Synthesis of trifluoromethylated analogues of β-l-fucofuranose and β-l-4,6-dideoxyxylohexopyranose

Article abstract of DOI:10.1016/j.jfluchem.2005.11.018

Efficient strategy to trifluoromethylated trans-disubstituted alkene 3 was developed starting from commercially available 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester 12. 6-Deoxy-6,6,6-trifluorosugars 21 and 30 were synthesized from 3 in high stereoselectivity and in a straightforward fashion. The key steps were Sharpless AD reaction, regioselective ring opening of trifluoromethylated cyclic sulfate, Horner-Wadsworth-Emmons reaction and TEMPO oxidation. It was noteworthy that the oxidation of alcohols 20 and 29 followed by deprotection and acetylation gave the single isomer target molecules 21 and 30, respectively.

Full text of DOI:10.1016/j.jfluchem.2005.11.018

Journal of Fluorine Chemistry 127 (2006) 580–587
www.elsevier.com/locate/fluor
Synthesis of trifluoromethylated analogues of b-L-fucofuranose
and b-L-4,6-dideoxyxylohexopyranose
Bing-Lin Wang a, Fei Yu a, Xiao-Long Qiu a, Zhong-Xing Jiang a, Feng-Ling Qing a,b,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
354 Fenglin Lu, Shanghai 200032, China
b College of Chemistry and Chemistry Engineering, Donghua University, 1882 West Yanan Lu, Shanghai 200051, China
Received 26 November 2005; accepted 28 November 2005
Available online 19 January 2006
Abstract
Efficient strategy to trifluoromethylated trans-disubstituted alkene 3 was developed starting from commercially available 4,4,4-trifluoro-3-oxo-
butyric acid ethyl ester 12. 6-Deoxy-6,6,6-trifluorosugars 21 and 30 were synthesized from 3 in high stereoselectivity and in a straightforward
fashion. The key steps were Sharpless AD reaction, regioselective ring opening of trifluoromethylated cyclic sulfate, Horner–Wadsworth–Emmons
reaction and TEMPO oxidation. It was noteworthy that the oxidation of alcohols 20 and 29 followed by deprotection and acetylation gave the single
isomer target molecules 21 and 30, respectively.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethylated compounds; Sugars; Stereoselectivity
1. Introduction
studies of transport, metabolism and enzymology of fluorinated
sugars [6]. Furthermore, what should be also regarded is that
Toyokuni group has proposed that replacement of the methyl
group in the fucose reside with the more hydrophobic
trifluoromethyl group might provide an artificial inhibitor for
Lex–Lex interaction [7]. After that, several groups [8] also
reported the independent synthesis of some other trifluor-
omethyl analogues of 6-deoxysugars. In spite of these
pioneering syntheses, however, many of their methodologies
suffered from low stereoselectivity and low yield. 6-Deox-
ysugars [9] are an interesting class of compounds, which are
broadly found in nature as the constituent sugars of various
antibiotics. For some of these groups of antibiotics the
saccharides have been implicated in the delivery and binding
of the biologically active agent to a target site [10].
Modification of these carbohydrate units could be of interest
as a mean of changing the biological activity of the parent
antibiotics. For example, Kondo group described that the
replacement of the six-membered fucose ring with five-
membered fucose ring of sialyl Lewis (sLeX) analogue could
also bind to a calcium ion on the E-selectin [11]. In addition,
Thiem and co-workers reported the synthesis of GDP-L-
xylohexose and analogues for transferase enzymatic studies
[12]. In view of the above facts, we herein report an efficient
and highly stereoselective synthesis of trifluoromethylated
The incorporation of fluorine atom(s) or fluoroalkyl groups
into organic compounds can have profound effects on the
material characteristics or biological activity of compounds by
changing their physico-chemical and/or pharmacological
properties [1]. However, fluorine has been identified only in
a relatively small number of tropical and subtropical plants,
microorganisms and actinomycetes [2]. Up to date, growing
interests in organofluorinated compounds have led to a lot of
syntheses of them. Among many fluorine-containing com-
pounds, ‘‘Fluoro Sugars’’ have recently attracted more and
more attentions from organic chemists and pharmaceutists [3].
Besides of modifying the chemical properties and biological
activity, lipophilicity is also an important consideration in the
design and synthesis of ‘‘Fluoro Sugars’’ since it often controls
absorption, transport, or receptor binding [4]. Notable in the
lipophilicity category is that fluorine atom(s) and fluoroalkyl
groups, especially trifluoromethyl group could influence the
lipophilicity of organic compounds [5]. In addition, it is well
known that trifluoromethyl groups might be suitable sensors in
* Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.11.018

B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
581
Scheme 1.
analogues of b-L-fucofuranose and b-L-4,6-dideoxyxylohex-
opyranose.
commercially available 4,4,4-trifluoro-3-oxo-butyric acid ethyl
ester 12. Compound 12 was first converted to (E)-a-
trifluoromethyl-a, b-unsaturated ester 13 by treatment with
sodium borohydride [14] and followed by dehydration with
phosphorus pentoxide [15]. Then, reduction of ester 13 with
LiAlH4/AlCl3 produced the allylic alcohol 14 in 88% yield
[16], which was treated with NaH/BnBr to smoothly afford the
desired trifluoromethylated trans-disubstituted alkene 3 in 96%
yield.
2. Results and discussion
The retrosynthetic analysis showed that fluoro sugars 1 and 2
could be reached from enantiopure diol 4 (Scheme 1). Our
group had developed procedures for preparation of compound 4
from trans-1-benzyloxy-4,4,4-trifluoro-2-butene 3 in high yield
and enantioselectivity [13]. Fluoro sugars 1 and 2 could result
from alcohols 7 and 8 via oxidation followed by intramolecular
cyclization. Asymmetric dihydroxylation of a, b-unsaturated
esters 5 and 6 would reach alcohols 7 and 8. Lengthening of
terminal carbon chain via HWE reaction of the key
intermediate 4 might realize the syntheses of compounds 5
and 6.
Previously, two synthetic strategies were developed to
prepare the trifluoromethylated trans-disubstituted alkene 3
[13], starting from 2-bromo-3,3,3-trifluoropropene 9 and trans-
3-bromo-allylic alcohol 10, respectively (Scheme 2). However,
the two strategies both suffered from some drawbacks. The
route starting from compound 9 gave the alkene 3 in very low
yield. Although the other route from alcohol 10 could produce
the desired compound 3 in high yield, it should be pointed that
alkene 3 was difficult to separate to give pure form by silica gel
chromatography because compound 11 could not always be
completely converted and the polarities of substrate 11 and
product 3 were very close to each other. Herein, a convenient
and efficient route to 3 was developed starting from
With trifluoromethylated trans-disubstituted alkene 3 in
hand, the Sharpless AD reaction was then carried out on 3 to
afford the chiral building block 4 [13]. In view of the
conveniences of following protecting group removal, the two
hydroxyl groups in the diol 4 were protected to the tert-
butyldimethylsilyl ether form and desired compound 15 was
furnished in almost quantitative yield (Scheme 3). Hydrogena-
tion of compound 15 under the catalysis of palladium
hydroxide on carbon afforded the expected alcohol 16 in very
high yield [17]. Using the recently reported methodology of
Giacomelli’s group [18], treatment of alcohol 16 with
trichloroisocyanuric acid (TCCA)/2,2,6,6-tetramethyl-1-piper-
idinyloxy (TEMPO) [19] (0.01 eq.) in CH2Cl2 successfully
produced the corresponding aldehyde, followed by Wittig–
Horner–Emmons condensation with triethyl phosphonoacetate
to give the desired (E)-conjugated ester 17 in 82% yield over
two steps. Under the Sharpless AD reaction condition with AD-
mix-a as chiral catalyst, diol 18 was successfully obtained in
97% yield and 98% de determined by 19F NMR from the ester
17. Silylation of hydroxyl groups of compound 18 with
Scheme 2.

582
B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
Scheme 3.
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf)
gave the tetra-TBS ester 19, which was then treated with
diisobutylaluminum hydride (DIBAL-H) in CH2Cl2 at ꢀ78 8C
to produce the alcohol 20 in 93% yield. Considering the
anomeric effect, the hydroxyl groups of compound 1 were
acetylated to give its O-acetyl form, which would facilitate
purification and prevent the conversion of sugar between
furanose and pyranose. Finally, oxidation of alcohol 20 with
TCCA/TEMPO followed by deprotection and acetylation gave
our desired trifluoromethylated sugar 21 in 85% yield for three
steps. It was noteworthy that the acetylation of carbohydrates
usually gave pyranoid sugars, whereas the acetylation of the
tifluoromethylated carbohydrate produced furanoid 21 exclu-
sively.
The stereochemistry of products 21 has been established by
1H NMR and 2D NMR NOESYexperiments (Fig. 1). The small
coupling constant (J = 4.5 Hz) of the anomeric proton (H-1)
indicated the H-1eq-H-2ax relationship. It showed that the
configuration of C-1 was S configuration and fluoro sugar 21
was the b-anomeric isomer. The strong NOE correlation
between H-1 and H-4 of compound 21 showed that the sugar 21
was furanose. In addition, the NOE correlations between H-2
and H-4 along with between H-3 and H-5 further confirmed the
configuration of asymmetric dihydroxylation of ester 17.
We also wanted to extend this strategy to the synthesis of L-
xylo-4,6-dideoxy-hexose 2 (Scheme 4). Diol 4 was first
converted to the 2,3-cyclicsulfite upon treatment with SOCl2,
which was further oxidized to the cyclic sulfate 22 with RuO4
Scheme 4.

B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
583
aqueous HCl (180 mL) was carefully added to decompose
excess LiAlH4. The aqueous layer was extracted with Et2O
(2 ꢁ 150 mL), and the combination was dried over Na2SO4,
filtered and evaporated to give 14 [22] (20.2 g, 85%): 1H NMR
(300 MHz, CDCl3) d 6.54–6.46 (m, 1H), 6.00–5.91 (m, 1H),
4.33–4.30 (m, 2H), 1.88 (br, 1H); 19F NMR (282 MHz, CDCl3)
d ꢀ64.47 (d, J = 9.0 Hz).
3.3. (E)-1-Benzyloxy-4,4,4-trifluoro-2-butene (3)
Fig. 1. NOE correlation from NOESY spectra of 21.
(generated in situ from NaIO4/catalylic RuCl3) in 91% yield for
two steps [20]. Nucleophilic ring opening of cyclicsulfate 22
with NaBH4 in N,N-dimethylacetamide (DMAC) occurred
exclusively at C2 position and the resultant compound was
directly treated with aqueous H2SO4 to give the desired alcohol
23 in almost quantitative yield [20]. Finally, applying the
similar route and reaction condition for synthesis of compound
21 from alcohol 4, trifluoromethylated sugar 30 was success-
To a suspension of NaH (7.68 g, 0.19 mol) in THF (100 mL)
at 0 8C was added a solution of alcohol 14 (20.17 g, 0.16 mol)
in THF (80 mL). After the mixture was stirred about 1 h, Bu4NI
(0.59 g, 1.60 mmol) and BnBr (32.83 g, 0.19 mol) were added.
After being stirred at room temperature for 5 h, the reaction
mixture was diluted with Et2O (150 mL), washed with H2O
(200 mL), brine (200 mL) and dried over anhydrous Na2SO4.
Filtration and removal of the solvent provided the compound 3
[13] (33.18 g, 96%): 1H NMR (300 MHz, CDCl3) d 7.41–7.29
(m, 5H), 6.49–6.41 (m, 1H), 6.04–5.94 (m, 1H), 4.58 (s, 2H)
4.16–4.11 (m, 2H); 19F NMR (282 MHz, CDCl3) d ꢀ64.54 (d,
J = 8.2 Hz).
1
fully prepared from alcohol 23. The H NMR, 13C NMR and
19F NMR of compound 30 indicated doubtlessly that it was also
single isomer.
In summary, we developed an efficient strategy to synthesis of
key intermediate trifluoromethylated trans-disubstituted alkene
3 starting from commercially available 4,4,4-trifluoro-3-oxobu-
tyric acid ethyl ester 12. Then, 6-deoxy-6,6,6-trifluorosugars 21
and 30 were designed and synthesized in highly stereoselectivity.
In our opinion, our methodology of synthesizing fluoro sugars 21
and 30 could be applied to prepare the other fluoro sugar isomers
by altering ligands of Sharpless AD reaction.
3.4. (2S,3R)-1-Benzyloxy-4,4,4-trifluoro-2,3-butanediol (4)
MeSO2NH2 (0.96 g, 10 mmol) was added to a stirring
mixture of t-BuOH (25 mL), water (25 mL) and AD-mix-b
(14.00 g). Then, the mixture was cooled to 0 8C and compound
3 (2.16 g, 10 mmol) was added. After the heterogeneous slurry
was stirred vigorously at room temperature for 4 days, Na2SO3
was added to quench the reaction. The resultant mixture was
stirred for 30 min and then extracted with ethyl acetate. The
combined organic layer was washed with 2N KOH and brine,
dried over anhydrous Na2SO4. After filtration and removal of
the solvent in vacuo, the resultant residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acet-
ate = 5:1) to give 4 [13] (2.40 g, 95% yield, 94% ee) as a white
3. Experimental
3.1. Ethyl 4,4,4-trifluorocrotonate (13)
To a solution of 12 (55.2 g, 0.300 mol) in Et2O (600 mL)
was added NaBH4 (12.4 g, 0.315 mol) in several portions over
30 min at 0 8C. The mixture was stirred at 0 8C for 1 h and at
room temperature overnight. Then, a solution of aqueous HCl
(10%, 300 mL) was carefully added to the reaction mixture and
the resultant solid was removed by filtration. The aqueous layer
was extracted with Et2O (2 ꢁ 150 mL) and the combined
organic phases were dried over anhydrous Na2SO4, filtered and
evaporated to give a clear oil (45.7 g). Then, phosphorus
pentoxide (16.9 g, 0.12 mol) was added to the above resultant
oil and the mixture was stirred at 100 8C for 1 h. After cooled to
room temperature, the mixture was distillated to yield 13 [21]
1
solid: H NMR (300 MHz, CDCl3) d 7.42–7.32 (m, 5H), 4.59
(s, 2H), 4.18–4.13 (m, 1H), 4.00–3.93 (m, 1H), 3.62 (d,
J = 6.0 Hz, 2H); 19F NMR (282 MHz, CDCl3) d ꢀ77.45 (d,
J = 7.1 Hz).
3.5. (2S,3R)-1-Benzyloxy-2,3-bis-[(tert-
butyldimethylsilyl)oxy]-4,4,4-trifluoro-butane (15)
To a solution of 4 (280 mg, 1.12 mmol) and DMAP (68 mg,
0.56 mmol) in DMF (2.2 mL) at 0 8C was added imidazole
(458 mg, 5.6 mmol), followed by TBDMSCl (844 mg,
5.6 mmol). Then, the mixture was warmed to room temperature
and stirred for 30 h. EtOAc (40 mL) was added and the
resulting mixture was washed with brine (3 ꢁ 15 mL). The
combined organic phases were dried over anhydrous Na2SO4.
After filtration and removal of the solvent, the resulting residue
was purified by flash chromatography (petroleum ether) to
1
(33.3 g, 66%): H NMR (300 MHz, CDCl3) d 6.83–6.73 (m,
1H), 6.50 (d, J = 15.9 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.33 (t,
J = 7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ65.94 (d,
J = 7.9 Hz).
3.2. (E)-4,4,4-Trifluoro-2-buten-1-ol (14)
A solution of 13 (31.6 g, 0.188 mol) in Et2O (90 mL) was
added to a suspension of LiAlH4 (15.7 g, 0.414 mol) and AlCl3
(25.1 g, 0.188 mol) in Et2O (320 mL) at 0 8C for 1 h. After the
mixture was stirred overnight at room temperature, 10%
21
afford 15 (536 mg, 100%) as a clear oil: ½aꢂD = +8.7 (c 1.19,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.36–7.27 (m, 5H), 4.52
(s, 2H), 4.10–4.02 (m, 2H), 3.63 (dd, J = 6.0 Hz, 9.0 Hz, 1H),

584
B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
3.43–3.38 (m, 1H), 0.91, 0.88 (2s, 18H), 0.10, 0.09, 0.05, 0.04
(4s, 12H); 19F NMR (282 MHz, CDCl3) d ꢀ73.70 (d,
J = 6.2 Hz); IR (thin film) 2932, 1474, 1464, 1257, 1170,
1149, 1122, 839, 779 cmꢀ1; MS (ESI) m/z 479.3 (M + H+),
(854 mg). The mixture was cooled to 0 8C and compound 17
(280 mg, 0.61 mmol) was added. After the heterogeneous slurry
was stirred vigorously at room temperature for 36 h, Na2SO3 was
added to quench the reaction. The resultant mixture was stirred
for 30 min and then extracted with ethyl acetate. The combined
organic layer was washed with 2N KOH and brine, dried over
anhydrous Na2SO4. After filtration and removal of the solvent in
vacuo, the residuewas purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate = 6:1) to give 18 (290 mg,
97% yield, 98% de) as a clear oil: ½aꢂ2D1 = +19.7 (c 1.52, CHCl3);
1H NMR (300 MHz, CDCl3) d 4.36–4.23 (m, 4H), 4.08 (d,
J = 9 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H), 3.05 (br, 1H), 2.82 (br,
1H), 1.32 (t, J = 6.9 Hz, 3H), 0.92, 0.90 (2s, 18H), 0.16, 0.14,
0.13, 0.11 (4s, 12H); 19F NMR (282 MHz, CDCl3) d ꢀ72.81 (d,
J = 7.1 Hz); 13C NMR (75.5 MHz, CDCl3) d 173.8, 124.7 (q,
J = 284.8 Hz), 72.8, 72.4 (q, J = 28.9 Hz), 69.6, 69.5, 62.1, 25.7,
25.5, 18.1, 14.2, 1.04, ꢀ4.6, ꢀ4.8, ꢀ5.2, ꢀ5.3; IR (thin film)
3531, 3461, 2933, 2860, 1730, 1475, 1391, 1261, 1169, 1147,
898, 780 cmꢀ1; MS (ESI) m/z 491.2 (M + H+), 508.4
+
496.3 (M + NH4 ); Anal. Calcd. for C23H41O3F3Si2: C, 58.70;
H, 8.63. Found: C, 58.45; H, 8.68.
3.6. (2S,3R)-1-Benzyloxy-2,3-bis-
[(tert-butyldimethylsilyl)oxy]-4,4,4-trifluorobutan-1-ol (16)
A suspension of 20% Pd(OH)2/C (145 mg) and 15 (536 mg,
0.86 mmol) in THF was stirred under a hydrogen atmosphere for
5 h. Filtration and removal of the solvent gave the crude product,
which was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate = 20:1) to give 16 [17] (432 mg,
100%) as an oil: 1H NMR (300 MHz, CDCl3) d 3.94–3.90 (m,
1H), 3.79–3.77 (m, 1H), 3.66–3.62 (m, 1H), 3.54–3.51 (m, 1H),
1.65 (s, 1H), 0.82, 0.79 (2s, 18H), 0.05, 0.03, 0.02, 0.01 (4s, 12H);
19F NMR (282 MHz, CDCl3) d ꢀ73.08 (d, J = 7.3 Hz).
+
(M + NH4 ), 529.2 (M + K+); HRMS (ESI) Calcd. for
3.7. (E)-(4S,5R)-Ethyl-4,5-bis-
[(tert-butyldimethylsilyl)oxy]-6,6,6–trifluoro-2-hexenoate
(17)
C20H41O6F3Si2Na 513.2286, found 513.2289.
3.9. (2S,3R,4S,5R)-Ethyl-2,3,4,5-tetra-
[(tert-butyldimethylsilyl)oxy]-6,6,6–trifluoro-hexenoate
(19)
2,2,6,6-Tetramethyl-1-piperidinyloxy (2.6 mg, 0.017 mmol)
was added at 0 8C to a solution of 16 (644 mg, 1.66 mmol) and
trichloroisocyanuric acid (405 mg, 1.74 mmol) in methylene
chloride (5 mL). Then, the mixture was warmed to room
temperature and stirred for 15 min. After filtration on silica gel,
the filtrate was concentrated in vacuo. The residue was used in
next reaction without further purification. To a suspension of
sodium hydride (60 mg, 2.49 mmol) in THF (8 mL) at 0 8C was
added triethyl phosphonoacetate (558 mg, 2.49 mmol). After
the mixture was stirred for 1 h at 0 8C, the above crude product
in THF (3 mL) was added dropwise. The reaction mixture was
allowed to warm up to room temperature over a period of 4 h
and then diluted with Et2O (20 mL). The resultant mixture was
washed with H2O (20 mL) and brine (30 mL), and dried over
Na2SO4. After filtration and removal of the solvent in vacuo, the
resultant residue was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate = 100:1) to give ester 17
TBSOTf (0.29 mL, 1.25 mmol) was added dropwise at 0 8C
to a solution of diol 18 (278 mg, 0.57 mmol) and 2,6-lutidine
(183 mg, 1.71 mmol) in CH2Cl2 (2 mL). The reaction mixture
was warmed up to room temperature and stirred for 1 h. The
mixture was then diluted with ether (7 mL) and the organic
layer was washed with 10% HCl (2 mL), saturated NaHCO3
(2 mL), H2O (2 mL) and brine (2 mL), and dried over Na2SO4.
After filtration and removal of the solvent in vacuo, the residue
was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 200:1) to give ester 19 (370 mg, 92%) as a
clear oil: ½aꢂD = +7.9 (c 4.25, CHCl3); H NMR (300 MHz,
CDCl3) d 4.61 (d, J = 1.5 Hz, 1H), 4.50 (dd, J = 6.3, 1.8 Hz,
1H), 4.24–4.13 (m, 3H), 3.94 (dd, J = 6, 1.8 Hz, 1H), 1.29 (t,
J = 7.2 Hz, 3H), 0.93, 0.90, 0.89, 0.87 (4s, 36H), 0.20, 0.16,
0.14, 0.10, 0.09, 0.06, 0.02, 0.01 (8s, 24H); 19F NMR
(282 MHz, CDCl3) d ꢀ75.13 (d, J = 6.8 Hz); IR (thin film)
2932, 2860, 1752, 1473, 1258, 1176, 881, 841, 778 cmꢀ1; MS
(ESI) m/z 719.5 (M + H+), 741.5 (M + Na+); Anal. Calcd. for
C32H69O6F3Si4: C, 53.44; H, 9.67. Found: C, 53.76; H, 9.65.
26
1
22
(614 mg, 82%) as a clear oil: ½aꢂD = +33.7 (c 1.11, CHCl3); 1H
NMR (300 MHz, CDCl3) d 7.04 (dd, J = 15.6, 3.9 Hz, 1H), 6.06
(dd, J = 15.6, 1.5 Hz, 1H), 4.45 (s, 1H), 4.26–4.16 (m, 2H),
4.01–3.93 (m, 1H), 1.30 (q, J = 7.2 Hz, 3H), 0.92, 0.91 (2s,
18H), 0.11, 0.09, 0.08, 0.05 (4s, 12H); 19F NMR (282 MHz,
CDCl3) d ꢀ73.34 (d, J = 5.4 Hz); IR (thin film) 2933, 2862,
1726, 1474, 1261, 1176, 1151, 839, 780 cmꢀ1; MS (ESI) m/z
3.10. (2S,3R,4S,5R)-2,3,4,5-Tetra-
[(tert-butyldimethylsilyl)oxy]-6,6,6–trifluoro-1-hexanol
(20)
457.4 (M + H+), 474.4 (M + NH4 ); Anal. Calcd. for
+
C23H41O3F3Si2: C, 52.60; H, 8.61. Found: C, 52.92; H, 8.75.
DIBAL-H (0.57 mL, 1.0 M in toluene, 0.57 mmol) was
added dropwise at ꢀ78 8C to a solution of ester 19 (135 mg,
0.19 mmol) in CH2Cl2 (1 mL). After stirring for 1.5 h, the
reaction was quenched with saturated Rochelle’s salt (2 mL) at
ꢀ78 8C. The mixture was stirred at room temperature for 1 h.
The aqueous phase was extracted with CH2Cl2 (2 ꢁ 3 mL), and
the combined organic layers were dried over Na2SO4. After
3.8. (2S,3R,4S,5R)-Ethyl-2,3-bis-hydroxy-4,5-bis-
[(tert-butyldimethylsilyl)oxy]-6,6,6–trifluoro-hexenoate
(18)
MeSO2NH2 (58 mg, 0.61 mmol) was added to a stirring
mixture of t-BuOH (4 mL), water (4 mL) and AD-mix-a

B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
585
filtration and removal of the solvent in vacuo, the residue was
purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate = 40:1) to provide ester 20 (120 mg, 93%) as a clear
vigorously stirred for 1 h at room temperature. After that, the
mixture was diluted with ether and the resultant organic layer
was filtered through a pad of Celite. The filtrate was washed
with water, saturated aqueous sodium bicarbonate and brine,
dried over anhydrous Na2SO4. After filtration and removal of
the solvent in vacuo, the residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acet-
ate = 10:1) to afford compound 22 [13] (701 mg, 91%) as a
22
oil: ½aꢂD = +2.8 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) d
4.95–4.86 (m, 1H), 4.07 (dd, J = 5.1, 2.7 Hz, 1H), 3.94–3.88 (m,
2H), 3.80–3.76 (m, 1H), 3.63 (dd, J = 8.1, 4.2 Hz), 3.38 (br, 1H),
0.95, 0.91 (2s, 36H), 0.18, 0.16, 0.14, 0.12, 0.11, 0.10, (6s, 24H);
19F NMR (282 MHz, CDCl3) d ꢀ75.67 (s); IR (thin film) 3455,
2933, 2861, 1474, 1391, 1259, 1120, 838, 779 cmꢀ1; MS (ESI)
1
clear oil: H NMR (300 MHz, CDCl3) d 7.40–7.32 (m, 5H),
+
m/z 694.5 (M + NH4 ); Anal. Calcd. for C30H67O5F3Si4: C,
53.21; H, 9.97. Found: C, 52.81; H, 9.90.
5.18 (dq, J = 5.9, 6.0 Hz, 1H), 5.03 (dt, J = 6.3, 3.6 Hz, 1H),
4.69 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 11.7 Hz, 1H), 3.92 (dd,
J = 3.6, 12.0 Hz, 1H), 3.78 (dd, J = 3.6, 12.0 Hz, 1H); 19F NMR
(282 MHz, CDCl3) d ꢀ77.30 (d, J = 6.2 Hz).
3.11. 1,2,3,5-Tetra-O-acetyl-6,6,6-trifluoro-b-L-
fucofuranose (21)
3.13. (3R)-4-Benzyloxy-1,1,1-trifluorobutan-2-ol (23)
2,2,6,6-Tetramethyl-1-piperidinyloxy (0.4 mg, 0.025 mmol)
was added at 0 8C to a solution of compound 20 (70 mg,
0.1 mmol) and trichloroisocyanuric acid (29 mg, 0.12 mmol) in
methylene chloride (5 mL). The reaction mixture was stirred for
15 min at room temperature. Filtration of the mixture and
removal of the solvent in vacuo gave a residue, which was used
without further purification. To a solution of the above residue in
THF (0.4 mL) was added TBAF (0.48 mL, 1.0 M in THF,
0.48 mmol). After stirring for 7 h, Ac2O (75 mL, 0.8 mmol) and
DMAP (1.2 mg, 0.01 mmol) were added. The reaction mixture
was stirred for 8 h. The reaction was quenched with saturated
NaHCO3. The aqueous phase was extracted with Et2O
(3 ꢁ 2 mL), and the combined organic layers were dried over
anhydrous Na2SO4. After filtration and removal of the solvent in
vacuo, the residuewas purified by flash chromatographyon silica
gel (petroleum ether/ethyl acetate = 5:1) to give compound 21
A solution of cyclic sulfate 22 (116 mg, 0.37 mmol) and
sodium borohydride (28 mg, 0.74 mmol) in DMF (2 mL) was
stirred for 4 h at 80 8C. Then, the solvent was carefully removed
under reduced pressure to give a residue. To this residue was
added THF (2 mL), water (5 mL) and sulfuric acid (15 mL) and
the resulting suspension was stirred for 20 min. After that, the
reaction mixture was filtered and the filtrate was concentrated in
vacuo to give a residue, which was purified by flash
chromatography (petroleum ether/ethyl acetate = 10:1) to
afford 23 [20] (87 mg, 95%) as a clear oil: 1H NMR
(300 MHz, CDCl3) d 7.40–7.26 (m, 5H), 4.54 (s, 2H), 4.21–
4.15 (m, 1H), 3.83–3.78 (m, 1H), 3.76–3.66 (m, 1H), 2.03–1.92
(m, 2H); 19F NMR (282 MHz, CDCl3) d ꢀ79.80 (d, J = 6.8 Hz).
3.14. (3R)-1-Benzyloxy-3-(tert-butyldimethylsilyl)oxy-
4,4,4-trifluoro-butane (24)
22
1
(32 mg, 85%) as a clear oil: ½aꢂD = ꢀ1.3 (c 1.10, CHCl3); H
NMR (300 MHz, CDCl3) d 6.32 (d, J = 4.5 Hz, 1H), 5.62 (t,
J = 6.3 Hz, 1H), 5.54 (dd, J = 6.3, 6.9 Hz, 1H), 5.35 (dd, J = 2.4,
4.8 Hz, 1H), 4.35 (dd, J = 1.5, 4.8 Hz, 1H), 2.19 (s, 3H), 2.15 (s,
3H), 2.10 (s, 3H) 2.09 (s, 3H); 19F NMR (282 MHz, CDCl3) d
ꢀ74.39 (d, J = 7.3 Hz); 13C NMR (75.5 MHz, CDCl3) d 169.8,
169.7, 169.1, 168.6, 122.0 (q, J = 251.3 Hz), 93.4, 75.4, 74.0,
73.9, 69.4 (q, J = 31.1 Hz), 20.9, 20.5, 20.4, 20.3. IR (thin film)
To a 0 8C solution of 23 (154 mg, 0.66 mmol) and DMAP
(8 mg, 0.07 mmol) in DMF (0.25 mL) was added imidazole
(68 mg, 1.0 mmol), followed by TBDMSCl (200 mg,
1.32 mmol). Then, the mixturewas warmed to room temperature
and stirred for 20 h. EtOAc (40 mL) was added and the resulting
mixture was washed with brine (3 ꢁ 5 mL). The combined
organic phases were dried over anhydrous Na2SO4. After
filtration and removal of the solvent, the resulting residue was
purified by flash chromatography (petroleum ether/ethyl
acetate = 60:1) to afford 24 (228 mg, 100%) as a clear oil:
1757, 1216 cmꢀ1; MS (ESI) m/z 404.0 (M + NH4 ), 409.0
+
(M + Na+), 425.0 (M + K+); HRMS (ESI) Calcd. for
C14H17O9F3Na 409.0717, found 409.0720.
21
1
3.12. (3R,4S)-3-Benzyloxymethyl-4-trifluoromethyl-2,2-
dioxo-1,3,2-dioxathiolane (22)
½aꢂD = ꢀ18.5 (c 0.34, CHCl3); H NMR (300 MHz, CDCl3) d
7.38–7.29 (m, 5H), 4.50 (dd, J = 12, 6.9 Hz, 2H), 4.24–4.14 (m,
1H), 3.65–3.53 (m, 2H), 2.09–1.98 (m, 1H), 1.84–1.55 (m, 1H),
0.89 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ78.87 (d, J = 6.2 Hz); IR (thin film) 2933, 2861,
1474, 1363, 1283, 1169, 840, 781 cmꢀ1; MS (EI) m/z 348 (M+,
3), 91 (100), 77 (13), 43 (26). Anal. Calcd. for C17H27O2F3Si: C,
58.59; H, 7.81; found: C, 58.58; H, 7.84.
To a solution of 4 (617 mg, 2.47 mmol) in methylene
chloride (7 mL) was added dropwise thionyl chloride (588 mg,
4.94 mmol) at 08 C during 10 min. The reaction mixture was
stirred for another 10 min at 0 8C and then diluted with cold
ether. The aqueous phase was extracted with ether. The
combined organic phases were washed with brine and
concentrated in vacuo. The residue was purified by a short
silica gel column to give crude cyclic sulfite. NaIO4 (634 mg,
2.96 mmol) and RuCl3ꢃ3H2O (1.0 mg) were added to the
mixture of the crude cyclic sulfite, water (4.5 mL), CH3CN
(3 mL) and CCl4 (3 mL). Then, the reaction mixture was
3.15. (3R)-3-(Tert-butyldimethylsilyl)oxy-4,4,4-
trifluorobutan-1-ol (25)
Compound 25 (221 mg, 100%) was prepared from
compound 24 (300 mg, 0.86 mmol) using the same conditions

586
B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
21
589.2 (M + H+), 606.2 (M + NH4 ), 611.2 (M + Na+); HRMS
(ESI) Calcd. for C26H55O5F3Si3Na 611.3202, found 611.3203.
+
as described for compound 16. ½aꢂD = ꢀ18.1 (c 1.03, CHCl3);
1H NMR (300 MHz, CDCl3) d 4.23–4.17 (m, 1H), 3.82–3.78
(m, 2H), 1.97–1.89 (m, 1H), 1.87–1.77 (m, 1H), 0.91 (s, 9H),
0.13 (s, 3H), 0.07 (s, 3H); 19F NMR (282 MHz, CDCl3) d
ꢀ78.62 (d, J = 7.3 Hz); 13C NMR (75.5 MHz, CDCl3) d 125.2
(q, J = 282.4 Hz), 68.2 (q, J = 31.3 Hz), 57.7, 33.4, 25.5, 18.0,
ꢀ5.2, ꢀ5.3; IR (thin film) 3356, 2935, 2862, 1474, 1282, 1169,
841, 781 cmꢀ1; MS (ESI) m/z 259.2 (M + H+); HRMS (ESI)
Calcd. for C10H21O2F3SiNa 281.1155, found 281.1159.
3.19. (2S,3R,5R)-2,3,5-Tri-[(tert-butyldimethylsilyl)oxy]-
6,6,6–trifluoro-1-hexanol (29)
Compound 29 (210 mg, 95%) was prepared from compound
28 (250 mg, 0.43 mmol) using the same conditions as described
25
1
for compound 20. ½aꢂD = ꢀ19.7 (c 1.11, CHCl3); H NMR
(300 MHz, CDCl3) d 4.15–4.09 (m, 1H), 3.90–3.60 (m, 4H),
2.02–1.93 (m, 1H), 1.78–1.70 (m, 1H), 0.90 (s, 27H), 0.12, 0.10
(2s, 18H); 19F NMR (282 MHz, CDCl3) d ꢀ78.38 (d,
J = 7.1 Hz); 13C NMR (75.5 MHz, CDCl3) d 125.3 (q,
J = 281.8 Hz), 73.8, 71.0, 68.5 (q, J = 30.6 Hz), 62.5, 34.0,
25.8, 25.7, 18.2, 18.0, 17.9, 1.0, ꢀ3.7, ꢀ4.1, ꢀ4.4, ꢀ4.6, ꢀ4.7,
ꢀ4.9, ꢀ5.0; IR (thin film) 3487, 2954, 2860, 1473, 1167, 1029,
839, 778 cmꢀ1; MS (ESI) m/z 547.2 (M + H+); HRMS (ESI)
Calcd. for C24H53O4F3Si3Na 569.3096, found 569.3095.
3.16. (E)-(5R)-Ethyl-5-(tert-butyldimethylsilyl)oxy-6,6,6–
trifluoro-2-hexenoate (26)
Compound 26 (107 mg, 80%) was prepared from compound
25 (107 mg, 0.41 mmol) using the same conditions as described
19
1
for compound 17. ½aꢂD = ꢀ11.4 (c 0.49, CHCl3); H NMR
(300 MHz, CDCl3) d 6.95–6.85 (m, 1H), 5.93 (d, J = 15.6 Hz,
1H), 4.20 (q, J = 7.2 Hz, 2H), 4.08–4.00 (m, 1H), 2.60–2.49 (m,
1H), 1.29 (t, J = 7.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s,
3H); 19F NMR (282 MHz, CDCl3) d ꢀ78.80 (d, J = 4.8 Hz);
13C NMR (75.5 MHz, CDCl3) d 165.8, 142.4, 125.0, 124.6 (q,
J = 283.0 Hz), 70.4 (q, J = 31.4 Hz), 60.3, 34.1, 25.5, 18.0,
14.2, ꢀ4.9, ꢀ5.1; IR (thin film) 2934, 2862, 1726, 1663, 1270,
1169, 841, 781 cmꢀ1; MS (ESI) m/z 327.2 (M + H+), 344.2
3.20. 1,2,3-Tri-O-acetyl-4,6-dideoxy-6,6,6-trifluoro-b-L-
xylo-hexopyranose (30)
Compound 30 (10 mg, 85%) was prepared from compound
29 (20 mg, 0.03 mmol) using the same conditions as described
25
(M + NH4 ), 349.2 (M + Na+); HRMS (ESI) Calcd. for
for compound 21. ½aꢂD = +50.1 (c 0.12, CHCl3); H NMR
(300 MHz, CDCl3) d 6.43 (d, J = 3.3 Hz, 1H), 5.30 (dt, J = 5.2,
10.3 Hz, 1H), 5.07 (dd, J = 3.3, 10.3 Hz, 1H), 4.40–4.29 (m,
1H), 2.43 (ddd, J = 12.8, 2.5, 5.2, 1H), 2.17 (s, 3H), 2.07 (s,
3H), 2.03 (s, 3H), 1.85 (q, J = 12.8 Hz, 1H); 19F NMR
(282 MHz, CDCl3) d ꢀ78.74 (d, J = 6.5 Hz); 13C NMR
+
1
C14H25O3F3SiNa 349.1417, found 349.1420.
3.17. (2S,3R,5R)-Ethyl-2,3-bis-hydroxy-5-(tert-
butyldimethylsilyl)oxy-6,6,6–trifluoro-hexenoate (27)
(75.5 MHz, CDCl3)
d 170.1, 169.7, 168.4, 121.9 (q,
Compound 27 (290 mg, 97% yield, 96% de) was prepared
from compound 26 (280 mg, 0.61 mmol) using the same
J = 216.4 Hz), 89.7, 69.6, 68.2 (q, J = 33.6 Hz), 66.0, 29.1,
20.8, 20.7, 20.4. IR (thin film) 2921, 2851, 1751, 1375, 1222,
1153, 1067 cmꢀ1; MS (ESI) m/z 346.0 (M + NH4 ); HRMS
20
conditions as described for compound 18. ½aꢂD = ꢀ19.8 (c
+
1
2.18, CHCl3); H NMR (300 MHz, CDCl3) d 4.38–4.14 (m,
(ESI) Calcd. for C12H15O7F3Na 351.0662, found 351.0663.
4H), 4.06 (d, J = 2.1 Hz, 1H), 2.01–1.92 (m, 1H), 1.81–1.72 (m,
1H), 1.31 (t, J = 7.2 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 6H); 19F
NMR (282 MHz, CDCl3) d ꢀ78.84 (d, J = 7.3 Hz); IR (thin
film) 3502, 2936, 2863, 1730, 1475, 1262, 1170, 1074, 840,
782 cmꢀ1; MS (ESI) m/z 361.2 (M + H+), 378.1 (M + NH4 ),
383.1 (M + Na+); Anal. Calcd. for C14H27O5F3Si: C, 46.65; H,
7.55; found: C, 46.63; H, 7.25.
Acknowledgements
+
We thank the National Natural Science Foundation of China
(Nos. 20325210, 20472105), Ministry of Education of China
and Shanghai Municipal Scientific Committee for funding this
work.
3.18. (2S,3R,5R)-Ethyl-2,3,5-tri-[(tert-
butyldimethylsilyl)oxy]-6,6,6–trifluoro-hexenoate (28)
References
[1] (a) J.D. Dunitz, Chem. Bio. Chem. 5 (2004) 614–621;
(b) P. Jeschke, Chem. Bio. Chem. 5 (2004) 570–589;
(c) C.M. Timperley, W.E. White, J. Fluorine Chem. 123 (2003) 65–70;
(d) F.M.D. Ismail, J. Fluorine Chem. 118 (2002) 27–33;
(e) B.E. Smart, J. Fluorine Chem. 109 (2001) 3–11;
(f) T. Hiyama, Organofluorine Compounds, Chemistry and Applications,
Springer, Berlin, 2000.
Compound 28 (310 mg, 99%) was prepared from compound
27 (193 mg, 0.54 mmol) using the same conditions as described
26
1
for compound 19. ½aꢂD = ꢀ15.5 (c 2.13, CHCl3); H NMR
(300 MHz, CDCl3) d 4.21–4.08 (m, 5H), 2.03–1.94 (m, 1H),
1.84–1.76 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 0.91, 0.90, 0.88 (3s,
27H), 0.14, 0.13, 0.10, 0.09, 0.07, 0.06 (6s, 18H); 19F NMR
(282 MHz, CDCl3) d ꢀ78.45 (d, J = 4.8 Hz); 13C NMR
(75.5 MHz, CDCl3) d 171.1, 129.0 (q, J = 283.1 Hz), 75.4,
70.9, 68.7 (q, J = 31.3 Hz), 60.6, 35.6, 25.7, 25.6, 18.3, 18.2,
18.1, 14.2, 1.0, ꢀ3.8, ꢀ4.1, ꢀ4.6, ꢀ5.0, ꢀ5.3; IR (thin film)
2933, 2860, 1753, 1474, 1176, 881, 778 cmꢀ1; MS (ESI) m/z
[2] D. O’Hagan, D.B. Harper, J. Fluorine Chem. 100 (1999) 27–33.
[3] (a) T. Tsuchiya, Adv. Carbohydr. Chem. Biochem. 48 (1990) 91–277;
(b) M.D. Burkart, Z.-Y. Zhang, S.-C. Hung, C.-H. Wong, J. Am. Chem.
Soc. 119 (1997) 11743–11746;
(c) L.A. Mikhailopulo, G.G. Sivets, Helv. Chim. Acta 82 (1999) 2052–
2065;
(d) R. Miethchen, M. Hein, Carbohydr. Res. 327 (2000) 169–183.

B.-L. Wang et al. / Journal of Fluorine Chemistry 127 (2006) 580–587
587
[4] Y. Takagi, K. Nakai, T. Tsuchiya, T. Takeuchi, J. Med. Chem. 39 (1996)
1582–1588.
[10] (a) T. Li, Z. Zeng, V.A. Estevez, K.U. Baldenius, K.C. Nicolaou, G.F.
Joyce, J. Am. Chem. Soc. 116 (1994) 3709–3715;
(b) A.C. Weymouth-Wilson, Nat. Prod. Rep. 14 (1997) 99–110.
[11] Y. Hiramatsu, H. Moriyama, T. Kiyoi, T. Tsukida, Y. Inoue, H. Kondo, J.
Med. Chem. 41 (1998) 2302–2307.
[5] R. Miethchen, J. Fluorine Chem. 125 (2004) 895–901.
[6] (a) M. Yokoyama, Carbohydr. Res. 327 (2000) 5–14 (references cited
therein);
(b) K. Toshima, Carbohydr. Res. 327 (2000) 15–26 (references cited
therein);
[12] H. Binch, K. Stangier, J. Thiem, Carbohydr. Res. 306 (1998) 409–419.
[13] Z.-X. Jiang, Y.-Y. Qin, F.-L. Qing, J. Org. Chem. 68 (2003) 7544–7547.
[14] E.G. Janzen, Y.-K. Zhang, M. Arimura, J. Org. Chem. 60 (1995) 5434–
5440.
(c) K. Dax, M. Albert, J. Ortner, B.J. Paul, Carbohydr. Res. 327 (2000)
47–86;
(d) R. Plantier-Royon, C. Portella, Carbohydr. Res. 327 (2000) 119–
146.
[15] E.T. McBee, O.R. Pierce, D.D. Smith, J. Am. Chem. Soc. 76 (1954) 3722–
3725.
[7] R.C. Bansal, B. Dean, S. Hakomori, T. Toyokuni, J. Chem. Soc., Chem.
Commun. (1991) 796–798 (references cited therein).
[8] (a) Y. Hanzawa, J. Uda, Y. Kobayashi, Y. Ishido, T. Taguchi, M. Shiro,
Chem. Pharm. Bull. 39 (1991) 2459–2461;
[16] T.-P. Loh, X.-R. Li, Angew. Chem. Int. Ed. 36 (1997) 980–983.
[17] T. Yamazaki, N. Okamura, T. Kitazume, Tetrahedron: Asymmetry 1
(1990) 521–524.
[18] L.D. Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 3 (2001) 3041–3043.
[19] P.L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 52 (1987) 2559–
2562.
(b) T. Yamazaki, K. Mizutani, T. Kitazume, J. Org. Chem. 58 (1993)
4346–4359;
(c) C.M. Hayman, L.R. Hanton, D.S. Larsen, J.M. Guthrie, Aust. J. Chem.
52 (1999) 921–927.
[20] Z.-X. Jiang, F.-L. Qing, J. Org. Chem. 69 (2004) 5486–5489.
[21] P.F. Bevilacqua, D.D. Keith, J.J. Roberts, J. Org. Chem. 49 (1984) 1430–
1434.
[9] J.F. Kennedy, C.A. White (Eds.), Ellis Horwood, Bioactive Carbohydrates
in Chemistry, Biochemistry, and Biology, Chichester, 1983 (Chapter 12).
[22] T.-P. Loh, X.-R. Li, Eur. J. Org. Chem. 8 (1999) 1893–1899.