Synthesis of (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol, a key precursor to inositol monophosphatase inhibitors, from (−)-quinic acid

J Schulz, M W Beaton, D Gani

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

A new and efficient route to homochiral (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol and its 2-benzyl ether derivative is described, starting 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 diastereoselectivity 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 to be a submicromolar competitive inhibitor of inositol monophosphatase, was prepared from the title epoxide in 5 steps in good overall yield. The compound proved to be a competitive inhibitor and displayed the expected potency confirming the stereochemical requirements for inhibition. The O-2-benzylated epoxide derivative could be stereospecifically alcoholysed using either BF3.(OEt)(2) or Yb(III)(OTf)(3) as catalysts without appreciable levels of benzyl ether protecting group cleavage. The preparation of the alcoholysis 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 synthesis and evaluation of the inhibitor (1R,2R,4R,6R,2'S)-6-(1'-hydroxy-3'-phenylpropan-2-yloxy)-2,4-dihydroxycyclohexyl phosphate and its diastereomer (1R,2R,4R,6R,2'R)-6-(1'-hydroxy-3'-phenylpropan-2-yloxy)-2,4-dihydroxycyclohexyl phosphate are described.

Original languageEnglish
Pages (from-to)943-954
Number of pages12
JournalJournal of the Chemical Society, Perkin Transactions 1
Issue number6
DOIs
Publication statusPublished - 2000

Keywords

  • ORGANIC-SYNTHESIS
  • ADENOSINE 2'-PHOSPHATE
  • ACTIVE CONFORMATION
  • SODIUM-BOROHYDRIDE
  • MECHANISTIC PROBES
  • PUTATIVE TARGET
  • LITHIUM-THERAPY
  • MAGNESIUM-ION
  • QUINIC ACID
  • O-ATOMS

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