Strict stereocontrol by 2,4- O -Di- tert -butylsilylene group on β-glucuronylations

Article abstract of DOI:10.1021/ol300634x

Strict β-controlled glucuronylations without classical neighboring-group participation were achieved by the assistance of a 2,4-O-di-tert-butylsilylene group. Comparison of activation conditions and conformational analysis indicated that the strict β-sele

Full text of DOI:10.1021/ol300634x

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2102–2105
Strict Stereocontrol by
2,4-O-Di-tert-butylsilylene Group
on β-Glucuronylations
Takayuki Furukawa, Hiroshi Hinou,* and Shin-Ichiro Nishimura
Graduate School of Life Science and Frontier Research Center for Post-Genome Science
and Technology, Hokkaido University, N21, W11, Kita-ku, Sapporo 001-0021, Japan
hinou@sci.hokudai.ac.jp
Received March 12, 2012
ABSTRACT
Strict β-controlled glucuronylations without classical neighboring-group participation were achieved by the assistance of a 2,4-O-di-tert-
butylsilylene group. Comparison of activation conditions and conformational analysis indicated that the strict β-selectivity was achieved by steric
hindrance of the 2,4-O-di-tert-butylsilylene group and not by complex glycosyl intermediates.
β-Glucuronides, abundant in polysaccharides and me-
tabolites, have been chemically constructed using classical
neighboring group participation (NGP) to form a 1,2-cis-
type cyclic oxonium intermediate in the glycosyla-
tion process.1,2 NGP can be a very reliable strategy for
strict stereocontrolled glycosylation, and reactions that
proceed by way of an orthoester intermediate also react
analogously.3 However, the low reactivity of the ortho-
esters often becomes problematic in the glycosylation of less
reactive acceptors such as secondary or tertiary alcohols or
the 4-OH group of hexopyranosides,2,3 and an alternative
methodology that did not generate such stable intermedi-
ates could have many advantages. Generally, 1,2-trans
glycoside formation without NGP requires consideration
of many different pathways; solvent effects of ethers
and nitriles,4 SN2-type reactions,5 formation of triflate
intermediates,6 and torsionalstraininfused-ring systems2,7
have all provided high stereoselectivities. However, the
stereoselectivity of these strategies for gluco-conformers is
affected by the reaction conditions, and the product is
often contaminated with small amounts of the anomeric
isomer.1,4,8 To our knowledge, there are no reports in the
literature regarding strict β-selective glucuronylations9,10
without NGP.
To achieve strict stereoselectivity without the action of
an O(2) participating group, bicyclic ring systems11,12 have
(6) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
(7) (a) Okada, Y.; Mukae, T.; Okajima, K.; Taira, M.; Fujita, M.;
Yamada, H. Org. Lett. 2007, 9, 1573. (b) Okada, Y.; Nagata, O.; Taira,
M.; Yamada, H. Org. Lett. 2007, 9, 2755.
(8) (a) Pedersen, C. M.; Marinescu, L. G.; Bols, M. Chem. Commun.
2008, 2465. (b) Crich, D.; Jayalath, P. J. Org. Chem. 2005, 70, 7252.
(9) (a) Garegg, P. J.; Olsson, L.; Oscarson, S. J. Org. Chem. 1995, 60,
2200. (b) Dinkelaar, J.; de Jong, A. R.; van Meer, R.; Somers, M.;
(1) (a) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926. (b) Crich, D.;
Li, L. J. Org. Chem. 2007, 72, 1681. (c) Crich, D.; Subramanian, V.;
Hutton, T. K. Tetrahedron 2007, 63, 5042. (d) Crich, D.; Vinogradova,
O. J. Org. Chem. 2006, 71, 8473.
(2) (a) Crich, D. Acc. Chem. Res. 2010, 43, 1144. (b) Mydock, L. K.;
Demchenko, A. V. Org. Biomol. Chem. 2010, 8, 497.
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Lodder, G.; Overkleeft, H. S.; Codee, J. D. C.; van der Marel, G. A.
(3) (a) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155. (b)
Furukawa, T.; Hinou, H.; Shimawaki, K.; Nishimura, S.-I. Tetrahedron
Lett. 2011, 52, 5567.
J. Org. Chem. 2009, 74, 4982. (c) Krog-Jensen, C.; Oscarson, S. Carbohydr.
Res. 1998, 308, 287. (d) van den Bos, L. J.; Codee, J. D. C.; Litjens, R. E.
J. N.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org.
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Chem. 2007, 3963.
(4) (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.;
Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927.
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(10) Polakova, M.; Pitt, N.; Tosin, M.; Murphy, P. V. Angew. Chem.,
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(b) Schmidt, R. R.; Rucker, E. Tetrahedron Lett. 1980, 21, 1421. (c)
Int. Ed. 2004, 43, 2518.
Schmidt, R.; Behrendt, M.; Toepfer, A. Synlett 1990, 694.
(5) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980,
19, 731.
(11) (a) Toshima, K.; Mukaiyama, S.; Nosaki, Y.; Inokuchi, H.;
Nakata, M.; Tatsuta, K. J. Am. Chem. Soc. 1994, 116, 9042. (b)
Oscarson, S.; Sehgelmeble, F. W. J. Am. Chem. Soc. 2000, 122, 8869.
r
10.1021/ol300634x
Published on Web 04/03/2012
2012 American Chemical Society

been employed, including for the formation of 2,6-
dideoxyhexopyranosides,11a β-fructofuranosides,11b and
β-galactosides.12 Among these, we focused on the di-tert-
butylsilylene group as the second rigidifying ring, and we
earlier employed the tactic for the high yielding R-selective
glycosylation of a 4,6-O-di-tert-butylsilylene-2-azidoga-
lactose derivative.12a Ando et al. have also reported that
this stereocontrol effect is stronger than that of an O(2)
NGP effect.12b However, 4,6-O-di-tert-butylsilylene deriv-
atives in gluco- or manno- configurations did not exert a
strong stereocontrolling effect.13 These results suggested
that at least one axially oriented hydroxyl group is required
for the silylene protecting group’s stereocontrolling effect.
Thus, we designed a 2,4-O-di-tert-butylsilylene-protected
glucuronate derivative 1 as a novel glycosyl donor for strict
stereocontrol in the formation of β-glucuronides. In addi-
yield via a one-pot reaction. The desired compound 1 was
obtained in 78% yield from 3 by treatment with di-tert-
butylsilyl bis(trifluoromethanesulfonate) (tBu2Si(OTf)2)
and 2,6-lutidine.
Scheme 1. Synthesis of Glycosyl Donor 1
1
tion, donor 1 has a C4 conformation which would be
expected to exhibit increased reactivity due to cooperative
conformational14 and anomeric effects. A method using
steric hindrance as the dominant factor could be a versatile
alternative strategy for β-glucuronylation. (Figure 1)
To clarify the reactivity of donor 1 in the glycosylation
reaction, seven acceptor substrates;benzyl alcohol 4,
cyclohexanol 5, 1-adamantanol 6, 6-O-unprotected gluco-
side derivative 7, 3-O-unprotected 2-azidegalactoside deri-
vative 8, 3-O-unprotected glucosaminide derivative 9, and
4-O-unprotected glucosaminide derivative 10;were se-
lected and reacted with donor 1, which was activated with
diphenylsulfoxide (Ph2SO)/triflic anhydride (Tf2O)/2,4,6-
tri-tert-butylpyrimidine (TTBP).17 This reagent system is
known to control stereoselectivity by the formation of
glycosyl triflate type intermediates (Figure 1, Table 1).
When benzyl alcohol 4 was employed as an acceptor, the
desired product 11 was obtained in high yield with strict
β-selectivity(Table1, entry 1). The relativelyhighyield and
strict β-selectivity of donor 1 were reproduced with accep-
tors 5À10 (Table 1, entries 2À7). Even for hindered
acceptors 1-adamantanol 6 and 4-OH unprotected glucos-
aminidederivative10, donor 1gavethe desired products 13
and 17, respectively, in good yields (Table 1, entries 3, 7).
The hydroxyl group at O-4 in 10 is notorious for its poor
nucleophilicity and is known to be a difficult glycosyl
acceptor.18 Yamada et al. reported that 2,3,4-tri-O-silyl-
protected glucose donors exhibit β-selective glucosidation,
but strict stereoselectivity and the glycosylation of a 4-OH
were not achieved.7a Thus, successful reactions with ac-
ceptors 6 and 10 clearly indicate the high reactivity of
donor 1 even with hindered acceptors.
Figure 1. Working hypothesis and designed donor 1.
The donor 1 was prepared from 215 in four steps as
shown in Scheme 1. Acetyl group deprotection, 2,2,6,6-
tetramethylpiperidine-1-oxy (TEMPO) radical/[bis-
(acetoxy)iodo] benzene (BAIB) oxidation16 at C-6, and
methyl esterification of 2 afforded precursor 3 in 48%
(12) (a) Kumagai, D.; Miyazaki, M.; Nishimura, S.-I. Tetrahedron
Lett. 2001, 42, 1953. (b) Imamura, A.; Ando, H.; Korogi, S.; Tanabe, G.;
Muraoka, O.; Ishida, H.; Kiso, M. Tetrahedron Lett. 2003, 44, 6725.
(13) (a) Ohnishi, Y.; Ando, H.; Kawai, T.; Nakahara, Y.; Ito, Y.
Carbohydr. Res. 2000, 328, 263. (b) Jensen, H. H.; Pedersen, C. M.;
Bols, M. Chem.;Eur. J. 2007, 13, 7576. (c) Dinkelaar, J.; Gold, H.;
In the 1C4 conformation, anomeric configurations can-
not be determined by 1H NMR spectroscopy because the
R and β anomers have similar coupling constants (J1,2) at the
anomeric proton. To confirm the stereoselectivity of donor
1, deprotections of 2,4-O-di-tert-butylsilylene groups were
ꢀ
Overkleeft, H. S.; Codee, J. D. C.; van der Marel, G. A. J. Org. Chem.
2009, 74, 4208.
(14) (a) Pedersen, C. M.; Marinescu, L. G.; Bols, M. C. R. Chimie
2011, 14, 17. (b) Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am.
Chem. Soc. 2007, 129, 9222.
(17) (a) Garcia, B.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269. (b)
Codee, J. D. C; Litjens, R. E. J. N.; den Heeten, R.; Overkleeft, H. S.; van
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(15) Codee, J.; Stubba, B.; Schiattarella, M.; Overkleeft, H. S.; van
Boeckel, C. A. A.; van Boom, J. H.; van der Marel, G. A. J. Am. Chem.
Soc. 2005, 127, 3767.
(16) van den Bos, L. J.; Litjens, R. E. J. N.; van den Berg, R. J. B. H.
Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519.
(18) (a) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819. (b)
Miermont, A.; Zeng, Y.; Jing, Y.; Ye, X.-S.; Huang, X. J. Org. Chem.
2007, 72, 8958.
N.; Overkleeft, H. S.; van der Marel, G. A. Org. Lett. 2005, 7, 2007.
Org. Lett., Vol. 14, No. 8, 2012
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Table 1. Glucuronylationsa Using the Glycosyl Donor 1 for
Various Acceptors
Table 2. Deprotection of 2,4-O-Di-tert-butylsilylene Groupsa
a HF/pyridine, 2 h at rt. S.M. = Starting Material. b HF/pyridine, 30
min at rt. c HF/pyridine, 2 h at rt, then Ac2O/pyridine. d Isolated yields.
outcomes differ19 between Ph2SO/Tf2O17 (preactivation
conditions to form β-triflate) and N-iodo succinimide
(NIS)/trifluoromethanesulfonic acid (TfOH) (direct acti-
vation condition) mediated activation. These results sug-
gested that the NIS/TfOH direct activation system might
show a different stereoselectivity profile than the glucosyl-
triflate intermediate of the 1-benzenesulfinyl piperidine20
and diphenyl sulfoxide reaction conditions.19
a Conditions: donor (1.3 equiv), acceptor (1.0 equiv), Ph2SO (1.5
equiv), Tf2O (1.5 equiv), TTBP (2.9 equiv), CH2Cl2 (0.05 M), À60 to
0 °C, 2 h. MP = para-methoxy phenol. b Isolated yields. c Isolated ratio.
Table 3. Behaviors of Donor 1 in Different Activation
Conditions
yielda,b (yield in
R/β
carried out with hydrogen fluoride (HF)/pyridine and each
coupling constant was analyzed (Table 2).
entrya
acceptors
products
Table 1)
ratioc
As shown in Table 2, the coupling constants of anomeric
protons (J1,2) converged to approximately 7.5À7.9 Hz,
allowing all anomeric configurations to be assigned as
β-forms. These results clarify that glycosylation reactions
using donor 1 proceed in a β-selective manner.
1
2
3
8
15
16
17
80% (71%)
46% (77%)
70% (63%)
β-only
β-only
β-only
9
10
a Conditions: donor (1.5 equiv), acceptor (1.0 equiv), NIS (1.5 equiv),
TfOH (0.2 equiv), CH2Cl2 (0.07 M), À40 to À10 °C, 2 h, b Isolated yields.
c Isolated ratio.
Next, our interest shifted to the mechanism of the high
β-stereoselectivity. Crich et al. reported that anomeric
(19) Crich, D.; de la Mora, M.; Vinod, A. J. Org. Chem. 2003, 68,
8142.
(20) (a) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198. (b) Crich, D.;
Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
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Org. Lett., Vol. 14, No. 8, 2012

Based on this hypothesis, donor 1 was reacted under the
NIS/TfOH conditions to estimate the influence of reaction
intermediates21 such as the glycosyltriflate.22 We selected
sugar hydroxyl groups 8À10 as acceptor substrates for
practical use (Table 3). The results show that every cou-
pling reaction afforded only β-glycosides and that no
significant differences in yield between the acceptors were
observed. We thus believe that these results indicate that
steric hindrance is the dominant factor and that reaction
intermediates have only a small influence on the stereo-
selectivity of the 2,4-O-di-tert-butylsilylene group.
Figure 3. MM calculated structure of donor 1.
Figure 2. Conformational analysis of donor 1 by NOESY.
affected by the activation system. It is thus believed that
the tert-butylgroup sterichindranceplays a significant role
in the stereoselectivity. This hypothesis is clearly supported
by NMR spectroscopy conformational analysis and donor
1 structural calculations. This stereocontrolled glycosyla-
tion method could be applied to the synthesis of other
glycosides having gluco-, ido-, allo-, talo-, ribo-, or xylo-
type configurations, including β-D-xyloside and R-L-iduro-
nate residues in glycosaminoglycans.
We then performed a two-dimensional nuclear Overhauser
enhancement spectroscopy (NOESY) measurement to
prove the effect of steric hindrance in fixed ring systems.
As shown in Figure 2, each ring proton correlates with tert-
butyl groups. As expected, strong interactions between the
endo-tBu group and the anomeric proton H-5 were ob-
served. This result indicates that the endo-tBu group
locates near C-1 and C-5 and shields the R-direction. The
structure of 1 was calculated using a macro model (MM)23
and supported the NOESY analytical data, showing that
the ring’s R-face was completely covered by the 2,4-O-di-
tert-butylsilylene group (Figure 3).
In conclusion, we have designed and synthesized a novel
glucuronyl donor 1 with a 2,4-O-di-tert-butylsilylene func-
tional group. This donor 1 showed excellent coupling
yields and complete β-selectivity for various acceptors,
including hindered tertiary alcohols and the 4-OH group
of GlcNAc. In addition, the strict β-selectivity is not
Acknowledgment. This work was supported partly by a
grant for a “Promotion for Young Research Talent and
Network” from Northern Advancement Center for
Science & Technology (NOASTEC) and Grant in Aid
for Scientific Research (B, no. 23350074) from MEXT
Japan. We also thank Dr. Toru Taniguchi and Prof. Kenji
Monde (Hokkaido Univ.) for MM calculations of com-
pound 1.
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(21) Bohe, L.; Crich, D. C. R. Chimie 2011, 14, 3.
(22) β-Triflate was not directly detected; however it will be more
preferential than R-one due to the anomeric effect and the steric reason.
(23) Conformational (distribution) search and energy calculation
were carried out with Spartan’10 (Wave function, Inc., Irvine, CA)
software using the MMFF molecular mechanics force field.
The authors declare no competing financial interest.
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