APPLICATION OF THE PRINS CYCLIZATION TO A SYNTHESIS OF THE TETRAHYDROPYRAN RINGS OF LASONOLIDE A DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ruth Figueroa, M. S. ***** The Ohio State University 2004 Dissertation Committee: ABSTRACT This thesis describes studies toward the synthesis of the tetrahydropyran- containing marine macrolide lasonolide A. A summary of studies done by Lee and coworkers, that led to a revision of the structure as well as its first total synthesis is presented. This is followed by a literature review of the partial and completed syntheses of lasonolide A reported by other groups. The studies presented are based on the use of a Prins cyclization as the key reaction. The cyclization uses vinylogous carbonates as the source to generate the oxocarbenium ion. Therefore, we first introduce the background that led to the development of this reaction. The Prins cyclizations were promoted using trifluoroacetic acid and the products were immediately hydrolyzed to afford in most of the cases the tetrahydropyran rings as the major product. The cyclization of alkyne derived vinylogous carbonates resulted in instability of the product to the reaction conditions. Also, formation of 5-membered ring was a competing pathway. Vinlogous carbonates derived from Z-alkenes gave the all cis-2,3,4,6-tetrahydropyran in 59-70% yield. The E-alkene derived enol ethers gave the C3 epimeric tetrahydrofuran. Inversion of the secondary alcohol in the tetrahydropyran ring was partially accomplished using a Mitsunobu reaction. This methodology led to the racemic and asymmetric syntheis of the B ring of lasonolide A. The racemic synthesis was accomplished in 8 steps from 3-buten- 1-ol. An asymmetric synthesis was also accomplished in 12 steps from (R)-malic acid. The quaternary stereogenic center of the A ring of lasonolide A was constructed via C-H insertion reaction using Doyle’s catalyst (Rh2(4R-MEOX)4). ii Dedicated to my family iii ACKNOWLEDGMENTS I wish to thank Dr. David J. Hart, my adviser, for his intellectual support, encouragement and enthusiasm for the work that made this thesis possible. Also, for his patience in correcting my scientific errors. This gratitude is further extended to the members of the Hart group. I am very grateful of my family. To my parents: William Figueroa and Eminelia Ares because only with their love and emotional support I have been able to go through a very significant step in this long process of achieving my academic goals. To my sisters: Arelis, Merari, Eminelia, Willnelia and Rose Mary, and to my brother Samuel for their unconditional love and encouragement. Finally, I will like to thank the technician support staff at The Ohio State University. iv VITA August 22, 1976………………………….. Born-Humacao, Puerto Rico 2000………………………………………. M. S. Chemistry, The Ohio State University 1999-Present ………………………………Graduate Teaching and Reasearch Assistant The Ohio State University PUBLICATIONS Research Publications 1. M. Ortiz-Marciales, E. Gonzalez, M. De Jesus, S. Espinosa, J. Martinez, W. Correa, R. Figueroa, “Efficient Synthesis of B-Alkylated Oxazaborolidines Derived from Ephedrine and Norephedrine” Organic Lett. 5, 3447 (2003). 2. M. Ortiz-Marciales, L. M. Tirado, R. Colon, L. M. Ufret, R. Figueroa, M. Lebron, M. De Jesus; J. Martinez, T. Malave, "N-tert-Butyldimethylsilyl Imines as Intermediates for the Synthesis of Amines and Ketones." Synth. Comm. 28, 4067 (1998). FIELDS OF STUDY Major Field: Chemistry v TABLE OF CONTENTS Page Abstract……………………………………………………………………………………ii Dedication………………………………………………………………………………...iii Acknowledgments………………………………………………………………………..iv Vita………………………………………………………………………………………..v List of Schemes…………………………………………………………………………viii List of Tables……………………………………………………………………………xiii List of Figures………………………………………………………………………….. xiv List of Abbreviations ...................................................................................................... xvi Chapters: 1. Lasonolide A: Isolation, biological activity and structure.......................................1 1.1 Introduction.......................................................................................................1 1.2 Structure description .........................................................................................2 1.3 Lasonolide A: Structure revision and first total synthesis ................................4 2. Review of previous (-) and (+) lasonolide A syntheses.........................................15 2.1 Lee’s synthesis of (-) and (+) lasonolide A.....................................................15 2.2 Kang’s synthesis of (+)-lasonolide A .............................................................20 2.3 Hart-Patterson-Unch formal synthesis of (+)-lasonolide A............................27 2.4 Partial syntheses of lasonolide A ....................................................................32 3. Background: The Prins cyclization reaction...........................................................35 vi 3.1 The Prins cyclization reaction.........................................................................35 3.2 Enol ethers to generate the oxonium ion in the Prins cyclization...................37 3.3 Bennett’s elaboration of the Fráter-Nussbaumer variation of the Prins cyclization.......................................................................................................40 4. Studies toward the synthesis of the A and B rings of lasonolide A........................52 4.1 Alkynes as the π-component in the Prins cyclization.....................................52 4.2 Prins cyclization with alkenes as the π-component of the Prins cyclization ..57 4.3 Studies toward inversion of the C9 stereogenic center...................................66 4.4 Studies toward a substituent other than methyl at the C10 position...............74 4.5 Studies toward elaboration of the C7 side chain of the A and B rings ...........80 4.6 Studies toward correction of the C9 relative stereochemistry in tetrahydropyran 321...............................................................................................87 4.7 Studies toward C-H insertion to construct the C22 quaternary center..........109 4.8 Preliminary studies in a new approach for the synthesis of the B ring.........123 4.9 Conclusion ....................................................................................................129 5. Experimental Section...........................................................................................131 List of references..............................................................................................................221 vii LIST OF SCHEMES Scheme Page 1.1 Lee’s retrosynthesis analysis of structure 1 .............................................................5 1.2 Lee’s synthesis of the A ring ...................................................................................7 1.3 Lee’s synthesis of the B ring....................................................................................8 1.4 Lee’s elaboration of B ring ......................................................................................9 1.5 Lee’s final steps for the synthesis of lasonolide A (1).......................................... 10 1.6 Lee’s synthesis of the branched chain of lasonolide A..........................................11 1.7 Some of the lasonolide A isomers synthesized by Lee and coworkers .................13 2.1 Lee’s preparation of A-ring carbon chains ............................................................17 2.2 Lee’s final steps in the total synthesis of (-)-lasonolide A (58).............................18 2.3 Lee’s elaboration of the branched chain of (-)-lasonolide A .................................19 2.4 Kang’s retrosynthesis analysis of (+)-lasonolide A (ent-58)................................ 21 2.5 Kang’s synthesis of the A-ring ..............................................................................23 2.6 Kang’s elaboration of the side chain of the A-ring................................................24 2.7 Kang’s synthesis of the B-ring...............................................................................25 2.8 Kang’s final steps for the synthesis of (+)-lasonolide A .......................................26 2.9 Key cyclization reaction for the construction of the A and B rings.......................27 2.10 Hart-Patterson synthesis of the A-ring...................................................................29 2.11 Hart-Unch synthesis of the B-ring .........................................................................31 viii 2.12 Gurjar’s cyclopropane sugar derivatives for the preparation of the A and B rings of lasonolide A (1)............................................................................. 32 2.13 Hoffman approach to the preparation of the A and B rings of lasonolide A (1) .. 33 2.14 Some of Shishido’s key intermediates for the preparation of the B-ring ..............34 3.1 The Prins cyclization..............................................................................................36 3.2 Fráter’s synthesis of (±)-(cis-6-methyltetrahydropyran-2-yl)acetic acid (177) and (±)-cis-α-irone (181) via Prins cyclization............................................38 3.3 Kozmin’s variation of the Prins cyclization...........................................................39 3.4 Vinylogous carbonates as the source for the oxocarbenium