Development Of A Spiroalkylation Method For The Stereoselective Construction Of Alpha Quaternary Carbons Its Application To The Total Synthesis Of R Puraquinoic Acid And Efforts Towards Hdac Hiv 1 Protease Hybrid Inhibitors

Author : Adam Elmehriki
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (125 download)

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Download or read book Development of a Spiroalkylation Method for the Stereoselective Construction of [alpha]-Quaternary Carbons, Its Application to the Total Synthesis of (R)-puraquinoic Acid, and Efforts Towards HDAC/HIV-1 Protease Hybrid Inhibitors written by Adam Elmehriki and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "[alpha]-Quaternary carbon stereocentres are a common yet challenging motif encountered in the synthesis of many organic molecules, ranging from natural products to molecules employed in medicinal chemistry endeavours. Herein, cyclic [alpha]-quaternary carbon stereocentres were prepared from biselectrophilic substrates and an easily prepared chiral bicyclic sulfonyl lactam. This was achieved in two steps by spiroalkylation, employing biphasic reaction conditions with a phase-transfer catalyst, followed by reduction and alkylation with a series of alkyl halide electrophiles. The products of this method were isolated in good yields with high levels of diastereoselectivity. Additionally, the methodology was employed in the enantioselective total synthesis of (R)-puraquinonic acid for a late-stage installation of the [alpha]-quaternary carbon stereocentre. This enabled the shortest total synthesis of (R)-puraquinonic acid to date, an eight-pot sequence providing an overall yield of 14%.Inspired by reports indicating that inhibition of histone deacetylase (HDAC) promotes reactivation of latent HIV reservoirs, a set of molecules were conceived and prepared which possessed both HDAC and HIV protease inhibitory activity. It was expected that such hybrid inhibitors could provide a means to clear HIV reservoirs by directly inhibiting viral protease function upon reactivation of latent HIV. The design of hybrid inhibitors was based on the known HDAC inhibitor vorinostat and the HIV-1 protease inhibitor darunavir. Initial biological testing proved that molecules of this design maintain their HDAC inhibitory function despite structural modifications made to incorporate HIV-1 protease inhibitory activity. Unfortunately, while the inhibitory activity against cytosolic HDAC6 of one hybrid inhibitor was comparable to the positive control (vorinostat) it was found to be over six-fold less potent against the desired nuclear target, HDAC3"--