1,2-: Cis -Selective glucosylation enabled by halogenated benzyl protecting groups

Article abstract of DOI:10.1039/d0ob00373e

We report on our initial results from a systematic effort to implement electron-withdrawing protecting groups and Lewis basic solvents/additives as an approach to 1,2-cis(α)-selective O-glucosylation. 1,2-cis-Selective O-glucosylations are reported with thioglucosides and glucosyl trichloroacetimidates and a range of acceptors. A correlation between electron-withdrawing effects and 1,2-cis selectivity has been established. This phenomenon may prove to be broadly applicable in the area of chemical O-glycosylation.

Full text of DOI:10.1039/d0ob00373e

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DOI: 10.1039/D0OB00373E
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1,2-cis-Selective Glucosylation Enabled by Halogenated Benzyl
Protecting Groups
Dancan K. Njeri,a Claude J. Pertuit a and Justin R. Ragains a,†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report on our initial results from a systematic effort to MBTGs/MPTGs represent rare examples of alkylthioglycosides
implement electron-withdrawing protecting groups and Lewis basic that are activated with catalytic acid. Acknowledging that
solvents/additives as an approach to 1,2-cis()–selective O- adaptation of any new O-glycosylation donor to 1,2-cis-selective
glucosylation. 1,2-cis-selective O-glucosylations are reported with O-glycosylation protocols is an important test in establishing its
thioglucosides and glucosyl trichloroacetimidates and a range of appeal to the synthetic community, we set out to develop a 1,2-
acceptors. A correlation between electron-withdrawing effects and cis-selective O-glycosylation using MBTGs and MPTGs. In the
1,2-cis selectivity has been established. This phenomenon may course of our studies, we have identified a strategy toward 1,2-
prove to be broadly applicable in the area of chemical O- cis selectivity that may prove broadly applicable. Our initial
glycosylation.
results are reported herein.
O-Glycosylation has been a relevant topic of research in organic
synthesis for over a century, and investigators have made great
strides to develop efficient, high-yielding O-glycosylations
whether by chemical or enzymatic means.1 While formation of
1,2-trans glycosidic linkages
(1, Figure 1) is relatively
straightforward due to implementation of participating groups
at 2-position oxygen or nitrogen, the efficient and highly
selective formation of 1,2-cis glycosidic linkages (2, Figure 1) is
a topic of ongoing investigation.2 A number of creative
solutions to this problem have been reported, and 1,2-cis-O-
glycosylation has proven to be an important vehicle for
discovery in carbohydrate chemistry.2a
Nevetheless, a
generalized approach to 1,2-cis selectivity remains elusive. An
approach that requires a minimal number of extra synthetic
steps in the synthesis of glycosyl donors as well as in the
subsequent manipulation of glycosidic products and their
protecting groups is especially desirable.
We reasoned that protonation of MBTGs/MPTGs (as
exemplified with MPTGs
glycosylsulfonium intermediates
sulfide from could result in stereospecific formation of 1,2-
cis-O-glycosides 9 4
Competing formation of oxocarbenium ion
would lead to unselective formation of both 1,2-cis and 1,2-
trans O-glycosides by SN1 mechanism. In instances in which
formation of is facile, addition of excess Lewis-basic additives
or Lewis-basic solvents (LB:) could ensure the formation of
adducts with equatorially disposed anomeric leaving groups.
3
,
Scheme 1) will result in
5
. Backside displacement of
We have recently reported the development of 4-(4-
methoxyphenyl)-3-butenylthioglycosides3a
methoxyphenyl)-4-pentenylthioglycosides3b
and
(MBTGs
4-(4-
and
6
5
.
7
MPTGs, respectively, Figure 1) as stable donors for glycosylation
that are nevertheless activated readily with catalytic
trifluoromethanesulfonic acid (HOTf) at room temperature.
7
8
a. Department of Chemistry, Louisiana State University
232 Choppin Hall, Baton Rouge, LA 70803
† Corresponding Author
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
In particular, additives/solvents such as tetraalkylammonium
bromides,5a N,N-dialkylamides,5b,c triphenylphosphine oxide,5c
and dialkyl ethers1a,5d promote 1,2-cis selectivity through
8
-like
adducts generated from hexopyranosyl donors. A critically
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important aspect of this strategy involves destabilizing
7
and on HOTf. This may not prove to be a problem with less stable
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DOI: 10.1039/D0OB00373E
stabilizing
5
/8
.
Therefore, implementation of electron- glycosyl O-trichloroacetimidates.5c
withdrawing and non-participating protecting groups
(symbolized as “EWG” in Scheme 1) should shift equilibria
toward
5
/8
.
Halogenated benzyl groups were particularly
appealing to us at the outset of these studies. Indeed,
protection with halobenzyl groups has been used to promote
1,2-cis O-glycosylation by Boltje,4c Zhang,6a and Hung6b when
more electron-rich benzyl groups failed to promote high
selectivity. Others have exploited this form of substitution for
stabilization of fucosidic linkages and orthogonality in multistep
synthesis.6c,d
At the outset of this project, we synthesized a series of
MBTGs and MPTGs (10-11, Table 1) derived from D-glucose and
protected at the 2, 3, 4, and 6-positions with benzyl (Bn), 4-
fluorobenzyl, 4-chlorobenzyl, and 4-trifluoromethylbenzyl
(CF3Bn) in preparation for studies on 1,2-cis-selectivity. These
groups were chosen because of synthetic practicability: the
benzyl halide precursors are commercially available in all cases
and can be installed using Williamson etherification.
Meanwhile, difficulties were incurred with 4-nitrobenzyl
protection while installation of 4-cyanobenzyl requires an extra
synthetic step.4c Further, we chose C-6 hydroxyl-bearing
-
methyl-2,3,4-tri-O-benzylglucoside (12) as the acceptor for
initial method development due to its history of poor 1,2-cis
selectivity.2 The results of our initial studies are depicted in
Table 1. Subjection of benzyl-protected MBTG substrate 10a to
previously reported standard conditions (10 mol. % HOTf,
o
CH2Cl2, 20 C)3 resulted in 84% yield of disaccharide 13a and a
poor selectivity for 1,2-cis (
, entry 1). We next repeated the conditions of entry 1 with
a sundry of additives predicted to behave as “LB:” (see
) to 1,2-trans () glycosides (1.8:1
8
,
Scheme 1) including thiophene and ethyl phenyl sulfide,4a
various dialkyl sulfides, DMF,5b,c and triphenylphosphine oxide
(TPPO).5c In the case of thiophene and sulfides, little if any
enhancement of 1,2-cis selectivity was noted (data not shown).
In the case of DMF and TPPO, reactions were sluggish to the
point of being impractical. This was likely due to the Bronsted
basicity of these additives and their attendant buffering effect
aUnless otherwise stated, 0.15 mmol of donors 10/11 and 0.075
mmol of acceptor 12 were implemented along with 40 mol. % HOTf
(relative to donor). Reactions were stirred magnetically at 20 C for
12 h. b10 mol. % HOTf was used. cAnomeric ratios were estimated
o
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from purified mixtures of anomers by integration of key signals in the promote the formation of glycosyl trifluoromethaneVsiuewlfoArntiicmleiOdnelisn.e8
1H NMR spectrum. dTf2NH was used as acid.
The role of these phenomena in the reported glycosylations is not
clear. The transient formation of glycosyl triflate analogs of 8
(Scheme 1) as an explanation for high 1,2-cis selectivity cannot be
ruled out at this time.
DOI: 10.1039/D0OB00373E
Switching solvent from CH2Cl2 to 1,4-dioxane (entry 2) and
implementation of 40 mol. % HOTf (reactions were sluggish with
lower loadings) resulted in 69% yield of a nearly 4:1 mixture of 13a
favoring 1,2-cis isomer. Use of ethereal solvents, especially 1,4-
dioxane,5d is known to promote 1,2-cis selectivity possibly through
the formation of adducts like 8 (Scheme 1). In effort to further
improve these results, we implemented MBTGs 10b, 10c, and 10d
wherein Bn is replaced with 4-fluorobenzyl, 4-chlorobenzyl, and 4-
trifluoromethylbenzyl (CF3Bn) as seen in entries 3,4, and 5,
respectively. We saw steadily improving selectivity up to ~9:1 in
favor of 1,2-cis that roughly follows the increasingly positive
Hammett  values for H, F, Cl, and CF3. We attribute this to steadily
increasing electron-withdrawing effects. We were encouraged by
this trend, however, the historically low reactivity of MBTGs toward
the most deactivated acceptors3a,b prompted us to also explore
MPTGs 11c and 11d which we predicted to be more reactive toward
the most deactivated acceptors. Entries 6 and 7 depict 1,2-cis-
selectivity with the implementation of 11c and 11d. Further, to rule
out the possibility that 1,2-cis selectivity with the halobenzyl groups
of 10/11 is not solvent dependent, we performed glycosylation of 12
with CF3Bn-protected 10d and 11d using CH2Cl2 as solvent and
observed dramatically decreased selectivities that were similar to
those of entry 1 (entries 8 and 9).
We conducted a short substrate scope study (Scheme 2)
screening a range of acceptor reactivities. We chose donor 11d due
to its predicted reactivity toward less reactive acceptors than 12 in
combination with conditions from entry 12 of Table 1. Reaction of
the 6-position of -phenylthioglucoside with 11d provided
a
satisfactory 7.2:1 1,2-cis/1,2-trans ratio (entry 1) while similar ratios
of 8.8:1 and 7.8:1 were obtained with the 2- and 4-positions of
tribenzylated methyl glucosides (entries 2 and 3). Reaction of 11d
with the 4-position of methyl glucuronate afforded a disappointing
ratio of 4.2:1 in favor of 1,2-cis. The counterintuitive decreasing
selectivity with decreasing acceptor reactivity compared to acceptor
12 as in entries 2-4 may reflect competition between more
associative (SN2-like processes as in 8→9, Scheme 1) and dissociative
(SN1) processes in which the less reactive acceptors undergo a higher
proportion of the latter. Reaction with cholesterol (entry 5) resulted
in comparable selectivity to that seen in entries 1-3 whereas the
highly reactive acceptor N-carbobenzyloxy-3-aminopropan-1-ol
(entry 6) provided lower selectivity.
We were intrigued by the potential roles of additional
parameters including temperature, concentration, and acid. We
conducted a series of experiments at 0 oC and -20 oC (data not
shown). Because of the high melting point of 1,4-dioxane (11.8 oC),
we implemented solvent mixtures with Et2O. Nevertheless,
glycosylation proceeded at prohibitively low rates under these
conditions. Dilution of reaction mixtures, to contrast, proved fruitful.
Lowering donor concentration from ~0.15 M to ~0.06 M by adding
2.5 mL instead of 1 mL solvent (entry 10) using donor 11d resulted in
an increased selectivity of ~9:1 in favor of 1,2-cis (see entry 7 for
comparison). Further decrease of donor concentration to ~0.03 M
(entries 11, 12) by adding 5 mL solvent using donors 10d and 11d
(respectively) resulted in further increases in selectivity (to ~ 13:1
(cis/trans) in the case of donor 11d). Once again (as with entries 8/9),
switching to CH2Cl2 at this higher dilution (~0.03 M) resulted in
dramatic decreases both in yield and selectivity (entry 13) compared
to the entry 12 results. Subsequent experiments performed at
higher dilution resulted in similar selectivity to that of entries 11 and
12 with dramatically decreased yield of product 13d (data not
shown). Finally, substituting HOTf (pKa = -14.7) with similarly acidic
trifluoromethanesulfonimide (Tf2NH, pKa = -12.3) as shown in entry
14 results in dramatically reduced 1,2-cis selectivity suggesting that
counteranions play a non-innocent role in these glycosylations.
There is a wealth of evidence that glycosyl triflates are generated in
the presence of glycosyl oxocarbenium ions7 whereas at least one
report suggests that trifluoromethanesulfonimide anion does not
aUnless otherwise stated, 0.15 mmol of donor 11d and 0.075
mmol of acceptors were implemented along with 40 mol. %
HOTf (relative to donor) and 5 mL 1,4-dioxane. Reactions were
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b
stirred magnetically at 20 oC for 12 h. Donor:acceptor ratio was protecting groups and 1,2-cis selectivity in addition to moderate to
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DOI: 10.1039/D0OB00373E
2.36:1. cDonor:acceptor ratio was 2.17:1. dDue to purification high yields at 20 oC. This phenomenon has proven applicable to
challenges, two chromatographic purifications were performed. MBTGs and MPTGs previously developed in our group as well as the
Anomeric ratios were determined after the first purification, more traditional glucosyl trichloroacetimidates.
and yields were determined after the second purification. investigations on electron-withdrawing benzylic and other non-
participating protecting groups and additional Lewis-basic additives
Further
At this stage, we were interested in determining what, if any, are underway in our lab and will be reported in due course. In
anomerization might be occurring after initial glycosylation particular, we will strive to develop methods that require less acid
considering the relatively high concentration of HOTf at room catalyst while exploring and perhaps even developing electron-
temperature (Scheme 3). Therefore, we conducted two withdrawing protecting groups that are installed with a level of ease
experiments with - and -20. We chose these cholesteryl and low cost that is similar to that of benzyl groups.
glucosides due to the relatively electron-rich aglycone
1
(increasing the odds of ionization) and ease of analysis with H
NMR. In both cases, we were not able to detect anomerization
of either stereoisomer after stirring for 12 h in the presence of
0.8 equiv. HOTf. We conclude that the stereoselectivities
reported herein are the result of kinetic control.
We were interested in probing the generality of the observed
protecting group phenomenon. For this purpose, we synthesized
glucosyl trichloroacetimidates protected with Bn and CF3Bn (22a and
22d, respectively) and subjected them to conditions similar to the
entry 10 and 12 conditions from Table 1 (see Table 2). A short
investigation indicated that donor/acceptor ratios of 1:0.7 and use of
1 equiv. of HOTf (relative to donor) provided the best yields of
products 13 (data not shown). Strikingly, we were able to reproduce
both the dilution effect (compare entries 2 and 4 of Table 2 with
entries 10 and 12 of Table 1) using trichloroacetimidate 22d. Further,
stereoselectivities increased dramatically when replacing Bn with
CF3Bn (compare entries 1/3 with 2/4 in Table 2). These observations
suggest that use of electron-withdrawing protecting groups and
Lewis-basic additives/solvents may provide a general solution to 1,2-
cis selectivity in O-glycosylation.
a0.15 mmol of donors 22 and 0.105 mmol of acceptor 12 were
implemented along with 1 equiv. HOTf (relative to donor) and either
2.5 or 5 mL 1,4-dioxane. Reactions were magnetically stirred at 20
oC for 12 h. bAnomeric ratios were estimated from purified mixtures
of anomers by integration of key signals in the 1H NMR spectrum.
Finally, we demonstrate the facile removal of Bn and CF3Bn
groups from substrate 13d using catalytic hydrogenolysis (Scheme
4).9
Conflicts of interest
There are no conflicts to declare.
Conclusions
Acknowledgments
Herein, we have reported on our initial results from a research
program designed to systematically study the synergy of electron-
withdrawing protecting groups with Lewis basic additives or solvents
in the generation of 1,2-cis glycosidic linkages. While observed
stereoselectivites with optimized procedures range from modest
(e.g. 4.2:1) to high (e.g. 13:1) in favor of 1,2-cis glycosides, there is a
correlation between the electron-withdrawing effects of the benzylic
This research was supported by the U.S. National Science
Foundation (CHE-1665208). We thank Ms. Connie David for
assistance with high-resolution mass spec., and we thank Dr.
Thomas Weldeghiorghis for assistance with NMR.
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Notes and references
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DOI: 10.1039/D0OB00373E
1
a) R.R. Schmidt, K.-H. Jung, In Carbohydrates in Chemistry and
Biology (Eds. B. Ernst; G.W. Hart; P. Sinaÿ), 2000, 5-59. b)
J.D.C. Codée, R.E.J.N. Litjens, L.J. van den Bos, H.S. Overkleeft,
G.A. van der Marel, Chem. Soc. Rev. 2005, 34, 769-782. c)
H.A. Chokhawala, X. Chen, Enzymatic Approaches to O-
Glycoside Introduction:
Glycosyltransferases.
In
Comprehensive Glycoscience; J.P. Kamerling, Ed., Elsevier Ltd.:
Oxford, 2007, Vol. 1, pp 415-451. d) K.M. Koeller, C.-H. Wong,
Chem. Rev. 2000, 100, 4465. e) Z. Wang, Z.S. Chinoy, S.G.
Ambre, W. Peng, R. McBride, R.P. de Vries, J. Glushka, J.C.
Paulson, G.-J. Boons, Science 2013, 341, 379. f) H. Li, H. Zhang,
W. Yi, J. Shao, P.G. Wang, ACS Symposium Series 2005, 900,
192.
2
3
a) S.S. Nigudkar, A.V. Demchenko, Chem. Sci. 2015, 6, 2687-
2704. b) A.V. Demchenko, Synlett 2003, 9, 1225-1240.
a) K.D. Lacey, R.D. Quarels, S. Du, A. Fulton, N.J. Reid, J.R.
Ragains, Org. Lett. 2018, 20, 5181-5185. b) S. Du, J.R. Ragains,
Org. Lett. 2019, 21, 980-983.
4
a) J. Park, S. Kawatkar, J.-H. Kim, G.-J. Boons, Org. Lett. 2007,
9, 1959-1962. b) J.-H. Kim, H. Yang, J. Park, G.-J. Boons, J. Am.
Chem. Soc. 2005, 127, 12090-12097. c) S.J. Moons, R.A.
Mensink, J.P.J. Bruekers, M.L.A. Vercammen, L.M. Jansen, T.J.
Boltje, J. Org. Chem. 2019, 84, 4486-4500. d) M.A. Fascione,
C.A. Kilner, A.G. Leach, W.B. Turnbull, Chem. Eur. J. 2012, 18,
321-333. e) L.K. Mydock, K.M. Kamat, A.V. Demchenko Org.
Lett. 2011, 13, 2928-2931.
a) R.U. Lemieux, K.B. Hendriks, K. James, J. Am. Chem. Soc.
1975, 97, 4056. b) S.-R. Lu, Y.-H. Lai, J.-H. Chen, C.-Y. Liu, K.-
K.T. Mong, Angew. Chem. Int. Ed. 2011, 50, 7315-7320. c) L.
Wang, H.-S. Overkleeft, G.A. van der Marel, J.D.C. Codée, J.
Am. Chem. Soc. 2018, 140, 4632-4638. d) A. Demchenko, T.
Stauch, G.-J. Boons, Synlett 1997, 818-820.
5
6
a) Z. Zheng, L. Zhang, Carbohydr. Res. 2019, 471, 56-63. b)
M.M.L. Zulueta, S.-Y. Lin, Y.-T. Lin, C.-J. Huang, C.-C. Wang, C.-
C. Ku, Z. Shi, C.-L. Chyan, D. Irene, L.-H. Lim, T.-I. Tsai, Y.-P.Hu,
S.D. Arco, C.-H. Wong, S.-C. Hung, J. Am. Chem. Soc. 2012
,
134, 8988-8995. c) N.L. Pohl, L.L. Kiessling, Tetrahedron Lett.
1997, 40, 6985-6988. d) O.J. Plante, S.L. Buchwald, P.H.
Seeberger, J. Am. Chem. Soc. 2000, 122, 7148-7149.
a) D. Crich, S. Sun, J. Am. Chem. Soc. 1997, 119, 11217-11223.
b) T. Nokami, A. Shibuya, H. Tsuyama, S. Suga, A.A. Bowers, D.
Crich, J.-I. Yoshida, J. Am. Chem. Soc. 2007, 129, 10922-10928.
c) L. Bohé, D. Crich, Carbohydr. Res. 2015, 403, 48-59.
Y. Isoda, K. Kitamura, S. Takahashi, T. Nokami, T. Itoh,
ChemElectroChem 2019, 6, 4149-4152.
7
8
9
N. Bensel, D. Klär, C. Catala, P. Schneckenburger, F.
Hoonakker, S. Goncalves, A. Wagner, Eur. J. Org. Chem. 2010
,
2261-2264.
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