Phenylthiomethyl glycosides: Convenient synthons for the formation of azidomethyl and glycosylmethyl glycosides and their derivatives

Article abstract of DOI:10.1002/anie.200904168

Without a trace: Phenylthiomethyl glycosides, which are prepared by glycosylation of phenylthiomethanol, serve as precursors to the hitherto unknown azidomethyl glycosides and then to the N-glycosylmethyl 1,4- and 1,5-substituted triazoles (see scheme; Bz

Full text of DOI:10.1002/anie.200904168

Communications
DOI: 10.1002/anie.200904168
Chemical Ligation
Phenylthiomethyl Glycosides: Convenient Synthons for the Formation
of Azidomethyl and Glycosylmethyl Glycosides and Their
Derivatives**
David Crich* and Fan Yang
Dedicated to Prof. Dr. Andrea Vasella
Click chemistry[1] has become one of the most important
reactions in the field of glycoscience enabling the rapid
assembly, under very mild conditions, of a vast array of
glycoconjugates.[2] We were struck, however, by the absence
of azidomethyl glycosides which necessarily excludes the
whole class of triazolylmethyl glycosides from the arsenal of
glycoconjugates accessible by Click chemistry.[3] Zhu and
Schmidt addressed the problem indirectly through the syn-
thesis of a series of azidomethyl thioglycosides,[4] but to date
the more native O-glycosides have not been described.
Seeking to remedy this deficiency we prepared phenyl-
thiomethanol 1[5] and investigated its use as a glycosyl
acceptor. Activation of tetrabenzoyl mannopyranosyl bro-
mide 2 with silver triflate in the presence of 1 afforded the
Scheme 1. Synthesis of phenylthiomethyl glycosides Bn=benzyl,
anticipated a-glycoside 3 in 61% yield (Scheme 1). When the
corresponding trichloroacetimidate donor 4[6,7] was activated
with a catalytic amount of silver triflate in the presence of 1 it
gave 3 in 65% yield. Interestingly, even thioglycoside donors
could be applied provided that a preactivation protocol was
employed. Thus, preactivation of a 4,6-O-benzylidene-pro-
tected b-mannopyranosyl donor 5 under our standard benze-
nesulfinyl piperidine (BSP)/trifluoromethanesulfonic anhy-
dride (Tf2O) conditions[8] resulted in the formation of a b-
glycoside 6 (Scheme 1).[9]
Bz=benzoyl, Tf=trifluoromethanesulfonyl, TTBP=2,4,6-tri(tert-butyl)-
pyrimidine.
Activation of 3 and 6 with N-iodosuccinimide (NIS) and
trifluoromethansulfonic acid in the presence of azidotrime-
thylsilane resulted in conversion into the corresponding
azidomethyl glycosides 7 and 8 in good yield (Scheme 2),
thereby affording the first examples of this class of compound.
By employing the propargyl a-mannoside 9 as a reaction
partner, the click reaction was investigated with the azido-
Scheme 2. Synthesis of azidomethyl glycosides. M.S.=molecular
sieves, TMS=trimethylsilyl.
methyl glycoside 7 under “classical” copper(I)-catalyzed
conditions,[1,2] leading preferentially to the 1,4-disubstituted
triazoles, and with a recent ruthenium-based system,[10] which
afforded the 1,5-isomer (Scheme 3). The application of
ruthenium catalysis in this manner, which, to our knowledge,
has yet to be reported in glycoconjugate synthesis, provides a
closer structural analogue to a branched trisaccharide motif
than the more extended array obtained under the copper-
catalyzed conditions.[11,12]
We next investigated the reaction of these novel azido-
methyl glycosides with thioacids, with a view to forming
amidomethyl glycosides. Perhaps not too surprisingly, in view
of the relatively electron-rich nature of the azide,[13] the
reaction of 7 with thioacetic acid required prolonged micro-
wave heating and afforded the unusual amidomethyl glyco-
[*] Prof. Dr. D. Crich
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles
Centre Nationale de la Recherche Scientifique
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax: (+33)1-6907-7752
E-mail: dcrich@icsn.cnrs-gif.fr
Prof. Dr. D. Crich, F. Yang
Department of Chemistry, Wayne State University
5101 Cass Avenue, Detroit, MI 48202 (USA)
[**] We thank the NIH (GM 62160) for support of this work and Dr.
Andrew Fieg and Nilshad Salim for help with isothermal titration
calorimetry.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904168.
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type have been previously prepared by either the reaction of
trimethylsilyl glycosides with formaldehyde acetals under
catalysis by trimethylsilyl triflate, or by the reaction of
anomeric hemiacetals with methylthiomethyl ethers in the
presence of NIS, where the products were obtained as
mixtures of stereoisomers.[16] Pleasingly, the reactions of
both 3 and 6 with NIS and TfOH in the presence of a suitable
acceptor alcohols provided the corresponding “acetal glyco-
sides” 15, 16, and 17 in excellent yield and as single anomers
(Scheme 6). Zemplen deacetylation of 16 gave the free
Scheme 3. Copper and ruthenium-catalyzed cycloaddition reactions
with 7. Cp*=pentamethylcyclopentadienyl, DMF=N,N-dimethylform-
amide, MW=microwave irradiation at 400W.
side 12 in 51% yield, together with 25% of unchanged 7
(Scheme 4).
Scheme 4. Reaction of 7 with thioacetic acid.
Better success in the formation of amidomethyl glycosides
was obtained by the Raines variant[14] on the traceless
Staudinger reaction.[15] Thus, a series of diphenylphosphinyl-
methyl thioesters were prepared in the form of their borane
adducts. After transfer of the borane to diazabicyclooctane
(DABCO) these substituted phosphines were treated with 7
and 8 and resulted in the formation of novel amidomethyl
glycosides in high yield (Scheme 5).
Scheme 6. Synthesis of alkoxymethyl glycosides.
“acetal glycoside” 18 in 91% yield (Scheme 7). The phenyl-
thiomethyl glycosides therefore provide a new, convenient,
and stereoselective means of entry into the “acetal glyco-
sides”, which are an unusual and somewhat limited class of
compounds that were previously investigated for their
potential as enzyme inhibitors.[17,18] We note that the synthe-
ses of both the azidomethyl glycosides (Scheme 2) and the
acetal glycosides (Scheme 6) likely proceed through a tran-
sient glycosyloxymethyl cation and that this intermediate is
trapped by the incoming nucleophile substantially more
rapidly than it undergoes decomposition to the glycosyl
cation and formaldehyde. As has been previously record-
ed,[17a] the acetal glycosides are considerably less stable to
Finally, in view of the successful conversion of 3 and 6 into
the azidomethyl glycosides 7 and 8 we turned our attention to
glycosidic bond formation. Simple “acetal glycosides” of this
Scheme 5. Synthesis of azidomethyl glycosides by the traceless Stau-
dinger reaction. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl.
Scheme 7. Deprotection of a glycosyloxymethyl glycoside.
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[2] a) A. Dondoni, Chem. Asian J. 2007, 2, 700 – 708; b) S. Dedola,
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[3] Simple azidomethyl ethers have been prepared from methylthio
ethers and chloromethyl ethers in the presence of azide anion,
and have been used as protecting groups in nucleoside chemistry
but the azidomethyl glycosides appear to be unknown; a) S.
Zavgorodny, M. Polyanski, E. Besidsky, E. Kriukov, A. Sanin, M.
Pokrovskaya, G. Gurskaya, H. Lꢁnnberg, A. Azhayev, Tetrahe-
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Pechenov, V. I. Shvets, A. I. Miroshnikov, Nucleosides Nucleo-
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Li, S. Shi, L. Yu, S. Kalachikov, J. J. Russo, N. J. Turro, J. Ju, Proc.
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[7] We note that the use of more than 1.1 equivalent of silver triflate
resulted in lower yields of product 3 and over activation leading,
for example, to the formation of phenylthiomethoxymethyl
glycosides. The moderate yields for the formation of 3 and 6 are
to some extent the result of the relative instability of phenyl-
thiomethanol under the coupling conditions.
[8] a) D. Crich, M. Smith, J. Am. Chem. Soc. 2001, 123, 9015 – 9020;
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[9] The moderate yield is most likely due to the persistence of
thiophilic species in the reaction mixture after the preactivation
step.
[10] B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao, Z.
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[11] Zemplen de-O-benzoylation of 10 and 11 gave mimics of methyl
aqueous acid than simple glycosides, nevertheless we
observed no difficulties in their purification by column
chromatography on silica gel—either before or after removal
of the protecting groups.
Overall, phenylthiomethyl glycosides may be obtained
from thioglycosides and/or trichloroacetimidates by reaction
with phenylthiomethanol under typical glycosylation condi-
tions. They are stable compounds that upon activation of the
phenylthiomethyl moiety provide direct access to the azido-
methyl methyl glycosides and the “acetal glycosides”. As the
anomeric carbon atom is not implicated in these transforma-
tions the anomeric configuration of the phenylthiomethyl
glycosides is completely retained. The azidomethyl glycosides
take part in “click” reactions with alkynes under copper- or
ruthenium-catalyzed conditions, thus providing access to new
classes of 1,4- and 1,5-triazole derivatives. Finally, the
azidomethyl glycosides readily take part in traceless Stau-
dinger reactions enabling the formation of amidomethyl
glycosides.
Experimental Section
Preparation of phenylthiomethyl tetra-O-benzoyl-a-d-mannopyrano-
side (3): 2,3,4,6-Tetra-O-benzoyl-a-d-mannopyranosyl bromide
(2.24 g, 3.41 mmol), phenythiomethanol (1.91 g, 13.6 mmol), and
activated 4 ꢀ powdered molecular sieves (900 mg) were mixed in
dichloromethane (17 mL) and stirred at room temperature for 10 min
before AgOTf (964 mg, 3.75 mmol) was added at 08C. The reaction
mixture was warmed to room temperature until the donor was
consumed (as evident by TLC; 2–4 h). Saturated aqueous NaHCO3
then was added at 08C, and the mixture was filtered, and the filtrate
was washed with brine. The organic layer was dried and concentrated
under reduced pressure and the product was isolated by column
chromatography on silica gel (eluent: n-hexane/ethyl acetate 20:1!
10:1) and gave 3 (1.58 g, 61%) as a white foam. ½aꢀ2D3 = + 42.0o (c =
2.6 g100cmꢁ3, CHCl3); 1H NMR (500 MHz, CDCl3): d = 8.15–8.13
(m, 2H), 8.11–8.10 (m, 2H), 7.99–7.97 (m, 2H), 7.88–7.86 (m, 2H),
7.64–7.59 (m, 4H), 7.54–7.51 (m, 1H), 7.47–7.43 (m, 5H), 7.41–7.37
(m, 4H), 7.34–7.29 (m, 3H), 6.17 (t, J = 10.0 Hz, 1H), 5.96 (dd, J = 3.5,
J = 10.5 Hz, 1H), 5.75 (m, 1H), 5.62 (d, J = 1.5 Hz, 1H), 5.27 (d, J =
12.0 Hz, 1H), 5.18 (d, J = 12.0 Hz, 1H), 4.72 (dd, J = 2.5, J = 12.5 Hz,
1H), 4.50 (dd, J = 4.5, J = 12.0 Hz, 1H), 4.41 ppm (m, 1H); 13C NMR
(125 MHz, CDCl3): d = 166.4, 165.74, 165.68, 165.6, 134.8, 133.81,
133.75, 133.5, 133.4, 131.3, 130.2, 130.1, 130.0, 129.5, 129.3, 129.2,
128.9, 128.8, 128.7, 128.6, 127.8, 94.9, 72.6, 70.6, 70.2, 69.9, 67.1,
63.0 ppm; HRMS (ESI): m/z calcd for C41H34O10S [M+Na]+:
741.1770; found 741.1738.
3,6-di-O-(a-d-mannopyranosyl)-a-d-mannopyranoside,
the
binding motif for the mannose-binding lectin concanavalin A.
These compounds were found—by isothermal titration calorim-
etry—to have binding constants of 80.0 and 13.7mꢁ1 ꢂ 103,
respectively, for binding to concanavalin A. In contrast, the
binding constant exhibited by methyl 3,6-di-O-(a-d-mannopyr-
anosyl)-a-d-mannopyranoside itself was 390mꢁ1 ꢂ 103. The sig-
nificantly reduced binding affinity exhibited by the two triazoles
is attributed in part to the absence of the hydroxyl groups at C2
and C4 of the “reducing sugar” in methyl 3,6-di-O-(a-d-
mannopyranosyl)-a-d-mannopyranoside, which are known to
contribute substantially to binding. G. H. Veeneman, G. A.
van der Marel, H. Vandenelst, J. H. van Boom, Recl. Trav. Chim.
Pays-Bas 1990, 109, 449 – 451.
Received: July 28, 2009
Revised: September 27, 2009
Published online: October 23, 2009
Keywords: acetals · glycosylation · ligation · Staudinger reaction ·
.
triazoles
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