Combined Lewis acid and Br?nsted acid-mediated reactivity of glycosyl trichloroacetimidate donors

Article abstract of DOI:10.1016/j.carres.2013.09.011

Biomimetic conditions for a synthetic glycosylation reaction, inspired by the highly conserved functionality of carbohydrate active enzymes, were explored. At the outset, we sought to generate proof of principle for this approach to developing catalytic systems for glycosylation. However, control reactions and subsequent kinetic studies showed that a stoichiometric, irreversible reaction of the catalyst and glycosyl donor was occurring, with a remarkable rate variance depending upon the structure of the carboxylic acid. It was subsequently found that a combination of Br?nsted acid (carboxylic acid) and Lewis acid (MgBr₂) was unique in catalyzing the desired glycosylation reaction. Thus, it was concluded that the two acids act synergistically to catalyze the desired transformation. The role of the catalytic components was tested with a number of control reactions and based on these studies a mechanism is proposed herein.

Full text of DOI:10.1016/j.carres.2013.09.011

Carbohydrate Research 382 (2013) 36–42
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Combined Lewis acid and Brønsted acid-mediated reactivity
of glycosyl trichloroacetimidate donors
⇑
Nathan D. Gould, C. Liana Allen, Brandon C. Nam, Alanna Schepartz, Scott J. Miller
Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520-8107, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2013
Received in revised form 26 September 2013
Accepted 27 September 2013
Available online 10 October 2013
Biomimetic conditions for a synthetic glycosylation reaction, inspired by the highly conserved function-
ality of carbohydrate active enzymes, were explored. At the outset, we sought to generate proof of prin-
ciple for this approach to developing catalytic systems for glycosylation. However, control reactions and
subsequent kinetic studies showed that a stoichiometric, irreversible reaction of the catalyst and glycosyl
donor was occurring, with a remarkable rate variance depending upon the structure of the carboxylic
acid. It was subsequently found that a combination of Brønsted acid (carboxylic acid) and Lewis acid
(MgBr2) was unique in catalyzing the desired glycosylation reaction. Thus, it was concluded that the
two acids act synergistically to catalyze the desired transformation. The role of the catalytic components
was tested with a number of control reactions and based on these studies a mechanism is proposed
herein.
Keywords:
Biomimetic
Catalytic
Schmidt
Glycosylation
Magnesium
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
nucleophile, attacks the anomeric carbon while the other carbox-
ylic acid donates a proton to the oxygen of the glycosidic bond,
The structural and functional characterization of carbohydrate
active enzymes holds a unique place in our evolving understanding
of sugar biochemistry as well as the structure and functionality of
biological catalysts in general.1 A prominent example of a carbohy-
drate active enzyme is lysozyme,2 a glycoside hydrolase which was
the first enzyme whose structure was solved by X-ray diffraction.3
Consequently, lysozyme was among the first enzymes for which a
detailed mechanistic proposal was put forth, which led to a more
generalized proposal for how enzymes accelerate chemical reac-
tions.4 The details of the mechanistic proposal5 and its potential
generality6 continue to be a fertile area of research.
Glycosyl transferases and hydrolases catalyze glycosidic bond
formation and hydrolysis with either retention or inversion of
the stereochemistry at the anomeric carbon. Both mechanisms typ-
ically employ two carboxylic acids contributed by either Glu or Asp
side chains. In enzymes that process these reactions with stereo-
chemical inversion at the anomeric center, the sugar substrate
and a nucleophile (water or the glycosyl acceptor) are positioned
such that one carboxylic acid donates a proton to the oxygen of
the glycosidic bond while the nucleophile, assisted by the other
carboxylate acting as a general base, attacks the anomeric carbon.
The reaction proceeds in a single step via an oxocarbenium ion-like
transition state. In retaining enzymes, one carboxylate, acting as a
generating a covalent intermediate. In a second step, a nucleophile
attacks the anomeric carbon, releasing the sugar with retention of
stereochemistry through a double inversion process.7 Enzymes
have been thoroughly exploited in the field of glycochemistry for
promoting glycosylation reactions, as their inherent reactivity
and tunable specificity allow glycosidic bonds to be formed with
complete regio- and diastereoselectivity.8 Despite these highly
attractive characteristics and the simultaneous circumventing of
many of the problems traditionally associated with chemical gly-
cosylation (such as extensive protecting group manipulations),9
enzymatic glycosylation reactions present their own challenges,
particularly when considering reaction scope and scale-up to
industrial applications.10 Synthetic mimics of glycosyl transferases
could provide alternatives worth consideration.11
Many important advances in the field of chemical glycosylation
have been made in the last decade,12 including optimization of
leaving groups at the anomeric position,13 catalytic glycosyl donor
activation under mild reaction conditions14 and even protecting
group free strategies.15 However, chemical glycosylation methods
still struggle to replicate the exceptional selectivity routinely dis-
played by enzymes. We therefore endeavored to develop synthetic
enzyme mimics (inspired by the proposed enzyme mechanisms)
that could encompass the advantages of chemical glycosylation
protocols while also displaying high efficiency and stereochemical
fidelity.
⇑
Corresponding author. Tel.: +1 2034329885.
E-mail address: scott.miller@yale.edu (S.J. Miller).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.09.011

N. D. Gould et al. / Carbohydrate Research 382 (2013) 36–42
37
Table 1
2. Results and discussion
2.1. Initial studies
Initial catalyst screena
HN
CCl3
The high structural variability of carbohydrate-activating en-
zymes with relatively conserved carboxylic acid active site resi-
dues1 prompted us to investigate how a small peptide presenting
convergent carboxylic acid functionalities (to mimic the conserved
functionality of carbohydrate active enzymes) might interact with
a carbohydrate and whether this knowledge could then be applied
to establish a general, catalytic glycosyl transfer reaction (Fig. 1a).
Based in part on our previous studies of glycosylation16 we
decided to initiate this research with a simple glycosyl donor that
is amenable to Brønsted acid catalysis, namely a glycosyl trichloro-
acetimidate17 (Fig. 1b). As shown in Table 1, in our initial catalyst
screening efforts we sought to compare the catalytic activity of
simple carboxylic acids with those derived from amino acids.
Our initial survey was characterized largely by low yields, per-
haps in part due to mismatched pKas—most of the carboxylic acids
we evaluated possess pKas which are well outside the domain pro-
ven competent for trichloroacetimidate activation. This mismatch
is well demonstrated by a comparison of the yields obtained when
using p-toluene sulfonic acid (pKa = À3) and benzoic acid (pKa = 4),
which are 92% and 0%, respectively (Table 1, entries 1 and 2).
3,3-Dimethylpentanedioic acid also did not catalyze the glycosyla-
tion of cyclohexanol with glycosyl donor 1 (Table 1, entry 3). A
small amount of the desired product 2 was formed with (N-Boc)As-
p(OMe) as catalyst (Table 1, entry 4), and a modest yield of 32%
was obtained with tetrapeptide 3 (Table 1, entry 5).
OH
O
O
O
O
Catalyst (10 mol%)
CH2Cl2, r.t., 18 h
BnO
BnO
BnO
+
OBn
BnO
OBn
OBn
OBn
2
1
Entry
115
Catalyst
Yield 2 (%)
O
S
O
OH
92 (1.5 h reaction time)
O
2
3
0b
0b
OH
CO2H
CO2H
O
OMe
Boc
4
12
N
H
CO2H
O
Me
HN
Me
N
O
O
HN
5
32
Whilst little to no glycosylation of the acceptor cyclohexanol
was observed, upon inspection of the product distribution after
the reactions were stopped we found a combination of unreacted
starting material and glycosylated catalyst, or ‘catalyst-rebound’
product. The low yields of glycosylated cyclohexanol can poten-
tially be attributed to catalyst consumption via ‘rebounding’ to
the glycosyl imidate substrate. Indeed, no reaction was observed
when subjecting the glycosylated catalyst to the same reaction
conditions.18
HO2C
NH
Boc
CO2CH3
CO2H
3
a
Ratio of a:b trichloroacetimidate donor varied in each reaction. Reactions were
all run multiple times and yield was unaffected by this initial donor ratio.
b
Not observed to a significant extent.
ature and the reaction progress followed by 1H NMR. The reaction
rate was estimated by performing regression analysis of multiple
runs. The 1H NMRs were compared with those of authentic sam-
ples of the glycosyl esters (see Supplementary data). We observed
a significant broadening of the imidate NH proton peak upon mix-
ing any of the acids with 1. This broadening was attributed to an
interaction between the carboxylic acid and the imidate, likely
indicating a fast interaction that reverts in a pre-equilibrium fash-
ion prior to the rate-determining bond forming reaction.
2.2. Kinetics studies
As enzyme-bound glycosyl esters have been proposed to be rel-
evant intermediates in retentive glycosyl transferases,19 we sought
to investigate the details of this transformation more thoroughly.
To this end, the kinetics of the rebound reaction of a number of car-
boxylic acids (including di-acids) was investigated and the results
displayed below in Table 2.
In each example, a stoichiometric amount of trichloroacetimi-
date 1 and carboxylic acid (or di-acid) was mixed at room temper-
It was found that the rebound reactivity of the carboxylic acids
studied varied by a remarkable range of ꢀ104 (at room tempera-
a
b
O
O
O
O
O
O
peptide
peptide
H
OR
H
O
OR
R
O
O
O
R
RO
RO
RO
RO
OR
OR
O
P
O
CCl3
NH
O
P OR'
OH OH
H
O
H
O
O
O
Figure 1. Proposed catalytic action of a peptide containing two carboxylic acid groups on (a) glucose bearing a diphosphate leaving group and (b) glucose bearing a
trichloroacetimidate leaving group (‘Schmidt glycosidation’).

38
N. D. Gould et al. / Carbohydrate Research 382 (2013) 36–42
Table 2
Rate of rebound reaction with various carboxylic acidsa
O
O
R
HN
CCl3
R
OH
O
O
O
O
(1 equiv.)
BnO
BnO
BnO
BnO
CDCl3, r.t., 1.5 h
OBn
OBn
OBn
OBn
4 - 8
1
Entry
1
Acid
Acid pKa
Product
Relative reactivity
Stereochemical outcomeb
Invertive
O
4.1
3.4
3.8
4
10À4
OH
O
10À4
Invertive
OH
2
3
5
6
O2N
Boc
CO2H
CO2H
10À2
>90% Invertive
O
OMe
4
2.1
7
1
Invertive
N
H
CO2H
O
Me
HN
Me
N
O
O
HN
5
2.1
8
4
1.5:1 Invertive:Retentive
HO2C
NH
Boc
CO2CH3
CO2H
3
a
Ratio of
a
:b trichloroacetimidate donor varied in each reaction. Reactions were each run multiple times and yield was unaffected by this initial donor ratio.
or pure b trichloroacetimidate donor (see Supplemenatry
b
Stereochemical outcome determined from synthesis of ‘NMR standards’ of the ester products, using pure
a
data).
ture). For example, both benzoic acid and p-nitro benzoic acid
(Table 2, entries 1 and 2) rebounded significantly more slowly than
(N-Boc)aspartate methyl ester (Table 2, entry 4). In contrast, the
di-acid 3 (Table 2, entry 5) rebounded four times faster than
(N-Boc)aspartate methyl ester. These large differences in rebound
reactivity might be rationalized by a difference in the stability of
the ionized carboxylates. This trend also generally inversely corre-
lates with the pKa of the carboxylic acid catalyst (higher pKa leads
to lower rate of reaction, as the stability of the corresponding car-
boxylate anion itself inversely correlates with the pKa value). The
more reactive acids also have the potential for intramolecular
hydrogen bond stabilization of the intermediate carboxylate ion
(9, Scheme 1).
The completely invertive nature of the rebound reaction indi-
cates that the intermediate ion pair(s) generated by reaction of
the carboxylic acid and imidate are likely intimate and not solvent
separated.20 The data also show that once a carboxylic acid has re-
bounded, the catalytic cycle stops (Scheme 1).
Divalent magnesium ions are prevalent in biological systems as
cofactors to enzymes and have been shown to enhance the cata-
lytic activity of such systems.21 Additionally, Lewis acids have pre-
viously been shown to promote glycosylation reactions of
trichloroacetimidates.22 With these observations in mind, magne-
sium bromide was investigated as an additive in this reaction, with
the hope that an increasingly biomimetic approach would lead to a
glycosylation protocol that was catalytic in carboxylic acid.
Indeed, when MgBr2ÁOEt2 is used as an additive, the ‘rebound’
product (glycosylated catalyst) is not observed. Moderate yields
of the desired glycosylated alcohol were achieved, along with
two major side products—(tetrabenzyl)-glucose, formed by
hydrolysis of the imidate and (tetrabenzyl)-glucosyl bromide
(14, Scheme 2). As is to be expected, formation of these two side
products appears to increase with decreasing nucleophilicity of
the alcohol. Unfortunately in this small substrate screen no
significant difference in diastereoselectivity was observed when
comparing (N-Boc)aspartate methyl ester with our peptide catalyst
(3, see Table 1, entry 4).
2.3. Mechanistic studies
In light of the biological relevance of combined catalytic carbox-
ylic acids and magnesium ions we found the effect of MgBr2ÁOEt2
to be an intriguing observation. A focused set of experiments was
then conducted to attempt to elucidate the role of MgBr2ÁOEt2 in
this reaction. Though Lewis acid activation of glycosyl trichloroace-
timidates is known,9 in this case the magnesium salt itself was not
a competent catalyst, giving very low yields of glycosylated prod-
uct in the absence of a carboxylic acid (Scheme 2, pathway A). Sim-
ilarly, subjecting the ‘rebound product’ 15 to MgBr2ÁOEt2 in the
presence of cyclohexanol led to no reaction (Scheme 2, pathway
B1), suggesting that the reaction does not proceed via the glycosyl
ester.
A glucosyl bromide side product, 14 is observed in crude NMR
spectra of the reactions shown in Table 3, and appears to be formed
by activation of the imidate by the carboxylic acid in the presence
of MgBr2ÁOEt2 (Scheme 2, pathway C). The bromide 14 was not

N. D. Gould et al. / Carbohydrate Research 382 (2013) 36–42
39
Cy
O
O
BnO
OH
BnO
OBn
O
OMe
O
OBn
Boc
O
N
H
HN
CCl3
OH
O
9
X
O
O
BnO
BnO
BnO
BnO
OBn
OBn
O
R
O
OBn
OBn
O
BnO
BnO
O
O
OMe
OBn
Cl3C
NH2
OBn
BocHN
HO
O
Scheme 1. Proposed reaction pathways.
O
R
O
O
MgBr2.OEt2
R'OH
O
O
BnO
BnO
BnO
BnO
R'
OBn
No reaction
OBn
B1
OBn
15
OBn
very slow
A
MgBr2.OEt2
R'OH
very slow
Mg2+
O
O
O
B2
Mg2+
HN
CCl3
O
R
R
O
H
N
H
N
O
O
CCl3
CCl3
R
OH
fast
BnO
BnO
H
O
H
O
O
O
OBn
BnO
BnO
BnO
BnO
OBn
OBn
OBn
1
OBn
OBn
D
C
Br
HBr (10 mol%)
E
R'OH
MgBr2.OEt2
R'OH
O
Br
OBn
O
O
BnO
BnO
BnO
BnO
R'
OBn
slow
OBn
OBn
14
Scheme 2. Summary of mechanistic investigations.
formed from the reaction of the imidate and MgBr2ÁOEt2 alone, nor
was it observed when the imidate was mixed with an alcohol in
the presence of MgBr2ÁOEt2 (Scheme 2, pathway A). In the presence
of both magnesium salt and carboxylic acid, the glucosyl imidate
forms a mixture of 14 and the ‘rebound product’ 15, however the
rate of formation of the glycosyl ester is much slower, indicating
that the magnesium is acting to inhibit this ‘rebound’ reaction, pos-
sibly via coordination to the carboxylate anion (Scheme 2, pathway

40
N. D. Gould et al. / Carbohydrate Research 382 (2013) 36–42
Table 3
Glycosylation of alcoholsa
HN
CCl3
R
O
Catalyst (10 mol%)
MgBr2.OEt2 (25 mol%)
O
O
O
BnO
BnO
BnO
BnO
ROH
CDCl3, r.t., 24 h
OBn
OBn
OBn
OBn
2, 10 - 13
1
Entry
1
Product
Equiv ROH
Catalyst
Conv.b (%)
Ratio a:b
O
O
1.2
1.2
(N-Boc)Asp(OMe)
3
67
52
1:0.43
1:0.43
BnO
BnO
Cy
OBn
OBn
2
O
O
1.2
1.2
(N-Boc)Asp(OMe)
3
32
21
1:0.09
1:0.01
BnO
BnO
OBn
2
3
OBn
10
1.5
1.5
(N-Boc)Asp(OMe)
3
56
58
1:0.25
1:0.24
OMe
OBn
OBn
OBn
O
O
O
BnO
BnO
OBn
OBn
11
Ph
O
O
O
HO
OMe
12
a:12b:13a:13b
1.5
(N-Boc)Asp(OMe)
32
0.28:0.27:1:0.50
O
O
BnO
BnO
OBn
4
OBn
12
OMe
O
O
Ph
O
O
OH
1.5
3
36
0.15:0.15:1:0.57
O
BnO
BnO
OBn
OBn
13
a
Ratio of a:b trichloroacetimidate donor varied in each reaction. Reactions were each run multiple times and both yield and stereochemical outcome were unaffected by
this initial donor ratio.
b
Conversion determined by 1H NMR peak comparison to a mesitylene internal standard.
B2). It is possible that the magnesium carboxylate also serves as a
base to assist with the alcohol coupling to the activated donor via
pathway B2 followed by pathway E.
The possibility that HBr is being generated in the reaction and
acting as a glycosylation catalyst cannot be excluded therefore
we set out to test this hypothesis directly. When the imidate was
glycosylation of the alcohol through a catalytically competent ion
pair. This species then undergoes displacement at the anomeric
center, either directly by the alcohol or by a bromide ion, the latter
generating a glucosyl bromide which can itself then act as glycosyl
donor to produce the desired glycosylated alcohol product.
treated with 10 mol % HBr, it was found that 10 mol % of glucosyl
bromide 14 was formed (Scheme 2, pathway D), along with a sig-
nificant amount of tetrabenzyl glucose. In a separate reaction, it
was also found that when glucosyl bromide 14 is exposed to
MgBr2ÁOEt2 in the presence of an alcohol, slow formation of the
glycosylated alcohol product was observed. Therefore, the genera-
tion of a glucosyl bromide which then acts as the glycosyl donor
cannot be excluded as a minor reaction pathway.
3. Conclusions
In conclusion, in this work we first examined the kinetic profiles
of the additions of various carboxylic acids to glucosyl trichloro-
acetimidates to yield glucosyl esters. We observed a significant dif-
ference in relative rate of reaction between the five carboxylic
acids studied. The stereochemical outcome of these reactions was
also studied. It was found that the mono-acids displayed com-
pletely invertive reactivity, while the two di-acids yielded a mix-
ture of inverted and retentive products.
Based on these observations, we tentatively propose a mecha-
nistic rational wherein the mild Lewis acid serves to promote

N. D. Gould et al. / Carbohydrate Research 382 (2013) 36–42
41
These findings were then exploited to develop a glycosylation
reaction in which divalent magnesium ions are proposed to inhibit
the undesired ‘rebound’ reaction pathway and allow the formation
of glycosylated alcohol and disaccharide products. While the addi-
tion of MgBr2ÁOEt2 to the reactions did indeed inhibit glycosyl ester
formation, the enantiopure amino acid co-catalysts did not influ-
ence the selectivity at the anomeric position. Further exploration
of metal ion assisted chemical glycosylation is ongoing in our
laboratory.
94.64 (C1), 82.09, 79.95, 77.86, 75.63, 75.24, 75.12, 73.41, 72.93,
70.02, 68.56, 33.32, 31.42, 25.60, 24.46, 24.17; IR of anomeric mix-
ture (ATR, thin film, cmÀ1): 3063 (w), 3030 (w), 2931 (s), 2857 (s),
2157 (m), 2033 (m), 1975 (m) 1496 (w), 1452 (m), 1362 (m); MS of
anomeric mixture (ESI, C40H46O6): Calcd: 645.32 (100.0%), 646.32
(43.3%), 647.33 (9.1%), Found: 645.22 (100.0%), 646.02 (49.2%),
647.77 (9.9%).
4.3. Kinetic data acquisition
To an oven dried, 4-mL vial were added trichloroacetimidate-
(2,3,4,6-O-benzyl)-glucose (1, viscous oil, 0.010 g, 0.015 mmol,
4. Experimental
1.5:1.0
a:b ratio, 1 equiv), and CDCl3 (0.5 mL). A stock solution of
4.1. General methods
NMR standard mesitylene in CDCl3 (0.05 mL, 0.005 mmol mesity-
lene) was then added to the vial. This solution was then transferred
to an NMR tube and a 1H NMR spectra taken to represent time = 0.
The appropriate carboxylic acid catalyst (see Table 2) was then
added (0.015 mmol in 0.05 mL CDCl3) to the NMR tube in a single
portion and 1H NMR spectra acquired periodically (typically every
two minutes) over the course of up to 1 h and 40 min. The resulting
1H NMRs were compared with those of authentic samples of the
glycosyl esters (see Supplementary data).
Proton NMR spectra were recorded on a 400 or 500 MHz spec-
trometer. Proton chemical shifts were reported in ppm (d) with the
residual protium in the NMR solvent as a reference (CHCl3, d 7.26
relative to tetramethylsilane). CDCl3 for kinetic experiments was
filtered through basic alumina immediately before use. The listed
spectral data are reported as follows: chemical shift (multiplicity
[singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m)], cou-
pling constants [J = Hz], integration; assignment if determined).
Carbon NMR spectra were recorded on a 100 or 126 MHz spec-
trometer with complete proton decoupling. Carbon chemical shifts
are reported in ppm (d) relative to the solvent signal (CDCl3, d
77.0). Analytical thin-layer chromatography (TLC) was performed
using Silica Gel 60 Å F254 pre-coated plates (0.25 mm thickness).
TLC visualization was accomplished by irradiation with a UV lamp,
an iodine chamber, and/or ceric ammonium molybdate stain
(CAM). Liquid chromatography–mass spectrometry (LC/MS) was
performed on a Waters Acquity instrument equipped with dual
atmospheric pressure chemical ionization (API)/electrospray ioni-
zation (ESI), a SQ mass spectrometer, and a photodiode array
detector. High-resolution liquid chromatography–mass spectrom-
etry (HR-LC/MS) was performed on a Waters XEVO instrument
equipped with ESI, a QToF mass spectrometer, and a photodiode
array detector. Analytical high-performance liquid chromatogra-
phy (HPLC) was performed on an Agilent 1100 Series instrument
equipped with a diode array detector. Medium-performance liquid
chromatography (MPLC) was performed on a Biotage SP4 instru-
ment equipped with a diode array detector and liquid handler. Tet-
rahydrofuran (THF), dichloromethane (CH2Cl2), and toluene were
purified by a Seca Solvent Purification System from GlassContour
(Nashua, NH). All other chemicals were commercially available
and used as received.
4.4. Mg2+ ion assisted glycosylation
Acid catalyst (0.0073 mmol, 0.1 equiv), alcohol (0.1095 mmol,
1.5 equiv), and MgBr2ÁEt2O (4.7 mg, 0.0183 mmol, 0.25 equiv) were
added to an oven-dried vial (A), fitted with a stir bar. 2,3,4,6-Tetra-
O-benzyl-glucopyranose
0.073 mmol, 1.0 equiv) was directly weighed into a separate vial
(B). CH2Cl2 (600 L) and mesitylene (1 L) were added to (B) and
trichloroacetimidate
1
(50 mg,
l
l
the solution was mixed. The solution in (B) was transferred into
(A) and that vial was capped, left to stir for 5 h before an 1H NMR
was taken. Basic alumina was added to quench the reaction and
the mixture was filtered over celite and washed thoroughly with
CH2Cl2. The solvent was removed under vacuum and the product
was chromatographed on silica gel (20–40% EtOAc/hexanes).
Acknowledgment
The authors are grateful to the W.M. Keck Foundation for finan-
cial support and encouragement.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.
09.011.
4.2. Cyclohexyl-(2,3,4,6-tetra-O-benzyl)-glucopyranose (2)
To an oven dried, 4-mL vial were added a stir bar, (2,3,4,6-tetra-
O-benzyl)-glucopyranosyl trichloroacetimidate (1, viscous oil,
References
0.045 g, 0.067 mmol, 1.5:1.0
a:b ratio, 1 equiv), and chloroform
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(0.5 mL). Cyclohexanol was then added (0.015 mL, 0.13 mmol,
2 equiv) and the vial flushed with nitrogen. The appropriate car-
boxylic acid catalyst (see Table 1) was then added (0.2 equiv)
and the reaction then allowed to stir at room temperature for
5 h. After 5 h the sample was loaded directly onto a silica column
and purified by column chromatography (0–20% ethyl acetate in
hexanes, slow gradient) before analysis. Compound 2, major (a)
anomer: 1H NMR (500 MHz, CDCl3); 7.46–7.15 (m, 20H), 7.10–
7.00 (m, 2H), 5.00–4.82 (m, 12H), 4.82–4.59 (m, 2H), 4.53 (dd,
J = 23.9, 11.6, 3H), 4.41 (t, J = 13.6, 2H), 3.93 (t, J = 9.3, 1H), 3.81
(d, J = 9.5, 1H), 3.67 (dd, J = 10.5, 3.3, 1H), 3.62–3.40 (m, 4H),
1.91–1.60 (m, 4H), 1.58–0.68 (m, 10H); 13C NMR (126 MHz, CDCl3):
138.96, 138.29, 138.22, 137.97, 128.37, 128.36, 128.35, 128.31,
128.08, 127.98, 127.90, 127.86, 127.77, 127.68, 127.62, 127.49,
ˇ
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