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. 2013 Mar 15;78(6):2275-88.
doi: 10.1021/jo3027774. Epub 2013 Mar 5.

Regioselective opening of myo-inositol orthoesters: mechanism and synthetic utility

Himali Y Godage  1 , Andrew M Riley, Timothy J Woodman, Mark P Thomas, Mary F Mahon, Barry V L Potter
Affiliations
Free PMC article

Regioselective opening of myo-inositol orthoesters: mechanism and synthetic utility

Himali Y Godage et al. J Org Chem. .
Free PMC article

Abstract

Acid hydrolysis of myo-inositol 1,3,5-orthoesters, apart from orthoformates, exclusively affords the corresponding 2-O-acyl myo-inositol products via a 1,2-bridged five-membered ring dioxolanylium ion intermediate observed by NMR spectroscopy. These C-2-substituted inositol derivatives provide valuable precursors for rapid and highly efficient routes to 2-O-acyl inositol 1,3,4,5,6-pentakisphosphates and myo-inositol 1,3,4,5,6-pentakisphosphate with biologically interesting and anticancer properties. Deuterium incorporation into the α-methylene group of such alkyl ester products (2-O-C(O)CD2R), when the analogous alkyl orthoester is treated with deuterated acid, is established utilizing the novel orthoester myo-inositol 1,3,5-orthobutyrate as an example. Such deuterated ester products provide intermediates for deuterium-labeled synthetic analogues. Investigation into this selective formation of 2-O-ester products and the deuterium incorporation is presented with proposed mechanisms from NMR experiments.

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Figures

Scheme 1
Scheme 1
Scheme 2
Scheme 2
Scheme 3
Scheme 3. Orthoacetates in Deuterated TFA
Scheme 4
Scheme 4. Acid Hydrolysis of 3 under Various Conditions
Figure 1
Figure 1
Proton NMR of the 1,2-bridged intermediate (±)-15 (labeled as I) and product 6 (labeled as P): (A) expansion of 3.90–6.45 ppm; (B) expansion of 7.40–8.50 ppm.
Scheme 5
Scheme 5. Acid Hydrolysis of Orthobenzoate Derivatives Proceeds Regioselectively via a 1,2-Bridged Intermediate
Scheme 6
Scheme 6. Synthesis of myo-Inositol 4,6-Di-O-methyl 1,3,5-Orthobenzoate 16
Scheme 7
Scheme 7. Reversible Opening of C-2 Hydroxyl-Protected Orthobenzoates
Scheme 8
Scheme 8. Acid Hydrolysis of 2,4,6-Tri-O-benzyl Orthobenzoate 25 in TFA/DCM; 1:1
Scheme 9
Scheme 9. Proposed Mechanism for the Acid Hydrolysis of Orthobenzoate 3
Figure 2
Figure 2
X-ray crystal structure of 7. Ellipsoids are represented at 30% probability.
Figure 3
Figure 3
Crystal packing diagram for compound 7 showing the extensive H-bonding network.
Scheme 10
Scheme 10. Proposed Mechanism for the Deuterium Exchange
Scheme 11
Scheme 11. Proposed Mechanism for the Formation of α-Methyl Deuterated Ester Products
Scheme 12
Scheme 12. No Deuterium Incorporation after Formation of Product
Scheme 13
Scheme 13. Synthesis of 2-O-Benzoyl myo-Inositol 1,3,4,5,6-Pentakisphosphate 9 and myo-Inositol 1,3,4,5,6-Pentakisphosphate 11
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