Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1991 Approaches to indole alkaloids Daniel W. Bougie Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Bougie, Daniel W., "Approaches to indole alkaloids " (1991). Retrospective Theses and Dissertations. 9923. https://lib.dr.iastate.edu/rtd/9923 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. UMI MICROFILMED 1991 I INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. 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Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor, Mi 48106-1346 USA 313/761-4700 800/521-0600 Order Number 9126180 Approaches to indole alkaloids Bougie, Daniel W., Ph.D. Iowa State University, 1901 UMI SOON.ZeebRd. Ann Arbor, MI 48106 Approaches to indole alkaloids by Daniel W. Bougie A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Department: Chemistty Major: Organic Chemistry Approved: Signature was redacted for privacy. In Ch ork Signature was redacted for privacy. 'or the Major Department Signature was redacted for privacy. For the Graduate College Iowa State University Ames, Iowa 1991 ii TABLE OF CONTENTS page DEDICATION iii GENERAL INTRODUCTION 1 PARTI: THE INTRAMOLECULAR DIELS-ALDER REACTION 2 AND THE INDOLE NUCLEUS HISTORICAL 3 RESULTS AND DISCUSSION 28 EXPERIMENTAL 33 REFERENCES 39 PART n: AN ATTEMPTED SYNTHESIS OF STRYCHNINE 42 HISTORICAL 43 RESULTS AND DISCUSSION 57 EXPERIMENTAL 80 REFERENCES 100 OVERALL CONCLUSION 103 ACKNOWLEDGMENTS 104 DEDICATION This dissertation is dedicated to my late grandparents, Joseph and Rose Bougie and Ruben and Henriette Van Vonderen. These are the people who, through direct contact and through my parents, have instilled the values of education and hard work into me. I would also like to dedicate this dissertation to the late Caitlin Rose Bougie, the newest member of our Bougie clan. 1 GENERAL INTRODUCTION The intramolecular Diels-Alder reaction has been known to organic chemists for decades. However, utilization of this reaction for the synthesis of indole containing natural products has been limited. We have studied the application of the intramolecular Diels-Alder reaction on indole derivatives to determine the requirements for the tether and have applied our new found knowledge towards the synthesis of strychnine. This dissertation is divided into two parts. The first part will deal with the intramolecular Diels-Alder reaction utilizing the indole nucleus. The second part will address our efforts toward the synthesis of strychnine. 2 PARTI: THE INTRAMOLECULAR DIELS-ALDER REACTION AND THE INDOLE NUCLEUS 3 HISTORICAL Since its discovery, the Diels-Alder reaction has been studied extensively and has become synthetically very useful. Its syntiietic utility has been proven in the synthesis of numerous natural and biologically active compounds. This reaction is useful because it has the capability of setting up to four stereogenic centers with predictable results. Its concerted mechanism yields this predictability through the endo transition state and secondary orbital interactions. An illustration of this reaction is depicted below. A diene and a dienophile come together with the activating groups near each other. The two components align such that the tc orbitals can interact. The stereochemical and regiochemical outcome is as depicted. (! ^ —> —0" A Diels-Alder reaction consists of two components, a An and a 2it system. Hence it is also known as a [4 + 2] cyclization. The 4n system is an electron-rich diene whereas the 2n system is an electron-deficient dienophile. These requirements are necessary to obtain the proper interactions between the HOMO (highest occupied molecular orbital) of the diene and the LUMO (lowest unoccupied molecular orbital) of the dienophile. 1 The intramolecular version simply connects both components together, but subtie aspects can affect the course of the reaction. Utilization of the intramolecular Diels-Alder reaction can be very advantageous from a synthetic point of view. This version of the [4 + 2] cyclization assembles two new rings 4 simultaneously and produces a product with functional groups for further manipulation. The intramolecular Diels-Alder reaction has been exhaustively reviewed within the last 15 years. These reviews cover many aspects of the intramolecular Diels-Alder reaction. One very important aspect is the tether that joins the diene and the dienophile. It appears that if the tether is short, the two n systems cannot align properly for cyclization and longer chains start to require similar conditions as their bimolecular counterparts.^^ Entropy considerations alone suggest that the rates should decrease in the order 3> 4> 5 membered chain lenghts.^® Thus, a series of 9-anthracenecarboxamides containing ethynyl dienophiles was studied with chain lengths of 3,4 and 5 atoms.^ These compounds Me 'Me chain lenght of 3,4 and 5 atoms cyclized at 110*C, 140*C and 220*C, respectively. The temperature required for the last example is similar to that for the corresponding bimolecular reaction. The most common tether length is three or four atoms, yielding 6-5 and 6-6 ring systems, respectively. Brieger reported the [4 + 2] cyclization of the cyclopentadiene derivative 1.^ The only product isolated was the norbomene 2 with no trace of the expected product. When substituted benzocyclobutenes^ were heated, the o-quinodimethanes generated in situ possessed chain lengths of three (n= 1), four (n= 2) and five (n= 3) atoms. The intermediates with chain lengths of three and four underwent [4 + 2] cyclization in excellent n= 1, 2, 3 n= 1-3 NH HN 6 yields. The intermediate with a chain length of five underwent competing [4 + 2] and [4 + 4] cyclizations. Another important aspect of the tether is the atoms that make up the tether. An all-carbon tether was utilized in the systematic investigation by House and Cronin^ of the intramolecular Diels-Alder reaction of acrylic esters. In the case of the trans-diene unit, cyclization occurred to give the trans-annulated product. When the cis-diene was submitted "'H CXX)Me COOMe Cf •"'COOMe COOMe I MeOOC - MB ^ _COOH COOH < J * to the same conditions, the cis-annulated product was obtained. Interestingly, the reactions proceed in the opposite direction as the bimolecular counterpart as evidenced by 7 no formation of the bridged product Molecular mechanics calculations^® indicate that even for tethers with as many as 6 atoms, the conformations leading to bridged products are much higher in energy that those for fused products. For all the chain lengths (3 to 6 atoms) studied, angle strain was the major reason for the difference in energy. Heteroatoms also play a major role as part of a tether for the intramolecular Diels-Alder reaction. In a classic set of experiments, Boeckman and Demko^ reported that while the C02Me ^ i?r 3. X= Hn 4. X= Ho x=o ether 3 (X= H, H) cyclized to form 4, the corresponding ester (X= O) could not be induced to cyclize. Surprisingly, the amine 5 would not cyclize, whereas the ammonium salt 6 cyclized at lOO'C^. no reaction .O. V .Et Amides have also been used as part of the tether.^ Again the trans-fused products were formed selectively when the precursors were trans-dienes. It should be noted that as 8 the size of the group attached to the nitrogen decreases, so does the rate of the reaction.^b o Unlike amides, esters as part of the tether are considered to hinder the reaction.^e This seems to be the rule, but there are a few exceptions. In these exceptions, the reactions employ strongly activated dienophiles as exemplified by Auerbach and Weinreb's^O work. .ph ^ Ph On the other hand, the ester 7 reacted in a bimolecular fashion rather than an r intramolecular fashion.^® This reduced reactivity may be attributed to the preference for the ester to exist in the transoid form and a relatively high energy barrier for interconversion of the two rotamers. 1 ^ In bimolecular Diels-Alder reactions, both the diene and the dienophile are activated in some way. Because the intramolecular Diels-Alder reaction holds these two components togetiier, there are fewer degrees of rotational and translational freedom that the diene and 9 dienophile can obtain.^a Proximity alone can be a strong enough factor for cyclization to occur.