Hydrophobically assisted switching phase synthesis: The flexible combination of solid-phase and solution-phase reactions employed for oligosaccharide preparation

Article abstract of DOI:10.1021/ja051737x

Hydrophobically assisted switching phase (HASP) synthesis is a concept that allows the choice between the advantages of solid-supported chemistry and those of solution-phase synthesis. Starting from the examination of adsorption and desorption properties of hydrophobic molecules to and from reversed-phase silica, we designed a dilipid as a quantitative and fully reversible HASP anchor, permitting final product release. The utility of this new tool in synthetic organic chemistry was demonstrated on oligosaccharide preparation. The synthesis of a pentarhamnoside was accomplished by repetitive glycosylation reactions. Glycosylations were conducted preferably in solution, whereas all protecting group manipulations were performed on solid support. Without the need for chromatographic purification of intermediates, the HASP system furnished the final product after 12 linear steps with average yields of 94% per step at a scale of 0.1 mmol, thus overcoming several of the limitations encountered in the solid-phase synthesis of complex carbohydrates. Copyright

Full text of DOI:10.1021/ja051737x

Published on Web 04/28/2005
Hydrophobically Assisted Switching Phase Synthesis: The Flexible
Combination of Solid-Phase and Solution-Phase Reactions Employed for
Oligosaccharide Preparation
Jo¨rg Bauer†,‡ and Jo¨rg Rademann*,†
Leibniz Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany, Institute for Chemistry, Organic
Chemistry, Free UniVersity of Berlin, 14195 Berlin, Germany, and Institute for Organic Chemistry,
Eberhard-Karls-UniVersity Tu¨bingen, 72076 Tu¨bingen, Germany
Received March 18, 2005; E-mail: rademann@fmp-berlin.de
Scheme 1a
Polymer-supported oligosaccharide synthesis has been for more
than three decades one of the most challenging fields for solid-
phase chemistry.1 Though progress has been made by the introduc-
tion of mildly activated carbohydrate donors2 and rugged linker
chemistries,3 the reported yields for repetitive glycosylations are
still unsatisfactory and the preparation of oligosaccharide-based
libraries has hardly ever been realized.
Recently, several protocols have been developed exploiting the
ease of solution-phase reactions together with preserving the
advantages of facilitated isolation procedures. Examples include
the oligosaccharide assembly on soluble (PEG) polymers,4 fluorous
tags,5 and thermoresponsive polymers.6
None of these methods has yet been satisfactory in respect to
yields, costs, and above all flexibility. Hydrocarbon-coated silica
supports are the inexpensive standard material in reversed-phase
chromatography. Hindsgaul et al. have described a hydrocarbon
a In hydrophobically assisted synthesis by switching phases, a suitable
hydrophobic anchor allows high-yielding reactions both in solution and
attached to a solid support.
tag for the preconcentration of samples by solid-phase extraction
(SPE).7 This system, however, required subsequent workup by
column chromatography and thus was never used for repetitive
reaction steps. We envisioned that a quantitative and fully reversible
anchor molecule would enable the hydrophobically assisted switch-
ing of phases (HASP) between solution and the solid support in
each single step (Scheme 1). Therefore, the completion and
quantitative reversibility of the adsorption and desorption processes
of various hydrophobic anchor molecules were investigated.
The retention of single hydrocarbon chains (C8-C20) depended
strongly on the polarity and charge of the headgroup, rendering
these molecules unsuitable as high-yielding and reversible tags. On
the contrary, a sufficiently long, hydrophobic double chain anchor
(C18) was both adsorbed and desorbed quantitatively. This effect
was independent of the size and polarity of the headgroup, at solvent
compositions permitting the quantitative removal of nontagged
byproducts without leaching the products.8a On the basis of these
findings, the double chain HASP anchor 5 was designed, a benzyl-
type linker for releasing the final product (Scheme 2).8b Compound
5 could be prepared from (()-epichlorohydrin and 1-octadecanol
as inexpensive starting materials. As an optimal sorbent combining
high yields with high loading capacity, hydrophobically end-capped
RP-18 silica with 120 Å pores and a grain size of 50 µm was
selected.
Scheme 2a
a Reagents and conditions: (a) 1-Octadecanol, Aliquat 336, 50% NaOH,
cyclohexane, 98%; (b) 1-octadecanol, BF3‚OEt2, DCM, 25 °C; (c) NaH,
abs. THF/abs. toluene, 90 °C, 71%; (d) NaOAc, DMF, 100 °C, 99%; (e)
NaOMe, DCM/MeOH, KHSO4, 90%.
Scheme 3a
The R-1,2-trans-glycosidic linkage found in the oligorhamnanes
has been a popular model linkage in polymer-supported glyco-
sylations, allowing direct comparison with previous results.2a,3a,4a
Glycolipids containing the L-rhamnopyranosyl-R-1,2 linkage9 dis-
played a surprisingly strong cytotoxic effect, the mechanism of
which has yet to be elucidated.10 For efficient donor preparation,
a Reagents and conditions: (a) TMOF, p-TosOH, MeOH, 95%; (b)
phenoxyacetic anhydride, DMAP, pyridine, 96%; (c) NBS, acetone/water,
85%; (d) trichloroacetonitrile, DBU, DCM, 73%.
the 3,4-hydroxy groups of thiorhamnoside 6 were protected
selectively employing the butane-2,3-diacetal (BDA) protecting
group (Scheme 3).11 This enabled protection of the 2-position with
† Leibniz Institute for Molecular Pharmacology.
‡ University of Tu¨bingen.
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10.1021/ja051737x CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4a
a Reagents and conditions: (a) 2 equiv of donor 10, 0.05 equiv of TMSOTf, abs. DCM, Ar, > 95%; (b) NaOMe, MeOH/water, > 92%; (c) TFA/water
> 72%; (d) 2 mol % Pd/C, H2, MeOH, > 93%.Total yield (12 steps) 45%, i.e. an average of 94% per step.
be extended to general organic synthesis. In addition, the described
hydrophobic anchor permits the direct immobilization of the
synthesized molecules on compartmentalized hydrophobic surfaces
and their incorporation in membrane models, liposomes, and cell
membranes.
Acknowledgment. This work was supported by the DFG with
a young research group fellowship to J.R. and by the graduate
college “Chemistry in Interphases” with a fellowship to J.B. For
MALDI-MS recording we are grateful to A. Frickenschmidt. This
article is dedicated to Prof. R. R. Schmidt on the occasion of his
70th birthday.
Figure 1. During HASP synthesis the full conversion of synthetic steps
can be monitored by MALDI-TOF-MS. Raw products of 12-n (n ) 1-4)
Supporting Information Available: Detailed experimental pro-
and 13-5.
cedures, yields, and fully assigned spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
an R-directing and orthogonally cleavable phenoxyacetyl group.12
The trichloroacetimidate donor 10 was furnished in multigram
amounts and employed in repetitive glycosylations in HASP
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