Diversity-oriented synthesis of fused thioglycosyl benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-ones by a sequence of palladium-catalyzed glycosyl thiol arylation and deprotection-lactonization reactions

Article abstract of DOI:10.1039/c5ob01603g

An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence of palladium-catalyzed glycosyl thiol arylation followed by deprotection-lactonization reactions has been reported. This diversity-oriented strategy enabled access to unknown complex cyclic scaffolds with polyhydroxylated appendages of biological interest.

Full text of DOI:10.1039/c5ob01603g

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Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
View Article Online
DOI: 10.1039/C5OB01603G
Journal Name
ARTICLE
Diversity-oriented
synthesis
of
fused
thioglycosyl
benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-5(2H)-
ones by a sequences of palladium-catalyzed glycosyl thiol arylation
and deprotection-lactonization reactions
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Riyadh Ahmed Atto AL-Shuaeeb, Gilles Galvani, Guillaume Bernadat, Jean-Daniel Brion, Mouad
Alami* and Samir Messaoudi*
www.rsc.org/
An efficient synthesis of thioglycosylated benzo[e][1,4]oxathiepin-5-one and benzothiazepinone derivatives by a sequence
of a palladium-catalyzed glycosyl thiols arylation followed by deprotection-lactonization reactions has been reported. This
diversity-oriented strategy enabled an access to unknown complex cyclic scaffolds with polyhydroxylated appendages of
biological interests.
Introduction
1
Glycosyl thiol
Coupling
Arylthioglycosides are an important family of natural or
I
O
R
cat. L
S
1
(AcO)3
synthetic products that exhibit various biological activities
O
R
R
SH
MeO
R
(
AcO)3
+
2
3
2
MeO C
including control of hyperglycemia in diabete, antibacterial
O
3
4
and anticancer activities. Moreover, they are a rich source of
building blocks to access complex architectures having various
2 Cyclization
R = OAc, NHAc
MeO
5
biological activities. Thus, continuing demand to synthesize
OH
O
glycosides-based drugs requires the development of fast and
easy synthetic methods. In this context, diversity-oriented
S
(
HO)3
S
S
N
AcO
Z
R
HN
4
O
6
O
S
O
synthesis continues to be an essential area to generate libraries
Thioglycosylated
benzoxathiepinone (Z = O) or
benzothiazepinone (Z = NAc)
of molecules by varying functional groups, building blocks,
stereochemistry, and molecular frameworks in order to obtain
molecular diversity. However, carbohydrates remain relatively
underexplored which is due in part to the difficulty associated
with the chemistry related to sugars.
As part of our efforts on the development of efficient methods
to functionalize carbohydrates via transition-metal catalysis for
generating an original collection of heterosides,7 we have
NMe2
kb-NB142-70
PKD Inhibitor
Diltiazem
nondihydropyridines (non-DHP)
calcium channel blocker
Scheme 1. General strategy to fused thioglycosyl
benzo[e][1,4]oxathiepin-5-ones and benzo[f][1,4]thiazepin-
5
(2H)-ones
3 could be utilized as partners in the synthesis of fused
thioglycosyl benzoxathiepinones or benzothiazepinones
through a cyclization reaction (Scheme 1). This modular strategy
is conceptually attractive in terms of diversifying the
benzoxathiepinone and benzothiazepinone frameworks with
the aim to identify novel scaffolds of biological interest such as
kb-NB142-70 , a protein kinase D inhibitor, or Diltiazem , a
marketed drug to treat hypertension, angina pectoris and some
types of arrhythmia (Scheme 1). Herein, we described our
findings on the sequential coupling/cyclization reactions of
easily accessed substituted methyl 2-iodobenzoate and a wide
range of glycosyl thiols to afford various fused thioglycosyl
benzoxathiepinone and benzothiazepinone derivatives of type
disclosed that
α- and β-glycosyl thiols can serve as effective
nucleophiles for Buchwald-Hartwig type-coupling reactions
using functionalized organic halides, including aryl, heteroaryl,
alkenyl and alkynyl halides.7a-c The functional group tolerance
on the electrophilic partner is typically high and anomer
selectivities of thioglycosides are high in all cases studied. In our
continuation to develop efficient methodologies to access
complex heterosides, we envisioned that thioglycosides of type
8
9
a.
Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique,
4
.
Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5
rue J.-B. Clément, Châtenay-Malabry, F-92296, France.
Email : samir.messaoudi@u-psud.fr, mouad.alami@u-psud.fr
b.
Results and discussion
†
Electronic Supplementary Information (ESI) available: 1H, 13C, COSY, HSQC,
To achieve successfully our goal, we initially prepared
HMBC and NOESY NMR spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
Table 1. Optimization of the synthesis of 4aa
View Article Online
Scheme 2: Pd-Catalyzed coupling of peracetylated glycosyl
thiols 1 with various methyl 2-iodobenzoates 2.
DOI: 10.1039/C5OB01603G
a
AcO
AcO
AcO
O
HO
HO
HO
O
base
(
x
equiv)
O
O
HO
O
S
S
HO
S
OAc
MeO C
HO
O
Pd(OAc)
Xantphos (2.5 mol%)
Et N (1.5 equiv) (AcO)
3
2
(5 mol%)
MeOH, RT,
time
3
a
2
4a
O
5a
O
O
R
I
S
O
R
3
+
SH
R
R
(AcO)
3
MeO
dioxane, 100 °C, 1 - 2 h
MeO C
2
Entry Base (x equiv)
T(°C) Time (h)
Ratio
Yield
(%)c
1
, R = OAc, NHAc
O
2
3
5ab
4a/
1
2
3
4
5
6
K
2
2
CO
CO
3
3
(2)
(1)
50
20
20
20
20
20
12
2
0/100
0/100
0/100
56/44
100/0
100/0
62
87
82
-
AcO
AcO
AcO
AcO
AcO
O
O
O
AcO
S
C
S
C
S
C
Me
Me
K
AcO
AcO
AcO
OAc
MeO
OAc
MeO
OAc
MeO
MeONa (1)
2
2
2
Me
2
a, 100%b
3b, 95%b
3c, 83%b
MeONa (0.5)
2
3
K
2
CO
3
(1)
0.16
0.5
99
99
AcO
O
S
AcO
AcO
2
K CO (0.3)
AcO
Cl
O
O
3
AcO
AcO
S
AcO
S
CO
2
Me
AcO
AcO
OAc
MeO
OAc
MeO
OAc
MeO
2
C
3f, 66%b
a
Conditions: To a mixture 3a (0.1 mmol) and base in MeOH (3 mL) was
2
C
2
C
Br
b
d, 92%b
3e, 73%b
stirred under argon atmosphere. The ratio 4a
/
5a was determined by
3
1
AcO OAc
AcO OAc
H NMR on the crude reaction mixture and is based on the chemical
AcO
O
S
O
O
AcO
S
C
S
C
shift of the anomeric proton signal (ppm) (4.76 ppm for 4a and 4.36
ppm for 5a) c Yield of isolated compound.
AcO
AcO
AcO
OAc
EtO
OAc
MeO
OAc
MeO
2
C
2
2
Me
3
g, 93%b
3h, 93%b
3i, 85%b
AcO OAc
O
β−anomers (
separation by flash chromatography column, compounds
-3l, -3m, -3m were easily isolated in 60%, 37%, 32% and
1%, respectively (Scheme 2).
β
-3l/
α
-3l 62:38;
β
-3m/
α
-3m 55:45). After a
AcO
AcO
AcO
AcO
AcO
O
O
O
S
C
AcO
O
S
C
S
C
β
-3l,
AcO
AcO
AcO
OAc
OAc
MeO
OAc
MeO
AcHN
MeO
2
α
3
β
α
2
Br
2
3
j, 63%b
3k, (
α/β
mixture 2:8), 92%b
β−3l, 60%b
AcO
AcO
AcO
OAc
O
OAc
O
Following the selective preparation of thioglycosides 3a-k, we
expected that after selective removing the O-acetyl groups, the
resulting OH at C2’ position of the sugar moiety can undergo
further lactonization with the ester function of the aromatic
nucleus to lead to disubstituted fused thioglycosyl
benzoxathiepinones 4a-k. To determinate the feasibility of the
CO
2
Me
O
AcO
AcO
AcO
S
AcHN
AcO
CO Me
2
S
AcHN
AcHN
S
MeO
2
C
Me
α−3l, 37%
b
3m, 32%
b
α−3m, 31%
b
Me
β−
a
Reactions of
1
(1 equiv) with
2
(1.2 equiv) were performed in a sealed
(5 mol%),
(1.5 equiv). b Yield of isolated product.
tube at 100 °C in dioxane (0.05 M) by using Pd(OAc)
Xantphos (2.5 mol%), NEt
2
C-2 lactonization of intermediates 3a-k, we examined at first,
3
the Zemplen
10,11
deprotection/cyclization sequence of 3a as a
model study. To this end, various reaction conditions (base,
selectively a series of thioglycosides of type 3 by coupling solvent and temperature) were screened and representative
various substituted methyl 2-iodobenzoates with peracetylated results from this study are summarized in Table 1. It was found
7
a
glycosyl thiols under our previously reported protocol
2 3
that the reaction of 3a (1 equiv) in the presence of K CO (2
[
Pd(OAc)
2
(5 mol%), Xantphos (2.5 mol%), NEt
3
(1.5 equiv), equiv) for 12 h at 50 °C furnished exclusively the non-expected
dioxane, 100 °C for 1 h] (Scheme 1).
sulfoxide 5a in a 62% yield (entry 1). Achieving the reaction at
room temperature for 2 h with only 1 equivalent of K
led to 5a but with a better 87% yield (entry 2). A Similar yield of
a (82%) was obtained when sodium methoxide was used
instead of K CO (entry 3). Of note, sulfoxide 5a arises from the
oxidation of 4a in the presence of base in methanol. These
results clearly indicate that the thioglycoside 4a is highly
sensitive to the oxidative process under our reaction conditions.
Interestingly, reducing the amount of MeONa to 0.5 equivalent
lead to a mixture of 4a/5a in a 56:44 ratio (entry 4), while the
desired non-oxidized thioglycoside 4a was isolated exclusively
2 3
CO also
As depicted in Scheme 2, peracetylated 1-thio-β-D-
glucopyranose was readily coupled with methyl 2-iodobenzoate
having para and meta electron-donating or electron
withdrawing substituents to give thioglycosylated products 3a-
f in good to excellent yields with complete β-selectivity. Z-
methyl-3-iodo-acrylate is also a suitable coupling partner with
5
2
3
1
2
thioglycoside 1 furnishing stereoselectively β-thioglycosidated
Z-alkene 3g without any thermal isomerization, clearly
demonstrating the mild nature of this cross-coupling reaction.
In addition, the reaction is general with respect to the sugar
when the reaction was performed in the presence of K
equiv) at room temperature with a short time of 10 min (entry
). In summary, the best conditions were found to require
thioglycoside 3a (1 equiv), K CO (30 mol%) in MeOH (3 mL) as
2 3
CO (1
configuration as peracetylated 1-thio-
acetyl-1-thio- -aminoglucopyranose as well as peracetylated
-thio- -cellobiose give the corresponding products 3h-k in
β-D-galactopyranose, N-
β-D
5
1
β-D
2
3
good yields. Of note, that longer reaction time was required (12
h vs 1 to 2 h) for achieving complete conversion of the reaction
the solvent at room temperature for 30 min. Under these
conditions, 4a was isolated in a quantitative yield (entry 6).
Motivated by these results, we next explored the scope of the
of methyl 2-iodobenzoate derivatives with N-acetyl-1-thio-
aminogluco-pyranose. In these cases, the coupling worked well
3l: 97%, 3m: 63%), but furnished a mixture of α− and
β-D-
deprotection/lactonization
sequence
with
previously
(
synthesized thioglycosides 3a-k. Gratifyingly, fused thioglycosyl
2
| J. Name., 2012, 00, 1-3
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View Article Online
2 3
anomer α−3l in the presence of only 1 equivalent of K CO , the
α−thioglycoside 4m was isolated in a quantitative yield and no
trace of benzothiazepinone oxide was observed (Scheme 4, eq.
2).
Scheme 3: Scope of the deprotection/cyclization reactionsa
DOI: 10.1039/C5OB01603G
O
S
K
2
CO
3
(0.3 equiv)
O
O
(AcO)
3
S
(HO)
3
OAc
MeO
2
C
R
R
MeOH, RT,
0 min to 1 h
O
3
3
4
To understand the influence of the electronic effects on the
aromatic nucleus in the outcome of the lactamization step, a
same study was conducted with α−3m and β−3m anomers
having an additional methyl group on the aromatic nucleus.
Surprisingly, the presence of this methyl group interferes in the
rate of the lactamization step. In the case of the anomer β−3m,
the cyclized product 4n was obtained in a 52% yield when β−3m
was stirred in the presence of 1 equivalent of the base during 3
days at room temperature, whereas, its anomer α−3m could
never be cyclized even when the reaction was performed at 50
HO
HO
HO
O
O
O
O
HO
S
HO
S
HO
S
Me
Me
HO
HO
HO
O
O
O
O
Me
O
4
a, 98%b
4b, 99%b
4c, 87%b
HO
HO
Cl HO
HO
HO
HO
HO
O
O
O
O
O
HO
S
S
S
CO
2
Me
HO
O
O
O
O
Br
4
d, 97%b
4e, 98%b
4f, 99%b
HO OH
O
OH
HO
OH
O
HO
HO
HO
O
S
S
S
°
C for 3 days. Under these conditions, the compound 6a,
HO
O
O
O
O
O
O
Me
resulting only from removal of the O-acetate groups of the
sugar moiety, was isolated in a 60% yield.
4
g, 98%b
4h, 97%b
4i, 97%b
OH OH
O
HO
HO
HO
HO
Scheme 4: lactamization conditions of
β
-3l,
α
-3l,
β
-3m,
α
-3m
a
O
O
O
S
O
S
HO
HO
eq.1
O
OH
AcO
O
O
Br
O
O
HO
AcO
S
K CO (5 equiv)
2
3
O
j, 96%b
4k α/β mixture 2:8), 98%b
HO
S
4
AcO
,
(
HO
NHAc
MeOH, RT,
7 days
AcN
a
MeO
2
C
Conditions: To a mixture
3
(0.1 mmol) and K
2
CO
3
(0.3 equiv) in MeOH
O
b
β−3l
5b, 99%
b
(1 mL) was stirred under argon atmosphere. Yield of isolated
compound.
HO
HO
O
HO
benzoxathiepinones 4 bearing a wide variety of functional
groups could be synthesized in good to excellent yields (Scheme
). Electron-donating and electro-withdrawing functions on the
aromatic ring, were well tolerated. The presence of C-Br and C-
Cl bonds in compounds 4d,e and 4j provided a handle for
further diversifications under transition metal-catalysis. It is
noteworthy that the lactonization reaction of vinylthioglycose
derivative 3g having a Z-double bond, succeeded and leads to
the formation of the bicyclic compound 4g in a 98% yield.
eq.2
O
S
K CO (2 equiv)
AcN
2
3
AcO
AcO
AcO
O
MeOH, RT,
2 days
3
O
c, 98%b
5
AcHN
S
C
HO
HO
O
α−
3
l
HO
MeO
2
K CO (1 equiv)
AcN
S
2
3
MeOH, RT,
12 h
O
4
m, 98%b
eq.3
eq.4
In a further set of experiments, we investigated the scope and
AcO
O
HO
HO
HO
AcO
S
K CO (1 equiv)
2
3
O
generality of the method with respect to substrates
β
-3l,
α
-3l,
AcO
S
NHAc
MeO C
MeOH, RT,
AcN
β
-3m and -3m bearing an N-acetyl function at C2’ position of
α
2
Me
3
days
O
Me
the sugar moiety (Scheme 4). It was found that the rate of the
cyclisation step strongly depends on the nature of the
nucleophile at the C2’ position (O- vs N-nucleophile). Thus,
when starting from 3a the lactonization reaction took place
within 10 min affording 4a in an excellent yield, whereas the
β−3m
4n, 52%
b
HO
HO
HO
AcO
AcO
AcO
K
CO
(1 equiv)
O
O
2
3
MeOH, 50°C,
days
AcHN
AcHN
S
S
3
α−3m
MeO
MeO C
Me
lactamization of the N-acetyl-1-thio-β-D-aminoglycoside β-3l
2
C
Me
2
6a, 60%
was found to be sluggish. The cyclization step occurs only when
five equivalents of the base were used during seven days stirring
at room temperature. Under these conditions, removal of the isolated compound.
a
Conditions: To a mixture
CO
β
-3l,
α
-3l,
β
-3m,
α
-3m (0.1 mmol) and
b
K
2
3
in MeOH (1 mL) was stirred under argon atmosphere. Yield of
O-acetate groups of the sugar moiety followed by the
lactamization step as well as the sulfur atom oxidation lead to
the benzothiazepinone oxide 5b in a 99% yield (Scheme 4, eq.
To gain a better insight into the lactamization step of both β−3l
and α−3l anomers (Scheme 4), we have carried out a
computational study on the corresponding acetamide
1). Interestingly, when thioglycoside α-3l was used instead of
1
3
intermediates at the B3LYP/6-31G* level. We have assumed
that deacylation of the hydroxyl groups belonging to the
pyrannose moiety happened early in this process, and that the
it’s anomer β−3l, only 2 equivalents of the base and 2 days
reaction time were required for total conversion, leading to
benzothiazepinone oxide 5c in a quantitative yield without any rate-limiting step was the attack of the methyl ester group on
anomerisation. This result clearly indicates that the the aromatic ring.
lactamization reaction of the anomer α−3l is faster than β−3l For each anomer, we have therefore tested two scenarios,
starting from the free-hydroxy anionic intermediate, namely
those in which the aromatic methyl ester is attacked on its Si or
probably for conformational considerations. In contrast to
thioglycoside β−3l, when achieving the cyclization step from the
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ARTICLE
Journal Name
Re face, and searched the potential energy surfaces for the
cyclisation transition states. Comparison of the corresponding
Conclusions
View Article Online
DOI: 10.1039/C5OB01603G
In conclusion, we developed an efficient and practical protocol
for the synthesis of substituted fused thioglycosyl
benzoxathiepinones
and
benzothiazepinones.
This
transformation exhibited broad substrate scope with respect to
both the aryl iodides and thiosugar partners. We believe that
this methodology should find broad applications in synthetic
organic chemistry, as well as in the combinatorial and
pharmaceutical sciences.
Experimental
Figure 1. "Energy diagrams for Energy diagram for the lowest
the two possible cyclisation energy cyclisation pathways of
pathways of the α−3l. Free the β−3l. Free energies are
energies are indicated in indicated in kcal/mol. IR1
kcal/mol. IR1 designates the designates the open anionic
open anionic intermediate, IR2 intermediate, IR2 the cyclised
and IR2' the cyclised tetrahedral tetrahedral intermediate and TS
intermediates and TS/TS' the the transition state (not shown)
respective transition states."
General experimental methods
The compounds were all identified by usual physical methods,
e.g., 1H NMR, 13C NMR, IR, MS (ESI). 1H and 13C NMR spectra
were measured in CDCl3, DMSO-d6 with a Bruker Avance-300.
1H chemical shifts are reported in ppm from an internal
standard TMS or of residual solvent peak. 13C chemical shifts
are reported in ppm from the residual solvent peak. IR spectra
were measured on a Bruker Vector 22 spectrophotometer.
Analytical TLC was performed on Merck precoated silica gel 60F
plates. Merck silica gel 60 (0.015–0.040 mm) was used for
column chromatography. Melting points were recorded on a
Büchi B-450 apparatus and are uncorrected. High resolution
mass spectra (HR-MS) were recorded on a Bruker MicroTOF
spectrometer, using ESI with methanol as the carrier solvent.
Nominal and exact m/z values are reported in Daltons.
free energy profiles (10.9 Kcal and 11.1 kcal for α−3l and β−3l,
respectively) (Figure 1) indicated that the pathways
involving α−3l anomer were kinetically favoured. Moreover, as
it is shown in Figure 2, no Si or Re face preference for the attack
on the ester is found. The two alternative transition states (A)
and (B) occur with a C−N distance of 2.00 and 1.98 A
respectively (Figure 2), and with an attack angle of 109.8 or
1
08.6° for (A) and (B), respectively.
General information
All reactions were conducted under argon atmosphere. Solvents:
Cyclohexane, Ethyl acetate (EtOAc), Methanol (MeOH), Acetone,
Dioxane and dichloromethane (CH
2
Cl
2
)
for extraction and
chromatography were technical grade
Experimental Section
Figure 2. Geometries calculated at the B3LYP/6-31G* level for
the two equiprobable transition states (A: Re face attack) and
Instrumentation
(
B: Si face attack) leading to cyclisation of the
α
-3l.
1
The compounds were all identified by usual physical methods, i.e.; H
Examination of the frontier molecular orbitals showed that the NMR, 13C NMR (J-MOD), IR, MS (ESI, APCI), 2D NMR. H and 13C NMR
1
HOMO was mostly located around the nucleophilic nitrogen spectra were measured in CDCl
3 4 6
, MeOD or DMSO4-d , with a Bruker
atom belonging to the acetamide, whereas the LUMO was
distributed all over the aromatic carbonyl system (Figure 3).
Moreover, a better overlap of the two FMO seemed possible in
the case of the α-anomer than in the case of the β one, probably
accounting for the difference of reactivity observed.
1
Avance-300. H chemical shifts are reported in ppm from an internal
standard TMS or of residual chloroform (7.27 ppm) or residual MeOH
(
(
3.3 ppm). The following observations are used: s (singlet), d
doublet), t (triplet), dd (douplet of doublet), m (multiplet), td (triplet
of doublet), q (quadruplet). 13C chemical shifts are reported in ppm
from the central peak of deteriorated chloroform (77.14 ppm) or
deteriorated methanol (49.0 ppm). IR spectra were measured on a
Bruker Vector 22 spectrometer and are reported in wave
-
1
numbers(cm ).Reaction courses and products were routinely
monitored by analytical TLC which were performed on Merk
precoated silica gel plates (60-F254).Flash chromatography was
performed on silica gel 60 (0.040-0.063 mm) and compounds were
visualized under a UVP Mineralight UVGL-58 lamp (254 nm) and with
Figure 3. HOMO and LUMO for the Re and Si face attacks in the
case of the anomer α-3l.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 12
Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Journal Name
ARTICLE
vanillin/Δ, or phosphomolybdic acid/Δ. Melting points (mp) were 5.25 (t, J = 9.3 Hz, 1H), 5.07 (td, J = 9.5, 7.8 Hz, 2H), 4.V8ie2w(Adr,ticJle=O1n0lin.1e
recorded on a Büchi B-450 apparatus and were uncorrected.
Hz, 1H), 4.19 (qd, J = 12.3, 3.9 Hz, 2H), 3.87 (sD, O3HI:)1,03.1.70389(/dCd5dO,BJ0=161003.0G,
13
5
.4, 2.4 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 2.02 (s, 6H), 1.99 (s, 3H); C
NMR (75 MHz, CDCl ) δ (ppm):170.9 (C=O), 170.6 (C=O), 169.8 (C=O),
69.60(C=O), 167.5 (C=O), 137.4 (C), 133.4 (CH), 132.4 (C), 132.1 (C),
31.6 (CH), 131.1 (CH), 85.2 (CH), 76.1 (CH), 74.4 (CH), 70.2 (CH), 68.7
), 52.6 (CH ), 21.2 (CH ), 21.2 (CH ), 21.1 (CH ), 21.0
); HR-MS(ESI): for C23 11(M + Na) : m/z calcd 535.1250,
Typical procedure for Pd-catalyzed coupling of thioglycosides (1)
with various substituted methyl 2-iodobenzoates (2).
A flame dried re-sealable Schlenk tube (5 ml) was charged with
Pd(OAc) (5 mmol%), Xantphos (2.5 mol%), thioglycosides (0.54
2
mmol, 1.5 equiv), methyl-2-iodobenzoates (0.36 mmol, 1.0 equiv).
The Schlenk tube was capped with a rubber septum, evacuated and
3
1
1
(
(
CH), 62.7 (CH
2CH
2
3
3
3
3
+
3
28
H O
found 535,1251.
backfilled with argon; then, dioxane (1.5 ml) and Et
3
N (0.36 mmol,
1.5 equiv) were added through the septum. The septum was (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(methoxycarbonyl)-4,5-
replaced with a Teflon screw cap. The Schlenk tube was sealed and dimethylphenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl
the mixture was stirred at 100 °C for 1 h. The resulting suspension (3c).
triacetate
was cooled to room temperature and filtered through celite eluting
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg, 0.54 mmol) and methyl 2-iodo-4,5-
dimethylbenzoate 2c (104.5 mg, 0.36 mmol) was heated for 1 h., The
residue was purified by flash chromatography over silica gel
(Cyclohexane: ethyl acetate 8:2) to afford the desired product 3c
(158 mg, 0.244 mmol, 83%) as a white solid; mp (114.5-115.5°C); TLC:
with ethyl acetate. The filtrate was concentrated and the residue
purified by flash chromatography over silica gel to afford the desired
intermediate products (3a-m).
(
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl
triacetate (3a).
f
R = 0.63 (Cyclohexane: ethyl acetate1:1); IR (thin film, neat)
−1
ν
1
8
max/cm : 1755 ,1746 ,1712 ,1603 ,1549, 1486, 1434, 1366, 1306,
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg, 0.54 mmol) and methyl 2-iodobenzoate 2a
285, 1225, 1209, 1161, 1124, 1089, 1062, 1034, 978, 937, 914, 828,
1
08, 784, 736, 702, 675, 645; H NMR(300 MHz, CDCl3) δ( ppm):7.64
(
94.5 mg, 0.36 mmol) was heated for 1 h. The residue was purified
by flash chromatography over silica gel (cyclohexane: ethyl acetate
:3) to afford the desired product 3a (179 mg, 0.36 mmol, 100%) as
a white solid; mp (136.5-137.5°C); TLC: R = 0.5 (Cyclohexane: ethyl
(
s, 1H), 7.36 (s, 1H), 5.31 – 5.22 (m, 1H), 5.07 (dd, J = 19.3, 8.0 Hz,
2
3
2
H), 4.84 (d, J = 10.1 Hz, 1H), 4.21 (dt, J = 25.8, 7.7 Hz, 2H), 3.86 (s,
H), 3.80 (dd, J = 7.7, 5.4 Hz, 1H), 2.30 (s, 3H), 2.25 (d, J = 5.6 Hz, 3H),
.07 (s, 3H), 2.03 (s, 6H), 1.99 (s, 3H); 13C NMR (75 MHz, CDCl
3
) δ
7
f
−1
acetate 1:1); IR (thin film, neat) νmax/cm : 1755, 1714, 1644, 1467,
435, 1367, 1253, 1212, 1112, 1037, 913, 829, 748; 1H NMR (300
MHz, CDCl ) δ ( ppm): 7.82 (dd, J = 7.8, 1.5 Hz, 1H), 7.52 (d, J = 7.2 Hz,
H), 7.39 (td, J = 7.7, 1.6 Hz, 1H), 7.23 (td, J = 7.7, 1.1 Hz, 1H), 5.22
dd, J = 12.0, 6.4 Hz, 1H), 5.04 (td, J = 9.8, 2.1 Hz, 2H), 4.82 (d, J = 10.1
Hz, 1H), 4.13 (qd, J = 12.3, 4.1 Hz, 2H), 3.83 (s, 3H), 3.79 – 3.69 (m,
H), 2.01 (s, 3H), 1.97 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H); 13C NMR (75
MHz, CDCl ) δ (ppm): 170.7 (C=O), 170.3 (C=O), 169.5 (C=O), 169.3 (2R, 3R, 4S, 5R, 6S) – 2 - (acetoxymethyl) - 6 - ( ( 5 – chloro – 2 -
C=O), 166.9 (C=O), 136.7 (C), 132.4 (CH), 131.0 (C) 130.9 (CH), 129.6 (methoxycarbonyl) phenyl ) thio ) tetrahydro - 2H – pyran – 3 , 4 ,5
CH), 126.5 (CH), 84.5 (CH), 77.2 (CH), 75.9 (CH), 74.1(CH), 69.9(CH), -triyl triacetate (3d).
8.5, 62.5 (CH ), 52.4 (CH ), 20.9 (CH ), 20.8 (CH ), 20.7 (2CH ); HR-
MS(ESI): for C22 11S (M + Na) : m/z calcd 521.1094, found
21.1099.
(
(
(
ppm): 170.7 (C=O), 170.3 (C=O), 169.5 (C=O), 169.3 (C=O), 167.1
C=O), 141.6 (C), 135.6 (C), 132.6 (C), 131.9 (CH), 131.8 (CH), 129.0
1
3
C), 84.9 (CH), 75.8 (CH), 74.5 (CH), 69.9 (CH), 68.4 (CH), 62.6 (CH
2.1 (CH ), 20.8 (CH ), 20.8 (CH ), 20.7 (2CH ), 20.3 (CH ), 19.3 (CH
HR-MS(ESI): for C24 11S (M + Na) : m/z calcd 549.1407 found
49.1409.
),
2
1
(
5
3
3
3
3
3
3
);
+
30
H O
5
1
3
(
(
6
2
3
3
3
3
+
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg, 0.54 mmol) and methyl 4-chloro-2-
iodobenzoate 2d (106.5 mg, 0.36 mmol) was heated for 1 h., The
residue was purified by flash chromatography over silica gel
(Cyclohexane: ethyl acetate 7:3 to 4:6) to afford the desired product
26
H O
5
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(methoxycarbonyl)-4-
methylphenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3b).
3
d (147 mg, 0.244 mmol, 92%) as a white to light yellow solid; mp
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg, 0.54 mmol) and methyl 2-iodo-5-
methylbenzoate 2b (99.5 mg, 0.36 mmol) was heated for 1 h. The
residue was purified by flash chromatography over silica gel
(
182-183°C), TLC: R = 0.64 (Cyclohexane: ethyl acetate 1:1); IR (thin
f
−1
film, neat) νmax/cm :1745, 1722, 1581, 1552, 1466, 1433, 1383,
1366, 1300, 1244, 1215, 1111, 1085, 1032, 975, 921, 834, 768, 736,
1
3
684; H NMR (300 MHz, CDCl ) δ ( ppm): 7.91 (d, J = 8.4 Hz, 1H), 7.58
(
3
°
ν
Cyclohexane: ethyl acetate 7:3 to 4:6) to afford the desired product
b (175.0 mg, 0.341 mmol, 95%) as a beige solid; mp (136.5-137.5
C); TLC: R = 0.5 (Cyclohexane: ethyl acetate 1:1); IR (thin film, neat)
max/cm : 1755, 1715, 1475, 1435, 1367, 1300, 1248, 1210, 1115,
090, 1036, 978, 914, 827, 785 ;1H NMR (300 MHz, CDCl
) δ
ppm):7.66 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 21.8 Hz, 1H),
(
d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.5, 2.0 Hz, 1H), 5.34 (dd, J = 11.1, 7.4
Hz, 1H), 5.14 (dt, J = 11.8, 9.8 Hz, 2H), 4.94 (d, J = 10.1 Hz, 1H), 4.23
d, J = 4.3 Hz, 2H), 3.95 (d, J = 4.0 Hz, 1H), 3.92 (s, 3H), 2.14 (s, 3H),
.08 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H); 13C NMR (75 MHz, CDCl
) δ (
ppm): 170.8 (C=O), 170.2 (C=O), 169.5 (C=O), 169.2 (C=O), 139.9 (C),
f
(
2
−1
3
1
3
(
138.8 (C), 132.3 (CH), 128.2 (CH), 128.0 (C), 126.2 (CH), 83.9 (CH),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Page 6 of 12
ARTICLE Journal Name
2 3
6.1 (CH), 74.1 (CH), 69.8 (CH), 68.4 (CH), 62.6 (CH ), 52.5 (CH ), 20.9 Following the general procedure of coupling, aViewmAirxtitculerOenlionef
7
(
CH
3 3 3
), 20.8 (CH ), 20.7 (2CH ); HR-MS(ESI): for C22H
25ClO11S (M + Na)+: thioglucose 1a (200 mg,0.54mmol) and (Z)-ethyl 3-iodoacrylate 2g
(81.5 mg,0.36 mmol) was heated for 1 h., The residue was purified
DOI: 10.1039/C5OB01603G
m/z calcd 555.00704, found 555.0702.
by flash chromatography over silica gel (Cyclohexane: ethyl acetate
(
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((4-bromo-2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl
7:3) to afford the desired product 3g (76 mg, 0.33 mmol, 93%) as a
white solid; mp (163-164°C); TLC: R = 0.5 (Cyclohexane:ethyl acetate
f
triacetate (3e).
−1
1
2
9
5
4
:1); IR (thin film, neat) νmax/cm : 3481, 3359, 3215, 3182, 3090,
188, 2161, 1756,1699, 1580, 1374, 1215, 1171, 1093, 1061, 1034,
15, 804; 1H NMR (300 MHz, CDCl
.99 (d, J = 10.1 Hz, 1H), 5.29 – 5.10 (m, 3H), 4.62 (d, J = 9.9 Hz, 1H),
.31 – 4.10 (m, 4H), 3.85 – 3.74 (m, 1H), 2.08 (s, 3H), 2.03 (s, 6H), 2.01
s, 3H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg,0.54mmol) and methyl 5-bromo-2-
iodobenzoate 2e (123 mg, 0.36 mmol) was heated for 1 h. The
residue was purified by flash chromatography over silica gel
(
3
3
) δ ( ppm): 7.29 – 7.16 (m, 1H),
(
3
) δ (ppm):
Cyclohexane: ethyl acetate 7:3 to 4:6) to afford the desired product
e (152.0 mg, 0.26 mmol, 73%)as a beige rosee solid; mp (114.5-
1
1
6
2
70.66(C=O), 170.22(C=O), 169.40(C=O), 169.14(C=O), 166.42(C=O),
42.21(CH), 115.73(CH), 83.05(CH), 76.57(CH), 73.86(CH), 70.15(CH),
1
15.5 °C); TLC: R = 0.64 (Cyclohexane: ethyl acetate 1:1); IR (thin film,
f
8.11(CH), 62.03(CH
0.65(2CH ), 14.38(CH
2
), 60.55(CH), 20.80(CH
3 3
), 20.70(CH ),
−1
neat) νmax/cm : 1755, 1719, 1461, 1435, 1366, 1299, 1240, 1208,
1
+
3
3
); HR-MS (ESI): for C19 11S (M + Na) : m/z
26
H O
1
114, 1088, 1030, 961, 913, 826, 782, 734, 702; H NMR (300 MHz,
calcd 485.1094, found 485.1096.
CDCl
.47 (d, J = 8.6 Hz, 1H), 5.31 – 5.21 (m, 1H), 5.13 – 5.03 (m, 2H), 4.83
d, J = 10.1 Hz, 1H), 4.18 (qd, J = 12.3, 4.0 Hz, 2H), 3.88 (s, 3H), 3.78
3
) δ (ppm): 8.00 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.6, 2.3 Hz, 1H),
7
(
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl
(
(
(
1
3
dd, J = 8.8, 4.3 Hz, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H); C NMR
75 MHz, CDCl ) δ (ppm): 171.0 (C=O), 170.7 (C=O), 169.9 (C=O),
triacetate (3h).
3
169.7 (C=O), 166.0 (C=O), 135.9 (C), 135.5 (CH), 134.1 (C), 133.1 (C), Following the general procedure of coupling, a mixture of
131.9 (CH), 120.9 (CH), 84.7 (CH), 76.4 (CH), 74.4 (CH), 70.3 (CH), 68.8 thiogalactose 1b (200 mg, 0.54 mmol) and methyl 2-iodobenzoate
(
(
CH), 62.8 (CH
2 3 3 3
), 53.1 (CH), 27.4 (CH ), 21.3 (CH ), 21.2 (CH ), 21.1 2a (94.5 mg, 0.36 mmol) was heated for 1 h. The residue was purified
+
2CH ); HR-MS(ESI): for C22
3
H
25BrO11S (M + Na) : m/z calcd 599.0199, by flash chromatography over silica gel (Cyclohexane:ethyl acetate
7:3-4:6) to afford the desired product 3h (167 mg, 0.33 mmol, 93%)as
found 599.0206.
f
a beige solid; mp (54.3-55.3 °C); TLC: R = 0.53 (Cyclohexane: ethyl
acetate 1:1); IR (thin film, neat) νmax/cm : 2922, 1746, 1712, 1588,
Dimethyl 2-(((2S,3R,4S,5R,6R)-3,4,5-triacetoxy-6-
acetoxymethyl)tetrahydro-2H-pyran-2-yl)thio)terephthalate (3f).
−1
(
1
1
565, 1468, 1435, 1367, 1295, 1253, 1208, 1144, 1110, 1083,1058,
039, 1015, 950, 917, 897, 828, 750, 734, 655; 1H NMR (300 MHz,
Following the general procedure of coupling, a mixture of
thioglucose 1a (200 mg, 0.54 mmol) and dimethyl 2-
iodoterephthalate 2f (104.5 mg, 0.36 mmol) was heated for 1 h., The
CDCl
.72 (td, J = 7.8, 1.6 Hz, 1H), 7.56 (ddd, J = 7.6, 6.7, 1.1 Hz, 1H), 5.74
dd, J = 3.2, 0.6 Hz, 1H), 5.68 – 5.56 (m, 1H), 5.38 (dd, J = 9.9, 3.4 Hz,
3
) δ ( ppm): 8.15 (dd, J = 7.8, 1.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),
7
(
residue was purified by flash chromatography over silica gel
1H), 5.15 (d, J = 10.0 Hz, 1H), 4.43 (qd, J = 11.3, 6.5 Hz, 2H), 4.30 (t, J
(
Cyclohexane: ethyl acetate 7:3) to afford the desired product 3f (85
mg, 0.15 mmol, 66%) as a light beige solid mp (155.5-156.5°C); TLC:
= 0.63 (Cyclohexane: ethyl acetate1:1); IR (thin film, neat)
=
6.5 Hz, 1H), 4.17 (s, 3H), 2.44 (s, 3H), 2.32 (d, J = 2.0 Hz, 6H), 2.26
13
(
s, 3H); C NMR (75 MHz, CDCl
3
) δ (ppm): 170.73(C=O), 170.61(C=O),
70.43(C=O), 169.69(C=O), 167.17(C=O), 137.25(C), 132.56(CH),
31.15(CH), 131.04(C), 129.73(CH), 126.63(CH), 85.12(CH),
4.83(CH), 72.45(CH), 67.70(CH), 67.30(CH), 62.23(CH ), 52.58(CH ),
); HR-MS (ESI): for C22
R
ν
1
f
1
1
7
2
+
−1
max/cm : 1746, 1722, 1433, 1383, 1365, 1288, 1246, 1215, 1153,
1
126, 1115, 1084, 1035, 979, 920, 897, 857, 828, 745; H NMR (300
2
3
MHz, CDCl3) δ ( ppm): 8.24 (d, J = 1.2 Hz, 1H), 7.92 (dt, J = 8.1, 4.7 Hz,
1.13(CH
3
), 21.06(2CH
3
), 20.97(CH
3
26
H O11S (M
2
1
1
H), 5.31 (dd, J = 11.1, 7.3 Hz, 1H), 5.16 (t, J = 9.6 Hz, 2H), 4.97 (d, J =
+
Na) : m/z calcd 521.1094, found 521.1091.
0.0 Hz, 1H), 4.29 (dd, J = 12.4, 5.2 Hz, 2H), 4.18 (dd, J = 12.4, 2.1 Hz,
13
H), 3.95 (s, 3H), 3.92 (s, 3H), 2.04 (d, J = 2.3 Hz, 9H), 2.01 (s, 3H); C
) δ (ppm): 170.8 (C=O), 170.2 (C=O), 169.5 (C=O),
69.3 (C=O), 166.2 (C=O), 165.7 (C=O), 137.7 (C), 133.7 (C), 133.5 (C),
30.9 (CH), 129.9(CH), 126.9 (CH), 84.1 (CH), 76.0(CH), 74.1 (CH), 69.8 Following the general procedure of coupling, a mixture of
), 52.7 (CH ), 52.6 (CH ), 30.0 (CH ), 20.7 thiogalactose 1b (200 mg, 0.54 mmol) and methyl 2-iodo-5-
); HR-MS(ESI): for C24
79.1148 found 579.1144.
(
2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(methoxycarbonyl)-4-
NMR (75 MHz, CDCl
3
methylphenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3i).
1
1
(
(
CH), 68.2 (CH), 62.1 (CH
CH ), 20.7 (2CH
2
3
3
3
+
3
3
H
30
O
11S (M + Na) : m/z calcd methylbenzoate 2b (94.5 mg, 0.36 mmol) was heated for 1 h., The
5
residue was purified by flash chromatography over silica gel
(
(
Cyclohexane: ethyl acetate 7:3-5:5) to afford the desired product 3i
131 mg, 0.22 mmol, 85%) as an intense beige solid; mp (95-96 °C);
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((Z)-3-ethoxy-3-oxoprop-1-
en-1-yl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3g).
f
TLC: R = 0.58 (Cyclohexane : ethyl acetate 1:1); IR (thin film, neat)
ν
1
−1
max/cm : 1747, 1713, 1475, 1435, 1367, 1299, 1247, 1205, 1153,
113, 1083, 1055, 1035, 950, 917, 897, 824, 785, 734, 702; 1H NMR
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 12
Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Journal Name
300 MHz, CDCl
ARTICLE
(
3
) δ ( ppm)7.63 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, CDCl
3
) δ (ppm): 170.6 (2C=O), 170.3 (2C=O), 169.9 V(i2eCw=AOrti)c,le1O6n9lin.5e
1
=
1
2
H), 7.22 (dd, J = 8.2, 1.6 Hz, 1H), 5.42 (d, J = 2.8 Hz, 1H), 5.28 (dd, J (2C=O), 169.4 (2C=O), 169.2 (2C=O), 169.1DO(2I:C1=0O.1)0,391/6C65.O8B(021C6=0O3G),
12.4, 7.6 Hz, 1H), 5.06 (dd, J = 9.9, 3.4 Hz, 1H), 4.79 (d, J = 10.0 Hz, 137.2 (C), 136.7 (C), 132.5 (CH), 132.4 (CH), 130.9 (2CH), 130.6 (C),
H), 4.12 (qd, J = 11.3, 6.5 Hz, 2H), 3.96 (t, J = 6.5 Hz, 1H), 3.85 (s, 3H), 130.4 (C), 129.5 (CH), 129.0 (CH), 126.3 (CH), 126.1 (CH), 100.9 (CH),
13
.33 (s, 3H), 2.13 (s, 3H), 2.01 (d, J = 1.3 Hz, 6H), 1.95 (s, 3H); C NMR 100.8 (CH), 84.1 (CH), 82.6 (2CH), 76.9 (CH), 76.6 (CH), 73.8 (2CH),
) δ (ppm): 170.8 (C=O), 170.7 (C=O), 170.5 (C=O), 73.1 (CH), 73.0 (CH), 72.1 (2CH), 71.7 (2CH), 70.7 (CH), 70.2 (CH), 69.9
69.8 (C=O), 167.5 (C=O), 137.2 (C), 133.3 (CH), 132.9 (C), 131.9 (C), (CH), 69.5 (CH), 67.8 (CH), 62.5 (2CH ), 61.9 (CH ), 61.6 (CH ), 52.5
), 20.79(4CH ), 20.66(8CH ); HR-MS
(
75 MHz, CDCl
3
1
1
2
2
2
31.6 (CH), 130.9 (CH), 85.8 (CH), 74.8 (CH), 72.5 (CH), 67.7 (CH), 67.4 (CH
), 52.6 (CH ), 21.2 (2CH ), 21.1 (2CH ), 21.0 (CH ); HR- (ESI): for C34
MS (ESI): for C23 11S (M + Na) : m/z calcd 535.1250, found
35.1252.
3
), 52.34(CH
3
), 20.91(2CH
3
3
3
+
(
CH), 62.2 (CH
2
3
3
3
3
H
42
O
19S (M + Na) : m/z calcd 809.1939, found 809.1940.
+
28
H O
Compounds β−3l and α−3l:
5
Following the general procedure of coupling, a mixture of
(
(
2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((4-bromo-2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4,5-triyl
(
2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-
mercaptotetrahydro-2H-pyran-3,4-diyl diacetate 1d (200 mg, 0.54
mmol) and methyl 2-iodobenzoate 2a (96 mg, 0.36 mmol) was
triacetate (3j).
Following the general procedure of coupling, a mixture of heated for 1 h. The residue was purified by flash chromatography
thiogalactose 1b (200 mg, 0.54 mmol) and methyl methyl 5-bromo- over silica gel (Cyclohexane: ethyl acetate 2:8) to afford products
2-iodobenzoate 2e (123 mg, 0.36 mmol) was heated for 1 h. The β−3l (109 mg, 0.22 mmol, 60%) and α−3l (66.6 mg, 0.133 mmol,
residue was purified by flash chromatography over silica gel 37%).
(
(
Cyclohexane: ethyl acetate 7:3-5:5) to afford the desired product 3j
131 mg, 0.22 mmol, 63%) as an intense beige solid; mp (95-96 °C);
(
(
2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4-diyl
f
TLC: R = 0.58(Cyclohexane: ethyl acetate 1:1); IR (thin film, neat)
ν
−1
diacetate (β−3l)
max/cm : 1747, 1718, 1593, 1461, 1435, 1367, 1298, 1239, 1209,
1
153, 1110, 1083, 1052, 1036, 966, 950, 917, 898, 821, 782, 734, 703;
1H NMR (300 MHz, CDCl
f
Dark yellow solid; mp (152-153 °C); TLC: R = 0.25 (Cyclohexane: ethyl
acetate 2:8); IR (thin film, neat) νmax/cm : 1746, 1716, 1685, 1666,
3
) δ ( ppm): 8.07 – 7.94 (m, 1H), 7.55 (d, J =
−1
1
1
.3 Hz, 2H), 5.46 (dd, J = 3.3, 0.9 Hz, 1H), 5.32 (dd, J = 14.2, 5.7 Hz,
H), 5.09 (dd, J = 9.9, 3.3 Hz, 1H), 4.82 (d, J = 10.0 Hz, 1H), 4.21 – 4.08
1
1
541, 1469, 1435, 1380, 1366, 1295, 1254, 1229, 1214, 1146, 1113,
089, 1040, 912, 749; 1H NMR (300 MHz, CDCl
) δ ( ppm): 7.82 (dd, J
arom), 7.63 (d, J = 7.9 Hz, 1H, Harom), 7.43 (td, J = 7.7,
.5 Hz, 1H, Harom), 7.32 (td, J = 7.5, 1.0 Hz, 1H, Harom), 5.95 (d, J = 8.7
3
(
m, 2H), 4.03 – 3.97 (m, 1H), 3.90 (s, 3H), 2.16 (s, 3H), 2.04 (d, J = 4.3
Hz, 6H), 1.98 (s, 3H); 13C NMR (75 MHz, CDCl
) δ (ppm): 170.43(C=O),
70.25(C=O), 170.15(C=O), 169.39(C=O), 165.66(C=O), 135.83(C),
35.04(CH), 133.68(CH), 132.57(C), 131.45(CH), 120.37(C),
4.77(CH), 74.72(CH), 72.11(CH), 67.34(CH), 66.93(CH), 61.88(CH ),
2.61(CH ), 29.82(CH ), 20.82(2CH ), 20.70(CH ); HR-MS (ESI): for
25BrO11S(M + Na) : m/z calcd 599.0199, found 599.0195.
= 7.7, 1.6 Hz, 1H, H
1
3
1
1
8
5
Hz, 1H, NH), 5.40 (t, J = 9.7 Hz, 1H, H3’), 5.15(d, J = 9.0 Hz, 1H, H1’,
anom), 5.07 (t, J = 10.0 Hz, 1H, H4’), 4.26 – 4.08 (m, 2H, H6’), 3.95 (m,
2
1
H, H2’), 3.89 (s, 3H, CO
OAc), 2.02 (s, 6H, OAc), 1.94 (s, 3H, NAc); 13C NMR (75 MHz, CDCl
ppm): 170.4 (C=O), 170.3 (C=O), 170.1 (C=O), 169.2 (C=O), 167.2
2
Me), 3.81 – 3.72 (m, 1H, H5’), 2.06 (s, 3H,
3
3
3
3
+
3
) δ
22
C H
(
(
2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((2R,3R,4S,5R,6S)-4,5-
diacetoxy-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3-
yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3k).
(C=O), 134.7(CIV.arom), 132.0 (CVI.arom),131.9 (CHIII.arom), 131.7
(CHIII.arom), 130.1 (CHIII.arom), 126.8 (CHIII.arom), 84.6 (CHanom), 75.4 (CH,
(
C
5’), 73.2 (CH, C3’), 68.3 (CH, C4’), 62.1 (CH2,
(CH3, CO Me), 23.0 (NHC(O)CH ), 20.4 (2 C(O)CH
HR-MS (ESI): for C22 27NO10S (M + Na) : m/z calcd 520.1253, found
C
6’), 53.6 (CH, C2’), 52.1
2
3
3
), 20.3 (C(O)CH );
3
+
H
Following the general procedure of coupling, a mixture of 520.1253.
thiocellobiose 1c (352.5 mg, 0.54 mmol) and methyl 2-iodobenzoate
2
a (94.5 mg, 0.36 mmol) was heated for 12 hrs. The residue was (2R,3S,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((2-
purified by flash chromatography over silica gel (Cyclohexane: (methoxycarbonyl)phenyl)thio)tetrahydro-2H-pyran-3,4-diyl
ethylacetate 7:3) to afford the desired product 3k as a mixture of diacetate (α−3l).
anomers α/β (2:8), (130 mg, 0.165 mmol, 92%) as a white solid; mp
f
Light yellow solid; mp (212-213 °C); TLC: R = 0.4 (Cyclohexane: ethyl
acetate 2:8); IR (thin film, neat) νmax/cm : 1744, 1721, 1657, 1535,
1467,1435, 1368, 1250, 1238, 1217, 1143, 1107, 1031, 915, 832, 744,
(
f
192-193 °C); TLC: R = 0.43 (Cyclohexane: ethylacetate 1:1); IR (thin
−1
−1
film, neat) νmax/cm : 1745, 1597, 1366, 1208, 1166, 1031, 905, 735,
03, 670, 654; 1H NMR (300 MHz, CDCl
7
1
2
–
3
3
) δ ( ppm): 7.92 (dt, J = 6.2,
6
89; 1H NMR (300 MHz, CDCl
3
) δ ( ppm): 7.93 (dd, J
1
= 7.8 Hz, J1 = 1.5
= 9.0 Hz, J
.0 Hz, 1H, 1H, Harom), 7.32 – 7.24 (m, 1H, Harom), 6.05 (d, J = 8.8 Hz,
H, NH), 5.80 (d, J = 5.5 Hz, 1H, H1’anom), 5.34 – 5.13 (m, 2H, H3’ and 4’),
.6 Hz, 2H), 7.62 (dd, J = 29.2, 7.4 Hz, 2H), 7.47 (td, J = 7.7, 1.6 Hz,
H), 7.35 – 7.26 (m, 2H), 5.34 – 5.05 (m, 4H), 5.01 – 4.85 (m, 2H), 4.58
4.50 (m, 2H), 4.41 (dd, J = 12.5, 4.4 Hz, 1H), 4.23 – 4.04 (m, 2H),
.94 (d, J = 13.2 Hz, 3H), 3.78 (dt, J = 24.7, 8.8 Hz, 3H), 2.12 (d, J = 5.8
Hz, 1H, Harom), 7.69 (d, J = 7.4 Hz, 1H, Harom), 7.47 (t, J
2
1
1
2
=
13
4.69 (dd, J = 10.9, 5.5 Hz, 1H, H2’), 4.50 – 4.39 (m, 1H, H5’), 4.28 (dd, J
Hz, 6H), 2.06 (dd, J = 5.1, 4.0 Hz, 12H), 2.01 (s, 3H); C NMR (75 MHz,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Page 8 of 12
ARTICLE
Journal Name
=
2
12.4, 4.5 Hz, 1H, H6’), 4.05 (d, J = 10.2 Hz, 1H, H6’), 3.94 (s, 3H, (CH), 86.0 (CH), 71.5 (CH), 69.0 (CH), 68.0 (CH), 62.0 (CH ), 52.5 (CH),
View Article Online
CO
2
Me), 2.05 (s, 3H, OAc), 2.04 (m, 6H, OAc), 1.95 (s, 3H, NHAc); 13
) δ (ppm): 171.1 (C=O), 170.3 (C=O), 169.9 (C=O), (ESI): for C23
69.1 (C=O), 166.6 (C=O), 136.8 (CIV.arom), 132.6 (CHarom), 130.8
CHarom), 129.2 (CIV.arom), 128.8 (CHarom), 125.8 (CHarom), 84.7 (CHanom),
1.0 (CH, C3’), 68.9 (CH, C5’), 67.9 (CH, C4’), 61.6 (CH2, 6’), 52.3 (CH,
C
52.0 (CH
3
), 30.5 (CH
H
3
), 23.0 (CH
3
), 21.0 (2CH
DOI: 10.1039/C5OB01603G
3
), 21.0 (CH
3
); HR-MS
+
NMR (75 MHz, CDCl
3
29NO10S(M + Na) : m/z calcd 534.1410, found 534.1396.
1
(
7
Typical procedure for cyclization of thioglycosides (3a-m) into fused
thioglycosyl benzoxathiepinones and benzothiapinones of type (4).
C
C
2’), 52.1 (CH3, CO
2
Me), 22.9 (CH3, COMe), 20.4 (2CH3, COMe), 20.3
2 3
A mixture of thioglycosides (3a-m) (1 equiv) and K CO (0.3 equiv) in
+
(
5
CH3, NHMe); HR-MS (ESI): for C22
20.1253, found 520.1261.
H27NO10S (M + Na) : m/z calcd
methanol (0.1M) were placed in a small ballon and the mixture was
stirred under argon at room temperature for 30 min. The crude
mixture was then filtered through celite and washed with 10 mL of
methanol and filtered during only 1 min. The filtrate was
Compounds β−3m and α−3m:
Following the general procedure of coupling, a mixture of concentrated under reduced pressure by rotavap at 25 °C for (1-2 h).
2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-
mercaptotetrahydro-2H-pyran-3,4-diyl diacetate 1f (200 mg,
.55mmol) and methyl 2-iodo-5-methylbenzoate 2b (99.5 mg, 0.366
(
(
2R,3S,4S,4aR,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-2,3,4,4a-
tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)-one
4a).
0
(
mmol) was heated for overnight(12 hrs. The residue was purified by
flash chromatography over silica gel (Cyclohexane:ethyl acetate 2:8)
to afford the products β−3m (52 mg, 0.13 mmol, 37%) and α−3m (44
mg, 0.08 mmol, 31%).
Following the general procedure of cyclization by mixing 3a (50 mg,
.1 mmol) with (4.5 mg, 0.03 mmol) of K CO in a small ballon (50
0
2
3
ml.) under argon at RT for 30 min. The residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 h) without purification by flash column
chromatography affording the desired product 4a (29 mg, 0.98
(
(
2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)-4-methylphenyl)thio)tetrahydro-2H-pyran-3,4-
diyl diacetate (β−3m)
mmol, 98%) as a light yellow solid; mp (206-207 °C); TLC: R
f
= 0.62
= 0.25 (Cyclohexane: (DCM: MeOH 85: 15); IR (thin film, neat) νmax/cm : 2835, 1701, 1646,
1449, 1402, 1317, 1259,1118, 1085, 1012, 748 H NMR (300 MHz,
528, 1474, 1434, 1370, 1302, 1245, 1207, 1109, 1032, 980, 916, 819, MeOD ) δ ( ppm): 7.88 (d, J = 1.5 Hz, 1H, Harom), 7.76 (dd, J = 8.1, 0.8
Hz, 1H, Harom), 7.51 (td, J = 9.0, 1.5 Hz, 1H, Harom), 7.27 (td, J = 7.7, 1.1
.6 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 8.1, 1.5 Hz, 1H), 6.16 Hz, 1H, Harom), 4.76 (d, J = 9.6 Hz, 1H, H1’,anom), 3.95 – 3.85 (m, 1H, H6’),
−1
Light yellow solid; mp (209 - 210°C); TLC: R
ethyl acetate 2:8); IR (thin film, neat) νmax/cm : 1744, 1725, 1658,
1
7
1
f
−1
;
1
4
83, 766, 749, 641 ; 1H NMR (300 MHz, CDCl
3
) δ ( ppm):7.59 (d, J =
d, J = 8.6 Hz, 1H), 5.34 (dd, J = 20.7, 10.8 Hz, 1H), 5.13 – 4.96 (m, 2H), 3.69 (dd, J = 12.1, 5.6 Hz, 1H, H6’), 3.50 – 3.37 (m, 4H, H2’, 3’, 4’, 5’); 13
C
(
4
4
.15 (ddd, J = 14.6, 12.2, 3.9 Hz, 2H), 3.93 (d, J = 8.7 Hz, 1H), 3.71 (dd, NMR (75 MHz, MeOD ) δ (ppm): 168.9 (C=O lactone), 139.9 (CIV.arom),
J = 8.9, 6.5 Hz, 1H), 2.35 (s, 3H), 2.05 (s, 3H), 2.00 (d, J = 3.0 Hz, 6H), 133.7 (CHarom), 131.5 (CHarom), 130.7 (CIV.arom), 130.1 (CHarom), 126.5
(CHarom), 87.5 (CH, C1’,anom), 81.9 (CH, C ), 79.8 (CH, C ), 73.9 (CH, C ),
1
.93 (s, 3H); 13C NMR (75 MHz, CDCl
3
) δ (ppm): 171.2 (C=O), 171.1
3’
4’
2’
(
C=O), 171.0 (C=O), 170.0 (C=O), 168.3 (C=O), 138.2 (C), 133.8 (CH), 71.4 (CH, C5’), 62.8 (CH2,
C
6’); HR-MS (APCI negative) m/z: for
+
1
33.4 (C), 133.2 (CH), 131.3 (CH), 131.1 (C), 85.8 (CH), 76.1 (CH), 74.2
CH), 69.1 (CH), 62.9 (CH ), 54.3 (CH), 52.9 (CH ), 23.8 (CH ), 21.4
); HR-MS (ESI): for
C
13
H
14
O
6
S (M – H ): m/z calcd 297.0438, found 297.0433.
(
(
2
3
3
(
2R,3S,4S,4aR,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-8-methyl-
,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)-
CH
C
3
), 21.3 (CH
3
), 21.3 (CH
3
), 21.14(CH
3
2
+
23
H29NO10S (M + Na) : m/z calcd 534.1410, found 534.1433.
one (4b).
(
(
2R,3S,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-((2-
methoxycarbonyl)-4-methylphenyl)thio)tetrahydro-2H-pyran-3,4-
Following the general procedure of cyclization by mixing 3b (50 mg,
2 3
0.097 mmol) with (4.0 mg, 0.03 mmol) of K CO in a small ballon (50
diyl diacetate (α−3m)
ml.) under argon at RT for 30 min. The residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 hr.) without purification by flash column
chromatography affording the desired product 4b (31 mg, 0.096
Beige solid; mp (83-84°C);TLC: R
f
= 0.46 (Cyclohexane: ethyl acetate
:8); IR (thin film, neat) νmax/cm :2956, 2923, 2853, 1745, 1715,
−1
2
1
1
684, 1666, 1539, 1475, 1435, 1378, 1366, 1300, 1249, 1228, 1207,
115, 1087, 1036, 977, 913, 824, 785, 735, 701, 645 ; 1H NMR (300
mmol, 99%) as a yellow solid; mp (202-203 °C); TLC: R
f
= 0.57 (DCM:
MeOH 85 : 15); IR (thin film, neat) νmax/cm : 2834, 1397, 1622, 1391,
367, 1312, 1256, 1214, 1115, 1022, 1014, 831, 704; 1H NMR (300
MHz, MeOD ): 7.63 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 8.5, 1.8 Hz, 1H),
.66 (d, J = 9.6 Hz, 1H), 3.95 – 3.78 (m, 1H), 3.78 – 3.34 (m, 4H), 3.26
(d, J = 8.5 Hz, 1H),2.32 (s, 3H); 13C NMR (75 MHz, MeOD
) δ (ppm):
69.1 (C=O), 137.1 (C), 135.6 (C), 134.4 (CH), 131.8 (CH), 131.4 (C),
−1
MHz, CDCl
.1 Hz, 1H), 6.07 (d, J = 8.9 Hz, 1H), 5.71 (d, J = 5.4 Hz, 1H), 5.33 – 5.07
m, 2H), 4.74 – 4.57 (m, 1H), 4.44 (d, J = 6.2 Hz, 1H), 4.27 (dd, J = 12.4,
3
) δ ( ppm):7.71 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.26 (d, J =
1
7
(
4
2
(
(
4
4
.4 Hz, 1H), 4.03 (dd, J = 12.3, 1.7 Hz, 1H), 3.91 (s, 3H), 2.34 (s, 3H),
.03 (d, J = 1.2 Hz, 9H), 1.94 (s, 3H); 13C NMR (75 MHz, CDCl
ppm):171.31(C=O), 170.5 (C=O), 170.0 (C=O), 169.5(C=O), 167.0
C=O), 136.5 (C), 133.5 (CH), 133.0 (C), 131.5 (CH), 130.0 (C), 130.0
3
) δ
4
1
1
30.9 (CH), 87.7 (CH), 81.9(CH), 79.7 (CH), 73.8 (CH), 71.3 (CH), 62.8
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 9 of 12
Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Journal Name
ARTICLE
(
2 3 16 6
CH ), 20.7 (CH ); HR-MS (APCI negative) m/z: for C14H O
S(M – H+): chromatography affording the desired product 4e(V3i2ewmArtgic,le0O.n0l8in4e
m/z calcd 311.0595, found 311.0589.
mmol, 98%) as a yellow solid; mp(205-206D°OC)I:; 1T0L.1C0:3R9 /f =C50O.5B0(1D6C0M3G:
−1
MeOH 85: 15); IR (thin film, neat) νmax/cm : 2918, 1704, 1652,1457,
311, 1248, 1082, 934, 832, 811, 780 ; 1H NMR (300 MHz, MeOD
) δ
ppm):7.98 (dd, J = 1.8, 0.7 Hz, 1H), 7.63 (d, J = 2.0 Hz, 2H),4.73 (d, J
(
2R,3S,4S,4aR,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-8,9-
1
4
dimethyl-2,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-
b][1,4]oxathiepin-6(11aH)-one (4c).
(
=
1
9.5 Hz, 1H), 3.88 (dd, J = 12.1, 2.0 Hz, 1H), 3.65 (dd, J = 12.1, 5.8 Hz,
H), 3.54 – 3.35 (m, 3H), 3.32 (d, J = 4.5 Hz, 1H); 13C NMR (75 MHz,
Following the general procedure of cyclization by mixing (50 mg,
4
MeOD ) δ (ppm): 147.5 (C=O), 139.9 (C), 136.4 (CH), 134.1 (CH),
0.094 mmol)of 3c with (4.0 mg, 0.03mmol) of K
2 3
CO in a small ballon
132.0 (C), 131.6 (CH), 119.6 (C), 87.1 (CH), 82.0 (CH), 79.7 (CH), 73.9
(
50 ml.) under argon at RT for 30 min.The residue was filtered
(
C
(81
CH), 71.3 (CH), 62.8 (CH
2
); HR-MS(APCI negative) m/z: for
through celite with methanol for 1 min, the solvent then evaporated
by rotavap at (25 °C) for (1-2 hrs.) without purification by flash
column chromatography affording the desired product 4c (27 mg,
+
79
13
H13BrO
6
S (M - H ): m/z calcd 374.9543 ( Br), 376.9524
79
81
Br),found 374.9529 ( Br), 376.9514 ( Br).
0
.08 mmol, 87%)as a yellow solid; mp (181-182°C); TLC: R
f
= 0.6
(
(
2R,3S,4S,4aR,11aS)
hydroxymethyl)-6-oxo-2,3,4,4a,6,11a-
– methyl 3 , 4 – dihydroxy – 2 -
−1
(
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 2918, 2850, 1701,
1
1
631, 1488, 1400, 1361, 1311, 1287, 1260, 1233, 1189, 1163, 1124,
hexahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepine-9-carboxylate
4f).
074, 1021, 936, 875, 831, 782, 734, 703, 617; 1H NMR (300 MHz,
(
MeOD
4
): 7.59 (d, J = 20.2 Hz, 2H), 4.66 (d, J = 9.6 Hz, 1H), 3.93 – 3.81
(
m, 1H), 3.63 (dd, J = 12.1, 6.3 Hz, 4H), 3.57 – 3.33 (m, 1H), 2.29 (s, Following the general procedure of cyclization by mixing (50 mg,
3
1
8
H), 2.24 (s, 3H); 13C NMR (75 MHz, MeOD
43.5 (C), 136.5 (C), 135.5 (C), 132.5 (CH), 131.6 (CH), 128.3 (C), (50 ml.) under argon at RT for 30 min. The residue was filtered
4 2 3
) δ (ppm): 169.0 (C=O), 0.089 mmol) of 3f with (4.0 mg, 0.03 mmol) of K CO in a small ballon
7.75(CH), 82.2 (CH), 79.8 (CH), 73.9 (CH), 71.5 (CH), 62.9 (CH
), 19.1 (CH ); HR-MS(APCI negative) m/z: for C15
m/z calcd 325.0751, found 325.0746.
2
), 20.1 through celite with methanol for 1 min, the solvent then evaporated
(
CH
3
3
H
18
O
6
S (M - H+) by rotavap at (25 °C) for (1-2 h.) without purification by flash column
chromatography affording the desired product 4f (28 mg, 0.089
f
mmol, 99%) as a white to light beige solid; TLC: R = 0.47 (DCM: MeOH
(
2
2R,3S,4S,4aR,11aS)-9-chloro-3,4-dihydroxy-2-(hydroxymethyl)-
,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)-
−1
8
1
9
5:15); IR (thin film, neat) νmax/cm : 2957, 2919, 2851, 1728, 1650,
558, 1476, 1434, 1384, 1313, 1290, 1259, 1192, 1119, 1060, 1034,
one (4d).
13, 828, 747, 670, 653; 1H NMR (300 MHz, MeOD
4
) δ ( ppm): 8.40
(
s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 6.6 Hz, 1H), 4.76 (d, J = 9.4
Following the general procedure of cyclization by mixing (50 mg,
Hz, 1H), 3.95 – 3.85 (m, 1H), 3.74 (dd, J = 13.1, 2.7 Hz, 1H), 3.50 – 3.35
0.093 mmol) of 3d with (4.0 mg, 0.03 mmol) of K
2 3
CO in a small ballon
(
(
(
6
-
m, 4H), 1.27 (s, 3H); 13C NMR (75 MHz, MeOD
) δ (ppm): 168.0
4
C=O), 167.4 (C=O), 140.9 (C), 134.7 (C), 134.2 (C), 131.6 (CH), 130.8
CH), 126.9 (CH), 87.5 (CH), 82.1 (CH), 79.8 (CH), 73.8 (CH), 71.0(CH),
(
50 ml.) under argon at RT for 30 min. The residue was filtered
through celite with methanol for 1 min, the solvent then evaporated
by rotavap at (25 °C) for (1-2 h.) without purification by flash column
chromatography affording the desired product 4d (30.5 mg, 0.09
2.5 (CH
2
), 30.8 (CH
3
); HR-MS(APCI negative) m/z: for C15
H
16
O
8
S (M
+
H ): m/z calcd 355.0493, found 355.0488.
mmol, 97%) as a light yellow solid; mp (182-183 °C); TLC: R
f
= 0.54
−1
(
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm :2834, 1684, 1576,
(
5aS,7R,8S,9S,9aR)-8,9-dihydroxy-7-(hydroxymethyl)-7,8,9,9a-
1
7
7
546, 1467, 1326, 1259, 1154, 1112, 1075, 1031, 1014, 879, 811,
81; 1H NMR (300 MHz, MeOD
) δ ( ppm): 7.85 (d, J = 8.4 Hz, 1H),
.75 (s, 1H), 7.24 (d, J = 10.5 Hz, 1H), 4.74 (d, J = 9.5 Hz, 1H), 3.86 (t, Following the general procedure of cyclization by mixing of 3g (50
mg, 0.1 mmol) with (5.0 mg, 0.03mmol) of K CO in a small ballon (50
) δ (ppm): 167.8 (C=O),143.2 (C), 140.0 (C), ml.) under argon at RT for 30 min.The residue was filtered through
33.1 (CH), 129.1 (CH), 128.3 (C), 126.3 (CH), 87.0 (CH), 82.1 (CH), celite with methanol for 1 min, the solvent then evaporated by
tetrahydropyrano[3,2-b][1,4]oxathiepin-2(5aH)-one (4g).
4
J = 10.2 Hz, 1H), 3.65 (d, J = 6.3 Hz, 1H), 3.39 (d, J = 26.4 Hz, 4H); 13
NMR (75 MHz, MeOD
C
2
3
4
1
7
9.8 (CH), 73.9 (CH), 71.3 (CH), 62.7 (CH
2
); HR-MS (APCI negative) rotavap at (25 °C) for (1-2 h.) without purification by flash column
chromatography affording the desired product 4g (27 mg, 0.98
mmol, 98%) as a light yellow solid; mp (184-185 °C); TLC: R = 0.43
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 1684, 1623, 1575,
371, 1312, 1252, 1183, 1086, 1051, 1026, 830, 803, 759; 1H NMR
300 MHz, MeOD ) δ ( ppm):7.55 (d, J = 10.3 Hz, 1H), 5.93 (d, J = 10.2
Hz, 1H), 4.50 (d, J = 9.4 Hz, 1H), 3.86 (dd, J = 12.0, 1.5 Hz, 1H), 3.66
dd, J = 12.1, 5.1 Hz, 1H), 3.41 – 3.31 (m, 4H); 13C NMR (75 MHz,
MeOD ) δ (ppm): 168.7 (C=O), 148.2 (CH), 113.8 (CH), 87.4(CH), 82.5
CH), 79.4 (CH), 74.5 (CH), 71.2 (CH), 62.7 (CH ); HR-MS(APCI
+
m/z: for C13
H
13ClO
6
S (M -H ): m/z calcd 331.0049, found.
f
(
2R,3S,4S,4aR,11aS)-8-bromo-3,4-dihydroxy-2-(hydroxymethyl)-
−1
(
1
(
2,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)-
one (4e).
4
Following the general procedure of cyclization by mixing (50 mg,
(
2 3
0.086 mmol) of 3e with (3.6 mg, 0.025 mmol) of K CO in a small
4
ballon (50 ml.) under argon at RT for 30 min. The residue was filtered
through celite with methanol for 1 min, the solvent then evaporated
by rotavap at (25 °C) for (1-2 h.) without purification by flash column
(
2
+
negative) m/z: for C
9
H
12
O
6
S (M - H ): m/z calcd 247.0282,
found 247.0273.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Page 10 of 12
ARTICLE
Journal Name
1
(
2R,3R,4S,4aR,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-2,3,4,4a-
tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)-one
4h).
1451, 1394, 1368, 1312, 1250, 1081, 1025, 1009, 830, 703; H NMR
View Article Online
(300 MHz, MeOD
Hz, 1H), 7.61 (dd, J = 8.7, 2.3 Hz, 1H), 4.70 (d, J = 9.7 Hz, 1H), 3.92 (d,
J = 3.3 Hz, 1H), 3.81 – 3.63 (m, 4H), 3.54 (dd, J = 9.1, 3.3 Hz, 1H); 13
NMR (75 MHz, MeOD ) δ (ppm): 167.5 (C=O), 140.6 (C), 136.7 (CH),
34.4 (CH), 131.9 (C), 131.7 (CH), 119.7 (C), 87.9 (CH), 80.9 (CH), 76.6
CH), 71.1 (CH), 70.7 (CH), 63.0(CH ); HR-MS(APCI negative) m/z: for
) δ ( ppm): 7.97 (d, J = 2.2DHOzI:,110H.1)0,379./6C95O(dB,0J16=083.G7
4
(
C
Following the general procedure of cyclization by mixing (50 mg, 0.1
mmol) of 3h with (4.5 mg, 0.03 mmol) of K CO in a small ballon (50
ml.) under argon at RT for 30 mins. The residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 hrs.) without purification by flash column
chromatography affording the desired product 4h (29 mg, 0.097
4
2
3
1
(
C
(81
2
+
79
13 6
H13BrO S (M - H ): m/z calcd 374.9543 ( Br), 376.9539
79
81
Br),found 374.9529 ( Br), 376.9520 ( Br).
mmol, 97%)as a white to light yellow solid; mp (190-192 °C); TLC: R
f
(2R,3S,4S,4aR,11aS)-4-hydroxy-2-(hydroxymethyl)-3-
−1
=
1
0.35 (DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 2939, 1704, (((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
646, 1448,1401, 1314, 1258, 1086, 1022, 866, 748; H NMR (300 2H-pyran-2-yl)oxy)-2,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-
1
MHz, MeOD
.8 Hz, 1H), 7.53 – 7.43 (m, 1H), 7.24 (td, J = 7.8, 1.1 Hz, 1H), 4.70 (d,
J = 9.7 Hz, 1H), 3.92 (d, J = 3.2 Hz, 1H), 3.82 – 3.62 (m, 4H), 3.53 (dd,
J = 9.1, 3.3 Hz, 1H); 13C NMR (75 MHz, MeOD
) δ (ppm):163.9 (C=O),
40.7 (C), 133.70 (CH), 131.6 (CH), 130.3 (C), 129.7 (CH), 126.2 (CH),
8.1 (CH), 80.6 (CH), 76.4 (CH), 70.9 (CH), 70.5 (CH), 62.7 (CH ); HR-
S (M - H ): m/z calcd 297.0438,
4
) δ ( ppm): 7.85 (dd, J = 7.8, 1.5 Hz, 1H), 7.78 (dd, J = 8.2, b][1,4]oxathiepin-6(11aH)-one (4k).
0
Following the general procedure of cyclization by mixing (50 mg, 0.06
mmol) 3m with (3.0 mg, 0.02 mmol) of K CO in a small ballon (50
2
3
4
ml.) under argon at RT for 24 h. The residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 h.) then purification by flash column
chromatography affording the desired product 4m (29 mg, 0.06
mmol, 98%) as a colorless oily mixture of α,β anomers (24:76); TLC:
1
8
2
+
14 6
MS (APCI negative) m/z: for C13H O
found 297.0434.
−1
(
2
2R,3R,4S,4aR,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-8-methyl-
f
R = 0.16 (DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 1701,
,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)- 1436, 1310, 1256, 1078, 1020, 830, 743, 670, 653; 1H NMR (300 MHz,
1
one (4i).
MeOD
4
) δ ( ppm): H NMR (300 MHz, MeOD) δ 7.90 (dd, J = 7.9, 1.4
Hz, 1H), 7.72-7.74 (m, 2H), 7.49-7.52 (m, 2H), 7.20-7.30 (m, 3H), 5.66
d, J = 5.3 Hz, 1H), 4.84 (d, J = 9.8 Hz, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.32-
.51 (m, 2H), 4.0-3.8 (m, 6H), 3.81-3.40 (m, 5H); 13C NMR (75 MHz,
) δ (ppm): 13C NMR (75 MHz, MeOD) δ 167.4, 160.7, 138.3,
MeOD
Following the general procedure of cyclization by mixing (40 mg,
(
4
2 3
0.075 mmol) of 3i with (1.1 mg, 0.03 mmol) of K CO in a small ballon
under argon at RT for 30 min.The residue was filtered through celite
with methanol for 1 min, the solvent then evaporated by rotavap at
4
1
1
7
32.3, 132.0, 130.2, 130.0, 129.6, 129.4, 128.6, 125.3, 125.1, 103.2,
03.1, 86.9, 85.7, 79.2, 79.0, 78.6, 76.7, 76.5, 76.4, 73.5, 72.7, 72.26,
1.9, 71.7, 69.9, 61.0, 60.4, 60.1, 51.4; HR-MS(APCI negative) m/z:
(
25 °C) for (1-2 h.) without purification by flash column
chromatography affording the desired product 4i (22 mg, 0.072
mmol, 97%) as a light yellow solid; mp (205-206 °C); TLC: R = 0.45
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm−1 : 2945 ,2833 ,
f
+
24
for C19H O11S (M - H ): m/z calcd 459.0967, found 459.0923.
(
1
700, 1623, 1398, 1369, 1306, 1025, 1007, 977, 831, 703 ; 1H NMR (2R,3S,4R)-5-acetyl-3,4-dihydroxy-2-(hydroxymethyl)-3,4,4a,5-
) δ ( ppm):7.71 – 7.53 (m, 2H), 7.27 (dd, J = 8.3, 1.5 tetrahydro-2H-benzo[f]pyrano[2,3-b][1,4]thiazepin-6(11aH)-one
Hz, 1H), 4.62 (d, J = 9.7 Hz, 1H), 3.88 (d, J = 2.8 Hz, 1H), 3.77 – 3.56 (4m).
m, 4H), 3.50 (dd, J = 9.1, 3.3 Hz, 1H), 2.28 (s, 3H); 13C NMR (75 MHz,
MeOD ) δ (ppm): 169.0 (C=O), 136.7 (C), 136.5 (C), 134.5 (CH), 131.9
CH), 130.7 (C), 130.4 (CH), 88.4 (CH), 80.5 (CH), 76.3 (CH), 70.9 (CH),
(
300 MHz, MeOD
4
(
Following the general procedure of cyclization by mixing (50 mg, 0.1
mmol) of 3m with (14 mg, 0.1 mmol) of K CO in a small ballon (50
4
2
3
(
ml.) under argon at RT for 24 h., the residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 hrs.) then purification by flash column
chromatography affording the desired product 4m (31 mg, 0.098
7
C
0.5 (CH), 62.7 (CH
H O S (M -H ): m/z calcd 311.0595, found 311.0589.
14 16 6
2
),20.6 (CH
3
); HR-MS(APCI negative) m/z: for
+
(
2R,3R,4S,4aR,11aS)-8-bromo-3,4-dihydroxy-2-(hydroxymethyl)-
2
,3,4,4a-tetrahydrobenzo[e]pyrano[3,2-b][1,4]oxathiepin-6(11aH)- mmol, 98%)as a white to light yellow solid; mp (215-216 °C); TLC: R
f
−1
one (4j).
= 0.32 (DCM: MeOH9:1); IR (thin film, neat) νmax/cm : 2988, 2960,
327, 1680, 1452, 1314, 1060, 1034, 892, 869, 777, 670 ; 1H NMR
300 MHz, MeOD ) δ ( ppm): 7.68 (d, J = 7.8 Hz, 2H, Harom), 7.44 – 7.30
2
Following the general procedure of cyclization by mixing (50 mg,
(
(
(
4
0.086 mmol) 3j with (3.0 mg, 0.02 mmol) of K
2 3
CO in a small ballon
td, J = 9.0, 1.1 Hz, 1H, Harom), 7.18 (td, J = 8.6, 1.1 Hz, 1H, Harom), 5.70
d, J = 5.3 Hz, 1H, H1’,anom), 4.04 (dd, J = 11.2, 5.3 Hz, 1H, H2’), 3.92 (dd,
(
50 ml.) under argon at RT for 30 min. The residue was filtered
through celite with methanol for 1 min, the solvent then evaporated
by rotavap at (25 °C) for (1-2 h.) without purification by flash column
chromatography affording the desired product 4j (31 mg ,0.082
J = 8.5, 5.0 Hz, 1H, H5’), 3.64-3.67 (m, 2H, H6’, 5’), 3.60 – 3.27 (m, 2H,
4’, 6’), 1.85 (s, 3H, NHAc); 13C NMR (75 MHz, MeOD
) δ (ppm): 173.8
C=O, Clactame), 168.9 (C=O, NAc), 138.4 (CIVarom), 133.3 (CHarom), 132.8
IVarom), 131.8 (CHarom), 131.2 (CHarom), 127.2 (CHarom), 87.3 (CH,
1’,anom), 75.2 (CH, C5’), 72.6 (CH, C3’), 72.4 (CH, C4’), 62.4 (CH2, 6’),
H
4
(
(
mmol, 96%) as a light yellow solid; mp (208-209 °C); TLC: R
f
= 0.54
C
−1
(
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 2948, 2835, 1711,
C
C
1
0 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 11 of 12
Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Journal Name
ARTICLE
5
C
6.2 (CH, C2’), 22.6 (CH3, NHAc); HR-MS(APCI negative) m/z: for rotavap at (25 °C) for (1-2 h.) affording the desired pVrioewduArctitcl5e bOn(l3in1e
+
DOI: 10.1039/C5OB01603G
15
H17NO
6
S (M - H ): m/z calcd 338.0704, found 338.0718.
mg, 0.099 mmol, 99%) as a yellow solid; mp (90-92°C); TLC: R
(
f
= 0.0
−1
DCM: MeOH 85:15); IR (thin film, neat) νmax/cm : 2987, , 2923,
(
2R,3S,4R,4aR,11aS)-5-acetyl-3,4-dihydroxy-2-(hydroxymethyl)-8-
1
8
–
1
1
1
650, 1621, 1557, 1543, 1454, 1400, 1374, 1304, 1169, 1098, 1071,
80, 836, 749, 670, 652; 1H NMR (400 MHz, DMSO4-
) δ ( ppm):7.56
methyl-3,4,4a,5-tetrahydro-2H-benzo[f]pyrano[2,3-
b][1,4]thiazepin-6(11aH)-one(4n).
d
6
7.48 (m, 2H), 7.26 (td, J = 7.7, 1.6 Hz, 1H), 7.15 (td, J = 7.5, 1.0 Hz,
H), 4.80 (d, J = 10.5 Hz, 1H), 3.90 – 3.70 (m, 3H), 3.42 (ddd, J = 25.3,
Following the general procedure of cyclization by mixing (50 mg,
1
3
7.3, 5.5 Hz, 3H), 1.96 (s, 3H); C NMR (101 MHz, DMSO4-
6
d ) δ(ppm):
0.097 mmol) 3n with (13.5 mg, 0.097 mmol) of K
2 3
CO in a small ballon
74.0 (C=O), 170.4 (C=O), 142.52 (C), 134.5 (C), 130.2 (2CH), 129.5
(
50 ml.) under argon at RT for 72 h., the residue was filtered through
(
(
C
CH), 127.05 (CH), 87.60 (CH), 82.0(CH), 77.5 (CH), 72.0 (CH), 62.0
celite with methanol for 1 min, the solvent then evaporated by
rotavap at (25 °C) for (1-2 h.), then purification by flash column
chromatography affording the desired product 4n (18 mg, 0.05
CH
2
), 56.0 (CH), 23.0 (CH
3
); HR-MS (APCI negative) m/z: for
+
15
H17NO
7
S (M -H ): m/z calcd 356.0804, found 356.0796.
mmol, 52%) as a white solid; mp (225-226°C) ;TLC: R
MeOH 85:15); IR (thin film, neat) νmax/cm : 2957, 2922, 2852, 2360,
f
= 0.3(DCM:
(
2R,3S,4R,11R)-5-acetyl-3,4-dihydroxy-2-(hydroxymethyl)-3,4,4a,5-
tetrahydro-2H-benzo[f]pyrano[2,3-b][1,4]thiazepin-6(11aH)-one
1-oxide (5c).
−1
1
1
704, 1657, 1538, 1461, 1376, 1315, 1287, 1252, 1213, 1119, 1087,
1
054, 996, 953, 913, 858, 815, 782, 722, 672, 644,62; 1H NMR (400
MHz, DMSO4-
d
6
) δ ( ppm): 7.61 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.33 Following the general procedure of cyclization by mixing (50 mg, 0.1
d, J = 8.1 Hz, 1H), 4.77 (d, J = 10.5 Hz, 1H), 3.78 (s, 1H), 3.72 – 3.59 mmol)of 3m with (27.5 mg, 0.2mmol) of K CO in a small ballon (50
m, 3H), 3.20 (d, J = 33.6 Hz, 2H), 2.28 (s, 3H), 1.79 (s, 3H); 13C NMR ml.) under argon at RT for 2 days., the residue was filtered through
101 MHz, DMSO4- ) δ (ppm): 166.6 (C=O), 163.7 (C=O), 135.9 (C), celite with methanol for 1 min, the solvent then evaporated under
34.7 (C), 133.6 (CH), 130.5 (CH), 128.7 (C), 128.0 (CH), 84.5 (CH), vacuum at (25 °C) for (1-2 h.) then purification by flash column
1.1 (CH), 75.7 (CH), 70.4 (CH), 61.1 (CH ), 54.4 (CH), 23.2 (CH ), 20.2 chromatography affording the desired product (34 mg , 0.098 mmol,
); HR-MS(APCI negative) m/z: for C16 S (M - H ): m/z calcd 98%) as a dark yellow solid; mp (244-245°C); TLC: R = 0.0(DCM:
52.0860, found 352.0871. MeOH 8:2); IR (thin film, neat) νmax/cm : 1665, 1636, 1576, 1554,
(
(
(
1
8
2
3
d
6
2
3
+
(
3
CH
3
H
19NO
6
f
−1
1
7
475, 1455, 1372, 1321, 1098, 1072, 1053, 977, 891, 851, 822, 751,
09, 625; 1H NMR (300 MHz, MeOD
) δ ( ppm): 7.49 (dd, J = 7.7, 1.2
(
3
2R,3S,4S,4aR,11S,11aS)-3,4-dihydroxy-2-(hydroxymethyl)-
,4,4a,11a-tetrahydro-2H,6H-benzo[e]pyrano[3,2-
4
Hz, 1H, Harom), 7.34 (dd, J = 7.3, 1.8 Hz, 1H, Harom), 7.20 – 7.05 (m, 2H,
H
H
b][1,4]oxathiepin-6-one 11-oxide (5a)
arom), 5.52 (d, J = 5.1 Hz, 1H, H1’, anom), 4.02 (dd, J = 11.0, 5.1 Hz, 1H,
2’), 3.92 (dd, J = 9.8, 4.3 Hz, 1H, H5’), 3.72 – 3.60 (m, 3H, H4’,6’), 3.35
Following the general procedure of cyclization by mixing 3a (50 mg,
0
argon at RT for 2 h. The residue was filtered through celite with
methanol for 1 min, the solvent then evaporated by rotavap at (25
13
(
dd, J = 20.6, 11.7 Hz, 1H, H3’), 1.81 (s, 3H, NHAc); C NMR (101 MHz,
MeOD ) δ (ppm): 173.9 (C=O, Clactam), 161.2 (C=O, NAc), 144.9 (C,
IVarom), 133.0 (C, CIVarom), 132.6 (CH, Carom), 129.7 (CH, Carom), 128.4
CH), 127.7 (CHarom), 88.8 (CH, C1’anom), 75.7 (CH, C5’), 72.8 (CH, 3’),
2.3 (CH, C4’), 62.4 (CH2, 6’), 56.3 (CH, C2’), 22.7 (CH3, NHAc); HR-
.1mmol) with (0.1 mmol) of NaOMe in a small ballon (50 ml.) under
4
C
(
7
°
C) for (1-2 h.) without purification by flash column chromatography
affording the desired product 5a (34 mg, 0.1 mmol, 98%) as a white
amorphous; TLC: R = 0.09 (DCM: MeOH 85: 15); IR (thin film, neat)
max/cm : 2958, 2923, 2852, 1575, 1540, 1467, 1401, 1378, 1260,
024, 989; 1H NMR (300 MHz, MeOD
) δ ( ppm): 7.74 – 7.68 (m, 1H),
C
+
6
MS(ESI positive) m/z: for C15H17NO S (M+H) : m/z calcd 356,0804,
found 356.0800.
f
−1
ν
1
7
1
3
1
1
6
4
methyl 2-(((2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-
.53 – 7.48 (m, 1H), 7.27 (dd, J = 5.6, 3.4 Hz, 2H), 4.55 (d, J = 9.4 Hz,
H), 3.93 – 3.87 (m, 1H), 3.75 (dd, J = 11.4, 4.8 Hz, 1H), 3.60 (s, 2H),
(
(
hydroxymethyl)tetrahydro-2H-pyran-2-yl)thio)-5-methylbenzoate
6a).
.56 – 3.46 (m, 2H); 13C NMR (75 MHz, MeOD
4
) δ (ppm):
67.80(C=O), 136.91(C), 126.21(C), 119.71(CH), 119.64(C), Following the general procedure of coupling, a mixture of
19.26(CH), 118.82(CH), 79.08(CH), 72.66(CH), 69.49(CH), 63.65(CH), (2R,3S,4R,5R,6S)-5-acetamido-2-(acetoxymethyl)-6-((2-
2.01(CH), 53.55(CH
2
); HR-MS(ES +) m/z: for C13
H
14NaO
7
S (M - H+): (methoxycarbonyl)-4-methylphenyl)thio)tetrahydro-2H-pyran-3,4-
m/z calcd 315.0538, found 315.0533.
diyl diacetate 3b (50 mg, 0.1 mmol) and with (13.5 mg, 0.1 mmol) of
2 3
K CO in a small ballon (50 ml.) under argon at (50 °C) for 36 h. The
(
(
2R,3S,4R,4aR,11S,11aS)-5-acetyl-3,4-dihydroxy-2-
hydroxymethyl)-3,4,4a,5-tetrahydro-2H-benzo[f]pyrano[2,3-
residue was filtered through celite with methanol for 1 min, the
solvent then evaporated by rotavap at (25 °C) for (1-2 h) then
purification by flash column chromatography affording the product
b][1,4]thiazepin-6(11aH)-one 11-oxide (5b).
6
=
1
7
1
n (22 mg, 0.06 mmol, 60%) as a white solid; mp (240-241°C); TLC: Rf
0.67(DCM: MeOH 8: 2); IR (thin film, neat) νmax/cm : 2921, 2841,
Following the general procedure of cyclization by mixing of (50 mg,
−1
2 3
0.1 mmol) of 3l with (70 mg, 0.5 mmol) of K CO in a small ballon (50
630, 1441, 1322, 1301, 1248, 1211, 1072, 1053, 980, 902, 854, 823,
ml.) under argon at RT for 7 days, the residue was filtered through
celite with methanol for 1 min, the solvent then evaporated by
84, 671; 1H NMR (400 MHz, DMSO
) δ ( ppm): δ 7.83 (d, J = 8.8 Hz,
4
H), 7.62 (d, J = 1.4 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.0,
J. Name., 2013, 00, 1-3 | 11
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Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge i mn si stry
Page 12 of 12
ARTICLE
Journal Name
2
3
+
.1 Hz, 1H), 4.77 (d, J = 10.4 Hz, 1H), 3.80 (s, 3H), 3.71 – 3.57 (m, 2H),
7
8
9
a) E. Brachet, J.-D. Brion, S. Messaoudi, M. AlamVii,ewAAdrvtic.leSyOnntlinhe.
Catal. 2013, 355, 477; b) E. Brachet, J.-D. Brion, M. Alami, S.
.17 (s, 3H), 2.30 (s, 3H), 1.78 (s, 3H); HR-MS(ESI): for C17
H
23NO
7
S (M
DOI: 10.1039/C5OB01603G
Messaoudi, Adv. Synth. Catal. 2013, 355, 2627; c) E. Brachet,
J.-D. Brion, M. Alami, S. Messaoudi, Chem. Eur. J. 2013, 19,
Na) m/z calcd 408.1093, found 408.1096.
15276; d) A. Bruneau, J.-D. Brion, M. Alami, S. Messaoudi,
Computational methods
Chem. Commun. 2013, 49, 8359; e) A. Bruneau, M. Roche, A.
Hamze, J.-D. Brion, M. Alami, S. Messaoudi, Chem. Eur. J,
2015, 21, 8375.
Conformations of reactants, products and transition states were fully
optimized without constraint using DFT10e method with the hybrid
Becke-3-parameter-Lee–Yang–Parr exchange-correlation functional
and the 6-31G* base as implemented in the Gaussian 09 software
a) K. M. George, M.-C Frantz, K. Bravo-Altamirano, C. R.
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package 14
.
Vibrational analysis within the harmonic approximation was
performed at the same level of theory upon geometrical
optimization convergence. Thermodynamic quantities at 298.15 K
were calculated using the zero-point and thermal energy corrections
derived from unscaled frequencies. Local minima and first-order
saddle points were characterized by their respective numbers of
a)http://pi.actavis.com/data_stream.asp?product_group=15
64&p=pi&language=E;
b)http://www.actavis.com/products/key-products/product-
search?searchtext=diltiazem&searchmode=anyword
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1
5
136, 5472; X. Meng, W. L. Yao, J. S. Cheng, X. Zhang, L. Jin, H.
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defined by the intrinsic reaction coordinate . Figures were rendered
1
6
with GaussView .
136, 4157; B. J. Beahm, K. W. Dehnert, N. L. Derr, J. Kuhn, J. K.
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Acknowledgements
Authors acknowledge support of this project by CNRS,
University Paris Sud and by La Ligue Nationale Contre le Cancer 11 Z. Wang, Comprehensive Organic Name Reactions and
Reagents, John Wiley & Sons, Inc., Hoboken, NJ, 2009.
throughout an Equipe Labellisée 2014 grant. The Ministère
d’Enseignement Irakien is gratefully acknowledged for a
doctoral fellowship to R.-A.-A A. Our laboratory (BioCIS UMR
1
2 Runningthe reaction of 4a in the presence of MeONa (1 equiv)
in methanol at room temperature for 10 min furnished the
sulfoxide 5a in a quantitative yield. However, no reaction
occurs when 4a is stirred in methanol without adding of the
base. In this case, 4a was recovered unchanged.
8076) is a member of the laboratory of excellence LERMIT
supported by a grant from ANR (ANR-10-LABX-33).
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