J. Schulz et al., Synthesis of (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol, a keyprecursor to inositol monophosphatase inhibitors, from (-)-quinic acid, J CHEM S P1, (6), 2000, pp. 943-954
A new and efficient route to homochiral (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzy
loxycyclohexan-2-ol and its 2-benzyl ether derivative is described, startin
g from (-)-quinic acid. The compounds are key intermediates in the solution
-phase and solid-phase synthesis of inhibitors for inositol monophosphatase
. The pivotal step involves a La3+-induced reversal of the diastereoselecti
vity for the borohydride reduction of an intermediate cyclohexan-4-one. (1R
,2R,4R,6R)-(O-6-Propyl)cyclohexane-1,2,4,6-tetraol 1-phosphate, predicted t
o be a submicromolar competitive inhibitor of inositol monophosphatase, was
prepared from the title epoxide in 5 steps in good overall yield. The comp
ound proved to be a competitive inhibitor and displayed the expected potenc
y confirming the stereochemical requirements for inhibition. The O-2-benzyl
ated epoxide derivative could be stereospecifically alcoholysed using eithe
r BF3.(OEt)(2) or Yb(III)(OTf)(3) as catalysts without appreciable levels o
f benzyl ether protecting group cleavage. The preparation of the alcoholysi
s products (1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-isopropyloxycyclohexanol and
(1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-(phenethyloxy)cyclohexanol, and the synt
hesis and evaluation of the inhibitor (1R,2R,4R,6R,2'S)-6-(1'-hydroxy-3'-ph
enylpropan-2-yloxy)-2,4-dihydroxycyclohexyl phosphate and its diastereomer
(1R,2R,4R,6R,2'R)-6-(1'-hydroxy-3'-phenylpropan-2-yloxy)-2,4-dihydroxycyclo
hexyl phosphate are described.