Regioselective acylation of diols and triols: The cyanide effect

Article abstract of DOI:10.1021/jacs.6b02454

Central topics of carbohydrate chemistry embrace structural modifications of carbohydrates and oligosaccharide synthesis. Both require regioselectively protected building blocks that are mainly available via indirect multistep procedures. Hence, direct pr

Full text of DOI:10.1021/jacs.6b02454

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Article
Regioselective Acylation of Diols and Triols: The Cyanide Effect
Peng Peng, Michael Linseis, Rainer Winter, and Richard R. Schmidt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02454 • Publication Date (Web): 22 Apr 2016
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Regioselective Acylation of Diols and Triols: The Cyanide Effect
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Peng Peng, Michael Linseis, Rainer Winter, Richard R. Schmidt*
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Department of Chemistry, University of Konstanz, D-78457 Konstanz, Germany
ABSTRACT: Central topics of carbohydrate chemistry embrace structural modifications of carbohydrates and oligosac-
charide synthesis. Both require regioselectively protected building blocks that are mainly available via indirect multistep
procedures. Hence, direct protection methods targeting a specific hydroxy group are demanded. Dual hydrogen-bonding
will eventually differentiate between differently positioned hydroxy groups. As cyanide is capable of various kinds of hy-
drogen-bonding and as it is a quite strong sterically non-demanding base, regioselective O-acylations should be possible
at low temperatures even at sterically congested positions, thus permitting formation and also isolation of the kinetic
product. Indeed, 1,2-cis-diols, having an equatorial and an axial hydroxy group, benzoyl cyanide or acetyl cyanide as acyl-
o
ating agent and DMAP as catalyst yield at -78 C the thermodynamically unfavorable axial O-acylation product; acyl mi-
gration is not observed under these conditions. This phenomenon was substantiated with 3,4-O-unproteced galacto- and
fucopyranosides and 2,3-O-unprotected mannopyranosides. Even for 3,4,6-O-unprotected galactopyranosides as triols
axial 4-O-acylation is appreciably faster than O-acylation of the primary 6-hydroxy group. The importance of hydrogen-
bonding for this unusual regioselectivity could be confirmed by NMR studies and DFT-calculations, which indicate favor-
able hydrogen-bonding of cyanide to the most acidic axial hydroxy group supported by hydrogen-bonding of the equato-
rial hydroxy group to the axial oxygen. Thus, the “cyanide effect” is due to dual hydrogen-bonding of the axial hydroxy
group which enhances the nucleophilicity of the respective oxygen atom, permitting even a faster reaction for diols than
for mono-ols. In contrast, fluoride as counterion favors dual hydrogen-bonding to both hydroxy groups leading to equato-
rial O-acylation.
INTRODUCTION
gents continued. Hence, organosilicon reagents,11 various
metal salts13-17 as well as organocatalysts18-22 and enzymes23
were studied. However, other drawbacks were often en-
countered with these reagents.
Regioselective O-protection of hydroxy groups of diols
and triols, in particular in carbohydrates, plays an im-
portant role, as it gives direct access to intermediates
required for structural modifications and as building
blocks for chain extension in glycosidation reactions.1-4
Thus, cumbersome protection and deprotection proce-
dures - often required to attain regioselective protection -
are dispensable. Such direct regioselective protection
procedures are also regarded as an important aspect of
“green” or “sustainable” chemistry.2,5 As under standard
partial O-acylation conditions, i.e. using acyl halide or
acid anhydride as acylating agent and trialkylamines or
pyridines, respectively, as base6 mainly mixtures of O-
acylated products are generated, reagents interacting with
two hydroxy groups of 1,2-cis-diol or of 1,3-diol systems
were studied. This way, inherent differences in acidity,
nucleophilicity and/or steric congestion at the hydroxy
groups can be amplified, which in turn results in in-
creased regioselectivities for O-acylation. Thus, with the
help of oxophilic organotin7-9 and organoboron10,11 rea-
gents, very good regioselectivities, for instance, for the
primary 6-hydroxy group and, particularly worth men-
tioning, for the equatorial secondary 3-hydroxy group of
galacto-, gluco- and mannopyranosides were obtained.
Because of toxicity problems12 and the cost of such rea-
gents the search for other regioselectivity mediating rea-
Recently, besides acid-base catalysis via hydrogen-
bonding effects,24 dual hydrogen-bonding gained consid-
erable interest for the regioselective activation of hydroxy
groups.5,17,25-27 For instance, dual hydrogen-bonding in an
acetate anion-supported deprotonation of a hydroxy
group and acetic anhydride based O-acetylation was stud-
ied. This apporach led to excellent regioselectivities for
the primary 6-hydroxy group and the secondary 3-
hydroxy group, respectively, of galacto-, gluco- and man-
nopyranosides.5,28 Although the axial 4-hydroxy group of
galactopyranosides is more acidic than the equatorial 3-
hydroxy group29 (as also confirmed by theoretical stud-
ies)5 and therefore strong hydrogen-bonding to the 4-
hydroxy group increasing the oxygen nucleophilicity is
expected, the often desirable but thermodynamically
unfavorable 4-O-acylation of 3,4-O-unprotected galacto-
pyranosides, if found at all, is not the main reaction under
these conditions. Commonly, steric effects are put for-
ward to explain the preference for 3-O-acylation over 4-
O-acylation.
It was found that the basicity of the counterion of the
acylating agent influences the acylation rate, thus reveal-
ing
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Table 1. Regioselectivity of the Benzoylation of 3,4-O-unprotected Galactopyranoside 1a.
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a Yields are based on isolated material.b 1 molar solution in THF.
the importance of the deprotonation of the hydroxy
group in the O-acylation reaction. The cyanide ion is
rather basic and increases the rate of acylation reactions
more than acetate or the halides chloride, bromide and
iodide, respectively. As a consequence, cyanide supported
acylation reactions can be carried out at lower tempera-
tures. Besides preferential hydrogen-bonding to the most
acidic hydroxy group, ambident cyanide is also capable of
dual hydrogen- bonding via the carbon or the nitrogen
atom or concomitantly via both, the carbon and the ni-
trogen atoms. Hence, differences of the acidities of the
two hydroxy functions of diols should lead to increased
differences in oxygen nucleophilicities and thus to higher
regioselectivities, particularly at low temperatures. Due to
the small size of the cyanide counterion, steric effects are
also minimized. Preferential O-acylation at the axial hy-
droxy group should thus be accessible, which is of great
importance for the direct regioselective protection of the
readily available 3,4-O-unprotected galacto- and fucopy-
ranosides, 2,3-O-unprotected manno- and rhamnopyra-
nosides, 1,2-/2,3-O-unprotected inositols or the 1,2-O-
unprotected α-anomeric hydroxy groups in gluco- and
galactopyranoses and related compounds. With cyanide
as quite strong base in organic solvents (see below) the
desired formation of the kinetically controlled axial O-
acyl product could be followed by a thermodynamically
controlled acyl migration; yet, acyl migration is not ex-
pected at low temperatures. Hence, there are good pro-
spects to replace the indirect ortho-ester procedure30 to
obtain 4-O-acylated galactopyranosides by a convenient
direct method, with cyanide as base at low temperatures.
RESULTS AND DISCUSSION
Cyanide as Counterion in O-Acylation Reactions of
Diols. Our first experiments were performed with 2,6-di-
O-benzyl protected galactopyranoside 1a as substrate and
with benzoyl cyanide (BzCN, 1 equiv) as acyl donor and 4-
dimethylaminopyridine (DMAP, 0.1 equiv) as catalyst. As
BzCN and DMAP lead to a cationic adduct with cyanide
as the counterion (equation 1),31,32 cyanide is available for
hydrogen-bonding to the hydroxy groups of 1a. Indeed,
with these reagents, even at room temperature mainly
axial 4-O-benzoylation takes place, leading to 2a and to
the 3,4-di-O-benzoylated product 4a (Table 1, entry 1). In
accordance with our expectations, at -78 oC essentially
only 2a was formed (entry 2).
Competition studies between substrate 1b and 4-O-
benzoylated 2a and between 1b and 3-O-benzoylated 3a,
respectively, with BzCN and DMAP at -78 oC showed that
4-O-benzoylation of 1b is by far faster than 3-O-
benzoylation of 2a or 4-O-benzoylation of 3a (Scheme 1).
The use of more polar nonprotic solvents (acetonitrile or
DMF) for the benzoylation reaction did not change regi-
oselectivities (Table 1, entries 3, 4).
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BzO
HO
BzO
BzO
OBn
O
OBn
O
with DMAP as catalyst practically exclusive 3-O-
benzoylation (→3a) took place (entry 7). With 0.1 equiva-
lents of tetrabutylammonium cyanide (TBACN) as base at
-78 oC no reaction was attained. However, with one
equivalent of TBACN the preference for axial 4-O-
benzoylation was observed again, though 2a was obtained
only in modest yields (entries 8, 9). As in organic solvents
the small fluoride anion is a particularly strong base
(H2O: pKa 3.17; DMSO: pKa 15)33 and fluoride is also capa-
ble to dual hydrogen-bonding, TBAF was selected as base
for the benzoylation with benzoic acid anhydride. At -10
oC some reaction was observed, however the “fluoride
effect”, favoring 4-O-benzoylation, was only modest (en-
tries 10, 11). Therefore, benzoyl fluoride as acylation agent
and DMAP as catalyst were selected; however, then a
clear preference for 3-O-benzoylation of 1a was attained
(entries 12, 13).
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OMp
STol
OMp
STol
(~3%)
BnO
BnO
4a
BzCN (1 equiv)
2a
1equiv
DMAP (0.1 equiv)
-78oC, DCM, 1h
BzO
HO
OBn
O
HO
HO
OBn
O
(75%)
(77%)
(<2%)
BnO
2b
BnO
1equiv
1b
BzCN (1 equiv)
HO
BzO
OBn
O
DMAP (0.1 equiv)
-78oC, DCM, 1h
4a
OMp
9
BnO
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3a
1quiv
Scheme 1. Competition reactions between 1b/2a and
1b/3a, respectively.
As cyanide is not only able to form hydrogen-bonds but is
also a rather strong base, particularly in organic solvents
(H2O: pKa 9.4; DMSO: pKa 12.9),33 we applied the same
procedure to benzoyl chloride. The chloride anion re-
leased on adduct formation is less prone to hydrogen-
bonding and also much less basic (H2O: pKa -8.0; DMSO:
pKa 1.8).33 Yet no reaction was observed with DMAP as
catalyst at -78 oC (entry 5). At room temperature the reac-
tion was still slow; after 48 h only 3-O-benzoylated 3a was
obtained in low yield (entry 6). Selection of benzoic acid
anhydride as acylating agent increased the basicity of the
counterion (H2O: pKa 4.2; DMSO: pKa 11.1)33 compared
with benzoyl chloride and, as expected, the reaction rate
was increased. In accordance with previous results,5 also
Transesterification of 2a or 3a with DMAP or TBACN as
o
o
base was not observed at -78 C. At 0 C with 2a as sub-
strate and TBACN as base after 24 h a 1:1.1 ratio of 2a : 3a
was obtained. No isomerization took place with DMAP at
0 oC. From these results it is evident that a cyanide specif-
ic effect supports kinetic 4-O-benzoylation of 1a. This
effect is particularly efficient with BzCN as acylating
agent and DMAP as catalyst. At ambient temperatures
these high regioselectivities may be compromised by
some 4-O-
3-O-migration of the acyl group.
Figure 1. 1H NMR spectra of 1a and 5 (1A, 1E) with addition of BzCN (1B), MeCN (1C) and TBACN (1D, 1F, 1G).
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In order to demonstrate the hydrogen-bonding between Table 1, entry 2 and Table 3, entry 1). Replacement of the
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hydroxy and nitrile groups or the cyanide ion, the effect
of addition of one equivalent of BzCN, of acetonitrile and
of cyanide, respectively, to a solution of 1a in CDCl3 was
methoxyphenoxy group by the tolylthio group at C-1, as in
1b, (entry 2) or variation of the steric bulk of 6-O-
protection, as in 1c (entry 3), did not change the regiose-
lectivity, thus leading in high yields to 2b and 2c, respec-
tively. Also electron withdrawing 2,6-di-O-benzoyl pro-
tection of the galactose moiety, as in 1d and 1e, (entries 4,
5) had no negative influence on the regioselective for-
mation of 2d and 2e, respectively. Even the 2,6-di-O-
acetyl protected β-D-galactopyranoside 1f (entry 6) led to
practically exclusive formation of the 4-O-benzoylated
product 2f when DCM/MeCN (2:1) was used as solvent;
under the reaction conditions practically no detrimental
acetyl group migration was observed. However, in DCM
as solvent, due to the low solubility of 1f, only a modest
yield of 2f (60%) was obtained, as the good solubility of 2f
in DCM permitted the competing formation of the 3,4-di-
O-benzoylated product.
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studied by H-NMR spectroscopy (Figure 1). Non-charged
BzCN and acetonitrile had practically no effect on the
chemical shifts of 1a (Fig 1, 1A-1C). However, as expected,
cyanide addition had a dramatic effect on the proton
shifts of the 3, 4- cis hydroxy groups but also the shifts of
the C-H protons were affected (Fig 1D). The same obser-
vations were also made for the 2,3-O-unprotected β-D-
galactopyranoside 5 where the two hydroxy groups are in
trans- orientation (Fig 1E, 1F). However, competition be-
tween 1a and 5 for the cyanide ion (addition of one equiv-
alent of TBACN to one equivalent each of 1a and 5) is
clearly in favor of 1a, as the C-H shifts in Fig 1G indicate.
Hence, hydrogen-bonding to the cis-diol in 1a is much
stronger than hydrogen-bonding to the 1, 2-trans-diol in
5.
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Table 3. Regioselective Benzoylation of Different cis-
Table 2. Regioselectivity of the Benzoylation of 2,3-O-
Diols.a
Unprotected Glycosides 5, 7 and 9.a
a The reactions are carried out with substrate (1 equiv), BzCN
b
(1.0 equiv), DMAP (0.1 equiv) at -78 oC in DCM for 4 h.
Yields are based on isolated material.
These observations prompted us to investigate also the
regioselectivity of the benzoylation of β-galactoside 5
possessing a trans-diol moiety. With BzCN (1.0 eq) and
DMAP (0.1 eq) in DCM at -78 oC practically exclusive 3-O-
benzoylation to compound 6a was observed (Table 2,
entry 1). With α-glucopyranoside 7 2-O-benzoylation to
8b and with α-galactopyranoside 9 a 2:5 mixture of 2-O
and 3-O-benzoylation (10a, 10b) was obtained (entries 2,
3). These results are in accordance with previous findings
that equatorial trans-diols, having a vicinal axial alkoxy
group, react preferentially at the hydroxy group next to
the axial alkoxy group, as accumulation of the lone pair
orbitals of the cis-oxygens leads to increased nucleophilic-
ity of the hydroxy group.34 The high regioselectivities
found for 5 and 7 in comparison with 9 are therefore not
due to a specific cyanide effect.
a All reactions are performed at ~0.03 molar concentration in
DCM with BzCN (1.0 equiv), DMAP (0.1 equiv), at -78 C for
o
4h. b Yields are based on isolated material. c DCM/MeCN (v/v
= 2:1) was used as solvent. dThe reaction is performed at
0.004 molar concentration in DCM with BzCN (1.05 equiv),
DMAP (0.3 equiv), at -78 oC for 10h (2i/3i = 5:1). 3i: ben-
zoylation of the equatorial OH group.
Also the reactions of 3,4-O-unprotected β-L-
fucopyranoside 1g (entry 7) and 2,3-O-unprotected α-D-
mannopyranoside 1h (entry 8) were in complete accord-
ance with our expectations and led in very good yields to
4-O-benzoylated fucoside 2g and to the 2-O-benzoylated
mannopyranoside 2h, respectively.35
Regioselective O-Acylation of Other 1,2-cis-Diols. To
further demonstrate the generality and usefulness of the
cyanide effect for the thermodynamically unfavorable
regioselective axial O-benzoylation of vicinal cis-diols,
different substrates, also with different protecting group
patterns, were studied under the reaction conditions that
were successful for the transformation of 1a into 2a (see
After investigating substrates with (i) different groups at
the anomeric position, (ii) different anomeric
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1,2-cis-diols with an equatorial and an axial hydroxy group, is
configurations, (iii) electron-donating as well as electron-
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evident.
withdrawing protecting groups, (iv) sterically demanding
protecting groups and (v) different sugars including a
deoxysugar, the important carbohydrate-related myo-
inositol was studied. To this end, derivative (±)-1i with a
1,2-cis-diol moiety was prepared. With BzCN and DMAP
at -78oC the desired axial O-benzoyl derivative (±)-2i was
also preferentially obtained in good yield.
Studies with Triols. The unexpected preference for the
axial O-acylation of cis-1,2-diols with the help of cyanide
as anion was by no means expected to hold for 6-O-
unprotected hexopyranosides, as generally the primary 6-
hydroxy group is (by far) more reactive than any of the
secondary hydroxy groups. Surprisingly, reaction of a
3,4,6-O-unprotected 2-azido-2-deoxy-galactopyranoside
with two equivalents of benzoyl cyanide in pyridine at 0
oC resulted in the preferential formation of the 4,6-di-O-
benzoylated product, as reported by the Paulsen
group30c,36. The authors did neither discuss nor further
investigate the origin of this unusual result. Therefore, we
studied the regioselectivity of the O-benzoylation of 3,4,6-
Table 4. Regioselective Acetylation of Different cis-
9
Diols with Acetyl Cyanide and DMAP.a
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tri-O-unprotected
galactopyranoside
12a
with
BzCN/DMAP (Table 5). In accordance with the results
described above, addition of two equivalents of BzCN led
exclusively to the 4,6-di-O-benzoyl derivative 15a (entry
1). However, with one equivalent of BzCN primarily not 6-
O-benzoylation to 14a but 4-O-benzoylation to 13a and
then further benzoylation to 4,6-di-O-benzoylated 15a
took place (entry 2). Hence, the rate of 4-O-benzoylation
is not only by far faster than that of 3-O-benzoylation but
is also faster than 6-O-benzoylation. By performing the
reaction in DCM/MeCN as solvent the reaction rates were
slowed down and 6-O-benzoylation competed even less
successfully with 4-O-benzoylation leading to 13a and 14a
in a 4:1 ratio (entry 3). Also the amount of 15a was re-
duced. By increasing the amount of acetonitrile in the
solvent and raising the temperature a higher yield of 13a
was accessible, yet the isomer ratio decreased to 7:3 (entry
4). The desired direct regioselective formation of the 4-O-
benzoylated product could be almost achieved with 12b as
triol substrate: compound 13b was obtained with high
preference (entry 5), thus providing a very useful building
block for oligosaccharide synthesis with the help of the
cyanide effect in a straightforward manner. With two
equivalents of BzCN 12b could be readily transformed
into the 4,6-di-O-benzoyl derivative 2d (entry 6); still no
3-O-benzoylation was observed.
a
All reactions are performed in DCM with AcCN (1.1 equiv),
DMAP (0.1 equiv), at -78 C for 4h.b Yields are based on iso-
o
lated material.
Extension of this method to an aliphatic acyl cyanide, namely
to acetyl cyanide as acetylating agent and DMAP as catalyst
led under the standard reaction conditions to similar regiose-
lectivities (see Table 4). Thus, 3,4-O-unprotected galactopy-
ranosides 1a, 1b, 1c and 1e furnished the 4-O-acetyl products
11a, 11b, 11c and 11e in very good yields (entries 1-4). Similarly,
3,4-O- unprotected fucopyranoside 1g and 2,3-O-unprotected
mannopyranoside 1h furnished 4-O- or 2-O-acetyl protection
in compounds 11g and 11h, respectively. Hence, the generali-
ty of the cyanide effect, strongly favoring axial O-acylation of
Table 5. Regioselective Benzoylation of 3,4,6-O-Unprotected Galactopyranosides 12a, b
a Yields are based on isolated material.
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DFT Calculations. In order to understand the “cyanide ation energy calculated from the energy difference to the
1
effect” on the mechanism and the regiochemical outcome
of the reaction, DFT-calculations were performed on the
B3LYP/6-311++G(d,p)/PCM(dichloromethane) level of
theory, which is known to be a reliable combination for
the conformational analysis of carbohydrates and the
analysis of hydrogen-bonding.37-40 2,3-O-Unprotected
mannopyranoside 1h (Table 3) was chosen as a test sub-
strate. As a starting point for the investigations and in
order to test if discrimination between the cis aligned
hydroxy functions is observable already in the stage of
deprotonation, the association of the cyanide ion with the
carbohydrate was studied. Considering that the ambident
cyanide base may approach a hydroxy function via its
carbon and/or nitrogen terminus, eight possible interme-
diates may be formed. In structures 3eq-C, 2ax-C, 3eq-N,
2ax-N (Figure 2) the cyanide approaches one hydroxy
function, forming an O-H⋅⋅⋅C or an O-H⋅⋅⋅N hydrogen
bond. In structures 2ax,3eq-C and 2ax,3eq-N the cyanide ion
associates with both hydroxy functions through either the
carbon or the nitrogen atom, forming a seven membered
ring. Alternatively, the cyanide ion may bridge both hy-
droxy functions in a “side-on” fashion, forming an eight
membered ring (structures 2ax-C/3eq-N and 2ax-N/3eq-C).
This multitude of association modes will likely result in a
shallow, complex and many-welled potential energy sur-
face (PES) with many intermediates that rapidly intercon-
vert.
separated fragments in their optimized structures in the
PCM model). It is 0.35 kcal mol-1 lower in energy than the
next stable associate 2ax-N (which would provide the same
product selectivity though) and 0.59 kcal mol-1 lower in
energy than the next stable associate 2ax,3eq-N, which
would not show any selectivity for one of the possible
products. However, at room temperature, association is
an endergonic process, as all associates have higher ΔG-
values than their separated constituents. The entropy
term in the Gibbs free energy exceeds the enthalpy term
because associates shown in Fig. 2 offer substantially
fewer degrees of freedom. 2ax-C remains the most favora-
ble associate, lying 0.81 kcal mol-1 above the minimum
representing the separate reaction partners. Additional
thermochemistry calculations were performed to model a
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reaction temperature of -78 C. At this temperature asso-
ciation is an exothermic process and 2ax-C is again the
most stable associate, lying 0.47 kcal mol-1 below 2ax-N.
The most stable associate to H-3eq (3eq-C) lies 1.00 kcal
mol-1 above the minimum.
N
C-
AlO
AlO
AlO
AlO
OH
OH
OH
OH
OH
OH
OH
OH
C-
N
O
O
O
O
C-
N
C-
O
O
O
O
O
O
O
O
N
Ph
Ph
Ph
Ph
Figure 3: Energy level diagram of the calculated local minima
for 1h∙∙∙CN ; energies are given in kcal mol-1, relative to the
3eq-C
2ax-C
2ax,3eq-C
2ax-C/3eq-N
C-
AlO
AlO
AlO
OH
AlO
OH
N
unassociated educts.
OH
OH
OH
OH
N
C-
O
O
O
O
N
C-
Upon cyanide coordination to H-2ax, the hydroxyl proton
of the 2-hydroxy functionality, a partial negative charge is
induced at the oxygen atom O-2ax, favoring acylation at
that position. The associate of the cyanide carbon with H-
3eq (3eq-C) is less stable by 1.00 kcal mol-1. This corre-
sponds to an equilibrium constant Keq = 13 at -78 oC. Simi-
lar results are obtained for cyanide nitrogen coordination
OH
OH
N
C-
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
3eq-N
2ax-N
2ax,3eq-N
2ax-N/3eq-C
Figure 2: Schematic structures of cyanide adducts and their-
naming scheme.
o
at -78 C to H-2ax (2ax-N) and to H-3eq (3eq-N). Under the
The energy surface was explored starting from structure
2ax, 3eq-C by placing a cyanide in close proximity to the
preoptimized substrate 1h. The C∙∙∙H or N∙∙∙H distances
were decreased in an internal redundant coordinate (IRC)
scan calculation in order to identify the most stable asso-
ciate and to model the deprotonation of the axial or equa-
torial OH-functions (the IRC-Scans are printed in Fig.
RW1 of the S.I.). Fig. 3 displays the energy level diagram
and the structures of the possible intermediates. The
association of the cyanide with the diol is exothermic. All
association modes are local minima and are lower in en-
ergy than the unassociated starting compounds. The two
association modes 2ax-C/3eq-N and 2ax-N/3eq-C were found
to be the transition states for the conversion of 2ax,3eq-C
to 2ax,3eq-N and were therefore not considered any further
(see Fig. RW2 in the S. I. for a IRC-scan). The most stable
associate 2ax-C has a BDE of 8.37 kcal mol-1 (bond dissoci-
reasonable assumption that the energy barrier for the
interconversion of intermediates 2ax-C and 3eq-C is small
compared with the transition state energy for their O-
benzoylation and that the O-acylation transition state
energy differences are reflected in the different energies
of the intermediates, these calculated energy differences
will also determine the corresponding differences in reac-
tion rates. Hence, in accordance with the experimental
o
observations the rate for the axial O-acylation at -78 C
should be >10 times higher than that for equatorial O-
acylation.41
The increasing reaction rates when using a diol as com-
pared to a simple alcohol (Scheme 1) can be rationalized
with a glance at the structures of the associates in Figure
2. In 2ax-C and 2ax-N intramolecular hydrogen bonds are
formed from negatively charged O-2ax to H-3eq with a
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The resulting, different selectivities for the acylation in
bond distance of 2.12 Å (Table RW1, S.I.). Similar distanc-
1
2
3
4
5
6
7
8
es are found for 3eq-C and 3eq-N (2.08-2.09 Å). Upon
deprotonation by cyanide, this strong hydrogen bond,
forming a highly stable five membered ring, will stabilize
the resulting anion. Hence, the driving force and the rate
increase. The regioselectivity of the cis-diol O-acylation is
thus not due to dual hydrogen-bonding of cyanide to
both hydroxy groups but to hydrogen-bonding to the
most acidic axial hydroxy group supported by hydrogen-
bonding of the equatorial hydroxy group to the axial oxy-
gen atom (Scheme 2). Thus, dual hydrogen-bonding in a
different manner as initially assumed seems to be respon-
sible for the cyanide effect.
the presence of fluoride as compared to cyanide are obvi-
ous. Strong hydrogen-bonding to both hydroxy groups of
a cis-diol does not seem to promote reactivity differences.
CONCLUSION
Cyanide as counterion in O-acylations of cis-diols and
triols leads to an increase in overall reaction rate and to a
strong preference for regioselective axial O-acylation. This
“cyanide effect”, supporting the thermodynamically unfa-
vorable product, could be confirmed for partially protect-
ed galacto-, fuco- and mannopyranosides as well as for
myo-inositol. Particularly worth mentioning is the faster
reaction rate of the axial 4-O-acylation of 3,4,6-O-
unprotected galactopyranosides over the 6-O-acylation of
the primary 6-hydroxy group; O-acylation of the 3-
hydroxy group was not observed. Thus, a wide scope for
this unprecedented reaction is available. DFT calculations
revealed that this effect is due to hydrogen-bonding of the
basic cyanide ion to the more acidic axial hydroxy group,
which in turn is supported by hydrogen-bonding of a
vicinal equatorial hydroxy group to the axial oxygen atom.
Thus, the axial oxygen undergoes dual hydrogen-bonding.
Fluoride as counterion favors dual hydrogen-bonding to
both hydroxy groups leading in the presence of DMAP as
catalyst to preferred formation of the equatorial O-
acylation product. This way, either the axial or the equa-
torial O-acyl products are directly accessible. Hence, the
proper choice of reagents and reaction conditions, en-
hancing subtle differences between identical functional
groups, permits highly regioselective reactions.
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HO
O
O
Ph
Ph
H
O
O
O
O
3eq-C
O
BzO
3h
O
practically
H
N C
not observed
OAll
OAll
BzCN, DMAP
DCM, -78oC
ꢀG=1kcal
[Bz-DMAP]
1h
HCN
C N
H
O
O
O
H
Ph
2h
2ax-C
O
O
OAll
DMAP
Scheme 2. Calculated structures of lowest energy
intermediates 2ax-C and 3eq-C of 1h.
GENERAL EXPERIMENTAL
Acylation with Acyl Cyanide and DMAP. To a solution
of compound 1a (70.8 μmol) and 4 Å molecular sieves in 3
mL of dry DCM was added benzoyl cyanide (76.3 μmol) at
room temperature under nitrogen atmosphere. After
cooling the reaction mixture to -78 oC, 4-
dimethylaminopyridine (DMAP) (7.1 μmol) was added.
The reaction was further stirred for 4 h at this tempera-
ture. After the TLC analysis showed the reaction was
complete, the reaction was quenched by addition of
NH4Cl (aq) and 100 μL of MeOH. Then the mixture was
diluted with 100 mL of DCM and the precipitate was fil-
tered off through a pad of Celite. The organic layer was
washed with NH4Cl (aq) and Na2S2O3 (aq), dried over
Na2SO4, filtered, and concentrated. The residue was puri-
fied by column chromatography on silica gel.
Figure 4: Energy diagram of the calculated local minima for
1h∙∙∙F
.
The same kind of calculations were performed for the
reaction of mannopyranoside 1h with fluoride to distin-
guish general effects arising from the association of a hard
anion from specific cyanide effects, in particular as cya-
nide and fluoride are not too different with respect to
basicity, at least in DMSO solution. However, the results
for fluoride are quite different from the cyanide case (Fig.
4). The strong hydrogen-bonding ability of fluoride makes
association exergonic at all temperatures considered. In
contrast to cyanide, the bridging 2ax,3eq-F association
mode is the most stable one at all temperatures with a
DFT Calculations. The ground state electronic structures
were calculated by density functional theory (DFT) meth-
ods using the Gaussian 09 program packages.42,43 The 6-
311++G(d,p) polarized triple-ζ basis sets44-47 were em-
ployed for all atoms together with the B3LYP hybrid func-
tional.48-51 Solvent effects werde described by the polariz-
able conductor model (PCM) in dichloromethane.52The
GaussSum program package was used to analyze the re-
sults,53 while the visualization of the results was per-
formed with the Avogadro program package.54 Graphical
representations of molecular orbitals were plotted using
the Gabedit program package in combination with POV-
Ray.55,56
o
ΔG-value of -13.9 kcal mol-1 at -78 C. 2ax-F (ΔG195 K = 2.80
kcal mol-1) and 3eq-F (ΔG195 K = 5.49 kcal mol-1) are consid-
erably less stable at both temperatures. Partial charges are
equally induced on both oxygen atoms O-3eq and O-2ax.
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(18) (a) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.;
ASSOCIATED CONTENT
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no, R.; Furuta, T.; Kan, K.; Sato, M.; Yamanaka, M.; Sasamori, T.;
Tokitoh, N.; Kawabata, T. Angew. Chem. Int. Ed. 2013, 52, 6445-
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Ed. 2015, 54, 11966-11970.
(19) (a) Sun, X.; Lee, H.; Lee, S.; Tan, K. L. Nat Chem 2013, 5,
790-795; (b) Blaisdell, T. P.; Lee, S.; Kasaplar, P.; Sun, X.; Tan, K.
L. Org. Lett. 2013, 15, 4710-4713.
Supporting Information. This material is available free
of charge via the Internet at http://pubs.acs.org.”
1
Full experimental details and H and 13C NMR spectra
forall new compounds.
AUTHOR INFORMATION
8
9
(20) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869-
8875.
(21) Mensah, E.; Camasso, N.; Kaplan, W.; Nagorny, P. Angew.
Chem. Int. Ed. 2013, 52, 12932-12936.
Corresponding Author
*E-mail: Richard.Schmidt@uni-konstanz.de
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Notes
(22) Chen, I. H.; Kou, K. G. M.; Le, D. N.; Rathbun, C. M.;
Dong, V. M. Chem. Eur. J. 2014, 20, 5013-5018.
(23) (a) Gonzalez-Sabin, J.; Moran-Ramallal, R.; Rebolledo, F.
Chem. Soc. Rev. 2011, 40, 5321-5335; (b) Chang, S. W.; Shaw, J. F.
New Biotechnol. 2009, 26, 109-116.
(24) (a) Kumar, A.; Kumar, V.; Dere, R. T.; Schmidt, R. R. Org.
Lett. 2011, 13, 3612-3615; (b) Kumar, A.; Geng, Y.; Schmidt, R. R.
Adv. Synth. Catal. 2012, 354, 1489-1499; (c) Geng, Y.; Kumar, A.;
Faidallah, H. M.; Albar, H. A.; Mhkalid, I. A.; Schmidt, R. R.
Angew. Chem. Int. Ed. 2013, 52, 10089-10092; (d) Peng, P.;
Schmidt, R. R. J. Am. Chem. Soc. 2015, 137, 12653-12659.
(25) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J.-i. J. Chem. Soc.,
Perkin Trans. 1 1999, 465-474; (b) Kurahashi, T.; Mizutani, T.;
Yoshida, J.-i. Tetrahedron 2002, 58, 8669-8677.
(26) Kattnig, E.; Albert, M. Org. Lett. 2004, 6, 945-948.
(27) Zhou, Y.; Rahm, M.; Wu, B.; Zhang, X.; Ren, B.; Dong, H.
J. Org. Chem. 2013, 78, 11618-11622.
(28) For exceptions see, for instance, ref. 17.
(29) Pederson, C. M.; Olsen, J.; Brka, A. B.; Bols, M. Chem. Eur.
J. 2011, 17, 7080-7086.
(30) (a) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754-
1769; (b) Lemieux, R. U.; Driguez, H. J. Am. Chem. Soc. 1975, 97,
4069-4075; (c) Paulsen, H.; Hasenkamp, T.; Paal, M. Carbohydr.
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(33) For pKa values see: Bordwell pKa Table:
http://www.chem.wisc.edu/areas/reich/pkatable/; Bordwell, F.
G. Acc. Chem. Res. 1988, 21, 456-463.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to the University of Konstanz for the support
of this work.
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