A definitive synthesis of D-myo-inositol 1,4,5,6-tetrakisphosphate and its enantiomer D-myo-inositol 3,4,5,6-tetrakisphosphate from a novel butane-2,3-diacetal-protected inositol.
New and rapid syntheses of the enantiomeric intracellular signalling molecules d-myo-inositol 1,4,5,6-tetrakisphosphate (1 a) and D-myo-inositol 3,4,5,6-tetrakisphosphate (1 b) are described. The synthetic strategy employs the novel butane-2,3-diacetal-protected (BDA-protected) myo-inositol (+/-)-3 ab, directly accessible from myo-inositol on a large scale, and an optical resolution with diastereoisomeric (R)-(-)-acetylmandelate esters. The X-ray crystal structure of (+/-)-4, an unusual side product of acid-catalysed reaction of myo-inositol with butanedione is also presented, and the absolute configurations of 1 a and 1 b are definitively assigned by conversion of key precursors into (+)-bornesitol and L-iditol hexaacetate, respectively. Biological activity of synthetic 1 b was confirmed in comparison with the natural polyphosphate.
Mills
Stephen J
SJ
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Riley
Andrew M
AM
Liu
Changsheng
C
Mahon
Mary F
MF
Potter
Barry V L
BV
D000080:Acetals / Q000737:chemistry*; D000085:Acetates / Q000737:chemistry; D000818:Animals; D002073:Butanes / Q000737:chemistry*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004852:Epoxy Compounds / Q000737:chemistry; D007294:Inositol / Q000737:chemistry*; D007295:Inositol Phosphates / Q000138:chemical synthesis* / Q000494:pharmacology*; D008956:Models, Chemical; D015394:Molecular Structure; D013237:Stereoisomerism; D013402:Sugar Alcohols / Q000737:chemistry
D000080:Acetals; D000085:Acetates; D002073:Butanes; C490693:D-myo-inositol 1,4,5,6-tetrakisphosphate; C490694:D-myo-inositol 3,4,5,6-tetrakisphosphate; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007295:Inositol Phosphates; D013402:Sugar Alcohols; D007294:Inositol; C007366:diepoxybutane; C046888:butane