University of Nevada, Reno Efficient Synthesis of Bicyclo[4.4.0]decanes by Tandem Double Diels-Alder A thesis submitted in partial fulfillment of the requirements for the degree of Bachelor of Science in Chemistry and the Honors Program by Amanda O’Loughlin Wesley Chalifoux, Ph.D., Thesis Advisor May 2016 UNIVERSITY OF NEVADA THE HONORS PROGRAM RENO We recommend that the thesis prepared under our supervision by AMANDA O’LOUGHLIN entitled Efficient Synthesis of Bicyclo[4.4.0]decanes by Tandem Double Diels-Alder be accepted in partial fulfillment of the requirements for the degree of BACHELOR OF SCIENCE, CHEMISTRY Wesley Chalifoux, Ph.D., Thesis Advisor Tamara Valentine, Ph.D., Director, Honors Program May, 2016 i ABSTRACT Polycyclic structures are frequently found in nature with specific and significant biological activity and their efficient synthesis is an important area of research. Economical syntheses have high significance in the pharmaceutical industry due to the potential to reduce step- count, waste streams, time, and money. This project’s tandem [4+2] cyclization of alkynes generates bicyclo[4.4.0]decane (cis-decalin) products in a succinct manner. The reaction includes the production of four new carbon-carbon bonds, two rings, and quaternary or vicinal quaternary centers in one pot. Successful preliminary reactions creating complex cis-decalin molecules were performed, and show promise for the synthesis of a large scope of products found in high-interest biologically active structures. ii ACKNOWLEDGMENTS Special thanks to my advisor, Dr. Wesley Chalifoux, for his knowledge, guidance, and support, and to graduate student, Jade Horton, who I worked closely with on this project for her mentorship, dedication, and knowledge. iii TABLE OF CONTENTS Page Abstract………………………….……………...……………………..……..………..…...i Acknowledgments……….………………………………..….…….…………....………..ii Table of Contents………………………….……………….…….…………..…………...iii List of Tables…………………………………………………………...……….….…......iv List of Figures……….…………….……….…………………………..……..….………..v List of Schemes……………….………………………………………..…………………vi Introduction..………………….…………………………….………..………….……...…1 1. cis-Decalin Substructure……………………………..……………………………2 2. Biological Relevance…….……………..………………………….....………..….3 3. Biosynthetic Pathways of cis-Decalins……………………………….........……...7 4. Literature Syntheses…………………….…….…………….…………....…...…...9 5. Diels-Alder Reaction…………………………………….…….…….….……......12 6. Methodology: Tandem Double Diels-Alder...…………….…….….…......….…..14 7. Results ………………….……………....………….………....……….................15 8. Discussion and Conclusion…………….…………………………..............…….21 9. Future Direction: Total Synthesis of Valerane…………………………...….…...22 References……………………….…………………………………………………...…..25 iv LIST OF TABLES Table Page [1]: Reaction scope of ynones with 2,3-dimethyl-1,3-butadiene………………………………………………………….17 [2]: Eli Lilly Screening Results………………………………………………………….18 v LIST OF FIGURES Figure Page [1]: Isoprene unit…………….…………………………………………....…………….…1 [2]: cis- and trans-Decalin conformations………………………….……………………..3 [3]: Natural products with biological activity containing cis-decalin backbone………….4 [4]: Neutral, normal, inverse demand Diels-Alder……………………....………….…...12 [5]: Molecular orbital diagram where Lewis acid coordination decreases the HOMO-LUMO gap……………...……………….….……….….……13 [6]: Diels-Alder reaction with alkyne dienophile to create asymmetric products………….…….…...…….………………………………….....14 [7]: Proposed double Diels-Alder of conjugated alkynes to yield bicyclo[4.4.0]decanes……………………………………………………………….14 [8]: 1H NMR study monitoring conversion of ynone 24a to bicyclized product 26a……………………………………………………....……....16 [9]: Srikrishna and colleagues’ 13 step total synthesis of valerane……………………...22 [10]: Proposed five step total synthesis of valerane via proposed tandem double Dies-Alder………….……………………………………………...23 vi LIST OF SCHEMES Scheme Page [1]: Biosynthetic [4+2] cyclization of cis-decalin solanapyrone A via enzyme Sol5…….…….…….………………………………………………….....8 [2]: Enantioselective synthesis of cis-decalin 18 using organocatalysis and sulfonyl Nazarov reagent 16…………………….…………………………..……….…………9 [3]: Transannular Diels-Alder (TADA) reaction with macrocycle 19 to generate cis-decalin 20………..…………………………………..……….……........…….….10 [4]: Intramolecular Heck reaction using palladium catalyst and chiral ligand (R)-BINAP to produce cis-decalin 21..........................................................................11 [5]: Intramolecular alkylation of ketone enolate to generate cis-decalin 23…….…….....11 [6]: Preliminary experiment of Lewis acid-catalyzed tandem double Diels-Alder cyclization of α,β-unsaturated ynone 24a to produce bicyclic product 26a………………………….………………………………..……..…...…..15 [7]: Lewis acid catalyzed Diels-Alder of 27 to make monocyclized intermediate 28……………………………………………………………………...19 [8]: Proposed addition of two different dienes by utilizing the rate difference between the cycloadditions to generate an asymmetric product……...…20 [9]: Lewis acid catalyzed tandem double Diels-Alder of ynone 24a with 1 equiv. of 2,3-dimethyl-1,3-butadiene and excess 1,3-butadiene to produce asymmetric bicyclic product 30…………………………………………....20 1 INTRODUCTION The specificity required in the structure of effective drugs presents many challenges for the synthesis of highly desirable pharmaceuticals.1 The development of efficient routes to complex targets is a large and significant area of research due to the potential to reduce step-count, waste streams, time, and money. Synthetic efficiency is measured by the number of steps, yield, cost, and time; these are important considerations in the drug design process. Pharmaceutical companies look for syntheses that will help them to arrive at complex molecules in the shortest and most reliable manner possible. Therefore, these types of economical syntheses have the potential to be used for large scale drug production. There are a number of terpenoid (and specifically sesquiterpenoid) natural products that have been found to have beneficial effects in the treatment of human diseases.2 Terpenoids are a class of natural products, often produced by plants, that are derived from isoprene units (Figure 1) and contain oxygen functional groups.3 Sesquiterpenoids are a subclass of terpenoids that have three isoprene units and 15 carbon atoms.3 Some terpenoids are found to have anticancer,4 antifungal,5-8 antitumor9, antibacterial,6,8 and antiparasitic10 properties, and continue to be important compounds for drug discovery.2 An economical synthesis of such structures has been a challenge in the past due to high step- counts and large expenses but should be possible via our “one-pot” methodology. A “one- pot” synthesis is a general term used to describe reactions that occur simultaneously or sequentially, and without isolation of intermediate products.11 This thesis focuses on the development of a methodology for the rapid synthesis of cis-decalin products with low step-count and high yield, as well as the exploration of a 2 scope of successful alkyne and diene substrates. We examine the biological activity of these compounds and investigate the total synthesis of compounds in the valerane family of natural products. The relative simplicity in the structure of valerane makes it a good starting point to prove that short total syntheses of this class of molecules is possible using our methodology. Valerane, and many terpenoid natural products with biological activity, contain a cis-decalin substructure. Compounds with the cis-decalin substructure are the focus of this thesis due to their reactivity, which will be discussed in Section 1. 1. cis-Decalin Substructure The cis-decalin motif is a bicyclic fused ring system in which the substituents on the bridgehead carbons are oriented in the same plane of space. The opposite of cis is trans, in which the substituents on the bridgehead carbons are not in the same plane of space. Cis and trans molecules are diastereomers because they have the same molecular and structural formulas, but are not mirror images of each other. Diastereomers can have different physical properties, chemical properties, and reactivities. The structural motif of cis-decalins has its advantages and disadvantages. Because the bridgehead substituents are cis, the two six-membered rings form chair conformations and the entire molecule adopts a tent-like shape. This tent-like shape creates a gauche interaction between the atoms on the bottom face and causes the cis-decalin to be less stable than the trans-decalin.12 An advantage of the cis-isomer is that its faces have different reactivity – the top (convex) face is more “exposed” and therefore more reactive than the bottom (concave) face (Figure 2). This difference in reactivity can be a beneficial tool for selectively synthesizing one diastereomer over the other.12 Important biological 3 implications of various cis-decalins are discussed in Section 2, and these implications along with the reactivity of this type of molecule, make cis-decalins attractive synthetic targets. 2. BIOLOGICAL RELEVANCE The cis-decalin substructure is found in many natural products with biological and pharmaceutical implications. Many decalins found in nature, including the ones in Figure 3, contain complex groups and are highly functionalized, contributing to their structural and functional diversity. Because of their range of biological activities, along with the decalin motif serving as a basic template for constructing entire molecules, cis-decalins