David J. Jenkins

A concise synthesis of neo-inositol

Abstract neo -Inositol was prepared on a multigram scale in five steps from myo -inositol without recourse to column chromatography. The synthesis includes a large-scale preparation of 1,6:3,4-bis-[ O -(2,3-dimethoxybutane-2,3-diyl)]- myo -inositol and a high-yielding inversion of configuration at C-5 employing solvolysis of the 5-triflate ester in aqueous dimethylacetamide.

Synthesis of adenophostin A and congeners modified at glucose

A convergent route is described to the super-potent 1D-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A (2) and analogues 5 and 7, in which the glucose bisphosphate unit is replaced by corresponding xylose bisphosphate and mannose bisphosphate units respectively. Adenosine was converted into its 2′,3′-O-p-methoxybenzylidene derivative 8ab, which was selectively N6-dimethoxytritylated by a transient protection method. 5′-O-Benzylation followed by reductive acetal cleavage gave, after separation from its 3′-O-p-methoxybenzyl isomer, the versatile glycosyl acceptor 5′-O-benzyl-N6-dimethoxytrityl-2′-O-p-methoxybenzyladenosine 13. Coupling of 13 with selectively protected glucopyranosyl, xylopyranosyl or mannopyranosyl dimethyl phosphites gave the required 3′-O-α-pyranosyl adenosine derivatives. Acidic hydrolysis gave corresponding N6-unprotected triols which were phosphitylated using bis(benzyloxy)(diisopropylamino)phosphine and imidazolium triflate without further N6-protection. Deprotection gave the target trisphosphates 2, 5 and 7. Synthetic adenophostin A (2) was identical with a sample of natural material in all respects. Analogues 5 and 7 will be useful for structure–activity studies on the adenophostins.

A disaccharide polyphosphate mimic of 1D-myo-inositol 1,4,5-trisphosphate

A concise route from D-glucose and D-ribose to a potent sugar polyphosphate second messenger mimic related to adenophostin A is described; a role for the adenine base of the adenophostins is suggested.

(2-Hydroxyethyl)-α-D-glucopyranoside-2′,3,4-trisphosphate: synthesis of a second messenger mimic related to adenophostin A

A concise synthetic route from D-glucose to a chiral, biologically active, phosphorylated analogue of the highly potent Ca2+-mobilising agonist adenophostin A has been developed, involving a regioselective dibenzylation of allyl α-D-glucopyranoside and a one-pot Lemieux-type allyl oxidation with subsequent reduction and neighbouring deketalisation, to provide the key intermediate for phosphorylation.

INFRAMOLECULAR STUDIES OF THE PROTONATION OF 1D-1,2,4/3,5-CYCLOPENTANEPENTAOL 1,3,4-TRISPHOSPHATE, A RING-CONTRACTED ANALOGUE OF 1D-MYO-INOSITOL 1, 4, 5-TRISPHOSPHATE

Abstract The protonation process of the individual phosphate groups of 1 d -1,2,4/3,5-cyclopentanepentol 1,3,4-trisphosphate has been investigated by 31P NMR titration experiments. The results are compared with those of 1 d -myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. From the NMR titration curves it can be shown that P3 and P4 strongly interact, whereas P1 behaves independently. In addition, P3 and P4 are much less influenced by their vicinal hydroxyls than P1. Accordingly, the calculated microscopic protonation constants indicate a higher basicity for P3 and P4 compared with the basicity of P1. The vicinal bisphosphate of the cyclopentane-based compounds seems to adopt a similar conformation to that of Ins(1,4,5)P3, although an analogous interaction with a hydroxyl group is not observed. Two cyclopentanepentaol trisphosphates were examined for their potency to release intracellular Ca2+ from rat hepatocytes. Both were found to be low-affinity agonists in this regard. The relationship of this activity to the physicochemical data is discussed for one example.

Convergent synthesis of adenophostin A analogues via a base replacement strategy

The first totally synthetic base-modified analogues of the natural product and potent D-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A were efficiently synthesised from D-xylose and D-glucose using methodology employing base and surrogate base addition to a common disaccharide intermediate.

Total synthesis, from D-xylose, of chiral, ring-contracted 1D-myo-inositol 1,4,5-trisphosphate and 1,3,4,5-tetrakisphosphate analogues with C-2 excised

A route to chiral, cyclopentane-based congeners of the second messenger 1D-myo-inositol 1,4,5-trisphosphate and its enigmatic metabolite 1D-myo-inositol 1,3,4,5-tetrakisphosphate, starting from D-xylose, is described. Reaction of allyl α-D-xylopyranoside 7 with 2,2,3,3-tetramethoxybutane gave a 1∶1 mixture of the 2,3- and 3,4-butanediacetal-protected derivatives 8 and 9. The latter was converted in four steps into 2-O-benzyl-3,4-bis-O-(p-methoxybenzyl)-D-xylopyranose 15, which on reduction with sodium borohydride gave 2-O-benzyl-3,4-bis-O-(p-methoxybenzyl)-D-xylitol 16. Swern oxidation followed by samarium(II) iodide-mediated pinacol coupling gave a 1∶3 mixture of 1L-1,2,3,4/5-1-benzyloxy-2,3-dihydroxy-4,5-bis-(p-methoxybenzyloxy)cyclopentane 18 and 1L-1,2,4/3,5-3-benzyloxy-1,2-dihydroxy-4,5-bis-(p-methoxybenzyloxy)cyclopentane 19. The identity of the latter was confirmed by conversion into known compounds, and further elaboration gave the target compounds, 1D-1,2,4/3,5-cyclopentanepentaol 1,3,4-trisphosphate 5 and 1D-1,2,4/3,5-cyclopentanepentaol-1,2,3,4-tetrakisphosphate 6.

Synthesis of D-2-deoxy-myo-inositol 1,3,4,5-tetrakisphosphate from D-glucose

A route to a novel, structurally modified D-myo-inositol 1,3,4,5-tetrakisphosphate analogue, D-2-deoxy-myo-inositol 1,3,4,5-tetrakisphosphate 3, is described, involving as the key steps a selective protection of methyl α-D-glucopyranoside and subsequent catalytic Ferrier rearrangement to a deoxyinosose. Thus, methyl α-D-glucopyranoside was converted by an improved procedure into methyl 4,6-O-benzylidene-α-D-glucopyranoside 4 and thence into methyl 3-O-benzoyl-2-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside 7 without recourse to column chromatography. Compound 7 was converted into methyl 3,4-di-O-benzoyl-2-O-benzyl-6-deoxy-α-D-xylo-hex-5-enopyranoside 12 via methyl 3,4-di-O-benzoyl-2-O-benzyl-6-bromo-6-deoxy-α-D-glucopyranoside 8. Rearrangement of enol ether 12 with mercury(II) trifluoroacetate provided (2S,3R,4S,5R)-2,3-dibenzoyloxy-4-benzyloxy-5-hydroxycyclohexanone 13 and (2S,3R,4S,5S)-2,3-dibenzoyloxy-4-benzyloxy-5-hydroxycyclohexanone 14. Attempts to invert the configuration at position 5 of compound 14 were unsuccessful, but provided a number of discrete products. Reduction of compound 13 and saponification furnished L-1-O-benzyl-3-deoxy-scyllo-inositol 23, which was phosphorylated and deprotected to give the target 3.

Synthesis of Novel Polyphosphate Analogues of Inositol 1,4,5-Trisphosphate

Abstract The synthesis of novel polyphosphate mimics of inositol 1,4,5-trisphosphate, including ring-contracted and conformationally restricted analogues is reported.

SYNTHETIC MODULATORS OF THE POLYPHOSPHOINOSITIDE PATHWAY OF SIGNAL TRANSDUCTION

Abstract Synthesis of regiochemically and structurally modified analogues of D-myo-inositol 1,4,5-trisphosphate are described to give second messenger mimics, enzyme inhibitors and receptor antagonists, demonstrating new leads for the design of agents to interfere with a key pathway of signal transduction.