The synthesis of enantiomerically pure inositol derivatives: from resolution to enzymatic desymmetrisation

Thesis

Many naturally occurring inositol derivatives are fundamental regulators of signalling, metabolism, and many other important cellular processes. Synthetic inositols and probes based on such scaffolds are essential to understanding these biological processes. It is thus important to develop efficient regio- and enantioselective syntheses of inositol derivatives. Our research focused on the syntheses of phosphatidylinositol phosphates (PtdInsP) and rhizopines. PtdInsP_ns possess distinct functions and sub-cellular distributions, which are tightly mediated by kinases and phosphatases. Dysregulation of the phosphoinositide metabolism has been implicated in diseases such as cancer. PtdInsP_n probes that fully retain their biological activity are essential to understanding these processes. We have developed a robust enantioselective synthesis of deuterated PtdIns4P and PtdIns5P. D6 4,6-di-O-Benzyl-myo-inositol was desymmetrised using Lipozyme TL-IM®, to provide the corresponding 1D-1-O-acetylated product in 98% yield and >99% e.e. From this intermediate, the synthesis of D₄₁ PtdIns4P (9 steps) and D₆ PtdIns5P (4 steps) was achieved. Rhizopines were identified as ideal signalling molecules for application in biotechnology. scyllo-inosamine and 3-O-methyl scyllo-inosamine were synthesised from myo-inositol, and their biosynthetic pathways proposed. In addition, we have completed the first enantioselective synthesis of (−)-1L- and (+)-1D-3-O methyl-scyllo-inosamine, in 13 steps, using a novel diastereoisomeric protection-resolution strategy. This enabled this identification of (−)-1L-3-O-methyl-scyllo-inosamine as the naturally active enantiomer of 3-O-methyl-scyllo-inosamine, using a rhizopine catabolism assay.

The synthetic routes developed will be invaluable for the synthesis of unsaturated and metabolically stable PtdInsP_n, but also for the synthesis of similar enantiomerically pure inositol derivatives.

Authors: Joffrin, AM

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Inositol Synthesis