Stereoselective Synthesis of Spirooxindole Amides and Cyanohydrin Alkyl Ethers by Chunliang Lu B.S., China University of Mining and Technology, Xuzhou, China, 2004 M.S., Dalian University of Technology, Dalian, China, 2007 Submitted to the Graduate Faculty of the Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2013 UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Chunliang Lu It was defended on October 1, 2013 and approved by Dr. Kay M. Brummond, Professor, Department of Chemistry Dr. Theodore Cohen, Professor, Department of Chemistry Dr. Xiang-Qun Xie, Professor, Department of Pharmaceutical Sciences Dissertation Advisor: Dr. Paul E. Floreancig, Professor, Department of Chemistry ii Copyright © by Chunliang Lu 2013 iii Stereoselective Synthesis of Spirooxindole Amides and Cyanohydrin Alkyl Ethers Chunliang Lu, PhD University of Pittsburgh, 2013 A new family of spirooxindole amides were synthesized by a sequence of hydrozirconation, acylation, and intramolecular cyclization reactions. Three of the four possible diastereomers can be obtained as the major isomers through this process. The spirooxindole structure has many points for diversification, and a 37-membered library was synthesized through this approach by collaborators. A comparison with known compound collections showed that this new spirooxindole library possessed good chemical diversity. Cyanohydrin alkyl ethers, the key intermediate in the above multi-component hydrozironation reaction, were effectively synthesized through a Brønsted acid-mediated hydrocyanation of vinyl ethers. The enantiomerically enriched product can be obtained by asymmetric hydrocyanation of vinyl ethers catalyzed by a chiral Brønsted acid, and the catalyst can be regenerated by PhOH. As far as we know, this research represents the first example of chiral Brønsted acid mediated intermolecular addition of silylated nucleophiles with vinyl ethers. The ion pair interaction between the conjugate base of the chiral Brønsted acid and the oxocarbenium ion was revealed by computational modeling, which explained the origin of the enantioselectivity and the substrate scope of this reaction. iv TABLE OF CONTENTS PREFACE .................................................................................................................................... XI 1.0 STEREOSELECTIVE SYNTHESIS OF SPIROOXINDOLE AMIDES THROUGH NITRILE HYDROZIRCONATION ..................................................................... 1 1.1 INTRODUCTION ............................................................................................... 1 1.2 MULTICOMPONENT AMIDE SYNTHESIS THROUGH NITRILE HYDROZIRCONATION .................................................................................................... 2 1.2.1 Previous work on amides formation from nitrile hydrozirconation ........... 3 1.2.2 Previous work on spirooxindole synthesis through nitrile hydrozirconation .......................................................................................................... 6 1.3 SPIROOXINDOLE SYNTHESIS THROUGH NITRILE HYDROZIRCONATION .................................................................................................... 8 1.3.1 Substrate Synthesis ........................................................................................ 10 1.3.2 Spirooxindole formation from acyclic indole substrates............................ 13 1.3.3 Further structure modification of the spirooxindole products ................. 19 1.3.4 Construction of a spirooxindole amide library ........................................... 20 1.4 CONCLUSIONS ................................................................................................ 23 2.0 STEREOCONTROLLED CYANOHYDRIN ETHER SYNTHESIS THROUGH CHIRAL BRØNSTED ACID-MEDIATED VINYL ETHER HYDROCYANATION........ 24 v 2.1 INTRODUCTION ............................................................................................. 24 2.2 SYNTHESIS OF ACHIRAL CYANOHYDRIN ALKYL EHTER THROUGH CYANATION OF ENOL ETHER .............................................................. 25 2.3 ASYMMETRIC CYANOHYDRIN ALKYL ETHER SYNTHESIS MEDIATED BY CHIRAL BRØNSTED ACID .............................................................. 30 2.3.1 Chiral Brønsted acid mediated cyanation of α-chloro ethers .................... 30 2.3.2 Chiral Brønsted acid catalyzed hydrocyanation of vinyl ethers ............... 31 2.3.3 Computational studies ................................................................................... 45 2.4 CONCLUSIONS ................................................................................................ 48 APPENDIX A .............................................................................................................................. 50 APPENDIX B .............................................................................................................................. 87 APPENDIX C ............................................................................................................................ 125 BIBLIOGRAPHY ..................................................................................................................... 133 vi LIST OF TABLES Table 1.1 Acid chloride scope for spirooxindole synthesisa ......................................................... 15 Table 1.2 Cyclization with N-methoxymethylindolesa ................................................................. 16 Table 1.3 Cyclizations with silyloxyindole substratesa ................................................................ 19 Table 2.1 Scope of the enol ether hydrocyanation reaction .......................................................... 29 Table 2.2 Catalyst screening ......................................................................................................... 36 Table 2.3 Condition optimizationa ................................................................................................ 39 Table 2.4 Substrate scope for the asymmetric reactiona ............................................................... 41 Table S3.1 Spirooxindole library and the related biological activity ......................................... 126 vii LIST OF FIGURES Figure 1.1 Structures of important spirooxdindoles ....................................................................... 1 Figure 1.2 Pederin, psymberin and their analogs ............................................................................ 5 Figure 1.3 Design of the substrate .................................................................................................. 9 Figure 1.4 Structure determination for diastereomers 1.52 and 1.53 ............................................ 14 Figure 1.5 Structure determination for 1.61' ................................................................................. 17 Figure 1.6 X-ray structure of 1.84 ................................................................................................ 22 Figure 2.1 Modeled structure of the ion pair from the reaction of ethyl vinyl ether with catalyst 2.26................................................................................................................................................ 47 Figure 2.2 Modeled structures of the ion pairs derived from 2.79 (B) and 2.16 (C) with catalyst 2.26................................................................................................................................................ 48 Figure S2.1 HPLC tracer of 2.4 .................................................................................................. 113 Figure S2.2 HPLC tracer of 2.68 ................................................................................................ 114 Figure S2.3 HPLC tracer of 2.9 .................................................................................................. 115 Figure S2.4 HPLC tracer of 2.70 ................................................................................................ 116 Figure S2.5 HPLC tracer of the derivative of 2.72 ..................................................................... 117 Figure S2.6 HPLC tracer of 2.25 ................................................................................................ 118 Figure S2.7 HPLC tracer of the derivative of 2.15 ..................................................................... 119 Figure S2.8 HPLC tracer of 2.74 ................................................................................................ 120 viii Figure S2.9 HPLC tracer of 2.77 ................................................................................................ 121 Figure S2.10 HPLC tracer of 2.19 .............................................................................................. 122 Figure S2.11 HPLC tracer of 2.80 .............................................................................................. 124 ix LIST OF SCHEMES Scheme 1.1 Diverse amides formation through nitrile hydrozirconation ....................................... 2 Scheme 1.2 Previous work on amides formation through nitrile hydrozirconation ....................... 4 Scheme 1.3 Synthesis of alkoxy carbamate 1.15 ............................................................................ 6 Scheme 1.4 Previous work on spirooxindole synthesis through nitrile hydrozirconation .............. 7 Scheme 1.5 Horne’s spirooxindole synthesis