And 7,3'-Linked Naphthylisoquinoline Alkaloids Via an Ortho-Arylation

Convergent synthesis of the 5,3’- and 7,3’-linked naphthylisoquinoline alkaloids via an ortho-arylation strategy

Jonathon Samuel Ryan

A Thesis Submitted in Fulfilment of the Requirements for the Degree of

Doctor of Philosophy in Chemistry

The University of New South Wales, Sydney

School of Chemistry

Faculty of Science

July 2019

Thesis Dissertation Sheet

Surname/Family Name : Ryan Given Name/s : Jonathon Samuel Abbreviation for degree as given in the University calendar : PhD Faculty : Science School : Chemistry Convergent synthesis of the 5,3’- and 7,3’-linked Thesis Title : naphthylisoquinoline alkaloids via an ortho-arylation strategy

Abstract 350 words maximum: This thesis describes investigations into the total synthesis of the sterically hindered biaryl natural products, the 5,3’- and 7,3’- linked naphthylisoquinoline alkaloids. Chapter 1 outlines the synthetic strategies that have been developed by other groups for accessing the unique structure of the naphthylisoquinoline alkaloids. Previous work in the Morris group on the development of a convergent ortho-arylation strategy is described and the motivation for this work explained. Chapter 2 describes the completion of the total synthesis of all known 5,3’-linked naphthylisoquinoline alkaloids. In this work, a model system was used to identify conditions for the oxidation of the 1,2,3,4-tetrahydroisoquinoline moiety (2.15) of the natural products to the corresponding 3,4-dihydroisoquinoline 1.135. The core the natural products was accessed in 8 steps via Pinhey-Barton ortho-arylation of naphthol 1.113 using isoquinoline-substituted lead(IV) triacetate 2.21. Protection of the naphthol as the MOM-ether was followed by oxidation to complete the total syntheses of ancistrotanzanine A (1.122) and ancistrotectorine D (1.123) in 12 steps, while ancistrotectorine C (1.124) was accessed in 10 steps via a reductive amination protocol. Biological testing of the three natural products as well as atrop-ancistrotectorine C (2.29) identified moderate anti- malarial activity and low cytotoxicity. Chapter 3 details the investigation into organobismuth(V) compounds as an alternative to the aryllead(IV) triacetates used previously in the group for sterically hindered biaryl couplings. This resulted in the preparation and ligand-selective coupling of unsymmetrically substituted bismuthonium 3.23 to naphthol 1.113 to assemble the core of the 5,3’-linked naphthylisoquinoline alkaloids. In Chapter 4 this methodology is extended to the 7,3’-linked natural products. This was enabled by the development of a 6-step, asymmetric synthesis of 7-bromotetrahydroisoquinoline 4.34, which was converted to the corresponding bismuthonium 4.6 and coupled to naphthol 1.113 to form the 7,3’-biaryl linkage. The atropselectivity of the coupling of 7-substituted bismuthonium 4.6 was similar to what was observed for the 5-substituted bismuthonium, though the yield and ligand selectivity were lower. Deprotection of the major atropisomer product resulted in formal syntheses of ancistrocladidine (1.132) and ancistrotectorine (1.133). The conclusions and future directions of the work are given in Chapter 5 and full experimental procedures have been provided in Chapter 6.

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Date ……………………………………………...... Acknowledgements

Undoubtedly, I have to thank my supervisor Professor Jonathan Morris, who has mentored me tirelessly since I first joined the group. Thank you for your support and for challenging and inspiring me in equal measure. I am grateful for the privilege I’ve had to work with you, and will no doubt continue to draw upon your knowledge and experience in the years to come.

I’ve worked alongside a few generations of Morris group members. The old guard, who welcomed me into the group while I was an undergraduate: Dr Hamish Toop, Dr Joana Da Rocha, Dr Veronica Tecchio, and Dr Elysha Taylor. In particular, I am indebted to Dr Hamish Toop, who taught me a lot that has carried me through this journey, for being a constant source of advice when asked, and for volunteering for some proofreading. Also, special thanks to Dr Elysha Taylor, my first fumehood buddy, who fostered/put up with me through my Honours year and has been a friend since. I’ve been accompanied through my PhD by Dr Tom Hawtrey (a hero), Iliya Dragutinovic (a real hero), Stephen Wearmouth (…), Jack Duncan and Stephen Butler. Thank you all, it’s been largely enjoyable. Latterly, David Neale and Tess Mutton have joined the group, and I wish them the best. Dave, my last fumehood buddy, you haven’t had it easy working next to me, thank you for being so tolerant.

To my colleagues, who are too many to name – Dr Christopher Barnett, Dr Peter Jurd, Dr Rebecca Hawker, Dr James McPherson, Ena Luis, Dr Neil Mallo, Timothy Elton, Matthew Mudge, I could keep going…Thank you all.

Thank you also to Dr Douglas Lawes, Dr Adelle Amoore, Dr Donald Thomas and Dr Jim Hook – your expertise and help has been invaluable over the years and you have been unstinting in your generosity with your time and your materials. Thank you very much.

I can’t begin to describe how much support my family has given me. There may not be a lot in what follows that you will understand, but you all were there for every word of it regardless, and every experiment; I couldn’t have done it without you.

Abstract

This thesis describes investigations into the total synthesis of the sterically hindered biaryl natural products, the 5,3’- and 7,3’-linked naphthylisoquinoline alkaloids. Chapter 1 outlines the synthetic strategies that have been developed by other groups for accessing the unique structure of the naphthylisoquinoline alkaloids. Previous work in the Morris group on the development of a convergent ortho-arylation strategy is described and the motivation for this work explained. Chapter 2 describes the completion of the total synthesis of all known 5,3’-linked naphthylisoquinoline alkaloids. In this work, a model system was used to identify conditions for the oxidation of the 1,2,3,4-tetrahydroisoquinoline moiety (2.15) of the natural products to the corresponding 3,4-dihydroisoquinoline 1.135. The core the natural products was accessed in 8 steps via Pinhey-Barton ortho-arylation of naphthol 1.113 using isoquinoline-substituted lead(IV) triacetate 2.21. Protection of the naphthol as the MOM-ether was followed by oxidation to complete the total syntheses of ancistrotanzanine A (1.122) and ancistrotectorine D (1.123) in 12 steps, while ancistrotectorine C (1.124) was accessed in 10 steps via a reductive amination protocol. Biological testing of the three natural products as well as atrop-ancistrotectorine C (2.29) identified moderate anti-malarial activity and low cytotoxicity. Chapter 3 details the investigation into organobismuth(V) compounds as an alternative to the aryllead(IV) triacetates used previously in the group for sterically hindered biaryl couplings. This resulted in the preparation and ligand-selective coupling of unsymmetrically substituted bismuthonium 3.23 to naphthol 1.113 to assemble the core of the 5,3’-linked naphthylisoquinoline alkaloids. In Chapter 4 this methodology is extended to the 7,3’-linked natural products. This was enabled by the development of a 6-step, asymmetric synthesis of 7- bromotetrahydroisoquinoline 4.34, which was converted to the corresponding bismuthonium 4.6 and coupled to naphthol 1.113 to form the 7,3’-biaryl linkage. The atropselectivity of the coupling of 7-substituted bismuthonium 4.6 was similar to what was observed for the 5- substituted bismuthonium, though the yield and ligand selectivity were lower. Deprotection of the major atropisomer product resulted in formal syntheses of ancistrocladidine (1.132) and ancistrotectorine (1.133). The conclusions and future directions of the work are given in Chapter 5 and full experimental procedures have been provided in Chapter 6.

Abbreviations

[α] Specific rotation Å Angstrom(s) aq Aqueous Ar Aryl Bn Benzyl Boc tert-Butoxycarbonyl bp Boiling point br Broad n-Bu Normal butyl t-Bu Tertiary butyl °C Degrees Celsius calc Calculated cm Centimetres cm-1 Wavenumbers δ Chemical shift in parts per million d Doublet DIBAL Diisobutylaluminium hydride DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Dichloromethane de Diastereomeric excess dec Decomposition DMAC N,N-Dimethylacetamide DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide dr Diastereomer ratio ee Enantiomeric excess eq Equivalent ESI Electrospray ionization Et Ethyl FDA US Food and Drug Administration g Gram (s) h Hour (s) HMBC Heteronuclear multiple bond correlation

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HPLC High performance liquid chromatography HRMS High resolution mass spectrometry HSQC Heteronuclear single quantum correlation Hz Hertz

IC50 Half maximal inhibitory concentration IR Infrared J Coupling constant L Litre LDA Lithium N,N-diisopropylamide lit Literature LLS Longest linear sequence µM Micromolar µL Microlitre µW Microwave m Multiplet m Meta M Molar M+ Parent ion MALDI Matrix-assisted laser desorption/ionization max Maximum Me Methyl mg Milligram MHz Megahertz min Minute (s) mL Millilitre mM Millimolar mmol Millimoles mol Moles MOM Methoxymethyl Mp Melting point MS Mass spectrometry MW Molecular Weight m/z Mass-to-charge ratio NBS N-Bromosuccinimide ND Not determined nM Nanomolar NMR Nuclear magnetic resonance viii

Nu Nucleophile o ortho p para Ph Phenyl ppm Parts per million Pr Propyl i-Pr Isopropyl q Quartet quant Quantitative

Rf Retention factor RP Reverse Phase rt Room temperature s Singlet SAR Structure-activity relationship sept Septet t Triplet TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMEDA N,N,N’,N’-tetramethyl-1,2-ethylene diamine TMS Trimethylsilyl p-tol para-Toluene Ts para-Toluenesulfonyl UV Ultraviolet Val Valine vdW Van der Waals 2D NMR Two-dimensional nuclear magnetic resonance spectroscopy

Table of Contents Chapter 1: The Naphthylisoquinoline Alkaloids ...... 1

1.1 Structure, biosynthesis and biological activity of the naphthylisoquinoline alkaloids ...... 2

1.2 Synthetic methodologies for biaryl synthesis ...... 5

1.2.1 The ‘lactone method’ ...... 6

1.2.2 Suzuki-Miyaura cross-coupling ...... 8

1.2.3 Meyers Biaryl Coupling ...... 11

1.3 ortho-Arylation of phenols ...... 13

1.3.1 Rh-catalysed intermolecular ortho-arylation ...... 14

1.3.2 Pd-catalysed ortho-arylation ...... 15

1.3.3 Pentavalent organobismuth reagents ...... 16

1.3.4 Aryllead triacetates ...... 20

1.4 Application of the Pinhey-Barton reaction to the 7,3-linked alkaloids...... 23

1.5 The 5,3’-linked naphthylisoquinoline alkaloids: an alternative approach ...... 26

Chapter 2: Total Synthesis of the 5,3’-linked Naphthylisoquinoline Alkaloids ...... 33

2.1 Work described in Chapter 2 ...... 34

2.2 Oxidation of 1,2,3,4-tetrahydroisoquinolines ...... 34

2.2.1 Investigations on a model system into the elimination of a Ts-protecting group ..... 36

2.2.2 Investigations on a model system into the direct oxidation ...... 38

2.3 Pinhey-Barton coupling ...... 39

2.4 Total syntheses of ancistrotectorine D and ancistrotanzanine A ...... 41

2.5 Total synthesis of ancistrotectorine C and atrop-ancistrotectorine C ...... 49

2.6 Anti-malarial activity of the 5,3’-linked alkaloids ...... 52

2.7 Atropselective biaryl coupling ...... 54

Chapter 3: Investigations into arylbismuth coupling methodologies ...... 56

3.1 Introduction ...... 57

3.2 Application of organobismuth(V) chemistry to the naphthylisoquinoline alkaloids ...... 58

3.3 Preparation of symmetrical triarylbismuth(III) reagents ...... 58

3.4 Preparation of unsymmetrical organobismuth compounds ...... 62

3.5 Preparation and coupling of an isoquinolinylbismuthonium salt ...... 69

Chapter 4: Convergent access to the 7,3’-linked naphthylisoquinoline alkaloids ...... 73

4.1 Previous work on the Ancistrocladaceae alkaloids ...... 74

4.2 Retrosynthesis ...... 75

4.3 Initial investigations ...... 77

4.4 Preparation of alternately substituted iodonitrile ...... 79

4.5 Synthesis of 7-bromo-3,4-tetrahydroisoquinoline 4.34 ...... 82

4.6 Synthesis and coupling of 7-substituted bismuthonium 4.6 ...... 85

4.7 Formal syntheses of ancistrocladidine 1.132 and ancistrotectorine 1.133 ...... 91

Chapter 5: Summary and Future Work ...... 93

5.1 Summary ...... 94

5.2 Future Directions ...... 97

Chapter 6: Experimental ...... 101

6.1 General Experimental ...... 102

6.2 Experiments Described in Chapter 2...... 104

6.3 Experiments Described in Chapter 3...... 118

6.4 Experiments described in Chapter 4 ...... 124

References ...... 136

Appendix: Crystallography ...... 146

Chapter 1

Chapter 1: The Naphthylisoquinoline Alkaloids

Chapter 1

1.1 Structure, biosynthesis and biological activity of the naphthylisoquinoline alkaloids The naphthylisoquinoline alkaloids are a family of biaryl natural products that are produced in small quantities by the Dioncophyllaceae and Ancistrocladaceae families of carnivorous flowering plants. The unique structure of these natural products was first identified by Govindachari and co-workers in 1971 with their isolation and characterization of ancistrocladine (1.1, Figure 1.1).1,2 Since then, more than 180 naphthylisoquinoline alkaloids have been reported in the literature, each consisting of the same basic structure of a naphthalene and isoquinoline moiety linked by a biaryl bond. As shown in Figure 1.1, the location of the biaryl bond linking the natural products’ two moieties is used to classify them.

Figure 1.1: Representative examples of the naphthylisoquinoline alkaloids

Restricted rotation around the biaryl bond means that a high proportion of these compounds exist as stable atropisomers (indicated by the notation ‘P’ and ‘M’). Other points of difference across the family of natural products include changes in the stereochemistry of the C1 and C3 methyl substituents on the isoquinoline moiety, along with the oxygenation pattern on the aryl rings of both moieties (for example the C6-OH of ancistrocladine (1.1) and the C6-H of dioncophylline B (1.2)).

Considering the biosynthesis of the naphthylisoquinoline alkaloids, the similarity of their structure to the larger family of isoquinoline natural products implies a shared biosynthetic origin. The biosynthetic pathway responsible for the production of almost all isoquinoline natural products begins from the amino acid tyrosine (1.5) and proceeds through an enzyme- catalysed Pictet-Spengler cyclisation of phenylethylamine and an aldehyde to form the core of over 5000 alkaloid natural products.3–5 As shown in Figure 1.2, in the case of the benzylisoquinoline alkaloids, tyrosine (1.5) is converted via a sequence of hydroxylation, 2

Chapter 1

decarboxylation and transamination into the Pictet-Spengler substrates dopamine (1.6) and 4- hydroxyphenylacetaldehyde (1.7). Norcoclaurine synthase (NCS) catalyses their condensation and cyclisation to give (S)-norcoclaurine (1.8), which can undergo further biosynthetic transformations en route to the 2500 structurally diverse natural products belonging to the benzylisoquinoline family including papaverine (1.9), morphine (1.10) and berberine (1.12).3

Figure 1.2: Shared biosynthetic pathway for over 2500 tetrahydroisoquinoline alkaloids, beginning from the amino acid tyrosine.

However, comparing the structures of the naphthylisoquinoline alkaloid ancistrobrevine D (1.3, Figure 1.3) with the benzylisoquinoline alkaloid papaverine (1.9) reveals several key differences. In particular, neither the C3-methyl group or the C8-oxygen common to all naphthylisoquinoline alkaloids is present in papaverine (1.9), or the benzylisoquinoline alkaloids more generally, suggesting that a unique biosynthetic pathway is responsible.

Figure 1.3: Ancistrobrevine D (1.3) and the benzylisoquinoline alkaloid papaverine (1.9). The C3- methyl and C8-OH substituted isoquinoline moiety is unique to the naphthylisoquinoline alkaloids, suggesting an alternative biosynthetic origin.

The presence of the acetate-derived naphthalene moiety of the naphthylisoquinoline alkaloids provided an early hint as to their biosynthetic origin, with further evidence coming from their 3

Chapter 1

co-isolation alongside acetogenic natural products such as plumbagin (1.13) and droserone (1.14, Figure 1.4), whose biosynthesis had been established as originating from β-polyketides derived from acetate and malonate units, a pathway that is more commonly found in the biosynthesis of fungal natural products.6–8 The first direct evidence for this pathway operating in plants was reported by Zenk and co-workers, who were able to isolate labelled plumbagin (1.13) from plant shoots fed 14C-labelled acetate and malonate.6 Following on from this work, Bringmann and co-workers investigated the biosynthesis of dioncophylline A (1.15) using [1,2-

13 C2]-labelled acetate in feeding experiments on cell cultures of Triphyophyllum peltatum (Dioncophyllaceae). Following incubation, fully 13C-labelled dioncophylline A (1.15) was isolated from the cell culture, leading the authors to propose the biosynthetic pathway shown in Figure 1.4, in which the naphthalene and isoquinoline moieties are each formed from six units of acetate. Aldol condensation and aromatisation of hexaketide 1.16 via ‘Mode F’ folding (a pathway specific to fungi) provides precursor phenol 1.17, at which point further aldol cyclisation gives rise to naphthalene 1.18, or by reductive amination and condensation affords isoquinoline 1.19. Formation of the biaryl bond joining the two moieties most likely occurs by phenolic oxidative coupling (the exact mechanism of which is still unknown), which, following O-methylation and reduction to the tetrahydroisoquinoline, results in the alkaloid dioncophylline A (1.15). In the absence of coupling, the same pathway can also lead to the naphthoquinone family of natural products (including plumbagin 1.13 and droserone 1.14) via oxidation of the naphthol moiety.

Figure 1.4: Proposed biosynthesis of naphthylisoquinoline alkaloids and related naphthoquinones showing isotope labelling (red) for dioncophylline A (1.15) and plumbagin (1.13), and presumed labelling sites for intermediates.

The plants responsible for this biosynthesis, coming from the Dioncophyllaceae and Ancistrocladaceae families, are found across southern and southeastern Asia and Africa and 4

Chapter 1

have been used for centuries in traditional medicine in some of these areas for the treatment of malaria and dysentery.9 By screening both crude extracts from these plants, as well as purified compounds, against strains of the malarial parasite Bringmann and co-workers were able to identify that the naphthylisoquinoline alkaloids were responsible for this anti-malarial activity.10 Subsequent reports have identified anti-feedant,11 molluscicidal,12 insect-growth retarding13 and anti-HIV activities.14–16 This diversity of biological activity that can be found across the family of natural products, in addition to their unique chemical structures, has made the naphthylisoquinoline alkaloids attractive targets for synthesis.

1.2 Synthetic methodologies for biaryl synthesis The key structural feature of the naphthylisoquinoline alkaloids is the biaryl bond linking the naphthalene and isoquinoline moieties. The biaryl motif itself is not unique to these natural products; rather, it is a ubiquitous feature in the chemical structures of a large range of compounds including pharmaceuticals, agrochemicals, natural products, ligands for catalysis, molecular switches and motors as well as many organic materials such as polymers, liquid crystal displays and light-emitting diodes (A, Figure 1.5). Consequently, the development of methodologies for the arylation of arenes has occupied synthetic chemists for over a century, beginning with the first report by Ullmann and Bielecki in 1901 on the homo-coupling of electron-deficient aryl halides in the presence of copper (B, Figure 1.5).17

Figure 1.5: A Biaryls (bold) are ubiquitous in the chemical structures of a diverse range of compounds, both natural and synthetic; B General schematic of the Ullmann reaction, the first aryl coupling reaction reported in the literature. Since that report, a huge diversity of methods for the preparation of biaryls have been reported, demonstrating both the importance of this synthetic transformation as well as the need for new 5

Chapter 1

and more efficient methodologies.18–21 In the case of the naphthylisoquinoline alkaloids, their unique structures have served as a testing ground for biaryl coupling strategies, in particular with the development of atropselective syntheses of biaryl bonds, as well as the coupling of sterically hindered substrates. A number of strategies have been developed for addressing these challenges, culminating in over 30 total syntheses of these natural products.

1.2.1 The ‘lactone method’ The first total synthesis of a naphthylisoquinoline alkaloid, the 7,1’-linked O- methyltetradehydrotriphyophylline (1.20, Scheme 1.1), was reported by Bringmann and Jansen in 1984.22 Initial attempts at an Ullmann-type intermolecular coupling of the brominated naphthalene and isoquinoline moieties led to only trace formation of mixed coupled products. Turning therefore to an intramolecular coupling reaction to form the biaryl axis, bridged ether 1.21 was prepared from the requisite Bn-protected isoquinoline 1.22 and dibrominated naphthalene 1.23 in 93 % yield (Scheme 1.1). Formation of the biaryl bond was achieved via photolysis of ether 1.21 to afford cyclic ether 1.24 in 15 % yield. The synthesis of O- methyltetradehydrotriphyophylline (1.20) was completed following reductive cleavage of the ether bridge and oxidation of the 1,2,3,4-tetrahydroisoquinoline ring to form the isoquinoline contained in the natural product.

+ Scheme 1.1: Reagents and yields a) BnN (n-Bu)3, CH2Cl2, NaOH (1 M aq.), 93 % yield; b) 254 nm,

22 cyclohexane, NEt3, 15 % yield.

The key step of the synthesis uses a tether to facilitate the intramolecular biaryl coupling. Cleavage of the cyclic ether 1.24 proved difficult and afforded a mixture of atropisomers, leading the authors to speculate that, despite its apparent planarity, ether 1.24 is configurationally

Chapter 1

unstable about the biaryl axis. Subsequent work by Bringmann and co-workers led to the use of a lactone in place of the ether linkage, with more exaggerated instability about the biaryl linkage.23,24 The so-called ‘lactone method’ formed the basis of Bringmann’s subsequent total syntheses of other members of the 7,1’-linked family as well as the 5,1’-, 5,8’- and 7,3’-linked families.25,26 As well as allowing a more efficient bond formation strategy and cleavage endgame, the lactone tether capitalized on the configurational instability of the lactone functional group to allow the selective preparation of either atropisomer via dynamic kinetic resolution.23,24

A representative example is the total syntheses of the 5,8’-linked korupensamine A (1.25) and its atropisomer korupensamine B (1.26).27 As shown in Scheme 1.2, an ester linkage was used to facilitate an intramolecular palladium-catalysed cross-coupling of bromide 1.27 exclusively to the 5-position of the isoquinoline ring, affording biaryl 1.28 as a mixture of its rapidly interconverting atropdiastereomers. Reductive cleavage of this mixture with the (R)-configured oxazaborolidine-borane 1.29 gave the P-configured biaryl 1.30 in 58 % yield and 88 % de, which could be elaborated to korupensamine A (1.25) in 7 further steps and 19 steps overall. Treatment with (S)-oxazaborolidine-borane 1.29 gave the M-configured biaryl 1.31 in 57 % yield and 92 % de, which could be elaborated to korupensamine B (1.26) via the same sequence.

Scheme 1.2: Reagents and yields a) Pd(OAc)2, P(p-tol)3, NaOAc, DMAc, 140°C, 74 % yield; b) BH3, (R)-

27 1.29, THF, - 30°C, 58 % yield (M:P = 6:94); c) BH3, (S)-1.29, THF, 0°C, 57 % yield (M:P = 96:4).

Chapter 1

Bringmann’s lactone method is a powerful strategy for accessing the naphthylisoquinoline alkaloids – and other axially chiral natural products25,26 – in an atropselective fashion. The lactone tether is not ‘traceless’ however, requiring multistep pre-functionalisation of the substrate prior to coupling as well as functional group manipulation in subsequent steps, which is a drawback of this strategy. The coupling of sterically hindered substrates also poses a challenge, given the decrease in yield associated with palladium-couplings in sterically congested environments.28 An example of this can be seen in the recently reported syntheses of the 7,3’-linked alkaloids ancistrocladidine (1.32) and ancistrotectorine (1.33) which, with four ortho-substituents are some of the most sterically hindered of the naphthylisoquinoline alkaloid family (Scheme 1.3).29,30 Initial experiments focussed on coupling lactone 1.34, accessed in 14 steps, were unsuccessful. Following a reversal of coupling partners (i.e. using lactone 1.35) and an extensive screening of reagents and conditions, biaryl 1.36 was eventually formed in 31 % yield by heating at 110 °C with 1.5 equivalents of phosphinous acid palladium 1.37. While successful, the harsh conditions, super-stoichiometric quantities of palladium and low yield are significant drawbacks and the synthesis of other sterically hindered biaryl natural products using this method have not yet been reported.

30 Scheme 1.3: Reagents and yields a) POPd 1.37 (1.5 eq), Cs2CO3, DMA, 110 °C, 45 min, 31 % yield.

1.2.2 Suzuki-Miyaura cross-coupling The 5,8’-linked naphthylisoquinoline alkaloids korupensamine A (1.25) and B (1.26) have received significant attention from the synthetic community, in large part due to the potent anti- HIV activity of their dimerization product michellamine B (1.38) – itself a natural product – which was selected by the U.S. National Cancer Institute for preclinical development at the time of its isolation in 1994 (Figure 1.6).14,31 In addition to Bringmann’s intramolecular approach using the ‘lactone method’, the groups of Dawson,32 Hoye,33 Uemura,34,35 Lipshutz36,37 and Tang38 have 8

Chapter 1

each reported total syntheses of korupensamines A (1.25) and B (1.26) en route to michellamine B (1.38), using the powerful Suzuki-Miyaura cross-coupling of aryl halides and boronic acids.

Figure 1.6: The potent anti-HIV compound michellamine B (1.38) is the heterodimerisation product of the 5,8’-linked korupensamines A (1.25) and B (1.26).

Non-atropselective syntheses were reported by Dawson and Hoye, using HPLC to separate the atropisomers.32,33 One of the first diastereoselective cross-coupling was reported by Uemura and co-workers, using the planar chiral chromium-arene complex 1.40 to couple to the naphthylboronic acid 1.39 (A, Scheme 1.4).34,35 The P-configured biaryl 1.41 could be converted into korupensamine A (1.25), or alternatively could be oxidized and isomerized around its biaryl axis by heating in xylenes to afford the M-configured biaryl 1.42, allowing access to korupensamine B (1.26) from the same chromium-arene complex.

Chapter 1

Scheme 1.4: A Reagents and yields a) 5 mol % Pd(PPh3)4, 0.1 M aq K3PO4, toluene, 95 °C, 30 min, 74 %

35 yield; b) TFAA, DMSO, CH2Cl2, then Et3N, 87% yield; c) Xylenes, 120 °C, 1 h, 65% yield. B Linkers attached at the C3 position can provide atropselectivity.36,37

An alternative strategy was developed by Lipshutz and co-workers using a hydroxymethyl handle at the C3 position of the isoquinoline ring to allow for the attachment of linkers to control the atropselectivity of the cross-coupling reaction with naphthalene 1.43 (B, Scheme 1.4).36,37 Thus, the ortho-diphenylphosphane functionalised substrate 1.44 exclusively afforded the P- configured atropisomer, with the stereoselectivity rationalised by the authors by consideration of the steric bulk of the palladium-ligated phosphane linker during the reductive elimination stage of the coupling. In contrast, the preparation of the M-atropisomer is believed to be directed by a π-stacking interaction between the electron deficient naphthalene linker 1.45 and the electron rich isoquinoline ring, which blocks the forward face, albeit not as efficiently. Chromatographic separation of the 8:92 mixture of atropisomers is required to afford optically pure material.

The most efficient synthesis of korupensamines A (1.25) and B (1.26) to date was reported by Tang and co-workers in 2014. Using the chiral phosphorus ligand 1.46 or its enantiomer, they

Chapter 1

were able to demonstrate an entantiodivergent cross-coupling of bromide 1.47 and naphthylboronic acid 1.39 (Scheme 1.5).38 Enantioselectivity is achieved through a polar-π interaction between the highly polarised BOP group on bromide 1.47 with the extended π- system of naphthylboronic acid 1.39, affording either atropisomer in both high yields and enantioselectivities. Elaboration of aldehydes 1.48 and 1.49 to the natural products was achieved in 9 steps via nitroaldol reaction, asymmetric hydrogenation and Bischler-Napieralski cyclisation to afford korupensamines A (1.25) and B (1.26) in 13 steps LLS.

Scheme 1.5: Reagents and yields a) Pd(OAc)2, 1.46, K3PO4, toluene/H2O (5/1), 96% yield, 93% ee; b)

38 Pd(OAc)2, ent-1.46, K3PO4, toluene/H2O (5/1), 96% yield, 93% ee.

The considerable challenge posed by the stereocontrolled synthesis of the 5,8’-linked korupensamines has led to the development of several novel asymmetric Suzuki-Miyaura cross- couplings, in each case utilising interactions between the Pd-catalyst and the modified substrates. However, as yet the 5,8’-linked naphthylisoquinoline alkaloids remain the only members of the family to be synthesised using these methods.

1.2.3 Meyers Biaryl Coupling The Meyers biaryl cross-coupling reaction involves the substitution of an aromatic alkoxy group by an aryl Grignard reagent. An oxazoline moiety in the ortho-position relative to the alkoxy leaving group is able to promote its displacement and can also be used to direct the stereochemical outcome of the reaction, if it is prepared from chiral starting materials.39,40 In 1989, Sargent and Rizzacasa reported the application of this cross-coupling reaction in a racemic synthesis of the 7,1’-linked dehydroancistrocladisine.41,42 An asymmetric variant using a chiral

Chapter 1

oxazoline moiety was subsequently reported in the syntheses of several 5,1’-linked naphthylisoquinoline alkaloids, including ancistrocladinine (1.50, Scheme 1.6).43,44 Reaction of Grignard reagent 1.51 with naphthalene 1.52 proceeded in 64 % yield, providing a 77:23 mixture of atropisomers with the desired configuration as the major product. The reaction is proposed to take place via the magnesium-chelated intermediate I which results from ipso-attack of the Grignard reagent into the carbon bearing the methoxy leaving group. In this case, the diastereoselectivity is ascribed to the increased chelating ability of the dioxolanyl group (R = A) over the competing -OBn substituent of Grignard 1.51. An increased diastereoselectivity (88:12) could be achieved when the steric bulk of the dioxolanyl-chelate was increased (R = B). Conversely, an even higher diastereoselectivity (92:8) could be achieved by removing one of the two competing chelating groups and replacing it with the non-chelating CH2OTBDMS group (1.53).45

Scheme 1.6: Reagents and yields a) THF, 66 °C, 20 h, 64 % yield, 54 % de.44

Using the Meyers biaryl coupling reaction, Sargent and Rizzacasa were able to prepare the biaryl axis of the 7,1’- and 5,1’-linked naphthylisoquinoline alkaloids with a high degree of atropselectivity, though the linearity of the strategy could be considered a drawback. In an extension of this strategy however, Rizzacasa and co-workers were able to demonstrate the preparation of intact tetrahydroisoquinoline Grignard 1.54 (Scheme 1.7). Addition of Grignard 1.54 to oxazoline 1.55 afforded biaryl 1.56 in 27 % yield over three steps and a ratio of 88:12 of

Chapter 1

atropisomers, which was elaborated to the natural product derivative O-methylancistrocline (1.57) in three steps.

Scheme 1.7: Reagents and yields a) THF, 66 °C, 23 h; b) TFA, H2O, THF, 26 h; c) Ac2O, pyridine, CH2Cl2, 0 °C to rt, 4 h, 27 % yield over three steps, 5 % yield of minor biaryl.46

Using the Meyers biaryl coupling reaction, Sargent and Rizzacasa have developed an atropselective and convergent strategy for the synthesis of the naphthylisoquinoline alkaloid scaffold. To date however, it has only been successfully applied to members of the 7,1’- and 5,1’- linked families. A subsequent attempt to extend it to the sterically hindered 7,3’-linked naphthylisoquinoline alkaloids was unsuccessful.47

1.3 ortho-Arylation of phenols A key drawback of the methodologies discussed above is the degree of functionalisation required for the key biaryl bond forming reaction, either through the substitution of activating groups such as boronic acids or halides or the attachment and removal of tethering groups between the naphthalene and isoquinoline moieties. An arylation strategy that does not require significant functional group manipulation would therefore be preferable, relying on the inherent reactivity of the aryl coupling partners to direct cross-coupling.

With regards to the naphthylisoquinoline alkaloids, consideration of their biosynthesis via phenol oxidative coupling suggests that the phenol motif – ubiquitous within the structure of all the members of this family of natural products – would be an ideal handle with which to direct reactivity. However, the coupling selectivity of phenolic oxidations are typically quite low, though the groups of Kozlowski and Pappo have demonstrated that it is possible to achieve selective cross-couplings of simple phenols using salen ligands such as 1.58 or tetraphenylporphyrin 1.59 to direct the site of arylation (Scheme 1.8).48–50 Despite these advances, it is not clear that the precise control of regio- and stereo-selectivity required for a total synthesis would be possible using these methods. 13

Chapter 1

Scheme 1.8: Reagents and yields a) 1.58 (5 mol %), 1,2-DCE, O2(g), 50 °C, 48 h, 55 % yield; b) 1.59 (1 mol %), t-BuOOH, HFIP, rt, 24 h, 77 % yield.48,49

An alternative strategy is an ortho-arylation reaction, harnessing the nucleophilicity of phenols in a cross-coupling with a functionalised electrophile (Scheme 1.9). This transformation has been reported to occur with Rh- and Pd-catalysis, as well as with organobismuth(V) and organolead(IV) compounds.

Scheme 1.9: General representation of the ortho-arylation of phenols.

1.3.1 Rh-catalysed intermolecular ortho-arylation The Rh-catalysed intermolecular ortho-arylation of phenols was reported independently by the groups of Bedford and Oi in 2003.51,52 The reaction involves the in situ transesterification of a phenol substrate with a triarylphosphinite ligand (I, Scheme 1.10), which can coordinate the Rh- catalyst, leading to ortho-metalation (II) and reductive elimination. Using bromobenzene and

[RhCl(cod)2] as catalyst, Oi and co-workers obtained mixtures of mono- and di-phenylated products in reasonable yields. Bedford and co-workers on the other hand were able to demonstrate the coupling of aryl bromides and chlorides with various phenols using Wilkinson’s catalyst, though the reaction only proceeds with 2-substituted phenols, as in the reaction between phenol 1.60 and bromide 1.61 (Scheme 1.10). In a subsequent report, commercially 14

Chapter 1

available chlorophosphine complexes were shown to be just as active, obviating the need for triarylphosphinite ligands, which are generally not commercially available.53 At present, the only application of this methodology has been in the synthesis of a small library of arylated tyrosine analogs.54

Scheme 1.10: Reagents and yields a) Cs2CO3, PiPr2(OC6H4-2-iPr) (15 mol %), [RhCl(PPh3)3] (5 mol %), PhMe, reflux, 10 h, 96 % yield.51

1.3.2 Pd-catalysed ortho-arylation The use of Pd-catalysis in the direct ortho-arylation of phenols is more prevalent. Rawal and co- workers reported the first systematic study into the intramolecular coupling of phenols with aryl halides in 1997, taking place with complete regioselectivity and in high yields in the presence of Hermann’s catalyst (1.63, Scheme 1.11).55

55 Scheme 1.11: Reagents and yields a) Cs2CO3, 1.63 (5 mol %), DMAc, 80 °C, 24 h, 97 % yield.

Based on Rawal’s precedent, as well as earlier work by Wiegand and Schäfer,56 Cuny and co- workers applied an ortho-arylation strategy in their total synthesis of the aporphine natural products lirinidine (1.66) and nuciferine (1.67, Scheme 1.12). While they saw no reaction using

Hermann’s catalyst, by changing to Pd(OAc)2 and using more forcing conditions they were able to access the ortho-arylated product 1.69 in good yield.57,58

Chapter 1

Scheme 1.12: Reagents and yields: (a) NaOAc, PCy3, Pd(OAc)2 (50 mol %), DMAc, 110 °C, 24 h, 64 % yield.57

More recently, Doucet and Beydoun have reported an intermolecular cross coupling strategy (Scheme 1.13). The isolated yields of ortho-arylated products from the coupling with electron- deficient aryl bromides are modest overall, requiring high temperatures and a significant excess of phenol substrate to suppress homo-coupling of the bromide. A switch in regioselectivity is observed when the base used in the reaction is changed from KOAc to K2CO3, suppressing ortho- arylation completely in favour of arylation at oxygen to form diaryl ether products.59

Scheme 1.13: Reagents and yields: a) KOAc, PdCl(C3H5)(dppb) (2 mol %), DMAc, 150 °C, 48 h, 41 % yield.

1.3.3 Pentavalent organobismuth reagents The ability of organobismuth(V) compounds to perform arylation reactions was first reported by Barton and co-workers in 1980.60 While investigating the oxidation of quinine (1.70) using an excess of triphenylbismuth carbonate they observed the formation of α-arylated quininone 1.71 in 92 % yield. The authors speculated that the reaction was occurring via coordination of an enolate intermediate to the bismuth(V) reagent, prompting them to investigate the reaction of triphenylbismuth carbonate with other enolates and phenols. Thus, repeating the reaction with 2-naphthol (1.72) in the presence of the base 1,1,3,3-tetramethylguanidine (TMG) led to the isolation of the ortho-arylated product 1.73 in 76 % yield (Scheme 1.14).60

Chapter 1

Scheme 1.14: Reagents and yields a) Ph3BiCO3 (2.5 eq), DCM, 40 °C, 92 % yield; b) Ph3BiCO3 (2.5 eq), TMG, THF, rt, 76 % yield.60

Subsequent reports by Barton and co-workers detailed the arylation of 2-naphthol (1.72) with a range of organobismuth compounds, conforming to the general formulae of Ph3BiX2, Ph4BiX, or

61–63 Ph5Bi, where X can be halide, carboxylate, trifluoroacetate or sulfonate. Additionally, they observed that the chemoselectivity of the reaction varied with the conditions, whereby ortho- arylation occurred readily for enolisable substrates and phenols under basic conditions, while under neutral or acidic conditions formation of the aryl ether would predominate (A, Scheme 1.15). Subsequent reports have demonstrated that metallic copper and copper salts are especially effective in directing arylation to oxygen and other heteroatoms such as nitrogen and sulfur.18,64,65 For example, a key step in the total synthesis of gravicycle (1.74, B, Scheme 1.15) reported by Hirama and co-workers involved the formation of the sterically crowded ether 1.75 in 68 % yield by reacting phenol 1.76 with organobismuth(V) diacetate 1.77 in the presence of copper metal.66

Scheme 1.15: Reagents and yields A a) Ph4Bi(OTFA), BTMG, THF, 94 % yield; b) Ph4Bi(OTFA), benzene,

63,67 66 reflux, 82 % yield. B a) NEt3, Cu (20 mol %), CH2Cl2, rt, 24 h, 68 % yield. 17

Chapter 1

With regard to the mechanism of the ortho-arylation reaction (Scheme 1.16), Barton and co- workers proposed that nucleophilic attack of a phenoxide (I) onto bismuth would give rise to a covalently bonded Bi(V)-O intermediate (II). Spectroscopic evidence for the existence of this intermediate was obtained by 1H NMR spectroscopic monitoring of reactions, along with the isolation and characterization of organobismuth 1.78 from the reaction of 2,6-di-tert- butylphenol (1.79) with Ph3BiCl2. Controlled thermal degradation of 1.78 led to biaryl 1.80, the product of ortho-arylation, via reductive elimination from the Bi(V) centre.18

Scheme 1.16: A Proposed mechanism for the ortho-arylation of phenol B Reagents and Conditions: a)

63 Ph3BiCl2, TMG, THF, 1h, 45 % yield; b) toluene, -20 °C to reflux, 82 % yield.

The ortho-arylation of phenols was explored extensively by Barton and co-workers.63 There are, however, few reports in the literature of its application in synthesis. One example comes from Finet and co-workers, describing a one-pot preparation of the benzo[b]pyran scaffold using acetate 1.81 which, following ortho-arylation of phenol 1.82, undergoes ring closure at the ortho-chloromethyl substituent to provide the ring-closed product 1.83 (Scheme 1.17).68

Scheme 1.17: Reagents and Yields a) NEt3, CH2Cl2, rt, 30 h, 48 % yield.

In contrast, the α-arylation of enolates with organobismuth(V) compounds has attracted significant attention, finding applications in total synthesis as well as the interception of in situ generated reactive intermediates to afford novel products. For example, Krische and Koeche have reported the α-arylation of enones and enals with a variety of triarylbismuth(V) compounds using phosphine as a catalyst (A, Scheme 1.18). Michael-type addition of tert-

Chapter 1

butylphosphine to enone 1.84 generates a transient β-phosphonioenolate which can coordinate to p-fluorophenylbismuth 1.85 and undergo ligand coupling to afford the α-arylated product 1.86 in 79 % yield, which was used in an asymmetric synthesis of anti-depressant (-)-paroxetine (1.87).69,70 Alternatively, Maruoka and co-workers have reported the first preparation of fluorotetraphenylbismuth(V) 1.88 (B, Scheme 1.18) and demonstrated its use as a mono-α- phenylating reagent for silyl enol ethers and ketene silyl acetals. The authors propose that the reaction is initiated by the formation of Me3SiF (observed spectroscopically) and a covalently linked Bi(V)-enolate intermediate, which can undergo ligand coupling to form the α-phenylated product.

Scheme 1.18: Reagents and Yields (a) PBu3 (10 mol %), (p-F-Ph)3BiCl2, i-Pr2NEt, CH2Cl2-t-BuOH (9:1), rt, 79 % yield; (b) 1.88, THF, -40 °C to rt, 92 % yield.

Diastereoselective arylations with organobismuth(V) compounds have been reported.

Investigating the α-arylation of nitroacetate 1.91 – a mixture of diastereomers – with Ph3BiCl2, Fornicola and co-workers isolated a 1:1 mixture of diastereomers of phenylated product 1.92 using TMG as base (Scheme 1.19 A).71 Changing to DBU, however, resulted in a significant shift in the product distribution, providing an 11:1 mixture of the diastereomers; it must be noted that a rationale for the change in diastereomeric ratios is not offered. A subsequent paper by Baran and co-workers on the synthesis of the carbon skeleton of the natural product maoecrystal V also reports a bias in the diastereomeric ratio of arylated product 1.93 in the reaction of enol 1.94 and organobismuth(V) 1.95 when using DBU as a base (B, Scheme 1.19). Unfortunately, they do not report attempting the reaction with any bases other than DBU, making a comparison difficult. However, the stereochemistry of the TBS-protected alcohol at C3 likely plays a role in directing the outcome of the arylation reaction.

Chapter 1

Scheme 1.19: Reagents and Yields A a) Ph3BiCl2, base, PhMe, rt, 30 h; B b) 1.95, DBU, toluene, rt, 12 h, 67 %.71,72

In order to gain some insight into the stereoselectivity of bismuth-mediated arylations, Finet and co-workers screened combinations of optically active organobismuth(V) compounds and chiral bases against a range of substrates.73 Only low enantioselectivies were observed – such as in the reaction of Ph3Bi(CSA)2 with cyclohexanone 1.96 and (-)-nicotine (1.97, Scheme 1.20) – which the authors speculated was a result of the stereocentres of the bases used lying distal from the bismuth atom during ligand coupling.

73 Scheme 1.20: Reagents and Yields a) Ph3Bi(CSA)2, 1.97, THF, 95 %.

A systematic investigation into the atropselective ortho-arylation of phenols has not been reported in the literature. However, as the previous examples demonstrate, it is possible to affect the stereochemical outcome of bismuth(V)-arylations either by choice of base or from steric factors arising from the substrate itself.

1.3.4 Aryllead triacetates The ortho-arylation of phenols using aryllead(IV) carboxylates was first reported by Pinhey and co-workers in 1976.74 As shown in Scheme 1.21, upon treatment of a solution of mesitol 1.99 and excess pyridine in chloroform with anisyllead 1.100, ortho-arylated product 1.101 was formed in 71 % yield, along with 20 % of the para-substituted product. Screening a number of different phenol substrates achieved similar results, each demonstrating the preponderance of aryllead triacetates to afford the ortho-substituted products.75 With the support of 1H NMR spectroscopic studies, Pinhey and co-workers proposed a reaction mechanism involving the 20

Chapter 1

covalent Pb(IV)-O bonded intermediate I, though they were unable to isolate the intermediate for full characterisation. The role of pyridine in the reaction was not determined, though a significant decrease in the rate of reaction is observed when the reaction is performed without pyridine, or with NEt3, suggesting that coordination of the base to lead is important for the reaction.76

Scheme 1.21: Reagents and yields a) pyridine, CHCl3, rt, 71 % yield.

Subsequently, Barton and co-workers set out to observe the intermediate that would be formed from the reaction of 3,5-di-tert-butylphenol 1.102 and 2,4,6-trimethoxyphenyllead triacetate 1.103, proposing that the high degree of steric hindrance would prevent the formation of product and stabilise the intermediate (Scheme 1.22).77 While they were unable to isolate an intermediate, they were able to demonstrate the ability of aryllead triacetates to couple substrates with a high degree of steric hindrance under mild conditions, isolating the diarylated product 1.104 in a remarkable 87 % yield.

77 Scheme 1.22: Reagents and yields a) pyridine, CHCl3, rt, 3 h, 87 % yield.

Further work by Barton and co-workers sought to investigate the possibility of a mechanism involving radicals by performing the experiment in the presence of a radical trapping agent. The yields of arylation were unaffected, leading them to conclude that the mechanism most likely involved a ligand-coupling reaction, similar to arylations with organobismuth(V) compounds.77– 79 In an analogous manner to the mechanism proposed for arylations with bismuth, they 21

Chapter 1

proposed that coordination of the phenol substrate to the lead(IV) complex (I) is followed by ligand coupling and reductive elimination of the aryl ligands to give the ortho-arylated product (II) and lead(II) acetate (Figure 1.7).

Figure 1.7: Proposed mechanism for the ortho-arylation of phenols with aryllead triacetates.

The potential for aryllead(IV) triacetates to perform atropselective arylations has been reported by Yamamoto and co-workers.28,80 As mentioned earlier, Pinhey and co-workers had shown that excess pyridine was important for the reaction between phenols and aryllead triacetates.75 By exchanging pyridine with optically active amine bases Yamamoto and co-workers were able to demonstrate the asymmetric coupling of a range of phenols and aryllead triacetates, with brucine (1.105) giving the largest enantioselectivities (Scheme 1.23). The atropselectivity was explained using a model involving the ligation of brucine (1.105) to the intermediate lead(IV) complex (I), whereby the steric bulk of brucine influences the ligand coupling of the coordinated aryl groups. It is possible though that the role of brucine (1.105) in the reaction is not adequately captured by this model, as evidenced by subsequent investigations reported by Moloney and co-workers, who noted the labile coordination environment of aryllead(IV) complexes in solution, with rapid ligand exchange hampering their efforts to achieve enantioselective couplings using chiral carboxylate ligands.81,82 Work performed independently in this group by Milena Czyz during her PhD also failed to achieve enantioselectivity when reaction conditions reported by Yamamoto and co-workers were repeated in the presence of chiral pyridine and 1,10-phenanthroline derivatives, such as II.83

Scheme 1.23: Reagents and yields a) 1.106 (2.5 eq), 4Å sieves, 1.105 (6 eq), PhMe, -20 °C, 21 h, 99 % yield; b) 1.106 (2.5 eq), 4Å sieves, 1.105 (6 eq), PhMe, -40 °C, 10 h, 86 % yield. 22

Chapter 1

Aryllead triacetates have been employed in the total synthesis of a number of natural products, particularly in sp2-sp3 cross couplings for the formation of quaternary centres.84–88 In the Morris group, a longstanding interest has been in the preparation of sterically hindered biaryls using the Pinhey-Barton ortho-arylation reaction, with a particular focus being the development of efficient access to the 7,3’- and 5,3’-linked naphthylisoquinoline alkaloids.

1.4 Application of the Pinhey-Barton reaction to the 7,3-linked alkaloids The isolation of the 7,3’-linked ancistrocladidine (1.32, Figure 1.8), one of the first naphthylisoquinoline alkaloids to be identified, was reported by Govindachari and co-workers in 1975. The S-configuration of the C3 methyl group, alongside the oxygen at C6, is representative of the Ancistrocladaceae derived alkaloids generally, including ancistrotectorine (1.33); the Dioncophyllaceae-type alkaloids, such as dioncophylline E (1.107), are commonly R-configured at the C3 methyl group, while the C6 position is devoid of oxygenation. The presence of four ortho substituents around the biaryl bond of ancistrocladidine (1.32) presents a particular challenge to its formation via the cross coupling methods discussed above, with Bringmann’s ‘lactone method’ affording it in just 31 % yield in the presence of excess palladium (see Chapter 1.2.1). The ability of aryllead(IV) triacetates to perform sterically hindered cross couplings, along with the presence of a phenol ‘handle’ on the naphthol moiety, prompted Christopher Bungard to undertake a total synthesis of ancistrocladidine (1.32) during the course of his PhD under the supervision of Jonathan Morris, with the intention of using the Pinhey-Barton reaction in the key biaryl bond forming step.

Figure 1.8: The 7,3’-linked naphthylisoquinoline alkaloids

In 2002, Bungard and Morris were able to report the first total synthesis of ancistrocladidine (1.32).29,89,90 Adopting a linear strategy, the key aryllead(IV) triacetate 1.108 was prepared in 3 steps from aryl iodide (1.109, Scheme 1.24). Protection of the aldehyde was performed under Dean-Stark conditions to afford acetal 1.110 in 99 % yield, which was followed by halogen- 23

Chapter 1

lithium exchange using t-BuLi at -95 °C in THF and quenching with Bu3SnCl to afford stannane 1.111 in 85 % yield. Transmetalation from stannane 1.111 proceeded cleanly under conditions reported by Pinhey and co-workers to afford aryllead triacetate 1.108 in 93 % yield. The hindered biaryl 1.112 was formed in 67 % yield by stirring aryllead triacetate 1.108 with naphthol 1.113 and pyridine in dichloromethane at room temperature, followed by treatment with H2SO4 to cleave the acetal protecting group. The ease with which the sterically hindered biaryl linkage of the 7,3’-linked alkaloids can be formed using the Pinhey-Barton methodology is a stark contrast to the harsh conditions and modest yield reported subsequently by Bringmann and co-workers using the lactone method (see Chapter 1.2.1).

Scheme 1.24: Reagents and yields a) 1,2-ethanediol, TsOH, C6H6, Dean-Stark, 99% yield; b) t-BuLi,

Bu3SnCl, THF, - 95°C to rt, 85 % yield; c) Pb(OAc)4, 10 mol % Hg(OAc)2, CH2Cl2, rt, 93 % yield; d) 1.113,

pyridine, CH2Cl2, rt, 67 % yield; e) CH3COCI, NEt3, CH2Cl2, 0 °C to rt, 97 % yield; f) POCl3, 2,4,6-

89,90 trimethylpyridine, CH3CN, reflux, 74 % yield.

Completion of the synthesis required a stereoselective preparation of amphetamine 1.114, which was achieved in 8 steps via a Katsuki-Sharpless asymmetric epoxidation to afford epoxide 1.115, followed by reduction and Mitsunobu inversion of the resulting alcohol. Finally, Bischler- Napieralski cyclisation afforded the dihydroisoquinoline moiety of ancistrocladidine (1.32), which was separated from its atropisomer by crystallisation. Overall, ancistrocladidine was prepared in 21 steps from commercially available starting materials. A convergent approach to ancistrocladidine (1.32) was proposed by Bungard, whereby the Pinhey-Barton coupling would take place between naphthol 1.113 and a dihydroisoquinoline-functionalised lead(IV) triacetate (A, Figure 1.9). However, he was unable to prepare the required lead(IV) triacetate, forcing him

Chapter 1

to abandon this approach (B, Figure 1.9). At the time, it was concluded that the isoquinoline nitrogen was coordinating to the lead reagent – a decomposition pathway that had been reported by Pinhey and co-workers – suggesting that a more deactivating protecting group was required.91

Figure 1.9: A Alternative retrosynthesis of ancistrocladidine (1.32) proposed by Bungard B Transmetallations attempted by Bungard during the total synthesis of ancistrocladidine.90

Following the successful synthesis of ancistrocladidine 1.32, attention in the group turned to the synthesis of other members of the family. In particular, the 7,3’-linked dioncophylline E (1.107) attracted attention due to its potent anti-malarial activity against both chloroquine sensitive

-1 strains of Plasmodium falciparum (NF54; IC50 22 ng mL ) as well as chloroquine resistant (KI; IC50 21 ng mL-1). Therefore, a total synthesis was initiated by Hamish Toop during the course of his PhD studies using a linear strategy similar to approach taken by Bungard. Formation of the biaryl linkage occurred early in the synthesis by reacting naphthol 1.113 and aryllead(IV) triacetate 1.116. Crucial for the success of the synthesis was Toop’s observation that the yield for the formation of aryllead 1.116 could be doubled by performing the transmetalation from boronic acid 1.117 rather than the equivalent stannane. The reduced reactivity of stannanes compared to boronic acids in the transmetalation of aryllead(IV) triacetates has been noted before in the literature,92 and perhaps contributed to the difficulties encountered by Bungard during his attempted convergent synthesis of ancistrocladidine (1.32). In the case of dioncophylline E (1.107) the overall step count for convergent and linear syntheses would be the same, therefore Toop continued with the linear strategy. Based on the reports of Davis and co-workers on the preparation of isoquinolines from chiral sulfinimines, and following investigations undertaken by Jason Brusnahan during the course of his PhD studies, annulation of biaryl 1.118 to form the isoquinoline moiety of dioncophylline E was achieved in only 3 steps, a marked improvement in step count compared to the 10 step endgame employed by Bungard.93–95 Thus, treatment of

Chapter 1

biaryl 1.118 with LDA followed by addition of sulfinime (S)-1.119 afforded sulfonamide 1.120 in 72 % as a single diastereomer. Dihydroisoquinoline 1.121 was generated in 67 % yield by treatment of sulfonamide 1.120 with DIBAL-H and stirring with aqueous 2 M HCl solution. After extensive screening, the trans-configuration of C1 and C3 methyl groups was formed selectively by addition of methyl cerium reagent in THF at -78 °C, in 61 % yield. Global deprotection with

BCl3 in the presence of hexamethylbenzene afforded dioncophylline E (1.107) in 85 % yield, and in an overall yield of 10 % over the 12 steps.

Scheme 1.25: Reagents and yields a) 10 mol % Hg(OTFA)2, Pb(OAc)4, 1,2-DCE, rt; b) 1.113, pyridine, 1,2-DCE, rt, 78% yield over two steps; c) NaH, DMF then BnBr, rt, 87% yield; d) LDA, THF, -78 °C then (S)- 1.119, THF, -78 °C, 72% yield; e) DIBAL-H, PhMe, 0 °C to rt then HCl (2 M aq.), THF, rt, 65% yield; f) MeLi,

96 CeCl3, THF, -78 °C to 0 °C, 75% yield; g) BCl3, C6HMe5, CH2Cl2, -78 °C, then TFA, CH2Cl2, 82% yield.

Using the Pinhey-Barton ortho-arylation methodology, the total syntheses of the 7,3’-linked alkaloids ancistrocladidine (1.32) and dioncophylline E (1.107) had been achieved. Attention in the group turned towards the extension of this work to the 5,3’-linked naphthylisoquinoline alkaloids which, alongside the 7,3’-linked alkaloids, display some of the most sterically hindered biaryl axes of this family of natural products.

1.5 The 5,3’-linked naphthylisoquinoline alkaloids: an alternative approach The first example of the 5,3’-linked naphthylisoquinoline alkaloids to be reported in the literature was ancistrotanzanine A (1.122, Figure 1.10), in 2003 by Bringmann and co-workers.97 In 2013, Hua and co-workers reported the isolation of the atropisomer of ancistrotanzanine A, which they named ancistrotectorine D (1.123), along with the N-methyl-tetrahydroisoquinoline analog, ancistrotectorine C (1.124), with the cis-configuration of the methyl groups at C1 and C3.98 Ancistrotanzanine A (1.122) was shown to have moderate anti-malarial activity against a

Chapter 1

-1 chloroquine resistant strain of Plasmodium falciparum (K1; IC50 0.3 µg mL ); ancistrotectorines C (1.124) and D (1.123) were not screened against the malarial parasite, but were instead shown to have mild anti-leukemic activity. All three compounds were isolated as single atropisomers.

Figure 1.10: Structures of the 5,3’-linked naphthylisoquinoline alkaloids ancistrotanzanine A (1.122),97 ancistrotectorine D (1.123)98 and ancistrotectorine C (1.124).98

As discussed in Chapter 1.4, access to the 7,3’-linked alkaloids was achieved via a linear strategy, with the formation of the biaryl bond occurring early in the sequence. Jason Brusnahan, as part of PhD studies under the supervision of Jonathan Morris, proposed applying a similar strategy to the synthesis of ancistrotanzanine A (Figure 1.11). Aryllead triacetate 1.125 would undergo Pinhey-Barton arylation with naphthol 1.113 to form biaryl intermediate 1.126. Annulation to form the dihydroisoquinoline moiety present in the natural product would be accomplished using the protocol of Davis and co-workers.

Figure 1.11: Brusnahan’s retrosynthetic analysis of ancistrotanzanine A (1.122) starting from simplified aryllead triacetate 1.125.

Aryllead triacetate 1.125 was prepared in three steps via a sequence of halogenation, lithiation/stannylation and transmetalation, in an overall yield of 79 % starting from commercially available tolyl nitrile 1.127 (Scheme 1.26). Arylation of naphthol 1.113 proceeded smoothly to give biaryl 1.126 in 77 % yield, which was then protected to afford the MOM ether 1.128. Following the protocol established by Davis and co-workers, ether 1.128 was treated with LDA followed by addition of enantiopure sulfinimine (R)-1.119; however, no reaction was

Chapter 1

observed. It was reasoned that the steric bulk of the naphthol was impeding lithiation of the methyl group ortho to the nitrile; if this was the case, then treatment with a less bulky base might be productive. The reaction was repeated therefore with LiNEt2 in place of LDA and this was successful in generating sulfonamide 1.129 in 75 % yield. Disappointingly however, the diastereoselectivity of the reaction – which had previously been observed at >97:3 – had dropped to a ratio of 85:15.

Scheme 1.26: Reagents and yields a) I2, Ag2SO4, EtOH, 0°C to rt, 81 % yield; b) t-BuLi, Bu3SnCl, THF, -95°C

to rt, 75% yield; c) Pb(OAc)4, Hg(OTFA)2, CH2Cl2, rt, 81 % yield; d) 1.113, py, CH2Cl2, rt, 77 % yield; e) NaH,

MOMCl, DMF, rt, 91 % yield; f) LiNEt2, THF, -78°C, then (R)-1.119, THF, -78°C, 75 % yield (dr (C3) = 85:15/M:P = 1:1). 95

Subsequent work carried out by Hamish Toop was able to demonstrate a clear relationship between the size of the substituent X and the diastereoselectivity of the alkylation (Figure 1.12).99 While no substituent (X = H) resulted in a dr of >97:3 – matching that reported by Davis and co-workers – with increasing steric bulk (H < I < Ph < Naphthol 1.113) the diastereoselectivity of the reaction was observed to decrease, along with the yield.

Chapter 1

Entry X = Base dra Yield (%) 1 H LDA >97:3 86 2 I LDA 93:7 56 3 Ph LDA 76:24 35 4 Naphthol 1.113 LDA na 0

5 Naphthol 1.113 LiNEt2 85:15 75

Figure 1.12: Changing the size of the substituent at C5 effects the diastereoselectivity of the sulfinimine alkylation. Reagents and yields a) Base, THF, -78°C, then (R)-119, THF, -78°C, see table for yield. aDetermined from 1H NMR spectrum of the crude reaction mixture by integration of the resonance corresponding to the C3 methyl group.

Despite this setback, annulation of sulfonamide 1.129 was achieved upon treatment with MeLi followed by 2 M aqueous HCl solution in 77 % yield, completing the synthesis of ancistrotanzanine A (1.122) in only 8 steps, albeit as an inseparable mixture of atropodiastereoisomers (Scheme 1.27).

Scheme 1.27: Reagents and yields a) MeLi, THF, -78°C to rt, then 2 M aq. HCl, 77 % yield (dr (C3) = 85:15/M:P = 1:1).95

Brusnahan was able to demonstrate that the Pinhey-Barton arylation, in sequence with Davis’ sulfinimine chemistry, was a viable strategy for accessing the 5,3’-linked naphthylisoquinoline alkaloids. However, generating the C3 methyl-bearing stereocentre with high stereoselectivity was clearly a challenge using that approach. Given that the diastereoselectivity of the reaction was excellent in less hindered systems, Hamish Toop – during his PhD studies – undertook a 29

Chapter 1

reversed sequence, using Davis’ chemistry to prepare an enantiopure isoquinoline which would be used to prepare the isoquinoline-substituted lead triacetate 1.130 for formation of the 5,3’- biaryl axis (Figure 1.13). Biaryl intermediate 1.131 could be elaborated to all three 5,3’-linked alkaloids in a convergent manner.

Figure 1.13: Toop’s retrosynthetic analysis starting from isoquinolinyl lead triacetate 1.130 with the stereochemistry at C3 established.

As discussed in Chapter 1.4, a similar retrosynthesis had been proposed by Bungard during the total synthesis of ancistrocladidine (1.32). However the formation of the required 7-substituted aryllead(IV) triacetate from the corresponding arylstannane had failed (A, Figure 1.14). At the time, it was concluded that the isoquinoline nitrogen was coordinating to the lead reagent – a decomposition pathway that had been reported by Pinhey and co-workers – suggesting that a more deactivating protecting group was required. Indeed, Konopelski and co-workers have reported the synthesis of the nitrogen containing aryllead triacetates 1.132 and 1.133, where the amine is deactivated with a Boc-protecting group (B, Figure 1.14).100 Additionally, from Toop’s own work it had been established that the transmetalation of boronic acids was superior to arylstannanes.101

Chapter 1

Figure 1.14: A Arylstannanes prepared by Bungard during the attempted synthesis of an isoquinoline- substituted lead(IV) triacetate;91 B Aryllead triacetates reported by Konopelski and co-workers.100

The initial focus of Toop’s work therefore was on the preparation of boronic acid 1.134 (Scheme 1.28). This was accessed in 6 steps from the same commercially available tolyl nitrile 1.127 used by Brusnahan. As expected, lateral lithiation with LDA followed by addition of sulfinimine (R)- 1.119 proceeded smoothly and with >97:3 diastereoselectivity. Treatment with MeLi followed by stirring with HCl afforded dihydroisoquinoline 1.135. Reduction with NaBH4 afforded the cis- configured 1,3-dimethyltetrahydroisoquinoline, which was protected using the Boc-protecting group to afford 1.136. Regioselective halogenation was followed by halogen-lithium exchange at low temperature in the presence of B(O-iPr)3 to give the boronic acid 1.134 required for the transmetalation.

Scheme 1.28: Reagents and yields a) LDA, THF, -78°C, then (R)-1.119, THF, -78°C, 63 % yield; b) MeLi,

THF, -78°C to rt, then 2 M aq. HCl, 62 % yield; c) NaBH4, MeOH, -10°C to rt; d) Boc2O, NEt3, CH2Cl2, 98 %

yield over steps; e) I2, Ag2SO4, EtOH, 0°Cto rt, 70% yield; f) t-BuLi, B(Oi-Pr)3, THF, -95°C to 0°C, 90 % yield.

Subjecting boronic acid 1.134 to the standard transmetalation conditions reported by Pinhey pleasingly resulted in conversion to the isoquinolinyl lead triacetate 1.137 (Scheme 1.29), as evidenced by the presence of 207Pb coupling in the 1H NMR spectrum. Finally, stirring this material with naphthol 1.113 in the presence of pyridine resulted in the isolation of the Boc- protected biaryl 1.138 as a 1:1 mixture of atropisomers. Unfortunately, following Boc- deprotection attempts to oxidize the material to the 3,4-dihydroisoquinoline present in

Chapter 1

ancistrotanzanine A (1.122) and ancistrotectorine D (1.123) led to decomposition, which was attributed to over-oxidation of both the isoquinoline and naphthol moieties.

Scheme 1.29: Reagents and yields a) Hg(OTFA)2, Pb(OAc)4, CH2Cl2, rt; (b) 1.113, pyridine, 1,2-DCE, rt, 50 % yield over two steps.

From Toop’s efforts, it can be seen that generating an intact isoquinolinyl lead triacetate allows ready access to the core of the 5,3’-linked naphthylisoquinoline alkaloids in a convergent manner and overcomes the issues previously encountered by Brusnahan in establishing the stereochemistry of the C3 methyl substituent. In order to complete the synthesis, access to the M- and P-configured atropisomers separately is required, as well as a procedure for the selective oxidation of the tetrahydroisoquinoline to the 3,4-dihydroisoquinoline motif of ancistrotanzanine A (1.122) and ancistrotectorine D (1.123), which will form the initial focus of this PhD.

The successful completion of a convergent ortho-arylation strategy for accessing the 5,3’-linked alkaloids opens up several avenues for investigation. In particular, key research questions include: whether this strategy can be extended to other naphthylisoquinoline alkaloids, such as the 7,3’-linked members of the family ancistrocladidine (1.32) and ancistrotectorine (1.33), which have previously been prepared via linear strategies; and can the ortho-arylation using stoichiometric lead be achieved using an alternative metal, without the associated toxicity.

Chapter 2

Chapter 2: Total Synthesis of the 5,3’-linked Naphthylisoquinoline Alkaloids

Chapter 2

2.1 Work described in Chapter 2 As discussed in Chapter 1.5, the late-stage biaryl coupling strategy developed by Toop was successful in accessing the core of the 5,3’-linked naphthylisoquinoline alkaloids. However, isolation of this material as a mixture of both atropisomers precluded its elaboration to the individual natural products and was further stymied by the difficult oxidation of the C1-N bond to form the 3,4-dihydroisoquinoline motif of ancistrotanzanine A (1.122) and ancistrotectorine D (1.123). Therefore, the initial aim of this project was to identify conditions for the formation of the dihydroisoquinoline motif of the 5,3’-linked natural products, using the tetrahydroisoquinoline moiety 2.1 as a model system (Figure 2.1). In addition to this, the isolation of the individual M- and P-configured atropisomers 2.3 and 2.4 – either by separation or through an atropselective coupling – would be investigated, being a key requirement of the directed synthesis of all three natural products.

Figure 2.1: A method for the formation of dihydroisoquinoline 2.1 from tetrahydroisoquinoline 2.2 and a strategy for separating the M- and P-configured atropisomers is required for the completion of the synthesis of the 5,3’-linked naphthylisoquinoline alkaloids.

2.2 Oxidation of 1,2,3,4-tetrahydroisoquinolines Given their prevalence in natural products and pharmaceuticals, a number of procedures have been reported for the formation of 3,4-dihydroisoquinolines (2.5) from the corresponding 1,2,3,4-tetrahydroisoquinolines (2.6).102–109 As shown in Figure 2.2, the use of strong oxidants including KMnO4, MnO2, IBX, PCC, V2O5, (KSO3)2NO and NaIO4 have all been demonstrated to

Chapter 2

selectively form the 3,4-dihydroisoquinoline motif, avoiding over-oxidation to form the fully aromatic isoquinoline 2.7. An alternative mechanism for the formation of dihydroisoquinoline 2.5 involves the base-induced elimination of a leaving group, which has been reported using halides as well as the toluenesulfonyl (Ts) group.110–112

Figure 2.2: Oxidation and elimination methods for the preparation of 3,4-dihydroisoquinoline 2.5 from tetrahydroisoquinoline 2.6.

The structure of the 1,2,3,4-tetrahydroisoquinoline moiety that is common to the Ancistrocladaceae naphthylisoquinoline alkaloids is shown in Scheme 2.1 A, with methyl substituents at both the C1 and C3 positions as well as methyl ethers at one (2.8 and 2.9) or both (2.10) of the C6 and C8 positions. These substituents have a marked impact on the reactivity of the tetrahydroisoquinoline; a report by Bringmann and co-workers has shown that the behaviour of this moiety is remarkably divergent, depending both on the stereochemical relationship between the C1 and C3 methyl groups (cis- vs. trans-configured) as well as the status of the C6 and C8 oxygens (free alcohol vs. methyl ether). Thus, trans-configured substrates (not shown) are completely stable in air. However, the cis-configured substrates with only one methoxy substituent at either C6 or C8 (2.8 and 2.9) cleanly oxidise on standing to give the corresponding 3,4-dihydroisoquinolines 2.11 and 2.12. In contrast, the equivalent dimethoxyisoquinoline 2.10 oxidises in air to give a mixture of both the 3,4-dihydroisoquinoline 2.13 along with the C1 epimer 2.14; the mechanism for how this occurs is not clear.113 In their synthesis of the 7,3-linked ancistrocladidine (1.32, Scheme 2.1 B, carried out concurrently with the work in this PhD) Bringmann and co-workers were able to bypass this reactivity by performing the oxidation with KMnO4 in THF under an inert atmosphere, following a procedure first reported by Misztal and co-workers in 1985.30,114 Interestingly, as mentioned in the Chapter

1.5, when Toop treated the 5,3’-linked system with KMnO4 he observed competing oxidation of the naphthol moiety, although his choice of conditions was slightly modified from that reported by Misztal or Bringmann, having chosen to use a mixed solvent system comprising of THF and 35

Chapter 2

H2O. Regardless, this result prompted us to first examine conditions that did not require strong oxidants such as KMnO4; specifically, the base-induced Ts-elimination chemistry mentioned earlier.

Scheme 2.1: A Differential reactivity of cis-1,3-dimethyltetrahydroisoquinolines; B Reagents and yields

30 a) KMnO4, THF, rt, 65 % yield.

2.2.1 Investigations on a model system into the elimination of a Ts-protecting group In order to study the base-induced elimination, we required cis-1,3-dimethyl-,1,2,3,4- tetrahydroisoquinoline 2.15 (Scheme 2.2), which we could access based on the work of Davis and co-workers, as well as the protocols established by Brusnahan and Toop.94,95,101 Thus, starting from commercially available tolylnitrile 1.127, treatment with LDA followed by addition of Ellman’s auxiliary (R)-1.119 afforded sulfonamide 2.16 as a single diastereomer in 77 % yield, as evidenced by the presence of signals at 1.10 ppm (singlet, 9H) and 1.38 ppm (doublet, 3H) in the 1H NMR spectrum, corresponding to the t-butyl and methyl groups of the chiral auxiliary. Treatment of sulfonamide 2.16 with MeLi in THF followed by stirring with dilute HCl solution effected the cyclisation to form the 3,4-dihydroisoquinoline 1.135 in 62 % yield. Stereoselective reduction of the imine was achieved according to the protocol of Bringmann and co-workers using NaBH4 in MeOH, and the resulting tetrahydroisoquinoline was immediately protected as the N-Ts compound using toluenesulfonyl chloride and NEt3 in dichloromethane to afford tetrahydroisoquinoline 2.15 in 81 % yield over the two steps.

Chapter 2

Scheme 2.2: Reagents and yields a) LDA, THF, -78°C, then (R)-1.119, THF, -78°C, 77 % yield; b) MeLi, THF,

-78°C to rt, then 2 M aq. HCl, 62 % yield; c) NaBH4, MeOH, -10°C to rt; d) TsCl, NEt3, CH2Cl2, 81 % yield over two steps.

With tetrahydroisoquinoline 2.15 in hand, our attention turned towards investigating the elimination of the tosyl-protecting group in the presence of base. Gao and co-workers have reported the elimination of the Ts-group from 1,2,3,4-tetrahydroisoquinoline 2.17 in the presence of LDA at -78 °C (Scheme 2.3).111 Therefore, as a starting point for our investigations we decided to apply these conditions to our substrate.

Scheme 2.3: Reagents and yields a) LDA, THF, -78 °C, 10 min, 95 %.111

Disappointingly, subjecting tetrahydroisoquinoline 2.15 to these conditions afforded only starting material (Figure 2.3). Increasing the reaction time or raising the temperature (Entries 2 and 3) likewise gave no reaction. As the elimination reaction depends on the initial abstraction of the hydrogen at C1, we reasoned that steric crowding from the geminal methyl group, as well as the neighbouring Ts- and methoxy-groups could be hindering the reaction. We therefore repeated the reaction with the less sterically hindered base n-BuLi, but with no change in outcome. Screening a number of other bases, such as the phosphazine base P2-tBu, were also unsuccessful in effecting the conversion. Finally, dihydroisoquinoline 1.135 was isolated in 32 % yield following addition of tetrahydroisoquinoline 2.15 to a freshly prepared solution of dimsyl sodium in DMSO.

Chapter 2

Entry Conditions Conversion to 1.135 (%) 1 LDA, THF, -78 °C 0 2 LDA, THF, -78 °C, 4 h 0 3 LDA, THF, 0 °C 0 4 n-BuLi, THF, -78 °C 0 5 P2-tBu, THF, -78 °C 0 6 Dimsyl sodium, DMSO, rt 32 Figure 2.3: A table listing conditions screened for base-induced elimination of the tosyl-protecting group.

2.2.2 Investigations on a model system into the direct oxidation Concurrent with our work on the base-induced elimination of the Ts-group was our investigation into conditions for the direct oxidation of the unprotected tetrahydroisoquinoline 2.10 (Figure 2.4). A literature search of oxidants for this transformation revealed significant overlap with the corresponding oxidation of naphthol to naphthoquinone, limiting the choice of reagents. The first conditions we explored therefore simply involved stirring tetrahydroisoquinoline 2.10 in DMF under an atmosphere of oxygen, which afforded 3,4-dihydroisoquinoline 1.135 in 35 % yield (Entry 1). A slightly lower yield was obtained using 1,10-phenanthroline-5,6-dione (“phd”), which was reported by Wendlandt and Stahl as a chemoselective oxidising agent for secondary amines (Entry 2).115 However, a significantly higher yield was obtained when using the conditions reported by Misztal and Cegla, and subsequently used by Bringmann and co-workers, in which solid KMnO4 is added portion-wise to a dilute solution (0.05 M) of 2.10 in THF under an inert atmosphere (Entry 3).

Entry Conditions Yield of 1.135 1 O2(g), DMF, 100 °C, 15 h 35 2 phd, MeCN, rt 24 3 KMnO4, THF (0.05 M) 83 Figure 2.4: A table listing conditions screened for oxidation of isoquinoline 2.10

Chapter 2

As mentioned earlier, the aqueous conditions used by Toop for the preparation of ancistrotanzanine A (1.122) did not afford the desired 3,4-dihydroisoquinoline, but rather a mixture of byproducts. However, of the two pathways explored using our model system for accessing the dihydroisoquinoline motif, oxidation with KMnO4 (under an inert atmosphere) afforded the highest yield of oxidised product 1.135. Therefore, in addition to examining the Ts- elimination conditions using dimsyl sodium, we decided it would be worthwhile re-examining the oxidation with KMnO4 of the biaryl core of the natural products.

2.3 Pinhey-Barton coupling As discussed in Chapter 1.5, previous work in the group performed by Toop had shown that, using the Boc-protected tetrahydroisoquinoline boronic acid 1.134, it was possible to prepare and couple the corresponding isoquinolinyllead(IV) triacetate 1.137 (Scheme 2.4). The role of the Boc-protecting group is twofold: firstly, it prevents epimerization of the stereocenter at C1 that has been observed for the unprotected tetrahydroisoquinolines (see Chapter 2.2); additionally, it reduces the nucleophilicity of the tetrahydroisoquinoline nitrogen and prevents coordination to the electrophilic lead(IV) atom during the transmetalation reaction, which leads to decomposition of the substrate. We reasoned that the Ts-protecting group would be able to serve a similar function and so we continued the synthesis with the Ts-protected tetrahydroisoquinoline 2.15 we had previously prepared.

Scheme 2.4: Reagents and yields a) Hg(OTFA)2, Pb(OAc)4, CH2Cl2, rt; (b) 1.113, py, 1,2-DCE, rt, 50 % yield over two steps.101

Regioselective halogenation of Ts-tetrahydroisoquinoline 2.15 was performed following a procedure reported by Sy using a mixture I2 and Ag2SO4 in EtOH to afford the 5-iodinated 2.19 as the exclusive product in 87 % yield (Scheme 2.5).116,117 Formation of the product was confirmed by the presence of a singlet at 6.15 ppm in the 1H NMR spectrum, integrating for one proton, along with analysis using mass spectrometry, which identified the correct exact mass. Boronic acid 2.20 was prepared by adding t-BuLi dropwise to a solution of iodide 2.19 and freshly 39

Chapter 2

distilled B(O-iPr)3 in THF at -95 °C. After stirring with saturated aqueous ammonium chloride solution and purification by flash column chromatography, boronic acid 2.20 was isolated in 83 % yield. Evidence for the successful formation of the boronic acid included the appearance of a downfield-shifted singlet in the 1H NMR spectrum at 6.26 ppm, along with a broad stretching mode in the infrared spectrum at 3437 cm-1. With boronic acid 2.20 in hand, transmetalation to form isoquinolinyllead(IV) triacetate 2.21 was performed by stirring with Pb(OAc)4 and catalytic

1 Hg(OTFA)2 for 15 h. Analysis of the H NMR spectrum of the crude material showed a mixture of the desired aryllead(IV) triacetate 2.21 (as evidenced by the characteristic 207Pb-satellites either side of the aromatic singlet at 6.59 ppm) and a small amount of demetallated isoquinoline 2.15. Purification of the mixture was attempted, though this led only to decomposition of the product to form the demetallated isoquinoline.

Scheme 2.5: Reagents and yields a) I2, Ag2SO4, EtOH, 0 °C to rt, 15 h, 87% yield; b) t-BuLi, B(Oi-Pr)3, THF, -

95°C to 0 °C, 1 h, 83 % yield; c) Hg(OTFA)2, Pb(OAc)4, CH2Cl2, rt, 15 h.

Therefore, the crude mixture was dissolved in 1,2-dichloroethane and stirred with naphthol 1.113 and excess pyridine (Scheme 2.6). Following workup, 1H NMR spectroscopic analysis of the crude material indicated the presence of two new singlets at 9.29 and 9.38 ppm, suggesting the formation of two products – presumed to be atropisomers formed as a result of the arylation – alongside a small amount of unreacted naphthol 1.113 and demetallated isoquinoline 2.15. Pleasingly, the two products could be separated by flash column chromatography. While this is perhaps not a surprising result, given that the two biaryls are diastereomers, difficulties separating atropisomeric mixtures of other naphthylisoquinoline alkaloids have been reported, with the mixtures often displaying similar retention times using HPLC.32,33,91,118 Separation of the M- and P-configured atropisomers allowed for their characterization; a comparison of a section of their 1H NMR spectra is shown in Figure 2.5, highlighting the significant differences in the shifts corresponding to the naphthol hydroxyl group and the C7-H and C1-H (highlighted). As we could not assign the axial chirality of each compound, the major product of the reaction was designated as biaryl 2.22 (top, Figure 2.5) and the minor as 2.23 (bottom, Figure 2.5).

Chapter 2

Scheme 2.6: Reagents and yields a) pyridine, 1,2-DCE, rt, 55 % yield over 2 steps (ratio = 58:42).

Figure 2.5: An overlay of sections of the 1H NMR spectra of the separated biaryls 2.22 (major atropisomer, top) and 2.23 (minor atropisomer, bottom).

2.4 Total syntheses of ancistrotectorine D and ancistrotanzanine A In order to complete the total synthesis of ancistrotanzanine A (1.122) and ancistrotectorine D (1.123), we would need to oxidise the tetrahydroisoquinoline moiety of the biaryls 2.22 and 2.23 to afford the 3,4-dihydroisoquinoline motif of the natural products. As discussed in Chapter 2.2, two protocols had been investigated for this transformation: a base-induced elimination of a Ts- group and a direct oxidation of unprotected tetrahydroisoquinoline motif (Figure 2.6).

Chapter 2

Figure 2.6: Formation of the dihydroisoquinoline-configured ancistrotanzanine A (1.122) and ancistrotectorine D (1.123) could be achieved via direct oxidation (X = H) or base-induced elimination (X = Ts).

With access to pure material of each atropisomer, we focussed our attention on the base- induced elimination of the Ts-protecting group, being the more direct route to the natural products. Thus, a solution of biaryl 2.23 was added to a solution of freshly prepared dimsyl sodium at room temperature (Scheme 2.7). The reaction was monitored by TLC, and upon consumption of the starting material and workup of the reaction mixture, we isolated only a complex mixture of products, with no recognisable peaks corresponding to either the structure of the starting material or the product. Specifically, evidence for the formation of the 3,4- dihydroisoquinoline product, which would be indicated by the absence of the quartet at 5.18 ppm (see Figure 2.5), corresponding to the proton at C1, along with the downfield shift of the methyl resonance at C1, was not observed. Considering the reaction conditions, it is possible the unprotected naphthalene hydroxyl group is incompatible with the strongly basic dimsyl sodium.

Scheme 2.7: Reagents and yields a) Dimsyl sodium, DMSO, rt.

While this was a disappointing result, our experiments on the model system had identified that the oxidation with KMnO4 afforded a significantly higher yield of the dihydroisoquinoline 1.135. In order to apply these conditions to the biaryl material, we would first need to cleave the Ts- protecting group. Using conditions similar to those reported reported by Lipshutz and Overman, a solution of biaryl 2.23 in THF at 0 °C was treated with LiAlH4 and allowed to warm to room 42

Chapter 2

temperature over 15 h (Scheme 2.8).37,119 Analysis of the 1H NMR spectrum of the crude reaction mixture indicated the absence of the characteristic doublets at 7.04 ppm and 7.53 ppm, corresponding to the aromatic protons on the para-substituted Ts-protecting group. As discussed in Chapter 2.2, cis-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines have been shown to be unstable, and we assumed that this would also be the case with the naphthyl-substituted

2.24. Therefore, the crude material was immediately dissolved in THF and solid KMnO4 was added portionwise over a period of 3 h, at which point TLC indicated complete consumption of the starting material. Examining the 1H NMR spectrum of the crude reaction mixture revealed that a complex mixture had formed. While it was possible to identify resonances corresponding to the dihydroisoquinoline product, it was clear that multiple products had formed as a result of the reaction. In particular, multiple resonances were visible in the region downfield of 9 ppm, which lead us to speculate that the naphthol moiety was participating in the reaction. We therefore decided to protect this functional group and repeat the oxidation conditions.

Scheme 2.8: Reagents and yields a) LiAlH4, THF, 0 °C to rt, 16 h; b) KMnO4, THF, rt, 3 h.

We chose to use the MOM-protecting group, as it would be stable to the deprotection conditions required for the cleavage of the Ts-group but is readily cleaved using only dilute aqueous acid. Protection of biaryl 2.23 was achieved by stirring with NaH in THF, followed by addition of MOM-Cl to afford the MOM-ether 2.25 in 92 % yield, as evidenced by the absence of a broad stretching frequency above 3000 cm-1 in the infrared spectrum, as well as the absence in the 1H NMR spectrum of the singlet at 9.29 ppm corresponding to the hydroxyl group (Scheme 2.9). Additionally, two sharp doublets were observed at 4.63 ppm and 4.70 ppm, integrating for

1H each, and a singlet at 2.53 ppm, integrating for 3H, which we assigned as the -CH2 and -CH3 protons of the MOM-protecting group respectively. A crystal suitable for single crystal X-ray diffraction was obtained by slow evaporation of a solution of compound in ethyl acetate and n-

Chapter 2

hexanes, providing confirmation of the compounds structure.1 The compound crystallised in the orthorhombic space group P212121, which is chiral. As well as allowing us to confirm the absolute stereochemistry at the C1 and C3 positions, we were also able to assign the P-configuration around the biaryl axis.

Scheme 2.9: Reagents and yields a) NaH, THF, rt then MOMCl, 92 % yield.

With ether 2.25 in hand, cleavage of the Ts-protecting group was effected by treating with LiAlH4

(Scheme 2.10). The deprotected tetrahydroisoquinoline was dissolved in THF and solid KMnO4 added portionwise. After 3 h, monitoring of the reaction by TLC indicated the complete consumption of the starting material, along with the appearance of a single new spot. After the crude material was isolated and purified, analysis of the 1H NMR spectrum indicated the absence of the C1 proton, along with the presence of a singlet at 2.86 ppm integrating for 3H, as would be expected for an allylic methyl. Additionally, analysis of the infrared spectrum revealed a stretching frequency at 1612 cm-1, which is indicative of the formation of an imine. Cleavage of the MOM-ether was performed in 87 % yield using dilute HCl solution. Comparing the spectroscopic data of the deprotected material with that reported by Hua and co-workers revealed several discrepancies in the 1H and 13C NMR spectra, as well as between the optical rotations. Table 2.1 lists the data reported by Hua and co-workers, along with the characterisation data obtained for the synthetic material. Multiple differences are apparent in the 1H NMR data, in particular the resonance corresponding to the naphthalene hydroxyl group (natural = 9.41 ppm, synthetic = 9.36 ppm). Differences are also apparent for a large number of the 13C NMR signals. However, comparison of the synthetic material to a sample of natural ancistrotectorine D (1.123), generously provided to us by Professor Hui-Ming Hua,

1 X-Ray diffraction data collected and solved by A/Prof Marcus Cole, School of Chemistry, UNSW Sydney. 44

Chapter 2

demonstrated complete agreement in the spectroscopic data of the two compounds. An overlay of their 1H NMR spectra is shown in Figure 2.7. Overall, the total synthesis of ancistrotectorine D (1.123) was completed in 12 steps (LLS) and 8 % yield.

Scheme 2.10: Reagents and yields a) NaH, THF, rt then MOMCl, 92 % yield; b) LiAlH4, THF, 0 °C to rt, 16

h; c) KMnO4, THF, rt, 3h, 65 % yield over two steps; d) 2 M aq. HCl, THF, rt, 87 % yield.

Figure 2.7: Overlay of the 1H NMR spectra of natural (bottom) and synthetic (top) ancistrotectorine D.

Chapter 2

Table 2.1: Spectroscopic properties of ancistrotectorine D (1.123)

Ancistrotectorine D Spectroscopic Data Natural (reported)98 Synthetic 1H NMR δ (300/600 MHz, DMSO-d6) δ (400 MHz, DMSO-d6) 1.04 (d, J = 6.5 Hz, 3H, 3-Me) 1.05 (d, J = 6.7 Hz, 3H) 1.76 (m, 1H, H4ax) 1.75 (dd, J = 15.8, 11.7 Hz, 1H) 1.92 (s, 3H, 2’-Me) 1.93 (s, 3H) 2.20 (m, 1H, H4eq) 2.18 (dd, J = 15.8, 4.7 Hz, 1H) 2.34 (s, 3H, 1-Me) 2.33 (d, J = 1.7 Hz, 3H) 3.17 (m, 1H, H3) 3.17 (m, 1H) 3.70 (s, 3H, 6-OMe) 3.71 (s, 3H) 3.92 (s, 3H, 8-OMe) 3.93 (s, 3H) 3.97 (s, 3H, 5’-OMe) 3.99 (s, 3H) 6.68 (s, 1H, H7) 6.68 (s, 1H) 6.86 (d, J = 8.0 Hz, 1H, H6’) 6.88 (dd, J = 6.4, 2.4 Hz, 1H) 7.21 (s, 1H, H1’) 7.22 (d, J = 1.0 Hz, 1H) 7.31 (d, J = 8.0 Hz, 1H, H7’) 7.30 – 7.37 (m, 2H) 7.32 (d, J = 8.0 Hz, 1H, H8’) 9.41 (s, 1H, 4’-OH) 9.36 (s, 1H). 13C NMR δ (100/151 MHz, DMSO-d6) δ (100 MHz, DMSO-d6) 20.1 116.5 20.1 116.4 21.4 118.3 21.5 118.2 27.3 120.4 27.3 118.4 31.4 125.7 31.5 120.4 50.7 126.5 50.7 126.0 55.7 135.7 55.4 135.4 55.7 137.4 55.7 137.4 55.9 141.6 56.1 139.5 94.0 151.6 94.5 150.5 103.6 156.3 103.7 155.7 106.1 158.0 111.8 157.8 112.9 159.4 112.9 159.1 161.6 161.1 IR 3370, 2957, 2920, 2841, 2359, 3365, 2933, 2893, 2837 1739, 1681, 1201, 654 + MS m/z calcd for C25H28NO4 (M+H) 406.2013 (M+H)+ = 406.2011 (HRESIMS) (M+H)+ = 406.2005 (HRESIMS) 25 25.6 α [훼]퐷 – 45.1 (MeOH; c 0.25) [훼]퐷 - 30 (MeOH; c 0.25)

Chapter 2

Following the successful preparation of the P-configured ancistrotectorine D (1.123), we turned our attention to the preparation of its atropisomer, ancistrotanzanine A (1.122). Taking the M- configured biaryl 2.22, the naphthalene -OH was protected to afford the MOM-ether 2.27 in 93

% yield (Scheme 2.11). Addition of LiAlH4 to a solution of MOM-ether 2.27 in THF at 0 °C afforded the deprotected tetrahydroisoquinoline, which was immediately re-dissolved in THF and to which KMnO4 was added portion-wise over 3 hours. Upon completion of the reaction, as indicated by TLC, the mixture was filtered and the 3,4-dihydroisoquinoline 2.28 was isolated in 55 % yield over two steps and identified based on the absence of the signal in the 1H NMR spectrum corresponding to the C1 proton, as well as the appearance of a doublet with fine splitting (J = 2.1 Hz) at 2.46 ppm, integrating for 3H. The MOM-ether was cleaved by addition of HCl, affording ancistrotanzanine A (1.122) as its HCl salt. It has already been noted by Brusnahan that the literature characterization data for ancistrotanzanine A (1.122) is of the TFA salt of the compound, not the free base as is reported.95 Therefore, in order to compare our synthetic material to reported data, the TFA salt of the synthetic material was prepared by stirring a solution of the HCl salt in THF over solid K2CO3, before adding a drop of TFA to its solution in dichloromethane. While the 1H NMR data was in good agreement with the literature, almost none of the 13C NMR data of the natural and synthetic material was in agreement.97 However, a 13C NMR spectrum of the natural material provided to us by Professor Gerhard Bringmann was in good agreement with the synthetic material, as shown in Table 2.2.120 Overall, ancistrotanzanine A (1.122) was prepared in 12 steps (LLS) and 7 % yield.

Scheme 2.11: Reagents and yields a) NaH, THF, rt then MOMCl, 93 % yield; b) LiAlH4, THF, 0 °C to rt; c)

KMnO4, THF, rt, 3h, 55 % yield over two steps; d) 2 M aq. HCl, THF, rt, 84 % yield.

Chapter 2

Table 2.2: Spectroscopic properties of ancistrotanzanine A (1.122) Ancistrotanzanine A Spectroscopic Data Natural (TFA salt)97,120 Synthetic (TFA salt) 1H NMR δ (400/600 MHz, MeOD-d4) δ (400 MHz, MeOD-d4) 1.33 (d, J = 6.8 Hz, 3H, 3-Me) 1.33 (d, J = 6.7 Hz, 3H) 2.06 (s, 3H, 2’-Me) 2.06 (s, 3H) 2.62 (m, 1H, H4) 2.61 – 2.65 (m, H) 2.81 (s, 3H, 1-Me) 2.81 (d, J = 1.2 Hz, 3H) 3.82 (m, 1H, H3) 3.75 – 3.87 (m, 1H) 3.90 (s, 3H, 6-OMe) 3.90 (s, 3H) 4.05 (s, 3H, 5’-OMe) 4.05 (s, 3H) 4.13 (s, 3H, 8-OMe) 4.13 (s, 3H) 6.81 (s, 1H, H7) 6.81 (s, 1H) 6.91 (dd, J = 6.8, 1.9 Hz, 1H, H6’) 6.91 (dd, J = 6.8, 1.8 Hz, 1H) 7.25 (s, 1H, H1’) 7.25 (s, 1H) 7.34 (t, J = 8.5 Hz, 1H, H7’) 7.34 (t, J = 8.4 Hz, 1H) 7.38 (dd, J = 7.6, 1.3 Hz, 1H, H8’) 7.37 (dd, J = 7.8, 1.3 Hz, 1H) 13C NMR δ (100/150 MHz, MeOD-d4) δ (100 MHz, MeOD-d4) 18.1 117.5 18.1 120.0 20.3 120.4 20.3 120.5 24.8 122.0 24.8 122.1 30.8 127.5 32.7 127.5 56.7 137.9 56.7 137.9 57.0 137.9 56.9 138.0 57.0 141.4 56.9 141.4 95.7 152.7 95.7 152.7 104.9 157.5 105.0 157.5 109.0 166.2 109.0 166.2 112.1 168.2 114.5 168.2 114.5 175.8 117.5 175.8

IR 3371, 2957, 2924, 2853, 2359, 2335, 3364, 2933, 2920, 2836 1739, 1681, 1201, 1088, 654 + MS m/z calcd for C25H28NO4 (M+H) 406.2013 (M+H)+ = 406 (ESIMS) (M+H)+ = 406.2008 (HRESIMS)

25 24.1 α [훼]퐷 + 69.5 (EtOH; c 0.10) [훼]퐷 + 40 (EtOH; c 0.10)

Chapter 2

2.5 Total synthesis of ancistrotectorine C and atrop-ancistrotectorine C Following the completion of the synthesis of the two 3,4-dihydroisoquinoline-bearing 5,3-linked naphthylisoquinoline alkaloids our attention turned to the remaining member of the family, ancistrotectorine C (1.124). Its isolation was reported in 2013 by Hua and co-workers – alongside ancistrotectorine D (1.123) – and its structure determined to be the N-methyl substituted configured 1,2,3,4-tetrahydroisoquinoline with a cis-relationship between the C1 and C3 methyl groups and M-configuration around its biaryl axis. No mention is made of its anti-malarial activity, but it was reported to display weak activity against human leukemia cells lines.

We proposed accessing ancistrotectorine C (1.124) from biaryl 2.22 via reductive amination of the unprotected isoquinoline nitrogen. Therefore, the tosyl-protecting group was cleaved by addition of LiAlH4 to a solution of biaryl 2.22 in THF at 0 °C, before warming to room temperature over 15 h (Scheme 2.12). The progress of the reaction was followed by TLC and upon consumption of the starting material the reaction was quenched by the addition of Rochelle’s salt. The removal of the protecting group was confirmed by the absence of the characteristic

1 singlet at 2.27 ppm in the H NMR spectrum, corresponding to the tosyl-CH3, along with the doublets at 6.99 ppm and 7.48 ppm. The lability of this compound meant that further characterization was not performed. Rather, reductive amination was performed by dissolving the deprotected material in MeOH and stirring with formaldehyde, followed by the addition of

NaBH4. Evidence for the formation of the N-Me compound was provided following analysis of the 1H NMR spectrum, which indicated the presence of an additional singlet at 2.32 ppm, integrating for 3 protons. Mass spectrometry confirmed the presence of a compound with the expected mass of 422.2318 m/z (calc. 422.2326 m/z for C26H32NO4). As with ancistrotectorine D (1.134, Chapter 2.4), a comparison of the 1H NMR data of the natural and synthetic material identified different chemical shifts for the resonance corresponding to the naphthalene hydroxyl group (natural = 9.40 ppm, synthetic = 9.35 ppm); large differences (> 3 ppm) are also apparent in the 13C NMR data.98 Following correspondence with Professor Hui-Ming Hua, copies of the original 1H and 13C spectra of the natural material were provided, with the values aligning closely with the synthetic material. An overlay of the 1H NMR spectra is shown in Figure 2.8, while Table 2.3 lists the updated spectroscopic data for the natural ancistrotectorine C (1.124), alongside the synthetic material (asterisked values have been taken from the original spectra). Ancistrotectorine C (1.124) was isolated in 54 % yield over two steps from biaryl 2.22, and in 8 % overall yield and 10 steps (LLS) from commercially available tolyl nitrile 1.127.

Chapter 2

Scheme 2.12: Reagents and yields a) LiAlH4, THF, 0 °C; b) CH2O, MeOH then NaBH4, 54 % yield over two steps.

Figure 2.8: Overlay of the 1H NMR spectra of natural (top) and synthetic (bottom) ancistrotectorine C (1.124).

Chapter 2

Table 2.3: Spectroscopic properties of ancistrotectorine C (1.124)

Ancistrotectorine C Spectroscopic Data Natural98,121 Synthetic 1H NMR δ (300/600 MHz, DMSO-d6) δ 400 MHz, DMSO-d6 0.93 (d, J = 6.5 Hz, 3H, 3-Me) 0.93 (d, J = 5.1 Hz, 3H) 1.28 (d, J = 6.5 Hz, 3H, 1-Me) 1.28 (d, J = 6.2 Hz, 3H) 1.90 (s, 3H, 2’-Me) 1.92 (s, 3H) 1.95 (m, 1H, H4ax) 1.91 – 1.99 (m, 1H) 2.24 (m, 1H, H4eq) 2.16 – 2.26 (m, 2H) 2.26 (m, 1H, H3) 2.35 (s, 3H, N-Me) 2.32 (s, 3H) 3.62 (s, 3H, 6-OMe) 3.63 (s, 3H) 3.67 (m, 1H, H1) 3.59 – 3.67 (m, 1H) 3.85 (s, 3H, 8-OMe) 3.86 (s, 3H) 3.98 (s, 3H, 5’-OMe) 3.99 (s, 3H) 6.59 (s, 1H, H7) 6.59 (s, 1H) 6.86 (dd, J = 7.5, 1.5 Hz, 1H, H6’) 6.87 (dd, J = 6.8, 1.9 Hz, 1H) 7.20 (s, 1H, H1’) 7.21 (s, 1H) 7.30 (t, J = 7.5 Hz, 1H, H7’) 7.31 (t, J = 8.0 Hz, 1H) 7.33 (dd, J = 7.5, 1.5 Hz, 1H, H8’) 7.33 (dd, J = 7.5, 1.3 Hz, 1H) 9.34 (s, 1H, 4’-OH)* 9.35 (s, 1H) 13C NMR δ (50/150 MHz, DMSO-d6) δ (100 MHz, DMSO-d6) 20.3* 115.7* 20.3 115.6 21.6 118.0* 21.4 118.0 22.6 119.5 23.2 119.2 35.7 120.4* 35.9 119.9 41.2 121.3 41.0 120.4 54.7 125.9* 54.5 125.8 55.3* 135.3* 55.2 135.3 55.4* 135.8 55.4 135.9 56.1* 137.2* 56.1 137.2 56.3 151.1* 56.2 151.1 93.9* 155.3 93.8 155.2 103.7* 155.5* 103.6 155.5 113.0* 155.7* 113.0 155.7 IR 2964, 2929, 2820, 1585, 1570, 1475, 3383, 2962, 2835, 2771 1258, 1200, 1070 + MS m/z calcd for C26H32NO4 (M+H) 422.2326 (M+H)+ = 422.2326 (HRESIMS) (M+H)+ = 422.2318 (HRESIMS) 25 23.7 α [훼]퐷 + 45.7 (MeOH; c 0.20) [훼]퐷 + 45 (MeOH; c 0.20)

Chapter 2

The P-configured biaryl 2.23 was submitted to the same conditions described above to afford atrop-ancistrotectorine C (2.29), which has not been observed in nature at this point in time (Scheme 2.13).

Scheme 2.13: Reagents and yields a) LiAlH4, THF, 0 °C; b) CH2O, MeOH then NaBH4, 45 % yield over two steps.

2.6 Anti-malarial activity of the 5,3’-linked alkaloids As discussed in Chapter 1.1, a broad range of biological activity is displayed across the naphthylisoquinoline alkaloid family of natural products. Remarkably, more than half of the almost 200 members of this family of natural products have been reported to display anti- malarial activity.122

Of the three 5,3’-linked naphthylisoquinoline alkaloids, only ancistrotanzanine A (1.122) was tested against the malarial parasite Plasmodium falciparum, exhibiting moderate activity (IC50 = 0.7 µM against K1 strain). Ancistrotectorines C (1.124) and D (1.123) were tested for their growth inhibitory activities against human leukemia cell lines and showed poor activity.

To verify the anti-malarial activity reported by Bringmann and co-workers and to ascertain if it was shared by the other two 5,3’-linked alkaloids, synthetic samples of all three natural products, along with the non-natural atrop-ancistrotectorine C (2.29), were sent to the laboratory of Prof. Vicky Avery at the Griffith Institute for Drug Discovery (GRIDD) and were screened against 3D7 and Dd2 strains of the Plasmodium falciparum parasite.2 The compounds were tested against the asexual, ring stage of the parasites, which is responsible for the symptoms associated with malarial infection and consequently is a key target of drug discovery programs. Following incubation of solutions of parasite and compound in 384-well plates at 37

2 All biological assays performed by Dr Leonardo Lucantoni, GRIDD. 52

Chapter 2

°C/5 % CO2, fluorescence imaging of individual wells provided a percentage inhibition value. The

IC50 values were obtained from dose-response curves and are shown below (Figure 2.9).

Figure 2.9: Anti-malarial data for the 5,3’-linked naphthylisoquinoline alkaloids and atrop- ancistrotectorine C (2.29). Assays performed by Dr Leonardo Lucantoni.

Of the four compounds, ancistrotanzanine A (1.122) displays the most potent anti-malarial activity against the 3D7 strain of the parasite (3.9 µM, a chloroquine-sensitive strain of the parasite) as well as the Dd2 strain (2.6 µM, a multi-drug resistant strain). Both activities are significantly lower than that reported by Bringmann and co-workers (0.7 µM), though a direct comparison is not possible given a different strain of the parasite was used for testing (K1 strain, also multi-drug resistant). The anti-malarial activities of ancistrotectorines C (1.124) and D (1.123) were not reported at the time of their isolation by Liu and co-workers. While ancistrotectorine D (1.123) displayed only weak activity – with values falling outside the upper range of testing concentrations – the activity of ancistrotectorine C (1.124) was approximately half the potency of ancistrotanzanine A (1.122).

Overall, the 5,3’-linked naphthylisoquinoline alkaloids display moderate activity against the malarial parasite. With only four compounds tested, definitive conclusions about the SAR of the 5,3’-linked scaffold cannot be drawn, though it is worth noting the activities of the M-configured atropisomers ancistrotanzanine A (1.122) and ancistrotectorine C (1.124) are both higher than their P-configured counterparts. Additionally, similar (or better) inhibition values are observed for the multi-drug resistant strain (Dd2) as for the chloroquine sensitive strain (3D7); by way of comparison, the activity of the chloroquine control decreased 20-fold from the 3D7 to the Dd2 strains in the same round of testing, which suggests that there is no cross-resistance shared between the 5,3’-linked scaffold and the current frontline small molecule therapeutics used in the treatment of malaria. Additionally, the cytotoxicity of all four compounds is low, with 53

Chapter 2

ancistrotectorines C (1.124) and D (1.123) and atrop-ancistrotectorine C (2.29) not displaying any cytotoxicity in the tested concentration range (0.4 nM to 40 µM). Overall, while their anti- malarial activity is moderate, the lack of cross-resistance and low cytotoxicity makes the 5,3’- linked alkaloids a promising scaffold for investigation, and the convergent strategy we have developed makes the synthesis of analogs for SAR studies viable.

2.7 Atropselective biaryl coupling As discussed in Chapter 1.3.4, an asymmetric variant of the Pinhey-Barton reaction has been reported by Yamamoto and co-workers.28,80 An early report by Pinhey noted an enhancement in the rate and yield of the ortho-arylation reaction when performed in the presence of excess pyridine; the exact role of pyridine, as either a σ-donor for lead or as a base to catalyse the keto- enol tautomerization of the substrate, has not been conclusively demonstrated.75 However, by replacing pyridine with the chiral tertiary amine brucine (1.105) in the arylation of various phenols, including 2-naphthol (2.30, Scheme 2.14), Yamamoto and co-workers were able to achieve arylations with up to 77 % ee. They argue that brucine (1.105) must be acting as a ligand, since it is critical for the observed stereoinduction, though they are unable to observe any intermediates in the reaction.

Scheme 2.14: Reagents and yields a) 1.106 (2.5 eq), 4Å sieves, 1.105 (6 eq), PhMe, -40 °C, 10 h, 86 % yield.

One of the initial goals of this project was to investigate an atropselective coupling to form the core of the 5,3’-linked naphthylisoquinoline alkaloids. We therefore decided to apply Yamamoto’s conditions to the coupling of aryllead triacetate 2.21 and naphthol 1.113, using an excess of brucine (1.105) as the base (Scheme 2.15). After stirring for 16 hours, the 1H NMR spectrum of the crude reaction mixture was examined. Disappointingly, the ratio of the integration of the naphthol -OH peaks of the M- and P-atropisomers was unchanged from the ratio we observed when pyridine is used (58:42).

Chapter 2

Scheme 2.15: Reagents and yields a) 1.105, 1,2-DCE, rt, 15 h, (M:P = 58:42), yield not determined.

The reason for the apparent lack of activity of brucine in affecting the stereoselectivity of the coupling reaction is not clear. Moloney and co-workers have demonstrated that the coordination environment around lead(IV)-carboxylates in solution is labile, with ligand exchange occurring rapidly.81,123,124 Given the steric bulk of brucine (1.105), as well as the naphthol and isoquinoline moieties that would be coordinated in the lead(IV)-intermediate, we speculated that brucine was being displaced from the complex and acting only as a base in the reaction. In view of the apparent lack of effect of brucine, as well as its acute toxicity,125,126 no further studies were undertaken to investigate this and we decided not to investigate its use any further.

Rather than continue investigations into an atropselective ortho-arylation using lead, we decided to turn our attention towards an alternative metal that could be used in its place, allowing us to move away from lead reagents in our synthesis. This will be described in Chapter 3.

Chapter 3

Chapter 3: Investigations into arylbismuth coupling methodologies

Chapter 3

3.1 Introduction Chapter 2 described the total syntheses of the three 5,3’-linked naphthylisoquinoline alkaloids via a convergent ortho-arylation strategy using the Pinhey-Barton reaction. Having now established that this strategy could readily generate the naphthylisoquinoline alkaloids, it was our ambition to extend the methodology and investigate whether the use of stoichiometric lead could be replaced by an alternative metal. In Chapter 1.3, methodologies for the ortho-arylation of phenols were reviewed. In comparison to the aryllead(IV) triacetates used up to this point in the Morris group, Barton’s organobismuth(V) compounds are the most analogous in terms of their reaction mechanism and reported substrate scope, and are well-studied, making them a suitable starting point for our investigations.18,127–132 Similar to lead(IV)-complexes, ortho- arylations with organobismuth(V) compounds occur via a ligand coupling pathway.18,63,77,79 However, while mono-aryl complexes such as 3.1 (Scheme 3.1) are the most common reactive species in aryllead(IV) chemistry, arylations with bismuth(V) compounds are most frequently performed with tri-aryl substituted complexes such as 3.2. Thus, the arylation of phenol (3.3) with triphenybismuth(V) dichloride (3.2) affords biphenyl 3.4 and diphenylbismuth(III) chloride (3.5), whereby two aryl ligands do not undergo coupling. This is the case for ortho-arylation of phenols, as well as arylations of enols, 1,3-dicarbonyls and heteroatoms such as oxygen and nitrogen, and is a significant limitation to performing arylations with triarylbismuth(V) compounds.18,100 For this reason, bismuth-mediated arylations reported in the literature are commonly confined to the transfer of relatively simple arene ligands, rather than complex or late-stage synthetic intermediates.71,128,133–137

Scheme 3.1: Representative examples of a mono-substituted aryllead(IV) triacetate and a tri-substituted organobismuth(V) compound.

However, there are two main advantages to the use of organobismuth(V) compounds, with the first being that they do not engender the toxicity concerns associated with aryllead(IV) triacetates, making their use in a total synthesis preferable.138,139 Additionally, the coordination environment of organobismuth(V) compounds does not display the lability in solution that has been observed for aryllead(IV) triacetates. The potential therefore to affect the stereochemical

Chapter 3

outcome of the ligand coupling step is higher, as has been reported by several groups (see Chapter 1.3.3).71–73

3.2 Application of organobismuth(V) chemistry to the naphthylisoquinoline alkaloids Our revised retrosynthesis for accessing the core of the 5,3’-linked alkaloids is shown in Figure 3.1. Instead of an aryllead(IV) triacetate, the biaryl bond of 5,3’-linked alkaloids would be prepared by the coupling of naphthol 1.113 with isoquinoline-substituted bismuth(V) species 3.6. While the ligand efficiency of this reaction is low, as only one of the isoquinoline moieties is able to undergo arylation with naphthol 1.113, it was decided that the symmetrically substituted 3.6 provided a direct approach to the core of the natural products and therefore was a suitable focus for our initial investigations. Access to organobismuth(V) 3.6 would be achieved via oxidation of the equivalent organobismuth(III) 3.7. This would intersect with iodide 2.19, which had been previously prepared in 5 steps from commercially available starting materials (Chapter 2.2).

Figure 3.1: Revised retrosynthetic analysis of the 5,3’-linked naphthylisoquinoline alkaloid core using organobismuth(V) 3.6.

3.3 Preparation of symmetrical triarylbismuth(III) reagents In order to access isoquinoline-substituted bismuth(V) species 3.6 we first required a synthesis of bismuthine(III) 3.7. Several methods exist for the preparation of organobismuth compounds, though the most common is the reaction of BiCl3 (A) with either a Grignard reagent or organolithium species (Figure 3.2).127,128 Oxidation of the resulting organobismuth(III) compound (B) can be performed using either SO2Cl2 or XeF2 to give the corresponding

Chapter 3

triarylbismuth(V) chloride or fluoride (C); alternatively, treatment with peroxide, perborate or hypervalent iodine affords the corresponding carboxylate (D). Type C and D compounds have both have been reported to participate in the ortho-arylation of phenols.61,63,129

Figure 3.2: Overview of the synthesis of organobismuth(III) and (V) compounds.

In our review of the literature, our attention was drawn to a report from Finet and co-workers investigating the role played by ortho-substituents on the coupling of pentavalent ortho-tolyl- and mesityl-bismuthines (3.8 and 3.9, A, Figure 3.3).140 Compared to arylation of 2-naphthol

(2.30) with Ph3BiCl2 (Entry 1), they observed a decrease in the rate of reaction with ortho-tolyl derivative 3.8 (Entry 2). A further decrease in rate was observed for mesityl derivative 3.9 (Entry 3), which required heating for 10 h at 50 °C in order to react completely, eventually affording a yield of 61 % of arylated product. A subsequent reaction with 3,5-di-tert-butylphenol afforded only 24 % arylated product, compared with a yield of 87 % reported by Barton and co-workers when the comparable aryllead(IV) triacetate was used (see Chapter 1.3.4).77 In this case, Finet and co-workers argue that the decreased rates of reaction and yields observed for the reactions with ortho-substituted derivatives 3.8 and 3.9 results from differences in the overlap of the π- systems of the incoming naphthol nucleophile and the aryl ligands attached to bismuth, which is crucial in the ligand coupling step of the reaction (B, Figure 3.3). In the case of the ortho-tolyl derivative 3.8 (I), the overlap of the π-systems of the nucleophile and at least one of the aryl ligands is relatively unhindered. This is not the case for the mesityl derivative 3.9 (II), in which the overlap between all three ligands and the nucleophile is impeded.

Chapter 3

Entry Conditions Yield

1 Ph3BiCl2, TMG, THF, rt, 4.5 h 90 % 2 3.8, TMG, THF, rt, 15 h 86 % 3 3.9, TMG, THF, rt, 17 h then 50 °C, 10 h. 61 %

Figure 3.3: A a) See table for reagents and yields; B Finet and co-worker’s rationale for the decrease in reaction rate and yield observed for organobismuth(V) compounds bearing ortho-substituted ligands.140

The decreases in rate of reaction and yield observed by Finet and co-workers for sterically hindered substrates is relevant to our goals of using a triarylbismuth(V) compound to form the biaryl bond of the 5,3-linked naphthylisoquinoline alkaloids, given that both the isoquinoline and naphthalene moieties are substituted at both ortho positions of the desired biaryl bond. Before attempting to prepare triisoquinolinylbismuth(III) 3.7 we therefore decided to investigate the coupling of an unsubstituted triarylbismuth(V) compound with naphthol 1.113. This would serve two purposes, in that it would demonstrate whether triarylbismuth(V) compounds generally are able to perform an arylation reaction on the doubly-ortho-substituted naphthol 1.113 that is common to all 3’-linked naphthylisoquinoline alkaloids, and if so, to provide a benchmark for subsequent coupling reactions using the more sterically congested isoquinoline as ligand.

Therefore, starting from triphenylbismuth(III), which can be purchased commercially, treatment with (diacetoxyiodo)benzene in dichloromethane afforded triphenylbismuth(V) diacetate 3.10 in 63 % yield following recrystallisation, with all characterisation data matching that reported in the literature (Scheme 3.2).141 Upon addition of diacetate 3.10 to a solution of naphthol 1.113 and TMG in THF, biaryl 3.11 was obtained in 75 % yield. The identity of the product was confirmed by analysis using mass spectrometry, which identified a peak at 265.1223 m/z,

+ 1 (calculated for C18H16O2 (M+H) 265.1223), in addition to the presence of a multiplet in the H

Chapter 3

NMR spectrum between 7.27 and 7.40 ppm integrating for 5H, as well as the downfield shift of the resonance corresponding to the hydroxyl group at 9.54 ppm. Alternatively, the same series of reactions could be performed in one pot to give biaryl 3.11 in an improved overall yield of 70 %.

Scheme 3.2: Reagents and Yields a) PIDA, dichloromethane, rt, 18 h, 63 % yield; b) 1.113, TMG, rt, 15 h, 75 % yield; c) (Diacetoxyiodo)benzene, dichloromethane, rt, 18 h then 1.113, TMG, rt, 22 h, 70 % yield.

Having established that naphthol 1.113 could undergo arylation with an unsubstituted organobismuth(V) compound, our attention turned to preparing the more complex isoquinoline-substituted bismuthine 3.7 required to access the 5,3’-linked scaffold (Figure 3.4).

We proposed preparing this compound from the reaction of BiCl3 with an in situ generated lithio- species, which could be prepared via halogen-lithium exchange. In Chapter 2.3, we performed halogen-lithium exchange on iodide 2.19 in order to prepare the equivalent boronic acid. To achieve this, the reaction was performed under Barbier conditions; that is, t-BuLi was added at low temperature to a solution containing both iodide 2.19 and the electrophile B(O-iPr)3. Performing halogen-lithium exchange prior to the addition of the electrophile led only to the isolation of the dehalogenated product 2.15, presumably via a protodemetallation pathway. Therefore, for our initial experiment we decided to use Barbier-type conditions for the preparation of organobismuth(III) compound 3.7. To do this, a solution of iodide 2.19 and BiCl3 in THF was cooled to -95 °C and treated with t-BuLi, before being allowed to warm to 0 °C and quenched. Disappointingly, analysis of the 1H NMR spectrum of the crude mixture indicated that the dehalogenated isoquinoline 2.15 was the only compound present in the sample, with no evidence of any other product (Entry 1). Our prior experience with the lithio-species prepared from iodide 2.19 indicated that it was highly reactive, even at low temperatures. In contrast to this, the formation of triarylbismuth(III) compounds in the literature is often performed at refluxing temperature in THF, conditions which are clearly incompatible with the low temperature required for halogen-lithium exchange of iodide 2.19.18,132,142 Therefore, we decided to investigate the other main synthetic route for preparing triarylbismuth compounds,

Chapter 3

which is via the addition of a Grignard reagent into BiCl3. Knochel and co-workers have reported extensively on the use of iPrMgBr for the preparation of functionalized organomagnesium reagents from their corresponding halides.143,144 Employing Knochel’s conditions and treating iodide 2.19 with iPrMgBr at -40 °C and monitoring via TLC was observed to give no reaction. Allowing the solution to stir at 0 °C for 4 h gave a similar result, as confirmed by analysis of the 1H NMR spectrum of the crude mixture (Entry 2). The rate of exchange of electron rich aryl halides is known to be slower than for electron poor susbtrates. Therefore, addition of iPrMgBr was carried out at 0 °C following by stirring for 16 h at ambient temperature, with TLC analysis indicating complete consumption of starting material. A solution of BiCl3 in THF was added, followed by heating at reflux for 3 h as per literature conditions (Entry 3).145 Disappointingly, analysis of the 1H NMR spectrum of the crude reaction mixture indicated the presence of only dehalogenated 2.15. Attempts at preparing the Grignard reagent from magnesium turnings were also unsuccessful. It is possible that the stability of the organometallic intermediate was too low for it to act efficiently as a nucleophile in the reaction with BiCl3.

Entry Conditions Isolated material 1 t-BuLi (2.1 eq), BiCl3, THF, -95 °C to 0 °C, 1 h 2.15 2 i-PrMgBr, THF, -40 °C to 0 °C, 4 h 2.19 3 i-PrMgBr, THF, 0 °C to rt °C, 16 h then BiCl3, THF, 2.15 66 °C, 3 h Figure 3.4: Table of conditions examined for the preparation of triisoquinolinylbismuthine 3.7. See table for reagents and yields.

Our efforts to generate the triisoquinolinylbismuthine 3.7 directly from BiCl3 and iodide 2.19 were unsuccessful, so our attention turned to alternative methods for the preparation of organobismuth(III) compounds, in particular unsymmetrically substituted compounds which would allow us to introduce the isoquinoline moiety at a later stage in the synthesis.

3.4 Preparation of unsymmetrical organobismuth compounds As mentioned in Chapter 3.2, a significant drawback in the use of symmetrically substituted organobismuth compounds for the ortho-arylation of phenols is the poor ligand efficiency of the aryl transfer, with two out of the three aryl ligands not undergoing arylation. Unsymmetrically substituted organobismuth compounds do not suffer from the same problem. Instead, the 62

Chapter 3

challenge of performing arylations with unsymmetrical organobismuth compounds is ensuring the desired ligand transfers onto the phenol substrate. Barton and co-workers have demonstrated that it is possible to selectively transfer aryl ligands on unsymmetrical

146 triarylbismuth(V) compounds, by considering the electron density of the CAr-Bi bond. As shown in Scheme 3.3, the reaction of carbonate 3.12 with 2-naphthol (1.72) gave a mixture of the p-tolyl- and p-nitrophenyl-substituted naphthols 3.13 and 3.14 in 86 % yield and a ratio of 1:4. Repeating this reaction with other unsymmetrical bismuth(V) carbonates allowed Barton and co-workers to calculate the relative migratory aptitude of each ligand (shown in Scheme 3.3), whereby less electron rich aryl ligands are expected to undergo ligand coupling with phenol substrates in a higher proportion.146,147

Scheme 3.3: Reagents and yields a) CH2Cl2, rt, 24 h, 86 % yield (ratio shown in Scheme).

The unsymmetrical bismuth(V) compounds used by Barton and co-workers were prepared by redistribution reaction of triarylbismuth(III) compounds with BiCl3, to afford mixtures of compounds of the type ArnBiX3-n (n=0-3), which were separated and reacted further with suitable Grignard reagents to form the desired unsymmetrical triarylbismuth compounds.128,131,148 As part of their research into chiral organobismuth compounds, Hitomi Suzuki and co-workers developed an iterative dearylation-rearylation methodology for the controlled preparation of unsymmetrical triarylbismuthines.149 As shown in Scheme 3.4, triflic acid generated in situ from the mixture of TMSOTf and MeOH effects the cleavage of an aryl ligand from trianisole 3.15. Addition of one equivalent of a Grignard reagent gives the mixed triarylbismuthine 3.16. Treatment of this compound with triflic acid removes the more electron rich aryl ligand, allowing for the insertion of the final Grignard to form the completely unsymmetrically substituted triarylbismuthine 3.17.149

Chapter 3

Scheme 3.4: Reagents and Yields a) TMSOTf, HMPA, dichloromethane/MeOH (10/1), 0 °C to rt, 0.5 – 2

h, 100 %; b) 4-ClC6H4MgBr, THF, 0 °C, 1 – 2 h, 86 % yield; c) TMSOTf, HMPA, dichloromethane/MeOH

(10/1), 0 °C to rt, 0.5 – 2 h, 100 %; d) 4-MeC6H4MgBr, THF, 0 °C, 1 – 2 h, 70 % yield.

In subsequent work, Suzuki and co-workers were able to demonstrate that the addition of a fourth aryl ligand can be achieved by treating triarylbismuth(V) difluorides such as 3.18 with an arylstannane in the presence of TMSCN and either BF3·OEt2 or TMSOTf to afford tetraarylbismuthonium 3.19 (Scheme 3.5).147 The same transformation can also be achieved under comparatively mild conditions by reacting difluorides with arylboronic acids and BF3·OEt2, such as the reaction of difluoride 3.20 with p-tolylboronic acid to form bismuthonium 3.21.150,151 Furthermore, they showed that addition of bismuthonium 3.21 to a solution of sodium 2- naphtholate afforded phenylnaphthol 3.22 as the major product in 88 % yield, along with 10 % yield of 1-tolyl-2-naphthol. This product distribution is in agreement with the relative migratory aptitudes calculated by Barton and co-workers.

Scheme 3.5: Reagents and Yields a) BF3·OEt2, dichloromethane, 0 °C, 1 h then TMSCN, rt, 5 h then 4-

MeOC6H4SnBu3, 40 °C, 20 h, 60 – 71 % yield; b) 4-MeC6H4B(OH)2, BF3·OEt2, dichloromethane, rt, 2h then

146,147,151 NaBF4 (aq.), rt, 20 min, 97 % yield; c) 2-naphthol, NaH, THF, -78 °C to rt, 88 %.

The relative migratory aptitudes of aryl ligands established by Barton and co-workers takes only the para-substituent into consideration. Based on this hypothesis, incorporating the dimethoxy- 64

Chapter 3

substituted isoquinoline moiety of the 5,3’-linked naphthylisoquinoline alkaloids into a Suzuki- type bismuthonium such as 3.23 (A, Scheme 3.6) would result in the preferential transfer of the less electron-rich phenyl ligands onto the phenol substrate. However, there are significant steric factors on the isoquinoline moiety that arise from the two ortho-substituents surrounding the

CAr-Bi bond. There are no reports in the literature directly investigating the effect of sterics on bismuth aryl couplings. However, Wiegand, Olah and Yamada have independently reported an “α-effect” in the reactions of several arylheteroatomic compounds with nucleophiles. Scheme 3.6 B shows an example from the work of Wiegand and co-workers, who studied the pyrolysis of arylphenyliodonium halides such as 3.24. In most cases, the product distribution was consistent with what would be expected if a SNAr mechanism was occurring, whereby the halide nucleophile preferentially attacks the substrate best able to accommodate a developing negative charge. However, in those cases with an ortho-methyl group on the aryl ring, such as 3.24, the product distribution was reversed, with a higher proportion of the halide being transferred onto the substituted aryl ring to afford 3.25 and 3.26 as the major products. The authors conclude that the decomposition follows the pathway that gives maximum relief of the steric strain around the heteroatom.152–155 For a Suzuki-type bismuthonium such as 3.23, this would lead to preferential transfer of the tetrahydroisoquinoline moiety over the three phenyl rings.

Scheme 3.6: Reagents and Yields a) 235 °C, 5 minutes 84 % yield of 3.25.154

Emboldened by this possibility, we decided to begin by investigating the preparation and coupling of the tolyl nitrile fragment originally used by Brusnahan to form the 5,3’-linked biaryl 3.27 in 77 % yield (Scheme 3.7).95 We reasoned that the steric bulk of the two ortho-substituents of the tolyl nitrile ligand of bismuthonium 3.28 is comparable to that of the 65

Chapter 3

tetrahydroisoquinoline ring, while the presence of the electron-withdrawing nitrile functional group would partially offset the two electron-donating methoxy substituents, which according to Barton’s proposal, should make it more labile.

Scheme 3.7: Reagents and conditions a) pyridine, dichloromethane, rt, 24 h, 77 % yield.

To investigate the coupling of naphthol 1.113 and bismuthonium 3.28, we would first require triphenylbismuth(V) difluoride 3.30 and boronic acid 3.31 (Scheme 3.8). In order to prepare triphenylbismuth(V) difluoride, commercially available triphenylbismuth(III) was oxidized using

SO2Cl2 in dichloromethane in 95 % yield to afford triphenylbismuth(V) dichloride 3.32. Ligand metathesis was performed using excess KF in a mixture of ethanol and de-ionised water over 18 h to give triphenylbismuth(V) difluoride 3.30 in 75 % yield, after purification by recrystallisation from a mixture of dichloromethane and Et2O. Boronic acid 3.31 was accessible in two steps from tolyl nitrile 1.127, following regioselective iodination, and halogen-lithium exchange of the resultant iodide 3.33 and quenching with B(O-iPr)3. The identity of the product was confirmed by comparison with the 1H NMR spectrum of iodide 3.33, with a shift downfield of the aromatic C-H resonance to 6.59 ppm, while analysis of the infrared spectrum confirmed the presence of an alcohol, with broad stretching frequencies at 2222 and 3423 cm-1. The material was not stable to purification, and so the crude material was used in the next step.

Chapter 3

Scheme 3.8: Reagents and Yields a) SO2Cl2, dichloromethane, 0 °C, 4 h, 90 % yield; b) KF, EtOH/H2O (2/1), rt, 15 h, 94 % yield; c) NIS, MeCN, 0 °C to rt, 15 h, 79 % yield; d) t-BuLi, THF, -95 °C, 15 minutes

then B(O-iPr)3, -95 °C to 0 °C, 5 h; e) 3.35, BF3·OEt2, dichloromethane, 0 °C, 2h then NaBF4 (aq.), rt, 20 min, 51 % yield over two steps.

Following the procedure reported by Suzuki and co-workers for the formation of bismuthonium tetrafluoroborate salts, a mixture of fluoride 3.30 and boronic acid 3.31 were dissolved in dichloromethane and cooled to 0 °C, followed by the dropwise addition of BF3·OEt2. The resulting solution was stirred for 2 hours, after which time an aqueous solution of NaBF4 was added and the biphasic mixture stirred vigorously for 30 minutes. Following workup and purification, the successful formation of bismuthonium 3.28 in 51 % yield over two steps was confirmed by analysis of the 1H NMR spectrum, with the singlet resonance corresponding to the aryl proton shifted downfield to 6.76 ppm, along with the presence of two sets of multiplets from 7.58 to 7.81 ppm, integrating for 15H, corresponding to the three phenyl ligands. Mass

+ spectrometry was consistent with a molecular formula of C28H25NO2Bi (calculated for (M) , 616.1684 m/z, found 616.1680 m/z). A crystal suitable for analysis by single crystal X-ray diffraction was also obtained (Figure 3.5).3 The compound crystallised in the monoclinic space group I2/c. The Bi-C bonds of all four ligands are similar in length, ranging from 2.196 Å to 2.201 Å, implying that the bond strengths are also similar; no conclusions therefore were able to be drawn regarding the lability of the tolyl ligand compared with the phenyl ligands.

3 X-Ray diffraction data collected and solved by Dr. Mohan Bhadbhade, Scientific Officer, Mark Wainwright Analytical Centre, UNSW Sydney. 67

Chapter 3

Figure 3.5: Single-crystal X-ray diffraction image of tolylnitrile-substituted bismuthonium 3.28.

With bismuthonium 3.28 in hand, our attention turned to its coupling with naphthol 1.113. Following deprotonation of naphthol 1.113 with sodium hydride in THF, bismuthonium 3.28 was added to the solution of naphtholate, resulting in a bright red solution – in agreement with observations recorded by Barton and co-workers63 – which gradually decolourised over several hours (Scheme 3.9). Following purification of the reaction mixture, biaryl 3.27 was isolated in 69 % yield, with spectroscopic data matching that reported by Brusnahan. The yield for the coupling of bismuthonium 3.28 with naphthol 1.113 is only slightly lower than Brusnahan’s coupling with aryllead triacetate 3.29 (77 %), as well as our earlier coupling with triphenylbismuth(V) diacetate 3.10 to form phenylnaphthol 3.11 (75 %, see Chapter 3.3).

Scheme 3.9: Reagents and Yields a) NaH, 1.113, THF, 0°C to rt, 15 minutes then 3.28, rt, 15 h, 69 % yield.

Interestingly, there was no evidence for the formation of phenylated product 3.11 in the reaction of bismuthonium 3.28 and naphthol 1.113, which is in accordance with the observations of Wiegand and co-workers, whereby the release of steric strain around a heteroatom can dictate the distribution of products in a ligand coupling reaction.

Chapter 3

3.5 Preparation and coupling of an isoquinolinylbismuthonium salt The successful preparation of the biaryl bond of the 5,3’-linked naphthylisoquinoline alkaloids using the Suzuki-type bismuthonium 3.28 provided a clear demonstration that organobismuth(V) compounds are capable of forming sterically hindered biaryl bonds. The only report in the literature in which a tetra-substituted biaryl bond is prepared via an organobismuth(V) compound was discussed in Chapter 3.3, from the group of Finet, where they obtained a 24 % yield (or 8 %, if the yield is calculated from the quantity of mesityl ligand in the reaction).

Having established the viability of this strategy, we returned to our goal of replacing the key aryllead triacetate-mediated coupling used in our total synthesis with an organobismuth(V) arylation of the intact tetrahydroisoquinoline moiety. To this end, a solution of freshly prepared boronic acid 2.20 and triphenylbismuth(V) difluoride 3.30 in dichloromethane at 0 °C was treated with BF3·OEt2 and stirred for 2 hours (Scheme 3.10). Following workup and purification by crystallization from a mixture of dichloromethane and Et2O, a white crystalline material was isolated in 81 % yield. Analysis using mass spectrometry identified the mass expected for

+ bismuthonium 3.23 (814.2393, calculated for C38H39NO4SBi (M) 814.2398).

Scheme 3.10: Reagents and Yields a) BF3·OEt2 (3.30), dichloromethane, 0 °C, 2h then NaBF4 (aq.), rt, 20 min, 81 % yield.

The structure was confirmed by means of single crystal X-ray diffraction analysis, with the

4 compound crystallising in the tetragonal space group P43212, which is chiral. As can be seen in Figure 3.6, the three phenyl ligands and the tetrahydroisoquinoline can be seen arranged in a tetrahedron about the bismuth atom. In contrast with the structure of the tolylnitrile- substituted bismuthonium 3.28, there is some divergence in the Bi-C bond lengths of the four

4 X-Ray diffraction data collected and solved by Ena Luis, PhD Candidate, School of Chemistry, UNSW Sydney. 69

Chapter 3

ligands. The Bi-C bond lengths of the three phenyl ligands are between 2.16 Å and 2.19 Å, while the tetrahydroisoquinoline Bi-C bond is 2.2 Å in length. The C6-oxygen is positioned directly opposite one of the phenyl ligands (C-Bi-O, 172.7°) and placed at a distance of 2.89 Å. Additionally, the Ts-protecting group can be seen to be almost entirely blocking one face of the tetrahydroisoquinoline aryl ring, with the distance between the two rings ranging from 3.32 Å to 4.40 Å.

Figure 3.6: Single-crystal X-ray diffraction image of tetrahydroisoquinoline-substituted bismuthonium 3.23.

1 An overlay of the H NMR spectra of Ph3BiF2 3.30, iodide 2.19 and bismuthonium 3.23 in CDCl3 is shown in Figure 3.7. The well resolved signals in the aromatic region of Ph3BiF2 can be seen to converge to a multiplet in bismuthonium 3.23, from 7.56 to 7.74 ppm. Additionally, a strong downfield shift can be seen with the singlet corresponding to the C7-H resonance of the isoquinoline, from 6.15 ppm for iodide 2.19 to 6.58 ppm for bismuthonium 3.23.

Chapter 3

Figure 3.7: An overlay of a section of the 1H NMR of fluoride 3.30 (top), iodide 2.19 (middle) and bismuthonium 3.23 (bottom).

Having prepared bismuthonium 3.23, we subjected it to the coupling conditions with naphthol 1.113 which we’d used previously. A solution of bismuthonium 3.23 in THF was added to the pre-formed sodium naphtholate, resulting in a deep red solution which was allowed to stir for 15 hours (Scheme 3.11). Following workup and purification, analysis of the 1H NMR spectrum indicated that the tetrahydroisoquinoline moiety had coupled successfully to form a 77:23 mixture of the biaryls 2.22 and 2.23 in 65 % yield, with spectroscopic data matching that observed previously (see Chapter 2.3). Of particular interest was the significant bias in favour of the M-atropisomer over the P-atropisomer, which we had not observed previously when performing the coupling with lead. While the reason for this is unclear, it is possible that the exaggerated placement of the Ts-protecting group of bismuthonium 3.23 over one face of the isoquinoline ring (which can be seen in the crystal structure) is biasing the outcome of the ligand coupling step of the reaction.

Chapter 3

Scheme 3.11 Reagents and yields a) NaH, 1.113, THF, 0°C to rt, 15 minutes then 3.23, rt, 15 h, 65 % yield.

The successful bismuth-mediated ortho-arylation of naphthol 1.113 with the intact tetrahydroisoquinoline moiety is the first application of an organobismuth(V) in the total synthesis of a naphthylisoquinoline alkaloid. In doing so, it achieves one of the goals of our research, allowing us to replace the aryllead(IV)-complexes we had previously relied on in the key step of our synthesis.

The complexity of the tetrahydroisoquinoline moiety also marks a significant shift from the bismuth(V)-mediated ortho-arylations previously described in the literature, which have mainly focused on simple arenes as a result of the poor ligand efficiency of symmetrical triarylbismuth(V) compounds. Furthermore, the incorporation and coupling of a single aryl ligand demonstrates that it is possible to achieve selectivity when using unsymmetrical bismuth compounds, by leveraging the release of steric strain around the metal.

Chapter 4

Chapter 4: Convergent access to the 7,3’-linked naphthylisoquinoline alkaloids

Chapter 4

Having successfully completed the total synthesis of the 5,3’-linked naphthylisoquinoline alkaloids via a convergent, bismuthonium-mediated ortho-arylation strategy, our attention turned towards extending this strategy to the 7,3’-linked members of the family, which display potent anti-malarial activity. There are two reported syntheses of the Ancistrocladaceae natural products ancistrocladidine (1.132) and ancistrotectorine (1.133, Figure 4.1). However, both syntheses are linear, taking 20 and 21 steps respectively, with limited utility for potential analog synthesis and SAR development. We therefore sought to apply our convergent strategy to an efficient synthesis of the 7,3’-linked scaffold.

4.1 Previous work on the Ancistrocladaceae alkaloids As discussed in Chapter 1.4, Bungard and Morris reported the first total synthesis of ancistrocladidine (1.132) in 2002, which was followed by a second synthesis by Bringmann and co-workers in 2015.30,89,90 The key step of the Morris synthesis involves the Pinhey-Barton ortho- arylation of naphthol 1.113 with aryllead(IV) triacetate 1.108, which can be performed on multi- gram scale. However, the overall synthesis suffers from a lengthy endgame (12 steps) to install the isoquinoline ring with the desired stereochemistry at the C3 position. In contrast, the key step of the Bringmann synthesis involves a 14-step sequence to access lactone 1.35 for the intramolecular biaryl coupling, which requires harsh conditions as well as 1.5 equivalents of palladium reagent and affords only 31 % yield of coupled material. A third approach, involving the coupling of an intact isoquinoline moiety to form ancistrocladidine in a single step was investigated by Bungard during the course of his PhD, though he was unable to convert stannane 4.1 into the aryllead triacetate 4.2 required for the coupling, forcing him to abandon this approach.91

Figure 4.1: Two reported syntheses of ancistrocladidine (1.132), and Bungard’s attempted convergent synthesis. 74

Chapter 4

4.2 Retrosynthesis Applying the strategy we’ve successfully used in the preparation of the 5,3’-linked naphthylisoquinoline alkaloids, we proposed accessing the biaryl core 4.3 of the Ancistrocladaceae natural products from 7-halo-substituted tetrahydroisoquinoline 4.4 (Figure 4.2). Preparation of boronic acid 4.5 would allow access to the required bismuthonium 4.6 for the preparation of the 7,3’-biaryl linkage. The 7,3’-linkage is more sterically congested than the 5,3’-linkage, due to the presence of the two ortho-methoxy groups; if successful, the formation of the 7,3’-linkage should therefore provide another demonstration of the tolerance of the bismuthonium chemistry to steric hindrance. Furthermore, in Chapter 3.5 we observed a bias in the coupling of the 5-substituted bismuthonium in favour of the P-configured atropisomer, which we speculated resulted from the positioning of the Ts-protecting group over one face of the isoquinoline moiety. Whether the Ts-protecting group would play a similar role in the coupling of the 7-substituted bismuthonium 4.6 was therefore a key research question we hoped to answer with this sequence. In order to complete the synthesis, biaryl 4.3 would be deprotected to afford isoquinoline 4.7, at which point our synthesis would intersect with that of Bringmann and co-workers, affording ancistrocladidine (1.132) in one step and ancistrotectorine (1.133) in two.

Figure 4.2: Retrosynthetic analysis of ancistrocladidine (1.132) and ancistrotectorine (1.133).

In order to access 7-substituted tetrahydroisoquinoline 4.4, we envisaged two approaches: the direct halogenation of tetrahydroisoquinoline 2.15; or the halogenation of tolyl nitrile 1.127, which could undergo alkylation and cyclisation to form the isoquinoline ring (Figure 4.3). 75

Chapter 4

Figure 4.3: Retrosynthetic analysis of 7-halo-tetrahydroisoquinoline 4.4.

The former approach requires a regioselective halogenation of the C7 position of tetrahydroisoquinoline 2.15, which presents a unique challenge; unlike the 5-substituted tetrahydroisoquinolines – which can be prepared by electrophilic halogenation – the C7 position is not readily functionalised. An attractive strategy would be to use the 1,3-relationship of the methoxy groups at C6 and C8 to direct metalation to the C7 position, followed by addition of iodine or another suitable electrophile. During the course of his PhD, Bungard screened conditions for this transformation. However, in each case he was unable to observe metalation (A, Scheme 4.1).91 In their synthesis of ancistrocladidine (1.132), Bringmann and co-workers demonstrated that a MOM-ether installed at the C8-oxygen of tetrahydroisoquinoline 4.8 is capable of directing lithiation to the C7 position, allowing them to prepare 7-iodinated tetrahydroisoquinoline 4.9 (B, Scheme 4.1). However, doing so entailed a sequence of 4 deprotection and protection reactions – in addition to the lithiation itself – which we wished to avoid.

Scheme 4.1: Reagents and yields A a) n-BuLi, Et2O, -35 °C to -78 °C then MeOD; B b) n-BuLi, TMEDA, THF,

-78 °C to 0 °C, 1 h then I2, 0 °C, 1 h, 90 %; C c) I2, Ag2SO4, EtOH, 0°C to rt, 81 % yield; d) LDA, THF, -78°C, then (R)-1.119, THF, -78°C, 77 % yield.30,91

The alternative approach to accessing 7-substituted 4.4 is via halogenation of tolyl nitrile 1.127, which could be elaborated to the tetrahydroisoquinoline. As with tetrahydroisoquinoline 2.15, 76

Chapter 4

the exclusive product of electrophilic halogenation is the 5-substituted iodide 3.38 (C, Scheme 4.1). On the other hand, treatment with LDA leads to lateral-lithiation at the C4-methyl – directed by the nitrile functional group – to afford alkylated products such as 2.16. Directed metalation between the methoxy groups of 1.127 would require conditions able to sidestep the directing ability of the nitrile functional group, whilst avoiding addition into the nitrile itself. However, if successful, it would intersect with the sequence we had previously used for the synthesis of the 5,3’-linked alkaloids and allow us to access the required 7-substituted tetrahydroisoquinoline 4.4 in only 5 steps. Therefore, we decided to investigate conditions for the directed metalation of the C3 position of tolyl nitrile 1.127.

4.3 Initial investigations As mentioned above, the biaryl axis of the 7,3’-linked alkaloids is more sterically congested than that of the 5,3’-linked alkaloids. Therefore, before beginning our investigations into the halogenation of tolylnitrile 1.127, we decided to test the coupling of 3,5-dimethoxytoluene (4.10, Scheme 4.2), a commercially available compound with a similar steric environment around the coupling site, and from which bismuthonium 4.11 could be prepared in two steps. Following literature precedent,156 a directed ortho-metalation with n-BuLi was performed, using the 1,3-relationship of the methoxy substituents to direct lithiation to the 4-position, followed by quenching with B(O-iPr)3. After stirring with a saturated solution of ammonium chloride, boronic acid 4.12 was isolated in 80 % yield. The infrared spectrum confirmed the presence of a hydroxyl, with a stretching frequency at 3478 cm-1, while the position of the boronic acid functional group on the aryl ring was confirmed by the analysis of the 1H NMR spectrum, which contained only 3 resonances – 2.34 ppm, 3.75 ppm and 6.43 ppm – as would be expected for a symmetrical compound. Treatment of a solution of boronic acid 4.12 and Ph3BiF2 3.30 in dichloromethane with BF3·OEt2 led smoothly to bismuthonium 4.11, which was purified by

1 crystallization from a mixture of dichloromethane and Et2O in 64 % yield. Analysis of the H NMR spectrum indicated the presence of additional resonances corresponding to the three phenyl ligands (Figure 4.4). Significant line broadening of the ipso-carbon of the dimethoxy ligand, as a result of interactions with the quadrupole moment of bismuth, meant it is not visible in the 13C NMR spectrum. However, performing a 2D HMBC experiment revealed a strong correlation at 111.9 ppm to the aryl proton resonance at 6.72 ppm.

Chapter 4

Scheme 4.2: Reagents and yields a) n-BuLi, THF, 0 °C to rt, 76 % yield; b) BF3·OEt2, 3.30, CH2Cl2, 0 °C to rt, 2 h, 64 %.

Figure 4.4: 1H NMR spectrum of bismuthonium 4.11 (top) and section of 1H-13C HMBC spectrum showing the correlation between aryl protons and the ipso-carbon (bottom).

The ortho-arylation of the naphthol 1.113 was performed by adding bismuthonium 4.11 to a pre-formed solution of the naphtholate in THF (Scheme 4.3). Following workup and purification, biaryl 4.13 was isolated in 60 % yield, evidenced by the downfield shift of the characteristic hydroxyl resonance from 9.24 ppm to 9.49 ppm in the 1H NMR spectrum, as well as the identification by mass spectrometry of the sodium adduct at 361.1410 m/z (calc. for C21H22O4Na, 361.1410 m/z). Interestingly, the phenylated product 3.11 (previously prepared in Chapter 3.3) 78

Chapter 4

was isolated in 8 % yield. The work of Barton and co-workers (discussed in Chapter 3.4) has shown that the migratory aptitude of electron rich aryl ligands such as the dimethoxy tolyl ligand of bismuthonium 4.11 is low compared to comparatively electron poor ligands such as phenyl, as a result of their relative Bi-C bond strengths. However, Wiegand and others have also demonstrated that the release of steric strain around heteroatoms during ligand coupling reactions can override other reaction mechanisms. In this instance, we hypothesized that the transfer of the dimethoxy tolyl ligand onto naphthol 1.113 would entail a significant steric release, favouring that product over phenylated biaryl 3.11. The yields of the two products supports this, especially after taking into account the 3:1 ratio of phenyl to dimethoxy ligands, with the calculated migratory aptitude of the dimethoxy ligand relative to the phenyl being 22.5.

Scheme 4.3: Reagents and yields a) 1.113, NaH, THF, 0 °C to rt then 4.11, 15 h, 60 % yield.

4.4 Preparation of alternately substituted iodonitrile Having confirmed that an ortho-dimethoxy substituted bismuthonium salt was capable of arylating naphthol 1.113, we turned our attention to the directed metalation of tolyl nitrile 1.127. To achieve this, we would need to bypass the directing ability of the nitrile functional group in favour of the two methoxy groups. Meyers and Avila have demonstrated that it is possible to switch between competing directing groups on an arene by careful selection of the base and solvent used in a metalation reaction (Scheme 4.4).157 As a test substrate, they treated oxazoline 4.14 with n-BuLi in Et2O at -45 °C, followed by addition of methyl iodide, to afford methylated derivative 4.15 as the major product in 25 % yield (62 % recovered starting material), as would be expected based on the superior directing ability of the oxazoline moiety over the methoxy groups. However, changing the solvent to THF gave the reversed product distribution, affording the methylated derivative 4.16 as the primary product in a ratio of 78:22 and 75 % yield.

Chapter 4

Scheme 4.4: Reagents and yields a) n-BuLi, solvent, -45 °C, 1.5 h then MeI, rt, 30 min.

The initial conditions we investigated therefore involved the treatment of tolyl nitrile 1.127 with n-BuLi, in THF at -45 °C, followed by addition of methyl iodide (Figure 4.5). Disappointingly, inspection of the 1H NMR spectrum indicated that the sole product of the reaction was the ketone 4.17, the product of the addition of n-BuLi into the nitrile, instead of 4.18 (Entry 1). A similar result was obtained using Et2O as the solvent (Entry 2), prompting us to investigate lower temperatures. However, at -78 °C no reaction was observed following treatment with one equivalent of n-BuLi (Entry 3). As discussed above, treatment with excess LDA at -78 °C affords the product of lateral lithiation at the tolyl substituent. We hypothesized that, following addition of LDA, subsequent addition of n-BuLi could result in a second lithiation on the aryl ring. Unfortunately, addition of either n- or t-BuLi afforded exclusively the methylated derivative 4.19 (Entry 4), resulting from nitrile-directed lateral lithiation. Experiments using Schlosser’s base or lithium tetramethylpiperidide, which have similarly been used in the selective metalation of arenes, gave no reaction.158–161

Entry Base Conditions Isolated compound 1 n-BuLi THF, -45 °C then MeI 4.17

2 n-BuLi Et2O, -45 °C then MeI 4.17 3 n-BuLi THF, -78 °C then MeI 1.127 4 LDA then n-BuLi or t-BuLi THF, -78 °C then MeI 4.19 Figure 4.5: Table of conditions examined for the directed metalation of tolyl nitrile 1.127.

Given the difficulties encountered in our attempt at selectively metalating tolyl nitrile 1.127, we sought an alternative methodology which could bypass the cross-reactivity of the nitrile functional group. We were intrigued by a recent report from Liu and co-workers on the radical- 80

Chapter 4

promoted cross-dehydrogenative silylation of arenes (A, Scheme 4.5). They showed that both electron-poor and -rich substrates demonstrated a strong para-selectivity, except for 1,3- dimethoxybenzene 4.20, which afforded exclusively the ortho-product 4.21 in 41 % yield. Pleasingly, applying the conditions reported by Liu and co-workers to tolyl nitrile 1.127 afforded, upon purification, silylated product 4.22 in 30 % yield, as indicated by the lone aromatic singlet at 6.49 ppm and the multiplet from 0.79-0.94 ppm integrating for 15 in the 1H NMR spectrum, along with the two upfield resonances in the 13C NMR spectrum at 4.8 and 7.9 ppm (B, Scheme 4.5). In order to confirm the position of the silyl group on the arene, we decided to prepare the equivalent aryl iodide 4.23, which we could compare with the spectroscopic data for iodide 3.38, which we had previously prepared (Chapter 3.4). This was accomplished by adding N- iodosuccinimide to a solution of silane 4.22 in acetonitrile. Following purification, we confirmed by comparison with the 1H and 13C NMR spectra of 3.38 that the desired iodide 4.23 had been formed with the halo-substituent between the methoxy groups. This was supported by 2D 1H- 13C HMBC experiments, which identified correlations between the hydrogen at C5 and the neighbouring methyl and methoxy groups. Unfortunately, the yield of the halogenation reaction was only 12 %, thus affording iodide 4.23 in just 4 % yield over the two steps. Attempts to optimise this reaction were stymied, however, by our inability to prepare sufficient quantities of silane 4.22; increasing the scale of the silylation reaction resulted in a significant increase in the formation of byproducts and decomposition of tolyl nitrile 1.127. Eventually, we decided to abandon this route and explore a different approach to accessing 7-substituted isoquinoline 4.4.

Scheme 4.5: Reagents and yields a) Et3SiH (12 eq), di-tert-butyl peroxide (18 eq), Cu2O (5 mol%), t-BuOH,

120 °C, 12 h then Et3SiH (12 eq), di-tert-butyl peroxide (18 eq), 12 h, 41 % yield; b) Et3SiH (12 eq), di-tert-

butyl peroxide (18 eq), Cu2O (5 mol%), t-BuOH, 120 °C, 12 h then Et3SiH (12 eq), di-tert-butyl peroxide (18 eq), 12 h, 30 % yield; c) NIS (1.5 eq), MeCN, 15 h,12 %.162

Chapter 4

4.5 Synthesis of 7-bromo-3,4-tetrahydroisoquinoline 4.34 The difficulty of preparing iodonitrile 4.23 on scale prompted us to look for an alternative route to accessing 7-substituted tetrahydroisoquinoline 4.4. During his thesis, Bungard had shown that 7-iodo-3,4-dihydroisoquinoline 4.24 could be accessed in 9 steps from iodide 4.25, using a Sharpless asymmetric epoxidation and Mitsunobu inversion to prepare the key chiral amphetamine 4.26 (Scheme 4.6). We proposed starting from the commercially available bromide 4.27, but instead of using the Sharpless epoxidation as the key stereodetermining step, we would instead use Ellman auxiliary (S)-4.28, which has been used extensively in the literature for the synthesis of chiral amines and which we had previously used in the synthesis of chiral 1,2,3,4-tetrahydroisoquinolines.163,164

Scheme 4.6: Reagents and yields a) AcCl, NEt3, dichloromethane, 0 °C to rt, 15 h, 96 %; b) POCl3, 2,4,6- trimethylpyridine, MeCN, 82 °C, 3 h, 89 %.90

Therefore, performing a Henry aldol reaction with nitroethane and commercially available bromide 4.27 afforded styrene 4.30 as a mixture of geometric isomers, which was purified by crystallisation from hot ethanol in 65 % yield (Scheme 4.7). Analysis of the 1H NMR spectrum indicated the presence of an additional broad singlet at 8.03 ppm, corresponding to the vinylic hydrogen, along with a doublet at 2.46 ppm, integrating for 3H, while stretching frequencies at 1556 and 1336 cm-1 were observed in the IR spectrum, confirming that the reaction had occurred. Reduction of styrene 4.30 to ketone 4.31 was carried out in 81 % yield by heating with iron powder in acetic acid at reflux for 5 hours. Along with the absence of the signal corresponding to the vinylic hydrogen in the 1H NMR spectrum, the presence of a signal at 205 ppm in the 13C NMR spectrum and a sharp stretching frequency at 1706 cm-1 in the infrared spectrum – diagnostic for the presence of ketone functional group – confirmed the structure of the product. 82

Chapter 4

Scheme 4.7: Reagents and yields a) NH4OAc, EtNO2, 114 °C, 65 %; b) Fe powder, HOAc, 118 °C, 81 %; c)

(S)-4.28, Ti(OEt)4, THF, 66 °C, 2 h then NaBH4, -45 °C, 15 h, 80 %.

With ketone 4.31 in hand, our attention turned to the preparation of sulfonamide 4.29 by condensation with (S)-4.28. The use of sulfinamides as chiral auxiliaries for the asymmetric preparation of amines has been developed extensively by the groups of Davis and Ellman.163–166 In particular, a one-pot procedure for the asymmetric synthesis of α-branched amines from ketones has been reported by Ellman and co-workers.167 Applying these conditions to our substrate involved the addition of Ti(OEt)4 to a solution of ketone 4.31 and (S)-4.28 in THF and heating at reflux for two hours, at which point TLC indicated complete consumption of ketone 4.31. The solution was cooled to -45 °C, sodium borohydride was added in a single portion and the solution allowed to slowly warm to room temperature over 15 hours. Upon workup, analysis of the 1H NMR spectrum indicated the formation of two products, in a ratio of 4:1. Following purification by flash column chromatography, the major product was isolated in 80 % yield. Pleasingly, a crystal suitable for X-ray diffraction analysis was obtained by slow evaporation from a mixture of ethyl acetate and n-hexanes (Figure 4.6).5 The compound crystallised in the orthorhombic space group P212121, which is chiral, allowing us to confirm both the identity of the major product as sulfonamide 4.29, and that it possessed the desired S-stereochemistry at the C3 methyl substituent that we would need for the synthesis of the 7,3’-linked alkaloids.

5 X-Ray diffraction data collected and solved by Dr. Mohan Bhadbhade, Scientific Officer, Mark Wainwright Analytical Centre, UNSW Sydney 83

Chapter 4

Figure 4.6: Single-crystal X-ray diffraction image of sulfonamide 4.29.

Cleavage of the sulfur auxiliary was performed by stirring in methanol with a 4 M solution of HCl in dioxane. Precipitation with Et2O afforded analytically pure chiral amine 4.32 in 92 % yield (Scheme 4.8). The infrared spectrum confirmed the presence of a primary amine, with two stretching frequencies at 3306 and 3471 cm-1, while the characteristic singlet around 1 ppm in the 1H NMR spectrum – corresponding to the tert-butyl group – was not present. This sequence was able to be carried out on gram scale.

Scheme 4.8: Reagents and yields a) HCl solution (4.0 M in dioxane), MeOH, 2 h, 92 %; b) AcCl, NEt3,

dichloromethane, 0 °C to rt, 15 h, 90 %; b) POCl3, 2,4,6-collidine, MeCN, 82 °C, 3 h, 84 %.

With chiral amine 4.32 in hand, our attention turned to its cyclisation under Bischler-Napieralski conditions. To achieve this, we first required acetamide 4.33, which was prepared by addition of acetyl chloride to a mixture of amine 4.32 and triethylamine in dichloromethane. Following workup, acetamide 4.33 was isolated in 90 % yield. The infrared spectrum confirmed the presence of an amide, with stretching frequencies at 1629 and 3314 cm-1, along with a peak at 169.6 ppm in the 13C NMR spectrum, corresponding to the carbonyl functional group. Acetamide

4.33 was subjected to Bischler-Napieralski cyclisation conditions, adding POCl3 to a solution of 4.33 in acetonitrile and heated at reflux for 3 hours. 2,4,6-Collidine was also added, in order to

Chapter 4

act as an acid scavenger to prevent dehalogenation, which had previously been observed by Bungard.91 Following workup and purification, 3,4-dihydroisoquinoline 4.34 was isolated in 84 % yield. The expected loss of symmetry about the aryl ring going from acetamide 4.33 to dihydroisoquinoline 4.34 was apparent on examination of the 1H and 13C NMR spectra, with additional resonances appearing for the two, formerly equivalent, methoxy substituents (Figure 4.7). Additional confirmation was obtained using mass spectrometry, which identified the

79 + expected mass (298.0433 m/z, calculated for C13H16 BrNO2 (M+H) 298.0437 m/z).

Figure 4.7: Overlay of sections of the 1H NMR spectra of acetamide 4.33 (top) and dihydroisoquinoline 4.34 (bottom).

4.6 Synthesis and coupling of 7-substituted bismuthonium 4.6 Having successfully prepared dihydroisoquinoline 4.34 on gram scale, in 6 steps and 29 % overall yield, our attention turned towards preparation of the corresponding bismuthonium salt and its coupling to naphthol 1.113. As discussed in Chapter 3.4, Suzuki and co-workers have reported two methods for the synthesis of bismuthonium salts from the reaction of triarylbismuth difluorides with either arylstannanes or arylboronic acids. With dihydroisoquinoline 4.34 in hand, we decided to investigate both pathways (Scheme 4.9). Applying the conditions reported by Bungard for the preparation of stannane 4.1 from the iodo-substituted dihydroisoquinoline 4.24, halogen-lithium exchange was performed by dropwise addition of t-BuLi to a solution of 85

Chapter 4

bromide 4.34 in THF at -95 °C. After 15 minutes, Bu3SnCl was added, and the solution allowed to warm to room temperature over 15 hours. Analysis of the 1H NMR spectrum of the crude mixture and comparison with the values reported by Bungard indicated the desired stannane

4.1 had formed. Following treatment of a solution of Ph3BiF2 3.30 in dichloromethane with TMSCN and TMSOTf at 0 °C, the crude mixture of stannane 4.1 was added via cannula and the reaction heated at reflux for 20 hours. Removal of an aliquot and analysis of the 1H NMR spectrum indicated the absence of product, with only starting materials present. Heating at reflux for a further 20 hours did not result in any product formation. While this result was disappointing, it is in agreement with observations made by Suzuki and co-workers, who noted the lower reactivity of sterically hindered substrates in the coupling of arylstannanes with difluoride 3.30.151

Scheme 4.9: Reagents and conditions a) t-BuLi, THF, -95°C then Bu3SnCl, - 95°C to rt, 15 h; b) t-BuLi, THF,

-95°C then B(O-iPr)3, - 95°C to rt; c) Ph3BiF2 (3.30), TMSCN, TMSOTf, CH2Cl2, 0° C, 1 h then 4.1, 40 °C; d)

Ph3BiF2 (3.30), BF3·OEt2, 4.36, CH2Cl2, 0 ° to rt, 20 h.

We had previously found success with the preparation of bismuthonium salts from boronic acids (Chapter 3.4). Therefore, boronic acid 4.36 was prepared according to the protocol used for

1 stannane 4.1, quenching with B(O-iPr)3 instead of Bu3SnCl. Analysis of the H NMR spectrum of the crude mixture indicated that a mixture of boronic acid 4.36 and dehalogenated dihydroisoquinoline 1.135 had formed. Attempts at purification resulted in decomposition of the product; therefore BF3·OEt2 was added to a solution of the crude material and Ph3BiF2 3.30 in dichloromethane. Unfortunately, following workup, analysis of the 1H NMR spectrum indicated that a complex mixture had formed, in which neither starting material or product was visible. It seemed likely that the addition of BF3·OEt2, a strong Lewis acid, was incompatible with the Lewis basic nitrogen of the dihydroisoquinoline substrate.

While the preparation of dihydroisoquinoline-substituted bismuthonium 4.35 was desirable, being a more direct route to ancistrocladidine (1.132), its preparation proved challenging. Given the success we encountered in our synthesis of the 5-substituted bismuthonium salt 3.28

Chapter 4

(Chapter 3.5) we decided to reduce dihydroisoquinoline 4.34 and protect the resulting amine with the Ts-protecting group. As well as decreasing the Lewis basicity of the nitrogen atom, an additional benefit of this approach is that it would allow us to directly compare the coupling of the 5- and 7-substituted tetrahydroisoquinolines, in terms of both yield and atropselectivity. Therefore, cis-selective reduction of dihydroisoquinoline 4.34 was carried out by addition of

1 NaBH4 to its solution in methanol at -10 °C (Scheme 4.10). Analysis of the H NMR spectrum of the crude material indicated the expected upfield shift of the C1-methyl resonance, from 2.48 ppm to 1.51 ppm, along with the appearance of a resonance at 4.28 ppm corresponding to the C1-H. The crude material was dissolved in dichloromethane and added to a solution of TsCl and

NEt3 to afford, following workup and purification, N-Ts tetrahydroisoquinoline 4.38 in 80 % yield over the two steps. Along with the expected resonances in the 1H NMR spectrum at 2.29, 7.06 and 7.49 ppm – corresponding to the methyl and aromatic protons of the Ts-protecting group –

79 mass spectrometry identified the expected mass of 476.0500 m/z (calculated for C20H24NO4S Br (M+Na)+ 476.0502 m/z).

Scheme 4.10: Reagents and yields a) NaBH4, MeOH, -10 °C to rt, 2 h; b) TsCl, NEt3, dichloromethane, 15 h, 80 % yield over two steps.

With access to Ts-protected tetrahydroisoquinoline 4.38, we could begin investigating its incorporation into a bismuthonium salt. In order to do this, we first required the equivalent 7- substituted boronic acid 4.39 (Scheme 4.11). We decided to apply the conditions we had previously used for the preparation of the 5-substituted boronic acid 1.134 (Chapter 2.3), which was achieved via halogen-lithium exchange under Barbier conditions. Therefore, t-BuLi was added to a solution of Ts-protected tetrahydroisoquinoline 4.38 and freshly distilled B(O-iPr)3 in THF at -95 °C, before warming to -10 °C and quenching with a saturated aqueous solution of ammonium chloride. Upon isolation of the material and inspection of the 1H NMR spectrum, we were able to determine that boronic acid 4.39 had formed alongside significant quantities of the dehalogenated product, in a ratio of 1:0.4 based on the integration of the aromatic signals of the tetrahydroisoquinoline rings. Attempts at purification by flash column chromatography resulted in decomposition, and subsequently repeating the reaction with both longer and shorter reactions times did not improve the ratio of desired product to dehalogenated 87

Chapter 4

byproduct. As a consequence, it was decided to subject the crude mixture to the conditions for the formation of bismuthonium salts, without attempting purification. Pleasingly, following treatment of the crude mixture and Ph3BiF2 3.30 in dichloromethane with BF3·OEt2, bismuthonium 4.6 was isolated in 61 % yield over two steps. As is characteristic for the bismuthonium salts we have prepared previously, the formerly well-resolved signals in the 1H

NMR spectrum corresponding to the 3 chemical environments of the phenyl ligands of Ph3BiF2 3.30 at 7.45, 7.65 and 8.22 ppm are, upon formation of the bismuthonium salt, instead a poorly resolved multiplet centred around 7.30 ppm. Additionally, analysis using mass spectrometry

+ identified a fragment peak at 814.2407 m/z, corresponding to C38H39NO4SBi (M-BF4) , as would

- be expected for an ionic compound, while the broad BF4 stretching frequency was visible in the IR spectrum, from 1100 to 900 cm-1.

Scheme 4.11: Reagents and yields a) t-BuLi, B(O-iPr)3, THF, -95 °C to -10 °C, 0.5 h; b) 3.35, BF3·OEt2

(3.30), CH2Cl2, 15 h, 61 % over two steps.

Having successfully prepared bismuthonium 4.6, our attention turned to its coupling with naphthol 1.113 to form the biaryl bond of the 7,3’-linked naphthylisoquinoline alkaloids (Figure 4.8). Upon addition of bismuthonium 4.6 to a solution of the sodium salt of naphthol 1.113, a dark red solution was formed. After stirring for 15 hours, analysis of the 1H NMR spectrum of the crude reaction mixture indicated the formation of several new products as well as the presence of unreacted naphthol 1.113. Following purification, the M- and P-configured biaryls 4.40 and 4.41 (axial chirality not assigned) were isolated as a 4:1 mixture, in a relatively modest yield of 22 % (Entry 1). Concerningly, phenylnaphthol 3.11 was isolated in 41 % yield. This compares with a 60 % yield for the coupling of dimethoxytoluene 4.9 (Chapter 4.3), in which only 8 % of the phenylnaphthol 3.11 was formed.

Chapter 4

Entry Conditions Yield of 4.40/4.41 (ratio) Yield of 3.11 1 1.113, NaH, THF, 0 °C to rt then 4.6, 15 h 22 % (4:1) 41 % 2 1.113, NaH, THF, 0 °C to rt then 4.6, -78 °C 46 % (4:1) 32 % to rt, 15 h 3 1.113, BTMG, THF, 0 °C to rt then 4.6, -78 °C 39 % (1:1) 38 % to rt, 15 h Figure 4.8: Conditions for the arylation of naphthol 1.113 with bismuthonium 4.6 a) See table for reagents and yields.

Literature conditions for the arylation of phenols with organobismuth(V) compounds have been reported across a range of temperatures, though the only other arylation using a bismuthonium – reported by Suzuki and co-workers – was carried out from -78 °C to room temperature (the reaction time is not indicated).147 We therefore repeated the reaction, lowering the temperature of the naphtholate solution to -78 °C prior to the addition of bismuthonium 4.6, and allowing it to slowly warm to room temperature over 15 hours. Following purification, we isolated biaryls 4.40 and 4.41 in an increased yield of 46 %, while the yield of phenylnaphthol was decreased to 32 % (Entry 2). As discussed in Chapter 1.3.3, the diastereoselectivity of arylations with organobismuth(V) compounds can be sensitive to the base used in the reaction. Therefore, we repeated the reaction using 2-tert-butyl-1,1,3,3,-tetramethylguanidine (BTMG) in place of NaH. Interestingly, while the yield of biaryls was lower, they were isolated as a 1:1 mixture of atropisomers. At the same time, the yield of phenylnaphthol 3.11 was also slightly increased to 38 % (Entry 3).

Unlike the 5,3’-linked biaryls 2.22 and 2.23 (Chapter 2.3), their 7,3’-linked isomers 4.40 and 4.41 were not separable using flash column chromatography, and the high degree of similarity between their 1H and 13C NMR spectra made characterisation difficult. HPLC analysis of a mixture of biaryls 4.40 and 4.41 was undertaken with a Waters C18 column, eluting with acetonitrile (0.5 % TFA) and water (0.5 % TFA), affording analytical pure samples. An overlay of their 1H NMR spectra is shown below (Figure 4.9). Incidentally, the largest differences in chemical shifts between the two atropisomers can be seen in the hydrogens furthest from the biaryl linkage; 89

Chapter 4

corresponding to the two hydrogens at C4 (occurring at 2.88 ppm for biaryl 4.40, and at 2.62 and 3.18 ppm for 4.41), the C3-H (4.04 ppm and 4.36 ppm) and the C3-Me (1.56 ppm and 1.13 ppm).

Figure 4.9: An overlay of the 1H NMR spectra of atropisomeric biaryls 4.40 (top) and 4.41 (bottom), with significant differences in chemical shift highlighted.

One of the HPLC fractions containing the major atropisomer 4.40, having been determined by 1H NMR spectroscopy to contain only one atropisomer, was able to be crystallised from an acetonitrile/water mixture (Figure 4.10).6 The compound crystallised in the monoclinic space group P21, which is chiral, and the M-configuration about the biaryl axis can be clearly seen (I). In contrast to the 5-substituted bismuthonium 3.28 (Chapter 3.5), the Ts-protecting group is twisted away from the isoquinoline ring (II). Additionally, while the methoxy substituent at C6 is co-planar with the tetrahydroisoquinoline ring, the methoxy at C8 is lying out of the plane at an angle of 114°, which is indicative of the steric crowding present around the lower portion of the molecule.

6 X-Ray diffraction data collected and solved by Ena Luis, PhD Candidate, School of Chemistry, UNSW Sydney. 90

Chapter 4

Figure 4.10: Single-crystal X-ray diffraction images of the front (I) and top-down (II) views of the M- configured 7,3-linked biaryl core.

4.7 Formal syntheses of ancistrocladidine 1.132 and ancistrotectorine 1.133 From the reaction of bismuthonium 4.6 with naphthol 1.113, the highest yield of coupled product (46 %) was obtained using NaH as base, affording a 4:1 mixture of the atropisomers 4.40 and 4.41. This is a similar ratio to what was observed in the coupling of the 5-substituted bismuthonium 3.23 (Chapter 3.5), which afforded the M-atropisomer as the major product. The M-configured biaryl was also the major product of the coupling of 7-substituted bismuthonium 4.6, matching the configuration of the 7,3-linked natural products ancistrocladidine 1.132 and ancistrotectorine 1.133. Bringmann and co-workers have reported their synthesis from the unprotected 1,2,3,4-tetrahydroisoquinoline.30 Removal of the Ts-protecting group of biaryl 4.40 would therefore allow us to intersect their synthesis. In Chapter 2.4, this was accomplished by treating with excess LiAlH4 at 0 °C. Applying these conditions to a mixture of biaryls 4.40 and 4.41 afforded the deprotected 1,2,3,4-tetrahydroisoquinoline products – as evidenced by the absence in the 1H NMR of the resonances corresponding to the Ts-protecting group – but with low mass recovery (<20 %). It was not apparent if decomposition of the substrate was occurring during the reaction, or if extraction of the material from the aluminium salts formed during the quenching of the reaction was inefficient. Regardless, we decided to investigate alternative deprotection conditions. The removal of Ts-protecting groups using sodium naphthalenide has

168 been reported. It has several advantages over LiAlH4, in that it can be performed at low temperatures and is self-indicating, potentially limiting the amount of excess reagent needed for the reaction. Pleasingly, treating a mixture of biaryls 4.40 and 4.41 at -78 °C with a freshly prepared solution of sodium naphthalenide afforded the deprotected material, with complete mass recovery. Repeating this procedure using a HPLC-purified sample of biaryl 4.40, isoquinoline 4.42 was isolated in 65 % yield following purification (Scheme 4.12). The 1H and 13C 91

Chapter 4

spectroscopic data for isoquinoline 4.42 was in agreement with that reported by Bringmann and co-workers.30 Analysis using mass spectrometry identified a peak corresponding to the H+ adduct

+ at 408.2176 m/z (calculated for C25H29NO4 (M+H) 408.2169). Our access to isoquinoline 4.42 therefore constitutes a formal synthesis of ancistrocladidine 1.132 in 13 steps and ancistrotectorine 1.133 in 14 steps.

Scheme 4.12: Reagents and yields a) Na/naphthalene, THF, -78 °C to -50 °C, 15 minutes, 65 % yield.

The successful preparation of the 7,3’-linked biaryl axis demonstrates that the convergent ortho- arylation strategy developed for the 5,3’-linked naphthylisoquinoline alkaloids can be used in the efficient synthesis of other members of the naphthylisoquinoline alkaloid family, and in doing so, establishes the unsymmetrically substituted bismuthonium salts as an alternative to the aryllead(IV) triacetates previously used in the Pinhey-Barton reaction. Additionally, access to the core of the 7,3-linked naphthylisoquinoline alkaloids has been achieved in 10 steps, and the formal syntheses of ancistrocladidine 1.132 and ancistrotectorine 1.133 completed in 13 and 14 steps, a significant improvement (7 steps) on the previous shortest synthesis, as well the first synthesis reported by our group in 2002. This strategy will allow for the synthesis of analogs and development of the SAR of this family of natural products.

The differing ratios of atropisomers formed in the ortho-arylation reaction when the base is changed is also significant, as it demonstrates that an atropselective coupling is achievable. Further investigations into the mechanism of the reaction are required, in particular into the role of the base and how it affects the ligand coupling step of the reaction.

Chapter 5

Chapter 5: Summary and Future Work

Chapter 5

5.1 Summary This thesis has described investigations into the total synthesis of the 5,3’- and 7,3’-linked naphthylisoquinoline alkaloids, two families of sterically hindered biaryl natural products. Their unique scaffold, which displays promising anti-malarial activity as well as low cytotoxicity, has made them attractive targets for total synthesis, and the discussion in Chapter 1 described the cross-coupling strategies that have been applied previously to the synthesis of other naphthylisoquinoline alkaloids, whilst highlighting the need for a convergent, atropselective strategy.

The work described in Chapter 2 resulted in the completion of the total synthesis of the 5,3’- linked naphthylisoquinoline alkaloids – ancistrotanzanine A (1.122), ancistrotectorine C (1.124) and ancistrotectorine D (1.123) – and the non-natural atrop-ancistrotectorine C (2.29). The initial goal was to establish suitable conditions for the formation of the 3,4-dihydroisoquinoline motif, either through a base-induced elimination of the Ts-protecting group or by direct oxidation of the deprotected tetrahydroisoquinoline. The Pinhey-Barton ortho-arylation of naphthol 1.113 with isoquinolinyllead(IV) triacetate 2.21 afforded the Ts-protected biaryl core of the natural products as a mixture of the M- and P-atropisomers, which were able to be separated using flash column chromatography (Figure 5.1). Neither base-induced elimination with dimsyl sodium or oxidation with KMnO4 were successful in affording the required dihydroisoquinoline. However, following protection of the naphthol as the MOM-ether, oxidation with KMnO4 proceeded cleanly and following MOM-deprotection, afforded ancistrotectorine D (1.123), in 12 steps overall from commercially available tolyl nitrile 1.127. The same sequence of steps using the M-configured atropisomer afforded ancistrotanzanine A (1.122), while the last member of the 5,3’-linked alkaloids, the N-Me configured ancistrotectorine C (1.124), was prepared in 10 steps overall following cleavage of the Ts- protecting group and reductive amination. The three natural products, as well as atrop- ancistrotectorine C (2.29), were tested for their anti-malarial activity and cytotoxicity by Dr Leonardo Lucantoni, in the laboratory of Professory Vicky Avery at the Griffith Research Institute for Drug Discovery, confirming that they possess moderate activity against chloroquine-sensitive (3D7) and multi-drug resistant (Dd2) strains of the parasite Plasmodium falciparum, as well as very low cytotoxicity. At the end of Chapter 1, we attempted unsuccessfully to control the atropselectivity of the Pinhey-Barton ortho-arylation by using the chiral amine brucine (1.105) in place of pyridine, following reports by Yamamoto and co-workers.28,80

Chapter 5

Figure 5.1: Total synthesis of the 5,3’-linked naphthylisoquinoline alkaloids.

Chapter 3 describes our investigations into organobismuth(V) compounds as potential replacements for the aryllead(IV) triacetates in the key step of our total syntheses. Preliminary work focussed on symmetrically substituted triarylbismuth(V) compounds, which are the most commonly used organobismuth(V) compounds reported in the literature despite the unfavourable stoichiometry of arylation. Following reports by Suzuki and co-workers on the preparation of unsymmetrical tetraarylbismuthonium(V) salts, we succeeded in preparing bismuthonium 3.28 and coupling it to naphthol 1.113 (A, Figure 5). Instead of a mixture of biaryls 3.27 and 3.11, we isolated 3.27 as the sole product of the arylation reaction, demonstrating that not only are organobismuth(V) compounds capable of coupling sterically hindered substrates in yields comparable to those previously obtained using aryllead(IV) triacetates, but also that high degrees of selectivity are possible during aryl transfer when using unsymmetrically substituted tetraarylbismuthonium(V) compounds. Extending this methodology to the intact tetrahydroisoquinoline moiety 2.20 of the 5,3’-linked naphthylisoquinoline alkaloids, we 95

Chapter 5

prepared 5-substituted bismuthonium 3.23 and coupled it to form the biaryl core of the natural products as a 77:23 mixture of the M- and P-configured atropisomers 2.22 and 2.23, allowing us to replace the aryllead(IV) triacetates used in the key step of our total syntheses.

Figure 5.2: A Selective ligand transfer using an unsymmetrical bismuthonium salt; B Coupling of the tetrahydroisoquinoline moiety to form the core of the 5,3’-linked natural products.

Chapter 4 describes our efforts to extend the bismuthonium methodology to the 7,3’-linked Ancistrocladaceae-type alkaloids, ancistrocladidine (1.132) and ancistrotectorine (1.133), which had previously been synthesised in 20 and 21 steps respectively. Several avenues for the synthesis of 7-bromodihydroisoquinoline 4.34 were explored, including directed metalation and radical silylation, eventually resulting in a 6 step synthesis starting from aldehyde 4.27. Conversion of 7-bromodihydroisoquinoline 4.34 to the corresponding bismuthonium salt was

Chapter 5

unsuccessful. However, the equivalent tetrahydroisoquinoline was successfully converted to unsymmetrical bismuthonium salt 4.6. Coupling of bismuthonium 4.6 to naphthol 1.113 proceeded in lower yields compared to the 5-substituted bismuthonium, but with a higher ratio of 4:1 of the M- and P-atropisomers when NaH was used as the base; BTMG on the other hand afforded a 1:1 mixture. Separation of the atropisomers was possible using HPLC and deprotection of the major product allowed for the completion of a formal synthesis of both ancistrocladidine 1.132 and ancistrotectorine 1.133.

Figure 5.3: Convergent access to the core of the 7,3’-linked Ancistrocladaceae-type naphthylisoquinoline alkaloids and formal synthesis.

5.2 Future Directions The work described in this thesis opens up several avenues of investigation for future work. With regards to the anti-malarial activity of the naphthylisoquinoline alkaloids, application of the bismuthonium arylation chemistry would allow for rapid access to analogs to develop the SAR of these natural products. Previous work in this area has identified the importance of the 1,3- dimethyl-1,2,3,4-tetrahydroisoquinoline moiety for activity.169,170 Simplified naphthalene analogs, as shown in A Figure 5.4, would provide insight into the importance of the naphthalene moiety and potentially lead to a simplification of the structure. Conversely, deprotection and ortho-arylation of 3,4-dihydroisoquinoline 5.1 (B, Figure 5.4) would allow for comparisons to be 97

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made between the different oxidation levels of the isoquinoline moiety. Following trans- selective reduction of the dihydroisoquinoline, the importance of the stereochemical configuration of the C1 and C3 methyl groups in compounds such as 5.3 could also be investigated.

Figure 5.4: Simplified naphthalene moieties for the preparation of analogs of the 7,3’-linked alkaloids.

A greater understanding is required of the atropselectivity observed in the coupling of the 5- and 7-substituted bismuthonium salts. Our initial work on the 5-substituted bismuthonium 3.23 led us to speculate that the observed atropselectivity was substrate-directed, resulting from the arrangement of the Ts-protecting group over the isoquinoline ring. However, subsequent results with the 7-susbtituted bismuthonium 4.6 indicated that the base used in the reaction also played a significant role in determining the stereochemical outcome, despite the absence of any inherent stereochemistry. Performing the reaction in the presence of an optically active base such as nicotine (1.97, Figure 5.5) may lead to further enhancements of this atropselectivity, while replacement of the Ts-protecting group with protecting groups of different sizes may also help to elucidate the role of the substrate in the stereo-determining step of the arylation reaction. Additionally, in order to investigate reagent-directed atropselectivity, optically active organobismuth(V) compounds such as 5.5 could be prepared and used in place of the three phenyl ligands used to date. These experiments should be performed using the 5-substituted bismuthonium 3.23, as the biaryls 2.22 and 2.23 are separable using flash column chromatography.

Chapter 5

Figure 5.5: Performing the bismuthonium-mediated arylation in the presence of chiral bases and with alternative protecting groups may lead to greater insight into the atropselectivity of the reaction.

The ortho-arylation of naphthol 1.113 to form the core of the 5,3’- and 7,3’-linked naphthylisoquinoline alkaloids leverages the release of steric strain provided by the doubly ortho-substituted aryl ligands around the bismuth atom to provide selectivity in the aryl transfer and minimise the transfer of the three phenyl spectator ligands, with varying degrees of success achieved on the 5- and 7-substituted bismuthonium salts. In order to extend the methodology beyond the naphthylisoquinoline alkaloids to other substrates – for example boronic acid 5.2, where X and Y can be any substituent – investigations into the spectator ligands that would be best suited for a generally applicable triarylbismuth(V) difluoride (5.3) are required (Figure 5.6). Barton and co-workers have demonstrated that electron rich aryl ligands are less likely to undergo transfer in competitive arylations of substrates that don’t contain ortho-substituents.146 Suitable aryl ligands therefore might include 4-methoxybenzene or 3,4-dimethoxybenzene.

Figure 5.6: The development of a triarylbismuth(V) difluoride that could be used as a general coupling partner for arylboronic acids would greatly expand the utility of the methodology.

Chapter 5

Additionally, investigations into making the reaction sequence shown in Figure 5.6 catalytic with regards to bismuth are currently under investigation in the group of Dr Liam Ball at the University of Nottingham.171 The development of a catalytic cycle, in combination with an increased understanding of the mechanism of the reaction , the role of the base and its potential to dictate the stereochemical outcome of the coupling, would greatly expand the utility of this methodology and provide the ideal strategy – efficient, convergent and atropselective – for the synthesis of the naphthylisoquinoline alkaloids and phenolic natural products more generally.

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Chapter 6: Experimental

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6.1 General Experimental Melting points were obtained on OptiMelt Automated Melting Point System with Digital Image Processing Technology and are uncorrected. 1H NMR and 13C NMR were recorded at the Nuclear Magnetic Resonance Facility within the Mark Wainwright Analytical Centre at The University of New South Wales on a Bruker Avance III 300 (300 MHz), Bruker DPX 300 (300 MHz), Bruker Avance III 400 (400 MHz), Bruker Avance III 500 (500 MHz), Bruker Avance III 600 (600 MHz) or Bruker Avance III 600 Cryo (600 MHz), with data acquired and processed using TopSpin 3.5 software. Chemical shifts are expressed in parts per million (PPM) on the δ scale. Chemical shifts

1 in (a) CDCl3 were referenced relative to CHCl3 (7.26 ppm) for H NMR and CHCl3 (77.16 ppm) for

13 1 C NMR, (b) MeOD were referenced relative to CD2HOH (3.31 ppm) for H NMR and CD3OD

13 (49.00 ppm) for C NMR, and (c) (CD3)2SO were referenced relative to CD3CD2HSO (2.50 ppm)

1 13 172 for H NMR and (CD3)2SO (39.52 ppm) for C NMR. Infrared spectra were obtained on a ThermoNicolet Avatar 370 FT–IR spectrometer and relevant absorptions are reported in wavenumbers (cm–1). Spectra were recorded neat or from thin films using NaCl plates. HRMS were performed at the Bioanalytical Mass Spectrometry Facility within the Mark Wainwright Analytical Centre at The University of New South Wales on an Orbitrap LTQ XL (Thermo Fisher Scientific, San Jose, Ca, USA) ion trap mass spectrometer using a nanospray (nano-electrospray) ionization source to generate ions from the analyte in solution. The instrument was calibrated with a standard calibration solution (as outlined in the instrument manual) on the day of analysis using direct infusion with the nanospray source. The instrument conditions were optimized for sensitivity on each compound of interest using LC tune software. The analysis was carried out in positive ion mode using the orbitrap FTMS analyser at a resolution of 100000. Samples, 5 µL, (1 µg/mL in methanol or acetonitrile), were injected into a glass needle and inserted into the nanospray source. Ions generated were measured over the mass range 150 to 2000. Data was acquired in full scan mode over 60 seconds. Data was analyzed using the Qual Browser feature in Xcaliber 2.1 (Thermo Fisher Scientific, San Jose, Ca, USA). Optical rotations (훼) were recorded on Rudolph Research Analytical Autopol 1 Automatic Polarimeter. Samples were prepared in 5 or 2.5 mL volumetric flasks at stated concentration (g/100 mL) in chloroform. Measurements were taken at 589 nm (sodium D line), at the stated temperature in a 1.0 or 0.5 dm path length optical cell. Values are reported as specific rotations ([훼]).

Unless otherwise stated all reactions were performed in flame dried glassware under an atmosphere of dry nitrogen. Reaction temperatures refer to the external bath temperature.

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Concentration of solvents was performed under reduced pressure on a rotary evaporator, after which residual solvent was removed under high vacuum (~0.1 mm/Hg).

Reagents and solvents were purchased from commercial sources and used without further purification, unless stated below. Reagents and solvents used in reactions were purified according to well established procedures.173 In particular, tetrahydrofuran (THF), diethyl ether

(Et2O) and 1,4-dioxane were freshly distilled from sodium and benzophenone under an inert atmosphere of argon. N,N-Dimethylformamide (DMF) was dried sequentially over three batches of 4Ǻ molecular sieves (3 × 24 h), before finally being stored over a fourth batch of 4Ǻ molecular sieves, under nitrogen. To remove residual N,N-dimethylamine from DMF, the solvent was evacuated (~0.1 mm/Hg) for at least 30 min prior to use. Methanol was distilled from magnesium and stored over 3Ǻ molecular sieves, under nitrogen. N,N-Diisopropylamine, pyridine, dichloromethane and 1,2-dichloroethane were distilled from calcium hydride immediately prior to use. Triisopropylborate was distilled from sodium immediately before use. Sodium hydride (60 % in mineral oil) was washed free of mineral oil by placing in a reaction flask to which dry n-hexane was added. The suspension was stirred for 5 min then the stirring was stopped, the suspension allowed to settle, and the liquid removed (this procedure was repeated two more times). Excess n-hexane was removed under high vacuum (~0.1 mm/Hg) before use. Lead(IV) tetraacetate (moistened with ~ 5% acetic acid) was dried over potassium hydroxide under high vacuum (~0.1 mmHg) for 1 h prior to use. n-Butyllithium in hexanes, t-butyllithium in pentanes and methyl lithium in diethyl ether were purchased from Sigma Aldrich and titrated using menthol and 2,2’-bipyridyl in THF as described by Eastham.174 Diisobutylaluminium hydride in hexanes was purchased from Sigma Aldrich and titrated using 4-anisaldehyde in THF

175 as described by Hoye. Bismuth(III) chloride was dried prior to use by heating at reflux in SOCl2. Cerium(III) chloride heptahydrate was dried by heating at 70°C under high vacuum (~0.1 mm/Hg) for 2 hours, then at 140 °C under high vacuum for 16 h.176 Analytical thin layer chromatography was conducted on Merck, aluminium-backed silica plates 60 F254 and visualised using UV light or stained with a dip of either potassium permanganate, vanillin or phosphomolybdic acid. Flash chromatography was routinely performed using Grace Davison Discovery Sciences, Davisil LC60A 40 – 63 micron silica gel, following published guidelines.177 Solvent was eluted using a Thomson SINGLE StEP pump at the flow rate recommended by the manufacturer (Thomson Instrument Company, Oceanside, Ca, USA). Deactivated silica gel was prepared by washing a column packed with silica gel with neat triethylamine (5 column volumes). After drying, the column was washed with n-hexane to remove any residual triethylamine. 103

Chapter 6

6.2 Experiments Described in Chapter 2 (1R,3S)-6,8-Dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (2.10)

Prepared in 3 steps from tolylnitrile 1.127 according to the protocol reported by Davis and co- workers, and modified by Brusnahan and Toop.94,95,101

(1R,3S)-6,8-Dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (2.15)

A solution of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 2.10 (2.91 g, 13.2 mmol) in dichloromethane (88 mL) was added via cannula to a stirred solution of p-toluenesulfonyl chloride (5.02 g, 26 mmol) and triethylamine (8.3 mL, 59 mmol) in dichloromethane (118 mL) at room temperature. The solution was stirred at room temperature for 16 h then poured onto water. The mixture was extracted with dichloromethane (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified by flash chromatography on silica gel, eluting with 20 % ethyl acetate/n-hexane, to afford the product 2.15 as a clear colourless gum (3.97 g, 80 %).

25.8 [훼]퐷 - 14 (0.5, CHCl3)

1 H NMR (400 MHz; CDCl3): δ 1.48 (d, J = 7.0 Hz, 3H), 1.51 (d, J = 6.6 Hz, 3H), 2.28 (s, 3H), 2.50 (dd, J = 15.7, 7.9 Hz, 1H), 2.71 (dd, J = 15.7, 6.9 Hz, 1H), 3.71 (s, 3H), 3.72 (s, 3H), 3.92 - 4.01 (m, 1 H), 5.29 (q, J = 7.1 Hz, 1H), 6.07 (d, J = 2.1 Hz, 1H), 6.14 (d, J = 2.1 Hz), 7.00 – 7.05 (m, 2H), 7.48 – 7.52 (m, 2H). 104

Chapter 6

13 C NMR (101 MHz; CDCl3): δ 21.5, 23.0, 25.6, 34.9, 47.9, 49.6, 55.3, 55.4, 96.2, 104.2, 119.5, 127.1, 129.1, 134.7, 137.1, 142.5, 156.0, 159.4

HRMS (ESI-MS): m/z calcd for C20H25NO4S [M+Na]+ 398.1397, found 398.1390.

(1R,3S)-5-Iodo-6,8-dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (2.19)

A solution of iodine (1.85 g, 7.3 mmol) in dry ethanol (24 mL) was added dropwise to a solution of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 2.15 (2.62 g, 6.9 mmol) and silver sulfate (4.3 g, 13.8 mmol) in dry ethanol (35 mL) at 0°C. The reaction mixture was allowed to slowly warm to room temperature in the cold bath over 16 h. The solution was filtered through a plug of Celite which was washed thoroughly with dichloromethane. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with 10% aqueous sodium thiosulfate solution, water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified using flash chomatography on silica gel, eluting with 15 % ethyl acetate/n-hexane, to afford the product 2.19 as a clear colourless gum (3.07 g, 88 %).

26.0 [훼]퐷 +20 (0.5, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 1.46 (d, J = 7.0 Hz, 3H), 1.54 (d, J = 6.5 Hz, 3H), 2.28 (s, 3H), 2.61 (dd, J = 16.2, 8.3 Hz, 1H), 3.06 (dd, J = 16.2, 7.0 Hz, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 3.95 (m, 2H), 5.32 (q, J = 7.0 Hz, 1H), 6.15 (s, 1H), 7.02 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H).

13 C NMR (101 MHz, CDCl3): δ 21.5, 22.7, 25.9, 39.5, 47.8, 50.0, 55.5, 56.7, 81.4, 93.4, 121.2, 127.0, 129.1, 136.7, 137.6, 142.6, 156.0, 157.7.

127 + HRMS (ESI-MS): m/z calcd for C20H23 INO4SNa [M+Na] 524.0363, found 524.0327.

((1R,3S)-6,8-dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-5-yl)boronic acid (2.20)

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A solution of t-butyllithium in n-pentane (4.70 mL, 1.4 M, 6.0 mmol) was added dropwise to a solution of iodide 2.19 (1.50 g, 3.0 mmol) [iodide 2.19 was dried azeotropically with benzene (× 3) and residual benzene was removed under reduced pressure immediately before use] and freshly distilled B(Oi-Pr)3 (1.40 mL, 6.0 mmol) in dry THF (60 mL) at -95°C. The solution was stirred for 15 min at this temperature and then the cold bath was replaced with a -10°C cold bath. The solution was stirred for a further 30 min then quenched with saturated aqueous ammonium chloride solution. The mixture was concentrated under reduced pressure then extracted with dichloromethane (× 4). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified by flash chromatography on silica gel, eluting with 50 % ethyl acetate/n-hexane, to afford the product 2.20 as a cloudy colourless gum (1.05 g, 84 %).

26.9 [훼]퐷 - 16 (0.5, CHCl3)

1H NMR (600 MHz, MeOD): δ 1.43 (d, J = 7.1 Hz, 3H), 1.52 (d, J = 6.3 Hz, 3H), 2.23 (s, 3H), 2.50 (dd, J = 15.6, 6.9 Hz, 1H), 2.61 (dd, J = 15.6, 10.3 Hz, 1H), 3.72 (s, 3H), 3.73 – 3.78 (m, 1H), 3.85 (s, 3H), 5.34 (q, J = 7.1 Hz, 1H), 6.26 (s, 1H), 7.04 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H)

13C NMR (151 MHz, MeOD): δ 21.2, 22.8, 26.7, 35.4, 49.3, 51.9, 55.9, 55.9, 93.0, 114.1 (b), 120.1, 128.1, 130.0, 137.1, 138.0, 144.1, 157.6, 162.9.

-1 IR (NaCl, neat): 3437 cm .

+ HRMS (ESI-MS): m/z calcd for C20H27BNO6S [M+H] 420.1647, found 420.1648.

2-((1R,3S)-6,8-Dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-8- methoxy-3-methylnaphthalen-1-ol (2.22/2.23)

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(a) A solution of boronic acid 2.20 (1.67 g, 4.0 mmol) in dry 1,2-dichloroethane (13 mL) was added dropwise to a solution of freshly dried lead(IV) tetraacetate (1.85 g, 4.2 mmol) and mercury(II) trifluoroacetate (0.170 g, 0.4 mmol) in dry 1,2-dichloroethane (30 mL). The solution was protected from light and stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with water, then dried (Na2SO4). The solution was filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure to afford crude aryllead triacetate 2.21 as a bright yellow gum. Due to the lability of this compound it was used immediately in the next step.

(b) A solution of crude aryllead triacetate 2.21 in dry 1,2-dichloroethane (13 mL) was added dropwise to a solution of naphthol 1.113 (0.750 g, 4.0 mmol) and dry pyridine (1.3 mL, 16 mmol) in dry 1,2-dichloroethane (27 mL) at room temperature. The solution was protected from light and stirred at room temperature for 18 h. The reaction mixture was poured onto saturated aqueous ammonium chloride solution and extracted with dichloromethane (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 25 % ethyl acetate/n-hexane, to afford the products 2.22/2.23 as separate atropisomers (1.27 g, 56 % over two steps).

P-Atropisomer (2.22): 24.1 [훼]퐷 + 20 (0.5, CHCl3).

1 H NMR (600 MHz, CDCl3): δ 1.40 (d, J = 6.5 Hz, 3H), 1.54 (d, J = 7.1 Hz, 3H), 2.02 (s, 3H), 2.17 (dd, J = 15.7, 8.5 Hz, 1H), 2.31 (s, 3H), 2.54 (dd, J = 15.7, 6.9 Hz, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 4.06 (s, 3H), 4.08 – 4.21 (m, 1H), 5.18 (q, J = 6.9 Hz, 1H), 6.17 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 7.04 (d, J = 7.9 Hz, 2H), 7.22 (s, 1H), 7.26 – 7.32 (m, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 9.29 (s, 1H).

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13 C NMR (151 MHz, CDCl3): δ 20.6, 21.6, 22.7, 26.1, 31.6, 47.8, 50.8, 55.1, 56.1, 56.2, 92.9, 103.3, 113.6, 117.2, 118.8, 119.0, 119.5, 121.4, 125.7, 127.4, 128.9, 134.4, 136.1, 137.3, 138.5, 142.0, 151.3, 154.9, 156.3, 156.8.

IR (NaCl, neat): 3378 cm-1.

+ HRMS (ESI-MS): m/z calcd for C32H35NO6S [M+Na] 584.2077, found 584.2067.

M-Atropisomer (2.23): 26.2 [훼]퐷 + 60 (0.5, CHCl3).

1 H NMR (600 MHz, CDCl3): δ 1.42 (d, J = 6.3 Hz, 3H), 1.54 (d, J = 7.1 Hz, 3H), 1.61 (s, 3H), 2.27 (s, 3H), 2.28 – 2.33 (m, 1H), 2.42 (dd, J = 16.2, 10.0 Hz, 1H), 3.48 – 3.59 (m, 1H), 3.63 (s, 3H), 3.87 (s, 3H), 3.99 (s, 3H), 5.56 (q, J = 7.1 Hz, 1H), 6.29 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 8.1 Hz, 2H), 7.15 (s, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 9.38 (s, 1H).

13 C NMR (151 MHz, CDCl3): δ 20.1, 21.4, 22.7, 26.4, 31.1, 48.2, 50.3, 55.4, 56.1, 56.2, 93.0, 103.4, 113.5, 116.7, 118.6, 118.7, 119.5, 121.3, 125.7, 127.3, 128.9, 134.3, 136.1, 136.3, 138.0, 142.3, 151.4, 154.9, 156.2, 156.7.

IR (NaCl, neat): 3385 cm-1.

+ HRMS (ESI-MS): m/z calcd for C32H35NO6S [M+Na] 584.2077, found 584.2065.

P-(1R,3S)-6,8-Dimethoxy-5-(8-methoxy-1-(methoxymethoxy)-3-methylnaphthalen-2-yl)-1,3- dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (2.25)

A solution of Ts-protected 2.22 (0.151 g, 0.27 mmol) in dry THF (2.7 mL) was added to a mixture of sodium hydride (60 % dispersion in mineral oil, 0.33 mg, 0.81 mmol) in dry THF (3.3 mL) and allowed to stir at room temperature for 2 h. Methoxymethyl chloride (0.06 mL, 0.81 mmol) was

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added and the mixture allowed to stir for 10 minutes, then poured onto saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified by flash column chromatography on silica gel, eluting with 25 % ethyl acetate/n-hexane afford the product 2.25 as a yellow gum (0.156 g, 92 % yield).

26.2 [훼]퐷 - 36 (0.5, CHCl3).

1 H NMR (500 MHz, CDCl3): δ 1.37 (d, J = 6.5 Hz, 3H), 1.53 (d, J = 6.9 Hz, 3H), 1.99 (s, 3H), 2.11 (dd, J = 16.3, 6.9 Hz, 1H), 2.35 (s, 3H), 2.53 (s, 3H), 2.56 (q, J = 16.3, 6.4 Hz, 1H), 3.67 (s, 3H), 3.84 (s, 3H), 3.93 (s, 3H), 3.93 – 4.00 (m, 1H), 4.63 (d, J = 5.3 Hz, 1H), 4.70 (d, J = 5.3 Hz, 1H), 5.37 (q, J = 6.9 Hz, 1H), 6.35 (s, 1H), 6.80 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.29 – 7.41 (m, 2H), 7.47 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H).

13 C NMR (151 MHz, CDCl3): δ 20.5, 21.6, 24.1, 25.2, 32.4, 47.6, 49.0, 55.5, 55.7, 56.0, 56.2, 92.9, 99.8, 105.5, 118.3, 118.6, 119.1, 120.6, 124.5, 126.1, 127.3, 128.7, 129.4, 133.9, 136.9, 137.1, 137.9, 142.5, 150.3, 155.3, 156.1, 157.0.

+ HRMS (ESI-MS): m/z calcd for C34H39NO7S [M+Na] 628.2339, found 628.2327.

P-(3S)-6,8-Dimethoxy-5-(8-methoxy-1-(methoxymethoxy)-3-methylnaphthalen-2-yl)-1,3- dimethyl-3,4-dihydroisoquinoline (2.26)

a) Lithium aluminium hydride (0.131 g, 3.5 mmol) was added in a single portion to a solution of MOM-ether 2.25 (0.156 g, 0.25 mmol) in dry THF (5 mL) at 0 ᵒC. The mixture was allowed to slowly warm to room temperature, in the cold bath, over 16 h. Saturated aqueous sodium sulphate was added until the mixture ceased effervescing and stirred for 1 h. The mixture was filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed

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under reduced pressure. Due to the lability of this compound it was used immediately in the next step. b) Potassium permanganate (0.118 g, 0.75 mmol) was added in a single portion to a solution of crude tetrahydroisoquinoline in THF (25 mL) at room temperature. The mixture was stirred at this temperature for 3 h and then filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure and the crude material purified by flash column chromatography on deactivated silica gel, eluting with 60 % ethyl acetate/n-hexane afford the product 2.26 as a yellow gum (0.073 g, 65 % yield over two steps).

25.8 [훼]퐷 - 14 (0.5, CHCl3).

1 H NMR (400 MHz, CDCl3): δ 1.19 (d, J = 6.8 Hz, 3H), 1.84 (dd, J = 15.9, 12.2 Hz, 2H), 2.03 (s, 3H), 2.39 (dd, J = 15.9, 4.6 Hz, 1H), 2.49 (s, 3H), 2.86 (s, 3H), 3.29 – 3.42 (m, 1H), 3.76 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.79 (d, J = 5.3 Hz, 1H), 4.95 (d, J = 5.3 Hz, 1H), 6.47 (s, 1H), 6.81 (dd, J = 7.2, 1.3 Hz, 1H), 7.31 – 7.40 (m, 2H), 7.51 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 20.5, 22.0, 27.9, 32.2, 51.2, 55.7, 55.8, 56.3, 56.3, 93.5, 100.3, 105.4, 112.8, 118.2, 119.1, 120.6, 124.6, 126.2, 128.7, 137.0, 137.2, 141.3, 150.2, 156.1, 158.8, 160.1, 163.4.

IR (NaCl, neat): 1612 cm-1.

+ HRMS (ESI-MS): m/z calcd for C27H31NO5 [M+H] 450.2275, found 450.2266.

Ancistrotectorine D (1.123)

A 2 M aqueous HCl solution (0.1 mL) was added to a solution of 2.26 (0.040 g, 0.09 mmol) in THF (1 mL) at room temperature and allowed to stir for 2 h. The solvent was removed under reduced pressure, the crude material dissolved in methanol and stirred with solid K2CO3 (0.2 g) for 10 minutes. The mixture was filtered through a short plug of Celite, eluting with methanol and the 110

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solvent removed under reduced pressure. The crude material purified by flash column chromatography on deactivated silica gel, eluting with 60 % ethyl acetate/n-hexane afford ancistrotectorine D (1.123) as a yellow gum (0.031 g, 87 % yield).

25.6 [훼]퐷 - 30 (0.25, MeOH).

1 H NMR (400 MHz, CDCl3): δ 1.19 (d, J = 6.7 Hz, 3H), 1.87 (dd, J = 15.9, 11.7 Hz, 1H), 2.05 (s, 3H), 2.37 (dd, J = 15.9, 4.6 Hz, 1H), 2.49 (d, J = 1.7 Hz, 3H), 3.35 (m, 1H), 3.77 (s, 3H), 3.94 (s, 3H), 4.01 (s, 3H), 6.51 (s, 1H), 6.73 (dd, J = 7.6, 1.0 Hz, 1H), 7.24 – 7.27 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.4, 1.0 Hz, 1H), 9.46 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 20.5, 21.7, 27.9, 31.8, 51.3, 55.6, 55.9, 56.1, 94.0, 103.4, 113.1, 113.6, 117.0, 118.8, 118.9, 121.4, 125.7, 136.2, 138.4, 141.1, 151.0, 156.3, 158.6, 159.6, 163.6.

1H NMR (400 MHz, DMSO-d6): δ 1.05 (d, J = 6.7 Hz, 3H), 1.75 (dd, J = 15.8, 11.7 Hz, 1H), 1.93 (s, 3H), 2.18 (dd, J = 15.8, 4.7 Hz, 1H), 2.33 (d, J = 1.7 Hz, 3H), 3.17 (m, 1H), 3.71 (s, 3H), 3.93 (s, 3H), 3.99 (s, 3H), 6.68 (s, 1H), 6.88 (dd, J = 6.4, 2.4 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H), 7.30 – 7.37 (m, 2H), 9.36 (s, 1H).

13C NMR (101 MHz, DMSO-d6): δ 20.1, 21.5, 27.3, 31.5, 50.7, 55.4, 55.7, 56.1, 94.5, 103.7, 111.8, 112.9, 116.4, 118.2, 118.4, 120.4, 126.0, 135.4, 137.4, 139.5, 150.5, 155.7, 157.8, 159.1, 161.1.

IR (NaCl, neat): 3365, 2933, 2893, 2837 cm-1.

+ HRMS (ESI-MS): m/z calcd for C25H28NO4 [M+H] 406.2013, found 406.2005.

M-(1R,3S)-6,8-Dimethoxy-5-(8-methoxy-1-(methoxymethoxy)-3-methylnaphthalen-2-yl)-1,3- dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (2.27)

A solution of Ts-protected 2.23 (0.100 g, 0.18 mmol) in dry THF (2.0 mL) was added to a mixture of sodium hydride (60 % dispersion in mineral oil, 0.021 g, 0.53 mmol) in dry THF (2.1 mL) and

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allowed to stir at room temperature for 2 h. Methoxymethyl chloride (0.04 mL, 0.53 mmol) was added and the mixture allowed to stir for 10 minutes, then poured onto saturated aqueous sodium bicarbonate and extracted with ethyl acetate (x 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified by flash column chromatography on silica gel, eluting with 25 % ethyl acetate/n-hexane to afford the product 2.27 as a yellow gum (0.105 g, 93 % yield).

26.2 [훼]퐷 + 34 (0.5, CHCl3).

1 H NMR (600 MHz, CDCl3): δ 1.42 (d, J = 6.3 Hz, 3H), 1.49 (d, J = 7.1 Hz, 3H), 1.58 (d, J = 0.9 Hz, 3H), 2.22 – 2.29 (m, 1H), 2.27 (s, 3H), 2.54 – 2.59 (m, 1H), 2.72 (s, 3H), 3.41 – 3.49 (m, 1H), 3.64 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 4.55 (d, J = 5.0 Hz, 1H), 4.95 (d, J = 5.0 Hz, 1H), 5.59 (q, J = 7.1 Hz, 1H), 6.24 (s, 1H), 6.79 (dd, J = 7.1, 1.9 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 7.30 – 7.38 (m, 2H), 7.43 (d, J = 1.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H).

13 C NMR (151 MHz, CDCl3): δ 20.0, 21.4, 22.5, 26.7, 31.5, 48.0, 50.6, 55.5, 55.8, 56.2, 56.2, 92.1, 100.0, 105.2, 117.5, 119.0, 119.3, 120.5, 124.4, 126.2, 127.3, 128.8, 129.4, 134.7, 136.0, 136.8, 136.8, 142.3, 150.2, 154.7, 155.9, 157.0.

+ HRMS (ESI-MS): m/z calcd for C34H39NO7S [M+Na] 628.2339, found 628.2337.

M-(3S)-6,8-Dimethoxy-5-(8-methoxy-1-(methoxymethoxy)-3-methylnaphthalen-2-yl)-1,3- dimethyl-3,4-dihydroisoquinoline (2.28)

a) Lithium aluminium hydride (0.072 g, 1.9 mmol) was added in a single portion to a solution of MOM-protected ether 2.27 (0.082 g, 0.14 mmol) in dry THF (2.8 mL) at 0 ᵒC. The mixture was allowed to slowly warm to room temperature, in the cold bath, over 16 h. Saturated aqueous sodium sulphate was added until the mixture ceased effervescing and stirred for 1 h. The

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mixture was filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure. Due to the lability of this compound it was used immediately in the next step. b) Potassium permanganate (0.062 g, 0.40 mmol) was added in a single portion to a solution of crude tetrahydroisoquinoline (0.085 g, 0.14 mmol) in THF (11 mL) at room temperature. The mixture was stirred at this temperature for 3 h and then filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure and the crude material purified by flash column chromatography on deactivated silica gel, eluting with 60 % ethyl acetate/n-hexane afford the product 2.28 as a yellow gum (0.035 g, 55 % yield over two steps).

25.8 [훼]퐷 + 20 (0.5, CHCl3).

1 H NMR (400 MHz, CDCl3): δ 1.27 (d, J = 6.8 Hz, 3H), 1.96 – 2.07 (m, 1H), 2.08 (s, 3H), 2.09 – 2.22 (m, 1H), 2.46 (d, J = 2.1 Hz, 3H), 2.82 (s, 3H), 3.10 (m, 1H), 3.77 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.70 (d, J = 5.3 Hz, 1H), 4.93 (d, J = 5.3 Hz, 1H), 6.47 (s, 1H), 6.81 (dd, J = 7.5, 1.4 Hz, 1H), 7.30 – 7.42 (m, 2H), 7.52 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 20.5, 22.7, 27.7, 32.7, 51.8, 55.7, 55.7, 56.2, 56.2, 93.3, 100.2, 105.4, 113.0, 117.6, 119.1, 120.6, 124.5, 126.2, 128.6, 136.7, 137.0, 142.0, 150.8, 156.0, 158.7, 159.9, 163.6.

IR (NaCl, neat): 1612 cm-1.

+ HRMS (ESI-MS): m/z calcd for C27H31NO5 [M+H] 450.2275, found 450.2274.

Ancistrotanzanine A (1.122)

2 M aqueous HCl solution (0.1 mL) was added to a solution of 2.28 (0.030 g, 0.07 mmol) in THF (1 mL) at room temperature and allowed to stir for 2 h. The solvent was removed under reduced 113

Chapter 6

pressure, the crude material dissolved in methanol and stirred with solid K2CO3 (0.2 g) for 10 minutes. The mixture was filtered through a short plug of Celite, eluting with methanol and the solvent removed under reduced pressure. The crude material purified by flash column chromatography on deactivated silica gel, eluting with 60 % ethyl acetate/n-hexane afford ancistrotanzanine A (1.122) as a pale-yellow gum (0.023 g, 84 % yield). For the purpose of comparison with the reported data, the compound was characterised as both the free base and the TFA salt (prepared by adding a drop of TFA to a solution of compound in methanol).

Ancistrotanzanine A:

24.1 [훼]퐷 + 40 (0.10, EtOH).

1 H NMR (400 MHz, CDCl3): δ 1.25 (d, J = 6.7 Hz, 3H), 2.02 – 2.19 (m, 2H), 2.08 (d, J = 0.9 Hz, 3H), 2.48 (d, J = 2.0 Hz, 3H), 3.15 (m, 1H), 3.78 (s, 3H), 3.94 (s, 3H), 4.00 (s, 3H), 6.51 (s, 1H), 6.73 (dd, J = 7.7, 1.0 Hz, 1H), 7.22 – 7.28 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.37 (dd, J = 8.4, 1.0 Hz, 1H), 9.44 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 20.5, 22.5, 27.8, 32.0, 51.7, 55.5, 55.8, 56.1, 93.9, 103.4, 113.1, 113.6, 116.5, 118.7, 118.7, 121.4, 125.7, 136.2, 137.9, 141.6, 151.6, 156.3, 158.7, 159.6, 163.8.

IR (NaCl, neat): 3364, 2933, 2920 2836 cm-1.

+ HRMS (ESI-MS): m/z calcd for C25H28NO4 [M+H] 406.2013, found 406.2008.

Ancistrotanzanine A (TFA salt):

1H NMR (600 MHz, MeOD): δ 1.33 (d, J = 6.7 Hz, 3H), 2.06 (s, 3H), 2.61 – 2.65 (m, 1H), 2.81 (d, J = 1.2 Hz, 3H), 3.81 (m, 1H), 3.91 (s, 3H), 4.05 (s, 3H), 4.13 (s, 3H), 6.81 (s, 1H), 6.90 (d, J = 7.2 Hz, 1H), 7.25 (s, 1H), 7.30 – 7.40 (m, 2H).

13C NMR (151 MHz, MeOD): δ 18.1, 20.3, 24.8, 32.7, 49.5, 56.7, 56.9, 56.9, 95.7, 105.0, 109.0, 114.5, 117.5, 120.0, 120.5, 122.1, 127.5, 137.9, 138.0, 141.4, 152.7, 157.5, 166.2, 168.2, 175.8.

Ancistrotectorine C (1.124)

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a) Lithium aluminium hydride (0.050 g, 1.3 mmol) was added in a single portion to a solution of Ts-protected 2.23 (0.053 g, 0.090 mmol) in dry THF (1 mL) at 0 ᵒC. The mixture was allowed to slowly warm to room temperature, in the cold bath, over 16 h. Saturated aqueous sodium sulphate was added until the mixture ceased effervescing and stirred for 1 h. The mixture was filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure. Due to the lability of this compound it was used immediately in the next step. b) Concentrated aqueous formaldehyde solution (0.070 mL, 38%, 0.9 mmol) was added to a solution of crude tetrahydroisoquinoline in methanol (1.8 mL) at room temperature. The solution was stirred at this temperature for 1 h then sodium borohydride (20 mg, 0.54 mmol) was added in one portion at room temperature. The solution was stirred at this temperature for 15 h then quenched with 1M aqueous hydrochloric acid solution. The mixture was neutralised with solid sodium bicarbonate then extracted with dichloromethane (x 4). The organic extracts were combined and washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on deactivated silica gel, eluting with 30 % DCM/n-hexanes to afford ancistrotectorine C (1.124) as a bright orange gum (20 mg, 54 % yield over two steps).

23.7 [훼]퐷 + 45 (0.20, MeOH).

1H NMR (400 MHz, DMSO): δ 0.93 (d, J = 5.1 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.92 (s, 3H), 1.94 (d, J = 13.4 Hz, 1H), 2.22 (d, J = 9.5 Hz, 2H), 2.33 (s, 3H), 3.64 (s, 3H), 3.86 (s, 3H), 4.00 (s, 3H), 6.60 (s, 1H), 6.88 (d, J = 6.7 Hz, 1H), 7.22 (s, 1H), 7.29 – 7.37 (m, 3H), 9.35 (s, 1H).

13C NMR (101 MHz, DMSO-d6): δ 20.3, 21.4, 23.2, 35.9, 41.0, 54.5, 55.2, 55.4, 56.1, 56.2, 93.8, 103.6, 113.0, 115.6, 118.0, 119.2, 119.9, 120.4, 125.8, 135.3, 135.9, 137.2, 151.1, 155.2, 155.5, 155.7.

IR (NaCl, neat): 3383, 2962, 2835, 2771 cm-1. 115

Chapter 6

+ HRMS (ESI-MS): m/z calcd for C26H32NO4 [M+H] 422.2326, found 422.2318.

atrop-Ancistrotectorine C (2.29)

a) Lithium aluminium hydride (0.049 g, 1.3 mmol) was added in a single portion to a solution of Ts-amine 2.22 (0.050 g, 0.089 mmol) in dry THF (1 mL) at 0 ᵒC. The mixture was allowed to slowly warm to room temperature, in the cold bath, over 16 h. Saturated aqueous sodium sulphate was added until the mixture ceased effervescing and stirred for 1 h. The mixture was filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure. Due to the lability of this compound it was used immediately in the next step. b) Concentrated aqueous formaldehyde solution (0.070 mL, 38%, 0.90 mmol) was added to a solution of crude tetrahydroisoquinoline in methanol (1.0 mL) at room temperature. The solution was stirred at this temperature for 1 h then sodium borohydride (20 mg, 0.54 mmol) was added in one portion at room temperature. The solution was stirred at this temperature for 15 h then quenched with 1M aqueous hydrochloric acid solution. The mixture was neutralised with solid sodium bicarbonate then extracted with dichloromethane (x 4). The organic extracts were combined and washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on deactivated silica gel, eluting with 60 % dichloromethane/n-hexanes to afford atrop-ancistrotectorine C (2.29) as an orange gum (17 mg, 45 % yield over two steps).

25.1 [훼]퐷 - 50 (0.12, MeOH).

1 H NMR (400 MHz, CDCl3): δ 1.11 (d, J = 5.3 Hz, 3H), 1.48 (d, J = 5.5 Hz, 3H), 2.05 – 2.25 (m, 2H), 2.09 (s, 3H), 2.26 -2.36 (m, 1H), 2.47 (s, 3H), 3.72 (s, 3H), 3.73 – 3.85 (m, 1H), 3.90 (s, 3H), 4.01 (s, 3H), 6.51 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 7.22 – 7.33 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 9.41 (s, 1H).

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13 C NMR (101 MHz, CDCl3): δ 20.6, 21.2, 22.7, 35.6, 41.3, 55.2, 55.4, 56.1, 56.3, 57.5, 94.0, 103.2, 113.5, 116.8, 118.9, 119.6, 121.4, 125.5, 136.1, 136.4, 138.7, 150.8, 155.9, 156.2, 156.3.

IR (NaCl, neat): 3385, 2960, 2812 cm-1.

+ HRMS (ESI-MS): m/z calcd for C26H32NO4 (M+H) 422.2326, found 422.2318.

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6.3 Experiments Described in Chapter 3 Triphenylbismuth(V) acetate (3.10)141

Iodobenzene diacetate (0.16 g, 0.50 mmol) was added in a single portion to a solution of triphenylbismuth (0.20 g, 0.45 mmol) in dichloromethane (4.5 mL) at ambient temperature and stirred for 18 hours. The reaction mixture was filtered and the solid rinsed with pentanes. The crude material was purified by recrystallisation from dichloromethane/pentanes (4:1) to afford diacetate 3.10 as a white solid (0.16 g, 63 %), with all the analytical data matching that reported in the literature.141

Mp: 170 - 174 °C, Lit (189 °C).141

1 H NMR (300 MHz, CDCl3): δ 1.82 (s, 6H), 7.44 – 7.52 (m, 3 H), 7.56 – 7.64 (m, 6H), 8.12 – 8.19 (m, 6H).

8-Methoxy-3-methyl-2-phenylnaphthalen-1-ol (3.11)

1,1,3,3-tetramethylguanidine (0.022 mL, 0.11 mmol) was added to a solution of naphthol 1.113 (0.017 g, 0.09 mmol) in THF (1 mL). Triphenylbismuth diacetate 3.10 (0.05 g, 0.09 mmol) was added and the mixture stirred for 15 hours. The resulting solution was poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 5 % ethyl acetate/n-hexanes, to afford the product 3.11 as a colourless oil (0.018 g, 75 %).

1 H NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 4.01 (s, 3H), 6.74 (d, J = 7.4 Hz, 1H), 7.23 (s. 1H), 7.27 – 7.40 (m, 5H), 7.43 – 7.50 (m, 2H), 9.54 (s, 1H).

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13 C NMR (101 MHz, CDCl3): δ 21.3, 56.3, 103.7, 113.6, 119.0, 121.3, 125.1, 125.8, 127.0, 128.4, 130.2, 135.9, 137.0, 138.0, 151.0, 156.4.

IR (neat): 3370 cm-1

+ HRMS: Electrospray Calcd for C18H16O2 (M+H) 265.1223, found 265.1223.

8-Methoxy-3-methyl-2-phenylnaphthalen-1-ol (3.11), one-pot procedure

Iodobenzene diacetate (0.14 g, 0.43 mmol) was added in a single portion to a solution of triphenylbismuth (0.20 g, 0.45 mmol) in dichloromethane (4.5 mL) at ambient temperature and stirred for 18 hours. Naphthol 1.113 (0.08 g, 0.42 mmol) was added to the reaction mixture, followed by 1,1,3,3-tetramethylguanidine (0.05 mL, 0.42 mmol), and stirred for a further 22 hours. The resulting solution was poured onto saturated aqueous ammonium chloride solution and extracted with ethyl acetate (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 5 % ethyl acetate/n-hexanes, to afford the product 3.11 as a colourless oil (0.07 g, 70 %), with all analytical data matching that previously recorded.

Triphenylbismuth(V) dichloride (3.32)178

Sulfuryl chloride (0.4 mL, 4.7 mmol) was added to a solution of triphenylbismuth (2.0 g, 4 mmol) in dichloromethane (20 mL) at 0 °C. The mixture was stirred at room temperature for 4 h, then concentrated to afford the product 3.32 as a white solid (1.84 g, 90 %) with all the analytical data matching that reported in the literature.178

Mp: 150-155 °C, Lit (152-154 °C).178

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1 H NMR (400 MHz, CDCl3): δ 7.52 – 7.57 (m, 3H), 7.63 – 7.70 (m, 6H), 8.50 – 8.55 (m, 6H).

Triphenylbismuth(V) difluoride (3.30)151

A solution of KF (2.1 g, 36 mmol) in water (9 mL) was added to a solution of triphenylbismuth dichloride 3.32 (1.84 g, 3.6 mmol) in ethanol (18 mL). The mixture was stirred vigorously at room temperature for 15 h, then diluted with water (18 mL). The ethanol was removed under reduced pressure and the residue extracted with dichloromethane (x 3). The organic extracts were combined and concentrated under reduced pressure to afford difluoride 3.30 as a white powder (1.63 g, 94 %) which was used without further purification. All analytical data matched that reported in the literature.151

Mp: 137-140 °C, Lit (148-153 °C).179

1 H NMR (400 MHz, CDCl3): δ 7.49 (t, J = 7.4 Hz, 3H), 7.66 (t, J = 7.7 Hz, 6H), 8.22 (d, J = 8.3 Hz, 6H).

3-Iodo-4,6-dimethoxy-2-methylbenzonitrile (3.33)

N-Iodosuccinimide (0.13 g, 0.6 mmol) was added to a solution of nitrile 1.127 (0.05 g, 0.3 mmol) in MeCN (0.5 mL) at 0 °C. The reaction was allowed to warm to room temperature over 15 h. Following addition of water, the mixture was extracted with dichloromethane (x 3). The combined organic extracts were washed with 10 % aqueous sodium thiosulfate solution, water, brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 20 % ethyl acetate/n- hexanes to afford iodide 3.33 as a white solid (67 mg, 79 % yield). All analytical data matched that previously reported.91

Mp: 160-164 °C.

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Chapter 6

1 H NMR (400 MHz, CDCl3): δ 2.66 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 6.28 (s, 1H).

(3-Cyano-4,6-dimethoxy-2-methylphenyl)triphenylbismuthonium(V) tetrafluoroborate (3.28)

a) A solution of t-butyllithium in pentane (3.7 mL, 1.3 M, 4.80 mmol) was added dropwise to a solution of iodide 3.33 (0.55 g, 1.83 mmol) in freshly distilled THF (18 mL) at -95°C. The reaction solution was stirred at -95°C for 15 min, at which time freshly distilled triisopropyl borate (1.1 mL, 4.80 mmol) was added dropwise. The solution was allowed to warm slowly to 0°C, in the cold bath, over 5 h, before being quenched with saturated aqueous ammonium chloride solution. After stirring for 15 minutes, the mixture was extracted with ethyl acetate (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure to afford the crude boronic acid 3.31 as a light- yellow oil (0.33 g). Due to the lability of this compound it was immediately used in the next step.

b) BF3·OEt2 (0.23 mL, 1.83 mmol) was added dropwise to a solution of difluoride 3.30 (0.875 g, 1.83 mmol) and crude boronic acid 3.31 (0.330 g, 1.83 mmol) in dichloromethane (18 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. An aqueous solution (0.2 M) of NaBF4 (91 mL) was added and the biphasic mixture stirred vigorously for 20 minutes and extracted with dichloromethane (x 3). The combined organic extracts were dried over Na2SO4 and filtered through a short plug of silica, eluting first with dichloromethane, followed by 10 % methanol/dichloromethane. The second fraction was concentrated under reduced pressure and the residue purified by recrystallisation from dichloromethane and Et2O to afford 3.28 as a white crystalline solid (0.660 g, 51 % over two steps).

Mp: 123-131 °C

1 H NMR (400 MHz, CDCl3): δ 2.35 – 2.40 (m, 3H), 3.69 – 3.76 (m, 3H), 3.98 – 4.04 (m, 3H), 6.76 (s, 1H), 7.58 – 7.70 (m, 9H), 7.72 – 7.81 (m, 6H).

13 C NMR (101 MHz, CDCl3): δ 23.5, 57.2, 57.5, 95.1, 115.2, 124.3, 132.1, 132.2, 132.4, 135.4, 135.7, 140.2, 150.1, 164.2, 167.3.

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IR (neat): 2219, 1100-900 cm-1.

+ HRMS: Electrospray Calcd for C28H25NO2Bi (M) 616.1684, found 616.1680

3-(1-Hydroxy-8-methoxy-3-methylnaphthalen-2-yl)-4,6-dimethoxy-2-methylbenzonitrile (3.27)

NaH (60 % dispersion in mineral oil, 13 mg, 0.31 mmol) was added to a solution of naphthol 1.113 (60 mg, 0.31 mmol) in THF (3 mL) at 0 °C. The solution was allowed to warm to room temperature and stirred for 15 minutes. Bismuthonium 3.28 (220 mg, 0.31 mmol) was added and the bright red solution stirred for 15 hours. Following addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (x 3). The combined organic extracts were washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 20 % ethyl acetate/n-hexanes to afford biaryl 3.27as a white solid (78 mg, 69 % yield). All analytical data matched that reported for biaryl 3.27.95

Mp: 225 – 229°C

1 H NMR (400 MHz, CDCl3): δ 2.04 (s, 3H), 2.19 (s, 3H,), 3.78 (s, 3H), 3.99 (s, 3H), 4.01 (s, 3H), 6.45 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 7.28 – 7.32 (m, 1H), 7.36 – 7.38 (m, 1H), 9.49 (s, 1H).

13 C NMR (101 MHz, CDCl3):  18.3, 20.3, 56.03, 56.06, 56.11, 92.7, 94.9, 103.5, 113.5, 116.9, 118.1, 119.0, 119.6, 121.3, 125.9, 136.2, 137.6, 143.7, 151.1, 156.2, 161.7, 162.9.

IR (neat): 3400, 2210, cm-1.

+ HRMS: Electrospray Calcd for C22H22NO4 (M+H) 364.1549, found 364.1553.

122

Chapter 6

((1R,3S)-6,8-Dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-5- yl)triphenylbismuthonium(V) tetrafluoroborate (3.23)

BF3·OEt2 (62 µL, 0.5 mmol) was added to a solution of difluoride 3.30 (0.24 g, 0.5 mmol) and boronic acid 2.20 (0.21 g, 0.5 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred for 2 hours at room temperature. An aqueous solution (0.2 M) of NaBF4 (25 mL) was added and the biphasic mixture stirred vigorously for 20 minutes and extracted with dichloromethane (x

3). The combined organic extracts were dried over Na2SO4 and filtered through a short plug of silica, eluting with 10 % methanol/ethyl acetate to afford a white solid which was recrystallised from a solution of DCM and Et2O (10:1) to afford bismuthonium 3.23 as white crystals (0.37 g, 81 %).

24.3 [훼]퐷 + 50.0 (c 0.24, CHCl3)

Mp: 156-165 °C

1 H NMR (400 MHz, CDCl3): δ 1.17 (d, J = 6.8 Hz, 3H), 1.42 (d, J = 6.8 Hz, 3H), 2.32 (s, 3H), 2.57 – 2.42 (m, 2H), 3.61 (s, 3H), 3.73 (q, J = 6.8 Hz, 1H), 3.89 (s, 3H), 5.30 (q, J = 6.8 Hz, 1H), 6.58 (s, 1H), 7.15 – 7.09 (m, 2H), 7.54 – 7.46 (m, 2H), 7.74 – 7.56 (m, 15H).

13 C NMR (101 MHz, CDCl3): δ 21.6, 22.0, 25.1, 35.9, 47.8, 49.2, 56.3, 57.0, 95.2, 120.6, 124.2, 127.1, 129.3, 132.3, 132.4, 135.3, 136.5, 139.7, 140.7, 143.2, 159.8, 160.0.

IR (neat): 1100-900 cm-1

+ HRMS: Electrospray Calcd for C38H39NO4SBi (M) 814.2398, found 814.2393.

123

Chapter 6

6.4 Experiments described in Chapter 4 (2,6-Dimethoxy-4-methylphenyl)boronic acid (4.12)

A 1.4 M solution of n-BuLi in hexanes (0.65 mL, 0.88 mmol) was added dropwise to a solution of 3,5-dimethoxytoluene 4.10 (0.112 g, 0.74 mmol) in THF (1.3 mL) at 0 °C. The solution was stirred at 0 °C for 2 hours before adding B(O-iPr)3 (0.2 mL, 0.88 mmol). The solution was allowed to warm to room temperature, and then stirred for 30 minutes. Following addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (x 3). The combined organic extracts were washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material to afford boronic acid 4.12 as yellow oil (0.11 g, 76 % yield).

1 H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 3.75 (s, 6H), 6.43 (s, 2 H).

13 C NMR (101 MHz, CDCl3): δ 22.2, 55.8, 105.3, 108.0, 142.9, 163.6.

IR (neat): 3478 cm-1.

+ HRMS: Electrospray Calcd for C9H14BO4 (M+H) 197.0980, found 197.0979.

(2,6-Dimethoxy-4-methylphenyl)triphenylbismuth(V) tetrafluoroborate (4.11)

BF3·OEt2 (0.07 mL, 0.56 mmol) was added dropwise to a solution of difluoride 3.30 (0.268 g, 0.56 mmol) and crude boronic acid 4.12 (0.110 g, 0.56 mmol) in dichloromethane (6.0 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. An aqueous solution (0.2 M) of NaBF4 (28 mL) was added and the biphasic mixture stirred vigorously for 20 minutes and extracted with dichloromethane (x 3). The combined organic extracts were dried over Na2SO4 and filtered through a short plug of silica, eluting first with dichloromethane, 124

Chapter 6

followed by 10 % methanol/dichloromethane. The second fraction was concentrated under reduced pressure and the residue purified by recrystallisation from dichloromethane and Et2O to afford 4.11 as a white crystalline solid (0.245 g, 64 %).

Mp: 161 - 165 °C

1 H NMR (400 MHz, CDCl3): δ 2.47 (s, 3H), 3.67 (s, 6H), 6.72 (s, 2 H), 7.57 – 7.76 (m, 15H).

13 C NMR (101 MHz, CDCl3): δ 22.6, 56.3, 107.2, 111.9, 132.1, 135.3, 137.6, 148.5, 161.3.

IR (neat): 1100-900 cm-1

+ HRMS: Electrospray Calcd for C27H26O2Bi (M) 591.1731, found 591.1733.

2-(2,6-Dimethoxy-4-methylphenyl)-8-methoxy-3-methylnaphthalen-1-ol (4.13)

NaH (60 % dispersion in mineral oil, 11 mg, 0.27 mmol) was added to a solution of naphthol 1.113 (50 mg, 0.27 mmol) in THF (2.7 mL) at 0 °C. The solution was allowed to warm to room temperature and stirred for 15 minutes. Bismuthonium 4.11 (185 mg, 0.27 mmol) was added and the bright red solution stirred for 15 hours. Following addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (x 3). The combined organic extracts were washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 20 % ethyl acetate/n-hexanes to afford biaryl 4.13 as an orange gum (55 mg, 60 % yield).

1 H NMR (400 MHz, CDCl3): δ 2.14 (d, J = 0.5 Hz, 3H), 2.44 (br s, 3H), 3.72 (s, 6H), 3.98 (s, 3H), 6.54 (br s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.7 Hz, 2H), 7.35 (d, J = 8.6 Hz, 1H), 9.47 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 20.6, 22.4, 56.00, 56.2, 103.0, 105.5, 112.2, 113.6, 117.6, 118.5, 121.4, 125.2, 136.1, 138.5, 139.1, 151.2, 156.3, 158.0.

IR (neat): 3382 cm-1 125

Chapter 6

+ HRMS: Electrospray Calcd for C21H22O4 (M+Na) 361.1410, found 361.1410.

2,4-Dimethoxy-6-methyl-3-(triethylsilyl)benzonitrile (4.22)

A mixture of 1.127 (0.05 g, 0.28 mmol), Et3SiH (0.81 mL, 5.08 mmol), di-tert-butyl peroxide (0.63 mL, 3.30 mmol), Cu2O (2 mg, 0.01 mmol) and t-BuOH (1.5 mL) was heated at 120 °C for 15 h in a sealed tube, at which time Et3SiH (0.81 mL, 5.08 mmol) and di-tert-butyl peroxide (0.63 mL, 3.30 mmol) was added and the reaction heated for a further 12 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel, eluting with 5 % ethyl acetate/n-hexane, to afford the product 4.22 as a yellow gum (0.024 g, 30 %).

1 H NMR (400 MHz, CDCl3): δ 0.79 – 0.87 (m, 6H), 0.87 – 0.94 (m, 9H), 2.50 (s, 3H), 3.79 (s, 3H), 3.95 (s, 3H), 6.49 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 4.8, 7.9, 21.1, 55.5, 62.5, 99.0, 107.3, 115.7, 117.1, 147.2, 168.6, 169.9.

IR (neat): 2217 cm-1

+ HRMS: Electrospray Calcd for C16H25NO2Si (M+Na) 314.1547, found 314.1541.

3-Iodo-2,4-dimethoxy-6-methylbenzonitrile (4.23)

N-Iodosuccinimide (0.109 g, 0.48 mmol) was added to a solution of 4.2 (0.094 g, 0.32 mmol) in MeCN (3 mL) at room temperature. The reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure, sodium thiosulfate added and extracted with EtOAc (x 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The

126

Chapter 6

solvent was removed under reduced pressure and the residue purified by flash column chromatography on silica gel, eluting with 5 % ethyl acetate/n-hexane, to afford the product 4.23 as a colourless gum (12 mg, 12 % yield).

1 H NMR (400 MHz, CDCl3): δ 2.51 (s, 3H), 3.93 (s, 3H), 4.00 (s, 3H), 6.51 (s, 1H).

IR (neat): 2215 cm-1

+ HRMS: Electrospray Calcd for C10H10INO2Na (M+Na) 325.9648, found 325.9644.

2-Bromo-1,3-dimethoxy-5-(2-nitroprop-1-en-1-yl)benzene (4.30)

A mixture of aldehyde 4.27 (10.0 g, 0.041mmol) and ammonium acetate (3.7 g, 0.048 mol) in nitroethane (35 mL) was heated at reflux for 5h. The reaction was concentrated, the residue poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (x 4). The organic extracts were combined and washed with water and brine, then dried

(Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by recrystallisation from ethanol to afford the product 4.30 as yellow crystals (7.94 g, 65 %), with all the analytical data matching that reported in the literature.180

Mp: 144 – 154 °C, Lit (121-121.5 °C).181

1 H NMR (400 MHz, CDCl3): δ 2.46 (d, J = 1.0 Hz, 3 H), 3.93 (s, 6H), 6.60 (s, 2), 8.01 – 8.04 (m, 1H).

IR (neat): 1556 and 1336 cm-1.

1-(4-Bromo-3,5-dimethoxyphenyl)propan-2-one (4.31)

A mixture of nitrostyrene 4.30 (7.94 g, 0.026 mol) and Fe powder (17.6 g) in glacial acetic acid (260 mL) was heated at reflux for 3 h. The resulting grey mixture was diluted with water (600 127

Chapter 6

mL) and extracted with Et20 (x 4). The organic extracts were washed with 1 M NaOH solution, water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by recrystallisation from Et2O and n-hexanes to afford the product 4.31 as a white solid (5.82 g, 81 %).

Mp: 63-68 °C

1 H NMR (400 MHz, CDCl3): δ 2.17 (s, 3H), 3.66 (s, 2H), 3.87 (s, 6H), 6.40 (s, 3H).

13 C NMR (101 MHz, CDCl3): δ 29.4, 51.3, 56.6, 99.8, 106.0, 134.9, 157.3, 205.8.

IR (neat): 1706 cm-1

79 + HRMS: Electrospray Calcd for C11H13 BrO3 (M+Na) 294.9940, found 294.9936.

(S)-N-((S)-1-(4-Bromo-3,5-dimethoxyphenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (4.29)

A solution of ketone 4.31 (5.82 g, 0.021 mol) in THF (140 mL) was transferred via cannula to a solution of (S)-(−)-2-methyl-2-propanesulfinamide (5.1 g, 0.042 mol) and Ti(OEt)4 (22.0 mL, 0.11 mol) in THF (105 mL). The reaction was heated at reflux for 4 hours until complete consumption of starting material, as indicated by TLC. After cooling to -45 °C (MeCN/N2(l) bath), NaBH4 (0.83 g, 0.022 mol) was added and the solution allowed to warm to room temperature over 15 h. MeOH was added dropwise until gas evolution ceased. The resulting solution was poured onto an equal volume of brine with rapid stirring and the suspension filtered through a plug of Celite, eluting with ethyl acetate. The filtrate was washed with brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 40 % ethyl acetate/n-hexane, to afford the product 4.29 as yellow crystals (6.40 g, 80 %).

22.5 [훼]퐷 + 83.3 (c 0.36, CHCl3)

Mp: 124 – 132 °C

128

Chapter 6

1 H NMR (400 MHz, CDCl3): δ 1.15 – 1.19 (m, 12H), 2.79 (dd, J = 6.3, 13.5 Hz, 1H), 2.85 (dd, J = 6.3, 13.5 Hz, 1H), 3.22 (br d, J = 5.3 Hz, 1H), 3.63 – 3.74 (m, 1H), 3.88 (s, 6H), 6.44 (s, 2H).

13 C NMR (101 MHz, CDCl3): δ 20.9, 22.7, 44.9, 51.5, 55.6, 56.6, 99.1, 106.4, 138.1, 157.1.

IR (neat): 3360, 3231, 2967 cm-1

79 + HRMS: Electrospray Calcd for C15H24 BrNO3S (M+Na) 400.0552, found 400.0547.

(S)-1-(4-Bromo-3,5-dimethoxyphenyl)propan-2-amine hydrochloride (4.32)

A 4 M HCl solution in dioxane (8.45 mL, 0.034 mol) was added dropwise to a solution of sulfinamide 4.29 (6.40 g, 0.017 mol) in MeOH (8.5 mL) and the resulting red solution stirred for

2 hours. Et2O was added to the reaction and the resulting precipitate filtered, washing with Et2O, to afford amine 4.32 as a white powder (4.82 g, 92 %).

22.6 [훼]퐷 + 28.9 (c 0.76, MeOH)

Mp: 252-257°C

1H NMR (400 MHz, MeOD): δ 1.31 (d, J = 6.4 Hz, 3H), 2.84 (dd, J = 7.7 and 13.5 Hz, 1H), 2.92 (dd, J = 6.9 and 13.5 Hz, 1H), 3.53 – 3.63 (m, 1H), 3.88 (s, 6H), 6.59 (s, 2H).

13C NMR (101 MHz, MeOD): δ 18.6, 42.1, 50.04, 56.9, 100.7, 106.9, 138.3, 158.8.

IR (neat): 3471, 3306, 2897 cm-1

79 + HRMS: Electrospray Calcd for C11H16 BrNO2 (M+H) 274.0437, found 274.0432.

(S)-N-(1-(4-Bromo-3,5-dimethoxyphenyl)propan-2-yl)acetamide (4.33)

129

Chapter 6

NEt3 (4.91 mL, 0.035 mol) was added to a suspension of amine 4.32 (4.82 g, 0.016 mol) in dichloromethane (155 mL) at 0 °C. Freshly distilled acetyl chloride (1.34 mL, 0.019 mol) was added dropwise and the solution allowed to warm to room temperature. After stirring for 15 h, the solution was diluted with dichloromethane and washed with 1 M HCl solution (x 3), water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure to afford acetate 4.33 as a white solid (4.57 g, 90 %).

24.4 [훼]퐷 - 83.3 (c 0.12, CHCl3)

Mp: 149 – 151 °C

1 H NMR (400 MHz, CDCl3): δ 1.13 (d, J = 6.7 Hz, 3H), 1.96 (s, 3H), 2.65 (dd, J = 7.4, 13.3 Hz, 1H), 2.87 (dd, J = 5.9, 13.3 Hz, 1H), 3.88 (s, 6H), 4.21 – 4.32 (m, 1H), 5.34 (br d, J = 6.7 Hz, 1H), 6.40 (s, 2H).

13 C NMR (101 MHz, CDCl3): δ 20.2, 23.7, 43.0, 46.2, 56.6, 99.1, 106.0, 139.0, 157.1, 170.0.

IR (neat): 3314, 1629 cm-1

79 + HRMS: Electrospray Calcd for C13H18 BrNO3 (M+Na) 338.0362, found 338.0357.

(S)-7-Bromo-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline (4.34)

2,4,6-trimethylpyridine (2.1 mL, 0.016 mol) was added to a solution of acetate 4.33 (4.57 g, 0.014 mol) in MeCN (72 mL). Freshly distilled POCl3 (1.50 mL, 0.016 mol) was added and the reaction was heated at reflux for 3 hours. The resulting solution was poured onto saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (× 3). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with ethyl acetate, to afford the product 4.34 as a yellow oil (3.63 g, 84 %).

23.2 [훼]퐷 + 45.2 (c 0.88, CHCl3)

130

Chapter 6

1 H NMR (400 MHz, CDCl3): δ 1.36 (d, J = 6.7 Hz, 3H), 2.31 (dd, J = 13.2, 15.4 Hz, 1H), 2.46 (d, J = 1.7 Hz, 3H), 2.60 (dd, J = 4.5, 15.4 Hz, 1H), 3.28 – 3.41 (m, 1H), 3.78 (s, 3H), 3.91 (s, 3H), 6.53 (s, 1H).

13 C NMR (101 MHz, CDCl3): δ 21.8, 26.3, 34.8, 51.5, 56.6, 62.0, 105.8, 106.9, 118.0, 141.0, 156.9, 158.4, 162.2.

IR (neat): 3366, 2962, 2929, 2853, 1609 cm-1

79 + HRMS: Electrospray Calcd for C13H16 BrNO2 (M+H) 298.0437, found 298.0433.

(1R,3S)-7-Bromo-6,8-dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinoline (4.38)

a) Sodium borohydride (0.46 g, 12.2 mmol) was added in one portion to a solution of dihydroisoquinoline 4.34 (1.81 g, 6.10 mmol) in methanol (120 mL) at -10°C. The reaction was allowed to warm to room temperature and stirred for 2 h, at which point the methanol was removed under reduced pressure. The residue was dissolved in dichloromethane and filtered through a short plug of Celite, eluting with dichloromethane. The solvent was removed under reduced pressure to afford the 1,2,3,4-tetrahydroisoquinoline (1.81 g) as a clear, pale yellow gum which was of sufficient purity to use in the next step without further purification. b) A solution of crude tetrahydroisoquinoline (1.81 g, 6.0 mmol) in dichloromethane (41 mL) was added via cannula to a stirred solution of p-toluenesulfonyl chloride (1.22 g, 6.4 mmol) and triethylamine (3.8 mL, 27.5 mmol) in dichloromethane (65 mL) at room temperature. The reaction was stirred for 15 h then poured onto water and extracted with dichloromethane (× 3).

The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material purified by flash chromatography on silica gel, eluting with 15 % ethyl acetate/n-hexane, to afford the Ts- protected 4.38 as clear needles (2.21 g, 80 % over two steps).

24.5 [훼]퐷 -87.5 (c 0.16, CHCl3)

Mp: 100-102 °C 131

Chapter 6

1 H NMR (400 MHz, CDCl3): δ 1.52 (d, J = 3.0 Hz, 3H), 1.54 (d, J = 2.3 Hz, 3H), 2.30 (s, 3H), 2.65 (dd, J = 9.0, 15.4 Hz, 1H), 2.79 (dd, J = 7.0, 15.4 Hz, 1H), 3.78 (s, 3H), 3.93 – 4.03 (m, 1H), 5.29 (q, J = 7.00 Hz), 6.31 (s, 1H), 7.06 (d, J = 8.13 Hz, 2H), 7.50 (d, J = 8.13 Hz, 2H).

13 C NMR (101 MHz, CDCl3): δ 21.5, 23.4, 25.9, 34.8, 48.6, 49.8, 56.6, 61.3, 104.8, 107.6, 125.8, 127.1, 129.3, 134.1, 136.5, 143.0, 154.1, 155.9.

79 + HRMS: Electrospray Calcd for C20H24NO4S Br (M+Na) 476.0502, found 476.0500.

((1R,3S)-6,8-Dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-7- yl)triphenylbismuth(V) tetrafluoroborate (4.6)

a) A solution of t-butyllithium in pentane (3.2 mL, 1.7 M, 5.50 mmol) was added dropwise to a solution of bromide 4.38 (1.25 g, 2.70 mmol) [bromide 4.38 was dried azeotropically with benzene (× 3) and residual benzene was removed under reduced pressure immediately before use] and freshly distilled B(O-iPr)3 (1.3 mL, 5.70 mmol) in freshly distilled THF (55 mL) at -95°C. The reaction was stirred at -95°C for 15 min, at which point the cold bath was replaced with a - 10 °C cold bath. The reaction was stirred for a further 30 min then quenched with saturated aqueous ammonium chloride solution. The mixture was concentrated under reduced pressure then extracted with dichloromethane (× 4). The organic extracts were combined and washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure to afford the crude boronic acid 4.39 (1.05 g). Due to the lability of this compound it was immediately used in the next step.

b) BF3·OEt2 (0.33 mL, 2.70 mmol) was added dropwise to a solution of difluoride 3.30 (1.29 g, 2.70 mmol) and crude boronic acid 4.39 (1.05 g) in dichloromethane (27 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 15 hours. An aqueous solution (0.2

M) of NaBF4 (2.96 g, 27.0 mmol) was added and the biphasic mixture stirred vigorously for 20 minutes and extracted with dichloromethane (x 3). The organic extracts were combined, washed with water and brine, then dried (Na2SO4) and filtered through a short plug of silica, eluting first with dichloromethane, followed by 10 % methanol/dichloromethane. The 132

Chapter 6

methanol/dichloromethane fraction was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 3 % methanol/dichloromethane to afford the product 4.6 as a brown oil (1.49 g, 61 % over two steps).

24.6 [훼]퐷 - 50.0 (c 0.24, CHCl3)

1 H NMR (400 MHz, CDCl3): δ 1.51 (d, J = 6.4 Hz, 3H), 1.58 (d, J = 7.2 Hz, 3H), 2.18 (s, 3H), 2.81 (dd, J = 8.4, 16.1 Hz, 1H), 2.91 (dd, J = 6.8, 16.1 Hz, 1H), 3.38 (s, 3H), 3.65 (s, 3H), 3.93 – 4.03 (m, 1H), 5.30 (q, J = 7.00 Hz), 6.79 (s, 1H), 7.05 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.59 – 7.71 (m, 9H), 7.73 – 7.80 (m, 6H).

13 C NMR (101 MHz, CDCl3): δ 21.5, 23.2, 25.1, 35.4, 48.8, 48.9, 56.8, 63.2, 109.9, 122.5, 126.5, 127.2, 129.6, 132.16, 132.2, 135.7, 136.9, 139.2, 142.9, 143.3, 157.9, 159.4.

IR (neat): 1100-900 cm-1

+ HRMS: Electrospray Calcd for C38H39NO4SBi (M-BF4) 814.2398, found 814.2407.

2-((1R,3S)-6,8-Dimethoxy-1,3-dimethyl-2-tosyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-8- methoxy-3-methylnaphthalen-1-ol (4.40/4.41)

NaH (60 % dispersion in mineral oil, 12 mg, 0.28 mmol) was added to a solution of naphthol 1.113 (52 mg, 0.28 mmol) in THF (3.0 mL) at 0 °C. The solution was allowed to warm to room temperature and stirred for 15 minutes. The reaction was cooled to -78 °C and a solution of bismuthonium 4.6 (250 mg, 0.28 mmol) in THF (1 mL) was added via cannula. The resulting bright red solution was allowed to warm slowly to room temperature over 15 hours. Following addition of saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (x 3). The organic extracts were combined, washed with water and brine, then dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel, eluting with 30 % ethyl acetate/n-hexanes to afford a mixture of biaryls 4.40/4.41 as a yellow oil (71 mg, 46 % yield). 133

Chapter 6

HPLC Analysis: HPLC for the separation of the atropisomers obtained from the ortho-arylation reaction was performed on an achiral analytical Symmetry-C18 (Waters, 4.6 x 250 mm) column with the eluents in acetonitrile/water (+ 0.05 % formic acid using a linear gradient (0 min 50% A, 15 min 5% A) with a flow rate of 4.0 mL/min. This gave a retention time of 13.08 min for biaryl 4.40 and a retention time of 13.84 min for biaryl 4.41.

Spectroscopic data for biaryl 4.40:

22.4 [훼]퐷 + 75 (c 0.10, CHCl3)

1 H NMR (600 MHz, CDCl3): δ 1.56 (d, J = 7.2 Hz, 3H), 1.63 (d, J = 6.1 Hz, 3H), 1.99 (s, 3H), 2.32 (s, 3H), 2.83 (dd, J = 9.4, 15.5 Hz, 1H), 2.93 (dd, J = 7.1, 15.7 Hz, 1H), 3.24 (s, 3H), 3.64 (s, 3H), 3.99 (s, 3H), 4.01 – 4.08 (m, 1H), 5.36 (q, J = 7.00 Hz), 6.46 (s, 1H), 6.70 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.22 (s, 1H), 7.24 – 7.30 (m, 1H), 7.35 (br d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 2H), 9.55 (s, 1H).

13 C NMR (151 MHz, CDCl3): δ 20.5, 21.6, 24.0, 26.6, 35.6, 48.7, 50.5, 56.0, 56.1, 60.5, 103.3, 106.3, 113.4, 117.28, 117.32, 118.8, 121.3, 124.3, 125.7, 127.3, 129.4, 134.3, 136.3, 137.5, 138.0, 142.6, 151.3, 154.7, 156.3, 156.9.

IR (neat): 3381 cm-1

+ HRMS: Electrospray Calcd for C32H36NO6 (M+H) 562.2257, found 562.2258.

Spectroscopic data for biaryl 4.41:

22.4 [훼]퐷 + 20 (c 0.05, CHCl3)

1 H NMR (600 MHz, CDCl3): δ 1.13 (d, J = 6.6 Hz, 3H), 1.53 (d, J = 6.7 Hz, 3H), 2.15 (s, 3H), 2.38 (s, 3H), 2.62 (dd, J = 4.9, 15.2 Hz, 1H), 3.17 (dd, J = 4.9, 15.2 Hz, 1H), 3.31 (s, 3H), 3.68 (s, 3H), 4.00 (s, 3H), 4.31 – 4.39 (m, 1H), 5.42 (q, J = 6.6 Hz, 1H), 6.51 (s, 1H), 6.71 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.24 – 7.30 (m, 2H), 7.36 (br d, J = 7.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 9.56 (s, 1H).

13 C NMR (151 MHz, CDCl3): δ 20.5, 20.9, 21.6, 24.2, 36.6, 49.2, 49.9, 56.0, 56.1, 60.6, 103.2, 107.5, 113.5, 117.4, 117.9, 118.9, 121.3, 124.3, 125.7, 127.0, 129.5, 134.6, 136.3, 138.0, 140.4, 142.8, 151.5, 154.8, 156.3, 157.0.

IR (neat): 3381 cm-1

134

Chapter 6

2-((1R,3S,7R)-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-8-methoxy-3- methylnaphthalen-1-ol (4.42)

A solution of sodium naphthalenide in 1,2-dimethoxyethane was prepared by adding sodium (60 mg, 0.023 atom) to a solution of naphthalene (360 mg, 28.2 mmol) in 1,2-dimethoxyethane (2.3 mL) and stirring the resulting mixture at room temperature for 2 h, forming a dark green solution. The sodium naphthalenide solution was added dropwise to a solution of biaryl 4.40 (19 mg, 0.03 mmol) in THF (0.3 mL) at -78 °C until a light green colour persisted. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (1-2 drops), which was filtered through a short plug of silica gel, eluting first with n-hexanes, followed by 10 % methanol/dichloromethane. The methanol/dichloromethane fraction was concentrated and the crude material purified by flash chromatography on deactivated silica gel, eluting with 0.5 % methanol/dichloromethane to afford the product 4.42 as an orange gum (9 mg, 65 %), with all analytical data matching that reported in the literature.30

26.1 [훼]퐷 – 30.0 (c 0.060, CH2Cl2)

1 H NMR (600 MHz, CDCl3): δ 1.17 (d, J = 6.3 Hz, 3H), 1.42 (d, J = 6.3 Hz, 3H), 2.11 (s, 3H), 2.50 (dd, J = 10.8, 15.4 Hz, 1H), 2.68 (dd, J = 2.6, 15.7 Hz, 1H), 2.81-2.90 (m, 1H, merged with solvent signal), 3.26 (s, 3H), 3.63 (s, 3H), 4.10 (s, 3H), 4.25 (q, J = 6.3 Hz), 6.54 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 7.22 (s, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 9.39 (s, 1H).

13 C NMR (151 MHz, CDCl3): δ 20.8, 22.7, 24.0, 40.5, 49.3, 50.7, 55.9, 56.6, 59.6, 104.2, 107.5, 114.3, 118.6, 118.9, 119.0, 121.7, 126.5, 137.0, 138.3, 138.9, 152.7, 157.0, 157.2, 157.9.

IR (neat): 3386, 2960, 2922, 1574, 1359, 1268, 1089 cm-1

+ HRMS: Electrospray Calcd for C25H29NO4 (M+H) 408.2169, found 408.2176.

135

References

References (1) Govindachari, T. R.; Parthasarathy, P. C. Tetrahedron 1971, 27 (5), 1013.

(2) Govindachari, T. R.; Nagarajan, K.; Parthasarathy, P. C.; Rajagopalan, T. G.; Desai, H. K.; Kartha, G.; Chen, S. L.; Nakanishi, K. J. Chem. Soc. Perkin Trans. 1 1974, 1413.

(3) Kutchan, T. M.; Dittrich, H.; Bracher, D.; Zenk, M. H. Tetrahedron 1991, 47 (31), 5945.

(4) Luk, L. Y. P.; Bunn, S.; Liscombe, D. K.; Facchini, P. J.; Tanner, M. E. Biochemistry 2007, 46 (35), 10153.

(5) Stöckigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chemie - Int. Ed. 2011, 50 (37), 8538.

(6) Durand, R.; Zenk, M. H. Tetrahedron Lett. 1971, 12 (32), 3009.

(7) Devi, S. P.; Kumaria, S.; Rao, S. R.; Tandon, P. Trop. Plant Biol. 2016, 9 (4), 267.

(8) Widhalm, J. R.; Rhodes, D. Hortic. Res. 2016, 3 (August), 1.

(9) Ruangrungsi, N.; Wongpanich, V.; Tantivatana, P.; Cowe, H. J.; Cox, P. J.; Funayama, S.; Cordell, G. A. J. Nat. Prod. 1985, 48 (4), 529.

(10) Francois, G.; Bringmann, G.; Phillipson, J. D.; Assi, L. A.; Dochez, C.; Ruebenacker, M.; Schneider, C.; Wery, M.; Warhurst, D. C.; Kirby, G. C. Phytochemistry 1994, 35 (6), 1461.

(11) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phytochemistry 1992, 31 (11), 3821.

(12) Bringmann, G.; Holenz, J.; Assi, A.; Zhao, C. X.; Hostettmann, K. Planta Med. 1996, 62 (6), 556.

(13) Bringmann, G.; Holenz, J.; Wiesen, B.; Nugroho, B. W.; Proksch, P. J. Nat. Prod. 1997, 60 (4), 342.

(14) Boyd, M. R.; Hallock, Y. F.; Cardellina, J. H.; Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit, R. W.; Bringmann, G.; Schäffer, M.; Cragg, G. M.; Thomas, D. W.; Jato, J. G. J. Med. Chem. 1994, 37 (12), 1740.

(15) Hallock, Y. F.; Manfredi, K. P.; Dai, J. R.; Cardellina, J. H.; Gulakowski, R. J.; McMahon, J. B.; Schäffer, M.; Stahl, M.; Gulden, K. P.; Bringmann, G.; François, G.; Boyd, M. R. J. Nat. Prod. 1997, 60 (7), 677.

136

References

(16) Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H.; McMahon, J. B.; Boyd, M. R.; Pannell, L. L.; Cragg, G. M. J. Med. Chem. 1991, 34 (12), 3402.

(17) Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34 (2), 2174.

(18) Abramovitch, R. A.; Barton, D. H. R.; Finet, J.-P. Tetrahedron 1988, 44 (11), 3039.

(19) Campeau, L. C.; Fagnou, K. Chem. Commun. 2006, No. 12, 1253.

(20) Hassan, J.; Svignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.; Se, M. 2002, 102 (5), 1359.

(21) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38 (8), 2447.

(22) Bringmann, G.; Jansen, J. R. Tetrahedron Lett. 1984, 24 (24), 2537.

(23) Bringmann, G.; Jansen, J. R.; Rink, H.-P. Angew. Chemie 1986, 98, 917.

(24) Bringmann, G.; Reuscher, H. Tetrahedron Lett. 1989, No. 39, 5249.

(25) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34 (8), 615.

(26) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111 (2), 563.

(27) Bringmann, G.; Ochse, M.; Götz, R. J. Org. Chem. 2000, 65 (7), 2069.

(28) Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124 (19), 5365.

(29) Govindachari, T. R.; Parthasarathy, P. C.; Rajagopalan, T. G.; Desai, H. K.; Ramachandran, K. S.; Lee, E. J. Chem. Soc., Perkin Trans 1 1975, 2134.

(30) Bringmann, G.; Manchala, N.; Büttner, T.; Hertlein-Amslinger, B.; Seupel, R. Chem. - A Eur. J. 2016, 22 (28), 9792.

(31) Boyd, I. M. R.; Francois, G.; Bringmann, G.; Hallock, Y. F. 1995, 4014 (1992), 4011.

(32) Hobbs, P. D.; Upender, V.; Liu, J.; Pollart, D. J.; Thomas, D. W.; Dawson, M. I. Chem. Commun. 1996, No. 8, 923.

(33) Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P. J. Org. Chem. 1999, 64, 7184.

(34) Watanabe, T.; Shakadou, M.; Uemura, M. Synlett 2000, 1141.

(35) Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura, M. J. Org. Chem. 2004, 69 (12), 4152.

137

References

(36) Lipshutz, B. H.; Keith, J. M. Angew. Chemie - Int. Ed. 1999, 38 (23), 3530.

(37) Huang, S.; Petersen, T. B.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132 (40), 14021.

(38) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W. J. Am. Chem. Soc. 2014, 136 (2), 570.

(39) Moorlag, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34 (44), 6989.

(40) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50 (8), 2297.

(41) Rizzacasa, M. A.; Sargent, M. V. J. Chem. Soc., Chem. Commun. 1989, 301.

(42) Rizzacasa, M. A.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1991, 841.

(43) Rizzacasa, M. A.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1991, 845.

(44) Rizzacasa, M. A.; Sargent, M. V. J. Chem. Soc., Perkin Trans 1 1991, 2773.

(45) Leighton, B. N.; Rizzacasa, M. A. J. Org. Chem. 1995, 60 (17), 5702.

(46) Chau, P.; Czuba, I. R.; Rizzacasa, M. A.; Bringmann, G.; Gulden, K. P.; Schäffer, M. J. Org. Chem. 1996, 61 (20), 7101.

(47) Comber, M. F.; Morris, J. C.; Sargent, M. V. Aust. J. Chem. 1998, 51, 19.

(48) Lee, Y. E.; Cao, T.; Torruellas, C.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136 (19), 6782.

(49) Shalit, H.; Libman, A.; Pappo, D. J. Am. Chem. Soc. 2017, 139 (38), 13404.

(50) Shalit, H.; Dyadyuk, A.; Pappo, D. J. Org. Chem. 2019, 84, 1677.

(51) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chemie - Int. Ed. 2003, 42 (1), 112.

(52) Oi, S.; Watanabe, S. I.; Fukita, S.; Inoue, Y. Tetrahedron Lett. 2003, 44 (48), 8665.

(53) Bedford, R. B.; Betham, M.; Caffyn, A. J. M.; Charmant, J. P. H.; Lewis-Alleyne, L. C.; Long, P. D.; Polo-Cerón, D.; Prashar, S. Chem. Commun. (Camb). 2008, No. 8, 990.

(54) Bedford, R. B.; Haddow, M. F.; Webster, R. L.; Mitchell, C. J. Org. Biomol. Chem. 2009, 7 (15), 3119.

(55) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62 (1), 2.

(56) Wiegand, S.; Schäfer, H. J. Tetrahedron 1995, 51 (18), 5341.

138

References

(57) Cuny, G. D. Tetrahedron Lett. 2003, 44 (44), 8149.

(58) Cuny, G. D. Tetrahedron Lett. 2004, 45 (26), 5167.

(59) Beydoun, K.; Doucet, H. Catal. Sci. Technol. 2011, 1 (7), 1243.

(60) Barton, D. H. R.; Lester, D. J.; Motherwell, W. B.; Papoula, M. T. B. J. Chem. Soc. Chem. Commun. 1980, 8 (5), 246.

(61) Barton, D. H. R. R.; Blazejewski, J.-C. C.; Charpiot, B.; Lester, D. J.; Motherwell, W. B.; Barros Papoula, M. T.; Papoula, M. T. B. J. Chem. Soc. Chem. Commun. 1980, No. 17, 827.

(62) Barton, D. H. R.; Charpiot, B.; Motherwell, W. B. Tetrahedron Lett. 1982, 23 (33), 3365.

(63) Barton, D. H. R.; Bhatnagar, N. Y.; Blazejewski, J.-C.; Charpiot, B.; Finet, J.-P.; Lester, D. J.; Motherwell, W. B.; Papoula, M. T. B.; Stanforth, S. P. J. Chem. Soc. Perkin Trans. 1 1985, 2657.

(64) Barton, D. H. R.; Blazejewski, J. C.; Charpiot, B.; Motherwell, W. B. J. Chem. Soc. Chem. Commun. 1981, 2 (10), 503.

(65) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron 1997, 53 (12), 4137.

(66) Ueda, K.; Sato, I.; Hirama, M. Chem. Lett. 2012, 41 (1), 87.

(67) Barton, D. H. R.; Blazejewski, J.; Charpiot, B.; Finet, J.-P.; Motherwell, W. B.; Papoula, M. T. B.; Stanforth, S. P. J. Chem. Soc., Perkin Trans 1 1985, 2667.

(68) Bolshakov, A. V.; Ganina, O. G.; Shavirin, A. S.; Kurskii, Y. A.; Finet, J. P.; Fedorov, A. Y. Tetrahedron Lett. 2002, 43 (46), 8245.

(69) Koech, P. K.; Krische, M. J. J. Am. Chem. Soc. 2004, 126 (17), 5350.

(70) Koech, P. K.; Krische, M. J. Tetrahedron 2006, 62 (45), 10594.

(71) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem. 2002, 63 (11), 3528.

(72) Krawczuk, P. J.; Schoene, N.; Baran, P. S. Org. Lett. 2009, 11 (21), 4774.

(73) Finet, J. P.; Fedorov, A. Y. Russ. Chem. Bull. 2004, 53 (7), 1488.

(74) Bell, H. C.; May, G. L.; Pinhey, J. T.; Sternhell, S. Tetrahedron Lett. 1976, No. 47, 4303.

(75) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32 (7), 1551.

139

References

(76) Pinhey, J. Aust. J. Chem. 1991, 44, 1353.

(77) Barton, D. H. R.; Donnelly, D. M. X.; Guiry, P. J.; Finet, J.-P. J. Chem. Soc. Perkin Trans. 1 1994, 2921.

(78) Barton, D. H. R.; Finet, J.-P.; Giannotti, C.; Halley, F. J. Chem. Soc., Perkin Trans 1 1987, 241.

(79) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans 1 1993, 1673.

(80) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943.

(81) Moloney, M. G.; Paul, D. R.; Thompson, R. M.; Wright, E. 1998, 560, 77.

(82) Buston, J. E. H.; Claridge, T. D. W.; Heyes, S. J.; Leech, M. A.; Moloney, M. G.; Prout, K.; Stevenson, M. Dalt. Trans. 2005, 3195.

(83) Czyz, M. L. PhD Thesis, UNSW Sydney, 2012.

(84) Orito, K.; Yorita, K.; Suginome, H. Tetrahedron Lett. 1991, 32 (42), 5999.

(85) Orito, K.; Sasaki, T.; Suginome, H. J. Org. Chem. 1995, 60 (19), 6208.

(86) Suginome, H.; Ishikawa, M.; Yorita, K.; Shimoyama, N.; Sasaki, T.; Orito, K. J. Org. Chem. 1995, 60 (10), 3052.

(87) Elliott, G. I.; Konopelski, J. P.; Olmstead, M. M. Org. Lett. 1999, 1 (11), 1867.

(88) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3 (19), 3001.

(89) Bungard, C. J.; Morris, J. C. Org. Lett. 2002, 4 (4), 631.

(90) Bungard, C. J.; Morris, J. C. J. Org. Chem. 2006, 71, 7354.

(91) Bungard, C. J. PhD Thesis, University of Canterbury, 2001.

(92) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans 1 1990, No. 2, 715.

(93) Davis, F. A.; Andemichael, Y. W. J. Org. Chem. 1999, 64 (23), 8627.

(94) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org. Lett. 2000, 2 (24), 3901.

(95) Brusnahan, J. S. PhD Thesis, University of Adelaide, 2009.

140

References

(96) Toop, H. D.; Brusnahan, J. S.; Morris, J. C. Angew. Chemie Int. Ed. 2017, 129 (29), 8656.

(97) Bringmann, G.; Dreyer, M.; Faber, J. H.; Dalsgaard, P. W.; Staerk, D.; Jaroszewski, J. W.; Ndangalasi, H.; Mbago, F.; Brun, R.; Reichert, M.; Maksimenka, K.; Christensen, S. B. J. Nat. Prod. 2003, 66, 1159.

(98) Jiang, C.; Li, Z. L.; Gong, P.; Kang, S. L.; Liu, M. S.; Pei, Y. H.; Jing, Y. K.; Hua, H. M. Fitoterapia 2013, 91, 305.

(99) Toop, H. D. Honours Thesis, University of Adelaide, 2009.

(100) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57 (27), 5683.

(101) Toop, H. D. PhD Thesis, UNSW Sydney, 2015.

(102) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126 (16), 5192.

(103) Murahashi, S. I.; Okano, Y.; Sato, H.; Nakae, T.; Komiya, N. Synlett 2007, 2 (11), 1675.

(104) Muller, P.; Gilabert, D. M. Tetrahedron 1988, 44 (23), 7171.

(105) Onto, K.; Hatakeyama, T.; Uchiito, S.; Tokuda, M.; Suginome, H. Tetrahedron 1998, 54 (29), 8403.

(106) Galletti, P.; Martelli, G.; Prandini, G.; Colucci, C.; Giacomini, D. RSC Adv. 2018, 8 (18), 9723.

(107) Young, S. D.; Mark Wiggins, J.; Huff, J. R. J. Org. Chem. 1988, 53 (5), 1114.

(108) Baxendale, I. R.; Ley, S. V.; Nessi, M.; Piutti, C. Tetrahedron 2002, 58 (32), 6285.

(109) Ronson, T. O.; Kitsiou, C.; Unsworth, W. P.; Taylor, R. J. K. Tetrahedron 2016, 72 (40), 6099.

(110) Pelletier, J. C.; Cava, M. P. J. Org. Chem. 1987, 52 (4), 616.

(111) Gao, Z.; Davis, L.; Chiang, Y.; Munson, R.; Hendrix, J. A. Tetrahedron Lett. 2012, 53 (33), 4429.

(112) Dong, J.; Shi, X. X.; Yan, J. J.; Xing, J.; Zhang, Q.; Xiao, S. European J. Org. Chem. 2010, No. 36, 6987.

(113) Bringmann, G.; Weirich, R.; I, H. R.; I, J. R. J.; Kinzinger, L. Liebigs Ann. Chemie 1993, 877.

141

References

(114) Misztal, S.; Cegla, M. Synthesis (Stuttg). 1985, 1134.

(115) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136 (1), 506.

(116) Sy, W.-W. Tetrahedron Lett. 1993, 34 (39), 6223.

(117) Bringmann, G.; Rüdenauer, S.; Bruhn, T.; Benson, L.; Brun, R. Tetrahedron 2008, 64 (23), 5563.

(118) Hobbs, P. D.; Upender, V.; Dawson. Synlett 1997, 965.

(119) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999, 121, 700.

(120) Bringmann, G. Private Correspondence.

(121) Hua, H. Personal Correspondence 2017,.

(122) Ibrahim, S. R. M.; Mohamed, G. A. Fitoterapia 2015, 106, 194.

(123) Buston, J. E. H.; Claridge, T. D. W.; Moloney, M. G. J. Chem. Soc., Perkin Trans 2 1995, 639.

(124) Claridge, T. D. W.; Nettleton, E. J.; Moloney, M. G. 1997, 35, 159.

(125) Malone, M. H.; John-Allan, K. M. S.; Bejar, E. J. Ethnopharmacol. 1992, 35 (3), 295.

(126) Teske, J.; Weller, J.-P.; Albrecht, U.-V.; Fieguth, A. J. Anal. Toxicol. 2011, 35 (4), 248.

(127) Freedman, L. D.; Doak, G. O. Chem. Rev. 1982, 82 (1), 15.

(128) Barton, D. H. R.; Finet, J.-P. Pure Appl. Chem. 1987, 59 (8), 937.

(129) Finet, J.-P. P. Chem. Rev. 1989, 89 (7), 1487.

(130) Suzuki, H.; Matano, Y. Organobismuth Chemistry; Elsevier Science B. V., 2001.

(131) Matano, Y. 2007, 425.

(132) Gagnon, A.; Dansereau, J.; Le Roch, A. Synth. 2017, 49 (8), 1707.

(133) Sinclair, P. J.; Wong, F.; Wyvratt, M.; Staruch, M. J.; Dumont, F. Bioorganic Med. Chem. Lett. 1995, 5 (10), 1035.

(134) Sinclair, P. J.; Wong, F.; Wyvratt, M.; Staruch, M. J.; Dumont, F. Bioorganic Med. Chem. Lett. 1995, 5 (10), 1035.

(135) Brands, K. M. J.; Dolling, U. H.; Jobson, R. B.; Marchesini, G.; Reamer, R. A.; Williams, J. 142

References

M. J. Org. Chem. 1998, 63 (19), 6721.

(136) Parrish, J. P.; Hughes, T. V.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2004, 126 (1), 80.

(137) Ooi, T.; Goto, R.; Maruoka, K. J. Am. Chem. Soc. 2003, 125 (35), 10494.

(138) Gordon, M. F.; Abrams, R. I.; Rubin, D. B.; Barr, W. B.; Correa, D. D. Mov. Disord. 1995, 10 (2), 220.

(139) Reynolds, P. T.; Abalos, K. C.; Hopp, J.; Williams, M. E. Int. J. Clin. Med. 2012, 03 (01), 46.

(140) Fedorov, A.; Combes, S.; Finet, J. P. Tetrahedron 1999, 55 (5), 1341.

(141) Combes, S.; Finet, J.-P. Synth. Commun. 1996, 26 (24), 4569.

(142) Condon, S.; Pichon, C.; Davi, M. Org. Prep. Proced. Int. 2014, 46 (2), 89.

(143) Krasovskiy, A.; Knochel, P. Angew. Chemie - Int. Ed. 2004, 43 (25), 3333.

(144) Ziegler, D. S.; Wei, B.; Knochel, P. Chem. - A Eur. J. 2019, 25 (11), 2695.

(145) Hébert, M.; Petiot, P.; Benoit, E.; Dansereau, J.; Ahmad, T.; Le Roch, A.; Ottenwaelder, X.; Gagnon, A. J. Org. Chem. 2016, 81 (13), 5401.

(146) Barton, D. H. R.; Bhatnagar, N. Y.; Finet, J. P.; Motherwell, W. B. Tetrahedron 1986, 42 (12), 3111.

(147) Matano, Y.; Miyamatsu, T.; Suzuki, H. Chem. Lett. 1998, 127.

(148) Urgin, K.; Aube, C.; Pichon, C.; Pipelier, M.; Blot, V.; Thobie-Gautier, C.; L??onel, E.; Dubreuil, D.; Condon, S. Tetrahedron Lett. 2012, 53 (15), 1894.

(149) Matano, Y.; Miyamatsu, T.; Suzuki, H. Organometallics 1996, No. 4, 1951.

(150) Matano, Y.; Begum, S. A.; Miyamatsu, T.; Suzuki, H. Organometallics 1998, 17 (20), 4332.

(151) Matano, Y.; Begum, S. A.; Miyamatsu, T.; Suzuki, H. Organometallics 1999, 18 (26), 5668.

(152) Wiegand, G. H.; McEwen, W. E. J. Org. Chem. 1968, 33 (7), 2671.

(153) Yamada, Y.; Okawara, M. Bull. Chem. Soc. Jpn. 1972, pp 1860–1863.

(154) Lancer, K. M.; Wiegand, G. H. J. Org. Chem. 1976, 41 (21), 3360.

(155) Olah, G. A.; Asensio, G.; Sakakibara, T. J. Org. Chem. 1978, 43 (3), 463.

143

References

(156) Seth, S.; Jhulki, S.; Moorthy, J. N. Eur. J. Org. Chem. 2013, No. 12, 2445.

(157) Meyers, A. I.; Avila, W. B. Tetrahedron Lett. 1980, 21, 3335.

(158) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47 (1), 34.

(159) Maggi, R.; Schlosser, M. J. Org. Chem. 1996, 61, 5430.

(160) Nguyen, T. H.; Castanet, A. S.; Mortier, J. Org. Lett. 2006, 8 (4), 765.

(161) Mack, K. A.; Collum, D. B. J. Am. Chem. Soc. 2018, 140 (14), 4877.

(162) Xu, Z.; Chai, L.; Liu, Z. Q. Org. Lett. 2017, 19 (20), 5573.

(163) Ellman, J. A. Pure Appl. Chem. 2007, 75 (1), 39.

(164) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110 (6), 3600.

(165) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli, D.; Thimma Reddy, R.; Zhou, P.; Carroll, P. J. J. Org. Chem. 1997, 62 (8), 2555.

(166) Davis, F. A.; Chen, B.-C. Chem. Soc. Rev. 1998, 27 (1), 13.

(167) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40 (37), 6709.

(168) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40 (34), 6181.

(169) Bringmann, G.; Rummey, C. J. Chem. Inf. Comput. Sci. 2003, 43 (1), 304.

(170) Ponte-Sucre, A.; Faber, J. H.; Guider, T.; Kajahn, I.; Pedersen, S. E. H.; Schultheis, M.; Bringmann, G.; Moll, H. Antimicrob. Agents Chemother. 2007, 51 (1), 188.

(171) Ball, L. Personal Correspondence 2018,.

(172) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29 (9), 2176.

(173) Armarego, W. L. F. Purification of Laboratory Chemicals, 8th ed.; Butterworth- Heinemann, 2017.

(174) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.

(175) Hoye, T. R.; Aspaas, A. W.; Eklov, B. M.; Ryba, T. D. Org. Lett. 2005, 7 (11), 2205.

(176) Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37 (37), 6787.

144

References

(177) Still, W. C.; Kahn, M.; Mitra, A. A. J. Org. Chem. 1978, 43 (14), 2923.

(178) Rahman, A. F. M. M.; Murafuji, T.; Ishibashi, M.; Miyoshi, Y.; Sugihara, Y. J. Organomet. Chem. 2004, 689 (21), 3395.

(179) Lermontov, S. A.; Rakov, I. M.; Zefirov, N. S. Russ. Chem. Bull. 1998, 47 (8), 1609.

(180) Dowd, C. S.; Herrick-Davis, K.; Egan, C.; DuPre, A.; Smith, C.; Teitler, M.; Glennon, R. A. J. Med. Chem. 2000, 43 (16), 3074.

(181) Barfknecht, C. F.; Nichols, D. E. J. Med. Chem. 1971, 14 (4), 370.

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Appendix

Appendix: Crystallography

Crystallography

Crystallographic information files (.cif) of each structurally characterised compound discussed within this thesis (shown below) is made available on the attached “Crystallography” USB stick.

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