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Stereocontrolled synthesis of polypropionates based on building block assembly strategies by lithiation-borylation methodologies

Periodic Reporting for period 1 - BBLOCK (Stereocontrolled synthesis of polypropionates based on building block assembly strategies by lithiation-borylation methodologies)

Período documentado: 2015-09-01 hasta 2017-08-31

Amongst all natural products, polyketides constitute a very important class due to their broad spectrum of biological activities (eg. antibiotic, antitumoral, antifungal, antiparasitic). Many of these compounds are referred to as polypropionates, which are characterized by sequences of methyl- and hydroxy-bearing stereogenic centres, enabling large numbers of possible stereochemical permutations. The importance of these natural products as therapeutic agents and as biomedical tools together with their structural complexity has made these molecules attractive targets for synthetic organic chemists. However, most of the methods available in literature often require redox processes between iterative chain extension steps which increase the step count. Furthermore, assembly of the carbon chain by introducing one propionate unit at a time occasionally leads to difficulties in accessing certain stereoisomers due to matched/mis-matched effects caused by substrate bias.
We have considered an alternative approach in which small, stereodefined building blocks are coupled together using our lithiation-borylation methodology in a fully stereocontrolled manner. The development of such an approach, which was achieved in this action, has significant potential because it (i) allows the synthesis of any stereoisomeric polypropionate motif with fully predictable stereochemistry (ii) enables the synthesis of non-natural analogues which can display improved therapeutic profiles.
We have designed a stereotriad (three stereocentres) boronic ester building block bearing a masked-hydroxy silyl substituent that can serve as useful platform for the synthesis of an array of short chain polypropionate fragments. We synthesised the eight possible stereoisomers applying the same synthetic sequence (lithiation-silaboration followed by lithiation-borylation) and just changing the chiral ligand and both enantiomers of the corresponding starting material. The high level of reagent-control of stereochemistry provided by the lithiated-carbamates prevented any matched/mismatched effects and resulted in uniformly excellent diastereoselectivities. Coupling of the stereotriads with chiral lithiated carbamates using lithiation-borylation methodology leads to the creation of short chain polypropionate fragments after oxidation of the masked groups. For more details, see final report.
AM has developed a novel, versatile and efficient synthesis of short chain polypropionate fragments. This general method can be easily applied for the synthesis of polypropionate fragments present in many natural products. The versatility of this method allows modifying the relative and absolute configuration of the hydroxyl-bearing stereogenic centers with excellent stereocontrol. This fact will permit the synthesis of natural and also non-natural derivatives that can raise new or modulated biological activities. Its application in the pharmaceutical chemistry (industry) could reduce the time required for the development of new drugs with the consequential benefits on both society and the economy. Furthermore, following the Personal Career Development Plan, the fellow has acquired training, skills and knowledge that she will apply in her new position as junior researcher in Spain. In this sense, transfer of knowledge and network created over the MSCA will benefit her new host institution and colleagues.
Overview of the project. DG=directing group; pin=pinacolato; Si=PhMe2Si