Cation clock reactions for the determination of relative reaction kinetics in glycosylation reactions: Applications to gluco- and mannopyranosyl sulfoxide and trichloroacetimidate type donors

Article abstract of DOI:10.1021/jacs.5b06126

The development of a cation clock method based on the intramolecular Sakurai reaction for probing the concentration dependence of the nucleophile in glycosylation reactions is described. The method is developed for the sulfoxide and trichloroacetimidate glycosylation protocols. The method reveals that O-glycosylation reactions have stronger concentration dependencies than C-glycosylation reactions consistent with a more associative, S_N2-like character. For the 4,6-O-benzylidene-directed mannosylation reaction a significant difference in concentration dependence is found for the formation of the β- and α-anomers, suggesting a difference in mechanism and a rationale for the optimization of selectivity regardless of the type of donor employed. In the mannose series the cyclization reaction employed as clock results in the formation of cis and trans-fused oxabicyclo[4,4,0]decanes as products with the latter being strongly indicative of the involvement of a conformationally mobile transient glycosyl oxocarbenium ion. With identical protecting group arrays cyclization in the glucopyranose series is more rapid than in the mannopyranose manifold. The potential application of related clock reactions in other carbenium ion-based branches of organic synthesis is considered.

Full text of DOI:10.1021/jacs.5b06126

Article
pubs.acs.org/JACS
Cation Clock Reactions for the Determination of Relative Reaction
Kinetics in Glycosylation Reactions: Applications to Gluco- and
Mannopyranosyl Sulfoxide and Trichloroacetimidate Type Donors
Philip O. Adero,† Takayuki Furukawa,†,§ Min Huang,‡,∥ Debaraj Mukherjee,†,⊥ Pascal Retailleau,‡
Luis Bohe,‡ and David Crich*,†
́
†Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
‡Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Universite
Gif-sur-Yvette, France
́
Paris-Sud, Avenue de la Terrasse, 91198
S
* Supporting Information
ABSTRACT: The development of a cation clock method based
on the intramolecular Sakurai reaction for probing the
concentration dependence of the nucleophile in glycosylation
reactions is described. The method is developed for the sulfoxide
and trichloroacetimidate glycosylation protocols. The method
reveals that O-glycosylation reactions have stronger concentration
dependencies than C-glycosylation reactions consistent with a
more associative, SN2-like character. For the 4,6-O-benzylidene-
directed mannosylation reaction a significant difference in
concentration dependence is found for the formation of the β-
and α-anomers, suggesting a difference in mechanism and a
rationale for the optimization of selectivity regardless of the type
of donor employed. In the mannose series the cyclization reaction employed as clock results in the formation of cis and trans-
fused oxabicyclo[4,4,0]decanes as products with the latter being strongly indicative of the involvement of a conformationally
mobile transient glycosyl oxocarbenium ion. With identical protecting group arrays cyclization in the glucopyranose series is
more rapid than in the mannopyranose manifold. The potential application of related clock reactions in other carbenium ion-
based branches of organic synthesis is considered.
According to Ingold and Hughes,5 the mechanism of a
INTRODUCTION
■
substitution reaction is characterized by its stereochemistry and
its kinetics, yet the enormous majority of glycosylation
reactions reported in the literature are discussed only in
terms of their stereoselectivity. There is no doubt that this
situation pertains because of the preparative significance of the
selectivity, but it is also to some extent due to the difficulty in
conducting kinetic studies on many glycosylation reactions.
The role of ion pairs in nucleophilic substitution reactions in
general has been appreciated6,7 since Winstein’s seminal
contribution,8 and in glycosylation in particular since the
work of the Vernon,9 Schuerch,10 and Lemieux groups,11 yet
the glycosylation literature is replete with depictions of naked
glycosyl oxocarbenium ions lacking their essential counterions,
a fact which is even more surprising when the sparse physical
evidence for existence of such glycosyl oxocarbenium ions is
taken into account.12−20 Even admitting the transient existence
of glycosyl oxocarbenium ions, the widespread (and dis-
puted21,22) application of basic stereoelectronic principles23,24
In the realm of glycoscience the formation of glycosidic bonds
reigns over all other covalent bond forming processes, being
central to the preparation of homogeneous glycoconjugates and
(oligo)saccharides of all shades. Dating back more than 130
years to the Michael synthesis of aryl glycosides,1 the Fischer
glycosidation,2 and the Koenigs−Knorr reaction,3 the chemical
synthesis of glycosidic bonds has been extensively researched
through the investigation of innumerable combinations of
glycosyl donors, glycosyl acceptors, promoters, solvents,
temperature and additives. Indeed, if the year 1994 is taken
as representative of the annual level of activity in the last several
decades,4 it could be suggested that the entire history of
glycosidic bond forming reactions can be classified as a century-
long, worldwide exercise in the combinatorial exploration of
reaction conditions. This situation arises in part because of the
enormous variety of glycosidic linkages possible, both natural
and artificial, but also because of uncertainty in the location of
any one particular reaction on the SN1-SN2 continuum of
mechanisms for nucleophilic substitution reactions. It follows
that any given glycosylation reaction might be more rationally
optimized if its mechanism could be pinpointed, or at least
localized, without undue expenditure of effort.
Received: June 12, 2015
© XXXX American Chemical Society
A
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to the rationalization of their face selectivity is of a relatively
recent vintage.25,26
Scheme 1. Cyclization of Protecting Groups at the 2-
Position onto the Anomeric Center
In our laboratory, driven by the desire to rationalize the
benzylidene-directed β-mannopyranosylation,27,28 and con-
scious of the major contribution of kinetic isotope effect
(KIE) measurements to the understanding of the mechanisms
of chemical and enzymatic glycosidic bond hydrolysis and
transfer,29−33 we have introduced34,35 variants on the Singleton
NMR method36 for the determination of kinetic isotope effects
in glycosylation reactions. Nevertheless, however informative
these experiments, they are highly instrument intensive and
consequently not routinely applicable. Therefore, we sought
simple alternative methods for the determination of the relative
kinetics and molecularity of glycosylation reactions, such as
might be applied in synthetic glycochemistry laboratories, and
so to inform the rational optimization of glycosylation
reactions. To this end we turned to the development of
competition experiments for assessing the relative kinetics of
two reactions, a concept that is deeply ingrained in the field of
organic (and inorganic) chemistry.37−54
sensitivity of such cyclizations to the structure and reactivity of
the nucleophilic function.
In carbohydrate chemistry the Jencks azide clock reaction
played an important role in estimating the lifetimes of transient
glycosyl oxocarbenium ions in aqueous media,49,50 but it is not
adaptable to the study of glycosylation reactions in organic
solution at low temperature. Seeking an operationally simple
method we focused on cyclization reactions as unimolecular
clocks for the investigation of intermolecular glycosylation
reactions. In this Article we report in full on our initial design55
of such glycosylation clock reactions, present further examples,
discuss the evidence for the transient formation of certain
glycosyl oxocarbenium ion intermediates, and apply the results
to rationalize the variation of glycosylation stereoselectivity
according to conditions. Although this article focuses on
glycosylation and oxocarbenium ions, we note that the concept
of cyclization reactions as simple cation clocks for estimating
the molecularity of nucleophilic attack on transient carbenium
ions should, with suitable adaptation, find application in
cognate fields.
Recalling Denmark’s use of allylsilanes as nucleophiles in a
series of cyclization-based probes designed to interrogate the
mechanism of the Lewis acid promoted reaction of allylsilanes
with acetals (Scheme 2),70 and other instances of the
Scheme 2. Use of an Intramolecular Allylsilane-Acetal
Reaction as a Probe of Mechanism
intramolecular Sakurai reaction,71 we designed an initial system
5 (Scheme 3) employing a 2-O-(2-trimethylsilylmethyl)allyl
Scheme 3. Initial Clock Cyclization Design
RESULTS AND DISCUSSION
■
Design. Our design of cyclization reactions for use as
intramolecular glycosylation clocks was informed by the general
concept of intramolecular aglycone delivery56−60 and, more
particularly, by two instances in our own laboratories of the
cyclization of protecting groups at O2 of glycosyl donors onto
the anomeric center in the course of previous studies (Scheme
1). Thus, it was observed61 that on warming above 5 °C in
CD2Cl2 the α-mannosyl triflate 1 underwent decomposition
with cyclization onto a benzyl group to give the tricyclic
product 2, which was isolated in 56% yield. On the other hand,
the corresponding α-mannosyl triflate derived by in situ
activation of the sulfoxide 3 underwent cyclization at −78 °C
in CH2Cl2 onto the naphthylpropargyl system in competition
with reaction with an external alcohol,62 with yields varying as
an inverse function of the reactivity of the external alcohol. In
contrast, simple allyl ethers,63−65 propargyl ethers66,67 and [3-
(4-trifluoromethylphenyl)propargyl] ethers68,69 may be em-
ployed as protecting groups for the O2-postion in mannosy-
lation reactions without complications arising from cyclization.
Thus, while the precedent certainly gave rise to the potential for
the use of a carbon−carbon bond forming cyclization reaction
onto an O2 protecting group as an intramolecular clock
reaction for glycosylation reactions, it also highlighted the
group as intramolecular nucleophile. In addition to excluding
the formation of an analysis-complicating additional stereogenic
center, as observed in the model cyclization of 3 to 4 (Scheme
1), this system takes advantage of the much increased
nucleophilicity of allylsilanes over simple alkenes in their
reaction with carbocations,72 thereby increasing the likelihood
that cyclization will compete with trapping by an external
alcohol nucleophile. Finally, the system envisaged finds
precedent in the well-known C-glycoside-forming intermolec-
ular reaction of allylsilanes with putative anomeric oxocarbe-
nium ions.25,26,73−90 The use of more potent tethered
nucleophiles, such as alcohols, for the clock cyclization was
not explored as it was considered that the high effective
molarity of an intramolecular alcohol would lead to an
excessively fast cyclization that would outcompete the
intermolecular process.
Because of the important role that the 4,6-O-benzylidene
protected α-mannopyranosyl triflates91 have played in the
current debate on glycosylation mechanisms,12,15−20,27,28,92−98
B
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the initial work was focused on the use of the mannosyl
sulfoxides as precursors of the mannosyl triflates. Conscious of
the ever-widening range of donor types capable of providing β-
mannopyranosides when used in conjunction with the 4,6-O-
benzylidene or related acetals,93,94,99−110 in this study we
extend the glycosyl clock method to include the use of the very
popular glycosyl trichloroacetimidates.111 The method is also
extended to the 3,4,6-tri-O-benzyl mannopyranoside and the 3-
O-benzyl-4,6-O-benzylidene-glucopyranoside series, although it
must be recognized that this does not permit direct
comparisons of relative glycosylation rates between the differing
series owing to structural differences in the clock cyclizations.
Synthesis. The synthesis of the 4,6-O-benzylidene man-
nopyranosyl sulfoxide clock began with phenyl 4,6-O-
benzylidene-α-D-thiomannopyranoside 7112−114 while that of
the corresponding trichloroacetimidate followed a similar path
from 2-phenylthioethyl 4,6-O-benzylidene-α-D-mannopyrano-
side 8 (Scheme 4), which was prepared by standard means
mixture of diastereomers in which the major isomer is assigned
the R configuration at sulfur consistent with the prece-
dent.118−120 Treatment of the phenylthioethyl glycoside with
lithium naphthenalide121 in THF at −78 °C gave the
mannopyranose 14 in 78% yield, which was converted to the
α-trichloroacetimidate 15 in 78% yield on reaction with
trichloroacetonitrile in the presence of DBU122 (Scheme 4).
The synthesis of the corresponding 3,4,6-tri-O-benzyl
mannopyranosyl sulfoxide clock 18 was achieved analogously
from phenyl 3,4,6-tri-O-benzyl-α-D-thiomannopyranoside 16123
(Scheme 5).
Scheme 5. Synthesis of the Perbenzyl Mannopyranosyl
Clock
Scheme 4. Synthesis of the 4,6-O-Benzylidene-protected
Mannopyranosyl Clocks
In the 4,6-O-benzylidene glucopyranose series (Scheme 6)
synthesis of the sulfoxide clock 21 set out from the 3-O-benzyl
derivative 19,124 of which alkylation with sodium hydride and
iodomethylallyl trimethylsilane in hot THF gave 20 albeit only
in poor yield. Oxidation with mCPBA then gave a 3:2 mixture
of the two isomers of the sulfoxide 21 in 76% yield (Scheme 6),
with the major isomer assigned as the R configuration at sulfur
consistent with the precedent.119,120 The two diastereomers of
21 were separable chromatographically but were typically used
as mixtures in the kinetic runs that follow. The synthesis of the
trichloroacetimidate clock 27 began with 2-phenylthioethyl 3-
O-benzyl-2,4,6-tri-O-acetyl-β-D-glucopyranoside 22,125 itself
obtained by standard means from 3-O-benzyl-1,2;5,6-di-O-
isopropylidene-α-D-glucofuranose (Supporting Information).
Thus, saponification of 22 gave the triol 23 onto which the
benzylidene group was installed in the usual manner to afford
2-phenylthioethyl 3-O-benzyl-4,6-O-benzilidene-β-D-glucopyra-
nose 24. Trimethylsilylmethallylation under the improved
conditions then gave 25 in 89% yield. Finally, cleavage of the
phenylthioethyl group was achieved with lithium naphthenalide
to give 26, and the trichloroacetimidate was installed with the
aid of sodium hydride122 affording the trichloroacetimidate
clock 27 (Scheme 6).
Clock Cyclization Reactions. Treatment of the 4,6-O-
benzylidene-protected mannosyl sulfoxide 13 with triflic
anhydride in dichloromethane at −72 °C in the presence of
the hindered non-nucleophilic base 2,4,6-tri-tert-butylpyrimi-
dine (TTBP) with quenching at −72 °C after stirring for 2.5 h
resulted in the isolation of two tricyclic products 28 and 29 in
45 and 25% isolated yield, respectively (Chart 1, Table 1, entry
1). Attempted activation of the corresponding trichloroaceti-
midate 15 with catalytic TMSOTf at the same temperature
resulted in a very slow reaction. However, raising the
temperature to −20 °C enabled a rapid smooth reaction
resulting in the isolation of 28 and 29 in 70 and 25% yields,
from pentaacetyl mannopyranose and phenylthioethanol
(Supporting Information). Standard115 regioselective mono-
benzylation of 7 and 8 with dibutyltin oxide, cesium fluoride
and benzyl bromide gave 9116 and 10, respectively, ready for
the installation of the allylsilane moiety. In the phenyl
thioglycoside series studied initially this was achieved with
sodium hydride and commercial 2-(chloromethyl)allyl trime-
thylsilane in hot THF and gave the anticipated product 11 in
47% yield after 7 days. Subsequently, working with the
phenylthioethyl glycosides, we have preferred initial conversion
of the chloromethylallysilane to the corresponding iodomethy-
lallylsilane117 with sodium iodide in acetone followed by
reaction with the substrate and sodium hydride in THF at 0 °C
in the presence of 15-crown-5, when the product 12 was
obtained in 81% with greatly reduced reaction times.
Controlled oxidation of the thioglycoside 11 with mCPBA in
dichloromethane at −72 °C gave the sulfoxide 13 as a 16:1
C
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Scheme 6. Synthesis of the 4,6-O-Benzylidene-protected Glucopyranosyl Clocks
and can typically be suppressed by working in the presence of a
sacrificial alkene.62,126 However, even working in the presence
of multiple equivalents of 1-octene or the highly reactive β-
pinene127,128 we were unable to obtain a satisfactory yield of 32
(Chart 1, Table 1, entry 4). This observation, coupled with the
relative paucity of such side reactions in the mannose series
(Table 1, entries 1−3), suggests an intramolecular process and
caused us to abandon the use of the gluco-configured sulfoxide
21 in clock reactions. Fortunately, the glucosyl trichloroaceti-
midate 27 behaved in the anticipated manner resulting in a 92%
isolated yield of the cyclization product 32 following activation
with TMSOTf in the presence of TTBP at −20 °C (Chart 1,
Table 1, entry 5).
Chart 1. Clock Cyclization Products
The structure of the manno-configured trans,trans-tricyclic
system 29, with the pyranose ring in the 1S5 twist boat
conformation and the benzylidene and newly formed rings in
chair conformations, was confirmed by X-ray crystallography
(CSD Refcode YEYDUD55). That the overall conformation of
29 does not change on going from the crystal to the solution
phase is apparent from the 10.5 Hz coupling constant of the
vicinal trans-pseudodiaxial hydrogen atoms at the bridgehead
positions of the newly formed ring. Crystals of the trans-fused
bicyclic analog 31 suitable for X-ray crystallographic analysis
could not be obtained, however, the 1S5 twist boat
conformation of the pyranose ring is again revealed by the
large coupling constant between the two bridgehead hydrogens.
The major cis-fused products 28 and 30 in the mannose series
were both examined crystallographically (CSD Refcode
YEYFAL55 and CCDC 1403928) and were both found to
contain only chair conformers of the various six-membered
rings. The single cyclization product 32 formed in the
glucopyranose series (Table 1, entries 4 and 5) also adopts
Table 1. Cyclization Reactions in the Absence of Added
External Nucleophile
products, % yield,
(pyranose conformation,
entry substrate
conditions
method)
1
13
Tf2O, TTBP, −72 °C
28, 45% (4C1, X-ray,
NMR) + 29, 25% (1S5,
X-ray, NMR)
2
3
15
18
TMSOTf, TTBP, −20 °C
28, 70% + 29, 25%
Tf2O, TTBP, −72 °C, 1-
30, 52% (4C1, X-ray,
NMR), + 31, 20% (1S5,
NMR)
octene
4
5
21
27
Tf2O, TTBP, −72 °C, 1-
octene or β-pinene
32, 20% (1S5, X-ray,
NMR)
TMSOTf, TTBP, −20 °C
32, 92%
respectively (Chart 1, Table 1, entry 2). We note that the
reported use of 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-α-D-
mannopyranosyl trichloroacetimidate as a β-selective mannosyl
donor was conducted at −50 °C.99 The 3,4,6-tri-O-benzyl
protected mannopyranosyl sulfoxide 18 cyclized smoothly on
activation with triflic anhydride in the presence of TTBP at −72
°C giving the two bicyclic products 30 and 31 in 52 and 20%
isolated yield, respectively (Chart 1, Table 1, entry 3). In the
glucopyranose series, however, working with the sulfoxide clock
21 complications arising from sulfenyl transfer to the allylsilane
were dominant and resulted in the formation of the anticipated
cyclization product 32 in only low yield. Sulfenyl group transfer
to substrate-based nucleophiles has been observed previously
1
the S5 twist boat conformation of the pyranose ring in the
crystal (CCDC 878445), while the benzylidene and newly
formed rings take up chair conformations. This conformation is
3
3
also retained in solution as indicated by the J1,2 and J2,3
(glucose numbering) coupling constants of 3.8 and 5.2 Hz,
respectively.
The formation of the trans-fused products 29 and 31 as
minor isomers from the cyclization of the mannopyranosyl
clocks 13, 15, and 18 (Table 1, entries 1−3) is instructive and
points to the formation of a mannopyranosyl oxocarbenium ion
as transient intermediate that populates the B2,5 or related
conformation. Thus, the mannosyl triflate 3391 formed on
D
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Scheme 7. Conformation and Selectivity of the Mannopyranosyl Oxocarbenium Ion
activation of the donor can be considered to be in equilibrium
Scheme 8. Conformation and Selectivity of the
Glucopyranosyl Oxocarbenium Ion
with the mannosyl oxocarbenium/triflate ion pair 34, which can
4
adopt several conformations. The H3 and B2,5 conformations
of 34 are accessible for both the 4,6-O-benzylidene and tri-O-
benzyl systems, while the latter, being less conformationally
3
constrained, also can access the H4 half-chair (Scheme 7). In
the B2,5 conformation the pendant allylsilane adopts a
pseudoequatorial position and is poised to react with either
face of the oxocarbenium ion, thereby enabling the formation of
the cis and trans-fused products (Scheme 7). Formation of the
3
trans-fused product is also possible from the H4 conformer in
the case of the tri-O-benzyl protected system. The major cis-
fused product can be formed from any of the three accessible
conformations (Scheme 7).
In the glucopyranose system there are only two con-
4
formations, H3 and B2,5, of the oxocarbenium ion/triflate ion
pair 36 in equilibrium with the initially formed covalent triflate
35, and both lead to the cis-fused product 32 (Scheme 8). The
excellent cis-selectivity observed in this kinetic ring closure
contrasts with the thermodynamic trans-selectivity seen on ring
closure of 2-O-(2-thioethyl)glucopyranosyl cations and related
systems to heterobicyclo[4.4.0]decane-like systems, which are
governed by the steric factors in the product.129−131 The
1
preference of the tricyclic glucose derivative 32 for the S5
4
conformation of the pyranose ring as opposed to the C1 chair
must arise because of a combination two unfavorable steric
interactions in the chair: the 1,3-diaxial interaction between the
axial anomeric CC bond and the axial C3−H3 bond and the
gauche butane interaction emphasized in red in Scheme 8. This
is because simple 4,6-O-benzylidene protected α-C-glucopyr-
anosides, with an axial substituent at C1 but lacking the third
valid for glycosylation reactions conducted with other activating
systems and leaving groups.
Competition Kinetics. For the sulfoxide donors competi-
tion kinetics were conducted at −72 °C in CH2Cl2 by addition
of triflic anhydride to a mixture of the donor and TTBP
followed by addition of incremental amounts of isopropanol or
methallyltrimethylsilane as glycosyl acceptor. After stirring for 5
min at −72 °C the reactions were quenched at that
temperature, worked up, and the product ratios analyzed by
UHPLC giving the data presented in Tables 2 and 4. The crude
reaction mixtures from multiple runs were combined and
subjected to purification over silica gel yielding pure samples of
the glycosides 37−41 (Chart 2). For the trichloroacetimidates
80,81
4
ring, exist predominantly as C1 conformers.
Schemes 7 and 8 employ triflate as the counterion given that
activations were conducted with either triflic anhydride or
TMSOTf for the sulfoxide and trichloroacetimidate donors,
respectively. This does not restrict the general concept of the
cation clock method to the use of triflate-based activating
systems and triflates as counterions. The concept is equally
E
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Table 2. O- and C-Mannosylation with Donor 13
entry
nucleophile
equiv (M conc)
β-gly/cycl
α-gly/cycl
c
c
37/(28+29)
2.17
38/(28+29)
0.15
a
1
iPrOH
0.8 (0.014)
1.2 (0.020)
1.5 (0.026)
2.5 (0.043)
3 (0.051)
4 (0.068)
5 (0.085)
8 (0.136)
a
2
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
3.66
0.28
a
3
5.36
0.44
a
4
10.99
13.09
15.75
19.38
24.34
39/(28+29)
0.06
0.99
a
5
1.28
a
6
1.14
a
7
1.53
a
8
1.60
c
b
9
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
2 (0.034)
4 (0.068)
8 (0.136)
12 (0.204)
15 (0.255)
20 (0.34)
30 (0.51)
b
10
0.18
b
11
0.40
b
12
0.55
b
13
0.69
b
14
0.87
b
15
1.40
a
b
Experimental conditions: TTBP (4 equiv), 1-octene (10 equiv), molecular sieves 4 Å, Tf2O (1.2 equiv) at −72 °C. Experimental conditions:
c
TTBP (4 equiv), molecular sieves 4 Å, Tf2O (1.2 equiv) at −72 °C. Molar ratios were determined by UHPLC/UV/MS.
Table 3. O- and C-Mannosylation with Donor 15
entry
nucleophile
equiv (M conc)
β-gly/cycl
α-gly/cycl
c
c
37/(28+29)
2.5702
38/(28+29)
0.30827
0.54899
1.33043
1.83040
3.20719
4.83401
a
1
iPrOH
0.81 (0.013)
1.63 (0.026)
2.4 (0.052)
3.25 (0.078)
4.88 (0.104)
8.12 (0.130)
a
2
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
5.0541
a
3
10.1031
13.3632
19.7443
24.2748
39/(28+29)
0.0729
a
4
a
5
a
6
c
b
7
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
2.1 (0.032)
5.3 (0.085)
10.7 (0.171)
16.0 (0.256)
21.3 (0.341)
26.7(0.427)
32.0 (0.512)
b
8
0.1046
b
9
0.2996
b
10
0.4712
b
11
0.6673
b
12
0.9509
b
13
1.1419
a
b
Experimental conditions: TTBP (0.3 equiv), TMSOTf (0.3 equiv) at −20 °C; molecular sieves 4 Å. Experimental conditions: TTBP (0.3 equiv),
TMSOTf(0.3 equiv) at −20 °C; molecular sieves 4 Å. Molar ratios were determined by UHPLC/UV/MS.
c
pooling of crude reaction mixtures afforded sufficient material
Table 4. O-Mannosylation with Donor 18
for the chromatographic purification and full characterization of
the glycosides 42−44 (Chart 2). The data from Tables 2−5 are
presented graphically in the form of plots of glycoside/cyclized
product ratios against acceptor concentration in Figures 1a−d.
Comparison of Figures 1a and b reveals that the 4,6-O-
benzylidene mannosyl donors 13 and 15 display largely parallel
behavior toward both isopropanol and methylallyltrimethylsi-
lane in spite of the different reaction temperatures and leaving
groups. Thus, with both 13 and 15 the formation of the β-
mannoside 37 shows a much stronger concentration depend-
ence than that of the α-anomer 38, with the latter showing a
slightly greater concentration dependence than the formation
of the β-C-mannoside 39. Consistent with earlier observations
only the β-anomer 39 is formed in the 4,6-O-benzylidene-
directed C-mannosylation.80 These observations are most
consistent with an SN2-like associative displacement of an
axial leaving group for the formation of the β-O-mannoside 37
and of a much more dissociative SN1-like reaction for the
entry nucleophile equiv (M conc)
β-gly/cycl
α-gly/cycl
b
b
40/(30+31)
0.27
41/(30+31)
0.27
a
1
2
3
4
5
6
7
8
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
1 (0.019)
2 (0.038)
2.5 (0.048)
3 (0.057)
4 (0.076)
5 (0.095)
7.5 (0.143)
10 (0.190)
a
a
a
a
a
a
a
0.95
0.85
1.11
1.08
1.27
1.20
1.60
1.39
1.75
1.67
1.84
1.73
1.87
1.78
a
Experimental conditions: TTBP (10 equiv), β-pinene (30 equiv),
b
molecular sieves 4 Å, Tf2O (1.2 equiv) at −60 °C. Molar ratios were
determined by UHPLC/UV/MS.
15 and 27, TMSOTf was simply added to preformed mixtures
of the donor and acceptors at −20 °C followed by continued
stirring at that temperature. After quenching at −20 °C reaction
mixtures were again analyzed by UHPLC (Tables 3 and 5), and
F
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Journal of the American Chemical Society
Article
40 and 41 to approximate that for the formation of the 4,6-O-
benzylidene protected α-mannoside 38 and strongly suggests
that 40 and 41 are formed by dissociative mechanisms that
involve the oxocarbenium ion 34 (Scheme 7, R = Bn) only
loosely associated with the counterion. This observation is
consistent with the strongly disarming nature of the 4,6-O-
benzylidene acetal,52,134−136 as compared to two benzyl ethers,
which in turn is a function of the imposition of the trans-gauche
conformation137 of the C5−C6 bond in which the electron-
Chart 2. Glycosides From Competition Kinetic Experiments
withdrawing effect of the C5−O5 bond is maximized.138−140
A
caveat to this argument concerns the use of different clock
reactions in Figures 1a and c; however, we believe that the
comparison is justified here in view of the similarity of the two
oxocarbenium ions (Scheme 7, 34, R = Bn and R-R = PhCH).
Comparison of Figures 1b and d reveals the very different
influence of the 4,6-O-benzylidene acetal protecting group in
the manno- and glucopyranose series. Thus, in contrast to the
benzylidene-protected O-mannosylation, both anomers 42 and
43 of the benzylidene-protected glucosides are formed with the
same concentration dependence. The formation of both O-
glucosides 42 and 43 shows a much stronger concentration
dependence than that of the corresponding C-glucoside 44
(Figure 1d), which was formed as a single α-anomer consistent
with previous reports.80,81 If C-glucoside formation is
interpreted as representative of the concentration dependence
of a dissociative SN1-like mechanism with a weak nucleophile as
in the mannose case, these results are again consistent with
primary 13C kinetic isotope effect studies on benzylidene-
protected O-glucosylation with triflate as leaving group which
point to both anomers being formed by associative SN2-like
mechanisms from a pair of rapidly equilibrating anomeric
glucosyl triflates.35 The inherent difference in cyclization rates
between the mannosyl and glucosyl clocks are most readily
appreciated from a direct comparison of C-glycoside formation
in the two series (Figure 1f). Thus, in order for C-glycosylation
to compete with the cyclization of 27 to 32 significantly more
methallylsilane is required than for C-glycosylation to compete
with the cyclization of 15 to 28 and 29 under the same reaction
conditions. It follows that C-glycosylation in the glucose series
is less concentration dependent than in the mannose series
suggesting that it is closer to a pure SN1 mechanism.
Table 5. O- and C-Glucosylation with Donor 27
equiv
(M conc)
entry
nucleophile
β-gly/cycl α-gly/cycl
c
c
42/(32)
0.0067
0.0243
0.0550
0.1143
0.4043
0.9845
43/(32)
0.0227
0.0708
0.1297
0.2498
0.5135
1.0176
44/(32)
0.0899
0.1078
0.1273
0.1957
0.2331
a
1
iPrOH
1 (0.048)
1.5 (0.072)
2 (0.096)
3 (0.144)
5 (0.239)
8 (0.382)
a
2
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
a
3
a
4
a
5
a
6
c
b
7
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
TMSCH2C(Me)CH2
23.8 (1.14)
35.7 (1.71)
47.6 (2.28)
59.5 (2.85)
71.4 (3.41)
b
8
b
9
b
10
b
11
a
Experimental conditions: TTBP (0.3 equiv), TMSOTf (0.3 equiv) at
b
−20 °C; molecular sieves 4 Å. Experimental conditions: TTBP (0.3
c
equiv), TMSOTf (0.3 equiv) at −20 °C; molecular sieves 4 Å. Molar
ratios were determined by UHPLC/UV/MS.
CONCLUSIONS
■
formation of the α-O-mannoside 38, as determined previously
using 13C-primary kinetic isotope effect measurements for the
case of triflate as leaving group in 4,6-O-benzylidene protected
mannosyl donors.35 The very low concentration dependence
observed for the formation of the C-mannoside 39 is consistent
with a highly dissociative mechanism proceeding via an
oxocarbenium ion 34 (Scheme 7, R-R = PhCH) that is only
loosely associated with the counterion.132 This in turn is
consistent with methallyltrimethylsilane being a much weaker
nucleophile than isopropanol and requiring the more potent
electrophile at the dissociative end of the mechanistic
spectrum.133
Comparison of Figures 1a and c reveals a very different
pattern of behavior between the 4,6-O-benzylidene and
perbenzyl protected mannosyl donors 13 and 18. Thus, in
contrast to the case of 13, both the β- and α-perbenzyl
mannosides 40 and 41 formed from 18 on coupling to
isopropanol display essentially the same concentration depend-
ence. Superposition of Figures 1a and c, as in Figure 1e, reveals
the very shallow concentration dependence for the formation of
A cation clock method based on the intramolecular Sakurai
reaction has been developed and used to probe the
concentration dependence of representative O- and C-
glycosylation reactions. The method is applicable to the use
of glycosyl sulfoxides with activation by triflic anhydride and for
the use of glycosyl trichloroacetimidates with activation by
trimethylsilyl triflate. 4,6-O-Benzylidene-directed β-mannosyla-
tion is demonstrated to proceed with a strong dependence on
the concentration of the acceptor alcohol, whereas the α-
anomer is much less concentration dependent. Concentration
therefore plays a critical role in the 4,6-O-benzylidene-directed
β-mannosylation process and can be used to optimize
selectivity. The reduced selectivity observed on trapping of
4,6-O-benzylidene-protected mannosyl donors by polymer-
supported alcohols141 can be understood in terms of the
reduced concentration of the acceptor. Analogous results are
observed in 4,6-O-benzylidene-directed β-mannosylation con-
ducted by the sulfoxide and trichloroacetimidate methods
suggesting a commonality of mechanism if not necessarily of
leaving group. In the 3,4,6-tri-O-benzyl protected mannopyr-
G
DOI: 10.1021/jacs.5b06126
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Journal of the American Chemical Society
Article
Figure 1. Graphic representation of clock reactions.
Present Addresses
anosyl and 3-O-benzyl-4,6-O-benzylidene glucopyranosyl sys-
tems the formation of both anomers of the isopropyl glycosides
display very similar concentration dependencies which, are
nevertheless, greater than that of the formation of C-glycosides.
The formation of trans-fused products from the clock reaction
in the mannopyranose series is interpreted in terms of transient
glycosyl oxocarbenium ions that are capable of accessing the
B2,5 and/or 3H4 conformers. Further development and
application of the method is in progress and will be reported
in due course.
Beyond the immediate context of carbohydrate chemistry
and the glycosylation reaction, the concept of competition
kinetics using a simple cyclization as clock reaction should find
broader application in estimating the molecularity of other
cation-based processes in organic synthesis. Such reactions
might include but are not limited to oxocarbenium-like ions in
the nucleophilic ring opening of chiral acetals in simple ether-
forming reactions and in Mukaiyama-type aldol reactions,
acylium ion-based processes, iminium and N-acyl iminium ion
chemistry, thiacarbenium ions in Pummerer-type chemistry,
and the many reactions of carbenium ions themselves.
§Graduate School of Health Science, Hokkaido University,
North 12, West 5, Kita-Ku, Sapporo, 060−0812 Japan.
∥School of Chemistry, The University of Manchester, Oxford
Road, Manchester M13 9PL, U.K.
⊥NPC Division IIIM-CSIR, Jammu, India.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM62160) and the ICSN for financial
support, the NSF for funds in support of the 600 MHz
spectrometer in the Lumigen Instrument Center at WSU
(MRI-084043), and Dr. Philip D. Martin in the Lumigen Core
X-ray Facility at Wayne State University for determining the
̀
structure of compound 31. M.H. is grateful to the Ministere de
l’Education Nationale, de la Recherche, et de la Technologie,
France for fellowship support, and D.M. thanks the Ministry of
Science and Technology, India, for a Boyscast Fellowship.
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* Supporting Information
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