The Development of Titanium-Catalyzed Enyne Cyclocarbonylations and Related Methodologies by Frederick A. Hicks B.S. Chemistry, University of Central Florida, 1993 Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology February 1999 © Massachusetts Institute of Technology, 1998 All Rights Reserved Signature of the Author Department of Chemistry September 10, 1998 Stephen L. Buchwald Thesis Supervisor Accepted by Dietmar Seyferth Chair, Departmental Committee on Graduate Studies MASSACHUSETTS INSTITUTE LIBRARIES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Gregory C. Fu Chairperson Professor Stephen L. Buchwald I- -- Thesis Supervisor Professor Peter H. Seeberger 2 The Development of Titanium-Catalyzed Enyne Cyclocarbonylations and Related Methodologies by Frederick A. Hicks Submitted to the Department of Chemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology ABSTRACT An improved titanium-catalyzed procedure for the synthesis of bicyclic iminocyclopentenes from the cyclocondensation of enynes and silylcyanides is described. The use of finely ground air- and moisture-stable Cp 2TiCI 2 in combination with n-BuLi and enynes allows for the in situ generation of titanacyclopentenes, which serve as precatalysts for the silylimine synthesis. This methodology represents a practical advance compared to the previously reported methodology employing Cp 2Ti(PMe 3)2. The silylimines can be hydrolyzed to the corresponding cyclopentenones utilizing established procedures. A protocol for reduction and acylation of the silylimine products has also been developed which provides allylic amides in good to excellent yields. A titanocene-catalyzed cyclocarbonylative route to bicyclic cyclopentenones employing commercially available Cp 2Ti(CO) 2, enynes, and CO is described. The synthetic scope of this protocol has been explored in detail with a variety of 1,6- and 1,7-enynes. Initial studies support a mechanism involving the carbonylation of a titanacyclopentene followed by reductive elimination to provide the enone product and regenerate the titanium catalyst. The first catalytic asymmetric Pauson-Khand type reaction is described. The catalyst, (S,S)-(EBTHI)Ti(CO) 2, is generated in situ from (S,S)-(EBTHI)TiMe 2 under a CO atmosphere. A variety of 1,6-enynes are converted to the corresponding bicyclic cyclopentenones with excellent enantioselectivity (87-96 % ee). The scope and limitations of this methology with respect to enyne substitution are discussed. The assignment of the absolute configuration for the enone products and a rationale for the observed absolute configuration and levels of asymmetric induction are presented. Thesis Supervisor: Professor Stephen L. Buchwald Title: Camille Dreyfus Professor of Chemistry 3 Acknowledgments I will certainly omit some people who deserve my gratitude for their assistance and support during my five years in the Buchwald group; everyone who I have had the pleasure of interacting with during my stay in Boston has contributed to this document in some way, and I am thankful to all of you. There are three men who are most responsible for my becoming a chemist, and they warrant special recognition. My grandfather, a chemistry professor, John Mariani, my high school chemistry teacher, and Dr. John Gupton, my undergraduate research advisor. Each of them showed a joy and a passion for teaching chemistry which were infectious to all who met them. Most people soon recovered from the disease, but I was too far gone to do to anything else. There have been three people with whom I have collaborated closely during my time in this group. I have learned an enormous amount about many different aspects of chemistry during my five years in the Buchwald lab, and for that I am indebted to my advisor Steve. He has given me the freedom to explore chemistry while providing guidance and support at the times when I needed it. Natasha Kablaoui not only developed chemistry upon which the majority of this thesis is based, she also rolled up her sleeves and helped me get the work in Chapter 2 off the ground. I am not sure what this thesis would look like without her influence, both as a scientist and a friend, but I owe much of its present state to her. I have also had the pleasure of introducing Shana Sturla to the joys of Group 4 chemistry. Her enthusiasm for research and general good spirits have certainly helped me at times when I myself was short on those qualities. The lab experience depends greatly on the rapport one develops with their baymate, and I have been blessed in this regard. In the beginning, Scott Berk and Mary Beth Carter were extremely patient and understanding as they helped me develop the tools and techniques I needed for research. Though we only shared a bay for one summer, I have found a good friend in Linda Molnar. From Kazumasa Aoki, I learned to handle the vicissitudes of research with the simple maxim "Shit Happens." Last and certainly not least, I have had the pleasure of working with Marcus Hansen. His friendship and support during the past few years at MIT have made all the difference. The extended network of friends that develops in graduate school is one of its greater rewards; everyone needs someone to chat with over a coffee or a beer. 4 Though I have already thanked some of them, Natasha Kablaoui, Marcus Hansen, Malisa Troutman, Seble Wagaw, Nora Radu, Jens Ahman, Shana Sturla and Dave Old all have shared more than a few beverages with me over the years, and hopefully there will be many more in the future. Throughout this process, one turns to their family for the support, encouragement, and unquestioning faith that only they can provide. My family, my wife's family, and two friends, Jeff Gibbs and Denise Main, who are family, have all helped me in ways they will never know. Finally, I want to thank my wife Jessica, without whom all of this means nothing. It has been rough at times, but she has held my hand and stood by my side throughout, and I promise to do the same for her forever. 5 Preface Parts of this thesis have been adapted from the following articles co-written by the author: Hicks, F. A.; Berk, S. C.; Buchwald, S. L. "A Practical Titanium-Catalyzed Synthesis of Bicyclic Cyclopentenones and Allylic Amines" J. Org. Chem. 1996, 61, 2713. Hicks, F. A.; Kablaoui, N. M.; Buchwald, S. L. "Titanocene-Catalyzed Cyclocarbonylation of Enynes to Cyclopentenones" J. Am. Chem. Soc. 1996, 118, 9450. Hicks, F. A.; Buchwald, S. L. "Highly Enantioselective Catalytic Pauson-Khand Type Formation of Bicyclic Cyclopentenones" J. Am. Chem. Soc. 1996, 118, 11688. 6 Table of Contents Introduction 9 Chapter 1. The Development of a Practical Titanium-Catalyzed Synthesis of Bicyclic Cyclopentenones and Allylic Amines 17 Introduction 18 Results and Discussion 21 Experimental Procedures 29 References 38 Chapter 2. The Intramolecular Titanocene-Catalyzed Pauson-Khand Type Reaction 42 Introduction 43 Results and Discussion 47 Experimental Procedures 69 References 93 Chapter 3. A Titanium-Catalyzed Asymmetric Pauson-Khand Type Reaction 97 Introduction 98 Results and Discussion 102 7 Experimental Procedures 113 References 122 Appendix A. Synthetic Procedures and Characterization Data for Novel Substrates not Prepared by the Author 127 Appendix B. X-ray Crystallographic Data for the Enone from Chapter 1, Table 1, Entry 5 132 8 Introduction In the field of organic chemistry, the search for new and more efficient methods of carbon-carbon bond formation for application in complex molecule total synthesis continues to be a major theme. Recently, an important area of investigation towards this end has involved transition metal-mediated cycloaddition reactions. This work has allowed for the combination of unsaturated functional groups in ways which are either difficult or impossible without the action of a transition metal complex. Examples of this approach include the intramolecular Diels-Alderi and Alder-Ene 2 cyclization of unactivated substrates, the homo-Diels-Alder reaction, 3 [2 + 2 + 2] alkyne cyclotrimerization,4 intramolecular triene-ene cyclization5, [5 +2] cyclopropyl enyne and diene 6 and [4 + 4] 1,3-diene cycloadditions.7 The possibility also exists for Figure 1 H HH H HM M HH M M HO"Cf H O O 0 Me estrone, [2+2+2] (+)-asteriscanolide, [4+4] (-)-sterepolide, enyne cycloisomerization M N N HH o H" Me (±)-yohimban, [4 + 2] (+)-Isoiridomyrmecin, triene-ene cyclization asymmetric induction with the use of chiral ligands. A number of excellent reviews on the progress in this field have been published recently.8 The proof of the utility of these methodologies lies in their elegant applications to total synthesis; select 9 examples are shown in Fig 1.9 An interesting subset of the aforementioned cycloaddition reactions is cyclocarbonylation, which involves the incorporation of one or more molecules of CO and leads to more highly functionalized products. Some of these reactions involve the opening of strained rings with subsequent ring expansion by insertion of an attached functional group and CO. Cyclopropenes substituted with aryl rings, alkenes or esters provide napthols, 10 phenols and x-pyrones1 1 upon treatment with the appropriate Ac H h Co2(CO)8 Ph (3) P Ph then Me H Cr(CO)6 PhP Ac2 0, NEt3 OAc P><P & Ph P P IrC1(CO)(PPh 3) M ' M (4) Ee Me 5 atm CO M ( Et (2) Me 0 Et H Y OEt M e-- Me OEt Me Me Fe(CO) 5 or [RhCI(CO)2] Et 1 atm CO Et H Ph PM Ph [Rh(cod)2]PF6 Ph E& Ph me N___Me--' (6) Me dppe, 1 atm CO Me 0 Ru 3 (CO) 12, PCy3 E rSitBuMe2 C -7 (7) HSit-BuMe , 50 2 atm CO E 'c]( OSitBuMe 2 E = CO 2Et metal complexes (eq 1 and 2).