Stereoselectivity of Conformationally Restricted Glucosazide Donors

Article abstract of DOI:10.1021/acs.joc.7b00470

Glycosylations of 4,6-tethered glucosazide donors with a panel of model acceptors revealed the effect of acceptor nucleophilicity on the stereoselectivity of these donors. The differences in reactivity among the donors were evaluated in competitive glycosylation reactions, and their relative reactivities were found to be reflected in the stereoselectivity in glycosylations with a set of fluorinated alcohols as well as carbohydrate acceptors. We found that the 2-azido-2-deoxy moiety is more β-directing than its C-2-O-benzyl counterpart, as a consequence of increased destabilization of anomeric charge development by the electron-withdrawing azide. Additional disarming groups further decreased the α-selectivity of the studied donors, whereas substitution of the 4,6-benzylidene acetal with a 4,6-di-tert-butyl silylidene led to a slight increase in α-selectivity. The C-2-dinitropyridone group was also explored as an alternative for the nonparticipating azide group, but this protecting group significantly increased β-selectivity. All studied donors exhibited the same acceptor-dependent selectivity trend, and good α-selectivity could be obtained with the weakest acceptors and most reactive donors.

Full text of DOI:10.1021/acs.joc.7b00470

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Article
Stereoselectivity of conformationally restricted glucosazide donors
Stefan van der Vorm, Herman S. Overkleeft, Gijsbert A. van der Marel, and Jeroen D. C. Codée
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00470 • Publication Date (Web): 12 Apr 2017
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Stereoselectivity of conformationally restricted glucosazide donors
Stefan van der Vorm, Herman S. Overkleeft, Gijsbert A. van der Marel, Jeroen D. C. Codée*
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
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*
e-mail: jcodee@chem.leidenuniv.nl
Decreasing donor reactivity
•
• •
•
•
•
β
•
•
•
α
ABSTRACT
Glycosylations of 4,6-tethered glucosazide donors with a panel of model acceptors reveal the effect of acceptor nucleophilicity on
the stereoselectivity of these donors. The difference in reactivity between the donors is evaluated in competitive glycosylation
reactions and their relative reactivity is reflected in the stereoselectivity in glycosylations with a set of fluorinated alcohols as well
as carbohydrate acceptors. The 2-azido-2-deoxy moiety is more β-directing than its C-2-O-benzyl counterpart, as a consequence
of increased destabilization of anomeric charge development by the electron withdrawing azide. Additional disarming groups
further decrease α-selectivity of the studied donors, while substitution of the 4,6-benzylidene acetal with a 4,6-di-tert-butyl
silylidene led to a slight increase in α-selectivity. The C-2-dinitropyridone group was also explored as an alternative for the non-
participating azide group but this protecting group significantly increases β-selectivity. All studied donors show the same
acceptor-dependent selectivity trend, and good α-selectivity can be obtained with the weakest acceptors and most reactive donors.
Introduction
Glucosamine is a key constituent in numerous important oligosaccharides and glycoconjugates, where it can be either α- or β-
linked. While the former type of linkage can be reliably installed by the use of neighboring group participation of an C-2-amide
or carbamate based protecting group, the latter type continues to present a synthetic challenge. A thorough understanding of the
glycosylation mechanism and the influence of both reaction partners and reaction conditions on glycosylation stereoselectivity is
needed to enable reliable and predictable glycosylation reactions. The in-depth research conducted on conformationally restricted
benzylidene mannose and glucose donors has provided important insight into the glycosylation mechanisms of this type of 1,2-cis
selective donors.
non-particpating azide.
1
–5
6
–8
9–17
To construct 1,2-cis linkages of glucosamine donors, the C-2-amino group is most commonly masked as the
1
8,19
Notably, benzylidene glucosazides have not been systematically investigated with respect to the
stereoselectivity of glycosylations in which they are employed. The extrapolation of the stereoselectivity of benzylidene glucose
donors to their glucosazide counterparts suggests that benzylidene or analogously protected glucosazides may represent an
attractive class of 1,2-cis selective glucosamine donor synthons.
2
0,21
Recently, we have advocated the use of a comprehensive set of partially fluorinated ethanols, of gradually decreasing
nucleophilicity, that can be used to map how the stereoselectivity of a given glycosylation system is dependent on the
nucleophilicity of the acceptor. The stereoselectivity of the benzylidene glucose donor system proved to be greatly affected by
2
2
2
3–27
the reactivity of the nucleophile.
In light of the demand for 1,2-cis selective glucosaminylations but also with the aim in mind
to further our understanding of the stereo-electronic effects exerted by the azido group we set out to systematically evaluate a
series of glucosazide donors in a set of glycosylation reactions involving the toolset of partially fluorinated ethanols and a
selection of carbohydrate acceptors. As we describe here, changes in the structure and reactivity of the donor can be effectively
mapped using our panel of model acceptors, and we observed a clear reactivity-selectivity relationship for the stereoselectivity of
the glycosylations of all donors studied. Differences between the donors and the stereochemical variation in the glycosylation
outcome are explained using competition experiments and the characterization of the reactive intermediates involved.
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Results and discussion
The set of (partially) fluorinated ethanol acceptors, which we recently employed to relate the glycosylation stereoselectivity to the
acceptor nucleophilicity, is depicted in Figure 1 (compounds 6-11). Glycosylating these acceptors with benzylidene mannose,
benzylidene glucose, mannuronic acid donors, as well as fucosazide donors bearing various protecting groups, established the
2
2,28
dependence of the stereoselectivity of the glycosylations with these donors on the nucleophilicity of the acceptor.
benzylidene protected glucose donor 1, the gradual decrease in acceptor nucleophilicity going from ethanol, monofluoroethanol
MFE), difluoroethanol (DFE), trifluoroethanol (TFE) to hexafluoro-iso-propanol (HFIP) led to a gradual shift of the
For
(
stereoselecivity from high β- to exclusive α-selectivity (See Table 3). Here we present our results in investigating the set of
conformationally restricted glucosamine donors depicted in Figure 1 (1-5). Variation in the structure of these donors is found in
the cyclic protecting groups (benzylidene vs silylidene), in the functionality at the C-3-OH (benzyl vs benzoyl) and the nature of
the C-2-N-protecting group (azide vs the dinitropyridone (DNPY) group). The DNPY is introduced here as a non-participating N-
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9,30
protecting group.
glucose donor 1.
The reactivity and selectivity of the set of glucosamine donors is related to the well studied benzylidene
9
,22
Figure 1: Glucose-configured donors 1-5 and model acceptors 6-11 used in this study.
Synthesis
3
1
32
We prepared benzylidene protected glucosazide donors 3 and 4 with either an O-benzyl or O-benzoyl at C-3, and a silylidene
protected donor 2, from common building block 12 as depicted in Scheme 1. Hydrolysis of all acetyl esters and the
trichloroacetamide was followed by a diazotransfer to install the desired C-2-azide. Subsequent introduction of the di-tert-
butylsilylidene (DTBS) or the benzylidene acetal gave intermediates 13 and 14. Benzylation of 14 and 13 and benzoylation of
3
3
3
4
3
1
3
5
1
3 gave the target donor compounds 2, 3, and 4, respectively. Donor 5 was prepared in two steps from thioglucoside 15 by
exchange of the phthaloyl group for the DNPY functionality. To this end, compound 15 was treated with ethylenediamine to give
amine 16, wich was treated with DNPY reagent 18
3
0,36
to furnish the target donor.
a
Scheme 1. Preparation of donors 2-5
a
34
Reagents and conditions: (a) i. K
2
CO
3
, EtOH, H
2
O; ii. CuSO
4 2
•5H O, imidazole-1-sulfonyl azide hydrochloride ; (b) di-tert-butylsilyl bis(trifluoromethanesulfonate),
O, 13: 78% (three steps); (d) BnBr, NaH, DMF, 2: 80%, 3: 89%; (e) BzCl, DMAP, pyridine, DCM, 90%;
pyridine, 14: 71% (three steps); (c) PhCH(OMe)
(f) ethylenediamine, EtOH, 88%; (g) 18, AcOH/pyridine (1/16, v/v), 98%; (h) K CO , NMP, 85% ; i) HNO , H SO , 60%.
2 3 3 2 4
2
, p-TsOH•H
2
Observation of anomeric triflates
With these five donors in hand, we investigated the formation of potential covalent reactive intermediates in low-temperature
37
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2 2
NMR studies. The donors were treated with the diphenyl sulfoxide/triflic anhydride (Ph SO/Tf O) combination of reagents in
deuterated dichloromethane. Figure 2 shows the results of these studies and Table 1 summarizes the anomeric chemical shifts of
the observed triflates and the temperature at which decomposition starts (Tdecomp) (See also SI). Activation of reference donor 1 led
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to the formation of two species, beside the anomeric triflate 19 also the oxosulfonium triflate 19α* (6.68 ppm, 3.6 Hz) is formed
2
as was confirmed by the activation of a sample containing additional Ph SO (See SI). Donors 2 and 3 are cleanly converted to
their anomeric α-triflates 20 and 21 respectively by treatment with the activation couple at -80°C. Activation of donor 4
proceeded more slowly and raising the temperature from -80°C to -35°C was required for complete activation. Donor 5 proved
difficult to study by low-temperature NMR due to significant line-broadening in the resonance sets for both the donor and the
products formed upon activation. Complete activation of the thioglycoside could only be achieved at -40°C, but at this
temperature decomposition of the reactive intermediates also sets in. Two anomeric signals can be discriminated in the spectrum
of the activated DNPY donor 5 (Figure 2) and we assign these as the intermediate triflate (6.06 ppm) and oxosulfonium triflate
6.54 ppm). Unfortunately complete characterization is hampered by the severe line broadening. The reactive intermediates
39
(
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formed all decomposed to give the glucal product 24. The formation of the glucal double bond is relatively fast as the proton at C-
is readily eliminated to provide the enol ether double bond that is conjugated to the DNPY aromatic ring.
2
Table 1: Anomeric triflates observed.
1
H
δ
13
C
δ
T
(°C)
decomp
Entry
1
Triflate
(ppm)a
3
(ppm)
J
H1-H2
6
.09
106.1
-20
3.4 Hz
6.00
2
104.8
-30
3.4 Hz
Ph
O
O
O
6
.07
BnO
3
4
105.0
104.5
-20
-10
N3
3.5 Hz
2
1
OTf
6.23
3.5 Hz
5
6.06
102.2
-40
a
values determined at -40°C
19
20
21
22
23
1
Figure 2: H-NMR spectra of activated donors 1-5 showing their respective anomeric triflates 19-23.
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Competitive glycosylations and relative reactivities.
To investigate the reactivity of donors 1-5 a series of competitive glycosylations were performed between the different
40–44
thioglycosides.
In these competition experiments we used an in situ activation protocol, employing NIS/TfOH as activator and
2,3,4-tri-O-benzyl-α-O-methyl glucose 25 as the acceptor, as is commonly done to determine the reactivity of thioglycoside
4
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donors.
It should be noted however that the reactivity of the thiophenyl donor does not directly compare with the reactivity of
an intermediate triflate in the glycosylation, but it does give an indication of the relative disarming or arming nature of the
protecting groups present on the different donors. It is apparent from Table 2 that the azide has a profound effect on the reactivity
0
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0
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0
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of donor 3 as it is completely outcompeted by the C-2-O-benzyl donor 1. Silylidene donor 2 is more reactive than donor 3, and
the disaccharide products derived from donor 2 and 3 are formed in a 6 : 1 ratio. C-3-O-benzyl donor 3 in turn outcompetes
benzoylated donor 4 slightly, as a result of the electron withdrawing nature of the benzoate, giving a 1.6 : 1 ratio of the addition
47–49
products 3C and 4C.
DNPY protected donor 5 is the least reactive of the set of donors as it does not provide any disaccharide
product in the competition experiment with donor 4.
Table 2: Competitive donor activations.
Ph
O
Ph
Ph
O
O
O
O
O
BnO
BzO
O
O
BnO
N3
O
O
BnO
BnO
BnO
BnO
1
C
BnO
4C
BnO
OMe
OMe
OMe
OMe
a
b
Si
O
Entry
Donor I
Donor II
Products
Yield
O
O
O
N
O
O
BnO
BnO
1
2
3
4
1
1
2
3
2
3
3
4
5
1C : 2C, 14 : 1
1C : 3C, 1 : 0
2C : 3C, 6 : 1
3C : 4C, 1.6 : 1
4C : 5C, 1 : 0
65 %
80 %
37 %
39 %
64 %
O
N3
O
O
O
BnO
BnO
BnO
BnO
2C
BnO
BnO
OMe
O N
2
NO2
O
Ph
O
c
O
O
5C
5
4
BnO
a
1
b
N3
O
BnO
BnO
Determined by H-NMR of the isolated disaccharide. The disaccharide
fraction was quantified after isolation by size-exclusion chromatography and
related to the limiting amount of NIS (see experimental section). Combined
O
c
BnO
3C
donor concentration 0.1 M, triflic acid was added at -20°C and the reaction
heated to +15°C overnight, then quenched (Et N).
3
Glycosylations
With the reactivity of these five donors established the series of glycosylations with model acceptors 6-11 and carbohydrate
50–52
acceptors 25-29
2 2
was undertaken using the Ph SO/Tf O pre-activation procedure. Table 3 list all glycosylations ordered by
acceptor and donor reactivity. A clear relation between acceptor nucleophilicity and stereochemical outcome of the glycosylation
reactions of all studied glucosamine donors was observed, in line with the results previously obtained with donor 1. When
comparing the outcome of the coupling reactions of glucosazide 3 to the results obtained with C-2-O-benzyl donor 1 it becomes
apparent that the latter donor reacts with higher α-selectivity. Donor 2, bearing the DTBS group, overall provides slightly more of
the α-linked products than its benzylidene counterpart 3. The stereoselectivity of the condensations of donor 4, bearing an
additional electron withdrawing protecting group (i.e. the C-3-O-benzoyl) group is very similar to the stereoselectivity observed
with C-3-O-benzyl donor 3. Finally, donor 5, carrying the strongly electron withdrawing DNPY group, is the most β-selective of
5
3
the series of donors listed in Table 3.
The selectivities of glycosylations with carbohydrate acceptors also proceed in a nucleophilicity-dependent fashion. The primary
perbenzylated acceptor 25 reacts like ethanol 7 to give primarily the β-linked products for all glucosamine donors studied.
Secondary carbohydrate acceptors that are less nucleophilic show variation in the selectivity with the proportion of α-product
increasing with decreasing acceptor reactivity. In line with our previous studies the nucleophilicity of the secondary equatorial
carbohydrate alcohols falls somewhere in between the reactivity of MFE and DFE, with the reactivity of the axial hydroxyls
approaching the reactivity of TFE. The differences in the reactivity of the donors are reflected both in the stereoselectivity of the
glycosylation that involve the model acceptors as well as the glycosylations with the carbohydrate acceptors. A recurring trend is
apparent for all acceptors, with the most reactive donor 1 providing most and the least reactive donor 5 giving least α-linked
product.
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Table 3: Glycosylations of donors 1-5 with model acceptors 6-11 and carbohydrate acceptors 25-29.
1
2
3
4
5
a
Product
α : β (yield)
Product
α : β (yield)
Product
α : β (yield)
Product
α : β (yield)
Product
α : β (yield)
b
1
A
2A
< 1 : 20
(65 %)
3A
< 1 : 20
(83 %)
4A
< 1 : 20
(86 %)
5A
< 1 : 20
(59 %)
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
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39
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41
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60
A
B
C
D
E
F
G
H
I
1 : 10
68 %)
(
1
B
2B
< 1 : 20
(77 %)
3B
< 1 : 20
(93 %)
4B
< 1 : 20
(91 %)
5B
< 1 : 20
(63 %)
1 : 5.1
(71 %)
1
C
2C
1 : 14
(92 %)
3C
< 1 : 20
(89 %)
4C
1 : 14
(79 %)
5C
< 1 : 20
(57 %)
1 : 2.7
(81 %)
1
D
2D
1 : 5
(79 %)
3D
1 : 6.7
(90 %)
4D
1 : 6.5
(83 %)
5D
< 1 : 20
(43 %)
F
OH
1 : 2.8
70 %)
8
(
1
1 : 1
79 %)
E
2E
1 : 3
(81 %)
3E
1 : 7
(88 %)
4E
1 : 6
(71 %)
5E
1 : 20
(55 %)
(
(
(
1F
5 : 1
90 %)
2F
3.3 : 1
(84 %)
3F
1.1 : 1
(93 %)
4F
1 : 1.4
(59 %)
5F
1 : 3.6
(30 %)
1G
5 : 1
70 %)
2G
2.7 : 1
(76 %)
3G
2.9 : 1
(64 %)
4G
2.7 : 1
(84 %)
5G
1 : 1
(59 %)
1
H
2H
7 : 1
(52 %)
3H
9 : 1
(75 %)
4H
4 : 1
(51 %)
5H
< 1 : 20
(52 %)
> 20 : 1
83 %)
(
1
I
2I
> 20 : 1
(85 %)
3I
9 : 1
(74 %)
4I
5 : 1
(73 %)
5I
1 : 1.3
(53 %)
> 20 : 1
80 %)
(
1
J
2J
> 20 : 1
(82 %)
3J
> 20 : 1
(94 %)
4J
> 20 : 1
(86 %)
5J
4 : 1
(58 %)
J
> 20 : 1
(64 %)
1
K
2K
> 20 : 1
(34 %)
3K
> 20 : 1
(53 %)
c
K
> 20 : 1
65 %)
-
32% 24
(
a
22 b
Glycosylation results of donor 1, previously reported in van der Vorm et al. Ratio and yield of isolated product after column chromatography, anomers were not
c
separated. Only hydrolysed donor was found.
Mechanistic discussion
Two major trends become apparent from the table of glycosylations. First, with decreasing acceptor nucleophilicity the α/β-ratio
increases; and second, decreasing donor reactivity corresponds with a decrease in the α/β-ratio. These trends have also come to
the fore during our previous studies involving benzylidene glucose, mannose, mannuronic acid and fucosazide donors.
reactive intermediates that can play a role in the glycosylations of the confromationally restricted glucosamine donors and the
reaction trajectories of the incoming nucleophiles are presented in Figure 3. Previous studies by the group of Crich have indicated
2
2,28
The
N
that substitutions on the benzylidene glucosyl triflate 19 proceed in an S 2-like manner. In these mechanistic studies, that
1
2,14
involved the determination of kinetic isotope effects and cation-clock methodology, iso-propanol was used as an acceptor.
In
the kinetic scenario that was proposed the relatively stable α-trilfate (observed by low temperature NMR studies) is in equilibrium
with its more reactive β-counterpart. In both species the triflate can be displaced by alcohols if they are nucleophilic enough. The
higher β-selectivity that is seen for the glucosazide and DNPY-glucosamine donors in comparison to donor 1 can be accounted for
by the stronger electron withdrawing effect of the azide with respect to the benzyl ether. This leads to a more stable covalent α-
triflate and favors an associative displacement mechanism. A similar effect has been observed by the group of Crich in
54
glycosylations of the analogous 2-deoxy-2-fluoro benzylidene glucosides. The DNPY group is even more electron withdrawing,
N
leading to a further increase of β-selectivity via associative displacement. However, an S 2-like reaction pathway is less likely for
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the weaker nucleophiles, such as TFE and HFIP. The high α-selectivity for these acceptors can be explained perhaps more
precisely by considering the involvement of more electrophilic intermediates such as the glycosyl oxocarbenium ion. The
benzylidene and silylidene protecting groups restrict the conformational space that the donor pyranosides can adopt and the
3
3
55,56
intermediate oxocarbenium ion likely adopt a E/ H
4
–like conformation.
Nucleophiles attack this envelope/half chair
57
conformer preferentially from the bottom face to lead to the α-linked prodcuts via a chair-like transition state. The more reactive
donors more readily dissociate to form an oxocarbenium ion and this accounts for the increased α-selectivity for these donors.
Donor 2, bearing the silylidene group is the most reactive of the studied glucosamine donors. It also is slightly more flexible than
the benzylidene restricted donors and these two factors allow the activated donor to more readily form a flattened oxocarbenium
ion-like intermediate. Consequently, it is the most α-selective of the studied glucosamine donors. Finally, it is notable that the C-
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
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9
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7
8
9
0
1
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3
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7
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9
0
3-O-benzoyl protected glucosazide 4 reacts in a slightly more β-selective fashion than its C-3-O-benzyl counterpart 3. In light of
the discussion above this makes sense as the electron withdrawing benzoyl stabilizes the anomeric α-triflate. It contrasts however
with the behavior of acyl groups at the C-3 position of benzylidene mannosyl donors. The 1,2-cis selectivity generally observed
for these donors can be completely changed to selectively give the α-linked products by installing a C-3-acyl group in the
5
8,59
donor.
The difference between the benzylidene mannose and benzylidene glucose series may be found in the different
geometries that the oxocarbenium ions adopts. For the benzylidene mannose system a B2,5-like structure is one of the lower energy
1
2,55,56
oxocarbenium ion conformers.
In this constellation, the C-3-benzoate can fold over to the electron depleted anomeric center
to provide stabilization, without a major skeletal rearrangement. For the benzylidene glucose on the other hand, a B2,5-like
structure such as 32 is significantly less favorable because this puts the C-2-azide in a flag-pole position. Given the selectivities
observed for this donor, influences arising from this boat conformation do not play a significant role here.
X
O
O
O
RO
Nu
N3
(1S3)
3
33 (1S3)
-face attack
3
33
-face attack
-face attack
strong O-nucleophiles
RO
OTf
X
O
X
X
O
O
O
O
OTf
X
O
O
O
4
O
O
OTf
O
4
O
RO
RO
RO
N3
N3
N3
N3
H
OTf
3
0
30
31 ( H3 / E)
32 (B2,5)
-face attack
moderate O-nucleophiles
-face attack
weak O-nucleophiles
R = Bn, Bz
-face attack
33 (4C1)
t
X = PhCH, ( Bu)2Si
X
33 (4C1)
O
O
O
RO
N3
Nu
3
3
Figure 3: Reactive intermediates and reaction pathways for the 4,6-tethered glucosazide donors.
Conclusions
A set of model acceptors of gradually changing nucleophilicity has been used to investigate how the stereochemistry of
glycosylations involving 4,6-tethered glucosamine donors relates to the nucleophilicity of the acceptor. The set of acceptors was
complemented by a suite of carbohydrate alcohols to translate the results obtained with the model acceptors to a more relevant
glycosylation setting. Four glucosamine donors were probed differing in the type of tether spanning the C-4 and C-6-alcohols, the
nature of the protecting group at the C-3-OH and the amino functionality at C-2. Similar to the previously described benzylidene
glucose donor 1, the stereoselectivity of the studied glucosamine donors show a strong correlation to the nucleophilicity of the
acceptor, with strong nucleophiles providing completely β-selective condensations and weak nucleophiles selectively leading to
the formation of the α-linked products. Benzylidene glucosazide donors are less α-selective than their C-2-O-benzyl congeners,
due to the increased electron withdrawal power of the azide, which retards the formation of an oxocarbenium ion species and
favors a more associative mechanistic pathway. We have also introduced a novel protecting group for the C-2-amino group: the
2
9,30,36
dinitropyridone functionality.
Although this group is easily installed and removed from the C-2-amine, its strongly electron
withdrawing character limits its use. In the 4,6-benzylidene glucosamine donor studied here it disarms the donor glycoside to the
extent that it turns into a suboptimal glycosyl donor. A major incentive for the reported study has been the good to excellent α-
selectivity that has previously been reported for benzylidene glucose donor 1. Unfortunately, installation of a 4,6-benzylidene on
the analogous glucosazide donors does not provide a reliable donor to affect 1,2-cis-selective glycosylations. Only with relatively
poor nucleophiles useful stereoselectivities are obtained. Changing the benzylidene for a silylidene group however turns the donor
into a more reactive glycosylating agent showing improved α-selectivity. This donor, attractive because of its fully orthogonal
protecting group scheme, may find application in the future assembly of oligosaccharides featuring α-glucosamines. Finally we
note that this study provides another illustration of the application of the toolset of partially fluorinated ethanols to efficiently map
the reactivity-selectivity relationship of a class of donor glycosides. Implementation of this methodology to investigate novel
donor systems will broaden our insights into the different mechanistic pathways at play during glycosylations and eventually
generate a complete picture how to tune both reaction partners to achieve stereoselective glycosylation reactions in a predictable
manner.
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The Journal of Organic Chemistry
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Supporting Information
1
NMR spectra of all new compounds, decomposition study and identification of anomeric triflates by NMR, H-NMR spectra of
isolated disaccharide fractions of competition experiments.
Experimental Section
General experimental procedures: All chemicals were of commercial grade and used as received unless stated otherwise. DCM was stored over activated 4 Å
molecular sieves for at least 24 h before use. Trifluoromethanesulfonic anhydride (Tf
Triethylamine (Et N) was distilled over CaH and stored over KOH pellets. Overnight temperature control was achieved by a FT902 Immersion Cooler (Julabo). FlaTsMh
column chromatography was performed on silica gel 60 Å (0.04 – 0.063 mm, Screening Devices B.V.). Size exclusion chromatography was performed on Sephadex
LH-20, GE Healthcare Life Sciences) by isocratic elution with DCM/MeOH (1/1, v/v). TLC-analysis was conducted on TLC Silica gel 60 (Kieselgel 60 F254, Merck)
with UV detection by (254 nm) and by spraying with 20% sulfuric acid in ethanol or by spraying with a solution of (NH Mo O (25 g/L) and
NH Ce(SO O (10 g/L) in 10% aq. sulfuric acid followed by charring at ±250 °C. High-resolution mass spectra (HRMS) were recorded on a Thermo Finnigan
LTQ Orbitrap mass spectrometer equipped with an electrospray ion source in positive mode (source voltage 3.5 kV, sheath gas flow 10, capillary temperature 275 � C)
2 2 5
O) was distilled over P O and stored at -20°C under an nitrogen atmosphere.
3
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 6
7 2
O24·H
(
)
4 4
4 4 2 2
) · H
1
13
with resolution R=60.000 at m/z=400 (mass range = 150-4000). H and C NMR spectra were recorded on a Bruker AV-400, Bruker DMX-400, Bruker AV-500 NMR
instrument. Chemical shifts (δ) are given in ppm relative to tetramethylsilane as internal standard or the residual signal of the deuterated solvent. Coupling constants (J)
13
are given in Hz. All given C-APT spectra are proton decoupled. NMR peak assignments were made using COSY and HSQC. If necessary additional NOESY, HMBC
and HMBC-GATED experiments were used to further elucidate the structure. The anomeric product ratios were based on careful analysis of the crude reaction mixture
1
and the purified reaction product by integration of representative H NMR signals. IR spectra were recorded on a Shimadzu FTIR-8300 IR spectrometer and are
-
1
reported in cm . Specific rotations were measured on a Propol automatic polarimeter or an Anton-Paar MCP-100 modular circular polarimeter at 589 nm unless
otherwise stated.
6
0
General procedure for Tf
coevaporated twice with dry toluene and dissolved in dry DCM (2 mL, 0.05 M donor). Activated 3Å molecular sieves (rods, size 1/16 in.) were added and the reaction
mixture stirred for 1 h at room temperature under a nitrogen atmosphere. The solution was cooled to -78°C and Tf O (22 ꢀl, 0.13 mmol, 1.3 eq.) was added. The
2 2 2
O/Ph SO mediated glycosylations: Donor (0.1 mmol), Ph SO (26 mg, 0.13 mmol, 1.3 eq.) and TTBP (62 mg, 0.25 mmol, 2.5 eq.) were
2
reaction mixture was allowed to warm to -60°C (donor 1, 2, 3), -45°C (donor 5), -35°C (donor 4), followed by recooling to -78°C and addition of the acceptor (0.2
mmol, 2 eq.) in DCM (0.4 mL, 0.5 M). The reaction mixture was allowed to warm to -40°C in approximately 90 min and stirred for an additional 0-18 h depending on
the acceptor. The reaction was quenched with Et
and water was added, the layers were separated and the water phase extracted once more with DCM. The combined organic layers were dried over MgSO
and concentrated in vacuo. Purification by silica gel flash column chromatography and when needed, sephadex LH-20 size exclusion chromatography yielded the
glycosylation product as a mixture of anomers.
3
N (0.1 mL, 0.72 mmol, 5.5 eq.) at -40 � C and diluted with DCM. The solution was transferred to a separatory funnel
, filtered,
4
TM
General procedure for the NIS/TfOH mediated competition experiments: Donor I (0.1 mmol, 1 eq.), donor II (0.1 mmol, 1 eq.) and acceptor 25 (0.2 mmol, 2 eq.)
were together coevaporated with dry toluene (2x). Dry DCM (4 mL, donor concentration 0.05 M), a Teflon stirring bar and 3Å activated molecular sieves (rods, size
1
/16 in.) were added and the mixture was stirred under a nitrogen atmosphere for 1 h at room temperature. The mixture was cooled to -40°C and NIS (0.1 mmol, 1 eq.)
was added. TfOH (50 µL of a freshly prepared 0.2 M stock solution in dry DCM, 0.1 eq.) was added and the mixture was allowed to warm to 0°C in 3 hours. Et N (0.1
mL) was added and the mixture was diluted with EtOAc, washed with sat. aq. NaS and brine, dried over Na SO and concentrated in vacuo. Size exclusion
3
2
O
3
2
4
TM
chromatography (Sephadex LH-20, 1/1 DCM/MeOH) enabled isolation of the disaccharide products and the monosaccharide rests, which were both analysed with
NMR spectroscopy. The yield of the disaccharide fraction was determined. For the competition between donors 4 and 5, a 0.1 M concentration, and a starting
temperature of -20°C was used, which was allowed to warm to +15°C in 18h.
General procedure for the low temperature NMR experiments: A mixture of donor (30 µmol) and Ph
the activation of donor 1 also TTBP (75 µmol) was added). Under a nitrogen atmosphere, CD Cl (0.6 mL) was added and the mixture transferred to a nitrogen flushed
NMR tube and closed with a NMR tube septum. The NMR magnet was cooled to -80°C, locked and shimmed and the sample was measure prior to activation. In a long
narrow cold bath (EtOH, -85°C) the sample was treated with Tf O (39 µmol), shaken thrice and cooled again after every shake. The cold sample was wiped dry and
quickly inserted back in the cold magnet. The first H NMR spectrum was immediately recorded. The sample was then reshimmed and spectra were recorded in 10°C
intervals with at least 5 min equilibration time for every temperature.
2
SO (39 µmol) was coevaporated with dry toluene twice (for
2
2
2
1
3
3
Phenyl 2-azido-4,6-O-benzylidene-2-deoxy-1-thio-β-
was added K CO (41.5 g, 300 mmol, 6 eq), and 20 mL H
added the diazo transfer reagent imidazole-1-sulfonyl azide hydrochloride (13.10 g, 62.5 mmol, 1.25 eq.) in 3 equal portions followed by a catalytic amount of
CuSO •5 H O (125 mg, 0.5 mmol, 0.01 eq.). After stirring for 5 hours, the solution was filtered and reduced to 1/4 of its volume in vacuo. H O (150 mL) and 1 M aq.
HCl (150 mL) were added to obtain an acidic (pH ≈ 3) solution which was extracted with EtOAc (3x 120 mL). The combined organic layers were washed with sat. aq.
D-glucopyranoside (13). To a suspension of thioglycoside 12 (27.14 g, 50 mmol, 1 eq.) in EtOH (200 mL)
61
2
3
2
O and the mixture was refluxed overnight. The flask was cooled to r.t. and to the crude free amine was
34
4
2
2
6
2
NaHCO
crude azide (≤50 mmol) was coevaporated with toluene twice and subsequently dissolved in DMF (50 mL) and MeCN (200 mL) to which benzaldehyde dimethyl
acetal (15 mL, 100 mmol, 2 eq.) and p-TsOH•H O (950 mg, 5 mmol, 0.1 eq.) were added. The reaction mixture was heated at 60°C overnight, followed by an
additional 5 hours of heating at 60°C under reduced pressure (300 mbar) to reduce the volume to 1/3. The reaction was quench by the addition of triethylamine (1 mL),
and diluted with EtOAc (350 mL), washed with H O (2x 100 mL), sat. aq. NaHCO (1x 100 mL), and brine (1x 100 mL). The organic layer was dried (MgSO ) and
3 4
(150 mL) and brine (150 mL), dried with MgSO and concentrated in vacuo to obtain crude azide; phenyl 2-azido-2-deoxy-1-thio-β-D-glucopyranoside. The
2
2
3
4
concentrated in vacuo. The crude mixture was purified by percipitation from hot EtOAc (100 mL) / heptane (300 mL) by adding petroleum ether (500 mL) while
stirring and slowly cooling to 0°C to obtain the title compound as a white powder (11.38 g, 29.5 mmol, 59%). The mother liquors were purified by flash column
chromatography (8/1 to 4/1 pentane/EtOAc) to obtain an additional batch of white solid product (3.8 g, 9.6 mmol, total yield = 39.1 mmol, 78%, 3 steps). A purified
sample could be recrystallized from either hot MeOH or EtOAc/petroleum ether to obtain white cotton like needles. R
f
: 0.50 (6/1 pentane/EtOAc). Spectroscopic data
, 400 MHz, HH-COSY, HSQC): δ 7.64 – 7.52 (m, 2H, CHarom), 7.50 – 7.43 (m, 2H, CHarom), 7.42 –
.32 (m, 6H, CHarom), 5.53 (s, 1H, CHPh), 4.54 (d, 1H, J = 10.1 Hz, H-1), 4.38 (dd, 1H, J = 10.5, 4.6 Hz, H-6), 3.85 – 3.70 (m, 2H, H-3, H-6), 3.52 – 3.40 (m, 2H, H-4,
31 1
were in accord with those previously reported. H NMR (CDCl
7
3
13
H-5), 3.35 (dd, 1H, J = 10.2, 9.0 Hz, H-6), 2.75 (bs, 1H, 3-OH); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 136.8 (C
29.3, 128.8, 128.5, 126.4 (CHarom), 102.1 (CHPh), 86.9 (C-1), 80.3 (C-4), 74.2 (C-3), 70.4 (C-5), 68.5 (C-6), 65.2 (C-2); HRMS: [M+H] calcd for C19
86.11690, found 386.11708.
q
CHPh), 133.8 (CHarom), 130.9 (C SPh), 129.6,
q
+
1
3
20 3 4
H N O S
Phenyl 2-azido-2-deoxy-4,6-O-di-tert-butylsilylidene-1-thio-β-
synthesized as described for compound 13) (≤10 mmol) was dissolved in pyridine (15 mL) and cooled to 0°C. Di-tert-butylsilyl bis(trifluoromethanesulfonate) (3.6
mL, 11 mmol, 1.1 eq.) was slowly added and the reaction was stirred for 1 h before being quenched with MeOH. The reaction mixture was diluted with 200 mL Et
and washed with 1M aq. HCl (3x 60 mL), sat. aq. NaHCO (60 mL), and brine (60 mL). The organic layer was dried with Na SO , filtered and concentrated in vacuo.
Purification by flash column chromatography (1-10% Et O/pentane) afforded the silylidene protected title compound as a colorless oil (3.10 g, 7.1 mmol, 71% over
O). [α]ꢀ = -42.6° (c = 1.0, CHCl ); IR (neat): 652, 733, 824, 1072, 1092, 1155, 1277, 1474, 2112, 2859, 2884, 2934, 2963,
, 400 MHz, HH-COSY, HSQC) δ 7.57 – 7.51 (m, 2H, CHarom), 7.36 – 7.31 (m, 3H, CHarom), 4.49 (d, 1H, J = 10.2 Hz, H-1), 4.21 (dd, 1H, J =
0.2, 5.1 Hz, H-6), 3.89 (t, 1H, J = 10.2 Hz, H-6), 3.64 (t, 1H, J = 9.1 Hz, H-4), 3.56 (td, 1H, J = 9.0, 1.2 Hz, H-3), 3.40 (ddd, 1H, J = 10.1, 9.3, 5.1 Hz, H-5), 3.31 (dd,
D-glucopyranoside (14). Crude triol phenyl 2-azido-2-deoxy-1-thio-β-D-glucopyranoside
(
2
O
3
2
4
2
ꢁꢂ
three steps). R
f
: 0.18 (19/1 pentane/Et
2
3
1
3449; H NMR (CDCl
3
1
t
t
13
3 3 3
1H, J = 10.2, 9.1 Hz, H-2), 2.92 (d, 1H, J = 1.6 Hz, 3-OH), 1.04 (s, 9H, CH Bu), 0.97 (s, 9H, CH Bu); C-APT NMR (CDCl , 101 MHz, HSQC): δ 133.7 (CHarom),
t t +
1
31.2 (C
q
), 129.2, 128.7 (CHarom), 86.8 (C-1), 77.4 (C-3), 76.6 (C-4), 74.4 (C-5), 66.0 (C-6), 64.4 (C-2), 27.5, 27.0 (CH
SSi 410.18213, found 410.18220.
3 q 2
Bu), 22.8, 20.0 (C Bu); HRMS: [M-N +H]
calcd for C20
H
32NO
4
Phenyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-1-thio-β-
and cooled to 0°C. Benzyl bromide (421 µL, 3.52 mmol, 1.1 eq.) and NaH (60% dispersion in mineral oil, 166 mg, 4.16 mmol, 1.3 eq.) were added and the reaction
was stirred for 2 h at 0°C and 1 h at r.t. The reaction mixture was quenched with MeOH and H O (100 mL) was added. The water phase was extracted three times with
0 mL Et O and the combined organic layers were washed with brine (2x), dried with Na SO
chromatography (1%-8% Et
D-glucopyranoside (2). Compound 14 (1.4 g, 3.2 mmol) was dissolved in DMF (15 mL)
2
3
2
2
4
and concentrated under reduced pressure. Purification by flash column
1
2
O/pentane) yielded compound 2 as a colorless oil (1.35 g, 2.56 mmol, 80%). Additional impurities as observed by H NMR originating
TM
ꢁꢂ
f 2
from the previous crude steps could be removed by size exclusion chromatography (Sephadex LH-20, 1/1 DCM/MeOH). R : 0.51 (19/1 pentane/Et O). [α]ꢀ = -85.0°
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The Journal of Organic Chemistry
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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
1
(c = 1.0, CHCl
3
); IR (neat): 654, 694, 746, 766, 826, 1059, 1078, 1099, 1159, 1474, 2110, 2859, 2884, 2934, 2963; H NMR (CDCl
.55 – 7.48 (m, 2H, CHarom), 7.43 – 7.37 (m, 2H, CHarom), 7.36 – 7.27 (m, 6H, CHarom), 4.99 (d, 1H, J = 10.7 Hz, CHH Bn), 4.81 (d, 1H, J = 10.7 Hz, CHH Bn),
.41 (d, 1H, J = 10.2 Hz, H-1), 4.21 (dd, 1H, J = 10.3, 5.1 Hz, H-6), 3.90 (t, 1H, J = 10.2 Hz, H-6), 3.87 (dd, 1H, J = 9.5, 8.7 Hz, H-4), 3.48 – 3.38 (m, 2H, H-3, H-5),
3
, 400 MHz, HH-COSY, HSQC): δ
7
4
3
t
t
13
.28 (dd, 1H, J = 10.2, 9.2 Hz, H-2), 1.07 (s, 9H, CH
3
Bu), 1.01 (s, 9H, CH
3
Bu); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 137.9 (C
Bn), 74.7 (C-5), 66.2 (C-6), 64.2 (C-2), 27.5, 27.1 (CH
+H] calcd for C27
q
Bn), 133.9 (CHarom), 130.9
t
(
2
C
q
SPh), 129.1, 128.7, 128.5, 128.5, 128.1 (CHarom), 86.4 (C-1), 84.2 (C-3), 77.8 (C-4), 75.7 (CH
2
3
Bu), 22.7,
SSi 500.22853, found 500.22839.
t
+
+
0.0 (CH
3
Bu); HRMS: [M+H] calcd for C27
H
38
N
3
O
4
SSi 528.23468, found 528.23451. and [M-N
2
H38NO
4
Phenyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside (3). Compound 13 (4.36 g, 11.3 mmol) was coevaporated once with dry toluene
and then dissolved in DMF (50 mL) and cooled to 0°C. Benzyl bromide (1.9 mL, 15.8 mmol, 1.4 eq.) and NaH (60% dispersion in mineral oil, 900 mg, 22.6 mmol, 2
eq.) were added in succession and the reaction mixture was stirred at r.t. for 4.5 h. MeOH (5 mL) was slowly added and the reaction mixture was diluted with EtOAc
O (2x 60 mL) and brine (50 mL). The organic layer was dried (MgSO ), filtered, and concentrated in vacuo. The crude product was
2 4
purified by crystallization (10 mL hot EtOAc, addition of 100 mL petroleum ether) to yield the title compound as a white cotton like solid (4.79 g, 10.1 mmol, 89%).
3
, 400 MHz, HH-COSY, HSQC): δ 7.56 (ddt, 2H, J
5.0, 3.4, 1.5 Hz, CHarom), 7.47 (dd, 2H, J = 7.5, 2.3 Hz, CHarom), 7.42 – 7.26 (m, 11H, CHarom), 5.57 (s, 1H, CHPh), 4.91 (d, 1H, J = 10.9 Hz, CHH Bn), 4.78 (d, 1H, J
(150 mL) and washed with H
31 1
R
=
f
: 0.71 (8/1 pentane/EtOAc). Spectroscopic data were in accord with those previously reported. H NMR (CDCl
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
= 10.9 Hz, CHH Bn), 4.49 (d, 1H, J = 10.2 Hz, H-1), 4.39 (dd, 1H, J = 10.6, 5.0 Hz, H-6), 3.79 (t, 1H, J = 10.3 Hz, H-6), 3.71 – 3.59 (m, 2H, H-3, H-4), 3.52 – 3.42 (m,
1
3
1
1
H, H-5), 3.41 – 3.32 (m, 1H, H-2); C-APT NMR (CDCl
28.4, 128.1, 126.0 (CHarom), 101.3 (CHPh), 86.5 (C-1), 81.3, 81.0 (C-3, C-4), 75.3 (CH
S 476.16385, found 476.16375.
3
, 101 MHz, HSQC): δ 137.6, 137.1 (C
), 134.0 (CHarom), 130.6 (C SPh), 129.2, 129.2, 128.8, 128.5, 128.4,
q q
Bn), 70.5 (C-5), 68.5 (C-6), 64.6 (C-2); HRMS: [M+H] calcd for
+
2
26 26 3 4
C H N O
Phenyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-1-thio-β-
and pyridine (1.4 mL, 34.8 mmol, 5 eq.) was added benzoyl chloride (0.61 mL, 5.22 mmol, 1.5 eq.) and DMAP (42 mg, 0.35 mmol, 0.1 eq.). The reaction mixture was
allowed to stir overnight after which H O and DCM were added. The organic layer was separated and washed with sat. aq. NaHCO and brine. The organic layer was
dried with MgSO and concentrated in vacuo. Flash column chromatography (19/1 to 8/1 pentane/EtOAc) afforded the title compound as a white solid (1.54 g, 3.15
mmol, 90%). The product could be recrystallized from EtOAc and petroleum ether to obtain a fluffy white solid. R : 0.53 (8/1 pentane/EtOAc). Spectroscopic data
, 400 MHz, HH-COSY, HSQC): δ 8.05 (d, 2H, J = 7.3 Hz, CHarom), 7.59 (dd, 2H, J = 6.5, 3.1 Hz,
CHarom), 7.53 (t, 1H, J = 7.4 Hz, CHarom), 7.44 – 7.33 (m, 7H, CHarom), 7.29 – 7.23 (m, 3H, CHarom), 5.52 (t, 1H, J = 9.6 Hz, H-3), 5.46 (s, 1H, CHPh), 4.69 (d, 1H, J =
D-glucopyranoside (4). To a 0°C solution of compound 13 (1.34 g, 3.48 mmol) in DCM (17 mL)
2
3
4
f
63 1
were in accord with those previously reported. H NMR (CDCl
3
1
3
1
1
0.1 Hz, H-1), 4.38 (dd, 1H, J = 10.5, 4.9 Hz, H-6), 3.79 (t, 1H, J = 10.2 Hz, H-6), 3.71 (t, 1H, J = 9.5 Hz, H-4), 3.62 – 3.53 (m, 2H, H-2, H-5); C-APT NMR (CDCl
01 MHz, HSQC): δ 165.3 (C=O Bz), 136.7 (C ), 133.7, 133.4 (CHarom), 130.8 (C ), 129.9, 129.3 (CHarom), 129.2 (C ), 129.1, 128.8, 128.5, 128.2, 126.1 (CHarom),
S 490.14312, found 490.14305.
3
,
q
q
q
+
24 3 5
101.3 (CHPh), 87.1 (C-1), 78.4 (C-4), 73.5 (C-3), 70.7 (C-5), 68.3 (C-6), 63.9 (C-2); HRMS: [M+H] calcd for C26H N O
35
Phenyl 2-amino-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside (16). Fully protected glycoside 15 (9.11 g, 15.7 mmol) was dissolved in 160
ml EtOH and heated to reflux upon which ethylene diamine (52 mL, 785 mmol, 50 eq.) was added in three portions and reflux was maintained overnight. The reaction
mixture was concentrated under reduced pressure and mixed with toluene (100 mL) and 45 g of silica gel, and the mixture evaporated to dryness. Column
chromatography (8/2 to 2/1 pentane/EtOAc) gave the free amine as a white solid (6.19 g, 13.76 mmol, 88%) which could be recrystallized in EtOAc/petroleum ether.
: 0.40 (2/1 pentane/EtOAc). m.p. 136.1-137.5 °C. [α] ꢁꢀ = -33.5° (c = 0.57, CHCl
ꢃ
); IR (thin film): 698, 748, 1026, 1069, 1123, 1371, 1452, 1583, 2870, 3030, 3059;
, 400 MHz, HH-COSY, HSQC): δ 7.56 – 7.44 (m, 4H, CHarom), 7.42 – 7.24 (m, 11H, CHarom), 5.59 (s, 1H, CHPh), 4.99 (d, 1H, J = 11.3 Hz, CHH Bn),
R
f
3
1
H NMR (CDCl
3
4
.68 (d, 1H, J = 11.2 Hz, CHH Bn), 4.58 (d, 1H, J = 9.9 Hz, H-1), 4.38 (dd, 1H, J = 10.5, 5.0 Hz, H-6), 3.81 (t, 1H, J = 10.3 Hz, H-6), 3.72 (t, 1H, J = 9.2 Hz, H-4),
13
3.59 (t, 1H, J = 9.0 Hz, H-3), 3.52 (td, 1H, J = 9.7, 4.9 Hz, H-5), 2.91 (t, 1H, J = 9.4 Hz, H-2), 1.75 (bs, 2H, NH
2
); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 138.2,
q q 2
), 133.0 (CHarom), 131.8 (C SPh), 129.1, 128.6, 128.4, 128.3, 128.3, 128.0, 126.0 (CHarom), 101.3 (CHPh), 89.6 (C-1), 82.2, 82.2 (C3, C-4), 75.1 (CH Bn),
+
1
7
37.4 (C
0.7 (C-5), 68.8 (C-6), 55.5 (C-2); HRMS: [M+H] calcd for C26
H
4
28NO S 450.17336, found 450.17238.
6
4
1
-(4-nitrophenyl)-4-pyridone (17). Following the procedure of You and Twieg 4-hydroxypyridine (14.3 g, 150 mmol), 4-chloronitrobenzene (22.9 g, 145 mmol)
CO (20.7 g, 150 mmol) were suspended in N-methyl-2-pyrrolidone (110 mL) and heated at 150°C for 2 h. The hot solution was then poured directly onto ice
and allowed to precipitate until all the ice had melted. The suspension was then filtered and washed four times with cold H O. The resulting solid was dried under
vacuum at 100°C until dry. Yield: 26.6 g, 123 mmol, 85%. IR (neat): 606, 692, 741, 752, 843, 1015, 1111, 1198, 1285, 1339, 1495, 1514, 1582, 1638, 3071; H NMR
(DMSO, 400 MHz, HH-COSY, HSQC): δ 8.38 (d, 2H, J = 9.1 Hz), 8.14 (d, 2H, J = 7.8 Hz), 7.86 (d, 2H, J = 9.1 Hz), 6.29 (d, 2H, J = 7.8 Hz); C-APT NMR (DMSO,
9 2 3
01 MHz, HSQC): δ 177.6, 147.1, 145.9, 139.2, 125.3, 123.2, 118.3; HRMS: [M+H] calcd for C11H N O 217.06077, found 217.06074.
and K
2
3
2
1
1
3
+
1
3
0
3,5-dinitro-1-(4-nitrophenyl)-4-pyridone (18). Modification of the procedure from Matsumura et al. , an ice cooled three-neck flask equipped with a condenser was
charged with 120 mL H SO (30% SO ) followed by the slow addition of 120 mL fuming 99% HNO . To the cold mixture pyridone 17 (21.6 g, 100 mmol) was added
in small portions. When addition was complete the mixture was slowly brought to 130°C and stirred for 40 h. The cooled down mixture was then poured over ice,
stirred for 3 h, filtered, and washed three times with cold water. Yield: 18.4 g, 60 mmol, 60%. Purity (NMR): 90%. Tetra-nitro (3,5-dinitro-1-(2,4-dinitrophenyl)-4-
pyridone H NMR (DMSO, 400 MHz): δ 9.42 (s, 2H), 9.05 (d, 1H, J = 2.6 Hz), 8.87 (dd, 1H, J = 8.8, 2.6 Hz), 8.32 (d, 1H, J = 8.7 Hz)) and di-nitro (3-nitro-1-(4-
nitrophenyl)-4-pyridone H NMR (DMSO, 400 MHz): δ 9.18 (d, 1H, J = 2.5 Hz), 8.43 (d, 2H, J = 9.0 Hz), 8.26 (dd, 1H, J = 7.8, 2.5 Hz), 7.99 (d, 2H, J = 9.1 Hz), 6.68
2
4
3
3
1
1
(d, 1H, J = 7.9 Hz)) impurities are present (ratios vary slightly upon repetition). IR (neat): 717, 768, 789, 853, 910, 1141, 1261, 1306, 1350, 1449, 1514, 1591, 1672,
076; H NMR (DMSO, 400 MHz): δ 9.38 (s, 1H), 8.47 (d, 1H, J = 9.0 Hz), 8.05 (d, 1H, J = 9.1 Hz); C-APT NMR (DMSO, 101 MHz): δ 159.3, 147.6, 145.5, 142.1,
+
1
13
3
7 4 7
141.6, 125.7, 125.1; HRMS: [M+H] calcd for C11H N O 307.03093, found 307.03123.
Phenyl 2-(3,5-dinitro-4-pyridone)-3-O-benzyl-4,6-O-benzylidene-2-deoxy-1-thio-β-
.8 mmol, 1.1 eq.) were dissolved in pyridine (48 mL) and AcOH (4 mL) and left to stir for 30 min. The mixture was diluted with EtOAc and washed with 1M aq. HCl
5x) and once with sat.aq. NaHCO . The organic layer was dried (MgSO ), filtered and concentrated under reduced pressure. Column chromatography: DCM until all
the nitroanaline had been removed, then 1% to 5% acetone in DCM. Yield 4.84 g, 7.8 mmol (98%) as a yellow solid. R
D-glucopyranoside (5). Free amine 16 (3.6 g, 8 mmol) and reagent 18 (2.7 g,
8
(
3
4
: 0.21 (DCM), [α]ꢁ = 10.5° (c = 0.5, CHCl
ꢃ
);
6
, 400 MHz, HH-COSY, HSQC): δ 8.74 (s,
f
ꢀ
3
1
IR (thin film): 604, 696, 746, 989, 1055, 1094, 1211, 1300, 1329, 1516, 1674, 2856, 2926, 3034, 3059; H NMR (Acetone-d
H, CH pyridone), 7.63 – 7.54 (m, 2H, CHarom), 7.51 – 7.39 (m, 5H, CHarom), 7.39 – 7.31 (m, 3H, CHarom), 7.21 – 7.14 (m, 3H, CHarom), 7.14 – 7.07 (m, 2H, CHarom),
.84 (s, 1H, CHPh), 5.73 (d, 1H, J = 10.4 Hz, H-1), 4.84 (d, 1H, J = 12.1 Hz, CHH Bn), 4.62 (d, 1H, J = 12.1 Hz, CHH Bn), 4.55 – 4.47 (m, 1H, H-3), 4.44 – 4.39 (m,
2
5
1
3
1H, H-6), 4.39 (t, 1H, J = 8.9 Hz, H-2), 4.06 – 3.91 (m, 3H, H-4, H-5, H-6); C-APT NMR (Acetone-d
38.5, 137.8 (C ), 133.4 (CHarom), 131.7 (C SPh), 130.3, 129.7, 129.5, 129.2, 129.0, 129.0, 127.0 (CHarom), 102.0 (CHPh), 85.9 (C-1), 83.0 (C-4), 77.0 (C-3), 74.7
CH Bn), 71.6 (C-2), 70.9 (C-5), 68.8 (C-6); HRMS: [M+H] calcd for C31
6 q 2
, 101 MHz, HSQC): δ 159.9 (C=O pyridone), 143.1 (C NO ),
1
q
q
+
(
2
28 3 9
H N O S 618.15408 found 618.15375.
Trifluoromethanesulfonyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-
D
-glucopyranoside (19).9 1H NMR (CD
H, J = 3.5 Hz, H-1), 5.59 (s, 1H, CHPh), 4.89 (d, 1H, J = 11.0 Hz, CHH Bn), 4.85 – 4.69 (m, 3H, CHH Bn, CH
Cl
2 2
, T = 213 K, 400 MHz, HH-COSY, HSQC): δ 6.08 (d,
Bn), 4.29 (dd, 1H, J = 10.3, 4.8 Hz, H-6), 4.09 – 3.94
2 2
Cl , T = 213 K, 101 MHz, HSQC): δ 106.1 (C-1), 100.8 (CHPh), 79.6 (C-4), 77.0 (C-3),
1
2
1
3
(m, 2H, H-3, H-5), 3.86 – 3.70 (m, 3H, H-2, H-4, H-6); C-APT NMR (CD
6.3 (C-2), 75.0, 74.1 (CH Bn), 67.4 (C-6), 65.8 (C-5).
7
2
Trifluoromethanesulfonyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-
D
-glucopyranoside (20). 1H NMR (CD
2
2
Cl , T = 243 K, 400 MHz, HH-COSY,
HSQC): δ 6.08 (d, 1H, J = 3.5 Hz, H-1), 5.64 (s, 1H, CHPh), 4.98 (d, 1H, J = 10.6 Hz, CHH Bn), 4.78 (d, 1H, J = 10.6 Hz, CHH Bn), 4.32 (dd, 1H, J = 10.4, 4.9 Hz,
H-6), 4.11 – 4.00 (m, 2H, H-3, H-5), 3.94 – 3.86 (m, 2H, H-2, H-4), 3.82 (t, 1H, J = 10.3 Hz, H-6); C-APT NMR (CD
136.7 (C ), 130.5, 128.4, 128.4, 125.9 (CHarom), 105.0 (C-1), 101.3 (CHPh), 80.6 (C-4), 76.4 (C-3), 75.3 (CH Bn), 67.6 (C-6), 66.2 (C-5), 61.4 (C-2).
13
2
2
Cl , T = 243 K, 101 MHz, HSQC): δ 137.2,
q
2
Trifluoromethanesulfonyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α-
D
-glucopyranoside (21). 1H NMR (CD
HSQC): δ 6.23 (d, 1H, J = 3.5 Hz, H-1), 5.80 (t, 1H, J = 10.0 Hz, H-3), 5.54 (s, 1H, CHPh), 4.36 (dd, 1H, J = 10.4, 4.9 Hz, H-6), 4.21 (td, 1H, J = 9.9, 4.9 Hz, H-5),
.12 (dd, 1H, J = 10.2, 3.5 Hz, H-2), 3.98 (t, 1H, J = 9.8 Hz, H-4), 3.86 (t, 1H, J = 10.3 Hz, H-6); C-APT NMR (CD Cl , T = 243 K, 101 MHz, HSQC): δ 104.5 (C-1),
2 2
2 2
Cl , T = 243 K , 400 MHz, HH-COSY,
1
3
4
101.8 (CHPh), 77.5 (C-4), 69.3 (C-3), 67.6 (C-6), 66.4 (C-5), 60.9 (C-2).
2 2
Trifluoromethanesulfonyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α-D Cl , T = 233 K, 400 MHz, HH-
-glucopyranoside (22). 1H NMR (CD
COSY, HSQC, HMBC): δ 6.00 (d, 1H, J = 3.4 Hz, H-1), 5.08 (d, 1H, J = 10.1 Hz, CHH Bn), 4.81 (d, 1H, J = 10.2 Hz, CHH Bn), 4.15 – 4.06 (m, 2H, H-4, H-6), 3.95 –
t
t
13
3
.84 (m, 3H, H-3, H-5, H-6), 3.79 (dd, 1H, J = 10.1, 3.4 Hz, H-2), 1.07 (s, 9H, CH
3
Bu), 1.00 (s, 9H, CH
3 2 2
Bu); C-APT NMR (CD Cl , T = 233 K, 101 MHz, HSQC,
t
HMBC): δ 118.9 (q, J = 317.6 Hz, CF
3
), 104.8 (C-1), 78.8 (C-3), 76.9 (C-4), 75.7 (CH Bn), 70.0 (C-5), 65.3 (C-6), 60.6 (C-2), 27.0, 26.4 (CH Bu), 22.5, 19.7 (C
2
3
q
t
13
2 2
Bu); C-HMBC NMR (CD Cl , 101 MHz): δ 104.8 (JC1-H1 = 187 Hz, C-1).
8
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-
D
-glucal (24). Off-white solid. R
f
1
: 0.20 (7/3 pentane/EtOAc). [α]ꢁꢂ = +85.9° (c = 0.32, DCM); IR
ꢀ
(thin film): 698, 720, 753, 1007, 1059, 1095, 1192, 1247, 1304, 1351, 1516, 1679, 2880, 2924, 3072; H NMR (Acetone-d
6
, 500 MHz, HH-COSY, HSQC): δ 8.72 (s,
2H, CH pyridone), 7.62 – 7.53 (m, 2H, CHarom), 7.49 – 7.37 (m, 4H, CHarom, H-1), 7.29 – 7.14 (m, 5H, CHarom), 5.88 (s, 1H, CHPh), 4.93 – 4.88 (m, 2H, CHH Bn, H-3),
4.68 (d, 1H, J = 11.8 Hz, CHH Bn), 4.46 (dd, 1H, J = 10.5, 5.2 Hz, H-6), 4.37 (dd, 1H, J = 10.4, 6.9 Hz, H-4), 4.30 (td, 1H, J = 10.2, 5.1 Hz, H-5), 4.03 (t, 1H, J = 10.3
1
3
Hz, H-6); C-APT NMR (Acetone-d
1
5
6
, 101 MHz, HSQC): δ 160.0 (C=O pyridone), 149.3 (C-1), 144.7 (CH pyridone), 142.8 (C
29.1, 129.0, 128.8, 127.0 (CHarom), 122.1 (C-2), 101.9 (CHPh), 80.2 (C-4), 74.7 (CH Bn), 74.6 (C-3), 70.7 (C-5), 68.2 (C-6); HRMS: [M+H] calcd for C25
08.13506, found 508.13465.
q 2 q
NO ), 138.4 (C Bn, Ph), 129.8, 129.2,
+
2
22 3 9
H N O
Ethyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-β-
Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (0% to 5% Et
5%, α:β = < 1:20) as a colorless oil. R
D
-glucopyranoside (2A). Donor 2 and ethanol were condensed using the general procedure for
O in pentane) to yield glycosylation product 2A (30 mg, 65 µmol,
O in pentane). [α]ꢁ = -69.6° (c = 0.5, CHCl
); IR (neat): 652, 768, 827, 962, 1082, 1161, 1474, 2112, 2859,
3
, 400 MHz, HH-COSY, HSQC): δ 7.46 – 7.40 (m, 2H, CHarom), 7.39 – 7.27 (m, 3H, CHarom), 4.99 (d, 1H, J = 11.0 Hz, CHH Bn), 4.81 (d, 1H, J
2
2
2
ꢂ
6
f
: 0.35 (5% Et
2
3
ꢀ
1
2932; H NMR (CDCl
=
10.9 Hz, CHH Bn), 4.31 (dd, 1H, J = 7.7, 1.7 Hz, H-1), 4.16 (dd, 1H, J = 10.3, 5.0 Hz, H-6), 3.98 – 3.87 (m, 3H, CHH-CH
3
Et, H-4, H-6), 3.61 (dq, 1H, J = 9.5, 7.1
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
t
t
13
Hz, CHH-CH
3
Et), 3.41 – 3.28 (m, 3H, H-2, H-3, H-5), 1.26 (t, 3H, J = 7.1 Hz, CH
3
Et), 1.08 (s, 9H, CH
3
Bu), 1.01 (s, 9H, CH
3
Bu); C-APT NMR (CDCl
3
, 101
MHz, HSQC): δ 138.3 (C
q
), 128.5, 128.4, 128.0 (CHarom), 102.1 (C-1), 82.4 (C-3), 78.1 (C-4), 75.4 (CH
2
Bn), 70.5 (C-5), 66.4 (C-6), 66.1 (CH
2
Et), 65.6 (C-2), 27.6,
t
t
+
27.2 (CH Bu), 22.8, 20.1 (C Bu), 15.2 (CH Et); HRMS: [M-N +H] calcd for C23H38NO Si 436.25138, found 436.25132.
3 q 3 2 5
Cyclohexyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-β-
procedure for Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (4/1 to 0/1 pentane/toluene) to yield glycosylation product 2B (40 mg,
7 µmol, 77%, α:β = < 1 : 20) as a colorless oil. R
D-glucopyranoside (2B). Donor 2 and cyclohexanol were condensed using the general
2
2
ꢁꢃ
7
f
: 0.43 (5% Et
, 400 MHz, HH-COSY, HSQC): δ 7.45 – 7.40 (m, 2H, CHarom), 7.38 – 7.27 (m, 3H, CHarom), 4.97 (d, 1H, J = 11.1 Hz, CHH Bn),
.81 (d, 1H, J = 11.1 Hz, CHH Bn), 4.42 (d, 1H, J = 7.8 Hz, H-1), 4.15 (dd, 1H, J = 10.3, 5.0 Hz, H-6), 3.99 – 3.89 (m, 2H, H-3, H-6), 3.64 (tt, 2H, J = 9.2, 3.8 Hz, CH
Cy), 3.40 – 3.24 (m, 3H, H-2, H-4, H-5), 1.96 – 1.83 (m, 2H, CH Cy), 1.80 – 1.71 (m, 2H, CH Cy), 1.55 – 1.48 (m, 1H, CH Cy), 1.47 – 1.37 (m, 2H, CH Cy), 1.34
Cy), 1.08 (s, 9H, Bu), 1.01 (s, 9H, Bu); C-APT NMR (CDCl , 101 MHz, HSQC): δ 138.4 (C ), 128.5, 128.3, 127.9 (CHarom), 100.7 (C-1), 82.3
C-4), 78.3 (CH Cy), 78.0 (C-3), 75.4 (CH Bn), 70.5 (C-5), 66.4 (C-6), 65.8 (C-2), 33.6, 31.7 (CH Cy), 27.6, 27.2 (CH
+H] calcd for C27 Si 490.29833, found 490.29811.
2 3
O in pentane). [α]ꢀ = -44.3° (c = 1.0, CHCl ); IR (thin film): 696, 768, 827, 961, 1080, 1163, 1364,
1
2112, 2859, 2934; H NMR (CDCl
4
3
2
2
2
2
t
t
13
– 1.20 (m, 3H, CH
(
2
3
q
t
t
2
2
3 2
Bu), 25.6 (CH Cy), 24.1, 23.9 (Cq Bu), 22.8,
+
20.1 (CH
2
Cy); HRMS: [M-N
2
H44NO
5
Methyl 6-O-(2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-ᴅ-glucopyranosyl)-2,3,4-tri-O-benzyl-α-ᴅ-glucopyranoside (2C). Donor
acceptor 25 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash column
chromatography (1/0 to 9/1 pentane/EtOAc) to yield glycosylation product 2C (81 mg, 92 µmol, 92%, α:β = 1:14) as a white solid. R
2 and
2
2
ꢁꢂ
f
: 0.42 (4/1 pentane/EtOAc). [α]
ꢀ
1
=
3 3
-18.6° (c = 1.0, CHCl ); IR (thin film): 654, 969, 735, 827, 962, 1028, 1070, 1161, 1362, 1454, 2112, 2859, 2931; H NMR (CDCl , 400 MHz, HH-COSY, HSQC,
HMBC): δ 7.45 – 7.39 (m, 2H, CHarom), 7.38 – 7.25 (m, 18H, CHarom), 4.99 (d, 1H, J = 11.0 Hz, CHH Bn), 4.98 (d, 1H, J = 10.9 Hz, CHH Bn), 4.94 (d, 1H, J = 11.1
Hz, CHH Bn), 4.85 – 4.76 (m, 3H, CHH Bn, 2xCHH Bn), 4.66 (d, 1H, J = 11.1 Hz, CHH Bn), 4.64 (d, 1H, J = 12.1 Hz, CHH Bn), 4.60 (d, 1H, J = 3.6 Hz, H-1), 4.17
(
d, 1H, J = 7.9 Hz, H-1’), 4.15 – 4.10 (m, 1H, H-6’), 4.05 – 3.96 (m, 2H, H-3, H-6), 3.96 – 3.87 (m, 2H, H-4’, H-6’), 3.76 (ddd, 1H, J = 9.9, 4.2, 1.7 Hz, H-5), 3.70 (dd,
1H, J = 10.7, 4.2 Hz, H-6), 3.59 (t, 1H, J = 9.5 Hz, H-4), 3.54 (dd, 1H, J = 9.6, 3.5 Hz, H-2), 3.40 (dd, 1H, J = 9.7, 7.9 Hz, H-2’), 3.37 – 3.26 (m, 5H, CH Ome, H-3’,
), 128.6, 128.5, 128.5, 128.4,
3
t
t
13
3 3 3 q
H-5’), 1.07 (s, 9H, CH Bu), 1.01 (s, 9H, CH Bu); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 138.9, 138.6, 138.2, 138.1 (C
128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 127.7 (CHarom), 102.2 (C-1’), 98.3 (C-1), 82.5 (C-3’), 82.2 (C-3), 79.9 (C-2), 77.9 (C-4’), 77.7 (C-4), 75.9, 75.4, 75.0, 73.6
t
t
1
(CH
2
Bn), 70.6 (C-5’), 69.7 (C-5), 68.6 (C-6), 66.3 (C-6’), 65.6 (C-2’), 55.3 (OMe), 27.5, 27.1 (CH
3
3
Bu), 22.8, 20.1 (C
, 400 MHz): δ 4.87 (d, 1H, J = 3.6 Hz, H-1’), 4.52 (d, 1H, J = 3.4 Hz, H-1); C-APT NMR (CDCl
49 67 4
C H N O10Si 899.46210, found 899.46246.
q
Bu); Diagnostic peaks α-anomer: H NMR
13
+
(CDCl
3
, 101 MHz): δ 98.1, 98.0, 68.3; HRMS: [M+NH
4
]
calcd for
2
-Fluoroethyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-
general procedure for Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/0 to 0/1 pentane/toluene to 2% Et
glycosylation product 2D (37.8 mg, 79 µmol, 79%, α:β = 1:5.5) as a colorless oil. R : 0.20 (toluene). Reported as a 1.00 : 0.18 mixture of anomers: IR (neat): 654, 768,
, 400 MHz, HH-COSY, HSQC): δ 7.45 – 7.40 (m, 2.36H, CHarom), 7.39 – 7.27 (m, 3.54H, CHarom),
), 4.99 (d, 1H, J = 10.9 Hz, CHH Bn ), 4.86 (d, 0.18H, J = 3.6 Hz, H-1 ), 4.82 (d, 0.18H, J = 10.6 Hz, CHH Bn ), 4.82 (d, 1H, J
), 4.71 – 4.61 (m, 1.18H, CHHF , CHHF ), 4.58 – 4.47 (m, 1.18H, CHHF , CHHF ), 4.37 (d, 1H, J = 7.6 Hz, H-1 ), 4.17 (dd, 1H, J = 10.3, 5.1 Hz,
), 4.12 – 3.78 (m, 5.26H, CH -CH , CH -CH , H-3 , H-4 , H-4 , H-5 , H-6 , H-6 , H-6 ), 3.44 – 3.29 (m, 3.18H, H-2 , H-2 , H-3 , H-5 ), 1.09 (s, 1.62H, CH
), 1.03 (s, 1.62H CH ), 1.01 (s, 9H, CH ); C-APT NMR (CDCl , 101 MHz, HSQC): δ 138.3 (Cq,α), 138.2 (Cq,β), 128.6 (CHarom
), 128.5 (CHarom Bn ), 128.4 (CHarom Bn ), 128.0 (CHarom Bnα,β), 102.4 (C-1 ), 98.3 (C-1
), 79.3, 79.0 (C-3 , C-4 ), 78.0 (C-4 ), 75.6 (CH Bn ), 75.5 (CH Bn ), 70.6 (C-5
), 66.3 (C-6 ), 65.5 (C-2 ), 62.5 (C-2 ), 27.5, 27.1 (CH
Si 454.24195, found 454.24188.
D-glucopyranoside (2D). Donor 2 and 2-fluoroethanol were condensed using the
2
2
2
O in toluene) to yield
f
1
8
5
27, 962, 1080, 1161, 1472, 2112, 2859, 2932; H NMR (CDCl
.06 (d, 0.18H, J = 10.7 Hz, CHH Bn
3
α
β
α
α
= 10.9 Hz, CHH Bn
H-6
β
α
β
α
β
β
β
2
2
F
α
2
2
F
Bu
α
β
α
α
β
α
α
α
β
α
β
β
β
3
t
t
t
t
13
α
Bu ), 1.08 (s, 9H, CH
), 128.5 (CHarom Bn
3
Bu
β
3
3
Bu
β
3
Bn
α
β
α
β
β
α
), 82.7 (d, J = 170.0 Hz, CH
2
β
F ), 82.4 (d, J = 170.6 Hz,
CH
CH
2
F
F
α
α
2
), 82.3 (C-3
), 66.8 (C-5
+H] calcd for C23
β
α
α
β
2
α
2
β
β
), 69.0 (d, J = 20.3 Hz, CH
2
-CH
), 20.1 (C
2
F
q
β
), 67.3 (d, J = 20.1 Hz, CH -
2
t
t
t
t
t
2
α
), 66.7 (C-6
α
β
β
α
3
Buα,β), 23.1 (C
q
Bu
α
), 22.8 (C
q
Bu
β
Bu
α
), 20.1 (C
q
β
Bu ); HRMS:
+
[M-N
H
37FNO
5
Methyl 4-O-(2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-
acceptor 26 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash column
chromatography (1/0 to 9/1 pentane/EtOAc) to yield glycosylation product 2E (72 mg, 82 µmol, 82%, α:β = 1:3) as a colorless oil. R : 0.23 and 0.41 (9/1
pentane/EtOAc). IR (thin film): 654, 696, 735, 768, 827, 962, 1090, 1159, 1271, 1362, 1454, 2110, 2859, 2932; Data for the β-anomer: H NMR (CDCl , 400 MHz,
HH-COSY, HSQC, HMBC): δ 7.44 – 7.39 (m, 2H, CHarom), 7.39 – 7.21 (m, 18H, CHarom), 4.98 (d, 1H, J = 10.8 Hz, CHH Bn), 4.83 – 4.74 (m, 4H, CHH Bn, CH Bn,
CHH Bn), 4.68 (d, 1H, J = 11.9 Hz, CHH Bn), 4.62 (d, 1H, J = 12.2 Hz, CHH Bn) 4.59 (d, 1H, J = 3.6 Hz, H-1), 4.44 (d, 1H, J = 11.9 Hz, CHH Bn), 4.23 (d, 1H, J =
8.0 Hz, H-1’), 3.97 (dd, 1H, J = 10.6, 3.0 Hz, H-6), 3.94 – 3.73 (m, 5H, H-3, H-4, H-4’, H-5, H-6’), 3.71 – 3.66 (m, 1H, H-6), 3.55 – 3.47 (m, 2H, H-2, H-6’), 3.38 (s,
D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-ᴅ-glucopyranoside (2E). Donor 2 and
2
2
f
1
3
2
t
t
13
3H, CH
3
OMe), 3.27 – 3.21 (m, 1H, H-2’), 3.20 – 3.14 (m, 1H, H-3’), 3.06 (td, 1H, J = 9.9, 5.1 Hz, H-5’), 1.06 (s, 9H, CH
3
Bu), 0.97 (s, 9H, CH
3
Bu); C-APT NMR
(
CDCl
3
, 101 MHz, HSQC, HMBC): δ 139.4, 138.4, 138.1, 137.9 (C
q
), 128.5, 128.5, 128.5, 128.4, 128.4, 128.2, 128.1, 128.0, 128.0, 127.9, 127.4, 127.3 (CHarom),
101.0 (C-1’), 98.4 (C-1), 82.6 (C-3’), 80.2 (C-3), 79.2 (C-2), 78.1 (C-4’), 77.0 (C-4), 75.3, 75.3, 73.6, 73.6 (CH
2
Bn), 70.2 (C-5’), 69.7 (C-5), 68.3 (C-6), 66.2 (C-6’),
t
1
66.1 (C-2’), 55.4 (OMe), 27.6, 27.1 (CH
3
Bu), 22.7, 20.0 (C
q
tBu); Diagnostic peaks α-anomer: H NMR (CDCl
3
, 400 MHz): δ 5.67 (d, 1H, J = 4.0 Hz, H-1), 5.11 (d,
1H, J = 10.6 Hz, CHH Bn), 5.06 (d, 1H, J = 10.6 Hz, CHH Bn), 4.87 (d, 1H, J = 10.6 Hz, CHH Bn), 4.79 (d, 1H, J = 10.6 Hz, CHH Bn), 4.75 (d, 1H, J = 12.0 Hz,
t
CHH Bn), 4.09 (t, 1H, J = 9.0 Hz, H-3), 3.56 (dd, 1H, J = 9.6, 3.5 Hz, H-2), 3.38 (s, CH
3
OMe), 3.21 (dd, 1H, J = 10.2, 4.0 Hz, H-2’), 1.06 (s, 9H, CH
3
Bu), 1.04 (s,
t
13
9
9
H, CH
7.7 (C-1, C-1’), 82.1 (C-3), 80.6 (C-2), 79.1, 79.0, 75.6, 75.1, 73.7, 73.4, 69.6, 69.2, 67.5, 66.5, 62.3 (C-2’), 55.4, 27.6, 27.2, 22.8, 20.1; HRMS: [M+NH
10Si 899.46210, found 899.46246.
3
Bu); C-APT NMR (CDCl , 101 MHz): δ 138.8, 138.3, 138.2, 138.0, 128.6, 128.4, 128.3, 128.1, 128.0, 128.0, 128.0, 127.9, 127.7, 127.6, 127.4, 127.3, 97.9,
3
+
4
] calcd for
49 67 4
C H N O
Methyl (methyl 4-O-[2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-
and acceptor 27 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash
column chromatography (1/0 to 9/1 pentane/EtOAc) to yield glycosylation product 2F (69 mg, 84 µmol, 84%, α:β = 3.3:1) as a white solid. R : 0.36 and 0.39 (9/1
, 400 MHz, HH-COSY, HSQC,
D-glucopyranosyl]-2,3-di-O-benzyl-α-ᴅ-glucopyranosyl uronate) (2F). Donor
2
2
2
f
1
pentane/EtOAc). IR (thin film): 654, 696, 735, 827, 1042, 1144, 1387, 1751, 2108, 2859, 2934; Data for the α-anomer: H NMR (CDCl
3
HMBC): δ 7.43 – 7.38 (m, 2H, CHarom), 7.37 – 7.25 (m, 13H, CHarom), 5.45 (d, 1H, J = 4.1 Hz, H-1’), 5.07 – 5.02 (m, 2H, 2xCHH Bn), 4.90 (d, 1H, J = 10.6 Hz, CHH
Bn), 4.84 – 4.78 (m, 1H, CHH Bn), 4.75 (d, 1H, J = 12.0 Hz, CHH Bn), 4.59 (d, 1H, J = 12.2 Hz, CHH Bn), 4.57 (d, 1H, J = 3.5 Hz, H-1), 4.21 – 4.17 (m, 1H, H-5),
4.09 – 4.01 (m, 3H, H-3, H-4, H-6’), 3.91 – 3.85 (m, 1H, H-4’), 3.83 – 3.73 (m, 5H, CH
3
CO
Bu), 1.05 (s, 9H, CH
q
), 128.7, 128.5, 128.5, 128.5, 128.3, 128.2, 128.0, 127.7, 127.6 (CHarom), 98.5, 98.4 (C-1, C-1’), 81.0 (C-3), 79.9 (C-2),
2
Me, H-3’, H-6’), 3.62 (td, 1H, J = 10.1, 5.0 Hz, H-5’), 3.58 – 3.53 (m, 1H,
t
t 13
H-2), 3.41 (s, 3H, CH
69.2 (C=O CO Me), 138.7, 138.2, 137.8 (C
79.0, 79.0 (C-3’, C-4’), 76.2 (C-4), 75.5, 75.4, 73.6 (CH
3
OMe), 3.23 (dd, 1H, J = 10.2, 4.1 Hz, H-2’), 1.07 (s, 9H, CH
3
3 3
Bu); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ
1
2
t
2
Bn), 70.2 (C-5), 67.0 (C-5’), 66.4 (C-6’), 62.4 (C-2’), 55.9 (OMe), 52.9 (CO
Bu); Diagnostic peaks β-anomer: H NMR (CDCl , 400 MHz): δ 4.98 (d, 1H, J = 10.9 Hz, CHH Bn), 4.39 (d, 1H, J = 7.7 Hz, H-1’), 4.02 – 3.96 (m, 1H), 3.82
s, 3H, CH CO Me), 3.52 (dd, 1H, J = 9.5, 3.6 Hz, H-2), 1.05 (s, 9H, CH
138.1, 128.6, 128.5, 128.4, 128.3, 128.3, 128.1, 128.0, 127.5, 127.3, 101.9 (C-1’), 98.9 (C-1), 82.5, 79.6, 79.4, 78.8, 78.0, 75.4, 73.9, 70.4, 69.9, 66.1, 55.9, 52.8, 27.5,
2 3
Me), 27.6, 27.2 (CH Bu), 22.9,
t
1
2
0.0 (C
q
3
t
t
13
(
3
2
3 3 3
Bu), 0.97 (s, 9H, CH , Bu); C-APT NMR (CDCl , 101 MHz): δ 170.2, 139.1, 138.1,
+
27.1, 22.8, 20.0; HRMS: [M+NH
4
]
61
calcd for C43H N
4
O
11Si 837.41006, found 837.41042.
2
,2-Difluoroethyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-
D-glucopyranoside (2G). Donor 2 and 2,2-difluoroethanol were condensed using
the general procedure for Tf
2
O/Ph
2
2
SO mediated glycosylations and purified by flash column chromatography (1/0 to 0/1 pentane/toluene to 2% Et O in toluene) to
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
6
7
8
9
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
f
yield glycosylation product 2G (38.1 mg, 76 µmol, 76%, α:β = 2.7:1) in two fractions (24.3 mg α only, 13.8 mg α:β = 0.3:1) as white solids. R : 0.43 β, 0.31 α (toluene).
IR (neat): 654, 766, 826, 1070, 1474, 2108, 2860, 2934; Data for the α-anomer: [α]ꢁ = +35.6° (c = 0.86, CHCl
ꢂ
); H NMR (CDCl
), 5.06 (d, 1H, J = 10.6 Hz, CHH Bn), 4.85 (d, 1H, J = 3.6 Hz, H-1), 4.82
(d, 1H, J = 10.7 Hz, CHH Bn), 4.13 – 4.08 (m, 1H, H-6), 3.98 – 3.92 (m, 1H, H-3/4), 3.92 – 3.72 (m, 5H, CH -CHF , H-3/4, H-5, H-6), 3.35 (dd, 1H, J = 10.1, 3.6 Hz,
), 128.6, 128.5, 128.1 (CHarom), 113.8 (t, J = 241.6 Hz,
1
ꢀ
3
3
, 400 MHz, HH-COSY, HSQC): δ
7
.45 – 7.40 (m, 2H, CHarom), 7.39 – 7.27 (m, 3H, CHarom), 5.95 (tt, 1H, J = 55.2, 4.1 Hz, CHF
2
2
2
t
t
13
H-2), 1.09 (s, 9H, CH
CHF ), 98.7 (C-1), 79.0, 78.9 (C-3, C-4), 75.7 (CH
Data for the β-anomer: H NMR (CDCl
Hz, CHF ), 4.99 (d, 1H, J = 10.9 Hz, CHH Bn), 4.81 (d, 1H, J = 11.0 Hz, CHH Bn), 4.35 (s, 1H, J = 7.7 Hz, H-1), 4.17 (dd, 1H, J = 10.3, 5.0 Hz, H-6), 4.02 – 3.74 (m,
3
Bu), 1.03 (s, 9H, CH
3
Bu); C-APT NMR (CDCl
Bn), 67.3 (t, J = 28.6 Hz, CH
, 400 MHz, HH-COSY, HSQC): δ 7.44 – 7.39 (m, 2H, CHarom), 7.38 – 7.29 (m, 3H, CHarom), 5.92 (tdd, 1H, J = 55.3, 5.1, 3.4
3
, 101 MHz, HSQC): δ 138.1 (C
q
t
t
2
2
2
-CHF ), 67.1 (C-5), 66.6 (C-6), 62.4 (C-2), 27.5, 27.1 (CH
2
3 q
Bu), 22.8, 20.1 (C Bu);
1
3
2
t
t
13
4
1
6
H, CH
2
-CHF
2
, H-4, H-6), 3.42 – 3.30 (m, 3H, H-2, H-3, H-5), 1.09 (s, 9H, CH
3
Bu), 1.01 (s, 9H, CH
3
, Bu); C-APT NMR (CDCl
Bn), 70.7 (C-5), 68.8 (dd, J = 29.3, 28.8 Hz, CH
3 q 2 36 2 5
6.2 (C-6), 65.4 (C-2), 27.5, 27.1 (CH Bu), 22.8, 20.1 (C Bu); HRMS: [M-N +H] calcd for C23H F NO Si 472.23253, found 472.23239.
3
, 101 MHz, HSQC): δ 138.1 (C
q
),
),
28.5, 128.4, 128.1 (CHarom), 114.1 (t, J = 241.4 Hz, CHF
2
), 102.5 (C-1), 82.2 (C-3), 77.9 (C-4), 75.5 (CH
2
2
-CHF
2
t
t
+
Methyl 4-O-(2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α/β-
acceptor 28 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash column
chromatography (1/0 to 9/1 pentane/EtOAc) to yield glycosylation product 2H (46 mg, 52 µmol, 52%, α:β = 7:1) as a colorless oil. R : 0.33 and 0.51 (9/1
, 400 MHz, HH-COSY,
HSQC, HMBC): δ 7.46 – 7.41 (m, 2H, CHarom), 7.41 – 7.23 (m, 18H, CHarom), 5.10 (d, 1H, J = 10.3 Hz, CHH Bn), 4.89 – 4.81 (m, 3H, CHH Bn, 2xCHH Bn), 4.79 (d,
D-glucopyranosyl)-2,3,6-tri-O-benzyl-β-ᴅ-galactopyranoside (2H). Donor 2 and
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
2
2
f
1
pentane/EtOAc). IR (thin film): 652, 696, 735, 826, 1001, 1036, 1206, 1364, 1454, 2108, 2859, 2932; Data for the α-anomer: H NMR (CDCl
3
1H, J = 3.7 Hz, H-1’), 4.72 (d, 1H, J = 10.6 Hz, CHH Bn), 4.68 (d, 1H, J = 13.0 Hz, CHH Bn), 4.58 – 4.44 (m, 3H, CH
2
Bn, H-5’), 4.23 (d, 1H, J = 7.6 Hz, H-1), 4.07
OMe), 3.48 (dd, 1H, J
Bu); C-APT NMR (CDCl , 101
–
3.99 (m, 2H, H-4, H-6), 3.99 – 3.88 (m, 3H, H-3’, H-4’, H-6’), 3.76 (t, 1H, J = 10.1 Hz, H-6’), 3.67 – 3.58 (m, 2H, H-2, H-6), 3.56 (s, 3H, CH
3
t
t
1
3
=
8.9, 5.5 Hz, H-5), 3.38 (dd, 1H, J = 10.0, 2.9 Hz, H-3), 3.33 (dd, 1H, J = 9.7, 3.7 Hz, H-2’), 1.06 (s, 9H, CH
3
Bu), 1.02 (s, 9H, CH
3
3
MHz, HSQC, HMBC): δ 138.8, 138.4, 138.2, 137.7 (C
q
), 128.6, 128.6, 128.5, 128.5, 128.5, 128.3, 128.2, 127.9, 127.8 (CHarom), 105.1 (C-1), 99.2 (C-1’), 79.9, 79.9
Bn), 72.9 (C-5), 72.6 (CH Bn), 67.1, 67.0 (C-6, C-6’), 66.9 (C-5’), 63.2 (C-2’), 57.5
, 400 MHz): δ 4.94 (d, 0.14H, J = 11.1 Hz, CHH Bn), 4.27 (d, 0.14H, J
, 101 MHz): δ 105.1 (C-1), 102.0 (C-1’), 82.3, 78.0, 75.4, 75.3, 73.7, 73.7, 73.5,
calcd for C49 10Si 899.46210, found 899.46243.
(
C-2, C-3’), 79.6, 79.4 (C-3, C-4’), 75.7, 75.6 (CH
2
Bn), 75.0 (C-4), 73.6 (CH
2
1
2
t
t
(OMe), 27.5, 27.3 (CH
Bu), 22.7, 20.2 (C Bu); Diagnostic peaks β-anomer: H NMR (CDCl
3 q 3
13
=
7.7 Hz, H-1), 3.22 – 3.16 (m, 0.28H), 3.20 – 3.09 (m, 2H); C-APT NMR (CDCl
3
+
73.4, 70.4, 69.6, 66.4, 65.6, 57.3, 27.6, 27.2, 22.8, 20.1; HRMS: [M+NH
4
]
67 4
H N O
Methyl 2-O-(2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α-
and acceptor 29 were condensed using the general procedure for Tf O/Ph
column chromatography (1/0 to 9/1 pentane/EtOAc) to yield glycosylation product 2I (67 mg, 85 µmol, 85%, α:β = > 20:1) as a white solid. R
D
-glucopyranosyl)-3-O-benzyl-4,6-O-benzylidene-α-ᴅ-mannopyranoside (2I). Donor 2
SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash
: 0.54 (9/1
); IR (thin film): 696, 827, 937, 1040, 1088, 1130, 1364, 2108, 2859, 2957; Data for the α-anomer: H NMR (CDCl
00 MHz, HH-COSY, HSQC, HMBC): δ 7.54 – 7.47 (m, 2H, CHarom), 7.46 – 7.41 (m, 2H, CHarom), 7.41 – 7.22 (m, 11H, CHarom), 5.65 (s, 1H, CHPh), 5.23 (d, 1H, J =
3.6 Hz, H-1’), 5.09 (d, 1H, J = 10.6 Hz, CHH Bn), 4.89 – 4.82 (m, 2H, CHH Bn, CHH Bn), 4.74 – 4.65 (m, 2H, CHH Bn, H-1), 4.31 – 4.21 (m, 2H, H-4, H-6), 4.11 –
.92 (m, 5H, H-2, H-3, H-3’, H-4’, H-6’), 3.92 – 3.76 (m, 4H, H-5, H-5’, H-6, H-6’), 3.36 (s, 3H, CH OMe), 3.27 (dd, 1H, J = 10.0, 3.7 Hz, H-2’), 1.09 (s, 9H), 1.05
), 129.0, 128.5, 128.5, 128.4, 128.3, 128.3, 128.0, 127.6, 127.5, 127.4, 126.2,
126.1 (CHarom), 101.7 (CHPh), 101.0 (C-1), 99.4 (C-1’), 79.3 (C-4), 79.1, 78.9 (C-3’, C-4’), 76.0, 75.6 (C-2, C-3), 75.6, 73.0 (CH Bn), 69.0 (C-6), 67.2 (C-5’), 66.6
Bu); Diagnostic peaks β-anomer: H NMR (CDCl , 400 MHz): δ 5.60 (s, 1H,
, 101 MHz): δ 101.6, 99.6, 81.8, 78.5, 77.8,
10Si 807.39950, found 807.39931.
2
2
f
ꢁꢃ
1
pentane/EtOAc). [α]ꢀ = +44.3° (c = 1.34, CHCl
3
3
,
4
3
3
1
3
3 q
(s, 9H); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 138.6, 138.4, 137.7 (C
2
t
t
1
(
C-6’), 64.1 (C-5), 62.6 (C-2’), 55.2 (CH
3
OMe), 27.5, 27.2 (CH
3
Bu), 22.8, 20.2 (C
q
3
13
CHPh), 4.98 (d, 1H, J = 11.3 Hz, CHH Bn), 4.39 (d, 1H, J = 8.2 Hz, H-1’), 3.57 – 3.48 (m, 1H); C-APT NMR (CDCl
76.4, 75.2, 74.4, 72.3, 70.9, 65.7, 55.1, 27.5, 27.1; HRMS: [M+NH ] calcd for C42H N O
4 59 4
3
+
2
,2,2-Trifluoroethyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α-
the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 30 min at -40°C) and purified by flash column chromatography (1/0 to 0/1
pentane/toluene to 2% Et O in toluene) to yield glycosylation product 2J (42.4 mg, 82 µmol, 82%, α:β = > 20:1) as a colorless oil. R
1.0, CHCl ); IR (neat): 654, 766, 826, 1036, 1082, 1159, 1279, 1472, 2108, 2859, 2930; H NMR (CDCl
CHarom), 7.38 – 7.27 (m, 3H, CHarom), 5.07 (d, 1H, J = 10.6 Hz, CHH Bn), 4.88 (d, 1H, J = 3.6 Hz, H-1), 4.82 (d, 1H, J = 10.6 Hz, CHH Bn), 4.14 – 4.07 (m, 1H, H-6),
D-glucopyranoside (2J). Donor 2 and 2,2,2-trifluoroethanol were condensed using
2
2
: 0.36 (toluene). [α]ꢁ = +32.6° (c
ꢂ
2
f
ꢀ
1
=
3
3
, 400 MHz, HH-COSY, HSQC): δ 7.45 – 7.39 (m, 2H,
t
t
13
4
.03 – 3.93 (m, 3H, CH Bu); C-APT
NMR (CDCl , 101 MHz, HSQC): δ 138.1 (C Bn), 67.4
3 3 q 2 35 3 5
C-5), 66.5 (C-6), 65.2 (q, J = 35.4 Hz, CH -CF ), 62.2 (C-2), 27.5, 27.1 (CH Bu), 22.8, 20.1 (C Bu); HRMS: [M-N +H] calcd for C23H F NO Si 490.22311, found
2
-CF
3
, H-4), 3.92 – 3.80 (m, 3H, H-3, H-5, H-6), 3.36 (dd, 1H, J = 10.0, 3.6 Hz, H-2), 1.09 (s, 9H, CH
3
Bu), 1.03 (s, 9H, CH
3
3
q
), 128.6, 128.5, 128.1 (CHarom), δ 123.5 (q, J = 278.4 Hz, CF3), 98.8 (C-1), 78.9 (C-3), 78.8 (C-4), 75.7 (CH
2
t
t
+
(
2
490.22292.
1
,1,1,3,3,3-Hexafluoro-2-propyl 2-azido-3-O-benzyl-2-deoxy-4,6-O-di-tert-butylsilylidene-α-
O/Ph SO mediated glycosylations (for an additional 72 hours at -40°C) and purified by flash column
chromatography (4/1 to 0/1 pentane/toluene) to yield glycosylation product 2K (20 mg, 34 µmol, 34%, α:β = > 20:1) as a white solid. R : 0.38 (9/1 pentane/Et O).
, 400 MHz, HH-COSY, HSQC, HMBC,
NOESY): δ 7.45 – 7.28 (m, 5H, CHarom), 5.12 – 5.04 (m, 2H, CHH Bn, H-1), 4.83 (d, 1H, J = 10.5 Hz, CHH Bn), 4.40 (hept, 1H, J = 5.7 Hz, CH HFIP), 4.09 (dd, 1H, J
D-glucopyranoside (2K). Donor 2 and 1,1,1,3,3,3-hexafluoro-2-
propanol were condensed using the general procedure for Tf
2
2
f
2
ꢁ
ꢃ
1
ꢀ
3 3
[α] = +31.2° (c = 0.50, CHCl ); IR (thin film): 689, 827, 1030, 1098, 1221, 1288, 1368, 2112, 2860, 2934; H NMR (CDCl
t
t
= 9.4, 4.0 Hz, H-6), 4.03 – 3.91 (m, 2H, H-4, H-5), 3.91 – 3.83 (m, 2H, H-3, H-6), 3.42 (dd, 1H, J = 10.2, 3.8 Hz, H-2), 1.08 (s, 9H, CH
3
Bu), 1.03 (s, 9H, CH
), 128.6, 128.5, 128.2 (CHarom), 100.4 (C-1), 78.7 (C-3), 78.4 (C-4), 75.8 (CH Bn), 73.3 (p, J = 33.2
Si 558.21050, found 558.21009.
3
Bu);
1
3
C-APT NMR (CDCl
3
, 101 MHz, HSQC, HMBC): δ 138.0 (C
q
2
t
t
+
Hz), 68.1 (C-5), 66.1 (C-6), 61.9 (C-2), 27.5, 27.0 (CH
3
q 2 34 6 5
Bu), 22.8, 20.1 (C Bu); HRMS: [M-N +H] calcd for C24H F NO
2 2
Ethyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside (3A). Donor 3 and ethanol were condensed using the general procedure for Tf O/Ph SO
mediated glycosylations and purified by flash column chromatography (1/0 to 0/1 hexane/toluene to 5% EtOAc in toluene) to yield glycosylation product 3A (34.3 mg,
ꢂ
83 µmol, 83%, α:β = < 1:20) as a white solid. R
f
: 0.58 (9/1 toluene/EtOAc). [α]ꢁ = -79.6° (c = 0.69, CHCl
3
); IR (neat): 692, 993, 1098, 1186, 1267, 1365, 1452, 2111,
ꢀ
1
2
878, 2979; H NMR (CDCl , 400 MHz, HH-COSY, HSQC): δ 7.50 – 7.46 (m, 2H, CHarom), 7.41 – 7.28 (m, 8H, CHarom), 5.57 (s, 1H, CHPh), 4.91 (d, 1H, J = 11.2 Hz,
3
CHH Bn), 4.79 (d, 1H, J = 11.3 Hz, CHH Bn), 4.37 (d, 1H, J = 8.2 Hz, H-1), 4.34 (dd, 1H, J = 10.6, 5.0 Hz, H-6), 3.96 (dq, 1H, J = 9.7, 7.1 Hz, CHH Et), 3.80 (t, 1H,
J = 10.3 Hz, H-6), 3.70 (t, 1H, J = 9.0 Hz, H-4), 3.66 (dq, 1H, J = 9.7, 7.2 Hz, CHH Et), 3.54 (t, 1H, J = 9.3 Hz, H-3), 3.44 (dd, 1H, J = 9.5, 8.0 Hz, H-2), 3.39 (td, 2H,
1
3
J = 9.8, 5.0 Hz, H-5), 1.29 (t, 3H, J = 7.1 Hz, CH
(
3
Et); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 138.0, 137.2 (C
Et), 66.3, 66.2 (C-2, C-5), 15.2 (CH
429.21325, found 429.21321.
q
), 129.2, 128.5, 128.4, 128.3, 128.0, 126.1
13
CHarom), 102.5 (C-1), 101.4 (CHPh), 81.7 (C-4), 79.1 (C-3), 75.0 (CH Bn), 68.7 (C-6), 66.3 (CH
2
2
3
Et); C-HMBC-GATED
+
NMR (CDCl
3
, 101 MHz): δ 102.5 (JC1,H1 = 161 Hz, C-1); HRMS: [M+NH
4
]
calcd for C22
H
29
N
4
O
5
Cyclohexyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-
Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/1 to 0/1 hexane/toluene to 5% EtOAc in toluene) to yield glycosylation product
B (43 mg, 93 µmol, 93%, α:β = < 1 : 20) as a white solid. R
D-glucopyranoside (3B). Donor 3 and cyclohexanol were condensed using the general procedure for
2
2
3
2
4
6
f
: 0.23 (toluene). [α]ꢁ = -60.5° (c = 0.86, DCM); IR (neat): 696, 748, 998, 1092, 1275, 1365, 1452, 2108,
ꢂ
ꢀ
1
858, 2933; Data for the β-anomer: H NMR (CDCl
.90 (d, 1H, J = 11.4 Hz, CHH Bn), 4.79 (d, 1H, J = 11.4 Hz, CHH Bn), 4.47 (d, 1H, J = 7.8 Hz, H-1), 4.32 (dd, 1H, J = 10.5, 5.0 Hz, H-6), 3.79 (t, 1H, J = 10.3 Hz, H-
), 3.74 – 3.64 (m, 2H, H-4, CH Cyc), 3.50 (t, 1H, J = 9.2 Hz, H-3), 3.44 (dd, 1H, J = 9.6, 7.8 Hz, H-2), 3.36 (td, 1H, J = 9.7, 5.0 Hz, H-5), 1.99 – 1.87 (m, 2H, CH
Cyc), 1.82 – 1.72 (m, 2H, J = 15.2, 4.4 Hz, CH
38.0, 137.3 (C
6.5 (C-2), 66.3 (C-5), 33.6, 31.8, 25.6, 24.1, 23.9 (CH
3
, 400 MHz, HH-COSY, HSQC): δ 7.50 – 7.44 (m, 2H, CHarom), 7.42 – 7.27 (m, 8H, CHarom), 5.56 (s, 1H, CHPh),
2
13
2
Cyc), 1.56 – 1.37 (m, 3H, CH
2
Cyc), 1.36 – 1.20 (m, 3H, CH
2
Cyc); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ
Bn), 68.8 (C-6),
3
Cyc); Diagnostic peaks α-anomer: H NMR (CDCl , 400 MHz): δ 5.59 (s, 0.04H, CHPh), 5.03 (d, 0.04H, J =
1
6
q
), 129.1, 128.5, 128.4, 128.3, 127.9, 126.1 (CHarom), 101.4 (CHPh), 101.0 (C-1), 81.6 (C-4), 79.0 (C-3), 78.5 (CH Cyc), 75.0 (CH
2
1
2
1
3
3
3.7 Hz, H-1), 4.12 (t, 0.04H, J = 9.5 Hz, H-3), 4.00 (td, 0.04H, J = 9.9, 4.8 Hz, H-5), 3.28 (dd, 0.04H, J = 10.0, 3.7 Hz, H-2); C-APT NMR (CDCl , 101 MHz): δ
01.4 (CHPh), 97.1 (C-1), 76.0 (C-3), 63.8 (C-2), 62.9 (C-5); HRMS: [M+NH ] calcd for C26H N O 483.26020 found 483.25991.
4 35 4 5
+
1
Methyl 6-O-(2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-ᴅ-glucopyranosyl)-2,3,4-tri-O-benzyl-α-ᴅ-glucopyranoside (3C). Donor 3 and acceptor 25 were
condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography (19/1 to
/1 pentane/EtOAc) to yield glycosylation product 3C (73.7 mg, 89 µmol, 89%, α:β = < 1:20) as a white solid. R : 0.42 (4/1 pentane/EtOAc). Spectroscopic data were
2
2
4
f
3
8
ꢁꢂ
1
in accord with those previously reported. [α] = -32.2° (c = 1.0, CHCl
3
); IR (neat): 696, 737, 999, 1028, 1070, 1090, 1277, 1362, 1497, 2108, 2876, 2926; H NMR
ꢀ
(
CDCl , 400 MHz, HH-COSY, HSQC, HMBC): δ 7.47 (dd, 2H, J = 7.3, 2.5 Hz, CHarom), 7.42 – 7.25 (m, 23H, CHarom), 5.55 (s, 1H, CHPh), 4.99 (d, 1H, J = 10.9 Hz,
3
CHH 3-OBn), 4.95 (d, 1H, J = 11.2 Hz, CHH 4-OBn), 4.91 (d, 1H, J = 11.2 Hz, CHH 3’-OBn), 4.85 – 4.76 (m, 3H, CHH 3-OBn, CHH 2-OBn, CHH 3’-OBn), 4.70 –
4.63 (m, 2H, CHH 4-OBn, CHH 2-OBn), 4.61 (d, 1H, J = 3.6 Hz, H-1), 4.30 (dd, 1H, J = 10.5, 5.0 Hz, H-6’), 4.23 (d, 1H, J = 7.9 Hz, H-1’), 4.07 (d, 1H, J = 8.9 Hz,
H-6), 4.00 (t, 1H, J = 9.3 Hz, H-3), 3.81 – 3.72 (m, 3H, H-5, H-6, H-6’), 3.69 (t, 1H, J = 9.1 Hz, H-4’), 3.60 (t, 1H, J = 9.3 Hz, H-4), 3.59 – 3.46 (m, 3H, H-2, H-2’, H-
10
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
3’), 3.37 (s, 3H, CH
1
7
3
OMe), 3.36 – 3.29 (m, 1H, H-5’); C-APT NMR (CDCl
28.5, 128.5, 128.4, 128.3, 128.3, 128.1, 128.1, 128.0, 127.9, 127.9, 127.7, 126.1 (CHarom), 102.4 (C-1’), 101.4 (CHPh), 98.4 (C-1), 82.2 (C-3), 81.5 (C-4’), 79.8 (C-2),
9.3 (C-3’), 77.6 (C-4), 75.9 (CH 3-OBn), 75.0, 75.0 (CH 3’-OBn, 4-OBn), 73.6 (CH 2-OBn), 69.6 (C-5), 68.7, 68.6 (C-6, C-6’), 66.3 (C-5’), 66.1 (C-2’), 55.4
calcd for C48 10 847.39127, found 847.39224.
3 q
, 101 MHz, HSQC, HMBC): δ 138.8, 138.5, 138.2, 137.8, 137.2 (C ), 129.2, 128.6,
2
2
2
+
(OMe); HRMS: [M+NH
4
]
55 4
H N O
2
-Fluoroethyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-
O/Ph SO mediated glycosylations and purified by flash column chromatography (1/0 to 0/1 pentane/toluene to 5% EtOAc in toluene) to yield
glycosylation product 3D (38.5 mg, 90 µmol, 90%, α:β = 1:6.7) as a white solid. R : 0.40 (19/1 toluene/EtOAc). IR (neat): 696, 748, 996, 1028, 1072, 1091, 1174, 1276,
, 400 MHz, HH-COSY, HSQC): δ 7.50 – 7.46 (m, 2H, CHarom), 7.41 – 7.36 (m, 5H, CHarom),
.36 – 7.25 (m, 3H, CHarom), 5.57 (s, 1H, CHPh), 4.91 (d, 1H, J = 11.2 Hz, CHH Bn), 4.79 (d, 1H, J = 11.3 Hz, CHH Bn), 4.69 – 4.64 (m, 1H, CHHF), 4.55 (dt, 1H, J =
.6, 2.9 Hz, CHHF), 4.42 (d, 1H, J = 7.9 Hz, H-1), 4.34 (dd, 1H, J = 10.5, 5.0 Hz, H-6), 4.11 (ddd, 0.5H, J = 12.2, 4.8, 2.9 Hz, CHH-CFH ), 4.03 (ddd, 0.5H, J = 12.2,
), 3.92 (ddd, 0.5H, J = 12.2, 5.9, 3.2 Hz, CHH-CFH ), 3.86 (ddd, 0.5H, J = 12.2, 6.0, 3.3 Hz, CHH-CFH ), 3.80 (t, 1H, J = 10.3 Hz, H-6), 3.71
t, 1H, J = 9.2 Hz, H-4), 3.56 (t, 1H, J = 9.2 Hz, H-3), 3.48 (dd, 1H, J = 9.5, 7.9 Hz, H-2), 3.39 (td, 1H, J = 9.7, 4.9 Hz, H-5); C-APT NMR (CDCl
HSQC): δ 137.8, 137.1 (C ), 129.2, 128.5, 128.4, 128.3, 128.0, 126.1 (CHarom), 102.7 (C-1), 101.4 (CHPh), 82.6 (d, J = 170.1 Hz, CFH ), 81.5 (C-4), 79.0 (C-3), 75.1
(CH Bn), 69.3 (d, J = 20.1 Hz, CH , 101 MHz): δ 102.7 (JC1,H1 = 162 Hz, C-1);
Diagnostic peaks α-anomer: H NMR (CDCl , 400 MHz, HH-COSY, HSQC): δ 5.58 (s, 0.15H, CHPh), 4.96 (d, 0.15H, J = 10.9 Hz, CHH Bn), 4.95 (d, 0.15H, J = 3.7
Hz, H-1), 4.81 (d, 0.15H, J = 11.0 Hz, CHH Bn), 4.29 (dd, 0.15H, J = 10.2, 4.9 Hz, H-6); C-APT NMR (CDCl
D-glucopyranoside (3D). Donor 3 and 2-fluoroethanol were condensed using the general
procedure for Tf
2
2
f
1
1368, 1454, 2108, 2873, 2917; Data for the β-anomer: H NMR (CDCl
3
7
4
2
4.7, 3.0 Hz, CHH-CFH
(
2
2
2
1
3
3
, 101 MHz,
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
q
2
13
2
2 2 3
-CFH ), 68.6 (C-6), 66.3 (C-5), 66.1 (C-2); C-HMBC-GATED NMR (CDCl
1
3
13
3
, 101 MHz, HSQC): δ 101.5 (CHPh), 98.8 (C-1), 82.8
+
1
3
(C-4), 76.2 (C-3), 75.2 (CH
2 3 4
Bn), 68.9 (C-6), 63.0, 62.9 (C-2, C-5); C-HMBC-GATED NMR (CDCl , 101 MHz): δ 98.8 (JC1,H1 = 172 Hz, C-1); HRMS: [M+NH ]
calcd for C22 447.20382 found 447.20355.
H
4 5
28FN O
Methyl 4-O-(2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-α-ᴅ-glucopyranoside (3E). Donor 3 and acceptor 26 were
condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography (19/1 to
/1 pentane/EtOAc) to yield glycosylation product 3E (73.3 mg, 88 µmol, 88%, α:β = 1:7) as a white solid. R : 0.51 α, 0.43 β (4/1 pentane/EtOAc). IR (neat): 696, 737,
, 400 MHz, HH-COSY, HSQC, TOCSY): δ 7.68 – 7.60 (m, 2H, CHarom), 7.52 – 7.18 (m,
3H, CHarom), 5.47 (s, 1H, CHPh), 4.89 (d, 1H, J = 11.2 Hz, CHH Bn), 4.87 (d, 1H, J = 10.9 Hz, CHH Bn), 4.81 (d, 1H, J = 10.9 Hz, CHH Bn), 4.78 (d, 1H, J = 12.2
2
2
4
1
2
f
1
049, 1092, 1362, 1454, 2110, 2868; Data for the β-anomer: H NMR (CDCl
3
Hz, CHH Bn), 4.75 (d, 1H, J = 11.2 Hz, CHH Bn), 4.71 (d, 1H, J = 12.0 Hz, CHH Bn), 4.63 (d, 1H, J = 12.1 Hz, CHH Bn), 4.60 (d, 1H, J = 3.7 Hz, H-1), 4.41 (d, 1H,
J = 12.0 Hz, CHH Bn), 4.19 (d, 1H, J = 7.6 Hz, H-1’), 4.11 (dd, 1H, J = 10.6, 5.0 Hz, H-6’), 4.00 – 3.90 (m, 2H, H-4, H-6), 3.85 (t, 1H, J = 9.3 Hz, H-3), 3.75 (dt, 1H,
J = 9.8, 2.4 Hz, H-5), 3.69 (dd, 1H, J = 10.8, 1.9 Hz, H-6), 3.56 (t, 1H, J = 9.0 Hz, H-4’), 3.51 (dd, 1H, J = 9.5, 3.7 Hz, H-2), 3.45 – 3.38 (m, 4H, H-6’, CH
3
OMe),
), 131.1, 129.4,
28.6, 128.4, 128.3, 128.2, 128.2, 128.1, 128.1, 127.9, 127.9, 127.6, 126.0, 124.8 (CHarom), 101.3, 101.2 (CHPh, C-1’), 98.4 (C-1), 81.7 (C-4’), 80.1 (C-3), 79.2 (C-3’),
1
3
3 q
3.36 – 3.27 (m, 2H, H-2’, H-3’), 3.00 (td, 1H, J = 9.8, 5.0 Hz, H-5’); C-APT NMR (CDCl , 101 MHz, HSQC): δ 139.3, 138.3, 137.8, 137.8, 137.3 (C
1
7
1
9.0 (C-2), 76.9 (C-4), 75.4, 74.7, 73.6, 73.5 (CH
2
Bn), 69.7 (C-5), 68.6 (C-6’), 68.0 (C-6), 66.6 (C-2’), 65.8 (C-5’), 55.4 (OMe); Diagnostic peaks α-anomer: H NMR
, 400 MHz): δ 5.71 (d, 1H, J = 4.0 Hz, H-1’), 5.53 (s, 1H, CHPh), 5.11 (d, 1H, J = 10.7 Hz, CHH Bn), 4.95 (d, 1H, J = 10.9 Hz, CHH Bn); C-APT NMR
, 101 MHz): δ 98.1, 97.8, 82.7, 82.1, 80.5, 76.2, 75.1, 73.3, 73.0, 69.4, 69.1, 68.7, 63.4, 62.9; HRMS: [M+Na] calcd for C48
1
3
(CDCl
3
+
(
CDCl
3
H
51
N
3
O10Na 852.34667, found
852.34668.
Methyl (Methyl 4-O-[2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl]-2,3-di-O-benzyl-α-ᴅ-glucopyranosyl uronate) (3F). Donor 3 and
acceptor 27 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column
chromatography (19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 3F (71.8 mg, 93 µmol, 93%, α:β = 1.1:1) as a white solid. R : 0.54 (4/1 pentane/EtOAc).
Spectroscopic data were in accord with those previously reported. IR (neat): 696, 735, 914, 989, 1028, 1045, 1090, 1267, 1369, 1454, 1749, 2108, 2870, 2916;
2
2
f
2
1
1
Reported as a 1 : 1 mixture of anomers: H NMR (CDCl
H, CHPh ), 5.51 (d, 1H, J = 3.9 Hz, H-1’ ), 5.47 (s, 1H, CHPh
Bn, 2xCHH Bn), 4.81 – 4.72 (m, 4H, 2xCHH Bn, 2xCHH Bn), 4.64 – 4.58 (m, 2H, 2xCHH Bn), 4.57 (d, 2H, J = 3.5 Hz, H-1α,β), 4.43 (d, 1H, J = 8.1 Hz, H-1’
(dd, 1H, J = 10.3, 4.8 Hz, H-6’ ), 4.24 – 4.19 (m, 2H, H-5 , H-5 ), 4.09 – 3.99 (m, 4H, H-3 , H-4 , H-4 , H-6’ ), 3.97 (t, 1H, J = 9.5 Hz, H-3’ ), 3.89 (t, 1H, J = 9.2 Hz,
H-3 ), 3.82 (s, 3H, CH CO Me), 3.81 (s, 3H, CH CO Me), 3.72 – 3.56 (m, 4H, H-2 , H-4’ , H-4’ , H-6’ ), 3.56 – 3.46 (m, 3H, H-2 , H-3’ , H-5’ ), 3.46 – 3.38 (m, 7H,
xCH OMe, H-6’ ), 3.36 – 3.29 (m, 2H, H-2’ , H-2’ ), 3.26 (td, 1H, J = 9.7, 5.0 Hz, H-5’ ); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 170.0, 170.0 (C=O
CO Me), 139.1, 138.5, 138.0, 137.9, 137.9, 137.8, 137.4, 137.2 (C ), 129.2, 129.1, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3, 128.3, 128.3, 128.2, 128.1, 128.0,
28.0, 127.8, 127.7, 127.5, 127.4, 126.1, 126.1 (CHarom), 102.3 (C-1’ ), 101.4 (CHPh ), 101.3 (CHPh ), 98.9, 98.6 (C-1 , C-1 ), 98.5 (C-1’ ), 82.4 (C-4’ ), 81.6 (C-4’ ),
1.1 (C-3 ), 79.6 (C-2 , C-4 ), 79.5 (C-3 ), 79.4 (C-3’ ), 78.7 (C-2 ), 76.3 (C-3’ ), 75.6 (CH Bn), 75.5 (C-4 ), 75.1, 75.0, 73.9, 73.7 (CH Bn), 70.0, 69.9 (C-5 , C-5 ),
, C-6 ), 66.7 (C-2’ ), 66.2 (C-5’ ), 63.0 (C-5’ ), 62.8 (C-2’ ), 55.9, 55.9 (OMe), 53.0, 52.8 (CO Me); HRMS: [M+NH
85.33923, found 785.34007.
3
, 400 MHz, HH-COSY, HSQC, HMBC): δ 7.48 – 7.41 (m, 4H, CHarom), 7.41 – 7.24 (m, 36H, CHarom), 5.53 (s,
), 5.04 (d, 1H, J = 10.5 Hz, CHH Bn), 4.94 (d, 1H, J = 11.0 Hz, CHH Bn), 4.91 – 4.82 (m, 4H, 2xCHH
), 4.26
1
α
α
β
β
α
α
β
β
α
β
β
α
α
3
2
3
2
β
α
β
α
α
β
α
1
3
2
3
β
α
β
β
3
2
q
1
8
β
β
α
α
β
α
α
β
β
β
β
α
β
α
α
2
α
2
α
β
+
68.5, 68.5 (C-6
α
β
β
β
α
α
2
4 49 4 11
] calcd for C42H N O
7
2,2-Difluoroethyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-
procedure for Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/0 to 0/1 pentane/toluene to 5% EtOAc in toluene) to yield
glycosylation product 3G (28.8 mg, 64 µmol, 64%, α:β = 2.9:1) as a white solid. R : 0.15 and 0.18 (toluene). IR (neat): 698, 747, 998, 1070, 1093, 1372, 1454, 2109,
, 400 MHz, HH-COSY, HSQC): δ 7.52 – 7.45 (m, 2.70H, CHarom), 7.43 – 7.26 (m, 10.80H,
), 5.94 (tt, 0.35H, J = 55.3, 3.8 Hz, CF ), 5.58 (s, 1H, CHPh ), 5.57 (s, 0.35H, CHPh ), 4.96 (d, 1H, J = 10.9 Hz, CHH
), 4.92 (d, 0.35H, J = 11.3 Hz, CHH Bn ), 4.80 (d, 1H, J = 11.0 Hz, CHH Bn ), 4.79 (d, 0.35H, J = 11.3 Hz, CHH Bn ), 4.40 (d,
), 4.34 (dd, 0.35H, J = 10.5, 5.0 Hz, H-6 ), 4.29 (dd, 1H, J = 10.2, 4.8 Hz, H-6 ), 4.08 (t, 1H, J = 9.5 Hz, H-3 ), 4.02 – 3.67 (m, 6.4H, H-4 , H-
, CH -CF , CH -CF ), 3.56 (t, 0.35H, J = 9.2 Hz, H-3 ), 3.50 – 3.35 (m, 1.70H, H-2 ); C-APT NMR (CDCl , 101 MHz, HSQC):
), 129.4, 129.3, 129.1, 128.6, 128.5, 128.5, 128.4, 128.1, 126.1 (CHarom), 114.0 (t, J = 241.5 Hz, CF ), 113.8 (t, J = 241.6 Hz, CF ),
), 75.1 (CH Bn), 69.0 (t, J = 29.0 Hz, CH
); HRMS: [M+H] calcd for C22
D-glucopyranoside (3G). Donor 3 and 2,2-difluoroethanol were condensed using the general
2
2
f
1
2867, 2934; Reported as a 1 : 0.35 mixture of anomers: H NMR (CDCl
CHarom), 5.95 (tt, 1H, J = 55.2, 4.2 Hz, CF
Bn ), 4.93 (d, 1H, J = 3.9 Hz, H-1
.35H, J = 7.9 Hz, H-1
, H-5 , H-6 , H-6
3
2
H
α
2
H
β
α
β
α
α
β
α
β
0
4
β
β
α
α
α
13
β
α
α
β
2
2
H
α
2
2
H
β
β
α
, H-2
β
, H-5
β
3
δ 137.8, 137.8, 137.1, 137.1 (C
02.8 (C-1 ), 101.6 (CHPh ), 101.5 (CHPh
CF ), 68.8 (C-6), 68.5 (C-6), 67.5 (t, J = 28.7 Hz, CH
448.16785, found 448.16761.
q
2
H
β
2 α
H
1
β
α
β
), 99.3 (C-1
α
), 82.6 (C-4
-CF
α
), 81.4 (C-4
), 66.4 (C-5
β
), 78.9 (C-3
β
), 76.0 (C-3
α
), 75.3 (CH
2
Bn
α
α
2
2
-
5
+
2
H
β
2
2
H
α
β
), 66.0 (C-2
β
), 63.3 (C-5
α
), 62.9 (C-2
H
24
F
2
N
3
O
Methyl 4-O-(2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-β-ᴅ-galactopyranoside (3H). Donor 3 and acceptor 28
were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography
19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 3H (62.2 mg, 75 µmol, 75%, α:β = 9:1) as a white solid. R : 0.52 (4/1 pentane/EtOAc). IR (neat): 696, 735,
, 400 MHz, HH-COSY, HSQC, HMBC): δ 7.50 – 7.46 (m, 2H,
2
2
(
9
f
1
95, 1030, 1072, 1090, 1368, 1454, 1497, 2106, 2862, 2920; Data for the α-anomer: H NMR (CDCl
3
CHarom), 7.42 – 7.25 (m, 23H, CHarom), 5.51 (s, 1H, CHPh), 4.98 (d, 1H, J = 10.7 Hz, CHH 3’-OBn), 4.90 (d, 1H, J = 11.0 Hz, CHH 2-OBn), 4.88 (d, 1H, J = 3.7 Hz,
H-1’), 4.84 – 4.76 (m, 3H, CHH 2-OBn, CHH 3’-OBn, CHH 3-OBn), 4.69 (d, 1H, J = 12.4 Hz, CHH 3-OBn), 4.59 – 4.51 (m, 2H, CH 6-OBn), 4.30 (td, 1H, J = 10.1,
.9 Hz, H-5’), 4.25 (d, 1H, J = 7.6 Hz, H-1), 4.14 – 4.07 (m, 2H, H-3’, H-4), 4.03 (t, 1H, J = 8.9 Hz, H-6), 3.80 (dd, 1H, J = 10.2, 4.9 Hz, H-6’), 3.70 – 3.60 (m, 3H, H-
2
4
1
3
2, H-4’, H-6), 3.55 (s, 3H, CH
3
OMe), 3.54 – 3.48 (m, 2H, H-5, H-6’), 3.44 – 3.36 (m, 2H, H-2’, H-3); C-APT NMR (CDCl
), 129.0, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3, 128.3, 128.2, 128.0, 127.7, 127.6, 126.1 (CHarom), 105.3 (C-1), 101.2 (CHPh), 99.4 (C-
’), 83.1 (C-4’), 80.1 (C-3), 78.9 (C-2), 77.0 (C-3’), 75.3 (CH 3’-OBn), 75.1 (CH 2-OBn), 74.7 (C-4), 73.6 (CH 6-OBn), 73.0 (CH 3-OBn), 72.9 (C-5), 68.9 (C-6’),
7.1 (C-6), 63.8 (C-2’), 62.9 (C-5’), 57.4 (OMe); Diagnostic peaks β-anomer: H NMR (CDCl , 400 MHz): δ 5.54 (s, 1H, CHPh), 3.92 (dd, 1H, J = 9.7, 7.7 Hz, H-2),
, 101 MHz): δ 105.1 (C-1), 102.6 (C-1’), 101.4, 81.5, 81.3, 79.5, 79.0, 74.0, 73.4,
10 847.39127, found 847.39206.
3
, 101 MHz, HSQC, HMBC): δ 138.7,
1
1
6
3
6
38.3, 138.1, 137.7, 137.6 (C
q
2
2
2
2
1
3
1
3
.76 – 3.71 (m, 1H, H-6), 3.22 (td, 1H, J = 9.7, 4.8 Hz, H-5’); C-APT NMR (CDCl
3
+
4 55 4
9.4, 68.6, 66.3, 66.0, 57.4; HRMS: [M+NH ] calcd for C48H N O
Methyl 2-O-(2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-3-O-benzyl-4,6-O-benzylidene-α-ᴅ-mannopyranoside (3I). Donor
acceptor 29 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column
chromatography (19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 3I (54.7 mg, 74 µmol, 74%, α:β = 9:1) as a white solid. R : 0.74 (7/2 pentane/EtOAc). IR
, 400 MHz, HH-COSY, HSQC, HMBC): δ 7.54
– 7.47 (m, 4H, CHarom), 7.44 – 7.25 (m, 16H, CHarom), 5.66 (s, 1H, CHPh), 5.60 (s, 1H, CHPh’), 5.39 (d, 1H, J = 3.7 Hz, H-1’), 5.00 (d, 1H, J = 11.0 Hz, CHH Bn),
3 and
2
2
f
1
(
neat): 696, 746, 997, 1036, 1074, 1090, 1128, 1371, 1454, 2106, 2862, 2922; Data for the α-anomer: H NMR (CDCl
3
4
1
.90 (d, 1H, J = 12.2 Hz, CHH Bn), 4.84 (d, 1H, J = 10.9 Hz, CHH Bn), 4.73 – 4.66 (m, 2H, H-1, CHH Bn), 4.34 – 4.24 (m, 3H, H-4, H-6, H-6’), 4.17 (dd, 1H, J =
0.2, 9.0 Hz, H-3’), 4.09 (dd, 1H, J = 3.1, 1.7 Hz, H-2), 4.00 (dd, 1H, J = 9.9, 3.1 Hz, H-3), 3.95 – 3.86 (m, 2H, H-5’, H-6), 3.83 – 3.70 (m, 3H, H-4’, H-5, H-6’), 3.36
(s, 3H, CH OMe), 3.32 (dd, 1H, J = 10.2, 3.8 Hz, H-2’); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 138.7, 138.0, 137.7, 137.2 (C ), 129.2, 129.0, 128.6,
3 3 q
28.5, 128.4, 128.3, 128.2, 128.0, 127.6, 127.4, 126.2, 126.0 (CHarom), 101.7 (CHPh), 101.5 (CHPh’), 101.0 (C-1), 99.8 (C-1’), 82.9 (C-4’), 79.4 (C-4), 75.9 (C-3), 75.6
1
3
1
1
(C-3’), 75.5 (C-2), 75.3, 73.3 (CH
2
3
Bn), 69.0, 68.9 (C-6, C-6’), 64.1 (C-5), 63.3 (C-5’), 63.0 (C-2’), 55.0 (OMe); Diagnostic peaks β-anomer: H NMR (CDCl , 400
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
5
6
7
8
9
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
1
3
3
MHz): δ 4.43 (d, 0.1H, J = 8.0 Hz, H-1’), 3.62 (dd, 0.1H, J = 9.6, 8.0 Hz, H-2’), 3.51 (t, 0.1H, J = 9.3 Hz, H-4); C-APT NMR (CDCl , 101 MHz): δ 102.0 (C-1’),
+
4 47 4
78.5 (C-4), 66.4 (C-2’); HRMS: [M+NH ] calcd for C41H N O10 755.32867, found 755.32921.
2
,2,2-Trifluoroethyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-
O/Ph SO mediated glycosylations (for an additional 1 h at -40°C) and purified by flash column chromatography (1/0 to 0/1 pentane/toluene to
% EtOAc in toluene) to yield glycosylation product 3J (44 mg, 94 µmol, 94%, α:β = > 20:1) as a colorless oil. R
D-glucopyranoside (3J). Donor 3 and 2,2,2-trifluoroethanol were condensed using the
general procedure for Tf
5
2
2
ꢁꢂ
f
: 0.24 (toluene). [α]ꢀ = +25.9° (c = 0.88, DCM); IR
, 400 MHz, HH-COSY, HSQC): δ 7.51 – 7.48 (m, 2H,
CHarom), 7.42 – 7.28 (m, 8H, CHarom), 5.58 (s, 1H, CHPh), 4.99 – 4.94 (m, 2H, CHH Bn, H-1), 4.80 (d, 1H, J = 10.9 Hz, CHH Bn), 4.29 (dd, 1H, J = 10.2, 4.8 Hz, H-6),
1
(neat): 697, 747, 1001, 1034, 1090, 1165, 1279, 1373, 2108, 2865, 2934; Data for the α-anomer: H NMR (CDCl
3
4.10 (dd, 1H, J = 10.0, 9.0 Hz, H-3), 3.98 (qd, 2H, J = 8.5, 3.1 Hz, CH
2
-CF
, 101 MHz, HSQC): δ 137.8, 137.1 (C
9.4 (C-1), 82.5 (C-4), 75.9 (C-3), 75.3 (CH
3
), 3.91 (td, 1H, J = 9.9, 4.8 Hz, H-5), 3.79 – 3.70 (m, 2H, H-4, H-6), 3.43 (dd, 1H, J = 10.0,
), 129.3, 128.6, 128.5, 128.3, 128.1, 126.1 (CHarom), 123.5 (q, J = 278.5 Hz), 101.6 (CHPh),
Bn), 68.7 (C-6), 65.4 (q, J = 35.4 Hz), 63.5 (C-5), 62.7 (C-2); C-HMBC-GATED NMR (CDCl
1
3
3
9
.7 Hz, H-2); C-APT NMR (CDCl
3
q
1
3
2
3
, 101 MHz): δ 102.5
1
(JC1,H1 = 173 Hz, C-1); Diagnostic peaks β-anomer: H NMR (CDCl , 400 MHz): δ 4.44 (d, 0.03H, J = 7.9 Hz, H-1), 4.34 (dd, 0.03H, J = 10.8, 5.3 Hz, H-6), 3.56 (t,
3
13
+
0
.03H, J = 9.2 Hz), 3.48 (dd, 0.03H, J = 10.0, 7.9 Hz, H-2); C-HMBC-GATED NMR (CDCl
483.18498 found 483.18463.
3
4
, 101 MHz): δ 102.4 (JC-H = 150 Hz, C-1); HRMS: [M+NH ] calcd for
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
22 26 3 4 5
C H F N O
1
,1,1,3,3,3-Hexafluoro-2-propyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α-
condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 72 h at -40°C) and purified by flash column chromatography (1/0 to
9/1 pentane/EtOAc) to yield glycosylation product 3K (28.1 mg, 53 µmol, 53%, α:β = > 20:1) as a colorless oil. [α] = +25.8° (c = 0.5, CHCl
D-glucopyranoside (3K). Donor 3 and 1,1,1,3,3,3-hexafluoroisopropanol were
2
2
ꢁ
ꢂ
ꢀ
3
); IR (neat): 689, 748,
, 400 MHz, HH-COSY, HSQC): δ 7.54 – 7.45 (m, 2H, CHarom), 7.44 – 7.27 (m, 8H, CHarom),
.59 (s, 1H, CHPh), 5.13 (d, 1H, J = 3.9 Hz, H-1), 4.99 (d, 1H, J = 10.8 Hz, CHH Bn), 4.82 (d, 1H, J = 10.8 Hz, CHH Bn), 4.40 (hept, 1H, J = 5.9 Hz, CH HFIP), 4.26
1
9
5
99, 1092, 1196, 1219, 1287, 1368, 2108, 2868, 2928; H NMR (CDCl
3
(dd, 1H, J = 10.3, 4.9 Hz, H-6), 4.10 (dd, 1H, J = 10.0, 9.1 Hz, H-3), 3.98 (td, 1H, J = 10.0, 4.9 Hz, H-5), 3.80 – 3.73 (m, 2H, H-4, H-6), 3.51 (dd, 1H, J = 10.1, 3.9 Hz,
1
3
H-2); C-APT NMR (CDCl
01.0 (C-1), 82.1 (C-4), 75.9 (C-3), 75.5 (CH
534.14582, found 534.14569.
3
, 101 MHz, HSQC): δ 137.6, 136.9 (C
), 129.3, 128.6, 128.5, 128.4, 128.2, 126.1 (CHarom), 120.9 (q, J = 283 Hz, CF ), 101.6 (CHPh),
q 3
Bn), 74.0, 73.7 (hept, J = 32.8 Hz, CH HFIP), 68.3 (C-6), 64.2 (C-5), 62.5 (C-2); HRMS: [M+H] calcd for
+
1
2
23 21 6 3 5
C H F N O
Ethyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-β-
Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/1/0 to 0/1/0 to 0/19/1 pentane/toluene/EtOAc) to yield glycosylation product 4A
36 mg, 85 µmol, 85%, α:β = < 1:20) as a white solid. R
3
180, 1263, 1375, 1726, 2110, 2872; Data for the β-anomer: H NMR (CDCl , 400 MHz, HH-COSY, HSQC): δ 8.11 – 8.05 (m, 2H, CHarom), 7.60 – 7.55 (m, 1H,
D-glucopyranoside (4A). Donor 4 and ethanol were condensed using the general procedure for
2
2
ꢁ
ꢂ
(
1
f
ꢀ
: 0.44 (19/1 toluene/EtOAc). [α] = -53.7° (c = 1.04, DCM); IR (thin film): 709, 1001, 1026, 1070, 1094,
1
CHarom), 7.48 – 7.43 (m, 2H, CHarom), 7.40 – 7.35 (m, 2H, CHarom), 7.32 – 7.27 (m, 3H, CHarom), 5.50 (s, 1H, CHPh), 5.40 (t, 1H, J = 9.8 Hz, H-3), 4.59 (d, 1H, J = 7.9
Hz, H-1), 4.38 (dd, 1H, J = 10.6, 5.0 Hz, H-6), 4.02 (dq, 1H, J = 9.5, 7.1 Hz, CHH Et), 3.83 (t, 1H, J = 10.3 Hz, H-6), 3.80 – 3.67 (m, 2H, H-4, CHH Et), 3.64 (dd, 1H,
13
J = 10.0, 7.9 Hz, H-2), 3.56 (td, 1H, J = 9.7, 5.0 Hz, H-5), 1.32 (t, 3H, J = 7.1 Hz, CH
33.4, 130.1 (CHarom), 129.7 (C
C-2), 15.2 (CH Et); Diagnostic peaks α-anomer: H NMR (CDCl
0.03H, J = 3.6 Hz, H-1), 4.32 (dd, 0.03H, J = 10.4, 4.9 Hz, H-6), 3.32 (dd, 0.03H, J = 10.3, 3.6 Hz, H-2); HRMS: [M+NH
43.19234.
3
Et); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 165.5 (C=O Bz), 136.9 (C
Et), 65.0
, 400 MHz, HH-COSY, HSQC): δ 5.88 (t, 0.03H, J = 9.9 Hz, H-3), 5.53 (s, 0.03H, CHPh), 5.06 (d,
q
),
1
(
q
), 129.2, 128.6, 128.3, 126.2 (CHarom), 102.8 (C-1), 101.6 (CHPh), 79.0 (C-4), 71.8 (C-3), 68.7 (C-6), 66.6, 66.6 (C-5, CH
2
1
3
3
+
4
27 4 6
] calcd for C22H N O 443.19251 found
4
Cyclohexyl 2-azido-3-O-benozyl-4,6-O-benzylidene-2-deoxy-β-
Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/1/0 to 0/1/0 to 0/19/1 pentane/toluene/EtOAc) to yield glycosylation product 4B
43.6 mg, 91 µmol, 91%, α:β = < 1:20) as a white solid. R
D-glucopyranoside (4B). Donor 4 and cyclohexanol were condensed using the general procedure for
2
2
ꢁꢂ
(
f
: 0.18 (toluene). [α]ꢀ = -41.2° (c = 0.87, DCM); IR (thin film): 613, 708, 999, 1096, 1263, 1730, 2110, 2859,
1
2934; H NMR (CDCl
3
, 400 MHz, HH-COSY, HSQC): δ 8.11 – 8.05 (m, 2H, CHarom), 7.61 – 7.54 (m, 1H, CHarom), 7.49 – 7.42 (m, 2H, CHarom), 7.41 – 7.35 (m, 2H,
CHarom), 7.31 – 7.27 (m, 3H, CHarom), 5.50 (s, 1H, CHPh), 5.38 (t, 1H, J = 9.9 Hz, H-3), 4.70 (d, 1H, J = 7.9 Hz, H-1), 4.37 (dd, 1H, J = 10.6, 5.0 Hz, H-6), 3.89 – 3.71
m, 3H, H-4, H-6, CHO Cyc), 3.64 (dd, 1H, J = 10.1, 7.9 Hz, H-2), 3.55 (td, 1H, J = 9.8, 5.0 Hz, H-5), 2.04 – 1.90 (m, 2H, 2xCHH Cyc), 1.85 – 1.73 (m, 2H, 2xCHH
(
1
3
Cyc), 1.58 – 1.40 (m, 3H, CHH Cyc, 2xCHH Cyc), 1.39 – 1.20 (m, 3H, 3xCHH Cyc); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 165.5 (C=O Bz), 136.9 (C
), 129.2, 128.5, 128.3, 126.2 (CHarom), 101.6 (CHPh), 101.2 (C-1), 79.0 (C-4), 78.8 (CH Cyc), 71.8 (C-3), 68.7 (C-6), 66.6 (C-5), 65.2 (C-2),
q
), 133.4,
1
3
30.0 (CHarom), 129.7 (C
3.7, 31.7, 25.6, 24.1, 23.9 (CH
q
+
2
4 33 4 6
Cyc); HRMS: [M+NH ] calcd for C26H N O 497.23946 found 497.23932.
Methyl 6-O-(2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-2,3,4-tri-O-benzyl-α-ᴅ-glucopyranoside (4C). Donor 4 and acceptor 25
were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography
19/1 to 3/1 pentane/EtOAc) to yield glycosylation product 4C (67 mg, 79 µmol, 79%, α:β = 1:14) as a white solid. R
.34, CHCl ); IR (thin film): 696, 748, 1002, 1028, 1068, 1092, 1263, 1313, 1369, 1452, 1730, 2110, 2872, 2918; Data for the β-anomer: H NMR (CDCl
HH-COSY, HSQC, HMBC): δ 8.09 – 8.04 (m, 2H, CHarom), 7.60 – 7.53 (m, 1H, CHarom), 7.48 – 7.41 (m, 2H, CHarom), 7.40 – 7.24 (m, 20H, CHarom), 5.47 (s, 1H,
CHPh), 5.42 (t, 1H, J = 9.8 Hz, H-3’), 5.00 (d, 1H, J = 10.9 Hz, CHH Bn), 4.95 (d, 1H, J = 11.1 Hz, CHH Bn), 4.84 (d, 1H, J = 11.0 Hz, CHH Bn), 4.80 (d, 1H, J =
2
2
ꢁꢃ
(
f
ꢀ
: 0.24 (4/1 pentane/EtOAc). [α] = -17.5° (c =
1
1
3
3
, 400 MHz,
1
2.2 Hz, CHH Bn), 4.68 – 4.63 (m, 2H, 2xCHH Bn), 4.61 (d, 1H, J = 3.5 Hz, H-1), 4.43 (d, 1H, J = 8.0 Hz, H-1’), 4.33 (dd, 1H, J = 10.5, 5.0 Hz, H-6’), 4.12 (d, 1H, J
= 9.1 Hz, H-6), 4.02 (t, 1H, J = 9.3 Hz, H-3), 3.84 – 3.72 (m, 4H, H-4’, H-5, H-6, H-6’), 3.69 (dd, 1H, J = 9.9, 8.0 Hz, H-2’), 3.57 (t, 1H, J = 9.2 Hz, H-4), 3.54 (dd, 1H,
13
J = 9.7, 3.6 Hz, H-2), 3.49 (td, 1H, J = 9.8, 5.0 Hz, H-5’), 3.39 (s, 3H, CH
38.2, 136.7 (CHarom), 133.5, 130.0 (CHarom), 129.4 (C Bz), 129.1, 128.6, 128.6, 128.5, 128.5, 128.3, 128.3, 128.1, 128.0, 128.0, 127.9, 127.9, 127.7, 126.1 (CHarom),
102.6 (C-1’), 101.5 (CHPh), 98.3 (C-1), 82.1 (C-3), 79.8 (C-2), 78.7 (C-4’), 77.7 (C-4), 75.8, 75.0, 73.6 (CH Bn), 71.9 (C-3’), 69.7 (C-5), 68.9 (C-6), 68.5 (C-6’), 66.6
, 400 MHz): δ 5.79 (t, 0.07H, J = 9.9 Hz, H-3’), 5.50 (s, 0.07H, CHPh), 5.08 (d,
3 3
OMe); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 165.4 (C=O), 138.7, 138.3,
1
q
2
1
(
0
C-5’), 65.2 (C-2’), 55.4 (CH
.07H, J = 3.5 Hz, H-1’), 4.24 (dd, 0.07H, J = 10.3, 4.8 Hz, H-6’), 3.41 (s, 0.21H, CH
(C-1), 82.1, 80.0, 79.7, 77.6, 75.8, 75.2, 70.0, 69.4, 67.0, 62.8, 62.1, 55.4; HRMS: [M+NH
3 3
OMe); Diagnostic peaks α-anomer: H NMR (CDCl
13
3
OMe); C-APT NMR (CDCl
] calcd for C48H N O11 861.37053, found 861.37064.
3
, 101 MHz): δ 101.7 (CHPh), 99.3 (C-1’), 98.1
+
4
53 4
2
-Fluoroethyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-
procedure for Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/1/0 to 0/1/0 to 0/16/1 pentane/toluene/EtOAc) to yield
glycosylation product 4D (36.6 mg, 83 µmol, 83%, α:β = 1:6.5) as a white solid. R : 0.41 (19/1 toluene/EtOAc). IR (thin film): 700, 748, 879, 1001, 1026, 1070, 1093,
, 400 MHz, HH-COSY, HSQC): δ 8.10 – 8.05 (m, 2H, CHarom), 7.61 – 7.54 (m, 1H, CHarom),
7.49 – 7.43 (m, 2H, CHarom), 7.41 – 7.36 (m, 2H, CHarom), 7.33 – 7.27 (m, 3H, CHarom), 5.50 (s, 1H, CHPh), 5.41 (t, 1H, J = 9.8 Hz, H-3), 4.69 (ddt, 1H, J = 4.6, 3.2, 1.8
Hz, CHH-CH F), 4.65 (d, 1H, J = 7.9 Hz, H-1), 4.58 (ddt, 1H, J = 4.5, 3.3, 1.8 Hz, CHH-CH F), 4.38 (dd, 1H, J = 10.5, 4.9 Hz, H-6), 4.14 (dddd, 1H, J = 30.3, 11.9,
.6, 3.1 Hz, CHHF), 3.95 (dddd, 1H, J = 27.1, 12.1, 5.5, 3.4 Hz, CHHF), 3.83 (t, 1H, J = 10.3 Hz, H-6), 3.79 (t, 1H, J = 9.5 Hz, H-4), 3.69 (dd, 1H, J = 10.0, 7.9 Hz, H-
D-glucopyranoside (4D). Donor 4 and 2-fluoroethanol were condensed using the general
2
2
f
1
1
179, 1261, 1722, 2108, 2868; Data for the β-anomer: H NMR (CDCl
3
2
2
4
2
1
6
1
3
), 3.57 (td, 1H, J = 9.7, 5.0 Hz, H-5); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 165.4 (C=O), 136.8 (C
F), 78.8 (C-4), 71.7 (C-3), 69.5 (d, J = 20.2 Hz, CH
, 400 MHz): δ 5.89 (t, 0.17H, J = 9.9 Hz, H-3), 5.53 (s, 0.17H, CHPh), 5.12 (d, 0.17H, J = 3.6 Hz,
q
Ph), 133.5, 130.0 (CHarom), 129.5 (C
q
Bz), 129.2, 128.6,
28.5, 128.3, 126.3, 126.2 (CHarom), 103.0 (C-1), 101.6 (CHPh), 82.5 (d, J = 170.5 Hz, CH
6.7 (C-5), 64.9 (C-2); Diagnostic peaks α-anomer: H NMR (CDCl
2
2
-CH
2
F), 68.5 (C-6),
1
3
1
3
H-1), 4.33 (dd, 0.17H, J = 10.4, 5.0 Hz, H-6), 3.38 (dd, 0.17H, J = 10.4, 3.6 Hz, H-2); C-APT NMR (CDCl
7
3
, 101 MHz): δ 101.8, 99.5 (C-1), 82.4 (d, J = 170.8 Hz),
9.6, 68.9, 67.8 (d, J = 20.2 Hz), 63.1, 61.8; HRMS: [M+NH ] calcd for C22H26FN O 461.18309 found 461.18292.
+
4
4
6
Methyl 4-O-(2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-α-ᴅ-glucopyranoside (4E). Donor 4 and acceptor 26
were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography
(19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 4E (60 mg, 71 µmol, 71%, α:β = 1:6) as a white solid. R : 0.67 (4/1 pentane/EtOAc). IR (thin film): 696,
33, 914, 999, 1026, 1045, 1090, 1177, 1263, 1314, 1366, 1452, 1730, 2108, 2866, 2899; Data for the β-anomer: H NMR (CDCl , 400 MHz, HH-COSY, HSQC,
3
HMBC): δ 8.10 – 8.04 (m, 2H, CHarom), 7.61 – 7.53 (m, 1H, CHarom), 7.49 – 7.24 (m, 22H, CHarom), 5.40 (s, 1H, CHPh), 5.19 (t, 1H, J = 9.8 Hz, H-3’), 4.90 (d, 1H, J =
10.8 Hz, CHH Bn), 4.83 (d, 1H, J = 10.8 Hz, CHH Bn), 4.81 – 4.73 (m, 2H, 2xCHH Bn), 4.67 – 4.60 (m, 2H, CHH Bn, H-1), 4.42 (d, 1H, J = 12.0 Hz, CHH Bn), 4.31
2
2
f
1
7
(
d, 1H, J = 8.0 Hz, H-1’), 4.17 (dd, 1H, J = 10.6, 5.0 Hz, H-6’), 4.08 – 3.98 (t, 1H, J = 9.4 Hz, H-4), 3.96 (dd, 1H, J = 10.8, 2.4 Hz, H-6), 3.86 (t, 1H, J = 9.3 Hz, H-3),
.79 – 3.74 (m, 1H, H-5), 3.71 (dd, 1H, J = 10.7, 1.7 Hz, H-6), 3.61 (t, 1H, J = 9.5 Hz, H-4’), 3.54 (dd, 1H, J = 9.6, 3.7 Hz, H-2), 3.52 – 3.45 (m, 2H, H-2’, H-6’), 3.39
3
13
(s, 3H, CH
3
OMe), 3.08 (td, 1H, J = 9.7, 5.0 Hz, H-5’); C-APT NMR (CDCl
Bz), 128.6, 128.5, 128.5, 128.3, 128.3, 128.2, 127.9, 127.8, 126.2 (CHarom), 101.5, 101.4 (CHPh, C-1’), 98.4 (C-1), 80.1 (C-3), 79.1 (C-2),
8.9 (C-4’), 76.8 (C-4), 75.6, 73.7, 73.6 (CH Bn), 72.0 (C-3’), 69.7 (C-5), 68.6 (C-6’), 67.8 (C-6), 66.1 (C-5’), 65.6 (C-2’), 55.5 (OMe); Diagnostic peaks α-anomer:
, 400 MHz): δ 5.91 (d, 0.17H, J = 3.9 Hz, H-1’), 5.80 (t, 0.17H, J = 10.0 Hz, H-3’), 5.47 (s, 0.17H, CHPh), 5.15 (d, 0.17H, J = 10.7 Hz, CHH Bn),
3 q
, 101 MHz, HSQC, HMBC): δ 165.3 (C=O), 139.3, 138.3, 137.6, 136.9 (C ), 133.4,
129.9 (CHarom), 128.9 (C
q
7
2
1
H NMR (CDCl
3
.74 (d, 0.17H, J = 12.0 Hz, CHH Bn), 4.09 (t, 0.17H, J = 9.2 Hz), 3.29 (dd, 0.17H, J = 10.5, 3.9 Hz, H-2’); C-APT NMR (CDCl , 101 MHz): δ 165.6, 138.6, 138.1,
3
1
3
4
12
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
137.9, 137.0, 133.4, 130.0, 129.6, 129.0, 128.6, 128.6, 128.5, 128.4, 128.2, 128.1, 127.6, 127.6, 127.4, 101.6 (CHPh), 98.6 (C-1’), 97.7 (C-1), 82.1, 80.7, 79.5, 75.0,
+
73.6, 73.3, 72.8, 69.5, 69.3, 68.9, 68.7, 63.7, 61.9, 55.5; HRMS: [M+NH
4
]
calcd for C48
53
H N
4
O
11 861.37053, found 861.37081.
Methyl (Methyl 4-O-[2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl]-2,3-di-O-benzyl-α-ᴅ-glucopyranosyl uronate) (4F). Donor 4 and
acceptor 27 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column
chromatography (19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 4F (46 mg, 59 µmol, 59%, α:β = 1:1.4) as a white solid. R : 0.56 (4/1 pentane/EtOAc). IR
thin film): 698, 750, 991, 1026, 1047, 1092, 1178, 1263, 1452, 1730, 2110, 2868, 2938; Reported as a 0.7 : 1 mixture of anomers: H NMR (CDCl , 400 MHz, HH-
COSY, HSQC, HMBC): δ 8.09 – 8.03 (m, 3.4H, CHarom), 7.61 – 7.52 (m, 1.7H, CHarom), 7.49 – 7.25 (m, 28.9H, CHarom), 5.76 (dd, 0.7H, J = 9.5, 10.3 Hz, H-3’ ), 5.70
(d, 0.7H, J = 3.9 Hz, H-1’ ), 5.47 (s, 0.7H, CHPh ), 5.41 (s, 1H, CHPh ), 5.36 (t, 1H, J = 9.8 Hz, H-3’ ), 5.10 (d, 0.7H, J = 10.6 Hz, CHH Bn ), 4.93 (d, 1H, J = 10.9
Hz, CHH Bn ), 4.87 (d, 1H, J = 10.9 Hz, CHH Bn ), 4.83 (d, 0.7H, J = 10.6 Hz, CHH Bn ), 4.79 (d, 1H, J = 13.6 Hz, CHH Bn ), 4.76 (d, 0.7H, J = 13.6 Hz, CHH Bn ),
.66 – 4.62 (m, 2H, CHH Bn , H-1’ ), 4.61 – 4.58 (m, 2.4H, CHH Bn , H-1 , H-1 ), 4.31 (dd, 0.7H, J = 10.0, 4.6 Hz, H-6’ ), 4.28 (d, 0.7H, J = 9.7 Hz, H-5 ), 4.23 (d,
1H, J = 9.9 Hz, H-5 ), 4.19 – 4.06 (m, 3.4H, H-3 , H-4 , H-4 , H-6’ ), 3.91 (t, 1H, J = 9.2 Hz, H-3), 3.85 (s, 2.1H, CH CO Me ), 3.83 (s, 3H, CH CO Me ), 3.79 –
, H-4’ , H-4’ , H-5’ , H-6’ ), 3.59 – 3.44 (m, 4H, H-2 , H-2’ , H-5’ , H-6’ ), 3.43 (s, 3H, CH OMe ), 3.42 (s, 2.1H, CH OMe ), 3.31 (dd, 1H, J =
); C-APT NMR (CDCl , 101 MHz, HSQC, HMBC): δ 170.2, 169.9 (C=O CO Me), 165.5, 165.3 (C=O Bz), 139.1, 138.4, 138.0, 137.7, 137.0,
Bn, CHPh), 133.4, 133.4, 130.0, 130.0 (CHarom), 129.5, 129.5 (C Bz), 129.1, 129.1, 128.7, 128.6, 128.5, 128.5, 128.5, 128.3, 128.3, 128.2, 128.1, 127.8,
27.7, 127.6, 127.5, 126.2, 126.2 (CHarom), 102.3 (C-1’ ), 101.7 (CHPh ), 101.5 (CHPh ), 99.0 (C-1’ ), 98.8 (C-1 ), 98.5 (C-1 ), 81.1 (C-3 ), 79.9 (C-2 ), 79.5, 79.5 (C-
, C-4 ), 79.2 (C-4’ ), 78.9, 78.7 (C-2 , C-4’ ), 75.7, 75.4 (CH Bn), 75.2 (C-4 ), 73.9, 73.6 (CH Bn), 71.9 (C-3’ ), 69.8, 69.8 (C-5 , C-5 ), 69.6 (C-3’ ), 68.5, 68.4 (C-
, C-6’ ), 66.5 (C-5’ ), 65.6 (C-2’ ), 63.2 (C-5’ ), 61.7 (C-2’ ), 56.0, 56.0 (CH OMe), 53.1, 53.0 (CH CO Me); HRMS: [M+NH calcd for C42 12 799.31850,
found 799.31869.
2
2
f
1
(
3
α
α
α
β
β
α
β
β
α
β
α
4
β
β
α
α
β
α
α
β
α
α
β
β
3
2
α
3
2
β
3
1
.59 (m, 3.8H, H-2
0.4, 3.9 Hz, H-2’
α
α
β
α
α
β
β
β
β
3
β
3
α
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
13
α
3
2
136.8 (C
q
q
1
3
6’
β
α
β
α
β
α
α
α
β
β
α
β
β
2
α
2
β
α
β
α
+
α
β
β
β
α
α
3
3
2
4
]
47 4
H N O
2
,2-Difluoroethyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-
procedure for Tf O/Ph SO mediated glycosylations and purified by flash column chromatography (1/1/0 to 0/1/0 to 0/19/1 pentane/toluene/EtOAc) to yield
glycosylation product 4G (38.6 mg, 84 µmol, 84%, α:β = 2.7:1) as a white solid. R : 0.49 (19/1 toluene/EtOAc). IR (thin film): 709, 997, 1026, 1069, 1094, 1265, 1726,
, 400 MHz, HH-COSY, HSQC): δ 8.11 – 8.05 (m, 2H, CHarom), 7.63 – 7.53 (m, 1H, CHarom), 7.50 – 7.36 (m, 4H,
CHarom), 7.34 – 7.27 (m, 3H, CHarom), 6.02 (tt, 1H, J = 55.1, 4.2 Hz, CHF ), 5.91 – 5.81 (m, 1H, H-3), 5.53 (s, 1H, CHPh), 5.11 (d, 1H, J = 3.6 Hz, H-1), 4.33 (dd, 1H, J
= 10.4, 4.9 Hz, H-6), 4.07 (ddd, 1H, J = 14.8, 6.4, 3.7 Hz, H-5), 3.99 – 3.77 (m, 4H, H-4, H-6), 3.42 (dd, 1H, J = 10.4, 3.6 Hz, H-2); C-APT NMR (CDCl
HSQC): δ 165.5 (C=O Bz), 136.8 (C ), 133.5, 130.1 (CHarom), 129.5 (C Bz), 128.5, 128.3, 126.2 (CHarom), 113.7 (t, J = 241.7 Hz, CHF ), 101.8 (CHPh), 99.8 (C-1),
9.4 (C-4), 69.3 (C-3), 68.7 (C-6), 67.6 (t, J = 29.0 Hz, CH -CHF ), 63.5 (C-5), 61.8 (C-2); Data for the β-anomer: H NMR (CDCl , 400 MHz): δ 5.97 (tdd, 0.37H, J =
), 5.51 (s, 0.37H, CHPh), 5.42 (t, 0.37H, J = 9.8 Hz, H-3), 4.63 (d, 0.37H, J = 7.9 Hz, H-1), 4.38 (dd, 0.37H, J = 10.5, 5.0 Hz, H-6), 4.12 – 3.99
D-glucopyranoside (4G). Donor 4 and 2,2-difluoroethanol were condensed using the general
2
2
f
1
2108, 2870; Data for the α-anomer: H NMR (CDCl
3
2
1
3
3
, 101 MHz,
q
q
2
1
7
2
2
3
55.2, 4.8, 3.5 Hz, CHF
2
1
3
(
(
m, 0.37H, CHH-CHF
CDCl , 101 MHz): δ 165.4, 136.7, 133.5, 130.0, 129.4, 129.2, 128.6, 126.2, 113.8 (t, J = 241.5 Hz), 103.1, 101.7, 78.7 (C-4), 71.5 (C-3), 69.1 (t, J = 29.0 Hz, CH
), 68.4 (C-6), 66.8 (C-5), 64.9 (C-2); HRMS: [M+H] calcd for C22
2 2
), 3.98 – 3.76 (m, 1.11H, CHH-CHF , H-4, H-6), 3.69 (dd, 0.37H, J = 10.0, 7.9 Hz, H-2), 3.58 (td, 0.37H, J = 9.8, 5.0 Hz, H-5); C-APT NMR
3
2
-
+
CHF
2
22 2 3 6
H F N O 462.14712, found 462.14699.
Methyl 4-O-(2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-β-ᴅ-galactopyranoside (4H). Donor 4 and acceptor 28
were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column chromatography
19/1 to 4/1 pentane/EtOAc) to yield glycosylation product 4H (43 mg, 52 µmol, 52%, α:β = 4:1) as a white solid. R : 0.36 (4/1 pentane/EtOAc). IR (thin film): 698,
, 400 MHz, HH-COSY, HSQC, HMBC): δ 8.12 – 8.05 (m, 2H,
2
2
(
7
f
1
37, 997, 1072, 1094, 1265, 1452, 1730, 2106, 2862, 2930; Data for the α-anomer: H NMR (CDCl
3
CHarom), 7.57 (t, 1H, J = 7.4 Hz, CHarom), 7.45 (t, 2H, J = 7.7 Hz, CHarom), 7.42 – 7.20 (m, 20H, CHarom), 5.85 (t, 1H, J = 9.9 Hz, H-3’), 5.44 (s, 1H, CHPh), 5.07 (d, 1H,
J = 3.9 Hz, H-1’), 4.93 (d, 1H, J = 11.0 Hz, CHH Bn), 4.84 (d, 1H, J = 10.9 Hz, CHH Bn), 4.79 (d, 1H, J = 12.4 Hz, CHH Bn), 4.74 (d, 1H, J = 12.4 Hz, CHH Bn),
4
1
2
.55 (s, 2H, CH
2
Bn), 4.46 (td, 1H, J = 9.9, 4.9 Hz, H-5’), 4.26 (d, 1H, J = 7.6 Hz, H-1), 4.17 (d, 1H, J = 3.1 Hz, H-4), 3.93 (t, 1H, J = 9.1 Hz, H-6), 3.85 (dd, 1H, J =
OMe, H-5, H-6’), 3.47 (dd, 1H, J = 10.4, 3.9 Hz, H-
, 101 MHz, HSQC, HMBC): δ 165.3 (C=O Bz), 138.7, 138.3, 137.6, 137.2 (C ), 133.3, 130.0 (CHarom),
), 128.9, 128.7, 128.6, 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 127.9, 127.7, 127.6, 127.6, 126.3, 126.2 (CHarom), 105.2 (C-1), 101.4
CHPh), 99.4 (C-1’), 80.0 (C-4’), 79.8 (C-3), 79.0 (C-2), 75.2 (CH Bn), 74.4 (C-4), 73.6, 73.2 (CH Bn), 72.6 (C-5), 70.2 (C-3’), 68.8 (C-6’), 67.1 (C-6), 62.8, 62.7
C-2’, C-5’), 57.0 (OMe); Diagnostic peaks β-anomer: H NMR (CDCl , 400 MHz): δ 5.47 (s, 0.25H, CHPh), 5.34 (t, 0.25H, J = 9.8 Hz, H-3’), 4.30 (d, 0.25H, J = 7.7
, 101 MHz): δ 105.1 (C-1), 102.7 (C-1’), 101.5 (CHPh), 81.2, 79.6, 78.9, 75.3, 74.6, 73.9, 73.6,
calcd for C48 11 861.37053, found 861.37067.
0.2, 5.0 Hz, H-6’), 3.81 – 3.70 (m, 2H, H-2, H-4’), 3.64 (dd, 2H, J = 9.1, 5.4 Hz, H-6), 3.57 – 3.50 (m, 5H, CH
’), 3.42 (dd, 1H, J = 10.0, 3.0 Hz, H-3); C-APT NMR (CDCl
3
1
3
3
q
129.8 (C
(
(
q
2
2
1
3
1
3
Hz, H-1’), 4.09 (d, 0.25H, J = 2.7 Hz, H-4); C-APT NMR (CDCl
3
+
73.3, 71.7, 69.4, 68.5, 66.2, 65.0, 57.3; HRMS: [M+NH
4
]
53 4
H N O
Methyl 2-O-(2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α/β-ᴅ-glucopyranosyl)-3-O-benzyl-4,6-O-benzylidene-α-ᴅ-mannopyranoside (4I). Donor 4 and
acceptor 29 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 h at -40°C) and purified by flash column
chromatography (19/1 to 3/1 pentane/EtOAc) to yield glycosylation product 4I (55 mg, 73 µmol, 73%, α:β = 5:1) as a white solid. R
2
2
f
: 0.36 (4/1 pentane/EtOAc). IR
, 400 MHz, HH-COSY, HSQC, HMBC): δ 8.15 – 8.04 (m, 2H, CHarom), 7.59 – 7.53
1
(thin film): 671, 750, 1037, 1092, 1265, 1373, 1730, 2108, 2913; H NMR (CDCl
3
(
m, 1H, CHarom), 7.53 – 7.25 (m, 17H, CHarom), 5.92 (dd, 1H, J = 10.4, 9.5 Hz, H-3’), 5.67 (s, 1H, CHPh), 5.54 (s, 1H, CHPh’), 5.51 (d, 1H, J = 3.8 Hz, H-1’), 4.94 (d,
H, J = 12.2 Hz, CHH Bn), 4.73 (d, 1H, J = 1.5 Hz, H-1), 4.69 (d, 1H, J = 12.2 Hz, CHH Bn), 4.39 (t, 1H, J = 9.7 Hz, H-4), 4.32 (dd, 1H, J = 10.4, 4.9 Hz, H-6’), 4.27
(dd, 1H, J = 10.3, 4.7 Hz, H-6), 4.14 (dd, 1H, J = 3.1, 1.6 Hz, H-2), 4.06 – 3.99 (m, 2H, H-3, H-5’), 3.95 (t, 1H, J = 10.3 Hz, H-6), 3.86 – 3.77 (m, 3H, H-4’, H-5, H-
1
1
3
6
1
(
’), 3.38 – 3.33 (m, 4H, CH
29.2, 128.9, 128.5, 128.4, 128.3, 128.3, 128.3, 128.3, 127.6, 127.6, 127.4, 126.2, 126.2, 126.2, 126.1 (CHarom), 101.7, 101.6 (CHPh), 100.9 (C-1), 100.1 (C-1’), 79.7
Bn), 69.2 (C-3’), 68.9 (C-6), 68.8 (C-6’), 64.1 (C-5), 63.3 (C-5’), 61.9 (C-2’), 54.9 (OMe); Diagnostic peaks β-
, 400 MHz): δ 5.60 (s, 0.2H, CHPh), 5.50 (s, 0.2H, CHPh), 5.40 (t, 0.2H, J = 9.8 Hz, H-3’), 4.87 (d, 0.2H, J = 1.4 Hz, H-1), 4.80 (d, 0.2H, J =
3 3 q q
OMe, H-2’); C-APT NMR (CDCl , 101 MHz, HSQC): δ 165.5 (C=O Bz), 138.8, 137.7, 136.8 (C ), 133.4, 130.1 (CHarom), 129.6 (C ),
C-4’), 79.5 (C-4), 75.9, 75.9 (C-2, C-3), 73.6 (CH
2
1
anomer: H NMR (CDCl
1
7
3
13
2.3 Hz, CHH Bn), 3.57 (td, 0.2H, J = 9.9, 4.3 Hz), 3.40 (s, 0.6H, CH
6.4, 74.4, 72.4, 71.5, 68.9, 68.5, 66.9, 65.1, 64.2, 55.2; HRMS: [M+NH
3
OMe); C-APT NMR (CDCl
3
, 101 MHz): δ 101.8 (C-1’), 100.0 (CHPh), 99.4 (C-1), 78.7, 78.5,
+
4
] calcd for C41H N O11 769.30793, found 769.30780.
45 4
2,2,2-Trifluoroethyl 2-azido-3-O-benzoyl-4,6-O-benzylidene-2-deoxy-α-
general procedure for Tf O/Ph SO mediated glycosylations (for an additional 30 min at -40°C) and purified by flash column chromatography (19/1 to 17/3
pentane/EtOAc) to yield glycosylation product 4J (41 mg, 86 µmol, 86%, α:β = > 20:1) as a white solid. R
D-glucopyranoside (4J). Donor 4 and 2,2,2-trifluoroethanol were condensed using the
2
2
: 0.15 (toluene). [α]ꢁ = +78.9° (c = 1.03, CHCl
ꢃ
); IR (thin
, 400 MHz, HH-COSY, HSQC): δ 8.13 – 8.03 (m, 2H, CHarom), 7.60 – 7.53 (m, 1H, CHarom),
.48 – 7.38 (m, 4H, CHarom), 7.33 – 7.28 (m, 3H, CHarom), 5.87 (t, 1H, J = 10.0 Hz, H-3), 5.53 (s, 1H, CHPh), 5.14 (d, 1H, J = 3.6 Hz, H-1), 4.33 (dd, 1H, J = 10.4, 4.9
f
ꢀ
3
1
film): 702, 989, 1085, 1177, 1275, 1717, 2112, 2864; H NMR (CDCl
3
7
13
Hz, H-6), 4.14 – 3.97 (m, 4H, CH
2
CF
3
, H-5), 3.84 (t, 1H, J = 9.5 Hz, H-4), 3.80 (t, 1H, J = 10.3 Hz, H-6), 3.44 (dd, 1H, J = 10.4, 3.6 Hz, H-2); C-APT NMR (CDCl
), 133.5, 130.0 (CHarom), 129.5 (C Bz), 129.2, 128.5, 127.6, 126.2 (CHarom), 123.42 (q, J = 278.6 Hz), 101.8 (CHPh), 99.9
C-1), 79.3 (C-4), 69.1 (C-3), 68.6 (C-6), 65.41 (q, J = 35.6 Hz), 63.7 (C-5), 61.6 (C-2); HRMS: [M+NH
3
,
101 MHz, HSQC): δ 165.5 (C=O), 136.7 (C
q
q
+
(
4 24 3 4 6
] calcd for C22H F N O 497.16425 found 497.16425.
Ethyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-
procedure for Tf O/Ph SO mediated glycosylations (for an additional 1 hour at -40°C) and purified by flash column chromatography (19/1 to 8/2 pentane/EtOAc) to
yield glycosylation product 5A (32 mg, 59 µmol, 59%, α:β = <1:20) as a yellow solid alongside donor 5 (14 mg). R
D-glucopyranoside (5A). Donor 5 and ethanol were condensed using the general
2
2
ꢁꢂ
f
: 0.60 (7/3 pentane/EtOAc). [α]ꢀ = +156.9° (c =
, 400 MHz, HH-COSY, HSQC): δ 8.58 (s, 2H, CH pyridone), 7.56
dd, 2H, J = 7.4, 2.2 Hz, CHarom), 7.45 – 7.38 (m, 3H, CHarom), 7.06 – 6.97 (m, 5H, CHarom), 5.66 (s, 1H, CHPh), 5.32 (d, 1H, J = 8.3 Hz, H-1), 4.70 (d, 1H, J = 11.7 Hz,
CHH Bn), 4.57 (dd, 1H, J = 10.2, 8.7 Hz, H-3), 4.53 (d, 1H, J = 11.6 Hz, CHH Bn), 4.43 (dd, 1H, J = 10.3, 4.6 Hz, H-6), 3.99 – 3.81 (m, 4H, CHH Et, H-4, H-5, H-6),
1
3 3
0.64, CHCl ); IR (thin film): 698, 998, 1093, 1213, 1303, 1330, 1516, 1679, 2930; H NMR (CDCl
(
1
3
3.72 (dd, 1H, J = 10.3, 8.3 Hz, H-2), 3.60 (dq, 1H, J = 9.9, 7.1 Hz, CHH Et), 1.08 (t, 3H, J = 7.1 Hz, CH
3
Et); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 160.6
(
(
C=O pyridone), 141.7 (C
C-4), 75.4 (C-3), 74.9 (CH
q
NO
2
pyridone), 141.4 (CH pyridone), 137.1, 136.6 (C
3 28 3
Et), 65.7 (C-5), 15.1 (CH Et); HRMS: [M+H] calcd for C27H N O10 554.17692, found 554.17642.
q
), 129.4, 128.9, 128.7, 128.5, 128.5, 126.3 (CHarom), 101.9 (CHPh), 99.3 (C-1), 82.8
+
2
Bn), 73.8 (C-2), 68.7 (C-6), 66.5 (CH
2
Cyclohexyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-
general procedure for Tf O/Ph SO mediated glycosylations (for an additional 1 hour at -40°C) and purified by flash column chromatography (19/1 to 8/2
pentane/EtOAc) to yield 51 mg of glycosylation product 5B as an inseperable mixture with donor 5 (13 mg 5, 38 mg 5B, 63 µmol, 63%, α:β =< 1:20) as a yellow solid.
D-glucopyranoside (5B). Donor 5 and cyclohexanol were condensed using the
2
2
1
R
f
: 0.75 (7/3 pentane/EtOAc). R
(CDCl , 400 MHz, HH-COSY, HSQC): δ 8.60 (s, 2H, CH pyridone), 7.56 (d, 2H, J = 4.7 Hz, CHarom), 7.48 – 7.33 (m, 3H, CHarom), 7.10 – 6.96 (m, 5H, CHarom), 5.65 (s,
H, CHPh), 5.41 (d, 1H, J = 8.2 Hz, H-1), 4.71 (d, 1H, J = 11.7 Hz, CHH Bn), 4.66 – 4.50 (m, 2H, CHH Bn, H-3), 4.44 (dd, 1H, J = 10.6, 5.2 Hz, H-6), 3.98 – 3.80 (m,
H, H-4, H-5, H-6), 3.79 – 3.61 (m, 2H, CH Cy, H-2), 1.91 – 1.77 (m, 1H, CH Cy), 1.71 – 1.54 (m, 2H, CH Cy), 1.54 – 1.45 (m, 1H, CH Cy), 1.43 – 0.96 (m, 6H,
pyridone), 141.4 (CH pyridone), 137.1, 136.7 (C ), 128.8, 128.6, 128.4,
f
: 0.55 (7/3 pentane/EtOAc); IR: (thin film): 697, 718, 749, 789, 910, 997, 1092, 1212, 1302, 1330, 1516, 1623, 1674, 2931; H NMR
3
1
3
CH
2
2
2
13
2
Cy); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 160.5 (C=O pyridone), 141.6 (C
q
NO
2
q
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
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2
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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
2 2
126.3 (CHarom), 101.9 (CHPh), 98.1 (C-1), 82.7 (C-4), 78.8 (CH Cy), 75.6 (C-3), 74.8 (CH Bn), 74.0 (C-2), 68.8 (C-6), 65.7 (C-5), 33.3, 31.7, 25.3, 23.9, 23.6 (CH
Cy); HRMS: [M+H] calcd for C31H N O10 608.22387, found 608.22352.
34 3
+
Methyl 6-O-(3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-ᴅ-glucopyranosyl)-2,3,4-tri-O-benzyl-α-ᴅ-glucopyranoside (3C). Donor 5 and
acceptor 25 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash column
chromatography (9/1 to 7/3 pentane/EtOAc) to yield glycosylation product 5C (55 mg, 54 µmol, 54%, α:β = <1:20) as a yellow solid. R : 0.45 (7/3 pentane/EtOAc).
, 400 MHz, HH-COSY, HSQC,
2
2
f
ꢁ
ꢃ
1
[
ꢀ
3 3
α] = +90.5° (c = 0.92, CHCl ); IR (thin film): 698, 1001, 1069, 1094, 1213, 1331, 1454, 1522, 1678, 2868; H NMR (CDCl
HMBC): δ 8.19 (s, 2H, CH pyridone), 7.54 (dd, 2H, J = 7.6, 2.1 Hz, CHarom), 7.45 – 7.38 (m, 3H, CHarom), 7.34 – 7.22 (m, 13H, CHarom), 7.20 – 7.12 (m, 5H, CHarom),
7.04 (dd, 2H, J = 6.6, 2.9 Hz, CHarom), 5.66 (s, 1H, CHPh), 4.92 (d, 1H, J = 11.0 Hz, CHH Bn), 4.85 (d, 1H, J = 8.3 Hz, H-1’), 4.83 – 4.66 (m, 2H, 2xCHH Bn), 4.72 (d,
1
4
H, J = 10.9 Hz, CHH Bn), 4.69 (d, 1H, J = 12.0 Hz, CHH Bn), 4.60 (d, 1H, J = 12.2 Hz, CHH Bn), 4.60 (d, 1H, J = 12.0 Hz, CHH Bn), 4.46 (d, 1H, J = 3.4 Hz, H-1),
.39 (dd, 1H, J = 10.6, 5.0 Hz, H-6’), 4.34 (d, 1H, J = 11.3 Hz, CHH Bn), 4.10 (t, 1H, J = 7.9 Hz, H-3’), 4.01 (dd, 1H, J = 10.8, 1.8 Hz, H-6), 3.91 (t, 1H, J = 9.2 Hz,
H-3), 3.89 – 3.82 (m, 2H, H-4’, H-6), 3.77 – 3.69 (m, 2H, H-2’, H-5), 3.65 (td, 1H, J = 9.7, 5.0 Hz, H-5’), 3.52 (dd, 1H, J = 10.8, 7.1 Hz, H-6), 3.39 (dd, 1H, J = 9.6,
1
3
3
.5 Hz, H-2), 3.21 (s, 3H, CH
pyridone), 140.2 (CH pyridone), 138.6, 138.0, 138.0, 136.7, 135.8 (C
126.1 (CHarom), 101.8 (CHPh), 100.1 (C-1’), 97.9 (C-1), 82.3 (C-4’), 81.6 (C-3), 79.8 (C-2), 78.2 (C-4), 75.7, 74.8, 74.3, (CH
3
OMe), 3.13 (dd, 1H, J = 9.9, 8.9 Hz, H-4); C-APT NMR (CDCl
), 129.5, 129.1, 129.0, 128.6, 128.5, 128.5, 128.5, 128.2, 128.1, 128.0, 128.0, 127.9, 127.7, 127.6,
Bn), 74.0 (C-3’), 73.3 (CH Bn), 72.7
, 101 MHz): δ 100.1 (J = 163 Hz, C-1’); HRMS: [M+H] calcd
3 q 2
, 101 MHz, HSQC, HMBC): δ 159.4 (C=O pyridone), 141.7 (C NO
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
q
2
2
13
+
(
C-2’), 70.4 (C-6), 69.3 (C-5), 68.4 (C-6’), 66.1 (C-5’), 55.1 (OMe); C-HMBC-GATED NMR (CDCl
3
for C53 15 972.35494, found 972.35546.
54 3
H N O
2
-Fluoroethyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-
the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 1 hour at -40°C) and purified by flash column chromatography (19/1 to 8/2
pentane/EtOAc) to yield glycosylation product 5D (24 mg, 43 µmol, 43%, α:β =< 1:20) as a yellow solid alongside donor 5 (15.6 mg). R : 0.42 (3/2 pentane/EtOAc).
, 400 MHz, HH-COSY, HSQC):
D-glucopyranoside (5D). Donor 5 and 2-fluoroethanol were condensed using
2
2
f
ꢁ
ꢂ
1
ꢀ
3 3
[α] = +142.9° (c = 0.48, CHCl ); IR (thin film): 698, 752, 1070, 1096, 1213, 1304, 1331, 1518, 1680, 2870, 3064; H NMR (CDCl
δ 8.58 (s, 2H, CH pyridone), 7.63 – 7.49 (m, 2H, CHarom), 7.47 – 7.36 (m, 3H, CHarom), 7.09 – 6.96 (m, 5H, CHarom), 5.66 (s, 1H, CHPh), 5.46 (d, 1H, J = 8.3 Hz, H-1),
4.71 (d, 1H, J = 11.7 Hz, CHH Bn), 4.57 (dd, 1H, J = 10.3, 8.7 Hz, H-3), 4.53 (d, 1H, J = 11.7 Hz, CHH Bn), 4.48 – 4.42 (m, 2H, CHHF, H-6), 4.33 (t, 1H, J = 4.1 Hz,
1
3
CHHF), 4.09 – 3.81 (m, 5H, CH
41.5, 141.5 (C NO , CH pyridone), 137.0, 136.6 (C
CH F), 75.3 (C-3), 74.9 (CH Bn), 73.6 (C-2), 69.5 (d, J = 19.5 Hz, CH
72.16705.
2
-CH
2
F, H-4, H-5, H-6), 3.77 (dd, 1H, J = 10.3, 8.4 Hz, H-2); C-APT NMR (CDCl
3
, 101 MHz, HSQC): δ 160.6 (C=O pyridone),
1
q
2
q
), 129.4, 129.0, 128.7, 128.6, 128.5, 126.3 (CHarom), 101.9 (CHPh), 99.8 (C-1), 82.7 (C-4), 82.5 (d, J = 169.4 Hz,
+
2
2
2 2 3
-CH F), 68.6 (C-6), 65.8 (C-5); HRMS: [M+H] calcd for C27H27FN O10 572.16760, found
5
Methyl 4-O-(3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-α-ᴅ-glucopyranoside (5E). Donor 5 and
acceptor 26 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash column
chromatography (9/1 to 7/3 pentane/EtOAc) to yield glycosylation product 5E (54 mg, 56 µmol, 56%, α:β = <1:20) as a yellow solid. R : 0.37 (7/3 pentane/EtOAc).
2
2
f
ꢁ
ꢂ
1
[
ꢀ
3 3
α] = +83.3° (c = 0.84, CHCl ); IR (thin film): 696, 734, 997, 1028, 1039, 1092, 1209, 1302, 1327, 1454, 1522, 1682, 2862, 2900, 3030, 3065; H NMR (CDCl , 500
MHz, HH-COSY, HSQC, HMBC, NOESY): δ 7.74 (s, 2H, CH pyridone), 7.57 – 7.53 (m, 2H, CHarom), 7.49 – 7.38 (m, 8H, CHarom), 7.36 – 7.25 (m, 13H, CHarom), 7.04
– 7.00 (m, 2H, CHarom), 5.57 (s, 1H, CHPh), 4.90 (d, 1H, J = 11.7 Hz, CHH Bn), 4.77 (d, 1H, J = 12.1 Hz, CHH Bn), 4.74 (d, 1H, J = 12.3 Hz, CHH Bn), 4.69 (d, 1H, J
=
11.7 Hz, CHH Bn), 4.66 (d, 1H, J = 12.0 Hz, CHH Bn), 4.63 (d, 1H, J = 12.1 Hz, CHH Bn), 4.56 (d, 1H, J = 12.3 Hz, CHH Bn), 4.54 (d, 1H, J = 3.6 Hz, H-1), 4.35
d, 1H, J = 8.2 Hz, H-1’), 4.27 – 4.20 (m, 2H, CHH Bn, H-6’), 3.92 (t, 1H, J = 9.5 Hz, H-4), 3.70 (t, 1H, J = 9.3 Hz, H-3), 3.67 (t, 1H, J = 9.0 Hz, H-4’), 3.58 (t, 1H, J
= 10.4 Hz, H-6’), 3.53 – 3.45 (m, 2H, H-2, H-3’), 3.43 (dd, 1H, J = 11.4, 1.5 Hz, H-6), 3.40 – 3.34 (m, 1H, H-5), 3.31 (s, 2H, CH OMe), 3.18 (dd, 1H, J = 10.5, 8.3 Hz,
, 126 MHz, HSQC, HMBC): δ 159.3 (C=O pyridone), 141.8 (C
), 129.6, 129.3, 129.2, 129.0, 128.9, 128.6, 128.6, 128.5, 128.4, 128.1, 128.1, 127.8, 126.1
(CHarom), 101.8 (CHPh), 98.1 (C-1), 97.6 (C-1’), 82.4 (C-4’), 79.7 (C-2), 79.2 (C-3), 75.3 (CH Bn), 74.4 (C-4), 73.9, 73.6, 73.5 (CH Bn), 73.0 (C-3’), 72.5 (C-2’),
15 972.35494, found 972.35519.
(
3
1
3
H-2’), 3.04 (dd, 1H, J = 11.3, 2.6 Hz, H-6), 2.92 (td, 1H, J = 9.8, 5.1 Hz, H-5’); C-APT NMR (CDCl
NO pyridone), 139.6 (CH pyridone), 139.4, 138.1, 137.8, 136.8, 135.7 (C
3
q
2
q
2
2
+
6
54 3
9.2 (C-5), 68.4 (C-6’), 68.1 (C-6), 65.6 (C-5’), 55.7 (OMe); HRMS: [M+H] calcd for C53H N O
Methyl (Methyl 4-O-[3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-α/β-ᴅ-glucopyranosyl]-2,3-di-O-benzyl-α-ᴅ-glucopyranosyl uronate)
5F). Donor 5 and acceptor 27 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified
by flash column chromatography (9/1 to 7/3 pentane/EtOAc) to yield glycosylation product 5F (27 mg, 30 µmol, 30%, α:β = 1:3.6) as a yellow solid. R : 0.51 (7/3
pentane/EtOAc). IR (thin film): 648, 698, 733, 789, 910, 995, 1090, 1171, 1209, 1302, 1331, 1454, 1520, 1678, 1744, 2932; Data for the β-anomer: H NMR (CDCl
(
2
2
f
1
3
,
5
7
4
00 MHz, HH-COSY, HSQC, HMBC): δ 8.06 (s, 2H, CH pyridone), 7.50 (dd, 2H, J = 7.3, 2.0 Hz, CHarom), 7.45 – 7.35 (m, 6H, CHarom), 7.33 – 7.18 (m, 9H, CHarom),
.03 (dd, 2H, J = 6.9, 2.2 Hz, CHarom), 6.96 (dd, 1H, J = 14.5, 6.9 Hz, CHarom), 5.55 (s, 1H, CHPh), 5.17 (d, 1H, J = 8.2 Hz, H-1’), 4.92 (d, 1H, J = 11.3 Hz, CHH Bn),
.82 – 4.72 (m, 3H, CHH Bn, 2xCHH Bn), 4.61 – 4.55 (m, 2H, 2xCHH Bn), 4.51 (d, 1H, J = 3.3 Hz, H-1), 4.14 (dd, 1H, J = 10.6, 4.8 Hz, H-6’), 3.97 – 3.88 (m, 2H,
H-3’, H-4), 3.83 (d, 1H, J = 9.7 Hz, H-5), 3.82 – 3.73 (m, 2H, H-3, H-4’), 3.54 – 3.43 (m, 6H, CH
3
CO
Me), 159.5 (C=O pyridone), 141.5 (C
), 129.5, 129.2, 129.2, 129.1, 129.0, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.2, 128.2, 127.7, 127.7, 126.1, 126.0, 125.7 (CHarom), 101.7 (CHPh), 98.8 (C-
’), 98.3 (C-1), 82.3 (C-4’), 79.1 (C-3), 78.8 (C-2), 77.8 (C-4), 75.5, 74.2 (CH Bn), 74.0 (C-3’), 73.7 (CH Bn), 72.9 (C-2’), 68.8 (C-5), 68.2 (C-6’), 65.9 (C-5’), 56.1
, 101 MHz): δ 98.8 (J = 167 Hz, C-1’); Diagnostic peaks α-anomer: H NMR (CDCl
2
Me, H-2, H-2’, H-5’), 3.42 – 3.36 (m, 4H, CH
3
OMe, H-6’);
1
3
C-APT NMR (CDCl
35.7 (C
3
, 126 MHz, HSQC, HMBC): δ 170.0 (C=O CO
2
q
2
NO pyridone), 140.4 (CH pyridone), 139.1, 137.8, 136.7,
1
q
1
2
2
1
3
1
(OMe), 52.9 (CO
2
Me); C-HMBC-GATED NMR (CDCl
3
3
, 500 MHz, HH-COSY,
HSQC): δ 5.74 (d, 0.28H, J = 3.9 Hz, H-1’), 5.61 (s, 0.28H, CHPh), 5.03 (d, 0.28H, J = 12.7 Hz, CHH Bn), 4.70 (d, 0.28H, J = 12.3 Hz), 4.62 (d, 0.28H, J = 12.2 Hz,
CHH Bn), 4.46 (d, 0.28H, J = 12.3 Hz, CHH Bn), 4.37 (dd, 0.28H, J = 10.5, 4.9 Hz, H-6’), 4.29 (d, 0.28H, J = 9.9 Hz, H-5), 4.08 (t, 0.28H, J = 9.4 Hz), 3.69 (dd,
1
3
0.28H, J = 10.6, 3.9 Hz, H-2’); C-APT NMR (CDCl
6
9
3
, 126 MHz, HSQC): δ 169.7, 159.2, 141.2, 101.8 (CHPh), 96.8 (C-1’), 82.6, 80.7, 79.8, 74.5, 74.4, 73.1, 72.2,
1
3
+
9.6, 69.5, 68.1, 63.0, 56.1, 53.3; C-HMBC-GATED NMR (CDCl
10.30315.
3 48 3
, 101 MHz): δ 96.8 (J = 181 Hz, C-1’); HRMS: [M+H] calcd for C47H N O16 910.30291, found
2
,2-Difluoroethyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-α/β-
O/Ph SO mediated glycosylations (for an additional 1 hour at -40°C) and purified by flash column chromatography (19/1
to 8/2 pentane/EtOAc) to yield glycosylation product 5G (17.3 mg, 29 µmol α anomer, 17.8 mg 30 µmol β anomer. α:β = 1:1, 59%) as a yellow solids alongside donor
D-glucopyranoside (5G). Donor 5 and 2,2-difluoroethanol were
condensed using the general procedure for Tf
2
2
1
5
(11 mg). R
Acetone-d , 400 MHz, HH-COSY, HSQC): δ 8.91 (s, 2H, CH pyridone), 7.61 – 7.53 (m, 2H, CHarom), 7.48 – 7.37 (m, 3H, CHarom), 7.25 – 7.10 (m, 5H, CHarom), 6.16
tt, 1H, J = 55.0, 3.7 Hz, CHF ), 5.83 (s, 1H, CHPh), 5.56 (d, 1H, J = 3.7 Hz, H-1), 4.91 (d, 1H, J = 11.9 Hz, CHH Bn), 4.79 (dd, 1H, J = 10.7, 3.7 Hz, H-2), 4.71 –
.62 (m, 2H, CHH Bn, H-3), 4.37 (dd, 1H, J = 10.1, 4.9 Hz, H-6), 4.18 – 4.06 (m, 2H, CHH-CHF , H-5), 4.03 (dd, 1H, J = 9.6, 8.6 Hz, H-4), 3.96 – 3.83 (m, 2H, CHH-
NO pyridone), 142.6 (CH pyridone), 138.6, 138.5 (C ), 129.8, 129.2,
), 102.1 (CHPh), 98.8 (C-1), 83.5 (C-4), 75.0 (CH Bn), 74.7 (C-3), 69.9 (C-2), 68.9 (C-6), 67.93 (t, J
), 63.9 (C-5); Data for the β-anomer: H NMR (CDCl , 400 MHz, HH-COSY, HSQC): δ 8.67 (s, 2H, CH pyridone), 7.60 – 7.52 (m, 2H, CHarom),
7.46 – 7.37 (m, 3H, CHarom), 7.03 – 6.93 (m, 5H, CHarom), 5.75 (tt, 1H, J = 54.9, 3.9 Hz, CHF ), 5.65 (s, 1H, CHPh), 5.59 (d, 1H, J = 8.3 Hz, H-1), 4.76 – 4.64 (m, 2H,
CHH Bn, H-3), 4.50 (d, 1H, J = 11.6 Hz, CHH Bn), 4.45 (dd, 1H, J = 10.4, 4.9 Hz, H-6), 4.05 (td, 1H, J = 9.7, 5.0 Hz, H-5), 4.00 – 3.80 (m, 4H, CH -CHF , H-4, H-6),
pyridone), 141.5 (CH pyridone), 137.0, 136.7
Bn), 73.7 (C-2), 68.9 (t, J =
f
: 0.12 and 0.30 (7/3 pentane/EtOAc). IR (thin film): 698, 997, 1069, 1094, 1211, 1300, 1339, 1520, 1684, 2922; Data for the α-anomer: H NMR
(
(
4
6
2
2
13
CHF
2
, H-6); C-APT NMR (Acetone-d
6
, 101 MHz, HSQC): δ 160.0 (C=O pyridone), 142.9 (C
q
2
q
129.0, 129.0, 128.9, 127.0 (CHarom), 115.0 (t, J = 239.2 Hz, CHF
2
2
1
=
27.3 Hz, CH
2
-CHF
2
3
2
2
2
13
3
.77 (dd, 1H, J = 10.3, 8.4 Hz, H-2); C-APT NMR (CDCl
(C
7.8 Hz, CH
3
, 101 MHz, HSQC): δ 160.9 (C=O pyridone), 141.7 (C
q
NO
2
q
), 129.4, 128.8, 128.6, 128.5, 128.4, 126.4 (CHarom), 113.4 (t, J = 241.5 Hz, 102.0 (CHPh), 99.9 (C-1), 82.6 (C-4), 75.5 (C-3), 75.1 (CH
2
+
2
2
-CHF
2
), 68.6 (C-6), 65.8 (C-5); HRMS: [M+H] calcd for C27
H
26
2
F N
3
O
10 590.15808, found 590.15741.
Methyl 4-O-(3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-β-ᴅ-glucopyranosyl)-2,3,6-tri-O-benzyl-β-ᴅ-galactopyranoside (5H). Donor 5
and acceptor 28 were condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified by flash
column chromatography (9/1 to 7/3 pentane/EtOAc) to yield glycosylation product 5H (51 mg, 52 µmol, 52%, α:β = <1:20) as a yellow solid. R : 0.49 (7/3
, 400 MHz, HH-COSY,
HSQC, HMBC): δ 8.20 (s, 2H, CH pyridone), 7.55 – 7.49 (m, 2H, CHarom), 7.47 – 7.40 (m, 3H, CHarom), 7.40 – 7.15 (m, 18H, CHarom), 7.07 – 7.00 (m, 2H, CHarom),
.63 (s, 1H, CHPh), 5.03 (d, 1H, J = 8.3 Hz, H-1’), 4.80 (d, 1H, J = 12.2 Hz, CHH Bn), 4.64 (d, 1H, J = 10.4 Hz, CHH Bn), 4.61 (d, 1H, J = 12.3 Hz, CHH Bn), 4.57
(d, 1H, J = 12.2 Hz, CHH Bn), 4.50 (s, 2H, CH Bn), 4.47 (d, 1H, J = 12.3 Hz, CHH Bn), 4.29 (d, 1H, J = 10.4 Hz, CHH Bn), 4.20 (dd, 1H, J = 10.5, 5.0 Hz, H-6’),
.13 (d, 1H, J = 7.6 Hz, H-1), 3.91 (d, 1H, J = 2.6 Hz, H-4), 3.88 – 3.78 (m, 2H, H-3’, H-4’), 3.74 (t, 1H, J = 10.3 Hz, H-6’), 3.70 (dd, 1H, J = 9.9, 8.4 Hz, H-2’), 3.66
2
2
f
ꢁꢃ
1
3 3
pentane/EtOAc). [α]ꢀ = +35.5° (c = 0.85, CHCl ); IR (thin film): 698, 750, 999, 1072, 1094, 1213, 1454, 1522, 1682, 2868; H NMR (CDCl
5
2
4
–
13
3.52 (m, 2H, H-6, H-6), 3.46 (s, 4H, CH
pyridone), 141.6 (C
3
OMe, H-5), 3.41 – 3.33 (m, 2H, H-3, H-5’), 2.93 (dd, 1H, J = 9.6, 7.6 Hz, H-2); C-APT NMR (CDCl
3
, 101 MHz, HSQC,
HMBC): δ 159.4 (C
q
q
NO pyridone), 140.5 (CH pyridone), 138.2, 138.0, 137.6, 136.6, 135.6 (C ), 129.6, 129.3, 129.1, 129.1, 128.9, 128.7, 128.6,
2
q
2
128.6, 128.4, 128.4, 128.1, 128.0, 127.7, 127.5, 126.1 (CHarom), 104.8 (C-1), 101.8 (CHPh), 99.6 (C-1’), 82.3 (C-4’), 80.2, 80.2 (C-2, C-3), 75.4 (CH Bn), 74.6 (C-4),
14
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
3
74.5, 74.4 (CH
2 2 3
Bn), 74.2 (C-3’), 73.5 (CH Bn), 72.5 (C-5), 72.3 (C-2’), 68.6 (C-6), 68.2 (C-6’), 66.2 (C-5’), 57.3 (OMe); C-HMBC-GATED NMR (CDCl , 101
+
MHz): δ 104.8 (J = 159 Hz, C-1), 99.6 (J = 165 Hz, C-1’); HRMS: [M+H] calcd for C53
54 3
H N O15 972.35494, found 972.35542.
Methyl
5I). Donor 5 and acceptor 29 were condensed using the general procedure for Tf
by flash column chromatography (9/1 to 7/3 pentane/EtOAc) to yield glycosylation product 5I (47 mg, 53 µmol, 53%, α:β = 1:1.3) as a yellow solid. R
7/3 pentane/EtOAc). IR: (thin film): 646, 696, 731, 789, 908, 997, 1090, 1123, 1211, 1302, 1333, 1454, 1518, 1624, 1674, 2910; Reported as a 0.8 : 1 mixture of
2-O-(3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-α/β-ᴅ-glucopyranosyl)-3-O-benzyl-4,6-O-benzylidene-α-ᴅ-mannopyranoside
O/Ph SO mediated glycosylations (for an additional 18 hours at -40°C) and purified
: 0.34 and 0.49
(
2
2
f
(
1
anomers. H NMR (CDCl
11.8H, CHarom), 6.99 – 6.94 (m, 1.6H, CHarom), 5.67 (s, 1.8H, CHPh’
H, J = 8.3 Hz, H-1’ ), 4.84 (d, 1H, J = 12.1 Hz, CHH Bn ), 4.79 (d, 0.8H, J = 12.2 Hz, CHH Bn
CHH Bn ), 4.67 (d, 0.8H, J = 1.1 Hz, H-1 ), 4.64 (d, 1H, J = 12.1 Hz, CHH Bn ), 4.57 (d, 0.8H, J = 12.2 Hz, CHH Bn
(dd, 1H, J = 10.3, 8.2 Hz, H-3’ ), 4.46 – 4.41 (m, 1H, H-6’ ), 4.33 (d, 0.8H, J = 11.1 Hz, CHH Bn ), 4.34 – 4.26 (m, 1.6H, H-6
), 4.10 – 3.96 (m, 4.4H, H-2 , H-2’ , H-2’ , H-5’ , H-6 ), 3.95 – 3.83 (m, 8.2H, H-3 , H-3 , H-4 , H-4’ , H-4’ , H-5’ , H-6
), 3.61 (dq, 1H, J = 9.0, 4.5 Hz, H-5 ), 3.50 (t, 1H, J = 10.3 Hz, H-6 ), 3.38 (s, 2.4H, CH OMe ), 3.15 (s, 3H, CH OMe
), 141.7 (C NO pyridone), 140.9 (CH pyridone ), 140.8 (C
), 129.6, 129.4, 129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3, 128.3, 127.8, 127.8, 127.6, 126.2, 126.1,
26.1 (CHarom), 101.9, 101.8 (CHPh’α,β), 101.6, 101.6 (CHPhα,β), 100.7 (C-1 ), 99.8 (C-1’ ), 99.2 (C-1 ), 98.8 (C-1’ ), 83.1 (C-4’ ), 82.4 (C-4’ ), 79.6 (C-4 ), 79.1 (C-
), 78.5 (C-4 ), 76.1 (C-2 ), 75.0 (C-3 ), 74.5, 74.5, 74.3 (CH Bn), 74.2 (C-3 , C-3’ ), 72.9 (C-2’ ), 72.7 (CH Bn), 72.5 (C-3’ ), 69.9 (C-2’ ), 68.5, 68.5, 68.4 (C-6α,β
), 63.7 (C-5 ), 63.3 (C-5 ), 55.1, 55.1 (OMe); C-HMBC-GATED NMR (CDCl , 101 MHz): δ 99.8 (J = 176 Hz, C-1’ ), 98.8 (J = 164
15 880.29234, found 880.29252.
3
, 400 MHz, HH-COSY, HSQC, HMBC): δ 8.48 (s, 2H, pyridone
, CHPh’ ), 5.62 (s, 0.8H, CHPh
), 4.75 (d, 1H, J = 12.1 Hz, CHH Bn
), 4.52 (d, 0.8H, J = 11.1 Hz, CHH Bn
, H-6’ ), 4.22 – 4.15 (m, 2.8H, H-1
, H-6’ , H-6’ ), 3.81 – 3.74 (m, 1.6H,
); C-APT NMR (CDCl , 101 MHz,
NO pyridone), 138.2, 137.6, 137.4,
β
), 8.33 (s, 1.6H, pyridone
α
), 7.58 – 7.26 (m, 22.8H, CHarom), 7.23 – 7.01 (m,
), 5.27 (d, 0.8H, J = 3.9 Hz, H-1’ ), 5.24 (d,
), 4.70 (d, 1H, J = 12.2 Hz,
), 4.50
, H-
α
β
α
), 5.53 (s, 1H, CHPh
β
α
1
β
β
α
β
β
α
β
α
α
β
β
α
α
α
β
2
β
, H-3’
α
α
α
β
α
β
α
β
β
α
β
β
α
α
β
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
13
H-4
α
, H-5
α
β
β
3
α
3
β
3
HSQC, HMBC): δ 159.9, 159.7 (C=O pyridone), 142.1 (CH pyridone
α
q
2
β
q
2
1
1
2
37.4, 136.8, 136.6, 136.5, 136.0 (C
q
α
α
β
β
α
β
α
α
β
β
α
2
β
1
β
β
2
α
α
,
3
C-6’α,β), 66.1 (C-5’
Hz, C-1’ ); HRMS: [M+H] calcd for C46
β
β
α
), 63.1 (C-5’
α
3
α
+
β
H
46
N
3
O
2
,2,2-Trifluoroethyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-(3,5-dinitro-4-pyridone)-α/β-
condensed using the general procedure for Tf O/Ph SO mediated glycosylations (for an additional 1 hour at -40°C) and purified by flash column chromatography (19/1
to 8/2 pentane/EtOAc) to yield glycosylation product 5J (28 mg, 46 µmol α anomer and 7 mg, 12 µmol β anomer. α:β = 4:1, 58%) as a yellow solids alongside glucal
4 (4 mg) and donor 5 (13 mg). R : 0.15 and 0.67 (7/3 pentane/EtOAc). IR (thin film): 698, 754, 1001, 1071, 1096, 1169, 1215, 1279, 1304, 1331, 1520, 1680, 2855,
2924, 3065; Data for the α-anomer: H NMR (Acetone-d
D-glucopyranoside (5J). Donor 5 and 2,2,2-trifluoroethanol were
2
2
2
f
1
6
, 400 MHz, HH-COSY, HSQC): δ 8.92 (s, 2H, CH pyridone), 7.60 – 7.54 (m, 2H, CHarom), 7.47 – 7.37 (m,
H, CHarom), 7.24 – 7.13 (m, 5H, CHarom), 5.84 (s, 1H, CHPh), 5.65 (d, 1H, J = 3.7 Hz, H-1), 4.92 (d, 1H, J = 11.8 Hz, CHH Bn), 4.84 (dd, 1H, J = 10.7, 3.7 Hz, H-2),
.73 (dd, 1H, J = 10.7, 8.4 Hz, H-3), 4.70 (d, 1H, J = 11.8 Hz, CHH Bn), 4.51 – 4.38 (m, 1H, CHH-CF ), 4.38 (dd, 1H, J = 10.1, 4.7 Hz, H-6), 4.30 – 4.17 (m, 1H,
3
4
3
3
1
CHH-CF
3
), 4.12 (dd, 1H, J = 9.8, 4.7 Hz, H-5), 4.09 – 4.02 (m, 1H, H-4), 3.93 (t, 1H, J = 10.0 Hz, H-6); C-APT NMR (Acetone-d
NO pyridone), 142.6 (CH pyridone), 138.6, 138.5 (C ), 129.8, 129.2, 129.0, 129.0, 128.9, 127.0 (CHarom), 124.72 (q, J = 277.4 Hz, CF
CHPh), 98.8 (C-1), 83.4 (C-4), 75.1 (CH Bn), 74.6 (C-3), 69.8 (C-2), 68.8 (C-6), 65.84 (q, J = 35.0 Hz, CH
, 400 MHz, HH-COSY, HSQC): δ 8.61 (s, 2H, CH pyridone), 7.56 (dd, 2H, J = 6.6, 2.9 Hz, CHarom), 7.41 (dd, 3H, J = 5.0, 1.7 Hz, CHarom), 7.00 (s, 5H, CHarom),
6
, 101 MHz, HSQC): δ 160.0 (C=O
pyridone), 142.9 (C
(
q
2
q
3
), 102.1
1
2
2 3
-CF ), 64.1 (C-5); Diagnostic peaks β-anomer: H NMR
(CDCl
3
5
3
.66 (s, 1H, CHPh), 5.58 (d, 1H, J = 8.3 Hz, H-1), 4.75 – 4.62 (m, 2H, CHH Bn, H-3), 4.52 (d, 1H, J = 11.7 Hz, CHH Bn), 4.46 (dd, 1H, J = 10.5, 4.8 Hz, H-6), 4.17 –
.99 (m, 3H, CH -CF , H-5), 3.91 – 3.82 (m, 2H, H-4, H-6), 3.78 (dd, 1H, J = 10.0, 8.5 Hz, H-2); HRMS: [M+H] calcd for C27H F N O10 608.14865, found
2 3 25 3 3
+
608.14825.
References
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(2)
(3)
(4)
(5)
(6)
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