A type 2 Ferrier rearrangement-based synthesis of d-myo-inositol 1,4,5-trisphosphate

The synthesis of d-myo-inositol 1,4,5-trisphosphate (InsP3) from methyl α-d-glucopyranose, via a type 2 Ferrier rearrangement is reported. A key intermediate in this synthesis possesses orthogonal protecting groups at the 1-, 4- and 5-position, making it a versatile starting point for the synthesis of unnatural InsP3 derivatives. Biological evaluation of the synthetic InsP3 demonstrates that this compound evokes selective Ca2+ release via activation of InsP3 receptors.

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Methyl 4,6-O-anisylidene-α-d-glucopyranosideC15H20O7Ee = 100%[α]D20=+104.8 (c 1.00, CHCl3)Source of chirality: d-glucose

Methyl 2-O-benzyl-4,6-O-anisylidene-α-d-glucopyranosideC22H26O7Ee = 100%[α]D20=+32.0 (c 1.00, CHCl3)Source of chirality: d-glucose

2-O-Benzyl-3-O-triisopropylsilyl-4,6-O-anisylidene-α-d-glucopyranosideC31H46O7SiEe = 100%[α]D20=-13.5 (c 0.97, CHCl3)Source of chirality: d-glucose

Methyl 2-O-benzyl-4-O-(4-methoxybenzyl)-3-O-triisopropylsilyl-α-d-glucopyranosideC31H48O7SiEe = 100%[α]D20=+64.6 (c 1.56, CHCl3)Source of chirality: d-glucose

Methyl 6-O-acetyl-2-O-benzyl-4-O-(4-methoxybenzyl)-3-O-triisopropylsilyl-α-d-glucohex-5-enopyranosideC33H48O8SiEe = 100%[α]D20=-8.6 (c 1.32, CHCl3)Source of chirality: d-glucose

3-O-Benzyl-2-hydroxy-5-O-(4-methoxybenzyl)-4-O-triisopropylsilyl-6-oxocyclohexyl acetateC32H46O8Si[α]D20=-28.9 (c 3.02, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-1-O-Acetyl-3-O-benzyl-5-O-(4-methoxybenzyl)-4-O-triisopropylsilyl-myo-inositolC32H48O8Si[α]D20=+17.1 (c 1.00, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-1-O-Acetyl-3-O-benzyl-2,6-O-bisbenzyloxymethyl-5-O-(4-methoxybenzyl)-4-O-triisopropylsilyl-myo-inositolC48H64O10Si[α]D20=-40.7 (c 0.75, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-3-O-Benzyl-2,6-O-bisbenzyloxymethyl-5-O-(4-methoxybenzyl)-4-O-triisopropylsilyl-myo-inositolC46H62O9Si[α]D20=-17.9 (c 1.47, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-3-O-Benzyl-2,6-O-bisbenzyloxymethyl-4-O-triisopropylsilyl-myo-inositolC38H54O8Si[α]D20=+3.6 (c 2.45, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-3-O-Benzyl-2,6-O-bisbenzyloxymethyl-myo-inositolC29H34O8Si[α]D20=+27.3 (c 0.11, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-3-O-Benzyl-2,6-O-bisbenzyloxymethyl-myo-inositol 1,4,5-tris(dibenzyl phosphate)C71H73O17P3[α]D20=-18.1 (c 1.00, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose

d-myo-Inositol 1,4,5-trisphosphate hexakis sodium saltC6H9Na6O15P3[α]D20=-19.2 (c 0.25, H2O)Source of chirality: Ferrier rearrangement from d-glucose

d-3-O-Benzyl-2,6-O-bisbenzyloxymethyl-5-O-(4-methoxybenzyl)-myo-inositolC37H42O9[α]D20=-16.9 (c 0.54, CHCl3)Source of chirality: Ferrier rearrangement from d-glucose