Inositol phosphates, scheme

Inositol hexakisphosphate (InsP6) 564 Inositol phosphates, scheme 565 Inositol polyphosphates... 

Fig. 8.9. Crosslinking of signal proteins with the help of protein modnles. A hypothetical protein is shown which contains SH2, SH3, PTB and PH domains. Recognition of phosphotyrosine residues occurs with the help of SH2 or PTB domains SH3 domains bind to proline-rich sequences (Pro in Protein 3) whilst the pleckstrin homology domains (PH domains) mediate binding to phosphatidyl-inositol-phosphates (PtdInsP) in the membrane. In an idealized scheme, the modular protein can associate several proteins (Protein 1 - Protein 3) and mediate interactions between these proteins (shown as broken arrows). The PH domain helps to recruit the complex to the cell membrane favoring interactions with other membrane-associated proteins (Protein X).

Figure 11-9 Scheme showing synthesis and release of diacylglycerol and inositol phosphates and their regulation of calcium concentration in response to hormonal stimulation. 

At this stage it is important to briefly examine the biosynthesis of carbocyclic polyols, concentrating on six membered rings. Myo-inositol derivatives, for example, are formed from D-glucose 6-phosphate 1 by a stereospecific ring-closure under the catalytic influence of inositol cyclase (Scheme 1) [lb]. 

Scheme 4.30 Fluoromethyl phosphonate analogs of phosphoenol pyruvate (irreversible inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase) [71], of cyclic inositol phosphate (lipolipase C inhibitor) [72], and of the transition state of the purine nucleoside phosphorylase (PNP) reaction [73].

To achieve total synthesis of inositol phosphates and related derivatives, multiple phosphorylation of polyol derivatives is the most crucial step. Use of dianilinophosphoric chloride 8 was the only method of choice for this purpose. However, its reactivity is not satisfactory for perphosphorylation of inositols and furthermore spontaneous deprotection of several dianilinophosphoric esters in the same molecules is quite difficult, while phosphorylation of D-2,3,6-tribenzyl-myo-inositol 9 with the chloride 8 giving 11 in 60% yield was accomplished after exploring proper reaction conditions in the first total synthesis of Ins(l,4,5)P3 (Scheme 2-1).However, the phosphorylation product 12 was not formed at all from 10, a positional isomer of 9 under similar conditions. In 1987, it was reported that the reaction of tetrabenzyl pyrophosphate (TBPP, 13) with alkoxides generated in situ by the action of a strong base such as NaH.l c KH, - or butyllithium b on inositols smoothly gave the desired polyphosphorylated products in good yields. Examples are shown in Scheme 2-1. 

Cyclohexylidene and isopropylidene monoketals 47 and diketals 48, 49, and 50 are well-known protected myo-inositol derivatives (Scheme 3-1). Compounds 47 ketalized at the 1,2-cis-positions have been utilized conveniently for the synthesis of various inositol phosphates since 47 can be regioselectively functionalized and prepared in good yield by the conventional ketalization procedure and subsequent partial deprotection of the less stable trans-type ketals from the diketal mixture formed first in the reaction.22 Three diketals S have been also often employed for the synthesis of target inositol derivatives, because they have the following advantages (1) A trans vicinal hydroxyl moiety as well as the 1,2-... 

The reaction of 1,2-cyclohexylidene-myo-inositol 47a with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPS-CI2) takes place in a completely regioselective manner to afford the 3,4-disiloxane derivative 76 in quantitative yield. 5- - Compound 76 has been shown to be a very useful synthetic intermediate by the synthesis of various inositol phosphates and phospholipids (Scheme 3-9). The usefulness... 

In efforts to elucidate the metabolism of inositol phosphates, a few enzymes have been isolated and their substrate specificity determined. In particular, studies by Majerus and coworkers allow the description of a minimal metabolic scheme for the inositol phosphates (Connolly et al., 1986 1987). 

Novozyme 435 has also been applied by a Novartis group for the synthesis of optically pure 2,6-di-O-henzoyl-myo-inositol ((-)-99) and its monoacetate (-)-lOO. These intermediates are precursors for the rare and expensive inositol phosphates d-101 and l-101 (Scheme 30) [95], compounds which are essential for a number of physiological processes in differentiated higher cells, e.g., the activation of thrombocytes in the blood clotting process or hormone signal transduction. The key intermediate rac-99 could be prepared in four chemical steps, and the Novo 435-catalyzed asymmetric acetylation afforded monoacetate (-)-lOO besides unconverted inositol derivative (-)-99 with optical purities of >99%, respectively. The subsequent chemical hydrolysis of (-)-lOO quantitatively yielded the antipode of (-)-99, and a phosphorylation. 

Novozyme 435 has also been applied by a Novartis group for the synthesis of optically pure 2,6-di-O-benzoyl-m/o-inositol ((-)-99) and its monoacetate (-)-lOO. These intermediates are precursors for the rare and expensive inositol phosphates d-101 and l-101 (Scheme 30) [95], compounds which are essential for a number of physiological processes in differentiated higher cells,... 

Two synthetically in iortant variants of the Ferrier carbocyclization reaction have been reported. One is a rearrangement of enol acetate 24 (Scheme 12.7). Reaction of 24 with a stoichiometric amount of Hg salt afforded an organomercurial intermediate 25, which was then treated with NaCl to induce the cyclization affording inosose derivatives 26a and 26b with good stereoselectivity. As biologically inportant myo-inositol derivatives, such as d-myo-inositol phosphates, are optically active, the enol-acetate version of the Ferrier carbocyclization would be effective for the preparation of enantiomerically pure inositol derivatives. 

D-x //( -Hexos-5-ulose 6-phosphate (317) cyclized in base to give two inosose phosphates (Scheme 112), thus simulating the cyclization step that occurs in the biosynthesis of inositols. ... 

The acidic phospholipids are synthesized by a completely different pathway, in which the phosphate group in PtdOH is retained in the product. In this scheme, PtdOH is converted to the liponucleotide CMP-PtdOH (CDP-DAG) (Fig. 3-8). CDP-DAG reacts with inositol to form PI... 

D-Glucose 6-phosphate is converted enzymically into L-wyo-inositol 1-phosphate (20) in a process which requires NAD+. The base-catalysed cyclization of d-xylo-hexos-5-ulose 6-phosphate (21), followed by reduction with borohydride, leads to (20) and epi-inositol 3-phosphate (22) (Scheme 3).59 This has been put forward as a chemical model for the enzymic synthesis. The phosphorylation of inositols with polyphosphoric acid has been described80 and the p-KVs of inositol hexaphosphate have been determined by 31P n.m.r.61... 

For all the substrates discussed so far the peptide catalysts employed had to differentiate between enantiomeric substrate molecules. Miller et al. subsequently screened peptide libraries for members able to selectively functionalize enantio-topic hydroxyl groups of meso inositols. In particular, they were able to convert myo-inositol 35 to either monophosphorylated D-myo-inositol-l-phosphate 37 or d-myo-inositol-3-phosphate ent-37 in high yield and excellent ee (98% Scheme 12.18) [38, 39], This remarkable result was achieved by use of either of the penta-... 

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