Tổng hợp alkaloid indole đa vòng - Luận án tiến sĩ Tao Wu

Synthetic studies on polycyclic indole alkaloids by Tao Wu A dissertation submitted to the graduate faculty in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Major: Organic Chemistry Program of Study Committee: George A. Kraus, Major Professor Richard C. Petrich Donald Lee Reynolds Iowa State University Ames, Iowa 2006 Copyright © Tao Wu, 2006. All rights reserved.

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Box 1346 Ann Arbor, MI 48106-1346 ii TABLE OF CONTENTS TABLE OF CONTENTS ii LIST OF ABBREVIATION iv ACKNOWLEGEMENT vii ABSTRACT ix GENERAL INTRODUCTION 1 CHAPTER I. HKI 0231A AND HKI 0231B SYNTHESES Introduction 2 Results and Discussion 7 Experimental Section 24 References 47 CHAPTER II. SYNTHESIS OF ABEO-ERGOLINES AND THEIR ANALOGS Introduction 51 Results and Discussion 58 Experimental Section 70 References 85 CHAPTER III. BENZOCYCLOBUTENOL CHEMISTRY Introduction 89 iii Results and Discussion 96 Experimental Section 109 References 123 GENERAL CONCLUSIONS 129 iv LIST OF ABBREVIATIONS AIBN azodiisobutyronitrile app apparent aq aqueous Bn benzyl br broad Bu butyl calcd calculated CSA camphorsulfonic acid δ chemical shift in ppm downfield from Me4Si d doublet dd doublet of doublets ddd doublet of doublets of doublets DDQ 2,3-dicyano-5,6-dichloro-1,4-benzoquinone DIPEA diisopropylethylamine DMAP 4-(dimethylamino)pyridine DME glyme DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide dt doublet of triplets EI electron impact equiv equivalent g gram(s) h hour(s) Hz hertz v HMDS potassium bis(trimethylsilyl)amide HMTA hexamethylene tetramine HRMS high-resolution mass spectrum IC50 inhibitory concentration 50% J coupling constant KHMDS potassium hexamethyldisilazamide L liter(s) LDA lithium diisopropylamide LAH lithium aluminum hydride LiTMP lithium 2,2,6,6-tetramethylpiperidide μ micro m milli, multiplet (NMR) M moles per liter mg milligram(s) mmol millimole(s) mp melting point MHz megahertz min minute(s) mol mole(s) mp melting point m/z mass to charge ratio NMP N-methylpyrrolidinone NMR nuclear magnetic resonance p para PCC pyridinium chlorochromate pH hydrogen ion concentration ppm parts per million vi ppt precipitate PPTS pyridinium 4-toluenesulfonate q quartet quint quintuplet rt room temperature s singlet (NMR) t triplet TBAC tetrabutylammonium chloride TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMEDA N,N,N',N'-tetramethylethylenediamine TMSCl trimethylsilyl chloride UV ultraviolet vii Acknowledgements First of all, I would like to thank my advisor Professor George A.

Kraus for allowing me to join his group and for all his support and advice over the years. He is a brilliant chemist, as well as a wonderful teacher. I will never forget witnessing his many creative ideas and how his training turned me into an organic chemist. I would like to thank Professor Richard C.

Larock for his letters of recommendation. Rich is a brilliant chemist. His group has been the place for me to take advice on transition-metal chemistry. And his big book has been the place for me when I need information of organic transformations.

I would like to thank Professor William Jenks. I thank him for bringing chemistry with fun to the classroom. As a devoted teacher, the door of his office is always open, even for many of my silly questions. He seems to be always there ready to offer his helpful discussions and suggestions.

I would like to thank Professor Jacob Petrich and Professor Donald Reynolds for serving on my POS committee. I thank them for their time and suggestions. I thank Professor John Verkade for his letters of recommendations. I would like to thank all the current and former members of the Kraus group for their friendship.

It has been a wonderful experience being part of the group. Special thanks to Dr. Jingqiang Wei, who offered his hands in and outside Gilman Hall; and to Dr. Yi Yuan for his ready support on computer and literature search.

My time in the chemistry department has been fun because of the really fantastic people I met here. Chengxiang Zhou for initiating our discussion group and relaxing tennis time; I thank Zhijian Liu for knowledge of palladium chemistry and I thank Dr. Weiping Su for being a big brother to me. I thank John for his proof-reading on viii my thesis.

I also should not forget to thank Jacob and Jesse for their frequent help with my English. My stay here at Iowa State would have been totally different without my wife Liping’s support along the way. Her understanding and patience are essential for the success of my graduate study. I thank my daughter Irene.

Her birth brightened my life. And I thank my mother for her endless love and constant encouragement for me to be a better person. Finally, thanks to all of my friends that I have met at Iowa State over the last five years. I will always look back on my time at Iowa State with fondness.

Tao Wu Ames, Iowa August 2006 ix Abstract The first part of this work details the formal total synthesis of HKI 0231B and the first total synthesis of both demethyl HKI 0231A and demethyl HKI 0231B. The formal synthesis used TBAF as a mild reagent to construct the indole. The total synthesis featured an efficient radical cyclization / oxidation step to construct the skeleton and a DDQ-mediated methoxylation reaction. The second part of this work is dedicated to the synthetic efforts towards the abeo- ergolines and the total synthesis of the abeo-ergoline analogs.

In the synthetic study toward the abeo-ergolines, a reaction between 4-lithioindole and the enaminone, which was prepared from the ketone and Brederick reagent, effectively brought together all the necessary carbons for the final product. The synthesis of the abeo-ergoline analogs was direct, as it had a 36% overall yield in 7 steps. This approach is also flexible enough to allow the synthesis of various structurally related abeo-ergoline analogs. The third part of this work describes the invention of a new strategy which allows the one-pot benzocyclobutenol synthesis and the corresponding three-component reactions.

In the reaction, acetaldehyde enolate and benzyne intermediates were generated in the same flask to produce benzocyclobutenoxides species which is in equilibrium with o- qunodimethide species. With protonation, benzocyclobutenols were prepared in a one-pot fashion. With the addition of dienophiles, three component reactions were achieved. This strategy was also successfully applied in the synthesis of the berbine natural products when cyclic imines were used as dienophiles.

1 GENERAL INTRODUCTION Organic synthesis is an essential part of chemistry. Over the years, many excellent examples have demonstrated the power of this subject. However, more synthetic routes are still desirable for the direct preparation of natural and unnatural compounds. HKI 0231 A and HKI 0231B are novel indole alkaloids, which were isolated recently in 2001.

They inhibit 3α-hydroxysteroid dehydrogenase, the key enzyme in the inflammatory process. Therefore, these two compounds are potential leads to anti-inflammatory agents. In chapter one, a formal synthesis of HKI 0231B and a concise synthetic route to demethyl HKI 0231A and demethyl HKI 0231B will be discussed. Ergot alkaloids have a wide spectrum of pharmacological activities.

Abeo-ergolines are derivatives of 9-hydroxyergolines through semi-synthesis. Some members of this class of compounds have high 5-HT1A affinity and selectivity and are potential therapeutical agents. In chapter two, our effort towards an enantioselective synthesis of abeo-ergolines from simple starting materials and an efficient synthetic route to racemic abeo-ergoline analogs will be discussed. Benzocyclobutenols are versatile building blocks in organic synthesis.

They are precursors of reactive o-quinodimethane intermediates under thermal or basic conditions. The conventional synthesis of benzocyclobutenols requires multiple steps. In chapter three, a one-pot synthesis of benzocyclobutenols and the corresponding three-component reactions will be discussed. 2 CHAPTER ONE HKI 0231B AND HKI 0231A SYNTHESIS 1.

Background and Introduction In 2001, the Grafe group reported the isolation of two structurally related indole alkaloids from the fermentation broth of Streptomyces sp.1 With the assistance of UV, NMR and MS techniques, the scientists assigned the structures of the two compounds – HKI 0231A and HKI 0231B as shown in Figure 1. HKI 0231A and HKI 0231B O O N N O O O O O HKI 0231A HKI 0231B HKI 0231A and HKI 0231B are structually novel indole alkaloids. Both possess a pentacyclic core structure. Both compounds display bright fluorescence, which is the result of a conjugated oxonapthopyrrole chromophore.

Since optical rotation (in methanol) measurements indicated that both compounds are inactive, then HKI 0231B could be a mixture of enantiomers. Biological tests revealed that both compounds have the ability to inhibit 3α- hydroxysteroid dehydrogenase (IC50 = 10.5 µg/mL, respectively), the key enzyme in the inflammatory process. Therefore, these compounds could possibly be developed into anti-inflammatory agents. 3 Because of their novel structure and potential use as anti-inflammatory agents, several groups started synthetic studies on HKI 0231A and HKI 0231B.

Among them, the Nakatsuka group first completed a synthesis of HKI 0231B. 2 The Nakatsuka synthesis featured a unique AlCl3-mediated cyclo-elimination reaction, which they developed to construct the benz[c,d]indol-3(1H)-one core. The reaction is shown in Scheme 1. AlCl3-Mediated Cyclo-elimination Reaction R' R O O R 5 equiv.

AlCl3 N N H H 1 2 R = H, Me; R' = H, OMe, NO2 They explained that this unusual transformation goes through an AlCl3-mediated intramolecular cyclization, followed by the elimination of the substituted phenyl group. The proposed mechanism is shown in Scheme 2. It was reported that the reaction worked well when the R’ substituent is a hydrogen or methyl group. Both strong electron-withdrawing groups (such as a nitro group) and strong electron-donating groups (such as a methoxyl group) retard either the cyclization or the elimination step, resulting in a poor yield of the desired tricyclic indole product.

Proposed Cyclo-elimination Mechanism R' R' AlCl3 AlCl3 O O R 5 equiv. AlCl3 R 1 2 N H N H AlCl3 AlCl3 The Nakatsuka synthesis started with expensive 7-methyl indole (3).3 After protecting the indole nitrogen with a pivaloyl group, a standard AlCl3-mediated Friedel-Crafts acylation of trans-p-methylcinnamoyl chloride at the 3-position of the indole and a subsequent deprotection step smoothly provided indole 4. Then the key cyclo-elimination reaction was achieved in 84% yield to afford the tricyclic indole 5 (Scheme 3). Application of the Cyclo-elimination Reaction in HKI 0231B Synthesis O O AlCl3 (CHCl2)2, 80 oC N N H 87%, 3 steps 84% H N H 3 4 5 With the tricyclic indole 5 in hand, Nakatsuka took advantage of the chemistry developed by Hegedus.4 After protection of the nitrogen, a regioselective conjugate addition with lithiated N, N-dimethyl-O-methylsalicylamide yielded naphthol 6.

This was deprotected and oxidized to compound 7 with air in the presence of CuCl. Cyclization of 7 in boiling toluene gave pentacyclic indole 8. Finally, HKI 0231B was obtained by a partial reduction of 5 8 with LAH at low temperature, followed by immediate treatment with CSA in methanol. This conversion was not efficient as the yield was only 14% for the two steps (Scheme 4).

This synthesis applied their novel cyclo-elimination reaction. Despite the poor transformation in the ending stage, the whole strategy was quite efficient. HKI 0231B was synthesized in 10 steps in 8. The weaknesses of this synthesis are: 1) expensive starting material; 2) low yield conversion in the last two steps; and 3) inability to synthesize the related compound HKI 0231A through this route.

Completion of the Nakatsuka Synthesis OH O 1)TsCl, Pyr. O2, KOH, CuCl 5 N N O O Ts O H O O O NMe2 NMe2 NMe2 2) 6 7 Li 81%, 2 steps O O 1) LAH PhMe 2) CSA, MeOH reflux N N 14% 97%, 2 steps O O O O 8 HKI 0231B The Kelly group at Boston College took a quite different approach in synthesizing HKI 0231A and HKI 0231B.5 Anionic reactions were applied extensively in their synthesis. Their synthesis was started with readily available para-methoxybenzyl chloride 9. Several standard transformations gave them the dibromo compound 10.

Then trianion chemistry produced the desired indole 11 in an almost quantitative yield after a cyclization and hydrolysis sequence (Scheme 5).