Chiral9-Phenyl-9H- Fluoren-9-Amines in Asymmetricinduction

Departm en t of Chem istry alto- Aa Essi Karppanen

32 C hi r a l 9 -p hen y l-9 H- / 2016 2016 ﬂuoren-9-amines in

iral phnyl-9 y hen -p 9 l a r hi C asymmetric induction

Essi Karppanen H -ﬂuoren-9-aminesasymmetricin induction

9HSTFMG*aggghh+ ISB N 978 -952-60-6667-7 (pr in ted) B USINESS + ISB N 978 -952-60-6668 -4 (pdf) ECONOMY ISSN-L 1799-493 4 ISSN 1799-493 4 (pr in ted) ART + ISSN 1799-4942 (pdf) DESIGN +

ARCHITECTURE iversity Un Aalto Aalto Un iversity School of Chem ical Techn ology SCIENCE + Departm en t of Chem istry TECHNOLOGY www.aalto.fi CROSSOVER DOCTORAL DOCTORAL DISSERTATIONS DISSERTATIONS

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ACKNOWLEDGEMENTS

The work presented in this doctoral thesis was carried out at the Aalto University School of Chemical Technology during 2010-2014. I would like to acknowledge and thank Aalto University for the financial support for this work.

First, I would like to thank my supervisor Professor Ari Koskinen for all the help, advice and fun times during the years. I truly admire his knowledge on organic chemistry and other fields as well. I also appreciate his encouragement in whatever I might want to pursue, in chemistry or other areas in life.

I would also like to thank Professor Petri Pihko, who accepted me as a part of his research group when I was an undergraduate student. I learned a lot of chemistry during that time and I really enjoyed working in the lab.

I would like to thank Associate Professor Annette Bayer and Professor Reko Leino for carefully revising this manuscript and providing valuable comments. I am grateful to Dr. Antti Kataja for revising the language of this thesis.

I would like to thank our laboratory staff members: Dr. Jari Koivisto for keeping the NMR facilities in shape, Tiia Juhala and Johanna Mareta for the HRMS analyses and Anneli Parvinen for handling all the administrative stuff. I would also like to thank Päivi Joensuu from Oulu University for HRMS analyses and Dr. Martin Nieger from University of Helsinki for crystallographic measurements.

I am grateful for Dr. Antti Pohjakallio, who was such a great and inspiring teacher when I first started working in the organic chemistry lab. I would like to thank all the other previous group members and post-docs as well for good times in the lab and of course chemistry related advice and guidance: Esa, Jatta, Laurent, Peter, Katja, Anna and Andreas. Also the newer group members deserve big thanks for contributing to the spirit in the lab: Aino, Saara, Annakaisa, Andrejs and Joel. I would also like to thank undergraduate students Miika, Reetta, Emilia and Lotta for all the help in the lab. I would like to thank Dr. Pekka Joensuu for all kinds of inspiring discussions.

I would like to give my warmest thanks to our current group members: Annika, Christopher, Oskari and Antti. We’ve had so much fun during the years, in and outside the lab!

Lastly, outside the lab, I want to thank my friends and family for all the love and support.

AUTHOR’S CONTRIBUTION

The author, Essi Karppanen, designed and carried out the experiments, recorded the analytical data (with exceptions mentioned in the Acknowledgements), and interpreted the results presented in this thesis. Certain parts of the work were done by other researchers in collaboration with the author. The aerobic oxidation catalyst screenings shown in Chapter 10 were designed by Dr. Esa Kumpulainen, and they were carried out by undergraduate student Miika Karjomaa under the supervision of the author.

Publications relevant to this thesis were written by the author.3

TABLE OF CONTENTS

Abstract

Tiivistelmä (Abstract in Finnish)

Acknowledgements

Author’s contribution

Table of contents

Abbreviations and symbols

1. Introduction 15

2. Amino acids 17

3. 9-Phenyl-9H-fluoren-9-yl group 19

3.1 Properties of the Pf group 19

3.2 Installation and cleavage of the Pf group 23

4. Phenethylamines 25

4.1 Biological implications of phenethylamines 26

4.2 Biosynthesis and metabolism of phenethylamines 27

4.3 Sympathomimetic phenethylamines 28

4.3.1 Ephedrine 28

4.3.2 Cathinone 28

4.3.3 Mescaline 29

4.3.4 Amphetamine 29

4.3.5 MDMA 30

4.4 Synthetic routes to phenethylamines 31

4.5 L-Dopa 32

4.5.1 Industrial synthesis of L-dopa 33

4.5.2 Other methods to obtain L-dopa 35

5. Transition metal-catalyzed cross-coupling reactions 36

5.1 Palladium-catalyzed cross-coupling reactions 36

5.1.1 The Kumada-Tamao-Corriu type cross-coupling 37

5.2 Cross-couplings catalyzed by iron 39

6. Synthesis of allylamines 42

6.1 Pd- and Fe-catalyzed synthesis of Pf-allylamines 42

6.2 N-Pf-alanine methyl ketone 47

6.3 Allyl silanes in the synthesis of allylamines 49

7. Asymmetric hydrogenation 53

7.1 General considerations of asymmetric hydrogenation 53

7.2 Rhodium-catalyzed asymmetric hydrogenation 54

7.3 Ruthenium-catalyzed asymmetric hydrogenation 57

7.4 Hydrogenation of simple olefins by iridium catalysts 59

7.4.1 Mechanistic overview of the iridium-catalyzed

hydrogenation 60

7.4.2 General selectivity based on iridium(III) dihydride 62

7.5 Hydrogenation of allylamines 64

8. Other selected N-Pf-amines 67

8.1 Reduction of amino ketones 67

8.2 Knoenevagel reaction and conjugate additions with

N-Pf-Phenylalanine 68

9. Sphingolipids 72

9.1 Introduction 72

9.2 Traditional approaches in sphingosine synthesis 73

9.3 Obscuraminols 77

9.4 Allylic allylation and synthetic studies towards

obscuraminol A 79

10. Catalytic aerobic oxidation with copper 84

10.1 General considerations for the copper-TEMPO

oxidation of primary alcohols 84

10.2 Optimization of the copper-TEMPO oxidation

of primary alcohols 88

10.3 Substrate scope for the copper-TEMPO oxidation 92

11. Conclusions 95

12. Experimental section 96

12.1 General considerations 96

12.2 Synthesis of the general N-Pf-compounds 97

12.3 Synthesis of N-Pf-phenethylamines 103

12.4 Selected N-Pf-amines 112

12.5 Copper-TEMPO oxidation experiments 126

12.6 Crystal structures of selected N-Pf-compounds 130

12.7 Relevant analytical data for N-Pf-phenethylamines 134

12.8 Typical colour changes in aerobic

copper-TEMPO oxidations 137

13. References 138

ABBREVIATIONS

AADC aromatic L-amino acid decarboxylase

Ac acetyl acac acetyl acetonate

ADH aldehyde dehydrogenase

ADHD attention deficit hyperactivity disorder aq. aqueous

AZADO 2-azaadamantane N-oxyl

BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl

Boc tert-butoxycarbonyl bpy 2,2’-bipyridine

Cbz carboxybenzyl

CDI 1,1’-carbonyldiimidazole

COD 1,5-cyclooctadiene

Cy cyclohexyl

DABCO 1,4-diazabicyclo[2.2.2]octane

DBH dopamine-β-dehydroxylase

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

DIPAMP 1,2-bis[(2-methoxyphenyl)(phenylphosphino)ethane]

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide ee enantiomeric excess

Fmoc 9-fluorenylmethoxycarbonyl

IBX 2-iodoxybenzoic acid

KHMDS potassium hexamethyldisilazide

LDA lithium diisopropylamide

LSD D-lysergic acid diethylamine

MAO monoamine oxidase

MDMA 3,4-methylenedioxy-N-methylamphetamine

MTPA α-methoxy-α-trifluoromethylphenylacetic acid

Ms mesyl, methanesulfonyl

NMI N-methylimidazole

NMT N-methyltransferase

NMP N-methylpyrrolidone

PCC pyridinium chlorochromate

PDC pyridinium dichromate

Pf 9-phenyl-9H-fluoren-9-yl

PFC prefrontal cortex

Ph phenyl

PNMT phenylethanolamine N-methyltransferase py pyridine

R arbitrary substructure rt room temperature

TBHP tert-butyl hydroperoxide

TEMPO 2,2,6,6-tetramethylpiperine-1-oxyl, free radical

THF tetrahydrofuran

TMEDA N,N,N’N’-tetramethylethylenediamine

TMS trimethylsilyl

Tr trityl

Ts tosyl, para-toluenesulfonyl

Chiral 9-phenyl-9H-fluoren-9-amines in asymmetric induction

1. Introduction

Chiral amines are present in numerous active pharmaceutical ingredients, bioactive natural products and pharmaceutical building blocks. 1 Therefore the sustainable production of chiral amines has been identified as a key research priority by the pharmaceutical industry.2 Nearly all biological receptors are chiral and can distinguish between the two enantiomers of a substrate or a ligand, indicating that the pharmacological properties of a chiral compound are usually different compared to its enantiomer or racemate. The differences can be manifested in taste or odor, or in drug effectiveness and safety in biological systems. The access to enantiopure compounds in general is required in other areas of organic synthetic chemistry as well: perfumes, cosmetics, nutrients, flavors, pesticides and vitamins.

There are different methods for obtaining enantiopure compounds, which include isolation from natural sources, (kinetic) resolution, crystallization via diastereomeric derivatives and asymmetric synthesis. However, the first three have the downside of producing a lot of waste products, not to mention the ineffectiveness and environmental concerns related to isolation from natural sources. Asymmetric synthesis is a term used to describe stereocontrolled synthetic processes, and it is the basis of this thesis.

Asymmetric information can originate from either the starting material or the reagent. Asymmetric induction, introducing chirality in the emerging centers of the molecule, can be achieved by three principal ways. In internal asymmetric induction the chiral information is present in the starting material molecule(s) and is an integral part of the final product. In external asymmetric induction the chiral information is brought from outside of the reacting molecules, typically in the form of catalytic reactions using chiral catalysts and/or ligands. In relayed asymmetric induction the chiral information is brought in transiently using for example chiral auxiliaries.

The reservoir of naturally occurring, readily available materials, such as amino acids, sugars and terpenes, is known as the chiral pool. It is an excellent source of chiral, naturally enantiopure starting materials for asymmetric syntheses. The work in thesis is based on internal asymmetric induction using amino acids as the starting materials. The acidic α-proton present in amino acids makes them prone to racemization during synthetic transformations, which makes it challenging if not even impossible to ensure the enantiopurity of the starting material throughout the synthetic sequence. Common

15 nitrogen protecting groups (Boc, Cbz, Fmoc) do not always fare particularly well in protecting the enantiomeric purity of α-chiral amino carbonyl compounds, while the 9- phenyl-9H-fluoren-9-yl (Pf) has proven to be an outstanding choice for protecting the α- center of the amino acid derivatives 3 and it is used as the nitrogen protecting group throughout the work presented in this thesis.

In this thesis I describe the synthesis of a number of phenethylamine derivatives and other pharmacologically interesting amines. I take a brief look at the properties of the Pf- protecting group, after which I present some of the most important phenethylamines, the related biochemistry and existing synthetic methods. A chapter is dedicated to sphingolipids, biologically essential naturally occurring amino alcohols. The traditional approaches to sphingolipid synthesis and my efforts to develop a different kind of general synthesis are presented. In this thesis, I also explore and elucidate the potential of the catalytic aerobic copper-TEMPO oxidation as an economically feasible and environmentally friendly synthetic method. The reaction conditions were optimized by screening and adjusting the catalyst composition, and substrate scope was investigated. The results are presented in the last part of this thesis.

2. Amino acids

Amino acids, biologically important compounds containing both amino (-NH2) and carboxylic acid (-COOH) groups, are the building blocks for peptides and proteins. Nowadays there are over 500 known amino acids, of which 21 are so-called proteinogenic amino acids, from which natural peptides and proteins are built. The discovery of amino acids dates back to the early 19th century, when the earliest observatios were made. Cystine and leucine were the first ones discovered, in 1810 and 1819 respectively, while glycine was the first one isolated as a product of hydrolysis of proteins in 1820,4 and the rest were identified mainly during the following 100 years. Circa 240 amino acids occur in free form in nature, while some are observed only as intermediates in metabolism.5

Amino acids, with the exception of glycine, are chiral molecules. The different enantiomers of chiral compounds can be described using established nomenclature. The configuration of a chiral center can be determined by the Cahn-Ingold-Prelog priority rules and described using letters R (rectus for right) and S (sinister for left). Another way to designate the enantiomers is to use the labels (+) and (-) that arise from the fact that two enantiomers rotate plane-polarized light in opposite directions. The (+)-enantiomer gives positive rotation and rotates plane-polarized light to the right (dextrorotatory enantiomer), while the (-)-enantiomer gives negative rotation and rotates plane-polarized light to the left (laevorotatory enantiomer). The L and D labels arise from the time when chiral compounds were compared and named after their relation to the two known enantiomers of glyceraldehyde, D for dextro ((+)-enantiomer) and L for laevo ((-)- enantiomer). Today the D and L nomenclature is used only for certain well-known natural molecules, such as L-amino acids and D-sugars, where their use is established by tradition. Nearly all of the amino acids in biological systems, especially the proteinogenic ones, have the same L-configuration, and the absolute stereochemistry of the asymmetric carbon is S. This is the most common configuration found overall in nature, from which only certain microbial products differ. However, D-Amino acids often occur in bacterial cell walls. The R/S, (+)/(-) and L/D nomenclatures arise from different observations and one property cannot be deduced from another. All of these descriptions are used throughout this text.

Naturally occurring amino acids are a great starting point for the synthesis of chiral amines. They are easily accessible and naturally enantiopure, which makes them ideal for the synthesis of many kinds of pharmaceutically interesting compounds. In addition to their natural enantiopurity, the abundance of amino acids and their usually affordable price make them an ideal chiral pool of starting materials for the asymmetric syntheses of

17 biologically active amino compounds. The majority of the work presented in this thesis is based on syntheses using amino acids as starting materials. The structures of the 20 most common amino acids are presented in Figure 1.

Figure 1. The most common amino acids.

3. 9-Phenyl-9H-fluoren-9-yl group

3.1 Properties of the Pf group

The t-butyl and phenylmethyl carbamates (Boc, Cbz, Fmoc) are common and widely used protecting groups for amines, but their ability to protect the stereogenic center in chiral amines is limited. Trityl groups (Tr) were first introduced to protect the α-center, and N- trityl amino compounds were observed to retain their enantiopurity with >90% ee. 6 However, the acid lability of the resulting tritylamines was a limiting factor in their use, and alternative protecting groups of similar size were needed. The 9-phenyl-9H-fluoren- 9-yl (Pf) group resembling structurally the Tr group, was known to be solvolytically >6000 times more acid stable than trityl7 and it entered in the picture in the 1980s.8 Pf and the other common amine protecting groups are presented in Figure 2.

Figure 2. 9-Phenyl-9H-fluoren-9-yl group (Pf) and other common amine protecting groups Tr, Fmoc, Boc and Cbz.

The strength of Pf is based on its sterically demanding size that protects the α-center of the amine. Calculations have suggested that in an N-Pf α-amino derivative, the steric bulk of the Pf group forces the compound to adopt a conformation in which the dihedral angle between the carbonyl group and the α-hydrogen is ~0° or 180°.9 In this conformation, the overlap between C-Hα σ orbital and the C=O π* orbital is minimized leading to a lowered acidity of the α-proton. In cyclic compounds the Pf group forces the α-hydrogen into an equatorial position.10 This is illustrated in Figure 3.

Figure 3. Early conformational analysis of cyclic and acyclic N-Pf-compounds.

Not only its sterically large size, but also stereoelectronics has an important role in the ability of the Pf-group to protect the α-center. For example in the case of esters this could be explained as follows: the most favorable conformation for deprotonation is one in which the α-hydrogen-carbon bond lies on an orthogonal plane to the carbonyl system, allowing for maximum orbital overlap as the α-carbon rehybridizes from sp3 to sp2. However, as mentioned above, in N-Pf-protected esters the α-proton and the carbonyl group are nearly coplanar. Thus the rate of α-protonation would be stereoelectronically retarded in an ester for which such a conformation is highly favored.

Investigation of the stability of N-Pf compounds under basic conditions has confirmed that the racemization of these compounds is very unlikely.8-9 Experimental results have shown that in strongly basic conditions the Pf anion can act as a leaving group, thus giving rise to an imine. Treating Pf-protected alaninal 1 with triethylamine in refluxing THF leads to circa 50% loss of the starting material. However, no deterioration of ee was observed in the remaining aldehyde. The other main product from the reaction was 9- phenylfluorene, which indicates that the elimination of an aromatic 9-phenylfluorenyl anion occurs faster/easier than the inversion and reprotonation of the stereocenter on the aldehyde10 (Scheme 1).

Scheme 1. The decomposition of N-Pf amino aldehyde in basic conditions.

Extended conformational analysis by molecular model calculations has been executed in our research group. 11 Calculations were done with a general Pf-protected amino acid derivative (Figure 4). The results varied slightly depending on the chosen force field. The reproduced calculations (MM2*, MM3*) supported the previous calculations of the antiperiplanarity of the α-hydrogen, but the more recently developed force fields (MMFF, OPLC-2005) gave a dihedral angle of -155° and -139°, respectively, which were further supported by crystal structure analyses.

Figure 4. Generic Pf-protected α-amino carbonyl compound. Numbering of the relevant atoms is meant to simplify the conformational discussion and does not follow IUPAC guidelines.

The calculated conformational analysis was complemented with the crystal structures of eight Pf-protected amino acid derivatives 2-9. It clearly showed that the Pf group is in close proximity to the α-hydrogen, but the C-H bond and the C-O bond do not necessarily adopt a synperiplanar or antiperiplanar conformation as previously suggested. In all but one structure the α-hydrogen is situated at the very center over the fluorenyl ring structure, which was also supported by the lowest energy conformation calculations on N-Pf- alanine methyl ester 2. Compound 8, N-Pf-proline methyl ester, is an exception, adopting a conformation in which the α-hydrogen is aligned in the space between the fluorenyl ring structure and the phenyl ring of the Pf group. This was supported by a simple 1D-CSSF-

NOESY NMR experiment. Selective pulsing of H(4) gave correlation peaks with the Pf group, which indicated that in solution the α-hydrogen H(4) and Pf group are in close contact with each other. The rather low chemical shift of the α-hydrogen (δ = 2.78 ppm, compared to the chemical shift of the corresponding α-hydrogen in N-benzyl-L-alanine methyl ester δ = 3.37 ppm12) can thus be explained by the resulting anisotropic effect.11

Examining the crystallographic data might rationalize the preferred elimination of Pf according to Scheme 1. The orbitals of the H(4)-C(3) bond and the N(6)-C(7) bond involved in the elimination are almost anti periplanar and prealigned for a concerted E2 syn-elimination, making it kinetically favourable compared to enolization. Achieving a stereoelectronically favourable conformation during deprotonation would require the ester group to rotate into the region of space already occupied by the Pf group, which would result in allylic strain in the enolate-like transition state. The close proximity of the α-ester group and the fluorenyl ring is strongly supported by the fact that 1H NMR shows an unusual upfield chemical shift for a methyl ester resonance at 2.92 ppm. This has been observed in earlier studies as well, in the context of alkylation of N-Pf-glutamate.13

Table 1. X-Ray crystal structure data of selected Pf-protected amino acids.

Compound Dihedral angle [°] Dihedral angle [°] Dihedral angle [°] H(4)-C(3)-C(2)-O(1) H(4)-C(3)-N(6)-C(7) C(3)-N(6)-C(7)-C(8) 2 -120 5 -175 3 -147 23 172 4 19/23 (44/45) -12.5/- 24 (19/15) 178/178(179/177) 5 -149 26 177 6 -153 31 176 7 -153/-150 29/32 -177/179 8 -149 3 61 9 -161 28 174

3.2 Installation and cleavage of the Pf group

Phenylfluorenylation of amines was originally carried out by modifying and applying the existing method for making N-trityl compounds.8 In this traditional method 9-bromo-9- phenyl-9H-fluorene 10 (PfBr) was used. The amino acid can be used either as the free acid, when it has to be temporarily protected with TMSCl, or as the corresponding methyl ester HCl salt 11.14 PfBr 10 is made by bromination of phenylfluorenol 12, which is made from fluorenone 13 and phenylbromide 14. During the course of this thesis both of these methods were repeated several times in mol scales and the yields were consistently excellent.

Scheme 2. Traditional phenylfluorenylation.

The major drawbacks in the phenylfluorenylation reaction are the long reaction times (2– 3 days) and the use of toxic lead salt. As such, the reaction is based on improving bromine’s role as a leaving group with halogenophilic lead nitrate. Thus, a less toxic way of introducing the Pf group would be of upmost importance in order to make it more widely used.

Phenylfluorenyl cation has been made from fluorenol 12 by protonating the alcohol group with strong acids such as sulfuric or triflic acid and subsequent SN1 elimination. In solution the cation is deep red with an absorption maximum at λmax = 494 nm, and quenching with methanol gives Pf methyl ether 15 as the main product.15,16 Quenching the cation with an amine instead of methanol would indicate another possible way of introducing the Pf to the nitrogen on amino acids. Inspired by this idea, preliminary tests were done. The phenylfluorenyl cation was easily obtained by treatment with any strong acid, but addition of an amine did not lead to the corresponding phenylfluorenylated amine but instead to numerous other products. The observation that while Pf-bromide is not reactive enough and the cation is in turn too reactive, implies that the most convenient conditions for the phenylfluorenylation reaction would require the right choice of the

23 leaving group and a possible counterion. Bromide in 10 could be replaced by chloride, iodide, trifluoromethanesulfonate (triflate, Tf), tosyl (Ts), mesylate (Ms), nonaflate (Nf) or fluorosulfonate, for example. The synthesis of PfBr 10, PfOMe 15, the formation of Pf-cation 12a and suggested syntheses to derivative 10a-b and 15a-b are presented in Scheme 3.

Scheme 3. The synthesis of PfBr 10, PfOMe 15, the formation of Pf-cation 12a and suggested syntheses for derivatives 10a-b and 15a-b.

The Pf group is usually removed by hydrogenolysis17 and solvolysis under strongly acidic conditions.10 It can also be removed by lithium in ammonia solution,18 by TMSOTf in the presence of triethyl silane19 or by iodine in methanol.20

4. Phenethylamines

“phen-ethyl-amine \fen-'eth-al-a-,men\ n. [phenyl fr. F. phène, fr. Gk. phainein, to show (from its occurrence in illuminating gas)+ ethyl ( + yl) + amine fr. NL ammonia] 1: A naturally occurring compound found in both the animal and plant kingdoms. It is an endogenous component of the human brain. 2: Any of a series of compounds containing the phenethylamine skeleton, and modified by chemical constituents at appropriate positions in the molecule.” 21

Phenethylamines are a diverse group of naturally occurring and synthetic amines that share the common 2-phenylethylamine structure. They are found throughout nature, in both plants and animals. Most of the naturally occurring phenethylamines have important roles as neurotransmitters in the central nervous system. These include the so-called monoamine neurotransmitters such as dopamine 16, adrenaline 17 and noradrenaline 18, and the so-called trace amines, such as β-phenethylamine 19 (β-PEA) and octopamine 20, which are present in the human body only in trace amounts and likewise act as neuromodulators. Some phenethylamines can act as psychoactive stimulants, like amphetamine 21 and methamphetamine 22, mescaline 23 and MDMA 24. In addition to their presence in mammals, phenethylamines are found in many other organisms and foods such as chocolate, wine and cheese. Some of the phenethylamines, ephedrine 25 and cathinone 26 for example, are also found in the diet derived from plants, bacteria, fungi and herbal plants. Examples of common phenethylamines are presented in Figure 5.

Figure 5. Examples of common phenethylamines.

4.1 Biological implications of phenethylamines

Many phenethylamines act as sympathomimetic compounds, producing physiological effects resembling those caused by the action of the sympathetic nervous system. A common feature of synthetic phenethylamines is their stimulative nature. The accepted mechanism for the responses to phenethylamines is that they act indirectly as sympathomimetic amines through the release of noradrenaline from sympathetic neurons. Amphetamine-like compounds have the ability to stimulate the release of monoamines 5- HT, dopamine and noradrenaline.22 The common effects of such activity are euphoria, excitability, hyperactivity and restlessness. The common adverse effects are mydriasis, blurred vision, nausea and vomiting, diarrhea, dehydration, hyperthermia, bruxism, insomnia, increased blood pressure and increased heart rate. Psychosis is possible in extreme cases.

4.2 Biosynthesis and metabolism of phenethylamines

The biosynthesis of the main trace amines is shown in Scheme 4. Phenylethylamine 19 and tyramines 29 are formed from their precursor amino acids L-phenylalanine and L- tyrosine, respectively, by enzymatic decarboxylation with amino acid decarboxylase. 23 The tyramines can be converted to octopamines by dopamine-β-hydroxylase.

Scheme 4. Biosynthesis of phenethylamines. AADC L-aromatic amino acid decarboxylase; ADH aldehyde dehydrogenase; DBH dopamine-β-hydroxylase; L-DOPA L-dihydroxyphenylalanine; MAO monoamine oxidase; NMT N-methyl transferase, PNMT phenylethanolamine N-methyltransferase.

4.3 Sympathomimetic phenethylamines

Many phenethylamines, obtained from their natural sources, have been used for centuries for different purposes and have culturally and sociologically important value. Some of the phenethylamines are known to have psychotomimetic activity. For example mescaline 23 is a known hallucinogene, whereas amphetamine 21 is not despite their structural similarities. The relationship between the hallucinogenic potency and the structure regarding the methoxy substituent of phenethylamines has been investigated.24 Here are short presentations of some of the most important phenethylamines.

4.3.1 Ephedrine

Figure 6. Ephedrine.

The pioneer of all synthetic amphetamines is ephedrine ((1R, 2S)-2-(methylamino)-1- phenylpropan-1-ol, 25) (Figure 6), the active constituent in ephedra. It has been used in traditional Chinese medicine, known as Ma Huang, for over 5000 years as an herbal remedy for asthma, hay fever and the common cold. 25 The source of ephedrine is primarily E. sinica species of the Ephedra family, which has a total alkaloid content of 1- 3% dry weight of which ephedrine constitutes 40–90%.26 Ephedra is a stimulant and has been used in weight loss and in sports to enhance performance. 27 However, the use of ephedra-containing supplements was banned by FDA in 2004, because of their adverse effects.

4.3.2 Cathinone

Figure 7. Cathinone.

Cathinone (2-amino-1-phenylpropanone, 26) (Figure 7) is a sympathomimetic amine found as the main alkaloid in the shrub Catha edulis, also known as khat. Other compounds present in khat are norephedrine and norpseudoephedrine, which are also metabolites of cathinone.28 The chewing of khat (or qat) leaves is a traditional ritual in East Africa and parts of The Middle East such as the Yemen where it has deep-rooted

28 social and cultural functions.29 A medieval Arabic medical treatise recommends it to avoid hunger and fatigue and to ease social interaction. Cathinone has effects similar to amphetamine and MDMA: euphoria, excitability, hyperactivity, restlessness and anorexia.

4.3.3 Mescaline

Figure 8. Mescaline.

Mescaline (3,4,5-trimethoxyphenethylamine, 23) (Figure 8) is a naturally occurring psychedelic phenethylamine. It occurs in several cacti: the peyote cactus (Lophophora williamsii), the San Pedro cactus (Echinopsis pachanol) and in the Peruvian torch (Echinopsis peruviana), and has been utilized in religious rituals of several Native American Indian tribes for thousands of years. The structure of mescaline differs from other major psychedelics such as LSD, psilocybin and harmaline which belong to the indole family. The psychic effects caused by psychotomimetic drugs are believed to arise from perturbation of basic brain mechanisms, such as inhibition of serotonin systems, and potentiation of noradrenaline systems. It has been observed that the psychotomimetic properties of mescaline depend on the presence and configuration of all three 3,4,5- methoxy groups, and when it comes to phenethylamines, the 4-methoxy group is essential for the compound to be hallucinogenic. Mescaline is used as the standard in the examination for psychedelic activity of other compounds, in which context the so-called mescaline-units are used.30

4.3.4 Amphetamine

Figure 9. Amphetamine.

Amphetamine (phenylisopropylamine, 21) (Figure 9) is a synthetic sympathomimetic amine with central stimulant properties. It was discovered over 100 years ago and first synthesized in 1887.31 It has transformed from a panacea for a broad range of disorders, available without prescription in the early 20th century, into a highly restricted controlled substance with therapeutic use restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy.

The pharmacological effect of amphetamine is predominantly mediated by monoamine release, and is complemented by reuptake inhibition and probable inhibition of monoamine oxidase (MAO). Both D- and L-isomers of amphetamine are active, but have somewhat different potencies. These combine additively and/or synergistically to increase synaptic monoamine concentrations. Amphetamine acts as a competitive reuptake transport substrate, and also inhibits MAO. Amphetamine releases noradrenaline, (which increases the extracellular concentration of noradrenaline in the prefrontal cortex (PFC) and in the striatum), dopamine and 5-HT from synaptosomes, and adrenaline from the peripheral sympathetic nervous system.32

In the 1930’s amphetamine was marketed over-the-counter as Benzedrine to treat nasal congestion. Amphetamines (racemic amphetamine, D-amphetamine and methamphetamine) were widely used during World War II to promote wakefulness, which led to large increase in production and it became readily available. Racemic amphetamine is no longer available, but it has been sold under several different trade names including Benzedrine, Actedron, Allodene, Adipan, Sympatedrine, Psychedrine, Isomyn, Isoamyne, Mecodrine, Norephedrame, Novydrine, Elastonon, Ortedrine, Phenedrine, Profamina, Propisamine, Sympamine and Sympatedrin.

Nowadays pharmaceutical amphetamine is usually prescribed as Adderall to treat ADHD and narcolepsy, but also for depression, obesity and nasal congestion. 33 It is generally accepted that ADHD is caused by a dysregulation of the brain catecholaminergic systems in the PFC and its connections to subcortical regions, such as the striatum, having reduced dopaminergic function in various dopamine rich areas of the brain. 34 Since amphetamine increases the amount of dopamine, it is a logical choice for the treatment of the disease.

4.3.5 MDMA

Figure 10. MDMA.

MDMA (3,4-methylenedioxy methamphetamine, 24) (Figure 10) is a synthetic phenethylamine, first synthesized in 1966 and subsequently suggested as a means to deepen the self-exploration in psychotherapy by Alexander Shulgin.37 Like other phenethylamines, MDMA administration induces neurotransmitter activation across the main neural pathways, which means it can induce a range of mood changes. MDMA is an example of an entactogenic substance, meaning it has both positive and negative effects

30 on mood. MDMA has been suggested to have possible beneficial effects on some mental disorders, but these remain rather vague, since the compound also has adverse effects on health in the form of defective neurochemical recovery, which can be counterproductive in some individuals. Functional and structural defects in the serotogenic neurotransmitter system, as well as other psychological and biological problems have been found among MDMA users. MDMA became widely popular and misused outside of psychotherapeutic contexts in the 1980’s, having the trade name Ecstasy. It was also classified as an illegal substance, which it is still today.35

4.4 Synthetic routes to phenethylamines

Phenethylamines have traditionally been made by a reaction between an appropriate aldehyde or olefin and a nitroalkane followed by reduction of the resulting nitrostyrene. Syntheses of amphetamine and its derivatives usually use phenyl acetone as the starting 36 37 material. Reduction was commonly done with LiAlH4 in ether of THF, but also amalgamated zinc and hydrochloric acid or palladium have been used. A longer path starts with the conversion of a substituted benzyl alcohol to the corresponding chloride, followed by cyanation and reduction to the amine. Naturally occurring materials, such as coumarin and piperonal, have been used as starting materials for derivatives of mescaline. Traditional routes to phenethylamines are presented in Scheme 5.

All of the above-mentioned routes to phenethylamines suffer from relatively poor yields and lack of enantioselectivity. Separation of the enantiomers can be done by optical resolution. 38 Some of the phenethyl-like amines have been separated by fractional crystallization or distillation of the diastereomeric salts,39 chromatographic separation of diastereomeric amides40 or by microbial hydrolysis of an N-acyl derivative.41

Scheme 5. Traditional synthesis routes for phenethylamines.

Amphetamine 21, for example, can be prepared in 30% yield in a one-pot procedure by refluxing phenylacetone 46 in ethanol with ammonia, aluminium grit and a small amount of mercuric chloride, a process similar to the one described for pervitin (methamphetamine) by Laboratoires Amido.42 The process is illustrated in Scheme 6.

Scheme 6. Synthesis of amphetamine.

4.5 L-Dopa

Figure 11. L-Dopa.

L-Dopa (L-3,4-dihydroxyphenylalanine, levodopa, 38) (Figure 11) is a chemical that is part of the normal biology of humans, some animals and plants. It was first isolated from seedlings of broad bean Vicia faba in 1913, but concluded to be biologically inactive. However, in 1927 it was discovered to cause a fall in arterial blood pressure. Later, in 1938 it was found out that L-dopa decarboxylates into dopamine in mammalian tissue. In the 1950’s the field studying catecholamines as neurotransmitters gained momentum and the role of dopamine in Parkinson-like conditions was discovered.

L-Dopa is biosynthesized from L-tyrosine, and it is the precursor to the neurotransmitters dopamine 16, adrenaline 17 and noradrenaline 18. The first clinical results on the effect of L-dopa to Parkinson’s disease were reported during the 1960’s, and it has been used to treat Parkinson’s disease since its FDA approval in 1970.43 In 1997 three new drugs, called Mirapex, Requip and Tasmar, were approved by FDA and are used in conjunction with L-dopa to alleviate symptoms with decreased L-dopa doses.44

Parkinson’s disease is a degenerative disease of the central nervous system resulting from depletion of dopamine-producing cells in the brain, in the area called substantia nigra.45 The treatment of Parkinson’s disease has conventionally focused on relieving the symptoms by increasing the amount or mimicking the action of dopamine. While being the golden standard for the treatment of Parkinson’s disease, the L-dopa therapy is by no

32 means problem-free. First of all, L-dopa 38 is metabolized to dopamine 16 in the human body by an enzyme called aromatic L-amino acid decarboxylase (AADC). L-Dopa can cross the blood-brain barrier, and the amount that passes into the brain is converted into dopamine, while dopamine itself cannot cross the blood-brain barrier. AADC exists also outside the brain, meaning that before passing into the central nervous system, some of the L-dopa is peripherally metabolized into dopamine. For that reason L-dopa is usually administered as a mixture of L-dopa and carbidopa 57, an inhibitor of peripheral AADC. Thus, the amount of L-dopa available for crossing the blood-brain barrier is increased. In addition, L-dopa needs to be taken in large doses, and with long-term usage the body’s responsiveness to L-dopa decreases and even bigger doses are needed. It also causes dyskinesia as a result of L-dopa-induced synaptic dysfunction and inappropriate signaling between motor cortex and striatum. Furthermore, the use of orally administered L-dopa results in diminished production of endogenous L-dopa. Therefore, at the moment, it is typically used in conjuction with other drugs. In addition to carbidopa, other typical options to be administered with L-dopa are tolcapone 58, topinirol 59 and pramipexole 60 (Figure 12).

Figure 12. Carbidopa 57, Tasmar (tolcapone) 58, Requip (ropinirol) 59 and Mirapex (pramipexole) 60.

4.5.1 Industrial synthesis of L-dopa

The industrial synthesis of L-dopa is known as the Monsanto process, which has an important role in the history of synthetic organic chemistry. The Monsanto process was the first commercialized catalytic asymmetric synthetic process using a chiral transition metal complex, and it has been in use since its inauguration in 1974. It was a significant contributor to the explosive growth of research aimed at the development of asymmetric reactions in the following years. William S. Knowles and Ryoji Noyori were awarded half of the 2001 Nobel Prize in Chemistry for their work on the asymmetric catalytic hydrogenation, a key reaction in the the process. 46

The racemic Hoffmann-LaRoche synthesis of L-dopa utilizes the vanillin 61 as the starting material for the process. The prochiral enamide 62, generated from the reaction of 61 and benzoylglycine 63, produces DL-dopa intermediate after hydrogenation. The

33 enantiomers are separated by resolution and the final product is obtained after simple hydrolysis. The Hoffmann-LaRoche synthesis is presented in Scheme 7.

Scheme 7. Hoffman-LaRoche process for the production of L-DOPA.

The selective Monsanto process, presented in Scheme 8, likewise begins from 61. It is reacted with the acetamido acetic acid 66, following the Erlenmeyer azlactone procedure creating the azlactone 67, which creates a prochiral enamide 68. The key step in the synthesis is the catalytic hydrogenation of this enamide 68 with a >Rh(R,R)-

DiPAMP)COD@+BF4 which affords the protected amino acid 69 in quantitative yield and 95% ee. The synthesis is completed by a simple acid-catalyzed hydrolysis.

Scheme 8. Monsanto process for the production of L-dopa.

4.5.2 Other methods to obtain L-dopa

L-Dopa can also be produced by enzymatic and electroenzymatic processes.47 One option is to use isolated tyrosinase, multifunctional copper-containing oxidoreductase widely distributed in nature, as the catalyst. It is possible to produce L-dopa by a process that utilizes intact micro-organisms having high Tpl-activity, such as Erwinia herbicola or Stizolobium hassjoo. 48 Tpl is a tyrosine-inducible enzyme that catalyzes the α,β- elimination of tyrosine to produce pyruvate, ammonia and phenol producing L-dopa as a secondary metabolite. Tyrosinase can catalyze both the ortho-hydroxylation of tyrosine to L-dopa 38, and the subsequent oxidoreduction of L-dopa to dopaquinone 70. The latter can be reduced back to L-dopa by chemical reductants such as ascorbic acid, NADH and

NH3OH. A simplified scheme of the process is presented in Scheme 9.

Scheme 9. Enzymatic synthesis of L-dopa.

5. Transition metal catalyzed cross-coupling reactions

5.1 Palladium catalyzed cross-coupling reactions

The formation of carbon-carbon bonds is a fundamental reaction in organic chemistry and its importance cannot be overestimated. The reaction is a routine tool for the preparation of fine chemicals and pharmaceutically active compounds in the laboratory and industrial scale.49 Modern cross-coupling chemistry emerged in the early 1970’s when Corriu et al. and Kumada et al. independently reported nickel-catalyzed reactions between Grignard reagents and alkenyl and aryl halides.50,56 Shortly thereafter it was noticed that replacing nickel with palladium gained advantages.51 In addition, Kochi reported the use of iron salts in similar purposes.52 From that on, the field has expanded and a variety of transition metal catalyzed couplings between different coupling partners are known. The field is dominated by the use of palladium and nickel complexes as the catalysts. The best substrates for the palladium- and nickel-catalyzed cross-couplings are aryl or alkenyl bromides, triflates and iodides. The most important palladium-catalyzed coupling reactions are: Suzuki-Miyaura53, Stille54, Negishi55, Kumada56, Hiyama57, Sonogashira58, Heck59 and Buchwald-Hartwig60 couplings (Figure 13).

Figure 13. Palladium-catalyzed coupling chemistry.

5.1.1 The Kumada-Tamao-Corriu type cross coupling

Relevant to the work presented in this thesis is the Kumada-Tamao-Corriu type cross- coupling between a halide and a Grignard reagent. The typical Kumada-coupling is presented in simplified form in Scheme 10.

Scheme 10. The typical Kumada-coupling.

Numerous alternatives to traditional aryl halide electrophiles have reportedly been used in this reaction, including aryl-oxygens (triflates and O-carbamates, 61 tosylates, 62 mesylates,63 phosphates,64 alkyl ethers,65 acetates,66 diaryl sulfates,67 phenolic salts68) and aryl-sulfur69 (thiols, sulfides, sulfones,70 sulfoxides,71 O-alkyl sulfonates,72 sulfonamides73) and aryl-nitrogen74 derivatives. In addition to nickel and palladium catalysts, the cross- coupling between Grignard reagents and organic halides is induced by a number of other transition metal halides, such as silver, copper and iron halides.75

The mechanism of palladium-catalyzed cross-coupling of the Kumada-type has been carefully examined and a commonly accepted version can be found in all modern text books of organic/organometallic chemistry. The reaction involves palladium(0) and palladium(II) species. The sequence starts with the oxidative addition of the aryl halide to palladium(0), which results in a palladium(II) species. This species is transmetallated with Grignard reagent, and the subsequent reductive C-C coupling of the dihydrocarbyl- palladium(II) intermediate forms the Ar-R compound (Scheme 11).

Scheme 11. The mechanism of Pd-catalyzed Kumada coupling.

Alongside to traditional halide electrophiles,76 alkenyl phosphates have emerged to be convenient coupling partners.77,78 Enol phosphates are more stable, easier to prepare and generally less expensive than for example triflates and nonaflates. Kumada et al. have examined a Ni-catalyzed coupling of unactivated aryl phosphates with aryl Grignard reagents,79 and some reports have been published on the couplings of unactivated vinyl phosphates with Grignard reagents. 80 Skrydstrup et al. have reported ligand-free Pd- catalyzed Kumada-Corriu couplings of O-cyclohexenyl, cycloalkenyl, alkylvinyl and arylvinyl phosphates in moderate to good yields (26–94%).81 These ligand-free conditions perform similar transformations effectively, despite the fact that more reactive alkenyl tosylates have been reported to require an electron-rich phosphine ligand for promoting

38 the Pd-catalyzed coupling with Grignard reagents. It has been suggested that Pd(II) salts form reactive nanopalladium particles in the presence of aryl magnesium halides.82

Scheme 12. PdCl2-catalyzed Kumada coupling of alkenyl phosphates and Grignard reagents.

The formation of homocoupling side products is a known feature of the reaction.77a,79b Work by Kumada has demonstrated that carefully selecting the phosphine ligand could be effective at controlling the pathways that lead to undesired byproducts.83 Great progress has been made in tuning the nature of the phosphine-based ligands,84 but a ubiquitous solution still has not been found, especially for Grignard reagents. The absence of a coordinating ligand or additive, as in reactions catalyzed by PdCl2 strongly favor β- hydride elimination to afford the protio-quenched product.

β-Hydride elimination of alkyl palladium(II) intermediates is an important elementary transformation in organometallic chemistry, in which a hydride (hydrogen atom) is transferred from the β-position of the ligand into the metal center. This process leads to the formation of a metal hydride and an olefin. In many instances this β-hydride elimination step leads to the formation of side products. The general mechanism of the transition metal catalyzed β-hydride elimination is illustrated in Scheme 13.

Scheme 13. β-Hydride elimination in transition metal catalysis. M = transition metal, L = ligand.

5.2 Cross-couplings catalyzed by iron

Palladium and nickel are the most popular transition metal used in cross-coupling reactions, but they have limitations. For example, some of the ligands used in the complexes are expensive and/or sensitive to air and moisture. Iron is one of the most abundant, inexpensive and environmentally friendly metals on Earth, thus being a great candidate for transition metal catalyzed processes in organic synthesis. Iron-catalyzed cross-coupling reactions have been extensively studied 85 and iron has been shown to

39 catalyze cross-coupling reactions of Grignard or organomanganese reagents with alkenyl halides,86 alkenyl sulfones,87 acid chlorides or thiolester88 and with vinyl halides 89 and phosphates,90 for example.

The development and designing of ligands for iron catalysis has been rather limited. The scope of the reaction is rather limited in comparison to palladium- and nickel-catalyzed methods Iron is associated with many accessible oxidation states, and several different mechanisms may operate simultaneously. It has been speculated that the catalytically relevant intermediates would be Fe(0) or Fe(I) species, but no evidence has yet been obtained.91,89 The involvement of iron(I) and iron(III), and a catalytic cycle analogous to that of palladium and nickel-catalyzed reactions has been suggested based on the studies of reactions between alkyl or alkenyl bromides and alkylmagnesium reagents. The oxidative addition of an organohalide to iron(I) species (turnover-limiting step) is followed by transmetallation of the Grignard reagent, which is then followed by reductive elimination.92 However, experiments with reactions between methyllithium and alkenyl bromides with a catalytic amount of FeCl3 have suggested an involvement of iron(II) and iron(IV) species in the catalytic cycle.93 In addition, a mechanism involving iron(III) and single-electron transfer processes has been supported by experiments. 94 The two overlapping catalytic cycles are presented in Scheme 14.

Scheme 14. The mechanism of iron catalyzed cross-coupling.

On the other hand, studies indicate the presence of [Fe(MgX)2], the so-called “inorganic Grignard reagent” readily soluble in ethereal solvents such as THF, in the catalytic cycle.94 The Grignard reagent generates the active catalyst by reducing the iron salt, and the catalytic cycle is a typical sequence of oxidative addition, transmetallation and reductive elimination. The [Fe(MgX)2] is formed when FeCl2 reacts with R-MgX. Studies indicate that [Fe(MgX)2] consists of small clusters that incorporate magnesium and iron centers connected via covalent intermetallic bonds. 95 The stoichiometry of the reaction depicted in Scheme 15 implies that the reduction process does not stop at zerovalent iron. Fe(0) is formed but it is transformed into a species bearing a formal negative charge at iron. Thus it becomes highly nucleophilic and without stabilizing ligands it is able to

40 oxidatively add to aryl halides. The resulting organometallic (formal Fe(0)) iron compounds are alkylated by the excess Grignard reagent, which is followed by reductive elimination of the organic ligands, giving the desired product and regenerating the propagating Fe(II) species. The process is illustrated in Scheme 15.

Scheme 15. Suggested mechanism of the iron-catalyzed cross-coupling involving the inorganic Grignard reagent.94

Only a limited number of ligands have been found to promote cross-coupling with iron. The most commonly used additives are N-methylpyrrolidone (NMP) or tetramethylethylenediamine (TMEDA), but usually the iron salt is used as such. The coupling of Grignard reagents with terminal dienol and trienol phosphates catalyzed by 90 Fe(acac)3 has been reported. Advances in the field of “inorganic Grignard reagents” raises a call for a re-evaluation of iron-catalyzed cross-coupling reactions in a broader context.

One of the major limiting factors in palladium-catalyzed cross-coupling reactions is the reducing ability of Grignard reagents. They act as nucleophiles in the presence of palladium complex catalysts, causing precipitation of palladium black and inhibiting the catalytic turnover. In contrast, iron-catalyzed cross-couplings rely on this exact property. The toxicologically and environmentally benign character of the iron salts makes their use favourable. The fact that aryl chlorides, tosylates and triflates are better coupling partners compared to bromides or iodides is a further advantage.

6. Synthesis of allylamines

Chiral allylamines are important building blocks in the preparation of a variety of important classes of compounds, such as α- and β-amino acids,96 alkaloids,97 carbohydrate derivatives98, among other compounds.99 Allylamines are also of industrial interest and several methods for making racemic allylamines have been reported. 100 The general methods for the synthesis of chiral allylamines are amination of enantiopure allyl alcohols or their derivatives,101 asymmetric amination of nonfunctional alkenes102 or olefination of amino aldehydes.103 However, amination of allyl alcohols and alkenes is not an enantio-, regio- or stereoselective method. The syntheses involving a Wittig olefination of α-amino aldehydes104 are limited by the possibility of racemization during the reaction.

6.1 Palladium and iron-catalyzed synthesis of Pf-allylamines

In this work, Pf-protected phenethylamines were synthesized starting from alanine the key reaction step being the synthesis of allylamines. The reaction was accomplished with two different transition metal catalyzed couplings, one being palladium-catalyzed ligand free coupling between the N-Pf-alanine derived enol phosphate 71 and Grignard reagents (Scheme 16).

Scheme 16. Synthesis of N-Pf-phenethylamines 75 via enol phosphate 71.

The scope of the Pd-catalyzed ligand free cross-coupling reaction was examined by coupling the N-Pf-alanine derived enol phosphate 71 with different aromatic Grignard reagents to afford a series of allylamines. The enolate was regioselectively made from the ketone 5 by using KHMDS, subsequently reacted with diphenyl chlorophosphate 72 to give 71 in a 60-70% yield. The enol phosphate 71 was reacted slowly with Grignard reagents during approximately 2 h using syringe pump. The long addition time was required for the completion of the reaction, and to avoid side product formation via homocoupling. The coupling of the allyl phosphate with Grignard reagents produced

42 allylamines in varied yields depending on the nature of the aromatic ring. The simplest Grignard reagent, phenylmagnesium bromide 76 gave a modest result of 58% yield. An electron rich p-methoxyphenylmagnesium bromide 77 led to full conversion upon addition, giving a likewise a modest yield of 44%. The reaction with more electron poor p-chlorophenylmagnesium bromide 78 needed a longer reaction time and addition of more Grignard reagent to reach full conversion, and the isolated yield of the product was only 27%. Another electron-poor substrate, 3,5-bis(trifluoromethyl)phenylmagnesium bromide 79, did not react at all. Heteroaromatic substrates, 2-thienylmagnesium bromide 80 and 2-pyridinemagnesium bromide 81 reacted sluggishly and incompletely, but desired products were formed. Thienylmagnesium bromide 80 gave 24% yield of the wanted product and 30% yield of recovered starting material, while the pyridine substrate gave a crude mixture from which the product was not isolable. Morpholinomethylphenylmagnesium bromide 82 reacted but did not give the expected product. Instead, benzyl morpholine 83 (44%) and recovered starting material (33%) were isolated.

The results for the coupling of enol phosphate with Grignard reagents are presented in Table 2.

Table 2. Ligand-free PdCl2-catalyzed Kumada-Corriu coupling of 71.

Entry Grignard reagent Product Time (h) Yield (%)

1 2 58

2 2 44

3 4 27

4 6 days - (No reaction)

5 27 24

6 26 Nd.a

7 26 44

8 27 30b

a: crude, b: approximated conversion, not purified.

As mentioned, the reaction was sensitive to the addition time of the Grignard reagent. The conversion was incomplete if the addition was performed too quickly, and this could not be compensated with a longer reaction time. The catalyst seemed to lose its efficiency. The other difficulty was the formation of side products, which was a serious issue when there were any substituents or heteroatoms in the aromatic ring of the Grignard reagent. Homocoupling products were major side product, which is a known issue with these reactions.77a,79b

Another iron catalyzed coupling to afford the allylamines was performed between enol triflate 91 and aromatic Grignard reagents. A similar reaction has been reported previously.105 The enol triflate was first made by treating the N-Pf-alanine methyl ketone

5 with Tf2O, freshly prepared by dehydration of triflic acid by phosphorus pentoxide P2O5.

However, reaction of Tf2O with ketone 5 led to a mess, and the isolated yield of the desired product 91 was only 18%. When using Comins’ reagent (N-(5-chloro-2-pyridyl) bis(trifluoromethanesulfonimide)) 92 as the triflating agent, triflate 91 was successfully made from ketone 5 via its enolate in a nearly quantitative yield (97%) in scales below 20 mmols. In larger scales the reaction became sluggish and full conversion was not achieved. The triflate was not stable if stored at rt and it was noticed to partly decompose on silica gel. The syntheses of the phosphate 71 and the triflate 91 are presented in Scheme 17.

Scheme 17. The formation enol phosphate 71 and enol triflate 91.

The coupling reaction between the triflate 91 and Grignard reagents was performed in a similar manner to the palladium-catalyzed reaction. The enol triflate was reacted slowly with Grignard reagents using syringe pump, but Fe(acac)3 was used as the catalyst. When phenylmagnesiumbromide was used as the coupling partner, the reaction time was 3 hours and the yield was good (90%). However, with substituted Grignard reagents full conversions were not achieved, and the yields were in the same range (20-40%) as in the palladium-catalyzed coupling. The 3,5-bis(trifluoromethyl)phenylmagnesium bromide 79, 3,4,5-methoxyphenylmagnesium bromide 84 and 3,4-(methylenedioxy)phenylmagnesium

45 bromide 93 reacted with the starting material in these reaction conditions, and the desired products were identified. The substrate scope and the results for the iron-catalyzed coupling are presented in Table 3.

Table 3. The iron catalyzed coupling reaction between enol triflate and aromatic Grignard reagents.

Entry Grignard reagent Product Time (h) Yield (%)

1 3 90

2 24 44

3 24 32

4 24 40a

5 24 40a

6 24 40a

a: approximated conversion, not purified.

6.2 N-Pf-Alanine methyl ketone

The key compound for the synthesis of the allylamines mentioned above, and for other amines prepared and included in this thesis, was the N-Pf alanine-derived methyl ketone 5. Amino ketones in general are useful building blocks for all sorts of pharmaceutically interesting amines. There are several methods for making amino ketones, 106 from α- haloketones, epoxides or other selected precursors, by adding the nitrogen to the compounds from an outside source such as ammonia. These methods are not covered further here.

Amino ketones are synthesized from the corresponding amino acids by addition of a suitable carbanion equivalent to an activated form of the acid. Esters are usually too reactive towards organometallics and give tertiary alcohols instead, since the ketone which is formed first is more reactive than the starting ester. The challenge of over- addition can be avoided by using less reactive nucleophilic species with more reactive ester derivatives. The most common amino acid derivatives are perhaps N-methoxy-N- methylamides (the so-called Weinreb amides), which have been developed to enable the direct transformation of carbonyl compounds into corresponding aldehydes and ketones.107

The most straightforward ways were tested first. With N-Pf-protected alanine as the substrate, we discovered that the free acid 4, as well as the ester 2, were both completely unreactive towards methyllithium 95 and methylmagnesium bromide 96. Weinreb amide 3, was either completely unreactive or on the other hand too reactive, depending on the reaction temperature, and led to either no product at all or the tertiary alcohol 97 as the only product. Morpholine derivative 98 was also prepared and found unreactive.

A detour was taken and the methyl ketone was accessed through an oxazolidinone 73, which was easily made from the free acid 4 in nearly quantitative yield in several hundred mmol scales. The methylation of the oxazolidinone 73 with MeLi 95 then proceeded cleanly. The main obstacle with the reaction was the poor solubility of the oxazolidinone, which was an actual practical problem when the reaction was scaled up. Incompletely dissolved starting material led to incomplete conversion.

Direct addition of 95 to the α-amino acid to form the corresponding methyl ketone has reportedly been done,108 but as stated above, in our case it simply did not work, nor did the use of Weinreb amide. Different temperatures and Lewis acids as well as other additives were tested, without success. It became obvious that if we wanted to avoid the oxazolidinone step, we needed another approach. We discovered that Weinreb amides can be converted to ketones by a non-classical Wittig reaction using

47 methyltriphenylphosphonium bromides, which in our case worked fine.109 A summary of the different methylation methods are presented in Table 4.

Table 4. Synthesis of methyl ketone.

Starting material Methylating reagent 5 (%) 97 (%) No reaction 4 R = OH MeLi - - - MeMgBr - - - 2 R = OMe MeLi - - - MeMgBr - -

Ph3PCH3-Br+n-BuLi - - 30% sm 3 R = N(Me)OMe MeLi - 100 - MeMgBr - 100 - MeMgCl+LiCl - - -

Ph3PCH3-Br+n-BuLi 38-quant. - 98 R = morpholine MeLi - - - MeMgBr - - -

Ph3PCH3-Br+n-BuLi - - - The reactions were run in 1 mmol scale in andhydrous THF (1 mL).

The alternative synthesis route to allyamines is presented in Scheme 18. Alanine methyl ester 2 was phenylfluorenylated, followed by the formation of N-Pf-alanine Weinreb amide 3, which was then reacted with methyltriphenylphosphonium bromide 99 affording the N-Pf-alanine methyl ketone 5. That was transformed into the triflate enolate 91 and coupled with phenylmagnesiumbromide to afford the N-Pf-alanine allyl amine 74. With all the intermediates being crystalline, except for the triflate that could be used as a crude, no chromatographic purification was needed until the final product which was obtained in 63% yield over 6 steps.

Scheme 18. Alternative synthesis route to N-Pf-allylamines.

6.3. Allyl silanes in the synthesis of allylamines

Allylsilanes are generally versatile compounds in synthesis110 and can be prepared from e.g. esters. 111 The reaction is usually performed by reacting the ester with trimethylsilylmethylmagnesium bromide 100 or TMS-methyllithium 101 in the presence of cerium chloride, which leads first to a tertiary alcohol. Elimination of trimethylsilanol from this tertiary alcohol results in the allylsilane (Scheme 19).

Scheme 19. Synthesis of allylsilanes from esters.

The synthesis of N-Pf-allylamines would be shortened if the allylamines could be made in one step from the N-Pf-amino esters. Treating the N-Pf ester 2 with 100 mol-% of TMS- methylmagnesium bromide 100 or TMS-methyllithium 101 would form the corresponding TMS-methyl ketone 102, which would then be reacted with phenylmagnesium bromide 103 or PhLi 104, or vice versa, resulting in the tertiary alcohol 105. Elimination of trimethylsilanol from this tertiary alcohol would form the desired allylamine 74 (Scheme 20).

Scheme 20. The proposed synthesis route for N-Pf-allylamines via N-Pf-allylsilanes.

In the model experiments methyl benzoate 107 and methyl hexanoate 108 were treated with TMS-methylmagnesiumbromide 100 and TMS-methyl lithium 101. However, no reaction was observed. In the literature procedures, cerium chloride is often used in conjunction with the Grignard reagent. Thus it was added to the experimental procedure.

The cerium reagent was carefully prepared beforehand: CeCl3.7H2O was powdered and then dried for several days under vacuum at a high temperature (120 °C). Disappointingly, no reaction or formation of product was observed when it was used with the Grignard reagent.

Scheme 21. Silylation of the model compounds methyl benzoate and methyl heptanoate.

Despite these rather discouraging results with the model compounds, the reaction was performed with the real substrate 2. The compound reacted, albeit extremely sluggishly, with both TMS-methylmagnesium bromide 100 and TMS-methyllithium 101 affording the tertiary TMS-methyl alcohol 109. The same outcome was achieved when the ester was reacted with phenyllithium. The tertiary alcohol 110 was instantly formed, but this time in a quantitative isolated yield. Further experimentation was carried out with the nucleophilic reagents (Ph-Li/PhMgBr vs TMS-methyllithium vs TMS-methylMgBr) and their addition orders, amounts and reaction times as well as reaction temperatures, but the formation of either 109 or 110 seemed to be inevitable. In one instance, however, when PhLi 104 and TMS-methyllithium 101 were added subsequently (100 mol% each) to 2,

50 the desired product 105 was observed in HRMS analysis as a mixture with 109 and 110. The reaction is presented in Scheme 22.

Scheme 22. The attempted synthesis of 105.

Changing the starting material from N-Pf-alanine methyl ester 2 to the N-Pf-alanine Weinreb amide 3 changed the situation slightly and more control over the product formation was possible. Thus the phenylketone 106, N-Pf-protected cathinone, was isolated in 16% yield (Scheme 23).

Scheme 23. Synthesis of N-Pf-cathinone 106.

The formation of the tertiary alcohol as the main product was inevitable, but the ketone intermediate was isolatable, albeit in minor amounts. When this isolated ketone was reacted with TMS-methyllithium 101, HRMS analysis revealed we had 109 instead of 105. With the previous observation that 105 was formed as part of the crude mixture, it was decided to perform the hydrolysis on the crude product to see if it was possible to obtain the desired allylamine product without isolating the intermediate. Several different conditions were tested, which are presented in Table 5, but N-Pf-allylamine 74 was not formed.

Table 5. Hydrolysis conditions.

Hydrolysis agent Result Silica in DCM - Amberlyst 15 -

BF3AcOH - KH in THF - NaH in HMPA - 1M HCl - H2SO4 in THF - MsCl in TEA - NaOAc in Ac2O - NaOAc in AcOH -

7. Asymmetric hydrogenation

Asymmetric catalytic hydrogenation is one of the most important methods for preparing optically active compounds for the pharmaceutical, petrochemical and fine chemical industries. The initial reports of catalytic asymmetric hydrogenation date back to 1933,112 and the first reports of asymmetric hydrogenation by chiral catalysts were published in 1968 by Knowles113 and Horner.114 From then on, the field has expanded to industrial success, and the Nobel Prize in Chemistry was awarded to Knowles115 and Noyori116 in 2001. For a long time the field was dominated by chiral rhodium- and ruthenium- diphosphine complexes, but their limited abilities to hydrogenate substrates not having any coordinating groups eventually led to the discovery of iridium-N,P-complexes.

7.1 General considerations of modern asymmetric hydrogenation

The most commonly used catalytic systems for the asymmetric hydrogenation are composed of ruthenium (Ru(I)) or rhodium (Rh(II)) species bearing (chiral) diphosphine ligands (P,P-ligands). Nowadays a plethora of chiral phosphine ligands are known, and with rhodium and ruthenium catalysts they exhibit very high enantioselectivities. The 117 discovery of Wilkinson’s catalyst [RhCl(PPh3)3] in 1965 initiated a systematic development of asymmetric reduction of olefins catalyzed by rhodium complexes with chiral phosphine ligands. Typical examples of chiral ligands, such as BINAP 111, 118 DIPAMP 112,119 and DuPHOS 113120 are presented in Figure 14.

Figure 14. Typical examples of chiral phosphine ligands.

7.2 Rhodium-catalyzed asymmetric hydrogenation

DIOP 115 developed by Henry Kagan, was one of the earliest well-working ligands for catalytic asymmetric hydrogenation.121 As a Rh-complex it was applied to the synthesis of L-dopa 38. The level of asymmetric induction was good, but the ligand was developed further for the actual commercial process. The asymmetric hydrogenation step in the industrial Monsanto process, presented as a whole in Chapter 4.4.2, using Rh-DIPAMP complex is presented in Scheme 24.

Scheme 24. Catalytic asymmetric hydrogenation reaction in the Monsanto process for the synthesis of L-dopa.

Generally these systems require the presence of a coordinating functional group, for example carbonyl or allylic alcohol, adjacent to the C=C bond, in order to achieve high selectivities. Typical substrates for the evaluation of the Ru/Rh-phosphine ligand complex catalyzed hydrogenations are α-hydroxycarbonyl substituted enamides 68a (Scheme 25).

Scheme 25. Typical scheme for evaluating the ligands developed for the hydrogenation.

The mechanism for the process is fairly well studied and understood.122 The so-called “unsaturated/dihydride mechanism” is illustrated in Scheme 26. Rh forms a complex with the R,R ligand and solvate [(R)-117], which reversibly forms a complex 117b with the enamide. This complex 117b undergoes irreversible oxidative addition of molecular H2 to the Rh-center, forming Rh(III)dihydride species 117c. Both hydrides migrate from the Rh onto the C-C double bond of the substrate. The first migration to the C3 position generates a five-membered alkyl-hydride complex 117d. Reductive elimination of the hydrogenation product regenerates 117a and completes the catalytic cycle. The stereochemistry is thought to be determined at the first irreversible step, 117b→117c, but another possibility is that the process 117b→117c is reversible and the 117c→117d is the turnover-limiting step.123

Scheme 26. Unsaturated/dihydride mechanism.for the catalytic hydrogenation of N- acylated dehydroaminoesters. The β-substituents in the substrates are omitted for clarity. (P-P = (R,R)-DIPAMP, (R,R)-CHIRAPHOS or (R)-BINAP; L = solvent or a weak ligand).

BINAP 111, DIPAMP 112, CHIRAPHOS 114 and DIOP 115 are chiral diphosphines with C2-symmetry and form chelate complexes with transition metals. The chiral environment of (R)-BINAP-transition metal complex is presented in Figure 15, and it is also valid for (R,R)-CHIRAPHOS and (R,R)-DIPAMP. In this template, P-phenyl rings transmit the chiral information of the binaphthyl backbone to the four coordination sites. The “equatorial” phenyl rings affect sterically the in-plane coordination sites, and out-of- plane coordination sites are influenced by the “axial” phenyl rings. Two kinds of quadrants are differentiated spatially: the second and fourth quadrants are sterically congested, while the first and the third ones are relatively spacious.

Figure 15. The (R)-BINAP-transition metal complex. (M = metallic element, CS* = coordination site out of the P1-M-P2 plane, CS = coordination site in the P1-M-P2 plane.)

The Rh-enamide complex 117b, presented in Scheme 24, has two possible diastereomeric structures that are presented in Figure 16. Depending on the Si/Re-face selection at C2, either R or S hydrogenation product is formed. Therefore, the relative equilibrium ratio

55 and reactivity of the favored and unfavored 117b determine the enantioselectivity of the reaction. In31P NMR that the Rh-complex with an enamide substrate shows a single signal for the thermodynamically more favored 117b. In the less favoured 117b there is nonbonded repulsion between an equatorial phenyl ring of the (R)-BINAP ligand and the carboxylate function of the substrate, and it reacts faster with H2 than the more stable form 117b, leading to the S isomer as the major product. 124

Figure 16. Molecular models of diastereometric (R)-BINAP/enamide/Rh complexes 1 117B (Z = CO2R , ax = axial, eq = equatorial).

This mechanistic feature can be considered as counterintuitive, but it can be solved when the more stable intermediate gives the major enantiomeric product. A Rh-complex with a

C1-symmetric chiral P/S-ligand catalyzes hydrogenation of methyl (Z)-2- (acetamido)cinnamate giving the S-product. It is suggested that in this system, the major S product is obtained via the more stable diastereomer of 117b. The only visible system among four possible diastereomers has been observed to be the unfavored but more reactive 117b and it is presented in Figure 16. The bulky t-butyl group is essential for the high enantiofacial selectivity, and it is placed at the axial position to avoid steric hindrance with the ligand backbone. The two phenyl groups on phosphorus take axial and equatorial positions. The high enantiodiscriminatory ability of the complex is explained by examining the quadrant model of the complex. The electron donating olefin functionality of the enamide binds to Rh at the trans position to the less electron-donating sulfur atom instead of phosphorus. The first and the fourth quadrants are unfavourable for electronic reasons. The third and fourth quadrants are blocked by equatorial P-phenyl and bulky S-t-butyl. Thus, the only quadrant available for the approach of the methoxycarbonyl (Z) is the second one.

The unsaturated/dihydride mechanism is not the only possible mechanism for enamide hydrogenation, but also a different catalytic cycle can be applied. Hydrogenation of enamides catalyzed by a (R,R)-t-Bu-BisP*, C2-symmetric, fully alkylated diphosphine with chiral center at P, -Rh complex leads to S isomer as the major product with excellent ee. This is suggested to proceed via the “dihydride/unsaturated” mechanism, presented in Scheme 27. The difference compared to the “unsaturated/dihydride” mechanism is the order of the reaction of the substrate and H2. Here, the catalyst (R)-118a first reacts reversibly with H2, giving 118b, which is followed by interaction of the enamide substrate to form a substrate-RhH2 complex 118c. The stereochemistry is determined in the first irreversible step, 118c→118d. Now there are two kinds of quadrants in the chiral template. The first and the third quadrants are crowded by the P-t-butyl groups, but the second and the fourth quadrants are occupied only the small methyl groups, and thus are open for the substrate to approach. The hydrogenation catalyzed by a PHANEPHOS-Rh- complex is suggested to proceed via this mechanism.

Scheme 27. Dihydride/unsaturated mechanism.for the catalytic hydrogenation of N- acylated dehydroaminoesters. The β-substituents in the substrates are omitted for clarity. [P-P = (R,R)-t-Bu-BisP*; L = solvent or a weak ligand].

7.3 Ruthenium catalyzed asymmetric hydrogenation

In BINAP-metal –based systems, rhodium can be replaced by ruthenium. Different Ru-

BINAP systems, Ru(OAc)2BINAP for example, catalyze the hydrogenation of a variety of substrates. It is noteworthy that changing the metal from Rh to Ru leads to an opposite sense of enantioface selection. The hydrogenation of methyl (Z)-α-(acetamido)cinnamate

57 with the (R)-BINAP-Ru catalyst gives the R product as the major one. The monohydride/unsaturated mechanism is illustrated in Scheme 28. The RuH(OAc) species

119b, which acts as the real catalyst, is formed by the heterocatalytic cleavage of H2 from the precatalyst 119a. The Ru-hydride species coordinates to the substrate forming 119c.

Migratory insertion gives 119d, and the Ru-C bond is cleaved by H2 and alcoholic solvent to some extent. The absolute configuration of the product is determined in the irreversible step. The molecular models for the Ru-based complexes are presented in Figure 17.

Scheme 28. Monohydrate/unsaturated mechanism for the BINAP-Ru-catalyzed hydrogenation of methyl (Z)-α-acetamidocinnamate. The β-substituents in the substrates are omitted for clarity.

Figure 17. Molecular models of diastereomeric (R)-BINAP/enamide/Ru complexes. The enantioface selection is opposite compared to Rh complexes.

7.4 Hydrogenation of simple olefins by iridium catalysts

The range of olefins that can be hydrogenated with Ru-/Rh-diphosphine complexes with high enantiomeric excess is limited, since these catalyst systems need the existence of adjacent functionality in order to give excellent results. Unfunctionalized olefins, such as tri- and tetrasubstituted olefins devoid of heteroatoms are typically unreactive and give unsatisfactory enantioselectivity, which limits their use. Iridium catalysts are relatively new in the field of asymmetric hydrogenation compared to the rhodium and ruthenium based systems. Their ability to rapidly hydrogenate olefins were discovered by Crabtree et al.125 If Wilkinson’s catalyst 120 was the pioneer for the development of the catalyst- ligand complexes in the asymmetric hydrogenation of functionalized substrates, Crabtree’s catalyst 121 was the pioneer for the simple olefins. The catalysts are presented in Figure 18.

Figure 18. Wilkinson’s and Crabtree’s catalysts.

+ − Crabtree’s catalyst, [(COD)Ir(PCy3)(py)] [PF6] catalyzes the hydrogenation of 1-hexene 100 times faster than Wilkinson’s catalyst. It performs better in diastereoselective functional-group-oriented hydrogenation of cyclic olefins controlling the stereochemistry of the new stereocenter better than the related Ru- and Rh-catalysts.125b Crabtree’s catalyst also catalyzes the hydrogenation of tri- and tetrasubstituted olefins, towards which Wilkinson’s catalyst is inactive.126 In the late 1990s, the Pfaltz group discovered a new class of chiral iridium N,P-ligand complexes which showed exceptionally high activity in the hydrogenation of unfunctionalized tri- and tetrasubstituted olefins. 127 Resembling Crabtree’s catalyst, phosphine and pyridine ligands of the Crabtree’s catalyst were replaced by phosphinooxazoline (PHOX) ligands. Typical PHOX-ligands are presented in Figure 19.

Figure 19. Typical PHOX-ligands.

7.4.1 Mechanistic overview of the iridium-catalyzed hydrogenation

Deactivation of Crabtree’s catalyst is a known problem, which is believed to be caused by the formation of inactive hydride-bridged trinuclear complexes. 128 Extensive experimentation with Ir-PHOX catalyst with tetrakis[3,5- bis(trifluoromethyl)phenyl]borate (BArF-) as the counter ion has shown that the counterion plays an essential role in the success of the reaction.129 Practically all iridium + - - catalysts of the form [Ir(L*)(COD)] [X] for asymmetric hydrogenation of olefins BArF - 130 have performed better in cases where PF6 has failed to reach full hydrogenation. The - experiments have shown that with PF6 as the counterion, the rate dependency of olefin - - concentration is first order, and with BArF it is close to zero. This suggests that PF6 might form such a tight ion pair, or coordinate so strongly, that the addition of the olefin to the catalyst is slowed down to the extent of becoming the rate-limiting step. In contrast, bulky and weakly coordinating anions do not interfere with the olefin coordination, and the catalyst remains saturated. The critical step in the catalysis must be the reaction of the Ir-hydride intermediate with the olefin.

Scheme 29. Comparison of Crabtree’s catalyst with the [BArF]− anion.131

The mechanism of the iridium-catalyzed hydrogenation is still fairly poorly understood, despite numerous studies.132 A possible mechanism is suggested for the complexes of the type [(A∩B)Ir(COD)]+[BArF]−. In the early stages, the COD ligand is hydrogenated to cyclooctane and lost from the catalyst precursor, leaving a coordinatively unsaturated iridium cation. This cation must be transformed into one bearing both the olefin substrate and at least one hydrogen atom to be able to induce asymmetry. Therefore, it must react with H2 and the substrate to form a cationic Ir(III) dihydride complex. The structure of this complex is crucial for the stereoselection, since the H-atom transfers from metal to olefin from this complex. It has been speculated with the help of computational studies that the electronic effects, especially the trans influence, play a crucial role in dictating the structure of the complex, sterics having a secondary role.132f,g,h The hydrides are very strong σ-donors and cannot be trans to one another, which places them mutually cis. They also prefer not to be trans to the next strongest trans-influence ligand, which usually is phosphine or carbene in these systems. The existence of the cis-dihydride complex is supported by calculations, the X-ray structure of the chlorocarbon solvated + - iridium compound [Ir(H)2(PPh3)2(ClCH2CH2Cl)] [BArF] and NMR studies (in THF-d8).

However, a mixture of hydrido species were observed in CD2Cl2, which indicates that the situation under the catalytic conditions is complicated.

The presence of the iridium(III) dihydride complex is widely accepted. However, its exact role in the mechanism of the asymmetric hydrogenation is an issue of some contention. Experimental and theoretical studies on the iridium-catalyzed asymmetric hydrogenation have been performed on different systems: various catalysts, substrates and reaction conditions have been used, which makes the subject even more complicated. Two possible, simplified, catalytic cycles are presented in Scheme 30. Brandt, Burgess and Hall suggest the mechanistic pathway proceeds via Ir(III) and Ir(V) intermediates. In contrast, Buriak133 and Chen132i suggest and have published data supporting a cycle that proceeds via Ir(II) and Ir(III). It cannot be dismissed that also multiple pathways for a single system can be possible. However, the Ir(I)/Ir(III) and Ir(III)/Ir(IV) cycles both proceed via Ir(III) intermediate complex, from which the transfer of H to olefin occurs.

Examining the geometry of this complex gives a useful model for predicting the basis for the enantioselectivity.

Scheme 30. Two possible catalytic cycles for hydrogenation of olefins by chiral iridium complexes with the common Ir(III) dihydride complex. At left, generalized cycle with Ir(I) and Ir(III) intermediates, based on drawings by Chen132i and Pfaltz134. At right, generalized cycle with Ir(III) and Ir(IV) complexes based on drawings Brandt132f and Burgess and Hall132h. S = solvent; Y = phosphine or carbene.

7.4.2 General selectivity based on iridium (III) dihydride

Olefin coordination can occur at two sites: (1) in the plane of the chelate → trans to the stronger trans-terminus of the chiral ligand or (2) in the remaining axial position → cis to the chiral ligand. The facial selectivity of olefin binding can be seen by examining the complex 127 from the olefin-binding site perspective. This is illustrated in Figure 20. The olefin and nitrogen terminus of the ligand are cis to each other, which is why the olefin prefers to bind to the metal so that its smallest substituent points towards the bulky group on that part of the ligand (quadrant IV). If the substrate is trisubstituted, as it often is, this smallest substituent is a hydrogen atom. The next smallest substituent is placed on quadrant II, which is partly hindered by the other end of the ligand. The largest substituents are located in the relatively unhindered quadrants I and III, which makes them trans to each other. This model explains why the 1,1-disubstituted and tetrasubstituted olefins are difficult for iridium-catalyzed asymmetric hydrogenation. The quadrant model in more detail as presented by P. Andersson is illustrated in Figure 21.

Figure 20. Generalized iridium (III) dihydride complex 127 with bound olefin and the schematic view of the sterics from the perspective of olefin. R1 = the smallest olefin substituent; NR = chiral N-containing ligand (often oxazoline); YXn = strong trans- influence ligand (phosphine, carbene, etc); Z = H2 or solvent.

Figure 21. The quadrant model for the iridium-catalyzed hydrogenation.

Iridium hydrogenation catalysts do not rely on coordinating groups to direct the reaction, which makes them suitable for the hydrogenation of certain types of olefins having non- coordinating functional groups. A number of different substrates have been successfully hydrogenated with iridium catalysts. The results are presented in Figure 22.

Figure 22. Results for the iridium-catalyzed asymmetric hydrogenation of different substrates.135

7.5 Hydrogenation of allylamines

Hydrogenation of allylamines has been carried out with a number of selected simple catalysts and catalyst-ligand-combinations. Since rhodium-, ruthenium- and iridium catalysts have been extensively studied, mainly palladium was used in the context of this work. However, platinum, ruthenium and iridium-based systems were tested. Iridium did not catalyze the hydrogenation of the N-Pf-allyl compound. This can be explained by the fact that iridium is known to bind strongly to nitrogen, and compounds containing nitrogen act as ideal ligands rather than substrates for the iridium-catalyzed hydrogenation.135

The hydrogenation reaction produced a 1:2 mixture of stereoisomers 75a:75b, the 75a trans isomer being the major one with Wilkinson’s catalyst and PdCl2. In comparison, the selectivity was 1:3 with Pd/C and 2:3 with Pt/C. Adding a chiral ligand into the reaction

64 mixture containing either Pd/C or Pt/C improved the reaction selectivity to 1:5. The reaction times were relatively short in all conditions and full conversion was obtained in less than an hour. Palladium acetate based complexes, [R-BINAP]PdCl2-complex or Red- Al were unreactive. The results for the hydrogenation of N-Pf-allyl amine 74 are presented in Table 6.

Table 6. Hydrogenation of the N-Pf alanine allyl amine 74.

Entry Catalyst Ligand Solvent Results 1 Wilkinson - toluene 1:2

2 [R-BINAP]PdCl2 - MeOH No reaction

3 PdCl2 - MeOH 1:2 4 Red-Al - THF No reaction

5 Pd(OAc)2 R-BINAP MeOH/THF No reaction

6 Pd(OAc)2 R-BINAP toluene No reaction

7 Pd(OAc)2 R-DIOP toluene No reaction

8 Pd(OAc)2 R-PHANEPHOS toluene No reaction 10 Pd/C - toluene No reaction 11 Pd/C - EtOAc 1:3 12 Pt/C - EtOAc 2:3 13 Pd/C R-BINAP EtOAc 1:5 14 Pd/C R-SEGPHOS EtOAc 1:5 15 Pd/C S-BINAP EtOAc 1:5

Stereoselectivity was consistently the same and did not alter by changing the ligand. R- BINAP and S-BINAP gave the same isomer with equal selectivity. This might be partly explained by considering the spatial arrangement of the substrate. A 3D illustration of N- Pf-allyl amine is shown in Figure 23. The double bond points towards relatively open space, shielded somewhat by a methyl group from one direction, whereas the aromatic moieties point toward the opposite direction. Placing this structure in the quadrant model, it can be seen that the double bond is not substantially sterically hindered but the other quadrants are quite crowded.

Figure 23. N-Pf-alanine allyl amine 74.

8. Other selected Pf-amines

8.1 Reduction of amino ketones

Amino alcohols are a common structural unit in several natural products and pharmaceuticals. In addition to the interest in total synthesis of pharmaceutical products, the synthetic community has been interested in the use of amino alcohol moiety as ligands and as chiral auxiliaries.136 Due to their importance, synthesis of amino alcohols has been extensively studied, and there indeed exist a number of methods for accessing them.

There are three main ways of synthesising amino alcohols. The first two of them are the addition of nucleophiles to amino acid derived amino aldehydes (monoprotected, doubly N-protected and Garner’s aldehyde) and ketones. The nucleophile can be for example a hydride ion, which results in reduction. Reduction of α,β-unsaturated amino ketones likewise leads to amino alcohols. The third way is the oxidation of an amino acid derived allyl amine to give an epoxide or a diol. The overall outcomes of the additions depend on the substrate, protecting groups used, the nature of the nucleophile and external conditions. A recently published review covers broadly the synthesis of 1,2-amino alcohols.137

Enantioselective synthesis of 1,2-aminoalcohols is commonly based on introduction of chiral information into an achiral substrate by using a chiral catalyst, auxiliary or reagent. Amino acids provide the ideal starting material for the substrate controlled synthesis of 1,2-aminoalcohols, since the amino functionality is already in place with the desired L or D configuration. The N-Pf-alanine methyl ketone 5 was a suitable substrate for reduction, and a small screen of different reducing agents were tested. The reduction was performed using two different aluminium hydrides (DIBAL and LAH) and two organoborane compounds (L-Selectride and 9-BBN) as the reducing agents. The diastereoselectivity varied from 1.5:1 to 2.4:1 depending on the reducing agent. The results were analyzed by NMR and HPLC and are presented in Table 7.

Table 7. Diastereomeric ratios with different reducing agents.

Reducing agent dr (syn:anti) DIBAL 2.4:1 LAH 2.4:1 L-Selectride 2.4:1 9-BBN 1.5:1

The substrate is relatively unhindered, as can be seen in the crystal structure presented in Figure 24. Examination of the crystal structure shows there is a fairly open space around the carbonyl functionality. The Pf protecting group at the opposite face does not shield the carbonyl group and thus is not substantially interfering with the addition of the hydride, which explains the modest stereoselectivity of the reaction. The Pf group thus cannot be exploited in a chelation control in the same way as carbamate-based protecting groups.

Figure 24. The crystal structure of N-Pf-alanine methyl ketone 5.

8.2 Knoevenagel reaction and conjugate addition with Pf-phenylalanine

The Knoevenagel condensation, a modification of the aldol condensation, is a reaction between a carbonyl compound and a carbon acid compound, such as diethyl malonate, Meldrum’s acid or nitromethane, resulting in conjugated enones. The N-Pf-protected phenylalanine-derived ketonitrile 142 was readily synthesized in 90% yield from the corresponding methyl ester 143 by addition of deprotonated acetonitrile into the reaction mixture, which was followed by silica gel filtration (Scheme 31). The ketonitrile 142 was condensed with benzaldehyde 144a to give 145a in 3 hours in 88% isolated yield. The same procedure was performed with dichlorobenzaldehyde 144b as well to give 145b.

Scheme 31. Synthesis of 145 by a Knoevenagel reaction.

These kinds of substrates have been observed to undergo an interesting cyclization leading to 3-oxo-pyrrolidines. 138 In synthetic sense, however, this kind of 5-endo-trig cyclization would be forbidden according to the Baldwin guidelines.139 In Karjalainen’s work, doubly protected amino acids undergo an allylative 5-endo heterocyclization. The reaction mechanism was suggested to involve an intramolecular allyl group migration. Despite having a differently protected amino acid derivative at hand, a number of different reaction conditions were tested. Undoubtedly, the role of the allyl protecting group was essential for the reaction to succeed, since no ring-forming reaction was observed with 145a or 145b. The reaction conditions and results are presented in Table 8.

Table 8. Attempted ring-closing reactions.

Entry Reagent Result 1 NBS 145c

2 BF3OEt2 No reaction a 3 Pd(PPh3)4 No reaction a 4 TiCl4 No reaction a 5 AlCl3+n-BuLi No reaction

6 Cu(OTf)2+n-BuLi Pf and CN cleavage a The reaction was run also in microwave.

However, we observed other interesting results, which are presented in Scheme 32. When NBS was used as the reagent, NMR analysis of the crude mixture showed the absence of the α-proton. This implicated that an imine was formed in the reaction in the α-position, which should not be possible with Pf as the protecting group.

Another interesting result was observed when the substrate was treated with Cu(OTf)2 and n-BuLi. The reaction proceeded to a full conversion of the starting material into 9- phenylfluorene 146 and phenylalanine. In addition, the CN-group had been cleaved. This

69 indicated a possible new way of removing the Pf group. The reaction was run in DCM and THF and the same result was observed. However, the removal of Pf was not observed when the reaction was tested with other Pf-protected substrates.

Scheme 32. The reaction between compound 145a and NBS and Cu(OTf)2.

The synthesis and the use of p-methoxy phenyl substituted Knoevenagel product 147 would have rationalized the occurrence of the desired cyclization, but the path was not examined during the course of this work. The mechanism rationalizing the cyclization reaction is presented in Scheme 33.

Scheme 33. Possible mechanism for a successful cyclization.

The ketonitrile 142 was subjected also to a 1,4-conjugate addition reaction. (Scheme 34) The starting nitrile 142 was reacted at room temperature with nitrovinylbenzene 148 (120 mol-%) in the the presence of a catalytic amount of different bases. Quinine, imidazole, DIPEA and DABCO were used as the bases. With quinine pure product 149 was obtained, while DIPEA, imidazole and DABCO led to a formation of a side product.

Scheme 34. Asymmetric Michael addition between N-Pf-phenylalanine ketonitrile 142 and nitrovinylbenzene 148.

The stereochemistry of the product can be estimated by a closer look into the transition state of the reaction. The hydroxyl group in quinine 150 can form a hydrogen bond with the carbonyl group of the N-Phe ketonitrile 142, while the quinine nitrogen abtracts the proton next to the nitrile group. The new bond is formed on the opposite side of the N-Pf moiety, so it is trans to the α-hydrogen. This is presented in Figure 25.

Figure 25. The suggested transition state for the quinine-catalyzed reaction and the suggested stereochemistry of the product.

9. Sphingolipids

9.1 Introduction

Sphingolipids, lipids derived from sphingosine, are a class of naturally occurring long- chain amino alcohols, which vary in chain length, number, position and stereochemistry of double bonds, hydroxyl groups and other functionalities. The term ”sphingosin” was first described by J. L. W. Thudichum in 1884, and the compound was structurally characterized as 151 (Figure 26) by Herb Carter in 1947.140 In 1998 International Union of Pure and Applied Chemists-International Union of Biochemists Joint Commission on Biochemical Nomenclature proposed that “Sphingoids are long-chain aliphatic amino alcohols…represented by the compound originally called ‘dihydrosphingosine’ [(2S,3R)- 2-aminooctadecane-1,3-diol]…[and]… imply a chain length of 18 carbon atoms.”141 The terms sphingosines, sphingolipids, sphingoid bases, are often seen used interconvertibly, although “sphingosine” should be reserved for the original structure 151 (Figure 26).

Sphingolipids are ubiquitous constituents of membrane lipids in eukaryotes and are abundantly located in all plasma membranes plus in some intracellular organelles such as endoplasmic reticulum, Golgi complex and mitochondria.142 Most of the sphingolipids are essential for the growth of cells, and modulate various cellular events such as proliferation, differentiation and apoptosis, while some disrupt normal sphingolipid metabolism and cause plant and animal disease.

Structurally sphingolipids are formed from three moieties: the basic amino alcohol sphingosine, a polar head group and a fatty acid. The common unit in nearly all sphingolipids in eukaryotic cells is the [(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1- ol)], D-erythro-sphingosine. There are over 60 other sphingoid base structures, such as phytosphingosines, found elsewhere in nature.143

There are three major structural classes of spingolipids: phospholipids (sphingomyelins), glycosphingolipids (cerebrosides, gangliosides, globosides) and ceramides. The common sphingolipid classes are presented in Figure 26. There are a large number of sphingolipid subspecies varying in the lipid backbones and phospho- and glycogroups because of the combinatorial nature of the sphingolipid biosynthesis. The biosynthesis of most sphingolipids starts from the condensation of L-serine and palmitoyl-CoA by serine palmitoyl transferase, upon which 3-ketosphinganine, the sphingolipid skeleton, is formed.144

Figure 26. Common sphingosines and sphingolipid classes.

Disorders associated with abnormal sphingolipid metabolism are for example Tay-Sachs,

Sandhoff, Gaucher, Fabry, Nieman-Pick and Krabbe diseases as well as GM1 gangliosidosis, metachromatic leukodystrophy, fucosidosis and Farber lipogranulomatosis. The symptoms vary from mental retardation, blindness, early mortality, kidney failure and skin rashes, celebral degeneration, thickened skin, and muscle spasticity to hepatosplenomegaly and painful swollen joints.

9.2 Traditional approaches in sphingosine synthesis

This group of compounds has important biological functions, and developing sphingoid base analogues for pharmaceutical use is of great interest. The first synthesis of epimeric sphingosine was performed by Shapiro and Segal in 1953, followed by an improved version in 1958.145 They utilized a modified Japp-Klingemann reaction in which phenyl diazonium salt was coupled with the alkyl-substituted acetoacetic ester in the presence of an ammonium salt (Scheme 35).

Scheme 35. The first synthesis of sphingosine.

Grob and Gadient published a different approach, which was based on the condensation of nitroethanol 159 and hexadecynal 160, followed by reduction of both nitro groups and the triple bond.146 The synthesis is presented in Scheme 36.

Scheme 36. The synthesis of sphingosines according to Grob and Gadient.

Synthetic strategies toward sphingosines can be divided into four different categories depending on the source of chirality. The first one is based on using carbohydrates as the starting materials and source of chirality. 147 A whole range of natural sugars is thus available as starting materials. Syntheses by Zimmermann and Schmidt and Kiso et al. utilized 2,4-O-protected threoses, obtained from D-galactose, D-arabinose and D-xylose, which were subjected to Wittig olefination with triphenylphosphonium ylide. 148 The resulting unprotected 2-hydroxy moiety was converted to azidosphingosine, and subsequent deprotection followed by reduction with NaBH4 gave sphingosines 151 and 151a (Scheme 37).

Scheme 37. Sphingosine synthesis with carbohydrates as starting materials.

Another way of achieving chirality is through catalytic reactions using chiral ligands, such as the Sharpless epoxidation, 149 which is illustrated for example in the synthesis by Julina et al.149c The enynol 172, derived from epichlorohydrin, was subjected to catalytic asymmetric epoxidation, which was followed by regioselective intramolecular opening of the oxirane via the N-benzyluretane. The synthesis was completed by the reduction of the triple bond and the hydrolysis of the oxazolidinone ring (Scheme 38).

Scheme 38. Chirality through catalysis in the synthesis of sphingosine.

The aldol reaction was not used in the early sphingosine syntheses,150 but the synthesis of Nicolaou is an example of how it can be used in this context.151 The sphingosine carbon skeleton was constructed from the boron enolate of chiral N-acyloxazolidinone 175 in the aldol reaction with hexadecenal 176. The bromine was substituted to azide and the secondary alcohol silylated to obtain 177c. Compound 178, a sphingosine precursor, was obtained when the chiral auxiliary was removed. Removal of the silyl protection and azide reduction followed by acetylation resulted in the triacetyl D-erythro-sphingosine 179 in 42% overall yield (Scheme 39).

Scheme 39. Chirality through relayed asymmetric induction in the synthesis of sphingolipids.

The fourth and the most popular approach is based on using amino acids as the source of chirality. Serine has been used in numerous syntheses and it is only logical since it has the correct S-configuration at C-2 and provides the C-1 hydroxyl groups and the acid functionalities in the correct orientations, not to mention that it is one of the biosynthetic precursors of sphingosine.152 One example of a synthesis is that of Herold,152i where all possible isomers can be synthesized depending on the selection of the reaction conditions. The fully protected serine 180 was reduced to the corresponding aldehyde 181, which was then alkylated to form 182. Deketalization followed by reduction of the triple bond afforded the N-protected sphingosine isomers 151b-e (Scheme 40).

Scheme 40. Chirality from serine in the synthesis of sphingolipids.

9.3 Obscuraminols

Many natural sphingosine-like vicinal amino alcohols isolated from marine sources have antifungal, antimicrobial or cytotoxic activities. 153 These sphingosine-like natural products include amaminols, crucigasterins, xestoaminols and obscuraminols. Obscuraminols are natural products isolated from the tunicate Pseudodistoma obscurum in 2000.154 They have mild activity against the tumor cell lines of mouse lymphoma P-

388, human lung carcinoma A-549 and human colon cell carcinoma HT-29. Only obscuraminol A (184a) could be tested in its natural form, while the others were tested as their diacetyl derivatives. Obscuraminols A-F (184-189) are presented in Figure 27.

Figure 27. Examples of obscuraminols.

There are no reported total syntheses of obscuraminols. However, synthesis of a general precursor to a number of acyclic (2R,3S)-2-amino-3-ols has been reported. 155 The synthesis route started with fully protected dihydroxypyrrolidinone 190, which was first fully O-deprotected in acidic medium. The diol 191 was selectively mesylated in 75% yield to give 192, after which it was converted to the iodo derivative and hydrogenolyzed to give 193. The lactam ring was opened in the presence of KCN and converted to 194 by alcoholysis (Scheme 41).

Scheme 41. Synthesis of a general precursor for acyclic amino alcohols.

9.4 Allylic alkylation and the synthesis towards obscuraminol A

The retrosynthetic analysis of obscuraminol A is presented in Scheme 42. The N-Pf- alanine methyl ketone 5 would be converted to corresponding enolate that would be alkylated with a long chain allylic bromide to obtain obscuraminol A 184.

Scheme 42. Retrosynthetic analysis of obscuraminol A.

Allyl bromide 197 was chosen to model the allyl partner. Methyl ketone 5 was easily enolized with KHMDS, but the alkylation proved to be tricky. The problem was the easy overalkylation to the doubly allylated product 198 (Scheme 43). When the reaction was run at a low temperature of -78 °C, the reaction was sluggish and the yield of the monoalkylated product 199 was 10% at highest, while the amout of overalkylated compound 198 was at least 30%. In addition to KHMDS, LiHMDS, NaH and LDA were tested as the bases, but the results were similar.

Scheme 43. Allylation of N-Pf-methyl ketone 5.

In the quest for eliminating the overalkylation problem and improving the yield of the desired product, the use of different ketone equivalents was examined. Three different ketone equivalents 200-202 were synthesized (Figure 38).

Figure 38. N-Pf-alanine derived β-ketocompounds 200, 201 and 202.

N-Pf-Alanine β-ketoester 200 was prepared from N-Pf-alanine 4 with malonate derived magnesium reagent 203. The magnesium reagent was made in situ from monoethylmalonate 204 and methylmagnesium chloride, and then reacted with N-Pf- alanine 4 in the presence of CDI. The reaction was run at rt for 2 days, and recrystallization from EtOAc gave the desired product 200 in 50% yield. The process is presented in Scheme 44.

Scheme 44. The synthesis of N-Pf-alanine β-ketoester 200.

Another ketone equivalent was the N-Pf alanine diphenylphosphoryl ketone 201. Methyldiphenylphosphine oxide 205 was reacted with n-BuLi, creating the nucleophile, which was then added to N-Pf-alanine methyl ester 2. The reaction was run at -78 °C for one hour, and after purification 201 was obtained in 54% yield. The synthesis is presented in Scheme 45.

Scheme 45. The synthesis of N-Pf alanine diphenylphosphoryl ketone 201.

The N-Pf-alanine β-ketoallyl ester 202 was synthesized by treating N-Pf-alanine 4 with CDI and in situ prepared LDA-allylacetate in 44% yield. The synthesis is presented in Scheme 46.

Scheme 46. The synthesis of N-Pf-alanine β-ketoallyl 202

The β-ketoesters 200 and 202 were enolized using KHMDS (or LiHMDS), and allyl bromide 197 was used as the allylating agent. The reaction proceeded rather sluggishly with both substrates and the main product was the doubly allylated one. However, the allylation of the allyl-β-ketoester yielded the monoallylated product 208a as a 2:1 mixture of diastereomers in 45% yield, while the yield of the doubly allylated one was only 9%. The allylation of 200 and 202 is presented in Scheme 47.

Scheme 47. The allylation of N-Pf-alanine β-keto ethylester 200 and β-keto allylester 202.

Different results were observed when N-Pf-alanine-phosphoryl 201 derived enolate was reacted with allylbromide. Two products were formed, and the desired product 209 was isolated in 31% yield while the major product (66%) was identified as O-allylated N-Pf- alanine phosphoryl 210 (Scheme 48).

Scheme 48. Allylation of the N-Pf-alanine-phosphoryl 201.

Allylation partner was changed from allyl bromide 197 to allyl acetate 206. When the β- ketoester 200 was reacted with 500 mol % of allylacetate in the presence of a catalytic amount of palladium(0), the desired product 207a was obtained in 24% yield after 3 days (Scheme 49).

Scheme 49. The succesful allylation of N-Pf-alanine β-ketoester 200 with allylacetate in the presence of 5 mol-% Pd(Ph3)4.

However, when the simple N-Pf-alanine methyl ketone was reacted with allyl acetate in the presence of palladium(0), the isolated product was allyl phenylfluorenyl 211 (Scheme 50).

Scheme 50. The reaction leading to allyl phenyl fluorenyl 211.

The removal of the β-keto moiety was attempted using excess KOH or AcOH, but both bases were unreactive towards the compound at rt. The reactivity was improved only by

82 refluxing the reaction mixture for a minimum of 24 h, which in turn caused the cleavage of the Pf group and general decomposition of the starting material (Scheme 51).

Scheme 51. Attempted removal of the β-keto moiety.

To conclude, the monoallylation of the β-ketoester was successfully carried out in moderate yield. Since the removal of the β-keto moiety did not succeed, this approach was not applied to the total synthesis of obscuraminol. However, improving the control of the reaction would offer a method to synthesize sphingosine-like long-chain amino alcohols in a short enantiospecific route.

10. Catalytic aerobic oxidation with copper

10.1 General considerations for the copper-TEMPO odixation of primary alcohols

The oxidation of alcohols to carbonyl compounds is a pivotal reaction both in nature and in organic synthesis. Numerous classical reagents and methods for the oxidation reactions have been reported, such as PDC, PCC, IBX156, activated manganese dioxide157,158 and Dess-Martin periodinane 159 . However, these oxidants are either toxic, hazardous or required in stoichiometric amounts or in excess. Hence there is a demand for environmentally benign methods suitable for large-scale applications. These would ideally be catalytic reactions utilizing clean oxidants such as O2 or H2O2. Many of the recently developed catalytic aerobic alcohol oxidation reactions are based on complexes of noble metals such as Pd160,161 and Ru162, but they suffer from inactivation, inhibition by coordinating functional groups and slow catalytic turnover rates.

One of the synthetically most important classes of oxidations is the oxidation of primary aliphatic alcohols to aldehydes, and it is also one of the most challenging. Recently, extensive efforts have been made on the aerobic oxidation methods based on catalytic systems including copper salts in combination with TEMPO (2,2,6,6- tetramethylpiperidine-N-oxyl). 163 The first copper/nitroxyl-radical catalysts for aerobic oxidation of alcohols were identified in 1966 by Brackman and Gaasbeck when they reported the oxidation of methanol with a (phenantroline)Cu(II)/di-tert-butylnitroxyl cocatalyst system. 164 Later, the first copper/TEMPO-system was reported in 1984 by Semmelhack and consisted of Cu(I)Cl/TEMPO in DMF.165 The field has expanded from there, and extensive studies have been made by Kumpulainen166, Sheldon167, Stahl168 and Markó169. Optimization of the system, including the choice of copper source and base, substrate scope, as well as mechanistic studies and elucidating the reaction kinetics has been studied. Some aspects of the catalytic system have been clarified.

A standard setting for the reaction has the following components: a copper source (CuI or CuII), a ligand (bipy), a nitroxyl radical (TEMPO or AZADO) and a base (NMI, possibly DBU). The reaction is run in acetonitrile at room temperature in an open vessel, but also

O2 balloons may be used. Markó’s method differs from this protocol, having CuCl/phen/DBAD complex instead of Cu/TEMPO/bpy. Markó’s system has been improved to be capable of aerobic oxidation of all classes of alcohols, including primary allylic and benzylic as well as secondary aliphatic, allylic and benzylic alcohols under neutral conditions. With a simple additive, this system consisting of CuCl, phenantroline,

DBAD, C6H5F, t-BuOK, possibly NMI as an additive, is also able to oxidize primary aliphatic alcohols when the reaction is run at elevated temperatures (70-80 °C).

During the course towards the total synthesis of amaminol, Kumpulainen needed an efficient and mild method for the oxidation of an intermediate allylic alcohol. The product aldehyde is so extremely sensitive to heat, light, strong Brønstedt and Lewis acids, that traditional oxidation methods would have been too harsh. The copper/TEMPO catalytic system seemed promising and was developed further to become a more general oxidation method.

Kumpulainen made an extensive study on effect of the catalyst components in the aerobic copper-TEMPO oxidations of alcohols to carbonyl compounds and developed a reproducible oxidation method.170 A number of similar optimization, kinetics and reaction mechanism studies have been made by Stahl, Sheldon and Markó as well.160,163,167,169,171 Some aspects of the reaction are in consensus and proved by all studies, such as the dependence of the reaction time on the copperI/II source, copper I leading to shorter reaction times, but the reaction mechanism, for example, is under speculation.

The mechanism suggested by Semmelhack is presented simplified in Scheme 52.165 It involves an oxoammonium mechanism, key step being a one electron oxidation of TEMPO to TEMPO+ by the reduction of Cu(II) to Cu(I). The alcohol is oxidized into the aldehyde by TEMPO+, and TEMPO is regenerated from TEMPOH.

Scheme 52. The nitrosonium ion centered mechanism.

However, Sheldon et al. suggest a mononuclear copper centered mechanism where the role of the oxygen is to reoxidize TEMPOH to TEMPO, and the role of TEMPO is to reoxidize Cu(I) to Cu(II).167 Cu(I) complex undergoes one-electron oxidation by TEMPO and forms a piperidinyloxy Cu(II) complex. The alkoxy group is replaced by the substrate, a second TEMPO coordinates and abstraction of β-hydrogen leads to the desired aldehyde, TEMPOH and regenerated Cu(I). The mechanism, similar to that of galactose oxidase, is presented in Scheme 53.

Scheme 53. Cu-TEMPO oxidation mechanism for primary and secondary aliphatic alcohols.

On the other hand, Kumpulainen’s findings support a binuclear copper system, and the mechanism is illustrated in Scheme 54.170 The kinetic studies indicated a rate constant for copper being 2.24, while for TEMPO it was 1.15, which means that the copper concentration has a higher effect on the rate of the reaction. The transition state suggested by Sheldon would require identical kinetic factors for Cu(II) and TEMPO. In the Kumpulainen mechanism, the catalytic cycle starts with reduction of Cu(II)complex I to Cu(I), while the alcohol is oxidized and TEMPO is reduced to TEMPOH. The amount and strength of the base is important, since a strong base such as DBU is required to reduce the Cu(II) complex I to the Cu(I) complex. The substrate coordinates to the Cu(I) catalyst and is oxidized into the binuclear Cu(II) complex VI. Rate determining step (RDS) involves the oxidation of the alcohol to the corresponding aldehyde and regeneration of TEMPO to TEMPOH by a radical mechanism. Formation of Cu(II)- alkoxide complex is possible, but it reacts rapidly with TEMPO forming the Cu(I) complex and the product aldehyde. It should be noted that bipy(CuOH) species VII can be oxidized into Cu(OH)2, which results in the deactivation of the catalyst. Formation of the mononuclear Cu(I) species, suggested by Sheldon et al., is possible, but it is thought to react so fast that it is not part of the RDS.

Scheme 54. Cu-TEMPO oxidation mechanism suggested by Kumpulainen et al. (L =

ROH, MeCN or NR3-type neutral σ-donor ligand.

A mechanism for the Cu(I)/TEMPO oxidation has been suggested by Hoover and Stahl, and it is illustrated in Scheme 55.168 Unlike the Cu(II) systems, Cu(I) systems do not require the presence of a strong base, but otherwise the catalytic cycle resembles the one suggested by Kumpulainen. First, the copper coordinates with both bpy and NMI, and oxidizes into a radical peroxyintermediate. This species coordinates with another (bpy)Cu(I)(NMI)-complex, forming a transition state similar to what Kumpulainen suggested, albeit without the coordination of the substrate. Similarly, TEMPOH is then oxidized to TEMPO and the binuclear complex breaks into Cu(II)-peroxyintermediate.

After H2O2 formation, the substrate alkoxy group coordinates, and the product aldehyde is formed in the oxidation step. TEMPO is reduced to TEMPOH and Cu(II) is reduced to Cu(I).

Scheme 55. Mechanism for Cu(I)-TEMPO catalytic system suggested by Hoover and Stahl.

The binuclear mechanism was disputed by a recent study, in which no direct redox reaction between TEMPO and Cu(I)/Cu(II) was observed. The role of TEMPO was suggested to be the activation and fixation of O2 in a proposed active intermediate -. (bpy)(NMI)Cu(II)-O2 -TEMPO, formed by electron transfer from Cu(I) to molecular 172 O2.

10.2 Optimization of the copper-TEMPO oxidation of primary alcohols

Kumpulainen’s catalyst system for the oxidation was already a reproducible oxidation method in which environmental concerns and general availability of the reagents are taken into account. However, we wanted to examine and show that there was a suitable copper-additive pair to demonstrate that even a cheaper combination of reagents would perform in a similar manner in a Cu/TEMPO catalytic system. The developed and optimized system would be applied to the allylic oxidation step in the total synthesis of amaminol A, but this was not executed during the course of this thesis.

Decanol 212 was chosen as the model compound, as it is one of the challenging aliphatic substrates for the oxidation in general. A series of reactions with copper(I) and copper(II) sources in combination with different additives was run. For the purpose of comparison, reactions using the traditional Stahl and Kumpulainen methods were also done.

The reactions were run on 3 mmol scale at room temperature in an open vessel with MeCN as solvent, and o-xylene was used in the reaction mixture as the internal standard. The reactions were monitored by GC. The GC samples were prepared taking 0.1 mL of the reaction mixture and diluted into 1 mL with DCM, and they were taken at 0.5, 1, 2, 4 and 22 hours. The variables, copper source and possible additives are presented in Table 9. Many catalyst systems produced excellent conversions (>98%), which we were expecting based on the control experiments done in Stahl’s group. The results are presented in Table 9 and Figures 30-33.

Table 9. The screening of different copper sources. Reaction conditions: 3 mmol scale, 1 M solution of decanol in MeCN, TEMPO 3% bipy 3%, open vessel, rt.

Copper source Additives (4%) Base(s) Conversion (%)

Cu(OTf)2 - NMI + DBU 99.6

Cu(BF4)2-H2O - NMI +DBU 61.2

Cu(ClO4)2-6 H2O - NMI + DBU 99

(MeCN)4Cu(OTf) - NMI + DBU 99.8

(MeCN)4Cu(BF4) - NMI + DBU 99.8

(MeCN)4Cu(PF6) - NMI + DBU 99.3

CuCl2 NaBF4 NMI + DBU 95.1 CuCl - NMI 51.4 CuCl NaCl NMI 52.9

CuCl NaBF4 NMI 100

CuCl NaPF6 NMI 99.1 CuCl NaOTf NMI 86.7 CuBr - NMI 70.1 CuBr KBr NMI 70.8 CuBr NaBr NMI 59.2

CBr NaBF4 NMI 94

CuBr NaPF6 NMI 89.2 CuI - NMI 98.3 CuI KI NMI 90.1 CuI NaI NMI 86

CuI NaBF4 NMI 98.7

CuI NaPF6 NMI 98.5 CuI NaOTf NMI 99

As can be seen, many catalytic systems were able to produce excellent conversions (over 98%), which are in consensus with the results reported earlier. The control reactions using

(MeCN)4CuOTf, (MeCN)4CuBF4 and (MeCN)4CuPF6 reached full conversion in 2 hours compared to Cu(OTf)2, Cu(BF4)2·H2O or Cu(ClO4)2·6H2O, of which Cu(BF4)2·H2O gave only 60% conversion and for the other two it took 4-6 hours to reach 100% conversion. Of the tested simple copper sources, CuBr and CuCl showed similar behavior and did not react all the way to a full conversion without any additives, while CuI performed well reaching full conversion after 6 hours. The reaction rates of the simple copper sources compared to the copper sources used in the control reactions are illustrated in Figure 29.

120,0

100,0

80,0 Cu(BF4)2*H2OCu(BF4)2*H2O Cu(ClO4)2*6H2OCuCl(ClO ) *6H O 60,0 4 2 2 Cu(Otf)2Cu(OTf)2 40,0 CuClCuCl Conversion (%) CuBrCuBr 20,0 CuICuI 0,0 123456 Time (h)

Figure 29. Control reactions vs simple copper sources in the copper oxidation.

- - The sodium salts of tetrafluoroborate (BF4 ), hexafluorophosphate (PF6 ) and triflate (OTf-) anions were examined as additives. They clearly improved the conversions, which was to be expected since they can act as ligands for the Cu-catalyst. A trend was seen among the different additives. BF4 and PF6 were clearly enhancing the reaction rate, while OTf was not quite as effective, and the simplest sodium and potassium salts were actually inhibiting the reaction. It was observed that the reaction time with CuCl, together with NaBF4 as the additive, was less than 4 hours, therefore being preferable to the slightly slower CuI. It was not quite as fast as the previously reported systems including

(MeCN)4, CuBF4 or PF6 or OTf (reaction time 2 h), but it is a much less expensive set of components. The results and comparisons are presented in Figures 30-33.

120,0

100,0

80,0 CuClCuCl + + NaCl NaCl

CuClCuCl + + NaBF4 NaBF4 60,0 CuClCuCl + + NaPF6 NaPF6 40,0 CuClCuCl + + NaOTf NaOTf Conversion (%)Conversion CuClCuCl 20,0 CuCl2CuCl2 + + NaBF4 NaBF4

0,0 123456 Time (h)

Figure 30. The effect of the additive in CuCl catalyzed oxidation.

120,0

100,0 CuBrCuBr 80,0 CuBrCuBr + +KBr KBr 60,0 CuBrCuBr + +NaBr NaBr

CuBrCuBr ++ NaBF4 NaBF4 40,0 CuBrCuBr + +NaPF6 NaPF6 Conversion (%)Conversion 20,0

0,0 123456 Time (h)

Figure 31. The effect of additive in the CuBr catalyzed oxidation.

120,0

100,0 CuICuI 80,0 CuICuI + + NaI NaI 60,0 CuICuI + + KI KI

CuICuI + + NaBF4 NaBF4 40,0 Conversion (%)Conversion CuICu I+ + Na(Otf) NaOTf

20,0 CuICuI + + NaPF6 NaPF6

0,0 123456 Time (h)

Figure 32. The effect of additive in the CuI catalyzed oxidation.

120,0

100,0 CuClCuCl 80,0 CuBrCuBr

60,0 CuICuI CuCl+NaBF4CuCl + NaBF4 40,0 CuBr + NaBF4

Conversion (%) CuBr + NaBF4 CuI + NaBF 20,0 CuI + NaBF46

0,0 123456 Time (h)

Figure 33. Comparison of CuCl, CuBr and CuI catalytic systems and the representative systems with NaBF4 additive.

10.3 Substrate scope for the Cu/TEMPO oxidation

Based on the results the CuCl + NaBF4 system was chosen as the model system for further examination with different substrates. The rationale for this choice was the shortest reaction time to reach full conversion (98% after 4 h, 100% after 24 hours) and relatively inexpensive price of the components. CuI was considered as an alternative as well, but it had the downside of the reaction being slower with 91% conversion after 4 hours and 98% after 24 hours.

The substrate scope for the CuCl/NaBF4 catalytic system is presented in Table 10. The catalyst system has been optimized for aliphatic substrates, but a few allylic and benzylic substrates were tested as well. Only primary alcohols were screened. Secondary alcohols presumably need a slightly modified system with less hindered nitroxyl radical instead of TEMPO, for example AZADO that also has an enhanced reactivity compared to TEMPO. The reactions were run on 10 mmol scale.

Table 10. Substrate scope for the oxidation. (CuCl/NaBF4/TEMPO/NMI/bipy)

Conv. Yield Entry Substrate Product (%) (%)

1 100 76

2 100 51

3 63.1 68

4 99.4 87

5 99.9 81

Not 6 5.4 isolated

7 100 97

8 40 36

120,0

benzyl214 alcohol 100,0

hexenol215 80,0 geraniol217 60,0 S-perillyl219 alcohol 40,0 Conversion (%)Conversion N-methyl221 piperidine methanol 20,0 cinnamyl223 alcohol

decanol 0,0 212 1234 Time (h)

Figure 34. The oxidation rates with different substrates.

Full conversion (100%) was observed in the oxidation of 1-decanol 212 to decanal 213, but the isolated yield was only 76%. Likewise, a lower yield than expected was observed with other substrates that gave conversions of over 90%. The compound 221 was not oxidized by this catalytic system. Instead, N-demethylation and the formation of a double bond were observed. In the CuCl/TEMPO catalytic system the presence of H2O2 is probable and it may act as an oxidant in the N-demethylation of 221. This is supported by the fact that CuCl-catalyzed demethylations have been reported taking place in t-BuOH with TBHP. 173 Compound 225, an intermediate in the synthesis of amaminol, was oxidized and isolated in 36% yield.

11. Conclusions

The purpose of this work was to develop synthesis routes for accessing pharmacologically interesting chiral amines using amino acids as the starting materials. A number of chiral amines were successfully synthesized, including a selection of phenethylamine derivatives. Two robust and short synthesis routes to chiral N-Pf- protected phenethylamine derivatives utilizing transition metal catalyzed coupling reactions were developed. Ligand-free Pd-catalyzed coupling between enol phosphate and aromatic Grignard reagents and Fe-catalyzed coupling of enol triflate with aromatic Grignard reagents were examined. Both of the couplings produced desired products, however neither reaction being superior to another.

In addition to the series of phenethylamine derivatives, a range of other chiral, pharmacologically interesting amines were made using amino acids as the starting materials. The synthesis of amino ketones was examined, and a rather non-traditional reaction in the context of my substrates was successful and utilized in the synthesis of 5, one of the key compounds. The use of ketone 5 among other ketone derivatives in a very short total synthesis of sphingolipids but unfortunately the studies did not give satisfactory results. The ketonitrile 142 was another highly useful intermediate, and subjected successfully to Knoevenagel and 1,4-conjugate addition reactions. Only a brief look was taken into the 1,4-conjugate addition, and with the right choice of reaction conditions it has the potential to become a useful asymmetric organocatalytic reaction with excellent selectivity.

The effect of Pf-protecting group in asymmetric induction was briefly examined in the context of asymmetric hydrogenation of allyl amines and reduction of amino ketones. The sterics and electronic effects of the Pf group were observed to have an impact on the diastereoselectivities, but more profound examination is needed to gain insight of the abilities and the potential of the protecting group to direct the selectivities. One interesting aspect not examined during this work would be to study whether the Pf- protected compounds could act as chiral ligands in asymmetric reactions.

In the other part of the thesis, the conditions and the catalyst composition of the catalytic aerobic copper-TEMPO oxidation were succesfully optimized. The substrate scope for the oxidation of primary alcohols was examined. The already practical and environmentally friendly process was polished to an even more economically feasible synthetic transformation. The next step would be to utilize the improved conditions in the total synthesis of amaminols.

12. Experimental section

12.1 General considerations

All reactions were carried out under an argon atmosphere in flame-dried glassware at rt unless otherwise noted. Nonaqueous reagents were transferred under argon via syringe or cannula and dried prior to use. Dry solvents were obtained with MB SPS-800 solvent drying system. Other commercial reagents and solvents were used as obtained from supplier, without further purification, unless otherwise noted.

Analytical thin-layer chromatography (TLC) was performed using Merck silica gel F254 (230-400 mesh) plates and analyzed by UV light and by staining upon heating with ninhydrin solution (1 g ninhydrin, 100 mL ethyl alcohol, 0.2 ml glacial acetic acid),

KMnO4 solution (1 g KMnO4, 6.7 g K2CO3, 1.7 mL 1M NaOH, 100 mL H2O) or PMA- solution (12 g phosphomolybdic acid, 250 mL EtOH). For silica gel chromatography, the flash chromatography technique was used, with Merck silica gel 60 (230-400 mesh) and p.a. grade solvents unless otherwise noted. All reactions were monitored by TLC and quenched after all starting material was consumed, unless otherwise noted.

The 1H NMR and 13C NMR spectra were recorded on a Bruker Avance 400 (1H 399.98 MHz; 13C 100.59 MHz) spectrometer. The chemical shifts are reported in ppm relative to 1 13 SiMe4 (δ 0.00 for H NMR) or residual solvent signals (CDCl3 δ 77.0 for C NMR, 13 MeOD-d4 δ 49.0 for C NMR). Melting points (mp) were determined in open capillaries using Stuart Melting Point Apparatus SMP30. IR-spectra were recorded on a Perkin- Elmer spectrum One FT-IR spectrometer. Optical rotations were obtained with a Perkin- Elmer 343 polarimeter. High resolution mass spectrometric data were measured using MicroMass LCT Premier Spectrometer. Enantio- and diastereomeric ratios were determined by HPLC using chiral stationary phase columns with Waters 501 pump and Waters 2487 UV dual absorbance detector.

Oxidation experiments were carried out in non-dry acetonitrile (Rathburn HPLC grade) and monitored by Shimadzu GC-2010 gas chromatograph equipped with FID detector and Zebron ZB-35 column.

12.2 Synthesis of the general N-Pf-compounds

12.2.1 9-Bromo-9-phenyl-9H-fluorene (10)

A solution of bromobenzene 14 (158 mL, 1.5 mol, 150 mol %) in anhydrous Et2O (800 mL) was precooled to 0 °C with an ice-bath. To this solution was added n-butyl lithium (720 mL, 1.15 mol, 115 mol %, 1.6 M solution in hexanes) via cannula during 1 h. The reaction mixture was stirred for 20 min, after which a solution of fluorenone 13 (180 g, 1 mol, 100 mol%) in anhydrous THF (300 mL) was added during 15 min. The cooling bath was removed and the mixture was allowed to reach room temperature. The reaction mixture was stirred for 2 h in all, during which a precipitate (LiBr) was formed. H2O (250 mL) was added to dissolve the precipitate. The phases were separated. The organic phase was washed with H2O (800 mL) and saturated NaCl aqueous solution (800 mL), after which the solvents were evaporated. The residual yellow solid (12) was dissolved in toluene (800 mL) and aqueous HBr (400 mL, 48% solution) was added. The reaction mixture was stirred at rt for 2 d, after which the phases were separated. The aqueous phase was extracted with toluene (400 mL). The combined organic phases were dried

(Na2SO4), filtered and concentrated to give an orange solid (418 g). The product was recrystallized from i-octane (1.25 L) to give bromophenylfluorene 10 (219.5 g, 69%) as a pale yellow solid.

13 Mp. 99 °C (lit. mp. 99 °C); Rf = 0.54 (30% EtOAc in hexane); C NMR (100 MHz,

CDCl3): δ 149.5, 141.0, 138.0, 128.9, 128.4, 128.3, 128.0, 127.3, 126.0, 120.3, 67.5. NMR data match those reported in the literature. 174

12.2.2 (S)-2-((9-Phenyl-9H-fluoren-9-yl)amino)propanoic acid (4)

To a solution of L-alanine (13.4 g, 150 mmol, 100 mol %) in a mixture of anhydrous

CH2Cl2 (280 mL) and acetonitrile (75 mL) was added TMSCl (19 mL, 150 mmol, 100

97 mol %) at rt. The reaction mixture was heated to reflux for 2 h, after which the oil bath was removed and the mixture was let to cool down to rt. NEt3 (46 mL, 330 mmol, 220 mol %) was added during 5 min. The formed milky mixture was stirred at rt for 15 min, after which Pb(NO2)3 (33.1 g, 100 mmol, 70 mol %) was added. After 5 min, a solution of PfBr 10 (58.3 g, 180 mmol, 120 mol%) in anhydrous CH2Cl2 (100 mL) was added. The reaction mixture was stirred at rt for 3 d, after which MeOH (15.2 mL) was added. The reaction mixture was stirred for 15 min, after which it was filtered through a pad of silica. The solvents were evaporated and the residue was partitioned between 5% aqueous citric acid (700 mL) and Et2O (700 mL). The organic layer was extracted with 1M NaOH (300 mL). The aqueous layer was cooled to 0 °C and neutralized with AcOH (16 mL).

The off-white precipitate was extracted into a mixture of CH2Cl2 (300 mL) and i-propanol

(250 mL). The organic layer was washed with brine (300 mL), dried (Na2SO4), filtered and concentrated to yield N-Pf-alanine 4 (23 g, 47%) as white crystals.

1 Mp. 159 °C (lit. mp. 158-161 °C); H NMR (400 MHz, CDCl3): δ 7.75-7.69 (m, 2H), 7.46-7.19 (m, 11H), 2.76 (q, 1H, J = 7.28 Hz), 1.14 (d, 3H, J = 7.24 Hz); 13C NMR (100

MHz, CDCl3): δ 176.7, 147.1, 146.0, 142.2, 140.9, 140.5, 129.2, 129.2, 128.6, 128.3, 128.2, 127.8, 125.9, 125.7, 125.1, 120.4, 120.3, 73.1, 65.8, 52.4, 20.8, 19.6. NMR data match those reported in the literature.174

12.2.3 Alanine methyl ester hydrochloride (11)

To a 0 °C precooled MeOH (500 mL) was added dropwise AcCl (142 mL, 2 mmol, 200 mol %). The mixture was stirred for 30 min, after which L-alanine (89 g, 1 mol, 100 mol %) was added. The reaction mixture was stirred at rt for 24 h, after which it was concentrated to give 11 quantitatively as white amourphous solid.

1 H NMR (400 MHz, MeOD-d4): δ 4.88 (s, 4H), 3.84 (s, 3H), 4.11 (q, 1H, J = 6.55 Hz), 13 1.54 (d, J = 7.09); C NMR (100 MHz, MeOD-d4): δ 170.4, 52.8, 48.9, 15.2; NMR data match those reported in the literature.174

12.2.4 (S)-Methyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propanoate 2

To a solution of L-alanine methyl ester 11 (34 g, 244 mmol, 100 mol %) were added

K3PO4 (110 g, 512 mmol, 210 mol %), Pb(NO3)2 (69 g, 208 mmol, 85 mol %) and 9- bromo-9-phenylfluorene 2 (98 g, 305 mmol, 125 mol %). The pale yellow milky reaction mixture was stirred at rt for 22 h, after which MeOH (100 mL) was added. The mixture was stirred for 30 min, and filtered through a pad of celite. The filter cake was washed with chloroform until no UV chromophore was detected on TLC. The solvents were evaporated to give the crude product as a yellowish oil. The product was crystallized from MeOH (300 mL) to give N-Pf-alanine methyl ester 2 (34.46 g, 41%) as white crystals.

1 Mp. 88-90 °C; Rf = 0.45 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.20 - 7.70 (m, 13H), 3.30 (s, 3H), 2.96 (br., 1H), 2.78 (br. m, 1H), 1.12 (d, J = 7.1 Hz, 3H). 13C

NMR (100 MHz, CDCl3) δ 177.1, 149.4, 148.9, 144.5, 140.8, 140.1, 128.2, 127.8, 127.4,

127.1, 126.1, 126.0, 125.0, 120.0, 119.8, 73.0, 51.5, 51.4, 21.5; [α]D (S) -226.4 (c 0.55 in -1 CH2Cl2); (R) +225.4 (c 0.55 in CH2Cl2); IR νmax/cm 3478, 3314, 3061, 2978, 1731, 1447,

1198, 1144, 732, 699; HRMS: m/z calc. for C23H21NNaO2 366.1470, found [M + Na] 366.1473.

12.2.5 Hydrolysis of N-Pf-alanine methyl ester to give (S)-2-((9-phenyl-9H-fluoren-9- yl)amino)propanoic acid (4)

To a solution of N-Pf-Alanine methyl ester (34.3 g, 100 mmol, 100 mol %) in THF (50 mL) and MeOH (50 mL) was added LiOH (8.3 g, 200 mmol, 200 mol %). The reaction mixture was stirred at rt for 24 h, after which H2O (50 mL) was added. The phases were separated and the organic phase was concentrated to yield a yellowish precipitate. The residue was treated with 1M HCl (100 mL). The white oily solid was dissolved in EtOAc

(150 mL) and H2O (100 mL) was added. The aqueous phase was extracted with Et2O (100 mL). The combined organic phases were washed with brine (100 mL), dried

(Na2SO4), filtered and concentrated to give the product quantitatively as a foam. NMR data match those reported for compound 4.

12.2.6 (S)-4-Methyl-3-(9-phenyl-9H-fluoren-9-yl)oxazolidin-5-one (73)

To a clear, yellowish solution of N-Pf-alanine 4 (21 g, 64 mmol, 100 mol %) in THF (500 mL) were added formaldehyde 227 (105 mL, 1280 mmol, 2000 mol %) and p-TsOH·H2O (1.1 g, 6.4 mmol, 10 mol %). The pale, yellowish solution was stirred at rt for 24 h, after which the reaction was quenched with sat. aq. NaHCO3 (500 mL) and CH2CL2 (500 mL) was added. The organic phase was washed with H2O (500 mL) and brine (500 mL), dried

(Na2SO4), filtered and concentrated to yield oxazolidinone 73 (13.34 g, 61%) as white amorphous solid.

1 Rf = 0.25 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.72-7.67 (m, 2H), 7.46-7.25 (m, 11H), 5.24 (d, 1H, J = 7.52 Hz), 5.10 (d, 1H, J = 7.48 Hz), 3.13 (q, 1H, J = 13 7.31 Hz), 1.25 (d, 3H, J = 7.32 Hz); C NMR (100 MHz, CDCl3): δ 177.7, 146.9, 145.6, 142.3, 141.0, 139.9, 129.4, 129.0, 128.7, 128.4, 128.2, 127.9, 126.9, 125.7, 125.3, 120.4, 82.9, 77.2, 54.8, 16.4. NMR data match those reported in the literature. 175

12.2.7 (S)-3-((9-Phenyl-9H-fluoren-9-yl)amino)butan-2-one (5)

A clear, yellowish solution of oxazolidinone 73 (19.53 g, 59 mmol, 100 mol %) in anhydrous THF (750 mL) was cooled to -78 °C. MeLi 95 (110 mL, 177 mmol, 300 mol %) was added via cannula during 30 min. An orange, clear solution was formed and it was stirred at -78 °C for 2 h. Ethyl formate (14.7 mL, 177 mmol, 300 mol %) was added, followed by AcOH (50.6 mL, 885 mmol, 1500 mol %) 10 minutes later. Pale, lime yellowish solution was formed. The cooling bath was removed, and the reaction mixture was allowed to warm up to rt. Stirring was continued for 20 h after which sat. aq.

NaHCO3 (400 mL) was added, followed by EtOAc (250 mL). The organic phase was

100 washed with H2O (300 mL) and brine (300 mL), dried (Na2SO4), filtered and concentrated to yield pale yellowish oil. The crude product was purified by flash chromatography (5% EtOAc to give 5 (17.4g, 90%) as white crystals.

1 Mp. 117 °C; Rf = 0.34 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.73-7.72 (m, 2H), 7.23-7.14 (m, 11H), 3.43 (br s, 1H), 2.74 (q, 1H, J = 7.12 Hz), 1.66 (s, 3H), 1.02 13 (d, 2H, J = 7.12 Hz). C NMR (100 MHz, CDCl3); δ 212.3, 176.2, 140.9, 140.0, 129.1, 128.4, 128.2, 128.0, 127.7, 127.1, 126.2, 126.1, 125.4, 125.3, 124.8, 119.9, 119.7, 73.1, 57.4, 26.9, 26.9, 20.6. NMR data match those reported in the literature.175

12.2.8 (S)-N-Methoxy-N-methyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propanamide (3)

To a mixture of N-Pf-alanine methyl ester 2 (30 g, 87 mmol, 100 mol %) and N,O- dimethylhydroxylamine hydrochloride 228 (11.11 g, 97 mmol, 130 mol %) in anhydrous THF (90 mL) was added i-PrMgBr (114 mL, 227 mmol, 260 mol %, 2 M solution in THF) dropwise over 30 min at 0 °C. The reaction mixture was stirred at 0 °C for 90 min, after which it was quenched with 5% aq. citric acid (150 mL). The reaction mixture was let to warm up to rt. The aqueous phase was extracted with EtOAc (3 x 90 mL). The organic phase was washed with brine (150 mL), dried (Na2SO4), filtered and concentrated to give 3 (30.85 g, quant) as a white foam.

1 Mp. 125-128 ºC; Rf = 0.20 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.46- 7.40 (m, 5H), 7.33-7.15 (m, 8H), 3.56 (br s, 1H), 2.94-2.86 (m, 7H), 1.06 (d, 3H, J = 7.0 13 Hz); C NMR (100 MHz, CDCl3): δ 177.2, 150.3, 149.4, 144.9, 141.2, 139.9, 128.2, 128.2, 128.1, 128.0, 127.5, 127.0, 126.8, 126.1, 125.4, 119.6, 119.5, 73.3, 60.3, 48.2, 31.9,

21.9; [α]D = -236.0 (c = 1.3 in CH2Cl2); IR (film) νmax 3298, 3061, 2935, 1650, 1446, 1382, -1 1178, 991, 727, 698 cm ; HRMS: m/z calc. for [M+H] C24H2N2O2 373.1917, found 373.1907.

101

12.2.9 (S)-3-((9-Phenyl-9H-fluoren-9-yl)amino)butan-2-one (5)

To a mixture of bromo(methyl)triphenylphosphorane 99 (64.3 g, 180 mmol, 220 mol %) in anhydrous THF (400 mL) at 0 °C was added n-BuLi (82 mL, 172 mmol, 210 mol %, 2.1 M solution in hex) dropwise over 30 min. The reaction mixture was stirred at 0 °C for 90 min, after which a solution of N-Pf-alanine Weinreb amide 3 (30.4 g, 82 mmol, 100 mol %) in anhydrous THF (80 mL) was added dropwise. The reaction mixture was let warm to rt and stirred for 48 h, after which the reaction was quenched with 1 M HCl (240 mL) and Et2O (300 mL) was added. The aqueous phase was extracted with Et2O (3 x 300 mL). The combined organic phases were washed with H2O (800 mL) and brine (800 mL), dried (Na2SO4), filtered and concentrated to give 42 g of a viscous oil. The crude product was purified by flash chromatography (5% EtAOc in hexanes) to yield N-Pf-alanine methyl ketone 5 (24 g, 90%) as white solid. The NMR data match those reported for the compound 5.

12.2.10 (S)-1-Morpholino-2-((9-phenyl-9H-fluoren-9-yl)amino)propan-1-one (98)

To a solution of N-Pf-alanine methyl ester 2 (5.15 g, 15 mmol, 100 mol %) in anhydrous THF (10 mL) was added morpholine 229 (1.96 mL, 22.5 mmol, 150 mol %, freshly distilled from KOH). The clear solution was cooled to -40 °C with a MeCN/dry ice bath. i-PrMgCl (22.5 mL, 45 mmol, 300 mol %, 2 M solution in THF) was added with a syringe pump over 50 min, after which the cooling bath was removed and the reaction mixture was allowed to warm up to rt. Gas formation occurred when the mixture warmed up. The reaction mixture was stirred at rt for 2 h, after which it was cooled to 0 °C with an ice bath and quenched with sat. aq. NH4Cl (20 mL). EtOAc (20 mL) and H2O (20 mL) were added. The aqueous phase was extracted with CH2Cl2 (40 + 40 mL). The combined organic phases were washed with brine (80 mL), dried (Na2SO4), filtered and concentrated to yield 98 (4.86 g, 81%) as white solid.

102

1 Mp. 189-192 °C; Rf = 0.566 (EtOAc); H NMR (CDCl3, 400 MHz): δ 7.69-7.64 (m, 2H), 7.42-7.14 (m, 11H), 3.74 (br s, 1H), 3.45-3.40 (m, 1H), 3.31-3.20 (m, 4H), 2.98-2.93 (m, 13 1H), 2.81-2.73 (m, 2H), 2.50-2.44 (m, 1H), 1.01 (d, 3H, J = 7 Hz); C NMR (CDCl3, 400 MHz): δ 175.1, 150.1, 149.2, 144.4, 140.9, 139.6, 128.1, 128.0, 127.4, 126.9, 126.8,

125.9, 125.2, 119.5, 119.44, 119.4, 73.2, 66.4, 65.8, 46.9, 44.8, 41.8, 21.7; IR (film) νmax -1 3328, 2964, 2921, 2859, 1631, 1427, 1114, 1028, 733, 702 cm ; [D]D = -244° (c = 1,

CH2Cl2); HRMS: m/z calc. for [M+H] C26H27N2O2 399.2073, found 399.2086.

12.3 Synthesis of N-Pf-phenethylamines

12.3.1 (S)-Diphenyl (3-((9-phenyl-9H-fluoren-9-yl)amino)but-1-en-2-yl)phosphate (71)

To a solution of crude N-Pf-alanine methyl ketone 5 (6 g, 17 mmol, 100 mol %) in anhydrous THF (70 mL) at -78 °C was added diphenyl phosphoryl chloride 72 (5.3 mL, 25.5 mmol, 150mol %). After 10 min, KHMDS (51 mL, 25.5 mmol, 150 mol %, 0.5 M solution in toluene) was added dropwise over 20 min. The reaction mixture was stirred at

-78 °C for 2 h, after which the reaction was quenched with 3% NH3 solution (70 mL).

Et2O (150 mL) was added to the mixture and the cooling bath was removed. The reaction mixture was let to warm up to rt. The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (10% EtOAc in hexanes) to yield 71 (5.75 g, 64%) as yellowish oil.

1 Rf = 0.33 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.68-7.66 (m, 2H), 7.29-7.07 (m, 22H), 4.62-4.61 (q, 1H), 4.21 (t, 1H), 2. 77-2.72 (q, 1H, J = ), 2.17 (br s, 13 2H), 0.92 (d, 3H, J = 6.88 Hz); C NMR (100 MHz, CDCl3): δ 157.6, 157.5, 150.5, 150.5, 150.4, 150.3, 149.8, 149.1, 145.1, 140.8, 139.9, 129.8, 129.7, 128.2, 128.1, 128.0, 127.7, 127.5, 127.0, 126.2, 126.1, 125.4, 124.8, 120.1, 120.0, 119.8, 119.5, 96.1, 73.0, -1 51.7, 51.6, 21.5; IR (film) νmax 3314, 3061, 1948, 1655, 1590, 1489, 1449 cm ; [D]D (S) =

+182.0 (c = 1, CH2Cl2), (R) = -210.0; HRMS: m/z calc. for [M+H] C35H31NO4P 560.1991, found 560.1978.

103

12.3.2 (S)-9-Phenyl-N-(3-phenylbut-3-en-2-yl)-9H-fluoren-9-amine (74)

To a heterogenous mixture of phosphate 71 (3.87 g, 6.9 mmol, 100 mol %) and PdCl2 (61 mg, 0.35 mmol, 5 mol %) in anhydrous THF (7 mL) at rt was added phenylmagnesium bromide 76 (10.35 mL, 10.35 mmol, 150 mol %, 1 M solution in THF) with a syringe pump over 2 h. The reaction mixture was stirred at rt for 2 h, after which the reaction was quenched with MeOH (5 mL). The mixture was concentrated, and the crude product was purified by flash chromatography (2.5% EtOAc in hexanes) to yield 74 (1.71 g, 64%) as an off-white foam.

1 Rf = 0.57 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.71-7.65 (m, 2H), 7.49-7.64 (m, 2H), 7.40-7.32 (m, 2H), 7.62-7.04 (m, 12H), 6.90-6.87 (m, 2H), 5.46 (q, 1H, J = 1.1 Hz), 5.00 (d, 1H, J = 1.8 Hz), 3.08 (q, 1H, J = 6.67 Hz), 2.15 (br s, 1H), 0.81 (d, 13 3H, J = 6.86 Hz); C NMR (100 MHz, CDCl3): δ 155.2, 150.7, 149.1, 145.6, 141.6, 140.9, 140.1, 128.2, 128.1, 128.0, 127.8, 127.7, 127.4, 127.0, 126.9, 126.89, 126.5, 126.2,

124.9, 119.8, 119.5, 112.2, 73.6, 52.7, 23.9; IR (film) νmax 3646, 3330, 3020, 1951, 1811, -1 1627, 1598, 1491, 1448 cm ; [D]D (S) = +42.4, (R) = -58.0 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C29H26N 388.2066, found 388.2060. HPLC analysis (Chiralpak 1B, 99:1 Hex:EtOH, 0.8 mL/min): Retention times (S) 10.7 min, (R) 5.5 min, ee = 98.6%.

12.3.3 (S)-N-(3-(4-Methoxyphenyl)but-3-en-2-yl)-9-phenyl-9H-fluoren-9-amine (85)

To a heterogenous mixture of phosphate 71 (1.11 g, 2.0 mmol, 100 mol %) and PdCl2 (19 mg, 0.10 mmol, 5.2 mol %) in anhydrous THF (4 mL) at rt was added 4- methoxyphenylmagnesium bromide 77 (3.1 mL, 3.1 mmol, 150 mol %) with a syringe pump over 1 h 45 min. The reaction was quenched with MeOH (2 mL) immediately after the addition was completed. The mixture was concentrated and the crude product was purified by flash chromatography (2% EtOAc in hexanes) to yield 85 (370 mg, 44%) as a white amorphous solid.

104

1 Rf = 0.46 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.68 (d, 1H, J = 7.76 Hz), 7.64 (d, 1H, J = 7.76 Hz), 7.49-7.03 (m, 13 H), 6.92-6.66 (m, 5H), 5.26 (s, 1H), 4.96 (s, 1H), 3.74 (s, 1H), 3.66 (s, 3H), 3.07 (q, 1H, J = 6.60 Hz), 2.1 (br s, 1H), 0.81 (d, 3H, J 13 = 6.67 Hz); C NMR (100 MHz, CDCl3): δ 158.7, 158.6, 154.5, 150.7, 149.2, 145.6, 140.8, 140.1, 139.9, 133.4, 128.2, 128.1, 127.9, 127.91, 127.7, 127.6, 127.4, 127.0, 126.4,

126.2, 124.9, 119.7, 119.5, 114.1, 113.2, 111.0, 73.6, 55.2, 55.0, 52.7, 23.9; IR (film) νmax -1 3400, 2095, 1643, 1509, 1499, 1449, 1244, 644 cm ; [D]D = +271 (c = 1, CH2Cl2);

HRMS: m/z calc. for [M+H] C30H28NO 418.2172, found 418.2184.

12.3.4 (S)-N-(3-(4-Chlorophenyl)but-3-en-2-yl)-9-phenyl-9H-fluoren-9-amine (86)

To a heterogenous mixture of phosphate 71 (1.3 g, 2.1 mmol, 100 mol %) and PdCl2 (20 mg, 0.11 mmol, 5 mol %) in anhydrous THF (4 mL) at rt was added 4- chlorophenylmagnesium bromide 79 (3.4 mL, 3.35 mmol, 150 mol %) with a syringe pump over 1 h 50 min. The reaction mixture was stirred at rt for 1 h, after which a second lot of 4-chlorophenylmagnesium bromide (1.1 mL, 1.1 mmol, 50 mol %) was added over 30 min. The reaction was stirred at rt for 1 h, after which it was quenched with MeOH (2 mL). The mixture was concentrated and the crude product was purified by flash chromatography (2% EtOAc in hexanes) to yield 86 (263 mg, 27%) as yellowish oil.

1 Rf = 0.49 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.71 (dt, 1H, J = 7.56 Hz), 7.63 (dt, 1H, J = 7.56 Hz), 7.47-7.01 (m, 15H), 6.81 (dt, 2H, J = 8.76 Hz), 5.32 (t, 1H), 4.98 (d, 1H, J = 1.60 Hz), 3.00 (q, 1H, J = 6.61 Hz), 2.1 (br s, 1H), 0.82 (d, 3H, J = 13 6.61 Hz); C NMR (100 MHz, CDCl3): δ 154.0, 150.5, 149.0, 145.5, 141.0, 140.1, 140.0, 132.7, 128.22, 128,20, 128.0, 127.9, 127.8, 127.4, 127.1, 126.5, 126.2, 124.8, 119.8,

119.5, 112.8, 73.6, 52.6, 23.9; IR (film) νmax 3328, 3062, 2966, 1627, 1595, 1489, 1449, -1 1092, 733 cm ; [D]D = +53.6 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C29H25ClN 422.1676, found 422.1691.

105

12.3.5 (S)-9-Phenyl-N-(3-(thiophen-2-yl)but-3-en-2-yl)-9H-fluoren-9-amine (88)

To a heterogenous mixture of phosphate 71 (1.08 g, 1.9 mmol, 100 mol %) and PdCl2 (17 mg, 0.1 mmol, 5 mol %) in anhydrous THF (4 mL) at rt was added thiophen-2- ylmagnesium bromide 80 (2.85 mL, 2.85 mmol, 150 mol %, 1 M solution in THF) with a syringe pump over 1h 45 min. The reaction mixture was stirred at rt for 1h 30 min, after which more thiophen-2-ylmagnesium bromide (1 mL, 0.95 mmol, 50 mol%) was added over 15 min. The reaction mixture was stirred at rt for 23 h, after which a second lot of

PdCl2 (17 mg, 0.095 mmol, 5 mol %) was added. After stirring for 1 h, the reaction was quenched with MeOH (2 mL) and then concentrated. The crude product was purified by flash chromatography (15% EtOAc in hex) to give the product 88 (177 mg, 24%) as yellow oil and recovered starting material 71 (330 mg, 30%).

1 Rf = 0.56 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 7.72-7.70 (dt, 1H J = 7.47 Hz),7.60 (m, 1H), 7.49 (dt, 2H, J = 6.86 Hz), 7.40-7.11 (m, 35H), 6.98 (dd, 10H, J = 3.68 Hz) 6.87 (dd, 1H, J = 3.5 Hz), 6.82 (dd, 1H, J = 1.3 Hz), 4.95 (d, 1H, J = 1.26 Hz), 4.7 (s, 1H), 3.06 (q, 1H, J = 6.64 Hz), 1.14 (br s, 1H), 0.97 (d, 3H, J = 6.82 Hz); 13C

NMR (100 MHz, CDCl3): δ 150.3, 149.0, 147.0, 145.6, 142.8, 141.3, 139.8, 137.4, 129.8, 128.2, 128.1, 127.9, 127.7, 127.3, 127.1, 126.6, 126.5, 126.3, 124.6, 124.3, 123.9, 123.7,

119.7, 119.4, 111.2, 73.7, 53.9, 23.9; IR (film) νmax 3105, 3069, 2865, 1790, 1443, 1417, -1 1206, 817, 734, 693 cm ; [D]D = +131 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H]

C27H24NS 394.163, found 394.1644.

12.3.6 (S)-9-Phenyl-N-(3-(pyridin-3-yl)but-3-en-2-yl)-9H-fluoren-9-amine (89)

To a heterogenous mixture of phosphate 71 (1.01 g, 1.8 mmol, 100 mol %) and PdCl2 (16 mg, 0.09 mmol, 5 mol %) in anhydrous THF (4 mL) at rt was added pyridine-3-

106 ylmagnesium bromide 81 (2.7 mL, 2.7 mmol, 150 mol %, 1 M solution in THF) with a syringe pump over 1 h 30 min. The reaction was stirred at rt for 15 h, after which the mixture was heated to reflux for 4 h, then let to cool back to rt. The reaction mixture was stirred at rt for 20 h, after which the reaction was quenched with MeOH (2 mL) which also dissolved the precipitates. After a rigorous effort at chromatographic purification (from 20% EtOAc in hex to MeOH) two fractions were collected and the solvents were evaporated to yield crude material of 89 (1.47 g) as brownish oil.

1 Rf = 0.00 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.56-8.35 (m, 1H), 7.76-7.65 (m, 2H), 7.45-6.80 (m, 13H), 4.66 (s, 1H), 3.93 (s, 1H), 2.65-2.60 (q, 13 1H, J = 6.6 Hz), 0.71 (d, 3H, J = 6.6 Hz); C NMR (100 MHz, CDCl3): δ 157.0, 152.1, 149.1, 147.5, 140.3, 140.0, 136.4, 134.6, 129.6, 129.3, 128.9, 128.2, 128.1, 127.6, 127.0, 126.0, 125.9, 125.6, 125.3, 123.8, 123.3, 120.2, 119.9, 119.7. 119.5, 119.3, 115.5, 73.1,

49.9, 25.7, 20.7, 15.2; IR (film) νmax 3615, 3062, 1950, 1649, 1593, 1490, 1444, 1265, -1 1116, 924, 735, 693, 536 cm ; [D]D = +93.2 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] 176 C28H25N2 389.2018, found 389.2022.

12.3.7 3-Pyridinylmagnesium bromide 83 (Several methods tested, this was the successful procedure)

To a heterogenous mixture of magnesium turnings (292 mg, 12 mmol, 120 mol %) in anhydrous THF (6 mL) was added dropwise bromoethane 230 (0.15 mL, 2 mmol, 20 mol %) at rt. After a few minutes the reaction mixture became hot. After the mixture had cooled back down near to rt, 3-bromopyridine 81a (0.963 mL, 10 mmol, 100 mol %) was added with a syringe pump over 1h 15 min. The slow addition prevented the reaction mixture from overheating. Upon addition, the liquid turned first from colourless to orange, later deep blood red. The solution was diluted by anhydrous THF (4 mL) while stirring at rt.

12.3.7.1 The Grignard reagent 81 was titrated as follows.177

107

A solution of I2 (254 mg, 1 mmol) in anhydrous THF (5 mL) was saturated with LiCl by adding pre-dried solid LiCl. This brown solution was cooled down to 0 °C. 3- Pyridinylmagnesium bromide 81 (stirred at rt for 3 d) was added dropwise until the colour of the solution turned substantially lighter (1 mL of Grignard reagent added). Addition of more Grignard caused the reaction mixture to become darker again, thus the molarity was determined to be 1 M.

12.3.8 (S)-9-Phenyl-N-(3-(3,4,5-trimethoxyphenyl)but-3-en-2-yl)-9H-fluoren-9-amine (90)

To a heterogenous mixture of phosphate 71 (1.12 g, 2.0 mmol, 100 mol %) and PdCl2 (19 mg, 0.10 mmol, 5 mol %) in anhydrous THF (4 mL) at rt was added 3,4,5- trimethoxyphenylmagnesium bromide 84 (3 mL, 3 mmol, 150 mol %) with a syringe pump over 2 h. The reaction mixture was stirred at rt for 20 h, after which the reaction was quenched with MeOH (2 mL). The mixture was filtered through a short pad of silica gel and concentrated to yield 90 (382 mg, 40%) as a yellowish oil.

1 Rf = 0.33 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 8.6 (s, 2H), 7.69-7.65 (m, 5H), 7.4-7.1 (m, 8H), 6.7 (s, 2H), 4.67-4.66 (d, 1H, J = 3.44 Hz), 4.43-4.42 (d, 1H, J = 3.48 Hz), 3.8 (s, 9H), 3.5-3.4 (q, 1H, J = 6.99 Hz), 0.98-0.97 (d, 3H, J = 7.14 Hz); 13C

NMR (CDCl3, 400 MHz): δ 153.5, 149.3, 143.8, 139.7, 135.9, 129.0, 128.4, 128.2, 127.8, 127.2, 126.4, 126.2, 125.5, 125.4, 124.9, 120.0, 119.8, 105.4, 83.5, 73.2, 60.7, 57.6, 56.0, -1 20.6. IR (film) νmax 1590, 1489, 1234, 1186, 1110, 1006, 958, 729, 687, 644 cm ; [D]D =

+241 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C32C32NO3 478.2383, found 478.2391. 176

12.3.9 (S)-3-((9-Phenyl-9H-fluoren-9-yl)amino)but-1-en-2-yl trifluoromethanesulfonate (91)

108

To a solution of N-Pf-methyl ketone 5 (1.96 g, 6 mmol, 100 mol %) in anhydrous THF (6 mL) was added KHMDS (24 mL, 12 mmol, 200 mol %) dropwise. The solution was stirred for 45 min, after which a solution of Comins’ reagent 92 in anhydrous THF was added. The reaction mixture was stirred at -78 °C for 2 h, after which it was quenched by satd. NH4Cl2 (6 mL) and the mixture was let to warm up to rt. The mixture was diluted by addition of H2O (15 mL) and Et2O (15 mL). The organic phase was washed with H2O (20 mL) and brine (20 mL), then dried (Na2SO4) and concentrated. The crude product was purified by filtering through a short pad of silica to give 91 (2.66 g, 95%) as a pale yellowish oil.

1 Rf = 0.45 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 8.07-7.31 (m, 13H), 4.95 (d, 1H, J = 3.5 Hz) 4.70 (d, 1H, J = 3.5 Hz), 3.11 (q, 1H, J = 6.51 Hz), 2.35 (br S, 13 1H), 1.28 (d, 3H, J = 6.76 Hz); C NMR (100 MHz, CDCl3): δ 158.8, 149.5, 148.6, 147.9, 144.7, 141.6, 141.1, 140.0., 140.6, 139.8, 128.8, 128.7, §18.6, 128.4, 128.3, 128.0, 127.9, 127.8, 127.5, 127.3, 126.8, 126.5, 126.1, 125.6, 125.3,c 125.2, 124.7, 119.9, 119.8, -1 119.6, 102.0, 73.1, 54.4, 51.1, 20.9; IR (film) νmax 1443, 1206, 929, 732, 699, 606 cm ;

[D]D = +205 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C24H21 F3NO3S 460.1195, found 460.1194. 176

12.3.10 Representative experimental procedure for the iron-catalyzed coupling reaction: (S)-9-Phenyl-N-(3-phenylbut-3-en-2-yl)-9H-fluoren-9-amine (74)

To a solution of N-Pf enol triflate 91 (1.3 g, 2 mmol, 100 mol %) in anhydrous THF (4 mL) was added Fe(acac)3 (49 mg, 0.14 mmol, 5 mol %). After stirring for 15 minutes, phenylmagnesium bromide 76 (3 mL, 3 mmol, 150 mol %) was added over 60 min with a syringe pump. The reaction mixture was stirred for 1 h, after which it was quenched with sat. aq. NH4Cl (2 mL) and diluted with Et2O (5 mL). The organic phase was washed with

H2O (5 mL), brine (5 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography (2.5% EtOAc in hexane) to give 74 (696 mg, 90%). NMR data match those reported for compound 74.

109

12.3.11 (S)-N-(3-(Benzo[d][1,3]dioxol-5-yl)but-3-en-2-yl)-9-phenyl-9H-fluoren-9-amine (94)

To a solution of N-Pf enol triflate 91 (1.3 g, 2 mmol, 100 mol %) in anhydrous THF (4 mL) was added Fe(acac)3 (49 mg, 0.14 mmol, 5 mol %). After stirring for 15 minutes, 3,4-(methylenedioxy)phenylmagnesium bromide 93 (3 mL, 3 mmol, 150 mol %) was added over 60 min with a syringe pump. The reaction mixture was stirred for 24 h, after which the reaction was quenched with sat. aq. NH4Cl (2 mL) and the mixture was diluted with Et2O (5 mL). The organic phase was washed with H2O (5 mL), brine (5 mL), dried

(Na2SO4) and concentrated. The product was filtered through a short pad of silica gel to give 94 (345 mg, 40%) as a yellowish oil.

1 Rf = 0.36 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 8.57-8.56 (m, 1H), 7.88-7.85 (m, 2H), 7.7-7.6 (m, 5H), 7.4-6.8 (m, 8H), 6.0-5.9 (m, 2H), 4.67-4.66 (d, 1H , J = 3.52 Hz), 4.4 (s, 1H), 2.73-2.67 (q, 1H, J = 7.06 Hz), 0.99-0.97 (d, 3H, J = 7.08 Hz); 13 C NMR (CDCl3, 400 MHz): δ 149.4, 129.1, 128.5, 128.4, 127.3, 126.33, 126.29, 125.6,

125.0, 124.0, 120.3, 120.2, 108.6, 107.6, 83.7, 73.3, 57.7, 20.5. IR (film) νmax 1475, 1442, -1 1208, 1123, 1035, 928, 731, 697, 645 cm ; [D]D = +185 (c = 1, CH2Cl2); HRMS: m/z calc. 176, 178 for [M+H] C30H26NO2 432.1964.

12.3.12 (S)-N-(3-(2,4-Bis(trifluoromethyl)phenyl)but-3-en-2-yl)-9-phenyl-9H-fluoren-9- amine (87)

To a solution of N-Pf enol triflate 91 (1.3 g, 2 mmol, 100 mol %) in anhydrous THF (4 mL) was added Fe(acac)3 (49 mg, 0.14 mmol, 5 mol %). After stirring for 15 minutes, 3,5-bis(trifluoromethyl)phenylmagnesium bromide 79 (3 mL, 3 mmol, 150 mol %) was added over 60 min with a syringe pump. The reaction mixture was stirred for 24 h, after

110 which the reaction was quenched with sat. aq. NH4Cl (2 mL) and the mixture was diluted with Et2O (5 mL). The organic phase was washed with H2O (5 mL), brine (5 mL), dried

(Na2SO4) and concentrated. The product was filtered through a short pad of silica gel to give 87 (420 mg, 40%) as a yellowish oil.

1 Rf = 0.42 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 8.3-7.9 (m, 3H), 7.7- 7.4 (m, 13H), 4.96-4.95 (d, 1H , J = 3.52 Hz), 4.72-4.71 (d, 1H, J = 3.44 Hz), 3.0-2.96 (q, 13 1H, J = 7.07 Hz), 1.27-1.26 (d, 3H, J = 7.08 Hz); C NMR (CDCl3, 400 MHz): δ 150.8, 149.4, 143.9, 139.7, 139.5, 135.9, 128.4, 128.3, 126.4, 126.3, 120.1, 117.8, 73.3, 57.6, -1 20.6; IR (film) νmax 1442, 1349, 1279, 1212, 1122, 1016, 908, 732, 698, 636 cm ; [D]D = 176,178 +190 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C31H24 F6N 524.1814.

12.3.13 9-Phenyl-N-((2S)-3-phenylbutan-2-yl)-9H-fuoren-9-amine 9 (75)

To a solution of (S)-9-phenyl-N-(3-phenylbut-3-en-2-yl)-9H-fluoren-9-amine 74 (63 mg, 0.16 mmol, 100 mol %) in EtOAc (1.5 mL) at rt was added Pt/C (32 mg, 0.016 mmol, 10 mol %). The reaction mixture was subjected to H2 at atmospheric pressure, and stirred at rt for 30 min, after which the mixture was filtered through a short pad of celite and concentrated. Crude yellow oil (66 mg) was analyzed by 1H and 13C NMR and the diastereomers were analyzed by UPLC [98% (H2O + 0.1 FA) 2% (CAN + 0.1 FA), 0.5 mL/min]. dr = 2:3.

1 Rf = 0.56 (20% EtOAc in hex); H NMR (400 MHz, CDCl3): δ 7.70-7.63 (m, 5H), 7.40- 7.05 (m, 8H), 6.88-6.79 (m, 5H), 2.67-2.52 (m, 1H), 2.37-2.29 (m, 1H), 1.85 (br s, 1H), 1.20 (m, 3H), 0.51 (d, 1H, J = 6.52 Hz), 0.43 (d, 1H, J = 6.52 Hz); 13C NMR (100 MHz,

CDCl3): δ 171.1, 151.7, 151.1, 149.8, 149.5, 146.2, 145.9, 144.9, 144.8, 140.6, 140.4, 140.2, 140.1, 128.3, 128.1, 128.1, 128.0, 127.93, 127.91, 127.8, 127.78, 127.6, 127.56, 127.5, 127.3, 126.9, 126.8, 126.1, 126.0, 125.9, 125.8, 125.5, 125.4, 125.2, 124.2, 124.1, 120.0, 119.8, 119.7, 119.6, 73.1, 72.9, 60.3, 53.9, 53.4, 46.7, 45.7, 21.0, 20.5, 18.1, 16.3, -1 14.2, 14.0; IR (film) νmax 1448, 1276, 734, 698 cm ; HRMS: m/z calc. for [M+H] 179 C29H28NO 390.2222, found 390.2143.

111

12.3.14 Representative experimental procedure for the screening of ligands

To a solution of amine 74 (142 mg, 0.37 mmol, 100 mol %) in EtOAc (1 mL) were added Pd/C (39 mg, 0.037 mmol, 10 mol %, 10 wt %) and ligand (0.037 mmol, 10 mol %). The reaction mixture was subjected to H2 atm and stirred at rt. The product was filtered through a short pad of celite to give a mixture of 75a and 75b.

12.4 Selected Pf-amines

12.4.1 (1S,2S)-1-Phenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propan-1-ol X and (1R,2S)- 1-phenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propan-1-ol (141a+141b)

To a solution of ketone 5 (177 mg, 0.54 mmol, 100 mol %) in EtOH was added NaBH4 (20.4 mg, 0.54 mmol, 100 mol %). A milky mixture was formed. The reaction mixture was stirred at rt for 30 min, after which the solvents were evaporated and the resulting white solid was analyzed by NMR and HPLC.

1 Rf = 0.23 (20% EtOAc in hexane); H NMR (CDCl3, 400 MHz): δ 7.71-7.63 (m, 6H), 7.40-7.11 (m, 36H), 3.24-3.18 (m, 1H), 3.14-3.08 (m, 1H), 2.13-2.06 (m, 1H), 1.97-1.90 (m, 1H), 0.91-0.89 (d, 3H, J = 6.04 Hz), 0.79-0.78 (d, 1H, J=6.59 Hz), 0.66-0.64 (d, 1H, 13 J=6.72 Hz), 0.51-0.50 (d, 3H, J = 6.39 Hz); C NMR (CDCl3, 400 MHz): δ 150.6, 139.5, 129.0, 128.9, 128.3, 128.3, 128.2, 128.1, 127.7, 127.1, 127.1, 125.8, 125.6, 125.3, 125.1, -1 124.8, 120.0, 119.9, 71.4, 54.9, 19.0; IR νmax 2970, 1448, 751, 734, 699 cm .. HRMS: m/z calc. for [M+H] C23H24NO 330.1859, found 330.1869.

112

12.4.2 (S)-Methyl 3-phenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propanoate (143)

To a solution of L-phenylalanine methyl ester 231 (21.5 g, 100 mmol, 100 mol %) were added K3PO4 (44.6 g, 210 mmol, 210 mol %), Pb(NO3)2 (15 g, 85 mmol, 85 mol %) and 9-bromo-9-phenylfluorene 10 (40 g, 125 mmol, 125 mol %). The pale yellow milky reaction mixture is stirred at rt for 22 h, after which MeOH (50 mL) was added. The mixture was stirred for 30 min, and filtered through a pad of celite. The filter cake was washed with dichloromethane until no UV chromophore was detected on TLC. The solvents were evaporated to yield the crude as brownish oil. The product was purified by flash chromatography (5% EtOAc in hexane) to yield 143 (41.9 g, 90%) as white crystals. The product can be further purified by recrystallization from EtOH in 85% yield.

1 Mp. 150-151 °C; Rf = 0.31 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.66- 7.57 (m, 5H), 7.35-7.13 (m, 9H), 7.03-7.01 (m, 2H), 6.95-6.91 (m, 2H), 6.63 (td, 2H, J = 7.38 Hz), 3.44 (t, 1H, J = 7.04 Hz), 3.17 (s, 6H), 2.28 (br s, 2H), 1.17 (t, 1H, J = 7.04 Hz); 13 C NMR (100 MHz, CDCl3) δ 176.1, 148.6, 148.4, 144.5, 140.9, 139.8, 137.5, 129.7, 128.9, 128.2, 128.1, 128.0, 127.9, 127.7, 127.1, 127.0, 126.3, 126.1, 126.0, 125.0, 119.7,

119.6, 72.8, 57.5, 51.2, 41.3; [α]D (S) -206.7 (c = 1.2, CH2Cl2), (R) +208.3 (c = 1.1 in

CH2Cl2); IR νmax 3649, 3027, 1734, 1652, 1489, 1435, 1339, 1169, 1082, 988, 752, 733, -1 698 cm ; HRMS: m/z calc. for [M+Na] C29H25NO2Na 442.1785, found 442.1780.

12.4.3 (S)-3-Oxo-5-phenyl-4-((9-phenyl-9H-fluoren-9-yl)amino)pentanenitrile (142)

To a clear solution of n-BuLi (52 mL, 119 mmol, 170 mol %, 2.25M solution in hex) in anhydrous THF (70 mL) at -78 °C was added MeCN (määrä?) dried overnight over 4 Å molecular sieves). This white, milky mixture was stirred at -78 °C for 75 min, after which a solution of N-Pf-phenylalanine methyl ester 143 (29 g, 70 mmol, 100 mol %) in

113 anhydrous THF (70 mL) was cannulated into the reaction mixture. The orangeish milky mixture was stirred at -78 °C for 80 min, after which the reaction was quenched with 1 M

HCl (150 mL). The mixture was let to warm up to rt, after which it was diluted with Et2O

(150 mL). The organic phase was washed with H2O (150 mL) and brine (150 mL), dried

(Na2SO4) and concentrated to yield N-Pf-phenylalanine ketonitrile 142 (29 g, 96%) as white foam.

1 Rf = 0.29 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.68-7.63 (m, 2H), 7.38-7.14 (m, 11H), 7.07-7.01 (m, 2H), 6.89-6.87 (m, 3H), 6.79 (d, 1H, J = 7.5 Hz), 3.09 (br s, 1H), 2.79 (m, 1H), 2.65- 2.61 (m, 2H), 2.23 (d, 1H, J = 19 Hz), 13C NMR (100 MHz,

CDCl3): δ 202.6, 148.8, 148.3, 143.3, 140.9, 139.6, 129.2, 129.0, 128.7, 128.4, 128.3, 128.1, 128.0, 127.4, 127.0, 126.8, 125.9, 124.8, 120.1, 119.7, 113.2, 72.8, 67.9, 62.3, 40.3,

30.2, 25.5; [α]D -191 (c = 1.0, CH2Cl2); IR (film) νmax 3301, 1738, 1714, 1449, 753, 734, -1 700 cm ; HRMS calc. for [M+H] C30H25N2O 429.1968, found 429.1968.

12.4.4 (S,E)-2-Benzylidene-3-oxo-4-((9-phenyl-9H-fluoren-9-yl)amino)pentanenitrile (145a)

To a clear solution of N-Pf-ketonitrile 142 (600 mg, 1.7 mmmol, 100 mol %) in anhydrous DCM (4 mL) was added molecular sieves (0.41 g), benzaldehyde 144a (208 μL, 2.04 mmol, 120 mol %) and morpholine 229 (34 μL, 0.39 mmol, 23 mol %). The reaction mixture was stirred at rt for 3 h, after which silica gel was added, the mixture was filtered and concentrated to yield 145a (667 mg, 88%) as a bright yellow foam.

1 Rf = 0.33 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.77 (m, 2H), 7.68 (m, 2H), 7.60 (m, 5H), 7.53-7.16 (m, 13H), 7.07-6.99 (m, 5H), 3.47 (q, 1H, J = 6.84 Hz), 2.54 13 (br s, 3H), 1.11 (d, 3H, J = 6.84 Hz); C NMR (100 MHz, CDCl3): δ 198.9, 152.6, 143.1, 139.5, 133.1, 131.0, 129.0, 128.3, 128.1, 127.1, 125.3, 124.7, 120.0, 116.1, 107.5, 83.5,

72.9, 53.5, 20.5; [α]D -96.6 (c = 1, CH2Cl2) IR (film) νmax 3059, 1811, 1697, 1585, 1449, -1 1169, 1103, 1029, 916, 733, 699, 643 cm ; HRMS m/z calc. for [M+H] C37H29N2O 517.2281, found 517.3433.176

114

12.4.5 (S,E)-2-(2,6-Dichlorobenzylidene)-3-oxo-4-((9-phenyl-9H-fluoren-9- yl)amino)pentanenitrile (145b)

To a clear solution of N-Pf-ketonitrile 142 (2.3 g, 6.5 mmol, 100 mol %) in anhydrous DCM (12 mL) were added 4 Å molecular sieves (1.4 g), 2,6-dichlorobenzaldehyde 138b (1.37 g, 7.8 mmol, 120 mol %) and morpholine 229 (112 μL, 1.3 mmol, 23 mol %). The reaction mixture was stirred at rt for 22 h, after which silica gel (table spoonful) was added. The mixture was stirred at rt for 1 h, after which it was filtered and concentrated to yield 3.08 g of crude material. The product was purified by flash chromatography (10% EtOAc in hex), to give 145b (907 mg, 27%) as white foam.

1 Rf = 0.30 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.68- 7.62 (m, 5H), 7.47-7.45 (m, 3H), 7.36-7.13 (m, 13H), 4.07 (q, 1H, J = 6.74 Hz), 3.37 (q, 1H, J = 7.49 Hz), 2.51 (br s, 3H), 1.97 (s, 1H), 1.20 (d, 3H, J = 7, 68 Hz); 13C NMR (100

MHz, CDCl3): δ 196.1, 150.4, 143.1, 139.5, 134.0, 129.0, 128.4, 128.3, 127.1, 126.2.

125.3, 124.7, 120.0, 83.5, 73.1, 60.4, 55.2, 20.6; [α]D -128 (c = 1, CH2Cl2); IR (film) νmax -1 3749, 3648, 1507, 1449, 1275, 750, 699 cm ; HRMS calc. for [M+H] C37H27Cl2N2O 585.1501.176,178

12.4.6 (4S)-2-(2-Nitro-1-phenylethyl)-3-oxo-5-phenyl-4-((9-phenyl-9H-fluoren-9- yl)amino)pentanenitrile (149)

To a clear solution of N-Pf-phenylalanine ketonitrile 142 (214 mg, 0.5 mmol, 100 mol %) in anhydrous DCM (1 mL) was added quinine (16 mg, 0.05 mmol, 10 mol %), followed

115 by E-(2-nitrovinyl)benzene 148 (89 mg, 0.6 mmol, 120 mol %) 5 min later. The reaction mixture was stirred at rt for 2.5 h, after which the reaction was quenched with sat. aq.

NH4Cl (1 mL). H2O (3 mL) and DCM (3 mL) were added. The organic phase was washed with H2O (3 mL) and brine (3 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography (20% EtOAc in hex) to yield 149 (174 mg, 60%) as a yellowish oil that turned slowly crystalline.

1 Rf = 0.55 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.72-7.45 (m, 2H), 7.39-7.11 (m, 16H), 6.92-6.77 (m, 4H), 6.55 (t, 1H, J = 7.68 Hz), 6.09 (d, 1H, J = 7.59 Hz), 5.98 (d, 1H, J = 7.68 Hz), 4.62-4.40 (m, 2H), 4.25 (dd, 0.4H, J = 5.62, 12.6 Hz), 3.14 (m, 1H), 2.83 (dd, 1H, J = 3.29, 14.11 Hz), 2.45 (d, 1H, J = 10.55 Hz), 2.03 (s, 3H); 13 C NMR (400 MHz, CDCl3): δ 171.0, 169.8, 168.7, 146.7, 145.6, 144.9, 142.4, 142.3, 140.7, 140.5, 139.9, 137.6, 137.0, 135.1, 134.8, 129.2, 129.2, 129.1, 128.9, 128.8, 128.6, 128.6, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 127.1, 125.9, 125.6, 125.2, 123.4, 123.3, 120.4, 119.9, 119.7, 116.8, 116.6, 83.4, 82.6, 77.6, 77.4, 72.1, 72.0, 60.3,

55.8, 55.7, 40.7, 39.9, 39.3, 20.9; [α]D -130 (c = 1, CH2Cl2); IR (film) νmax 3749, 3648, -1 1606, 1553, 1455, 1375, 750, 699 cm ; HRMS calc. for [M+H] C38H32N3O3 578. 578.2444, found 578.2441.176

12.4.7 (S)-2-((9-Phenyl-9H-fluoren-9-yl)amino)hept-6-en-3-one (199) and (S)-4-allyl-2- ((9-phenyl-9H-fluoren-9-yl)amino)hept-6-en-3-one (198)

To a solution of N-Pf-alanine methyl ketone 5 (164 mg, 0.5 mmol, 100 mol %) in anhydrous THF (0.5 mL) at -78 °C was dropwise added KHMDS (2 mL, 1 mmol, 200 mol %, 0.5 M solution in toluene). The reaction mixture stayed clear and turned orange, and was stirred at -78 °C for 10 minutes. Allylbromide 197 (0.087 mL, 1 mmol, 200 mol %) was added. The reaction mixture was stirred at -18 °C for 20 h, after which it was quenched with satd. NH4Cl aq. solution (1 mL) and let to warm up to rt. The mixture was

116 diluted with Et2O (2 mL) and the phases were separated. The organic phase was concentrated. The crude product was purified by flash chromatography, giving compounds 199 (19 mg, 10%) and 198 (74 mg, 36%).

1 199: Rf = 0.46 (20% EtOAc in hex) H NMR (400 MHz, CDCl3): δ 7.70-7.67 (m, 2H), 7.42-7.10 (m, 12H), 5.59-5.50 (m, 1H), 4.87-4.82 (m, 2H), 3.44 (br s, 1H), 2.70 (q, 1H, J = 6.43 Hz), 2.21-2.00 (m, 1H), 1.99-1.87 (m, 2H), 1.60 (m, 1H), 0.98 (d, 3H, J = 7.21 Hz); 13 C NMR (100 MHz, CDCl3): δ 213.7, 149.9, 144.5, 141.0, 139.9, 137.0, 128.2, 128.0, 127.7, 127.1, 126.4, 126.1, 125.2, 119.8, 119.7, 114.9, 73.1, 56.7, 39.0, 27.3, 20.8; IR - (film) νmax 3294, 3064, 2977, 2982, 1953, 1709, 1640, 1599, 1488, 915, 753, 734, 644 cm 1 ; HRMS: m/z calc. for [M+H] C26H26NO 368.2015, found 368.2020.

1 198: Rf = 0.58 (20% EtOAc in hex) H NMR (400 MHz, CDCl3): δ 7.81-7.79 (m, 5H), 7.48-7.21 (m, 8H), 5.62-5.41 (m, 2H), 5.30-5.21 (m, 2H), 5.01-4.75 (m, 8H), 3.60 (br s, 1H), 3.30 (m, 2H), 2.81 (q, 1H, J = 7.43 Hz), 2.38 (m, 2H), 2.05 (m, 4H), 1.50 (m, 2H), 13 1.04 (d, 3H, J = 7.16 Hz), 0.91 (d, 1H, J =7.43 Hz); C NMR (100 MHz, CDCl3): δ 214.3, 151.3, 149.6, 144.9, 141.1, 135.6, 135.1, 133.6, 133.5, 128.3, 128.2, 128.1, 128.1, 128.0, 127.9, 127.4, 127.2, 126.7, 126.4, 126.1, 125.9, 125.5, 124.6, 119.9, 119.8, 119.6, 118.0, 117.8, 116.8, 73.0, 58.4, 56.6, 47.8, 42.2, 38.6, 34.9, 33.9, 20.9; HRMS: m/z calcd. for [M+H] C29H30NO 408.2328 found 408.2326.

12.4.8 (S)-1-(Diphenylphosphoryl)-3-((9-phenyl-9H-fluoren-9-yl)amino)butan-2-one (201)

To a solution of methyldiphenylphosphine oxide 205 (3.1 g, 14.4 mmol, 150 mol %) in anhydrous THF (25 mL) at 0 °C was added n-BuLi (7.3 mL, 15.4 mmol, 160 mol %, 2.1 M in hexanes). The reaction mixture was stirred at 0 °C for 15 min, after which it was cooled to -78 °C. To this solution was added via cannula a precooled (to -78 °C) solution of N-Pf-Alanine methyl ester 2 (3.3 g, 9.6 mmol, 100 mol %) in anhydrous THF (5 mL). The reaction mixture was stirred at -78 °C for 1 h. The reaction was quenched with sat. aq.

NH4Cl (25 mL), after which the mixture was allowed to warm up to rt, and then Et2O (25 mL) was added. The organic phase was washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4) and concentrated to give the crude product as a yellowish foam (4.64 g).

117

Purification by flash chromatography (60% EtOAc in hex) gave 201 (2.74 g, 54%) as a white amourphous solid.

1 Rf = 0.45 (EtOAc) Mp. 161 °C; H NMR (400 MHz, CDCl3): δ 7.61-7.10 (m, 24 H), 3.39 (q, 1H, J = 14.8 Hz), 3.12 (t, 2H, J = 14.2 Hz), 2.80 (q, 1H, J = 6.8 Hz), 0.84 (d, 3H, J = 13 7Hz); C NMR (100 MHz, CDCl3): δ 207.3, 149.9, 149.5, 144.3, 140.8, 140.0, 132.0, 131.0, 130.9, 128.6, 128.4, 128.38, 128.2, 128.1, 127.7, 127.1, 126.1, 126.0, 125.2, 120.0,

119.9, 72.9, 58.5, 44.0, 43.0, 19.0; IR (film) νmax 3056, 1706, 1591, 1437, 1194, 1119, -1 1028, 735, 696, 508 cm ; [D]D = -191.0 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H]

C35H31NO2P 528.2093, found 528.2111.

12.4.9 (2S)-4-(Diphenylphosphoryl)-2-((9-phenyl-9H-fluoren-9-yl)amino)hept-6-en-3-one (209) and (S)-1-((allyloxy)diphenylphosphoranylidene)-3-((9-phenyl-9H-fluoren-9- yl)amino)butan-2-one (210)

To a solution of N-Pf-alanine phosphine oxide 201 (2.64 g, 5 mmol, 100 mol %) in anhydrous THF (15 mL) was added KHMDS (10.5 mL, 5.25 mmol, 105 mol %) at rt. This clear, pale yellow solution was stirred at rt for 1 h, after which it was cannulated into a solution of allyl bromide 197 (3.0 mL, 35 mmol, 700 mol %) in anhydrous THF (2 mL) at rt. The cloudy orangeish solution was stirred at rt for 3 h, after which the reaction was quenched with sat. aq. NH4Cl (25 mL), and Et2O (25 mL) was added. The organic phase was washed with H2O (25 mL) and brine (25 mL), then dried (Na2SO4) and concentrated to give the crude product as yellowish foam (3.03 g). The two products that were formed in the reaction were isolated by flash chromatography (40% EtOAc in hexanes) to yield 209 (896 mg, 31%) and 210 (1.88 g, 66%) as white sparkling foams.

118

1 209: Mp. 76 °C; Rf = 0.60 (EtOAc); H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m, 2H), 7.67-7.03 (m, 25H), 5.35 (td, 1H), 5.15 (qd, 1H), 4.83 (m, 2H), 3.11 (d, 1H, J = 8.0 Hz), 2.75 (q, 1H), 2.46 (m, 1H), 2.25 (m, 1H), 0.83 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz,

CDCl3δ 210.5, 151.1, 144.9, 140.2, 134.9, 134.7, 132.3, 132.1, 132.0, 131.9, 131.5, 131.4, 128.9, 128.8, 128.4, 128.3, 128.3, 128.2, 128.1, 127.8, 126.8, 126.1, 125.5, 125.4, 120.0,

119.9, 116.9, 72.8, 60.7, 59.6, 49.5, 32.4, 19.3; IR (film) νmax 3060, 2225, 1708, 1437,

1184, 1117, 910, 734, 697; [a]D = +2.5 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H]

C38H35NO2P 568.2406, found 568.2398.

1 210: Mp.86-88°C; Rf = 0.47 (EtOAc); H NMR (400 MHz, CDCl3): δ 7.93-7.88 (m, 0.5H), 7.75-7.05 (m, 33H), 5.67-5.57 (m, 1H), 5.39-5.10 (m, 1H), 5.01-4.96 (m, 2H), 4.12 (m, 1H), 3.87-3.81 (m, 1H), 2.63-2.25 (m, 4H), 0.82 (d, 1H), 0.34 (d, 3H), -0.26 (d, 13 0.35H); C NMR (100 MHz, CDCl3): δ 205.3, 171.4, 131.9, 131.5, 131.4, 131.37, 131.3, 128.5, 128.4, 128.2, 128.1, 127.9, 127.3, 126.0, 125.9, 125.6, 120.1, 119.9, 117.0, 73.0,

60.4, 59.6, 57.7, 53.3, 52.1, 32.5, 21.6, 17.6, 14.2; IR (film) νmax 3060, 2225, 1708, 1437, -1 1184, 1117, 910, 734, 697 cm ; [a]D = -7.5 (c = 1, CH2Cl2); HRMS: m/z calcd. for [M+H]

C38H35NO2P 568.2406, found 568.2406.

12.4.10 9-Allyl-9-phenyl-9H-fluorene (211)

To a solution of N-Pf-Alanine methyl ketone 5 (512 mg, 1.56 mmol, 100 mol %) in anhydrous toluene (3 mL) were added allylacetate 206 (0.85 mL, 7.8 mmol, 500 mol %) and Pd(PPh3)4 (180 mg, 0.156 mmol, 10 mol %) at rt. This clear, yellow solution was stirred at rt for 1 h, after which heating was started. The reaction mixture was refluxed for 16 h, during which it turned into a brown mixture. It was then allowed to cool to rt, and concentrated. The crude material was purified by flash chromatography (2% EtOAc in hex) to give 211 (390 mg, 68%) as white amourphous solid.

1 Rf = 0.49 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.74-7.59 (m, 3H), 7.39-6.97 (m, 19 H), 5.2 (m, 1H), 5.0 (m, 1H), 4.75 (m, 1H), 4.65 (m, 1H), 3.17 (m, 2H); 13 C NMR (100 MHz, CDCl3): δ 151.1, 147.8, 144.2, 141.5, 140.9, 140.5, 133.5, 128.6, 128.3, 128.3, 127.4, 127.2, 127.2, 126.7, 126.6, 126.4, 125.3, 124.6, 119.8, 117.8, 58.4, 178 54.4, 42.2; HRMS: m/z calc. for [M+Na] C22H18Na 305.1309.

119

12.4.11 Magnesium enolate of monoethyl malonate (203)

To a solution of freshly distilled monoethyl malonate 204 (2.2 mL, 20 mmol, 100 mol %) in THF (5 mL) at 0 °C was carefully added methyl magnesium chloride (6.7 mL, 20 mmol, 100 mol %, 3 M solution in THF) during 20 min. Significant gas evolution occurred. This clear, colourless solution was stirred at 0 °C for 5 min, then at rt for 1 h. The product was immediately used as such in the following reaction.

12.4.12 (S)-Ethyl 3-oxo-4-((9-phenyl-9H-fluoren-9-yl)amino)pentanoate (200)

To a solution of N-Pf-alanine 4 (3.49 g, 10 mmol, 100 mol %) in THF (5 mL) was added CDI 207 (2.34 g, 15 mmol, 150 mol %) at rt. The mixture was stirred at rt for 1 h. To this solution was added the magnesium enolate 233 (14 mL, 20 mmol, 200 mol %, as a solution of monoethyl malonate 20 mmol and MeMgCl 20 mmol in THF) via cannula at rt during 20 min. A heterogeneous mixture was formed. The reaction was stirred at rt for

2 d, quenched with 10% citric acid (10 mL), and extracted with Et2O (20 mL). The organic phase was washed with H2O (20 mL), brine (20 mL), dried (Na2SO4) and concentrated. The crude product (3.79 g) was recrystallized from EtOAc (3 mL) to give 200 (2 g, 50%) as pale yellow crystals.

1 Mp. 108 °C; Rf = 0.34 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.70- 7.67 (m, 2H), 7.41-7.14 (m, 11H), 4.09-4.04 (q, 2H, J = 7.12 Hz), 3.10 (d, 1H, J = 15.76 Hz), 3.1 (br s, 1H), 2.92 (d, 1H, J = 15.76 Hz), 2.76 (q, 1H, J = 7.08 Hz), 1.19 (t, 3H, J = 13 7.16 Hz), 1.00 (d, 3H, J = 7.04 Hz); C NMR (100 MHz, CDCl3): δ 206.6, 166.9, 149.7, 149.0, 144.3, 140.6, 140.2, 128.5, 128.4, 128.3, 128.0, 127.9, 127.2, 126.1, 126.0, 125.1,

119.9, 119.8, 73.1, 61.1, 57.4, 46.3, 20.2, 14.0. IR (film) νmax 3301, 1738, 1714, 1449, -1 753, 734, 700 cm ; [α]D = -113.0 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H]

C26H26NO3 400.1913, found 400.1915.

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12.4.13 Ethyl 2-((S)-2-((9-phenyl-9H-fluoren-9-yl)amino)propanoyl)pent-4-enoate (207a)

To a solution of β-ketoester 200 (622 mg, 1.56 mmol, 100 mol %) in anhydrous toluene

(3 mL) were added allylacetate 206 (0.85 mL, 7.8 mmol, 500 mol %) and Pd(PPh3)4 (180 mg, 0.156 mmol, 10 mol %) at rt. The reaction was stirred at rt for 3 d, after which it was concentrated. The crude mixture was purified by flash chromatography (2% EtOAc in hex) to yield 207a (167 mg, 24%).

1 Rf = 0.44 (20% EtOAc in hexanes); H NMR (400 MHz, CDCl3): δ 7.69-7.60 (m, 3H), 7.49-7.10 (m, 16H), 5.5 (m, 1H), 4.90 (m, 3H), 4.10 (m, 1H), 3.95 (m, 2H), 2.85 (m, 2H), 13 2.45 (m, 1H), 1.23 (m, 2H), 1.1 (m, 8 H); C NMR (100 MHz, CDCl3): δ 207.8, 206.8, 170.9, 168.5, 168.4, 149.6, 149.5, 149.2, 148.9, 144.6, 144.4, 141.0, 140.6, 140.1, 139.7, 134.3, 134.3, 128.3, 128.3, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7, 127.1, 126.3, 126.1, 126.0, 125.9, 125.4, 125.2, 125.1, 124.7, 119.8, 119.8, 119.7, 117.0, 116.8, 73.0, 72.9, 61.1, 60.9, 60.2, 57.1, 56.6, 55.8, 54.77, 32.1, 31.7, 20.9, 20.8, 20.5, 14.1, 13.9, 13.8.

12.4.14 (S)-Allyl 3-oxo-4-((9-phenyl-9H-fluoren-9-yl)amino)pentanoate (202) and (S)- allyl 2-((9-phenyl-9H-fluoren-9-yl)amino)propanoate (202a)

To a solution of N-Pf-alanine 4 (1.65 g, 5 mmol, 100 mol %) in THF (10 mL) was added CDI 232 (851 mg, 5.25 mmol, 105 mol %). The reaction mixture was stirred at rt. Meanwhile, LDA-allylacetate was prepared as follows: To a solution of DIPA (2.45 mL,

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17.5 mmol, 350 mol %) in THF (2.5 mL) at 0 °C was added n-BuLi (811 mL, 17.5 mmol, 350 mol %, 1.6 M solution in hexane). The mixture was stirred at 0 °C for 20 min, after which and the mixture was cooled to -78 °C, and allylacetate 206 (1.89 mL, 17.5 mmol, 350 mol %) was added. This mixture was stirred at -78 °C for 20 min, after which it was added dropwise into the reaction mixture prepared previously. Upon addition a precipitate was formed. The now heterogenous reaction mixture was stirred for 25 min, after which it was quenched with H2O (25 mL) and let to warm up to rt. The aqueous phase was extracted with Et2O (25 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The product was purified by flash chromatography (5% EtOAc in hex) to give 202 (847 mg, 41%) as a colourless oil and the side product 202a (300 mg, 16%).

1 202: Rf = 0.45 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.40-7.14 (m, 11H), 5.87-5.77 (m, 1H), 5.29-5.18 (m, 2H), 3.13 (d, 1H, J = 16.09 Hz), 3.07 (br s, 1H), 2.93 (d, 1H, J = 16.09 Hz), 2.77 (q, 1H, J = 6.09 Hz), 1.00 (d, 3H, J = 13 7.44 Hz); C NMR (100 MHz, CDCl3) δ 206.5, 166.5, 149.6, 149.0, 144.2, 140.6, 140.2, 131.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.2, 126.1, 126.0, 125.1, 119.9, 119.9, 118.5,

73.1, 65.6, 57.4, 46.1, 20.1; [α]D -189 (c = 1, CH2Cl2); IR νmax 2928, 1714, 1449, 1155, -1 989, 930, 753, 699, 459 cm ; HRMS: m/z calc. for [M+Na] C27H25NO3Na 434.1734, found 434.1732.

1 202a: Rf = 0.57 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.66-7.63 (m, 2H), 7.43-7.14 (m, 11H), 5.66-5.55 (m, 1H), 5.08-5.03 (m, 2H), 4.24-4.20 (m, 1H), 4.13- 4.01 (m, 1H), 3.00 (br s, 1H), 2.81 (q, 1H, J = 6.74 Hz), 1.13 (d, 3H, J = 7.04 Hz); 13C

NMR (100 MHz, CDCl3) δ 176.2, 149.3, 148.8, 144.5, 140.7, 140.0, 131.8, 128.2, 127.7,

127.3, 127.1, 126.9, 125.9, 125.0, 120.0, 119.7, 117.9, 72.9, 65.0, 51.3, 21.6; [α]D -189 (c

= 1, CH2Cl2); IR νmax 3313, 3062, 3035, 2977, 2932, 2313, 1953, 1732, 1598, 1449, 1372, 1279, 1182, 1144, 930, 753, 734, 700, 617, 511 cm-1; HRMS: m/z calc. for [M+Na]

C25H23NO2Na 392.1629, found 392.1636.

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12.4.15 Allyl 2-((S)-2-((9-phenyl-9H-fluoren-9-yl)amino)proanoyl)pen-4-enoate (208a and 208b)

To a solution of β-ketoester 202 (411 mg, 1 mmol, 100 mol %) in anhydrous THF (1 mL) at -78 °C was dropwise added KHMDS (4 mL, 2 mmol, 200 mol %). The reaction mixture was stirred at -78 °C for 1 h, after which allylbromide 197 (0.17 mL, 2 mmol, 200 mol %) was added. The reaction mixture was stirred at -78 °C, after which it was let to warm up to rt. The reaction mixture was stirred at rt for 2 d, after which it was quenched with H2O (2 mL) an diluted with Et2O (3 mL). The aqueous phase was extracted with Et2O (2 mL), and the organic phase was washed with brine (2 mL), dried

(Na2SO4) and concentrated. Purification by flash chromatography (2% EtOAc in hex) gave 208b (201 mg, 45%) and 208a (45 mg, 9%).

1 208a: Rf = 0.44 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 2H), 7.39-7.11 (m, 12H), 5.75-5.67 (m, 1H), 5.61-5.51 (m, 1H), 5.43-5.34 (m, 1H), 5.26- 5.12 (m, 4H), 4.98-4,82 (m, 3H), 4.45-4.35 (m, 3H), 3.33 (br s, 1H) 2.88-2.83 (m, 2H), 2.39-2.30 (m, 1H), 2.18-2.10 (m, 1H), 1.62-1.57 (m, 1H), 1.03 (d, 3H, J = 6.69 Hz); 13C

NMR (100 MHz, CDCl3) δ 207.7, 168.2, 149.6, 149.6, 149.2, 148.9, 144.4, 141.0, 139.8, 134.3, 242.4, 128.3, 128.2, 128.0, 127.9, 127.1, 126.3, 125.9, 125.2, 119.9, 119.7, 118.4,

116.9, 72.9, 65.7, 57.2, 55.6, 32.1, 20.8; IR νmax 3305, 3076, 2929, 1954, 1735, 1706, 1640, 1488, 1448, 1275, 1204, 922, 754, 734, 699, 644 cm-1; HRMS: m/z calc. for

[M+Na] C30H29NO3Na 474.2047, found 474.2054.

1 208b: Rf = 0.48 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.69-7.66 (m, 2H), 7.38-7.17 (m, 15H), 5.67-5.64 (m, 1H), 5.53-5.43 (m, 1H), 5.22-5.15 (m, 3H), 4.99- 4.90 (m, 6H), 4.43-4.32 (m, 2H), 3.37 (br s, 1H), 2.13 (q, 1H, J = 6.69 Hz), 2.54-2.40 (m, 13 2H), 2-13-2.08 (m, 2H), 0.93 (d, 3H, J = 6.69 Hz); C NMR (100 MHz, CDCl3) δ 208.4, 170.8, 148.9, 141.0, 132.8, 131.9, 131.3, 128.3, 128.2, 127.9, 127.1, 126.1, 125.3, 119.9,

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119.8, 119.2, 119.2, 118.8, 72.9, 65.8, 60.9, 55.6, 36.9, 36.7, 21.3; IR νmax 3305, 3076, 2929, 1954, 1735, 1706, 1640, 1488, 1448, 1275, 1204, 922, 754, 734, 699, 644 cm-1;

HRMS: m/z calc. for [M+H] C33H34NO3 492.6279, found 492.2539.

12.4.16 (S)-3-((9-Phenyl-9H-fluoren-9-yl)amino)-1-(trimethylsilyl)2- ((trimethylsilyl)methyl)butan-2-ol (109)

To a clear, colourless solution of amide 3 (372 mg, 1 mmol, 100 mol %) in anhydrous THF (2 mL) at -78 °C was dropwise added TMS-methyllithium 101 (3.5 mL, 3.5 mmol, 350 mol %). The reaction mixture was stirred at -78 °C for 2 h, after which it was let to warm up to 0 °C. The stirring was continued at 0 °C for 2 h, after which the reaction was quenched with sat. aq. NH4Cl (3 mL). The mixture was let to warm up to rt. EtOAc (2 mL) and H2O were added and the organic phase was washed with H2O (3 mL) and brine

(3 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (2% - 10% EtOAc in hexanes) to give 109 (76 mg, 15%)

1 Rf = 0.66 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.58-7.49 (m, 2H), 7.24-7.04 (m, 11H), 3.77 (br s, 1H), 2.08 (q, 1H, J = 7.54 Hz), 0.90 (d, 1H, J = 15.84 Hz), 0.87 (d, 1H, J = 15.84 Hz), 0.55 (t, 2H, J = 14.08 Hz), 0.32 (d, 3H, J = 6.28 Hz), -0.52 (s, 13 6H); C NMR (100 MHz, CDCl3) δ 151.3, 148.7, 145.3, 140.8, 140.0, 128.3, 127.6,

127.2, 126.0, 125.9, 125.3, 120.0, 119.9, 77.1, 72.3, 56.9, 29.3, 27.7, 18.7, 0.9, 0.1; [α]D -

68.7 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C30H42NOSi2 488.2806, found 488.2811.

12.4.17 (S)-1,1-Diphenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propan-1-ol (110)

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To a clear, colourless solution of N-Pf-alanine methyl ester 2 (343 mg, 1 mmol, 100 mol %) in anhydrous THF (1 mL) at -78 °C was dropwise added phenyllithium (1.67 mL, 3 mmol, 300 mol %). The reaction mixture was stirred at -78 °C for 30 minutes, after which it was quenched with sat. aq. NH4Cl (4 mL) and the mixture was let to warm up to rt. The mixture was diluted and partitioned with Et2O (5 mL) and H2O (3 mL). The organic phase was washed with H2O (6 mL), brine (6 mL), dried (Na2SO4) and concentrated to give 110 in quantitative yield.

1 Rf = 0.47 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.74 (m, 2H), 7.42-7.11 (m, 24H), 4.66 (br s, 1H), 3.53 (q, 1H, J = 6.35 Hz), 2.25 (br s, 1H), 0.32 (d, 3H, J = 6.63 13 Hz); C NMR (100 MHz, CDCl3) δ 151.4, 147.9, 145.5, 144.2, 140.5, 139.6, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.1, 127.0, 126.5, 126.5, 125.4, 125.3, 120.2, 120.1,

80.2, 72.1, 55.8, 17.1. [α]D -77.8 (c = 1, CH2Cl2); HRMS: m/z calc. for [M+H] C34H30NO 468.2328, found 468.2315.

12.4.18 N-Pf-Cathinone: (S)-1-Phenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propan-1-one (106)

To a clear, colourless solution of amide 3 (372 mg, 1 mmol, 100 mol %) in anhydrous THF (1 mL) at 0 ºC was added phenyllithium 102 (1.67 mL, 3 mmol, 300 mol %). The dark brown reaction mixture was stirred at 0 ºC for 15 minutes, after which it was quenched with sat. aq. NH4Cl (5 mL). The mixture was diluted with Et2O (5 mL), and the cooling bath was removed. The mixture was allowed to warm up to rt. The organic phase was washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4) and concentrated. The product was purified by flash chromatography (10% EtOAc in hexanes) to yield N-Pf- cathinone 106 as a yellowish oil (65 mg, 16%).

1 Rf = 0.54 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.80-6.97 (m, 18H), 3.74 (br s, 1H), 3.63 (q, 1H, J = 6.98 Hz), 1.06 (d, 1H, J = 7.08 Hz); 13C NMR (100 MHz,

CDCl3) δ 205.1, 150.0, 149.4, 144.5, 140.8, 140.0, 135.1, 132.6, 128.2, 128.1, 128.0,

127.7, 127.6, 127.1, 126.4, 126.2, 125.3, 119.8, 119.5, 73.1, 52.4, 22.2; [α]D -135.9 (c = 1, -1 CH2Cl2); IR νmax 3060, 1489, 1448, 1176, 1081, 753, 733, 699 cm ; HRMS: m/z calc. for

[M+Na] C28H23NONa 412.1680, found 412.1690.

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12.4.19 (S)-Dimethyl (2-oxo-3-((9-phenyl-9H-fluoren-9-yl)amino)butyl)phosphonate (232)

To a clear, colourless solution of dimethyl methylphosphonite 233 (11.55 mL, 106 mmol, 410 mol %) in anhydrous THF (100 mL) at -78 ºC was added n-BuLi (46 mL, 104 mmol, 400 mol %) during 10 min. The mixture was stirred at -78 ºC for 50 min, after which a solution of N-Pf-alanine methyl ester 3 (8.9 g, 26 mmol, 100 mol %) in anhydrous THF (70 mL) was cannulated into it during 5 min. The reaction mixture was let to warm up to rt and stirred for 15 h, after which the reaction was quenched with sat. aq. NH4Cl (200 mL). The mixture was diluted with EtOAc (150 mL) and H2O (100 mL). The aqueous phase was extracted with EtOAc (150 mL). The combined organic phases were washed with H2O (200 mL), brine (200 mL), dried (Na2SO4) and concentrated. The residue was dissolved in EtOAc and filtered through a pad of silica gel using EtOAc for washing. The solvent was evaporated to give 232 as a slightly yelllowish oil (10.55 g, 93%).

1 Rf = 0.54 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.67-7.64 (m, 2H), 7.40-7.14 (m, 11H), 3.53 (dd, 4H, J = 11.22, 16.6 Hz), 3.14 (br s, 1H), 2.78 (m, 1H, J = 13 7.18 Hz), 2.53 (m, 1H), 0.98 (d, 3H, J = 7.18 Hz); C NMR (100 MHz, CDCl3) δ 205.4, 149.3, 148.9, 144.0, 140.4, 139.7, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 127.5, 126.9, 125.8, 125.7, 125.1, 124.8, 119.6, 119.5, 119.4, 82.9, 72.7, 57.7, 52.3, 37.8, 36.5, 19.9. NMR data match those reported in the literature.180

12.5 Aerobic copper-TEMPO oxidation experiments

12.5.1 General procedure for the oxidation of decanol with Cu(II) catalysts

1-Decanol 212 (572 μL, 3 mmol, 100 mol %) was dissolved in acetonitrile (3 mL) in a round bottom flask and internal standard o-xylene (362 μL, 1 mmol, 100 mol %) was added. CuCl2 (12 mg, 0.09 mmol, 3 mol %) was added resulting in a yellow solution, followed by an additive NaBF4 (13 mg, 0.12 mmol, 4 mol %) and bipy (14 mg, 0.09 mmol, 3 mol %), which resulted in a turquoise solution. TEMPO (14 mg, 0.09 mmol, 3

126 mol %), NMI (7 μL, 0.09 mmol, 3 mol %) and DBU (13 μL, 0.09 mmol, 3 mol %) were added and the colour of the solution turned to blue and finally to dark brown. The reaction mixture was stirred in an open vessel at rt. The deep brown colour of the solution changed gradually to greenish and finally to blue. The time of this transformation depended on the reaction kinetics of the particular catalyst. Samples (0.1 mL) were taken regularly and diluted with CH2Cl2 (1 mL) for GC analysis. The reaction was monitored by TLC as well. The optimal catalyst system was based on GC conversions and no workup was performed.

12.5.2 General procedure for the oxidation of decanol with Cu(I) catalysts

1-Decanol 212 (572 μL, 3 mmol, 100 mol %) was dissolved in acetonitrile (3 mL) in a round bottom flask and internal standard o-xylene (362 μL, 1 mmol, 100 mol %) was added. CuCl (9 mg, 0.09 mmol, 3 mol %) was added forming a yellow solution, followed by an additive NaBF4 (13 mg, 0.12 mmol, 4 mol %) and bipy (14 mg, 0.09 mmol, 3 mol %), which resulted in a turquoise solution. TEMPO (14 mg, 0.09 mmol, 3 mol %) and NMI (7 μL, 0.09 mmol, 3 mol %) were added and the colour of the solution turned to dark brown. The reaction mixture was stirred in an open vessel at rt. The deep brown colour of the solution changed gradually to a mixture of blue solution and green particles. The time of this transformation depended on the reaction kinetics of the particular catalyst.

Samples (0.1 mL) were taken regularly and diluted with CH2Cl2 (1 mL) for GC analysis. The reaction was monitored by TLC as well. The optimal catalyst system was based on GC conversions and no workup was performed.

12.5.3 Typical oxidation experiment for substrates with CuCl-catalyst

1-Decanol (1.91 mL, 10 mmol, 100 mol %) was dissolved in acetonitrile (10 mL). Copper chloride (30 mg, 0.3 mmol, 3 mol %) was added, followed by NaBF4 (44 mg, 0.4 mmol, 4 mol %), bipy (47 mg, 0.3 mmol, 3 mol %), TEMPO (47 mg, 0.3 mmol, 3 mol %) and NMI (48 μL, 0.6 mmol, 6 mol %). The deep brown reaction mixture was stirred at rt. The colour was transformed gradually from brown to green to blue. H2O (30 mL) was added, resulting in a dark blue aqueous phase and a pale pink organic phase. The aqueous layer was extracted with hexanes (3 x 20 mL). The combined organic layers were washed with

127

0.5 M H3PO4 aq. solution (30 mL), brine (30 mL), dried (Na2SO4) and concentrated. No further purification was needed.

12.5.4 Decanal (213)

1 Rf = 0.64 (20% EtOAC in hexane); H NMR (400 MHz, CDCl3): δ 9.76 (t, 1H, J = 1.86 Hz), 2.42 (td, 2H, J = 1.87, 7.36 Hz), 1.59-1.66 (m, 2H), 1.27-1.30 (m, 12H), 0.88 (t, 3H, 13 J = 6.88 Hz) C NMR (100 MHz, CDCl3): δ 202.8, 31.8, 29.31, 29.28, 29.2, 29.1, 22.6, 22.0, 14.0. NMR data match those reported in the literature.181

12.5.5 Benzaldehyde (144a)

1 Rf = 0.53 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): 1H NMR (400 MHz,

CDCl3) δ 10.07 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.67-7.70 (m, 1H), 7.56-7.60 (m, 2H); 13 C NMR (100 MHz, CDCl3): δ 191.9, 134.1, 129.2, 128.6. NMR data match those reported in the literature.181

12.5.6 (E)-hex-2-enal (216)

1 Rf = 0.52 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 9.51 (d, J = 7.88, 1H), 6.86 (dt, 1H, J = 6.79, 15.5 Hz), 6.12 (dd, 1H, J = 7.88, 15.6 Hz), 2.33 (q, 2H, J = 6.78), 13 1.51-1.60 (m, 2H), 0.97 (t, 3H, J = 7.36 Hz); C NMR (100 MHz, CDCl3): δ 193.3, 157.9, 132.3, 33.9, 20.3, 12.8. NMR data match those reported in the literature.181

12.5.7 Geranial (218)

1 Rf = 0.54 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 10.01 (d, 1H, J = 8.04), 5.90 (d, 1H, J = 8.04), 5.08-5.11 (m, 1H), 2.21-2.25 (m, 4H), 2.18 (d, 3H, J = 1.16 Hz), 13 1.71 (s, 3H), 1.63 (s, 3H); C NMR (100 MHz, CDCl3): δ 191.0, 163.5, 132.6, 127.2, 122.3, 40.4, 25.5., 25.4, 17.5, 17.3. NMR data match those reported in the literature.181

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12.5.8 Cinnamaldehyde (224)

1 Rf = 0.49 20% EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 9.70 (d, J = 7.64, 1H), 7.54-7.56 (m, 2H), 7.42-7.44 (m, 4H), 6.71 (dd, 1H, J = 16.0, 7.7 Hz); 13C NMR (100

MHz, CDCl3): δ 193.1, 152.2, 133.6, 130.7, 128.6, 128.1, 128.0. NMR data match those reported in the literature.181

12.5.9 (S)-(-)-perillaldehyde (220)

1 Rf = 0.62 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 9.46 (s, 1H), 6.83- 6.84 (m, 1H), 4.81 (t, 1H, J = 1.3 Hz), 4.76 (s, 1H), 2.45-2.53 (m, 2H), 2.09-2.28 (m, 3H), 13 1.92-1.96 (m, 1H), 1.79 (s, 3H), 1.42-1.52 (m, 1H); C NMR (100 MHz, CDCl3): δ 193.5, 150.3, 148.0, 140.9, 109.2, 40.4, 31.4, 26.0, 21.2, 20.4. NMR data match those reported in the literature.181

12.5.10 (2E,6E,8E,10E)-trideca-2,6,8,10-tetraenal (225)

1 Rf = 0.65 (20% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 9.54 (d, 1H, J = 7.88 Hz), 6.86 (dt, 1H, J = 6.9, 15.5 Hz), 6.04-6.26 (m, 5H), 5.65-5.84 (m, 2H), 1.46-1.63 (m, 13 6H), 1.03-1.08 (m, 3H) C NMR (100 MHz, CDCl3): δ 194.1, 158.6, 137.0, 133.1, 131.1, 129.3, 32.6, 25.9, 13.7. NMR data match those reported in the literature.166

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12.6 Crystal structures of selected Pf-protected compounds

12.6.1 N-Pf-Alanine Weinreb amide 3

130

12.6.2 N-Pf-Alanine methyl ketone 5

131

12.6.3 N-Pf-Alanine β-ketoester 200

132

12.6.4 (S)-Methyl 3-(9-phenyl-9H-fluoren-9-yl)-1,3-oxazinane-4-carboxylate (237)

12.6.5 (S)-tert-Butyl 3-(9-phenyl-9H-fluoren-9-yl)-1,3-oxazinane-4-carboxylate (238)

133

12.7 Relevant analytical data for N-Pf-phenethylamines 12.7.1 N-Pf-Phenethylamine 75 7.80 7.78 7.70 7.69 7.63 7.40 7.40 7.06 7.05 6.89 6.89 6.87 6.87 6.87 6.82 6.81 6.79 2.67 2.65 2.64 2.63 2.62 2.60 2.59 2.57 2.56 2.56 2.54 2.53 2.37 2.36 2.35 2.34 2.34 2.33 2.33 2.33 2.32 2.31 2.31 2.30 2.30 2.29 1.86 1.26 1.24 1.22 1.22 1.20 1.18 1.16 0.51 0.49 0.45 0.43

NHPf NHPf

0.5 ppm 0.878 1.265

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm 1.73 1.01 0.74 0.69 1.00 3.31 0.88 1.27 12.90

12.7.2 Selectivity with the BINAP-ligands

7.86 7.84 7.80 7.78 7.67 7.66 7.66 7.65 7.65 7.65 7.62 7.57 7.56 3.11 3.10 3.09 3.08 3.08 3.06 1.24 1.22 1.21 1.20 1.18 1.16 0.83 0.81 0.78 0.76 0.76 0.74 0.45 0.43

H2 NH Pd/C (R)-BINAP NH NH toluene

1.2 1.0 0.8 0.6 ppm 4.648 2.029 3.045 1.898 0.445 2.091

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm 1.00 4.65 2.03 3.05 1.90 0.45 2.09 65.03

Pd/C + (S )-B IN AP

1.35 1.30 1.25 1.20 1.15 1.10 1.05 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 ppm

4.597 2.074 3.028 1.736 0.431 1.806

134

12.7.3 UPLC separation for the N-Pf-phenethylamines

The eluent 98% (H2O + 0.1 FA) 2% (CAN + 0.1 FA), 0.5 mL/min.

12.7.4 1H NMR data for N-Pf-alanine amino alcohols

7.71 7.67 7.40 7.39 7.39 7.38 7.36 7.36 7.29 7.27 7.27 7.27 7.25 7.22 7.20 3.28 3.28 3.27 3.26 3.26 3.25 3.25 3.24 3.15 3.15 3.15 3.14 3.14 3.13 3.13 3.04 3.03 3.02 2.14 2.13 2.13 2.12 2.12 2.11 2.11 1.96 1.95 1.93 1.90 0.95 0.94 0.84 0.82 0.71 0.69 0.55 0.53

OH OH

NHPf NHPf

1.0 0.8 0.6 ppm 1.384 1.085 1.074 1.324

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.66 9.27 1.05 1.00 1.38 1.09 1.07 1.32

135

12.7.5 HPLC separation for the N-Pf-alanine amino alcohols Eluent 1% EtOH in hexanes, 0.7 mL/min.

12.7.5.1 Representative chromatogram for the reduction from the crude mixture.

136

Results for the different reducing agents.

DIBAL L-Selectride LAH 9-BBN Peak Area Ratio Area Ratio Area Ratio Area Ratio 1 13825043 2.5 1799418 2.5 1715953 2.5 11378462 77.8 2 29008539 5.2 11060871 15.5 2352708 3.4 298896 2.0 3 12084187 2.2 4512569 6.3 948653 1.4 188438 1.3 4 5555907 1.0 715562 1.0 692869 1.0 146227 1.0

12.8 Typical colour changes in the aerobic copper-TEMPO oxidation.

Observed colour changes after the addition of 1. Cu(OTf)2, 2. bipy, 3. TEMPO, 4. NMI, 5. DBU, 6. After stirring the reaction for 1h, 7. After stirring the reaction for 24h.

137

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101 Examples from allyl imidates: (a) Celter, M.; Hollis, T. K.; Overman, L. E.; Ziller, J.; Zipp, G. G. J. Org. Chem. 1997, 62, 1449-1456. (b) Metz, P.; Mues, C.; Schoop, A. Tetrahedron 1992, 48, 1071-1080. From allylic esters by transition metal catalyzed amination: (c) Togni, A.; Burckhardt, U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem. Soc. 1996, 118, 1031-1037. (d) Burckhardt, U.; Baumann, M.; Trabesinger, G.; Gramlich, V.; Togni, A. Organometallics 1997, 16, 5252-5259. (e) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089-4090. (f) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761-6762. (g) Wang, Y.; Ding, K. J. Org. Chem. 2001, 66, 3238-3241. (h) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164- 15165. (i) Tollabi, M.; Framery, E.; Goux-Henry, C.; Sinou, D. Tetrahedron: Asymmetry 2003, 14, 3329-3333. (j) Faller, J. W.; Wilt, J. C. Org. Lett. 2005, 7, 633-636. From vinyl epoxides: (k) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99-102. From allyl ethers: (l) Enders, D.; Finkam, M. Synlett 1993, 401-402.

102 Examples of asymmetric nitrene insertion reaction: (a) Na¨geli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran, M.; Mu¨ller, P. HelV. Chim. Acta 1997, 80, 1087- 1105. Based on the ene reaction: (b) Takada, H.; Nishibayashi, Y.; Ohe, K.; Uemura, S.; Baird, C. P.; Sparey, T. J.; Taylor, P. C. J. Org. Chem. 1997, 62, 6512-6518. (c) Kurose, N.; Takahashi, T.; Koizumi, T. J. Org. Chem. 1996, 61, 2932-2933. (d) Braun, H.; Felber, H.; Kresse, G.; Ritter, A.; Schmidtchen, F. P.; Schneider, A. Tetrahedron 1991, 47, 3313- 3328.

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116 Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.

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146

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123 Landis, C. R.; Hilfenhaus, P.; Feldgus, S. J. Am. Chem. Soc, 1999, 121, 8741.

124 Ohkuma, T.; Kitamura, M.; Noyori, R. New Frontiers in Asymmetric Catalysis (eds. Mikami, K.; Lautens, M.) 2007, John Wiley & Sons, Inc., pp. 1-32.

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126 (a) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072. (b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655. (c) Bueno, J. M.; Coteron, J. M.; Chiara, J. L.; Fernandez-Mayoralas, A.;.Fiandor, J. M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379.

127 (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Che. Int. Ed. 1998, 37, 2897. (b) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Hörmann, E.; McIntyre, S.; Menges, F.; Schönleber, M.; Smidt, S. P.; Wüstenberg, B.; Zimmermann, N. Adv. Synth. Catal. 2002, 345, 33.

128 Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331.

129 Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem. Int. Ed. 1998, 37, 2897.

130 Wüstenberg, B.; Pfaltz, A. Adv. Synth. Catal. 2008, 250, 174.

131 Woodmansee, D. H.; Pfaltz, A. Top. Organomet. Chem. 2011, 34, 31-76.

132 (a) Cui, X.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 14212. (b) Blackmond, D. G.; Lightfoot,A.; Pfaltz, A.; Rosner, T.; Schnider, P.; Zimmermann, N. Chirality 2000, 12, 442. (c) Cui, X.; Fan, Y.; Hall, M. B.; Burgess, K. Chem. Eur. J. 2005, 11, 6859. (d) Hou, D.-R.; Reibenspies, J.; Colacot, T. J.; Burgess, K. Chem.-Eur. J. 2001, 7, 5391. (e) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess, K. J. Am. Chem. Soc. 2001, (f) Brandt, P.; Hedberg, C.; Andersson, P.G.; Chem. Eur. J. 2003, 9, 339123, 8878. (g) Mazet, C.; Smidt, S.P.; Meuwly, M.; Pfaltz, A. J. Am. Chem. Soc. 2004, 126, 14176. (h) Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B. J. Am. Chem. Soc. 2004, 126, 16688. (i)

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133 V´azquez-Serrano, L. D.; Owens, B. T.; Buriak, J. M. Chem. Commun. 2002. 2518.

134 Roseblade, S. J.; Pfaltz, A. C. R. Chim. 2007, 10, 178.

135 Reviews considering iridium-catalyzed asymmetric hydrogenation: (a) Woodmansee, D. H.; Pfaltz, A. Top. Organomet. Chem. 2011, 34, 31-76. (b) Church, T. L.; Andersson, P. G. Coordination Chemistry Reviews, 2008, 252, 513-531.

136 Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767-796.

137 Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2012, 10, 4311-4326.

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140 See a review of Biodiversity of Sphingolipids: Pruett, S. T.; Bushnev, A.; Hagedorn, K.; Adiga, M.; Haynes, C. A.; Sullards, M. C.; Liotta, D. C.; Merrill, A. H. Jr. Journal of Lipid Research, 2008, 49, 1621-1639.

141 Chester, M. A. Eur. J. Biochem. 1998, 257, 239-298.

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143 Karlsson, K.-A. Lipids, 1970, 5, 878.

144 An introductionary review on sphingolipid metabolism and analysis: Chen, Y. Liu, Y.; Sullards, M. C.; Merrill Jr., A. H. Neuromol. Med. 2010, 12, 306-319.

145 (a) Shapiro, D.; Segal, H. J. Am. Chem. Soc. 1954, 76, 5894-5895. (b) Shapiro, D.; Segal, H.; Flowers, H. M. J. Am. Chem. Soc. 1958, 80, 1194-1197.

146 Grob, C. A.; Gadient, F. Helv. Chim. Acta 1957, 40, 1145-1156.

147 See a review of recent literature of sphingosine synthesis, and the references therein: Koskinen, A. M. P.; Koskinen, P. M. Synthesis, 1998, 1075-1091.

148

148 (a) Kiso, M.; Nakamura, A.; Tomita, Y.; Hasegawa, A. Carbohydr. Res. 1986, 158, 101-111. (b) Schmidt, R. R.; Zimmermann, P. Tetrahedron Lett. 1986, 27, 481-484. (c) Zimmermann, P.; Schmidt, R. R. Liebigs. Ann. Chem. 1988, 663-667.

149 (a) Bennet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494. (b) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752-3757. (c) Julina, R.; Hertzig, T.; Bernet, B.; Vasella, A. Helv. Chim. Acta 1986, 69, 368-373. (d) Shibuya, H.; Kawashima, K.; Ikeda, M.; Itagawa, I. Tetrahedron Lett. 1989, 30, 7205-7208.

150 Schmidt, R. R.; Kläger, R. Angew. Chem. Int. Ed. 1982, 94, 215-216; Angew. Chem. Int. Ed. Engl. 1982, 21, 210-211.

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152 (a) Newman, H. J. Am. Chem. Soc. 1973, 95, 4096-4098. (b) Tkaczuk, P.; Thornton, E. R. J. Org. Chem. 1981, 46, 4393-4398. (c) Mori, K.; Funaki, Y. Tetrahedron 1985, 41, 2379-2382. (d) Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320-5327. (e) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A. J. Chem. Soc. Chem. Commun. 1988, 10. (f) Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta, D. Tetrahedron Lett. 1988, 29, 3037-3040. (g) Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395-4398. (h) Radunz, H. E.; Devant, R. M.; Eiermann, V. Liebigs Ann. Chem. 1988, 1103. (i) Herold, P. Helv. Chim. Acta 1988, 71, 354-362. (j) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990, 55, 1439-1446. (k) Polt, R.; Peterson, M. A. Tetrahedron Lett. 1990, 31, 4985-4986.

153 (a) Gulavita, N. K.; Scheuer, P. J. J. Org. Chem. 1989, 54, 366-369. (b) Jiménez, C.; Crews, P. J. Nat. Prod. 1990, 53, 978-982. (c) Jares-Erijman, E. A.; Bapat, C. P.; Lithgow-Berteloni, A.; Rinehart, K. L.; Sakai, R. J. Org. Chem. 1993, 58, 5732-5737. (d) Sata, N.; Fusetani, N. Tetrahedron Lett. 2000, 41, 489-492. (e) Kobayashi, J.; Ishibashi, M. Heterocycles 1996, 42, 943-970.

154 Garrido, L.; Zubía, E.; Ortega, M. J.; Naranjo, S.; Salvá, J. Tetrahedron 2001, 57, 4579-4588.

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156 Jacobs, W. C.; Christmann, M. Synlett. 2008, 247-251.

157 Selkälä, S. Total synthesis of Amaminol A, 2003, TKK Dissertations, Organic Chemistry Report 2/2003, ISBN 951-22-6721-7.

149

158 Selkälä, S. A.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005, 1620-1624.

159 Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616- 11617.

160 For reviews, see: (a) (a) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854–3867. (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420. (c) Sheldon, R. A.; Arends, I. W. C. E.; ten Brink, G.-J.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774– 781.

161 For leading references, see: (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750–6755. (b) Schultz, M. J.; Park, C. C.; Sigman, M. S. Chem. Commun. 2002, 3034–3035. (c) ten Brink, G.-J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G.; Sheldon, R. A. Adv. Synth. Catal. 2003, 345, 1341–1352. (d) Mueller, J. A.; Goller, C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724–9734. (e) Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org. Chem. 2005, 70, 3343–3352. (f) Bailie, D. S.; Clendenning, G. M. A.; McNamee, L.; Muldoon, M. J. Chem. Commun. 2010, 7238–7240.

162 For leading references, see: (a) Lenz, R.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1997, 3291–3292. (b) Hasan,M.; Musawir, M.; Davey, P. N.; Kozhevnikov, I. V. J. Mol. Catal. A 2002, 180, 77–84. (c) Mizuno, N.; Yamaguchi, K. Catal. Today 2008, 132, 18– 26.

163 (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400−3420. (b) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901−16910. (c) Hoover, J. M.; Steves, J. E.; Stahl, S. S. Nat. Protoc. 2012, 7, 1161−1166. (d) Hoover, J. M.; Stahl, S. S. Org. Synth. 2013, 90, 240−250. (d) Sheldon, R. A.; Arends, I. W. C. E.; Brink, G-J. T.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774-781. (e) Gamez, P.; Arends, I. W. C. E.; Reedijk, J.; Sheldon, R. A. Chem. Commun. 2003, 2414−2415. (f) Gamez, P.; Arends, I. W. C. E.; Sheldon, R. A.; Reedijk, J. Adv. Synth. Catal. 2004, 346, 805−811.

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165 Semmelhack, M. F.; Schmid, C. R.; Cortés, D. A.; Chou, C. S. J. Am. Chem. Soc. 1984, 106, 3374-3376.

166 Kumpulainen, E. Total synthesis of Amaminols, Doctoral Dissertation 2010, TKK Dissertations 219, ISBN 978-952-60-3092-0.

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168 a) Hoover, H. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357-2367. b) Hoover, H. M.; Ryland, B. L.; Stahl, S. S. ACS Catal. 2013, 3, 2599-2605. c) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901-16910. c) Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742-15745. d) Greene, J. F.; Hoover, J. M.; Mannel, D. S.; Root, T. W.; Stahl, S. S. Org. Proc. Res. Dev. 2013, 17, 1247-1251.

169 (a) Markó, I. E.; Gautier, A.; Dumeunier, R.; Doda, K.; Philippart, F.; Brown, S. M.; Urch, C. J. Angew. Chem. Int. Ed. 2004, 43, 1588-1591. (b) Markó, I. E.; Gautier, A.; Mutonkole, J.-L.; Dumeunier, R.; Ates, A.; Urch, J. J.; Brown, S. M. J. Organomet. Chem. 2001, 624, 344. (c) Markó, I. E.; Gautier, A.; Chellé-Regnaut, I.; Giles, P. R.; Tsukazaki, M. Urch, C. J.; Brown, S. M. J. Org. Chem. 1998, 63, 7576.

170 Kumpulainen, E. T. T.; Koskinen, A. M. P. Chem. Eur. J. 2009, 15, 10901-10911.

171 (a) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901-16910. (b) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854–3867.

172 Rabeah, J.; Bentrup, U.; Stöβer, R.; Brückner, A. Angew. Chem. Int. Ed. 2015, 54, 11791-11794.

173 Liao, Q.; Xi, C.-J. Chem. Res. Chinese U. 2009, 25, 861-865.

174 Jamison, T. F., Lubell, W. D.; Dener, J. M.; Krisché, M. J.; Rapoport, H. Org. Syntheses, 1998, 9, 220-225.

175 Paleo, M. R.; Calaza, M. I.; Sardina, F. J. J. Org. Chem. 1997, 62, 6862-6869.

176 1H NMR data reported as it should be. The sample contained minor impurities in the aromatic region.

177 Krasovsky, A.; Knochel, P. Synthesis, 2006, 5, 0890-0891.

178 HRMS analysis results were not achieved in time for the thesis.

179 NMR data for a mixture of diastereomers.

180 Sauerland, S. J. K.; Castillo-Mendez, J. A.; Naettinen, K.; Rissanen, K.; Koskinen, A. M. P. Synthesis, 2010, 5, 757-762.

151

181 This material is commercially available.

152

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