An improved synthesis of 4-O-benzoyl-2,2-difluorooleandrose from L- rhamnose. Factors determining the synthesis of 2,2-difluorocarbohydrates from 2-uloses

Article abstract of DOI:10.1021/jo971846x

4-O-Benzoyl-2,2-difluorooleandrose (16) has been synthesized from L- rhamnose. The key steps are the formation of a difluoromethylene group in 12 by reacting ulose 11 with DAST and the chemoselective methylation of diol 13 to give compound 14. To obtain the 2,2-difluoro compound 12, the substituents in the neighborhood of the carbonyl group in ulose 11 must be equitorial and the sugar ring must have restricted conformational mobility. This was done using 1,1,2,2-tetramethoxycyclohexane (TMC) to protect the hydroxyls at positions 3 and 4 in the sugar ring.

Full text of DOI:10.1021/jo971846x

2184
J . Org. Chem. 1998, 63, 2184-2188
An Im p r oved Syn th esis of 4-O-Ben zoyl-2,2-d iflu or oolea n d r ose fr om
L-Rh a m n ose. F a ctor s Deter m in in g th e Syn th esis of
2,2-Diflu or oca r boh yd r a tes fr om 2-Uloses
M. Isabel Barrena, M. Isabel Matheu, and Sergio Castillo´n*
Departament de Quı´mica, Universitat Rovira i Virgili, Pc¸a. Imperial Tarraco 1, 43005 Tarragona, Spain
Received October 6, 1997
4-O-Benzoyl-2,2-difluorooleandrose (16) has been synthesized from L-rhamnose. The key steps are
the formation of a difluoromethylene group in 12 by reacting ulose 11 with DAST and the
chemoselective methylation of diol 13 to give compound 14. To obtain the 2,2-difluoro compound
12, the substituents in the neighborhood of the carbonyl group in ulose 11 must be equatorial and
the sugar ring must have restricted conformational mobility. This was done using 1,1,2,2-
tetramethoxycyclohexane (TMC) to protect the hydroxyls at positions 3 and 4 in the sugar ring.
Avermectines1 are polycyclic macrolides from the mil-
bemycin family that have a potent antiparasitary activ-
ity. Structure-activity relationship studies have shown
that the disaccharide di-R-L-oleandrose and especially the
terminal oleandrose unit have a crucial role;2 thus,
avermectine B1a monosaccharide has only about 25%
of the biological activity of the parent compound 1
(Figure 1).
It is well-known that the glycosidic bond in 2-deoxy-
carbohydrates is easily hydrolyzed, and this must be
avoided if its activity, in biologically active compounds
incorporating these units, is to be preserved. One way
of modifying organic molecules and improving their
biological activity is to introduce fluorine.3 In particular,
introducing fluorine at position 2 of a carbohydrate helps
to stabilize the glycosidic bond.4 To this end, Lukacs et
al.5 synthesized 2-R- and 2-â-fluorooleandrose and intro-
duced it as the terminal unit in the disaccharide of
avermectine B1a (Figure 1, compounds 2a and 2b).
Subsequently, with the aim of making the glycosidic bond
in these compounds more stable, the same authors
published the synthesis of 2,2-difluorooleandrose (as
glycosyl fluoride),6 the key step being the addition of CF3-
OF to a 2-fluoroglycal. One of the drawbacks of this
synthesis is the difficulty of activating a glycosyl fluoride
with two fluorine atoms in the neighboring position.
F igu r e 1.
This report discusses a more efficient procedure of
synthesis of 2,2-difluorooleandrose based on the reaction
of a 2-ulose with DAST. A key aspect in the synthesis is
the use of 1,1,2,2-tetramethoxycyclohexane (TMC) as
protecting group.7
Resu lts a n d Discu ssion
Two different strategies are usually used in the syn-
thesis of gem-difluorinated carbohydrates:8 (1) the car-
bohydrate is formed from an appropriate gem-difluoro
synthon, such as (bromodifluoromethyl)acetylene,9 or
ethyl bromodifluoroacetate,4,10 commonly via a Refort-
masky reaction, and (2) by reacting carbonyl groups with
(diethylamino)sulfur trifluoride (DAST).11 We previously
studied the reaction of 2-uloses with DAST and found
that the axial orientation of the anomeric group gives rise
* To whom correspondence should be addressed. E-mail: castillon@
quimica.urv.es.
(1) Burg, R. W.; Miller, B. M.; Buker, E. E.; Birnbaum, I.; Currie,
S. A.; Hartman, R.; Kong, Y. L.; Monaghan, R. L.; Olson, G.; Putter,
I.; Tunac, J . B.; Wallik, H.; Stapley, E. O.; Oiwa, R.; Omura, S.
Antimicrob. Agent. Chemother. 1979, 15, 361.
(2) Fisher, M. H.; Mrozik, H. in Macrolide Antibiotics; Omura, S.,
Ed.; Academic Press: New York, London, 1984.
(3) For reviews about biologically active organofluorine compounds
see: (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry, J ohn Wiley & Sons: New York, 1991. (b) Welch, J . T.
Tetrahedron 1987, 43, 3123. (c) Selective Fluorination in Organic and
Bioorganic Chemistry; Welch, J . T., Ed.; ACS Series 456; American
Chemical Society: Washington, D.C., 1991. (d) Biomedical Frontiers
of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.;
ACS Series 639; American Chemical Society: Washington, D.C., 1996.
(4) Fried, J .; Ann Hallinan, E.; Szwedo, M. J . J . Am. Chem. Soc.
1984, 106, 3871.
(5) Bliard, C.; Cabrera Escribano, F.; Lukacs, G.; Olesker, A.; Sarda,
P. J . Chem Soc., Chem. Commun. 1987, 368.
(6) Bliard, C.; Herczegh, P.; Lukacs, G.; Olesker, A. J . Carbohydr.
Chem. 1989, 8, 103.
(7) Ley, S. V.; Priepke, H. W. M.; Warriner, S. L. Angew. Chem.,
Int. Ed. Eng. 1994, 33, 22, 2290.
(8) For
a review on methods for the synthesis of gem-difluoro
compounds see: Tozer, M. J .; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(9) Hansawa, Y.; Izanawa, K.; Kon, A.; Aoiki, H.; Kobayhasi, Y.
Tetrahedron Lett. 1987, 28, 659.
(10) Wohlrab, F.; J amieson, A. T.; Hay, J .; Mengel, R.; Guschlbauer,
W. Biochim. Biophys. Acta 1985, 824, 233.
(11) (a) Sharma, R. A.; Kawai, I.; Fu, Y. L.; Bobek, M. Tetrahedron
Lett. 1977, 39, 3433. (b) An, S.; Bobek, M. Tetrahedron Lett. 1986, 27,
3219.
S0022-3263(97)01846-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

Synthesis of 4-O-Benzoyl-2,2-difluorooleandrose
J . Org. Chem., Vol. 63, No. 7, 1998 2185
Sch em e 1
Sch em e 2
system. The faster reaction of the R-anomer together
with the â to R isomerization produced during the long
reaction time required for their completion may be
another explanation.
to 1,2-migrations to afford 1,2-difluoro-2-alkoxy com-
pounds, while gem-difluorination is produced in good
yield if both neighboring groups are equatorial (Scheme
1).12
Compound 3 (Scheme 2) was an intermediate in the
synthesis of difluorooleandrose.6 The substituents were
all in the equatorial position. Therefore, the oxidation
and subsequent reaction with DAST should give the
difluoro derivative.
We believe that the first reason is more probable, and
consequently, the restriction of the conformational mobil-
ity in the carbohydrate ring would be a supplementary
condition for the gem-difluorination of 2-uloses by reac-
tion with DAST.
The presence of an additional trans-fused ring at
positions 3 and 4 would provide the required rigidity.
Recently, Ley has developed different protecting groups,
such us 3,3′,4,4′-tetrahydro-6,6′-bi-2H-pyran (bis-DHP)17
and TMC,7 able to protect trans-diequatorial diols in the
presence of cis ones.18
With this aim, compound 3 was oxidized with PCC to
give the ulose 4 (ν ) 1757 cm-1), which was an insepa-
rable anomeric mixture, according to NMR data, the
anomer â being the major one. The use of other oxidation
agents such as PDC or CrO3-Py led to the same results.
We thought that the slight traces of HCl present in the
CDCl3 could favor the isomerization, but when CD2Cl2
was used the behavior was similar. Isomerization may
also take place during the purification, so we decided not
to isolate the ulose 4 but treated it directly with DAST
in methylene chloride at room temperature. Under these
conditions, compound 5, in which a 1,2-transposition has
been produced, was isolated in 50% yield. When the
reaction took place in benzene or in the presence of Et3N,
the same product was obtained.
With this aim, we prepared the benzyl R-L-rhamnopy-
ranoside (6)19 in 69% yield from rhamnose by reacting
benzyl alcohol in the presence of AcCl20 (Scheme 3). This
compound was treated with bis-DHP, and a 79% yield of
a 3:2 mixture of 3,4- and 2,3-diprotected products was
obtained.21 Despite studying the reaction conditions, we
were unable to improve on this result.
On the other hand, when compound 6 was treated with
TMC under the reported conditions (trimethyl orthofor-
mate, methanol, CSA, reflux) a 1:1 mixture of methyl and
benzyl glycosides 7 and 8, respectively, was obtained in
an overall yield of 80%. That is, a transglycosylation took
place in the acid conditions required to form the cyclo-
hexane 1,2-diacetal (CDA) protecting group. It should
also be taken into account that the 3,4-diprotected
product is the thermodynamic while the 2,3-diprotected
product is the result of kinetic control.18b This means
that heating for a long time will give rise to improve the
formation of the 3,4-diprotected compound 8 but these
conditions will also favor transglycosylation to give
compound 7.
1
The structure of compound 5 was determined by H,
13C, and 19F NMR spectroscopy on the basis of the
following spectroscopic data: (1) the coupling constants
for protons H-1 indicate the presence of fluorine at this
position;13,14 (2) two similar groups of signals (double
doublets) appear in the 13C NMR spectrum in the 100-
110 (J ) 223, 44 Hz) region corresponding to C-1 of both
1
isomers (C-2 cannot be seen), and the high value for J C,F
coupling indicates a fluoroalkoxy substitution for this
carbon;13,15 (3) the presence of four signals in the 19F NMR
spectrum, two double doublets (J ) 64, 9 and J ) 64, 7
Hz, respectively), characteristic of F-1, and two quintu-
plets (J ) 7 Hz), corresponding to F-2 of both isomers;
and (4) the coupling constants H-1/F-2 and H-3/F-2, 0
and 14.7, respectively, indicate that F-2 is equatorially
oriented.13,16
One possible explanation for this is that 1,2-transposi-
tion also takes place from the â anomer because the
conformational mobility of compound 4 is greater than
that of the model compounds (see Scheme 1) in which
the oxo group is incorporated in a trans-decaline-like ring
When the reaction took place in methanol (with no
trimethyl orthoformate) and the reaction time was con-
trolled the yield of compound 8 increased to 61%,
although under these conditions the product of kinetic
control, benzyl 2,3-O-(1′,2′-dimethoxycyclohexane-1′,2′-
(17) (a) Ley, S. V.; Woods, M.; Zanotti-Gerosa, A. Synthesis 1992,
52. (b) Ley, S. V.; Leslie, R.; Tiffin, P. D.; Woods, M. Tetrahedron Lett.
1992, 33, 4767.
(18) More recently, new reagents for the selective protection of
diequatorial 1,2-diols have been described. (a) 2,2,3,3-Tetramethox-
ybutane (TMB): Montchamp, J . L.; Tian, F.; Hart, M. E.; Frost, J . W.
J . Org. Chem. 1996, 61, 3897. (b) R-Diketones: Douglas, N. L.; Ley, S.
V.; Osborn, H. M. I.; Owen, D. R.; Priepke, H. W. N.; Warriner, S. L.
Synlett 1996, 793.
(19) Brimacombe, J . S.; Cook, M. C.; Tucker, L. N. C. J . Chem. Soc.
1965, 2292.
(20) Ogawa, T.; Kaburagi, T. Carbohydr. Res. 1982, 103, 53.
(21) Ley, S. V.; Boons, G.-T.; Leslie, R.; Woods, M.; Hollinshead, D.
M. Synthesis 1993, 689.
(12) El-Laghdach, A.; Echarri, R.; Matheu, M. I.; Barrena, M. I.;
Castillo´n, S.; Garc´ıa, J . J . Org. Chem. 1991, 56, 4556.
(13) Csuk, R.; Gla¨nzer, B. I. Adv. Carbohydr. Chem. Biochem. 1988,
46, 73,
(14) Wray, V. J . Chem. Soc., Perkin Trans. 2 1974, 928.
(15) (a) Bock, K.; Pedersen, C. Acta Chim. Scand. 1975, B29, 682.
(b) Wray, V. J . Chem. Soc., Perkin Trans. 2 1976, 1598.
(16) Phillips, L.; Wray, V. J . Chem Soc. B 1971, 1618.

2186 J . Org. Chem., Vol. 63, No. 7, 1998
Barrena et al.
Sch em e 3a
13. Interestingly, selective methylation of 3-OH in 13
was successfully achieved by reacting with Bu2SnO to
form the stannylene derivative and then treating it with
methyl iodide to give compound 14 in an 80% yield. The
protection of 4-OH was performed by adding benzoyl
chloride to a solution of compound 14 in pyridine. That
allowed the indirect confirmation of the methylation
position.
The anomeric benzyl group was deprotected by hydro-
genolysis, leading to an anomeric mixture of the target
product 16 in quantitative yield. The presence of the
unprotected anomeric hydroxyl makes it possible to
introduce different leaving groups in order to perform the
glycosylation reaction.
In conclusion, 4-O-benzoyl-2,2-difluorooleandrose (16)
has been synthesized from L-rhamnose. The key steps
are the formation of a difluoromethylene group in 12 by
reaction of ulose 11 with DAST and the chemoselective
methylation of diol 13 to give compound 14. To obtain
the 2,2-difluorocompound 12 two conditions are required,
neighboring substituents to carbonyl group in ulose 11
must be equatorial and the sugar ring must have
restricted the conformational mobility. The last condition
has been achieved by using 1,1,2,2-tetramethoxycyclo-
hexane (TMC) as the protecting group of hydroxyls at
positions 3 and 4 of the sugar ring.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were uncorrected.
Optical rotations were measured at the indicated temperature
in 10 cm cells. 1H, 13C, and 19F NMR spectra were recorded
on a 300 MHz (300, 75.4, and 282.3 MHz, respectively)
apparatus, using CDCl3 as solvent. Elemental analyses were
performed at the Servei de Recursos Cientifics (Universitat
Rovira i Virgili). Flash column chromatography was per-
formed using silica gel 60 A CC (230-400 mesh). TLC plates
a
(a) PhCH2OH/AcCl; (b) CDA, MeOH, H+; (c) H2, Pd/C, MeOH/
AcOEt; (d) Bu2SnO, BnBr, benzene; (e) PCC, CH2Cl2; (f) DAST,
CH2Cl2; (g) TFA-H2O; (h) Bu2SnO/MeI; (i) BzCl, Py; (j) H2, Pd/C,
MeOH/AcOEt.
diyl)-R-L-rhamnopyranoside (17), was also obtained in
16% yield.
were prepared by using Kieselgel 60 PF254
. Solvents for
chromatography were distilled at atmospheric pressure prior
to use. Dichloromethane was distilled from P2O5 and stored
over molecular sieves. Methanol was distilled from clean dry
magnesium turnings and iodine and stored over molecular
sieves. Pyridine was distilled from solid KOH and stored over
molecular sieves.
The substituents at position 1 and 3 also had to be
arranged equatorially, and to do so, the configuration of
the anomeric group had to be inverted. This was done
by deprotecting the anomeric group by hydrogenolysis to
give compound 9 and benzylating the resulting free
hydroxyl through the cyclic stannylene intermediate to
obtain the â-glycoside 10 with an overall yield of 68%
for the two steps.
4-O-Ben zoyl-2-O-ben zyl-2-flu or o-3-O-m eth yl-r,â-L-r h am -
n op yr a n osyl F lu or id e (5). In a light-protected flask, 138
mg (0.64 mmol) of pyridinium chlorochromate, 210 mg (2.56
mmol) of anhydrous sodium acetate, 732 mg of 4 Å molecular
sieves (previously activated), and 4.5 mL of CH2Cl2 were
introduced and stirred under argon atmosphere. A solution
of compound 3 (60 mg, 0.16 mmol) was added to the suspension
obtained, and then the resulting reaction mixture was heated
to reflux for 2 h. When the reaction finished, it was diluted
with ethyl ether and filtered through a Cellite-silica gel pad
to separate the chromium salts formed. The remaining
solution was evaporated to dryness, and the resulting oil was
used in the subsequent reaction without purification. DAST
(0.14 mL, 1 mmol) was added dropwise to a solution of this
reaction crude (48 mg) in anhydrous CH2Cl2 (1 mL). After 24
h, standard workup gave an oil, which was purified by
preparative thin-layer chromatography (7/1 hexane/ethyl ac-
etate), yielding the difluoro compound 5 (26 mg, 50% overall
yield) as an anomeric mixture. Major isomer (R, F axial in
C1) extracted from the spectrum of the mixture: 1H NMR
(CDCl3) δ 8.00-7.25 (m, 10H), 5.34 (d, 1H, J ) 63.7 Hz), 5.24
(m, 1H), 4.95 (d, 1H, J ) 11.9 Hz), 4.74 (dd, 1H, J ) 11.9, 2.0
Hz), 4.32 (dd, 1H, J ) 14.7, 5.3 Hz), 4.23 (m, 1H), 3.46 (s, 3H),
1.19 (s, 3H); 13C NMR (CDCl3) δ 165.6, 133.5-128.0 (12C),
106.4 (dd, J ) 224.3, 43.7 Hz), 83.9 (d, J ) 20.6 Hz), 81.7,
80.6, 72.0, 59.4, 20.4; 19F NMR (CDCl3) δ -140.89 (dd, J )
63.7, 9.0 Hz), -119.15 (m). Minor isomer (â, F equatorial in
The ulose 11 was efficiently obtained by oxidizing the
alcohol 10 with PCC. This product was stable enough
to be purified by chromatography. The reaction of 11
with DAST led to the key gem-difluoro compound 12 in
a 69% yield. The structure of compound 12 was estab-
lished by 1H, 13C, and 19F NMR spectroscopy on the basis
of the following facts: (1) In the 13C NMR spectrum there
is a triplet (114.7 ppm, J ) 252.8 Hz) that is character-
istic of a difluoromethylene group, a double doublet (96.9
ppm, J ) 26.7, 19.0 Hz) that corresponds to a ketalic
carbon coupled with two fluorine atoms, and a triplet
(70.3 ppm, J ) 18.3 Hz) that were assigned to C-2, C-1,
and C-3, respectively. (2) In the 19F NMR spectrum there
are two signals at -125.07 ppm and -140.63 ppm
showing a J ) 241.6 Hz characteristic of fluorine-
fluorine geminal coupling.14 (3) The H-1 appears as a
doublet at 4.52 ppm (J ) 14.5 Hz), which should cor-
respond to an axial-axial proton-fluorine coupling.14,17
Once the 2,2-difluoromethylene group was formed, the
diketalic protecting group was easily deprotected by
reaction with aqueous trifluoroacetic acid to give the diol

Synthesis of 4-O-Benzoyl-2,2-difluorooleandrose
J . Org. Chem., Vol. 63, No. 7, 1998 2187
C1) extracted from the spectrum of the mixture: 1H NMR
(CDCl3) δ 5.33 (d, 1H, J ) 64.0 Hz), 3.39 (s, 3H), 1.48 (s, 3H);
13C NMR (CDCl3) δ 165.6, 133.5-128.0, 106.3 (dd, J ) 224.7,
4.12-3.50 (m, 5H), 3.22 (s, 3H), 3.21 (s, 3H), 3.00 (d, 1H, J
)3.0 Hz), 1.80-1.70 (m, 4H), 1.60-1.50 (m, 2H), 1.45-1.33
(m, 2H), 1.31 (d, 3H, J ) 6.1 Hz); 13C NMR (CDCl3) δ 99.0
(2C), 94.8, 70.8, 70.3, 70.1, 68.4, 47.0, 46.6, 27.0, 26.9, 21.3
(2C), 16.5. Anal. Calcd for C14H24O7: C, 55.26; H, 7.90.
Found: C, 55.29; H, 8.04.
44.2 Hz), 84.2 (d, J ) 22.8 Hz), 81.8, 80.7, 71.8, 59.4, 20.3; 19
F
NMR (CDCl3) δ -144.37 (dd, J ) 64.0, 7.3 Hz), -119.00 (m,
F2).
Ben zyl r-L-Rh a m n op yr a n osid e (6). Rhamnose mono-
hydrated (1.82 g, 10 mmol) was added to a solution of acetyl
choride (0.5 mL) in benzyl alcohol (10 mL) and was stirred at
60 °C for 24 h (complete disappearance of starting sugar). Then
the reaction was quenched with K2CO3 (4.0 g), stirring was
continued for 1 h, and ethyl acetate (20 mL) was added. The
precipitated salts were filtered and washed with ethyl acetate
(2 × 10 mL), and the organic phase was concentrated to half
volume and diluted with hexane (80 mL). The resulting
emulsion was left to stand for 2 h in the refrigerator and then
the solvent was decanted, obtaining a syrup that was purified
by flash chromatography eluting first with dichloromethane
(600 mL) to separate the remaining benzyl alcohol and then
with ethyl acetate (400 mL) to give 1.5 g of compound 6. A
subsequent elution column with ethyl acetate/ethanol 19:1 (500
mL) provided 0.25 g of compound 6 as an R/â anomeric
Ben zyl 3,4-O-(1′,2′-Dim eth oxycycloh exa n e-1′,2′-d iyl)-â-
L-r h a m n op yr a n osid e (10). Bu2SnO (74 mg, 0.30 mmol) was
added to a solution of compound 9 (82 mg, 0.27 mmol) in
benzene (90 mL) and was then heated to reflux overnight with
water exclusion. Then the reaction mixture was concentrated
to one-fourth of the initial volume, and Bu4NBr (87 mg, 0.27
mmol) and BnBr (35 µL) were added. The resulting reaction
mixture was again heated to reflux for 24 h and was then
evaporated to dryness. The resulting residue was purified by
flash chromatography, eluting first with hexane to separate
the excess of BnBr and then with hexane/ethyl acetate 2:1.
Compound 10 (72 mg, 68%) was obtained as a crystalline
solid: mp 140-141 °C; [R]25 -19.4° (c ) 0.85, CHCl3); 1H
D
NMR (CDCl3) δ 7.25-7.30 (m, 5H), 4.87 (d, 1H, J ) 11.8 Hz),
4.58 (d, 1H, J ) 11.8 Hz), 4.46 (s, 1H), 3.94 (s, br, 1H), 3.86 (t,
1H, J ) 10.1 Hz), 3.70 (dd, 1H, J ) 10.1, 2.9 Hz), 3.42 (m, 1H
J ) 10.1, 6.2 Hz), 3.12 (s, 6H), 2.35 (s, 1H), 1.85-1.53 (m, 4H),
1.50-1.39 (m, 2H), 1.38-1.30 (m, 2H), 1.29 (d, 3H, J ) 6.2
Hz); 13C NMR (CDCl3) δ 136.8, 128.4, 128.4, 128.0, 99.0, 98.5,
98.3, 70.6, 70.6, 70.4, 70.0, 68.6, 46.8, 46.5, 27.0, 26.9, 21.3
(2C), 16.5. Anal. Calcd for C21 H30 O7: C, 63.96; H, 7.61.
Found: C, 64.05; H, 7.55.
Ben zyl 3,4-O-(1′,2′-Dim eth oxycycloh exa n e-1′,2′-d iyl)-â-
L-r h a m n op yr a n osid -2-u lose (11). A mixture of compound
10 (80 mg, 0.20 mmol), PCC (175 mg, 0.81 mmol), sodium
acetate (66 mg, 0.80 mmol), and 4 Å activated molecular sieves
(230 mg) was placed in a light protected flask under argon,
and then anhydrous CH2Cl2 (2 mL) was added. After 1 h, the
reaction mixture was diluted with CH2Cl2, silica gel was added,
and the mixture was evaporated to dryness. The resulting
residue was purified by flash chromatography (hexane/ethyl
1
mixture: total yield 69%; H NMR (CDCl3) δ 7.35-7.23 (m,
5H), 4.79 (s, 1H), 4.62 (d, 1H, J ) 11.8 Hz), 4.42 (d, 1H, J )
11.8 Hz), 3.90 (d, 1H, J ) 2.5 Hz), 3.75 (dd, 1H, J ) 9.3, 2.5
Hz), 3.63 (m, 1H, J ) 9.3, 6.2 Hz), 3.45 (t, 1H, J ) 9.3 Hz),
2.19 (s, 2H), 2.12 (s, 1H), 1.25 (d, 3H, J ) 6.2 Hz); 13C NMR
(CDCl3) δ 137.0-127.9 (6 C), 99.0, 72.6, 71.7, 70.9, 69.1, 68.2
(2C), 17.5. Anal. Calcd for C13 H18 O5: C, 61.41; H, 7.09.
Found: C, 61.75; H, 6.95.
Ben zyl 3,4-O-(1′,2′-Dim eth oxycycloh exa n e-1′,2′-d iyl)-r-
L-r h a m n op yr a n osid e (8). CSA (308 mg, 1.33 mmol) was
added to a solution of compound 6 (3.46 g, 13.6 mmol) and
1,1,2,2-tetramethoxycyclohexane (4.60 g, 22.5 mmol) in anhy-
drous MeOH (8.5 mL), and the mixture was heated to reflux
for 75 min. The resulting solution was neutralized with solid
NaHCO3 (0.5 g) and evaporated to dryness. The residue
obtained was purified by flash chromatography (hexane/ethyl
acetate 3:1), and 3.27 g (61%) of compound 8 was obtained
together with 850 mg (16%) of product protected at position
acetate 3:2) to obtain 76 mg (97%) of compound 11 as a syrup:
1
[R]26 -38.0° (c ) 0.56, CHCl3); IR (KBr) 1756 cm-1 (νCO); H
D
NMR (CDCl3) δ 7.35-7.23 (m, 5H), 4.84 (d, 1H, J ) 12.1 Hz),
4.76 (s, 1H), 4.64 (d, 1H, J ) 12.1 Hz), 4.53 (d, 1H, J ) 10.8
Hz), 3.92-3.73 (m, 2H) 3.13 (s, 3H), 3.10 (s, 3H), 1.82-1.53
(m, 4H), 1.50-1.40 (m, 2H), 1.34 (d, 3H, J ) 6.0 Hz), 1.30-
1.20 (m, 2H); 13C NMR (CDCl3) δ 195.1, 136.0, 128.4, 128.2,
128.0, 99.0, 98.2, 97.4, 74.4, 73.0, 71.1, 70.0, 47.2, 46.6, 27.8,
27.4, 21.2 (2C), 17.3. Anal. Calcd for C21 H28 O7: C, 64.28; H,
7.14. Found: C, 64.25; H, 7.10.
2,3 with the R configuration (17). 8: mp 50-52 °C; [R]25
D
-146.80° (c ) 0.76, CHCl3); 1H NMR (CDCl3) δ 7.26-7.22 (m,
5H), 4.78 (d, 1H, J ) 1.5 Hz), 4.63 (d, 1H, J ) 11.8 Hz), 4.42
(d, 1H, J ) 11.8 Hz), 4.08 (m, 1H), 3.90 (dd, 1H, J ) 3.2, 1.5
Hz), 3.84 (m, 2H), 3.14 (s, 3H), 3.12 (s, 3H), 2.69 (s, br, 1H),
1.73-1.60 (m, 4H), 1.50-1.40 (m, 2H), 1.38-1.22 (m, 2H), 1.20
(d, 3H, J ) 5.7 Hz); 13C NMR (CDCl3) δ 137.2, 128.3, 128.1,
127.7, 99.1, 98.9, 98.6, 70.2, 69.0, 69.0, 66.9, 46.9, 46.5, 27.0,
26.9, 21.1, 16.4. Anal. Calcd for C21 H30 O7: C, 63.96; H, 7.61.
Found: C, 63.55; H, 7.85.
Ben zyl 2,2-Diflu or o-3,4-O-(1′,2′-dim eth oxycycloh exan e-
1′,2′-d iyl)-â-L-r h a m n op yr a n osid e (12). A solution of com-
pound 11 (45 mg, 0.12 mmol) in anhydrous CH2Cl2 (0.9 mL)
was treated with DAST (124 µL, 0.94 mmol) under argon at
room temperature. The reaction mixture was stirred for 6 h
and was then quenched by adding a saturated solution of
NaHCO3 in water. The organic phase was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
organic phase was dried with anhydrous sodium sulfate,
filtered, and evaporated to dryness. The resulting syrup was
purified by flash chromatography (hexane/ethyl acetate 8:1)
17: 1H NMR (CDCl3) δ 7.28-7.25 (m, 5H), 4.96 (s, 1H), 4.62
(d, 1H, J ) 11.6 Hz), 4.43 (d, 1H, J ) 11.6 Hz), 4.37 (d, 1H, J
) 6.2 Hz), 4.17 (t, 1H, J ) 6.3 Hz), 3.66 (m, 1H), 3.35 (t, br,
1H), 3.25 (s, 3H), 3.19 (s, 3H), 2.71 (s, br, 1H), 1.80-1.55 (m,
4H), 1.55-1.30 (m, 4H), 1.21 (d, 3H, J ) 6.3 Hz); 13C NMR
(CDCl3) δ 137.0, 128.4-127.4 (5C), 111.0, 101.2, 96.8, 78.5,
77.0, 74.3, 69.2, 66.2, 50.0, 49.0, 35.7, 30.6, 22.8, 21.5, 17.8.
3,4-O-(1′,2′-Dim eth oxycycloh exan e-1′,2′-diyl)-r,â-L-r h am -
n op yr a n ose (9). Palladium on charcoal was added to a
solution of compound 8 (100 mg, 0.254 mmol) in a mixture
MeOH/AcOEt (3 mL). This solution was vigorously stirred
under hydrogen (1 bar) at room temperature for 7 h. Then
the reaction mixture was filtered through a Celite pad and
evaporated to dryness. Compound 9 was obtained (quantitative
yield) in pure form as a white solid.
Spectroscopic data of 9R extracted from the spectrum of the
mixture: 1H NMR (CDCl3) δ 5.22 (dd, 1H, J ) 2.1, 1.2 Hz),
4.19 (ddd, 1H, J )10.4, 3.1, 1.2 Hz), 4.10 (m, 1H), 4.02-3.86
(m, 2H), 3.24 (s, 3H), 3.20 (s, 3H), 3.02 (d, 1H, J ) 3.1 Hz),
2.72 (d, 1H, J ) 2.1 Hz), 1.80-1.70 (m, 4H), 1.60-1.50 (m,
2H), 1.45-1.33 (m, 2H), 1.27 (d, 3H, J ) 6.2 Hz). 13C NMR
(CDCl3) δ 99.0 (2C), 94.8, 70.2, 69.0, 68.5, 67.0, 47.0, 46.6, 27.0,
26.9, 21.3 (2C), 16.5.
to give 33 mg (69%) of the gem-difluorinated product 12 as a
1
syrup: [R]25 -39.6° (c ) 0.675, CHCl3); H NMR (CDCl3) δ
D
7.38-7.36 (m, 5H), 4.98 (d, 1H, J )12.2 Hz), 4.72 (d, 1H, J
)12.2 Hz), 4.52 (d, 1H, J )14.5 Hz), 3.96 (ddd, 1H, J ) 21.6,
10.4, 5.1 Hz), 3.72 (dt, 1H, J )10.4, 2.0 Hz), 3.58 (m, 1H, J
)10.4, 6.0, 0.9 Hz), 3.22 (s, 3H), 3.20 (s, 3H), 1.90-1.50 (m,
8H), 1.36 (d, 3H, J ) 6.0 Hz); 13C NMR (CDCl3) δ 136.3, 128.5,
128.1, 114.7 (t, J ) 252.8 Hz), 99.0, 98.5, 96.9 (dd, J ) 26.7,
19.0 Hz), 71.0, 70.7, 70.3 (t, J ) 18.3 Hz), 70.2 (d, J ) 6.2 Hz),
47.0, 46.7, 27.0, 26.7, 21.3 (2C), 16.4; 19F NMR (CDCl3) δ
-125.07 (dd, J ) 241.6, 5.1 Hz), -140.63 (ddd, J ) 241.6, 21.6,
14.5 Hz). Anal. Calcd for C21 H28 O6F2: C, 60.87; H, 6.76.
Found: C, 60.90; H, 6.72.
Ben zyl 2-Deoxy-2,2-diflu or o-â-L-r h am n opyr an oside (13).
A solution of compound 12 (40 mg, 0.096 mmol) in trifluoro-
acetic acid-water (95/5) (3 mL) was stirred at room temper-
ature for 20 min. The reaction was monitored by TLC in
Spectroscopic data of 9â extracted from the spectrum of the
mixture: 1H NMR (CDCl3) δ 4.80 (dd, 1H, J ) 11.3, 1.0 Hz),

2188 J . Org. Chem., Vol. 63, No. 7, 1998
Barrena et al.
hexane/ethyl acetate 1:1. The reaction mixture was evapo-
rated to dryness and immediately purified by flash chroma-
tography (hexane/ethyl acetate 1:1) to obtain 22 mg (82%) of
compound 13 as a syrup: [R]26D +69.56° (c ) 0.35, CHCl3). 1H
NMR (CDCl3) δ 7.37-7.32 (m, 5H), 4.96 (d, 1H, J ) 12.2 Hz),
4.69 (d, 1H, J ) 12.2 Hz), 4.50 (d, 1H, J ) 15.4 Hz), 3.60 (ddd,
1H, J ) 19.2, 9.0, 7.2 Hz), 3.37 (m, 2H), 3.20 (s, br, 2H), 1.37
(d, 3H, J ) 5.6 Hz); 13C NMR (CDCl3) δ 136.0, 128.5, 128.2,
128.1, 115.5 (t, J ) 252.4 Hz), 96.2 (dd, J ) 26.6, 19.0 Hz),
maintained by stirring for 3 h. The reaction mixture was
evaporated to dryness and then purified by flash chromatog-
raphy (hexane/ethyl acetate 5:1) to obtain 31 mg (84%) of
compound 15: [R]25 ) +94.24° (c ) 0.65, CHCl3); 1H NMR
D
(CDCl3) δ 8.04-7.32 (m, 10H), 5.15 (dt, 1H, J ) 9.8, 1.5 Hz),
5.01 (d, 1H, J ) 12.4 Hz), 4.75 (d, 1H, J ) 12.4 Hz), 4.55 (d,
1H, J ) 14.8 Hz), 3.64 (m, 2H), 3.54 (s, 3H), 1.32 (d, 3H, J )
6.2 Hz); 13C NMR (CDCl3) δ 165.0, 136.0-128.1 (12C), 116.2
(t, J ) 255.5 Hz), 96.0 (dd, J ) 26.7, 19.1 Hz), 81.0 (t, J )
19.2 Hz), 73.9 (d, J ) 8.4 Hz), 70.9, 70.5, 61.5, 17.4; 19F NMR
(CDCl3) δ -120.12 (dd, J ) 248.2, 4.8 Hz), -138.90 (ddd, J )
248.2, 19.5, 14.8 Hz). Anal. Calcd for C21 H22 O5 F2: C, 64.28;
H, 5.61. Found: C, 64.39; H, 5.69.
74.4 (d, J ) 6.7 Hz), 74.2 (t, J ) 19.4 Hz), 71.8, 71.2, 18.8; 19
F
NMR (CDCl3) δ -122.76 (dd, J ) 244.0, 7.2 Hz), -141.04 (ddd,
J ) 244.0, 19.2, 15.4 Hz). Anal. Calcd for C13 H16 O4F2: C,
56.93; H, 5.84. Found: C, 56.90; H, 5.88.
Ben zyl 2-Deoxy-2,2-diflu or o-3-O-m eth yl-â-L-r h am n opy-
r a n osid e (14). Bu2SnO (31 mg, 0.121 mmol) was added to a
solution of compound 13 (30 mg, 0.109 mmol) in benzene (90
mL), and the resulting mixture was heated to reflux for a night
with water exclusion. The reaction mixture was evaporated
to dryness and coevaporated twice with anhydrous toluene,
and the remaining syrup was dissolved in anhydrous toluene
(3 mL), treated with Bu4NBr (37 mg 0.115 mmol) and MeI (70
µL, 1.1 mmol), and heated to reflux. Every 2 h, MeI (50 µL)
was added until the starting material disappeared. The
reaction was monitored by TLC in hexane/ethyl acetate (3:1).
After the reaction mixture was evaporated to dryness, the
resulting reaction crude was purified by flash chromatography
to yield 25 mg (80%) of compound 14: [R]26D +86.38° (c ) 0.585,
CHCl3); 1H NMR (CDCl3) δ 7.40 (m, 5H), 4.99 (d, 1H, J ) 12.2
Hz), 4.72 (d, 1H, J ) 12.2 Hz), 4.48 (d, 1H, J ) 15.1 Hz), 3.66
(s, 3H), 3.40 (m, 2H), 3.17 (ddd, 1H, J ) 19.5, 9.1, 5.0 Hz),
2.45 (s, br, 1H, OH), 1.40 (d, 3H, J ) 5.8 Hz); 13C NMR (CDCl3)
δ 136.1, 128.5-128.0 (5C), 116.5 (t, J ) 255.8 Hz), 96.0 (dd, J
) 26.9, 19.1 Hz), 83.1 (t, J ) 17.8 Hz). 73.6 (d, J ) 7.7 Hz),
71.6, 70.9, 61.4, 17.4; 19F NMR (CDCl3) δ -118.94 (dd, J )
247.3, 5.0 Hz), -139.2 (ddd, J ) 247.3, 19.5, 15.1 Hz). Anal.
Calcd for C14 H18 O4F2: C, 58.33; H, 6.25. Found: C, 58.30;
H, 6.28.
4-O-Be n zoyl-2-d e oxy-2,2-d iflu or o-3-O-m e t h yl-r,â-L-
r h a m n op yr a n ose (16). Palladium on charcoal 10% (18 mg)
was added to a solution of compound 15 (27 mg, 0.069 mmol)
in a mixture of MeOH/AcOEt (1.5 mL). The reaction mixture
was placed under a hydrogen atmosphere (1 bar) and vigor-
ously stirred at room temperature until the starting material
completely disappeared. The reaction was monitored by TLC
in hexane/ethyl acetate 6:1. The reaction mixture was then
filtered through a Celite pad and evaporated to dryness.
Compound 16 was obtained in quantitative yield as an
anomeric mixture.
Spectroscopic data of 16R extracted from the spectrum of
the mixture: 1H NMR (CDCl3) δ 8.02-7.40 (m, 5H), 5.14 (d,
1H, J ) 6.3 Hz), 5.06 (dt, 1H, J ) 9.9, 1.8 Hz), 4.22 (m, 1H, J
) 9.9, 6.3 Hz), 4.06 (s, br, 1H), 3.90 (ddd, 1H, J ) 21.0, 9.9,
4.2 Hz), 3.60 (s, 3H), 1.15 (d, 3H, J ) 6.3 Hz); 13C NMR (CDCl3)
δ 165.4, 133.5-128.6 (6C), 118.0 (t, J ) 254.4 Hz), 91.5 (dd, J
) 35.2, 27.3 Hz), 78.0 (t, J ) 19.4 Hz), 74.3 (d, J ) 8.0 Hz),
70.2, 65.7, 17.1; 19F NMR (CDCl3) δ -120.96 (dd, J ) 254.4,
4.2 Hz), -124.70 (ddd, J ) 254.4, 21.0, 6.3 Hz).
Spectroscopic data of 16â extracted from the spectrum of
the mixture: 1H NMR (CDCl3) δ 8.02-7.40 (m, 5H), 4.80 (d,
1H, J ) 15.2 Hz); 19F NMR (CDCl3) δ -120.47 (dd, J ) 248.4,
4.5 Hz), -142.72 (ddd, J ) 248.4, 19.7, 15.2 Hz).
Ben zyl 4-O-Ben zoyl-2-d eoxy-2,2-d iflu or o-3-O-m eth yl-
â-L-r h a m n op yr a n osid e (15). (Dimethylamino)pyridine (0.24
mg) and, dropwise, benzoyl chloride (20 µL, 0.17 mmol) were
added to a solution of compound 14 (27 mg, 0.094 mmol) in
anhydrous pyridine (1 mL) cooled to 0 °C. The bath was
allowed to warm to room temperature, and the reaction was
Ack n ow led gm en t. Financial support by DGICYT
(Ministerio de Educacio´n y Ciencia, Spain), project
PB92-0510, is gratefully acknowledged.
J O971846X