The marine sponges (e.g. orderVerongida and most recently Suberea mollis) are widely known to produce a series of a-oximinotyrosine derived monomeric and dimeric spiroisoxazolines with a broad spectrum of pharmacological activities including antiviral,antimicrobial,anti-HIV,antifungal,antifouling,Na+/K+ ATPase inhibition,HDAC inhibition,and antineoplastic properties. The scant synthetic strategies along with frequently used most crucial oxidative step aroused our interest in developing novel synthetic strategy to this class of natural products. Our synthesis basically relies on two approaches, a non aromatic approach towards the spiro-diketone followed by multifunctionalization to furnish the desired molecular architecture resembling the natural product core. In doing so, the spiro-diketone was converted to its methoxyenone derivatives which were further converted to the corresponding spiro-diene and spiro-quinone derivatives via two different functional group transformation approaches. Although the first approach (LiHMDS, PhSeCl and then H2O2) successfully afforded the spiro-diene and spiro-quinone, a further bromination step was found to be abortive for the spiro-diene in contrast to spiro-quinone moiety. However, the second approach (LiHMDS and Br2) was found to be beneficial to expedite our synthetic plan. Under this reaction environment, the allylic geminal dibromo compound was formed and was treated with DABCO in situ to afford the mono bromo spiro-diene and spiro-quinone systems. Further bromination of adjacent to the carbonyl was achieved either by NBS-dark or by PTB reaction conditions. Finally, the diastereoselective reduction of spiro-ketone with Zn(BH4)2afforded the desired spiroisoxazoline core structures in a 4:1 diastereomeric ratio.  On the other hand the dibromo-quinone derivative could also be utilized to synthesize a series of quinine-based spiro-isoxazolines as novel analogues of biological interest. The project described was supported by NIH/NIGMS (Award Number: SC3GM094081-04) and the Analytical and NMR CORE Facilities were supported by NIH/NCRR (Award Number: G12RR013459) and NIH/NIMHD (Award Number: G12MD007581).

Model study for the concise synthesis of bromotyrosine derived spiroisoxazoline natural products and analogous core structures

247th National Meeting (2014)

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