Enantioselective Synthesis Of Bio-Active Bicyclic Acetals, Cyclic Ethers And Lactones

Abstract

The thesis entitled “Enantioselective synthesis of bio-active bicyclic acetals, cyclic ethers and lactones” demonstrates the utility of chiral pool tartaric acid as the source in the synthesis of natural products. The results are discussed in three chapters; 1) Enantioselective synthesis of bio-active bicyclic acetals, 2) Enantioselective synthesis of bio-active cyclic ethers and 3) Enantioselective synthesis of bio-active lactones. A brief introduction is provided in each chapter to keep the present work in proper perspective. Compounds (in bold) and references (in superscripts) are sequentially numbered differently for each chapter and references are given as foot notes. Experimental procedures are given differently for each chapter and placed at the end of chapter. Scanned 1H and 13C NMR spectras are given with description of signals. Chapter 1 describes the enantioselective synthesis of bicyclic acetal containing insect pheromones. First part of this chapter deals with the enantiodivergent synthesis of both enantiomers of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin starting from a single chiral compound, bis-Weinreb amide derived from L-(+)-tartaric acid. Controlled addition of Grignard reagent to bis-Weinreb amide followed by diastereoselective reduction of the resultant ketone was employed as the key step for the enantiodivergent synthesis of hydroxy-exo-brevicomin and 2-hydroxy-exo-brevicomin. In the second part, enantioselective synthesis of exo-brevicomin, iso-exo-brevicomin and formal synthesis of frontalin comprising similar framework is demonstrated, utilizing á -benzyloxy aldehydes derived from L-(+)-tartaric acid as chiral building block. Second Chapter describes the enantioselective synthesis of bio-active cyclic ethers, disparlure, centrolobine and isolaurepan. Employing á-benzyloxy aldehydes derived from L-(+)-tartaric acid as the chiral building block, synthesis of both enantiomers of insect pheromone disparlure is achieved involving the diastereoselective addition of allyltributyl tin to the á-benzyloxy aldehyde and cross metathesis of the resultant homoallylic alcohol with 4-methyl-1-pentene. Formal synthesis of centrolobine and isolaurepan are accomplished. Pivotal step involved in the synthesis of centrolobine is iron(III) mediated cyclization of 1,5-diol derived from L-(+)-tartaric acid, while Lewis acid mediated reductive cyclization of the hydroxy ketone derived from á-benzyloxy aldehyde is the key step in the synthesis of isolaurepan. Third chapter in the thesis deals with the enantioselective synthesis of bio-active lactones muricatacin, 6-acetoxy-5-hexadecanolide and boronolide. Utilizing á-benzyloxy aldehyde as the building block, synthesis of five and six membered lactones, muricatacin and 6-acetoxy-5-hexadecanolide were accomplished via the diastereoselective addition of 3-butenylmagnesium bromide and allyltributyl tin to á-benzyloxy aldehyde, respectively. Stereoselective formal synthesis of boronolide was described, starting from D-(–)-tartaric acid. Key reaction sequence includes the elaboration of ã-hydroxy amide obtained by a combination of controlled Grignard addition and diastereoselective reduction from bis- Weinreb amide derived from D-(–)-tartaric acid.