Asymmetric Syntheses and Applications of Propargylic Alcohols and Amines Jun Ying Fenghua, Zhejiang, China B.S. Pharmacy East China University of Science and Technology, 2011 A Dissertation presented to the Graduate Faculty of the University of Virginia in Candidacy for the Degree of Doctor of Philosophy Department of Chemistry University of Virginia August, 2016 i Abstract Asymmetric Syntheses and Applications of Propargylic Alcohols and Amines Chiral propargylic alcohols and amines are important building blocks for the synthesis of numerous pharmaceuticals, biologically active compounds and natural products. A number of catalytic systems have been reported for the highly enantioselective alkynylation of aldehydes and imines to access chiral propargylic alcohols and amines. Using the chiral propargylic alcohols prepared from the asymmetric alkyne i addition to aldehydes catalyzed by the BINOL-Ti(O Pr)4-Et2Zn-Cy2NH catalyst system, we have prepared a series of chiral propargylic triene-ynes with high enantiomeric purity (up to 92% ee). We have found that these compounds can undergo an efficient one-pot Rh(I)-catalyzed domino PK/DA cycloaddition to generate the multicyclic products with high chemoselectivity and stereoselectivity (up to 94% ee). These products contain the core structure of mangicol A, a natural product possessing significant anti-inflammatory activity. A series of chiral propargyl 2,4-hexadienyl ethers are also found to undergo a highly chemo- and stereoselective PK/DA cycloaddition to generate the tetracyclic products (up to 88% ee). This strategy is very efficient for the asymmetric synthesis of polycyclic compounds such as polyquinanes. A 3,3’-di(1-diphenylmethylpiperazinyl)methyl H8BINOL compound has been developed to catalyze the asymmetric reaction of both alkyl and aryl alkynes with ii i N-(diphenylphosphinoyl)imines in the presence of Et2Zn and Ti(O Pr)4. It exhibits unprecedented high enantioselectivity (up to 85% ee) for the alkyl alkyne addition to the N-(diphenylphosphinoyl)imines. A Au(III)-catalyzed regiospecific hydration of N-(diphenylphosphinoyl) propargylic amines has been developed to produce various β-amino ketones under mild conditions. The high enantiomeric purity of a chiral N-(diphenylphosphinoyl) propargylic amine (85% ee) is maintained after the hydration which makes method useful for the asymmetric synthesis of chiral β-amino ketones. iii Acknowledgements I would like to thank Prof. Pu for providing me the opportunity to pursue my graduate studies. I greatly appreciate his guidance and training during my graduate career. I would also like to thank Prof. Gunnoe, Prof. Harman and Prof. McGarvey for serving on my committee. I greatly appreciate all that they taught me in and out of class. I especially appreciate Prof. Wu’s willingness to serve as the outside member of my committee. I also am thankful for my labmates and friends who have helped me a lot, especially Wei Chen, Shanshan Yu, Chao Wang, Shifeng Nian, Xuedan Wu and Gengyu Du. I am grateful for my family for supporting me and praying for me during my graduate career. I could not have made it through without their endless love, encouragement, trust and support. iv Table of Contents Abstract............................................................................................................................................ i Acknowledgements........................................................................................................................ iii Table of Contents............................................................................................................................iv List of Figures.................................................................................................................................vi List of Schemes ............................................................................................................................ viii List of Tables.................................................................................................................................xvi Chapter 1. Introduction to Asymmetric Syntheses and Applications of Propargylic Alcohols and Amines.......................................................................................................................................1 1.1 Introduction.........................................................................................................................1 1.2 Asymmetric alkynylzinc addition to aldehydes...................................................................3 1.2.1 Nitrogen–containing ligands ....................................................................................5 1.2.2. BINOL/ H8BINOL ligands....................................................................................14 1.2.3. BINOL-based derivatives......................................................................................19 1.2.4. Summary ...............................................................................................................22 1.3. Application of chiral propargylic alcohols .......................................................................23 1.3.1 Diverse transformations of chiral propargylic alcohols..........................................23 1.3.2 Application in total synthesis .................................................................................27 1.3.3 Summary ................................................................................................................30 1.4 Asymmetric alkyne addition to imines..............................................................................31 1.4.1 Copper-based methods ...........................................................................................31 1.4.2 Zinc-based methods................................................................................................38 1.4.3 Other metals-based methods ..................................................................................41 1.4.4 Summary ................................................................................................................42 1.5. Application of chiral propargylic amines .........................................................................43 1.5.1 Diverse transformations of chiral propargylic amines............................................43 1.5.2 Application in total synthesis .................................................................................46 1.5.3 Summary ................................................................................................................49 References...............................................................................................................................50 Chapter 2. A Facile Asymmetric Approach to the Multicyclic Core Structure of Mangicol A .........................................................................................................................................................57 2.1 Introduction.......................................................................................................................57 2.1.1 Mangicols and neomangicols .................................................................................57 2.1.2. Biosynthesis of mangicols and neomangicols.......................................................58 2.1.3. Approaches to mangicols and neomangicols.........................................................60 2.1.4. Summary ...............................................................................................................68 2.2 Construction of the core structure of mangicol A .............................................................69 2.2.1 Preliminary investigation of PK/DA strategy.........................................................71 2.2.2 Asymmetric approach to the multicyclic core structure of mangicol A .................72 2.3. Further conversions of the pentacyclic compound 2.59...................................................84 2.4 Summary ...........................................................................................................................89 v Experimental and Characterization .........................................................................................91 References.............................................................................................................................116 Chapter 3. Rh(I)-Catalyzed Chemo- and Stereoselective Domino Cycloaddition of Optically Active Propargyl 2,4-Hexadienyl Ethers...................................................................................120 3.1 Introduction.....................................................................................................................120 3.1.1 Co-catalyzed Pauson-Khand-based domino reactions .........................................121 3.1.2 Rh-catalyzed Pauson-Khand-based domino reactions .........................................123 3.2 Rh(I)-catalyzed domino PK/DA cycloaddition of optically active propargyl 2,4-hexadienyl ethers ............................................................................................................125 3.2.1 Preparation of chiral propargylic alcohols by the catalytic asymmetric alkyne addition to aldehydes.....................................................................................................125 3.2.2 Preparation of the chiral propargylic ether-based dienediynes.............................127 3.2.3 Catalytic domino PK/DA cycloaddition of the chiral