Solution and Solid-Phase Stereocontrolled Synthesis of 1,2-cis-Glycopyranosides with Minimally Protected Glycopyranosyl Donors Catalyzed by BF3-N,N-Dimethylformamide Complex

Article abstract of DOI:10.1021/acs.orglett.6b01263

Methods are described for the stereoselective synthesis of 1,2-cis glycopyranosides in the d-galacto, d-gluco, and 2-azido-2-deoxy-d-glucopyranoside series utilizing minimally protected (3-bromo-2-pyridyloxy) β-d-glycopyranosyl donors in the presence of BF₃-N,N-dimethylformamide (DMF) as a catalyst and a variety of alcohol acceptors relying on the "remote activation concept". Precursors to antifreeze glycopeptide components are synthesized in excellent yields and high α/β ratios. The method is adaptable to one-pot sequential glycosidation as well as to solid-supported synthesis giving access to diverse sets of minimally protected α-d-glycopyranosides as major products.

Full text of DOI:10.1021/acs.orglett.6b01263

Letter
pubs.acs.org/OrgLett
Solution and Solid-Phase Stereocontrolled Synthesis of 1,2-cis-
Glycopyranosides with Minimally Protected Glycopyranosyl Donors
Catalyzed by BF3−N,N‑Dimethylformamide Complex
Gabrielle St-Pierre and Stephen Hanessian*,*
*Department of Chemistry, Universite
́ ́ ́ ́
de Montreal, P.O. Box 6128, Succ., Centre-ville, Montreal, Quebec, Canada, H3C 3J7
S
* Supporting Information
ABSTRACT: Methods are described for the stereoselective
synthesis of 1,2-cis glycopyranosides in the D-galacto, D-gluco,
and 2-azido-2-deoxy-D-glucopyranoside series utilizing mini-
mally protected (3-bromo-2-pyridyloxy) β-D-glycopyranosyl
donors in the presence of BF3−N,N-dimethylformamide
(DMF) as a catalyst and a variety of alcohol acceptors relying
on the “remote activation concept”. Precursors to antifreeze
glycopeptide components are synthesized in excellent yields
and high α/β ratios. The method is adaptable to one-pot sequential glycosidation as well as to solid-supported synthesis giving
access to diverse sets of minimally protected α-D-glycopyranosides as major products.
n spite of major advances in the chemistry and biology of
carbohydrates and their derivatives, the stereocontrolled
The presently reported method of glycoside synthesis using
(3-bromo-2-pyridyloxy) glycopyranosyl donors in conjunction
with BF3−DMF as a mild Lewis acid offers a number of
practical and operational advantages.10
I
synthesis of 1,2-cis-glycopyranosides remains as a major
challenge.1−3 The polyfunctional nature of sugar molecules
acting as glycopyranosyl donors in natural product an
oligosaccharide synthesis has necessitated the extensive use of
O- and N-protecting groups and the exploitation of a variety of
anomeric leaving groups in the quest for stereocontrolled
glycoside formation.4Therefore, continued exploration of
glycosidation methods that minimize hydroxyl or amino
group protection are worthy of study.5
The crystalline catalyst is a convenient “solid form” of BF3
which is released in the medium and catalytically recycled. It is
stable to air, can be used in 5−20 mol % quantities, and is
compatible with a variety of protective groups and other
reactive functionalities. The comparable α/β ratios of product
glycosides and the mildness of the reaction conditions, allowing
the use of minimal equivalents of alcohols if needed, are
important assets compared to the use of MeOTf.11 We suggest
that the BF3 released from the BF3−alcohol/BF3−DMF
complexes activates the β-3-bromo-2-pyridyloxy moiety of the
donor.12 The resulting oxycarbenium/BF3-coordinated 3-
bromo-2-pyridyloxy ion-pair intermediate is displaced with
the alcohol in an SN2-like reaction.13 The departing 2-hydroxy-
3-bromopyridine (or 2-pyridone tautomer) releases the bound
BF3 which resumes its catalytic cycle. In fact, the 2-hydroxy-3-
bromopyridine BF3 complex, prepared independently, acts as a
competent catalyst. A plausible mechanism is shown in Scheme
1.
2-Acetamido-2-deoxy-α-D-galactopyranosyl serine and threo-
nine derivatives are important constituents of immunologically
relevant glycoproteins (TN antigen).14 They are also
components of antifreeze glycopeptides15 which inhibit the
formation of ice; hence, they are essential for marine life at
subzero temperatures. All reported methods for their synthesis
require O-protecting groups and employ various anomeric
activating groups. Yields and anomeric ratios in favor of the α-
anomer have been generally acceptable.16
Herein we describe versatile methods for the solution and
solid-phase stereocontrolled synthesis of 1,2-cis-hexopyranosides
exemplified by a prototypical (3-bromo-2-pyridyloxy) β-D-
galactopyranosyl donor containing a single 6-O-tert-butyldiphe-
nylsilyl protecting group using a variety of alcohol acceptors. A
novel feature of this glycosylation reaction is the anomeric
heterocyclic leaving group with 5−20 mol % quantities of the
BF3−N,N-dimethylformamide (DMF) complex6 which is
utilized as a mild Lewis acid in glycoside synthesis for the
first time. Upon addition of an alcohol to a dichloromethane
solution containing the β-D-galactopyranosyl donor and the
catalyst, a rapid reaction takes place at −20 to 0 °C with the
formation of the 1,2-cis-D-galactopyranoside as the major
product in the cases studied, accompanied by the liberation
of the highly chromophoric 2-hydroxy-3-bromopyridine there-
by allowing easy monitoring of the progression of the reaction.
The variety of alcohol acceptors listed in Table 1 attests to
the versatility of the method which is based on our original
“remote activation concept”.7 The impact of this type of remote
anomeric activation was already demonstrated for the first time
in the successful glycosylation of the aglycones of complex
carbohydrate-containing natural products such as erythromycin
A8 and avermectin B1a9 using 2-pyridylthio glycosyl donors.7a
Received: May 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01263
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Letter
(Scheme 2). Treatment of the 3 with Cbz-Ser-OMe in the
presence of BF3−DMF led to 4 in 20:1 selectivity and 89%
Table 1. BF3−DMF Mediated Synthesis of Alkyl, Aryl, and
Aminoacyl α-D-Galactopyranosides
Scheme 2. Stereocontrolled Synthesis of Antifreeze
Glycoprotein Subunits and TN Antigen as 2-Azido
Precursors
yield. The same reaction afforded 5 in 8.0:1 selectivity and 90%
yield. Reaction times were a little longer in comparison with the
same donor having a 2-hydroxy functionality. This might
possibly be due to the participation of the 2-hydroxyl group in
the activation step of the 3-bromo-2-pyridyloxy moiety.
Stereocontrolled alkyl α-D-galactopyranoside synthesis can be
also efficiently accomplished on solid phase with yields
comparable to reactions in solution. The (3-bromo-2-
pyridyloxy) β-D-galactopyranosyl donors were immobilized via
silyl ether tethers on polystyrene beads17 and then treated with
the appropriate alcohol in the presence of BF3−DMF complex
to give the corresponding α-D-galactopyranosides as major
isomers in good to excellent yields (Table 2).
Table 2. BF3−DMF Mediated Glycoside Synthesis on Solid
Support
a
10 equiv of ROH, except for entries 6, 7, 8, 9, and 12, where 5 equiv
b
of ROH were used. Yields α/β isolated from flash chromatography;
c
d
α- and β-anomers are separable. Ratio from 1H NMR (400 MHz). 5
mol % BF3−DMF, rt, 20 h, 59% conversion, 8.0:1 (α:β); see
Supporting Information.
Scheme 1. Plausible Mechanism for the “Remote Activation
Concept” Glycosylation of Alcohols Catalyzed by BF3−DMF
a
Herein we describe an expeditious method for the synthesis
of 2-azido-2-deoxy-α-D-galactopyranosyl N-Cbz serine and N-
Cbz threonine methyl esters in excellent yields and high α/β
selectivities using only 1.1 equiv of the amino acid derivatives
Yields α/β of acetylated compounds; after flash chromatography; α-
b
and β-anomers are separable. Ratio from 1H NMR (400 MHz) of the
crude. See Supporting Information. 2e as in Table 1; TBDPSCl,
imidazole, DMF after step 3; see Supporting Information.
c
d
B
DOI: 10.1021/acs.orglett.6b01263
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The differential reactivity of 3- and (6-bromo-2-pyridyloxy)
β-glycopyranosyl donors in the D-gluco and D-galacto series led
us to explore one-pot sequential glycosidations with two
different alcohols. Previous one-pot glycoside syntheses have
required O- and N-protecting groups and different anomeric
activation protocols such as thioglycosides vs trichloroacetimi-
date glycopyranosyl donors or glycopyranosyl fluorides.18
In the presently described method, sequential glycosylation
reactions occur with minimal protection using a bromo-2-
pyridyloxy leaving group from two different β-D-glycopyranosyl
donors in one reaction vessel (Scheme 3). The reactivity of the
pyridyl moiety is modulated by the position of the bromo
substituent, which affects the electronic character of the
nitrogen atom.19
In conclusion, we have reported practical and expeditious
methods for the stereocontrolled synthesis of otherwise
arduously accessible α-D-galacto-, α-D-gluco-, and 2-azido-2-
deoxy-α-D-glycopyranosides with minimal O-protection using
the hitherto seldom used BF3−DMF as a mild Lewis acid, in
solution and on solid phase. The method allows facile
monitoring of the reactions with the release of the
chromophoric 3-bromo-2-hydroxypyridine which is an asset
when adapted to solid phase glycosidations.
The sequential formation of diverse 1,2-cis-glycosides as
major products offers the opportunity to exploit the remote
activation concept toward the synthesis of sets of anomerically
functionalized carbohydrates including esters as prodrugs,20 as
substrates for enzyme inhibition,21 and in carbohydrate
mediated drug delivery.22
Scheme 3. Sequential One-Pot Glycosidation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01263.
Experimental procedures for synthesis of glycopyranosyl
donors, general glycosidation procedure, characterization
data, and NMR spectra of all new obtained compounds
(PDF)
These prototypical one-pot sequential glycosidations are
exemplified by the use of D-galacto and D-gluco donors and
different alcohol acceptors (Scheme 3, Table 3). Thus, the
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stephen.hanessian@umonreal.ca.
Notes
Table 3. Sequential One-Pot Glycosidation in Solution
a
a
The authors declare no competing financial interest.
Reaction 1
Reaction 2
b
c
b
c
R1OH
(%)
64
α:β
R2OH
(%)
68
α:β
ACKNOWLEDGMENTS
We thank NSERC for financial assistance.
■
1
2
2-Naphthol
6.5:1
2d
(−)-Menthol
2.3:1
8
4-OMe-Phenol
67
6.8:1
2c
Cbz-Ser-OMe
65
7.8:1
9
REFERENCES
■
(1) For relevant reviews, see: (a) Alphert, E.; van der Marel, G. A.;
a
b
Reaction 1 time: 0.5 h. Reaction 2 time: 48 h. Yields (%) α/β
obtained from flash chromatography; α- and β-anomers are separable
with a careful chromatography. Ratio of α- and β-anomers from H
Codee
́
, J. D. C. In Modern Synthetic Methods in Carbohydrate
Chemistry; Werz, D. B., Vidal, S., Eds.; Wiley-VCH: Weinheim,
2014; pp 97−124. (b) Komanova, B. S.; Ustyuzhanina, N. E.;
Tsvetkov, Y. E.; Nifantev, N. E. In Modern Synthetic Methods in
Carbohydrate Chemistry; Werz, D. B., Vidal, S., Eds.; Wiley-VCH:
Weinheim, 2014; pp 125−159. (c) Crich, D. J. Org. Chem. 2011, 76,
9193−9209. (d) Nigudkar, S. S.; Demchenko, A. V. Chem. Sci. 2015, 6,
2687−2704.
c
1
NMR (400 MHz).
more reactive 1 is consumed within 30 min in the presence of
only 1.5 equiv of 2-naphthol with the release of 2-hydroxy-3-
bromopyridine and the formation of the 2d as the major
product (α:β = 6.5:1). Adding (−)-menthol as a second
alcohol, now in excess, to the solution containing the still
unreacted 7, leads to the corresponding α-D-8 as the major
product, albeit requiring a longer reaction time for a hindered
secondary alcohol. The sequential glycosidation of 4-methox-
yphenol followed by Cbz-Ser-OMe furnishes the corresponding
α-D-galactopyranoside (α:β = 6.8:1) and α-D-glucopyranoside
(α:β = 7.8:1) respectively. The progress of the second
glycosylation reaction can be monitored directly by LC-MS
and TLC with the appearance of the 2-hydroxy-6-bromopyr-
idine. This protocol allows for the one-pot synthesis of diverse
sets of glycosides with appropriate alcohols as acceptors, simply
by choosing the more reactive donor and the less accessible
alcohol in the first pass. Applications to solid-supported
syntheses are possible.
(2) (a) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am.
Chem. Soc. 1975, 97, 4056−4063. (b) Lemieux, R. U.; Ratcliffe, R. M.
Can. J. Chem. 1979, 57, 1244−1251.
(3) (a) Christensen, H. M.; Oscarson, S.; Jensen, H. H. Carbohydr.
Res. 2015, 408, 51−95. (b) Zhu, X.; Schmidt, R. R. Angew. Chem., Int.
Ed. 2009, 48, 1900−1934. (c) Jung, K.-H.; Muller, M.; Schmidt, R. R.
Chem. Rev. 2000, 100, 4423−44424.
(4) (a) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001,
40, 1576−1624. (b) Gamblin, D. P.; Scanlan, E. M.; Davis, B. G. Chem.
Rev. 2009, 109, 131−163. (c) Yang, Y.; Zhang, X.; Yu, B. Nat. Prod.
Rep. 2015, 32, 1331−1355.
(5) For example, see: (a) Davis, B. G.; Wood, S. D.; Maughan, A. T.
Can. J. Chem. 2002, 80, 555−558. (c) Gudmundsdottir, A. V.; Nitz, M.
Org. Lett. 2008, 10, 3461−3463. (d) Mamidyala, K. S.; Finn, G. M. J.
Org. Chem. 2009, 74, 8417−8420. (e) Tanaka, T.; Matsumoto, T.;
Noguchi, M.; Kobayashi, A.; Shoda, S.-I. Chem. Lett. 2009, 38, 458−
459. (f) Park, T.-J.; Weïwer, M.; Yuan, X.; Baytas, S. N.; Munoz, E. M.;
Murugesan, S.; Linhardt, R. J. Carbohydr. Res. 2007, 342, 614−620.
C
DOI: 10.1021/acs.orglett.6b01263
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(g) Meng, B.; Zhu, Z.; Baker, C. D. Org. Biomol. Chem. 2014, 12,
5182−5191. (h) Williams, R. J.; Paul, C. E.; Nitz, M. Carbohydr. Res.
2014, 386, 73−77. (i) Armada, D. H.; Santos, J. T.; Richards, M. R.;
Cairo, C. W. Carbohydr. Res. 2015, 417, 109−116. See also:
(j) Hanessian, S.; Lou, B. Chem. Rev. 2000, 100, 4443−4464.
(6) Muetterties, E. J.; Rochow, E. G. J. Am. Chem. Soc. 1953, 75,
490−491.
Wan, W. B.; Low, A.; Yu, J.; Chappell, A. E.; Gaus, H.; Kinberger, G.
A.; Østergaard, M. E.; Migawa, M. T.; Swayze, E. E.; Seth, P. P. Bioorg.
Med. Chem. Lett. 2015, 25, 4127−4130.
(7) (a) Hanessian, S.; Bacquet, C.; Lehong, N. Carbohydr. Res. 1980,
80, C17. (b) Hanessian, S. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Dekker: New York, 1997, 381−388. See also:
(c) Koide, K.; Ohno, M.; Kobayashi, S. Tetrahedron Lett. 1991, 32,
7065−7068.
(8) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.; Ward,
D. E.; Au-Yeung, B. W.; Balaram, P.; Browne, L. J.; Card, P. J.; Chen,
C. H. J. Am. Chem. Soc. 1981, 103, 3215−3217. For an alternative
approach, see: Toshima, K.; Nozaki, Y.; Mukaiyama, S.; Tamai, T.;
Nakata, M.; Tatsuta, K.; Kinoshita, M. J. Am. Chem. Soc. 1995, 117,
3717−3727.
(9) (a) Hanessian, S.; Ugolini, A.; Dube,
J. Am. Chem. Soc. 1986, 108, 2776−2778. (b) Hanessian, S.; Ugolini,
A.; Hodges, P. J.; Beaulieu, P.; Dube, D.; Andre, C. Pure Appl. Chem.
1987, 59, 299−316.
́
D.; Hodges, P. J.; Andre, C.
́
(10) The 3-bromo-2-pyridyloxy donors are shelf stable crystalline
solids that can be prepared in quantity and used as needed. See
Supporting Information.
(11) Different BF3-coordinated species can be observed by 11B and
19F NMR. See Supporting Information.
(12) Lou, B.; Reddy, G. V.; Wang, H.; Hanessian, S. In Preparative
Carbohydrate Chemistry; Hanessian, S., Ed.; Dekker: New York, 1997;
pp 389−412.
(13) (a) Woerpel, K. A.; Yang, M. T. J. Org. Chem. 2009, 74, 545−
553. (b) Woerpel, K. A.; Beaver, M. G. J. Org. Chem. 2010, 75, 1107−
1118. (c) Hosoya, T.; Takano, T.; Kosma, P.; Rosenau, T. J. Org.
Chem. 2014, 79, 7889−7894.
(14) Ju, T.; Otto, V. I.; Cummings, R. D. Angew. Chem., Int. Ed. 2011,
50, 1770−1791.
(15) (a) Harding, M. M.; Anderberg, P. I.; Haymet, A. D. J. Eur. J.
Biochem. 2003, 270, 1381−1392. (b) Gamblin, D.-P.; Scanlan, E. M.;
Davis, B. G. Chem. Rev. 2009, 109, 131−163. (c) Bang, J. K.; Lee, J. H.;
Murugan, R. N.; Lee, S. G.; Do, H.; Koh, H. Y.; Shim, H.-E.; Kin, H.-
C.; Kim, H. Mar. Drugs 2013, 11, 2013−2041.
(16) For selected examples, see: (a) Polt, R.; Szabo, L.; Treiberg, J.;
Yushun, L.; Hruby, J. I. J. Am. Chem. Soc. 1992, 114, 10249−10258.
(c) Yule, J. E.; Wong, T. C.; Gandhi, S. S.; Qiu, D.; Riopel, M. A.;
Koganty, R. R. Tetrahedron Lett. 1995, 36, 6839−6842. (d) Elofsson,
M.; Salvador, L. A.; Kihlberg, J. Tetrahedron 1997, 53, 369−390.
(e) Rodriguez, E. C.; Winans, K. A.; King, D. S.; Bertozzi, C. R. J. Am.
Chem. Soc. 1997, 119, 9905−9906. (f) Monasson, O.; Sizun-Thome,
́
G.; Lubin-Germain, N.; Uziel, J.; Auge, J. Carbohydr. Res. 2012, 352,
́
202−205. (h) Nagel, L.; Budke, C.; Erdmann, R. S.; Dreyer, A.;
Wennemers, H.; Koop, T.; Sewald, N. Chem. - Eur. J. 2012, 18,
12783−12793.
(17) Savin, K. A.; Woo, J. C. G.; Danishefsky, S. J. J. Org. Chem. 1999,
64, 4183−4186.
(18) For one-pot glycoside synthesis, see: (a) Tanaka, H.; Adachi,
M.; Takahashi, T. Chem. - Eur. J. 2005, 11, 849−862. (b) Wu, C.-Y.;
Wong, C.-H. Top. Curr. Chem. 2010, 301, 223−252 and refrences cited
therein.
(19) Gordon, A.; Katritzky, A. R.; Roy, S. K. J. Chem. Soc. B 1968, 0,
556−561.
(20) (a) Hanessian, S.; Mascitti, V.; Lu, P.-P.; Ishida, H. Synthesis
2002, 2002, 1959−1968. (b) Hanessian, S.; Lu, P.-P.; Ishida, H. J. Am.
Chem. Soc. 1998, 120, 13296.
(21) (a) Park, S.; Hyun, S.; Yu, J. Bioorg. Med. Chem. Lett. 2011, 21,
2441−2444. (b) Viana, P. A.; de Rezende, S. T.; de A. Alves, A.;
Manfrini, R. M.; Alves, R. J.; Bemquerer, A. P.; Santoro, M. M.;
Guimaraes, V. M. Carbohydr. Res. 2011, 346, 602−605.
(22) (a) Ahmad, M. U.; Ali, S. M.; Ahmad, A.; Sheikh, S.; Chen, P.;
Ahmad, I. Chem. Phys. Lipids 2015, 186, 30−38. (b) Prakash, T. P.;
D
DOI: 10.1021/acs.orglett.6b01263
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