β-selective mannosylation with a 4,6-silylene-tethered thiomannosyl donor

Article abstract of DOI:10.1021/ol403722f

Mannosylations using the new conformationally restricted donor phenyl 2,3-di-O-benzyl-4,6-O-(di-tert-butylsilylene)-1-thio-α-d-mannopyranoside (6) have been found to be β-selective with a variety of activation conditions. The simplest activation conditions were NIS/TfOH, in which case it is proposed that the β-mannoside is formed from β-selective glycosylation of the oxocarbenium ion 25 in a B_2,5 conformation.

Full text of DOI:10.1021/ol403722f

Letter
pubs.acs.org/OrgLett
β‑Selective Mannosylation with a 4,6-Silylene-Tethered
Thiomannosyl Donor
Mads Heuckendorff, Jesper Bendix, Christian M. Pedersen,* and Mikael Bols*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark
S
* Supporting Information
ABSTRACT: Mannosylations using the new conformationally restricted donor phenyl 2,3-di-O-benzyl-4,6-O-(di-tert-
butylsilylene)-1-thio-α-D-mannopyranoside (6) have been found to be β-selective with a variety of activation conditions. The
simplest activation conditions were NIS/TfOH, in which case it is proposed that the β-mannoside is formed from β-selective
glycosylation of the oxocarbenium ion 25 in a B2,5 conformation.
t has long been recognized that the synthesis of β-
mannosides is one of the most challenging and difficult
I
glycosylations in carbohydrate chemistry.1 Although many
protocols for β-mannoside synthesis have been reported, there
is little doubt that the most direct and general procedure is the
one developed by Crich et al. a decade ago (Scheme 1).2 In this
Scheme 1. Crich’s Method for β-Mannoside Synthesis
Figure 1. Synthesis of 6 and crystal structure of 5 (below).
method, tethering the 4- and 6-OH groups of the mannosyl
donor is important, and this is commonly done with 4,6-O-
benzylidene acetal protection.3 The details of activation are also
important, with a preactivation procedure at low temperature,
of a sulfoxide or thioglycoside, being required in order to form
an α-mannosyl triflate that reacts with inversion to produces
the β-mannoside.4 Subsequently, several modifications have
been reported,5 but none of these appear to be as general or as
well understood.
As a part of our ongoing research in glycosylation with
conformationally restricted donors, where we have employed
the di-tert-butylsilylene (DTBS)6 group, we became curious
whether a 4,6-O-silylene group could be used in a Crich-type β-
mannosylation.7 We were intrigued by the reactivity differences
observed between silylene and benzylidene donors,6f and since
the β-selectivity is believed to be caused by the deactivating
influence of the benzylidene group, we considered that
substitution might influence the selectivity.
widely used benzylidene analogue. Though crystallization of 6
was unsuccessful, an X-ray structure of the crystalline
intermediate 5 could be obtained (Figure 1). The crystal
4
structure revealed that the diol adopted an almost perfect C1
conformation, but the silylene acetal is flattened out6a to an
approximate envelope conformation with C5 out of the plane
to avoid steric conflicts between the tert-butyl groups in the
DTBS protective group. This is in contrast to the conformation
of the benzylidene ring in a mannosyl donor 1, which is a
perfect chair. The conformational change is due to the longer
bonds (1.65 Å vs ca. 1.44 Å in a benzylidene protected
mannoside8) between O−Si and O−C, respectively.
Mannosylation of a series of acceptors (Figure 2) that
previously had been glycosylated with 1 was carried out with 6
using the Crich preactivation procedure (Table 1).9 In this, an
activation reaction is performed between 6 and the reagents
Hence, we decided to investigate a 4,6-silylene-protected
mannosyl donor in detail. The mannosyl donor 6 was
synthesized in two straightforward steps from the thiomanno-
side 4 in yields (Figure 1) comparable with the synthesis of the
Received: December 23, 2013
Published: February 6, 2014
© 2014 American Chemical Society
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Letter
Table 2. Results of Reaction of Mannosyl Donors with
Acceptor Alcohols Using NIS and Various Acid Catalysts in
a
CH2Cl2
main
yield
(%)
entry donor acceptor product acid temp (°C)
β/α
1
6
7
14a
15a
16a
17a
18a
14a
14a
14a
14a
14a
14c
A
A
A
A
A
A
C
D
B
A
A
−78 → 0
−78 → 0
−78 → 0
−78 → 0
−78 → 0
25
99
88
67
73
78
80
88
82
86
99
87
6/1
9/1
3/1
10/1
2/1
4/1
1/10
6/1
5/1
6/1
1/1
2
6
8
3
6
9
4
6
10
11
7
5
6
Figure 2. Acceptor alcohols 7−11, mannosyl donors 12 and 13 and
products 14−18.
6
6
7
6
7
−78 → 0
−78 → 0
25
8
6
7
(BSP, Tf2O, TTBP), which converts the thioglycoside into a
leaving group and forms the α-triflate. Upon subsequent
addition of the alcohol substitution with inversion occurs. In
our experiments with this protocol (Table 1) preactivation
times of 5 or 30 min were attemped with no notable difference
in the results. As is evident from Table 1, the donor 6 gave the
β-mannosides with high selectivity and yield, and these results
are essentially similar to those reported previously in the
literature with 1 (Table 1, columns 7−8). Activation using the
modified protocol reported by the Leiden group10 was also
successful (Table 1, entry 2).
9
6
7
10
11
12
13
7
−78 → 0
−78 → 0
7
a
Key: (A) TfOH (catalytic); (B) AgClO4/t-BuBr; (C) TMSOTf (1.1
equiv); (D) TMSOTf (0.1 equiv).
To further investigate the reactivity difference between 1 and
6, a competition experiment was performed with 1 equiv of
each donor, 1 equiv of promoter, and 5 equiv of acceptor 7
(Scheme 2). This experiment showed mainly the conversion of
When acceptors with a 4-OH group were used, the
stereoselectivity dropped (entries 4 and 6), particularly with
acceptor 11. As a control, glycosylation with stereoisomeric
thioglycoside 12 (prepared as outlined in Figure 1 but from the
β-analogue of 4) was performed (Table 1, entry 7) with no
significant difference from the results obtained with 6 (entry 1).
All of these experiments are consistent with the mechanistic
scheme proposed by Crich (Scheme 1) wherein the α-triflate
intermediate is formed during the preactivation period and then
converted mainly to the β-mannoside when the acceptor is
added.11
Scheme 2. Competition Experiment between the
Benzylidene-Tethered Donor 1 and the Silylene-Tethered 6
When carrying out the glycosylation of 7 with 6 using NIS/
TfOH in CH2Cl2 at −78 °C followed by slow heating to 0 °C
(Table 2, entry 1) we saw, to our surprise, that the β-glycoside
(yield: 99%, selectivity: 6:1, separation not possible) was
obtained. Repeating this reaction with other acceptors (entries
2−5) also gave good to excellent yield and β-selectivity.
Starting and running the reaction at 25 °C did not change the
yield or selectivity significantly (entry 6), which means that the
NIS/TfOH protocol is the easiest protocol to make a β-
mannoside using 6.
The silylene-protected donor 6 was found to be somewhat
more reactive than the benzylidene analogue 1. When the
reaction of 6 with 7 was initiated at −78 °C a color change,
indicating the beginning of the reaction, occurred at −20 °C.
This activation temperature is between that of 1 and the
perbenzylated donor 13.
6, confirming that the silylene donor is the more reactive; i.e.,
the oxocarbenium intermediate more stabilized. On the other
hand, an attempt to couple 6 to the donor/acceptor alcohol 1a
failed, which indicates that the reactivity difference between the
silylene and benzylidene donor is minor.12
From a mechanistic point of view, the β-selectivity observed
with NIS/TfOH is surprising as the acceptor is present during
activation, which normally would be supposed to result in α-
mannoside formation.2 Ambiguous results are found in the
literature regarding the use NIS/triflate in β-mannosylations.13
For example, You et al. obtained β/α ratios between 3/1 to 7/1
with various sugar acceptors when activating an ethylthio
Table 1. Results of Reaction of 6 with Acceptor Alcohols Using the Crich Protocol (BSP, TTBP, Tf2O, CH2Cl2, −60 °C)
entry
acceptor
product
yield (%)
β/α
JCH, β/α
yield with 1 (%)
β/α with 1 (%)
1
7
14a
14a
15a
16a
17a
18a
14a
99
75
79
61
96
99
99
9/1
9/1
9/1
5/1
9/1
2/1
6/1
153/167
889a
>9/19a
a
2
7
9610
>9:110
3
4
5
6
8
156/164
156/171
154/172
156/170
9
909b
779
10/19b
>9:19
10
11
7
b
7
a
b
The Leiden protocol (Ph2O, TTBP, Tf2O, CH2Cl2, −78 °C) was used. The donor 12 was used rather than 6.
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analogue of 1 with NIS and catalytic TfOH at 0 °C.14 On the
other hand, the reaction of 1 and 7 with NIS and TMSOTf (1.1
equiv) at 0 °C was reported to give a disappointing 1/1 β/α
ratio.3 For this reason, we also tried TMSOTf. When activation
was performed with 1.1 equiv (Table 2, entry 7) we observed
α-selectivity (β/α = 1/10), but when catalytic TMSOTf was
used, β-selectivity returned (entry 8, β/α = 6/1). However, this
discrepancy was found to be due to anomerization. When an
NMR tube with β-mannoside 14a in chloroform was treated
with TMSOTf, complete anomerization from β to α was
observed in 15 min. We therefore conclude that, in the silylene
case, the main kinetic product of NIS/TMSOTf glycosylation is
the β-mannoside. It is also noteworthy that triflate is not
necessary in order to obtain β-selectivity. Activation of 6 under
triflate-free conditions using AgClO4 also gave mainly β-
mannoside (entry 9).15
A reaction with the β-analogue of 6, i.e., 12, and the acceptor
7 was also performed (Table 2, entry 10), and this gave exactly
the same results as when using 6: yield of 99% and a β/α ratio
of 6:1. This precludes a mechanism of direct SN2-substitution
of an iodoniumsulfide by the acceptor alcohol as was proposed
in the ethylthio benzylidenemannoside case14 since that would
result in different product ratios from 6 and 12. Reaction of
perbenzylated donor 13 with 7 gave, as expected, no selectivity
(entry 11) and confirms the importance of the 4,6-tethering
group for obtaining the β-selectivity.
the stereoisomeric triflates and intimate ion pairs should be in
equilibrium. Another possible route from α- to β-triflate is
through an ion triplet 21 as suggested in halide isomer-
izations.18 However, an ion triplet requires the presence of
triflate ions to form and can therefore not be expected to play a
major role in reactions where only catalytic triflate is used. It is
therefore clear that α-triflate will only be formed in the reaction
of 6 with NIS and catalytic TfOH by isomerization through
solvent-separated oxocarbenium ion triflate 24/25. The
oxocarbenium ion 24/25 is obviously much more reactive
than any triflate and must react with the acceptor when formed.
The conclusion of these considerations is that the preferential
β-mannoside formation seen from both 6 and 12 in NIS-
promoted glycosylations can only be a result of β-selective
addition of the acceptor to the solvent-separated oxocarbenium
ionpair 24/25.
Normally, one would expect that this ion would adopt a 4H3
conformation (24), a conformation that is likely to be attacked
by an alcohol from the α-face.19 However, the 4H3
conformation is very unfavorable having equatorial OR groups
in the 3 and 4 positions20 and the 6-OR in the tg
conformation.21 The more electronically favorable axial rich
3H4 conformation cannot be adopted due to the tethering
influence of the 4,6-silylene group. We propose that the
oxocarbenium ion adopts a B2,5 conformation22 25 whereby the
3-OR group is moved to a more favorable pseudoaxial
position.23 Furthermore, the 2-H is axial, which allows
hyperconjugative stabilization of the oxocarbenium ion.24 The
geometries of the two suggested conformations, 24 and 25,
were optimized using DFT calculations on truncated models,
where the tert-butyl and benzyl groups were substituted by
methyl groups (see the Supporting Information for details).The
B2,5 conformation was found to be energetically favored over
the 4H3, both in vacuum and in different solvents. The
difference is, however, small (0.59 kcal/mol in CH2Cl2; 0.73
kcal/mol in MeCN) but supports the proposed mechanism in
Scheme 3. Attack on 25 is highly β-selective due to an axial
The above experiments show that it is not plausible that
glycosylations with NIS follow a mechanism involving
formation and subsequent SN2 substitution of an α-triflate
(Scheme 3). Activation of thioglycosides with NIS/TfOH is
Scheme 3. Proposed Mechanism for the Glycosylation of 6
(or 1) Using NIS/TfOH
1
approach of the alcohol, which results in a S5 conformation.
4
4
This transfers into the low energy C1 via a H5 conformation,
without significant staggering in the silylene ring. α-Attack on
O
25 leads to a more strained and unfavorable S2 conformation.
4
Axial (α) attack by an acceptor on the less favorable H3
conformation 24 results directly in the low energy 4C1
1
conformation, whereas a β-attack results in a less stable S3
conformation. The observed selectivities can also be justified by
studying the geometry-optimized models of 24 and 25.
Looking at the Newman projection along the C1−C2 axis, a
β-attack on 25 results in an approach of the nucleophile in a
staggered fashion, whereas an α-attack would result in eclipsing
interactions between the nucleophile and the almost axial 2-H
(Figure 3). In 24, a β-attack would eclipse with the pseudoaxial
2-OBn and be highly disfavored, whereas an α-attack would be
nearly staggered, since the 2-H is pseudoequatorial.
initiated by formation of catalytic amounts of I+TfO− or
alternatively IHNIS+TfO−.16 One of these intermediates reacts
with the thioglycoside 6 or 12 resulting in an iodonium sulfide
with a triflate counterion (19 or 22). This iodonium sulfide is
not substituted directly by the acceptor alcohol (dashed
arrows) since if it did 12 would give α-mannoside, which it
does not (entry 10). Rather, it must collapse to a triflate or an
oxocarbenium ion/triflate intimate ion pair (20 or 23). The
most plausible stereochemistry of a triflate or triflate intimate
ion pair is that the triflate is on the other side of the leaving
group, i.e., inversion as it is known that halogenation of
thioglycosides initially gives the inverted glycosyl halide.17
From the intimate ion pairs a solvent-separated oxocarbenium
ion triflate 24/25 can be formed, and through this intermediate
Figure 3. Newman projections of the nucleophilic attack on the two
suggested oxocarbenium ion conformations 24 and 25.
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Organic Letters
Letter
(12) For the reactivity differences required to have chemoselective
glycosylation see: Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am.
Chem. Soc. 2007, 129, 9222 and references cited therein.
(13) Tanifum, C. T.; Chang, C.-W. T. J. Org. Chem. 2009, 74, 634.
Wang, S.; Lafont, D.; Rahkila, J.; Picod, B.; Leino, R.; Vidal, S.
Carbohydr. Res. 2013, 372, 35.
In summary, we have found that 6 is a readily available
glycosyl donor that can be used to produce β-mannosides using
simple and popular NIS/TfOH activation with no preactivation
or low-temperature chemistry necessary.
ASSOCIATED CONTENT
(14) You, M.; Shin, Y.; Chun, K. H.; Shin, J. E. N. Bull. Korean Chem.
Soc. 2000, 21, 562.
■
S
* Supporting Information
(15) It cannot be excluded that perchlorate forms a covalent glycosyl
perchlorate as such have been made; see: Igarashi, K.; Honma, T.;
Irisawa, J. Carbohydr. Res. 1970, 15, 329. In that work, a covalent α-
mannosyl perchlorate gave α-mannosides by reaction with alcohols
and was presumed to react through an oxocarbenium ion.
(16) Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org.
Chem. 1993, 58, 3194.
(17) Kovac, P.; Lerner, L. Carbohydr. Res. 1988, 184, 87.
(18) Lemieux, R. U.; Hendrix, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056.
Experimental procedures, characterization data, competition
experiments, NMR spectra, crystallographic data (CIF), and
DFT calculations. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: cmp@chem.ku.dk.
*E-mail: bols@chem.ku.dk.
Notes
(19) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem. 2006, 4, 1195.
(20) Jensen, H. H.; Bols, M. Acc. Chem. Res. 2006, 39, 259.
(21) (a) Jensen, H. H.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc.
́
2004, 126, 9205. (b) Frihed, T. G.; Walvoort, M. T. C.; Codee, J. D.
The authors declare no competing financial interest.
C.; van der Marel, G. A.; Bols, M.; Pedersen, C. M. J. Org. Chem. 2013,
78, 2191.
ACKNOWLEDGMENTS
■
(22) For studies where a boat conformation has been proposed in β-
The financial support of FTP is acknowledged.
glycoside formation, see: (a) Nukada, T.; Ber
Carbohydr. Res. 2002, 337, 765. (b) Moume-Pymbock, M.; Crich, D. J.
Org. Chem. 2012, 77, 8905. (c) Huang, M.; Retailleau, P.; Bohe, L.;
Crich, D. J. Am. Chem. Soc. 2012, 134, 14746. (d) Satoh, H.; Hansen,
́
ces, A.; Whitfield, D. M.
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