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TRANSITION METAL-CATALYZED REACTIONS of ALLENES in DIVERSITY-ORIENTED SYNTHESIS by Branko Mitasev B.Sc. Chemistry, Davis And

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TRANSITION METAL-CATALYZED REACTIONS of ALLENES in DIVERSITY-ORIENTED SYNTHESIS by Branko Mitasev B.Sc. Chemistry, Davis And TRANSITION METAL-CATALYZED REACTIONS OF ALLENES IN DIVERSITY-ORIENTED SYNTHESIS by Branko Mitasev B.Sc. Chemistry, Davis and Elkins College, 2000 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2006 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES DEPARTMENT OF CHEMISTRY This dissertation was presented by Branko Mitasev It was defended on December 20th, 2006 and approved by Professor Dennis P. Curran, Department of Chemistry Professor Peter Wipf, Department of Chemistry Professor Billy W. Day, Department of Pharmaceutical Sciences Thesis Director: Professor Kay M. Brummond, Department of Chemistry ii Transition Metal-Catalyzed Reactions of Allenes in Diversity-Oriented Synthesis Branko Mitasev, Ph.D. University of Pittsburgh, 2006 Abstract Transition metal-catalyzed cyclization reactions involving allenes were demonstrated as useful methods for the synthesis of novel heterocyclic compounds. Multiple scaffolds were accessed from pivotal allenic amino-ester intermediates by varying the reaction conditions. Rhodium(I)-catalyzed allenic Alder-ene reaction of allenynes afforded cross-conjugated trienes in high yields. Double bond selectivity in the allenic cyclocarbonylation reaction of allenynes was accomplished by utilizing either rhodium(I)-catalyzed or molybdenum-mediated conditions, thus gaining access to 4-alkylidene or α-alkylidene cyclopentenones, respectively. In addition, a detailed study of the molybdenum-mediated reaction uncovered an unexpected diastereocontrol element based on the amino acid side chain. Furthermore, replacement of the alkyne with an alkene led to discovery of a novel rhodium(I)-catalyzed cycloisomerization of ene-allenes affording tetrahydroazepines. The novel molecular scaffolds obtained in this manner were studied in complexity generating reactions that were employed in the synthesis of libraries of compounds for biological evaluation. For example, stereoselective sequential Diels-Alder reactions of the cross-conjugated trienes allowed rapid access to polycyclic molecular skeletons. Additionally, a Stetter/Paal-Knorr reaction sequence was developed to gain access to novel tricyclic pyrroles. iii Acknowledgements I would like to thank my research advisor Professor Kay M. Brummond for her mentorship and guidance during my Ph. D. studies. Her enthusiasm regarding every aspect of our work creates an ideal environment for conducting exciting research. I would specially like to thank Professors Wipf, Curran, Lazo and Day for helpful advice and discussion on many occasions. I extend my appreciation to Professor Floreancig for mentorship and advice regarding my proposal defense. I would also like to thank my college mentor Prof. Joseph Kent for encouraging me to pursue a Ph. D. degree in organic chemistry. Thanks to all former and present members of the Brummond group, many of whom have been a great source of knowledge and inspiration. I would particularly like to thank Drs. Sang-phyo Hong and Hongfeng Chen for mentorship during the early years of my studies. During my time in the Brummond group, I have had a chance to collaborate with many chemists from other research groups within the P50 project. I thank Drs. Stefan Fischer and Sukhdev Manku from the Curran group. I thank everybody from the UPCMLD with whom I have collaborated on library syntheses, including Dr. Stefan Werner, Dr. Dhana Kasi, Pravin Iyer, David Turner and our biological collaborators. I would like to thank Dr. Steven Geib for X-ray analysis, Drs. Fu-Tyan Lin and Damodaran Krishnan for help with NMR spectroscopy and Drs. Kasi Somayajula and John Williams for mass spectral analysis. I thank the University of Pittsburgh for an Andrew Mellon pre-doctoral fellowship. I would like to thank my dad Jordan, mom Liljana and brother Lazar in Macedonia for supporting me in everything I do. Finally, with all my heart I thank my wife Barbara for her love, patience and encouragement. Thank you! Благодарам! Grazie! iv List of Abbreviations Ac acetyl AcOH acetic acid aq. aqueous Ar aryl ATP adenosine triphosphate BICPO 2,2’-bis(diphenylphosphino)-1,1’-dicyclopentane BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn benzyl Boc tert-butoxycarbonyl Bu butyl Bz benzoyl Cbz carbobenzyloxy CN cyano CO carbon monoxide COD 1,5-cyclooctadiene Cp cyclopentadienyl Cy cyclohexyl DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DEPT distortionless enhancement by polarization transfer DIBALH diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide DOS diversity-oriented synthesis dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppm bis(diphenylphosphino)methane dppp 1,3- bis(diphenylphosphino)propane DPS dimethylphenylsilyl EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl Et ethyl fod tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octadienoate) h hours HMAF hydroxymethylacylfulvene HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography i-Bu isobutyl i-Pr isopropyl IR infrared LDA lithium diisopropylamide LHMDS lithium hexamethyldisalazide v Me methyl min minutes MAPK mitogen activated protein kinase MKP mitogen activated protein kinase phosphatase µw microwave nbd norbornadiene NBS N-bromosuccinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Ph phenyl PPTS pyridinum p-toluenesulfonate PS polymer supported PTSA p-toluenesulfonic acid RI refractive index sat’d saturated TBAF tetrabutylammonium fluoride TBS or TBDMS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFE trifluoroethanol THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl Tol toluene Tos toluenesulfonyl UPCMLD University of Pittsburgh Center for Chemical Methodologies and Library Development wt. weight vi Table of Contents 1.0 Introduction.................................................................................................................... 1 1.1 The Role of Diversity-Oriented Synthesis in Modern Biomedical Research... 1 1.1.1 Transition Metal-Catalyzed Reactions in Diversity-Oriented Synthesis.9 2.0 Design and Synthesis of the Pivotal Intermediates ................................................... 15 2.1 Design of the Pivotal Intermediates................................................................... 15 2.2 Synthesis of the Pivotal Intermediates .............................................................. 17 2.2.1 Synthesis of Allenic Amino Esters............................................................. 17 2.2.1.1 Claisen Rearrangement via an Oxazole............................................ 17 2.2.1.2 Ester-enolate Claisen Rearrangement .............................................. 20 2.2.2 N-Alkylation of Allenic Amino Esters....................................................... 26 3.0 Synthesis and Use of Cross-Conjugated Trienes....................................................... 30 3.1 Transition Metal-Catalyzed Ene-type Cycloisomerization Reactions ........... 30 3.1.1 Allenic Cycloisomerization Reaction......................................................... 33 3.2 Rhodium(I)-Catalyzed Allenic Cycloisomerization Reaction of Amino-Ester Tethered Allenynes ............................................................................................. 37 3.2.1 Preparation of Enol-ether Trienes via an Allenic Cycloisomerization Reaction ...................................................................................................... 41 3.3 Diversification of Cross-Conjugated Trienes via Diels-Alder Reaction ........ 46 vii 3.3.1 Intermolecular Diels-Alder Approach – First Generation Triene ......... 46 3.3.2 Intermolecular Diels-Alder Approach-Second Generation Triene........ 50 3.3.3 Intra-/Intermolecular Diels-Alder Approach for the Synthesis of Complex Polycyclic Scaffolds.................................................................... 63 3.4 Rhodium(I)-Catalyzed Cycloisomerization of Ene-Allenes ............................ 72 4.0 Synthesis and Use of Amino-Acid Derived Cyclopentenones .................................. 80 4.1 Transition Metal Catalyzed Cyclocarbonylation – Pauson-Khand Reaction 80 4.1.1 Mo(CO)6-Mediated Cyclocarbonylation Reaction................................... 82 4.1.2 Late Transition Metal-Catalyzed Cyclocarbonylation Reaction............ 83 4.1.3 Allenic Cyclocarbonylation Reaction........................................................ 85 4.2 Rhodium(I)-Catalyzed Cyclocarbonylation of Amino-Ester Tethered Allenynes for Preparation of 4-Alkylidene Cyclopentenones ......................... 91 4.3 Diversification of 4-Alkylidene Cyclopentenones ............................................ 99 4.4 Mo(CO)6-Mediated Cyclocarbonylation Reaction for Preparation of α- Alkylidene Cyclopentenones ............................................................................ 104 4.5 Diversification of α-Alkylidene Cyclopentenones.......................................... 112 4.5.1 Studies Towards the Synthesis of Tricyclic Pyrroles............................. 112 4.5.2 Synthesis of a Library of Tricyclic Pyrroles........................................... 121 4.5.3 Biological Evaluation of Tricyclic Pyrroles ............................................ 126 4.6 Synthesis of α-Alkylidene Cyclopentenones via a Rhodium(I)-Catalyzed Allenic Cyclocarbonylation Reaction.............................................................
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