Synthesis of the enantiomers of myo-inositol
1,2,4,5-tetrakisphosphate, a regioisomer of
myo-inositol 1,3,4,5-tetrakisphosphate
Abstract
Routes for the synthesis of racemic myo-inositol
1,2,4,5-tetrakisphosphate
DL-Ins(1,2,4,5)P4
5ab and the chiral antipodes D- and
L-myo-inositol
1,2,4,5-tetrakisphosphate 5a and 5b, respectively, are described. For
the synthesis of racemate 5ab,
3,6-di-O-benzoyl-1,2:4,5-di-O
-isopropylidene-myo-inositol 7ab is prepared in two
steps from myo-inositol. The ketals are hydrolysed
under acidic conditions to give
DL-1,4-di-O-benzoyl-
myo-inositol 8ab. Phosphitylation of compounds 8ab using
chloro(diethoxy)phosphine in the presence of base, followed by oxidation
and a three-step deprotection strategy, gives
DL-Ins(1,2,4,5)P4
5ab.The chiral tetrakisphosphates 5a and 5b are synthesized using a
different route. The 4,5-isopropylidene group of
DL-3,6-di-O
-benzyl-1,2:4,5-di-O-isopropylidene-myo
-inositol 13ab are selectively removed under mild acidic conditions
to give diol 14ab. p-Methoxybenzylation at the
4,5-positions followed by acid hydrolysis of the
cis-isopropylidene ketal affords
cis-diol 16ab. Selective coupling of
(S)-(+)-O
-acetylmandelic acid with diol 16ab at the equatorial hydroxy group
provides two diastereoisomers 18 and 19, which are separated by
chromatography. Basic hydrolysis of the individual diastereoisomers
provides the enantiomers 16a and 16b. Acidic hydrolysis gives
D- and
L-3,6-di-O-benzyl-
myo-inositol 20a and 20b, respectively. Phosphitylation and
oxidation of tetraols 20a and 20b gives the fully blocked derivatives,
which are deprotected to give tetrakisphosphates 5a and 5b,
respectively. The absolute configuration of compound 20a is established
by a chemical method.
DL-1,2:4,5-Di-O
-isopropylidene-myo-inositol 12ab is coupled to
(S)-(+)-O
-acetylmandelic acid to give a mixture of bis-esters 26 and 27 and
crystallisation of the mixture of diastereoisomers affords pure isomer
27. Basic hydrolysis gives the pure enantiomer 12a (for which the
absolute configuration is known) and benzylation followed by acid
hydrolysis gives tetraol 20a with the same physical properties as
compound 20a prepared by a different route described previously.
D-Ins(1,2,4,5)P4
5a is a potent mobiliser of intracellular Ca2+
ions in permeabilised platelets, while
L-Ins(1,2,4,5)P4
5b is inactive.
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