Selectively protected galactose derivatives for the synthesis
of branched oligosaccharides
Reko L. Lehtila
¨
,
a,b
,
*
,
†
Juho O. Lehtila
¨
,
a
Mattias U. Roslund
a,b
,
‡
and Reko Leino
a,b
,
*
,
‡
a
Biotie Therapies Corp., Viikinkaari 9, FIN-00710 Helsinki, Finland
b
Department of Organic Chemistry, A
˚
bo Akademi University, FIN-20500 A
˚
bo, Finland
Received 14 November 2003; revised 3 February 2004; accepted 25 February 2004
Abstract—Synthesis and characterization of several new anomerically pure galactose derivatives, based on simple and effective protective
group manipulations of benzyl
b
-
D
-galactopyranoside, are reported. The monosaccharides described contain selectively protected/depro-
tected hydroxyl functionalities at their 1,2,3,4- and 6-positions rendering them useful as building blocks for construction of branched
oligosaccharides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Carbohydrates and glycoconjugates play a central role in
various biological recognition processes.
1
Recent years
have seen a rapid extension of the field of glycobiology with
carbohydrate-derived therapeutics now entering clinical
trials.
2
The limited availability of pure and structurally
defined specific oligosaccharides nevertheless remains a
major impediment to the study of carbohydrates in
biological applications. Besides the traditional chemical
synthesis techniques, enzymatic
3
and automated solid-phase
synthetic
4
methods have been successfully applied for
constructing stereo- and regiospecific glycosidic linkages in
complex oligosaccharide structures. However, both of these
methods suffer from limitations in scale-up. An additional
concern is the inability of fermentation techniques to
produce unnatural branched oligosaccharides. Thus, in
many cases, conventional organochemical synthesis
remains the method of choice for the preparation of
multigram amounts of chemically defined oligosaccharides
and the improvement and development of efficient protec-
tive group strategies and purification methods remains an
important and actively investigated area of carbohydrate
chemistry.
5
Of particular significance is the preparation of
partially protected carbohydrate building blocks, where the
protecting groups can be manipulated such that each can be
selectively removed during the course of the synthetic route.
In this regard, galactose is a particularly interesting
monosaccharide due to its occurrence as a building block
in various biological structures. In plants it is one of the
main constituents of galactoglucomannans
6
and arabino-
galactans.
7
In humans, it is one of the main constituents of
human milk oligosaccharides
8
and polylactosamines.
9
The
latter structures consisting of N-acetyllactosamine units
[
b
-
D
-galactopyranosyl-(1!4)-N-acetyl-
D
-glucosamine]
with galactose residues at their non-reducing ends have been
extensively studied as anti-inflammatory agents. Further-
more, the axial 4-OH group of galactose renders it an
optimal starting material for exploitation of various
protective group strategies. Here, we report the preparation
of some new anomerically pure galactose derivatives,
obtained by simple and efficient protective group manipula-
tions of benzyl
b
-
D
-galactopyranoside (1). The present
paper continues our recently initiated studies on the
synthesis and conformational behavior
10
of galactose-
containing mono- and oligosaccharides. The galactose
derived monosaccharides described here contain selectively
protected hydroxyl functionalities in their 1,2,3,4- and/or
6-positions, thus potentially serving as useful building
blocks for the construction of branched oligosaccharide
libraries.
2. Results and discussion
Benzyl
b
-
D
-galactopyranoside (1) was prepared from
b
-
D
-galactose pentaacetate in 66% overall yield following
a slightly modified literature procedure.
11
Protecting group
manipulations of 1 are summarized in Scheme 1. The
following strategy was designed in order to create
selectively deprotected hydroxyl functionalities on the
1,2,3,4- and 6-positions of a fully protected galactose
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.054
Tetrahedron 60 (2004) 3653–3661
†
Present address: CSC-Scientific Computing Ltd, PO Box 405, FIN-02101
Espoo, Finland.
‡
Present address: Department of Organic Chemistry A
˚
bo Akademi
University, FIN-20500 A
˚
bo, Finland.
*
Corresponding authors. Tel.: þ358-2-2154132; fax: þ358-2-2154866;
e-mail addresses: reko.leino@abo.fi; reko.lehtila@csc.fi
Keywords: Galactose; Protecting groups; Monosaccharides;
Oligosaccharides.