Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1723–1728
Advances in analysis and synthesis of myo-inositol-derivatives
through resolution by crystallisation
Wolfgang Wewers,a,* Hartmut Gillandtb, and Henner Schmidt Trauba
aUniversity of Dortmund, Department of Biochemical and Chemical Engineering, Chair of Plant Design,
Emil Figge Str. 70, 44221 Dortmund, Germany
bSirius Fine Chemicals (SiChem) GmbH, Fahrenheitstr. 1, 28359 Bremen, Germany
Received 23 December 2004; accepted 28 March 2005
Abstract—A simple method for the preparation of both enantiomers of tetra-O-benzyl-myo-inositol is presented. This method is
based on the resolution of stereoisomers by crystallisation. Starting with the known synthesis of four diastereomers using D-cam-
phor dimethyl acetal as chiral auxiliary, one diastereomer is separated by crystallisation from methanol and is converted to
D-1,4,5,6-tetra-O-benzyl-myo-inositol. A second synthetic route was carried out with the mother liquor of the crystallisation, which
has so far been neglected in former sequences [Am. Chem. Soc. 1992, 6361]. This approach leads to a non-racemic mixture of tetra-
O-benzyl-myo-inositols, from which D-3,4,5,6-tetra-O-benzyl-myo-inositol can be separated by crystallisation from 1-propanol in its
enantiopure form. The yield of this crystallisation step was determined by its eutectical point and the ratio of the diastereomers in
the mother liquor of crystallisation step 1. For this purpose, an analytical HPLC separation for the fast elucidation of the diaste-
reomeric ratio has been developed. With this analytical method, it is possible to optimise the ratio of the diastereomers by changing
the reaction conditions.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
that inhibits the conductance of Ca2+ activated Clꢀ
channels in the plasma membrane. Modified membrane
permeable derivatives of Ins(3,4,5,6)P4 with antagonis-
tic effects have been tested in the treatment of cystic
fibrosis,9 with Ins(1,4,5,6)P4 levels in human colonic
epithelial cells dramatically increasing in response to
Salmonella invasion.10
Inositol phosphates as molecules in biology have been
known for 85 years.2 A new area of research was started
in 1983, after the discovery that myo-inositol 1,4,5-tris-
phosphate is a Ca2+ releasing second messenger.3
Over the last 25 years, many other natural myo-inositol
phosphates have been discovered. It has been realised
that this group of phosphorylated myo-inositols plays
an important role in various biological processes, such
as cellular signal transduction, calcium mobilisation,
chloride secretion, exocytosis, cytoskeletal regulation,
insulin stimulation, intracellular trafficking of vesicles
and anchoring of proteins to cell membranes.4–8
Both enantiomers seem to play different roles in the cel-
lular signal transduction. Herein, we report the use of
the derivatives as pharmaceutically active substances
and emphasise the necessity of a highly effective and
simple way to synthesise the enantiopure key molecules.
2. Results and discussion
Herein, we report the preparation of key enantiopure
molecules for the synthesis of two prominent InsP4
enantiomers, D-myo-inositol 3,4,5,6-tetrakisphosphate
Ins(3,4,5,6)P4 and Ins(1,4,5,6)P4 and the derivatives of
both. Ins(3,4,5,6)P4 behaves as an intracellular signal
In former synthetic sequences, the preparation of enan-
tiopure tetra-O-benzyl-myo-inositol derivatives was
achieved by the separation of diastereomers. For this
reason, D or L-camphor dimethyl acetal, used as a chiral
auxiliary, has to be introduced into the myo-inositol
structure. The synthetic strategy is shown in the left
route of Figure 1 and was first described by Bruzik
et al. in 1989 and improved upon in 1992.11,1 Starting
*
Corresponding author. Tel.: +49 (0231) 7556190; e-mail: wolfgang.
Tel.: +49 (0421) 2208227; e-mail: hgillandt@sichem.de
0957-4166/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.03.033