Formation of and Glycosylation with Per-O-Acetyl Septanosyl Halides: Rationalizing Complex Reactivity En Route to p-Nitrophenyl Septanosides

Article abstract of DOI:10.1002/ejoc.201800310

Protein–carbohydrate interactions are at the heart of many biological processes. For lectins, those interactions result simply in the association of two species, whereas for enzymes like glycosidases, association ultimately leads to cleavage and formation

Full text of DOI:10.1002/ejoc.201800310

A Journal of
Accepted Article
Title: Formation of and glycosylation with per-O-acetyl septanosyl
halides: Rationalizing complex reactivity en route to p-nitrophenyl
septanosides
Authors: Aditya Pote, Raghu Vannam, alissa Richard, Jose Gascon,
and Mark Wayne Peczuh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800310
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800310
Supported by

10.1002/ejoc.201800310
European Journal of Organic Chemistry
Formation of and glycosylation with per-O-acetyl septanosyl halides: Rationalizing
complex reactivity en route to p-nitrophenyl septanosides
Aditya R. Pote, Raghu Vannam, Alissa Richard, José Gascón and Mark W. Peczuh*
Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT 06269-
3060 U.S.A.
Email: mark.peczuh@uconn.edu
URL: peczuh.uconn.edu
TOC Graphic
First Order Reaction Rates
7
6
5
4
3
2
1
0
19
17
18
Compound
Key Topic
Carbohydrate Synthesis
Short Text
Glycosylation in the new old-fashioned way. A synthetic method to attach ring-expanded, septanose
sugars to other compounds has been developed. Septanosyl halides were the key donors the
glycosylations. The p-nitrophenyl septanoside products will be particularly useful tool compounds to
evaluate septanose-glycosidase interactions.
Abstract
Protein-carbohydrate interactions are at the heart of many biological processes. For lectins, those
interactions result simply in the association of two species, whereas for enzymes like glycosidases,
association ultimately leads to cleavage and formation of covalent bonds. We have investigated lectin-
septanose interactions in the past. Here we report on a route to synthesize p-nitrophenyl septanosides via
the corresponding setpanosyl halides. During the investigation we observed differential rates of glycosyl
halide formation of the per-O-acetyl septanoses based on the stereochemistry at C1 and C2. Further, we
observed unexpected stereoselectivities in glycoside bond formation that depended on a number of
factors including the electrophilic sugar species, the incoming nucleophile, and reaction conditions. The
results provided new parameters to consider when approaching septanose glycosylations. Even more
importantly, the synthesis of p-nitrophenyl septanosides will enable them to be used to interrogate
septanose-glycosidase binding and hydrolysis.
Keywords
septanose carbohydrate; glycosylation; Koenigs-Knorr; kinetics;
1
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Introduction
Homologated nucleosides, amino acids, and monosaccharides are related by the manner in which they
mimic the corresponding naturally-occurring metabolites. The addition of another atom into their
monomer structures sets up a situation where new, unique properties are manifested in addition to the
original properties.[1] We have applied the homologation approach to pyranose sugars by investigating
the synthesis and properties of seven membered-ring septanose carbohydrates.[2,3] An early question
addressed was, “Can septanoses act as proxies for pyranoses in protein-carbohydrate interactions?” As
shown in Figure 1, the question gets at how proteins may or may not be able to recognize the larger ring
septanose sugars. An investigation on the binding of septanosides by the model lectin Concanavalin A
provided interesting details on the interaction and confirmed that they can, in fact, act as ligands. [4] Key
observations made in that study were that β- configured septanosides were bound instead of α- ones
(opposite to the preference observed for pyranosides), affinity was approximately one order of
magnitude lower than pyranosides, and that septanosides were binding competitively at the pyranoside
binding site. Computational models of the complexes supported a binding mode with a similar set of
hydrogen bonds between the protein and the monosaccharides and that binding was primarily enthalpy
driven. Modeling also suggested that the orientation of septanosides in the monosaccharide binding
pocket were ratcheted relative to pyranosides. That is, the C7 exocyclic hydroxymethyl group of
septanoses was equivalent to C6 of pyranoses, C5 of septanoses was the cognate of pyranose C4, and so
on. These principles were recently applied to the design and synthesis of septanose ligands of the E. coli
lectin FimH, which is implicated in a majority of urinary tract infections. [5]
a) Lectins
HO
HO
OCH3
OH
OH
H
O
O
OCH3
OH
HO
HO
O
O
HO
HO
O
O
HO
HO
H
H
H
N
N
O
O
b) Glycosidases
NH
NH
OpNP
O
O
OpNP
HO
HO
OH
OH
?
HO
OH
HO
OH
HO
H
HO
OH
H
N
N
H
H
O
O
2
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
Figure. 1. Modes of protein-carbohydrates interaction, organized by class of protein: a) typical
interactions in a lectin-ligand interaction; b) typical glycosidase-substrate interactions.
Another broad class of proteins that bind pyranosides is composed of glycoside hydrolase enzymes
(glycosidases).[6] A logical extension of our investigation of protein-septanose interactions, therefore, is
to inquire whether septanosides can act as substrates for transformations by glycosidases (Fig. 1). Stütz
and coworkers previously reported on this question.[7] Their approach was rooted in the fact that 1,6-
dideoxy-1,6-imino-iditol 1 is an inhibitor of glycosidases, so structurally related glycosides should be
substrates. Their results showed that glycosides such as 2 and 3 were, in fact, weak substrates of
glycosidases and that there was a selectivity for the configuration of the C1 anomeric position. Alpha
configured septanoside 2 was preferred over β- septanoside 3 as a substrate for an α-glucosidase from
Saccharomyces, for example. The aglycon of the septanosides was important to the investigation; the
UV-vis activity of p-nitrophenol and its conjugate base, the p-nitrophenyate anion provide clear and
quantifiable evidence of hydrolysis. To explore the possibility that the D-glycero- septanosides that had
been previously investigated by us (that contain an exocyclic hydroxymethyl group) would also be
substrates of glycosidases, the development of a new method to prepare p-nitrophenyl (pNP) septanoside
substrates was required.
H
N
OpNP
OpNP
O
O
OH
OH
HO
HO
OH
HO
HO
HO
OH
OH
HO
OH
1
2
3
Reported methods for the synthesis of septanose glycosides have followed two main strategies, both of
which ultimately rely on natural pyranoses as starting materials. [3] The first method directly adds a
carbon to a glycal via a cyclopropanation reaction followed by a ring opening, which is concomitant
with glycoside bond formation. In the other method, a pyranose ring is expanded by any of number of
different routes to species containing functionality that enable glycosylation in subsequent steps. These
“glycosyl donors” are analogs of their pyranose counterparts and glycosylations using them use similar
reagents and conditions. For example, carbohydrate based oxepines 4 and 5 as in Scheme 1 contain
cyclic enol ethers that can be converted to the 1,2-anhydroseptanose by epoxidation (e.g., 6). The
anhydroseptanose is then susceptible to regioselective (and diastereoselective) ring opening via attack by
nucleophiles that set the glycosidic bond, giving septanosides such as 7 and 8.[8,910,11 ] We have also
shown that thioglycosides such as 9 and anomeric fluorides like 15 (Scheme 2) can be activated by
3
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
thiophilic reagents or Lewis acids, respectively, to generate electrophilic species that are trapped by
nucleophiles to again give glycosides 7 and 16.[12] It should be noted that, whereas thiophenyl glycoside
9 was itself prepared from an oxepine, glycosyl fluoride 13 arose by a longer sequence of steps. Vinyl
Grignard addition on protected pyranose lactol 10 gave a diastereomeric mixture of allylic alcohols 11
and 12 (Scheme 2). After separation, ozonolysis of 11 yielded hemiacetals like 13 or 14. The hemiacetal
like 13 with a specific C2 configuration, was then converted to glycosyl fluoride 15, and ultimately
glycosides such as 16. [13,14 ]
Scheme 1. Oxepine-Based Routes for the Synthesis of Septanosyl Glycosides
O
O
O
BnO
BnO
DMDO
BnO
BnO
BnO
BnO
4
6
LiSPh
R'OH
OBn
OR'
OBn
NIS, AgOTf
R'OH
O
O
BnO
BnO
BnO
BnO
SPh
BnO
BnO
9
7
BnO
BnO
O
O
OR'
BnO
BnO
BnO
BnO
BnO
BnO
OH
8
5
Scheme 2. Synthesis of and glycosylation with a septanosyl fluoride
BnO
OH
BnO
O
MgBr
Et2O
BnO
BnO
BnO
BnO
C3
OH
OH
BnO
BnO
11 C3 = α
12 C3 = β
10
O3;
PPh3
OH
F
BnO
BnO
O
BnO
BnO
O
OH
DAST
BnO
BnO
C2
OH
BnO
BnO
15 X = F
16 X = OR
TMSOTf
ROH
13 C2 = α
14 C2 = β
4
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The target p-nitrophenyl glycosides carried with them some considerations that had to be addressed as
we embarked on their synthesis. Benzyl protected donors, for example, were incompatible with our
approach. We reasoned that, during the deprotection of the benzyl groups via hydrogenolysis, the nitro-
aryl moiety would also be reduced to the anilino glycoside. Further, because p-nitrophenol is a weak
nucleophile, the benzyl ethers would compete as nucleophiles, potentially forming 1,4-
anhydroseptanoses, which we had observed previously. [15] Also, anomeric fluorides such as 15 would
likely be prone to formation of α-linked glycosides only. [13,14] Another consideration was the interplay
between the C2 stereochemistry and mechanistic pathway of the glycosylation reactions. Specifically,
we wanted to learn if groups at C2 would participate and how that would influence anomeric
stereochemistry. With these considerations in mind, acyl protected sugars, like per-O-acetyl septanoses
17-20 in Figure 2 were chosen for the synthesis of the pNP septanosides. Inspiration for targeting per-O-
acyl sugars as starting materials came from the known versatility of per-O-acetyl pyranoses in
glycosylation reactions,[16,17,18] as well as from our recent synthesis of acetate protected carbohydrate
based oxepines where per-O-acetyl septanoses were key intermediates.[19] Here we report the conversion
of the glucose-derived per-O-acetyl septanoses to anomeric halides and their subsequent glycosylations,
including formation of the pNP septanosides. We further report on the influence the stereochemistry at
C1 (anomeric) and C2 has on the rate and distribution of products of these reactions.
AcO
AcO
OAc
O
AcO
AcO
O
AcO
AcO
X
AcO
AcO
X
OAc
17 X = OAc
21 X = Br
19 X = OAc
22 X = Br
AcO
OAc
OAc
OAc
AcO
O
AcO
AcO
O
AcO
AcO
AcO
AcO
OAc
20
18
AcO
O
AcO
AcO
AcO
23
Figure 2. Per-O-acetyl septanoses, their corresponding α-anomeric bromides, and oxepine 23.
Results and Discussion
Formation of Septanosyl Bromides
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In our recent synthesis of oxepines, per-O-acetyl septanoses (i.e., 17-20) were the key intermediates.
They were prepared by vinyl Grignard addition to benzyl-protected pyranose lactols, followed by
ozonolysis and protecting group manipulations.[19,20,21] Once in hand, the per-O-acetates were converted
to their anomeric bromides (21, 22) and then the cyclic enol ether (oxepine) 23 via reductive elimination
of bromide and acetate across the C1-C2 bond. In that synthesis, the configurations of C1 and C2 were
ultimately of no consequence because they were removed en route to the oxepine product. Anomeric
mixtures of 17-20 (four diastereomers!) were therefore directly subjected to the sequence of bromination
and reductive elimination in that process. Using a similar logic, we reasoned that anomeric mixtures of
each of the C2 diastereomers could be used in the formation of the corresponding septanosyl bromides.
The fact that the compounds were mixtures of two anomers was of little concern to us because we
assumed that the C1 center would coalesce to the α-configuration upon formation of the anomeric
bromide. Compounds 17 and 18 were the α- and β-anomers of one C2 series (“2R series”) and 19 and 20
the other (“2S series”).
The anomeric mixtures were transformed to the septanosyl bromides under standard reaction
conditions: anhydrous HBr in acetic acid with methylene chloride as solvent at room temperature.
1
13
Product anomeric bromides were characterized by H and C NMR spectroscopy after work up, but
without extensive purification. Prolonged storage resulted in hydrolysis, forming the acetate protected
lactols. Spectral data to support the assignment of α-configuration included the following. For 21, H1 δ
3
13
3
= 6.43 ppm, JH1,H2 = 4.6 Hz, and δ C of C1 = 84.5 ppm; for 22, H1 δ = 6.12 ppm, JH1,H2 = 8.2 Hz,
13
and δ C of C1= 87.1 ppm. The spectra for 21 and 22 were therefore consistent with the selective
formation of only one anomer of relatively high purity (See Supplementary Information).
Synthesis of septanose glycoconjugates using bromides as donors
Having established a method to synthesize septanosyl bromides 21 and 22, we next endeavored to use
them in glycosylation reactions. Glycosyl bromides are venerable glycosyl donors, being the
glycosylating agents used in Koenigs-Knorr reactions.[16,22] Activation of septanosyl bromide 21 or 22
with AgOTf in the presence of methanol yielded 24 and 25, respectively, in 29% and 52% yields (Table
1 and Fig. 3). Glycosylation of n-octanol with 22 under the same reaction conditions yielded septanoside
26 in 38% yield, accompanied by 13% of the α-anomer (structure not shown). Finally, when diacetone
D-galactose was then reacted with 22 under the Koenigs-Knorr conditions, α-septanoside 27 was the
only product, albeit in modest yield (21%). Whereas the selective formation of β-septanoside 24 from 21
6
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European Journal of Organic Chemistry
can be rationalized by neighboring group participation, the trend for glycosylations involving 22 are less
intuitive. It was noted, though, that with increased steric bulk of the acceptor, the formation of α-
septanoside increased. The results were counterintuitive because the acetate protecting group at C2 in
the donors was expected to be participatory.
Glycosides from 21
Glycosides from 22
AcO
AcO
OAc
OCH3
OAc
OCH3
AcO
O
AcO
O
O
O
AcO
AcO
AcO
AcO
O
O
AcO
OAc
O
7
AcO
AcO
AcO
AcO
7
O
O
AcO
AcO
AcO
24
AcO
28
AcO
26
AcO
25
OAc
OAc
AcO
O
AcO
AcO
N3
OAc
SAc
OAc
N3
27
SAc
O
AcO
AcO
O
O
AcO
AcO
AcO
AcO
O
O
O
AcO
AcO
AcO
AcO
O
AcO
29
AcO
31
AcO
30
AcO
32
OAc
OAc
Figure 3. Products of glycosylation reactions using anomeric bromides 21 and 22.
Table 1. Glycosylation reactions of anomeric bromides 21 and 22
entry donor
acceptor
con.
A
A
product yield
1
2
3
21
22
22
24
25
26
29a
52b
38c
methanol
n-octanol
A
diacetone-
D-galactose
4
22
A
27
21
4
5
6
7
8
9
21
22
21
22
21
22
21
22
B
B
C
C
D
D
E
E
24
25
28
26
29
30
31
32
46
56
32a
43
47
51
60
33
methanol
n-octanol
KSAc
10
11
NaN3
Conditions: A: AgOTf, DCM, 0 oC-rt; B: I2, DCM, 0 oC-rt; C: I2, DDQ, DCM,
0 oC-rt; D: KSAc in acetone, rt; E: NaN3 in DMF, 60 °C
a 17 was also recovered from this reaction: 9% (entry 1), 10% (entry 6).
b 1,4-Anhydro product 33 was also isolated from this reaction (23%).
c The α-product was also isolated in 13%. See Supplementary Information.
Notably, in the Koenigs-Knorr glycosylation of 22 to form methyl septanoside 25, a side product was
isolated in appreciable amounts (23%) from the reaction mixture. The other product proved to be, after
spectroscopic characterization, 1,4-anhydro adduct 33 (Scheme 3), a compound we have previously
characterized.[15] Similarly, attempted glycosylation of phenol[23] with 22 under these conditions, or
activation of 22 in the absence of any acceptor at all, led only to isolation of the 1,4-anhydro product in
25% yield in both cases. We originally saw formation of the 1,4-anhydrosugar when we attempted to
7
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European Journal of Organic Chemistry
form the 3,4,5,7-tetra-O-benzyl-2-O-acetyl α-septanosyl bromide from its corresponding diacetate 34;
[15]
instead, we isolated 1,4-anyhdroseptanose 35 from that reaction. The benzyl protecting groups were
converted to acetates to facilitate its characterization. Because of the ample precedent of benzyl ethers
acting as nucleophiles in cyclization reactions,[24] a mechanism that explained the conversion of 34 to 35
was readily apparent. A mechanism to describe the cyclization for the per-acetyl bromides such as 22,
on the other hand, escaped us. We decided, therefore, to explore related activation methods in an effort
to gain more understanding about the initial observations made in these reactions.
Scheme 3. Routes to formation of 1,4-anhydroseptanose 33
OAc
O
22
O
AcO
OAc
OAc
33
1) H2, Pd/C
2) Ac2O, pyr.
OBn
OAc
BnO
OAc
O
O
BnO
BnO
HBr
O
AcOH
BnO
OAc
OBn
BnO
34
35
In an effort to avoid the formation of the 1,4-anhydro product, we decided to utilize a milder Lewis
acid as activator. [25] Activation of septanosyl bromides 21 and 22 with iodine in the presence methanol
afforded the corresponding β-septanosides 24 and 25 with a high degree stereocontrol, forming the β-
septanosides in yields that were slightly better (46% and 56%, respectively) than the Koenigs-Knorr
reactions (Table 1). Glycosylation of n-octanol similarly yielded 26 and 28 as the major products in
moderate yields (36% and 43%) with the β-glycoside as a major product in both the cases.[26] In the case
of the Koenigs-Knorr and iodine mediated glycosylations, reactions proceeded through some version of
cyclic oxocarbenium intermediate formed due to removal of bromide anion. [27] The intermediate was
then presumably trapped with the incoming nucleophile to deliver the products selectively. In the case of
24 and 28 (Fig. 3), the C2 acetate is likely participatory, therefore preventing nucleophilic attack on the
α-face. This is not the case during glycosylations to form 25 and 26; formation of β-products in
glycosylation by 22 was unexpected, and we originally anticipated formation of α-septanosides using
this donor.
8
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We have struggled to compose a model that explains the formation of β-septanosides from donor 22
under the two glycosylation conditions used. Two observations support, but do not necessarily explain,
the observed selectivity. First, DFT minimization of 2S-series methyl septanosides 25 and 36 in Figure
4, showed that β-anomer 25 was more stable than α-anomer 36 by 6.5 kcal/mol. In its lowest energy
conformation, the ring of 25 adopted a O,1C4 conformation, where the aglycone was positioned
pseudoaxially to optimize stereoelectronic stabilization.[28,29,30] This conformation is adjacent on the
septanose conformational itinerary to those adopted by similar septanosides.[30,31] While it is speculative,
it could be that the conformation of the oxocarbenium ion is such that it favors attack from the β-face.
At some point, unfavorable interactions between bulkier nucleophiles and the C2 acetate group may
favor formation of the α-septanoside. Take, for example, the series of Koenings-Knorr glycosylations of
methanol, n-octanol, and diacetone-D-galactose using 22. The distribution of isolated products goes
from exclusively β-septanoside in the case of methanol (25) to exclusively α- in the case of galactose
(27). Second, in the case of the mannose per-acetate pyranose system reported by Field and co-
workers,[26] β-glycosides were the major product in the iodine mediated glycosylations involving per-O-
acetyl mannose. We repeated the reaction reported there by converting per-O-acetyl mannose to its
bromide and then activating it using iodine and DDQ with n-octanol as acceptor. Product analysis
showed that only one product was formed in the reaction. Isolation and characterization of that product
by NMR spectroscopy proved that it was the octyl per-O-acetyl-β-mannoside as reported.[26,32 ]
OCH3
O
AcO
OAc
AcO
OAc
AcO
25
OCH3
O
AcO
OAc
AcO
OAc
AcO
36
9
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Figure 4. DFT structures of the lowest energy conformers of methyl septanosides 25 and 36.
The attack of anionic nucleophiles on 21 and 22 resulted in the formation of β-septanosides. Reactions
using either sodium azide or potassium thioacetate and respective bromides cleanly gave β-septanosides
29, 30, 31 and 32 in good yields (Table 1 and Fig. 3).[33,34,35,36] Formation of β-septanosides in these
cases strongly suggested SN2-type substitution by the anionic nucleophiles to α-septanosyl bromides.
Once deprotected, the anomeric azides may find use as surrogate substrates for glycosidases or glycosyl
3
transferases. The assignment of the anomers of septanosides was done based on J couplings between
H1 and H2 as well as their chemical shifts in 13C NMR spectra (See Supporting Information.).
Septanoses, like their six-membered analogs, show multiple mechanisms (e.g., oxocarbenium ion
formation, direct SN2 displacement) to produce glycosidic bonds under different reaction conditions.
The reactions that are involved in the septanose glycosides are generally easy to handle and scalable.
The newly synthesized thio- and azido-septanosides will be tested for functionalization at the hetero-
atom to prepare novel septanose glycoconjugates or nucleoside mimics.
Kinetics study on the conversion of per-O-acetyl septanoses to their anomeric iodides
When purifying reaction mixtures where 21 was the glycosyl donor, unreacted per-O-acetate, 17, was
also isolated (Table 1). Considering this observation, we speculated that the individual anomers, 17 and
18, might react at different rates during glycosyl bromide formation. To investigate this and to better
understand the yields of 24 and 28 with Lewis acid activation, we set out to quantitate the rate of
septanosyl halide formation for each of the per-O-acetate isomers 17-20. One of the isomers, 20, was
present in such small quantities that it could not be isolated. We therefore investigated only compounds
17-19 in the kinetics studies. Following a similar kinetics study reported by Gervay-Hague and co-
1
workers, we opted to characterize the rates by H NMR integrations.[37] Disappearance of the starting
material was monitored with 1.5 eq. of TMSX in CD2Cl2 over a period of seven hours at 273 K. We
began by attempting to monitor per-O-acetyl septanose 18 with bromotrimethyl silane (TMSBr). The
TMSBr reaction proceeded very slowly, however, with low conversion over the timeframe of the
experiment. The more reactive iodotrimethyl silane (TMSI) was utilized, therefore, to study the relative
reactivities. Diminution of the integral value for the H1 protons of each anomeric acetate was measured
at ten-minute intervals over the course of the experiment. The integration was then converted to
concentration using the eretic quantitation module in Bruker Topspin 3.5pl7.
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Macroscopic rate constants were calculated by fitting plots of the decrease in the natural logarithm of
starting material concentration as a function time. The experiments confirmed that 17 was consumed at a
significantly slower (40 times) pace than both 18 or 19 (Fig. 5 and Table 2). It (17) is also unique in
being the only 1,2-cis anomeric acetate, whereas 18 and 19 are both trans. The data were fit linearly,
approximating a mechanism where the rate determining step was unimolecular (Fig. 5 a-c). Formation of
an oxocarbenium ion from a silylated anomeric acetate is likely the key step in the mechanism (See
Supplementary Information). As depicted in Figure 6, anchimeric assistance by the C2 acetate likely
accelerated oxocarbenium ion formation for species like 18 and 19 (not shown), whereas there was no
such participation in the case of 17. The first order (linear) fits for 18 and 19 showed excellent
correlation with the model, but less so for 17, and suggested that competing processes are likely at
play.[37] With per-O-acetyl septanose 17 being the least reactive, it explains the fact that it was isolated
from glycosylations. It presumably did not completely react during activation via HBr in acetic acid, and
decreased the isolated yields for glycosylation as a consequence.
18
17
19
5.1
5.09
5.08
5.07
5.06
5.05
5
4.5
4
5
4.8
4.6
4.4
4.2
4
a
b
c
3.5
3.8
0
5000
10000 15000 20000 25000
(seconds)
0
5000
10000 15000 20000 25000
0
5000
10000 15000 20000 25000
t (seconds)
t
t
(seconds)
17 (Second Order)
First Order Reaction Rates
0.0064
7
6
5
4
3
2
1
0
d
e
f
0.00635
0.0063
0.00625
0.0062
0.00615
19
17
18
0
5000
10000 15000 20000 25000
Compound
t
(seconds)
Figure 5. Kinetics of septanosyl iodide formation for per-O-acetyl septanoses 17, 18, and 19. Plots in a,
b, and c show first order fits, plot d shows a second order fit for 17; e compares rates and f shows
structures of the compounds.
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European Journal of Organic Chemistry
Table 2. Kinetics data of septanosyl iodide formation
kobs
t1/2
(sec)
entry cmpd
R2
(sec-1)
1
2
3
4
17
18
19
17
1.70 × 10 -6
6.85 × 10 -5
4.47 × 10 -5
4.09 × 10 5
1.01 × 10 4
1.56 × 10 4
0.944
0.997
0.990
0.944
1.06 × 10 -8a ND
a Units for the second order fit should be M-1•sec-1.
AcO
AcO
O
O
AcO
AcO
AcO
AcO
OTMS
O
AcO
AcO
Ac
O
OAc
37
39
OTMS
AcO
AcO
O
O
O
AcO
AcO
AcO
AcO
O
AcO
38
AcO
39
O
O
O
Figure 6. Depiction of oxocarbenium ion formation from 17 and 18.
Synthesis of p-nitrophenyl septanosides
Colorimetric assays have been widely used to monitor glycosidase activity in vitro.[38] Saccharide
substrates containing a pro-chromogenic aglycone absorb more strongly upon cleavage of the glycosidic
bond. Drawing on inspiration from pyranose glycoside substrates, we chose to synthesize p-nitrophenyl
(pNP) septanosides. Glycosylations of p-nitrophenol with glycosyl bromides are well established in
pyranose systems including a wide variety of glycosylation protocols. We investigated these protocols
with septanose donors 21 and 22. [39] The glycosylation reaction of septanosyl bromide 21 using BF3 as a
promoter resulted in no product formation,[40] whereas activation with Ag2CO3 delivered the glycoside
40 in only 20% yield.[41] The low yield of the reaction may be attributed to lower nucleophilicity of the
p-nitrophenol. Hence, glycosylations of p-nitrophenol under basic conditions were also explored in the
presence of phase-transfer-catalysts. Using tetrabutylammonium bromide (TBAB) as the phase-transfer
catalyst in a two-phase system consisting of aqueous sodium hydroxide and dichloromethane gave 15%
of β-pNP-septanoside 40.[42] Alternatively, glycosylations using tetrabutylammonium hydrogensulfate
(TBAS) gave the β-pNP-septanoside 40 in 33% yield at room temperature. A mixture of products were
observed if the reaction temperature was elevated to 35 °C. [43]
12
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European Journal of Organic Chemistry
OR
O
RO
RO
NO2
RO
RO
O
O
O
RO
RO
RO
RO
NO2
OR
40 R = OAc
42 R = H
41 R = OAc
43 R = H
While modest, the glycosylation protocol with tetrabutylammonium hydrogensulfate (TBAS) was the
best amongst the methods tested and, hence, was utilized to synthesize the 2S series pNP septanoside.
When starting from anomeric bromide 22, the product formed was the 1,2-trans, α-configured glycoside,
41 in 35% yield. The preference for α-glycoside formation might be explained by one of two conditions,
or even a combination of them. First, it may reflect the size and nucleophilicity of the p-nitrophenol
acceptor, akin to the observed trend in the Koenigs-Knorr glycosylations. On the other hand, a double-
displacement mechanism that invokes a reactive, β-glycosyl sulfate could also be operative. In the case
of the acetate protected pNP septanosides 40 and 41, the H1 chemical shift is not resolved, but amongst
other signals of the product. Hence, the stereochemistry at the anomeric carbon was assigned after the
deprotection because the H1 signals were visible and coupling constants could be assigned.[44] The pNP
septanosides 42 and 43 were characterized extensively using NMR spectroscopy for the assignment of
the stereochemistry at C1. We are currently investigating protocols to optimize the reaction conditions
and yields for pNP septanosides by directly utilizing per-O-acetyl septanoses 17, 18 and 19 as donors
under Lewis acidic conditions.[45,46]
Conclusion
Here we have developed a glycosylation method that uses septanosyl bromides as donors in reactions
to prepare new p-nitrophenyl septanosides. The method also enabled the synthesis of septanosides using
various hetereoatom acceptors, which had been difficult via previous glycosylation methods. We
observed differential rates of conversion of the per-O-acetyl septanose precursors to the anomeric
bromides based on the relative stereochemistry at C1 and C2. Specifically, 1,2-trans relationships
resulted in faster activation whereas 1,2-cis was slower; we invoked a kinetic rationale for this based on
the mechanism of the reaction. Another key finding related to the stereoselectivity of glycoside
formation. Considerations that were included in the explanation of selectivity were the reaction
mechanism, which could be either SN2-like or involve an oxocarbenium intermediate, and the nature
(e.g., size, reactivity) of the acceptor. Importantly, we used product conformational optimization to help
support our argument for selectivity. Ultimately, the method has delivered p-nitrophenyl septanosides
that can be utilized as substrates to evaluate glycosidase activity. As such, it will allow the exploration
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
of protein septanose interactions in the context of a new class of proteins. Results of these investigations
will be reported in due course.
Experimental Section
General procedure for the formation per-acetylated glycosyl iodides (NMR Kinetics experiment). Three isomers
of per-O-acetyl septanoses (1 eq.) were dissolved in CD2Cl2 (0.6 mL) and placed in an NMR tube.
Iodotrimethylsilane (1.5 eq.) was added directly into the NMR tube at ~0 °C, mixed well and the reaction was
1
followed by NMR spectroscopy at 273.2K using a Bruker 400 spectrometer. H NMR spectra was taken at every
10 minutes for next 8 hours. Concentration of products for the kinetic plots were calculated using the eretic
quantitative module in Bruker Topspin 3.5pl7. The integration region for H1 of the per-O-acetyl septanose at each
time point was imported from t = 0 forward, and calculated against one of the acetate methyl integrations or a
]
proton other than the anomeric proton signal; these reference signals served as internal standards.[47
Minimization and conformational optimization of methyl septanosides. Starting structures for methyl α-
septanoside 25 and methyl β-septanoside 36 were adapted from our previous conformational analysis of 5-O-
31
methyl septanosides[ a] by using the Maestro GUI included in the Schrodinger software suite.[48] Modifications of
the preexisting -OH moieties were converted to -OAc groups manually. The respective septanoside structures
were minimized by Density Functional Theory (DFT) using the functional B3LYP and basis set 6-31G**.
Conformational searches were accomplished on each minimized septanoside to identify the existence of any
lower-energy conformations by the MacroModel program within the Schrodinger software suite. Conformations
were systematically searched for by mixed torsional and low-mode sampling, a hybrid technique where specific
torsions may vary outside a standard low mode search. Any redundant conformers are removed from the data set.
This resulted in 192 unique conformers for α-septanoside 25 and 193 β-septanoside 36. The top ranked (lowest
energy) conformers were re-minimized by DFT at the same level of theory, B3LYP/ 6-31G**, to acquire each
septanoside conformers' energy (See Supplementary Information for Cartesian coordinates of the DFT structures.)
General procedure for debenzylation and per-O-acetylation. To di-O-acetyl-tetra-O-benzyl septanoses (1.00 g,
1.50 mmol, 1 eq.) dissolved in THF (20 mL per g starting material), was added 20% weight of 10% Pd/C (0.20 g)
and the mixture was stirred for 12 h at rt under an atmosphere of hydrogen gas. The solution was then filtered
through celite, washed with excess methanol and the combined filtrates were concentrated under reduced
pressure. After TLC analysis showing the absence of starting material and no UV active spots, the crude reaction
mixture was then dissolved in pyridine (5 mL g−1 starting material), and acetic anhydride (7.2 mL g−1) was added
at 0 °C and stirred it for 6-8 h at rt. The mixture was concentrated under reduced pressure and purified by column
chromatography using hexane: ethyl acetate as solvent system to give the respective per-O-acetyl septanoses.
14
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1,2,3,4,5,7-hexa-O-acetyl-α-D-glycero-D-guloseptanose (17). Obtained after column chromatography as a
colorless oil (407 mg, 42%) using the general two-step procedure described above; note that β-anomer 18 (below)
1
was also isolated from the same reaction. Rf 0.4 (1:1 Hex: EtOAc); [α]D +75.8 (c 0.8, CHCl3); H NMR (400
MHz, CDCl3) δ 6.19 (d, J = 4.9 Hz, 1H), 5.64–5.59 (dd, J = 10.1, 8.5 Hz, 1H), 5.57–5.55 (dd, J = 4.9, 0.9 Hz),
5.27–5.24 (dd, J = 10.2, 1.0 Hz, 1H), 5.08–5.03 (dd, J = 10.4, 8.5 Hz, 1H), 4.54–4.49 (ddd, (J = 8.4, 5.8, 2.5 Hz,
1H), 4.20–4.15 (dd, J = 12.0, 5.9 Hz, 1H), 3.98–3.95 (dd, J = 12.0, 2.5 Hz, 1H), 2.26 (s, 3H), 2.04 (s, 3H), 2.03
(s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.0, 169.6, 169.5, 169.3,
168.1, 89.0, 71.9, 71.5, 71.3, 69.5, 69.2, 63.6, 20.9, 20.8, 20.7; HRMS (DART-TOF) m/z calcd. for C19H30NO13
[M+NH4] + 480.1717, obs. 480.1718.
1,2,3,4,5,7-hexa-O-acetyl-β-D-glycero-D-guloseptanose (18). Obtained as a colorless oil (498 mg, 52%). Rf 0.5
1
(1:1 Hex: EtOAc); [α]D +3.1 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3) δ 5.79 (d, J = 6.9 Hz, 1H), 5.43–5.41
(dd, J = 7.9, 2.4 Hz, 1H), 5.33–5.29 (m, 2H), 5.03–4.99 (dd, J = 9.5, 3.9 Hz, 1H), 4.18–4.12 (m, 2H), 4.06–4.00
(m, 1H), 2.09 (broad s, 9H), 2.06 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 169.4,
169.2 (2), 169.1 (2), 95.4, 75.5, 71.7, 70.6, 70.3, 69.1, 63.7, 21.0, 20.9, 20.8 (2); HRMS (DART-TOF) m/z calcd.
for C19H30NO13 [M+NH4] + 480.1717, obs. 480.1720.
1,2,3,4,5,7-hexa-O-acetyl-α-D-glycero-D-idoseptanose (19). Obtained as colorless oil in 83% yield (440 mg) after
two steps using the general procedure. Rf 0.3 (3:2 Hex: EtOAc); [α]D +39.2 (c 0.4, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 5.96 (d, J = 6.7 Hz, 1H), 5.39–5.29 (m, 3H), 5.03–4.98 (ddd, J = 8.3, 8.3, 3.9 Hz, 1H), 4.26–4.20 (ddd,
J = 8.8, 6.2, 2.5 Hz, 1H), 4.14–4.09 (dd, J = 12.0, 6.2 Hz, 1H), 3.93–3.88 (dd, J = 12.0, 2.5 Hz, 1H), 2.04 (s, 3H),
13
1.99 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H), 1.93 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.5, 169.6,
169.3, 169.0, 168.9, 168.8, 92.9, 74.8, 70.5, 69.3, 69.2, 67.8, 63.6, 21.0, 20.7(2), 20.5, 20.4(2); HRMS (DART-
TOF) m/z calcd. for C19H30NO13 [M+NH4] + 480.1717, obs. 480.1724.
General procedure for septanosyl bromide formation. To a solution of per-O-acetyl septanose (0.50 g, 1.1 mmol,
1 eq.) in DCM (5 mL) was added a 30% HBr in acetic acid (2.5 mL) solution at 0 °C. After complete
consumption of the starting material (usually ∼12 h) as observed by TLC, the reaction mixture was poured
directly into a 100-mL beaker half full of ice. Additional DCM was added to this mixture and it was then
transferred to a separatory funnel. The water was removed and the organic phase was washed with cold, sat’d
NaHCO3 (2 × 40 mL), water (40 mL) and brine (40 mL) and dried with Na2SO4. The solvents were removed
under reduced pressure to give the respective septanosyl bromides.
1-Bromo-2,3,4,5,7-hexa-O-acetyl-α-D-glycero-D-guloseptanose (21). Obtained as yellow oil in 93% yield [83 mg
obtained from 86 mg (0.186 mmol) of the starting material] using the general procedure for bromide formation.
1
The product was further utilized for glycosylation reactions without purification. Rf 0.6 (1:1 Hex: EtOAc); H
15
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NMR (400 MHz, CDCl3) δ 6.49 (d, J = 4.7 Hz, 1H), 5.60-5.57 (dd, J = 7.6, 2.1 Hz, 1H), 5.19-5.12 (m, 2H), 4.58-
4.53 (ddd, J = 10.5, 7.6, 2.5 Hz, 1H), 4.27-4.23 (dd, J = 12.2, 5.2 Hz, 1H), 4.13-4.10 (dd, J = 14.2, 7.2 Hz), 4.05-
4.01 (dd, J = 12.2, 2.3 Hz), 2.31 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 170.8, 170.0, 169.5, 168.9, 84.5, 73.1, 71.8, 71.4, 70.1 (2), 62.5, 21.0 (2), 20.9, 20.8.
1-Bromo-2,3,4,5,7-penta-O-acetyl-α-D-glycero-D-idoseptanose (22). Obtained as yellow oil in 95% yield [117
mg obtained from 118 mg (0.255 mmol) of the starting material] using the general procedure for bromide
1
formation. Rf 0.6 (1:1 Hex: EtOAc); H NMR (400 MHz, CDCl3) δ 6.12 (d, J = 8.2 Hz, 1H), 5.69-5.62 (dd, J =
10.0, 8.3 Hz, 1H), 5.39-5.34 (dd, J = 9.4, 8.5 Hz, 1H), 5.25-5.18 (dd, J = 6.1, 6.1 Hz, 1H), 5.18-5.13 (dd, J = 9.9,
8.6 Hz, 1H), 4.40-4.35 (ddd, J = 10.1, 5.0, 2.4 Hz, 1H), 4.28-4.22 (dd, J = 12.2, 5.0 Hz, 1H), 4.10-4.05 (dd, J =
13
12.2, 2.5 Hz, 1H), 2.06 (s, 6H), 2.01 (s, 3H), 1.98 (s, 3H), 1.97 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.6,
169.5, 169.4, 169.0, 168.3, 87.1, 74.4, 73.5, 72.0, 69.5, 68.6, 62.3, 20.9, 20.7, 20.6, 20.4; HRMS (DART-TOF)
m/z calcd. for C17H23BrNaO11 [M+Na] + 505.0321, found 505.0258.
Methyl-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-guloseptanose (24). Method A. To a solution of 21 (46 mg,
0.095 mmol) in DCM (2 mL), was added 4Å mol. sieves (0.2 g) and MeOH (0.2 mL, 5.712 mmol),
stirred for 10 minutes in an ice bath under N2 atmosphere in dark conditions. AgOTf (37 mg, 0.144
mmol) was added to the resulting solution and was stirred allowing the reaction mixture to come to the
room temperature. The reaction progress was monitored by TLC. The reaction mixture was then
quenched, filtered and extracted with DCM (3 x 15 mL), washed with sat. NaHCO3 solution, water,
brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue
was purified by column chromatography to obtain the desired product as yellowish oil (29% yield). Rf
0.4 (1:1 Hex: EtOAc). Method B. To a solution of 21 (50 mg, 0.103 mmol) in DCM (3 mL), was added
4Å mol. sieves (0.1 g) and I2 crystals (26 mg, 0.103 mmol), stirred for 10 minutes in an ice bath under
N2 atmosphere in dark conditions. MeOH (0.8 mL) was added to the resulting solution and was stirred
overnight allowing the reaction mixture to come to the room temperature. The reaction mixture was then
quenched with ice, extracted with DCM (3 x 20 mL), washed with sat. Na2S2O3 solution, water, brine
and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was
purified by column chromatography to obtain the desired product as yellowish oil. (46% yield) Rf 0.4
1
(1:1 Hex: EtOAc); [α]D +1.6 (c 0.2, CHCl3); HNMR (400 MHz, CDCl3) δ 5.43-5.39 (dd, J= 8.2, 2.3
Hz, 1H), 5.37-5.33 (dd, J= 8.3, 4.5 Hz, 1 H), 5.24-5.21 (dd, J= 5.7, 2.3 Hz, 1 H), 5.08-5.03 (dd, J= 9.9,
4.4 Hz, 1H), 4.57 (d, J=5.7 Hz, 1 H), 4.17- 4.13 (m, 2H), 4.05- 4.01 (m, 1H), 3.51 (s, 3H), 2.10 (s, 3H),
13
2.09 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H); CNMR (100 MHz, CDCl3) δ 170.7, 169.6, 169.4, 169.2 (2),
104.9, 73.7, 72.6, 71.9, 70.7, 69.4, 64.4, 56.6, 21.1, 20.9 (2); HRMS (DART-TOF) m/z calcd. for
16
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European Journal of Organic Chemistry
C12H27O12 [M+H] + 435.1503, obs. 435.1505.
Methyl-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-idoseptanose (25). Method A. To a solution of 22 (47 mg,
0.097 mmol) in DCM (2 mL), was added 4Å mol. sieves (0.2 g) and MeOH (0.24 mL, 5.835 mmol),
stirred for 10 minutes in an ice bath under N2 atmosphere in dark conditions. AgOTf (37.5 mg, 0.146
mmol) was added to the resulting solution and was stirred allowing the reaction mixture to come to the
room temperature. The reaction progress was monitored by TLC. The reaction mixture was then
quenched, filtered and extracted with DCM (3 x 15 mL), washed with sat. NaHCO3 solution, water,
brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue
was purified by column chromatography to obtain the desired product as yellowish oil. (52% yield) Rf
0.3 (13:7 Hex: EtOAc). Method B. To a solution of 22 (94 mg, 0.194 mmol) in DCM (3 mL), was added
4Å mol. sieves (0.25 g) and I2 crystals (49 mg, 0.194 mmol), stirred for 10 minutes in an ice bath under
N2 atmosphere in dark conditions. MeOH (0.8 mL) was added to the resulting solution and was stirred
overnight allowing the reaction mixture to come to the room temperature. The reaction mixture was then
quenched with ice, extracted with DCM (3 x 20 mL), washed with sat. Na2S2O3 solution, water, brine
and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was
purified by column chromatography to obtain the desired product as yellowish oil. (56% yield) Rf 0.3
(13:7 Hex: EtOAc); [α]D -15.5 (c 1.7, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.40-5.36 (m, 1H), 5.28–
5.25 (m, 3H), 4.68 (d, J = 2.3 Hz, 1H), 4.24–4.20 (dd, J = 12.0, 6.0 Hz, 1H), 4.16–4.12 (dd, J = 12.0
Hz, 2.6 Hz, 1H), 3.93–3.90 (m, 1H), 3.47 (s, 3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H),
13
1.99 (s, 3H); C NMR (100 MHz, CDCl3) δ 170.7, 170.0, 169.4, 169.2, 169.0, 102.3, 76.2, 72.2, 71.7,
70.6, 70.4, 64.0, 56.5, 20.9, 20.8, 20.7, 20.6; HRMS (DART-TOF) m/z calcd. for C12H30NO12 [M+NH4]
+ 452.1768, obs. 452.1762.
Octyl-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-idoseptanose (26). Method A. To a solution of 22 (29 mg,
0.060 mmol) in DCM (2.5 mL), was added 4 Å mol. sieves (0.2 g) and 1-Octanol (29 µL, 0.180 mmol),
stirred for 10 minutes in an ice bath under N2 atmosphere in dark conditions. AgOTf (23 mg, 0.090
mmol) was added to the resulting solution and was stirred allowing the reaction mixture to come to the
room temperature. The reaction progress was monitored by TLC. The reaction mixture was then
quenched, filtered and extracted with DCM (3 x 15 mL), washed with sat. NaHCO3 solution, water,
brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue
was purified by column chromatography to obtain the desired product as colorless oil. (38% yield) Rf
0.4 (3:2 Hex: EtOAc). Method B. To a solution of I2 crystals (40 mg, 0.153 mmol) and n-octanol (72 µL,
17
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0.459 mmol) in DCM (2 mL), was added DDQ (18 mg, 0.077 mmol), stirred at 0 °C under inert
atmosphere for 10 minutes under dark conditions. To this solution, was added 22 (74mg, 0.153mmol)
dissolved in DCM (2 mL) and the resulting solution was allowed to come to room temperature slowly.
The reaction progress was monitored by TLC. The reaction mixture was then quenched with ice cold
water, extracted with DCM (3 x 15 mL), washed with sat. Na2S2O3 solution, water, brine and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was purified by
column chromatography to obtain the desired product as colorless oil. (43% yield) Rf 0.3 (7:3 Hex:
1
EtOAc); [α]D -91.3 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ 5.42–5.38 (m, 1H), 5.30–5.24 (m,
3H), 4.76 (d, J = 2.4 Hz, 1H) 4.23–4.19 (dd, J = 12, 6 Hz, 1H), 4.15–4.12 (dd, J = 12, 2.6 Hz, 1H),
3.91–3.82 Hz (m, 2H), 3.44–3.39 (app dt, J = 9, 6.8 Hz), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 2. 00
(m, 6H), 1.61–1.56 (m, 2H), 1.26 (m, 10H), 0.89–0.86 (t, J = 6.7Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.8, 170.0, 169.5, 169.2, 169.0, 101.1, 76.3, 72.6, 71.6, 70.7, 70.5, 69.5, 64.2, 31.9, 29.5, 29.4(2),
26.1, 22.8, 20.9, 20.8, 20,7, 20.6, 14.3; HRMS (DART-TOF) m/z calcd. for C25H44NO12 [M+NH4] +
550.2864, obs. 550.2848.
(1,2,3,4-Di-O-isopropylidene-D-galactopyranosyl)-2,3,4,5,7-penta-O-acetyl-α-D-glycero-D-idoseptanose
(27). To a solution of 22 (57 mg, 0.118 mmol) in DCM (2 mL), was added 4Å mol. sieves (0.25 g) and
Di-acetone-D-galactose (92 mg, 0.354 mmol) dissolved in DCM (1 mL), stirred for 10 minutes in an ice
bath under N2 atmosphere in dark conditions. AgOTf (45 mg, 0.177 mmol) was added to the resulting
solution and was stirred allowing the reaction mixture to come to the room temperature. The reaction
progress was monitored by TLC. The reaction mixture was then quenched, filtered and extracted with
DCM (3 x 15 mL), washed with sat. NaHCO3 solution, water, brine and dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure and residue was purified by column chromatography
to obtain the desired product as colorless oil. (21% yield) Rf 0.4 (3:2 Hex: EtOAc); [α]D +8.2 (c 0.1,
1
CHCl3); HNMR (400 MHz, CDCl3) δ 5.48 (d, J = 5.1 Hz, 1H), 5.33-5.25 (m, 3H), 5.13-5.09 (dd, J =
10.2, 7.9 Hz, 1H), 4.88-4.85 (m, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.60-4.57 (dd, J = 7.7, 2.5 Hz, 1H), 4.31-
4.29 (dd, J = 5.0, 2.5 Hz, 1H), 4.24-4.20 (m, 2H), 4.14-4.12 (m, 1H), 3.92-3.89 (m, 1H), 3.63-3.60 (m,
1H), 2.08 (m, 1H), 2.03 (m, 1H), 1.99 (m, 1H), 1.98 (m, 3H), 1.97 (m, 3H), 1.52 (m, 1H), 1.41 (m, 3H),
13
1.32 (m, 3H), 1.30 (m, 3H); C NMR (100 MHz, CDCl3) δ 170.9, 169.7, 169.6, 169.3, 168.8, 109.5,
108.8, 100.8, 96.5, 74.9, 71.0, 70.8, 70.7, 70.5, 67.7, 67.3, 67.2, 66.1, 63.6, 62.9, 26.3, 26.2, 25.1, 24.8,
+
21.0, 20.9, 20.7, 20.6; HRMS (DART-TOF) m/z calcd. for C29H42NaO17 [M+Na] 685.2309, found
685.2354.
18
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Octyl-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-guloseptanose (28). To a solution of I2 crystals (25 mg, 0.097
mmol) and 1–Octanol (46 µL, 0.291 mmol) in DCM (1.5 mL), was added DDQ (11 mg, 0.049 mmol),
stirred at 0oC under inert atmosphere for 10 minutes under dark conditions. To this solution, was added
21 (47 mg, 0.097 mmol) dissolved in DCM (1.5 mL) and the resulting solution was allowed to come to
room temperature slowly. The reaction progress was monitored by TLC. The reaction mixture was then
quenched with ice cold water, extracted with DCM (3 x 15 mL), washed with sat. Na2S2O3 solution,
water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and
residue was purified by column chromatography to obtain the desired product as colorless oil. (32%
yield) Rf 0.4 (3:2 Hex: EtOAc); [α]D +8.1 (c 0.1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.43–5.41 (dd,
J = 8.3, 2.7 Hz, 1H), 5.36–5.33 (dd, J = 8.3, 4.5 Hz, 1H), 5.23–5.21 (dd, J = 5.7, 2.3 Hz, 1H), 5.07–5.04
(dd, J = 9.9, 4.5 Hz, 1H), 4.63 (d, J = 5.8 Hz, 1H), 4.14–4.12 (m, 2H), 4.04–3.99 (ddd, J = 9.6, 5.9, 3.6
Hz, 1H), 3.90–3.85 (app dt, J = 9.4, 6.5 Hz, 1H), 3.47–3.41 (app dt, J = 9.7, 6.8 Hz, 1H), 2.1 (s, 3H),
2.09 (s, 3H) 2.08 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.61–1.57 (m, 2H) 1.27 (m, 10 H), 0.9–0.86 (t, J =
13
6.8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.6, 169.3, 169.2, 169.0, 168.9, 103.7, 73.5, 72.5, 71.8,
70.6, 69.4, 69.2, 64.3, 31.8, 29.3 (2), 29.2, 25.9, 22.6, 20.8, 20.7 (2), 20.6, 14.1; HRMS (DART-TOF)
m/z calcd. for C25H40KO12 [M+K] +, calc. 571.2157, obs. 571.5152.
(1-S-Acetyl)-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-guloseptanose (29). To a solution of 21 (100 mg, 0.2
mmol) in Acetone (2 mL), was added KSAc (35 mg, 0.31 mmol). Resulting solution was stirred
overnight at room temperature under inert atmosphere in dark conditions. The reaction mixture was then
quenched with ice cold water, extracted with EtOAc (3 x 15 mL) and washed with water, brine and dried
over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was purified by
column chromatography to obtain the desired product as brownish oil. (47% yield) Rf 0.48 (1:1 Hex:
1
EtOAc); [α]D +1.7 (c 0.3, CHCl3); H NMR (400 MHz, CDCl3) δ 5.48-5.44 (d, J = 7.7 Hz, 1H), 5.41-
5.37 (m, 3H), 5.07-5.02 (m, 1H), 4.22-4.17 (m, 1H), 4.13-4.04 (m, 2H), 2.38 (s, 3H), 2.11 (s, 3H), 2.09
13
(s, 6H), 2.07 (s, 3H), 2.03 (s, 3H); CNMR (100 MHz, CDCl3) δ 192.7, 170.9, 169.4, 169.3, 169.2,
83.9, 79.2, 71.8, 70.6, 70.4, 69.9, 63.9,31.0, 20.9, 20.8 (2); HRMS (DART-TOF) m/z calcd for
C19H26O12S (M+NH4)+ 496.1462, found 496.1489; 13C NMR (100 MHz, CD3OD) δ 165.3, 143.1, 126.8,
117.3, 94.5, 78.4, 74.3, 71.1, 70.8, 70.6, 65.0; HRMS (DART-TOF) m/z calcd. for C19H26NaO12S
[M+Na] + 354.0801, found 354.0769.
(1-S-Acetyl)-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-idoseptanose (30). To a solution of 22 (121 mg, 0.25
mmol) in Acetone (4 mL), was added KSAc (57 mg, 0.5 mmol). Resulting solution was stirred overnight
19
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at room temperature under inert atmosphere in dark conditions. The reaction mixture was then quenched
with ice cold water, extracted with EtOAc (3 x 15 mL) and washed with water, brine and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was purified by
column chromatography to obtain the desired product as brownish liquid. (51% yield) Rf 0.39 (3:2 Hex:
1
EtOAc); [α]D -26.2 (c 3.0, CHCl3); H NMR (400 MHz, CDCl3) δ 5.63 (d, J = 2.6 Hz, 1H), 5.42–5.40
(m, 1H), 5.39–5.35 (m, 2H), 5.23–5.18 (app t, J = 9.2 Hz, 1H), 4.14–4.09 (m, 3H), 1.36 (s, 3H), 2.08 (s,
3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.9, 170.8,
169.5, 169.2, 169.1, 84., 81.0, 74.9, 71.7, 70.7, 70.2, 63.4, 30.8, 20.9, 20.7(2), 20.6, 20.5; HRMS
(DART-TOF) m/z calcd. for C19H27O12S [M+H] + 479.1223, obs. 479.1244.
Azido-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-guloseptanose (31). To a solution of 21 (90 mg, 0.186 mmol)
in DMF (1.5 mL), was added NaN3 (35 mg, 0.46 mmol). Resulting solution was stirred overnight at 70
°C under inert atmosphere in dark conditions. Solvent was removed under reduced pressure, crude
mixture was taken up with water, extracted with EtOAc (3 x 15 mL), washed with water, brine and dried
over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was purified by
column chromatography to obtain the desired product as colorless liquid. (60% yield) Rf 0.3 (1:1 Hex:
1
EtOAc); [α]D +8.8 (c 0.5, CHCl3); H NMR (400 MHz, CDCl3) δ 5.40-5.37 (dd, J = 8.0, 1.7 Hz, 1H),
5.35-5.32 (dd, J = 8.0, 3.8 Hz, 1 H), 5.10-5.08 (dd, J = 6.5, 1.7 Hz, 1H), 5.05 (d, J = 6.6 Hz, 1H), 5.03-
13
4.99 (m, 1H), 4.17- 4.12 (m, 3H), 2.11 (s, 3H), 2.10 (broad s, 6H) 2.08 (s, 3H), 2.04 (s, 3H); CNMR
(100 MHz, CDCl3) δ 170.8, 169.2, 169.1 (2), 91.3, 76.0, 72.1, 71.7, 70.6, 69.3, 64.3, 20.9, 20.8 (2);
HRMS (DART-TOF) m/z calcd. for C17H27N4O11 [M+NH4] + 463.1676, found 463.1645.
Azido-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-idoseptanose (32). To a solution of 22 (140 mg, 0.289 mmol)
in DMF (2 mL), was added NaN3 (57 mg, 0.869 mmol). Resulting solution was stirred overnight at 70
°C under inert atmosphere in dark conditions. Solvent was removed under reduced pressure, crude
mixture was taken up with water, extracted with EtOAc (3 x 15 mL), washed with water, brine and dried
over anhydrous Na2SO4. The solvent was removed under reduced pressure and residue was purified by
column chromatography to obtain the desired product as colorless liquid. (32% yield) Rf 0.19 (3:1 Hex:
1
EtOAc); [α]D -33.0 (c 1.6, CHCl3); H NMR (400 MHz, CDCl3) δ 5.35–5.5.27 (m, 2H), 5.25–5.19 (m,
2H), 5.10 (d, J = 2.5 Hz, 1H), 4.28–4.24 (dd, J = 12.0, 6.7 Hz, 1H), 4.17–4.13 (dd, J = 12.0, 2.3Hz,
1H), 4.07–4.02 (ddd, J = 9.2, 6.7, 2.5 Hz, 1H), 2.14 (s ,3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.02 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 170.8, 169.7, 169.3, 169.1, 168.8, 88.8, 77.7, 72.3, 71.9, 71.5, 70.2, 63.7,
20.9, 20.7, 20.6; HRMS (DART-TOF) m/z calcd. for C17H27N4O11 [M+NH4] + 463.1676, obs. 463.1689.
20
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2,3,5,7-Tetra-O-acetyl-1,4-anhydro-D-glycero-D-idoseptanose (33). To a solution of phenol (40 mg,
0.422 mmol) in DCM (3 mL), was added AgOTf (65 mg, 0.253 mmol) in presence of 4Å mol. sieves
(0.5g), stirred at 0 °C under inert atmosphere for 10 minutes under dark conditions. To this solution, was
added 22 (102 mg, 0.211mmol) dissolved in DCM (3 mL) and the resulting solution was allowed to
come to room temperature slowly and kept overnight. The reaction mixture was then quenched with
DIEA (0.8 mL), diluted with 5 mL of DCM and the residue was filtered off. The solvent was removed
under reduced pressure and residue was purified by column chromatography to obtain the desired
product as colorless oil/semisolid. (25% yield) Rf 0.35 (3:2 Hex: EtOAc); [α]D -77.9 (c 0.8, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 5.43 (d, J = 2.1Hz, 1H), 5.19 (s, 1H), 5.10–5.08 (m, 1H), 5.04–5.01 (dd, J =
10.1, 3.7 Hz, 1H), 4.94–4.91 (dd, J = 6.2, 3.9 Hz, 1H), 4.28–4.23 (m,1H), 4.19–4.13 (m,2H), 2.12 (s,
3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.00 (s,3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.6, 170.1, 169.1,
101.1, 79.7, 78.4, 73.6, 71.4, 65.1, 62.9, 20.9(2), 20.8, 20.6; HRMS (DART-TOF) m/z calcd. for
C15H21O10 [M+H] + 361.1135, obs. 361.1107.
(4-Nitrophenyl)-2,3,4,5,7-penta-O-acetyl-β-D-glycero-D-guloseptanose (40). To a solution of 21 (130 mg,
0.274 mmol) in DCM (4 mL), was added p–nitrophenol (75 mg, 0.54 mmol), TBAS (93 mg, 0.274
mmol), stirred for 15 minutes under dark condition. To the resulting solution/suspension, was added 1M
aq. NaOH solution (4 mL), stirred vigorously, and monitored by TLC. The organic phase was washed
with cold 1M aq. NaOH solution (2 x 10 mL), water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and residue was purified by column chromatography to obtain the
1
desired product as yellow liquid. (33% yield) Rf 0.3 (1:1 Hex: EtOAc); [α]D -43.6 (c 0.3, CHCl3); H
NMR (400 MHz, CDCl3) δ 8.17 (d, J= 9.1 Hz, 2H), 7.10 (d, J = 9.1 Hz, 2H), 5.52- 5.48 (m, 2H), 5.42-
5.38 (m, 2H), 5.04-5.01 (dd, J = 9.8, 4.6 Hz, 1H), 4.28- 4.23 (ddd, J = 9.6, 7.3, 2.1 Hz, 1H), 4.20-4.17
(dd, J = 12.2, 2.1 Hz, 1H), 4.07-4.02 (m ,1H) 2.11 (s, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 2.05 (s, 3H), 2.03
13
(s, 3H); CNMR (100 MHz, CDCl3) δ 170.3, 169.3, 169.2, 169.1, 169.0, 161.3, 143.2, 125.8, 116.8,
100.5, 74.2, 72.0, 71.6, 70.3, 69.1, 64.4, 20.9, 20.9, 20.8 (2), 20,7; HRMS (DART-TOF) m/z calcd. for
C23H31N2O14 [M+NH4] + 559.1778, found 559.1778.
4-Nitrophenyl-β-D-glycero-D-guloseptanose (41). To a solution of 40 (100 mg, 0.185 mmol) in Methanol (5
mL), was added NaOMe (6 mg, 0.11 mmol), stirred overnight under N2 atmosphere in dark conditions.
The progress of a reaction was monitored by TLC. After the completion, the reaction mixture was
neutralized using Amberlite® 120 resin. Residue was filtered and the solvent was removed under
21
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
reduced pressure and residue was purified by column chromatography, then dissolved in minimum
amount of water and subjected to lyophilization to obtain the desired product as yellowish powder. (74%
yield) Rf 0.42 (1:4 MeOH: DCM); 1H NMR (400 MHz, CD3OD) δ 8.21-8.19 (dd, J = 7.2, 2.1 Hz, 2H),
7.28-7.26 (dd, J = 7.1, 2.1 Hz, 2H), 5.35 (d, J = 4.7 Hz, 1H), 4.84 (s, 5H), 4.20-4.18 (dd, J = 4.7, 2.3 Hz,
13
1H), 3.95-3.88 (m, 4H), 3.60-3.55 (dd, J = 11.9, 7.2 Hz, 1H), 3.43-3.39 (dd, J = 9.9, 5.8 Hz, 1H); C
NMR (100 MHz, CD3OD) δ 163.7, 143.8, 126.7, 117.9, 105.2, 81.0, 75.6, 75.4, 74.9, 72.7, 64.4; HRMS
(DART-TOF) m/z calcd. for C13H17NNaO9 [M+Na] + 354.0801, found 354.0975.
(4-Nitrophenyl)-2,3,4,5,7-penta-O-acetyl-α-D-glycero-D-idoseptanose (42). To a solution of 22 (183 mg, 0.379
mmol) in DCM (5 mL), was added p–Nitrophenol (116 mg, 0.834 mmol), TBAS (154 mg, 0.454mmol),
stirred for 15 minutes under dark condition. To the resulting solution/suspension, was added 1M aq.
NaOH solution (3 mL), stirred vigorously, and monitored by TLC. The organic phase was washed with
cold 1M aq. NaOH solution (2 x 10 mL), water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and residue was purified by column chromatography to obtain the
1
desired product as yellow liquid. (35% yield) Rf 0.28 (3:2 Hex: EtOAc); [α]D -68.9 (c 1.1, CHCl3); H
NMR (400 MHz, CDCl3) δ 8.23–8.20 (d, J = 9.2 Hz, 2H), 7.16–7.13 (d, J = 9.2Hz, 2H), 5.61–5.57 (m,
2H), 5.43-5.41 (dd, J = 8.1, 1.9 Hz, 1H) 5.38–5.32 (m, 2H), 4.25–4.17 (m, 3H), 2.14 (s, 3H), 2.07 (s,
3H), 2.03 (s, 3H), 2.01 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 169.7, 169.5, 169.1,
168.9, 161.1, 143.4, 125.9, 117.1, 97.9, 75.2, 73.1, 71.2, 69.9, 69.7, 63.7, 20.8, 20.7, 20.6; HRMS
(DART-TOF) m/z calcd. for C23H28NO14 [M+H] + 559.1775, obs. 559.1788.
4-Nitrophenyl-α-D-glycero-D-idoseptanose (43). To a solution of 42 (44 mg, 0.081 mmol) in Methanol (4
mL), was added NaOMe (5 mg, 0.09 mmol), stirred overnight under N2 atmosphere in dark conditions.
The progress of a reaction was monitored by TLC. After the completion, the reaction mixture was
neutralized using Amberlite® 120 resin. Residue was filtered and the solvent was removed under
reduced pressure and residue was purified by column chromatography, then dissolved in minimum
amount of water and subjected to lyophilization to obtain the desired product as yellowish powder. (73%
1
yield) Rf 0.4 (1:4 MeOH: DCM); H NMR (400 MHz, CD3OD) δ 8.21-8.19 (dd, J = 7.3, 2.0 Hz, 2H),
7.21-7.19 (dd, J = 7.3, 1.9 Hz, 2H), 5.13 (d, J = 8.0 Hz, 1H), 4.84 (s, 5H), 4.55-4.53 (dd, J = 7.9, 3.0 Hz,
1H), 4.25-4.24 (app t, J = 3.5 Hz, 1H), 4.00-3.99 (dd, J = 3.8, 0 Hz, 1H), 3.94-3.93 (dd, J = 8.4, 0.7 Hz,
1H), 3.90-3.88 (dd, J = 5.4, 3.2 Hz, 1H), 3.83-3.80 (dd, J = 11.4, 3.4 Hz, 1H), 3.66-3.64 (dd, J = 11.4,
13
5.4 Hz, 1H); C NMR (100 MHz, CD3OD) δ 165.3, 140.1, 126.8, 117.3, 94.5, 78.4, 74.3, 71.1, 70.8,
70.6, 65.0; HRMS (DART-TOF) m/z calcd. for C13H17NNaO9 [M+Na]+ 354.0801, found 354.0792.
22
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Supplementary Information
Supplementary information for this article is given via a link at the end of the document.
Acknowledgements
M. W. P. and A.P. thank Zack Cannone and Kelli M. Rutledge for assistance in synthesizing per-O-
acetyl septanoses 17-19. Dr. Nicholas Eddy is acknowledged for his assistance on the NMR kinetics
experiments. The NSF supported this work through a grant to MWP (CHE-1506567).
References
[1] a) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101, 3219-3232; b) M.
Winnnacker, E.T. Kool, Angew. Chem. Int. Ed. 2013, 52, 12498-12508.
[2] J. Saha, M. W. Peczuh, Adv. Carb. Chem. & Biochem. 2011, 66, 121-186.
[3] R. Vannam, M. W. Peczuh, Eur. J. Org. Chem. 2016, 1800-1812.
[4] a) S. Castro, M. Duff, N. L. Snyder, M. Morton, C. V. Kumar, M. W. Peczuh, Org. Biomol. Chem.
2005, 3, 3869-3872; b) M. R. Duff, W. S. Fyvie, S. D. Markad, A. E. Frankel, C. V. Kumar, J. A.
Gascón, M. W. Peczuh, Org. Biomol. Chem. 2011, 9, 154-164.
[5] C. P. Sager, B. Fiege, P. Zihlmann, R. Vannam, S. Rabbani, R. P. Jakob, R. C. Preston, A. Zalewski,
T. Maier, M. W. Peczuh, B. Ernst, Chem. Sci. 2018, ASAP, DOI: 10.1039/c7sc04289b
[6] Carbohydrate Active Enzymes (CAZY) database, http://www.cazy.org/ ; b) V. Lombard, H.
Golaconda Ramulu, E. Drula, P. M. Coutinho, B. Henrissat, Nucleic Acids Res. 2014, 42, D490–D495.
[7] A. Tauss, P. Greimel, K. Rupitz, A. J. Steiner, A. E. Stütz, S. G. Withers, T. M. Wrodnigg,
Tetrahedron: Asymmetry 2005, 16, 159-165.
[8] W. S. Fyvie, M. Morton, M. W. Peczuh, Carbohydr. Res. 2004, 339, 2363-2370.
[9] a) S. Markad, S. Xia, B. Surana, M. D. Morton, C. M. Hadad, M. W. Peczuh, J. Org. Chem. 2008,
73, 6341-6354; b) M. W. Peczuh, N. L. Snyder, W. S. Fyvie, Carbohydr. Res. 2004, 339, 1163-1171.
[10] a) S. Castro, M. W. Peczuh, J. Org. Chem. 2005, 70, 3312-3315; b) M. W. Peczuh, N. L. Snyder,
Tetrahedron Lett. 2003, 44, 4057-4061.
[11] W. S. Fyvie, M. W. Peczuh, J. Org. Chem. 2008, 73, 3626-3629.
[12] S. Castro, W. S. Fyvie, S. Hatcher, M. W. Peczuh, Org. Lett. 2005, 7, 4709-4712.
[13] J. Saha, M. W. Peczuh, Tetrahedron Lett. 2012, 53, 5667-5670.
23
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
[14] a) J. Saha, M. W. Peczuh, Chem. Eur. J. 2011, 17, 7357-7365; b) J. Saha, M. W. Peczuh, Org. Lett.
2009, 11, 4482-4484.
[15] R. Vannam, A. R. Pote, M. W. Peczuh, Tetrahedron 2017, 73, 418-425.
[16] K. Igarashi, Adv. Carb. Chem. & Biochem. 1977, 34, 243-283.
[17] R.J. Ferrier, N. J. Prasad, J. Chem. Soc. C 1969, 570-575.
[18] K. Toshima, K. Tatsuta, Chem. Rev. 1993, 93, 1503-1531.
[19] R. Vannam, M. W. Peczuh, Org. Biomol. Chem. 2016, 14, 3989-3996.
[20] R. Vannam, M. W. Peczuh, Org. Lett. 2013, 15, 4122-4125.
[21] A scheme depicting the entire synthesis is in the Supplementary Information.
[22] S. S. Nigudkar, A. V. Demchenko, Chem. Sci. 2015, 6, 2687-2704.
[23] C-S. Tsai, Y-K. Li, L-C. Lo, Org. Lett. 2002, 4, 3607-3610.
[24] a) R. Cribiu, E. Borbas, I. Cumpstey, Tetrahedron 2009, 65, 2022–2031; b) R. Cribiu, I. Cumpstey,
Chem. Commun. 2008, 1246–1248.
[25] C. S. Bennett, D. Benito-Alifonso, C. M. Galan, Selective Glycosylations: Synthetic Methods and
Catalysts 2017, 155-172.
[26] a) K. P. R. Kartha, M. Aloui, R. A. Field, Tetrahedron Lett. 1996, 37, 8807-8810; b) Whereas
glycosylation with the mannosyl iodide showed only β-glycoside formation with n-octanol, the glucosyl
iodide gave an α/β mixture. See: R. M. van Well, K. P. R. Kartha, R. A. Field, J. Carb. Chem. 2005, 24,
463-474.
[27] a) M. G. Beaver, T. M. Buscagan, O. Lavinda, K. A. Woerpel, Angew. Chem. Int. Ed. 2016, 55,
1816-1819; b) A. Martin, A. Arda, J. Désiré, A. Martin-Mingot, N. Probst, P. Sinaÿ, J. Jiménez-Barbero,
S. Thibaudeau, Y. Blériot, Nat. Chem. 2016, 8, 186-191; c) D. Whitfield, Adv. Carb. Chem. & Biochem.
2009, 62, 83-159.
[28] a) "The Anomeric Effect and Associated Stereoelectronic Effects." American Chemical Society,
Washington, D.C., 1993; b) P. Deslongchamps, "Stereoelectronic Effects in Organic Chemistry." Wiley,
New York, 1983; c) "Anomeric Effect: Origins and Consequences." American Chemical Society,
Washington, D.C., 1979; d) A. J. Kirby, "The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen." Springer Verlag, New York, 1983.
[29] a) S. Desilets, M. St. Jacques, Can. J. Chem., 1992, 70, 2650-2658; b) S. Desilets, M. St. Jacques, J.
Am. Chem. Soc. 1987, 109, 1641-1648.
[30] A conformational itinerary for septanose conformations is provided in the Supporting Information.
See also: J. F. Stoddart, "Stereochemistry of Carbohydrates." Wiley & Sons, New York, 1971.
24
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10.1002/ejoc.201800310
European Journal of Organic Chemistry
[31] a) M. DeMatteo, S. Mei, R. Fenton, M. Morton, D. M. Baldisseri, Hadad, C. M.; Peczuh, M. W.; J.
Carbohydrate Research 2006, 341, 2927-2945; b) M. DeMatteo, N. L. Snyder, M. Morton, D. M.
Baldisseri, C. M. Hadad, M. W. Peczuh, J. Org. Chem. 2005, 70, 24-38.
[32] T. K. Lindhorst, J. Schmidt-Lassen, Med. Chem. Commun. 2014, 5, 1218–1226.
[33] P. M. Moyle, C. Olive, M.-F. Ho, M. Pandey, J. Dyer, A. Suhrbier, Y. Fujita, I. Toth, J. Med.
Chem. 2007, 50, 4721-4727.
[34] V. Sureshbabu, R. Venkataramanarao, Synlett. 2007, 16, 2492-2496.
[35] K. P. R. Kartha, P. Cura, M. Aloui, S. K. Readman, T. J. Rutherford, R. A. Field, Tetrahedron:
Asymmetry 2000, 11, 581-593.
[36] H. N. Yu, C-C. Ling, D. R. Bundle, J. Chem. Soc., Perkin Trans. 2001, 8, 832-837.
[37] T. N. Nguyen, M. J. Hadd, J. Gervay, Carbohydr. Res. 1997, 300, 119-125.
[38] a) M. P. Kötzler, S. M. Hancock, S. G. Withers, 2014. Glycosidases: Functions, Families and Folds,
in eLS (encyclopedia of Life Sciences), DOI: 10.1002/9780470015902.a0020548.pub2; b) P. Bojarová,
V. Křen, Trends Biotechnol. 2009, 27, 199–209; c) J. E. Blanchard, S. G. Withers, Chemistry & Biology
2001, 8, 627-633.
[39] See table in the Supplementary Information.
[40] Y. S. Lee, E. S. Rho, Y. K. Min, B. T. Kim, K. H. Kim, J. Carbohydr. Chem. 2001, 20, 503-506.
[41] D. E. Green, C. L. Ferreira, R. V. Stick, B. O. Patrick, M. J. Adam, C. Orvig, Bioconjugate Chem.
2005, 16, 1597-1609.
[42] L. Kroger, J. Thiem, Carbohydr. Res. 2007, 342, 467-81.
[43] a) J. Wei, X. Lv, Y. Lü, G. Yang, L. Fu, L. Yang, J. Wang, J. Gao, S. Cheng, Q. Duan, C. Jin, X.
Li, Eur. J. Org. Chem. 2013, 12, 2414-2419; b) K. Sangseethong, M. H. Penner, Carbohydr. Res. 1998,
314, 245-250.
[44] During the deprotection of 27, a pNP pyranoside side product was formed in 9% yield. Structural
data on this compound is in the Supplementary Information.
[45] Y. Li, H. Mo, G. Lian, B. Yu, Carbohyd. Res. 2012, 363, 14-22.
[46] H. M. Burke, T. Gunnlaugsson, E. M. Scanlan, Org. Biomol. Chem. 2016, 14, 9133-9145.
[47] a) S. Akoka, L. Barantin, M. Trierweiler, Anal. Chem. 1999, 71, 2554-2557; b) F. Franconi, C.
Chapon, L. Lemaire, V. Lehmann, L. Barantin, S. Akoka, Magn. Reson. Imaging 2002, 20, 587-592; c)
R. K. Harris, Analyst 2006, 131, 351-373; d) D. J. Hoult, Concepts Magn. Reson. 2000, 12, 173-187.
[48] Schrödinger Release 2016-2: Maestro, Schrödinger, LLC, New York, NY, 2017.
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