improve the arabinonucleotide synthesis.7 Recently, this
methodology was applied to the chemoenzymatic synthesis
of DHAP. The glycidol ring opening with Na2HPO4 genera-
ted D,L-glycerol 3-phosphate, and DHAP was obtained in
28% overall yield by enzymatic oxidation of L-glycerol
3-phosphate.8
The ring opening of 1 was first attempted with dibenzyl
phosphate in benzene9 or dichoromethane11 at room tem-
perature and afforded the desired product 2 in moderate to
low yields (Table 1, entries 1 and 4) with the formation of
byproducts resulting from the degradation of the starting
material.
All of of these reactions have been performed in aqueous
solution, limiting the application of this procedure in organic
synthesis. However, protected phosphates such as dibenzyl
or diethyl phosphate have also been used to open polycyclic
aromatic hydrocarbon epoxides as a model for the reaction
of the carcinogenic epoxy diols derived from benzopyrene
diol with nucleic acids.9 In all cases, the phosphotriesters
were formed in benzene or THF with yields around 80% by
regiospecific and by stereospecific opening of the epoxide
with the phosphate reacting at the benzylic position in an
SN2 mechanism.9a A one-pot synthesis using phosphoric acid
diesters in the epoxide opening of 1,2-anhydrosugars was
investigated for the convenient synthesis of glycosyl phos-
phates, powerful glycosylating agents.10
Phosphorylated dibenzyl conduritol-B derivatives, ideal
intermediates for the synthesis of myo-inositol phosphates
which play key functions in biological systems as free
compounds or as part of more complex structures, were also
prepared by a double allylic epoxide opening of diepoxy-
cyclohexene with dibenzyl phosphate in dichloromethane
with a yield of 55%.11
In these examples, the epoxide ring opening occurred
either by using inorganic phosphate, or by opening alicyclic
epoxide with partially protected phosphates in organic
solvents. These features limit the synthetic utility of this
reaction.
To optimize our synthesis of DHAP,12 we investigated the
nucleophilic ring opening of the commercially available
racemic benzylglycidol 1 with dibenzyl phosphate to prepare
the precursor of DHAP 2 (Scheme 1).
Table 1. Ring Opening of the Epoxide 1 with Dibenzyl
Phosphate in Various Solvents at Room Temperature
entry
solvent
time (h)
yield (%)
1
2
3
4
benzene
toluene
THF
96
48
120
36
13
20
9
CH2Cl2
33
These results compared to those described in the literature
are probably due to the thermodynamically less favored ring
opening of benzylglycidol compared to the strained oxirane
ring in the fused systems described in the literature.9,11 The
yield of the reaction was not significantly affected by
changing the solvent (toluene, THF) (Table 1, entries 2 and
3), and accordingly, the reactions were performed in dichloro-
methane.
In all cases, the ring opening reaction appeared to be
regiospecific, and the nucleophilic attack occurring at the
C-3 position of the benzylepoxide was observed.
To improve the yield of the reaction, we chose to increase
the phosphate nucleophilicity by forming in situ the anion
of the dibenzyl phosphate with different bases such as NaH,
NEt3, collidine, Na2CO3, and Cs2CO3 in different solvents
such as toluene, THF, and diethyl ether. Under these
conditions no reaction occurred, and the starting products
were recovered.
To circumvent these problems, we then turned our
attention to the use of Lewis acids which have been found
to be effective mediators of regio- and stereoselective epoxide
openings. Indeed, high regioselectivity (attack at C-3 vs C-2)
ring opening of 2,3-epoxy alcohols by nucleophiles has been
observed with a catalytic amount of BF3/Et2O13 or CuI14 and
with a stoichiometric amount of Ti(O-i-Pr)4.15 These last
results were rationalized by invoking the coordination of the
epoxy alcohol to the titanium metal center in the rigid,
bidentate manner.15
Scheme 1. Ring Opening of Benzylglycidol with Dibenzyl
phosphate
However, when we first examined the ring opening of
benzylglycidol 1 in CH2Cl2 with 2 equiv of dibenzyl
After oxidation of the secondary alcohol and removal of
all protecting groups, DHAP was obtained in three steps.
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