Efficient installation of β-mannosides using a dehydrative coupling strategy

Article abstract of DOI:10.1021/ol051038p

(Chemical Equation Presented) A new coupling procedure for the construction of the challenging β-mannosidic bond is described. Dehydrative mannosylation using 4,6-O-benzylidene mannopyranoses allows for the formation of β-mannosides in excellent yield. Th

Full text of DOI:10.1021/ol051038p

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3251-3254
Efficient Installation of
Using a Dehydrative Coupling Strategy
Jeroen D. C. Code´e, Laila H. Hossain, and Peter H. Seeberger*
â-Mannosides
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, Wolfgang-Pauli Strasse 10,
8093 Zu¨rich, Switzerland
seeberger@org.chem.ethz.ch
Received May 5, 2005
ABSTRACT
A new coupling procedure for the construction of the challenging
â-mannosidic bond is described. Dehydrative mannosylation using 4,6-O-
benzylidene mannopyranoses allows for the formation of -mannosides in excellent yield. The stereoselectivity is generally good but influenced
â
by the exact nature of the glycosylating agent and the nucleophile.
The development of efficient glycosylation methods is crucial
for further advances in the rapid assembly of complex
carbohydrates, particularly by automated solid-phase syn-
thesis.1 The stereoselective formation of 1,2-cis-glycosidic
bonds still presents a major challenge in contemporary
carbohydrate research.2 This holds especially true for the
â-mannose linkage, which is present in many biologically
relevant oligosaccharides and glycoconjugates, including the
N-linked core pentasaccharide3 common to all N-linked
glycoproteins.
assembly, are generated during coupling.6 To extend the
repertoire of complex carbohydrates accessible with the
automated oligosaccharide synthesizer, we set out to develop
efficient glycosylation methods for the construction of the
â-mannosidic bond employing monomeric building blocks
compatible with the solid-phase format. Our attention was
focused on the use of 4,6-O-benzylidene mannopyranoses
for the synthesis of â-mannosides. Activation of 1-hydroxyl
sugars can be readily achieved by a combination of a
sulfoxide reagent such as diphenyl sulfoxide and trifluo-
romethane sulfonic anhydride7 to provide an anomeric
sulfonium triflate as the actual glycosylating species (Scheme
1). These sulfonium triflates should be more stable than their
anomeric triflate counterparts as reflected by the higher
reaction temperatures and longer reaction times required for
glycosylations involving these species. A productive dehy-
drative condensation regenerates the starting sulfoxide with
concomitant formation of triflic acid, which can be scavenged
by an appropriate nonnucleophilic base.8 The dehydrative
protocol presents an efficient glycosylation method, but thus
far it has found little application in the synthesis of complex
Crich and co-workers developed several highly stereose-
lective â-mannosylation protocols based on the generation
of R-mannosyl triflates from mannosyl sulfoxides or thio-
mannosides, a breakthrough in â-mannoside synthesis.4
However, the immense reactivity of the anomeric triflates
renders them too hydrolytically and thermally unstable for
manipulation during automated synthesis.5 In addition, elec-
trophilic side products that can interfere with the integrity
of the pentenol-linker system, often applied in solid-phase
(1) (a) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001,
291, 1523. (b) Seeberger, P. H.; Haasse, W. C. Chem. ReV. 2000, 100,
4339.
(5) For these reasons, Crich and Smith developed a donor-bound polymer-
supported strategy for the synthesis of â-mannosides: Crich, D.; Smith,
M. J. Am. Chem. Soc. 2002, 124, 8867.
(6) (a) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der Marel, G. A.
Tetrahedron 2004, 60, 1057. (b) Crich, D.; Li, W.; Li, H. J. Am. Chem.
Soc. 2004, 126, 15081.
(7) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122,
4269.
(2) Demchenko, A. V. Synlett 2003, 1225.
(3) For a previous automated solid-phase assembly using a â-mannosidic
dimer building block, see: (a) Ratner, D. M.; Swanson, E. R.; Seeberger,
P. H. Org. Lett. 2003, 5, 4717. (b) Wu, X.; Grathwohl, M.; Schmidt, R. R.
Angew. Chem., Int. Ed. 2002, 41, 4489.
(4) (a) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435. (b) Crich,
D.; Sun, S. Tetrahedron 1998, 54, 8321. (c) Crich, D.; Smith, M. J. Am.
Chem. Soc. 2001, 123, 9015. (d) Crich, D. J. Carbohydr. Chem. 2002, 21,
667.
10.1021/ol051038p CCC: $30.25
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Published on Web 06/23/2005

protection of the C-4 hydroxyl group in 1 was effected by
the formation of the dibutyltinketal that was reacted regi-
oselectively with (p-methoxy)benzyl chloride to provide
mannoside 4 after silylation of the remaining alcohol. Direct
silylation of 1 and benzylation gave fully protected mannose
5. The anomeric hydroxyl groups in 4 and 5 were exposed
under the aegis of PdCl2 in HOAc/H2O to furnish mannosides
8 and 9.
Scheme 1. Putative Mechanism of Dehydrative
Mannosylations
The sulfoxide/Tf2O-mediated dehydrative condensations
(Table 1) proceeded in excellent yield, with moderate to very
good â-selectivities. The stereoselectivity of the condensation
of 2,3-dibenzylated mannosides 6 and 7 with a variety of
secondary hydroxyl acceptors (entries 1-5) remains good
at temperatures as high as -25 °C.10 The condensation of
1-hydroxyl mannoside 7 with thiomannoside 15 allowed for
efficient access to the â-linked thiodisaccharide 16, which
can be used immediately in the next glycosylation.11 For
example, dimer 16 can find application in the assembly of
(1f2)-linked â-mannans.12 The use of more reactive primary
hydroxyl nucleophiles such as n-pentenol and 1,2:3,4-
diacetone galactose 23 leads to erosion in selectivity (entries
7 and 8). The pentenol moiety is stable under the condensa-
tion conditions (entries 6 and 7).
oligosaccharides.9 No detailed studies on the stereoselectivity
of Ph2SO/Tf2O-mediated glycosylations have been reported.
Here we present the use of the dehydrative glycosylation
protocol for the solution-phase synthesis of â-mannosides.
To explore the scope and limitations of the dehydrative
â-mannosylation protocol, we initially synthesized a set of
1-hydroxyl mannosides 6-9 (Scheme 2). Starting from 1-O-
To enhance the â-selectivity for mannosylations involving
23, we aimed to favor formation of the anomeric sulfoxonium
triflate, or a close ion pair, over the generation of the
promiscuous oxacarbenium ion by the use of a more apolar
solvent system (toluene/CH2Cl2 5:1). Unfortunately, the
solvent change did not have the desired effect (entry 8b).
Tuning of the sulfoxide reagent by increasing the electron
density on the sulfur atom of the anomeric sulfonium triflate
should stabilize this glycosylating agent and shift the
equilibrium between the covalent sulfonium triflate and the
oxacarbenium ion toward the covalent bond.13 However, no
change in selectivity was observed when ditolyl sulfoxide
was employed in combination with Tf2O (entry 8c). Ad-
ditionally, the use of BSP/Tf2O4c also proved to be futile.
In line with the findings of Crich,14 we observed that the
use of 3-O-TBS-protected mannoside 9 completely eroded
the stereoselectivity of the condensation. Also, no beneficial
change in the stereochemical outcome of this reaction was
observed by either lowering the reaction temperature or
changing the polarity of the solvent.15
Scheme 2. Synthesis of Differentially Protected 1-Hydroxyl
Mannoses 6-9
The last entry shows the use of a 1-hydroxyl mannose
donor with a TBS group at the C-2 hydroxyl. As a result of
(9) Gin’s dehydrative glycosylation methodology has recently been
employed in the synthesis of the complex triterpene glycoside QS-21A
(Wang, P.; Kim, Y.-J.; Navarro-Villalobos, M.; Rohde, B. D.; Gin, D. Y.
J. Am. Chem. Soc. 2005, 127, 3256) and in the assembly of heparin
oligosaccharides (Code´e, J. D. C.; 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).
(10) Condensations were started at this temperature and then allowed to
warm slowly to room temperature. No fine-tuning of the reaction temper-
ature has been investigated. It is clear, however, that relatively high reaction
temperatures are tolerated by the reported glycosylation system.
(11) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1947.
(12) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126,
14930.
allyl-4,6-O-benzylidene-R-D-mannose 1, building blocks 6
and 7 were readily obtained by (p-methoxy)benzylation,
KOtBu-induced allyl isomerization, and subsequent cleavage
of the resulting enol ether by treatment with iodine. Selective
(8) In this work, tri-tert-butylpyrimidine (TTBP) was used as a nonnu-
cleophilic base. Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001,
323.
(13) For tuning of the sulfoxide reagent in dehydrative sialylations, see:
Haberman, J.; Gin, D. Y. Org. Lett. 2003, 5, 2539.
(14) Crich, D.; Dudkin, V. Tetrahedron Lett. 2000, 41, 5643.
3252
Org. Lett., Vol. 7, No. 15, 2005

Table 1. Dehydrative â-Mannosylations
a Typically, the glycosylating agent (1.5 equiv) was preactivated by sulfoxide (3 equiv)/Tf2O (1.5 equiv) in the presence of TTBP (3.75 equiv) at -40 to
-20 °C before addition of the acceptor glycoside (1 equiv). b Anomeric configurations were assigned on the basis of the very characteristic mannose H-5
shift.4 c Ratios of >9:1 are conservative minima; no R-product was isolated.
the steric bulk of this protecting group, the stereoselectivity
is somewhat impaired when compared to the 2-O-benzyl
case, while the yield was unaffected.
The repeating trimannoside 29 of the O5 antigen of the
opportunistic gram-negative pathogen Klebsiella16 was as-
sembled by the new method. The mild conditions employed
Org. Lett., Vol. 7, No. 15, 2005
3253

to induce glycosylation makes it possible to utilize acid-labile
protecting groups such as benzylidene acetals and PMB
ethers throughout the synthesis. Global deprotection can be
readily achieved at the final stage of the synthesis by mild
acidolysis, thereby obviating the need for heterogeneous
catalysis or Birch reduction. This protecting group strategy
can present a significant advantage in future solid-phase
oligosaccharide assembly.
Scheme 3. Assembly of a Trimannoside Antigen of
Klebsiellaa
Thus, the â-(1f2)-mannosidic bond in 28 was stereose-
lectively installed by Ph2SO/Tf2O-mediated dehydrative
condensation of glycosylating agent 7 and dimannoside 27
(Scheme 3). Deprotection of the three benzylidene acetals
and four PMB-ethers was then readily effected by treatment
of 28 with 5% TFA in CH2Cl2, in the presence of 1,2-
ethanedithiol as a cation scavenger, to provide the target
trisaccharide in good yield. Transformation of 29 into deca-
O-acetate 30 simplified purification and characterization.
In conclusion, we have shown that the challenging
â-mannosidic linkage can be efficiently installed using a
dehydrative glycosylation protocol. Secondary alcohol nu-
cleophiles showed good to excellent selectivities. Manno-
sylation of reactive primary alcohols on the other hand
proceeded only with moderate selectivity. The effects of
protecting groups in the glycosylation agent parallel those
observed for Crich’s thioglycoside/glycosyl sulfoxide method.
Finally, the dehydrative glycosylation method is compatible
with n-pentenol functional groups, a key feature in anticipa-
tion of automated solid-phase oligosaccharide assembly. The
global use of acid-labile protecting groups throughout the
construction of the oligosaccharides is also significant in the
context of the overall efficiency of oligosaccharide prepara-
tion.
Acknowledgment. We thank the Swiss National Science
Foundation (SNF, Grant 200020-109555), the ETH, and the
Netherlands Organisation for Scientific Research (NOW,
postdoctoral fellowship for J.D.C.C.) for financial support.
Supporting Information Available: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The Crich laborarory recently employed the 2-O-propargyl ether
as a minimally intrusive protecting group to overcome this poor selectiv-
ity: Crich, D.; Jayalath, P. Org. Lett. 2005, 7, 2277.
(16) Griffiths, A, J.; Davies, D. B. Carbohydr. Polym. 1991, 14, 241.
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