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2017 Thermal Cycloisomerizations of 1,6-Enynes for the Synthesis of Illudinine and Other High-Value Polycyclic Aromatic Structures Alec Edouard Morrison

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COLLEGE OF ARTS AND SCIENCES

THERMAL CYCLOISOMERIZATIONS OF

1,6-ENYNES FOR THE SYNTHESIS OF ILLUDININE AND

OTHER HIGH-VALUE POLYCYCLIC AROMATIC STRUCTURES

By

ALEC EDOUARD MORRISON

A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy

2017 Alec Morrison defended this dissertation on April 10, 2017. The members of the supervisory committee were:

Gregory B. Dudley Professor Directing Dissertation

Thomas Miller University Representative

Igor Alabugin Committee Member

Kenneth Hanson Committee Member

The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements.

ii

This work is dedicated to my family who has supported me through my entire academic career.

iii ACKNOWLEDGMENTS

I would like to thank Dr. Dudley for guiding me through the frustrations, setbacks, and successes of this academic journey which would not have been possible without him. I couldn’t have asked for a better advisor and am truly indebted to his patience and encouragements.

Particular thanks go to my committee members for their helpful discussions, direction, and reminder of how much I have yet to learn, and to Tae for his endless advice. Thank you to

JJ, Nick, Mélodie, Tristan and Gabe along with everyone else that I’ve had the pleasure of interacting with in the FSU chemistry department over the past few years.

Finally, I would like to acknowledge my parents for constantly pushing me and helping me through my academic career and life, I don’t know how I will ever repay you. You are the real MVP.

iv TABLE OF CONTENTS

List of Schemes ...... vi List of Tables ...... ix List of Figures ...... x Abstract ...... xi

1. Benzannulation ...... 1

1.1 Introduction ...... 1 1.2 Metal-Catalyzed Cycloadditions ...... 3 1.3 Thermal, Photochemical, and Lewis Acid Promoted Benzannulation ...... 11

2. Dehydro-Diels-Alder Methodology for the Synthesis of Isoquinoline Derivatives and Polycyclic Chromophores ...... 26

2.1 Thermal Cycloisomerization of Putative Allenylpyridines for the Synthesis of Isoquinoline Derivatives ...... 26 2.2 Solution and Solid-State Molecular Photophysics of gem-Dimethylcyclopentane Derivatives ...... 35 2.3 Triazabicyclodecene: An Optimized Reagent for Base-Mediated Isomerization of Alkynyl- to Allenyl-Pyridines in the Synthesis of Isoquinoline Derivatives ...... 43 2.4 Experimental Data ...... 51

3. Total Synthesis of Illudinine: A Densely Substituted Isoquinoline ...... 75

3.1 Introduction ...... 75 3.2 Results and Discussion ...... 82 3.3 Experimental Data ...... 89

Appendices ...... 96

A. 1HNMR and 13CNMR Spectroscopies for Chapter 2 ...... 96 B. 1HNMR and 13CNMR Spectroscopies for Chapter 3 ...... 127 C. List of Experimental Terms ...... 134

References ...... 137

Biographical Sketch ...... 155

v LIST OF SCHEMES

Scheme 1. Inter- and Intramolecular Diels-Alder Reactions ...... 2

Scheme 2. Traditional Methods for the Synthesis of Polysubstituted Benzene Derivatives ...... 3

Scheme 3. Metal-Catalyzed [2+2+2] Alkyne Cyclotrimerization ...... 5

Scheme 4. CpCo(CO)2-Catalyzed [2+2+2] Cyclotrimerization ...... 6

Scheme 5. Application of a CpCo(CO)2-Catalyzed [2+2+2] Cyclotrimerization to the Synthesis of Estrone ...... 7

Scheme 6. Pd-catalyzed [4+2] Benzannulation of Conjugated Enynes ...... 8

Scheme 7. Proposed Mechanism of Pd-catalyzed [4+2] Benzannulation of Enynes and Diynes ...9

Scheme 8. Au(I)-Catalyzed Formal [4+2] Benzannulation of Enynes and Alkynes ...... 11

Scheme 9. The Bergman Cyclization ...... 12

Scheme 10. Application of the Bergman Cyclization to the Synthesis of Polyaromatics ...... 13

Scheme 11. Danheiser Benzannulation ...... 15

Scheme 12. Application of First and Second-Generation Benzannulation Strategies to the Total Synthesis of (-)-Ascochlorin and Salvilenone ...... 16

Scheme 13. Intramolecular [4+2] Benzannulations of Conjugated Enynes ...... 17

Scheme 14. Mechanism of the Intramolecular [4+2] Benzannulation of Conjugated Enynes .....19

Scheme 15. Dehydro-Diels-Alder Variants ...... 19

Scheme 16. Dehydro-Diels-Alder Reaction of Styrene-Ynes ...... 20

Scheme 17. Ueda and Johnson’s Alkyne-Diyne Dehydro-Diels-Alder Reaction ...... 22

Scheme 18. The Hexadehydro-Diels-Alder Reaction ...... 23

Scheme 19. Application of the Hexadehyrdro-Diels-Alder Reaction to the Synthesis of Mahanimbine ...... 24

Scheme 20. Identifying the Reactivity Limits of Malonate-Tethered Diynylpyridine 111 ...... 26

vi Scheme 21. Classical (left) and Recent (right) Approaches to the Isoquinoline Core ...... 29

Scheme 22. Central Hypothesis and Experimental Design ...... 30

Scheme 23. Tandem Fragmentation/Olefination Methodology for the Synthesis of 1,6-Enynes .31

Scheme 24. Synthesis of Phenylthio-enyne Substrates and Tandem (Cyclo)Isomerization / Elimination ...... 32

Scheme 25. Expanding the Benzannulation Scope through Further Synthetic Elaboration ...... 34

Scheme 26. Synthesis of Pentacyclic Phenanthridine 146 ...... 36

Scheme 27. Synthesis Strategy for gem-Dimethylcyclopentane-Fused Arenes ...... 37

Scheme 28. Synthesis of Dichloroanthracene and Dibenzo[g,p]chrysene Derivatives ...... 38

Scheme 29. Synthesis of Triphenylene 151 ...... 39

Scheme 30. Diverging Pathways for the Synthesis of Naphthalene and Phenanthrene Derivatives ...... 40

Scheme 31. Proposed Mechanistic Pathways ...... 44

Scheme 32. Deuterium-labeling Experiments Involving Methanol-d1 ...... 45

Scheme 33. Propargyl-Allene Isomerizations Facilitated by Bicyclic Guanidine Bases ...... 51

Scheme 34. Woodward and Hoye’s Synthesis of Illudinine ...... 79

Scheme 35. Deiter’s Synthesis of Illudinine ...... 81

Scheme 36. Synthetic Approach to Illudinine ...... 82

Scheme 37. Synthesis of Enyne 193 via Tandem Fragmentation/Knoevenagel-Type Condensation...... 83

Scheme 38. Dehydro-Diels-Alder Reactions of Tethered Enynes ...... 83

Scheme 39. Microwave-Assisted Oxidative Cycloisomerizations ...... 84

Scheme 40. Tandem SNAr/Lossen Rearrangement ...... 87

Scheme 41. Trimethylsilyldiazomethane Reaction Pathway to 197 and 191 ...... 88

vii Scheme 42. Optimized Procedure for O-Methylation of 8-Hydroxyisoquinoline 196 and Saponification of Illudinine Ethyl Ester ...... 89

viii LIST OF TABLES

Table 1. Data Collection and Structure Refinement Parameters for 146 ...... 74

Table 2. SNAr and Metal-Catalyzed Aryl Ether Formation Efforts ...... 86

Table 3. Methylation Optimization ...... 87

ix LIST OF FIGURES

Figure 1. Importance of the Isoquinoline Structural Motif ...... 28

Figure 2. Examples of gem-Dimethylcyclopentane-Fused Natural Products ...... 29

Figure 3. Three-Dimensional Representation of a gem-Dimethylcyclopentane-Fused Isoquinoline...... 30

Figure 4. Sonogashira Couplings for the Synthesis of Benzannulation Precursors ...... 33

Figure 5. Synthesis of Isoquinolines (and Quinolines) via DBU-Promoted Benzannulation ...... 34

Figure 6. (Top) Phenanthridine Derivatives. (Bottom) gem-Dimethylcyclopentane-Fused Arene Targets...... 37

Figure 7. UV-vis Absorption Spectra and Normalized Emissions of Parent Molecules and gem- Dimethylcyclopentane Derivatives in Methylene Chloride ...... 41

Figure 8. (Left) Normalized Steady-State Emission Spectra of Phenanthridine in DCM and Crystalline Phenanthridine. (Middle) Normalized Steady-State Emission Spectra of 146 in DCM and Crystalline 146. (Right) Normalized Steady-State Emission Spectra of Crystalline 146 and Crystalline Phenanthridine ...... 42

Figure 9. (a) Crystal Packing of 146. (b) Phenanthridine Itself ...... 42

Figure 10. Relative Energies (G) from DFT Calculations ...... 46

 Figure 11. Hyperconjugative C-H C-S Interaction in Truncated Intermediate 118d ...... 47

Figure 12. (Left) Comparison of Bicylic Amidines and Guanidines. (Right) Proposed Stepwise and Concerted Mechanisms for Guanidine Catalyzed 1,3-Proton Transfer ...... 49

Figure 13. Representative Protoilludane Natural Products ...... 75

Figure 14. Proposed Biosynthesis of Sesquiterpenes in the Basidiomycotina Subdivision...... 76

x ABSTRACT

The longstanding challenge of constructing polysubstituted benzene derivatives has benefited from over one-hundred years of imaginative solutions to the same problem. This dissertation focuses on the many evolutions of benzannulation strategy with an emphasis on how evolving cycloaddition methodology has paved the way for insightful improvements and creative applications to complex synthetic challenges. Here, we (Dudley Group) describe efforts to harness increasingly unsaturated variations of the Diels-Alder cycloaddition to develop methodology for the synthesis of natural products and other high-value aromatic scaffolds.

A cascade (cyclo)isomerization / elimination process is discussed which produces novel isoquinoline derivatives and polycyclic aromatic structures of potential interest for pharmaceutical, biomedical, and energy-related research. Mechanistic experiments support a putative allenylpyridine (reminiscent of the Garratt–Braverman cyclization) as a key intermediate in the cascade process.

Finally, a concise total synthesis of the illudalane sesquiterpene illudinine was realized in eight steps and 14% overall yield from commercially available dimedone. The synthesis demonstrates the benefits of evolving benzannulation methodology in the context of synthetic efficiency. The approach features tandem fragmentation / Knoevenagel-type condensation and microwave-assisted oxidative cycloisomerization to establish the isoquinoline core. Completion of the synthesis involves a recently reported cascade SNAr / Lossen rearrangement on a densely functionalized aryl bromide and an optimized procedure for O-methylation of 8- hydroxyisoquinolines. The oxidative cycloisomerization proceeds by way of a novel inverse- demand intramolecular dehydro-Diels–Alder cycloaddition, which has a potentially broader appeal for preparing substituted isoquinolines.

xi CHAPTER 1

BENZANNULATION

1.1 Introduction

Organic chemistry is characterized by the painstaking contributions of minor breakthroughs which continually change the way we think about making chemical bonds. Our ability to access increasingly sophisticated molecular scaffolds provided by Nature is limited only by the evolution of our current synthetic methods.1 An imaginative solution to a complex synthesis may arise from the insight to improve the knowledge of past efforts or the creativity to invent new methodology.2 To this end, discovering reactions which rapidly and efficiently assemble functionalized cyclic structures remains a persistent challenge.

Given the growing topological complexity of modern synthetic targets, considerable efforts have gone into the design of transformations which form multiple bonds at once while maintaining control over chemo-, regio-, and enantioselectivity.3 Cycloadditions feature prominently in this domain as they can be highly atom-economical and also achieve maximum complexity from simplified starting materials. Among the oldest and most powerful of these transformations is the venerable Diels-Alder cycloaddition between a diene and a dienophile which allows for two-bonds and up to four contiguous stereocenters to be created simultaneously.4 Not only are cyclohexene and cyclohexadiene rings generated from alkene and alkyne dienophiles, respectively, but the use of a tether allows for the construction of multiple rings at once5-6 (Scheme 1). Moreover, because the stereochemical outcome of the reaction is governed by the Alder endo rule, the diastereoselectivity is easily rationalized.7 Where synthetic

1 design is concerned - the Diels-Alder reaction is nearly ideal in terms of predictability, selectivity, and atom economy.1

Since its discovery, the classical Diels-Alder reaction has progressed to systems of higher unsaturation8, cascade processes, and metal catalysis.9-10 Creative insights and extensions of this cycloaddition methodology beyond what was originally envisioned by Otto Diels and Kurt Alder has provided us with a plethora of entries into polycyclic systems otherwise thought to be inaccessible from traditional methods.11

Scheme 1. Inter- and Intramolecular Diels-Alder Reactions

Polysubstituted benzene derivatives figure among the main beneficiaries of evolving cycloaddition methodology as they have a wide range of applications12-17 and prevalence in natural products18 yet remain synthetically non-trivial. The classical approach to functionalized benzenoids relies heavily on stepwise introduction of functional groups on a preformed benzene

(Scheme 2). The main drawback to this method is the regiochemical ambiguity associated with electrophilic (Scheme 2, eq 1) and nucleophilic (Scheme 2, eq 2) aromatic substitution reactions.

Harsh reaction conditions which typically involve environmentally unfriendly reagents make for poor functional group tolerance and low atom economy. Alternative classical methods such as

2 directed ortho-metalation (Scheme 2, eq 3) have also been explored but are limited in scope and substitution patterns.19

Scheme 2. Traditional Methods for the Synthesis of Polysubstituted Benzene Derivatives

The strategic solution to this problem was to construct benzene from acyclic building blocks. Rather than manipulate the aromatic core through sequential ring functionalization which requires long synthetic sequences and tedious separation of ortho- meta- para- mixtures, benzannulation strategies build up a fully substituted acyclic precursor and, in a single step, provide access to substitution patterns not easily attained via conventional routes. In addition to the possibility of extensive substitution pattern control, the high exothermicity associated with aromatizing might be sufficient to drive the reaction for even sterically hindered substrates.20

This chapter aims to highlight some of the many evolutions of benzannulation strategy which paved the way for this dissertation.

1.2 Metal-Catalyzed Cycloadditions

A milestone in benzannulation methodology was the nickel-catalyzed [2+2+2] cyclotrimerization of alkynes to polysubstituted benzenes discovered by Reppe et al. in 1948.21

3 The reaction forms three carbon-carbon bonds simultaneously while incorporating up to six different substituents (Scheme 3, eq 1). The commonly accepted mechanism begins by sequential displacement of two ligands on the metal by two of the alkyne starting materials to form coordination complex 1. Oxidative coupling to metallocyclopentadiene 2 occurs with simultaneous formation of a carbon-carbon bond. Complexation to a third alkyne molecule gives

3, which may either insert to form metallocycloheptatriene 4 or undergo a Diels-Alder type cycloaddition to give complex 5. Finally, reductive elimination from either 4 or 5 generates a polysubstituted benzene derivative.

The metal-catalyzed [2+2+2] cycloaddition strategy has since been extended to a variety of metals including Rh, Pd, Co, Ta, and Cr9, 22-24 and works well for symmetric alkynes with low steric-bulk. For example, good regioselectivity for 1,2,4-substituted benzenes can be achieved by judicious choice of catalyst23 combined with sufficient size disparity between the substituents on the alkyne (Scheme 3, eq 2). Here, selectivity is a direct result of the proposed mechanism.

During the oxidative coupling of metal complex 1 to metalallocyclopentadiene 2 (Scheme 3), the metal prefers to orient the bulkier substituents towards the most vacant site (as depicted in intermediate 7) to avoid the large steric repulsion associated with 8.25 Consequentially, the carbon-carbon bond in the metallocyclopentadiene is between the least hindered alkyne carbons.

Complexation to a third acetylene molecule to give 9 ultimately results in 1,2,4 selectivity for 10; however, regioselectivity can still be strongly dependent on the catalyst employed and 1,3,5 products are often formed in varying amounts. Mixtures are frequently encountered when using less biased alkynes and the cyclotrimerization of the third acetylene with itself can be problematic, as well.23 Efforts26 to improve the poor regio- and chemoselectivity by preforming metallocyclopentadiene 2 and using a third alkyne that cannot be trimerized have been met with

4 some success27-29 but are limited by multistep procedures and stoichiometric amounts of metal.

Despite the advantages of this method over conventional ring functionalization, the utility of the totally intermolecular metal-catalyzed [2+2+2] cycloaddition for making polysubstituted benzene derivatives is limited to specialized systems.

Scheme 3. Metal-Catalyzed [2+2+2] Alkyne Cyclotrimerization

Work from Vollhardt22 using cobalt in the form of the dicarbonyl(-cyclopentadienyl) derivative CpCo(CO)2 transformed metal-catalyzed [2+2+2] cycloadditions into a versatile tool for organic synthesis. The key insight was to tether two of the acetylene units (sometimes even all three) to create a partially intramolecular reaction and to use a third alkyne that could not be 5 trimerized (Scheme 4, eq 1).30 The flexibility of this approach can be seen in Scheme 4, eq 2.

Addition of diyne 11 dissolved in n-octane to a refluxing solution of TMS-acetylene 12 in the presence of CpCo(CO)2 affords benzocyclobutene 13 in over 60% yield.

Several important innovations are immediately realized: (a) the regiochemical ambiguity associated with the fully intermolecular [2+2+2] is no longer a hindrance; (b) TMS-acetylenes reduce self-trimerization and allow for further functionalization of electrophilic substituents

(1314that would otherwise hamper the reaction;31 (c) Benzocyclobutenes are versatile synthetic building blocks via the intermediacy of their o-xylylene isomers;32 (d) Inherent atom economy results from using catalytic amounts of Co and the incorporation of almost all of the starting materials; (e) Synthetic efficiency is realized from the simultaneous formation of multiple bonds and rings.

Vollhardt’s total synthesis of estrone (Scheme 5) is an elegant application of the Co- catalyzed [2+2+2] in a cascade sequence.33 Subjecting enediyne 15 to refluxing bis(trimethylsilyl)acetylene in the presence of CpCo(CO)2 for 41 hr furnishes benzocyclobutene

16. Further heating in refluxing decane cycloisomerizes 16 to the Diels-Alder adduct 17 which undergoes a thermal [4+2] cycloaddition to give 18 in 71% overall yield en route to estrone.

Scheme 4. CpCo(CO)2-Catalyzed [2+2+2] Cyclotrimerization

6 The partially or completely intramolecular metal catalyzed [2+2+2] cyclotrimerization of alkynes can also be catalyzed by a number of metals, most notably Ni,34-35 Rh,36 and Pd37-38 complexes, and when employed in a completely intramolecular sense remains one of the most efficient ways to construct polycyclic systems fused to benzene.39

Scheme 5. Application of a CpCo(CO)2-Catalyzed [2+2+2] Cyclotrimerization to the Synthesis of Estrone

A totally intermolecular metal-catalyzed benzannulation with excellent regio- and chemoselectivity was realized by Yamamoto’s group in 1996.40 The non-regiocontrolled assembly of metallocyclopentadiene 2 was circumvented by instead catalyzing a [4+2] benzannulation of enynes with enynophiles. Conjugated enynes allow for better regiocontrol than

[2+2+2] cycloadditions since only the regioselectivity of two bonds are in jeopardy.41 Indeed, heating a toluene solution of 2-substituted enyne 19 in the presence of a catalytic amount of

Pd(0) successfully dimerized the starting material to obtain 1,4-disubstituted benzene derivative

20 in good to high yield (Scheme 6). The regioisomeric 1,3-disubstituted benzene 21 and

7 chemoisomeric trimer 22 were not detected and the reaction tolerated hydroxyl and carbonyl functionalities, as well. These observations suggest that the regiospecific mechanism by which

20 is formed does not follow the traditional metal-catalyzed [2+2+2] alkyne cyclotrimerization.

Scheme 6. Pd-Catalyzed [4+2] Benzannulation of Conjugated Enynes

The underlying mechanism for enyne-diyne cross-benzannulation and enyne-enyne homo-dimerization is debated; however, it is well accepted that alkenyl or alkynyl activating groups on the enynophile are required to achieve regiospecificity (Scheme 7).40-42 The process begins by reversible alkyne coordination of enyne 23 and enynophile 24 to palladium to form bis-alkynylpalladium complex 26 (Scheme 7). At this stage, formation of a metallocyclopentadiene via the [2+2+2] mechanism would certainly form two regioisomers depending on the orientation of 24. Consequently, the observed regiospecificity must arise from coordination of palladium to the alkenyl or alkynyl activating groups in palladacycle 27.42 This is in agreement with the exclusive formation of 25, the fact that simple alkynes such as acetylene do not act as enynophiles in the reaction,42 and the well-characterized existence of -propargyl palladium complexes.43-44 Thus, metallocycloaddition of 26 to 27 is strongly directed by coordination of palladium to the 3-propargyl moiety. Diverging pathways from 27 to 25 have been discussed.45 Reductive elimination to the strained cyclic allene intermediate 28 followed by

8 a 1,5-hydride shift to benzene 32 and release of Pd(0) back into the catalytic cycle furnishes 25.

Alternatively, 1,3-sigmatropic shift from complex 27 to palladaheptatriene 31, followed by reductive elimination arrives at 32.

Scheme 7. Proposed Mechanism of Pd-catalyzed [4+2] Benzannulation of Enynes and Diynes

The intermediacy of 28 has since been questioned45 as it does not explain the exclusive migration of deuterium from the E-position in a monodeuterated 23 transformed into 28.42 Being planar, 28 should not exhibit any stereoselective preference during the [1,5]-shift to 32.

Furthermore, 28 does not account for why mono-, di-, and tri- substituted enynes can be efficiently converted to tri-, tetra, and pentasubstituted benzene derivatives, respectively, so long

9 as 1-substituted enynes are either in the Z-geometry or contain an electron-withdrawing-group

(EWG) in the 1-position. Presumably, the E-isomer thermally isomerizes under the reaction conditions which is consistent with the longer reaction times and higher temperatures required for 1-E-EWG-substituted enynes.46

The use of Lewis acids47 and bases dramatically improves this process by promoting Z/E isomerization and accelerating the rate of [4+2] cycloaddition.45 The rate acceleration may be explained by the ionic pathway suggested by Gevorgyan45 for the 1,3-hydrogen migration from

27 to 31 where the protonation/deprotonation process from 27 to cationic 29 or anionic 30 is clearly facilitated by Lewis acid or base catalysis. DFT calculations provide strong evidence that the exclusive migration of the E-hydrogen atom is more favorable than the Z-hydrogen in either pathway. The steric environment of the Z-hydrogen is crowded by nearby substituents and the aryl rings of the phosphine ligands on palladium, making E-hydrogen atom abstraction much more facile from either 27 to 30 or 29 to 31.

The scope of the Pd-catalyzed [4+2] benzannulation has been extensively investigated41-

42 and broadened to the synthesis of phenols,48 aryl ethers,49 coumaranones,49 and anilines,50 amongst others.24,46 Other transition metal-catalyzed51 [4+2] benzannulations of enynes with alkyne enynophiles have also been investigated.52-53 For example, a mechanistically distinct two- step intermolecular benzannulation of enynes and alkynes using Au(I)-catalysis was by reported by Toste (Scheme 8).54 Intermolecular cyclopropanation of enyne 33 with propargyl ester 34 via the intermediacy of gold carbenoid55 35 produces 1,5-enyne 36 in 84% yield with high cis- diastereoselectivity. Here, the regioselectivity of the final benzannulation is imparted during the cyclopropanation rather than metal complexation to an alkenyl or alkynyl activating group (vide supra). Judicious choice of the silver salt cocatalyst in combination with triarylphosphitegold(I)

10 chloride selectively benzannulates 36 to either styrene 37 or fluorene 38 in good yield. Once cationic gold coordinates to the alkyne moiety in 36, 5-endo-dig cyclization generates a tertiary carbocation 39. Migration of the pivaloyloxy group to the more stable tertiary allylic carbocation

40 followed by cyclopropane ring opening to 41 and aromatization/gold dissociation leads to benzannulated 42. Finally, 37 and 38 arise from either E1 or Friedel-Crafts alkylation from 43, respectively.

Scheme 8. Au(I)-Catalyzed Formal [4+2] Benzannulation of Enynes and Alkynes

1.3 Thermal, Photochemical, and Lewis Acid-Promoted Benzannulation

One of the earliest examples of a thermally-promoted annulation reaction for making benzene derivatives was the Bergman cyclization (Scheme 9).56-58 Bergman and Jones initially reported that gas-phase pyrolysis of deuterated cis-1,5-hexadiyn-3-ene 44 (where deuterium was incorporated in the acetylenic positions) caused complete scrambling of deuterium between the acetylenic and vinyl positions resulting in a mixture of 44 and 46 (Scheme 9, eq 1).56 The labeling experiment suggested that a thermal isomerization probably proceeds through an aromatic diradical59 transition state intermediate 45. This idea was confirmed upon heating cis- 11 1,5-hexadiyn-3-ene 47 in different solutions (Scheme 9, eq 2) and trapping the postulated 1,4- diradical 48. Indeed, benzene was obtained in quantitative yield by heating 47 in 2,6,10,14- tetramethylpentadecane, while 1,4-dichlorobenzene and benzyl alcohol were obtained in carbon tetrachloride and methanol, respectively. The cycloaromatization process has been considered to be an interrupted Cope rearrangement60 because the destruction of two  bonds and the formation of a  bond results in the generation of a p-benzyne intermediate stabilized by the nature of the orthogonal -system aromaticity.61

Scheme 9. The Bergman Cyclization

Several years after its discovery, the reaction became widely popular due to its relevance to the DNA cleaving chemistry of enediyne natural products.61-63 The majority of studies related to the Bergman cyclization are aimed at understanding parameters which control the kinetics of the cycloaromatization process to improve and design novel anticancer agents. Consequently, the synthetic utility of the Bergman cyclization is often overshadowed by its relevance to enediyne antibiotic function. Nevertheless, the advantages for assembling polycyclic frameworks and

12 polymers are well recognized.64 Substituted aromatic polymers are synthesized without the use of exogenous chemical catalysts or reagents if the intermediate 1,4-diradical monomer is not trapped.65-66 Alternatively, both radicals formed from the initial cycloaromatization can be used in subsequent intramolecular radical cyclizations to rapidly increase complexity.67 Furthermore, the wealth of knowledge generated from studying the mechanism61 ensures efficient synthetic design of cycloaromatization precursors with the added benefit of atom economy and functional group tolerance.

Scheme 10. Application of the Bergman Cyclization to the Synthesis of Polyaromatics

A rationally designed application of the Bergman cyclization to a radical cascade was demonstrated by Basak and coworkers for the synthesis of [4]helicenes (Scheme 10).68 o-iodo propargyl amines 49 were converted over 6 steps to aryl enediynes 50 with varying substituents on the external ring. Tethering the alkynyl substituents to induce strain is known to destabilize the reactants and facilitates the cyclization,69 while the external styrene was strategically placed 13 to trap the intermediate diradical intramolecularly. Prolonged heating of 50 in DMSO afforded

[4]helicines 51 in good yield. The tandem cyclization was likely initiated by cycloaromatization of 50 to p-benzyne 52. Subsequent trapping of the radical through disruption of aromaticity in the proximal ring creates conjugated radical 53. Finally, H-atom abstraction on the naphthalene ring in 53 followed by solvent quenching of the naphtyl diradical 54 and concerted extrusion of

65 70 67 H2 completes the sequence. Polyphenylenes, porphyrins, indenes and other benzannulated compounds71 have been synthesized by similarly controlled radical cyclizations; however, the use of the Bergman cyclization as a generalized tool for synthesizing polysubstituted benzenes remains underexplored.

The Danheiser group has provided a number of contributions to annulation methods for the synthesis of highly substituted benzene derivatives. The most notable of which are two complementary benzannulation approaches to phenols based on the reaction of substituted alkynes with in-situ generated vinylketenes (Scheme 11).72-73 Both intermolecular annulations proceed through a series of at least three pericyclic reactions in one step. Heating cyclobutenone

56 results in reversible four electron electrocyclic ring-opening to produce a transient vinylketene 59. Ketenophile 55 immediately intercepts 59 in a regioselective [2+2] cycloaddition to furnish cyclobutenone 60. A second reversible four electron electrocyclic ring-opening generates dienylketene 61, which is primed for 6 electron electrocyclic ring-closure and tautomerization to the highly substituted phenol 57 in good to excellent yield. The second generation of their annulation method73 expands the scope of the reaction to access polycylic aromatic and heteroaromatic systems which were not attainable using cyclobutenone starting materials. The key difference being that irradiation of unsaturated -diazo ketones 58 allows for the generation of either vinyl- or arylketene intermediates 62 after photochemical Wolff

14 rearrangement. Various aryl and heteroaryl diazo ketones cleanly provide highly substituted naphthalene, benzofuran, benzothiophene, indole, and carbazole derivatives.

Scheme 11. Danheiser Benzannulation

Both aromatic annulation strategies are highly efficient in terms of the regiocontrol imparted from the [2+2] cycloaddition, the atom economy resulting from four thermally and/or photochemically-promoted pericyclic reactions, and the net gain in topological complexity from simple starting materials. The use of this benzannulation methodology has significantly streamlined the synthesis of several natural products74-77 such as (-)-Ascochlorin78 and

Salvilenone.79 An effective application of the first-generation annulation method is exemplified by the convergent synthesis of the former (Scheme 12, eq 1) where the benzannulation strategy employed was significantly more efficient than previous approaches.80-81 The pivotal step in the synthesis involved an aromatic annulation of chlorocyclobutenone 64 with advanced benzyloxyacetylene intermediate 63. In the event, prolonged irradiation followed by additional

15 heating provided pentasubstituted benzene 65 in 65% yield en route to the natural product. The latter synthesis is characterized by the implementation of an -diazo ketone as an arylketene precursor in the pivotal benzannulation step (Scheme 12, eq 2). The key cyclization precursor - benzosuberone 66 was prepared in three steps from 2-methylcyclopentanone. Irradiating 66 in a solution of 1,2-dichloroethane in the presence of siloxyalkyne 67 followed by further heating at

80 oC successfully contracted the cycloheptane ring while simultaneously providing the densely substituted polyaromatic 68. Completion of the synthesis provided the phenalenone diterpene in half as many steps the previously reported synthesis82 which required traditional linear substitution methods.

Scheme 12. Application of First and Second-Generation Benzannulation Strategies to the Total Synthesis of (-)-Ascochlorin and Salvilenone

Several years after reporting their second-generation annulation method, the Danheiser group described an intramolecular [4+2] cycloaddition of conjugated enynes with alkenes and alkynes as a general route to dihydroaromatic and aromatic compounds (Scheme 13).83 At the time, several examples84 of Diels-Alder cycloadditions between arylacetylenes and alkynes to give substituted naphthalenes had been known for over 100 years. Initially, Michael and Bucher 16 reported as early as 1895 that phenylpropiolic acid 69 could be dimerized to anhydride 70 in the presence of refluxing acetic anhydride (Scheme 13, eq 1). Subsequent literature on this type of

Diels-Alder variant were limited to oxygen based tethers and closely related to Michael and

Bucher’s dimerization.

Scheme 13. Intramolecular [4+2] Benzannulations of Conjugated Enynes

Danheiser and coworkers generalized this process with the use of a carbon tether and enynes not limited to arylacetylenes (Scheme 13, eq 2) and, more recently, to the synthesis of indolines and indoles.85 In the course of their study, they found that the use of phenolic solvents and protic or Lewis acids had a profound effect on the yield of the reaction. Lewis acid catalysts are known to decrease the activation energy required for Diels-Alder cycloadditions by reducing the energy gap between the LUMO of the dienophile and the HOMO of the diene.86 Indeed, heating a toluene solution of enediyne 73 to 180 oC for 16-18 hr in the presence of 3 equivalents of butylated hydroxytoluene (BHT) furnished benzannulated 74 in 78% yield. Performing the same reaction in methylene chloride at 0 oC with either 2.5 equivalents of methanesulfonic acid or 1.1 equivalent of aluminum trichloride improved the yield to 87% and 90%, respectively, and finished in as few as 30 min.

17 Other than simply activating the dienophile, the protic and Lewis acid induced rate improvement may be explained by the nature of the mechanism involved (Scheme 14). While it is generally accepted that the cycloaddition process begins by an intramolecular [4+2] cycloaddition of 71 to produce strained cyclic cumulene87 75, non-concerted [4+2] cycloaddition and diverging mechanistic pathways from the cyclic allene to benzene 72 have been discussed88-

90 and extensively studied by Johnson91-94 and Saa.95-97 Ring constraints in cyclic allenes have been suggested to promote planarity at C1-C3, leading to several possible electronic configurations.87 For this reason, the electronic structure of 75 may be better represented by diradical 76 or zwitterion 77 which benefit from allylic stabilization.89 The most straightforward pathway from 75 to 72 would be a thermally allowed [1,5]-H shift, although computational evidence suggests a series of [1,2]-H shifts from - diradical 76 to carbene 78 and then again from 78 to 72 to have a smaller barrier.90 Alternatively, the hydrogen migration from 75 to 72 might be explained by the protonation of zwitterionic 77 to cationic 79. The presence of a proton source (alcoholic cosolvent and/or protic or Lewis acid) in the reaction mixture would favor this pathway and is further corroborated by the aforementioned rate acceleration.

Regardless of which pathway prevails, the stepwise mechanism behind the intramolecular

[4+2] enyne-alkyne cycloaddition is fundamentally different from the traditional Diels-Alder reaction. For this reason, when one or both of the alkenes on the diene component are replaced by triple bonds the reaction is referred to as the “dehydrogenated” or dehydro-Diels-Alder

(DDA).8,98 Several variants of the DDA which lead to aromatic rings have been reported

(Scheme 15)8,98 and are considered complementary to the intermolecular Pd-catalyzed [4+2] benzannulation of conjugated enynes (vide supra). DDA reactions usually proceed through

18 strained cyclic allene intermediates (Scheme 15, eq 2-4) and in some cases require further oxidation by release of molecular hydrogen (Scheme 15, eq 2, 3) to achieve aromaticity.

Scheme 14. Mechanism of the Intramolecular [4+2] Benzannulation of Conjugated Enynes

Scheme 15. Dehydro-Diels-Alder Variants

When aromatic products are desired, higher degrees of unsaturation in the DDA are usually employed (Scheme 15, eq 3-4); however, there are several examples of DDA reactions which evolve molecular hydrogen en route to the aromatic product. For example, the DDA

19 reaction between an alkyne dienophile and diene (Scheme 15, eq 1) in the form of styrene has been the subject of much research for the synthesis of substituted naphthalene derivatives.98,99

Functionalized naphthalenes are known to be valuable building blocks in a variety of pharmaceutical,100 chemical,101 and material102 applications. Recently, Matsubara and coworkers have studied the DDA of tethered alkynylstyrene 80 for the production of substituted naphthalene 81 (Scheme 16, eq 1).103 They found that simply heating xylene solutions of 80 at

160 oC for 48 h produced 81 in good to excellent yields without the need of external oxidants,

Lewis acids, or transition metal catalysts.

Scheme 16. Dehydro-Diels-Alder Reaction of Styrene-Ynes

20 Brummond99,104-108 later expanded the scope and demonstrated that the same reaction could be accelerated through the use of microwave irradiation (Scheme 16, eq 2). She also found that the preference for styrene-ynes such as 82 to aromatize to naphthalene 83 rather than dihydronaphthalene 84 could be influenced by judicious choice of the reaction environment and tether.108 In the event, heating a 0.06 M DCE solution of carbon tethered 82 in the microwave at

180 oC gives naphthalene 83 in quantitative yield after 30 min (Scheme 16, eq 3), while performing the same reaction with a heteroatom tether gives a mixture of 30% of aromatized 86 and 56% of dihydronaphthalene 87 (Scheme 16, eq 4). Brummond and Tantillo108 have suggested that the product distribution is due to diverging mechanistic pathways following the initial [4+2] cycloaddition to from tetraene 88. Concerted extrusion of molecular hydrogen from

88 leads directly to naphthalene 86. Alternatively, hydrogen-atom abstraction by triplet oxygen

(or heat alone) provides trisallylic radical intermediate 89 which isomerizes to 90 and restores aromaticity. Propagation of the radical process and formation of dihydronaphthalene 87 occurs by further hydrogen-atom abstraction from 88. Despite theoretical calculations which predict the radical process to be more favorable than loss of molecular hydrogen by 9.8 kcal/mol, careful employment of radical scavengers, solvents with low dielectric constants, low concentrations, higher temperatures, and/or longer reaction times were shown to improve the selectivity for naphthalene formation. High yields, short reaction times, and the ease of operation associated with thermally-promoted reaction conditions make the DDA of styrene-ynes a powerful benzannulation strategy.

The most highly oxidized version of the DDA reaction is between a diyne and alkyne dienophile (Scheme 15, eq 4). The reaction was independently proposed by both Ueda109 and

Johnson92 in 1997, although it did not receive much attention until 2012.110 Ueda’s report on the

21 intramolecular cyclization of tetrayne derivative 91 at 25 oC over 4 days was proposed to involve a multistep radical process to arrive at cyclized 92 (Scheme 17, eq 1). Meanwhile, Johnson claimed that flash vacuum thermolysis of 93 at 580 oC and 10-2 torr was required to furnish indan

94 in 86% yield along with indene 95 in 14% yield. Taken together, the delay in interest for this

DDA variant is not surprising.

Scheme 17. Ueda and Johnson’s Alkyne-Diyne Dehydro-Diels-Alder Reaction

Numerous reports111-115 from the Hoye group have since validated the alkyne-diyne DDA now commonly referred to as the hexadehydro-Diels-Alder (HDDA) reaction as a viable method for synthesizing structurally complex benzenoids. In their initial publication, ketotriyne 96 cleanly transformed into the hexasubstituted, tetracyclic indenone 97 in excellent yield at essentially room temperature (Scheme 18). An initial [4+2] cycloaddition produces intermediate benzyne 98 which is trapped intramolecularly by the nearby nucleophilic oxygen in the - silyloxyethyl group to give zwitterion 99. Subsequent desilylation furnishes 97 in 93% yield after

46 h. The reaction tolerates several heteroatom and carbon-based tethers in addition to intermolecular benzyne trapping agents. Mechanistic studies have shown that the HDDA cycloisomerization reaction probably proceeds in a stepwise manner through a diradical

22 intermediate to access o-benzyne rather than a concerted [4+2] cycloaddition.116 This is exemplified by the observation that non-radical-stabilizing, yet electron-withdrawing groups such as CF3 on the alkyne dienophile react slowest of the substrates studied. Presumably, an initial radical isomerization of triyne 100 produces transient diradical 101 in the rate determining step (Scheme 18). Facile recombination of the diradical generates o-benzyne which is represented by the resonance forms 102 and 103. Finally, a rapid benzyne trapping event occurs to furnish the highly substituted benzene derivative 104.

Scheme 18. The Hexadehydro-Diels-Alder Reaction

The utility of the HDDA reaction in total synthesis was recently demonstrated through the efficient construction of the mahanine alkaloid mahanimbine (Scheme 19).112 While exploring the regioselectivity of benzyne trapping reactions that involve inequivalent trapping atoms, Hoye and coworkers were able to initiate a sequence of reactions from an HDDA which

23 produced the core of the natural product. DFT calculations suggest that ring distortion in arynes is the cause of regioselectivity shown by unsymmetrical trapping agents (“Nu-El”).117-119 For this reason, following the HDDA of triyne 105 to o-benzyne 107, the regioselective addition of the aldehyde nucleophile from citral depicted in Scheme 19 was easily predicted. Indeed, heating

105 in DCE at 90 oC with two equivalents of citral for 15 h cleanly provided the tetracyclic pyranocarbozole core 106 in 89% yield. In a cascade of reactions initiated by an HDDA, regioselective addition of the oxygen nucleophile to 107 results in a formal [2+2] cycloaddition to benzoxetene 109 via zwitterion 108. From here, four electron electrocyclic ring-opening to

110 and 6-electron electrocyclic ring-closure produces 106. Finally, global deprotection with

TBAF gives mahanimbine in 91% yield. The overall transformation from 105 to 106 only requires heat and is highly efficient (five bonds and three rings in one step), regioselective, and atom economical.

Scheme 19. Application of the Hexadehyrdro-Diels-Alder Reaction to the Synthesis of Mahanimbine

Follow-up work in the Lee group using silver catalysts to trap the intermediate benzyne as a metal-stabilized aryl cation has expanded the HDDA to C-H insertions120-121 and the

24 incorporation of a number of substituents previously unavailable through purely thermal conditions.122-123 The net gain in structural complexity from the combination of a DDA reaction and designed trapping of the transiently formed o-benzyne makes the HDDA reaction a significant strategic advancement for the synthesis of polysubstituted benzene derivatives.

In conclusion, the evolution of benzannulation methodology in the past 100 years has had a significant impact on the way we think about constructing polycyclic frameworks. Numerous strategies have been invented, fine-tuned, and re-invented based on the careful and cumulative work of many dedicated scientists. The recurring explosion of interest in novel ways to create highly substituted benzene derivatives underscores the value of this transformation to organic chemistry.

25 CHAPTER 2

DEHYDRO-DIELS-ALDER METHODOLOGY FOR THE SYNTHESIS OF ISOQUINOLINE DERIVATIVES AND POLYCYCLIC CHROMOPHORES

Reprinted (Adapted) with permission from: Alec E. Morrison, Jeremy J. Hrudka, and Gregory B. Dudley “Thermal Cycloisomerization of Putative Allenylpyridines for the Synthesis of Isoquinoline Derivatives” Org. Lett. 2016, 18 (16), 4104-4107. DOI: 10.1021/acs.orglett.6b02034. Copyright 2016 American Chemical Society.

2.1 Thermal Cycloisomerization of Putative Allenylpyridines for the Synthesis of Isoquinoline Derivatives

One of the perpetual challenges in chemical synthesis is to identify and push outwards the limits of reactivity. Cyclization of entropically biased (e.g., tethered) -systems has been a powerful tool for addressing this challenge,1,124-125 as it enables one to focus on enthalpy parameters. We have identified an aspirational transformation that lies beyond the limits of chemical reactivity (Scheme 20). Malonate-tethered diynylpyridine 111 was prepared126 by non- selective Sonogashira arylation of the known dipropargyl malonate127 and heated at temperatures up to and exceeding 200 oC in an effort to produce isoquinoline 112, but only unreacted starting material and/or unidentifiable decomposition products were observed.

Scheme 20. Identifying the Reactivity Limits of Malonate-Tethered Diynylpyridine 111

26 This hypothetical cycloaromatization61,128 process could be described as a modified

Garratt-Braverman cyclization129-132 and/or a dehydro-Diels-Alder reaction (see section 1.3 in chapter 1); such methodologies receive considerable attention for their favorable reaction thermodynamics, mechanistic nuances, and recognized synthetic utility. In this case, however, it seems that the kinetic barrier to thermal cycloaddition is too high, which results in competing decomposition of the substrate.

There are several reasons why the prospective isoquinoline synthesis shown in Scheme

20 may exceed the limits of reactivity. Most significantly, to produce the postulated cycloaddition intermediate 113 would require introduction of a strained cyclic allene and disruption of pyridine aromaticity. Despite this, dehydro-Diels-Alder-based benzannulation processes with transient loss of aromaticity are known (see section 1.3 in chapter 1) and certain reactions involving ynamides are postulated to proceed via dearomatized cyclic allenes under some conditions.133-134 Secondary considerations include the unactivated alkyne dienophile and malonate ester functionality. Alkyne -bonds in the former are stronger than alkene -bonds, which can translate into larger activation barriers for reactions that break those -bonds,135 while the latter provides the desired Thorpe–Ingold conformational bias136-137 but may also introduce competing decomposition pathways.

The central objective of this methodology is to extend the reactivity limits of thermal pericyclic cycloadditions for the synthesis of novel isoquinolines. Isoquinolines are ubiquitous in synthetic and medicinal chemistry, and new isoquinolines are potentially attractive for pharmaceutical discovery (Figure 1).138-143 The present benzannulation-centered isoquinoline synthesis strategically complements venerable reactions such as the Pictet-Spengler,144 Bischler-

Napieralski,145 and Pomeranz-Fritsch146-147 isoquinoline syntheses, as well as several more recent

27 transition-metal catalyzed pathways,148-152 the vast majority of which involve annulation of a pyridine ring onto a pre-formed benzene core (Scheme 21). Sparse reports153 exist of annulating benzene onto the pyridine ring which severely limits the substitution patterns available to the benzene core. Novel methods for isoquinoline synthesis are needed to explore chemical structure space that cannot be conveniently accessed by these and related heterocyclization methods. Thus, in exploring the scope of this new benzannulation approach to isoquinolines, we focused on preparing previously unreported isoquinolines that pass in silico screening in the Eli Lilly Open

Innovation Drug Discovery (OIDD) platform.

Figure 1. Importance of the Isoquinoline Structural Motif

The first strategic step was to address the aforementioned secondary considerations. We replaced the malonate functionality with the gem-dimethyl group, which is arguably the simplest and most innocuous structural feature that still provides Thorpe-Ingold effects. Furthermore, the

28 incorporation of a gem-dimethylcyclopentane motif, which differentiates these from previous synthetic isoquinolines, is ubiquitous in natural products (Figure 2)154-159 but conspicuously absent from most synthetic pharmaceutical screening libraries. The rigid, hydrophobic topology of gem-dimethylcyclopentanes (Figure 3) is expected to impart specific pharmacological perturbations to 114 that will be of interest to medicinal chemistry research. For example, our recent work on neoprofen – a rigidified analogue of ibuprofen containing a gem- dimethylcyclopentane structural motif – displays altered biomolecular interactions relative to its conformationally more flexible analogues.160

Scheme 21. Classical (left) and Recent (right) Approaches to the Isoquinoline Core

Figure 2. Examples of gem-Dimethylcyclopentane-Fused Natural Products

We then turned our attention to the unactivated alkyne dienophile in 111. In an effort to address the higher activation barrier associated with breaking alkyne -bonds, we reasoned that an alkene dienophile bearing a leaving group “X” would be a suitable alkyne surrogate for achieving benzannulation. Mechanistically speaking, an intramolecular DDA reaction of

29 neopentyl-tethered 1,6-enyne 116 coupled with loss of “HX” in favor of aromaticity would be analogous to a DDA reaction of enediyne 115 to 117 (Scheme 22, eq 1). We envisioned replacing the alkyne dienophile with a vinyl sulfide (Scheme 22, eq 2) would be suitable for the desired transformation. Sulfides are good electron-donating groups for Diels–Alder-type reactions (e.g., with electron-deficient -systems),161 and vinyl sulfides are at the same oxidation level as alkynes. Late-stage extrusion of thiophenol was envisioned en route to the target isoquinolines.

Figure 3. Three-Dimensional Representation of a gem-Dimethylcyclopentane-Fused Isoquinoline

Scheme 22. Central Hypothesis and Experimental Design

Access to neopentyl-tethered 1,6-enynes was recently streamlined by a tandem fragmentation/olefination methodology developed in our lab (Scheme 23).162 We previously found that vinylogous hemiacetal triflate 120 (prepared in two high-yielding steps from 5,5- dimethyl-1,3-cyclohexanedione 119) could undergo base-promoted fragmentation to ynal 122.

30 Once formed, the base-labile alkynyl aldehyde is immediately subject to olefination by Horner-

Wadsworth-Emmons (HWE) reagent 121 generated in situ from the excess base present in the reaction mixture. The tandem fragmentation/olefination process provides convenient and efficient access 1,6-enynes in good to excellent yield.

Scheme 23. Tandem Fragmentation/Olefination Methodology for the Synthesis of 1,6-Enynes

A logical yet untested extension of this methodology to incorporate a thiophenol moiety into the HWE phosphonate rather than an electron-withdrawing group would facilitate the synthesis of key dehydro-Diels-Alder precursor 118. Furthermore, production here of electron- rich alkenes would represent an important conceptual expansion of our previously reported tandem fragmentation/olefination methodology which exclusively produced electron-deficient alkenes. To this end, we prepared alkynylpyridines 118 and 128 by tandem fragmentation and olefination of triflate 123 followed by Sonogashira coupling of the resulting phenylthio-enynes

(126 and 127) with 4-iodopyridine (Scheme 24). Initial attempts at tandem thermal cycloisomerization and elimination (118  114) focused on high-boiling, nonpolar solvents from which the desired isoquinoline could be separated easily. No desired product (114) was 31 observed in the absence of base; excess DBU was selected (e.g., for base-mediated elimination of thiophenol) following a brief and qualitative screening of different bases. In the end, isoquinolines 114 and 129 were obtained in 81% and 73% yield, respectively, after heating the corresponding alkynylpyridines along with DBU (30 equiv) in o-dichlorobenzene (o-DCB) at

210 °C for 2.5 days, followed by direct chromatographic purification of the reaction mixture on silica gel. Shorter reaction times and less DBU resulted in lower yields and/or recovery of alkynylpyridine.

Scheme 24. Synthesis of Phenylthio-enyne Substrates and Tandem (Cyclo)Isomerization / Elimination

With the optimal conditions in hand, we reasoned that differential substitution on the heterocycle may best be accomplished by judicious choice of the pyridine partner, as examined in experiments recounted in Figure 5. Sonogashira coupling of the terminal alkyne of phenylthio- enyne 118 with several commercially available halopyridines provided us with a small but diverse array of benzannulation precursors in good to excellent yields (Figure 4). These test

32 substrates comprise alkyl (130-131), halo (133), and fused arene (134-135) substructures to probe the effect of substitution patterns on regioselectivity and yield. Regioselectivity was poor

(Figure 5) for the distally substituted (relative to the alkyne) pyridines (131137a/band

132138a/b) and good for proximally substituted (133139) and/or electronically differentiated substrates (134140and 135141). Benzannulated products 138b, 140, and 141 suggest that this methodology is similarly amenable to producing quinolines, phenanthridines, and probably other polycyclic (hetero)aromatics, as long as the substrate-associated regioselectivity biases are sufficient for the needs at hand.

Figure 4. Sonogashira Couplings for the Synthesis of Benzannulation Precursors

Future efforts are planned for establishing and expanding the scope and potential impact of this methodology. For example, differential substitution of the isoquinoline benzene core can be achieved by choice of olefination partner in the initial phenylthio-enyne synthesis (cf 124 or

33 125, Scheme 24), and/or by site-selective substitution of the derived isoquinolines. Along these lines, dibromination of 114 (142) and monobromination of 129 ( 143) proceeded smoothly using conditions described by Gouliaev (Scheme 25, eq 1-2),163 and dimethylisoquinoline 136 is amenable to site-selective metalation for further functionalization (Scheme 25, eq 3).

Figure 5. Synthesis of Isoquinolines (and Quinolines) via DBU-Promoted Benzannulation

Scheme 25. Expanding the Benzannulation Scope through Further Synthetic Elaboration

34 Metalation of 136 occurs regioselectively as removal of the indicated proton (Scheme 25) does not interrupt aromatic character and clearly demonstrates the possibility of synthetic elaboration with other electrophiles. Finally, incorporation of aryl-halides in 139, 142, and 143 provides functional group handles for metal catalyzed couplings on either the pyridine or benzene ring which expands the utility of these isoquinoline derivatives. Efforts to expand the scope and mechanistic understanding of the isoquinoline synthesis and harness unique physical and pharmacological properties of gem-dimethylcyclopentane-fused arenes are discussed in sections 2.2 and 2.3.

2.2 Solution and Solid-State Molecular Photophysics of gem-Dimethylcyclopentane Derivatives

Harnessing DDA reaction methodology to synthesize cyclopentane-fused fluorescent-dye molecules has received increasing attention99,113 due to its versatility in the rational design of their aromatic cores. In the course of synthesizing a small library of novel isoquinolines, we noted that the solution- and/or solid-state molecular photophysics of gem-dimethylcyclopentane- fused derivatives may be of interest for bioimaging and/or light-harvesting applications.164-165

With the knowledge that fusion of the gem-dimethylcyclopentane motif to known pharmacophores significantly alters their three-dimensional topology and, as a result, efficacy

(see sections 2.1 and 3.1), we became interested in exploring its impact on excited-state properties of established chromophores in solution and the solid-state. Our working hypothesis is that annealing a rigid, five-membered-ring to light absorbing units may change the electrostatic interaction of transition dipole moments in the excited-state.166

We decided to target simple polyaromatic parent molecules whose photophysical data were well-documented in the literature and hoped that their elaboration to gem-

35 dimethylcyclopentane derivatives might be possible by simple exploitation of our isoquinoline benzannulation methodology. We began by synthesizing pentacyclic phenanthridine derivative

146. The photophysical properties of phenanthridine itself are well-documented, and tetracyclic phenanthridine derivatives 140 and 141 were already in hand. Chloroisoquinoline 139 can be recycled through our two-step process (Sonogashira to 145 and benzannulation) to produce 146 in excellent yield (Scheme 26).

Scheme 26. Synthesis of Pentacyclic Phenanthridine 146

It came to our attention that constructing 146 might be amenable to an expanded synthesis strategy (Scheme 27) of polycyclic chromophores167-169 without a pyridine ring.

Sonogashira coupling of phenylthio-enyne 126 with the appropriate aryl-halide would produce aryl-alkyne 147. Regiocontrolled benzannulation to 148 with our optimized protocol might be best achieved by employing a proximally substituted (relative to the alkyne) halogen or aromatic ring as a steric bias. Incorporation of a halogen would also serve as a functional group handle for further synthetic manipulations and is otherwise easily removed. To this end, gem- dimethylcyclopentane-fused naphthalene 149, dichloroanthracene 150, triphenylene 151,

36 dibenzo[g,p]chrysene 152, and phenanthrene 153 emerged as attractive substrates to be derived from commercially available materials (Figure 6).

Scheme 27. Synthesis Strategy for gem-Dimethylcyclopentane-Fused Arenes

Figure 6. (Top) Phenanthridine Derivatives. (Bottom) gem-Dimethylcyclopentane-Fused Arene Targets

Dichloroanthracene derivative 150 and dibenzo[g,p]chrysene 152 were synthesized through our two-step strategy from 1,4-dichloro-2,5-diiodobenzene and 6,12-dibromochrysene, respectively (Scheme 28). Sonogashira coupling of 126 proceeded smoothly in both cases to give

154 and 155, whereas only the benzannulation of the electron-deficient enyne 154 produced

37 aromatized product in good yield. The low yield (28%) observed from 155 to 152 may be attributed to the electronic demands of our inverse-demand DDA as all of our previous enyne substrates were electron-deficient and therefore better matched with the electron-donating vinyl sulfide (See section 2.3 for further discussion).

Scheme 28. Synthesis of Dichloroanthracene and Dibenzo[g,p]chrysene Derivatives

Similar trends in yield for the cycloaddition step were observed in the syntheses of all other substrates, as well. Heptacylic triphenylene 151 required two applications of our metal coupling and benzannulation pathway from 1-iodo-3,5-dichlorobenzene (Scheme 29). In the event, Sonogashira coupling to 156 and DBU-promoted thermal cycloisomerization provided dichloronaphthalene 157 in 74% yield over two steps. Aryl-chrloides are known to be suboptimal metal-catalyzed coupling partners;170 however, copper-free Sonogashira coupling conditions in the presence of the bulky phosphine ligand XPhos generated 1,4-diyne 158 in good yield. The

38 functional group handles in 157 make it a flexible substrate for potential elaboration to other useful gem-dimethylcyclopentane-fused arenes. Thermal cyclization of the electron-rich enyne proceeded in modest yield (30%), consistent with the synthesis of 152.

Scheme 29. Synthesis of Triphenylene 151

Naphthalene 149 and phenanthrene 153 were the products of diverging pathways from bromonaphthalene 160 – an intermediate procured in two efficient steps from 2- bromoiodobenzene (Scheme 30). Simple halogen-metal exchange with n-butyllithium and quenching with methanol cleanly removed the bromo substituent from 160 to give 149 in 93% yield. Alternatively, Sonogashira coupling to 161 and benzannulation gave phenanthrene 153 in

36% yield. Although the key cyclizations only proceeded in good yield for electron-deficient enynes, the two-step strategy described here is easily implemented (crude products from

Sonogashira couplings with 126 are usually advanced to the next step without further

39 purification after filtering), produces flexible intermediates, and arrives at the desired products in

2-4 steps from 126.

Scheme 30. Diverging Pathways for the Synthesis of Naphthalene and Phenanthrene Derivatives

With a small array of gem-dimethylcyclopentane-fused chromophores in hand, we proceeded with investigations into their solution and solid-state molecular photophysics to compare with the parent compounds. The UV-vis absorption and emission spectra of 149-153

(ex = 285 nm for 149, 150, 151, 153 and 320 nm for 152) in methylene chloride are depicted in

Figure 7 and are mostly bathochromically shifted by ~10 nm compared to their respective parent compounds. Only dichloroanthracene 150 and dibenzo[g,p]chrysene 152 show a bathochromic shift in both the UV-vis absorption spectra and normalized emission, while 149 and 151 exhibit no shift in emission whatsoever. On the other hand, both the absorption and emission spectra for heteroaromatic derivatives 140, 141, and 146 (ex = 295 nm) in methylene chloride are bathochromically shifted relative to the parent phenanthridine (Figure 7).

Excitation of crystalline phenanthridine at 310 nm in the solid-state results in a ~10 nm bathochromic shift (Figure 8, left) relative to in methylene chloride solution which may be 40 explained by - interactions in the solid-state. Conversely, crystalline phenanthridine derivative

146 appears to be energetically similar in solution and the solid-state as the normalized emission peaks are in the same position (Figure 8, middle), indicating little to no aggregation in the solid- state. Direct comparison of the steady-state emission of crystalline 146 with the parent phenanthridine shows a 20 nm bathochromic shift for 146 when excited at 310 nm (Figure 8, right).

2.5 1.0 0.6 Napthalene 1.0 Dichloroanthracene Napthalene Dichloroanthracene 149 2.0 150 149 150 0.8 0.8 0.4 1.5 0.6 0.6

1.0 0.4 0.4 0.2 0.2 0.2 0.5

Absorbance (a.u)

Absorbance(a.u) 0.0 0.0 0.0 0.0

Normalized Emission (a.u.) NormalizedEmission 240 260 280 300 320 340 360 380 400 (a.u.) NormalizedEmission 300 320 340 360 380 400 420 440 250 300 350 400 450 500 400 450 500 550 600 Wavelength (nm) Wavelength (nm) Wavelength (nm) Wavelength (nm)

1.50 0.6 1.0 1.0 Chrysene 1.25 Triphenylene Chrysene 151 Triphenylene 152 151 152 0.8 1.00 0.8 0.4 0.6 0.75 0.6

0.50 0.2 0.4 0.4

0.25 0.2 0.2

Absorbance (a.u.)

Absorbance(a.u.) 0.00 0.0 0.0 0.0 240 260 280 300 320 340 360 380 400 (a.u.) NormalizedEmission 300 350 400 450 500 250 300 350 400 450 500 (a.u.) NormalizedEmission 350 400 450 500 550 Wavelength (nm) Wavelength (nm) Wavelength (nm) Wavelength (nm)

1.0 1.0 Phenanthridine 1.0 Phenanthridine Phenanthrene 1.5 Phenanthrene 140 140 153 153 0.8 141 141 146 146 1.0 0.6 0.5 0.5 0.4 0.5 0.2

Absorbance (a.u) 0.0 0.0

0.0 0.0 NormalizedAbsorbance

Normalized Emission (a.u.) Normalized Emission 240 260 280 300 320 340 360 380 400 300 350 400 450 500 240 260 280 300 320 340 360 NormalizedIntensity (counts) 350 400 450 500 Wavelength (nm) Wavelength (nm) Wavelength (nm) Wavelength (nm)

Figure 7. UV-vis Absorption Spectra and Normalized Emissions of Parent Molecules and gem- Dimethylcyclopentane Derivatives in Methylene Chloride

These observations become clearer from single-crystal X-ray analysis which reveals that crystal packing of 146 (Figure 9, left) is quite distinct from that of the parent phenanthridine171

(Figure 9, right). Phenanthridine itself packs in a herringbone pattern, with edge-to-face interactions at a distance of 2.92 Å, whereas gem-dimethylcyclopentane-fused phenanthridine

41 146 packs in a loosely staggered arrangement which shows no direct - stacking. It appears the hydrophobic wings on 146 form a well-layered, rigid three-dimensional topology which prevents direct - stacking of the central phenanthridine moieties in the solid-state structure.

1.0 Solution 1.0 146 Crystal 1.0 Phenanthradine

0.8 Solution 0.8 0.8 Crystal

0.6 0.6 0.6

0.4 0.4 0.4

NormalizedEmission

NormalizedEmission

NormalizedEmission

0.2 0.2 0.2

0.0 0.0 0.0 340 360 380 400 420 440 460 480 500 340 360 380 400 420 440 460 480 500 340 360 380 400 420 440 460 480 500 Wavelength (nm) Wavelength (nm) Wavelength (nm)

Figure 8. (Left) Normalized Steady-State Emission Spectra of Phenanthridine in DCM and Crystalline Phenanthridine. (Middle) Normalized Steady-State Emission Spectra of 146 in DCM and Crystalline 146. (Right) Normalized Steady-State Emission Spectra of Crystalline 146 and Crystalline Phenanthridine.

Figure 9. (a) Crystal Packing of 146. (b) Phenanthridine Itself.

The preliminary solid-state emission data combined with the X-ray crystal analysis is consistent with our central hypothesis: annealing a gem-dimethylcyclopentane motif to

42 polycyclic chromophores perturbs their photophysical properties. Differences in the crystal packing of the parent compound and the derivative likely alter the electrostatic interactions of their transition dipole moments in the excited state, resulting in a bathochromic shift in the emission spectra. It appears that the rigid topology of the gem-dimethylcyclopentane when fused to phenanthridine prevents direct - stacking, which may have applications in aggregation prevention in solution and/or the solid state. X-ray crystallography data and solid-state photophysics of 149-153 are underway and the potential utility of gem-dimethylcyclopentane derivatives of other fluorescent dye molecules is being explored.

2.3 Triazabicyclodecene: An Optimized Reagent for Base-Mediated Isomerization of Alkynyl- to Allenyl-pyridines in the Synthesis of Isoquinoline Derivatives

Harsh reaction conditions (high temperature, long reaction time, and a large excess of base) severely limit our benzannulation methodology to specialized substrates. In an effort to broaden the utility of the present transformation we set out to address these shortcomings through focused mechanistic investigations. Based on the need for a large excess of DBU, we inferred that the role of DBU was not limited to base-mediated elimination of thiophenol. Three alternative mechanistic hypotheses are outlined in Scheme 31. The most conceptually straightforward pathway is illustrated in black: thermal [4 + 2] cycloaddition of 118 to produce dearomatized cyclic allene 118a, followed by isomerization to dihydroisoquinoline 118b and elimination to 114. The first alternative, depicted in red, bypasses cyclic allene 118a en route to

114 via initial DBU-mediated isomerization of alkynyl- to allenyl-pyridine (118  118c), cycloaddition (118c  118d), and finally isomerization and elimination. A third possibility

(illustrated in blue) is that DBU acts as a nucleophilic catalyst172 by adding to alkynylpyridine

43 118 (along with adventitious H+) prior to cycloaddition (118  118e  118f  4), thereby also bypassing cyclic allene 118a en route to 114.

Scheme 31. Proposed Mechanistic Pathways

Important mechanistic insights came from deuterium-labeling experiments involving methanol-d1 (10 equiv, Scheme 32). We imagined three possible outcomes for external deuterium incorporation into 114 from 118 (Scheme 32, top). Direct thermal [4 + 2] cycloaddition of 118 (black pathway) or a nucleophilic DBU catalyst (blue pathway) would likely result in deuterium incorporation in the benzene ring resulting in 114ab or 114ef, respectively. Alternatively, an alkyne to allene isomerization event (red pathway) would probably occur with simultaneous deuterium incorporation in the methylene bridge and benzene core (114cd). In the event, subjecting 118 to our optimized reaction conditions in the presence of

10 equivalents of methanol-d1 resulted in 40% deuterium incorporation in the methylene hydrogens (Scheme 32, eq 1). The four benzylic methylene hydrogens in the 1HNMR spectrum of 114 appear as a singlet that integrates to 4.0 hydrogens. The corresponding singlet in the

1HNMR spectrum of 114-d integrates to 3.6 hydrogens, which we interpret as 40% deuterium

44 incorporation. As a control experiment, we subjected 114 to the same conditions and observed no more than 10% deuterium incorporation into the benzylic methylene hydrogens (Scheme 32, eq

2).

Scheme 32. Deuterium-Labeling Experiments Involving Methanol-d1

Surprisingly, we observed 0% deuterium incorporation on the benzene core, although we do not identify any concerted intramolecular mechanisms for delivering hydrogen to this position. We interpret this result as being consistent with a stepwise intramolecular isomerization event in which a proton or hydrogen atom is rapidly translocated across a molecular surface within the transient solvent cage. Such rapid-stepwise “remove-and-return” isomerization events 45 can be envisioned for 118a 118b and also for 118  118c. On the other hand, it is harder to rationalize 0% deuterium incorporation on the benzene ring for the reaction pathway that commences with DBU•H+ addition to the alkynylpyridine (118  118e). Deuterium incorporation at the benzylic methylene position is clearly most consistent with the intermediacy of 118d, which we interpret as evidence in support of the initial isomerization of 118 to allenylpyridine 118c (red pathway).

Figure 10. Relative Energies (G) from DFT Calculations

Computational studies (SMD=o-DCB)/UM06-2X/6-31+G(d,p) on the black and red pathways correlate well with the observed deuterium incorporation. The energy diagram depicted in Figure 10 shows a comparison between the relevant species involved in either a direct [4+2]

46 cycloaddition of 118 to cyclic allene 118b (black pathway) or an indirect [4+2] cycloaddition of putative allenylpyridine 118c produced by base-promoted isomerization of 118 (red pathway). At

210 ˚C in o-DCB the magnitude of the computed free energy of activation (G‡) for the direct

[4+2] cycloaddition to high energy intermediate 118a is 45.4 kcal/mol. Meanwhile, the G‡ for the indirect [4+2] cycloaddition of allenylpyridine 118c was calculated to be 13.9 kcal/mol lower in energy than the direct [4+2] (35.5 kcal/mol versus 45.4 kcal/mol), and the overall energies of reaction from 118 to tetraene intermediate 118d are exergonic by 15.7 kcal/mol. Aromatization and/or elimination of thiophenol from 118d to 114 is likely initiated by the proton depicted in blue (Figure 11) as a truncated version of 118d (methyl groups were replaced with hydrogens to

 alleviate calculations) was found to bear a hyperconjugative C-H C-S interaction (5.3 kcal/mol) corroborated by the highest NBO charge localization in the molecule (+0.292).

 Figure 11. Hyperconjugative C-H C-S Interaction in Truncated Intermediate 118d

Although we were not successful in locating transition state structures corresponding to a concerted or stepwise 1,3-proton transfer, base-promoted isomerization to 118c appears to be

47 favorable by 4 kcal/mol (Figure 10). Based on exclusive deuterium incorporation in the methylene bridge and a lower transition state barrier for an indirect allenylpyridine cycloaddition, we propose isomerization of the alkynyl- to allenyl-pyridine (118  118c) as the first and key step in this new isoquinoline synthesis.

In our quest for milder reaction conditions, the strong evidence for an isomerization pathway coupled with an undesired excess of base (30 equiv) led us to reevaluate DBU as the optimal reagent for the transformation. One of the many unproductive bases we initially investigated for its mechanistic nuances in alkyne isomerizations was the alkali metal amide of

1,3-diaminopropane, otherwise known as the “acetylene zipper”.173 The zipper reagent is thought to mediate migration of a triple bond to the terminus of a carbon chain through a series of cyclic concerted bimolecular 1,3-proton transfers by way of an intermediate allene; however, the intermediacy of discrete carbanion formation has been suggested.174 Concerted and stepwise 1,3- proton transfers in allene-acetylene rearrangements have been discussed for a number of other bases, as well.175-179 In our case, finding a base similar to the acetylene zipper which might facilitate either process would be advantageous.

Bicyclic guanidines have received increasing attention in organocatalysis for their strong

Bronsted basicity and recognized hydrogen bonding capability.180 The bicyclic framework locks the nitrogens in an orientation where alignment of their lone-pairs with the central sp2 carbon facilitates delocalization of the protonated species. Such favorable orbital overlap in the cationic form results in increased basicity for guanidine bases compared to amidine bases such as DBU which contain one less nitogen lone pair (Figure 12, left).181 There are several examples of guanidine bases outperforming their amidine counterparts,182 and we reasoned that the charge delocalization in a bicyclic guanidine combined with a fortuitously placed hydrogen in proximity

48 to the alkyne would facilitate delivery of the second proton to the allenyl carbon in our 1,3- proton transfer (Figure 12, right). Such an event would probably take place in either a concerted manner analogous to metallated 1,3-diaminopropane, or through a stepwise deprotonation/protonation sequence (Figure 12, right). Indeed, replacing DBU with commercially available bicyclic guanidine 1,5,7-Triaza-bicyclo-[4.4.0]dec-5-ene (TBD) resulted in a comparable yield while at a lower temperature, shorter reaction time, and with fewer equivalents (Scheme 33, eq 1). In the event, heating 118 along with TBD (2 equiv) in o- dichlorobenzene (o-DCB) at 180 °C overnight, followed by direct chromatographic purification of the reaction mixture on silica gel produced isoquinoline 114 in 78% yield (81% with 30 equiv

DBU, 210 °C, 2.5 days). Attempts at shorter reaction times and sub-stoichiometric quantities of

TBD resulted in lower yields and/or recovery of alkynylpyridine.

Figure 12. (Left) Comparison of Bicylic Amidines and Guanidines. (Right) Proposed Stepwise and Concerted Mechanisms for Guanidine Catalyzed 1,3-Proton Transfer

Based on the absence of deuterium incorporation into the aromatic core, we imagine that hydrogen transfer from the propargyl position to the base may result in an ion-pair complex

49 which rapidly translocates the same abstracted proton across the -surface to the allenyl carbon.

Ion-pair complexes with protonated DBU (DBU-H+) and TBD (TBD-H+) are easily rationalized

+ as the resulting vacant p-orbital is stabilized by nNp delocalizinginteractions. Intermolecular hydrogen-bond donation from the deprotonating species has been shown computationally to stabilize propargyl anions in propargyl-allene isomerizations.183 If a deprotonation/reprotonation sequence is in fact the predominant pathway, then hydrogen-bond donation from TBD/DBU-H+ to the resulting anion may play a secondary role in stabilizing intermediates 162 and 163. Such secondary considerations could bolster the argument for TBD’s success in our system since guanidinium ions are excellent single and dual hydrogen-bond donors to a single substrate in a variety of reactions. For example, bicylic guanidine 165 was recently shown to be an effective catalyst for isomerization of 3-alkynoates 164 to chiral allenoate 166184 via stabilized hydrogen- bond ion-pair complexes with the intermediate propargyl anion (Scheme 33, eq 2).185-186 Thus, we propose that the isomerization event facilitated by TBD may benefit from secondary interactions with the intermediate anion in 162 and 163, resulting in a substrate-TBD ion-pair complex that is more stable than the analogous substrate-DBU complex.

In conclusion, we identified and optimized a base-mediated cascade of

(cyclo)isomerizations and elimination to produce novel isoquinoline derivatives of potential interest for pharmaceutical, biomedical, and energy-related research. The cascade process is thought to involve an allenylpyridine intermediate as the 4 component in an intramolecular [4s

+ 2s] cycloaddition, thereby avoiding the intermediacy of the strained cyclic allene that would be produced by direct cycloisomerization of the alkynylpyridine substrate (cf. 118  118a,

Scheme 31). Electron-rich vinyl sulfides purportedly act as the 2 component of inverse-demand cycloadditions; the substrates are prepared by an important extension of our previous

50 fragmentation / olefination methodology. This new isoquinoline synthesis anneals a benzenoid structure onto a pre-existing pyridine, strategically complementing most established methods for isoquinoline synthesis.

Scheme 33. Propargyl-Allene Isomerizations Facilitated by Bicyclic Guanidine Bases

2.4 Experimental Data

General Information

1H-NMR and 13CNMR spectra were obtained on a 400 or 600 MHz spectrometer using

CDCl3 as the deuterated solvent. Chemical shifts are reported in parts per million (ppm) relative

1 13 to residual CHCl3 (7.26 ppm for H-NMR and 77.0 ppm for CNMR). Coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on an FT-IR spectrometer with diamond

ATR accessory as thin film. Mass spectra were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Melting points were taken using an electrothermal Mel-Temp © apparatus. All chemicals were used as received without further purification and all reactions were run under nitrogen atmosphere. Glassware was oven-dried prior to use and all purifications were performed by flash chromatography using silica gel with

40-63 micron particle size. Absorption spectra data were recorded on an Agilent 8453 51 UV−visible photo diode array spectrophotometer in a quartz cuvette with a path length of 1 cm.

Steady-state emission data were collected at room temperature using an Edinburgh FLS980 spectrometer. Samples were excited using light output from a housed 450 W Xe lamp passed through a single grating (1800 λ/mm, 250 nm blaze) Czerny-Turner monochromator and finally a

1 nm bandwidth slit. Emission from the sample was passed through a single grating (1800 λ/mm,

500 nm blaze) Czerny-Turner monochromator (1 nm bandwidth) and detected by a peltier-cooled

Hamamatsu R928 photomultiplier tube.

Literature Preparation of Fragmentation/Olefination Precursors

3-hydroxy-5,5-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (123)

To a suspension of 5,5-dimethyl-1,3-cyclohexanedione (1.38 g, 9.8 mmol, 1 equiv.) in dichloromethane (50 mL) was added pyridine (1.59 mL, 19.6 mmol, 2 equiv.). The resulting mixture was stirred at -78 ˚C for 10 minutes before trifluoromethanesulfonic anhydride (1.98 mL, 11.8 mmol, 1.2 equiv.) was added dropwise via syringe. The reaction was stirred at -78 ˚C for 20 minutes, warmed to 0˚C for 20 minutes, and room temperature for 30 minutes. When complete consumption of the starting dione was observed by TLC, the reaction was quenched using 1 M HCl solution (20 mL) and extracted 3 times with diethyl ether (3x10mL). The organic layers were combined and washed with aqueous Na2CO3 solution and water, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 2/98) to yield 2.54 g vinyl triflate in 95% yield as a colorless oil. Spectroscopic data was identical to the reported data from the literature.162

To 40 mL THF solution of vinyl triflate (see above) (2.67 g, 9.81 mmol, 1 equiv.) at -78

˚C was slowly added 11.77 mL DIBAL-H (1.0 M solution in toluene, 1.2 equiv.). The reaction

52 mixture was stirred at -78 ˚C for 10 minutes, warmed to 0 ˚C for 10 minutes, and room temperature for 30 minutes. The reaction was diluted with ether, cooled to 0 ˚C and quenched by adding 15% NaOH and water. The mixture was stirred for 15 minutes until a gel formed, and

MgSO4 was then added. After the addition of MgSO4, the mixture was stirred for an additional

15 minutes. Vacuum filtration and evaporation gave the crude vinylogous hemiacetal triflate 123.

Purification flash column chromatography with gradient eluent from EtOAc/Hexane = 5/95 to

EtOAc/Hexane = 20/80 yielded 2.61 g of 123 (97%). Spectroscopic data was identical to the reported data from the literature.162

diethyl ((phenylthio)methyl)phosphonate (124)

To a round-bottom flask equipped with a reflux condenser and magnetic stir bar was added chloromethyl phenyl sulfide (0.63 g, 4 mmol, 1 equiv.) and triethyl phosphite (1.66 g, 10 mmol, 2.5 equiv.). The resulting mixture was heated at 150˚C for 48 hours before being purified by Kugelrohr distillation to give diethyl phenylthiomethylphosphonate (0.967 g, 93%) as colorless oil. Spectroscopic data was identical to the reported data.187

diethyl (1-(phenylthio)ethyl)phosphonate (125)

To 4.22 mL THF solution of phosphonate 124 (0.439 g, 1.69 mmol, 1 equiv.) at -78 ˚C was slowly added 1.16 mL of n-BuLi (1.6 M solution in hexanes, 1.1 equiv.). The reaction mixture was stirred at -78 ˚C for 2 hours before iodomethane (0.263 g, 1.87 mmol, 1.1 equiv.) was added dropwise via syringe. The reaction was maintained at -78 ˚C for an additional 30 minutes, warmed to 0 ˚C for 5 minutes, room temperature for 15 minutes, and heated in an oil bath at 45 ˚C for 18 hours. After 18 hours, the reaction mixture was cooled to room temperature and quenched with saturated NH4Cl. The aqueous layer was extracted with diethyl ether 3 times and the combined organic layers were washed with saturated NaCl, dried over MgSO4, and

53 concentrated in vacuo. The crude product was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 65/35) to give 125 (0.338 g, 70%) as a colorless oil. Spectroscopic data was identical to the reported data.187

Synthesis of Phenylthio-enyne Substrates

(4,4-dimethylhept-1-en-6-yn-1-yl)(phenyl)sulfane (126)

To 70 mL THF solution of diisopropylamine (0.1 M) at -78 °C was slowly added 4.15 mL of n-BuLi (1.6 M solution in hexanes, 2.1 equiv.). The mixture was stirred at -78 °C for 10 minutes, warmed to 0 °C for 30 minutes, and then cooled to -78 °C before the addition of vinylogous hemiacetal triflate 123. To the LDA solution (6.62 mmol, 2.1 equiv) at -78 °C was added vinylogous hemiacetal triflate 123 (0.784 g, 2.86 mmol, 1 equiv) and phosphonate 124

(0.82 g, 3.15 mmol, 1.1 equiv) successively. The resulting mixture was stirred at -78 °C for 10 minutes, warmed to 0 °C for 10 minutes, room temperature for 30 minutes, and heated in an oil bath at 60 °C for 2 hours. After 2 hours, the reaction mixture was cooled to room temperature and half-saturated NH4Cl was added to quench the reaction. The mixture was extracted with diethyl ether 3 times. The organic layers were combined and washed with water, dried over

MgSO4 and concentrated. The residue was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 10/90) to give the desired enyne 126 (0.547 g, 83%, E:Z = 3.7:1) as a colorless oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 7.35-7.28 (m, 5H), 6.20 (dt, J = 14.82, 0.84

Hz, 1H), 5.97 (dt, J = 14.82, 7.80 Hz, 1H), 2.19 (dd, J = 7.74, 1.02 Hz, 2H), 2.10 (d, J = 2.64,

2H), 2.01 (t, J = 2.64, 1H), 1.00 (s, 6H) ppm;

54 1 HNMR cis isomer (600MHz, CDCl3): δ 7.22-7.18 (m, 5H), 6.32 (dt, J = 9.42, 1.08 Hz,

1H), 5.86 (dt, J = 9.36, 7.74 Hz, 1H), 2.30 (dd, J = 7.68, 1.14 Hz, 2H), 2.15 (d, J = 2.64, 2H),

2.01 (t, J = 2.64, 1H), 1.04 (s, 6H) ppm;

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 136.38, 136.33, 132.81, 129.36,

128.98, 128.95, 128.64, 126.25, 126.19, 125.39, 123.96, 82.30, 82.19, 70.24, 70.18, 44.54, 40.61,

34.55, 34.07, 31.63, 31.38, 26.65, 26.52 ppm;

IR: νmax 3300, 3067, 3016, 2958, 2926, 2116, 1583, 1479, 1439, 1386, 1367, 1090, 1024,

952, 737, 689.

+ + HRMS (APCI) calcd for C15H19S [(M+H) ]: 231.12020, found 231.11998

(5,5-dimethyloct-2-en-7-yn-2-yl)(phenyl)sulfane (127)

Following the same procedure for 126, phosphonate 125 (0.25 g, 0.89 mmol, 2.1 equiv.) gave enyne 9 (0.145 g, 73%, E:Z = 2.7:1) as a colorless oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 7.33-7.28 (m, 5H), 5.89 (td, J = 7.89, 1.32

Hz, 1H), 2.15 (d, J = 7.92 Hz, 2H), 2.10 (d, J = 2.64 Hz, 2H), 2.00 (t, J = 2.64 Hz, 1H), 1.90 (s,

3H), 1.00 (s, 6H) ppm;

1 HNMR cis isomer (600MHz, CDCl3): δ 7.22-7.19 (m, 5H), 5.84 (td, J = 7.53, 1.08 Hz,

1H), 2.38 (dd, J = 7.56, 0.72 Hz, 2H), 2.13 (d, J = 2.64 Hz, 2H), 2.00 (t, J = 2.64 Hz, 1H), 1.92

(d, J = 1.02 Hz, 3H), 1.02 (s, 6H) ppm;

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 135.19, 134.77, 131.80, 131.39,

131.19, 130.93, 130.48, 130.42, 128.93, 128.81, 126.52, 126.31, 82.45, 82.33, 70.17, 70.12,

41.37, 40.39, 34.68, 34.44, 31.63, 31.51, 26.64, 24.61, 18.25 ppm

IR: νmax 3301, 2956, 2868, 1711, 1580, 1477, 1439, 1230, 1023, 821, 739, 688.

+ + HRMS (APCI) calcd for C16H19S [(M+H) ]: 243.12020, found 243.12000

55 Sonogashira coupling of aryl halides and 1,6-enynes

General Procedure A:

An oven-dried flask under the flow of N2 was charged with aryl halide (1 equiv.),

Pd(PPh3)2Cl2 (0.06 equiv.), and CuI (0.06 equiv.). The flask was further vacuumed and filled with N2 3 times before the addition of degassed NEt3 (0.1M). The mixture was stirred for 5 minutes before slow, dropwise addition of enyne 126 or 127 (1.13 equiv.) and heating to 60°C for 24 hours. After 24 hours the reaction mixture was passed through a plug of silica gel and celite using 80% EtOAc in hexanes as the eluent and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 10/90) to give the desired product.

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)pyridine (118)

Following the general procedure A, 4-iodopyridine (0.236 g, 1.15 mmol) and enyne 126

(0.30 g, 1.30 mmol) gave 118 (0.308 g, 87%, E:Z = 2.5:1) as a yellow oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 8.52 (d, J= 2.94 Hz, 2H), 7.34-7.24 (m,

7H), 6.22 (dt, J = 14.94, 0.86 Hz, 1H), 6.00 (dt, J = 14.88, 7.8 Hz, 1H), 2.34 (s, 2H), 2.23 (dd, J =

7.74, 0.86 Hz, 2H), 1.06 (s, 6H) ppm;

1 HNMR cis isomer (600MHz, CDCl3): δ 8.51 (d, J = 5.94 Hz, 2H), 7.25-7.18 (m, 7H),

6.35 (dt, J = 9.24, 1.14 Hz, 1H), 5.89 (dt, J = 9.30, 7.68 Hz, 1H), 2.38 (s, 2H), 2.36 (dd, J = 8.46,

1.14 Hz, 2H), 1.10 (s, 6H) ppm;

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 149.63, 149.57, 136.26, 136.19,

132.38, 132.27, 132.15, 129.15, 129.02, 128.87, 128.66, 126.29, 125.80, 125.62, 124.31, 93.87,

93.66, 80.47, 80.42, 44.85, 40.70, 35.15, 34.68 32.54, 32.31, 26.91, 26.83 ppm;

56 IR: νmax 3079, 3019, 2958, 2224, 1715, 1592, 1538, 1478, 1278, 1213, 1156, 988, 951,

819, 737, 689.

+ + HRMS (ESI+) calcd for C20H22NS [(M+H) ]: 308.14729, found 308.14826.

4-(4,4-dimethyl-7-(phenylthio)oct-6-en-1-yn-1-yl)pyridine (128)

Following the general procedure A, 4-iodopyridine (0.072 g, 0.353 mmol) and enyne 127

(0.110 g, 0.45 mmol) gave 128 (0.096 g, 85%, E:Z = 3.85:1) as a colorless oil.

1 HNMR E isomer (600MHz, CDCl3): δ 8.53 (d, J = 3.48 Hz, 2H), 7.52-7.18 (m, 7H),

5.91 (td, J = 7.92, 1.32 Hz, 1H), 2.34 (s, 2H), 2.20 (d, J = 7.80 Hz, 2H), 1.91 (d, J = 0.92 Hz,

3H), 1.06 (s, 6H) ppm

1 HNMR Z isomer (600MHz, CDCl3): δ 8.53 (d, J = 3.48 Hz, 2H), 7.52-7.18 (m, 7H),

5.87 (td, J = 7.50, 1.28 Hz, 1H), 2.45 (d, J = 6.40 Hz, 2H), 2.36 (s, 2H), 1.94 (d, J = 1.16 Hz,

3H), 1.08 (s, 6H) ppm

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 149. 57, 149.48, 135.03, 134.68,

132.37, 132.24, 131.47, 131.33, 131.27, 131.16, 130.54, 130.40, 128.95, 128.84, 126.63, 126.35,

125.80, 94.10, 93.89, 80.38, 41.46, 40.61, 35.26, 35.04, 32.59, 32.41, 26.93, 24.63, 18.26 ppm

IR: νmax 3067, 3031, 2958, 2926, 2225, 1593, 1530, 1475, 1439, 1262, 1213, 1168, 1024,

819, 740, 691.

+ + HRMS (ESI+) calcd for C21H24NS [(M+H) ]: 322.16294, found 322.16388

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)-2,6-dimethylpyridine (130)

Following the general procedure A, 4-bromo-2,6-dimethylpyridine (0.20 g, 1.075 mmol) and enyne 126 (0.297 g, 1.29 mmol) gave 130 (0.335 g, 93%, E:Z = 4:1) as a brown oil.

57 1 HNMR trans isomer (600MHz, CDCl3): δ 7.34-7.27 (m, 5H), 6.94 (s, 2H), 6.22 (dt, J

= 14.94, 0.78 Hz, 1H), 6.00 (dt, J = 14.82, 7.8 Hz, 1H), 2.47 (s, 6H), 2.31 (s, 2H), 2.22 (dd, J =

5.97, 0.78 Hz, 2H), 1.05 (s, 6H) ppm;

1 HNMR cis isomer (600MHz, CDCl3): δ 7.21-7.18 (m, 5H), 6.94 (s, 2H), 6.35 (dt, J =

9.3, 1.02 Hz, 1H), 5.89 (dt, J = 9.3, 7.62 Hz, 1H), 2.46 (s, 6H), 2.35 (s, 2H), 2.35 (dd, J = 8.58,

1.02 Hz, 2H), 1.09 (s, 6H) ppm;

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 157.67, 157.59, 136.33, 136.24,

132.49, 132.44, 129.29, 129.00, 128.85, 128.68, 126.26, 125.50, 124.24, 122.34, 122.30, 92.28,

80.89, 80.82, 44.83, 40.68, 35.13, 34.68, 32.52, 32.31, 26.92, 26.83, 24.29 ppm;

IR: νmax 3059, 3007, 2958, 2924, 2246, 2220, 1597, 1550, 1478, 1214, 1090, 1024, 950,

860, 737, 689.

+ + HRMS (ESI+) calcd for C22H26NS [(M+H) ]: 336.17859, found 336.17789

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)-2-methylpyridine (131)

Following the general procedure A, 4-bromo-2-methylpyridine (0.081 g, 0.47 mmol, 1.13 equiv.) and enyne 126 (0.096 g, 0.42 mmol, 1 equiv.) gave 131 (0.095 g, 71%, E:Z = 2.5:1) as a brown oil.

1 HNMR trans isomer (400MHz, CDCl3): δ 8.41 (d, J = 4.96 Hz, 1H), 7.35-7.17 (m,

5H), 7.13 (s, 1H), 7.06 (d, J = 4.08 Hz, 1H), 6.23 (dt, J = 14.88, 0.92 Hz, 1H), 6.00 (dt, J = 14.84,

7.76, 1H), 2.51 (s, 3H), 2.33 (s, 2H), 2.23 (dd, J = 7.76, 0.96 Hz, 2H), 1.06 (s, 6H) ppm

1 HNMR trans isomer (400MHz, CDCl3): δ 8.40 (d, J = 4.6 Hz, 1H), 7.35-7.17 (m, 5H),

7.13 (s, 1H), 7.06 (d, J = 4.08 Hz, 1H), 6.35 (dt, J = 9.32, 1.14 Hz, 1H), 5.89 (dt, J = 9.32, 7.68

Hz, 1H), 2.50 (s, 3H), 2.37 (s, 2H), 2.36 (dd, J = 7.67, 1.16 Hz, 2H), 1.09 (s, 1H) ppm

58 13 CNMR of mixture E and Z (600MHz, CDCl3): 158.34, 158.26, 149.00, 148.94,

136.31, 136.23, 132.39, 132.29, 129.20, 129.01, 128.86, 128.69, 126.27, 125.58, 125.34, 125.30,

124.31, 122.85, 122.83, 93.13, 92.92, 80.70, 80.65, 44.85, 40.85, 35.13, 34.67, 32.53, 32.31,

29.72, 29.38, 26.91, 26.84 ppm

IR: νmax 3067, 3020, 2958, 2926, 2234, 1598, 1536, 1479, 1439, 1386, 1283, 1090, 1024,

950, 833, 737, 689.

+ + HRMS (ESI+) calcd for C21H24NS [(M+H) ]: 322.16294, found 322.16272

3-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)pyridine (132)

Following the general procedure A, 3-iodopyridine (0.093 g, 0.45 mmol, 1.13 equiv.) and enyne 126 (0.092 g, 0.40 mmol, 1 equiv.) gave 132 (0.105 g, 85%, E:Z = 3.3:1) as a light-brown oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 8.63 (s, 1H), 8.49 (d, J = 3.84 Hz, 1H), 7.66

(d, J = 7.84 Hz, 1H), 7.35-7.27 (m, 5H), 7.22-7.17 (m, 1H), 6.23 (d, J = 14.88 Hz, 1H), 6.01 (dt,

J = 14.84, 7.76 Hz, 1H), 2.34 (s, 2H), 2.23 (d, J = 7.44 Hz, 2H), 1.06 (s, 6H) ppm

1 HNMR cis isomer (600MHz, CDCl3): δ 8.63 (s, 1H), 8.49 (d, J = 3.84 Hz, 1H), 7.67

(d, J = 7.84 Hz, 1H), 7.35-7.27 (m, 1H), 7.22-7.17 (m, 5H), 6.35 (d, J = 9.32 Hz, 1H), 5.90 (dt, J

= 9.32, 7.68 Hz, 1H), 2.38 (s, 2H), 2.36 (d, J = 7.72 Hz, 2H), 1.10 (s, 6H) ppm

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 152.36, 152.34, 148.03, 147.93,

138.47, 138.44, 136.32, 136.24, 132.60, 129.29, 129.00, 128.91, 128.67, 126.25, 125.53, 124.18,

122.92, 121.05, 91.92, 91.73, 79.44, 79.38, 44.85, 40.72, 35.11, 34.65, 32.56, 32.35, 29.71,

26.90, 26.82 ppm

IR: νmax 3027, 2958, 2926, 2222, 1583, 1560, 1476, 1439, 1406, 1184, 1096, 1023, 950,

802, 737, 704, 689.

59 + + HRMS (ESI+) calcd for C20H22NS [(M+H) ]: 308.14729, found 308.14811

3-chloro-4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)pyridine (133)

Following the general procedure A, 3-chloro-4-iodopyridine (0.150 g, 0.626 mmol, 1 equiv) and enyne 126 (0.172 g, 0.75 mmol, 1.2 equiv.) gave 133 (0.197 g, 92%, E:Z = 3:1) as a yellow oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 8.59 (s, 1H), 8.39 (d, J = 4.98 Hz, 1H),

7.34-7.27 (m, 6H), 6.25 (dt, J = 14.88, 0.85 Hz, 1H), 6.00 (dt, J = 14.82, 7.8 Hz, 1H), 2.40 (s,

2H), 2.27 (dd, J = 7.77, 0.84 Hz, 2H), 1.09 (s, 6H) ppm;

1 HNMR cis isomer (600MHz, CDCl3): δ 8.58 (s, 1H), 8.37 (d, J = 4.98 Hz, 1H), 7.21-

7.18 (m, 6H), 6.35 (dt, J = 9.36, 1.02 Hz, 1H), 5.89 (dt, J = 9.36, 7.74 Hz, 1H), 2.45 (s, 2H), 2.38

(dd, J = 7.74, 1.02 Hz, 2H), 1.13 (s, 6H) ppm;

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 149.23, 149.18, 147.18, 147.12,

136.26, 136.15, 133.02, 132.21, 131.57, 131.47, 129.07, 129.00, 128.90, 128.71, 126.65, 126.60,

126.28, 125.73, 124.44, 99.78, 99.59, 77.63, 77.59, 44.73, 40.77, 35.28, 34.81, 32.79, 32.50,

26.93, 26.82 ppm;

IR: νmax 3056, 3020, 2958, 2925, 2227, 1726, 1578, 1470, 1397, 1167, 1100, 1024, 951,

832, 736, 689.

+ + HRMS (ESI+) calcd for C20H21ClNS [(M+H) ]: 342.10832, found 342.10831

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)quinolone (134)

Following the general procedure A, 4-bromoquinoline (0.084 g, 0.404 mmol, 1.08 equiv) and enyne 126 (0.086 g, 0.373 mmol, 1 equiv.) gave 134 (0.090 g, 68%, E:Z = 1.56:1) as a yellow oil.

60 1 HNMR trans isomer (400MHz, CDCl3): δ 8.83 (d, J = 4.24 Hz, 1H), 8.26 (dd, J =

8.32, 0.96 Hz, 1H), 8.10 (d, J = 8.24 Hz, 1H), 7.75-7.71 (m, 1H), 7.59-7.55 (m, 1H), 7.44 (d, J =

4.44, 1H), 7.35-7.27 (m, 5H), 6.26 (dt, J = 14.84, 0.92 Hz, 1H), 6.04 (dt, J = 14.84, 7.72 Hz, 1H)

2.51 (s, 2H), 2.31 (dd, J = 7.72, 0.92 Hz, 2H), 1.14 (s, 6H) ppm

1 HNMR cis isomer (400MHz, CDCl3): δ 8.82 (d, J = 4.04 Hz, 1H), 8.30 (dd, J = 8.30,

0.96 Hz, 1H), 8.09 (d, J = 8.44 Hz, 1H), 7.74-7.70 (m, 1H), 7.59-7.55 (m, 1H), 7.45 (d, J = 4.44,

1H), 7.27-7.17 (m, 5H), 6.38 (dt, J = 9.36, 1.12 Hz, 1H), 5.93 (dt, J = 9.36, 7.68 Hz, 1H) 2.55 (s,

2H), 2.44 (dd, J = 7.66, 1.12 Hz, 2H), 1.18 (s, 6H) ppm

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 149.76, 148.09, 148.07, 136.23,

136.12, 132.15, 130. 69, 130.55, 129.81, 129.75, 129.72, 129.02, 128.93, 128.76, 128.18, 127.04,

126.98, 126.32, 126.17, 125.99, 125.83, 124.54, 123.81, 98.63, 98.43, 78.79, 78.77, 44.98, 40.88,

35.31, 34.85, 33.01, 32.71, 27.04, 26.95ppm

IR: νmax 3058, 2956, 2925, 2228, 1718, 1683, 1614, 1578, 1504, 1388, 1156, 1023, 896,

761, 739, 689.

+ + HRMS (ESI+) calcd for C24H24NS [(M+H) ]: 358.16294, found 358.16297

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)isoquinoline (135)

Following the general procedure A, 4-bromoisoquinoline (0.082 g, 0.392 mmol, 1.13 equiv) and enyne 126 (0.080 g, 0.347 mmol, 1 equiv.) gave 135 (0.109 g, 88%, E:Z = 3.3:1) as a yellow oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 9.16 (s, 1H), 8.65 (s, 1H), 8.22 (d, J = 8.34

Hz, 1H), 7.97 (d, J = 8.16 Hz, 1H), 7.75-7.72 (m, 1H), 7.64-7.61 (m, 1H), 7.35-7.26 (m, 5H),

6.26 (dt, J = 14.94, 0.9 Hz, 1H), 6.05 (dt, J = 14.82, 7.8 Hz, 1H) 2.50 (s, 2H), 2.31 (dd, J = 7.83,

0.9 Hz, 2H), 1.14 (s, 6H) ppm

61 1 HNMR cis isomer (600MHz, CDCl3): δ 9.16 (s, 1H), 8.65 (s, 1H), 8.27 (d, J = 8.34 Hz,

1H), 7.96 (d, J = 7.92 Hz, 1H), 7.74-7.71 (m, 1H), 7.63-7.61 (m, 1H), 7.20-7.17 (m, 5H), 6.38

(dt, J = 9.36, 1.02 Hz, 1H), 5.95 (dt, J = 9.30, 7.68 Hz, 1H) 2.54 (s, 2H), 2.44 (dd, J = 7.65, 1.02

Hz, 2H), 1.18 (s, 6H) ppm

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 151.33, 151.25, 146.39, 136.30,

136.20, 135.93, 135.91, 132.48, 130.94, 130.88, 129.24, 129.01, 129.00, 128.93, 128.70, 127.88,

127.81, 127.72, 127.68, 126.27, 125.67, 125.28, 125.10, 124.31, 95.98, 95.81, 77.77, 77.74,

44.94, 40.88, 36.69, 35.25, 34.78, 33.01, 32.71, 27.02, 26.93, 24.72 ppm

IR: νmax 3060, 3019, 2958, 2925, 2222, 1716, 1683, 1614, 1578, 1504, 1388, 1156, 1023,

896, 761, 739, 689.

+ + HRMS (ESI+) calcd for C24H24NS [(M+H) ]: 358.16294, found 358.16259

Synthesis of malonate-tethered diynyl-pyridine 111 (unoptimized)

Following the general procedure A, 4-iodopyridine (0.077 g, 0.375 mmol, 1.00 equiv) and diethyl 2,2-di(prop-2-yn-1-yl)malonate (0.100 g, 0.42 mmol, 1.13 equiv.) - prepared according to a previously optimized procedure127 - gave 111 (0.042 g, 36%) as a brown oil.

diethyl 2-(prop-2-yn-1-yl)-2-(3-(pyridin-4-yl)prop-2-yn-1-yl)malonate (111)

1 HNMR (600MHz, CDCl3): δ 8.52 (d, J = 5.94 Hz, 2H), 7.21 (d, J = 6.00 Hz, 2H), 4.24

(q, J = 7.08 Hz, 4H), 3.22 (s, 2H), 3.01 (d, J = 2.64 Hz, 2H), 2.05 (t, J = 2.64 Hz, 1H), 1.26 (t, J =

7.14 Hz, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 168.53, 149.69, 131.24, 125.77, 89.36, 81.33, 78.35,

71.89, 62.18, 56.48, 23.52, 22.82, 14.06 ppm

IR: νmax 3287, 2982, 2936, 2230, 1733, 1593, 1541, 1465, 1446, 1426, 1406, 1367, 1323,

1290, 1241, 1189, 1053, 1010, 856, 821.

62 + + HRMS (ESI+) calcd for C18H20NO4 [(M+H) ]: 314.13923, found 314.13832

Synthesis of Isoquinolines (and Quinolines) via DBU-promoted Benzannulation

General Procedure B:

To a 1,2-dichlorobenzene solution (0.01M) of the appropriate aryl-alkyne (1 equiv.) in a sealed tube was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (30 equiv.). Once sealed, the mixture was heated to 210°C for 2.5 days. After 2.5 days the reaction mixture was allowed to cool to room temperature before being purified without concentration by flash column chromatography with gradient eluent from EtOAc/Hexane = 1/99 to EtOAc/Hexane = 10/90 to give the desired isoquinolines and quinolines.

7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (114)

Following the general procedure B, aryl-alkyne 118 (0.160 g, 0.52 mmol) afforded 114

(0.102 g, 81%) as a yellow solid.

1 HNMR (600MHz, CDCl3): δ 9.14 (s, 1H), 8.41 (d, J = 3.72 Hz, 1H), 7.71 (s, 1H), 7.57

(s, 1H), 7.56 (d, J = 3.72 Hz, 1H), 2.88 (s, 2H), 2.87 (s, 2H), 1.17 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 151.71, 148.22, 144.64, 142.07, 135.57, 128.44, 122.29,

121.22, 120.30, 47.58, 47.26, 40.73, 28.25 ppm

IR: νmax 3053, 2955, 2933, 2867, 1924, 1715, 1634, 1587, 1463, 1447, 1367, 1274, 1210,

907, 867, 809.

+ + HRMS (ESI+) calcd for C14H16N [(M+H) ]: 198.12827, found 198.12959

MP: 73-77˚C

7,7,9-trimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (129)

Following the general procedure B, aryl-alkyne 128 (0.075 g, 0.23 mmol) afforded 129

(0.036 g, 73%) as a white paste.

63 1 HNMR (600MHz, CDCl3): δ 9.38 (s, 1H), 8.43 (d, J = 4.44 Hz, 1H), 7.55 (d, J = 5.52

Hz, 1H), 7.44 (s, 1H), 2.88 (s, 2H), 2.85 (s, 2H), 2.64 (s, 3H), 1.18 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): 148.50, 147.63, 142.74, 141.88, 136.03, 129.65, 120.64,

119.28, 107.26, 48.01, 46.33, 39.88, 29.71, 28.60 ppm

IR: νmax 2955, 2921, 2853, 1593, 1463, 1377, 1364, 1228, 870.

+ + HRMS (ESI+) calcd for C15H18N [(M+H) ]: 212.14392, found 212.14394

1,3,7,7-tetramethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (136)

Following the general procedure B, aryl-alkyne 130 (0.100 g, 0.298 mmol) afforded 136

(0.056 g, 84%) as a beige solid.

1 HNMR (400MHz, CDCl3): δ 7.81 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 2.89 (s, 3H), 2.87

(s, 2H), 2.84 (s, 2H), 2.62 (s, 3H), 1.17 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 157.11, 149.21, 147.42, 143.31, 136.40, 125.13, 121.34,

120.29, 117.08, 47.47, 40.67, 28.79, 28.32, 24.16, 22.50 ppm

IR: νmax 2957, 2927, 2867, 2833, 1980, 1637, 1599, 1567, 1465, 1429, 1366, 1297, 1174,

909, 889, 867.

+ + HRMS (ESI+) calcd for C16H20N [(M+H) ]: 226.15957, found 226.16145

MP: 42-43˚C

1,7,7-trimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (137a)

3,7,7-trimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (137b)

Following the general procedure B, aryl-alkyne 131 (0.025 g, 0.08 mmol) afforded 137a

+ 137b (0.015 g, 91% combined yield) as a 1:0.4 mixture of 137a:137b regioisomers which were not separated.

64 1 HNMR of 137a (600MHz, CDCl3): δ 8.29 (d, J = 5.04 Hz, 1H), 7.86 (s, 1H), 7.55 (s,

1H), 7.42 (d, 5.64 Hz, 1H), 2.92 (s, 3H), 2.90 (s, 2H), 2.87 (s, 2H), 1.18 (s, 6H) ppm

1 HNMR of 137b (600MHz, CDCl3): δ 9.05 (s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.38 (s,

1H), 2.85 (s, 4H), 2.66 (s, 3H), 1.16 (s, 6H) ppm

13 CNMR of mixture 137a and 137b (600MHz, CDCl3): δ 157.64, 151.12, 150.57,

148.10, 147.54, 144.44, 143.55, 140.83, 136.40, 135.58, 127.06, 126.62, 122.12, 121.96, 121.76,

120.63, 120.39, 119.17, 118.35, 47.57, 47.47, 47.18, 40.73, 40.67, 29.71, 28.30, 28.27, 22.70,

22.50 ppm

+ + HRMS (ESI+) calcd for C15H18N [(M+H) ]: 212.14392, found 212.14376

7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (138a)

7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]quinolone (138b)

Following the general procedure B, aryl-alkyne 132 (0.020 g, 0.065 mmol) afforded 138a

+ 138b (0.0094 g, 73%) as a 1:1 mixture of 138a:138b regioisomers which were not separated.

1 HNMR of 138a (400MHz, CDCl3): Refer to compound 114 (above).

1 HNMR of 138b (400MHz, CDCl3): δ 8.83 (d, J = 4.08 Hz, 1H), 8.08 (d, J = 8.2 Hz,

1H), 7.87 (s, 1H), 7.58 (s, 1H), 7.34-7.31 (m, 1H), 2.94 (s, 2H), 2.90 (s, 2H), 1.20 (s, 6H) ppm

13 CNMR of mixture 138a and 138b (600MHz, CDCl3): δ 151.62, 149.03, 148.30,

148.08, 147.42, 144.71, 143.89, 141.94, 135.60, 131.69, 127.59, 126.87, 124.07, 122.32, 122.32,

122.22, 121.24, 120.61, 120.00, 47.60, 47.27, 47.26, 47.20, 40.89, 40.74, 29.71, 28.31, 28.25 ppm

+ + HRMS (ESI+) calcd for C14H16N [(M+H) ]: 198.12827, found 198.12852

4-chloro-7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (139)

65 Following the general procedure B, aryl-alkyne 133 (0.160 g, 0.47 mmol) afforded 139

(0.076 g, 71%) as a beige solid.

1 HNMR (400MHz, CDCl3): δ 9.01 (s, 1H), 8.47 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 2.94

(s, 2H), 2.91 (s, 2H), 1.19 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 150.37, 149.64, 145.64, 141.07, 133.17, 129.24, 128.13,

122.41, 118.11, 47.78, 47.18, 40.83, 28.21 ppm

IR: νmax 3015, 2951, 2937, 2861, 1730, 1637, 1577, 1466, 1232, 1094, 912, 902, 859.

+ + HRMS (ESI+) calcd for C14H15ClN [(M+H) ]: 232.08930, found 232.09180

MP: 57-62˚C

9,9-dimethyl-9,10-dihydro-8H-cyclopenta[j]phenanthridine (140)

Following the general procedure B, aryl-alkyne 134 (0.075 g, 0.21 mmol) afforded 140

(0.044 g, 86%) as a yellow solid.

1HNMR (400MHz, CDCl3): δ 9.20 (s, 1H), 8.54 (d, J = 7.40 Hz, 1H), 8.39 (s, 1H), 8.16

(d, J = 7.92 Hz, 1H), 7.80 (s, 1H), 7.70 (td, J = 7.48, 1.20 Hz, 1H), 7.64 (td, J = 7.56, 1.28 Hz,

1H), 2.99 (s, 2H), 2.94 (s, 2H), 1.22 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 153.42, 148.61, 144.36, 144.30, 131.82, 129.97, 128.04,

126.67, 125.84, 124.52, 124.03, 122.10, 117.26, 48.10, 47.32, 40.89, 28.43 ppm

IR: νmax 3071, 2947, 2930, 2862, 1630, 1588, 1574, 1456, 1373, 1363, 1181, 1096, 949,

939, 863, 753.

+ + HRMS (ESI+) calcd for C18H18N [(M+H) ]: 248.14392, found 248.14452

MP: 100-104˚C

9,9-dimethyl-9,10-dihydro-8H-cyclopenta[b]phenanthridine (141)

66 Following the general procedure B, aryl-alkyne 135 (0.040 g, 0.11 mmol) afforded 141

(0.027 g, >95%) as a yellow solid.

1 HNMR (600MHz, CDCl3): δ 9.21 (s, 1H), 8.57 (d, J = 8.28 Hz, 1H), 8.36 (s, 1H), 8.02

(d, J = 7.74 Hz, 1H), 7.95 (s, 1H), 7.82 (td, J = 7.65, 1.26 Hz, 1H), 7.66 (td, J = 7.47, 0.66 Hz,

1H), 2.97 (s, 2H), 2.96 (s, 2H), 1.22 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 152.22, 145.83, 144.09, 143.91, 132.82, 130.66, 128.67,

126.80, 126.08, 125.30, 122.79, 121.74, 117.32, 47.76, 47.61, 41.02, 29.71, 28.51 ppm

IR: νmax 3068, 2951, 2922, 2854, 1769, 1715, 1616, 1585, 1574, 1479, 1455, 1444, 1364,

1251, 1097, 1028, 863, 793, 748.

+ + HRMS (ESI+) calcd for C18H18N [(M+H) ]: 248.14392, found 248.14447

MP: 76-82 ˚C

Synthesis of Brominated Isoquinolines

5,9-dibromo-7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (142)

Compound 142 was prepared according to a procedure adapted from Gouliaev.163 To stirred, concentrated H2SO4 (0.3 mL) was added isoquinoline 114 (0.027 g, 0.136 mmol, 1 equiv.). The mixture was cooled to 0 ˚C and N-bromosuccinimide (0.053 g, 0.2992 mmol, 2.2 equiv.) was slowly added. After 5 minutes at 0 ˚C, the mixture was allowed to warm to room temperature for 18 hours before being diluted with H2O. The pH was adjusted to 9 with NH4OH and the reaction mixture was extracted with methylene chloride 4 times. The combined organic layers were washed with one portion of 1M NaOH, saturated NaCl, and dried over MgSO4 before being concentrated in vacuo. The crude residue was passed through a silica plug with eluent EtOAc/Hexanes = 40/60 to give pure 142 (0.038 g, 80%) as an off-white solid.

67 1 HNMR (600MHz, CDCl3): δ 9.53 (s, 1H), 8.64 (d, J = 5.7, 1H), 7.93 (d, J = 5.82, 1H),

3.07 (s, 4H), 1.24 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 151.16, 148.52, 145.40, 144.51, 135.98, 118.63, 118.18,

117.22, 50.83, 50.29, 38.81, 28.68 ppm

IR: νmax 3061, 2949, 2919, 2853, 1916, 1621, 1585, 1460, 1415, 1252, 1093, 1050, 937,

918, 815.

+ + HRMS (ESI+) calcd for C14H14Br2N [(M+H) ]: 353.94930, found 353.94871

MP: 156-160˚C

5-bromo-7,7,9-trimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline (143)

Following the same procedure as 142, to stirred, concentrated H2SO4 (0.25 mL) was added isoquinoline 129 (0.016 g, 0.075 mmol, 1 equiv.). The mixture was cooled to 0 ˚C and N- bromosuccinimide (0.015 g, 0.082 mmol, 1.1 equiv.) was slowly added. After 5 minutes at 0 ˚C, the mixture was allowed to warm to room temperature for 18 hours before being diluted with

H2O. The pH was adjusted to 9 with NH4OH and the reaction mixture was extracted with methylene chloride 4 times. The combined organic layers were washed with one portion of 1M

NaOH, saturated NaCl, and dried over MgSO4 before being concentrated in vacuo. The crude residue was passed through a silica plug with eluent EtOAc/Hexanes = 40/60 to give pure 143

(0.015 g, 68%) as a light-brown solid.

1 HNMR (600MHz, CDCl3): δ 9.36 (s, 1H), 8.57 (d, J = 5.64, 1H), 7.96 (d, J = 5.82),

2.99 (s, 1H), 2.98 (s, 1H), 2.62 (s, 3H), 1.22 (s, 1H) ppm

13 CNMR (600MHz, CDCl3): δ 148.44, 148.31, 143.15, 142.91, 134.88, 129.38, 128.38,

119.25, 115.39, 50.22, 47.50, 38.95, 29.71, 28.80, 14.52 ppm

68 IR: νmax 3059, 2948, 2922, 2862, 1912, 1717, 1622, 1589, 1465, 1420, 1373, 1272, 1178,

1028, 915, 817.

+ + HRMS (ESI+) calcd for C15H17BrN [(M+H) ]: 290.05444, found 290.05431

MP: 125-129˚C

Site-selective substitution of 136

1-(4-bromophenyl)-2-(3,7,7-trimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinolin-1- yl)ethan-1-ol (144)

To 0.32 mL THF solution of isoquinoline 136 (0.0145 g, 0.064 mmol, 1 equiv.) at -78 ˚C was slowly added 0.04 mL of n-BuLi (1.6 M solution in hexanes, 1 equiv.). The reaction mixture was stirred at -78 ˚C for 30 minutes before 4-bromobenzaldehyde (0.036 g, 0.193 mmol, 3 equiv.) in 0.1 mL of THF was added dropwise via syringe. The reaction was immediately warmed to 0 ˚C for 5 minutes before being brought to room temperature for 1.5 hours. After 1.5 hours, the reaction mixture was quenched with H2O, extracted with diethyl ether 3 times, and the combined organic layers were washed with saturated NaCl, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by flash column chromatography with gradient eluent from EtOAc/Hexane = 10/90 to EtOAc/Hexane = 20/80 to give 144 (0.0235 g, 89%) as a yellow solid.

1 HNMR (600MHz, CDCl3): δ 7.69 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.40

(d, J= 8.34 Hz, 2H), 7.32 (s, 1H), 5.34 (dd, J = 9.9, 2.16 Hz, 1H) 3.62 (d, J = 16.32, 1H), 3.32

(dd, J = 12, 10.02 Hz, 1H), 2.85 (s, 2H), 2.82 (s, 2H), 2.65 (s, 3H), 1.16 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 158.07, 144.06, 143.49, 136.82, 131.64, 131.42, 128.58,

127.78, 124.81, 121.66, 120.93, 119.26, 117.82 ppm

69 IR: νmax 3488, 3254, 2952, 2922, 2852, 1717, 1640, 1602, 1564, 1485, 1461, 1425, 1067,

1009, 908, 881, 820.

+ + HRMS (ESI+) calcd for C23H25BrNO [(M+H) ]: 410.11195, found 410.11127

MP: 93-96˚C

Synthesis of Pentacyclic Phenanthridine 146

4-(4,4-dimethyl-7-(phenylthio)hept-6-en-1-yn-1-yl)-7,7-dimethyl-7,8-dihydro-6H- cyclopenta[g]isoquinoline (145)

Compound 145 was prepared according to a procedure adapted from Buchwald.170 An oven-dried flask under the flow of N2 was charged with PdCl2(CH3CN)2 (0.006 g, 0.0023 mmol,

0.01 equiv.), XPhos (0.0033 g, 0.0069 mmol, 0.03 equiv.), and Cs2CO3 (0.15 g, 0.46 mmol, 2 equiv.),. The flask was further vacuumed and filled with N2 3 times before the addition of 0.5 mL of degassed CH3CN (0.5M) and aryl chloride 139 (0.054 g, 0.23 mmol, 1 equiv.). The slightly yellow suspension was stirred for 25 minutes before slow, dropwise addition of enyne

126 (0.069 g, 0.30 mmol, 1.3 equiv.) and heating to 80°C for 3 hours. After 3 hours the reaction mixture was allowed to cool to room temperature, diluted with 15 mL of H2O, and extracted with diethyl ether (4 x 20 mL). The combined organic layers were dried over MgSO4, concentrated, and the residue was purified by flash column chromatography (eluent mixture: EtOAc/Hexane =

10/90) to give 145 (0.071 g, 72%, E:Z = 3.3:1) as a yellow oil.

1 HNMR trans isomer (600MHz, CDCl3): δ 9.02 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.70

(s, 1H), 7.35-7.27 (m, 5H), 6.27 (d, J = 14.88 Hz, 1H), 6.06 (dt, J = 14.82, 7.8 Hz, 1H) 2.88 (s,

2H) 2.87 (s, 2H), 2.49 (s, 2H), 2.32 (d, J = 7.8 Hz, 2H), 1.16 (s, 6H), 1.14 (s, 6H) ppm

70 1 HNMR cis isomer (600MHz, CDCl3): δ 9.02 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.70 (s,

1H), 7.23-7.16 (m, 5H), 6.37 (d, J = 9.36, 7.68 Hz, 1H), 5.95 (dt, J = 9.3, 7.68 Hz, 1H) 2.88 (s,

2H), 2.87 (s, 2H), 2.54 (s, 2H), 2.44 (d, J = 7.62, 2H), 1.17 (s, 6H) ppm

13 CNMR of mixture E and Z (600MHz, CDCl3): δ 150.53, 149.08, 149.02, 145.60,

145.07, 145.02, 136.32, 136.26, 135.68, 135.66, 132.77, 129.37, 129.26, 129.15, 128.99, 128.98,

128.61, 127.53, 126.28, 126.22, 125.64, 124.14, 122.54, 122.48, 120.03, 119.88, 119.47, 116.18,

95.19, 95.03, 78.26, 78.21, 47.78, 47.74, 47.21, 44.90, 40.89, 40.76, 36.67, 35.25, 34.78, 33.08,

32.71, 29.71, 28.25, 27.02, 26.91 ppm

IR: νmax 3067, 3020, 2953, 2925, 2866, 2234, 1717, 1683, 1575, 1463, 1365, 1157, 907,

894, 788, 689.

+ + HRMS (ESI+) calcd for C29H32NS [(M+H) ]: 426.22554, found 426.22566

2,2,9,9-tetramethyl-1,2,3,8,9,10-hexahydrodicyclopenta[b,j]phenanthridine (146)

Following the general procedure B, aryl-alkyne 145 (0.060 g, 0.14 mmol) afforded 146

(0.044 g, >95%) as a white solid.

1 HNMR (600MHz, CDCl3): δ 9.11 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.75

(s, 1H), 2.95 (s, 2H), 2.94 (s, 4H), 2.91 (s, 2H), 1.21 (s, 6H), 1.20 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 152.10, 148.10, 145.03, 143.82, 143.54, 132.03, 128.64,

125.51, 125.15, 123.79, 123.16, 117.17, 117.06, 48.07, 47.76, 47.59, 47.28, 40.96, 40.83, 28.53,

28.44 ppm

IR: νmax 2953, 2921, 2862, 1629, 1589, 1575, 1502, 1451, 1364, 1246, 1166, 1098, 931,

855.

+ + HRMS (ESI+) calcd for C23H26N [(M+H) ]: 316.20652, found 316.20826

MP: 145-147˚C

71 1HNMR and 13CNMR Data for gem-Dimethylcyclopentane-fused Arenes

5,11-dichloro-2,2,8,8-tetramethyl-1,2,3,7,8,9-hexahydrodicyclopenta[b,i]anthracene

(150)

1 HNMR (600MHz, CDCl3): δ 8.25 (s, 4H), 2.93 (s, 8H), 1.20 (s, 12H) ppm

13 CNMR (600MHz, CDCl3): δ 144.70, 128.65, 126.61, 119.24, 47.47, 40.68, 28.27 ppm

2,2,11,11-tetramethyl-1,2,3,10,11,12-hexahydrodibenzo[g,p]dicyclopenta[b,k]chrysene

(152)

1 HNMR (400MHz, CDCl3): δ 8.68 (d, J = 7.56 Hz, 2H), 8.64 (d, J = 7.92 Hz, 2H), 8.46

(s, 2H), 8.45 (s, 2H), 7.65-7.56 (m, 4H), 2.99 (s, 4H), 2.92 (s, 4H), 1.22 (s, 12H) ppm;

13 CNMR (600MHz, CDCl3): δ 143.05, 142.87, 131.18, 129.61, 129.14, 128.91, 128.36,

127.20, 126.12, 125.76, 124.25, 123.48, 119.26, 47.94, 47.92, 40.82, 28.66 ppm

5,8-dichloro-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[b]naphthalene (157)

1 HNMR (600MHz, CDCl3): δ 8.04 (s, 2H), 7.38 (s, 2H), 2.91 (s, 4H), 1.18 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 145.47, 131.19, 130.43, 124.85, 119.81, 47.47, 40.82,

28.30 ppm

5-bromo-2,2-dimethyl-2,3-dihydro-1H-cyclopenta[b]naphthalene (160)

1 HNMR (400MHz, CDCl3): δ 7.99 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.42

Hz, 1H), 7.58 (s, 1H), 7.21 (t, J = 7.84 Hz, 1H), 2.90 (s, 2H), 2.87 (s, 2H), 1.17 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 144.98, 144.02, 134.32, 131.47, 128.88, 127.45, 125.10,

123.04, 122.43, 121.88, 47.56, 47.20, 40.75, 28.35 ppm

2,2,9,9-tetramethyl-1,2,3,8,9,10-hexahydrodicyclopenta[b,h]phenanthrene (153)

1 HNMR (400MHz, CDCl3): δ 8.43 (s, 2H), 7.61 (s, 2H), 7.58 (s, 2H), 2.94 (s, 4H), 2.89

(s, 4H), 1.20 (s, 12H) ppm

72 13 CNMR (600MHz, CDCl3): δ 143.07, 142.54, 130.95, 129.43, 125.79, 123.66, 117.87,

47.93, 47.43, 40.76, 28.57 ppm

2,2-dimethyl-2,3-dihydro-1H-cyclopenta[b]naphthalene (149)

1 HNMR (600MHz, CDCl3): δ 7.73 (dd, J = 6.12, 3.24 Hz, 2H), 7.59 (s, 2H), 7.36 (dd, J

= 6.18, 3.24 Hz, 2H), 2.84 (s, 4H), 1.16 (s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 143.06, 132.98, 127.39, 124.75, 122.58, 47.37, 40.65,

28.39 ppm

X-ray Crystallography of 146

Crystal packing: (a) gem-dimethylcyclopentane-fused phenanthridine 146 packs in a loosely staggered arrangement whereas phenanthridine itself (b) packs in a herringbone pattern, with edge-to-face interactions at a distance of 2.92 Å.

Methods: Single crystals of 146 were grown via sublimation in a thick-walled Pyrex tube under dynamic vacuum (100 mTorr) at 90 C over 2 days. For single-crystal X-ray diffraction experiment, the crystal was removed from solution, covered in Paratone oil, and mounted on a cryoloop (Hampton Research). The mounted crystal was quickly positioned under a cold N2 stream of the Bruker AXS SMART X-ray diffractometer with an APEX-II CCD detector. The data set was recorded as ω-scans at 0.3° stepwidth and integrated with the Bruker SAINT software package [Bruker, SMART and SAINT; Bruker AXS Inc.: Madison, WI, USA, 2007]. A multi-scan adsorption correction was applied based on fitting a function to the empirical transmission surface as sampled by multiple equivalent measurements (SADABS) [G. M.

Sheldrick SADABS; University of Gottingen: Gottingen, Germany, 1996]. The space group determination was performed with XPREP [G. M. Sheldrick, XPREP. Space group determination and reciprocal space plots], while the solution and refinement of the crystal

73 structures were carried out using the SHELX programs [G. M. Sheldrick, Acta Crystallogr. Sect.

A 2008, A64, 112]. The final refinement was performed with anisotropic atomic displacement parameters for all but H atoms. All H atoms were placed in calculated positions. A summary of pertinent information relating to unit cell parameters, data collection, and refinement is provided in Table 1.

Table 1. Data Collection and Structure Refinement Parameters for 146.

Formula C23H25N T, K 110(2) CCDC number 1486383 Formula weight 315.44 – Space group P1 a, Å 7.153(2) b, Å 10.925(2) c, Å 12.115(3) , deg 75.115(3) , deg 77.430(3) γ, deg 81.256(3) V, Å3 888.4(3) Z 2 Crystal color clear Crystal size, mm3 0.120.040.03 –3 dcalc, g cm 1.179 , mm–1 0.07 , Å 0.71073

2max, deg 28.213 Total reflections 3908 Rint 0.0272 Unique reflections 2417 Parameters refined 221 Restraints used 0 a R1, wR2 [I > 2(I)] 0.057, 0.155 R1, wR2 (all data) 0.107, 0.189 Goodness of fitb 1.027 Diff. peak/hole, e Å–3 0.36, –0.24

a 2 2 2 2 2 ½ R1 = ||Fo|–|Fc||/|Fo|; wR2 = [[w(Fo –Fc ) ]/[w(Fo ) ]] b 2 2 2 ½ Goodness-of-fit = [[w(Fo –Fc ) ]/(Nobs–Nparams)] , based on all data

74 CHAPTER 3

TOTAL SYNTHESIS OF ILLUDININE: A DENSELY SUBSTITUTED ISOQUINOLINE

Reprinted (Adapted) with permission from: Alec E. Morrison, Tung T. Hoang, Mélodie Birepinte and Gregory B. Dudley “Synthesis of Illudinine from Dimedone” Org. Lett. 2017, 19 (16), 4104-4107. DOI: 10.1021/acs.orglett.6b03887. Copyright 2017 American Chemical Society.

3.1 Introduction

The evolution of chemical synthesis can be tracked in terms of the ability to produce increasingly complex structures by increasingly efficient synthetic sequences.2 Diverse molecular architectures inspire novel methods and strategies, and emerging methodologies enable new approaches to goal structures. We have been inspired by the illudalane family of 3,3- dimethylcyclopentane-fused aromatic sesquiterpenes, which present an attractive array of structural complexities and unresolved biological activities (Figure 13).

Figure 13. Representative Protoilludane Natural Products

The biogenesis of protoilludane natural products isolated from the Basidiomycetes Fungi subdivision is thought to originate from Humulene (Figure 14).188 Humulene, derived from the 75 cyclization of farnesyl pyrophosphate, can be further cyclized to a protoilludyl cation. The protoilludane skeleton is susceptible to a variety of rearrangements to relieve the strain of the cyclobutane moiety, which may result in hirsutane, sterpurane, or isolactarane type cores.

Alternatively, Matsumoto has described a deprotonation of the protoilludyl cation to form 6- protoilludene, which may be oxidized to the corresponding allylic alcohol 167 or its equivalent

168.189 From here, formation of an allylic cyclobutyl cation probably rearranges via solvolytic processes to arrive at marasmane, lactarane, illudane, and illudalane type carbon skeletons.

Figure 14. Proposed Biosynthesis of Sesquiterpenes in the Basidiomycotina Subdivision

76 These structures all feature a densely substituted benzene core fused to a 3,3- dimethylcyclopentane moiety. Substituted benzenes and 3,3-dimethylcyclopentanes each pose formidable synthetic challenges. The convergent synthesis of substituted benzene derivatives has attracted considerable attention, and new methods continue to emerge (see Chapter 1). On the other hand, direct synthesis of 3,3-dimethylcyclopentanes remains largely an unresolved problem, which typically has been circumvented by serial manipulation of tactically over- oxidized intermediates.158-159,190-192

Interest in the illudalane sesquiterpenes has long been driven by their associated synthetic challenges and, more recently, by our emerging understanding of their pharmaceutical potential.

Illudalic acid emerged from high-throughput screening of over 40,000 compounds and extracts as a promising and uniquely selective phosphatase inhibitor.193 The comparatively simpler alcyopterosins - natural metabolites of a deep-water Antarctic sponge - were identified as anti- feedants that also offer anti-cancer activity. Preliminary structure–activity relationship (SAR) studies suggest that the 3,3-dimethylcyclopentane is important for potency in both cases.194

Notwithstanding intriguing preliminary data such as these, the pharmacological potential of 3,3- dimethylcyclopentanes is largely unexplored. For example, the biological significance of illudinine is unknown.

The illudalane sesquiterpenes share a carbon skeleton with illudalic acid and its alkaloid congener, illudinine (Figure 13). Illudinine is a metabolite of the jack o-lantern mushroom

(Clitocybe illudens); it was isolated and characterized along with illudalic acid and illudacetalic acid in 1969.157 These three natural products first succumbed to total synthesis in 17–19 steps as described in a 1977 report by Woodward and Hoye,195 who developed a unified approach based on aromatic substitution chemistry. Shen reported a 16-step synthesis of illudalic acid by a

77 similar strategy in 2008 as a means of securing material for biological evaluation.194 Meanwhile,

Deiters developed an alkyne cyclotrimerization strategy that produced illudinine in 14 steps.156

Various alcyopterosins, which have the same carbon skeleton, have also been prepared.196-199

Woodward and Hoye’s synthesis of illudinine begins with Friedel-Crafts acylation of indan 169 with -chloropropionyl chloride to give choro ketone 170 in 84 % yield (Scheme 34).

Cyclization of 170 in concentrated sulfuric acid results in a mixture of regioisomers 171 and 172, which is carried through three subsequent synthetic steps. Double -methylation of the benzylic ketone in 172 followed by Clemmensen reduction of hindered ketone 173 and purification via short-path distillation separates the regioisomers to provide 3,3-dimethylcyclopentane 174 in

36% yield over three steps. From here, treating 174 with bromine in nitromethane afforded 1,4- dibromo 175 in 80% yield. The bromo substituents were differentiated by halogen-metal exchange in the presence of n-BuLi at -78˚C followed by trapping of the aryl anion with trimethylborate and standard hydrogen peroxide oxidation to produce bromophenol 176 in 56% yield over two steps. Heating an acetone solution of 176 with potassium carbonate and dimethyl sulfate protected the alcohol as the methyl-ether in 96% yield, thus paving the way for an aryl-

Grignard trapping event with excess methyl chloroformate to furnish methoxy-ester 177 in 98% yield. With the benzene core of illudinine established, ring-opening of the unsubstituted cyclopentane ring towards the key dialdehyde 181 would need to commence with a chemoselective benzylic oxidation of 177 to 178. In the event, oxidation of the position proximal to the electron-donating methoxy group in the cyclopentane ring proceeded with poor selectivity and provided 178 in 52% yield after recycling overoxidized byproducts back to 177. Elaboration to dialdehyde 181 occured via quantitative osmium tetroxide dihydroxylation and sodium metaperiodate cleavage starting from cyclopentene 179, prepared from 178 in two high yielding

78 steps of sodium borohydride reduction (96%) and dehydration (100%). Sodium metaperiodate cleavage in water was found to occur with preferential formation of hydrated bishemiacetal 182 rather than direct isolation of dialdehyde 181. Completion of the synthesis was achieved by first treating bishemiacetal 182 with excess ammonium acetate in acetic acid to give illudinine methyl ester 183 in 94% yield. Finally, 183 succumbed to standard saponification conditions in quantitative yield leading to illudinine in 17 steps and 5.9% overall yield.

Scheme 34. Woodward and Hoye’s Synthesis of Illudinine 79 Deiter’s synthesis of illudinine avoids the regiochemical ambiguity and poor chemoselectivity associated with Woodward and Hoye’s electrophilic aromatic substitution/benzylic oxidation strategy by constructing the aromatic core and 3,3- dimethylcyclopentane moiety from acyclic precursors (Scheme 35).

Starting from known diyne 184, (synthesized in 6 steps and 33% overall yield from isophorone),156 lithiation at both terminal triple bonds and carboxylation with ethyl chloroformate provides diester 185 in 70% yield. As was the case for a model substrate, subjecting a toluene solution of 185 and protected amine 186 to a catalytic amount of

Ni(CO)2(PPh3)2 and microwave irradiation for 2 minutes cleanly provided the [2+2+2] cycloadduct 187 in 84% yield. Introducing the phenolic group through a Hock rearrangement200 first required differentiating the two esters based on sterics. Such a transformation was realized by treating indane 187 with excess methyl lithium in the presence of cerium chloride to deliver tertiary alcohol 188 in 84% yield. Oxidation to the phenol and simultaneous removal of the Boc protecting group to 189 in 92% yield was mediated by boron trifluoride etherate and hydrogen peroxide. The combination of formaldehyde and a sodium acetate buffer assembles the carbon skeleton via a classical Pictet-Spengler reaction, which is directly converted to the methyl ether with trimethylsilyldiazomethane to furnish PMB-protected amine 190 in 66% yield over 2 steps.

Finally, oxidation of 190 to illudinine ethyl ester was conducted by Pd/C in mesytilene at

185˚C to construct the pyridine ring in 58% yield. Saponification gave way to illudinine in 14 steps and 5.8% overall yield. The overall synthetic efficiency of Deiter’s route is significantly affected by the inefficient construction of neopentyl-tethered diyne 184, which reveals a lack of convenient methodology to prepare these types of 3,3-dimethylcyclopentane precursors.

80

Scheme 35. Deiter’s Synthesis of Illudinine

3,3-Dimethylcyclopentanes are ubiquitous in natural products, but they are virtually nonexistent in typical small molecule libraries used for pharmacological screening. This is perhaps a consequence of limited synthetic accessibility. For example, after illudalic acid emerged from high-throughput screening as a promising and uniquely selective phosphatase inhibitor, most of the follow-up pharmacology focused on simplified analogues that lacked the

3,3-dimethylcyclopentane. These structural simplifications came at the cost of potency.193-194,201-

202 Likewise is true for alcyopterosin A pharmacology, which was largely examined with the 3,3- dimethyl substitution omitted for synthetic expediency at the cost of potency.192 Efficient access

81 to 3,3-dimethylcyclopentanes is needed to explore this naturally validated but pharmaceutically underexplored chemical space.160

3.2 Results and Discussion

Our approach to illudinine hinged on two hypothetical key steps (Scheme 36). The first - tandem fragmentation / olefination (Scheme 37) - required a logical but untested expansion of recent methodology from our laboratory.162 We previously concluded that hydroxy triflate 123 can undergo anionic fragmentation to aldehyde 122, which can be intercepted in situ by Horner–

Wadsworth–Emmons (HWE)-type phosphonate nucleophiles to give 1,6-enynes (Scheme 23).

Here, we report that phosphonate activation is not needed in the case of ethyl (4-pyridyl)acetate

(192); reaction of 123 with 192 yields 1,6-enyne 193 in 75% yield as a mixture of alkene isomers

(ca. 2:1). Considering the anion-stabilizing properties of the 4-pyridyl substituent, this new process is perhaps best classified as a tandem fragmentation/Knoevenagel-type condensation, and it suggests a broader potential of our prior methodology.

Scheme 36. Synthetic Approach to Illudinine

The second pivotal step in our synthetic approach to illudinine is a proposed oxidative cycloisomerization by way of an intramolecular inverse-demand dehydro-Diels–Alder reaction.

Dehydro-Diels–Alder reactions of tethered alkynyl styrenes (see section 1.3 in chapter 1) have received increasing attention recently (Scheme 38, Eq 1). Inverse-demand Diels–Alder reactions involving (unstrained) alkynes are rare, even in tethered systems,203-205 and we could find no

82 examples involving styrene-type dienes (vinylarenes). However, styrene-type dienes have not been as thoroughly examined as other diene classes. Because of their aromatic character, one must extrapolate with caution from other diene classes to vinylarenes. Our recent isoquinoline synthesis (see section 2.1 in chapter 2) established an alternative inverse-demand dehydro-Diels–

Alder pathway (Scheme 38, Eq 2), but it does not provide all of the requisite functionality for illudinine.

Scheme 37. Synthesis of Enyne 193 via Tandem Fragmentation/Knoevenagel-Type Condensation

Scheme 38. Dehydro-Diels-Alder Reactions of Tethered Enynes

One of the major challenges posed by electron-deficient dienes is their tendency to dimerize,206 oligomerize, or otherwise decompose207 faster than they react with unstrained alkyne dienophiles. The dimerization pathway208 is suppressed in vinylarenes, and it is not unreasonable to anticipate a differential impact of aromaticity on other competing reaction pathways. 83 Therefore, despite a lack of encouraging precedent, we proceeded with focused investigations into the pivotal dehydro-Diels–Alder reaction (Scheme 39).

Scheme 39. Microwave-Assisted Oxidative Cycloisomerizations

Our investigations into the proposed dehydro-Diels–Alder reaction began with 4- pyridylenyne 193. Enyne 193 was heated at increasing temperatures in various solvents without success. In general, the starting enyne either decomposed or was recovered unchanged. A brief screening of metal catalysts was likewise unproductive. No reaction products consistent with dehydro-Diels–Alder reaction were ever identified in our (non-exhaustive) survey of conditions, although we cannot rule out the feasibility of this pathway.

Meanwhile, we were mindful that terminal functionality on the alkyne would not be inconsistent with our end goals, so we also investigated bromoalkyne 194, as well as silyl- and iodo-alkynes (X = Me3Si or I). Bromination of terminal alkyne 193 under standard conditions provided 194 in essentially quantitative yield. Bromoalkynes can be competent dienophiles209 and computational data suggest that alkyne -bonds are weaker in bromoalkynes than in terminal

84 alkynes.210-211 Indeed, productive thermal reactivity was observed by heating a 0.06 M solution of 194 in o-dichlorobenzene (o-DCB) at 200 °C in the microwave (300 W) in a sealed vial under air for 12 hours to produce a 40% isolated yield of isoquinoline 195. Conventional heating experiments in an oil bath at 200 °C were slower (2 days vs. 12 h), likely due to better bulk heating in the microwave, although microwave-specific thermal effects cannot be ruled out.212-216

The aforementioned silyl- and iodo-alkynes were not viable substrates. Presumably, thermal inverse-demand dehydro-Diels–Alder cycloaddition of 194 yields intermediate 194a (Scheme

39), which oxidizes to 195 under the reaction conditions. Oxidation may occur by concerted extrusion of hydrogen108 or possibly by serial hydrogen atom abstraction via stabilized radical intermediate 194b. Brummond and Tantillo examined similarly diverging dehydrogenation pathways experimentally and computationally in their related system (Scheme 38, Eq 1 and section 2.1 in chapter 2). They report that concerted release of molecular hydrogen is the productive pathway for Scheme 38, Eq 1, and that the competing hydrogen atom abstraction event triggers a radical chain reaction process that leads to dihydronaphthalenes. We do not observe the analogous dihydroisoquinolines, and we are mindful of important electronic differences between their “normal” and our “inverse-demand” system. On-going efforts to understand and improve this key step in our illudinine synthesis, coupled with preliminary explorations into illudinine pharmacology, will be reported in due course. In the end, the operationally simple thermal cyclization of 194 provides convenient access to isoquinoline 195 en route to illudinine.

With bromoisoquinoline 195 in hand, the final hurdle to be cleared before reaching the target illudinine system was a bromomethoxy substitution event (Table 2). After preliminary attempts at traditional SNAr substitution were not encouraging (entries 1-2), efforts came to

85 center around metal-catalyzed aryl ether formation. Perhaps the best way to underscore the challenge of this particular transformation is to describe the core bromobenzene as fully substituted and fused to a potential catalyst inhibitor. In our hands, copper-catalyzed reactions217-

220 were effective in simpler bromoarene systems but not for the desired transformation, perhaps due to catalyst poisoning by the isoquinoline nitrogen (entries 3-6). The combination of palladium and bulky phosphine ligands (entries 7-10)221-226 was not effective either; major identifiable products included the reduced arene (dehalogenation), and recovered 195 along with complex mixtures. However, treatment of 195 with acetohydroxamic acid and base (Maloney-

Fier conditions227) produced hydroxyisoquinoline 196 in 89% yield (Scheme 40), presumably via tandem SNAr/Lossen rearrangement.

Table 2. SNAr and Metal-Catalyzed Aryl Ether Formation Efforts

O-Methylation of 196 would generate illudinine ethyl ester (191), but N- vs. O-selectivity is a challenge.228-230 Most methylation conditions overwhelmingly favored N-methylation to

86 zwitterion 197 (Table 3, entries 1-4). Trimethylsilyldiazomethane (TMSCHN2) has been shown to be good for O-methylation of phenols and enols in the presence of nucleophilic heterocycles.228-230 Here, Aoyama and Shioiri’s conditions228 (Table 3, entry 5) produced a mixture of 197 and 191 that, although favoring 197, was sufficiently encouraging to warrant further optimization for the synthesis of 191.

Scheme 40. Tandem SNAr/Lossen Rearrangement

Table 3. Methylation Optimization

entry conditions 197:191

1 K2CO3, MeI, acetone, 50 °C 100:0 2 NaH, MeI, DMF, 0 °Crt 100:0

3 Me2CO3, DBU, 90 °C 100:0

4 MeOH, DEAD, PPh3, THF, 0 °Crt >95:<5

5 TMSCHN2, DIPEA, MeCN/MeOH (9:1) 65:35

6 TMSCHN2, toluene/MeOH (9:1) 55:45

7 TMSCHN2, toluene/i-BuOH (9:1) 40:60

8 TMSCHN2, benzene/MeOH (9:1) 55:45

9 TMSCHN2, benzene/i-BuOH (9:1) 30:70

10 TMSCHN2, benzene/i-BuOH (19:1) —

87 Mechanistic studies231-232 support a reaction pathway involving desilylation and

+ protonation of TMSCHN2 to produce an intermediate methyldiazonium (CH3N2 ) phenoxide salt, which decomposes to either 197 or 191 with loss of N2 (Scheme 41). We reasoned that a tight contact ion pair would favor O-methylation, so we explored the use of less-polar reaction media (Table 3, entries 6–10). Switching solvents from acetonitrile to toluene provided a slightly improved ratio with respect to 191 (Table 3, entries 5 and 6; note that DIPEA did not alter product ratios), whereas switching the alcohol cosolvent from methanol to isobutyl alcohol had an important impact (Table 3, entry 7). Larger aliphatic alcohols (not shown) and/or less of the alcoholic cosolvent created problems with solubility and resulted in poor conversion. A similar trend was observed in benzene (Table 3, entries 8–10), with the optimal conditions (Table 3, entry 9) producing illudinine ethyl ester (191) in 63% yield after purification by silica gel chromatography (Scheme 42). Finally, known saponification conditions for 191 gave rise to illudinine in quantitative yield (Scheme 42).

Scheme 41. Trimethylsilyldiazomethane Reaction Pathway to 197 and 191

In conclusion, the synthesis of illudinine has been accomplished in 8 steps (14% overall yield) from dimedone. Key steps include the tandem fragmentation/Knoevenagel-type condensation of triflate 120 to give enyne 193 and the oxidative cycloisomerization of enyne 194 to deliver isoquinoline 195, each of which represents a substantial extension of previous

88 knowledge. Tactical hurdles en route from 195 to illudinine were overcome in ways that are broadly instructive. In terms of synthetic strategy, serial execution of ring-opening fragmentation and ring-closing cycloisomerization reactions provides an attractive and general approach to diverse value-added synthetic targets, especially 3,3-dimethylcyclopentane derivatives that are otherwise difficult to prepare. Efforts to develop strategically related approaches to other terpenoid natural products and to novel polycyclic aromatic systems are in progress.

Scheme 42. Optimized Procedure for O-Methylation of 8-Hydroxyisoquinoline 196 and Saponification of Illudinine Ethyl Ester

3.3 Experimental Data

General Information

1H-NMR and 13C-NMR spectra were obtained on a 400 or 600 MHz spectrometer using

CDCl3 as the deuterated solvent (≥99.8 atom % D, contains 0.03% (v/v) TMS. Chemical shifts

1 are reported in parts per million (ppm) relative to residual CHCl3 (7.26 ppm for H-NMR and

77.0 ppm for 13CNMR). Coupling constants (J) are reported in Hertz (Hz). IR spectra were recorded on an FT-IR spectrometer with diamond ATR accessory as thin film. Mass spectra were recorded using electrospray ionization (ESI) or atmospheric pressure chemical ionization

(APCI). Microwave experiments were performed using a CEM Discover SP microwave reactor at a fixed temperature setting in a sealed vial and the temperature was monitored using an external IR sensor. Melting points were taken using an electrothermal Mel-Temp© apparatus.

89 All chemicals were used as received without further purification and all reactions were run under nitrogen atmosphere. Glassware was oven-dried prior to use and all purifications were performed by flash chromatography using silica gel with 40-63 micron particle size.

Literature Preparation of Fragmentation/Olefination Precursors

3-hydroxy-5,5-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (123)

To a suspension of 5,5-dimethyl-1,3-cyclohexanedione (dimedone, 3.00 g, 21.4 mmol, 1 equiv.) in dichloromethane (107 mL) was added pyridine (3.46 mL, 42.8 mmol, 2 equiv.). The resulting mixture was stirred at -78 ˚C for 10 minutes before trifluoromethanesulfonic anhydride

(4.3 mL, 260 mmol, 1.2 equiv.) was added dropwise via syringe. The reaction was stirred at -78

˚C for 20 minutes, warmed to 0˚C for 20 minutes, and room temperature for 30 minutes. When complete consumption of the starting dione was observed by TLC, the reaction was quenched using 1 M HCl solution and extracted 3 times with diethyl ether. The organic layers were combined and washed with aqueous Na2CO3 solution and water, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was purified by flash column chromatography

(eluent mixture: EtOAc/Hexane = 2/98) to yield 5.54 g vinyl triflate in ≥95% yield as a colorless oil. Spectroscopic data were identical to the previously reported data.162

To 86 mL THF solution of vinyl triflate (5.54 g, 20.3 mmol, 1 equiv.) at -78 ˚C was slowly added 24 mL DIBAL-H (1.0 M solution in toluene, 1.2 equiv.). The reaction mixture was stirred at -78 ˚C for 10 minutes, warmed to 0 ˚C for 10 minutes, and room temperature for 30 minutes. The reaction was diluted with ether, cooled to 0 ˚C and quenched by adding 15% NaOH and water. The mixture was stirred for 15 minutes until a gel formed, and MgSO4 was then added. After the addition of MgSO4, the mixture was stirred for an additional 15 minutes.

Vacuum filtration and evaporation gave the crude vinylogous hemiacetal triflate 123.

90 Purification flash column chromatography with gradient eluent from EtOAc/Hexane = 5/95 to

EtOAc/Hexane = 20/80 yielded 5.41 g of 123 (97%). Spectroscopic data were identical to the reported data from the literature.162

Methods for The Synthesis of Illudinine

Ethyl 5,5-dimethyl-2-(pyridine-4-yl)oct-2-en-7-ynoate (193)

To a 118 mL THF solution of 11.3 mL lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 11.3 mmol, 2.1 equiv) at -78 ˚C was added 1.62 g vinylogous hemiacetal triflate 123

(5.90 mmol, 1.1 equiv) and 886 mg ethyl-4-pyridylacetate 192 (5.36 mmol, 1 equiv) successively. The resulting mixture was stirred at -78 °C for 10 minutes, warmed to 0 °C for 10 minutes, room temperature for 30 minutes, and heated in an oil bath at 60 °C for 2 hours. After 2 hours, the reaction mixture was cooled to room temperature and half-saturated NH4Cl was added to quench the reaction. The mixture was extracted with diethyl ether 3 times. The organic layers were combined and washed with water, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 10/90) to give the desired enyne 193 as a 2:1 mixture of alkene isomers (1.09 g, 75%).

1 HNMR major isomer (400MHz, CDCl3): δ 8.62 (dd, J = 4.6, 1.30Hz, 2H), 7.20 (t, J =

7.90Hz, 1H), 7.11 (dd, J = 4.40, 1.5Hz, 2H), 4.22 (q, J = 7.10Hz, 2H), 2.12 (d, J = 7.90Hz, 2H),

2.06 (d, J = 2.60Hz, 2H), 1.92 (t, J = 2.60Hz, 1H), 1.25 (t, J = 7.10Hz, 3H), 0.98 (s, 6H) ppm

13 CNMR of major isomer (400MHz, CDCl3): δ 165.76, 149.42, 143.70, 142.70,

133.56, 124.91, 81.40, 70.58, 61.14, 40.19, 34.36, 31.61, 26.69, 14.11 ppm

+ + HRMS (ESI+) calcd for C17H22NO2 [(M+H) ]: 272.1651, found 272.1641

Ethyl 8-bromo-5,5-dimethyl-2-(pyridine-4-yl)oct-2-en-7-ynoate (194)

91 To a solution of 575 mg enyne 193 in 10.6 mL acetone was added AgNO3 (109 mg, 0.3 equiv) and NBS (452 mg, 1.1 equiv) consecutively. The flask was wrapped in aluminum foil and stirred at room temperature for 1 hour. The reaction mixture was filtered through a 1 inch silica plug using diethyl ether as the eluent and then concentrated under reduced pressure. Purification by flash column chromatography using gradient eluent from 5% to 30% EtOAc in hexane yielded bromoalkyne 194 (740 mg, >99%) as yellow oil. Major and minor isomers were not separated and the E/Z ratio was not determined. 1HNMR data of major and minor isomers are listed separately in the text for clarity but the data was taken from a 2:1 isomeric mixture (vide infra). Best results were obtained when using new glassware and a new stir bar as trace metals adversely affected the reaction.

1 HNMR major isomer (400MHz, CDCl3): δ 8.63 (d, J = 5.12Hz, 2H), 7.18 (t, J = 7.90,

1H), 7.11 (d, J = 5.92Hz, 2H), 4.22 (q, J = 7.10Hz, 2H), 2.10 (d, J = 7.92Hz, 2H), 2.07 (s, 2H),

1.25 (t, J = 7.10Hz, 3H), 0.97 (s, 6H) ppm

1 HNMR minor isomer (400MHz, CDCl3): δ 8.56 (d, J = 3.84Hz, 2H), 7.26 (d, J =

6.00Hz, 2H), 6.39 (t, J = 7.94Hz, 1H), 4.32 (q, J = 7.12Hz, 2H), 2.52 (d, J = 8.00Hz, 2H), 2.19 (s,

2H), 1.34 (t, J = 7.12Hz, 3H), 1.06 (s, 6H) ppm

13 CNMR of mixture of major and minor isomers (400MHz, CDCl3): δ 166.74,

165.67, 149.68, 149.36, 145.21, 143.61, 142.43, 138.58, 134.51, 133.56, 124.82, 121.62, 77.80,

77.52, 61.10, 61.07, 40.97, 40.14, 39.89, 39.75, 34.75, 34.64, 32.99, 32.67, 26.78, 26.70, 14.13,

14.06 ppm

+ + HRMS (ESI+) calcd for C17H21NO2Br [(M+H) ]: 350.0756, found 350.0759

Ethyl 9-bromo-7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-carboxylate

(195)

92 A solution of 328 mg of bromoalkyne 194 (0.939 mmol, 1 equiv) in 15.6 mL o- dichlorobenzene (o-DCB) was heated in a sealed reaction vessel in a microwave reactor at 200

˚C. After 12 hours, the reaction was cooled and transferred directly into a flash column equipped with silica gel and 1% EtOAc/Hexane. The eluent was maintained at 1% until all of the o-DCB was out. Then the polarity of the eluent was gradually increased to 30% EtOAc/Hexane to obtain bromoisoquinoline 195 (130 mg, 40%) as a brown solid.

1 HNMR (400MHz, CDCl3): δ 9.58 (s, 1H), 8.58 (d, J = 6.00Hz, 1H), 8.15 (d, J =

6.00Hz, 1H), 4.49 (q, J = 7.10Hz, 2H), 3.17 (s, 2H), 2.98 (s, 2H), 1.46 (t, J = 7.10Hz, 3H), 1.20

(s, 6H) ppm

13 CNMR (600MHz, CDCl3): δ 166.91, 151.32, 149.57, 145.36, 144.42, 134.80, 126.19,

123.46, 122.80, 117.67, 61.53, 49.76, 49.22, 39.16, 28.52, 14.41 ppm

+ + HRMS (ESI+) calcd for C17H19NO2Br [(M+H) ]: 348.0599, found 348.0611

MP: 107-110˚C

Ethyl 9-hydroxy-7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-carboxylate

(196)

To a screw-cap vial under N2 was added 111 mg acetohydroxamic acid (1.48 mmol, 6 equiv), 341 mg K2CO3 (2.47 mmol, 10 equiv), and 86 mg of bromoisoquinoline 195 (0.247 mmol, 1 equiv). The vial was purged and refilled with N2 before the addition of 0.82 mL of

DMSO, such that the final substrate concentration was 0.3M. The mixture was heated at 80 ˚C for 20 hours before being cooled to room temperature and slowly quenched with 4.2 mL 1M HCl

(4.20 mmol, 17 equiv). After stirring at room temperature for 10 minutes, the vial was placed in an ice bath without stirring for a further 10 minutes. The precipitate was filtered, washed with cold water, and dried under vacuum. Purification by flash column chromatography using

93 gradient eluent from 20% to 80% EtOAc in hexane yielded hydroxyisoquinoline 196 (63 mg,

89%) as a bright yellow solid. 1HNMR was run at a concentration of 4.6 mg of substrate per 1 mL of CDCl3.

1 HNMR (600MHz, CDCl3): δ 9.76 (s, 1H), 8.55 (d, J = 6.00Hz, 1H), 8.39 (d, J =

6.00Hz, 1H), 4.46 (q, J = 7.12Hz, 2H), 3.16 (s, 2H), 2.90 (s, 2H), 1.45 (t, J = 7.08Hz, 3H), 1.18

(s, 6H) ppm

13 CNMR (600MHz, CD3OD): δ 167.27, 154.98, 148.61, 145.98, 142.77, 140.49, 138.13,

136.20, 125.85, 113.45, 60.51, 49.93, 42.92, 39.18, 27.46, 13.35 ppm

+ + HRMS (ESI+) calcd for C17H20NO3 [(M+H) ]: 286.1443, found 286.1441

MP: 198-202˚C

Ethyl 9-methoxy-7,7-dimethyl-7,8-dihydro-6H-cyclopenta[g]isoquinoline-5-carboxylate

(191)

To a solution of 19.2 mg of hydroxyisoquinoline 196 (0.067 mmol, 1 equiv) in 0.7 mL i-

BuOH/benzene (1:9) at room temperature was slowly added 0.05 mL of

(trimethylsilyl)diazomethane (2M solution in hexane, 0.1 mmol, 1.5 equiv). Once complete consumption of the starting alcohol was observed by TLC (12-18h), the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (eluent mixture: EtOAc/Hexane = 40/60) to give illudinine ethyl ester 191 (12.6 mg, 63%) as a slightly orange solid.

1 HNMR (600MHz, CDCl3): δ 9.54 (bs, 1H), 8.54 (bs, 1H), 8.24 (d, J = 4.70Hz, 1H),

4.48 (q, J = 7.10Hz, 2H), 4.06 (s, 3H), 3.08 (s, 2H), 2.98 (s, 2H), 1.46 (t, J = 7.10Hz, 3H), 1.18

(s, 6H) ppm

94 13 CNMR (600MHz, CDCl3): δ 167.23, 155.16, 153.31, 147.48, 144.06, 135.16, 130.72,

118.93, 61.12, 60.92, 49.05, 44.71, 40.18, 28.34, 14.45 ppm (Consistent with Dieters’ report, not all quaternary carbons observed).

+ + HRMS (ESI+) calcd for C18H22NO3 [(M+H) ]: 300.1600, found 300.1600

MP: 63-65˚C

Illudinine

To a solution of 10 mg illudinine ethyl ester 191 in 1 mL 95% EtOH was added 20 drops of 40% KOH at room temperature. The mixture was stirred for 20 hours before being neutralized

(to ca. pH 3) with 10% HCl, and poured into pH 7 buffer (14 mL). The aqueous mixture was extracted with Et2O (x4) and the combined organic layers were dried with MgSO4, filtered, and concentrated to give illudinine (9 mg, 99%) as a white solid.

1 HNMR (400MHz, CD3OD + 1 drop TFA): δ 9.72 (s, 1H), 9.01 (d, J = 6.96Hz, 1H),

8.51 (d, J = 6.92Hz, 1H), 4.30 (s, 3H), 3.28 (s, 2H), 3.25 (s, 2H), 1.22 (s, 6H) ppm

13 Error! Bookmark not defined. CNMR (600MHz, CD3OD) : δ 168.64, 163.68, 157.27, 143.37,

139.44, 133.71, 132.87, 123.89, 123.15, 120.78, 61.77, 50.78, 46.28, 41.28, 28.23 ppm

+ + HRMS (ESI+) calcd for C16H18NO3 [(M+H) ]: 272.1287, found 272.1277

MP: 218 to 225˚C

95 APPENDIX A

1HNMR AND 13CNMR SPECTROSCOPY FOR CHAPTER 2

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126 APPENDIX B

1HNMR AND 13CNMR SPECTROSCOPY FOR CHAPTER 3

127

128

129

130

131

132

133 APPENDIX C

LIST OF EXPERIMENTAL TERMS

Ac Acetyl

APCI Atmospheric Pressure Chemical Ionization

Ar Aryl

BHT Butylated Hydroxytoluene

Bu Butyl i-Bu Isobutyl t-Bu Tertbutyl t-BuXPhos 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl

13CNMR Carbon-13 Nuclear Magnetic Resonance

DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene o-DCB Ortho-dichlorobenzene

DCE Dichloroethane

DCM Dichloromethane

DDA Dehydro-Diels-Alder

DIBAL Diisobutyl Aluminum Hydride

DIPEA N,N-Diisopropylethylamine

DFT Density Functional Theory

DMG Directed Metallation Group

DMSO Dimethyl Sulfoxide

DNA Deoxyribonucleic Acid

El Electrophile

134 ESI Electrospray Ionization

Et Ethyl

EtOAc Ethyl Acetate

EWG Electron-Withdrawing-Group

G‡ Gibb’s Free Energy of Activation

HDDA Hexadehydro-Diels-Alder

1HNMR Proton Nuclear Magnetic Resonance

HOMO Highest Occupied Molecular Orbital

HRMS High Resolution Mass Spectrometry

HWE Horner-Wadsworth-Emmons

Hz Hertz

IR Infrared

LA Lewis-Acid

LDA Lithium Diisopropylamide

LiHMDS Lithium bis(trimethylsilyl)amide

LUMO Lowest Unnoccupied Molecular Orbital

Me Methyl

MP Melting Point

NBS N-Bromosuccinamide

Nu Nucleophile

Ph Phenyl

PMB Paramethoxybenzene ppm Parts-Per-Million

135 r.d.s. Rate Determining Step

SNAr Nucleophilic Aromatic Substitution

TBAF Tetra-n-butylammonium Fluoride

TBD Triazabicyclodecene

TBS Tert-Butyldimethylsilyl

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilyl

UV Ultraviolet

XPhos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

136

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154 BIOGRAPHICAL SKETCH

Alec E. Morrison was born in Geneva, Switzerland and lived in Accra, Ghana for three years before moving to Chicago, Illinois. After eighth grade he moved back to Switzerland to attend high-school where he received a bilingual IB diploma and fostered an interest in chemistry, rugby, and traveling. In May of 2012 Alec graduated from Worcester Polytechnic

Institute in Massachusetts with a B.S. majoring in biochemistry and minoring in chemical engineering. He is currently working under the guidance of Professor Gregory Dudley at the

Florida State University on new methodology development for the synthesis of complex natural products.

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