Studies Toward the Synthesis of Nodulisporic Acids A and D

(1)

University of Pennsylvania

ScholarlyCommons

Publicly Accessible Penn Dissertations

1-1-2014

Studies Toward the Synthesis of Nodulisporic

Acids A and D

Jason Melvin

University of Pennsylvania, [email protected]

Follow this and additional works at:

http://repository.upenn.edu/edissertations

Part of the

Organic Chemistry Commons

This paper is posted at ScholarlyCommons.http://repository.upenn.edu/edissertations/1370 For more information, please [email protected].

Recommended Citation

(2)

Studies Toward the Synthesis of Nodulisporic Acids A and D

Abstract

The dissertation herein presents efforts toward the synthesis of the potent insecticidal indole diterpenes, nodulisporic acids A and D. Chapter one details the isolation of the nodulisporic acid family of compounds by Merck, as well as the efforts at Merck to utilize (+)-nodulisporic acid A as a veterinary medicine lead

structure. Further, chapter one reviews the previous strategies employed by the Smith group toward the syntheses of the nodulisporic acid family. Lastly, the development of a modular and highly convergent strategy to access the nodulisporic acids exploiting a one-pot tandem Buchwald-Hartwig/Heck cascade to generate a common central indole core is described.

Chapter 2 will describe the development of a revised synthetic strategy to access the required western hemisphere chloroindoline for the synthesis of nodulisporic acid A.

Chapter 3 outlines the synthesis of the eastern hemisphere common to both nodulisporic acids A and D. The development of a new strategy for the construction of the C-3 and C-12 stereocenters now allow for the synthesis of sufficient quantity of the eastern hemisphere for coupling studies.

Chapter 4 describes the development and implementation of an Enders alkylation and a Stille-Kelly coupling to generate the western hemisphere of nodulisporic acid D.

Chapter 5 disclosed our results attempting to implement the one-pot tandem Buchwald-Hartwig/Heck cascade to access nodulipsoric acids A and D. Furthermore, future plans for the further development of the Buchwald-Hartwig/Heck(Barluenga) cascade tactic are described.

Degree Type Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group Chemistry

First Advisor Amos B. Smith

(3)

STUDIES TOWARD THE SYNTHESIS OF NODULISPORIC ACIDS A AND D Jason E. Melvin

A DISSERTATION in

Chemistry

Presented to the Faculties of the University of Pennsylvania in

Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

2014

Supervisor of Dissertation

_________________________

Professor Amos B. Smith, III, Rhodes-Thompson Professor of Chemistry

Graduate Group Chairperson _________________________

Professor Gary A. Molander, Hirschmann-Makineni Professor of Chemistry

Dissertation Committee

Marisa C. Kozlowski, Professor of Chemistry Jeffrey D. Winkler, Merriam Professor of Chemistry

(4)

(5)

Dedicated to my family; Mom, Dad, Jeff, Jen, Ashley, Grandma and Grandpa Abram, and Grandma and Papa Melvin; who have offered nothing but encouragement and support through

(6)

! iv!

ACKNOWLEDGMENT

My journey has taken some strange ups and downs, but throughout all of it I have never had a shortage of people that guided and supported me. I had the good fortune to be educated by some really interesting mentors that inspired me to continue on in science. First, I thank my parents who have supported me in every way imaginable and always pushed me to be the best person that I can be. They instilled a love for science, nurtured passion for learning, and always encouraged me to be creative. Without their love and support, I would probably still be sorting mail at DXO communications (or worse…). I know I didn’t end up being an astronaut or president, but their direction and care led me to making it through a professional degree program at an Ivy League University. Who would have “thunk” that a decade ago? Even Grandma Melvin thought, “How the hell did you get in there, honey?” when I told her about my UPenn acceptance. To the best of my knowledge, no one knows! But, I’ve tried to make the best of the opportunity.

Experiencing the trials and tribulations of graduate school at the same time as my brother was… I won’t say a wonderful experience, but one that I most certainly won’t forget. It gave me someone that I could vent to and had an honest understanding of the difficulties associated making it through a graduate program.

(7)

(8)

! vi!

all right. Drugs… I’m an organic chemist, I can go up to my lab and make them. And sex… your sex isn’t kinky enough.” That was the moment that I realized that organic chemistry didn’t have to be serious all of the time. After spending more time talking to Prof. Hauser, I realized that it could actually be fun! Who knew that aerosolized Me3Al solution is what they use to start the spaceship rockets??? The common perception of chemistry was completely wrong, thinking about reactions were more like solving a Sudoku puzzle than experiencing a root canal. After the realization that I truly enjoyed organic chemistry, AMRI showed me that you could actually make a career out of it! I will always be thankful to Vikki Casey-Ahmed and Chad Thompson for allowing me the chance to take on responsibilities that were probably outside of my job description. While I didn’t actively work in any of the medchem or process labs, I had the opportunity to work with them. I became close friends with Feryan Ahmed and Jonathon Salibury, and they both were instrumental in directing my career.

The string of events in Albany that led me to graduate school were set into motion by some of my best friends and biggest supporters in life, the Sawyers. Bryan asked me to move to Albany with him in the summer of 2004 and convinced me it was time to go back to school. The support I got from Bryan, Julie and the Calingasans early on, really helped me to settle into school again and succeed.

(9)

ABSTRACT

STUDIES TOWARD THE SYNTHESIS OF NODULISPORIC ACIDS A AND D Jason E. Melvin

Amos B. Smith, III

The dissertation herein presents efforts toward the synthesis of the potent insecticidal indole diterpenes, nodulisporic acids A and D. Chapter one details the isolation of the nodulisporic acid family of compounds by Merck, as well as the efforts at Merck to utilize (+)-nodulisporic acid A as a veterinary medicine lead structure. Further, chapter one reviews the previous strategies employed by the Smith group toward the syntheses of the nodulisporic acid family. Lastly, the development of a modular and highly convergent strategy to access the nodulisporic acids exploiting a one-pot tandem Buchwald-Hartwig/Heck cascade to generate a common central indole core is described.

Chapter 2 will describe the development of a revised synthetic strategy to access the required western hemisphere chloroindoline for the synthesis of nodulisporic acid A.

Chapter 3 outlines the synthesis of the eastern hemisphere common to both nodulisporic acids A and D. The development of a new strategy for the construction of the C-3 and C-12 stereocenters now allow for the synthesis of sufficient quantity of the eastern hemisphere for coupling studies. Chapter 4 describes the development and implementation of an Enders alkylation and a Stille-Kelly coupling to generate the western hemisphere of nodulisporic acid D.

Chapter 5 disclosed our results attempting to implement the one-pot tandem Buchwald-Hartwig/Heck cascade to access nodulipsoric acids A and D. Furthermore, future plans for the further development of the Buchwald-Hartwig/Heck(Barluenga) cascade tactic are described.

N O

O HO

Me Me

Me

OH

CO2H Me Me

H

(+)-Nodulisporic Acid A H

O

TESO

Me Me

Me

OTES

CO2Me Me H

H Cl

NH

TIPSO _Me

(10)

! viii!

List of Schemes

Scheme 1.1 Indole Terpene Natural Products……….1

Scheme 1.2. 2D NMR Studies to Determine the Carbon Connectivity of (+)- Nodulisporic Acid A (NSAA)………...2

(12)

! x!

Scheme 1.4. Mavalonate Pathway………..…4

Scheme 1.5. Members of the Nodulisporic Acid Family………...5

Scheme 1.6. Nodulisporic Acid A Biosynthetic Pathway……….6

Scheme 1.7. Potent Insecticides……….7

Scheme 1.8. Pharmacophore………...8

Scheme 1.9. Medicinal Chemistry Aldehyde Intermediate and Thiazole Analog………...9

Scheme 1.10. Madelung Indole Synthesis………..10

Scheme 1.11. Smith Modified Madulung Indole Synthesis………10

Scheme 1.12. Penitrem D Indole Coupling Strategy………11

Scheme 1.13. Biomimetic Retrosynthetic Approach to (+)-Nodulisporic Acid A………12

Scheme 1.15. Synthesis of (+)-Nodulisporic Acid F………14

Scheme 1.16. Potential Disconnections to Synthesize the D-ring of (+)-Nodulisporic Acid A………..15

Scheme 1.17. C-24 Hydroxyl Lability………...16

Scheme 1.18. Revised Dissection of Nodulisporic Acid A………17

Scheme 1.19. CDE Tricycle Fused Indole Model Studies………..18

Scheme 1.20. Stille Coupling/Buchwald-Hartwig Cyclization Strategy Retrosynthetic Analysis………19

Scheme 1.21. Estrone Model Coupling Studies………...19

Scheme 1.22. Buchwald-Hartwig Indole Formation Studies……….20

Scheme 1.23. Overman Sulfinic Acid Ejection……….21

Scheme 1.24. One-Pot Barluenga Indole Formation………...22

Scheme 1.25. One-Pot Indole Formation Model Studies………23

Scheme 1.26. Third Generation Retrosythetic Analysis……….24

Scheme 2.1. The Stille/Buchwald-Hartwig Union Strategy………28

Scheme 2.2. Western Hemisphere Retrosynthetic Analysis……….29

Scheme 2.3. Second-generation Western Hemisphere Synthesis for Nodulisporic Acid A………..30

Scheme 2.4 Nodulisporic Acid A Second-generation Western Hemisphere Synthesis…....31

Scheme 2.5. Trifluorosulfinic Acid Ejection………..32

Scheme 2.6. Third Generation Buchwald-Hartwig/Heck Coupling Strategy……….34

Scheme 2.7. Retrosynthetic Analysis of Western Hemisphere 2.23………...35

Scheme 2.8. Enders Hydrazone Synthesis………35

Scheme 2.9. Enders SAMP Aldol……….……….36

Scheme 2.10. Third-Generation Western Hemisphere Synthesis………37

Scheme 2.11. The Third-Generation Western Hemisphere Synthesis (cont.)………..37

(13)

Scheme 2.13. Completion of the Fused Ring System of the Western Hemipshere…………40

Scheme 2.14. Completion of the Western Hemisphere………..41

Scheme 3.1. Eastern Hemisphere Retrosynthetic Analysis………..45

Scheme 3.2. C-4-Me-Weiland-Meischer Ketone………47

Scheme 3.3. Koga Protocol to Access the C-3/C12 Stereocenters……….48

Scheme 3.4. Cuprate Addition/Fluoride-Mediated Methylation………49

Scheme 3.5. Separation of Diastereomers……….50

Scheme 3.6. Comparison of Coupling Approaches……….51

Scheme 3.7. Third Generation Eastern Hemisphere Retrosynthetic Analysis……….52

Scheme 3.8. Third Generation Eastern Hemisphere Synthesis………53

Scheme 3.9. Third Generation Eastern Hemisphere Synthesis (cont.)………..54

Scheme 3.10. Failed Hydrolysis Recovery……….56

Scheme 3.11. Vinyl Cuprate Addition/Methylation………..57

Scheme 3.13. Horner-Wadsworth-Emmons Aldehyde Precursor………58

Scheme 3.14. Previous Synthesis of the Phosphonate Side Chain………59

Scheme 3.15. Side Chain Phosphonate Synthesis………..60

Scheme 3.16. Snapper Aldehyde Elaboration Strategy………..61

Scheme 3.17. Eastern Hemisphere Model………..62

Scheme 3.18. Eastern Hemisphere Model………..63

Scheme 3.19. Eastern Hemisphere Model Deprotection………64

Scheme 3.20. Completion of the Third Generation Hemisphere………..64

Scheme 4.1 Retrosynthetic Analysis of (–)-Nodulisporic Acid D……….69

Scheme 4.2 Retrosynthetic Analysis of the Western Hemipshere of (–)-Nodulisporic Acid D………..70

Scheme 4.3 Synthesis of 2-Chloro-4-iodo-aniline………71

Scheme 4.4 Synthesis of the Enders Alkylation Benzyl Bromide………72

Scheme 4.5 Enders Alkylation………...…73

Scheme 4.6 Synthesis of the Western Hemisphere of Nodulisporic Acid D……….74

Scheme 5.1. Buchwald-Hartwig/Heck Model Studies………..76

Scheme 5.2. Truncated Western Hemisphere/Estrone Model Coupling Studies……….77

Scheme 5.3. Nodulisporic Acid A Western Hemisphere/Estrone Model Coupling………….78

Scheme 5.4. Kurth Computational Studies………80

Scheme 5.5. Nodulisporic Acid D Mechanistic Possibilities……….81

Scheme 5.6. (–)-Nodulisporic Acid D Coupling……….83

Scheme 5.7. Truncated (–)-Nodulisporic Acid D Coupling………84

(14)

! xii!

List of Figures

A1.1. 1H NMR Spectrum of 2.11 in CDCl3………...………..137

A1.2. 1H NMR Spectrum of S2.1 in CDCl3……….138

A1.3. 13C NMR Spectrum of S2.1 in CDCl3………..139

A1.4. 1H NMR Spectrum of S2.2 in CDCl3……….140

A1.5. 13C NMR Spectrum of S2.2 in CDCl3………..141

A1.6. 1H NMR Spectrum of 2.9 in CDCl3………...142

A1.7. 13C NMR Spectrum of 2.9 in CDCl3……….143

A1.8. 1H NMR Spectrum of 2.12 in CDCl3……….144

A1.9. 13C NMR Spectrum of 2.12 in CDCl3………...145

A1.10. 1H NMR Spectrum of S2.3 in CDCl3………..146

A1.11. 13C NMR Spectrum of S2.3 in CDCl3………147

A1.12. 1H NMR Spectrum of (–)-2.13 in CDCl3……….148

A1.13. 13C NMR Spectrum of (–)-2.13 in CDCl3………..149

A1.14. 1H NMR Spectrum of S2.4 in CDCl3………..150

A1.16. 1H NMR Spectrum of (+)-2.8 in CDCl3………...152

A1.17. 13C NMR Spectrum of (+)-2.8 in CDCl3……….153

A1.18. 1H NMR Spectrum of S2.5 in CDCl3………..…………154

A1.20. 1H NMR Spectrum of S2.6 in CDCl3………..…156

A1.22. 1H NMR Spectrum of (+)-2.34 in CDCl3………158

A1.23. 13C NMR Spectrum of (+)-2.34 in CDCl3………159

A1.24. 1H NMR Spectrum of 2.35 in CDCl3……….…………160

A1.25. 13C NMR Spectrum of 2.35 in CDCl3………161

A1.26. 1H NMR Spectrum of S2.7 in CDCl3………..…………162

A1.27. 1H NMR Spectrum of S2.7 in CDCl3………..………163

A1.28. 1H NMR Spectrum of (+)-2.36 in CDCl3……….………164

A1.29. 13C NMR Spectrum of (+)-2.36 in CDCl3………..……165

A1.30. Infrared Spectrum of (+)-2.36 in CDCl3……….…166

A1.31. 1H NMR Spectrum of (+)-2.37 in CDCl3………..…..167

A1.32. 1H NMR Spectrum of (+)-2.37 in CDCl3………..…..…168

A1.33. Infrared Spectrum of (+)-2.37 in CDCl3……….………169

(15)

A1.35. 13C NMR Spectrum of (+)-3.32 in CDCl3………..………171

A1.36. 1H NMR Spectrum of 3.Ketodiol in CDCl3………...………172

A1.37. 1H NMR Spectrum of 3.Ketodiol in CDCl3………...……173

A1.38. 1H NMR Spectrum of (+)-3.4 in CDCl3………...…174

A1.39. 1H NMR Spectrum of 3.48 in CDCl3………...…175

A1.40. 1H NMR Spectrum of (+)-3.3 in CDCl3………...176

A1.41. 13C NMR Spectrum of (+)-3.3 in CDCl3……….……177

A1.42. Infrared Spectrum of (+)-3.3 in CDCl3………...……178

A1.43. 1H NMR Spectrum of (–)-3.23 in CDCl3……….……179

A1.44. Infrared Spectrum of (–)-3.23 in CDCl3……….……180

A1.47. Infrared Spectrum of S3.1 in CDCl3………...……183

A1.50. Infrared Spectrum of S3.2 in CDCl3………..……186

A1.52. Infrared Spectrum of S3.3 in CDCl3………...……188

A1.53. 1H NMR Spectrum of (–)-3.31 in CDCl3……….…………189

A1.54. 13C NMR Spectrum of (–)-3.31 in CDCl3………..…190

A1.55. Infrared Spectrum of (–)-3.31 in CDCl3……….………191

A1.56. 1H NMR Spectrum of S3.4 in CDCl3………..……192

A1.57. 13C NMR Spectrum of S3.4 in CDCl3……….………...………193

A1.58. Infrared Spectrum of S3.4 in CDCl3………...………194

A1.59. 1H NMR Spectrum of (–)-3.35 in CDCl3……….…………195

A1.60. 13C NMR Spectrum of (–)-3.35 in CDCl3………..………196

A1.61. Infrared Spectrum of (–)-3.35 in CDCl3……….………197

A1.62. 1H NMR Spectrum of S3.5 in CDCl3………..………198

A1.64. Infrared Spectrum of S3.5 in CDCl3………..…200

A1.65. 1H NMR Spectrum of S.36 in CDCl3………..………201

A1.67. Infrared Spectrum of S3.6 in CDCl3………..………203

A1.68. 1H NMR Spectrum of (–)-.330 in CDCl3……….………204

A1.69. 1CC NMR Spectrum of (–)-3.30 in CDCl3………..………205

A1.70. 1H NMR Spectrum of 2.42 in CDCl3………...………206

(16)

! xiv!

A1.72. 1H NMR Spectrum of 3.38 in CDCl3………...……208

A1.73. 13C NMR Spectrum of 3.38 in CDCl3……….……209

A1.74. 1H NMR Spectrum of 3.49 in CDCl3………...…………210

A1.79. 13C NMR Spectrum of 3.53 in CDCl3……….……215

A1.82. 1H NMR Spectrum of (–)3.26 in CDCl3………..………218

A1.83. 1H NMR Spectrum of 4.15 in CDCl3……….…..………219

A1.84. 13C NMR Spectrum of 4.15 in CDCl3………220

A1.85. Infrared Spectrum of 4.15 in CDCl3………...………221

A1.87. 13C NMR Spectrum of 4.16 in CDCl3……….………223

A1.89. 1H NMR Spectrum of 4.17 in CDCl3……….…………..…………225

A1.90. 13C NMR Spectrum of 4.17 in CDCl3……….………226

A1.92. 1H NMR Spectrum of 4.9 in CDCl3……….………228

A1.93. 13C NMR Spectrum of 4.9 in CDCl3………...………229

A1.94. Infrared Spectrum of 4.9 in CDCl3……….……230

A1.95. 1H NMR Spectrum of (+)-4.8 in CDCl3………...…231

A1.96. 13C NMR Spectrum of (+)-4.8 in CDCl3……….………232

A1.97. Infrared Spectrum of (+)-4.8 in CDCl3………...…233

A1.98. 1H NMR Spectrum of (–)-4.18 in CDCl3………234

A1.99. 13C NMR Spectrum of (–)-4.18 in CDCl3………..………235

A1.100. Infrared Spectrum of (–)-4.18 in CDCl3………...…………236

A1.101. 1H NMR Spectrum of (+)-4.19 in CDCl3………..…………237

A1.102. 13C NMR Spectrum of (+)-4.19 in CDCl3………238

A1.103. Infrared Spectrum of (+)-4.19 in CDCl3………...………239

A1.104. 1H NMR Spectrum of 4.20 in CDCl3……….……240

A1.105. 13C NMR Spectrum of 4.20 in CDCl3………..………241

A1.106. 1H NMR Spectrum of (–)-4.2 in C6D6………...…………242

A1.107. 13C NMR Spectrum of (–)-4.2 in C6D6……….…………243

(17)

(18)

CHAPTER 1. (+)-NODULISPORIC ACID A AND

(–)-NODULISPORIC ACID D – BACKGROUND

1.1. THE ISOLATION AND EVALUATION OF BIOLOGICAL ACTIVITY OF

THE NODULISPORIC ACID FAMILY

1.1.1. ISOLATION AND STRUCTURAL DETERMINATION BY MERCK

!

In 1997, the Merck Research Laboratories reported a novel insecticide, (+)-nodulisporic acid A (1.1), isolated from the fungus Nodulsporium sp.1_{Nodulisporic acid} A (NSAA) is a potent indole diterpene that bears resemblance to many other previously isolated indole terpene compounds (Scheme 1.1).2_{They all contain a central indole} unit, fused to a common tricycle eastern hemisphere.

Scheme 1.1 Indole Terpene Natural Products

! ! ! ! ! ! ! !

Two of the key structural differences of note are the additional ketopyrrolidine ring system that is fused to the indole portion of the molecule that appears to be unique to

N O HO H Me Me Me H OH OH O O

1.1 (+)-Nodulisporic Acid A

N H Me Me H O O H H OH H OH 9 9 N H Me Me H O O H OH 9 OH O

1.3 Penitrem D 1.4 Shearinine B

N H Me Me H O O OH 9 O

(19)

(+)-nodulisporic acid A, and the absence of the tertiary hydroxyl group at C-9, that is common in many of the other indole terpenes. When compared to the shearinine and janthritrem families of molecules, the western hemisphere is the same, but with the ring fusion inverted.

Nodulisporic acid A (+)-1.1 is comprised of 8 fused rings, with the fused tricyclic core standing out as a unique feature. Workers at Merck performed exhaustive studies to assign the structure of (+)-nodulisporic acid A. To confirm and fully elucidate the structure of (+)-nodulisporic acid A, COSY, TOCSY, HMBC, HMQC and INADEQUATE NMR studies were utilized to determine the carbon connectivity through the fused ring systems (Scheme 1.2).

Scheme 1.2. 2D NMR Studies to Determine the Carbon Connectivity of (+)-

Nodulisporic Acid A (NSAA)

ROESY and NOESY experiments in particular were used to determine the relative stereochemistries of the eastern and western hemispheres. The Merck group hoped that X-ray crystallography would permit determination of the absolute stereochemistry of (+)-nodulisporic acid A. In order to generate an X-ray quality crystal, reaction of the nodulisporic acid A methyl ester with bromobenzoyl chloride furnished the C-7 benzoate. The crystal of the nodulisporic acid A derivative permitted determination of

1.1 (+)-Nodulisporic Acid A COSY/TOCSY Correlations N O HO H H OH OH O O 9 3 12 10 18 19 24 23 1' _2' 1" 5" 6" 6 N O HO H H OH OH O O 9 3 12 10 18 19 24 23 1' _2' 1" 5" 6" 6

1.1 (+)-Nodulisporic Acid A 13_C-13_{C INADEQUATE}

(20)

the relative stereochemistry, but the quality of the crystal was not sufficient to permit assignment of the absolute stereochemistry. To determine the absolute stereochemistry, Mosher ester analysis3_{was applied at the C-7 hydroxyl group.}

1.1.2. DEGREDATION OF (+)-NODULISPORIC ACID A (NSAA)

!

During the course of the isolation and NMR experiments, the Merck group found that NSAA is sensitive to both light and oxygen, degrading to two major compounds (Scheme 1.3). The first degradation pathway entails oxidation of the highly strained central indole ring, which was observed to undergo oxidative cleavage of the fused ring system to give the 8-membered ketoamide ring. The stereochemistry of the dieneoate was also found to undergo isomerization during NMR experiments in CD3CN.

N O

HO H

H

OH

OH O

O O O

N O

HO H

H

OH O

O O

OH O

1.5 1.6

N O

HO

H Me

Me Me H

OH

OH O

O

1.1 (+)-Nodulisporic Acid A 9

(21)

1.2. PROPOSED BIOSYNTHESIS OF (+)-NODULISPORIC ACID A

1.2.1. PRECURSOR STUDIES

In 2001, Merck reported the successful elucidation of the biosynthetic pathway for the synthesis of (+)-nodulisporic acid A.4_{The workers at Merck were able to access}13_C enriched (+)-nodulisporic acid A utilizing 2-13_C-acetate _{1.7, that is known to be} metabolized via the mevalonate pathway (Scheme 1.4). The mevalonate pathway is essential for the conversion of acetate to isopentenylpyrophosphate 1.8, which is the crucial intermediate in the synthesis of all terpenoid natural products.

Scheme 1.4. Mavalonate Pathway

Using this strategy, each isoprenyl group that is incorporated into the molecule would have an enhanced 13_{C NMR signal. It was confirmed that the eastern hemisphere,} western hemisphere and indoline ring system all arose from isopentenylpyrophosphate.

N O

HO H

H

OH

OH O

O

1.1 (+)-Nodulisporic Acid A 9 O

O O

O OH OH

OPP

PPO

1.7 1.8

1.9

(22)

To determine if the central indole was derived from tryptophan, 13_{C enriched tryptophan} was prepared, as has been employed previously to determine the origin of the indole in similar molecules. No 13_{C incorporation was observed; Merck then turned their attention} to the possibility that anthranilic acid was the indole precursor. This work demonstrated that the indole ring is actually generated from anthranilic acid and ribose.

1.2.2. ISOLATION OF RELATED MEMBERS OF THE NODULISPORIC ACID

FAMILY

!

During the isolation and biosynthetic studies, related members of the nodulisporic acid family of molecules were isolated, giving clues about the biosynthetic pathway (Scheme 1.5).5_{The simplest member of the family is (+)-nodulisporic acid F}_(1.12), which is comprised of only the central indole ring and the eastern hemisphere. Nodulisporic acid D [(–)-1.11] was also isolated, whereas the western hemisphere is now appended. It is believed that both of these compounds are intermediates on the pathway to (+)-nodulisporic acid A (1.1).

Scheme 1.5. Members of the Nodulisporic Acid Family

N O

O HO

Me Me

Me OH

CO₂H Me Me

H

3 12

1' 2'

H 24

N H

O _{Me Me}

OH Me H

H

N H

Me Me OH Me H

H

CO2H Me

H

CO2H Me 1.1 (+)-Nodulisporic Acid A

1.11 (–)-Nodulisporic Acid D

(23)

Merck proposed that beginning with (+)-nodulisporic acid F (1.12), the indole ring is bis-prenylated to furnish nodulisporic acid E (1.13, Scheme 1.6). Following bis-prenylation, the isoprenyl group is then oxidized twice and in turn undergoes cyclization to form the bicyclic western hemisphere. Subsequently, the allylic position of the side-chain is oxidized and eliminated to provide (–)-nodulisporic acid D (1.11). Prenylation of the indole would then lead to nodulisporic acid C (1.14). After an oxidation, cyclization onto the nitrogen of the indole and elimination would complete the synthesis of (+)-nodulisporic acid A (1.1).

Scheme 1.6. Nodulisporic Acid A Biosynthetic Pathway

N H

O _{Me Me}

OH Me H H

H

CO₂H Me

1. Prenylation 2. [O]

N H

O _{Me Me}

OH Me H H

H

CO₂H Me

Me Me HO

1. [O] then phosphorylation 2. SN2' 3. [O] N H Me Me OH Me H H

CO₂H Me 1.12 (+)-Nodulisporic Acid F

N H Me Me OH Me H H

CO₂H Me 1.13 Nodulisporic Acid E Bis-Prenylation

1. [O] 2. Cyclization 3. Allylic [O] 4. Elimination

1.11 (–)-Nodulisporic Acid D

1.14 Nodulisporic Acid C

N O O HO Me Me Me OH

CO₂H Me Me

H

(24)

1.3. BIOLOGICAL ACTIVITY AND MEDICINAL CHEMISTRY STUDIES

1.3.1. BIOLOGICAL ACTIVITY OF (–)-NODULISPORIC ACID A

Shortly after isolation, (–)-nodulisporic acid A (1.1) was discovered to have very promising biological activity against fleas. In fact, in some studies, (–)-nodulisporic acid actually performed better than the well-known, very potent, insecticide, ivermectin (1.15)6_{. Both ivermectin and (–)-nodulisporic acid A were subsequently determined to} have similar modes of action. They both selectively target an insect specific glutamate gated chloride channel. Their interaction with the chloride channel disrupts the normal trans-membrane electrolyte potential, leading to cell death, mainly in neurons. Nodulisporic acid A was also shown to be more selective than ivermectin, possibly hitting only a subset of channels that ivermectin is active against. However, in analogous GABA-gated chloride channels, ivermectin is still highly active, while nodulisporic acid A shows little to no activity.

Scheme 1.7. Potent Insecticides

O O

OH OH O

O O O

H O

O O O O HO

1.15 Ivermectin B1a

N O

O HO

Me Me

Me OH

CO₂H Me Me

H

(25)

1.3.2. MEDICINAL CHEMISTRY STUDIES

!

Following the promising results of the initial biological studies, Merck decided to undertake a medicinal chemistry campaign to determine the key components to the noduliporic acid A pharmacophore.

Scheme 1.8. Pharmacophore

These studies demonstrated that any modification to the core structure resulted in

significantly less active compounds in the flea assays (Scheme 1.8). More interesting however, the Merck group found that a large range of modifications were permissible at

the dienoate side-chain, the latter prepared by the oxidative cleavage of the dienoic acid to aldehyde 1.17 (Scheme 1.9).7_{The aldehyde was then employed as a handle to} construct analogs with novel, unnatural side chains. Analogs with simple substitutions, such as conversion of the carboxylic acid to a dimethyl ester, or more complex substitutions, such as thiazol 1.18, revealed increased potency against ticks.8

N O

O HO

Me Me

Me OH

CO2H Me Me

H

(+)-Nodulisporic Acid A 1.1 3

12

1' 2'

H 24

Modification Impermissible

(26)

Scheme 1.9. Medicinal Chemistry Aldehyde Intermediate and Thiazole Analog

1.4. THE FIRST GENERATION SMITH SYNTHESIS FOR (+)-NODULISPORIC

ACID A

1.4.1. APPLICATION OF THE SMITH–MODIFIED MADELUNG INDOLE

SYNTHESIS

The Smith group has had a long-standing interest in the synthesis of indole terpene natural products.9,_!10,11_{The group has successfully demonstrated how the application of} a modified Madelung indole synthesis can be a powerful strategy for the construction of very complex natural products. The original Madelung indole synthesis typically proceeds by treatment of an acylated toluyl aniline with strong base at high temperatures to generate the desired indole (Scheme 1.10). Extremely harsh reaction conditions are required to generate the dianion intermediate and in turn eliminate water to achieve aromatization to the indole.

CO₂H Me Me

H

N O O TESO Me Me Me OTES Me H H H O OH 1. KMnO4, H2O,

CH2Cl2, Alumina 2. TESOTf N O O TESO Me CHO Me Me OTES Me H H H KMnO4, H2O,

CH2Cl2, Alumina

1.16 1.17 N O O HO Me Me Me OH Me H H H N S _O N

(27)

Scheme 1.10. Madelung Indole Synthesis

!

These conditions would hardly be applicable in the context of complex natural product synthesis. The Smith group recognized that if the dianion derived from a 2-alkyl-N-trimethylsilyl aniline were treated with an ester, the resulting intermediate could undergo an aza-Peterson olefination, at lower temperatures than a typical Madulung indole reaction, and then tautomerize to generate the indole under much milder conditions.

Scheme 1.11. Smith Modified Madulung Indole Synthesis

NH 2 equiv base TMS N TMS OR2 O R1 N TMS Li Li R1 O Li N Si Me3 O R1 Li aza-Peterson Olefination N R1 N H R1 Tautomerization

1.25 1.26 1.27

1.28 1.29 1.30

R2 NH R1 O 2 equiv base R2 N R1 O N R2 O R1 N H R2 O R1 Protonation N H R1 R2 Elimination

of H2O and tautomerization M

M

1.20 1.21 1.22

(28)

The Smith modified Madelung indole formation/union strategy would go on to be used in many indole natural products in the Smith Laboratories. One case that truly highlights the high degree of complexity that can be successfully incorporated into the coupling fragments is the synthesis of penitrem D (Scheme 1.12).10_{In this case, aniline fragment} 1.31 was first metalated with n-BuLi. The lithium anion of the aniline was then trapped as the tetramethylsilyl aniline using chlorotetramethylsilane. Both the benzylic position and the TMS aniline were then deprotonated utilizing sec-BuLi to generate the dianion. The dianion intermediate was in turn reacted with lactone 1.32 to generate the aza-Peterson olefination precursor. Treatment with silica gel completed construction of the highly functionalized indole 1.33 in a very good yield via an in situ aza-Peterson olefination, which was then carried forward to complete the total synthesis of pentram D.

Scheme 1.12. Penitrem D Indole Coupling Strategy

OTMS H H

NH2 O

O O

H

OH

OTES H

H TIPSO

H

1. i. 1.1 eq. n-BuLi, THF –78 °C → r.t. ii. 1.1 eq. TMSCl, 0 °C iii. 2.1 eq. s-BuLi, 0 °C iv. 0.1 eq. 1.32 THF-Et2O (1:1), 0 °C 2. Silica Gel, CHCl3 81 % from 1.32

OTMS H H H TIPSO

N

H HO

O HO

H H

OTES

(29)

1.4.2. RETROSYNTHETIC ANALYSIS OF (+)-NODULISPORIC ACID D:

APPLICATION OF THE SMITH MODIFIED MADELUNG INDOLE

SYNTHESIS

!

Taking inspiration from successful generation of the highly functionalized indole

intermediate of penitrem D, the Smith group turned their attention to applying the

coupling strategy to other complex indole terpenes. The first generation strategy taken

by the Smith group for (+)-nodulisporic acid A was inspired by the proposed

biosynthesis (Scheme 1.13).

Scheme 1.13. Biomimetic Retrosynthetic Approach to (+)-Nodulisporic Acid A

CO2H Me Me H H H N H

O _{Me Me}

OH Me H H

H

CO2H Me

1. Prenylation

2. [O] _N

H

O _{Me Me}

OH Me H H

H

CO2H Me

Me Me

HO

1. [O] then phosphorylation 2. SN2'

3. [O] C E C E D N H

O _{Me Me}

OTBS Me H

H

H TESO

1.14 Nodulisporic Acid C 1.11 (–)-Nodulisporic Acid D

O _{Me Me}

(30)

The medicinal chemistry studies on (+)-nodulisporic acid A done at Merck suggested

that the dienoic acid could be installed at the end of the synthesis. As there was no

precedent for the synthesis of the highly strained CDE fused tricyclic core, the first strategy required focus on generating the full ring system of NSAA without ring D. Then, as in nature, the D ring would be generated from intermediate 1.34, which contains all of the remaining carbons of the fused ring system of (+)-nodulisporic acid A. It was

envisioned that indole 1.34 could be constructed utilizing the Smith modified Madelung indole synthesis from aniline 1.35 and lactone 1.36.

1.4.3. THE SYNTHESIS OF (+)-NODULISPORIC ACID F: A MODEL STUDY

To determine if the indole coupling strategy might be viable to access the nodulisporic

acid family of natural products, the Smith group reasoned that the coupling strategy

should first be attempted on one of the biosynthetic precursors to (+)-nodulisporic acid

A. Efforts toward the synthesis of (+)-nodulisporic acid F were thus initiated as a proof

of concept (Scheme 1.13).12_! _{The eastern hemisphere} _(1.38)_{, envisioned as the}

precursor for the coupling strategy, would be similar for all of the members of

nodulisporic acid family of molecules. The major differences between the nodulisporic

(31)

Pleasingly, the indole formation strategy proved viable for (+)-nodulisporic acid F (1.12),

however the aza-Peterson olefination did not procede precisedly as anticipated

(Scheme 1.15), presumably due to the steric congestion at the C-3 quaternary center.

Fortunately, the desired indole was still accessible employing an acid catalyzed

dehydration of the initially derived ketoaniline 1.39. The synthesis of (+)-nodulisporic

acid F was then completed in six steps from indole 1.40.

Scheme 1.15. Synthesis of (+)-Nodulisporic Acid F

1.4.4. PROBLEMS ASSOCIATED WITH THE D-RING FORMATION

VIS-A-VIS THE SMITH-MODIFIED MADELUNG INDOLE SYNTHETIC STRATEGY

!

Confident that the central indole could be formed through the Smith modified Madelung

indole synthesis strategy, attention turn to potential strategies to construct the D-ring of

(+)-nodulisporic acid A13_{(Scheme 1.16). Retrosynthetic strategies to dissect the D-ring}

Me Me OTBS Me H O H O NH2 Me 1.37 1.38 Me Me OTBS Me H H OH NH2 O i. n-BuLi (1 eq.)

ii. TMSCl iii. s-BuLi (2.1 eq.) iv. 1.36 98% 1.39 Me Me OTBS Me H H OH N H p-TsOH (5 mol%)

reflux, 95% 1.40 N H Me Me OH Me H H

CO₂H Me 1.12 (+)-Nodulisporic Acid F 6 steps Me Me OTBS Me H O H O NH2 Me 1.37 1.38 N H Me Me OH Me H H

CO₂H Me

1.12 (+)-Nodulisporic Acid F Smith-modified

Madelung Indole Synthesis

(32)

through cleavage of the three possible bonds were considered. If the “a” bond were to be dissected, the D-ring could possibly be accessed through a carbonylative Heck process using a vinyl halide and an enamine precursor.

Scheme 1.16. Potential Disconnections to Synthesize the D-ring of (+)-Nodulisporic Acid A

If bond “b” was dissected, the D-ring could possibly be constructed through an intermolecular Dieckmann condensation of a diester precursor. Dissection of the bond “c” on the other hand would lead to two possible synthetic strategies to form the D-ring. One strategy would entail cyclization to the indole via an alkyl halide in an SN2 fashion. The other possibility would be a rhodium catalyzed carbene addition to the indole nitrogen. All of these strategies were investigated, but unfortunately none proved promising.

N H O

N2

N H O

Br N Br

N MeO2C

N

X R

a c

b

N O

N O N

O CO2Me

bases Rh catalysts

bases Pd0_{, CO}

Me

CO2Me

C D

E

Disconnection a:

Carbonylative Heck Cyclization

Disconnection b:

Intramolecular Dieckmann Condensation

Disconnection c:

D D

(33)

Another potential issue was discovered when attempting the Smith indole synthesis for

the construction of (–)-nodulisporic acid A.14_{Specifically, the C-24 hydroxyl group in the}

western hemisphere proved extremely labile (Scheme 1.17). When C-24 hydroxyl

group was protected as the TES ether, exposure to strong base during the indole

syntheses led to elimination. The elimination problem was circumvented by the use of

the free hydroxyl, wherein the trianion of aniline 1.41 permitted the coupling reaction to

proceed without perturbing the C-24 alcohol. After generating ketoaniline 1.42, attempts

to remove the Boc group and close the indole ring under acidic conditions also led to

the elimination of the C-24 hydroxyl. This result, along with the difficult D-ring synthesis,

led the Smith group to reevaluate their coupling strategy.

Scheme 1.17. C-24 Hydroxyl Lability

Me Me Me H O H O 1.36 OTBS OTBS O LiO

CH2Li

NLi Boc H

HMPA, Et2O, –25 °C

(34)

1.5. A SECOND–GENERATION SMITH APPROACH: A

STILLE/BUCHWALD-HARTWIG COUPLING STRATEGY

1.5.1. MODEL STUDIES FOR THE FORMATION OF THE CDE TRICYCLIC

CORE OF (+)-NODULISPORIC ACID A

A second-generation strategy was developed based on the lessons learned from the

Madelung indole synthesis approach. The CDE strained tricyclic core would have to be

approached via a different tactic (Scheme 1.18).13 Instead of dissecting through the D

-ring to form the indoline, a dissection through the E-ring to generate the indole ring with

the pyrrolidine ring already fused to the C-ring was envisioned (Scheme 1.18).

Scheme 1.18. Revised Dissection of Nodulisporic Acid A

A multi-step approach was developed in a model system to determine how to generate

such a ring system (Scheme 1.19). First, stannylindoline 1.45 was found to undergo a

palladium catalyzed Stille coupling with iodoenone 1.46 to furnish enone 1.47.

Reduction of the enone in a 1,4 fashion with L-Selectride, followed by trapping with the

Comins reagent15_{led to vinyl triflate}_1.48_{. The Boc group was then removed with}

trimethylsilyl iodide to reveal the unprotected indoline 1.49. Subjecting 1.49 to

N O

O HO

Me Me

Me

OH

CO₂H Me Me

H

C E D

1.1 (+)-Nodulisporic Acid A Stille/Buchwald-Hartwig

Approach Dissection

(35)

Buchwald-Hartwig conditions completed the construction of the E-ring to produce the

tricyclic core 1.50 in an acceptable yield (ca. 55%).

Scheme 1.19. CDE Tricycle Fused Indole Model Studies

1.5.2. ANALOG MODEL STUDIES EXPLORATION ESTRONE

!

Following the model studies to determine a strategy to access the central tricyclic ring

system, new eastern and western hemispheres were proposed (Scheme 1.20). Smith

envisioned that (+)-nodulisporic acid A (1.1) could still be dissected at the indole ring,

now with the possibility of devising hemispheres containing a higher degree of

complexity.16 The requisite hemispheres for the new coupling strategy would comprise

a western hemisphere stannylindoline (1.51) and an eastern hemisphere iodoenone

(1.52).

SnBu₃

O I +

L-Selectride -78 °C;

TMSI

CH2Cl2, –78 °C (90%)

Pd2(dba)3, Xantphos

Cs2CO3, THF (55%)

N NBoc

NBoc NH

NBoc

OTf OTf

O

N NTf Tf

Cl _Comins' reagent

(87%) Pd2(dba)3, P(2-tol)3, CuI

N-Methylpyrrolidone (NMP) 120 °C, 2 h (80%)

1.45 1.46 1.47

(36)

Scheme 1.20. Stille Coupling/Buchwald-Hartwig Cyclization Strategy Retrosynthetic Analysis

Following completion of the synthesis of the western hemisphere 1.51 by Dr. Vlad Simov, a model system employing estrone was developed, to determine if the multistep

coupling tactic would be compatible with more complex substrates (Scheme 1.21). Towards this end, an estrone derived eastern hemisphere model system (1.54) was proposed as an alternative for iodoenone 1.52.

Scheme 1.21. Estrone Model Coupling Studies

N O HO Me Me Me OH

CO₂H Me Me H H O TBSO Me Me Me OTBS H H O SnBu3 NH SEMO _Me I O H H ● ● 1.51 1.52 OTBS

I Me H H H OMe O O TBSO SnBu3 H

1. NiCl2•6H2O

NaBH4

MeOH/THF, rt (94%)

2. BTPP, PhNTf2

THF, 90 °C (58%)

O TBSO Me H H H OMe OTf H O TBSO Me H H H OMe OTf H TMSOTf 2,6-di-t-Bu-4-Me

-pyridine

CH2Cl2, 0 °C

NBoc TESO NBoc SEMO SEMO TESO NH SEMO TESO O TBSO Me H H H OMe O

Pd2(dba)3

P(2-furyl)3, CuI

(37)

Stille coupling of stannane 1.53 with iodoenone 1.54 led to enone 1.55. L-Selectride

however was found to be ineffective for the required conjugate reduction of enone 1.55.

Fortunately, this tranformation could be accomplished with nickel boride. Following the

reduction, the resulting ketone was subjected to enolization with the bulky phosphazine

base (BTPP) and trapped as vinyl triflate (1.56) with phenyl triflamide. The Boc group

was then removed with TMSOTf to reveal the free indoline 1.57.17,18,16

With 1.57 in hand, having the first of the two bonds constructed, the Buchwald-Hartwig

ring closure was attempted on the estrone model system (Scheme 1.22). Unfortunately,

none of the desired coupling product was observed. Instead, enone 1.55 was assigned

to be the major product.

Scheme 1.22. Buchwald-Hartwig Indole Formation Studies

NH O

TBSO SEMO

OTf

OMe

OTES H

Pd2(dba)3 Xantphos, Cs2CO3

THF/dioxane, 90 °C 1.5 hr

N O

H TBSO

SEMO TBSO

Me

OMe

NH

SEMO

O Me

S O

O CF3

TESO

N

SEMO O

Me

TESO H

NH O

TBSO SEMO

O

OMe

OTES H

1.57

1.58

(38)

This observation suggests that oxidative addition into the vinyl triflate was very slow,

and instead the ß position was deprotonated, leading to the ejection of sulfinic acid.

While this result was surprising, it was not without precedent. Overman reported a

similar reaction with vinyl triflates to generate enones (Scheme 1.23). 19

Scheme 1.23. Overman Sulfinic Acid Ejection

1.6. A THIRD GENERATION SMITH APPROACH – A ONE-POT

BUCHWALD-HARTWIG/HECK CASCADE REACTION

1.6.1. INTRODUCTION OF THE BARLUENGA ONE-POT INDOLE

SYNTHESIS

In 2005, Barluenga reported a novel method for the one-pot synthesis of indoles from

vinyl bromides and chloroanilines20_{(Scheme 1.24)}_{. The report comprised the reactions}

of vinyl bromides, principally bromoanilines with some attention given to the

choroanilines. Barluenga, et al. found that in the bromoaniline case, the cyclization step

would only take place when DavePhos was employed as the ligand. Alternatively when

choroanilines were required as the coupling partner, DavePhos was found to be

ineffective. The ligand XPhos proved to be the best ligand for the cyclization with

chloroaniline, suggesting that indole construction might be highly ligand specific. We

thus envision that some optimization would be necessary if we were to attempt to apply

the Barluenga coupling strategy to the nodulisporic acid family.

OTf O

SPh SPh

2,6-lutidine DMSO, 80 °C

(39)

Scheme 1.24. One-Pot Barluenga Indole Formation

Barluenga also reported that sodium tert-butoxide was the optimum base in all cases. Multiple solvent systems could also be tolerated, as both dioxane and toluene were shown to proceed with similar yields. The reaction was also reported to tolerate substitution at the 1 or the 2 position of the vinyl halide, but disubstituted vinyl halides were not viable substrates.

1.6.2. MODEL STUDIES TO ASSESS THE FEASIBLITY OF A ONE-POT

INDOLE FORMATION STRATEGY

!

We reasoned that the Barluenga strategy had promise, but the original report still held some drawbacks. If we were to apply the Buchwald-Hartwig/Heck cascade to the real system, 1,2-disubstituted vinyl halides would have to be permissible in the reaction. Initial studies to determine if the Barluenga strategy could be applied to the nodulisporic acid family were undertaken by Drs. Steve Gonzales and Junha Jeon.18 Model studies were initially conducted using 2-bromoindoline as the western hemisphere; the vinyl triflate derived from estrone was employed to model the eastern hemisphere of nodulisporic acid A.

Br

NH2 Br Ph N

H Ph Pd2(dba)3, DavePhos

NaOt-Bu toluene, 100 °C, 24 h

(64%)

Br

NH2 Cl Ph N

H Ph Pd2(dba)3, XPhos

NaOt-Bu toluene, 110 °C, 20 h

(65%)

1.56 1.57 1.58

(40)

Scheme 1.25. One-Pot Indole Formation Model Studies

Initially they found that under a series of screened conditions, the bromoindoline

unfortunately coupled with itself preferentially. To lower the reactivity of the indoline

fragment, chloroindoline was chosen as the coupling partner (Scheme 1.23). Pleasingly

they now discovered that the coupling could be achieved with either RuPhos or XPhos

as the ligand, employing either toluene or dioxane. These observations suggested that

we might have some flexibility with reaction conditions as we moved to more

complicated substrates.

1.6.3. A REVISED RETROSYNTHETIC ANALYSIS

To employ the one-pot Buchwald-Hartwig/Heck (Barluenga) coupling strategy, we

envisioned chloroanine 1.62 as the western hemisphere and vinyl bromide 1.63 as the

eastern hemisphere.

Pd2dba3

RuPhos or XPhos

NaOt-Bu, PhMe 110 °C

(40%)

OMe H H

H Me Br NH Cl

N

OMe H H

H Me

(41)

Scheme 1.26. Third Generation Retrosythetic Analysis

!

The chapters that follow will report our progress on the nodulisporic acid A synthetic program. Specifically I achieved:

A) Revision of the required protecting group strategy that led to completion of a third-generation synthesis of the western hemisphere of (+)-nodulisporic acid A (Chapter 2);

B) Optimization of a 2-step cuprate addition/methylation procedure to permit consistent access the C-3/C-12 stereogenic centers required for the successful synthesis the eastern hemisphere common to (+)-nodulisporic acid A and (–)-nodulisporic acid D (Chapter 3);

C) The total synthesis of the complete common eastern hemisphere for noduliporic acids A and D (Chapter 3);

D) Completion of the third-generation synthesis for the western hemisphere of nodulispoic acid D (Chapter 4) and

E) Studies to explore the application of the one-pot Buchwald-Hartwig/Heck (Barluenga) union strategy. (Chapter 5)

N O

O HO

Me

Me Me

OH

CO2H

Me Me

H

(+)-Nodulisporic Acid A 1.1

3 12

1' 2'

H 24

O

TESO

Me

Me Me

OTES

CO₂Me

Me H

H Cl

NH

TIPSO _Me

H

Br

(42)

1.7. REFERENCES FOR CHAPTER 1

!

1. Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goetz, M. A.; Zink, D. L.;

Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski, A. W.; Polishook, J. D.; Ostlind,

D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B., Nodulisporic Acid A, a Novel and Potent

Insecticide from a Nodulisporium Sp. Isolation, Structure Determination, and Chemical

Transformations. J. Am. Chem. Soc. 1997,119 (38), 8809-8816.

2. (a) De Jesus, A. E.; Steyn, P. S.; Van Heerden, F. R.; Vleggaar, R.; Wessels, P.

L.; Hull, W. E., Structure and biosynthesis of the penitrems A-F, six novel tremorgenic

mycotoxins from Penicillium crustosum. J. Chem. Soc., Chemical Communications 1981, (6), 289-291; (b) Belofsky, G. N.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F., Antiinsectan alkaloids: Shearinines A-C and a new paxilline derivative from the

ascostromata of Eupenicillium shearii. Tetrahedron 1995,51 (14), 3959-3968. 3. Dale, J. A.; Dull, D. L.; Mosher, H. S.,

.alpha.-Methoxy-.alpha.-trifluoromethylphenylacetic acid, a versatile reagent for the determination of

enantiomeric composition of alcohols and amines. The J. Org. Chem. 1969,34 (9), 2543-2549.

4. Byrne, K. M.; Smith, S. K.; Ondeyka, J. G., Biosynthesis of Nodulisporic Acid A:

Precursor Studies. J. Am. Chem. Soc. 2002,124 (24), 7055-7060.

5. Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha, S. N.;

Dahl-Roshak, A.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W.; Tkacz, J. S., Nodulisporic

(43)

6. Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y.; Hunt, D. C.; Ayer, M.

B.; Wallace, M. A.; Chaudhary, A. G.; Egan, M. A.; Meinke, P. T.; Dean, D. C.; Garcia,

M. L.; Cully, D. F.; Smith, M. M., Ivermectin and Nodulisporic Acid Receptors in

Drosophila melanogaster Contain Both g-Aminobutyric Acid-Gated Rdl and

Glutamate-Gated GluClg Chloride Channel Subunits. Biochem. 2002,41 (20), 6548-6560.

7. Chakravarty, P. K.; Tyagarajan, S.; Shih, T. L.; Salva, S.; Snedden, C.; Wyvratt,

M. J.; Fisher, M. H.; Meinke, P. T., Synthesis of Side Chain Truncated 3' '-Aldehyde, 3'

'-Carboxylic Acid, and 1' '-Aldehyde from Nodulisporic Acid A. Org. Lett. 2002,4 (8),

1291-1294.

8. Berger, R.; Shoop, W. L.; Pivnichny, J. V.; Warmke, L. M.; Zakson-Aiken, M.;

Owens, K. A.; deMontigny, P.; Schmatz, D. M.; Wyvratt, M. J.; Fisher, M. H.; Meinke, P.

T.; Colletti, S. L., Synthesis of Nodulisporic Acid 2"-Oxazoles and 2"-Thiazoles. Org.

Lett. 2001,3 (23), 3715-3718.

9. Smith, A. B.; Cui, H., Total Synthesis of (−)-21-Isopentenylpaxilline. Org. Lett.

2003,5 (4), 587-590.

10. Smith, A. B.; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz, R. A.;

Cho, Y. S.; Cui, H.; Moser, W. H., Tremorgenic Indole Alkaloids. The Total Synthesis of

(−)-Penitrem D. J. A Chemical Society 2003,125 (27), 8228-8237.

11. Smith, A. B.; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J., Total syntheses of

(+)-paspalicine and (+)-paspalinine. J. Am. Chem. Soc. 1990,112 (22), 8197-8198.

12. Smith, A. B.; Davulcu, A. H.; Kurti, L., Indole Diterpenoid Synthetic Studies. The

Total Synthesis of (+)-Nodulisporic Acid F. Org. Lett. 2006,8 (8), 1665-1668.

13. Smith, A. B.; Kurti, L.; Davulcu, A. H.; Cho, Y. S.; Ohmoto, K., Indole Diterpene

Synthetic Studies: Development of a Second-Generation Synthetic Strategy for

(44)

14. Smith, A. B.; Davulcu, A. H.; Kurti, L., Indole Diterpenoid Synthetic Studies.

Construction of the Heptacyclic Core of (-)-Nodulisporic Acid D. Org. Lett. 2006,8 (8),

1669-1672.

15. Comins, D. L. D., Ali, Pyridine-derived triflating reagents: An improved

preparation of vinyl triflates from metallo enolates. Tetrahedron Lett. 1992,33 (42),

6299–6302.

16. Simov, V. Part 1. Total Synthesis of (-)-Clavosolide A; Part 2. Synthesis of the

Western Hemisphere of (+)-Nodulisporic Acid A. University of Pennsylvania,

Philadelphia, 2009.

17. Jeon, J., Unpublished Results. University of Pennsylvania: 2012.

18. Gonzales, S. Synthetic Studies Of (+)-Nodulisporic Acid A: Development Of An

Efficient Route To Eastern Hemisphere Sub-Targets. University of Pennsylvanita, 2011.

19. Hynes, J.; Nasser, T.; Overman, L. E.; Watson, D. A., Preparation of α-Sulfenyl

Enones by Thermal Fragmentation of β-Sulfenyl Enol Triflates. Org. Lett.2002,4 (6),

929-931.

20. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C., Cascade Alkenyl

Amination/Heck Reaction Promoted by a Bifunctional Palladium Catalyst: A Novel

One-Pot Synthesis of Indoles from o-Haloanilines and Alkenyl Halides. Chem. Eur. J. 2005,

11 (8), 2276-2283.

!

Studies Toward the Synthesis of Nodulisporic Acids A and D

University of Pennsylvania

ScholarlyCommons

Publicly Accessible Penn Dissertations

1-1-2014

Studies Toward the Synthesis of Nodulisporic

Acids A and D

Jason Melvin

Follow this and additional works at:

http://repository.upenn.edu/edissertations

Part of the

Organic Chemistry Commons

Recommended Citation

Studies Toward the Synthesis of Nodulisporic Acids A and D

TABLE OF CONTENTS

List of Schemes

List of Figures

CHAPTER 1. (+)-NODULISPORIC ACID A AND

(–)-NODULISPORIC ACID D – BACKGROUND

1.1. THE ISOLATION AND EVALUATION OF BIOLOGICAL ACTIVITY OF

THE NODULISPORIC ACID FAMILY

1.1.1. ISOLATION AND STRUCTURAL DETERMINATION BY MERCK

Scheme 1.2. 2D NMR Studies to Determine the Carbon Connectivity of (+)-

1.1.2. DEGREDATION OF (+)-NODULISPORIC ACID A (NSAA)

1.2. PROPOSED BIOSYNTHESIS OF (+)-NODULISPORIC ACID A

1.2.1. PRECURSOR STUDIES

1.2.2. ISOLATION OF RELATED MEMBERS OF THE NODULISPORIC ACID

FAMILY

Scheme 1.6. Nodulisporic Acid A Biosynthetic Pathway

1.3. BIOLOGICAL ACTIVITY AND MEDICINAL CHEMISTRY STUDIES

1.3.1. BIOLOGICAL ACTIVITY OF (–)-NODULISPORIC ACID A

1.3.2. MEDICINAL CHEMISTRY STUDIES

Scheme 1.8. Pharmacophore

Scheme 1.9. Medicinal Chemistry Aldehyde Intermediate and Thiazole Analog

1.4. THE FIRST GENERATION SMITH SYNTHESIS FOR (+)-NODULISPORIC

ACID A

1.4.1. APPLICATION OF THE SMITH–MODIFIED MADELUNG INDOLE

SYNTHESIS

Scheme 1.12. Penitrem D Indole Coupling Strategy

1.4.2. RETROSYNTHETIC ANALYSIS OF (+)-NODULISPORIC ACID D:

APPLICATION OF THE SMITH MODIFIED MADELUNG INDOLE

SYNTHESIS

Scheme 1.13. Biomimetic Retrosynthetic Approach to (+)-Nodulisporic Acid A

1.4.3. THE SYNTHESIS OF (+)-NODULISPORIC ACID F: A MODEL STUDY

1.4.4. PROBLEMS ASSOCIATED WITH THE D-RING FORMATION

VIS-A-VIS THE SMITH-MODIFIED MADELUNG INDOLE SYNTHETIC STRATEGY

Scheme 1.17. C-24 Hydroxyl Lability

1.5. A SECOND–GENERATION SMITH APPROACH: A

STILLE/BUCHWALD-HARTWIG COUPLING STRATEGY

1.5.1. MODEL STUDIES FOR THE FORMATION OF THE CDE TRICYCLIC

CORE OF (+)-NODULISPORIC ACID A

1.5.2. ANALOG MODEL STUDIES EXPLORATION ESTRONE

Scheme 1.22. Buchwald-Hartwig Indole Formation Studies

Scheme 1.23. Overman Sulfinic Acid Ejection

1.6. A THIRD GENERATION SMITH APPROACH – A ONE-POT

BUCHWALD-HARTWIG/HECK CASCADE REACTION

1.6.1. INTRODUCTION OF THE BARLUENGA ONE-POT INDOLE

SYNTHESIS

1.6.2. MODEL STUDIES TO ASSESS THE FEASIBLITY OF A ONE-POT

INDOLE FORMATION STRATEGY

Scheme 1.25. One-Pot Indole Formation Model Studies

1.6.3. A REVISED RETROSYNTHETIC ANALYSIS

Scheme 1.26. Third Generation Retrosythetic Analysis

1.7. REFERENCES FOR CHAPTER 1