, J = 25.9 Hz), 99.7 (q, J = 2.3 Hz), 125.1 (q, J = 285.7 Hz),
19
128.2, 128.3, 128.8, 137.8 ppm; F nmr (acetone-d ) δ 4.31 ppm
6
+
+
to method A. R value: 0.7 (eluent: ethyl acetate); Yield: 1.42 g
(s, 3F); ms m/z = 308 [M] (< 1), 217 [M - Bn] (3), 201 [M -
f
+
+
+
(41%) 7b colorless oil; [α] = +129.8° (c = 0.9, CHCl ); ir
OBn] (9), 171 [M - OBn, - CH O] (12), 107 [BnO] (10), 91
D
3
2
-1
1
+
(Nujol) ν 2924, 1460, 1382 cm ; H nmr (CDCl ): δ 1.40 (s,
[C H ] (100).
3
7
7
3H), 1.60 (s, 3H), 3.32 (s, 1H, C(2)-OH), 4.05 (dd, 1H, J = 13.6
Hz, J = 3.2 Hz), 4.13 (dd, 1H, J = 13.6 Hz, J = 1.4 Hz), 4.30 (dd,
1H, J = 6.5 Hz, J = 2.2 Hz), 4.51 (d, 1H, J = 11.6 Hz), 4.56 (d, 1H,
Anal. Calcd. for C
Found: C, 50.49, H, 4.79.
H F O (308.26): C, 50.65; H, 4.90.
13 15 3 5
(+)-Methyl-2-C-trifluoromethyl-β-L-ribopyranoside (8a).
J = 6.5 Hz), 4.74 (d, 1H, J = 11.6 Hz), 5.01 (s, 1H), 7.26 - 7.35
13
ppm (m, 5 H); C nmr (CDCl ): δ 25.1, 26.4, 58.6, 69.0 (q, J =
3
Methyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-L-
ribopyranoside (7a) 1.36 g (5.0 mmol) were treated with aqueous
acetic acid according to the general protocol. Yield: 1.04 g (90%)
1.9 Hz), 70.4 (q, = 26.3 Hz), 70.7, 70.8, 97.0 (q, J = 1.5 Hz),
110.1, 125.0 (q, J = 286.5 Hz), 128.4, 128.7, 129.0, 136.6 ppm;
19
+
F nmr (CDCl ): δ 0.56 ppm (s, 3F); ms m/z = 348 [M] (< 1),
3
8a, mp 180.5 - 182 °C, colorless crystals; [α] = + 129.5 ° (c =
D
+
+
333 [M - CH ] (4), 257 [M - Bn] (7), 199 [M- Bn, -
CH COCH ] (12), 153 [C H O ] (6), 97 [C H O ] (32), 91
[C H ] (100), 59 [C H O] (18), 42 [C H ] (40).
3
1.04, acetone); ir (KBr). ν 3343, 2933, 1452, 1266, 1201, 1146
+
+
+
-1
1
3
3
8
9
3
5 5 2
cm ; H nmr (acetone-d ): δ 3.38 (s, 3H), 3.73 (dd, 1H, J = 12.6
6
+
+
+
7
7
3
7
3 6
Hz, J = 1.8 Hz), 3.91 (d, 1H, J = 12.6 Hz), 3.97 (m, 1H), 4.02 (d,
1H, J = 3.4 Hz), 4.18 (d, 1H, C(3)-OH, J = 9.2 Hz), 4.68 (m, 1H),
4.94 (d, 1H, C(4)-OH, J = 4.9 Hz), 5.31 ppm (s, 1H, C(2)-OH);
Anal. Calcd. for C
H F O (348.33): C, 55.17; H, 5.50.
16 19 3 5
Found: C, 55.05; H, 5.41.
13
C nmr (acetone-d ) δ 55.2, 63.4, 64.7, 70.3, 76.4 (q, J = 25.9
6
Synthesis of O-Glycosides (2 → 3).
19
Hz), 101.4 (q, J = 2.2 Hz), 125.0 ppm (q, J = 285.3 Hz); F nmr
General Procedure.
+
(acetone-d ): δ 3.97 ppm (s, 3F); ms m/z = 217 [M - CH ] (2),
6
3
+
+
215 [M - OH] (49), 201 [M - OCH ] (1), 173 [M - OCH , -
3,4-O-Isopropylidene-2-C-trifluoromethylribopyranoside (2)
10.0 mmol were dissolved in 10 ml aqueous acetic acid (v/v =
3:2, CH CO H/H O) and stirred at room temperature for 24
3
3
+
+
+
CO] (2), 157 [M - CH O, - CO ] (11), 143 [C H F O ] (6),
3
2
4 6 3 2
+
+
+
114 [C H O ] (5), 98 [C H O ] (28), 85 [C H O ] (16), 69
5
6
3
5
6
2
4 5 2
3
2
2
+
+
+
[CF ] (34), 58 [C H O] (35), 41 [C H ] (100).
hours. After evaporation of the solvents in vacuo compounds 3
were obtained as colorless crystals. The O-glycosides are analyt-
ically pure after recrystallization from THF/hexanes.
3
3
6
3 5
Anal. Calcd. for C H F O (232.16): C, 36.22; H, 4.78.
Found: C, 36.49; H, 4.94.
7
11 3 5
(-)-Methyl-2-C-trifluoromethyl-β-D-ribopyranoside (3a).
(+)-Benzyl-2-C-trifluoromethyl-β-L-ribopyranoside (8b).
Methyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-D-ribo-
pyranoside (2a) 1.36 g (5.0 mmol) were treated with 10 ml aque-
ous acetic acid according to the general protocol. Yield: 1.10 g
Benzyl-3,4-O-isopropylidene-2-C-trifluoromethyl-β-L-ribo-
pyranoside (7b) 1.74 g (5.0 mmol) were treated with 10 ml aque-
ous acetic acid according to the general protocol. Yield: 1.46 g
(95%) 3a, mp 180.5 - 182 °C, colorless crystals; [α] = - 130.9°
(95%) 8b, mp 184.5 - 186 °C, colorless crystals; [α] = + 138.7°
D
D
-
(c = 1.1, acetone); ir (KBr) ν 3344, 1342, 1307, 1267, 1200, 1146
(c = 1.24, acetone); ir (KBr) ν 3341, 1268, 1204, 1185, 1113 cm
-1
1
1
1
cm ; H nmr (acetone-d ): δ 3.38 (s, 3H), 3.73 (dd, 1H, J = 12.8
; H nmr (acetone-d ): δ 3.79 (dd, 1H, J = 12.7 Hz, J = 2.2 Hz),
6
6
Hz, J = 1.6 Hz), 3.90 (d, 1H, J = 12.8 Hz), 3.98 (m, 1H), 4.02 (d,
4.01 (d, 1H, J = 12.7 Hz), 4.04 (1H, m), 4.10 (dd, 1H, J = 9.2 Hz,
J = 3.2 Hz), 4.20 (d, 1H, C-(3)-OH, J = 9.2 Hz), 4.56 (d, 1H, J =
J = 3.4 Hz), 4.18 (d, 1H, C(3)-OH, J = 9.4 Hz), 4.68 (s, 1H), 4.94
13
(s, 1H, C(4)-OH, J = 5.2 Hz), 5.31 ppm (s, 1H, C(2)-OH);
C
11.8 Hz), 4.77 (d, 1H, J = 11.8 Hz), 4.93 (s, 1H), 4.96 (s, 1H,
13
nmr (acetone-d ): δ 56.4, 64.6, 65.8, 71.5, 77.5 (q, J = 25.0 Hz),
C(4)-OH), 5.34 (s, 1H, C(2)-OH), 7.32 - 7.39 ppm (m, 5H);
C
6
19
101.5 (q, J = 2.7 Hz), 126.2 ppm (q, J = 285.7 Hz); F nmr (ace-
tone-d ): δ 3.97 ppm (s, 3F); ms m/z = 232 [M] (2), 215 [M -
OH] (12), 201 [M - OCH ] (7), 183 [M - OCH , - H O] (5),
nmr (acetone-d ): δ 63.8, 64.7, 69.9, 70.5, 76.5 (q, J = 25.9 Hz),
6
+
19
99.7, 125.1 (q, J = 285.7 Hz), 128.2, 128.3, 128.8, 137.8 ppm;
F
6
+
+
+
+
nmr (acetone-d ): δ 4.31 ppm (s, 3F); ms m/z = 308 [M] (< 1),
3
3
2
6
+
+
+
+
+
171 [M - OCH , - CH O] (4), 155 [M - OCH , - CH O ] (9),
231 [M - C H ] (< 1), 217 [M - Bn] (1), 201 [M - OBn] (5),
3
2
3
2 2
6
5

334
U. Eilitz, C. Böttcher, L. Hennig, K. Burger, A. Haas, S. Gockel and J. Sieler
Vol. 40
+
+
+
-1 1
171 [M - OBn, - CH O] (6), 141 [C H F O ] (2), 107 [BnO]
cm ; H nmr (acetone-d ): δ 1.25 (s, 3H), 3.55 (dd, 1H, J = 11.4
2
4
4
3
2
6
+
(5), [C H ] (100)
Hz, J = 7.2 Hz), 3.69 (s, 3H), 3.75 (d. 1H, J = 11.4 Hz, J = 4.0
Hz), 4.02 (dd, 1H, J = 7.2 Hz, J = 4.0 Hz), 4.54 (d, 1H, J = 12.2
7
7
Anal. Calcd. for C
H F O (308.26): C, 50.65; H, 4.90.
13 15 3 5
Hz), 4.56 (s, 1H), 4.78 (d, 1H, J = 12.0 Hz), 7.30 - 7.38 ppm (m,
Found: C, 50.58; H, 4.81.
13
5H); C nmr (acetone-d ): δ 21.3, 63.9, 66.8, 70.2, 72.6, 73.8,
6
(-) 2-C-Trifluoromethyl-D-ribose (5).
102.0, 128.0, 128.3, 128.8, 138.7 ppm; ms m/z = 223 [M -
+
+
+
CH O] (1), 177 [M - C H ] (2), 159 [M - C H , - H O] (1),
Compound 3a 0.46 g (0.2 mmol), or 0.62 g (0.2 mmol) 3b
were heated in 10 ml of a CF CO H/H O mixture (v/v 7:3) under
reflux until compound 3 was completely consumed (TLC analy-
sis). Then the solvent was evaporated in vacuo and the remaining
oil was purified by column chromatography (eluent: ethyl
acetate/methanol, 2:1).Yield: 0.40 g (90%) 5, mp 96 - 97 °C, col-
3
6
5
6
5
+
2
+
145 [M - Bn, - H O] (149), 130 [M - OBn, - OH] (3), 117 [M -
OBn, - CH O] (28), 91 [C H ] (100), 43 [C H ] (59).
2
3
2
2
+
+
+
2
7
7
3 7
Anal. Calcd. for C
H O (254.29): C, 61.40; N, 7.14. Found:
13 18 5
C, 61.17; N, 6.97.
(-)-2-C-Methyl-D-ribose (13).
orless crystals; [α] = -2.5° (c = 0.33, H O), after 1 day [α] = -
D
2
D
Method A: A solution of 0.26 g (0.1 mmol) 12 in 5 ml of dry
methanol was stirred for 24 hours in an atmosphere of hydrogen
in the presence of a Pd-catalyst (10% on char coal). After filtra-
tion of the catalyst and evaporation of the solvent in vacuo, 13
was obtained as pure compound.
17°; for further data see [9b].
(+)-2-C-Trifluoromethyl-L-ribose (10).
Compound 8a 0.46 g (0.2 mmol) or 0.62 g (0.2 mmol) 8b were
heated in 10 ml of CF CO H/H O mixture (v/v = 7:3) under
3
2
2
Method B: 0.26 g (0.1 mmol) 12 were heated with 10 ml
diluted sulfuric acid (5%) under reflux. After cooling to room
reflux until compound 8 was completely consumed (TLC analy-
sis). Then the solvent was evaporated in vacuo and the remaining
oil was purified by column chromatography (eluent: ethyl
acetate/methanol, 2:1). Yield: 0.38 g (85 %) 10, mp 96 - 97 °C,
temperature, the mixture was neutralized with NH OH and evap-
4
orated to dryness. The residue was dissolved in methanol and fil-
tered off. After evaporation of the solvent compound 13 was ana-
lytically pure. Yield: 0.15 g (90%) method A, 0.14 g (87%)
method B, mp 93 - 94 °C, colorless crystals; lit. mp 93-95 °C
[29]; [α] = - 3.0 ° (c = 0.41, H O), after 1 day [α] = - 15.0°.
colorless crystals; [α] = + 1.0° (c = 0.52, H O), after 1 day [α]
D
2
D
= + 15.3°.
Synthesis of 2-Methyl-D-ribose.
D
2
D
(-)-Benzyl-3,4-O-isopropylidene-2-C-methyl-β-D-ribopyra-
noside (11).
Acknowledgements.
The authors thank the European Community (Training -
Mobility - Research: Contract no. ERBFMRXCT 970120:
“Fluorine a Unique Tool for Engineering Chemical
Properties”) and the Funds of the Chemical Industry for finan-
cial support.
To a solution of 2.80 g (10.0 mmol) benzyl-3,4-O-isopropyli-
dene-β-D-erythro-pentopyranosid-2-ulose (1b) in 10 ml dry
diethyl ether at -78 °C, 10 mmol methyl magnesiumbromide (3 M
in ether) were slowly added via syringe. The reaction mixture was
slowly warmed up to -10 °C and quenched with a saturated solu-
tion of NH Cl. After extraction with diethyl ether, the organic
4
REFERENCES AND NOTES
phase was dried with MgSO . Then the solvent was distilled off
4
under reduced pressure and the remaining product was purified by
[*] Corresponding author. Tel.: (49) 341-9736529; Fax: (49) 341
9736599; E-mail address: burger@organik.chemie.uni-leipzig.de
[+] New address: Mendonstraße 17, D-14362 Kleinmachnow/-
Berlin.
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column chromatography (eluent: methylene chloride, R value:
f
0.6). Yield: 1.62 g (55%) 11, colorless oil; [α] = - 125.2 ° (c =
D
-1
1
1.2, CHCl ); ir (Nujol) ν 2984, 1455, 1375, 1161 cm ; H nmr
3
(CDCl ) δ 1.30 (s, 3H), 1.31 (s, 3H), 1.46 (s, 3H), 3.13 (s, 1H,
3
C(2)-OH), 3.58 (dd, 1H, J = 12.2 Hz, J = 2.3 Hz), 4.08 (dd, 1H,
J-= 12.2 Hz, J = 2.9 Hz), 4.18 (d, 1H, J = 7.0 Hz), 4.27 (dt, 1H, J =
7.0 Hz, J = 2.3 Hz, J = 2.9 Hz), 4.57 (d, 1H, J = 11.9 Hz), 4.60 (s,
13
1H), 4.84 (d, 1H, J = 11.9 Hz), 7.27 - 7.33 ppm (m, 5H); C nmr
(CDCl ) δ 24.8, 25.5, 26.5, 63.5, 69.9, 70.0, 73.2, 77.8, 98.6,
3
+
110.1, 128.3, 128.5, 128.9, 138.1 ppm; ms m/z = 279 [M - CH ]
(4), 203 [M - Bn] (2), 170 [M - BnO, - OH] (2), 157 [C H O ]
3
+
+
+
6
5 5
+
+
(25), 145 [M - Bn, - CH COCH ] (8), 99 [C H O ] (36), 91
3
3
5 7 2
+
+
+
[C H ] (100), 59 [C H O] (38), 43 [C H ] (82).
7
7
3
7
3 7
Anal. Calcd. for C
H O (294.35): C, 65.32; H, 7.54. Found:
16 22 5
C, 65.25; H, 7.71.
(-)-Benzyl-2-C-methyl-β-D-ribopyranoside (12).
Compound 11 0.59 g (0.2 mmol) were stirred with 5 ml aque-
ous acetic acid (v/v = 3:2) at room temperature for 48 hours.
After evaporation of the solvent under reduced pressure the
remaining solid was recrystallized from THF/hexane. Yield: 0.43
[6]
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D

Mar-Apr 2003
Synthesis of Homochiral 2-C-Trifluoromethyl D-and L-Ribose
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