Reversal of anomeric selectivity with O-glycosyl trichloroacetimidates as glycosyl donors and thiols as acceptors under acid/base catalysis

Article abstract of DOI:10.1002/ejoc.201200138

Boron trifluoride or trimethylsilyl trifluoromethanesulfonate catalysed the generation of thioglycosides from O-glucopyranosyl or O-galactopyranosyl trichloroacetimidates and thiols giving mainly or exclusively α-thioglycosides. However, the same reaction

Full text of DOI:10.1002/ejoc.201200138

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200138
Reversal of Anomeric Selectivity with O-Glycosyl Trichloroacetimidates as
Glycosyl Donors and Thiols as Acceptors Under Acid/Base Catalysis
Amit Kumar[a] and Richard R. Schmidt*[a,b]
Keywords: Carbohydrates / Glycosylation / Thioglycosylation / Reaction mechanisms
Boron trifluoride or trimethylsilyl trifluoromethanesulfonate
catalysed the generation of thioglycosides from O-glucopyr-
anosyl or O-galactopyranosyl trichloroacetimidates and thi-
ols giving mainly or exclusively α-thioglycosides. However,
the same reactions with phenylboron difluoride as catalyst
are highly β-selective. An SN2-type reaction course under
acid/base catalysis is invoked by these and previous results.
found for glycosyltransferase-catalysed glycosidation reac-
tions.[8] As boron has a lower affinity to the sulfur of thiols
than to the oxygen of alcohols,[9] it was of interest to deter-
mine whether PhBF2 will catalyse the reactions with thiols
at all and when thioglycosides are obtained if prior
PhBF2·thiol adduct formation (IV; X = S) will lead under
acid/base catalysis via SN2-type transition state V to a re-
versal of the anomeric selectivity and to β-thioglycoside
1Zβ. Thus, further strong support for this reaction course
would be obtained.
Introduction
Glycosidation reactions catalysed by boron trifluoride
with O-glucopyranosyl trichloroacetimidate 1α as donor,[1,2]
alkanethiols as acceptors (HXR: X = S) and molecular
sieves as drying agent in CH2Cl2 as solvent at –42 °C af-
forded α-anomeric alkyl thioglycosides with retention of
configuration (Scheme 1).[2] Because alcohols (HXR: X =
O) exhibit under these acid catalysis reaction conditions
much lower α selectivity,[3] the generally accepted SN1-type
mechanism (Scheme 1, path a)[4,5] via BF3–donor adduct I,
the generation of glycosyl cation intermediate II and the
subsequent more or less diastereocontrolled reaction with
the acceptor to yield 1Zα and 1Zβ was questioned for the
quite nucleophilic alkanethiols. Instead, an intramolecular
Results and Discussion
The main focus of this work was on the use of PhBF2 as
reaction course via an initial attack of the thiol group at the catalyst; for comparison, some studies with BF3·OEt2 and
activated iminium carbon leading to adduct III and then trimethylsilyl trifluoromethanesulfonate (TMSOTf) as cata-
rearrangement of the adduct to the α-product 1Zα was dis- lysts are reported (Table 1). As previously found, the reac-
cussed (Scheme 1, path b).[2]
tion of glucosyl donor 1α with isopropanethiol (A) as ac-
Recently it was found that phenylboron difluoride ceptor (Figure 1) in the presence of molecular sieves (4 Å)
(PhBF2) is unable to activate glycosyl donor 1α. However, and BF3·OEt2 as catalyst afforded at –42 °C under the nor-
the PhBF2·alcohol adduct leads, with inversion of configu- mal procedure (NP: addition of the catalyst to a solution
ration, readily to glycosides with high β selectivity, particu- of the donor and acceptor) the α anomer 1Aα (entry 1).[2,10]
larly when the inverse procedure (IP) was applied (i.e., ad- When this reaction was carried out under IP conditions at
dition of the donor to a solution of the acceptor and cata- –78 °C without the addition of molecular sieves, a mixture
lyst).[6] For these highly stereocontrolled reactions a hydro- of anomers with a slight preference for 1Aβ was obtained
gen-bond-mediated acid/base-catalysed intramolecular (entry 2). With the widely employed TMSOTf as catalyst
SN2-type reaction course was proposed (Scheme 1, path c, under NP and IP conditions, practically the same results
X = O) that is also supported by other results.[6,7] This reac- were obtained with a preference for the α anomer (entries 3
tion course is closely related to the reaction mechanism and 4) and with B(SC3H7)3 as acceptor and TMSOTf as
catalyst a very slow reaction was observed under these con-
ditions (entry 5). Hence, the result with PhBF2 as catalyst
was of great interest as this reagent is too weak to activate
donor 1α in the absence of an acceptor. Only the adduct IV
(Scheme 1, X = S) will react and indeed 19F NMR analysis
indicated an interaction between PhBF2 and the thiol
groups (no change was observed in the 1H NMR spectrum).
The reaction of 1α with A under NP conditions led mainly
[a] Fachbereich Chemie, Universität Konstanz, Fach 725,
78457 Konstanz, Germany
Fax: +49-7531-883135
E-mail: richard.schmidt@uni-konstanz.de
[b] Chemistry Department, Faculty of Science, King Abdulaziz
University,
Jeddah 21589, Saudi Arabia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200138.
Eur. J. Org. Chem. 2012, 2715–2719
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Kumar, R. R. Schmidt
SHORT COMMUNICATION
Scheme 1. Activation of O-glycosyl trichloroacetimidates with boron fluorides in the presence of thiols and alcohols as acceptors.
Table 1. Reactions of 1α–4α with different thiols as acceptors and different glycosidation catalysts in CH2Cl2 as solvent.
Entry
Donor
Acceptor
Cat.
(0.1 equiv.)
Reaction conditions
Product[b]
(% yield)
β/α[c]
Procedure[a]
T [°C]
t [h]
1
2
3
1α
1α
1α
1α
1α
A
BF3·OEt2
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
n.p.
i.p.
n.p.
i.p.
–42
–78
–78
–78
–78
1
1A (85%)
1A (88%)
α[d]
1.5:1
1:2.4
1:2.4
–
A
0.5
0.2
0.2
0.7
A
A
1A (81%)
4
1A (80%)
slow reaction
5[e]
B(SC3H7)3
n.p.
6
7
8
1α
1α
1α
A
A
A
PhBF2
PhBF2
2-PhC6H4BF2
n.p.
i.p.
i.p.
–78
–78
–78
1
1
0.7
1A (84%)
1A (79%)
1A (83%)
5:1
8:1
8:1
9
1α
1α
1α
1α
B
C
D
E
PhBF2
PhBF2
PhBF2
PhBF2
i.p.
i.p.
i.p.
i.p.
–78
–78
–78
–78
1
1.2
1
1B (81%)
1C (76%)
1D (78%)
1E (65%)
7:1
15:1
10:1
4:1
10
11
12
2
13
14
15
2α
2α
2α
A
B
C
PhBF2
PhBF2
PhBF2
i.p.
i.p.
i.p.
–78
–78
–78
1
0.7
1
2A (73%)
2B (81%)
2C (76%)
15:1
16:1
16:1
16
17
18
3α
3α
3α
A
B
C
PhBF2
PhBF2
PhBF2
i.p.
i.p.
i.p.
–78
–78
–78
2
1.5
2
3A (77%)
3B (78%)
3C (71%)
15:1
16:1
16:1
19
20
21
22
4α
4α
4α
4α
A
B
C
E
PhBF2
PhBF2
PhBF2
PhBF2
i.p.
i.p.
i.p.
i.p.
–78
–78
–78
–78
1.2
1
1.2
2
4A (72%)
4B (70%)
4C (76%)
4E (67%)
25:1
15:1
16:1
10:1
[a] n.p.: normal procedure; i.p.: inverse procedure; for an explanation, see text. [b] Isolated yields. [c] The α/β ratio was determined by
1H NMR signal integration. [d] Reported in ref.[1]. [e] With 1 equiv. of TMSOTf as promoter a slow reaction to an anomeric mixture of
1B took place (2 h, yield 55%, β/α ≈ 1:2).
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Reversal of Anomeric Selectivity
decanethiol (C), cyclohexanethiol (D) and methyl 2,3,4-tri-
O-benzyl-6-deoxy-6-mercapto-α-d-glucopyranoside (E),[11]
showed similar strong preferences for the β anomers 1Bβ,[12]
1Cβ,[13] 1Dβ[14] and 1Eβ, respectively (entries 9–12). Also,
other glycosyl donors, such as lactosyl trichloroacetimidate
2α,[6] 2-azido-α-d-glucopyranosyl trichloroacetimidate
3α[15] and α-d-galactosyl trichloroacetimidate 4α,[16] gave
under the standard reaction conditions mainly β products
(2Aβ–2Cβ, 3Aβ–3Cβ, 4Aβ, 4Bβ,[10] 4Cβ[17] and 4Eβ; en-
tries 13–22). Hence, the envisaged reversal of anomeric
selectivity in comparison with the more common glycosid-
ation procedures (entries 1 and 3) was confirmed, thus
strongly supporting the initial formation of an adduct be-
tween PhBF2 and the thiol group and subsequent SN2-type
reaction with the glycosyl donor.
Because boron has a higher affinity to hydroxy groups
than thiols,[9] comparison studies were of interest. To this
end, 4-mercaptobutanol (F) was selected as the acceptor
and under the standard conditions it was treated with do-
nors 1α–3α (Scheme 2). As expected, only β-selective reac-
tions at the hydroxy group of F were observed leading es-
sentially to 1Fβ–3Fβ, respectively; these compounds were
characterized as their S-acetyl derivatives 1Faβ–3Faβ. The
observed chemoselectivity offers various possibilities for
Figure 1. Glycosyl donors and acceptors investigated in this study.
to β anomer 1Aβ (entry 6). However, as expected, IP condi- targeted functional group variations without resorting to
tions enhanced the formation of 1Aβ (entry 7), thereby sup- protecting group manipulations. Therefore, as a more inter-
porting the proposed SN2-type transition state
V
esting case, 2,3,4-tri-O-benzyl-α-d-glucopyranosylthiol
(Scheme 1). Therefore these reaction conditions were em- (G)[18] was also investigated as acceptor with 1α as donor.
ployed in the following studies. The introduction of an o- With PhBF2 as catalyst under the standard reaction condi-
phenyl group into the phenylboron moiety (entry 8) had tions in a highly β-selective reaction exclusive hydroxy
only a minor effect on the result although an influence on group attack was observed leading mainly to 1Gβ.[18] Thus,
the conformational preferences in the transition state was the strong interaction between boron and oxygen outbal-
expected. Other acceptors, such as propanethiol (B), do- ancing the greater nucleophilicity of the sulfur is confirmed.
Scheme 2. Reactions with mercapto-containing alcohols. Reagents and conditions: (a) i.p.: PhBF2, CH2Cl2, –78 °C; (b) Ac2O, Pyr, DMAP,
r.t.
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A. Kumar, R. R. Schmidt
SHORT COMMUNICATION
DMAP were added to a stirred solution of the hydroxy compound
in dry CH2Cl2 (2 mL) at room temperature. The reaction mixture
was stirred at room temperature until TLC indicated complete con-
sumption of the starting material (12 h). Then the reaction mixture
was diluted with CH2Cl2 (10 mL) and washed with diluted HCl.
The organic layer was dried with MgSO4 and concentrated in
vacuo. The residue was purified by flash column chromatography
with petroleum ether/EtOAc as eluent.
Conclusions
O-Glycosyl trichloroacetimidates as donors and thiols as
acceptors gave under standard acid catalysis conditions
preferentially or exclusively α-thioglycosides whereas acid/
base catalysis with PhBF2 led mainly to β-thioglycosides.
As the glycosyl donors employed do not provide anchimeric
assistance the β selectivity strongly supports the previously
invoked hydrogen-bond-mediated acid/base-catalysed intra-
molecular SN2-type reaction course. Acceptors with unpro-
tected thiol and hydroxy groups exhibit a high affinity for
boron through the hydroxy groups as only β-selective glyco-
sidation reactions with the hydroxy moieties were observed
with PhBF2 as catalyst.
4-Mercaptobutyl 2,3,4,6-Tetra-O-benzyl-β-D-glucopyranoside (1F):
The general procedure A for glycosylation afforded 1F as a viscous
oil; yield 74%; α/β 1:25. Rf = 0.5 (petroleum ether/EtOAc, 7:3).
1
[α]D = +40.5 (c = 1.1, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.47–7.25 (m, 18 H, Ar-H), 7.21–7.11 (m, 2 H, Ar-H), 4.95 (dd, J
= 11.0, 4.7 Hz, 2 H, PhCH), 4.80 (br. t, Japp = 10.4 Hz, 2 H,
PhCH), 4.72 (d, J = 11.0 Hz, 1 H, PhCH), 4.62–4.56 (m, 2 H,
PhCH), 4.53 (d, J = 11.0 Hz, 1 H, PhCH), 4.41 (d, J = 7.8 Hz, 1
H, 1-H), 4.03–3.96 (m, 1 H, 1Ј-H), 3.73 (dd, J = 9.0, 5.3 Hz, 1 H,
6a-H), 3.69–3.64 (m, 2 H, 5-H, 6e-H), 3.61 (br. d, Japp = 8.4 Hz, 1
H, 3-H), 3.56–3.54 (m, 1 H, 1Ј-H), 3.47–3.44 (m, 2 H, 2-H, 4-H),
2.57 (q, J = 6.8 Hz, 2 H), 1.77–1.71 (m, 4 H), 1.33 (t, J = 8.0 Hz,
1 H, SH) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.8, 138.7,
138.4, 138.3, 128.6, 128.5, 128.2–127.4 (m), 103.6 (C-1), 84.7, 82.5,
78.1, 76.6, 75.6, 75.9, 75.2, 75.1, 75.0, 73.7, 69.5, 69.2, 30.8, 28.7,
24.6 ppm. HRMS: calcd. for C38H44NaO6S [M + Na]+ 651.2751;
found 651.2773.
Experimental Section
General Methods: Solvents were purified by standard procedures.
1H and 13C NMR spectra were recorded at 22 °C with a Bruker
spectrometer (1H: 400 MHz; 13C: 100 MHz). Tetramethylsilane
(TMS) or the resonance of the undeuteriated solvent were used as
internal standards (solvent CDCl3: 1H: δ = 7.24 ppm; 13C: δ =
77.25). Mass spectra were recorded with a Bruker ESI MS mass
spectrometer. Thin-layer chromatography was performed on Merck
silica gel (60 F254) plastic plates. Compounds were visualized by
treatment with a solution of (NH4)6Mo7O24·4H2O (20 g) and
Ce(SO4)2 (0.4 g) in sulfuric acid (10%, 400 mL) and then heating
to 120 °C. Flash chromatography was performed on MN Silica gel
60 (230–400 mesh) at a pressure of 0.2 bar. Optical rotations were
measured at 22 °C with a Büchi Polar-Monitor using the sodium
D line. Some of the thiols were used as commercial grade. Starting
materials were obtained by following literature procedures. All re-
actions were performed in oven-dried glassware under dry nitrogen.
4-Acetylthiobutyl 2,3,4,6-Tetra-O-benzyl-β-D-glucopyranoside (1Fa):
Acetylation under standard conditions (Procedure C) afforded 1Fa
as a white solid; yield 80%. Rf = 0.4 (petroleum ether/EtOAc, 7:3).
1
[α]D = +23.8 (c = 1.1, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.45–7.23 (m, 18 H, Ar-H), 7.23–7.12 (m, 2 H, Ar-H), 4.94 (app
dd, Japp = 11.0, 2.1 Hz, 2 H, PhCH), 4.83 (app t, Japp = 11.0 Hz,
2 H, PhCH), 4.74 (d, J = 11.1 Hz, 1 H, PhCH), 4.62 (d, J =
12.2 Hz, 1 H, PhCH), 4.55 (dd, J = 11.5, 7.8 Hz, 2 H, PhCH), 4.40
(d, J = 7.8 Hz, 1 H, 1-H), 4.03–3.91 (m, 1 H, 1Ј-H), 3.75 (dd, J =
10.8, 2.0 Hz, 1 H, 6a-H), 3.71–3.66 (m, 1 H, 6e-H), 3.66–3.61 (m,
1 H, 5-H), 3.56–3.53 (m, 2 H, 1Ј-H, 3-H), 3.50–3.40 (m, 2 H, 2-H,
4-H), 2.98–2.89 (m, 2 H), 2.33 (s, 3 H, COCH3), 1.78–1.64 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.8, 138.7, 138.5,
138.2, 138.1, 128.3, 128.2–127.4 (m), 103.6 (C-1), 84.7, 82.2, 77.9,
75.6, 75.0, 74.88, 74.85, 73.5, 69.2, 68.9, 30.6, 28.88, 28.86,
26.3 ppm. HRMS: calcd. for C40H46NaO7S [M + Na]+ 693.2856;
found 693.2871.
Representative Procedures for the Thioglycosylation Reactions
Procedure A Ϫ Inverse Procedure: The catalyst [PhBF2, TMSOTf
or BF3·OEt2 (0.1 equiv.) in CH2Cl2] was added to a solution of the
acceptor (1 equiv.) in CH2Cl2 at room temperature. The reaction
mixture was then cooled to –78 °C. The donor (1 equiv.) was dis-
solved in a minimum amount of CH2Cl2 and after cooling to
–78 °C it was added to the reaction mixture at once. The mixture
was stirred at the same temperature until TLC indicated complete
consumption of the starting material. The reaction was quenched
with aqueous NaHCO3 and extracted with CH2Cl2. The organic
layer was washed with water, dried with MgSO4 and concentrated
in vacuo. The crude product was purified by flash column
chromatography with petroleum ether/EtOAc as eluent to afford
the desired glycoside. This way in most cases only the major an-
omer was obtained (see data of the compounds).
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic methods and physical data for new compounds and
1H and 13C NMR spectra of all synthesized compounds.
Acknowledgments
This work was supported by the University of Konstanz and the
Fonds der Chemischen Industrie.
Procedure B Ϫ Normal Procedure: The catalyst [PhBF2 or TMSOTf
(0.1 equiv.) in CH2Cl2] was added dropwise to a cooled solution
(–78 °C) of the donor (1 equiv.) and acceptor (1 equiv.) in CH2Cl2.
The mixture was stirred at the same temperature until TLC indi-
cated complete consumption of the starting material. The reaction
was then quenched with aqueous NaHCO3 and extracted with
CH2Cl2. The organic layer was washed with water, dried with
MgSO4 and concentrated in vacuo. The crude product was purified
by flash column chromatography with petroleum ether/EtOAc as
eluent to afford the desired glycosides.
[1] R. R. Schmidt, J. Michel, Angew. Chem. 1980, 92, 763–764;
Angew. Chem. Int. Ed. Engl. 1980, 19, 731–732.
[2] R. R. Schmidt, M. Stumpp, Liebigs Ann. Chem. 1983, 1249–
1256.
[3] a) R. R. Schmidt, Angew. Chem. 1986, 98, 213–236; Angew.
Chem. Int. Ed. Engl. 1986, 25, 212–235; b) R. R. Schmidt, W.
Kinzy, Adv. Carbohydr. Chem. Biochem. 1994, 50, 21–123.
[4] A. V. Demchenko, Handbook of Chemical Glycosylation, Wiley-
VCH, Weinheim, 2008.
Procedure C Ϫ Representative Procedure for the Acetylation: Acetic
anhydride (0.5 mL), dry pyridine (0.5 mL) and a few crystals of
[5] X. Zhu, R. R. Schmidt, Angew. Chem. 2009, 121, 1932–1967;
Angew. Chem. Int. Ed. 2009, 48, 1900–1934.
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Reversal of Anomeric Selectivity
[6] A. Kumar, V. Kumar, R. T. Dere, R. R. Schmidt, Org. Lett.
2011, 13, 3612–3615.
[7] A. Kumar, Y. Geng, R. R. Schmidt, Adv. Synth. Cat., accepted;
DOI: 10.1002/adsc.201100933.
[8] a) F. V. Rao, J. R. Rich, B. Rakic´, S. Buddai, M. F. Schwartz,
K. Johnson, C. Bowe, W. W. Wakarchuk, S. DeFrees, S. G.
Withers, N. C. J. Strynadka, Nature Struct. Mol. Biol. 2009, 16,
1186–1188; b) J. I. Rearick, J. E. Sadler, J. C. Paulson, R. L.
Hill, J. Biol. Chem. 1979, 254, 4444–4451; c) see also: K.-H.
Jung, M. Müller, R. R. Schmidt, Chem. Rev. 2000, 100, 4423–
4442.
[12]
[13]
[14]
[15]
F. K. Griffin, D. E. Paterson, P. V. Murphy, R. J. K. Taylor,
Eur. J. Org. Chem. 2002, 1305–1322.
H. Matsui, J.-I. Furukawa, T. Awano, N. Nishi, N. Sakairi,
Chem. Lett. 2000, 326–327.
T. Sato, Y. Fujita, J. Otera, H. Nozaki, Tetrahedron Lett. 1992,
33, 239–242.
Y. Du, J. Liu, R. J. Linhardt, J. Carbohydr. Chem. 1997, 16,
1327–1344.
[16] B. Wegmann, R. R. Schmidt, J. Carbohydr. Chem. 1987, 6, 357–
375.
[17] S.-H. Son, C. Tano, T. Furnike, N. Sakairi, Tetrahedron Lett.
2008, 49, 5289–5292.
[18] R. T. Dere, A. Kumar, V. Kumar, X. Zhu, R. R. Schmidt, J.
Org. Chem. 2011, 76, 7539–7545.
[9] D. J. Grant, D. A. Dixon, J. Phys. Chem. A 2009, 113, 777–
787.
[10] Y. Du, M. Zhang, F. Yang, G. Gu, J. Chem. Soc. Perkin Trans.
1 2001, 3122–3127.
[11] S.-S. Weng, Y.-D. Liu, C.-T. Chen, Org. Lett. 2006, 8, 5633–
5636.
Received: February 7, 2012
Published Online: April 5, 2012
Eur. J. Org. Chem. 2012, 2715–2719
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