MSc Chemistry Molecular Sciences Literature Thesis _____________________________________________________________________________________ Asymmetric synthesis utilizing cascade reactions Application of cascade reactions in total synthesis of complex natural compounds _____________________________________________________________________________________ _________ By Jurgen van Schaijk, 11958782 February 2021 12 EC Primary examiner: Prof. Dr. Jan van Maarseveen Secondary examiner: --- Van ‘t Hoff Institute for Molecular Sciences Synthetic Organic Chemistry Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis 2 Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis ABSTRACT Total synthesis of natural products can usually become quite a lengthy series of synthetic steps. Although through this method the goal of the project can be reached, the issue is that the lengthy process is not only lengthy but also not atom economic. A partial solution to shorten these lengthy synthetic schemes and increase the atom economy, cascade reactions can be utilized. Cascade reactions, also known as domino or tandem reactions, is a chemical process consisting of at least two subsequent reactions where one transformation only occurs due to the previously formed chemical functionality. Isolation of intermediates is usually not observed, this is due to spontaneous nature of the sequence of reactions. In this literature thesis we cover the different groups of cascade reactions and their applications in natural product synthesis. The cascade reactions can be categorized in the following groups: Nucleophilic-, electrophilic-, oganocatalytic-, pericyclic-, and radical cascades. 3 Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis LIST OF ABBREVIATIONS AcOH acetic acid AIBN azobisisobutyronitrile Boc/Boc2O tert-Butoxycarbonyl/di-tert-butylcarbonate DABCO 1,4-diazabicyclo[2.2. 2]octane DCC N,N′-Dicyclohexylcarbodiimide DCM dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL diisobutylaluminium DMAP 4-dimethylaminopyridine DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide KHMDS potassium bis(trimethylsilyl)amide KI potassium iodide LDA lithium diisopropylamide MOM methoxymethyl Phth phthalimide PPA polyphosphoric acid PTC phase-transfer catalysts Py pyridine TBAF tetra-n-butylamonium fluoride TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEA triethyl amine TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid THF tertrahydro furan TMS tetrramethylsilane TMSO trimethylsilyl ether D2-He 4 Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis CONTENTS Abstract ......................................................................................................................................................... 3 List of Abbreviations ...................................................................................................................................... 4 Introduction ................................................................................................................................................... 6 Early work in Cascade reactions ................................................................................................................ 8 Types of cascades ...................................................................................................................................... 9 Nuclephillic / electrophilic cascades ...................................................................................................... 9 Organocatalytic cascades ..................................................................................................................... 10 Radical cascades ................................................................................................................................... 11 Pericyclic cascades ............................................................................................................................... 12 Goals of this thesis....................................................................................................................................... 14 Cascade reactions in asymmetric synthesis ................................................................................................ 15 Chiral auxiliaries ....................................................................................................................................... 15 Cation-mediated cascade reactions ........................................................................................................ 15 Anion-mediate asymmetric cascade reactions ........................................................................................ 23 Pericyclic cascades ................................................................................................................................... 27 Radical cascades ...................................................................................................................................... 32 Conclusion and OUTLOOK ........................................................................................................................... 36 Acknowledgements ..................................................................................................................................... 38 References ................................................................................................................................................... 39 5 Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis INTRODUCTION Development over the past decades in synthetic organic chemistry has influenced the field in fascinating ways. A considerable number of highly selective procedures have come to light which allow for the synthesis of complex molecules with excellent regio-, chemo-, diastereo-, and enantioselectivity.1 Amongst these is an incredible example for the synthesis of palytoxin, which contains 64 stereogenic centers and of which over 1019 different stereoisomers could exist.2 Despite such a great success, society’s image of chemistry has deteriorated, which could be explained by the increasing importance of environmental issues and the negative influence organic chemistry can have on the ecological balance.2 It is no longer only important what we can synthesize, but also how we go about it. Important issues in chemical production are the handling of chemical waste, the search for environmentally friendly/tolerable procedures, preservation of resources, and the increase of efficiency. Solution to these problems are not only important for the environmental concerns, but these also aid in the reduction of production costs. FIGURE 1. STRUCTURE OF PALYTOXIN. 6 Recent Advances in Asymmetric Cascade Reactions: Applications in Polycyclic Natural Product Synthesis Traditional procedures for the synthesis of compounds are usually conducted in a stepwise fashion, forming individual bonds one step at a time. A viable alternative to such a stepwise procedure would be the utilization of cascade type reactions. The utilization of cascade reactions grants organic chemists the ability to synthesize complex structures in one-pot reactions without the necessity to isolate intermediates. Chemical transformations with such an approach offer efficiency, economic benefits and relatively ecologically benign synthesis; a must for every organic chemist.3 The usefulness of cascade reactions is correlated by the number of bonds which are formed in a single sequence (called bond-forming efficiency), the increase in structural complexity, and whether it is suitable for general application.2 Cascade reactions can fall under the banner of “green chemistry”, this is due to the considerable savings involved when a single reaction step carries out several transformations.4 Consideration to follow the guidelines of “green chemistry” will become increasingly important in the future because both chemists and society in general will strive for increasingly more efficient and responsible methods for the management of natural resources. In their review of cascade reactions (2006), Nicolaou et al. wrote: “Target-oriented synthesis provides the ultimate test of reaction design and applicability. The design of cascades to provide specific targeted molecules of considerable structural and stereochemical complexity poses a significant intellectual challenge and can be one of the most impressive activities in natural product synthesis. Cascade reactions therefore contribute immeasurably to both the science and art of total synthesis, bringing not only improved practical efficiency but also enhanced aesthetic appeal to synthetic planning. The recognition of these dual benefits is, of course, by no means an exclusively modern phenomenon. Indeed, cascade reactions (either as designed sequences or serendipitous discoveries) have attracted the attention of organic chemists since the formative years of total synthesis.”4 Tietze has defined a domino/cascade as reaction which involves two or more bond-forming transformations which take place under the same reaction conditions without adding additional reagents or catalysts, and in which the subsequent reactions only result as a consequence of the functionality formation derived from a previous