Synthesis of inositol phosphates

S. V. Ley, Stereoselective synthesis of inositol phosphates, Pure Appl. Chem. 1990, 62, 2031-2034. 

The year has seen an increase in reported results with an emphasis on the synthesis of phosphonic and phosphinic acid derivatives, and on the synthesis of inositol phosphates. 

Selective Reactions and Total Synthesis of Inositol Phosphates... 

Several review articles and books concerning the synthesis of inositol phosphates and phospholipids are available.14 This text does not cover all reports on the synthesis of inositols but principally deals with synthetic strategies and total synthesis of inositol derivatives which involve selective reactions such as stereoselective and regioselective ones. 

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. 

The carbohydrate mimics 43 and 44 of inositol 1,4,5-trisphosphate have been synthesized in eight steps from allyl a- or P-D-xylopyranoside and allyl o-d-glucopyranoside, respectively, and methyl 2,3,4-trisphospho-a-D-mannopyrano-side has been prepared in three steps from methyl 6-O-trityl-a-D-mannopyrano-side as a mimic of lD-wyo-inositol-trisphosphate, The synthesis of inositol phosphates is covered in Chapter 18. 

Synthesis of inositol by animals is limited and n/i/o-inositol is sometimes classified as a vitamin. Mice grow poorly and lose some of their hair if deprived of dietary inositol. Various phosphate esters of inositol... 

Plant foods contain relatively large amounts of inositol phosphates, including the hexaphosphate, phytic acid. Phytate chelates minerals, such as calcium, zinc, and magnesium, forming insoluble complexes that are not absorbed. However, both intestinal phosphatases and endogenous phosphatases (phytase) in many foods dephosphorylate a significant proportion of dietary phytate. The inositol released can be absorbed and utilized for phosphatidylinositol synthesis. 

Synthesis of inositol phosphoglycans (IPGs) (71), analogues to second messengers of insulin, has been described. These derivatives contain the glucosamine (a 1-6) myo-inositol 1,2 cyclic phosphate motif and the thiol-terminated spacers for efficient coupling to maleimide functionalized solid phases or proteins. ... 

The mode of action is not fully understood. The main effect of lithium is probably to inhibit hydrolysis of inositol phosphate, so reducing the recycling of free inositol for synthesis of phosphatidylino-... 

Three potential sources for cellular inositol are diet, de novo biosynthesis, and recycling of inositol. Inositol is biosynthesized from glucose in the brain and testes, and other tissues to a lesser extent. The rate-limiting step in the inositol biosynthetic pathway appears to be the synthesis of inositol-3-phosphate from glucose-6-phosphate (C.P. Downes,... 

J. R. Falck and A. Abdali, in A. B. Reitz (Ed), ACS Symposium Series 463, Inositol Phosphates and Derivatives, Synthesis, Biochemistry, and Therapeutic Potential. Chapter 11 Enantiospecific Synthesis of Inositol Polyphosphates, Phosphatidylinositid.es, and Analogues from (-)-Quinic Acid, American Chemical Society, Washington, D.C., 1991, pp 145-154. 

A straightforward synthesis of the phosphate derivative (28), from commercially available myo-inositol 1,3,5-orthoformate has been carried out by Hung and Patil in nine steps in 13% overall yield. 

We were drawn to the catalytic, asymmetric phosphorylation of inositol for several reasons [20-22]. First, wyo-inositol possesses six hydroxyl groups, any one of which could potentially be phosphorylated by a chiral catalyst. Second, the diverse phosphorylation patterns of inositol phosphates correspond to equally diverse biological functions [23] excellent strategies for their synthesis existed. 

Because of the widespread occurrence of m /o-inositol in animals, plants, yeasts, molds, and bacteria, many attempts have been made at its synthesis. The chemical syntheses have been considered earlier in this chapter. Biochemical synthesis of inositol from n-glucose or D-glucose phosphate by action of a plant cyclase has been reported 126). The evidence for this transformation is a positive Scherer test there has been no definitive evidence in the form of isolation of myo-inositol. Evidence for synthesis in the animal body is based on the isolation of C Mabeled myo-inositol after the administration of C -labeled n-glucose 32h). 

A review on the preparation and separation of inositol tetrakisphosphates and the establishment of enantiomeric configuration by use of L-iditol dehydrogenase has appeared. The synthesis and biological evaluation of inositol derivatives as inhibitors of phospholipase C (PLC) has been reviewed. A review on the chemistry, preparation and enzymatic reactions of inositol phosphates and a review on the biochemistry, stereochemistry and nomenclature of inositol phosphates has also been reported. A part review on phosphonate analogues of myo-inositol triphosphate has appeared. ... 

Several symposia have been held on the synthesis of inositol polyphosphates as follows those derived from quinic acid " novel routes to inositol phosphates using Pseudomonas putida oxidation of arenes new myo-inositol derivatives containing phosphate, sulfate and sulfonamido groups synthesis and calcium releasing activity of... 

The synthesis of dolichyl phosphates from a tetrasaccharide obtained from mannosidosis-affected calves is referred to in Ghapter 4, and inositol phosphates are covered in Ghapter 18. Treatment of... 

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... 

In summary, the release of nenrotransmitter from a presynaptic neurone into a synaptic cleft occurs via the process of exocytosis, which is regulated by the increase in Ca " ion concentration in the presynaptic terminal. The increase in Ca " ion concentration is achieved by release of Ca " ions by opening of the Ca ion channel in the endoplasmic reticulum, which is controlled by the concentration of IP3. Failure to release inositol from the inositol phosphates reduces the free inositol concentration, which interferes in the synthesis of PIP2. The phospholipase no longer catalyses a zero order reaction. Consequently, sufficient IP3 to activate the ion channel is released in the presynaptic neurone, so that less nenrotransmitter is released into the synaptic cleft (Figure 12.19). 

Miller has reported a minimal kinase for the phosphorylative enantioselective desymmetrization of a meio-inositol derivative. Peptide 132, identihed from a small library, provided the highest selectivity using the meso-tno 130 as substrate. This approach was applied to a hve-step synthesis of D-myoinositol-1-phosphate from readily available myoinositol ... 

---