Copyright by Kenneth Stanley Matthews 2005 The Dissertation Committee for Kenneth Stanley Matthews Certifies that this is the approved version of the following dissertation: THE TOTAL SYNTHESIS OF (±)-RENIERAMYCIN G AND STUDIES TOWARD THE SYNTHESIS OF (±)-LEMONOMYCIN AND (±)-SAFRAMYCIN B Committee: Philip D. Magnus Stephen F. Martin Eric V. Anslyn Sean M. Kerwin Hung-wen Liu THE TOTAL SYNTHESIS OF (±)-RENIERAMYCIN G AND STUDIES TOWARD THE SYNTHESIS OF (±)-LEMONOMYCIN AND (±)-SAFRAMYCIN B by Kenneth Stanley Matthews, B.S. Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin August, 2005 Dedication To my father, mother, and brother, for all your love and support. Acknowledgements Ms. Robin Spalty: you got the ball rolling and I am forever grateful that you taught chemistry long enough to teach its wonders. Dr. Christopher Creighton: thank you for giving me a chance, getting me into organic chemistry, and all the advice that has taken me so far. Dr. Jamie Reuter: your patience and generosity were exactly what I needed, and your passionate management style still can not be beat. Dr. Konrad Fiechtinger: you taught me so much chemistry I could not begin to thank you. You are a great boss and an inspiring chemist. Prof. Murray Goodman: you let me in your group with so little experience and I will forever thank you for giving me that first chance. Dr. Gary Snyder: the only organic chemistry teacher that was clear, concise, and thorough. Thank you for giving the best foundation to be a researcher. Prof. John C. Wheeler: your excitement for chemistry and demand of students helped me focus and achieve far above my own expectations. Dr. Luca Araldi: your training has allowed me to understand so much of the chemistry process and your patience and happy spirit were the best to work with. Dr. Jean Cui: your drive to do great things is unmatched. I am very grateful to have learned not only chemistry from you but how to work in the midst of circumstance. v Dr. Odile Levy: a truly great boss, you were so very keen on keeping me focused, and your leadership showed me how it all gets done. Dr. Scott Kemp: I can not thank you enough for teaching me the ways of the Jedi. Without your insight and vigilant teaching I would have been lost in graduate school. Mr. Maxwell Lawrence: you gave me so much advice on how to be successful in chemistry and taught me the essential lesson of doing it right the first time. Dr. Jennifer Kreisburg: you helped me get into a great research group and gave me great advice throughout graduate school. I am very grateful. Prof. Cyril Olivier: I owe you for all the helpful discussions and advice. Your knowledge and passion for chemistry were an inspiration. Dr. Trevor Rainey: anyone who can stand five years sitting next to me deserves praise, and thank you for the countless discussions and sharing your knowledge. Dr. Rachel Turnbull: thank you for all your writing advice and time editing. I would have been lost without it. Mr. Vincent Lynch: your skills as an X-ray crystallographer saved the day many a time, and I thank you for all the helpful discussions. Mr. Steve Sorey and Dr. Ben Shoulders: thank you for the countless discussions about NMR interpretation and for dealing with my nagging. Prof. Philip D. Magnus: you gave me a chance in your group and a wonderful project. I enjoyed all the guidance and support that you have provided. vi THE TOTAL SYNTHESIS OF (±)-RENIERAMYCIN G AND STUDIES TOWARD THE SYNTHESIS OF (±)-LEMONOMYCIN AND (±)-SAFRAMYCIN B Publication No._____________ Kenneth Stanley Matthews, Ph.D. The University of Texas at Austin, 2005 Supervisor: Philip Douglas Magnus Herein is described our synthetic approach to the tetrahydroisoquinoline alkaloids. The first chapter describes relevant background related to the biological significance of these alkaloids. The analysis of various syntheses of saframycins, renieramycins, and lemonomycin is also discussed. Chapter 2 describes the development of a new synthesis of 1,3-cis-substituted tetrahydroisoquinolines and a novel lactam formation in our approach to (±)-saframycin B. Chapter 3 applies the new tetrahydroisoquinoline formation toward the synthesis of (±)-lemonomycin. The bicyclo[3.2.1] system is constructed from an intramolecular N-acyliminium cyclization and leads to the synthesis (±)-lemonomycinone amide. Chapter 4 reports the total synthesis of (±)-renieramycin G from an advanced intermediate used in our approach to (±)-lemonomycin, demonstrating a divergent approach to the tetrahydroisoquinoline alkaloids. Chapter 5 contains the experimental details and characterization data for all new reported compounds. vii Table of Contents Chapter 1: Tetrahydroisoquinoline Alkaloids..........................................................1 1.0. Introduction ................................................................................................1 1.1. Biological Activity.....................................................................................4 1.2. Mechanism of Action .................................................................................5 1.3. Biosynthesis................................................................................................7 1.4. Synthetic Approaches to Tetrahydroisoquinoline Alkaloids......................9 1.4.1. The Saframycins..............................................................................10 1.4.1.1. Fukuyama’s Total Synthesis of (±)-Saframycin B.................10 1.4.1.2. Kubo’s Total Synthesis of (±)-Saframycin B.........................13 1.4.1.3. Fukuyama’s Total Synthesis of (±)-Saframycin A.................15 1.4.1.4. William’s Studies Toward the Saframycins...........................17 1.4.1.5. Corey’s Enantioselective Synthesis of (–)-Saframycin A......19 1.4.2. The Renieramycins..........................................................................21 1.4.2.1. Fukuyama’s Synthesis of (±)-Renieramycin A ......................21 1.4.2.2. Danishefsky’s Synthesis of Cribrostatin IV ...........................23 1.4.3. Lemonomycin..................................................................................28 1.4.3.1. Stoltz’s Synthesis of (–)-Lemonomycin.................................28 1.4.3.2. Fukuyama’s Studies Toward (–)-Lemonomycin....................31 1.5. Retrosynthetic Analysis ............................................................................35 1.6. Conclusion ................................................................................................37 1.7. References ................................................................................................38 Chapter 2: Toward the Synthesis of Saframycins B ..............................................42 2.0. Introduction ..............................................................................................42 2.1. Background: Enantioselective Alkylation of Isoquinolines.....................43 2.2. Results and Discussion.............................................................................51 2.2.1. Investigation of the Enantioselective Alkylation of Isoquionline ...51 2.2.2. Formation of 1,3-cis-Substituted Tetrahydroisoquinoline ..............55 2.2.3. 3-(Aminomethyl)-Isoquinoline .......................................................59 viii 2.2.4. Oxygen Analogue............................................................................67 2.2.5. Nitrogen Analogue for Pummerer Cyclization ...............................72 2.2.6. Formation of the Real System.........................................................76 2.2.7. Alkylation, Reduction, and Cyclization of the Real System...........80 2.3. Conclusion ................................................................................................85 2.4. References ................................................................................................87 Chapter 3: Toward the Synthesis of Lemonomycin ..............................................89 3.0. Introduction ..............................................................................................89 3.1. Results and Discussion.............................................................................91 3.1.1. Alkylation with Benzyloxymethyllithium.......................................91 3.1.2. Formation 1,3-cis-Substituted Tetrahydroisoquinoline...................97 3.1.3. Amide Coupling............................................................................103 3.1.4. Stereoselective Incorporation of C14-C15 ....................................107 3.1.5. Formation of the Bicyclo[3.2.1] System .......................................117 3.2. Conclusion ..............................................................................................123 3.3. References ..............................................................................................125 Chapter 4: The Total Synthesis of (±)-Renieramycin G......................................126 4.0. Introduction ............................................................................................126 4.1. Results and Discussion...........................................................................128 4.1.1. Benzyl Chloride Formation...........................................................128 4.1.2. Formation the Bicyclo[3.3.1] System............................................131 4.1.3. Completion of the Synthesis..........................................................137