Baeyer-Villiger oxidation of 6-oxotricyclo-[3.2.1.02,7]octanes; Regioselective opening of push-pull substituted cyclopropanes

Article abstract of DOI:10.1055/s-1997-1273

Cascade reactions of cyclic dienolates 1 with enantiopure Michael accepters 2 lead to 3. Oxidation of 3 under Baeyer-Villiger conditions gave solely the lactones 4. The double-push-pull substituted cyclopropane moiety of 4a was selectively opened upon hydrogenolysis to yield oxabicyclo[3.3.1]nonane 6. Reduction of lactone 4a gave the hemiacetal 7. It was converted to the vinylcyclopropane 10 which was hydrogenated to give the highly functionalized cycleheptane 11 and oxabicyclo[3.2.1]octanes 12.

Full text of DOI:10.1055/s-1997-1273

REVIEW
799
Chemistry of Glycosyl Fluorides
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama*
Department of Chemistry, Faculty of Science, Chiba University,Yayoi-cho, Inageku, Chiba 263-8522, Japan
Fax +81(43)2902874; E-mail: yokoyama@science.s.chiba-u.ac.jp
Received 23 December 1997; revised 24 February 1998
Abstract: In recent years glycosyl fluorides have been utilized as
versatile sugar donors in the field of organic synthesis including
natural product synthesis as well as carbohydrate chemistry. We
describe here an update on developments in the preparation and
the utility of C–O, C–C, C–N, and C–S bond formations, includ-
ing total syntheses of natural products.
3.
Reaction of Glycosyl Fluorides
3.1. C–O Bond Formation
3.1.1. Lewis Acids
3.1.2. Triflic Anhydride
3.1.3. Enzymes
3.2. C–C Bond Formation
3.2.1. Lewis Acids
3.2.2. Metal Reagents
3.3. C–N, C–S Bond Formation
3.3.1. Lewis Acids
Key words: glycosyl fluoride, preparation of glycosyl fluoride,
C–C or C–X bond formation, total synthesis of natural products
1.
2.
Introduction
Preparation of Glycosyl Fluorides
3.3.2. Metal Reagents
2.1. Hydrogen Fluoride
2.2. Diethylaminosulfur Trifluoride
2.3. Metal Fluorides
4.
Total Synthesis of Natural Products
4.1. BF3·OEt2
4.2. sCl2/AgX
4.3. Cp2MCl2/AgX
2.4. Others
acetylated sugars preferentially underwent the fluorina-
tion. The reaction of 1-O-acetyl-2,3,4,6-tetra-O-benzyl-
a-D-glucose (1) with this reagent afforded the desired
glycosyl fluoride in 89% yield with a-selectivity (Scheme
1).
1. Introduction
Glycosyl fluorides have drawn much attention in the field
of biochemistry due to their potential biological activity.
Several substituted glucosyl fluorides were found to be
enzyme inhibitors.1 In recent years extensive studies have
shown that they are not only useful biological probes but
also versatile substrates for the glycosidation reaction.
Glycosyl halides have been utilized as glycosyl donors in
organic chemistry. Glycosyl bromide, chloride, and some-
times iodide have been used with various activators for
the anomeric carbon to act as an electrophile in glycosidic
bond formation. Since 1981 glycosyl fluorides have been
utilized for effective glycosylation reactions2 because of
their enhanced stability, ease of handling, and higher ste-
reoselectivity compared with other glycosyl halides. This
paper provides an update on the recent advances in the
chemistry of glycosyl fluorides during the last decade.
Scheme 1
With this reagent, 6-deoxy-6,6-difluoro- a-D-glucopyra-
nosyl fluoride (4), which is a derivative of an enzyme in-
hibitor, was synthesized from methyl 2,3,4-tri-O-benzyl-
6-O-trityl-a-D-glucopyranoside (3) for its use in inhibi-
tion studies4 (Scheme 2).
2. Preparation of Glycosyl Fluorides
Many studies for preparing the glycosyl fluorides have led
to the development of useful fluorination reagents. In this
section, each reagent is discussed separately.
2.1 Hydrogen Fluoride
Scheme 2
Hydrogen fluoride has been applied to fluorination of
acetylated sugar derivatives. First, both 1-unprotected and In the field of furanoses, the synthesis of the glycosyl flu-
O-acetylated sugars were converted to the corresponding oride 6 was performed by treatment of the acetylated sug-
1-fluoro derivatives using a 50 to 70% hydrogen fluoride/ ar 5 with HF/Py.5 It was envisioned that it would be
pyridine mixture [pyridinium poly(hydrogen fluoride)] converted into an intermediate 7 of the model compound
(HF/Py).3 Compared with l-unprotected sugars, the O- of an antibiotic agent. However, the treatment of 6 with 1

800
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
eqivalent each of PhONa and PhOH gave only the Further, N-glycosyl triazole derivatives devised as a new
deacetylated compound 8 in place of the desired 7 glycosyl donor, were reacted with hydrogen fluoride/pyri-
(Scheme 3).
dine for preparing the corresponding glycosyl fluorides6,7
(Scheme 4). This method resolved many difficulties en-
countered in the usual approaches.
DAST (diethylaminosulfur trifluoride) is known as the
best reagent for fluorination reacts with sugar hemiacetals
to give the glycosyl fluorides in good yield, but it is rela-
tively expensive. Even the reaction between acyl glyco-
sides and HF/Py incurs some problems. While this reagent
is preferable to anhydrous HF, a large excess is needed to
complete the reaction. Therefore, it is not suitable for
acid-sensitive sugar derivatives. From a synthetic point of
view, this procedure using the triazole derivative can be a
good method for glycosilation due to the low temperature
and use of small excess of the reagent.
Treatment of the triazole 9 derived from the correspond-
ing azide with HF/Py complex furnished the correspond-
Scheme 3
Biographical Sketches
Miyuki Shimizu was born in Tokyo in 1974 and graduated from the Faculty of Science
of Chiba University in 1996. At present she is a student of a masters course in the Grad-
uate School of Science and Technology of Chiba University. Her research interests are
in organonucleic acid chemistry.
Hideo Togo was born in Ibaraki in 1956. He completed his doctoral thesis in 1983 under
the supervision of Professor Shigeru Oae in Tsukuba University. He then became a post-
doctoral fellow at University de Lausanne (Professor Manfred Schlosser) in Switzerland
(1983–1984) and then at ICSN of CNRS (Professor Derek H. R. Barton) in France
(1984–1985). He became a research associate at Tsukuba University in 1987 and then at
the present University in 1989. He has been an associate professor since 1994. His re-
search interests are free radical reactions and their synthetic uses with hypervalent iodine
and silicon compounds for organic synthesis.
Masataka Yokoyama was born in Formosa in 1935 and graduated from Ibaraki Univer-
sity in 1958. He obtained his PhD from Tokyo Metropolitan University (Professor Kazuo
Hata) in 1972. He spent a year as a postdoctoral fellow under Professor D. C. Dittmer at
Syracuse University in 1975. He was visiting professor of Nijmegen University and
North Eastern Hill University. Since 1985 he has been full professor of organic chemis-
try at Chiba University. His research interests are organonuceic acid chemistry, sugar
chemistry and heterocyclic chemistry.

June 1998
Chemistry of Glycosyl Fluorides
801
anhydride, O-pivaloyl protected glycosyl fluoride was ob-
tained. In addition, after the free hydroxyl groups of a-L-
rhamnopyranoside 19 were modified, a-L-altropyranosyl
fluoride 20 was obtained in 74% yield by using this re-
agent (HF/MeNO2/Ac2O)10 (Scheme 7).
Scheme 4
ing glycosyl fluoride 10 with a b-configuration. In this
reaction, the ratio of the a- and b-anomers of the resultant
fluoride depends on the protecting group and on the reac-
tion conditions. As a glycosyl donor, (1-phenyl-1H-tetra-
zol-5-yl)glycoside was prepared to be transformed into
the corresponding fluoride with hydrogen fluoride/
pyridine8 (Scheme 5, Table 1).
Scheme 6
Scheme 5
Scheme 7
Table 1. Reaction of OTet Glycosides with HF/Pyridine
2.2 Diethylaminosulfur Trifluoride (DAST)
Entry OTet Glycoside Equiv Temp Time Glycosyl
Fluoridea
Yield
(%)
Since diethylaminosulfur trifluoride (DAST) was found
as the best fluorinating reagent for a free anomeric hy-
droxyl group,11 it has been utilized widely as the most
preferable fluorinating reagent. The conversion of an al-
cohol to the corresponding fluoride is performed by expo-
sure to DAST. In addition, it is noteworthy that the ratio
of a/b of the glycosyl fluoride depends on the solvent.
When 2,3,5-tri-O-benzyl-D-ribose (21) is allowed to react
with DAST in THF, the anomeric ratio of the correspond-
ing glycosyl fluoride 22 becomes 9:91. The a/b ratio be-
comes 20:80 with the use of CHCl3 as the solvent12
(Scheme 8).
(a-D/b-D)
(°C)
(min) (a-D/b-D)
1
2
3
4
5
11 (100:0)
11 (82:18)
11 (63:37)
12 (100:0)
14 (100:0)
160
5
5
10
5
0
0
0
0
0
30
10
10
10
3
2 (90:10) 95
2 (88:12) 89
2 (57:43) 90
13 (100:0) 76
15 (100:0) 46
16 (100:0) 12
15 (92:8) 72
16 (100:0) 10
6
14 (100:0)
5
–20
10
a
By the use of HF/Py, benzylated-D-glucopyranoside 11
and a-D-mannopyranoside 12 could be converted into the
corresponding fluorides 2 and 13 in good yields, respec-
tively. The stereoselectivity seems independent of the
anomeric configuration of OTet glycosides, but is depen-
dent on the reaction conditions. The reaction of a-D-man-
nofuranoside 14 bearing an acid-sensitive group with 5
equivalents of HF/Py at 0 °C for 3 minutes gave the cor-
responding fluoride 15 (46%) along with the diol 16
(12%). When the reaction was performed at lower temper-
ature, the yield of 15 increased to 72%.
Scheme 8
The alcohol 23 was allowed to react with DAST easily to
give the corresponding fluoride 24 in 94
%
yield13 (Scheme 9). Although the coupling of 24 with
methanol was supposed to occur under the standard con-
ditions, 24 was recovered intact.
On the other hand, by using a homogeneous reagent/cata-
lyst/solvent combination, the synthesis of 6-O-substituted
2,3,4-tri-O-acetyl- a-D-galactopyranosyl fluorides 18 was
carried out from 6-O-substituted 1,2;3,4-di-O-isopropyl-
idene-a-D-galactopyranoses 17.9 (Scheme 6). When piv-
alic anhydride was chosen as the solvent in place of acetic Scheme 9

802
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
The treatment of 2,3,4,6-tetra-O-acetyl-5-thioglucopyra- Not only mono-fluorinated compounds but also gem-di-
nose (25) with DAST gave the glycosyl fluoride 26 in fluorinated compounds have received wide attention in
57% yield. The MCPBA oxidation of 26 afforded the cor- the carbohydrate field. The gem-difluorinated compounds
responding sulfoxides with axial 27a and equatorial 27b are synthesized by the treatment of 2-uloses with DAST.
isomers14 (Scheme 10).
Methyl 3-O-benzyl-4,6-O-benzylidene-a-D-arabino-he-
xopyranoside-2-ulose (34) was allowed to react with
DAST to give the compound 35 via the migration of the
OMe group19 (Scheme 14). When the b-anomer of 34 was
used, methyl 4,6-O-benzylidene-2-deoxy-2,2-difluoro-3-
O-benzyl derivative 36 was obtained. The 1,2-migration
takes place only when the anomeric group has axial orien-
tation. Similarly, O-benzyl derivative 37 was also con-
verted to the desired gem-difluoro compound 38 in 68 %
yield20 (Scheme 14).
Scheme 10
Furthermore, the conversion of thioglycosides into glyco-
syl fluorides can be demonstrated by the treatment of
DAST and NBS.15 The reaction of phenyl thioglycoside
28 with the reagent (DAST/NBS) afforded the desired flu-
oride 29 in 79% yield16 (Scheme 11).
Scheme 14
Scheme 11
On the contrary, the transformation of thioglycoside 30
into the fluoride 31 under the same conditions did not take
place.17 It was considered that the competitive attack of
NBS to both the PhS and Me2N groups led to the failure.
In order to make a selective attack to the PhS group, HF/
Py was added as a coactivator under the standard condi-
tions at lower temperature to give the desired 31 in 77%
yield (Scheme 12).
Scheme 15
Fluorination with DAST; General Procedure:12
To the alcohol (4.52 mmol) in a stirred solution of THF (12 mL) at
–30 °C under argon gas was added DAST (1.2 equiv). After the cool-
ing bath was removed, stirring at room temperature for 20 min com-
pleted the reaction. The reaction mixture was cooled to –30 °C and
MeOH (0.3 mL) was added. The solution was neutralized with aq
NaHCO3 solution and extracted with Et2O. The organic layer was
dried (MgSO4) and evaporated to yield a crude mixture of fluorides
which was separated by column chromatography (eluent; hexane/
EtOAc, 2:1).
Scheme 12
The glycosyl fluorides can be also formed from glycosyl
chlorides in two steps. At first, the direct transformation of
the chloride 32 with AgF gave the desired fluoride 33 in
40% yield.18 However, the chloride 32 when treated with
AgOTf in MeCN followed by DAST in CH2Cl2 at –78 °C
gave the fluoride 33 in 98% overall yield (Scheme 13).
2.3 Metal Fluorides (MFn)
Metal fluorides have been employed to transform the gly-
cosyl bromides and chlorides directly into glycosyl fluo-
rides via the nucleophilic halide exchange. Silver fluoride
is the most common fluorination reagent for this purpose.
3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-a-D-mannopyrano-
syl bromide (40) prepared in situ from the glycal 39 was
allowed to react with AgF in MeCN to give a monofluori-
Scheme 13

June 1998
Chemistry of Glycosyl Fluorides
803
nated compound, 3,4,6-tri-O-acetyl-2-bromo-2-deoxy-a-
D-mannopyranosylfluoride (41) stereoselectively in 88%
yield21 (Scheme 16). The same reaction was performed
with benzoyloxyiminoglycosyl bromide 42 to give the b-
fluoride 43 in 60% yield with the benzoyloxyimino group
intact22 (Scheme 17).
Scheme 20
onium ion intermediate with the assistance (anchimeric
assistance) of the acetyl group in the C-2 position.
In addition, the conversion of a glycosidic OH-group into
an F-group was investigated by using this reagent. Under
the same conditions as described for glycosyl bromide 46,
the reaction resulted in a poor conversion. However,
2,3,4,6-tetra-O-acetyl-D-glucose (48) when treated with
CF3ZnBr·2MeCN and TiF4 in dichloromethane gave the
desired fluoride 47 in good yield (Scheme 21).
Scheme 16
Scheme 17
The reactions of zinc fluoride with acetyl protected a-D-
glucosyl bromides also occurred in MeCN with b-selec-
tivity. Crystalline zinc fluoride is only soluble in refluxing
acetonitrile; therefore, the reaction of acetobromo-a-D-
cellobiose 44 with ZnF2 was performed at a high
temperature23 (Scheme 18).
Scheme 21
In this process, TiF4 catalyzed the formation of the oxo-
carbenium ion intermediate as shown in Scheme 22. How-
ever, the Lewis acid also stimulated the formation of a-
glycosyl fluoride, because it retarded the anchimeric as-
sistance of the acetyl group (Scheme 22).
Scheme 18
When the reaction was carried out in the presence of 2,2¢-
bipyridine, the yield of 45 increased to 69% without re-
markable acceleration of the reaction rate (Scheme 18).
The precipitation of a 2,2¢-bipyridine/ZnBr2 complex
from the reaction mixture would reduce the concentration
of the bromide ion followed by a shift of the equilibrium
between bromides and fluorides.
Scheme 22
2.4 Others
Tetrabutylammonium fluoride (TBAF) is used for the
preparation of glycosyl fluorides from 1,2-anhydro- a-D-
hexopyranose derivatives via the epoxidation of the gly-
cals.25 The perbenzylated 1,2-anhydro-a-D-hexopyranose
50 prepared by epoxidation of the corresponding glycal 49
reacted with TBAF to afford the b-glycosyl fluoride 51 in
53% yield by SN2 pathway (Scheme 23).
Trifluoromethylzinc bromide is used as the fluorinating
reagent of glycosyl bromides.24 This reagent is assumed to
exist in equilibrium as shown in Scheme 19.
Scheme 19
2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl bromide 46
was allowed to react with this reagent to afford the corre-
sponding fluoride 47a in a b-selective manner (Scheme
20). This result can be explained by the presence of the ox- Scheme 23

804
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
a-Fluoroenamine was found to be an effective reagent for
the conversion of various furanose and pyranose hemiac-
etals into the corresponding glycosyl fluoride.26 This re-
agent does not affect some kinds of hydroxy-protecting
groups such as benzyl, benzoyl, acetyl, acetonide, or silyl
functionalities owing to the fluorination under natural
conditions. By the use of this reagent, 2,3,4,6-tetra-O-ben-
zyl-D-glucopyranosyl fluoride (2) could be obtained from
the corresponding hemiacetal 52 with the a/b ratio =
28:72 (Scheme 24). The reaction takes place in the man-
ner as indicated in Scheme 25, on account of the presence
of an only byproduct, N,N-diisopropylisobutyramide.
Scheme 27
the axial side (Scheme 28). However, when an a-phe-
nylthio derivative of tetra-O-benzyl-D-glucose was al-
lowed to react with the reagent, it underwent an SN2
displacement to give the corresponding b-glycosyl fluo-
ride. The reaction with selenoglycoside was also exam-
ined.29 The 2-deoxyphenylselenoglycoside 57 provided
the glycosyl fluoride 58 by using the same reagent via an
SN2 inversion (Scheme 29).
Scheme 24
Scheme 25
Scheme 28
Scheme 29
Glycosyl fluorides can also be obtained by modification
of the Mitsunobu reaction27 (Scheme 26). By exposure to
triphenylphosphine, diethyl azodicarboxylate (DEAD)
3. Reaction of Glycosyl Fluorides
–
and triethyloxonium tetrafluoroborate (Et3O+BF4 ), diiso-
propylidenemannofuranose 53 was converted into the flu-
oride 15a. This reaction proceeds via the unstable
oxyphosphonium salt 54, which decomposes via the stabi-
lized carbenium ion forming the fluoride 15a.
Glycosyl fluorides have been known as a good sugar do-
nor for glycosidation reactions. Therefore, they are avail-
able for C–O, C–N, and C–C bond formations under the
activation of various promoters. To achieve high stereose-
lectivity and good yields under mild conditions, numerous
studies have been carried out on the reaction of glycosyl
fluorides. The following description deals with three types
of bond formations according to the kind of promoter.
3.1 C–O Bond Formation
3.1.1 Lewis Acids
O-Glycosidation is composed of a glycosyl donor which
is activated as an electrophile at the anomeric carbon, an
alcohol as the glycosyl acceptor, and Lewis acid as the
promoter. The reaction undergoes a Friedel–Crafts type
pathway as represented in Scheme 30. The Lewis acid at-
Scheme 26
The reaction of thioglycosides with hypervalent iodo-
arene was reported for the preparation of the correspond-
ing fluorides. The thioglycosides were allowed to react
with 4-methyl(difluoroiodo)benzene to introduce the flu-
orine into the glycosyl donors via the pathway shown in
Scheme 27.28
When the axial acetate existed at the C-2 position, an in-
termediate oxocarbenium ion was stabilized by the anchi-
meric assistance and the attack of fluoride occurred from
Scheme 30

June 1998
Chemistry of Glycosyl Fluorides
805
tacks the fluoride to form an oxocarbenium ion, which is yield: 76%). As for the conditions, variations of the Lewis
followed by the addition of an alcohol to give the corre- acid, solvents, and bases were tried, but no conditions
sponding O-glycoside.
gave better results than that mentioned above. Further-
more, the phenols with an electron-donating group exhib-
ited high b-selectivity.
Lithium Perchlorate
Lithium perchlorate (LiClO4) is a milder Lewis acid than This reagent can also be applied to a variety of glycosyl
others used commonly, such as SnCl2/AgClO4, BF3 ·OEt2, substrates. The fluoride 64 derived from lactone 63 in two
and TMSOTf. Owing to its mild conditions, it is utilized steps was reacted with the glycosyl acceptor in the pres-
for the glycosidation of acid-sensitive sugars such as fu- ence of BF3·OEt2 to give the corresponding disaccharide
cose.30 The disaccharide 61 of fucose was built up by the 65 in 58% yield32 (Scheme 34). When bis(cyclopentadie-
coupling of a fucose donor 59a with an acceptor 60 in the nyl)zirconium dichloride/silver tetrafluoroborate was em-
presence of LiClO4 and 1 equivalent of CsF as acid scav- ployed as the activator in place of BF3 ·OEt2, the reaction
enger (Scheme 31).
proceeded similarly to give 65 in 59% yield.33
Scheme 31
Scheme 34
Boron Trifluoride Etherate
Since 1985, boron trifluoride etherate has been adopted as
the Lewis acid in order to promote the reaction of glycosyl
fluorides.27 It catalyzes the condensation of the fluorides
and the alcohols in the same manner as that of other Lewis
acids (Scheme 32).
Moreover, the octasaccharide 69 was constructed from
glycosyl fluorides using BF3·OEt2 (Scheme 35). First,
34
the introduction of an azide group at the 1¢-position was
interestingly accomplished by the reaction of the fluoride
66 with trimethylsilyl azide under a catalytic amount of
BF3·OEt2 in two steps. The condensation of compound 67
with the glycosyl fluoride, a derivative of 66 in the pres-
ence of BF3·OEt2 resulted in the formation of the disac-
Scheme 32
It was reported that the stereoselectivity of glycosidation
of phenols in the presence of BF3·OEt2 depended on the
coexistence of an amine base, 1,1,3,3,-tetramethyl-
guanidine31 (Scheme 33).
Scheme 33
When o-chlorophenol (X = o-Cl) was used in the presence
of 1,1,3,3,-tetramethyl guanidine, the desired compound
62 was formed quantitatively in the ratio of a/b = 10:90
(Scheme 33). On the other hand, in the absence of the
CA = chloroacetyl, Mp = p-methoxyphenyl, Phth = phthaloyl, PMB
= p-methoxyphenylmethyl
amine base, the ratio turned to a-selectivity (a/b = 80:20, Scheme 35

806
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
charide 68. Modification of 68 in 10 steps afforded the The protected diterpene glycoside, baiyunoside (74) was
desired octasaccharide 69 as a precursor for the core-fu- synthesized from the reaction of 72 derived from 3,4,6-tri-
cosylation of N-glycans.
O-acetyl-a-D-glucopyranosyl chloride (71) with glycosyl
fluoride 73 in the presence of TMSOTf37(Scheme 39).
Gallium Compounds
Gallium compounds were employed as promoters for the
reaction of glycosyl fluorides because of their strong af-
finity to fluoride.35 The reagents were allowed to react
with free alcohols to give the corresponding acetals
(Scheme 36).
Scheme 36
Several kinds of Gallium reagents were prepared to exam-
ine the difference in reactivity (Scheme 37, Table 2).
Scheme 39
As for the coupling reaction of two sugars, it was expected
that 74 would be formed by the reaction of glycosyl ha-
lides and unsilylated alcohol of 72 under Köenigs–Knorr
conditions. However, the reaction was unsuccessful, al-
though, the coupling of 72 and glycosyl fluoride 73 under
the conditions using TMSOTf gave disaccharide 74 and
its stereoisomer in a ratio of 62:38.
Scheme 37
Table 2. lnfluence of Gallium Reagents in the Reaction of Fluoride
2a with Alcohols (Scheme 37)
A novel approach for coupling of three sugars in one step
was reported38, namely the reaction between glycosyl flu-
oride and the sugar protected by a five-membered ring
stannane in the presence of TMSOTf. Mannosyl fluoride
75 reacted with the stannane compound 76 to form the
trisaccharide 77 stereoselectively (Scheme 40). In this
method, by changing the equivalent amount of TMSOTf,
the disaccharide was obtained as the major product.
Entry
GaX3
Solvent
Yield (%)
a/b
1
2
3
4
Me2GaOTf
Me2GaOTfa
Me2GaCl
toluene
toluene
toluene
CH2Cl2
79
88
quant.
quant.
50:50
48:52
31:69
17:83
Me2GaCl
a TMS ether of cyclohexanol was used as a nucleophile.
As shown in Table 2, it is obvious that the readily avail-
able Me2GaCl is suitable for the glycosidation either in
toluene, CH2Cl2, or MeCN. The solvent effect was ob-
served in this reaction; the use of CH2Cl2 or acetonitrile
resulted in relatively high b-selectivity. The reaction pro-
ceeded very slowly in acetonitrile probably because of the
coordination of the lone pair electrons of the solvent to the
gallium atom. When silylated alcohol was used instead of
free alcohol, the reaction proceeded rapidly, but no differ-
ence was observed in the yield and stereoselectivity.
Scheme 40
Silyl Compounds
Stannous(II) Chloride
Silyl compounds were employed in the reaction of glyco-
syl fluorides as a promotor by Noyori and coworkers in
1984.36 A silyl compound such as trimethylsilyl triflate
(TMSOTf) promotes the condensation of the silyl ether
and the glycosyl fluoride (Scheme 38). Even if the reagent
is weakly toxic, it is suitable for a large-scale reaction.
Stannous(II) chloride was used first as an activator of the
glycosyl fluoride with a combination of silver salts in
1981 by Mukaiyama and coworkers for the O-
glycosydation39 (Scheme 41).
Scheme 41
Scheme 38

June 1998
Chemistry of Glycosyl Fluorides
807
The fluoride 78 derived from L-fucose was easily reacted Usually, the stannous salt needs a coactivator such as a sil-
with the acceptor glycoside 79 in the presence of SnCl2/
AgClO4 to afford the corresponding disaccharide 80 in
57% yield with only an a-anomer40 (Scheme 42). After
deacetylation followed by methylation, the compound 80
was converted into the skeleton of polycavernoside A.
ver salt so that the reaction proceeds smoothly. Some re-
searchers reported the results achieved on changing the
coactivators to improve the stereoselectivity and the yield.
Thus, the b-selective coupling of mannosides encountered
a problem, namely that the mannoside disfavored stereo-
electronically b-linkage formation, although the desired
b-mannoside 87 could be synthesized as a major product
from a-mannosyl fluoride 13 by changing the
coactivator43 (Scheme 45, Table 3).
Scheme 42
The preparation of sialic acid derivatives is a difficult prob-
lem. To overcome the difficulty, the reaction of N-acetyl-
neuraminic acid derivatives with glycosyl fluoride was
performed in the presence of SnCl2/AgOTf by Ogawa and
coworkers.41 The reaction led to the O-glycoside 83 with
an a-isomer as the major product (Scheme 43). When Et2O
was used as solvent, the reaction proceeded with lower
yield (56%) and lower stereoselectivity (a/b = 87:13).
Scheme 45
Table 3. Effect of Coactivator in the Preparation of 85 (Scheme 45)
Entry
Coactivator
Yield (%)
a/b
1
2
3
4
5
BF3·OEt
80
54
25
85
99
39:61
76:24
40:60
29:71
27:73
TiCl4
Yb(OTf)3
La(ClO4)3·nH2O
La(ClO4)3·nH2Oa
a 2.4 equiv of Sn(OTf)2 was used.
As shown in Table 3, the combination of Sn(OTf)2 and
La(ClO4)3·nH2O as a coactivator was the most effective
promoter for b-mannosylation. When SnCl2 was em-
ployed in place of Sn(OTf)2, the yield decreased to 47%
with poor selectivity (a/b = 46:54).
Scheme 43
Kunz and coworkers also synthesized N-acetylneuraminic
acid derivatives by using O-acetylated glycosyl fluo- O-Glycosidation Under SnCl2/AgClO4 System; General Proce-
dure:39
ride.42 The fluoride 84 activated by BF3·OEt2 in dichlo-
To a mixture of stannous chloride (0.2 mmol), silver perchlorate
(0.2 mmol), and molecular sieves 4A was added an ether solution
(4 ml) of the alcohol (0.17 mmol) and the glycosyl fluoride (0.2 mmol)
at –15 °C and the reaction mixture was stirred at the same temperature
romethane reacted with the alcohol 82 to form
preferentially the disaccharide 85 with the b-configura-
tion (a/b = 17:83, Scheme 44).
for 24 h. After filtration, the filtrate was washed with aqueous sodium
bicarbonate, dried over Na2SO4 and evaporated. The purification of the
residue by TLC (silica gel) gave the desired compound.
Rare Earth Metal Salts
Recently, rare earth metal salts were reported as Lewis ac-
ids to promote the reaction of glycosyl fluorides due to the
large dissociation energies of rare earth metals–fluorine.44
(Scheme 46)
Scheme 46
Scheme 44

808
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
To investigate their characteristics, various kinds of rare
earth metal salts were used45,46 The reaction of the flu-
oride 2b with silylated or free alcohol 88 revealed their re-
activity and stereoselectivity (Scheme 47, Table 4). It is
noteworthy that the glycosidation did not proceed in
the presence of Gd(ClO4)3·nH2O, Ho(ClO4)3·nH2O,
Yb(ClO4)3·nH2O, and Y(ClO4)3·nH2O. This fact sug-
gests that the rare earth perchlorates with a certain range
of ionic radii can act as effective activators. When silylat-
ed or free alcohol was examined for the glycosidation, the
silylated alcohol proved more favourable. Furthermore,
when Et2O was used instead of MeCN as a solvent, the
glycosidation was turned to a-selectivity.
Scheme 48
Scheme 49
Scheme 50
Scheme 47
Table 4. Influence of Rare Earth Metal Salts in the Reaction of 2b
with 88 (Scheme 47)
Entry Ln(ClO4)3·nH2O
R
Solvent Yield (%) a/b
1
2
3
4
5
6
7
La(ClO4)3·nH2O
Ce(ClO4)3·nH2O
Pr(ClO4)3·nH2O
Eu(ClO4)3·nH2O
Yb(OTf)3
La(OTf)3
La(ClO4)3·nH2O
TMS
TMS
TMS
TMS
H
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Et2O
82
89
80
61
63
36
94
8:92
b
b
15:85
6:94
b
attack of Et2O coordinated with TiF4 in an SN2-like man-
ner followed by a second attack of the nucleophile from
the a-face. In the case of hexane, the nucleophile attacks
the anomeric carbon as coordinated only by TiF4 in an
SN2 mechanism to give rise to the b-isomer.
H
TMS
a
O-GlycosidationwithRareEarthMetalSalts;GeneralProcedure:46
An activator (a rare earth metal salt, 1.2 equiv to a glycosyl donor),
and an inorganic base (4.0 equiv of K2CO3 or CaCO3) and molecular
sieves 4Å were dried at ca. 110 °C under vacuum for 2 h. A solution
(1 mL) of glycosyl fluoride (0.055 mmol) and glycosyl acceptor
(1.2 equiv) was then added. After the reaction was complete, sat. aq
NaHCO3 solution was added and filtered. The usual workup with the
filtrate gave a product which was purified by silica gel column chro-
matography.
Bis(cyclopentadienyl)metal Derivatives
Group IVB metallocenes (Cp2MCl2 ; M = Ti, Zr, Hf) were
presented by Suzuki and coworkers as a mild activator of
glycosyl fluorides in 1988.16, 17 The reagent itself is inert
as an activator. Nevertheless, the addition of an equimolar
amount of AgClO4 proceeds the reaction smoothly
(Scheme 51). The activation mechanism can be explained
by the cationic complex (A) which may act as a highly flu-
orophilic species as illustrated in Scheme 52.
Titanium Tetrafluoride
The stereoselective coupling of 2-deoxy glycosyl fluoride
was carried out with use of TiF4 as a catalyst in 1986.47
When the glycosyl fluoride 58 was allowed to react with
sugar 82 in the presence of TiF4 in Et2O, the reaction pro-
ceeded in an a-selective manner (a/b = 83:17). However,
when the reaction was performed in hexane, a b-isomer of
the disaccharide 89 was obtained as the major product (a/
b = 40:60)48 (Scheme 48).
Scheme 51
Their reactivities were examined by using cyclohexyl-
methanol as the model compound (Scheme 53).
These facts can be explained by the coordination of the
solvent or nucleophile to TiF4 as shown in Schemes 49
and 50. With Et2O as a solvent, the reaction starts with the
The rough order of their reactivities was found to be Zr =
Hf > Ti. The stereoselectivity of the Zr-system relied on

June 1998
Chemistry of Glycosyl Fluorides
809
94, the reaction gave rise to the desired O-glycoside 95 to-
gether with 5% of C-glycoside, 2-(2,3,5-tri-O-methyl-D-
ribofuranosyl)phenol.
To achieve a-selective glycosidation of perbenzylated D-
mannosyl fluoride, the coactivator of Cp2ZrCl was im-
proved.50 The system of Cp2ZrCl/AgBF4 was found to be
more effective in benzene as the most preferable solvent.
The reaction of the fluoride 13 with the alcohol 82 was ex-
amined in the presence of AgBF4 or AgClO4 as a common
coactivator (Scheme 55). Compared with AgClO4, AgBF4
increased the yield of 96 from 56% to 92% and the a-se-
lectivity to a/b = 96:4.
Scheme 52
Scheme 53
the solvent. For example, Et2O showed a-selectivity and
benzene showed b-selectivity as described for titanium
tetrafluoride.
Scheme 55
Cp2MCl2/AgClO4-Promoted Glycosidation; General Proce-
dure:16
Indeed, this reagent can be applied to various sugars. The
combination of Cp2HfCl2/AgClO4 was allowed to react To a mixture of glycosyl fluoride (0.0542 mmol), alcohol (2 equiv)
with four types of sugars49 (Scheme 54, Table 5).
and powdered molecular sieves (4Å) in CH2Cl2 (2.5 mL) was added
Cp2MCl2 (5 equiv) followed by AgClO4 (5 equiv). After the addition
of sat. aq NaHCO3 solution and filtration through a Celite pad, the
mixture was extractively worked up. Purification by TLC (eluent,
hexane/Et2O = 1:1) gave the corresponding glycoside.
3.1.2 Triflic Anhydride
Among the Lewis acids used for the glycosidation of gly-
cosyl fluorides, triflates are indispensable. Therefore,
some triflates were examined to compare their reactivities
for the glycosidation with an unreactive glycosyl accep-
tor.51 As shown in Scheme 56, trimethylsilyl triflate, stan-
Scheme 54
Table 5. Compounds 91–93, 95 Prepared
Entry
Fluoride
Temp (°C)
Product Yield (%) a/b
1
2
3
4
2a
13
31
94
–78 to –30
–78 to –20
0 to r.t.
91
92
93
95
82
90
93
74a
48:52
a
69:3l
24:76
–78
a 5% of C-glycoside was isolated.
As for the perbenzylated fluorides 2a and 13, the reaction
proceeded cleanly at –30°C with high yield. In addition, a
characteristic of this reagent that the anomeric activation
was not interrupted by the basic amino group was re-
vealed in this study (Entry 3, Table 5). With use of pentose
Scheme 56

810
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
nous chloride / silver triflate, and titanium tetrafluoride
were compared in synthesis of trisaccharide 98 under sim-
ilar conditions. The reaction occurred in a Königs–Knorr
manner to suggest the relative reactivity (TMSOTf <
SnCl2/AgClO4 ≤ Tif4 < TfOTf).
3.1.3 Enzymes
Cellulase
Many efforts have been dedicated to the stereoselective
preparation of cellulose having a b-(1 ® 4) glycosidic
linkage. In the 1990s a novel method for synthesis of oli-
gosaccharide using cellulase was devised, From several
studies, the most suitable conditions were determined by
changing the solvents, enzymes, and concentration.52–55
By exposure to cellulase (from Trichoderma viride), elon-
gation of the disaccharide 99 was carried out with com-
plete stereoselectivity (Scheme 57). As the starting
material, the disaccharide 99 was chosen because the
smallest subunit recognized by the enzyme may be a dis-
accharide. In addition, the b-fluoride 99 was employed as
the starting material in order to form a b-(1 ® 4) linkage
via a “double displacement mechanism” on the active site
of the enzyme as shown in Figure 1. With respect to the
monosaccharide acceptor, sugars with an axial group at
the 1 or 3 position were not suitable for this method, be-
cause the axial group prevents the binding to the enzyme.
Scheme 58
1,3-1,4-b-Glucanase
Scheme 57
Enzymatic synthesis of b-D-glucooligosaccharide was re-
ported in 1997 by reacting glycosyl fluoride with 1,3-1,4-
b-glucanase.57 In maleate buffer/MeCN (2:3), the reaction
of b-laminaribiosyl fluoride (106) with methyl glycoside
(107) occurred to afford tetrasaccharide 108. Next, the re-
action mixture was fully acetylated and purification gave
the compound 109 in 46% yield. Treatment of 109 with
Figure 1. Double Displacement Mechanism on the Active Site of the
Enzyme.
Cyclodextrin Glucosyltransferase (CGTase)
Glycosyl fluoride can also be a good substrate for cyclo-
dextrin glycosyltransferase (CGTase).56 The reaction
starts with incubation of the glycosyl fluoride and CGTase
for 20 hours. By treatment with enzyme, 6¢-O-methylmal-
tosyl fluoride (102) could be converted into a-cyclodex-
trin (103) in 42 % yield together with b-cyclodextrin
(104) and g-cyclodextrin (105) in 16 and 13% yields, re-
spectively (Scheme 58).
Scheme 59

June 1998
Chemistry of Glycosyl Fluorides
811
MeONa in MeOH provided the free methyl tetrasaccha-
ride 108 in 40% overall yield (Scheme 59).
The reaction mechanism is presented in Scheme 60. Gly-
cosidation takes place on the free b-face followed by eli-
mination of enzyme.
Scheme 61
Table 6. Compounds 110–112 Prepareda
Entry Fluoride Accep- Activator Temp (°C) Prod- Yield (%)
tor
uct
(–78 to T)
(a/b)
1
2
3
94
a
BF3·OEt2 – 5
SnCl2 –10
Cp2HfCl2/ –20
AgClO4
110 45 (83:17)
110 51 (80:20)
110 71 (7:93)
(a/b = 50/50)
Ref. 58
4
5
94
(b)
Ref. 59
b
BF3·OEt2 –10
111 81 (6:94)
112 11 (b)
Cp2HfCl2/ –10
AgClO4
111 83 (6:94)
112
8 (b)
a
is suited for this reaction rather than SnCl2. The reaction
with Cp2HfCl2/AgClO4 gave exclusively b-C-glycoside as
the major product. In Entries 4 and 5, the formation of a
small amount of regioisomer 112 by the direct Friedel–
Crafts type coupling (not via the rearrangement) is noted.
Scheme 60
As an extension of this study, total synthesis of Vineomy-
cine B2 methyl ester (115) was performed using this meth-
od.60 In the step of C-glycosidation, Cp2HfCl2/AgClO4
was employed with reference to the results in Table 6
(Scheme 62).
3.2 C–C Bond Formation
Recently, C–C bond formation of glycosides, the so-
called C-glycosidation, has attracted much attention
among chemists and biologists. Since C-glycosides such
as showdomycin have been isolated from nature and
showed biological activities as an antitumor and antivirus
agent, a highly stereoselective and efficient method for
the synthesis of C-glycoside has been strongly desired.
3.2.1 Lewis acids
In the same manner as C–O bond formation with Lewis
acids, C-glycosidation can proceed with Lewis acids. It
was observed that C-glycosidation took place via the rear-
rangement of O-glycoside under Lewis acids.58 The two-
step process is as follows: The O-glycosidation proceeded
rapidly at –78 °C within 10 minutes in standard operation
and, after the formation of O-glycoside, gradual warming
results in the formation of C-glycoside via rearrangement.
As shown in Scheme 61 (Table 6), it is evident that
BF3·OEt2 is totally ineffective and that Cp2HfCl2/AgClO4
Scheme 62

812
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
When 1,2-difluorocarbohydrate was used as the sugar do- yield in EtCN, the use of CH2Cl2/EtCN (Entry 3, Table 7)
nor, both O-glycosidation and C-glycosidation occurred resulted in a-selectivity with good yield. As a general ten-
at the same time under specific conditions.61 The products dency of the reaction temperature, a high temperature
depended on the equivalent of the used alcohol (Scheme gave the b-isomer while a low temperature gave the a-iso-
63). By treatment with 2 equivalents of benzyl alcohol, mer. The relation between temperature and stereoselectiv-
the isochroman derivative 117 was derived from difluoro- ity was investigated in detail with use of EtNO2. When the
sugar 116 in 70% yield. However, with 5 equivalents of reaction was performed at –78 °C, the ratio of a/b was
alcohol, tribenzyl compound 118 was obtained in 26% 86:14. However, with warming up, the ratio turned to 9:91
yield together with the cyclic compound 117 (25%). which showed an equilibrium value at –15 °C.
From these results, it is implied that an oxocarbenium ion
is produced when the OBn group attaches to the carbon at 3.2.2 Metal Reagents
position 2. Furthermore, tribenzyl product 118 was ob-
The reactions between glycosyl fluoride and metal re-
tained as the only product by reaction with 10 equivalents
agents without Lewis acids were reported. The aluminated
of PhCH2OH.
furan was allowed to react with 2,3,4,6-tetra-O-benzyl-D-
glucopyranosyl fluoride 2 to give the corresponding C-
glycoside 120 in moderate yield63 (Scheme 65).
Scheme 65
Scheme 63
The reaction of the fluoride 2 and the aluminated furan
Further, the stereocontrolled glycosidation reaction was
proceeded b-dominantly with the ratio of a/b = 29:71,
demonstrated by changing solvents and temperature in the
while the a-isomer of 2 gave the product 120 with a/b =
presence of BF3·OEt2.62 The reaction of 2,3,5-tri-O-ben-
75:25. Judging from these results, it can be said that the
zylribofuranosyl fluoride (22a) with N-phenylsulfonylin-
oxocarbenium ion is not an intermediate in this reaction.
dole in CH2Cl2 led to the corresponding C-nucleoside 119
with b-selectivity (Scheme 64, Table 7).
Grignard reagents can also react with glycosyl fluorides
easily without activators to afford C-glycosides64 (Scheme
66, Table 8). First, the reaction of b-fluoride 22a with 2-
thienylmagnesium bromide (121a) was achieved to yield
b- C-nucleoside 122a, predominantly. Since the same re-
sult was observed for both a- and b- fluorides, the ano-
meric configuration of 22 was not important in this
reaction. This result implies that the reaction proceeds
via the oxocarbenium ion as an intermediate. On the oth-
er hand, cadmium and zinc salts of thiophene did not ex-
hibit better results. In addition, the reaction did not
proceed in the presence of a Lewis acid.
Scheme 64
Table 7. Effect of Solvent on the Preparation of 119 (Scheme 64)
Entry Solvent
Temp (°C)
Yield (%) a/b
1
2
3
4
5
6
7
8
CH2Cl2
EtCN
CH2Cl2/EtCN (2.5%)
Et2NO2
Et2NO2
Et2NO2
Et2NO2
Et2NO2
–15
0
96
23
72
74
96
93
99
94
11:89
80:20
91:9
86:14
71:29
41:59
9:91
–78
–78
–60
–50
–40
–15
Scheme 66
9:91
Next, the introduction of benzene derivatives was exam-
ined. In contrast to thiophene, Grignard reagents of ben-
zene derivatives gave the expected C-glycosides 122
together with glycal 123 as shown in Table 8. It is noted
In contrast to CH2Cl2, the a-isomer of 119 was predomi-
nantly obtained with EtCN as a solvent. This result is
probably attributed to its affinity to the oxocarbenium ion
formed as an intermediate in this reaction. To improve the

June 1998
Chemistry of Glycosyl Fluorides
813
Table 8. Compounds 122, 123 Prepared
Entry Ar in 121
Temp (°C)
Yield (%)
a:b
122
123
1
2
3
4
5
2-thiophenyl
Ph
4-ClC6H4
4-MeOC6H4
1-naphthyl
r.t.
50
50
50
50
65
57
67
45
54
0
29
0
51
0
8/92
b
b
b
b
Scheme 68
that the yield of the glycal was increased along with the was formed predominantly in 79% yield (Scheme 69).
benzene derivatives bearing a strong electron-donating Compared with Cp2HfCl2, Cp2ZrCl2 was less reactive in
group. Furthermore, the benzyl-protected glycosyl fluo- this reaction. The reaction proceeds via an oxocarbenium
ride 2 was allowed to react with allyl magnesium chloride ion as an intermediate, since the same result was also ob-
to afford the C-glycoside 124 (a / b = 35 / 65) in 77% tained by use of the a-isomer of the starting material. In
yield (Scheme 67).
addition, with Ac or Bz groups in place of a Bn group as
O-protection, the fluoride 22 was inert against uracil de-
rivative 127.
Scheme 67
Coupling of Glycosyl Fluoride with Grignard Reagents; General
Procedure:64
To a solution of glycosyl fluoride (0.15 mmol) in THF (2 mL) was
added freshly prepared Grignard reagent (5 equiv) and the resulting
mixture was warmed up to 50°C. After the reaction was complete,
H2O was added and the mixture extracted with CHCl3. The organic
phase was dried (Na2SO4)and evaporated. Purification (2 times) by
preparative TLC (eluent; toluene/EtOAc, 40:1) afforded the desired
C-glycoside.
Scheme 69
In further investigation, silylated uracil 127 was intro-
duced to the vicinal difluorocompound 129 under the
same conditions. The coupling led to N-glycoside 130 in
85% yield with the ratio of a/b = 87:13 (Scheme 70).
3.3 C–N, C–S Bond Formation
C–N bond formation has been performed widely by use of
glycosyl fluorides, because the nucleosides in DNA are
composed of a C–N bond between the sugar and base moi-
eties. S-Glycosylation as well as N-glycosylation has been
utilized with glycosyl fluorides as sugar donors in total
synthesis of natural products.
3.3.1 Lewis Acids
Most C–N and C–S bond formations can be accomplished
in the presence of Lewis acids. A silylated adenine deriv-
ative was introduced to the glycosyl fluoride 125 by treat-
ment of a catalytic amount of SiF4 in good yield65
(Scheme 68). When other Lewis acids were employed in
place of SiF4, larger amounts of the activators were re-
quired to obtain high yields.
Scheme 70
Moreover, a stereocontrolled thioglycosidation was car-
ried out by changing the Lewis acid.68 When TiF4 was em-
ployed, the reaction proceeded with b-selectively at 0°C
in MeCN. On the other hand, the use of BF3·OEt2 as an
activator changed the reaction into an a-dominant manner
(Scheme 71).
Metallocene derivatives (Cp2MCl2/AgX; M = Hf, Zr, X =
ClO4, OTf) could promote C–N bond formation of glyco-
syl fluorides.66, 67 When the benzyl-protected ribosyl fluo-
ride was allowed to react with silylated uracil by the
activation of Cp2HfCl2/AgOTf, the b-N-nucleoside 128

814
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
Scheme 71
3.3.2 Metal Reagents
Glycosyl isocyanide can be converted into a wide variety
of derivatives. Many studies have been devoted to form
the glycosyl isocyanide. Using an aluminum reagent, the
synthesis of glycosyl isocyanide was achieved.69 By expo-
sure to diethylaluminum cyanide, mannosyl fluoride 15a
was converted into the corresponding glycosyl isocyanide
132 along with the byproduct, C-glycosyl cyanide 133
(Scheme 72).
Scheme 72
Scheme 73
4. Total Synthesis of Natural Products
Glycosyl fluorides are versatile sugar donors on account
of their stability and ease of handling compared with other
sugar halides. Consequently, they have been utilized for
the total synthesis of natural products. In total synthesis,
most sugar fluorides are allowed to react with acceptors in
the presence of Lewis acids such as Cp2MCl2/AgX (M =
Hf, Zr; X = ClO4, OTf), SnCl2/AgX (X = ClO4, OTf), and
BF3·OEt2.
4.1 BF3·OEt2
Lipopolysaccharide (LPS) derivative was constructed
from a trisaccharide intermediate 134.70 After deprotec-
tion of 134, alcohol 135 was connected to the glycosyl flu-
oride 136 in the presence of BF3·OEt2 to give the
tetrasaccharide 137, ready for deprotection to convert into
the expected LPS derivative 138 (Scheme 73).
Further, the synthetic method of D-myo-inositol mono-
mannnoside was reported using BF3·OEt2 as a catalyst.71
The glycosidation of glycosyl fluoride 75 with a protected
inositol acceptor was carried out in the presence of
BF3·OEt2 to give diastereoisomers of 139 in 97% yield,
which were then deprotected and separated by chromatog-
raphy. The following 5-step treatment provided the D-
myo-inositol monomannnoside 140 (Scheme 74).
Scheme 74
4.2 SnCl2/AgX (X = ClO4, OTf)
Sialyl Lewis X antigenic determinant (SLeX) has drawn
wide attention and many studies have been carried out on
the total synthesis of SLeX. Nicolaou and coworkers re-

June 1998
Chemistry of Glycosyl Fluorides
815
ported the total synthesis of trimeric LeX in 1990.72 Here,
only the construction of the basic framework is introduced
(Scheme 75). The coupling of galactosyl fluoride 141
with the sugar acceptor as shown in Scheme 75 under
SnCl2/AgClO4 system gave stereospecifically the corre-
sponding b-glycoside, which was deprotected to be disac-
charide 142. Further glycosidation took place with the
glycosyl fluoride 59 to give the basic skeleton 143, from
which the expected trimeric LeX was synthesized.
Scheme 76
Scheme 75
In addition, sialyl dimeric LeX was synthesized from 144
using Cp2HfCl2/AgOTf system73 (Scheme 76). The fluo-
ride 144 was converted into trihydroxy compound 145.
The 5-step dimerization of the LeX skeleton was carried
out with use of Cp2HfCl2/AgOTf as a catalyst to give the
compound 146. Similarly, the fluoride 146 was allowed to
react with 147 to give 148 in 51% yield.
As an extension of this study, the synthetic strategy of the
framework was improved.74 The fluoride 149 derived
from D-glucosamine was allowed to react with a glycosyl
acceptor in the presence of SnCl2/AgClO4 to form ste-
reospecifically b-linked glycoside 150, which was then
deprotected to give the compound 151. The glycosidation
reactions with the fluoride 152 and 151 gave 153, which
was converted to LeX framework 154 by coupling with 59
(Scheme 77).
On the other hand, Danishefsky and his coworkers applied
the glycals for the total synthesis of SLex.75 The coupling
of tri-O-benzyl fucosyl fluoride 59 with glycal 155 using
SnCl2/AgClO4 as an activator provide disaccharide 156 in
50 % yield together with 40 % of two isomers. Two gly-
cosidations on the disaccharide 156 led to the formation of
Scheme 77

816
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
a key intermediate, tetrasaccharide glycal 157. After 4
steps of treatments, SLeX 158 was entirely synthesized
(Scheme 78).
Scheme 79
Scheme 78
Moreover, Kunz and coworkers reported the total syn-
thesis of trimeric LeX.76 They synthesized oligosaccha-
ride chain at first using repeated chain extension with
glycosyl fluorides (Scheme 79). Subsequent introduc-
tion of the a-fucoside branchings achieved the total syn-
thesis. The lactosaminyl fluoride 159 derived from the
corresponding triazole reacted with the disaccharide in
the presence of BF3·OEt2 to afford a tetrasaccharide
160. Two glycosylation reactions of glycosyl fluorides
followed by a-fucosylation gave the desired trimeric
LeX 162.
In this context, Wong and coworkers designed 164 and
166 as the model compounds of SLeX.77,78 The sugar lac-
tone shown in Scheme 80 reacted with 59 under SnCl2/
AgClO4 system to afford disaccharide 163 in 58% yield
along with its b-anomer (18%). The compound 163 was
deprotected to give SLeX mimetic 164.
Scheme 80
Another mimetic compound 166 was prepared as follows.
L-Fucosyl fluoride 59 was reacted with 2-azidocyclohex-
anol to give the corresponding O-glycoside, which was re- With use of a glycal compound, the total synthesis of a hu-
duced easily to give amine 165. With amidation followed man breast tumor associated antigen (MBr1 antigen) was
by deprotection, the desired compound 166 was obtained achieved.79 The coupling of fucosyl fluoride 59 with gly-
(Scheme 81).
cal 167 led to the compound 168 in 47% yield. The fol-

June 1998
Chemistry of Glycosyl Fluorides
817
Scheme 81
Scheme 83
4.3 Cp2MCl2/AgX (M = Hf Zr; X = ClO4, OTf)
Scheme 82
Oligosaccharide synthesis using Cp2HfCl2/AgClO4 by
Ogawa and coworkers is a typical pattern of the reaction
between the glycosyl fluoride and Hf reagent system.82
The general strategy is indicated in Scheme 85.
lowing 7 steps converted compound 168 into MBr1
antigen 169 (Scheme 82).
The synthesis of heptasaccharide 186 adopting this meth-
od is given in Scheme 86.82 Disaccharide 181 was derived
from thioglycoside 179 under condition a. Elongation was
carried out by the reaction of fluoride 181 with acceptor
182 in the presence of Cp2HfCl2/AgClO4 to afford trisac-
charide 183. After one-sugar-elongation, heptasaccharide
186 was constructed by the reaction of thioglycoside 183
with deacetylated fluoride 184.
The antifungal agent Sch 38546 known as fluvirucin B1
was also synthesized in SnCl2/AgClO4 system.80 Diaste-
reoselective glycosylation was carried out with the fluo-
ride 170 and diene carbinol to afford O-glycoside 171 in
92% yield. Mo-catalyzed ring closure followed by
deprotection afforded Sch 38516 (172) in good yield
(Scheme 83).
Synthesis of cyclomaltohexaose was conducted by the use
of glycosyl fluorides in 21 steps.81 The fluoride 173 was
coupled with a glycosyl donor to afford tetrasaccharide
174 and its a-isomer in 80% yield with the ratio of a/b =
64:36. After deacetylation, elongation of 175 was carried
out under SnCl2/AgOTf system to afford a key glycosyl
fluoride 177. The last glycosidation followed by deprotec-
tion was performed to give cyclohexaose 178 in 21%
yield (Scheme 84).
Further, the synthesis of pentacosasaccharide 190 was es-
tablished by using four glycosyl fluorides.83 Started with
disaccharide, all coupling reactions consisted of a glyco-
syl fluoride in the presence of Cp2Hf(OTf)2 (Scheme 87).
The biatennary heptasaccharide-asparagine conjugate
was also formed by use of Cp2HfCl2 as a catalyst.84 The
glycosyl fluoride 191 prepared from mannosyl bromide
was allowed to react with a sugar acceptor smoothly to

818
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
Scheme 86
Scheme 84
Scheme 87
A partial structure of glycophorin A was constructed in 21
steps by utilizing glycosilation of the fluoride 19485,
86(Scheme 89). The a-fluoride 194 was coupled with L-
serine derivatives using Cp2ZrCl2/AgClO4 as a promotor
in CH2Cl2 to give the a-glycoside 195 and its b-isomer.
When Cp2HfCl2 was applied in place of Cp2ZrCl2, the a-
glycoside 195 was obtained in 67% yield together with b-
isomer 196 (12%). After a 7-step-transformation disac-
charide 197 was obtained. The compound 197 was con-
densed with L-valine derivative followed by coupling
with disaccharide to give the desired partial structure of
glycopforin 198.
Scheme 85
give trisaccharide 192 in 76% yield. After a 6-step proce-
dure containing two couplings reaction of sugars, the ben-
zylated heptasaccharide-asparagine conjugate 193 was
obtained (Scheme 88).

June 1998
Chemistry of Glycosyl Fluorides
819
In this context, an effective synthetic method was devel-
oped to prepare N-terminal glycopentapeptides.87 The
glycosidation of protected L-selin 199a or L-threonine
199b with the glycosyl fluoride 194 was carried out under
Cp2ZrCl2/AgClO4 and followed by 5-step-reaction to
convert into disaccharide 197 or 201, which was then con-
jugated to N-terminal glycopentapeptides 202 (Scheme
90).
Scheme 88
Scheme 90
Suzuki and coworkers made the first total synthesis of
Mycinamicin IV 206 using Cp2MCl2/AgClO4 (M = Hf,
Zr) as promoters.88 Mycinamicin IV is comprised of two
glycosyl bonds, which needed two glycosidations for its
construction. One was achieved by Cp2HfCl2 and the oth-
er by Cp2ZrCl2 (Scheme 91).
Scheme 89

820
Miyuki Shimizu, Hideo Togo, Masataka Yokoyama
SYNTHESIS
Scheme 92
Scheme 91
Later, Suzuki and coworkers synthesized an antibiotic
BE-12406A (210) via 208, prepared by the reaction of a
naphthol derivative with glycosyl fluoride 207 under ac-
tivation of Cp2HfCl2/AgClO4.89 At the stage of O-gly-
cosidation, SnCl2/AgClO4, TMSOTf, or BF3·OEt2 was
employed in place of Cp2HfCl2/AgClO4, but they uni-
formly gave C-glycoside 209. From the result of the sol-
vent effect, halogenated aromatic solvents such as
chlorobenzene and fluorobenzene were chosen (Scheme
92).
Two total syntheses of NodRm-IV (S) were reported re-
cently. The first synthesis was achieved by Nicolaou and
coworkers in 1992.90 Starting with O-glycosidation of the
fluoride 211, the pathway included two reactions of glyc-
osyl fluorides. After the carbohydrate skeleton was com-
pleted, an alkyl chain was substituted followed by
deprotection to give the desired compound, NodRm-
IV(S) 218 (Scheme 93).
The second report is that of Ogawa and his coworkers in
1994.91 The trisaccharide 220 was obtained by the reac-
tion of monosaccharide 219 with a glycosyl donor fol-
lowed by deprotection and acetylation. The fluoride 221
was coupled with compound 220 in the presence of a
Cp2HfCl2/AgOTf system. While alkylation was demon-
strated before deprotection in Nicolaou’s strategy, Ogawa
designed a key intermediate 222 containing free OH
groups before alkylation (Scheme 94).
Scheme 93

June 1998
Chemistry of Glycosyl Fluorides
821
Scheme 94
The synthesis of hexasaccharide of glycophosphatidyl
inositol (GPI) anchor was developed using glycosyl fluo-
ride as a sugar donor.92 The fluoride 224 was converted
into compound 225 by a successive treatment of
Cp2ZrCl2/AgClO4 and deacetylation. The other fluoride
226 was coupled with derived compound 225 in the pres-
ence of Cp2ZrCl2/AgClO4 to give tetrasaccharide 227 in
69% yield along with its b-epimer (7%). After 4 steps, the
desired hexasaccharide 228 was obtained (Scheme 95).
Scheme 95
The synthesis of neohancoside A was comprised of the re-
action of linalool with a glycosyl fluoride under Cp2ZrCl2/
AgClO4.93 Glycosylation of prepared glycosyl fluoride
229 with racemic linalool led to linalyl glycoside 230 in
46 % yield. Deprotection of the chloroacetyl group, and
separation of the diastereoisomer followed by debenzoy-
lation provided monoterpene diglycoside, neohancoside
A 231 (Scheme 96).
Scheme 96
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