Novel Conjugate Additions and Cyclizations on Multiyne Systems

This thesis consists of seven chapters focusing on extended conjugation addition chemistry and different modes of cyclization to synthesize important and unique heterocycles including natural products and biomolecules. Chapter 1 provides a novel route for the synthesis of 4-pyrones with broader substrate scope and functional group tolerance. The strategy relies on an initial 1,4-addition of piperidine, followed by a nitrogen assisted 6-endo-dig cyclization and hydrolysis. Further studies with numerous propargylic and ketone substituents suggested that both steric and electronic factors have a strong impact on 4-pyrone synthesis. Chapter 2 describes a novel hydrogen-bonding directed sequential 1,6/1,4-addition reaction with electron-deficient 1,3-diynes that are conjugated with an electron-withdrawing group such as ketone, ester, or imide functionalities to synthesize unique heterocyclic molecules like THPs, furans and pyrroles. Alcohols, amines, and thiols show excellent reactivity for the initial intermolecular 1,6-addition whereas the hydrogen bonding elements such as –OH, –NHTs, and –NHBoc moieties at the propargylic position demonstrates excellent intramolecular 1,4-addition. Chapter 3 shows a novel cycloaddition reaction of acylketenes with relatively less polarized alkyne functionality. Two effective ring forming reactions are described with broader substrate scope and functional group tolerance. The first reaction involves an in-situ tethering strategy wherein acetyl ketene is activated by a nucleophile connected to the 1,3-diynone moiety. This tethering promotes a sequential 1,6-addition with a C-nucleophile followed by a 1,4-addition with an O-nucleophile to generate 2-methylene-2H-pyrans. In the second approach, a zwitterionic intermediate generated from acetyl ketene and DABCO undergoes a Michael addition with terminal alkynyl ketones, followed by ring closure to form 3-acyl-substituted 4-pyrones. Chapter 4 provides a novel concise approach for the synthesis of Rapicone, a funicone class natural product, via the cycloaddition reactions developed with acylketene and alkynes. The key strategy to form the ynone intermediate involves a novel Fe/TEMPO catalyzed ether oxidation reaction. The synthesis is completed in 7 steps with 9.4% overall yield. Chapter 5 describes a formal enyne ring-closing metathesis (RCM) and carbocyclization reactions of enol ethers and enamines under thermal and metal-catalyzed conditions to generate novel molecular scaffolds. These enol/thioenol ethers and enamines are generated in situ from 1,3-diynyl ketones via hydrogen bonding directed tandem 1,6/1,4-addition. The 1,6/14-adducts of alcohols and thiols selectively generate formal enyne RCM products, whereas the 1,6/1,4-adducts of amines yielded carbocyclization products. In Chapter 6 we have developed three novel oxy-cyclization reactions of strategically designed terminal, trimethylsilyl and internal acetylenes containing 1,6/1,4 adducts under thermal, TBAF and silver-catalyzed reaction conditions to generate various 1,3-dihydroisobenzofuran derivatives. In addition, these 1,3-dihydroisobenzofuran derivatives contain novel frameworks with conjugated ��-systems, which may show interesting properties of fluorophores. Chapter 7 includes syntheses of spirocyclic derivatives via conjugate addition reactions and different modes of cyclization reactions of 1,3-diynes with long chained alcohol chains, homopropargylic alcohols and ��-hydroxyketones.