3234
J . Org. Chem. 1996, 61, 3234-3235
anism is preferred which involves an interesting rear-
Ster eoselective Deoxygen a tion of
m yo-In ositol Mon otosyla tes w ith Lith iu m
Tr ieth ylbor oh yd r id e
rangement.10 The hydrogen on the carbon with the
hydroxyl group undergoes a [1,2] shift to displace the
tosylate group with the probable formation of a ketone
intermediate that is quickly reduced by LTBH back to a
hydroxyl. This mechanism is less sensitive to steric
hinderance and it has been utilised to deoxygenate the
2′ position of adenosine10 and some hexose sugars.11
J inquan Yu and J onathan B. Spencer*
University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW, U.K.
We wanted to explore whether this reactivity could be
utilized for the selective deoxygenation of myo-inositol
and other suitably substituted cyclohexanes. Racemic
3,4,5,6-tetra-O-benzyl myo-inositol12 1 (1 mmol) was
selectively tosylated under solid/liquid phase-transfer
conditions13 at room temperature in CH3CN using dibu-
tyltin oxide (2 mmol), tosyl chloride (1 mmol), and
benzyltriethylammonium chloride (0.2 mmol) for 24 h to
give 2a in 92% yield. Reaction of 2a with LTBH in
anhydrous THF under argon at room temperature for 24
h, gave 2-deoxy-3,4,5,6-tetra-O-benzyl myo-inositol 3a in
79% yield. To investigate whether the tosylate group is
directly displaced or a more complicated mechanism
occurs, the reaction was carried out with lithium trieth-
ylborodeuteride (LTBD). The reaction proceeds smoothly
under the same conditions as before to give 3a with a
deuterium at the 1 position (Scheme 1). This eliminates
a simple SN2 displacement and implicates either a [1,2]
hydride shift as has been demonstrated in the deoxygen-
ation of 2′-O-tosyladenosine with LTBH10 or elimination
of the tosylate followed by protonation of the resulting
enolate; in either case the final step would be stereose-
lective reduction of the derived ketone. To distinguish
between these two possible mechanisms, the deuterated
alcohol 2b (scheme 1) was prepared by oxidizing 2a using
pyridinium chlorochromate (PCC) to give the ketone 7,
which was then reduced with NaBD4.14 2b was reacted
with LTBH at room temperature, which gave 3b with
the deuterium located solely in the axial position at C-2,
thus confirming a stereoselective [1,2] hydride shift.
Received February 29, 1996
myo-Inositol 1,4,5-triphosphate has been identified as
an important secondary messenger which is involved in
many intracellular signaling events.1 In particular, it has
been demonstrated to have a profound effect on neu-
rotransmitter release mechanisms.2 Selective inhibition
of some of the enzymes involved in formation and
breakdown of myo-inositol 1,4,5-triphosphate is of po-
tential therapeutic value in conditions such as manic
depression.3 A number of deoxy derivatives of myo-
inositol 1-phosphate have been demonstrated to be strong
inhibitors of myo-inositol monophosphatase, a key en-
zyme in recycling myo-inositol, which hydrolyzes both
myo-inositol 1-phosphate and myo-inositol 4-phosphate4
and of myo-inositol 1-phosphate synthase that catalyzes
the de novo biosythesis of myo-inositol 1-phosphate from
glucose 6-phosphate.5 We now report a high yield ste-
reoselective deoxygenation of myo-inositol that allows
convenient entry into this series of compounds.
Existing methods for the selective deoxygenation of
myo-inositol have, at best, been achieved in four steps
with a overall yield of 30%.6 In an attempt to find a more
convenient route we initially investigated the possibility
of utilizing Barton’s methodology7 for the reduction of
the phenoxythiocarbonyl derivative of 1 with tributyltin
hydride; however, this proved unsucessful because of the
formation of a stable cyclic thiocarbonate that could not
be reduced even under harsh conditions.8
Lithium triethylborohydride (LTBH) has been used for
the deoxygenation of primary alcohols by reduction of
their p-toluenesulfonyl esters.9 It has only found limited
application with secondary tosylates owing to the reaction
being sluggish or not occurring at all if the alcohol is
hindered. The mechanism in these cases has been
demonstrated to occur by SN2 displacement of the tosy-
late with the hydride from LTBH, but, if there is a
hydroxyl group next to the tosylate an alternative mech-
A likely sequence for the conversion of 2a into 3a would
involve a conformational change of the alkoxide trieth-
ylboron complex towards a boat conformation 4 (Scheme
2) to allow antiperiplanar migration of the hydride and
the expulsion of the tosylate. The resulting 2-deoxy
1-ketone 5 could then be stereoselectively reduced by
LTBH to give 3a . An interesting difference in the
deoxygenation of 2′-O-tosyladenosine10 is that in that case
the hydroxyl group suffers an inversion of configuration,
whereas in the case of 2a complete retention of config-
uration of the hydroxyl group is observed. To investigate
whether the stereoselectivity arises from the reduction
of the ketone 5 or whether a more “concerted” sequence
occurs as suggested in the deoxygenation of 2′-O-tosy-
ladenosine, 5 was made by oxidation of 3a with PCC.
Reduction of 5 with LTBH under identical conditions to
those used for the conversions of 2a into 3a , yielded
exclusively 3a . Using 5 as a standard, it was possible to
isolate a small quantity of this compound in the reaction
mixture when 2a was converted into 3a at low temper-
(1) (a) Berridge, M. J .; Irvine, R. F. Nature 1982, 312, 315. (b)
Nishizukay, Y. Nature 1984, 308, 693. (c) Altman, J . Nature 1988, 331,
119.
(2) (a) Rhee, S. G.; Suh, P. G.; Ryu, S. H.; Lee, S. Y. Science 1989,
244, 546. (b) Meldrum, E.; Parker, P. J .; Catozzi, A. Biochem. Biophys.
Acta 1991, 1092, 49. (c) Schoepp, D.; Bockaert, J .; Sladescsek, F. Trends
Pharmacol. Sci. 1990, 11, 508.
(3) (a) Agranoff, B. W.; Fisher, S. K. In Inositol Phosphates and
Derivatives: Synthesis Biochemistry and Therapeutic Potenial; Reitz,
A. B., Ed.; ACS Symposium Series 463; American Chemical Society:
Washington, DC, 1991; p 20. (b) Billington, D. C. The Inositol
Phosphates: Chemical Synthesis and Biological Significance; VCH:
New York, 1993.
(4) Gani, D.; Downes, C. P.; Bramham. J . Biochim. Biophys. Acta
1993, 1177, 253.
(5) Migaud, M. E.; Frost, J . W. J . Am. Chem. Soc. 1996, 118, 495.
(6) Baker, R.; Kulagowski, J . J .; Billington, D. C.; Leeson, P. D.;
Lennon, I. C.; Liverton, N. J . Chem. Soc., Chem. Commun. 1989, 1383.
(7) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc. Perkin Trans.
1 1975, 1574.
(8) Barton, D. H. R.; Subramanian, R. J . Chem. Soc., Perkin Trans.
1 1977, 1718.
(9) (a) Brown, H. C.; Krishnamurthy, S. J . Am. Chem. Soc. 1973,
95, 1669. (b) Krishnamurthy, S.; Schubert, R. M.; Brown, H. C. J . Am.
Chem. Soc, 1973, 93, 8486. (c) Krishnamurthy, S.; Brown H. C. J . Org.
Chem. 1976, 41, 3064.
(10) Hansske, F.; Robins, M. J . J . Am. Chem Soc. 1983, 105, 6736.
(11) Baer, H. H.; Hanna, H. R. Carbohydr. Res. 1982, 110, 19.
(12) Grigg, J .; Grigg, R.; Paynes, S.; Conant, R. Carbohydr. Res.
1985, 142, 132.
(13) Grouiller, A.; Buet, V.; Utezav, V.; Descotes, G. Synlett 1993,
221.
(14) Reduction of 7 with NaB2H4 gives a mixture (1:3) of 2b and its
epimer, which were separated by preparative TLC with chloroform
hexane (12:1) as the eluent.
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