A Dissertation entitled Applications of Ugi Four Component Cascade Coupling Reactions for the Synthesis of Bioactive Diverse Heterocyclic Molecules and Natural Products by Amarendar Reddy Maddirala Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry _________________________________________ Dr. Peter R. Andreana, Committee Chair _________________________________________ Dr. Joseph A. R. Schmidt, Committee Member _________________________________________ Dr. Jianglong Zhu, Committee Member _________________________________________ Dr. L. M. V. Tillekeratne, Committee Member _________________________________________ Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo May, 2016 Copyright 2016, Amarendar Reddy Maddirala This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Applications of Ugi Four Component Cascade Coupling Reactions for the Synthesis of Bioactive Diverse Heterocyclic Molecules and Natural Products by Amarendar Reddy Maddirala Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Chemistry The University of Toledo May, 2016 Isocyanide-based multicomponent reactions (IBMRs) have great advantages towards the assembly of complex molecules and are concise for the synthesis of higher ordered core structural motifs accomplished in a single synthetic transformation. Complexity generating reactions have become quite useful in assembling molecules containing a variety of stereocenters in an economical and time-saving manner. Particularly, the Ugi four component reaction sequence, followed by a variety of post condensation or transformational modifications allow the synthetic chemist to synthesize many biologically active molecules including those with diverse heterocyclic scaffolds and natural products. Of those types of molecules, 3-substituted-2-indolinone scaffolds have many important functions in biological systems including a wide-range of beneficial activities. From this perspective, the syntheses of 3-substituted-2-indolinones are an interesting target for an organic synthetic chemist to study the applications in medicinal chemistry. Our approach demands the efficient synthesis of 3-substituted-2-indolinones through microwave irradiation and selective intramolecular transamidation of the Ugi four component condensation derivative(s). Additionally, investigation for the ability of iii symmetrical versus unsymmetrical amine component(s) and carboxylic component(s) to eliminate the formation of rotameric mixtures obtained during the practice, simplifies NMR analysis and allows for further molecular design amplification. Likewise, the synthesis of spiro-[indoline-3,2'-pyrrolidine]-2,5'-diones via post-Ugi- 4CR/transamidation/cyclization sequential process has been achieved in three steps in a one-pot reaction using methyl isocyanide as a convertible isocyanide. Variation in the carboxylic acid moiety allows for the generation of new quaternary carbon centers under basic reaction conditions and provides the molecular diversity in a small library of spirocyclic oxindole -lactams. Finally, bioactive natural products, xenortides A-D and their stereoisomers, were synthesized in a one-pot, two-step reaction using the methodology learned from the Ugi four component reaction. iv Acknowledgements First of all I would like to express gratefulness to my research advisor Dr. Peter R. Andreana for giving me an opportunity to carry out my research by motivating, mentoring and teaching me through every challenge that came in my way throughout my graduate studies. I would like to thank my committee members Dr. Joseph A.R Schmidt, Dr. Jianglong Zhu, and Dr. L. M. V. Tillekeratne for helpful suggestions and criticisms for my Ph.D. Due acknowledgement is given to my past and present group members for the very useful discussions; chemistry related, maintenance of the laboratory and for keeping an extremely cordial environment in my work place. Also special thanks to my lab mate Krishnakant who was always there when I need help. My sincere appreciation for training and the help provided by Dr. Yong Wah Kim in NMR and MS experiments and Dr. Kristin Kirschbaum for providing X-ray crystallographic analysis, and Steve Moder for making new glassware and repairing broken glass ware. I really appreciated everyone from stockroom for their help and Charlene Hansen and Pam for their help related to administration and teaching. With deep gratitude I thank everyone from the department of chemistry and biochemistry at the University of Toledo, who helped me bring this graduate study to a successful completion and made my stay a meaningful one. I am extremely grateful to my family members and friends for their constant encouragement and support throughout my study which made the tedious research look simple and easy v Table of Contents Abstract .............................................................................................................................. iii Acknowledgements ..............................................................................................................v Table of Contents ............................................................................................................... vi List of Tables ................................................................................................................... ix List of Figures ......................................................................................................................x List of Schemes .................................................................................................................. xi List of Abbreviations ....................................................................................................... xiii List of Symbols ..................................................................................................................xv 1. Multicomponent Reactions Background..................................................................1 1.1. Introduction…………… ...................................................................................1 1.2. History of multicomponent reactions……………............................................2 1.3. History of isocyanides……………...................................................................3 1.3.1. Isocyanide synthesis………………...................................................3 1.4. Named isocyanide based multicomponent reactions ........................................7 1.4.1. Passerini reaction ...............................................................................7 1.4.2. Ugi reaction ........................................................................................9 1.4.3. Ugi-Smiles reaction .........................................................................10 1.5. Application of Ugi four component reaction ..................................................12 1.5.1. Heterocyclic scaffolds synthesis ......................................................12 1.5.2. Total synthesis of natural products ..................................................13 1.5.3. Applications in Drug discovery .......................................................16 vi References……. .....................................................................................................19 2. Synthesis of 3-Substituted-2-Indolinones via a Multicomponent Coupling Isocyanide Dependent Microwave-Assisted Intramolecular Transamidation Process....................................................................... ............................................25 2.1. Introduction…………… .................................................................................25 β.β. Results and Discussion…………… ...............................................................28 2.2.1. Feasibility study for intramolecular transamidation …………… ...28 2.2.2. Effect of isocyanide substitution and TFA catalyzed transamidation reactions …………… ................................................................................30 2.2.3. Rotamers formation and challenges in NMR analysis …………… 34 2.2.3.1. Studying the effect of amine component on rotamer formation………… ....................................................................................35 2.2.3.2. Studying the effect of carboxylic acid component on rotamer formation…………………………………………………………………37 β.γ. Conclusion…………… ..................................................................................38 Experimental Section …………… ........................................................................40 References…………… ..........................................................................................77 3. Methyl Isocyanide as a Convertible Functional Group for the Synthesis of Spirocyclic Oxindole –lactams via Post Ugi-4CR/Transamidation/Cyclization in a One-pot Three Step Sequence.......…..................................................................82 3.1. Introduction…………… .................................................................................82 γ.β. Results and Discussion…………… ...............................................................85 3.2.1. Feasibility studies for one pot, three step reaction …………… ......85 vii 3.2.2. Optimization studies for base catalyzed cyclization …………… ...87 3.2.3. Investigation of substrate scope …………… ..................................88