Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as potential inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1016/j.carres.2014.05.020

New derivatives of d-xylose with aglycons of the most efficient glucose derived inhibitors of glycogen phosphorylase were synthesized to explore the specificity of the enzyme towards the structure of the sugar part of the molecules. Thus, 2-(β-d-xylopyran

Full text of DOI:10.1016/j.carres.2014.05.020

Accepted Manuscript
Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as
potential inhibitors of glycogen phosphorylase
László Somsák, Éva Bokor, Beáta Czibere, Katalin Czifrák, Csenge Koppány,
László Kulcsár, Sándor Kun, Enikő Szilágyi, Marietta Tóth, Tibor Docsa, Pál
Gergely
PII:
S0008-6215(14)00228-6
DOI:
http://dx.doi.org/10.1016/j.carres.2014.05.020
CAR 6759
Reference:
To appear in:
Carbohydrate Research
Received Date:
Revised Date:
Accepted Date:
24 March 2014
26 May 2014
28 May 2014
Please cite this article as: Somsák, L., Bokor, É., Czibere, B., Czifrák, K., Koppány, C., Kulcsár, L., Kun, S.,
Szilágyi, E., Tóth, M., Docsa, T., Gergely, P., Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-
heterocycles as potential inhibitors of glycogen phosphorylase, Carbohydrate Research (2014), doi: http://
dx.doi.org/10.1016/j.carres.2014.05.020
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Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as
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potential inhibitors of glycogen phosphorylase
a*
a
a
a
a
László Somsák, Éva Bokor, Beáta Czibere, Katalin Czifrák, Csenge Koppány, László
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a
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b
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Kulcsár, Sándor Kun, Enikő Szilágyi, Marietta Tóth, Tibor Docsa, and Pál Gergely
a
Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen,
Hungary
b
Department of Medical Chemistry, University of Debrecen, Egyetem tér 1, H-4032
Debrecen, Hungary
Abstract
New derivatives of D-xylose with aglycons of the most efficient glucose derived inhibitors of
glycogen phosphorylase were synthesized to explore the specificity of the enzyme towards the
structure of the sugar part of the molecules. Thus, 2-(β-D-xylopyranosyl)benzimidazole and 3-
substituted-5-(β-D-xylopyranosyl)-1,2,4-triazoles were obtained in multistep procedures from
O-perbenzoylated β-D-xylopyranosyl cyanide. Cycloadditions of nitrile-oxides and O-
peracetylated exo-xylal obtained from the corresponding β-D-xylopyranosyl cyanide furnished
xylopyranosylidene-spiro-isoxazoline derivatives. Oxidative ring closure of O-peracetylated
β-D-xylopyranosyl-thiohydroximates prepared from 1-thio-β-D-xylopyranose and nitrile-
oxides gave xylopyranosylidene-spiro-oxathiazoles. The fully deprotected test compounds
were assayed against rabbit muscle glycogen phosphorylase b to show moderate inhibition for
3
-(2-naphthyl)-5-(β-D-xylopyranosyl)-1,2,4-triazole (IC = 0.9 mM) only.
50
*
Corresponding author – Tel.: +3652512900 ext. 22348, Fax: +3652512744, E-mail:
somsak.laszlo@science.unideb.hu
1

Keywords
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C-Glycosyl heterocycle; Glycosylidene-spiro-heterocycle; exo-Glycal; Xylose derivative;
Benzimidazole; 1,2,4-Triazole; Spiro-isoxazoline; Spiro-1,4,2-oxathiazole; Glycogen
phosphorylase; Inhibitor.
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1
. Introduction
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The quest for inhibitors of glycogen phosphorylases (GPs) has been based on and fuelled
1
-3
by the potential application of such compounds as medication in type II diabetes mellitus
4
,5
and also as possible therapeutic means in other diseased states like myocardial and
6,7
8-11
cerebral ischemias and tumors.
A large variety of compounds targeting one of the six binding sites of GP (catalytic,
inhibitor, allosteric, new allosteric, storage, and benzimidazole sites) have been developed to
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,12
reach the nanomolar range in their inhibitory efficiency. Catalytic site inhibitors are almost
13
exclusively glucose derivatives which have been designed and studied following the
observation that both anomeric forms of D-glucose (A and B in Chart 1) are modest inhibitors
1
4
of GP. Early inhibitor design resulted in glucopyranosylidene-spiro-hydantoins C and D
1
5,16
with low micromolar inhibition constants.
Most efficient representatives of N-
1
7,18
19-21
glucopyranosyl-1,2,3-triazoles
E and C-glucopyranosyl-benzimidazoles
F proved
similarly or somewhat less effective than the hydantoins. Among the recently designed and
synthesized 5-β-D-glucopyranosyl-3-substituted-1,2,4-triazoles submicromolar inhibitors of
22,23
GP (e. g. G) were found.
Best compounds in series of other types of anomeric spirocycles
24
25,26
like isoxazolines (e. g. H) and oxathiazoles
(e. g. I) showed inhibition approaching the
low nanomolar range. To explain the strong binding of these compounds extensive
*
interactions with the so-called β-channel of the enzyme were invoked besides the ideal fit of
1
2,13
the sugar moiety in the catalytic site.
Thus, the increasing binding strength must largely be
attributed to the aglycon part of the molecules.
Investigations into the specificity of GP towards various monosaccharides revealed that
changes in the sugar configuration or constitution resulted in a significant decrease of the
*
The β-channel of GPs is an empty space next to the active site in the direction of the β-substituent of the bound
D-glucose surrounded by amino acid side chains of both polar and apolar character.
3

inhibition: e. g. D-xylose (J) proved a ~13-60-fold weaker inhibitor in comparison to the D-
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glucose anomers A and B. Since the efficiency of the glucose derived inhibitors depended to
a large extent on the fit of the aglycon in the β-channel, the D-xylo configured analogues of
the best inhibitors were time to time synthesized and tested against GP to check if the
interactions of the aglycon might overbalance the worse binding of the ’truncated’ glycon. Up
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to now xylopyranosylidene-spiro-hydantoins K and L as well as N-(β-D-xylopyranosyl)-
,2,3-triazoles (e. g. M) together with similar derivatives of 5-thio-xylose and the related
1
2
8
cyclic sulfoxides and sulfones were studied, however, showed no significant effect against
RMGPb.
In this paper we report on the synthesis and enzymatic evaluation of xylose derived
analogues N-Q of the best glucose based inhibitors of rabbit muscle glycogen phosphorylase
b.
4

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Chart 1. Selected inhibitors of rabbit muscle glycogen phosphorylase b (RMGPb, K [μM])
i
R = CH OH
R =
H
2
R
R
14
14
1
7400
700
O
A α
B β
HO
HO
27
16
J
100 000
HO OH
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O
H
N
HO
HO
15
16
3.1
.2
C
K
11 500
HO
O
O
S
4
N
H
R
O
H
N
HO
HO
16
16
D
E
5.1
L
10 000
HO
O
N
H
Ar
Ar = 2-naphthyl
Ar = 2-naphthyl
No inhibition at
R
R
1
7
O
HO
HO
16
36
M
N
28
N
18
625 μM
HO
N
R’ = H
R'
2
0
9
1
9
HN
F
11
N
O
HO
HO
R’ = Me
N
21
HO
2.8
R
target
HN N
N
O
Ar = 2-naphthyl
HO
HO
G
H
O
P
compounds
of this work
with various
Ar groups
22,23
0.41
Ar
HO
O
R
R
HO
HO
Ar = 2-naphthyl
24
HO
0.63
Ar
Ar
O
N
O
HO
HO
Ar = 2-naphthyl
S
N
I
Q
25,26
HO
0.16
O
5

2
. Results and Discussion
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For the preparation of the desired C-xylosyl benzimidazole N, our recently published
2
1
29
reaction sequence was applied. Thus, 2,3,4-tri-O-benzoyl-β-D-xylopyranosyl cyanide (1,
Scheme 1) was hydrated to anhydro-aldonamide 2 which, on treatment by Et O·BF gave
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ethyl imidate 3. Reaction of 3 with 1,2-diamino-benzene furnished the protected
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benzimidazole 4 which was O-debenzoylated under Zemplén conditions to give the test
compound 5. Structure elucidation of the compounds was straightforward by NMR methods,
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and it is to be noted that line broadening of some resonances in the C spectra, due to fast
21
proton exchange of the two nitrogens, was observed similarly to earlier experiences.
Next, to get an intermediate for the preparation of C-xylosyl-1,2,4-triazoles O, imidate 3
2
2,31
1
was reacted with tosylhydrazine,
however, instead of the expected N -tosyl-(C-
xylopyranosyl)formamidrazone only its benzoic acid elimination product 6 could be isolated.
HN
O
O
BzO
BzO
RO
RO
R
OBz
OR
N
1
R = CN
4 R = Bz
(
80 %)
H N
2
HBr, AcOH
NaOMe,
MeOH
2
R = CONH2
H N
2
(
51 %)
Et OBF , CH Cl
2
CH Cl , 
2
2
3
4
2
5 R = H
(
81 %)
3
R = C(=NH)OEt
96 %)
(
O
BzO
NH
TsNHNH2
BzO
CH Cl
2
2
6 (27 %)
NHNHTs
Scheme 1. Some transformations starting from
O-perbenzoylated β-D-xylopyranosyl cyanide 1.
6

2
3
Therefore, we turned to an alternative route (Scheme 2) and, to this end, 1 was
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transformed to tetrazole 7 by TMSN –Bu SnO. Reactions of 7 with non-purified N-benzyl-
3
2
arenecarboximidoyl chlorides obtained from the corresponding carboxamides 8-10 gave the
O-perbenzoylated N-benzyl-1,2,4-triazoles 11-13. These compounds were first O-deprotected
30
by the Zemplén protocol or NaOH in MeOH to give 14 and 16, as well as 15, respectively,
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followed by catalytic hydrogenation to remove the N-benzyl protection to yield the test
compounds 17-19.
TMSN3
Bu SnO BzO
N NH
O
O
BzO
BzO
2
CN
N
BzO
PhCH ,
N
OBz
3
OBz
7 (91 %)
o
1
80 C
toluene
to 11
or
SOCl2
+
Cl
xylene
to 12, 13

O
Bn
Ar
N
Bn
Ar
N
H
N N
O
RO
RO
8
-10
Ar
OR
N
R'
Ar
Yield (%)
1
1
1-13 R = Bz,
R' = Bn
NaOMe,
MeOH
8
Ph
4-tBu-C H
11 14 17
68) (91) (91)
12 15* 18
(42) (63) (77)
13 16 19
(
9
0
6
4
4-16 R = H,
R' = Bn
1
2-naphthyl
H /Pd(C),
2
(
52) (76) (90)
MeOH, 
*
NaOH, MeOH, 
17-19 R = R' = H
Scheme 2. Synthesis of 3-(β-D-xylopyranosyl)-5-
substituted-1,2,4-triazoles 17-19.
*
32
The analogous O-peracetylated 5-(β-D-xylopyranosyl)tetrazole is known in the literature.
7

For the preparation of xylopyranosylidene-spiro-isoxazolines P, O-peracetylated β-D-
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xylopyranosyl cyanide 20 was transformed to the corresponding anhydro-aldose
3
5,36
37
tosylhydrazone 21 by applying our published method.
Bamford-Stevens reaction of 21
3
5,38
was performed by thermal decomposition of the intermediate salt
to give exo-xylal 22 in
39
excellent yield. 1,3-Dipolar cycloadditon of 22 and nitrile-oxides, generated in situ by
1
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bleach oxidation of the corresponding aromatic aldoximes, gave stereoselectively the
30
protected spiro-isoxazolines 23-28, which were O-deacetylated under Zemplén conditions to
obtain the test compounds 29-34. The configuration of the spiro-carbon was proven by
Nuclear Overhauser Effect (NOE) difference spectra showing spatial vicinity of the
isoxazoline methylene protons with H-2’ (but not with H-3’ and H-5’) of the sugar ring.
Similar exclusive stereoselectivity was observed in the formation of the glucose-derived
24
isoxazolines (Chart 1, H).
TsNHNH2
Raney-Ni
O
O
H
O
AcO
AcO
AcO
AcO
NaH
AcO
AcO
CN
N
N
Ts
1
,4-dioxane, 
OAc
NaH2PO2
OAc
OAc
22 (99 %)
H O, AcOH,
pyridine
2
2
0
21 (63 %)
Ar-CH=NOH
NaOCl, THF
Ar
Ph 4-tBu-C H 4-CF -C H 1-naphthyl 2-naphthyl 2-benzothiazolyl
6
4
3
6 4
Yield 23
(%) (74)
24
(67)
30
25
(57)
31
26
(60)
32
27
(44)
33
28
(71)
34
O
RO
RO
RO
Ar
2
(
9
90)
O
N
(98)
(91)
(79)
(85)
(65)
23-28 R = Ac
NaOMe, MeOH
2
9-34 R = H
Scheme 3. Synthesis of D-xylopyranosylidene-spiro-isoxazolines 29-34.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Synthesis of the xylopyranosylidene-spiro-oxathiazoles Q was started by the conversion
41
of O-peracetylated 1-thio-β-D-xylopyranose 35 to S-β-D-xylopyranosyl thiohydroximates
4
2
36-38 (Scheme 4). One of the generally applied methods to get S-glycosyl thiohydroximates
8

is the reaction of the corresponding 1-thio-sugars with nitrile-oxides. In addition to the above
mentioned oxidative processes, a frequently used way to obtain nitrile-oxides in situ is the
base-induced dehydrohalogenation of hydroximoyl halides which are isolable after
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halogenation (by e. g. Cl , NCS, or NBS) of aldoximes. Because of the sensitivity of thiols
2
to oxidation, nitrile oxides were generated from hydroximoyl chlorides by Et N (method a in
3
1
1
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Scheme 4) in the presence of 35. A recently reported procedure to perform the chlorination
and HCl elimination in one continuous operation (method b), suggested to be superior
4
3
especially for the preparation of glycosyl thiohydroximates, was also studied. Although both
methods gave good yields of the expected products 36-38, in our hands the conventional
dehydrochlorination of the isolated hydroximoyl chlorides gave better results (compare yields
for methods a and b in Scheme 4). Thiohydroximates 36-38 were deacetylated by the
3
0
Zemplén method to give the test compounds 39-41.
Ring closure of the thiohydroximates was effected by NBS under irradiation as reported
26,44,45
for the preparation of several glycoenzyme inhibitors of this spiro-oxathiazole type.
Expectedly, the formation of two spiro epimers was observed, however, in contrast to earlier
findings with hexopyranose derived compounds where the anomeric configuration of the
thiohydroximate was retained in the major cyclised product, in these reactions compounds of
the inverted configuration 42-44 were isolated as the main products. The minor products 45
and 47 having the same spiro configuration (1’S) as the glucose-derived inhibitors I in Chart 1
3
0
were deacetylated under Zemplén conditions to obtain the test compounds 48 and 49.
9

a) Ar-C(Cl)=NOH
Et N, CH Cl
3
2
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Yield (%)
O
or
O
AcO
AcO
RO
SH
S
Ar
RO
Ar Ph 1-naphthyl 2-naphthyl
OAc
b) Ar-CH=NOH
OR
NaOCl, Et N,
N
3
35
36-38 R = Ac
36
a) (63)
b) (62)
39
37
(83)
(68)
40
(98)
43
(23)
46
(7)
38
(91)
(77)
41
(92)
44
(32)
47
(12)
49
CH Cl
2
2
OH
NaOMe,
MeOH
NBS
CHCl3
h
39-41 R = H
(89)
42
(31)
45
(7)
48
(70)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
O
O
AcO
AcO
RO
O
+
S
RO
(60)
AcO
N
RO
Ar
48, 49 R = H
S
O
N
Ar
NaOMe
MeOH
42-44
45-47 R = Ac
Scheme 4. Synthesis of D-xylopyranosylidene-spiro-oxathiazoles 42-49.
Structural elucidation of the xylopyranosylidene-spiro-oxathiazoles 42-47 was based on
comparisons of their NMR spectral and optical rotation data to those of the D-gluco
counterparts where at least for one compound (I Ar = Ph in Chart 1) the structure was
4
4
determined by X-ray crystallography. For 42-47 the presence of a xylopyranose ring in the
4
1
C conformation was deduced from the vicinal coupling constants in the H NMR spectra. To
1
establish the configuration of the spiro centre, characteristic differences observed for the 1’R
and 1’S epimers of the D-gluco derivatives (Table 1, 50, 51, and 52, 53, respectively) were
sought for in the data of the D-xylo compounds. Thus, for the D-gluco configured epimeric
pairs 50, 51, and 52, 53 the change of the spiro configuration had practically no influence on
the chemical shifts of the H-2’ and H-4’ protons, but H-3’ and H-5’ showed ~0.5 and ~0.3
ppm difference, respectively, depending on the presence of an axial S vs. O atom in the spiro-
heterocycle. The same tendency was also present in the chemical shift values of the respective
protons of the D-xylo derivatives 42-44 vs. 45-47. The chemical shifts for the spiro carbons
were consistently higher for the 1’R than for the 1’S compounds in both series. Finally, the
1
0

1
’R derivatives were significantly more dextrorotatory than the 1’S compounds. The spiro
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
configurations were assigned by utilizing these coincidences.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
1
1

1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Table 1. Selected spectral data for spiro-oxathiazoles of D-glucose and D-xylose
R
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
O 1'
R
AcO
AcO
5'
O 1' S
AcO
O
AcO
AcO
5
'
'
3' AcO
N
3
S
Ar
O
N
Ar
1
’R
1’S
R = CH OAc
R = CH OAc

R = H
Ph
R = H
2
2
Ar
1-naphthyl
2-naphthyl
Ph
1-naphthyl
Ph
(45)
1-naphthyl
2-naphthyl Ph
1-naphthyl
(53)
(Compound) (42)
(43)
(44)
(50)
(51)
(46)
5.59
5.68
5.14
4.11
4.06
(47)
5.60
5.66
5.15
4.07
4.02
122.6
+61
(52)
H-2’
H-3’
H-4’
H-5’ax
H-5’eq
C-1’
5.52
5.13
5.07
3.79
4.19
126.6
+178
5.58
5.15
5.10
3.85
4.28
125.8
+151
5.56
5.17
5.11
3.83
4.22
126.7
+182
5.60
5.10
5.27
4.10
-
5.66
5.13
5.29
4.18
-
5.56
5.62
5.12
4.04
4.00
5.63
5.63
5.27
4.42
-
5.67
5.67
5.29
4.51
-
127.3
+179
126.3
+99
122.6 121.9
+78 +73
122.4
+53
121.8
+44
[
α]D
Data taken from ref.44
1
2

Enzymatic evaluation of the deprotected compounds against rabbit muscle glycogen
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
6
phosphorylase b (RMGPb) was carried out as described before. All but one of the
deprotected xylose derivatives had no inhibition at 625 μM concentration. The only
compound of the series having a moderate effect was 3-(2-naphthyl)-5-(β-D-xylopyranosyl)-
46
1
,2,4-triazole (19) with an IC value of 900 μM (calculated K = 491 μM). This inhibition is
5
0
i
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
more than three orders of magnitude weaker than that of the D-gluco counterpart (G in Chart
, K = 0.41 μM). However, a comparison of the ratio of inhibitor constants for the xylo/gluco
1
i
hydantoins (Chart 1, compounds K/C ~2800-3800), thiohydantoins (Chart 1, compounds L/D
2300), and 3-(2-naphthyl)-1,2,4-triazoles (Chart 1, compounds O(= 19)/G ~1200) shows a
~
clear tendency in making the binding stronger by the aglycons which fit better in the β-
channel. Although the findings reveal that the aglycons in these xylose derived compounds
(
provided that they indeed bind to the catalytic site of GP) still have no strong enough
interactions to fully overcompensate the loss of the CH OH side chain of the sugar moiety,
2
the above tendency may foreshadow much more efficient xylose-derived inhibitors of GP.
In conclusion, new C-xylopyranosyl benzimidazole and 1,2,4-triazoles as well as
xylopyranosylidene-spiro-isoxazolines and -oxathiazoles were prepared by adapting
procedures used for the syntheses of analogous glucose-derived inhibitors of glycogen
phosphorylase. Evaluation of the compounds as inhibitors of rabbit muscle glycogen
phosphorylase b showed very weak inhibition for 3-(2-naphthyl)-5-(β-D-xylopyranosyl)-
1
,2,4-triazole only, while all other compounds proved ineffective in a concentration of 625
μM. These observations show that the aglycons rendering their glucose derivatives to
nanomolar inhibitors, are not yet capable to completely override the effect of losing the side
chain of the glucose moiety. Nevertheless, the increase in the binding strength of the xylose
derivatives with the more efficient aglycons may predict strongly binding inhibitors derived
from sugars other than glucose.
1
3

1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
3
3
. Experimental
.1. General methods
Melting points were measured on a Kofler hot-stage and are uncorrected. Optical rotations
were determined with a Perkin–Elmer 241 polarimeter at rt. NMR spectra were recorded with
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
1
13
a Bruker 360 (360/90 MHz for H/ C) spectrometer. Chemical shifts are referenced to Me Si
4
1
13
(
H), or to the residual solvent signals ( C). Microanalyses were performed on an Elementar
Vario Micro cube instrument. ESI-MS spectra were measured with a Thermo Scientific LTQ
XL spectrometer. TLC was performed on DC-Alurolle Kieselgel 60 F254 (Merck) plates,
visualized under UV light and by gentle heating. For column chromatography Kieselgel 60
(Merck, particle size 0.063-0.200 mm) was used. CH Cl , CHCl , toluene and m-xylene were
2 2 3
distilled from P O and stored over 4 Å molecular sieves or sodium wires. MeOH was
4
10
purified by distillation after refluxing for a couple of hours with magnesium turnings and
iodine. 1,4-Dioxane was distilled from sodium benzophenone ketyl and stored over sodium
2
9
23
wires. 2,3,4-Tri-O-benzoyl-β-D-xylopyranosyl cyanide (1), N-benzyl-arenecarboxamides
34
(8-10), 2,3,4-tri-O-acetyl-β-D-xylopyranosyl-cyanide (20), 2,3,4-tri-O-acetyl-1-thio-β-D-
4
1
47
47
xylopyranose (35), arenecarbaldoximes, and N-hydroxy-arenecarboximidoyl chlorides
were synthesized according to published procedures.
30
3
.2. General procedure I for the Zemplén-deacylation
An O-acylated compound was dissolved in anhydrous MeOH (5 mL/100 mg, a few drops of
CHCl were added in case of incomplete dissolution) and a catalytic amount of a NaOMe
3
solution (~1 M in MeOH) was added. The mixture was kept at rt and monitored by TLC (7:3
CHCl
-MeOH). After disappearance of the starting material the mixture was neutralized with
3
+
a cation exchange resin Amberlyst 15 (H form), then the resin was filtered off and the
1
4

solvent removed. The residue was purified either by column chromatography or by
crystallization.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
3
.3. General procedure II for the synthesis of 4-benzyl-3-(2’,3’,4’-tri-O-benzoyl-β-D-
xylopyranosyl)-5-substituted-1,2,4-triazoles (11-13)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
23
An N-benzyl-arenecarboxamide (8-10, 4.63 mmol, 3 equiv.) was dissolved in SOCl (20
2
mL), and refluxed for 2 hours. After distilling off the excess of SOCl under reduced pressure,
2
anhydrous toluene (20 mL) was evaporated from the residue. 5-(2,3,4-Tri-O-benzoyl-β-D-
xylopyranosyl)tetrazole (7, 1.54 mmol, 1 equiv.) and anhydrous toluene or m-xylene (20 mL)
were added, the mixture was heated to reflux temperature, and the reaction was monitored by
TLC (1:1 EtOAc-hexane). After total consumption of the tetrazole the solvent was removed
and the residue was purified by column chromatography.
3
.4. General procedure III for the removal of benzyl protecting groups
A benzylated compound (0.5 mmol) was dissolved in anhydrous MeOH (25 mL), 10% Pd(C)
20 mg) was added, and H gas was bubbled through the reaction mixture at 50 °C. After
(
2
disappearance of the starting material (monitored by TLC, 7:3 CHCl -MeOH) the reaction
3
mixture was filtered through a pad of celite, the solvent was evaporated, and the residue was
purified by column chromatography.
3
.5. General procedure IV for the synthesis of (1’R)-2’,3’,4’-tri-O-acetyl-1’,5’-anhydro-
D-xylitol-spiro[1’,5]-3-aryl-4,5-dihydro-isoxazoles (23-28)
,4,5-Tri-O-acetyl-2,6-anhydro-1-deoxy-D-xylo-hex-1-enitol (22, 100 mg, 0.37 mmol) and an
arenecarbaldoxime (1.85 mmol, 5 equiv.) was dissolved in THF (4.8 mL) under N
atmosphere. To this stirred solution domestic bleach (5 % available chlorine, 3.86 mL) was
3
2
1
5

added with a syringe pump in 5 hours at rt. The reaction was stirred for additional 24 h. After
complete disappearance of the starting exo-xylal (TLC, 1:1 EtOAc-hexane) the reaction was
diluted with EtOAc (20 mL), the phases were separated, and the organic layer was washed
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
with water (3 × 15 mL), dried over MgSO , and the solvent was evaporated under reduced
4
pressure. The residue was purified by column chromatography (1:3 EtOAc-hexane).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
.6. General procedure V (method a) for the synthesis of 2,3,4-tri-O-acetyl-1-S-(Z)-
arylhydroximoyl-1-thio-β-D-xylopyranoses (36-38)
41
2
,3,4-Tri-O-acetyl-1-thio-β-D-xylopyranose (35, 0.29 g, 1 mmol) and the corresponding N-
hydroxy-arenecarboximidoyl chloride (1.5 mmol) were dissolved in anhydrous CH Cl (10
2
2
mL), Et N was added (3 mmol) and the reaction mixture was stirred at rt under Ar. After
3
completion of the reaction (1.5 h, monitored by TLC, 1:2 EtOAc-hexane) the mixture was
treated with 2 M HCl solution (20 mL), then the separated organic phase was washed with
water (2 × 20 mL). The organic layer was dried over MgSO , filtered and evaporated. The
4
residue was purified by column chromatography (1:2 EtOAc-hexane) to give an oil that was
crystallized from hexane.
4
3
3
.7. General procedure VI (method b) for the synthesis of 2,3,4-tri-O-acetyl-1-S-(Z)-
arylhydroximoyl-1-thio-β-D-xylopyranoses (36-38)
An arenecarbaldoxime (1.5 mmol) was dissolved in CH Cl (10 mL) and the solution was
2
2
extracted with domestic bleach (5 % available chlorine, 5 mL). After drying over MgSO the
4
organic phase was added dropwise to a solution of 2,3,4-tri-O-acetyl-1-thio-β-D-
41
xylopyranose (35, 0.29 g, 1 mmol) in CH Cl (10 mL). After addition of Et N (3 mmol) the
2
2
3
reaction mixture was stirred at rt under Ar, and monitored by TLC (1:2 EtOAc-hexane).
When the starting material was consumed (1.5 h) the mixture was treated with 2 M HCl
1
6

solution (20 mL), then the separated organic phase was washed with water (2 × 20 mL). The
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
organic layer was dried over MgSO , filtered and evaporated. The residue was purified by
4
column chromatography (1:2 EtOAc-hexane) to give an oil that was crystallized from hexane.
3
.8. General procedure VII for the synthesis of (1’S/1’R)-2’,3’,4’-tri-O-acetyl-1’,5’-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
anhydro-D-xylitol-spiro[1’,5]-3-aryl-1,4,2-oxathiazoles (42-47)
A 2,3,4-tri-O-acetyl-1-S-(Z)-arylhydroximoyl-1-thio-β-D-xylopyranose (36-38, 1 mmol) and
NBS (1.2 mmol) were dissolved in anhydrous CHCl
illuminated by a 250 W heat lamp. When TLC (1:2 EtOAc-hexane) showed total consumption
(20 mL) and the mixture was boiled and
3
of the starting material (1 h) the reaction mixture was diluted with CHCl (30 mL), extracted
3
with satd aq Na S O solution (40 mL), satd aq NaHCO solution (40 mL) and water (40 mL).
2
2
4
3
The organic layer was dried over MgSO , filtered and evaporated under reduced pressure. The
4
residue was purified by column chromatography.
3.9. Synthesis and characterization of the compounds
3.9.1. C-(2,3,4-Tri-O-benzoyl-β-D-xylopyranosyl)formamide (2)
2
9
2
,3,4-Tri-O-benzoyl-β-D-xylopyranosyl cyanide (1, 3.0 g, 6.4 mmol) was suspended in a
solution of HBr in AcOH (8 ml, 33% m/m) and the mixture was stirred at rt. After
disappearance of the starting material (3 h, monitored by TLC, 1:1 EtOAc-hexane) the
reaction mixture was poured into ice-water (40 mL) and extracted with CHCl (2 × 30 mL).
3
The combined organic phases were washed with satd aq NaHCO solution (2 × 30 mL), then
3
with water (30 mL), dried over MgSO , filtered and the solvent was removed. The remaining
4
oil was crystallized from Et O to give 1.58 g (51 %) of 2 as a white solid. Mp: 173-175 ºC;
2
1
[
α] = –15 (c 0.5, DMSO); H NMR (DMSO-d ) δ (ppm): 7.88-7.38 (17H, m, Ar, CONH ),
D
6
2
1
7

5
5
.89, 5.63 (2 × 1H, 2 pseudo t, J = 9.2, 9.2 Hz in each, H-2, H-3), 5.40 (1H, ddd, J = 10.5, 9.2,
.5 Hz, H-4), 4.35-4.32 (2H, m, H-1, H-5eq), 3.90 (1H, pseudo t, J = 11.2, 10.5 Hz, H-5ax);
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
3
C NMR (DMSO-d ) δ (ppm): 168.7 (CONH ), 165.1, 164.8, 164.4 (C=O), 133.7-128.6 (Ar),
6
2
7
6.7, 73.2, 70.0, 69.3 (C-1 – C-4), 65.3 (C-5). Anal. Calcd for C H NO (489.47): C, 66.25;
27 23 8
H, 4.74; N, 2.86. Found: C, 66.11; H, 4.83; N, 2.73.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
.9.2. Ethyl C-(2,3,4-tri-O-benzoyl-β-D-xylopyranosyl)formimidate (3)
C-(2,3,4-Tri-O-benzoyl-β-D-xylopyranosyl)formamide (2, 1.0 g, 2.04 mmol) and Et
1.16 g, 6.13 mmol, 3 equiv.) were stirred in anhydrous CH Cl (15 mL) at rt under Ar, and
O·BF
4
3
(
2
2
monitored by TLC (1:1 EtOAc-hexane). After completion of the reaction (24 h), the mixture
was diluted with CH Cl (50 mL), extracted with satd aq NaHCO solution (40 mL) and then
2
2
3
with water (40 mL). The organic phase was dried over MgSO , filtered and the solvent was
4
removed under diminished pressure. The pale yellow amorphous crude product (1.02 g, 96 %)
1
was used without further purification. R : 0.59 (1:1 EtOAc-hexane); H NMR (CDCl ) δ
f
3
(ppm): 8.00-7.23 (16H, m, Ar, NH), 6.00, 5.59 (2 × 1H, 2 pseudo t, J = 9.2, 9.2 Hz in each, H-
2
4
, H-3), 5.46 (1H, ddd, J = 10.6, 9.2, 5.3 Hz, H-4), 4.53 (1H, dd, J = 11.2, 5.3 Hz, H-5eq),
.14 (1H, d, J = 9.2 Hz, H-1), 4.12-3.92 (2H, m, CH ), 3.71 (1H, pseudo t, J = 11.2, 10.6 Hz,
2
1
3
H-5ax), 0.86 (3H, t, 7.3 Hz, CH ); C NMR (CDCl ) δ (ppm): 167.5, 165.4, 165.1, 164.9
3
3
(
C=O, C=NH), 133.2-128.0 (Ar), 75.1, 72.6, 70.3, 69.4 (C-1 – C-4), 66.0 (C-5), 61.8 (CH2),
1
3.2 (CH3).
3.9.3. 2-(2’,3’,4’-Tri-O-benzoyl-β-D-xylopyranosyl)-benzimidazole (4)
Ethyl C-(2,3,4-tri-O-benzoyl-β-D-xylopyranosyl)formimidate (3, 0.15 g, 0.29 mmol) and o-
phenylenediamine (63 mg, 0.58 mmol) were heated in anhydrous CH
Cl (3 mL) at reflux
2
2
temperature, and the reaction was monitored by TLC (1:1 EtOAc-hexane). After completion
1
8

of the reaction (5 h) the solvent was evaporated, and the residue was purified by column
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
chromatography (2:3 EtOAc-hexane) to give 0.13 g (80 %) pale yellow solid. Mp: 123-125
1

C; [α] = –96 (c 0.5, CHCl ); H NMR (CDCl ) δ (ppm): 11.17 (1H, br s, NH), 7.97-7.17
D
3
3
(19H, m, Ar), 6.06, 5.85 (2 × 1H, 2 pseudo t, J = 9.4, 9.4 Hz in each, H-2’, H-3’), 5.42 (1H,
ddd, J = 9.8, 9.4, 5.4 Hz, H-4’), 5.17 (1H, d, J = 9.4 Hz, H-1’), 4.42 (1H, dd, J = 11.3, 5.4 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
13
H-5’eq), 3.76 (1H, pseudo t, J = 11.3, 9.8 Hz, H-5’ax); C NMR (CDCl ) δ (ppm): 165.6,
3
1
65.4, 165.3 (C=O), 149.1 (C-2), 138.3 (C-3a, C-7a), 133.3-128.1 (Ar), 122.7 (C-5, C-6),
115.5 (C-4, C-7), 75.4, 73.2, 71.4, 69.7 (C-1’ – C-4’), 67.0 (C-5’). Anal. Calcd for
C H N O (562.57): C, 70.45; H, 4.66; N, 4.98. Found: C, 70.51; H, 4.80; N, 4.76.
33
26
2
7
3
.9.4. 2-(β-D-Xylopyranosyl)-benzimidazole (5)
From compound 4 (0.22 g, 0.39 mmol) according to General procedure I (section 3.2.).
Reaction time: 1.5 h. Purified by column chromatography (85:15 CHCl -MeOH ) to yield 79
3
mg (81 %) white amorphous solid. R : 0.45 (7:3 CHCl -MeOH); [α] = –18 (c 0.5, DMSO);
f
3
D
1
H NMR (DMSO-d ) δ (ppm): 12.53 (1H, s, NH), 7.56-7.48 (2H, m, benzimidazole), 7.17-
6
7
.16 (2H, m, benzimidazole), 5.21-5.14 (3H, m, 3 × OH), 4.31 (1H, d, J = 9.2 Hz, H-1’), 3.87
(1H, dd, J = 11.2, 5.3 Hz, H-5’eq), 3.64 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2’ or H-3’), 3.47
1H, ddd, J = 10.6, 9.2, 5.3 Hz, H-4’), 3.31 (1H, pseudo t, J = 9.2, 9.2 Hz, H-2’ or H-3’), 3.26
(
1
3
(1H, pseudo t, J = 11.2, 10.6 Hz, H-5’ax); C NMR (DMSO-d
) δ (ppm): 152.4 (C-2), 142.5,
34.1 (C-3a, C-7a), 122.1, 121.1, 118.7, 111.3 (C-4 ‒ C-7), 78.0, 76.9, 72.8, 70.2 (C-1’ – C-
’), 69.6 (C-5’). Anal. Calcd for C H N O (250.25): C, 57.59; H, 5.64; N, 11.19. Found: C,
6
1
4
5
12 14
2
4
7.51; H, 5.79; N, 11.13.
1
9

1
3
.9.5. N -Tosyl-C-(3,4-di-O-benzoyl-2-deoxy-D-threo-pent-1-
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
enopyranosyl)formamidrazone (6)
Ethyl C-(2,3,4-tri-O-benzoyl-β-D-xylopyranosyl)formimidate (3, 0.39 g, 0.76 mmol) and p-
toluenesulfonylhydrazide (0.21 g, 1.13 mmol, 1.5 equiv) were dissolved in anhydrous CH Cl
2
2
(12 mL), stirred at rt, and monitored by TLC (1:1 EtOAc-hexane). After completion of the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
reaction (3 days) the solvent was evaporated, and the residue was purified by column
chromatography (4:7 EtOAc-hexane). The resulting pale yellow oil was crystallized from
1
Et O to give 0.11 g (27 %) white solid. Mp: 120-121 C; [α] = –120 (c 0.5, CHCl ); H NMR
2
D
3
(
CDCl ) δ (ppm): 8.01-7.28 (14H, m, Ar), 5.97, 5.58-5-35 (5H, 3 br signals, H-2, H-3, H-4,
3
13
NH
), 4.54, 4.26 (2 × 1H, 2 br signals, H-5eq, H-5ax), 2.37 (3H, s, CH ); C NMR (CDCl ) δ
3 3
2
(
ppm): 165.3, 165.0 (C=O), 154.5, 148.2, 144.1 (C-1, C=N, Ts-C-1) 134.5-128.3 (Ar), 97.9
C-2), 67.2 (C-3 or C-4), 65.0 (C-5), 63.9 (C-3 or C-4), 21.5 (CH ). MS-ESI (m/z): calcd for
(
3
+
+
C H N O S [M+H] : 536.15. Found: 536.42.
27
26
3
7
3
.9.6. 5-(2’,3’,4’-Tri-O-Benzoyl-β-D-xylopyranosyl)tetrazole (7)
29
2
,3,4-Tri-O-benzoyl-β-D-xylopyranosyl cyanide (1, 2.00 g, 4.24 mmol), TMSN (2.23 mL,
3
16.96 mmol) and Bu SnO (0.10 g, 0.42 mmol) was dissolved in anhydrous toluene (60 mL)
2
and heated at 80 °C overnight. Toluene was then removed under reduced pressure, and the
residue was crystallized from MeOH to yield 1.98 g (91 %) white solid. Mp: 176-177 °C; [α]
D
1
=
−29 (c 1.02, CHCl ); H NMR (CDCl ) δ (ppm): 14.73 (1H, br s, NH), 7.99-7.19 (15H, m,
3
3
Ar), 6.08, 5.87 (2 × 1H, 2 pseudo t, J = 9.5, 9.4 Hz in each, H-2’, H-3’), 5.61 (1H, ddd, J =
1
0.8, 9.7, 5.7 Hz, H-4’), 5.26 (1H, d, J = 9.6 Hz, H-1’), 4.56 (1H, dd, J = 11.3, 5.3 Hz, H-
13
5
’eq), 3.80 (1H, pseudo t, J = 11.3, 10.8 Hz, H-5’ax); C NMR (CDCl ) δ (ppm): 165.9,
3
165.8, 165.5 (C=O), 152.3 (tetrazole C-5), 133.7-128.3 (Ar), 72.9, 72.2, 71.1, 69.7 (C-1’ – C-
2
0

4
’), 67.4 (C-5’). Anal: Calcd for C H N O (514.49): C, 63.03; H, 4.31; N, 10.89. Found: C,
27 22 4 7
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
2.99; H, 4.29; N, 10.90.
3
.9.7. 4-Benzyl-3-phenyl-5-(2’,3’,4’-tri-O-benzoyl-β-D-xylopyranosyl)-1,2,4-triazole (11)
From tetrazole 7 (0.70 g, 1.36 mmol) and N-benzyl-benzamide (8, 0.86 g, 4.08 mmol) in
toluene according to General procedure II (section 3.3.). Reaction time: 16 h. Purified by
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
column chromatography (1:1 EtOAc-hexane) to yield 0.65 g (68 %) white crystals. Mp: 230-
1
231 °C; [α]
= −33 (c 0.50, CHCl
); H NMR (CDCl
) δ (ppm): 7.96-7.05 (25H, m, Ar), 6.02,
D
3
3
5
.92 (2 × 1H, 2 pseudo t, J = 9.4, 9.5 Hz in each, H-2’, H-3’), 5.49 (1H, d, J = 16.3 Hz,
PhCH ), 5.41 (1H, ddd, J = 9.8, 9.4, 5.3 Hz, H-4’), 5.33 (1H, d, J = 16.3 Hz, PhCH ), 4.94
2
2
(1H, d, J = 9.6 Hz, H-1’), 4.46 (1H, dd, J = 11.1, 5.3 Hz, H-5’eq), 3.60 (1H, pseudo t, J =
13
1
1.1, 10.7 Hz, H-5’ax); C NMR (CDCl ) δ (ppm): 165.7, 165.4, 164.6 (C=O), 156.4, 150.2
3
(triazole C-3, C-5), 135.3-126.3 (Ar), 73.3, 73.3, 69.8, 69.7 (C-1’ – C-4’), 67.2 (C-5’), 48.0
PhCH ). Anal: Calcd for C H N O (679.72): C, 72.45; H, 4.89; N, 6.18. Found: C, 72.56;
(
2
41 33
3
7
H, 4.94; N, 6.12.
3.9.8. 4-Benzyl-3-(4-tert-butylphenyl)-5-(2’,3’,4’-tri-O-benzoyl-β-D-xylopyranosyl)-1,2,4-
triazole (12)
From tetrazole 7 (1.00 g, 1.94 mmol) and N-benzyl-4-tert-butylbenzamide (9, 1.56 g, 5.83
mmol) in m-xylene according to General procedure II (section 3.3.). Reaction time: 4 h.
Purified by column chromatography (2:3 EtOAc-hexane) to yield 0.60 g (42 %) white
1
crystals. Mp: 234-236 °C; [α] = −18 (c 0.52, CHCl ); H NMR (CDCl ) δ (ppm): 7.96-7.07
D
3
3
(
24H, m, Ar), 6.00, 5.90 (2 × 1H, 2 pseudo t, J = 9.4 Hz in each, H-2’, H-3’), 5.47 (1H, d, J =
16.5 Hz, PhCH ), 5.41-5.33 (2H, m, H-4’, PhCH ), 4.89 (1H, d, J = 9.7 Hz, H-1’), 4.44 (1H,
dd, J = 11.2, 5.1 Hz, H-5’eq), 3.57 (1H, pseudo t, J = 11.2, 10.7 Hz, H-5’ax), 1.30 (9H, s,
2
2
2
1

1
3
C(CH ) ); C NMR (CDCl ) δ (ppm): 165.8, 165.4, 164.5 (C=O), 156.5, 153.4 (triazole C-3,
3
3
3
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
C-5), 150.0, 135.5-123.7 (Ar), 73.4, 73.2, 69.8, 69.7 (C-1’ – C-4’), 67.2 (C-5’), 48.0 (PhCH2),
3
5
4.8 (C(CH ) ), 31.1 (C(CH ) ). Anal: Calcd for C H N O (735.82): C, 73.45; H, 5.62; N,
3 3 3 3 45 41 3 7
.71. Found: C, 73.50; H, 5.59; N, 5.67.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3.9.9. 4-Benzyl-3-(2-naphthyl)-5-(2’,3’,4’-tri-O-benzoyl-β-D-xylopyranosyl)-1,2,4-triazole
13)
From tetrazole 7 (1.00 g, 1.94 mmol) and N-benzyl-naphthalene-2-carboxamide (10, 1.52 g,
.82 mmol) in m-xylene according to General procedure II (section 3.3.). Reaction time: 3 h.
(
5
Purified by column chromatography (1:1 EtOAc-hexane) to yield 0.73 g (52 %) white
1
crystals. Mp: 226-227 °C; [α] = −39 (c 0.47, CHCl ); H NMR (CDCl ) δ (ppm): 7.97-7.08
D
3
3
(27H, m, Ar), 6.04, 5.95 (2 × 1H, 2 pseudo t, J = 9.5, 9.4 Hz in each, H-2’, H-3’), 5.55 (1H, d,
J = 16.4 Hz, PhCH ), 5.45-5.38 (2H, m, H-4’, PhCH ), 5.00 (1H, d, J = 9.6 Hz, H-1’), 4.47
2
2
13
(
1H, dd, J = 11.2, 5.3 Hz, H-5’eq), 3.62 (1H, pseudo t, J = 11.2, 10.7 Hz, H-5’ax); C NMR
(CDCl ) δ (ppm): 165.7, 165.4, 164.7 (C=O), 156.5, 150.3 (triazole C-3, C-5), 135.3-123.8
Ar), 73.3, 73.2, 69.9, 69.7 (C-1’ – C-4’), 67.2 (C-5’), 48.2 (PhCH ). Anal: Calcd for
3
(
2
C H N O (729.78): C, 74.06; H, 4.83; N, 5.76. Found: C, 74.11; H, 4.85; N, 5.72.
45 35
3
7
3
.9.10. 4-Benzyl-3-phenyl-5-(β-D-xylopyranosyl)-1,2,4-triazole (14)
From compound 11 (0.44 g, 0.63 mmol) according to General procedure I (section 3.2.).
Reaction time: 4 h. Purified by column chromatography (9:1 CHCl -MeOH) to yield 0.21 g
3
1
(91 %) white amorphous solid. R : 0.46 (4:1 CHCl -MeOH); [α] = −15 (c 0.50, DMSO); H
f
3
D
NMR (DMSO-d ) δ (ppm): 7.49-7.41 (5H, m, Ar), 7.23-7.22 (3H, m, Ar), 6.94 (2H, d, J = 6.3
6
Hz, Ar), 5.38 (1H, d, J = 19.2 Hz, PhCH
), 5.32 (1H, d, J = 18.2 Hz, PhCH ), 4.31 (1H, d, J =
2
2
9
.6 Hz, H-1’), 3.86 (1H, pseudo t, J = 9.1, 8.9 Hz, H-2’ or H-3’), 3.73 (1H, dd, J = 10.7, 5.8
2
2

Hz, H-5’eq), 3.43 (1H, ddd, J = 10.6, 9.4, 5.8 Hz, H-4’), 3.26 (1H, pseudo t, J = 9.1, 8.7 Hz,
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
3
H-2’ or H-3’), 3.16 (1H, pseudo t, J = 10.7, 10.6 Hz, H-5’ax); C NMR (DMSO-d ) δ (ppm):
6
1
7
54.8, 153.5 (triazole C-3, C-5), 136.2, 130.2, 129.0, 128.8, 128.7, 127.9, 127.3, 126.5 (Ar),
8.1, 73.3, 71.8, 69.5 (C-1’ – C-4’), 70.2 (C-5’), 47.0 (PhCH ). Anal: Calcd for C H N O
4
2
20 21
3
(367.40): C, 65.38; H, 5.76; N, 11.44. Found: C, 65.30; H, 5.78; N, 11.45.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
.9.11. 4-Benzyl-3-(4-tert-butylphenyl)-5-(β-D-xylopyranosyl)-1,2,4-triazole (15)
Triazole 12 (0.53 g, 0.63 mmol) was dissolved in anhydrous MeOH (4 mL), 1M
NaOH/MeOH (3 mL) was added and the mixture was refluxed for 1 hour. The excess of
NaOH was neutralized by AcOH. After evaporation the crude product was purified by column
chromatography (9:1 CHCl -MeOH) to yield 0.19 g (63 %) white amorphous solid. R : 0.56
3
f
1
(
4:1 CHCl -MeOH); [α] = −15.0 (c 0.50, DMSO); H NMR (DMSO-d ) δ (ppm): 7.42 (4H,
3 D 6
m, Ar), 7.26-7.24 (3H, m, Ar), 6.96 (2H, d, J = 6.5 Hz, Ar), 5.37 (1H, d, J = 18.1 Hz, PhCH2),
.32 (1H, d, J = 17.8 Hz, PhCH ), 4.23 (1H, d, J = 9.6 Hz, H-1’), 3.83 (1H, pseudo t, J = 9.1,
5
2
9.0 Hz, H-2’ or H-3’), 3.72 (1H, dd, J = 10.6, 4.7 Hz, H-5’eq), 3.40 (1H, ddd, J = 10.6, 9.1,
4
1
.7 Hz, H-4’), 3.21 (1H, pseudo t, J = 8.7, 8.7 Hz, H-2’ or H-3’), 3.12 (1H, pseudo t, J = 10.7,
1
3
0.6 Hz, H-5’ax), 1.25 (9H, s, C(CH ) ); C NMR (DMSO-d ) δ (ppm): 154.6, 153.3
3 3
6
(triazole C-3, C-5), 152.8, 136.2, 128.8, 128.4, 127.8, 126.3, 125.8, 124.4 (Ar), 78.0, 73.3,
7
1.7, 69.4 (C-1’ – C-4’), 70.1 (C-5’), 46.8 (PhCH ), 34.7 (C(CH ) ), 31.0 (C(CH ) ). Anal:
2
3 3
3 3
Calcd for C H N O (423.50): C, 68.06; H, 6.90; N, 9.92. Found: 68.19; H, 6.92; N, 9.91.
2
4
29
3
4
3.9.12. 4-Benzyl-3-(2-naphthyl)-5-(β-D-xylopyranosyl)-1,2,4-triazole (16)
From compound 13 (0.34 g, 0.47 mmol) according to General procedure I (section 3.2.).
Reaction time: 3 h. Purified by column chromatography (9:1 CHCl
-MeOH) to yield 0.15 g
3
1
(
76 %) white amorphous solid. R : 0.40 (4:1 CHCl -MeOH); [α] = −14 (c 0.50, DMSO); H
f
3
D
2
3

NMR (DMSO-d ) δ (ppm): 8.04-6.97 (12H, m Ar), 5.49 (1H, d, J = 18.3 Hz, PhCH ), 5.44
6
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
(
1H, d, J = 18.3 Hz, PhCH ), 4.39 (1H, d, J = 9.6 Hz, H-1’), 3.91 (1H, pseudo t, J = 9.1, 9.0
2
Hz, H-2’ or H-3’), 3.78 (1H, dd, J = 10.7, 4.8 Hz, H-5’eq), 3.45 (1H, ddd, J = 9.6, 9.0, 5.1 Hz,
H-4’), 3.29 (1H, pseudo t, J = 8.8, 8.7 Hz, H-2’ or H-3’), 3.13 (1H, pseudo t, J = 10.8, 10.8
13
Hz, H-5’ax); C NMR (DMSO-d ) δ (ppm): 154.7, 153.8 (triazole C-3, C-5), 136.3-124.7
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
(Ar), 78.1, 73.4, 71.8, 69.5 (C-1’ – C-4’), 70.2 (C-5’), 47.2 (PhCH ). Anal: Calcd for
2
C H N O (417.46): C, 69.05; H, 5.55; N, 10.07. Found: C, 68.99; H, 5.49; N, 10.12.
24
23
3
4
3
.9.13. 3-Phenyl-5-(β-D-xylopyranosyl)-1,2,4-triazole (17)
From compound 14 (0.20 g, 0.54 mmol) according to General procedure III (section 3.4.).
Reaction time: 2 h. Purified by column chromatography (9:1 CHCl -MeOH) to yield 0.14 g
3
1
(
91 %) white amorphous solid. R : 0.30 (4:1 CHCl -MeOH); [α] = −24 (c 0.48, MeOH); H
f
3
D
NMR (CD OD) δ (ppm): 7.90 (2H, br s, Ar), 7.40 (3H, m, Ar), 4.37 (1H, d, J = 9.6 Hz, H-1’),
3
4
.00 (1H, dd, J = 11.1, 5.3 Hz, H-5’eq), 3.80 (1H, br s, H-2’ or H-3’), 3.68 (1H, ddd, J = 10.1,
9.0, 5.3 Hz, H-4’), 3.49 (1H, pseudo t, J = 9.0, 9.0 Hz, H-2’ or H-3’), 3.36 (1H, pseudo t, J =
13
1
1
1.1, 10.8 Hz, H-5’ax); C NMR (CD OD) δ (ppm): 163.0, 156.9 (triazole C-3, C-5), 131.1,
3
29.9, 127.5 (Ar), 79.5, 77.2, 74.2, 71.1 (C-1’ – C-4’), 71.5 (C-5’). Anal: Calcd for
C H N O (277.28): C, 56.31; H, 5.45; N, 15.15. Found: C, 56.43; H, 5.49; N, 15.07.
13
15
3
4
3
.9.14. 3-(4-tert-Butylphenyl)-5-(β-D-xylopyranosyl)-1,2,4-triazole (18)
From compound 15 (0.18 g, 0.43 mmol) according to General procedure III (section 3.4.).
Reaction time: 2 h. Purified by column chromatography (9:1 CHCl -MeOH) to yield 0.11 g
3
1
(
77 %) white amorphous solid. R : 0.43 (4:1 CHCl -MeOH); [α] = −24 (c 0.49, MeOH); H
f
3
D
NMR (CD
OD) δ (ppm): 7.88 (2H, d, J = 8.2 Hz, Ar), 7.47 (2H, d, J = 8.2 Hz, Ar), 4.38 (1H,
3
d, J = 9.7 Hz, H-1’), 4.01 (1H, dd, J = 11.1, 5.3 Hz, H-5’eq), 3.83 (1H, pseudo t, J = 8.6, 8.3
2
4

Hz, H-2’ or H-3’), 3.68 (1H, ddd, J = 10.0, 9.2, 5.3 Hz, H-4’), 3.50 (1H, pseudo t, J = 9.0, 9.0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
3
Hz, H-2’ or H-3’), 3.37 (1H, pseudo t, J = 11.1, 10.0 Hz, H-5’ax), 1.29 (9H, s, C(CH ) ); C
3
3
NMR (CD OD) δ (ppm): 162.1, 158.4 (triazole C-3, C-5), 154.6, 127.4, 126.9 (Ar), 79.5,
3
7
7.3, 74.2, 71.1 (C-1’ – C-4’), 71.5 (C-5’), 35.6 (C(CH ) ), 31.6 (C(CH ) ). Anal: Calcd for
3 3 3 3
C H N O (333.38): C, 61.25; H, 6.95; N, 12.60. Found: C, 61.20; H, 6.96; N, 12.54.
17
23
3
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
.9.15. 3-(2-Naphthyl)-5-(β-D-xylopyranosyl)-1,2,4-triazole (19)
From compound 16 (0.14 g, 0.33 mmol) according to General procedure III (section 3.4.).
Reaction time: 16 h. Purified by column chromatography (9:1 CHCl -MeOH) to yield 0.10 g
3
1
(
90 %) white amorphous solid. R : 0.44 (4:1 CHCl -MeOH); [α] = −22 (c 0.47, MeOH); H
f
3
D
NMR (CD OD) δ (ppm): 8.36 (1H, s, Ar), 7.93 (1H, d, J = 8.2 Hz, Ar), 7.78-7.69 (3H, m,
3
Ar), 7.38-7.35 (2H, m, Ar), 4.40 (1H, d, J = 9.7 Hz, H-1’), 4.00 (1H, dd, J = 11.0, 5.3 Hz, H-
5’eq), 3.84 (1H, pseudo t, J = 8.9, 8.7 Hz, H-2’ or H-3’), 3.71 (1H, ddd, J = 9.9, 9.5, 5.3 Hz,
H-4’), 3.51 (1H, pseudo t, J = 8.9, 8.9 Hz, H-2’ or H-3’), 3.37 (1H, pseudo t, J = 11.0, 9.9 Hz,
1
3
H-5’ax); C NMR (CD
29.7, 129.5, 128.7, 128.1, 127.7, 127.2, 124.5 (Ar), 79.5, 77.2, 74.3, 71.1 (C-1’ – C-4’), 71.5
C-5’). Anal: Calcd for C H N O (327.33): C, 62.38; H, 5.23; N, 12.84. Found: C, 62.40;
OD) δ (ppm): 160.7, 159.0 (triazole C-3, C-5), 138.8, 135.3, 134.4,
3
1
(
17 17
3
4
H, 5.19; N, 12.80.
3
.9.16. C-(2,3,4-Tri-O-acetyl-β-D-xylopyranosyl)formaldehyde-tosylhydrazone (21)
To a vigorously stirred solution of pyridine (10 mL), AcOH (6 mL), and water (6 mL) an
aqueous suspension of Raney-Ni (2.60 g) was added at rt. 2,3,4-Tri-O-acetyl-β-D-
34
xylopyranosyl-cyanide (20, 0.50 g, 1.75 mmol), p-toluenesulfonylhydrazide (0.39 g, 4.43
mmol) and NaH
PO (1.30 g, 15 mmol) were then added to the mixture. When the reaction
2
2
was complete (TLC, 1:1 EtOAc-hexane) the insoluble materials were filtered off, and washed
2
5

with EtOAc (40 mL). The organic layer of the filtrate was separated, washed with 10% aq
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
HCl solution (3 ×10 mL), satd aq NaHCO solution (3 × 10 mL), water (10 mL), and then
3
dried over MgSO . The solution was concentrated under reduced pressure, the residue was
4
purified by column chromatography (1:1 EtOAc-hexane) to give 0.50 g (63 %) white crystals.
1
Mp: 143-147 °C; [α] = −14 (c 0.98, CHCl ); H NMR (CDCl ) δ (ppm): 9.20 (1H, s, NH),
D
3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
7.79 (2H, d, J = 8.1 Hz, Ph), 7.32 (2H, d, J = 8.0 Hz, Ph), 7.00 (1H, d, J = 6.4 Hz, CH), 5.25
1H, pseudo t, J = 9.5, 9.5 Hz, H-2 or H-3), 4.98 (1H, ddd, J = 11.1, 9.6, 5.5 Hz, H-4), 4.92
(
(1H, pseudo t, J = 9.6, 9.6 Hz, H-2 or H-3), 4.10 (1H, dd, J = 11.1, 5.5 Hz, H-5eq), 3.90 (1H,
dd, J = 9.7, 6.4 Hz, H-1), 3.32 (1H, pseudo t, J = 11.0, 10.9 Hz, H-5ax), 2.41 (3H, s, CH3),
13
2
.04 (6H, s, 2 × CH ) 1.75, (3H, s, CH ); C NMR (CDCl ) δ (ppm): 170.5, 170.1, 169.9
3 3 3
(C=O), 143.9 (CH=N), 135.1, 127.7, 129.5 (Ar), 77.9, 72.4, 69.5, 68.7 (C-1 ‒ C-4), 66.3 (C-
5
), 21.3, 20.5 (2 × CH ), 20.1 (CH ). Anal: Calcd for C H N O S (456.47): C, 49.99; H,
3
3
19 24
2
9
5.30; N, 6.14. Found: C, 50.06; H, 5.38; N, 6.19.
3.9.17. 3,4,5-Tri-O-acetyl-2,6-anhydro-1-deoxy-D-xylo-hex-1-enitol (22)
In a flame-dried three-necked flask NaH (95 %, 44 mg, 1.75 mmol) was added to anhydrous
1
,4-dioxane. This stirred suspension was heated to reflux and a solution of 21 (200 mg, 0.44
mmol) in anhydrous 1,4-dioxane (13 mL) was added dropwise during 1.5 h. The reaction was
refluxed until the complete disappearance of the starting material (TLC, 1:1 EtOAc-hexane).
After cooling to rt the insoluble material was filtered off and washed with anhydrous 1,4-
dioxane (10 mL). The filtrate was concentrated under reduced pressure and the residue was
purified by column chromatography (1:1 EtOAc-hexane) to yield 118 mg (99 %) white
1
amorphous solid. R : 0.59 (1:1 EtOAc-hexane); [α] = +8 (c 0.51, CHCl ); H NMR (CDCl )
f
D
3
3
δ (ppm): 5.38 (1H, ddd, J = 8.0, < 1 Hz, H-3), 5.11 (1H, pseudo t, J = 7.9, 7.8 Hz, H-4), 5.03
1H, ddd, J = 8.4, 7.9, 4.8 Hz, H-5), 4.73 (1H, pseudo t, J = 1.5, 1.5 Hz, H-1a), 4.47 (1H,
(
2
6

pseudo t, J = 1.5, 1.5 Hz, H-1b), 4.18 (1H, dd, J = 11.1, 4.8 Hz, H-6eq), 3.55 (1H, dd, J =
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
3
1
1
1.1, 8.4 Hz, H-6ax), 2.04 (3H, s, CH ), 2.09 (6H, s, 2 × CH ); C NMR (CDCl ) δ (ppm):
3 3 3
69.7 (2), 169.2 (C=O), 153.5 (C-2), 95.9 (C-1), 72.1, 68.7 (2) (C-3 ‒ C-5), 66.9 (C-6), 20.7
(
3 × CH ). Anal: Calcd for C H O (272.25): C, 52.94; H, 5.92. Found: C, 53.07; H, 5.99.
3 12 16 7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3.9.18. (1’R)-2’,3’,4’-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-phenyl-4,5-
dihydro-isoxazole (23)
From compound 22 (100 mg, 0.37 mmol) and benzaldoxime (222 mg, 1.85 mmol) according
to General procedure IV (section 3.5.) to yield 105 mg (74 %) white amorphous solid. Rf:
1
0
.38 (1:2 EtOAc-hexane); [α] = +34 (c 0.79, CHCl ); H NMR (CDCl ) δ (ppm): 7.59-7.19
D
3
3
(
5H, m, Ar), 5.49 (1H, pseudo t, J = 10.6, 9.2 Hz, H-3’), 5.29 (1H, d, J = 10.6 Hz, H-2’), 5.00
1H, ddd, J = 10.6, 9.2, 6.6 Hz, H-4’), 3.92-3.78 (2H, m, H-5’ax, H-5’eq), 3.25 (2H, br s,
(
13
CH ), 1.98 (9H, m, 3 × CH ); C NMR (CDCl ) δ (ppm): 170.3, 169.9, 169.7 (C=O), 157.7
2
3
3
(
C=N), 130.8, 128.8, 128.3, 126.8 (Ar), 107.0 (C-1’), 71.1, 69.4, 68.9 (C-2’ ‒ C-4’), 60.2 (C-
5’), 43.2 (CH ), 20.6 (3 × CH ). Anal: Calcd for C19 (391.38): C, 58.31; H, 5.41; N,
.58. Found: C, 58.42; H, 5.54; N, 3.62.
H21NO
8
2
3
3
3
.9.19. (1’R)-2’,3’,4’-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-(4-tert-
butylphenyl)-4,5-dihydro-isoxazole (24)
From compound 22 (100 mg, 0.37 mmol) and 4-tert-butylbenzaldoxime (327 mg, 1.85 mmol)
according to General procedure IV (section 3.5.) to yield 110 mg (67 %) white amorphous
1
solid. R : 0.54 (1:2 EtOAc-hexane); [α] = +29 (c 1.95, CHCl ); H NMR (CDCl ) δ (ppm):
f
D
3
3
7
.59 (2H, d, J = 8.5 Hz, Ar), 7.44 (2H, d, J = 8.5 Hz, Ar), 5.56 (1H, pseudo t, J = 9.9, 9.8 Hz,
H-3’), 5.36 (1H, d, J = 10.1 Hz, H-2’), 5.08 (1H, ddd, J = 10.5, 9.8, 6.2 Hz, H-4’), 3.96 (1H,
pseudo t, J = 11.0, 10.9 Hz, H-5’ax), 3.73 (1H, dd, J = 11.2, 6.2 Hz, H-5’eq), 3.31 (2H, s,
2
7

1
3
CH ), 2.06-2.04 (9H, m, 3 × CH ), 1.33 (9H, s, C(CH ) ); C NMR (CDCl ) δ (ppm): 170.3,
2
3
3 3
3
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
1
6
70.0, 169.7 (C=O), 157.5 (C=N), 125.5, 125.8, 126.6, 154.3 (Ar), 106.9 (C-1’), 71.1, 69.4,
8.9 (C-2’ ‒ C-4’), 60.2 (C-5’), 43.4 (CH ), 34.9 (C(CH ) ), 31.1 (C(CH ) ), 20.6 (3 × CH ).
2
3 3
3 3
3
Anal: Calcd for C H NO (447.48): C, 61.73; H, 6.53; N, 3.13. Found: C, 61.80; H, 6.61; N,
2
3
29
8
3
.24.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
.9.20. (1’R)-2’,3’,4’-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-(4-
trifluoromethylphenyl)-4,5-dihydro-isoxazole (25)
From compound 22 (100 mg, 0.37 mmol) and 4-(trifluoromethyl)benzaldoxime (327 mg, 1.85
mmol) according to General procedure IV (section 3.5.) to yield 96 mg (57 %) white
1
amorphous solid. R : 0.49 (1:2 EtOAc-hexane); [α] = +29 (c 2.07, CHCl ); H NMR (CDCl )
f
D
3
3
δ (ppm): 7.79-7.67 (4H, m, Ar) 5.58 (1H, pseudo t, J = 9.8, 9.8 Hz, H-3’), 5.38 (1H, d, J =
10.1 Hz, H-2’), 5.09 (1H, ddd, J = 10.0, 9.8, 6.5 Hz, H-4’), 3.96 (1H, pseudo t, J = 11.1, 11.0
Hz, H-5’ax), 3.91 (1H, dd, J = 11.2, 6.5 Hz, H-5’eq), 3.34 (2H, s, CH ), 2.07-2.05 (9H, m, 3 ×
2
1
3
CH
); C NMR (CDCl
) δ (ppm): 170.3, 170.0, 169.7 (C=O), 156.7 (C=N), 131.8, 127.1,
= 271.3, CF ), 107.5 (C-1’), 70.9, 69.4, 68.8 (C-2’ ‒ C-4’), 60.3
3
3
1
1
25.8 (Ar), 123.5 (q, J
(
C,F)
3
(C-5’), 42.6 (CH ), 20.6 (3 × CH ). Anal: Calcd for C H F NO (459.37): C, 52.29; H, 4.39;
2 3 20 20 3 8
N, 3.05. Found: C, 52.21; H, 4.52; N, 2.96.
3
.9.21. (1’R)-2’,3’,4’-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-(1-naphthyl)-4,5-
dihydro-isoxazole (26)
From compound 22 (100 mg, 0.37 mmol) and 1-naphthaldoxime (316 mg, 1.85 mmol)
according to General procedure IV (section 3.5.) to yield 100 mg (60 %) white amorphous
1
solid. R
: 0.40 (1:2 EtOAc-hexane); [α]
f
= +46 (c 0.81, CHCl
); H NMR (CDCl
) δ (ppm):
D
3
3
8
.98-7.45 (7H, m, Ar), 5.63 (1H, pseudo t, J = 9.9, 9.8 Hz, H-3’), 5.42 (1H, d, J =10.1 Hz, H-
2
8

2
’), 5.12 (1H, ddd, J = 10.2, 9.8, 6.2 Hz, H-4’), 4.04 (1H, pseudo t, J = 11.0, 10.9 Hz, H-
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
5
’ax), 3.93 (1H, dd, 1H, J = 11.0, 6.1 Hz, H-5’eq), 3.53 (2H, s, CH ), 2.07-2.06 (9H, m, 3 ×
2
13
CH ); C NMR (CDCl ) δ (ppm): 170.3, 170.0, 169.8 (C=O), 158.5 (C=N), 133.9-124.7 (Ar),
3
3
1
06.0 (C-1’), 71.2, 69.4, 69.0 (C-2’ ‒ C-4’), 60.3 (C-5’), 46.1 (CH ), 20.7 (3 × CH ). Anal:
2
3
Calcd for C H NO (441.44): C, 62.58; H, 5.25; N, 3.17. Found: C, 62.66; H, 5.31; N, 3.23.
2
3
23
8
1
1
1
1
1
1
1
1
1
1
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3
3
3
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3
.9.22. (1’R)-2,3,4-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-(2-naphthyl)-4,5-
dihydro-isoxazole (27)
From compound 22 (100 mg, 0.37 mmol) and 2-naphthaldoxime (316 mg, 1.85 mmol)
according to General procedure IV (section 3.5.) to yield 71 mg (44 %) white amorphous
1
solid. R : 0.42 (1:2 EtOAc-hexane); [α] = +12 (c 0.86, CHCl ); H NMR (CDCl ) δ (ppm):
f
D
3
3
7
.98-7.46 (7H, m, Ar), 5.61 (1H, pseudo t, J = 9.9, 9.8 Hz, H-3’), 5.41 (1H, d, J = 10.1 Hz, H-
2’), 5.12 (1H, ddd, J = 10.3, 6.2 Hz, H-4’), 4.00 (1H, pseudo t, J = 11.0, 10.9 Hz, H-5’ax),
13
3
.90 (1H, dd, J = 11.1, 6.1 Hz, H-5’eq), 3.45 (2H, br s, CH ), 2.06-2.05 (9H, m, 3 × CH ); C
2 3
NMR (CDCl
) δ (ppm): 170.3, 169.9, 169.7 (C=O), 157.8 (C=N), 134.2-123.0 (Ar), 107.1 (C-
3
1
’), 71.1, 69.4, 68.9 (C-2’ ‒ C-4’), 60.2 (C-5’), 43.2 (CH ), 20.6 (3 × CH ). Anal: Calcd for
2
3
C H NO (441.44): C, 62.58; H, 5.25; N, 3.17. Found: C, 62.51; H, 5.19; N, 3.26.
23 23
8
3
.9.23. (1’R)-2’,3’,4’-Tri-O-acetyl-1’,5’-anhydro-D-xylitol-spiro[1’,5]-3-(2-
benzothiazolyl)-4,5-dihydro-isoxazole (28)
From compound 22 (100 mg, 0.37 mmol) and benzothiazole-2-carbaldoxime (329 mg, 1.85
mmol) according to General procedure IV (section 3.5.) to yield 117 mg (71 %) yellow
1
amorphous solid. R : 0.40 (1:2 EtOAc-hexane); [α] = +1 (c 1.83, CHCl ); H NMR (CDCl )
f
D
3
3
δ (ppm): 8.05-7.45 (4H, m, Ar), 5.59 (1H, pseudo t, J = 9.8, 9.8 Hz, H-3’), 5.43 (1H, d, J =
0.1 Hz, H-2’), 5.17-5.09 (1H, m, H-4’), 3.98-3.95 (2H, m, H-5’ax, H-5’eq), 3.63 (1H, d, J =
1
2
9