Remote Electronic Effects by Ether Protecting Groups Fine-Tune Glycosyl Donor Reactivity

Article abstract of DOI:10.1021/acs.joc.6b00528

It was established that para-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the N-iodosuccinimide/triflic acid promoter system. Having electron donating p-methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing p-chloro (PClB) or p-cyanobenzyl ether (PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first armed-disarmed coupling between two benzylated glucosyl donors by tuning their reactivity. In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation and methoxylation of p-chlorobenzyl protected thioglycosides. The results of this paper regarding both the different electron withdrawing properties of various benzyl ethers and the efficient and multiple protecting group transformations are applicable in general organic chemistry and not restricted to carbohydrate chemistry.

Full text of DOI:10.1021/acs.joc.6b00528

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Article
Remote Electronic Effects by Ether Protecting
Groups Fine-Tune Glycosyl Donor Reactivity
Mads Heuckendorff, Lulu Teressa Poulsen, and Henrik Helligsø Jensen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00528 • Publication Date (Web): 25 May 2016
Downloaded from http://pubs.acs.org on June 3, 2016
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Remote Electronic Effects by Ether Protecting Groups
FineꢀTune Glycosyl Donor Reactivity
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Mads Heuckendorff, Lulu Teressa Poulsen and Henrik H. Jensen*
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
hhj@chem.au.dk
Reactivity in glycosylation
OBn
O
OBn
O
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
SPh
SPh
SPh
SPh
O
O
O
O
CN
Cl
H
OMe
1.25 mol% [Pd]
90%
1 mol% [Pd]
>90%
>
Abstract
It was established that paraꢀsubstituted benzyl ether protecting groups affect the reactivity of
glycosyl donors of the thioglycoside type with the Nꢀiodosuccinimide/triflic acid promoter system.
Having electron donating pꢀmethoxyꢀbenzyl ether (PMB) groups increased the reactivity of the
donor in comparison to having electron withdrawing pꢀchloro (PClB) or pꢀcyanobenzyl ether
(PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the
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parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first
armedꢀdisarmed coupling between two benzylated glucosyl donors by tuning their reactivity.
In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation
and methoxylation of pꢀchlorobenzyl protected thioglycosides. The results of this paper regarding
both the different electron withdrawing properties of various benzyl ethers and the efficient and
multiple protecting group transformations are applicable in general organic chemistry and not
restricted to carbohydrate chemistry.
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Introduction
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Efficient synthesis of oligosaccharides through chemical glycosylation remains a challenging task
and investigation of effects that govern donor reactivity and stereochemical outcome continues to
be performed in the hope of achieving some fundamental insight that eventually will lead to a
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general protocol for this intriguing reaction. Since the early days of carbohydrate chemistry it has
been known that protecting groups not only had an influence on the selectivity in glycosylation
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4,5
reactions, but also affected the reactivity of glycosyl donors. This difference in reactivity, the
6,7,8,9,10
degree of soꢀcalled armament, can be synthetically useful
rapid fashion as especially showed by Wong and coꢀworkers.
and provide oligosaccharides in a
1
1
Although generally agreed upon as being a challenging synthetic transformation, the glycosylation
reaction is just another reaction within the field of organic chemistry and controlling its
diastereoselectivity (anomeric selectivity) is a key issue.
Many scientists have offered much speculation when it comes to anomeric selectivity, but no rule
seems to be available and be widely known among experts in the field when it comes to reactions
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conducted without the use of participating protecting groups. Some text books states that the axial
glycoside will dominate as a consequence of the wellꢀknown anomeric effect, which has been
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brought into question since glycosylation, to a first approximation, must be under kinetic control.
There are many approaches for conducting a glycosylation reaction, which would fall into the
category of being a ‘standard protocol’, and the NIS/TfOH (cat) activation of a SPh thioglycoside
donor initiated at ꢀ78 °C and allowed to warm to a higher temperature arguably belongs to this
class. The slow warming of a reaction mixture is often used in organic chemistry for reactions in
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which diastereoselectivity is an issue to ensure as low a reaction temperature as possible. This,
however, only makes sense when the kinetic product is the desired outcome.
The Hammett equation and values derived from the pK values of substituted benzoic acids are
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fundamental in physical organic chemistry, and linear free relationships build on these have been
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widely used to interpret reaction mechanism in organic chemistry. In actual fact, the Hammett
constants, σ, have been found to correlate with pK
a
of phenylacetic acids (ρ = 0.489) and βꢀ
phenylpropionic acids (ρ = 0.212). Since the effects cannot be explained by resonance it is believed
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to be an inductive effect.
Scheme 1. Project outline: Does the nature of X have an influence on glycosyl donor reactivity and stereochemical outcome?
The present paper describes for the first time that benzyl ether pꢀsubstituents indeed can be used to
fine tune the reactivity of thioglycoside glycosyl donors undergoing NIS/TfOH activation (Scheme 1).
The results furthermore systematically show that the anomeric selectivity changes when varying the
benzyl ether pꢀsubstituent indicative of a temperature effect on glycosylation outcome (vide infra).
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Before this study, fully pꢀmethoxybenzyl (PMB) protected glycosyl donors have been used in
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glycosylations, when debenzylation by hydrogenolysis is not an option. pꢀChlorobenzyl (PClB)
protecting groups have been reported to render protected carbohydrates more prone to crystallize
and to stabilize the sensitive fucopyranoside linkage. There are no reports describing the use of pꢀ
cyanobenzylated (PCNB) glycosyl donors. Lately, however, highly selective benzyl protected
glycosyl donors with a 2ꢀOꢀ(oꢀcyanobenzyl) or a 2ꢀOꢀ(oꢀnitrobenzyl) group have been reported
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without the mention of their reactivity.
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Results and discussion
To investigate donor reactivity as a function of the benzyl ether pꢀsubstituent we started out by
synthesizing eight different glycosyl donors. In the glucoꢀseries perbenzylated (2), perꢀpꢀ
methoxybenzylated (3) and perꢀpꢀchlorobenzylated (4) phenyl thioglucosides were synthesized
under standard benzylation conditions in DMF with NaH as the base giving the donors in
reasonable yields (Scheme 2). In the galactoꢀseries the perbenzylated (6) and perꢀpꢀ
methoxybenzyled (7) donors were prepared in a similar fashion in good yields. To investigate the
effect of having only one pꢀsubstituted benzyl group; the 2ꢀO position was chosen due to its
proximity to the anomeric position. 2ꢀOꢀPMB, 2ꢀOꢀPClB and 2ꢀOꢀPCNB (9ꢀ11, respectively) were
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synthesized from 8 under published benzylation conditions.
Scheme 2. Synthesis of glycosyl donors
Investigating the influence of multiple electron withdrawing cyano groups on glycosyl donor
reactivity was also interesting, but the synthesis of a perꢀpꢀcyanobenzylated phenyl thioglucoside
was not possible under the standard benzylation conditions as described in Scheme 2. The reaction
proceeded sluggishly and the only isolable compound formed was the 6ꢀOꢀpꢀcyanobenzylated
product.
In 2000, Seeberger and Buchwald and coꢀworkers published a paper wherein pꢀhalobenzyl ethers
underwent HartwigꢀBuchwald amination using a variety of amines and Pd(dba)
2 2
or Pd(OAc) as
catalysts to arrive at an electron rich and hence more Lewis acid labile benzyl ether protecting
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group.
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The momentous progress witnessed in recent years in the area of palladium catalysis driven by
developments of highly active palladium ligands and palladium preꢀcatalysts have paved the way
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for new and mild reactions. In 2013, the Buchwald group published a safe method for performing
cyanation of arylchlorides, using
4 6 2
K [Fe(CN) ]·3H O and a palladium preꢀcatalyst system
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(
tBuXPhos Pd G3); having broad substrate scope, low catalyst loading and reaction times around
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h at 100 °C. Subjecting tetraꢀpꢀchlorobenzylated compound 4 to slightly modified conditions
gave the perꢀpꢀcyanobenzylated glucosyl donor 12 in 71% yield (92% for each cyano substitution),
2
2
(See Scheme 3). Delighted by the effective palladium catalyzed cyanation, we moved on to
perform cyanation of pꢀchlorobenzyl protected acceptors 13 and 14 with a free 4ꢀ or 6ꢀOH,
respectively. The free OH groups did not hamper the reactions, and the two desired compounds 15
and 16 were obtained in satisfactory yields of 85% and 84% (95% and 94 %, respectively for each
cyano substitution). Next, our attention was lead to another Buchwald publication, in which
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palladium catalyzed methoxylation of aryl chlorides under very mild conditions was described. To
investigate the methoxylation reaction on pꢀchlorobenzyl ethers the tetraꢀOꢀpꢀchlorobenzylated
compound 4 was again chosen as substrate. Upon treatment of 4 with 20 equivalents of methanol (5
t
equivalents per chloride), 5.6 equivalents of NaO Bu (1.4 equivalents per chloride) and 4 mol% (1
mol% per chloride) of the preꢀcatalyst system tBuBrettphos Pd G3 or RockPhos Pd G3 in dioxane
the perꢀpꢀmethoxybenzylated donor 3 was obtained in 89 % (97% for each methoxy substitution).
To further expand the method, we subjected the three disaccharides 17, 18 and 19 (vide infra)
bearing three PClB groups to the same conditions giving the products in around 90% yields. The
high yield obtained with low catalyst loading is a testament to the high turnꢀover frequency of this
system. The mild methoxylation reaction is highly recommendable and would allow a late stage
introduction of PMB groups by masking them as acid stable PClB groups.
Scheme 3. Palladium catalyzed cyanation and methoxylation of pꢀchlorobenzyl protected carbohydrates.
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Glycosylation and determination of donor reactivity in competition experiments
With the glycosyl donors in hand, we started out to compare their reactivity in glycosylation
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reactions. Standard activation conditions using NIS/TfOH(cat) were chosen in a nonꢀparticipating
2 2
solvent, CH Cl , using Lꢀmenthol (23) as an easily handled nonꢀhygroscopic acceptor. Since it can
be difficult to find an appropriate reaction temperature under which a given glycosylation takes
place, the reaction mixture was cooled to ꢀ78 °C prior to the addition of catalyst (TfOH). The
temperature was then allowed to slowly increase to 0 °C over several hours (Scheme 4). No reaction
throughout this study was found to take place at ꢀ78 °C, but all reactions were found to have
completed before reaching 0 °C. (Anomeric ratios were measured by comparison of integral
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intensities of the anomeric protons and anomeric carbons from HꢀNMR and CꢀNMR spectra of
crude reaction mixtures.)
As can be seen from Table 1, the reactions gave good yields and comparable βꢀselectivities for
donor 2 and 3 (Entry 1 and 2). The perꢀpꢀchlorobenzylated donor 4, however, was almost
unselective, which could be a result of a sluggish reaction due to the near equimolar amounts of
donor and promoter. Reaction completion for glycosylation with donor 4 was attained more easily
with 2 equiv. of NIS resulting in an increased βꢀselectivity (α/β 1:3) of the reaction to a level close
to that observed for the donors 2 and 3 (α/β 1:3 and 1:5, respectively). The increased amount of
NIS (2 equiv.) was also used for activation of perꢀpꢀcyanobenzyl protected donor 12 (Entry 4) in an
unselective reaction (α/β 1:1).
Scheme 4. General glycosylation reaction with Lꢀmenthol as acceptor.
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Table 1. Glycosylation results with
L
ꢀmenthol according to Scheme 4. Conditions: 1.1 equiv. NIS; 0.1 equiv. TfOH;
a
b
ꢀ
78 °C to 0 °C in CH Cl ; Isolated yield after chromatography; 2 equiv. NIS
2 2
a
Entry
1
Donor
α/β
1/3
Yield
100%
2
3
4
1/5
91%
81%
1
/1.1
b
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1
/3
80%
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85%
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93%
90%
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72%
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The remaining glucosyl donors (9ꢀ11) bearing three unmodified benzyl ether protecting groups, but
substituted benzyl ethers (PMB, PClB and PCNB, respectively) as protection of Oꢀ2 also gave good
to excellent chemical yields of the menthyl glucosides with very similar βꢀselectivity with only
slight excess (1.1 equiv.) of NIS as promoter. Identical conditions also provided the galactoside
products with perꢀOꢀbenzyl and perꢀOꢀpꢀmethoxybenzyl ether protecting groups from donors 6 and
7
.
Having established that all glycosyl donors gave high yields under the applied glycosylation
conditions, we went on to investigate their reactivity by performing competition experiments
between pairs of thioglycosides. This was undertaken by having 1 equivalent of each donor to
compete for 1 equivalent of NIS in the presence of excess acceptor, Lꢀmenthol (5 equiv.). Prior to
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the reactions, the donors were mixed and a CꢀNMR spectrum with a high signalꢀtoꢀnoise ratio was
recorded of the mixture to ensure that the donors were present in a 1:1 ratio by comparing the
2
4
13
anomeric (Cꢀ1) signals. After ended reaction and workꢀup a new CꢀNMR was recorded of the
crude reaction mixture and the anomeric signals of the unreacted donors were again integrated and
compared. It was thereby possible to obtain a ratio of donors before and after reaction that shows
how much of each donor has been consumed during the reaction and thus how reactive the donors
are compared to each other.
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Table 2. Competition experiments conducted with 5 equiv. of
L
ꢀmenthol (23); 1 equiv. NIS; 0.1 equiv. TfOH in CH Cl , ꢀ78 °C
2
2
to 0 °C. Before reaction anomeric carbons integrals were 1.0:1.0.
Competing donors
Integrals after
Entry
1
reaction (reciprocal)
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1:0.45
versus
(2.2:1)
1
:3
2
3
4
5
6
7
8
versus
versus
versus
versus
versus
versus
versus
(
(
0.33:1)
1
:7
0.14:1)
1:0.14
(7:1)
1
:0.4
(2.5:1)
1:0.67
(1.5:1)
1:1.2
(
(
0.83:1)
1
:1.6
0.63:1)
As seen from Table 2, the benzyl ether pꢀsubstituent significantly influences the reactivity of the
glycosyl donor. As expected from the Hammett constants the diminished electron withdrawing
ability of four PMB ethers renders donor 3 more reactive than 2 (Table 2, Entry 1) by causing less
destabilization to the oxacarbenium ionꢀlike transition state during donor activation. From the
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integrals it is apparent that twice as much of the PMB donor (3) is consumed during the reaction,
when compared to the benzylated donor (2) giving a 2.2:1 anomeric ratio of unreacted donors. This
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means that donor 3 is at least 2.2 times more reactive than 2. Furthermore, both the tetraꢀOꢀPClB
donor (4) and especially the tetraꢀOꢀPCNB donor (12) are less reactive than the benzylated donor
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(2) as expected (Table 2, Entry 2 and Entry 3). The reactivity difference between the two glucoꢀ
configured donors, the benzylated donor 2 and the tetraꢀOꢀPCNB donor (12) was furthermore found
to correspond to the reactivity difference between 2 and its galactoꢀconfigured congener 6 (Table 2,
Entry 4).
The competition experiment between donor 2 and 6 (Entry 4) enables a comparison of the method
used in this paper to reactivity differences known from the literature. The established ratio of
unreacted gluco:galacto donor being 7:1 is fully in accordance with observation by Wong and coꢀ
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workers, who observed a 6.4 fold difference in RRV’s between galactosyl and glucosyl donors.
From other glycosylation and hydrolysis studies a comparable rate difference has also been
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observed. The difference in reactivity between perꢀOꢀbenzyl and perꢀOꢀPMB was also compared
in the βꢀgalactoꢀseries (6 and 7, Entry 5) giving a similar result as in the glucoꢀseries (2 and 3,
Entry 1). From
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Table 2 (Entry 6ꢀ8) it is evident that glucosyl donors having only a pꢀsubstituted benzyl present on
the Oꢀ2 and unsubstituted benzyl ethers on Oꢀ3, Oꢀ4 and Oꢀ6 have an altered reactivity compared to
the tetraꢀOꢀbenzyl protected donor (2). The trend is the same as seen for the perꢀOꢀpꢀsubstituted
donors 3, 4 and 12; a PMBꢀether (9) increases reactivity, while PClBꢀ (10) and especially PCNBꢀ
ethers (11) decrease thioglycoside reactivity. The differences in reactivity between the parent donor
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2) and the singly altered donors (9ꢀ11) are reduced when compared to the fully altered donors (3, 4
and 12) as would be expected, but the magnitude, however modest, is still remarkable easily
observed.
Anomeric selectivity
Enticed by the relatively high βꢀselectivity in glycosylation with Lꢀmenthol, as described in
Table 1, we set out to investigate if this was an effect of the acceptor or whether the used conditions
generally offered a majority of βꢀanomeric product for the Bn, PMB and PClB protected donors (2,
3
and 4) in glycosylation reactions with a range of acceptors. As can be seen from the results listed
in Table 3, comparable yields and selectivity were obtained for the reactive acceptors 24 and 25 as
those obtained in reaction with ꢀmenthol (23).
L
Glycosylation with perꢀOꢀbenzyl and perꢀOꢀPMB donors (2 and 3) gave identical or very similar
glycosylation outcomes with regards to anomeric selectivity in reaction with acceptors 24ꢀ27 (Table
2
7
3
). The more reactive acceptors 3, 24 and 25 gave a moderate βꢀselectivity, whereas the selectivity
seemed to drop for reactions with the more sterically hindered secondary alcohols 26 and 27. For
the xylofuranose acceptor 27 (Entry 10ꢀ12) a reversed stereoselectivity was obtained for all three
donors and mostly αꢀproducts were isolated. Glycosylation of a similar xylofuranose based acceptor
2
8
with bulky 5ꢀOꢀTBDPS or 5ꢀOꢀTBDMS have previously been reported to give high αꢀselectivity.
We speculate that the reversed selectivity is due to steric reasons; the result underscores how
glycosylation selectivities can be very acceptor dependent.
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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
Table 3. Glycosylation results with carbohydrate based acceptor. Conditions: 1.1 equiv. NIS; 0.1 equiv. TfOH; ꢀ78 °C to 0 °C
a
b
in CH
2
Cl
2
; Isolated yield after chromatography; 2 equiv. NIS
Donor Acceptor α/β
/4
a
Entry
1
Yield
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
74%
2
1/4
90%
b
b
3
4
5
6
7
8
9
1/2
1/4
1/4
88%
86%
68%
b
b
1/3
86%
89%
68%
1/1.2
1/1.3
b
b
2/1
100%
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1
0
1
7/1
7/1
88%
58%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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48
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50
51
52
53
54
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56
57
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60
1
b
b
12
9/1
87%
Commenting on anomeric selectivity and the origin thereof must always be done with utmost
caution, but a glycosylation reaction must, at least initially, give the kinetic product as the major
13
product. The kinetic product could be the same as the thermodynamic product (expected to be the
axial glycoside) or the kinetic product could undergo anomerization to the thermodynamic product.
A certain trend, however, seems evident in that the less reactive PClB donor 4, in comparison to the
donors 2 and 3, returns a lower level of βꢀglycoside product. This is furthermore in agreement with
the results shown in
Table 1 including those of the PCNB protected donor 12. The eroding βꢀselectivity could be a result
of i) higher degree of postꢀglycosylation anomerization for the PClB and PCNB protected donors ii)
be a result of the reaction undergoing a different paths with respect to mechanism and
29,30
conformational preferences,
or iii) be a result of the less reactive donors undergoing
glycosylation at a higher temperature resulting in a smaller degree of selectivity. To shed light on
the origin of the changing selectivity when going to less reactive donors, a series of experiments
were conducted.
i) First, addressing the possibility of anomerization of the glycoside product under the reaction
conditions postꢀglycosylation was studied (Table 4). A glycosylation was carried out as previously
described between donor 2 and acceptor 24 but in the presence of menthyl βꢀglucoside 28. After the
reaction 28 could be reꢀisolated in near quantitative yield as the βꢀanomer (Table 4, Entry 1). Next,
the glycosylation between 2 and Lꢀmenthol (23) was carried out as earlier (
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2
2
2
2
2
2
3
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4
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6
0
1
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9
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9
0
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 1), but by letting the reaction mixture warm to ambient temperature (Entry 2). The outcome
with regards to both anomeric selectivity and yield was identical to that found for the experiment
described in
Table 1, Entry 1, where the reaction was quenched at 0 °C. These experiments show that no
anomerization occurs for the menthyl glycoside under the glycosylation conditions and between 0
°C and ambient temperature. Performing the reaction at ambient temperature however resulted in an
unꢀselective reaction yielding a 1:1 anomeric product ratio. This result is in accordance with the fact
that the yield of the kinetic product will be expected to drop at elevated temperatures (Entry 3).
a
Table 4. Investigation of the level of postꢀglycosylation anomerization. Conditions: 1.1 equiv. NIS; 0.1 equiv. TfOH; Isolated
b
yield after chromatography. Refers to
L
ꢀmenthyl glucoside 28.
a
Entry
Temperature
Donor
Acceptor α/β
Yield
b
1
β only
97%
ꢀ78 °C to 0 °C
2
ꢀ78 °C to r.t.
1/3
100%
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7
8
9
3
r.t. (isothermal)
1/1
93%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ii) Next, the stereochemical outcome of glycosylations performed under isothermal conditions at a
temperature at which activation of both donors were rapid was investigated. Benzylated donor 2 and
PClB protected donor 4 were accordingly reacted separately with
Lꢀmenthol as acceptor (NIS/10
mol% TfOH, CH Cl ) in the same cold bath at ꢀ10 °C. This resulted in an identical α/βꢀratio (1:2)
2
2
suggesting that the donors (2 and 4) are highly alike and reacts through the same conformation
despite their different reactivity.
Scheme 5. Glycosylation with acceptor 23 under isothermal conditions gives identical anomeric selectivity.
Collectively, the results of Table 4 and Scheme 5 show that the anomeric outcome of the conducted
glycosylations (
Table 1 and Table 3) are a result of the reaction’s intrinsic selectivity and not a result of a postꢀ
glycosylation anomerization reaction. In general, the benzylated donors were found to be βꢀ
12
selective and not αꢀselective as often claimed in literature. Furthermore, the observed eroding βꢀ
selectivity going from the benzylated donor over PClB to PCNB protected donors must be a result
of the reaction temperatures as mentioned under iii), which is generally accepted, but to the best of
3
1
our knowledge not previously studied in detail for glycosylations. The established α/β
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
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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
1
:2ꢀselectivty at ꢀ10 °C is in between the reactions carried out at ambient temperature (α/β 1:1) and
between ꢀ78 °C – 0 °C over approx. three hours (α/β 1:3) as would be expected. Another
glycosylation involving donor 2 and acceptor 23 (not shown) was carried out between ꢀ78 °C – ꢀ40
°C, which resulted in an improved α/β ratio of 1:5.
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
These findings underline the importance of temperature control during glycosylation and how the
selectivity can be significantly improved in favor of the kinetic product by cooling. Conducting
glycosylations at rising temperatures could benefit from considering the gradient with which the
temperature climbs.
Armedꢀdisarmed glycosylation
Having investigated reactivity and selectivity of the glycosyl donors, we moved on to explore the
possibility of performing chemoselective activation and thereby conducting armedꢀdisarmedꢀtype
couplings. The experiments were performed by taking one equivalent of donor to one equivalent of
thioglycoside acceptor, activating as previously described (Scheme 4). A successful coupling would
be indicative of a sufficiently large reactivity difference between the two reaction partners, while
the failure to produce a disaccharide in acceptable yield would suggest the opposite. As seen from
Table 5, Entry 1ꢀ2, benzyl and PMB protected donors (2 and 3, respectively) successfully gave the
disaccharide products in reaction with 6ꢀOHꢀPClB acceptor 13 with a level of βꢀselectivity
previously found for reactive primary acceptors (Table 3). To the best of our knowledge, the reaction
of 2 and 3 with the primary acceptor 13 are the first armed disarmedꢀtype couplings between two
benzylated donors and acceptors.
The same glucosyl donors (2 and 3) failed to give a useful result in reaction with the more sterically
hindered 4ꢀOHꢀPClB acceptor 14 (Entry 3). A reason for this could be that 14 is more reactive than
9c
1
3 thereby diminishing the reactivity gap between 2/3 and 14. In actual fact, Koeller and Wong
have reported that OH is an accelerating substituent compared to OBn and Withers and coꢀworkers
have shown that alterations at Cꢀ4 have greater influence on hydrolysis rates than alterations on Cꢀ
26d
6
.
Compared to the glucosyl donors 2 and 3, the more reactive galactosyl counterpart 6 smoothly made
the glycosylation possible on both the 6ꢀOH and 4ꢀOH of the PClB protected acceptors 13 and 14,
respectively (Entry 4 and Entry 5).
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The reactivity difference between benzyl and PCNB protected glucosyl donors were found to be
sufficient to allow for a 4ꢀOH glycosylation in reaction with 2 and acceptor 16 (Entry 6). Also the
PClB donor 4 was found to be able to provide disaccharide 31 in coupling with the more disarmed
PCNB protected acceptor (15) carrying a free primary alcohol (Entry 7). Again, the reaction
resulted in predominant formation of the βꢀanomer (α/β 1:2) but with a diminished degree of
selectivity as previously found for the PClB donor.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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43
44
45
46
47
48
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52
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54
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56
57
58
59
60
To this stage, the present results have shown that glycosyl donor reactivity can be modulated by
employment of different benzyl ethers and that the strongly electron withdrawing CNꢀgroup was
found to be the least reactive. To investigate whether the least reactive donor in this study thus far
i.e. perꢀOꢀPCNB donor 12 was still more reactive than a classically (ester protected) disarmed
donor, a coupling between triꢀOꢀbenzoylated acceptor 32 was attempted, which yielded the
disaccharide 33 in 79%. This demonstrates that the reactivity tuning with benzyl ether pꢀsubstituent
takes advantage of a previously unexploited area in the reactivity continuum.
Table 5. Glycosylation by chemoselective activation with 1 equiv. of both NIS, donor and acceptor; 0.1 equiv. TfOH; ꢀ78 °C to
0
°C in CH
2 2
Cl .
Entry
1
Donor
Acceptor
Product
α/β Yield
1/4 65%
2
3
4
1/3 66%
No disaccharide
product
2 or 3
ꢀ
0%
1/1 80%
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2
2
2
2
2
2
2
2
2
3
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6
3/1 57%
0
1
2
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0
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9
0
1
2
3
4
5
6
7
8
9
0
3/1 46%
7
8
1/2 49%
2/1 79%
9
In the elegant study by Wong and coꢀworkers it was noted that disaccharides generally are less
reactive than their monosaccharide counterparts suggesting a lowering of reactivity as a function of
carrying another glycosyl residue relative to a hydroxyl. An attempt to synthesize a trisaccharide,
coupling between disaccharide donor 20, 21 or 22 and PClB protected acceptor 13 failed, while
disaccharide 19 effectively reacted with the 6ꢀOH PCNB acceptor 15 giving 34 in 70% yield
(Scheme 6).
Scheme 6. Synthesis of trisaccharide 30.
Deprotection of PClB and PCNB groups
Given the results found in this study some synthetic utility could be obtained in certain cases by
fineꢀtuning donor reactivity as shown. PClB ethers have previously been used in rare cases but the
PCNB group is not wellꢀdescribed. The PClB protecting group could be cleaved in a twoꢀstep
3
process by first converting the Cl to OCH in a palladium catalyzed reaction as described, followed
by a standard PMBꢀdeprotection step. Direct conversion by catalytic hydrogenolysis has been
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3
2
described previously for the PClB protecting group, but not for the PCNB counterpart. To confirm
previous results for the PClB removal and explore the possibility of catalytic hydrogenolysis as a
means to remove the PCNB group, reactions were carried out on the menthyl glucosides 35 and 36.
Both were found smoothly to give the tetraꢀol 37 under standard conditions (Scheme 7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Debenzylation of PClB and PCNB groups by catalytic hydrogenolysis.
Conclusion
In conclusion, we have described the synthesis of several different glucosyl donors of the
thioglycoside type bearing different benzyl ether protecting groups. For the preparation it was found
that modern and commercially available palladium preꢀcatalysts and ligands efficiently preform the
conversion of multiple PClB groups into either PMB or PCNB groups. This reaction can be
expected to be generally applicable in organic synthesis.
Furthermore, it was found that the electron withdrawing power of the often used benzyl ether
protecting group changes as a function of its aromatic pꢀsubstituent despite the absence of
conjugative contact with the ether oxygen atom. This effect becomes measurable in NIS/TfOH
promoted glycosylation reactions with tetraꢀOꢀbenzylated thioglycoside donors where the order of
reactivity follows the trend established by the Hammett constants (OCH
3
>H>Cl>CN). Remarkably,
also donors having only one pꢀsubstituted (OCH , Cl or CN) benzyl ether on Oꢀ2, while having
3
unmodified 3,4,6ꢀtriꢀOꢀbenzyl groups, were found to have a measurable change in reactivity. The
reactivity tuning effects were in certain cases powerful enough to allow for chemoselective
activation of the more reactive glycosyl donors over less reactive ones, which made it possible to
synthesize a trisaccharide using the armedꢀdisarmed approach.
Temperature is generally accepted as a parameter that influences the stereochemical outcome of a
glycosylation reaction. As many others we have in this study added the promoter (TfOH) at ꢀ78 °C
where no color change is observed and therefore no reaction took place until the temperature was
allowed to climb. Under these conditions we observed the slower reacting donors carrying PClB
and PCNB protecting groups to give less of the major β−anomeric product than the more reactive
Bn and PMB protected donors in reaction with good nucleophiles like
Lꢀmenthol and primary
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2
2
2
2
2
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5
5
5
5
6
alcohols. We demonstrated that no post glycosylation anomerization occurred and therefore
concluded that the varying βꢀselectivity must be a consequence of the reaction temperature, which,
in turn, depends on the reactivity of the donor.
0
1
2
3
4
5
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9
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Experimental Section
General remarks
All reagents were used as purchased without further purification. Dry solvents were taken from a
solvent purification system. Glassware used for waterꢀfree reactions were dried for 12 h at 120 °C
before use. Columns were packed with silica gel 60 (230–400 mesh) as the stationary phase. TLC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
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50
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60
1
13
plates were visualized by 10% H SO in EtOH and heating until spots appeared. HꢀNMR and Cꢀ
2
4
NMR spectra were recorded on a 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm
relative to the residual solvent signal. Highꢀresolution mass spectral (HRMS) data were obtained on
an electrospray (ES) mass spectrometer analyzing timeꢀofꢀflight. NMR assignments were based on
DEPTꢀ135, COSY and HSQC NMR experiments.
Phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside
βꢀ
D
ꢀglucose pentaacetate (10 g, 25.6 mmol, 1.0 eq.) was dissolved in anhydrous CH
ꢁOEt (9.6 mL, 76.8 mmol, 3.0 eq.) were added at
°C. A color change from colorless to pink was observed after stirring for 18 h at rt. The reaction
2 2
Cl (50 mL).
Thiophenol (5.3 mL, 51.2 mmol, 2.0 eq.) and BF
3
2
0
3
was quenched with sat. aq. NaHCO until gas development ceased. The aqueous phase was
extracted with CH
and concentrated in vacuo. Recrystallization of the resulting residue from Et
thioglycoside as white flocculent crystals. 10.9 g, 96%, R 0.68 (EtOAc/pentane 2:1) [α]
Cl
2 2
and the combined organic phases were washed with brine, dried over MgSO
4
2
O instantly yielded
RT
f
D
ꢀ20.4 (c
3
3
34 1
1
.0, CHCl ), lit. ꢀ19.2. M 118.5–119.0 °C, lit. 118 °C. H NMR (400 MHz, CDCl ) δ 7.52 –
3
p
3
H
7
.47 (m, 2H, ArH), 7.37 – 7.27 (m, 3H, ArH), 5.22 (t, J 9.3 Hz, 1H, H3), 5.04 (t, J 9.8 Hz, 1H, H4),
.98 (dd, J 10.1, 9.2 Hz, 1H, H2), 4.71 (d, J 10.1 Hz, 1H, H1), 4.26 – 4.15 (m, 2H, H6 , H6 ), 3.75
3.75 (m, 1H, H5), 2.09 (s, 3H, CH ), 2.08 (s, 3H, CH ), 2.02 (s, 3H, CH ), 1.99 (s, 3H, CH ). C
4
a
b
13
–
3
3
3
3
NMR (100 MHz, CDCl
3
) δ
C
170.7, 170.3, 169.5, 169.4 (C=O), 133.2, 131.8, 129.1, 128.6 (Ar),
), 20.9 (CH ), 20.8
CH ), 20.7 (CH ). HRMS (ES): Calcd. for C H O SNa 463.1033; found 463.1034. Spectral
8
5.9 (C1), 75.9 (C5), 74.1 (C3), 70.1 (C2), 68.3 (C4), 62.3 (C6), 20.9 (CH
3
3
+
(
3
3
20 24
9
values were in accordance with those reported in ref. 33.
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5
5
5
5
6
Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀβꢀ
Dꢀglucopyranoside (2)
To a stirred solution of phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀ
D
ꢀglucopyranoside (21.8 g, 49.7
mmol) in MeOH a catalytic amount of Na(s) was added until a pHꢀvalue of 10 was reached. The
reaction mixture was stirred for 30 h at rt, then neutralized with DOWEX® Acidic Cation
Exchanger Resin in MeOH. The resin was filtered off by suction and the product mixture was
concentrated in vacuo. The product (13 g) was dissolved in anhydrous DMF (60 mL) and cooled to
0 °C. NaH (60% (w/w) dispersion in mineral oil, 15.9 g, 397 mmol) was added and the solution
became a slurry. BnBr (35.5 mL, 298 mmol) was then added dropwise to the suspension due to
vigorous gas development. The resulting mixture was stirred for 24 h before the reaction mixture
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
was cautiously transferred into a large volume of H
product precipitated. The aqueous phase was extracted with DCM (2 x 300 mL), dried over MgSO
and concentrated in vacuo. The residue was purified by flash column chromatography
(pentane/EtOAc 4:1) to afford the product as white crystals. 19.9 g, 63%, R 0.66 (pentane/EtOAc
2
O at 0 °C in which a minor amount of the crude
4
f
RT
35
35 1
5
:1). [α]
CDCl ) δ
4.85 (d, J 10.2 Hz, 1H, CHHPh), 4.81 (d, J 10.8 Hz, 1H, CHHPh), 4.79 (d, J 10.8 Hz, 1H, CHHPh),
.69 (d, J 10.3 Hz, 1H, CHHPh) 4.63 (d, J 9.8 Hz, 1H, H1), 4.57 (d, J 12.0 Hz, 1H, CHHPh), 4.55
d, J 10.8 Hz, 1H, CHHPh), 4.50 (d, J 12.0 Hz, 1H, CHHPh) 3.75 (dd, J 9.8 Hz, 1H, H6a), 3.72 –
D
+3.2 (c 1.0, CHCl
3
). lit. 3.
p
M : 91.5ꢀ92.5 °C. lit. 91ꢀ92 °C. H NMR (400 MHz,
3
H
7.57 – 7.52 (m, 2H, ArH), 7.37 – 7.14 (m, 23H, ArH), 4.86 (d, J 10.9 Hz, 1H, CHHPh),
4
(
3.64 (m, 2H, H6b, H3/H4), 3.61 (t, J 9.2 Hz, 1H, H3/H4) 3.50 – 3.44 (m, 1H, H5), 3.47 (dd, J 9.5
13
Hz, 8.6 Hz, 1H, H2). C NMR (100 MHz, CDCl ) δ 138.4, 138.3, 138.0, 133.8, 132.0, 128.9,
3
C
1
28.5, 128.5, 128.4, 128.3, 128.0, 127.9, 127.9, 127.9, 127.8, 127.7, 127.6, 127.5 (Ar), 87.5 (C1),
86.8 (C3/C4), 80.6 (C2/C5), 79.1 (C2/C5), 77.8 (C3/C4), 75.9 (CH
2
2
Ph), 75.5 (CH Ph), 75.1
+
(
CH Ph), 73.5 (CH Ph), 69.0 (C6).HRMS (ES): Calcd. for C H O SNa 655.2494; found
2
2
40 40
5
6
55.2488. Spectral values were in accordance with those reported in ref. 18.
Phenyl 2,3,4,6ꢀtetraꢀOꢀ(pꢀmethoxybenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (3) To a stirred solution
of phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (2.7 g, 6.1 mmol, 1.0 eq.) in MeOH a
catalytic amount of Na(s) was added until a pHꢀvalue of 10 was reached. After stirring for 4 h at rt
the reaction mixture was neutralized with DOWEX® Acidic Cation Exchanger Resin in MeOH.
The resin was filtered off and the mixture was concentrated in vacuo. The crude deacetylated
thioglycoside was dissolved in anhydrous DMF (50 mL) and NaH (60% (w/w) dispersion in
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mineral oil, (1.22 g, 30.5 mmol) was added at 0 °C. pꢀMethoxybenzyl chloride (4.1 mL, 30.5 mmol)
was added dropwise and the cloudy mixture was allowed to reach rt. After stirring for 3½ hours at rt
the reaction mixture was heated to 100 °C and stirred for further 2 hours to ensure completion. The
yellow mixture was quenched by pouring it into H
precipitated and was filtered off by suction. The filtrate was extracted with Et
combined organic phases were washed with H O (x 5), dried over Na SO and concentrated in
2
O (0 °C, 200 mL) upon which the crude product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
O (x 3) and the
2
2
4
vacuo leaving a white solid. Recrystallization of the combined crude products from Et
2
O afforded
RT
D
the product as white flocculent crystals. 3.02 g, 66%, R
f
0.31 (pentane/EtOAc 1:1). [α]
+9.6 (c
36
36 1
1
.0, CHCl ), lit. +12.5. M : 121 – 123 °C, lit. 122.0 – 122.5 °C. H NMR (400 MHz, CDCl ) δ
3
p
3
H
7.53 – 7.47 (m, 2H, ArH), 7.25 (d, J 8.2 Hz, 2H, ArH), 7.21 – 7.12 (m, 7H, ArH), 7.02 (d, J 8.2 Hz,
H, ArH), 6.83 – 6.72 (m, 8H, ArH), 4.79 – 4.68 (m, 1H, CHHAr), 4.76 (d, J 10.9 Hz, 1H,
2
CHHAr), 4.71 (d, J 10.5 Hz, 1H, CHHAr), 4.66 (d, J 10.5 Hz, 1H, CHHAr), 4.59 (d, J 10.4 Hz, 1H,
CHHAr), 4.56 (d, J 10.0 Hz, 1H, H1), 4.50 – 4.36 (m, 1H, CHHAr), 4.47 (d, J 11.6 Hz, 1H,
3
CHHAr), 4.39 (d, J 11.6, 8.9 Hz, 1H, CHHAr), 3.75 – 3.70 (m, 12H, 4xOCH ), 3.66 (d, J 10.2 Hz,
1
H, H6a), 3.62 – 3.54 (m, 2H, H6b, H3/H4), 3.50 (t, J 9.3 Hz, 1H, H4/H3), 3.39 (t, J 9.3 Hz, 1H,
1
3
H2), 3.39 – 3.35 (m, 1H, H5). C NMR (100 MHz, CDCl
3
) δ
32.0, 130.9, 130.5, 130.4, 130.4, 130.0, 129.7, 129.5, 129.5, 129.0, 127.5, 114.0, 114.0, 114.0,
13.9 (Ar), 87.6 (C1), 86.7 (C3/C4), 80.8 (C2), 79.3 (C5), 77.7 (C3/C4), 75.6 (CH Ar), 75.2
).HRMS (ES): Calcd. for
C
159.5, 159.4, 159.4, 159.3, 134.1,
1
1
2
(CH
2
2 2 3
Ar), 74.8 (CH Ar), 73.2 (CH Ar), 68.8 (C6), 55.4 (4xOCH
+
C H O SNH 770.3357; found 770.3361. Spectral values were in accordance with those reported
44 48
9
4
in ref. 36.
Phenyl 2,3,4,6ꢀtetra-Oꢀ(pꢀchlorobenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (4)
Phenyl 1ꢀthioꢀβꢀ
solution was cooled to 0 °C and added NaH (60% in mineral oil, 0.12 g, 3.0 mmol), TBAI (0.27 g,
.74 mmol) and pꢀchlorobenzyl chloride (0.48 g, 3.0mmol). The mixture was allowed to reach rt.
Dꢀglucopyranoside (0.1 g, 0.37 mmol) was dissolved in 2 mL of dry DMF. The
0
and stirred overnight, then quenched by adding a saturated aqueous solution of ammonium chloride.
The mixture was diluted with EtOAc and washed five times with water, once with aqueous 10%
Na S O solution then brine. The organic layer was dried over MgSO , filtered and evaporated to
2
2
3
4
dryness. The crude product was recrystallized from CH
2
Cl
2
and pentane. Yield: 181 mg, 64%. Rf:
RT
D
1
0
.52 (pentane/EtOAc 9:1). [α]
+14.4 (c 1, CHCl
3
). M
p
138ꢀ139 °C. H NMR (400 MHz, CDCl
3
):
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δ
H
7.56 (d, J 7.7 Hz, 2H, ArH), 7.39 – 7.22 (m, 15H, ArH), 7.15 (d, J 8.0 Hz, 2H, ArH), 7.08 (d, J
7
.9 Hz, 2H, ArH), 4.87 (d, J 10.5 Hz, 1H, CHHAr), 4.80 (d, J 11.5 Hz, 1H, CHHAr), 4.75 (d, J 11.5
Hz, 1H, CHHAr), 4.72 (d, J 11.5 Hz 1H, CHHAr), 4.66 (d, J 9.4 Hz, 1H, H1), 4.64 (d, J 10.5 Hz,
1H, CHHAr), 4.59 (d, J 12.1 Hz, 1H, CHHAr), 4.54 (d, J 11.5 Hz, 1H, CHHAr), 4.50 (d, J 12.1 Hz,
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
H, CHHAr), 3.76 (d, J 10.7 Hz, 1H, H6a), 3.70 (dd, J 10.7, 4.1 Hz, 1H, H6b), 3.68 – 3.58 (m, 2H,
13
H3, H5), 3.52 – 3.44 (m, 2H, H2, H4). C NMR (100 MHz, CDCl ): δ 136.8, 136.7, 136.5, 133.8,
3
C
133.8, 133.7, 133.6, 133.5, 131.9, 129.5, 129.1, 129.1, 129.1, 128.9, 128.7, 128.7, 128.7, 127.7
(Ar), 87.6 (C1), 86.7, 80.9, 79.1, 77.8, 75.0 (CH
2 2 2 2
Ar), 74.7 (CH Ar), 74.2 (CH Ar), 72.8 (CH Ar),
35
37
3
+
6
8.9 (C6). HRMS (ES): calcd. for C H Cl ClO SNH 788.1346; found 788.1387.
4
0
36
5
4
Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀβꢀ
galactopyranoside (6.33 g, 23.2 mmol) in 60 mL of dry DMF was cooled to 0 °C and added NaH
60% (w/w) dispersion in mineral oil, 7.44 g, 186 mmol). BnBr (16.6 mL, 139 mmol) was added
dropwise to the suspension due to vigorous gas development. The mixture was stirred overnight and
quenched by methanol before diluted with Et O and washed five times with water then brine. The
organic layer was dried over MgSO , filtered and evaporated to dryness. The crude compound was
crystallized from ethanol giving the product as white crystals. 11.3 g, 77%, R 0.8 (pentane/EtOAc
: 89ꢀ90 °C. lit. 88ꢀ89 °C. H NMR (400 MHz, CDCl
7.59 – 7.54 (m, 2H, ArH), 7.41 – 7.27 (m, 20H, ArH), 7.21 – 7.15 (m, 3H, ArH), 4.97 (d, J 11.5
Dꢀgalactopyranoside (6) A solution of phenyl 1ꢀthioꢀβꢀDꢀ
(
2
4
f
RT
D
37
37 1
5:1). [α]
+26 (c 1.0, CHCl
3
). lit. +1. M
p
3
)
δ
H
Hz, 1H, CHHPh), 4.81 – 4.68 (m, 4H, CH Ph, H1), 4.64 (d, J 9.7 Hz, 1H, CHHPh), 4.60 (d, J 11.5
2
Hz, 1H, CHHPh), 4.47 (d, J 11.7 Hz, 1H, CHHPh), 4.42 (d, J 11.7 Hz, 1H, CHHPh), 3.98 (d, J 2.5
13
Hz, 1H, H4), 3.93 (t, J 9.4 Hz, 1H, H2), 3.68 – 3.56 (m, 4H, H3, H5, H6). C NMR (100 MHz,
CDCl ) δ 138.8, 138.4, 138.3, 137.9, 134.2, 131.6, 128.9, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8,
3
C
127.8, 127.6, 127.6, 127.1 (Ar), 87.8 (C1), 84.2, 77.4 (CH
C4), 72.8 (CH Ph), 68.8 (C6). HRMS (ES): Calcd. for C40
Spectral values were in accordance with those reported in ref. 38.
2
2 2
Ph), 75.7 (CH Ph), 74.5 (CH Ph), 73.6
+
(
2
H
40
O
5
SNH
4
650.2935; found 650.2943.
Phenyl 2,3,4,6ꢀtetraꢀOꢀ(pꢀmethoxybenzyl)ꢀ1ꢀthioꢀβꢀ
Dꢀgalactopyranoside (7)
To a stirred solution of phenyl 1ꢀthioꢀβꢀ ꢀgalactopyranoside (2.5 g, 9.2 mmol) in 50 mL of dry
D
DMF was cooled to 0 °C and added NaH (60% (w/w) dispersion in mineral oil, 1.84 g, 46 mmol).
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pꢀMethoxybenzyl chloride (6.24 mL, 46 mmol) was added dropwise and the mixture was allowed to
reach rt. After stirring for 3 hours at rt. the reaction mixture was heated to 100 °C and stirred for
further 1 hour to ensure completion. The yellow mixture was cooled and the reaction was quenched
by adding methanol. The mixture was diluted with EtOAc and washed five times with water then
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
brine. The organic layer was dried over MgSO , filtered and evaporated to dryness. The residue was
purified by flash column chromatography (pentane as eluent with a gradient of EtOAc) giving the
RT
product as a white solid. 6.51 g, 94%, R
f
0.3 (pentane/EtOAc 3:1). [α]
09 – 110 °C. H NMR (400 MHz, CDCl ) δ
.27 – 7.17 (m, 7H, ArH), 6.95 – 6.82 (m, 8H, ArH), 4.89 (d, J 11.2 Hz, 1H, CHHAr), 4.73 (d, J 9.8
D
3 p
+10.6 (c 1.0, CHCl ), M :
1
1
7
3
H
7.61 – 7.53 (m, 2H, ArH), 7.36 – 7.29 (m, 3H, ArH),
Hz, 1H, CHHAr), 4.70 – 4.65 (m, 3H, ArH), 4.63 (d, J 9.7 Hz, 1H, H1), 4.55 (d, J 11.2 Hz, 1H,
CHHAr), 4.42 (d, J 11.3 Hz, 1H, CHHAr), 4.35 (d, J 11.3 Hz, 1H, CHHAr), 3.96 – 3.87 (m, 2H),
13
3
.86 – 3.79 (m, 12H, CH
3
), 3.64 – 3.52 (m, 4H). C NMR (100 MHz, CDCl
3
) δ
C
159.4, 159.4,
159.3, 159.2, 134.5, 131.5, 131.1, 130.7, 130.6, 130.1, 129.7, 129.6, 129.3, 128.9, 127.1, 113.9,
1
7
13.9, 113.7, 113.7 (Ar), 88.0 (C1), 84.1, 77.2, 76.9, 75.4 (CH
2
Ar), 74.1(CH
2
Ar), 73.3(CH
2
Ar),
3.2,
72.5
(CH
2
Ar),
68.7
(C6),
55.4
(CH ). HRMS (ES):
3
Calcd. for
+
C
44
H
48
O
9
SNH 770.3357; found 770.3370.
4
Phenyl 3,4,6ꢀtri-benzylꢀ2ꢀOꢀ(pꢀmethoxybenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (9)
18
Phenyl 3,4,6ꢀtriꢀbenzylꢀ1ꢀthioꢀβꢀ
D
ꢀ
glucopyranoside (0.50 g, 0.92 mmol) was dissolved in 10 mL
of dry DMF. The solution were added NaH (0.060 g, 1.4mmol), TBAI (0.50 g, 1.4 mmol) and pꢀ
methoxybenzyl chloride (0.19 mL, 1.4 mmol). The mixture was stirred overnight and quenched by
addition of a saturated aqueous solution of ammonium chloride. The mixture was diluted with
EtOAc and washed five times with water, once with aqueous 10% Na S O solution then brine. The
2
2
3
4
organic layer was dried over MgSO , filtered and evaporated to dryness. The crude compound was
purified by flash column chromatography with pentane as eluent with a gradient of EtOAc giving
RT
D
the product as a white solid. Yield: 451 mg, 74%. Rf: 0.3 (pentane/EtOAc 9:1). [α]
+11.4 (c 1,
3
9
39 1
CHCl ). Lit. +6.4 (c 1.29, CHCl ).
M 82.5ꢀ83.5 °C. Lit. 83ꢀ84 °C. H NMR (400 MHz,
p
3
3
CDCl
3
H
): δ 7.66 – 7.59 (m, 2H, ArH), 7.44 – 7.18 (m, 20H, ArH), 6.88 (d, J 7.9 Hz, 1H, ArH), 4.95
(d, J 10.8 Hz, 1H, CHHAr), 4.92 – 4.81 (m, 2H), 4.74 – 4.66 (m, 2H), 4.66 – 4.54 (m, 3H), 3.83 (s,
13
3H, OCH ), 3.79 – 3.63 (m, 3H), 3.54 (t, J 8.5 Hz, 2H). C NMR (100 MHz, CDCl ): δ 159.5,
3
3
C
1
38.6, 138.5, 138.2, 134.1, 132.0, 130.4, 130.0, 129.0, 128.6, 128.6, 128.5, 128.1, 127.9, 127.9,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
6
127.8, 127.7, 127.5, 114.0, 87.7, 86.9, 80.7, 79.2, 78.0, 75.9, 75.2, 73.6, 69.2, 55.4. HRMS (ES):
+
calcd. for C41
H
42
O
6
SNH
4
680.3040; found 680.3053. Spectral values were in accordance with
those reported in ref. 39 and 40.
0
1
2
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7
8
9
0
1
2
3
4
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7
8
9
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7
8
9
0
Phenyl 3,4,6ꢀtri-benzylꢀ2ꢀOꢀ(pꢀchlorobenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (10)
18
Phenyl 3,4,6ꢀtriꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (0.50 g, 0.92 mmol) was dissolved in 10 mL
of dry DMF. The solution were added NaH in minearal oil (60%, 0.060 g, 1.4 mmol), TBAI (0.50
g, 1.4 mmol) and pꢀchlorobenzyl chloride (0.19 mL, 1.4 mmol). The mixture was heated to 100 °C
for 30 min, cooled to rt and quenched by addition of a saturated aqueous solution of ammonium
chloride. The mixture was diluted with EtOAc and washed five times with water, once with
2 2 3 4
aqueous 10% Na S O solution then brine. The organic layer was dried over MgSO , filtered and
evaporated to dryness. The crude compound was purified by flash column chromatography with
pentane as eluent with a gradient of EtOAc giving the product as a white solid. Yield: 368 mg, 60%.
RT
1
R
f: 0.48 (pentane/EtOAc 9:1). [α]
CDCl ): δ 7.68 – 7.57 (m, 2H, ArH), 7.44 – 7.19 (m, 22H, ArH), 4.93 – 4.83 (m, 4H, CH
4.54 (m, 5H, CH
MHz, CDCl ): δ 138.5, 138.4, 138.1, 136.7, 133.9, 133.7, 132.0, 129.6, 129.1, 128.7, 128.6, 128.6,
128.5, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6 (Ar), 87.5 (C1), 86.9, 80.9, 79.3, 78.0, 75.9
D
+10 (c 1, CHCl
3
). M
p
102ꢀ103 °C. H NMR (400 MHz,
Ar), 4.76
2
Ar, H1), 3.87 – 3.64 (m, 4H, H6), 3.60 – 3.48 (m, 2H, H2). C NMR (100
3
H
2
13
–
3
C
(OCH
2
2 2 2
Ar), 75.2 (OCH Ar), 74.6(OCH Ar), 73.6(OCH Ar), 69.1 (C6). HRMS (ES): calcd. for
+
C
40
H
39ClO
5
SNH
4
684.2545; found 684.2552.
Phenyl 3,4,6ꢀtri-benzylꢀ2ꢀOꢀ(pꢀcyanobenzyl)ꢀ1ꢀthioꢀβꢀ
D
ꢀglucopyranoside (11)
18
Phenyl 3,4,6ꢀtriꢀbenzylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (0.50 g, 0.92 mmol) was dissolved in 10 mL
of dry CH CN. The solution were added NaH in mineral oil (60%, 0.060 g, 1.4 mmol) and pꢀ
3
cyanobenzyl chloride (0.15 g, 1.0 mmol). The mixture was stirred overnight and quenched by
methanol. The mixture was diluted with EtOAc and washed four times with water then brine. The
organic layer was dried over MgSO , filtered and evaporated to dryness. The crude compound was
4
purified by flash column chromatography with pentane as eluent with a gradient of EtOAc giving
RT
the product as a white plastic solid. Yield: 0.40 g, 66%. Rf: 0.48 (pentane/EtOAc 5:1). [α]
D
+20 (c
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1
1, CHCl
.0 Hz, 2H, ArH), 7.48 – 7.35 (m, 11H, ArH), 7.35 – 7.27 (m, 7H, ArH), 4.99 (d, J 11.1 Hz, 1H,
CHHAr), 4.97 (d, J 11.9 Hz, 1H CHHAr), 4.92 (d, J 10.8 Hz, 1H, CHHAr), 4.87 (d, J 11.1 Hz, 1H,
CHHAr), 4.85 (d, J 11.9 Hz, 1H, CHHAr), 4.77 (d, J 9.7 Hz, 1H, H1), 4.74 – 4.69 (m, 2H, CH Ar),
.64 (d, J 12.0 Hz, 1H, CHHAr), 3.90 (dd, J 10.9, 2.0 Hz, 1H, H6a), 3.84 (dd, J 10.7, 4.3 Hz, 1H,
3 p 3 H
). M 101ꢀ103 °C. H NMR (400 MHz, CDCl ): δ 7.68 – 7.63 (m, 4H, ArH), 7.51 (d, J
8
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
13
H6b), 3.82 – 3.75 (m, 2H), 3.65 – 3.55 (m, 2H). C NMR (100 MHz, CDCl ): δ 143.5, 138.2,
3
C
138.2, 137.9, 133.5, 132.1, 131.8, 129.0, 128.5, 128.4, 128.1, 127.9, 127.9, 127.8, 127.7, 127.6,
1
27.6, 127.6 (Ar), 118.9 (CN), 111.3 (Ar), 87.2 (C1), 86.6, 80.9, 79.1, 77.8, 75.8 (CH
2
Ar), 75.0
+
(
CH Ar), 74.1(CH Ar), 73.4(CH Ar), 68.9 (C6). HRMS (ES): calcd. for C H NO SNH
2 2 2 41 39 5 4
675.2887; found 675.2895.
Phenyl 2,3,4,6ꢀtetra-Oꢀ(pꢀcyanobenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (12)
To a 20 mL screwꢀtop vial equipped with a magnetic stir bar was added tBuXPhos Pd G3(15.5 mg,
.
5
mol%), tBuXPhos(8.3 mg, 5 mol%), K
,3,4,6ꢀtetraꢀOꢀ(pꢀchlorobenzyl)ꢀ1ꢀthioꢀβꢀ
4
[Fe(CN)
6
] 3H
2
O (329 mg, 0.78 mmol), and phenyl
2
D
ꢀglucopyranoside (300 mg, 0.39 mmol). After sealing
with a Teflonꢀlined screwꢀcap septum, the vessel was evacuated and backfilled with nitrogen (this
process was repeated for a total of three cycles). Dioxane (3.9 mL) and 0.05 M KOAc in degassed
water (3.9 mL) were then added to the reaction tube via syringe. The test tube was placed in an oil
bath preheated to 100 °C and stirred for 1 h with maximum stirring (1500 rpm). After 1 h the
reaction mixture was then cooled to room temperature and the contents of the test tube were
transferred to a separatory funnel using EtOAc and brine. The aqueous layer was further extracted
4
with EtOAc (total 2 x 15 mL). The combined organic layers were dried over MgSO , filtered, and
concentrated in vacuo. The residue was purified by flash column chromatography (pentane as eluent
with a gradient of EtOAc) giving the product as a plastic solid. Yield: 204 mg, 71%. Rf: 0.38
RT
D
1
(
pentane/EtOAc 3:2). M : 188ꢀ190 °C [α]
+31 (c 1, CHCl ). H NMR (400 MHz, CDCl ): δ
3 3 H
p
7
.57 – 7.41 (m, 10H, ArH), 7.35 (d, J 8.3 Hz, 2H, ArH), 7.31 (d, J 8.2 Hz, 2H, ArH), 7.23 – 7.15
(m, 7H, ArH), 4.89 (d, J 11.8 Hz, 1H, CHHAr), 4.77 (d, J 12.7 Hz, 1H), 4.71 (d, J 11.8 Hz, 2H,
CH Ar), 4.63 – 4.55 (m, 4H, CH Ar, H1), 4.50 (d, J 13.1 Hz, 1H, CHHAr), 3.75 – 3.66 (m, 2H,
H6), 3.64 – 3.56 (m, 2H, H3, H4), 3.49 – 3.39 (m, 2H, H2, H5). C NMR (100 MHz, CDCl
143.6, 143.4, 143.2, 143.1, 133.3, 132.3, 132.3, 131.8, 129.2, 128.0, 127.7, 127.5, 127.4, 127.4,
2
2
1
3
3
) δ
C
1
18.8 (CN), 118.7 (CN), 118.6 (CN), 118.6 (CN), 111.7, 111.7, 111.7, 111.5 (Ar), 87.4 (C1), 86.7,
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2
2
2
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4
5
5
5
5
5
5
5
5
5
5
6
81.2 (C2), 78.9 (C5), 78.0, 74.5 (CH
HRMS (ES): Calcd. for C44
2
2 2 2
Ar), 74.3(CH Ar), 73.9(CH Ar), 72.6(CH Ar), 69.3 (C6).
+
H
36
N
4
O
5
SNH
4
750.2745; found 750.2750.
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
Phenyl 4,6-Oꢀ(pꢀchlorobenzylidene)ꢀ1ꢀthioꢀβꢀ
Dꢀglucopyranoside
Phenyl 1ꢀthioꢀβꢀ glucopyranoside (2.92 g, 10.7 mmol) was dissolved in 10 mL of dry DMF. The
Dꢀ
solution was added 4ꢀchlorobenzaldehyde (4.52 g, 32.2 mmol) and pꢀTsOH (20 mg, 0.1mmol). The
solution was stirred on a rotary evaporator (60 °C, 30 mbar) for 3 hours. The reaction mixture was
then neutralized with trimethylamine and concentrated and coꢀevaporated with toluene. The crude
product was crystallized from CH Cl /pentane giving white crystals. Yield: 3.70 g, 87%. R 0.50
2
2
f:
RT
D
1
(pentane/EtOAc 1:1). [α]
ꢀ38.8 (c 1, CHCl
3 p 3 H
). M 174ꢀ175 °C. H NMR (400 MHz, CDCl ): δ
7
.52 (s, 2H, ArH), 7.41 (d, J 7.9 Hz, 2H, ArH), 7.33 (s, 5H, ArH), 5.48 (s, 1H, CHAr), 4.62 (d, J
9.7 Hz, 1H, H1), 4.40 – 4.31 (m, 1H, H6a), 3.82 (t, J 8.2 Hz, 1H), 3.75 (t, J 9.5 Hz, 1H, H6b), 3.56
13
–
1
3 C
3.37 (m, 3H, H2, H5), 3.03 (s, 2H, OH). C NMR (100 MHz, CDCl ): δ 135.5, 135.3, 133.1,
31.4, 129.3, 128.7, 128.6, 127.9 (Ar), 101.2 (CHAr), 88.7 (C1), 80.2, 74.6, 72.8, 70.5, 68.6 (C6).
+
4
HRMS (ES): calcd. for C19
H19ClO
5
SNH
412.0980; found 412.0984.
Phenyl
2,3,ꢀdi-Oꢀ(pꢀchlorobenzyl)ꢀ4,6-Oꢀ(pꢀchlorobenzylidene)ꢀ1ꢀthioꢀβꢀ
Dꢀglucopyranoside
Phenyl 4,6ꢀOꢀ(pꢀchlorobenzylidene)ꢀ1ꢀthioꢀβꢀ
D
ꢀglucopyranoside (3.70g, 9.4 mmol) was dissolved
in 20 mL of dry DMF. The solution were added TBAI (3.5 g, 9.4 mmol) and NaH in minearal oil
(60%, 1.5 g, 37 mmol). The solution was stirred for 5 minutes before 4ꢀchlorobenzyl chloride (6.0
g, 37 mmol) was added. The mixture was stirred overnight and quenched by addition of a saturated
aqueous solution of ammonium chloride. The mixture was diluted with EtOAc and washed five
2 2 3
times with water, once with aqueous 10% Na S O solution then brine. The organic layer was dried
over MgSO , filtered and evaporated to dryness. The crude product was crystallized from
4
RT
D
CH
2
Cl
2
/pentane giving white crystals. Yield: 4.40 g, 73%. Rf: 0.38 (pentane/EtOAc 10:1). [α]
ꢀ
1
1.8 (c 1, CHCl
3
). M
p
164ꢀ165 °C. H NMR (400 MHz, CDCl
3
): δ
H
7.55 – 7.48 (m, 2H, ArH), 7.40 –
Ar), 4.78 – 4.65 (m, 1H, 3H,
CH Ar, H1), 4.37 (dd, J 10.0, 4.5 Hz, 1H, H6a), 3.83 – 3.72 (m, 2H, H6b), 3.67 (t, J 9.3 Hz, 1H),
7
.18 (m, 15H, ArH), 5.53 (s, 1H, CHAr), 4.84 (d, J 11.4 Hz, 2H, CH
2
2
1
3
3.53 – 3.38 (m, 2H, H2, H5). C NMR (100 MHz, CDCl
3 C
): δ 136.8, 136.5, 135.7, 135.1, 133.8,
1
33.7, 133.0, 132.4, 129.4, 129.4, 129.2, 128.7, 128.7, 128.6, 128.1, 127.6 (Ar), 100.6 (CHAr), 88.4
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(C1), 83.0, 81.4, 80.6, 75.1 (CH
2
Ar), 74.5(CH
2 29
Ar), 70.2, 68.7 (C6). HRMS (ES): calcd. for C33H
3
5
37
+
Cl
2 5
ClO SH 645.0845; found 645.0870.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl 2,3,4ꢀtri-Oꢀ(pꢀchlorobenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (13)
Phenyl 2,3,ꢀdiꢀOꢀ(pꢀchlorobenzyl)ꢀ4,6ꢀOꢀ(pꢀchlorobenzylidene)ꢀ1ꢀthioꢀβꢀ
Dꢀglucopyranoside (310
mg, 0.48mmol) was dissolved in BH ·THF (1 M, 5.0 mL) at 0 °C. The mixture was stirred for 5
3
minutes and then added Bu
2
BOTf (0.5 mL 1M in DCM). The reactions was stirred for 90 mins and
then added Et N (0.5 mL) followed by addition of methanol. The reaction mixture was coꢀdistilled
3
with methanol 3 times and then purified by flash column chromatography with pentane as eluent
with a gradient of EtOAc giving the product as a white solid. Yield: 261 mg, 89%. Rf: 0.49
RT
D
1
(pentane/EtOAc 3:1). [α]
3 p 3 H
+18.2 (c 1, CHCl ). M 146ꢀ147 °C. H NMR (400 MHz, CDCl ): δ
7.56 – 7.51 (m, 2H, ArH), 7.37 – 7.27 (m, 11H, ArH), 7.22 – 7.13 (m, 4H, ArH), 4.89 (d, J 10.7 Hz,
1
H, CHHAr), 4.82 (d, J 11.4 Hz, 1H, CHHAr), 4.78 (d, J 11.4 Hz, 1H, CHHAr), 4.76 (d, J 11.1 Hz,
H, CHHAr), 4.73 (d, J 9.6 Hz, 1H, H1), 4.67 (d, J 10.7 Hz, 1H, CHHAr), 4.65 (d, J 11.1 Hz, 1H,
1
CHHAr), 3.92 (dd, J 12.2, 2.4 Hz, 1H, H6a), 3.73 (dd, J 12.2, 4.5 Hz, 1H, H6b), 3.68 (t, J 8.9 Hz,
1
1
H, H3), 3.60 (t, J 9.3 Hz, 1H, H4), 3.46 (dd, J 9.6, 8.9 Hz, 1H, H2), 3.40 (ddd, J 9.5, 4.5, 2.4 Hz,
13
3 C
H, H5), 2.23 (s, 1H, OH). C NMR (100 MHz, CDCl ): δ 136.8, 136.4, 133.7, 133.7, 133.5,
133.5, 131.7, 129.4, 129.2, 129.1, 128.8, 128.7, 128.7, 128.6, 127.8 (Ar), 87.6 (C1), 86.3 (C3), 81.1
(
C2), 79.4 (C5), 77.5 (C4), 74.8 (CH
2
Ar), 74.7(CH
2 2
Ar), 74.2(CH Ar), 61.9 (C6). HRMS (ES):
3
5
37
+
calcd. for C33
H
31 Cl
2
ClO
5
SNH
4
664.1267; found 664.1286.
Phenyl 2,3,6ꢀtri-Oꢀ(pꢀchlorobenzyl)ꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (14)
Phenyl 2,3,ꢀdiꢀOꢀ(pꢀchlorobenzyl)ꢀ4,6ꢀOꢀ(pꢀchlorobenzylidene)ꢀ1ꢀthioꢀβꢀ
Dꢀglucopyranoside (322
mg, 0.5 mmol) was dissolved in 5 mL CH Cl and the solution was cooled to ꢀ78 °C. The mixture
2
2
were added triethylsilane (0.24 mL, 1.5 mmol) and triflic acid (0.24 mL 1.5 mmol). The reaction
was stirred for 5 hours at ꢀ78 °C, and then quenched with Et N (0.21 mL, 1.5 mmol). The volatiles
3
were removed by evaporation and the remaining crude material purified by flash column
chromatography with pentane as eluent with a gradient of EtOAc giving the product as a white
RT
D
1
solid. Yield: 289 mg, 89%. Rf: 0.28 (pentane/EtOAc 3:1). [α]
ꢀ1.2 (c 1, CHCl
3
). M
p
93ꢀ95 °C. H
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