Synthesis of aminopolyol-derived structures to target master switches in regulating morphogen signalling

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


Libraries of structurally diverse aminopolyols will be synthesised to target cell surface, transmembrane, receptors involved in morphogen signalling. These libraries will be based on natural product scaffolds such as steroids, alkaloid hormones and sphingolipids, and include non-natural analogues such as deoxyamino, deoxyfluoro and truncated derivatives, as well as their stereoisomers. Latestage diversification will be key to this strategy. The key methodology employed will encompass asymmetric conjugate additions and stereospecific rearrangement processes for the introduction and repositioning of functionality within these molecular scaffolds. The synthesised libraries will be screened and optimised for activity targeted at the master switches in regulating morphogen signalling. The initial target for the project will be the preparation of stereodefined 2,6-disubstituted-piperidin-3-ol scaffolds, as found in a number of natural products. For example, conjugate addition of enantiopure lithium N-benzyl-(N-a-methylbenzyl)amide to tert-butyl crotonate followed by in situ enolate oxidation using (camphorsulfonyl)oxaziridine will give the corresponding anti-a-hydroxy-b-amino ester with very high levels of diastereocontrol and as a single enantiomer. Elaboration of this species via initial protection of the a-hydroxy group followed by conversion of the ester functionality to the corresponding aldehyde group, either directly using DIBAL-H or in a two-step process via the intermediacy of the corresponding primary alcohol (i.e., use of lithium aluminium hydride and then re-oxidation using a Swern protocol or iodoxybenzoic acid, for example) will then allow a Wittig-type olefination with the ylide ethyl 2-oxo-3-(triphenyl-l5-phosphaneylidene)propanoate (easily derived from the reaction of ethyl a-bromopyruvate with triphenylphosphine followed by treatment with a base such as aqueous potassium hydroxide) will set the stage for the key ring-closing step. This will involve tandem hydrogenolysis of the e-amino ketone (i.e., removal of both the N-benzyl and N-a-methylbenzyl) protecting groups and simultaneous hydrogenation of the carbon-carbon double bond to permit and intramolecular imine formation which will, in turn, be followed by in situ reduction to give the functionalised piperidine core. The C(6)-ester functionality will act as a synthetic handle to allow the introduction of a diverse range of substituents to the piperidine core and for example this may be elaborated via olefination to access alkaloids of the microgrewiapine family. This project falls within the EPSRC Physical sciences research area.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512333/1 01/10/2017 30/09/2021
1950373 Studentship EP/R512333/1 01/10/2017 31/03/2021 Cameron Edward Taylor
Description My work has involved the synthesis of the whole family of piperidine natural products, and in-depth analysis of the optical rotation and thus absolute stereochemistry of the natural products.
This synthetic work validates some of the currently reported structures of piperidines, and has corrected several errors in the reported natural product data.1,2 It is fascinating that both the synthetic piperidines and natural product extracts are not homochiral, certainly warranting further investigation into their biosynthetic origins.
Exploitation Route further investigation into their biosynthetic origins.
Sectors Agriculture, Food and Drink,Chemicals,Environment,Pharmaceuticals and Medical Biotechnology