Asymmetric Hydrogenation of Functionalized Olefins Using N,P-Ligated Iridium Complexes

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 983

TAIGANG ZHOU

ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-554-8503-0 UPPSALA urn:nbn:se:uu:diva-182648 2012 Dissertation presented at Uppsala University to be publicly examined in A1:107A, BMC, Husargatan 3, Uppsala, Thursday, November 29, 2012 at 10:15 for the degree of Doctor of Philosophy. The examination will be conducted in English.

Abstract Zhou, T. 2012. Asymmetric Hydrogenation of Functionalized Olefins Using N,P-Ligated Iridium Complexes. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 983. 59 pp. Uppsala. ISBN 978-91-554-8503-0.

Transition-metal-catalyzed asymmetric hydrogenation is one of the most efficient, straightforward, and well-established methods for preparing enantiomerically enriched compounds. Over the past decades, significant progress has been made with iridium, rhodium and ruthenium complexes to asymmetric hydrogenate a selection of olefins, such as, α,β- unsaturated carboxylic acid derivatives, ketones, imines and phosphonates. Although these metals have been applied successfully in the hydrogenation of olefins, they differ in their substrate tolerance. Ruthenium and rhodium based catalysts require a coordinating group in the vicinity of the C=C bond. However, iridium based catalysts do not require this coordinating group, hence, asymmetric hydrogenation with iridium catalysts has been widely used for both functionalized and unfunctionalized olefin substrates. This thesis focuses on expanding the substrate scope for asymmetric hydrogenation using chiral N,P-ligated iridium catalysts. Papers I and II investigate the asymmetric hydrogenation of prochiral N-heterocyclic compounds prepared by ring-closing metathesis using the iridium catalysts developed in our group. These substrates are interesting as they bear resemblance to pharmaceutically active compounds and therefore have tremendous value in medicinal chemistry. Excellent enantioselectivities, up to >99% ee and conversions were obtained. In papers III and IV we synthesized many unsaturated acyclic and cyclic sulfones with varying substitution patterns. The sulfones were subjected to hydrogenation using our N,P-ligated iridium catalysts, producing the chiral sulfone products in high enantiomeric excess (up to 99% ee). This methodology was combined with the Ramberg- Bäcklund reaction, offering a novel route to chiral allylic and homoallylic compounds. In addition to obtaining these chiral compounds in good yields, no decrease in enantiomeric excess was observed after the Ramberg-Bäcklund reaction. This strategy has been applied in the preparation of the chiral building block for renin inhibitors.

Keywords: asymmetric hydrogenation, iridium, Ramberg-Bäcklund reaction, sulfone, heterocycle, preclamol, remikiren

Taigang Zhou, Uppsala University, Department of Chemistry - BMC, Synthetical Organic Chemistry, Box 576, SE-751 23 Uppsala, Sweden.

ISSN 1651-6214 ISBN 978-91-554-8503-0 urn:nbn:se:uu:diva-182648 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182648)

To my parents

Scientific advisor

Prof. Pher G. Andersson Department of Chemistry-BMC Uppsala University

Faculty opponent

Prof. Hans Adolfsson Department of Organic Chemistry Stockholm University

Examination committee

Prof. Nina Kann Department of Chemical and Biological Engineering Chalmers University of Technology

Prof. Uno Mäeorg Institute of Chemistry University of Tartu

Prof. Ola F. Wendt Department of Chemistry Lund University

Assist. Prof. Peter Dinér Department of Chemistry-BMC Uppsala University

List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I J. Johan Verendel; Taigang Zhou; Jia-Qi Li; Alexander Paptchikhine; Oleg Lebedev and Pher G. Andersson. High Flex- ible Synthesis of Chiral Azacycles via Iridium-Catalyzed Hy- drogenation. Journal of the American Chemical Society, 2010, 132, 8880- 8881

II J. Johan Verendel; Jia-Qi Li; Xu Quan; Byron Peters; Taigang Zhou; Odd R. Gautun; Thavendran Govender and Pher G. An- dersson. Chiral Hetero- and Carbocyclic Compounds from the Asymmetric Hydrogenation of Cyclic Alkenes. Chemistry-A European Journal, 2012, 18, 6507-6513

III Taigang Zhou; Byron Peters; Matias F. Maldonado; Thaven- dran Govender and Pher G.Andersson. Enantioselective Synthe- sis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogena- tion: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds. Journal of the American Chemical Society, 2012, 134, 13592- 13595

IV Taigang Zhou; Byron Peters; Alban Cadu and Pher G. Anders- son. A Highly Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: An Elegant Method for the Synthesis of Imperanene. (Manu- script in preparation, supporting information)

Reprints were made with permission from the respective publishers.

Contribution report The author wishes to clarify his contribution to the papers I-IV in this thesis

I Performed a significant part of the experimental work and development of new methods for chiral separation of the products. Contributed in part to the interpretation of results and took part in the writing of the supporting information.

II Performed a small part in the synthesis of substrates, contributed in part to the interpretation of the results mainly concerning N-heterocyclic substrates.

III Performed most experimental work and development of new methods for chiral separation of the products. Contributed significantly to the interpretation of the results and wrote the entire paper.

IV Performed a significant part of the experimental work and development of new methods for chiral separation of the products. Contributed significantly to interpreting the results and writing the manuscript.

Contents

1 Introduction ...... 11 1.1 History of Chirality ...... 11 1.2 Chirality and Life ...... 11 1.3 Preparation of Chiral Compounds ...... 13 1.3.1 Chiral Pool ...... 13 1.3.2 Chiral Resolution ...... 14 1.3.3 Asymmetric Synthesis, Catalysis and Hydrogenation ...... 15 2 Research Performed in this Thesis ...... 20 3 Asymmetric Hydrogenation of N-Heterocyclic Olefins...... 22 3.1 Introduction ...... 22 3.2 Synthesis of N-Heterocyclic Olefins ...... 24 3.3 Hydrogenation of N-Heterocyclic Olefins ...... 26 3.4 Conclusions ...... 31 4 Asymmetric Hydrogenation of Unsaturated Sulfones ...... 32 4.1 Introduction ...... 32 4.2 Synthesis of Unsaturated Sulfones ...... 34 4.3 Hydrogenation of Unsaturated Sulfones ...... 35 4.4 Application ...... 42 4.4.1 Preparation of Chiral Allylic and Homoallylic Compounds via the Ramberg-Bäcklund Reaction ...... 42 4.4.2 Asymmetric Synthesis of Chiral Building Blocks for Renin Inhibitors ...... 44 4.4.3 Selectivity Model ...... 47 4.5 Conclusions ...... 49 5 Conclusion and Outlook ...... 50 Acknowledgements ...... 52 Summary in Swedish ...... 54 References ...... 56

Abbreviations

* Stereogenic center Ac Acetyl Ar Aryl - BArF Tetrakis[3,5bis(trifluoromethyl)phenyl]borate Cat. Catalyst Cbz Carbobenzyloxy COD Cyclooctadiene Conv. Conversion Cy Cyclohexyl DABCO 1,4-Diazabicyclo[2.2.2]octane DFT Density Functional Theory DIBAL Diisobutylaluminium hydride DKR Dynamic Kinetic Resolution DMAP 4-Dimethylaminopyridine DNA Deoxyribonucleic acid ee Enantiomeric excess Et Ethyl GC Gas Chromatography HPLC High Performance Liquid Chromatography iPr Isopropyl LAH Lithium aluminium hydride mCPBA meta-Chloroperoxybenzoic acid Me Methyl n-BuLi n-Butyllithium NMR Nuclear Magnetic Resonance o.n. Overnight Pd/C Palladium on carbon Ph Phenyl rac. Racemic r.t. Room Temperature tBu tert-Butyl RCM Ring closing metathesis RNA Ribonucleic acid TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran

Catalysts mentioned in this thesis:

1 Introduction

1.1 History of Chirality Chirality is one of the most amazing natural phenomena. There are many molecules that exist in two forms, like our hands, which are mirror-images of each other (left and right) and cannot be superimposed onto their mirror images. This property is referred to as chirality, which is derived from the Greek word χειρ(cheir), meaning hand, and these two forms are called enantiomers. Molecular chirality was first discovered in 1848 by French biologist and chemist Louis Pasteur.1 One of his contributions was the separation of left and right-handed crystals of sodium ammonium tartrate from one anoth- er with a pair of tweezers (Figure 1.1). He found that in solution left handed crystal rotated light to the left, the right handed crystal to the right, while for an equal mixture of the two crystals in solution, the net rotation of light was zero. This was the first demonstration that chirality existed in molecules. sodium ammonium tartrate

COO-Na+ COO-Na+ HO H H OH H OH HO H - + - + COO N H4 COO N H4 left-handed crystals right-handed crystals Figure 1.1 Structure of sodium ammonium tartrate.

1.2 Chirality and Life The molecules that make up living organisms (sugars, amino acids, pro- teins, enzymes, DNA and RNA) are all chiral. Following on from the lock- and-key hypothesis proposed by Hermann Emil Fischer,2 comes drug receptor theory, which is employed to explain the action of drugs in living sys- tems (Figure 1.2). As drug receptors are protein molecules, they are inher- ently chiral. Therefore, these receptors are extremely selective and have different interactions with the two enantiomers of a chiral drug. The active enantiomer binds tightly to the receptor active site and will express pharmacological activity.3 The other enantiomer binds weakly to the receptor active site and may result in undesired effects or, alternatively, no effect will occur (see Table 1.1).4

11 In 1992 the Food and Drug Administration (FDA) in the USA issued a policy statement for the development of new stereoisomeric drugs. They strongly urged companies to evaluate both racemates and enantiomers for new drugs and manufacture only the active enantiomer of a chiral drug.5 In the last 10 years, approximately 80% of “small-molecule” type drugs approved by the FDA were chiral, of which 75% were approved as a single enantiomer. For example, of the top 10 best-selling drugs in the USA in 2011, eight of them are chiral of which seven are manufactured and sold in a single enantiomeric form (Table 1.2).6 This emphasizes that single- enantiomer compounds have become a major focus for pharmaceutical companies. D enantiomers D

A C C A B B

a c a c b b

receptor (a) active enantiomer (b) inactive enantiomer tight binding with receptor active site weak binding with receptor active site Figure 1.2 Two enantiomers of a chiral drug binding to a receptor3

Table 1.1 Examples of chiral drugs and bioactivity4

Chiral drug Bioactivity F

(S)-Citalopram has the desired anti-depressant effect Citalopram N ! O (R)-Citalopram is the inactive form

! OH (S)-Naproxen is an anti-inflammatory Naproxen O (R)-Naproxen causes liver damage O

O (S)-Penicillamine is a chelator drug ! Penicillamine HS OH (R)-Penicillamine is toxic NH2

12 Table 1.2 Top 10 Best-Selling Drugs in US in 20116 Rank Product Active Ingredient Manufactured as 1 Lipitor Atorvastatin Single enantiomer 2 Plavix Clopidogrel Single enantiomer 3 Nexium Esomeprazole Single enantiomer 4 Abilify Aripiprazole Achiral 5 Advair Diskus Fluticasone/salmeterol Single enantiomer, racemate 6 Seroquel Quetiapine Achiral 7 Singulair Montelukast Single enantiomer 8 Crestor Rosuvastatin Single enantiomer 9 Cymbalta Duloxetine Single enantiomer 10 Humira Adalimumab Antibody

1.3 Preparation of Chiral Compounds Chiral compounds can be obtained mainly by three different approaches: chiral pool, chiral resolution and asymmetric synthesis.

1.3.1 Chiral Pool The use of the “chiral pool” in the preparation of chiral compounds repre- sents the easiest approach.7,8 It starts with an enantiomerically pure compound obtained from a natural source, such as an amino acid. One such example is oseltamivir phosphate (Tamiflu®), which is an antiviral drug. It is synthesized from the chiral precursor (-)-shikimic acid, which is extracted from Chinese star anise (Scheme 1.1).9 However, there are many factors that limit the chiral pool approach. First, it can be difficult to find a suitable enantiomerically pure starting material from nature; and second, there is often limited availability of some enantiomerically pure starting materials for large-scale production. Since 1990, there has been a decrease from 80% to 25% in the number of chiral drugs produced via the chiral pool strategy.10

13 COOEt COOEt

O NH +H PO - O 3 2 4 NR NHAc

Star anise oseltamivir phosphate 30 kg dried plant

COOH COOEt COOEt

HO OH O OMs O O OH O 1kg (-)-shikimic acid Scheme 1.1 Synthesis of oseltamivir phosphate from chiral pool (-)-shikimic acid.

1.3.2 Chiral Resolution The separation of racemic mixtures to obtain pure enantiomers is called chiral resolution. There are various methods, including kinetic resolution, bio-resolution and resolution by chromatography or crystallization. Chiral resolution is still an important technique for the preparation of enantiomerically pure compounds. However, one disadvantage of chiral resolution is that the maximum yield obtained is 50%, as only the desired enantiomer is utilized while the other is not. Although, sometimes the undesired enantiomer can be racemised and the resolution process repeated. The process of successive racemization and resolution is referred to as Dynamic Kinetic Resolution (DKR). One of the methods, among many, for the preparation of the chiral drug (S)-duloxetine (Cymbalta®), a serotonin and noradrenaline reuptake inhibitor for the treatment of major depressive disorder, involves DKR.11-13 For example, in 2011, Bäckvall and co-workers developed the dynamic kinetic resolution of racemic secondary alcohols 1 using candida Antarctica lipase B (CALB, N435) and a ruthenium catalyst to give β-cyano acetate 2 (an application, shown in Scheme 1.2) in high yield and excellent enantioselectivity.14 Chiral resolution is still an important technique in industry.

14 Ph Ph Ph Ph Ph CALB Ru OC Cl OAc O OH CO S CN S S CN OAc tBuOK racemate 1 (R)-enantiomer 2 87% yield, 98% ee

OH OH O O S S N N O S H H N H

(R)-Duloxetine

O S N H (S)-Duloxetine Scheme 1.2 Synthesis of (S)-Duloxetine and (R)-Duloxetine via Dynamic Kinetic Resolution.

1.3.3 Asymmetric Synthesis, Catalysis and Hydrogenation Asymmetric synthesis involves the creation of a chiral center by asymmetric induction. It is more efficient and accessible than other methods mentioned and has become widely used by the pharmaceutical industry. There exist many catalytic asymmetric methods to prepare enantiomerically pure compounds.15-19 Amongst these methodologies, transition-metal- catalyzed asymmetric hydrogenation has a particularly important role. It is one of the most efficient, straightforward, and well-established methods for preparing enantiomerically pure compounds.20-27 A number of chiral phar- maceuticals and agrochemicals such as L-DOPA, (S)-metolachlor, and (+)- biotin are manufactured on an industrial scale involving at least one transition-metal-catalyzed asymmetric hydrogenation step in their preparation (Scheme 1.3).28-30

15 O AcO AcO NHAc Ru/DIPAMP,H2 NHAc P H2O,IPA O COOH O COOH H O P + HO H3O NH2 HO COOH H DIPAMP L-DOPA

O O O Cl N [Ir(COD)Cl]2 HN N P Ligand, H 2 Fe 2

Ligand 80% ee (S)-Metolachlor

O O O P(t-Bu) PPh2 2 NHN Ru-Ligand NHN NHHN Ph Ph H H H H H OH 2 Fe O O O O S O 99 de (+)-Biotin Ligand Scheme 1.3 Use of asymmetric catalysis in the preparation of L-DOPA, (S)- Metolachlor and (+)-Biotin.

In 1964 Geoffrey Wilkinson (Nobel Prize in chemistry 1973) discovered the first highly active homogeneous hydrogenation catalyst, RhCl(PPh3)3 (Figure 1.3).31 R. Coffey also discovered this catalyst around the same time while he was working at Imperial Chemical Industries. Several years later, Knowles32 and Horner33 reported the first homogeneous asymmetric hydrogenation using a rhodium complex, replacing the triphenylphosphine ligands with chiral monophosphines, but these new catalysts had poor enantioselectivities. In the early 1970s, Kagan reported the first diphosphine ligand (DI- OP) for Rh-catalyzed asymmetric hydrogenation with an enantioselectivity of up to 80 % ee.34 Knowles used the chiral phosphine ligand (DIPAMP) in combination with rhodium. This resulted in the successful production of L- DOPA on an industrial scale via asymmetric hydrogenation using this new complex (Figure 1.3). Knowles was awarded the Nobel Prize in 2001 for this remarkable work. 35-37 Noyori was jointly awarded the Nobel Prize in 2001,38 for his work towards the discovery of the BINAP-Ru catalysts,39 and for the hydrogenation of a variety of substrates. Noyori’s system was not confined only to olefin substrates, it was shown that ketones could also be reduced in excellent enantioselectivities.40 Following the remarkable work by Knowles and Noyori, thousands of chiral phosphine ligands with rhodium or ruthenium for asymmetric hydrogenation were developed. With rhodium and ruthenium catalysts, excellent results have been achieved with a wide range of substrates.

16 The mechanism of rhodium and ruthenium catalyzed hydrogenation of functionalized olefins has been well established by Halpern, Noyori and others.41- 43 For example, N-acylated dehydroamino esters were hydrogenated by Rh complex (Scheme 1.4). In this catalytic cycle, cationic Rh(I) 3 first coordinates with the enamide substrate to form intermediate 4, which then undergoes oxidative addition into H2 to generate a Rh(III) dihydride species 5. The olefin then does a migratory insertion to give a five-membered organorhodi- um hydride 6. The last step is the reductive elimination of 6, releasing the hydrogenation product and cationic Rh(I) 3 species. Ruthenium catalysts also follow a similar catalytic cycle. Both rhodium and ruthenium catalysts require the substrate to have a coordinating group, e.g. an ester or amide, in the vicinity of the C=C bond. When these catalysts are used to hydrogenate unfunctionalized olefins, they usually show low reactivity and enantioselectivity.

Ph2 P (S)-BINAP Ru P Noyori Ph2 PPh3 Ph3P Rh Cl Ph3P O

Wilkinson's Catalyst P (R,R)-DIPAMP Rh Knowles and Homer O P

PF 6 BArF F3C O Cy P N 3 Ir B R1 P N 2 Ir 4 R F3C

BArF Crabtree's Catalyst Pfaltz's Catalyst

Figure 1.3 Transition metal catalysts in asymmetric hydrogenation.

17 COOR1 P H2 2S ! Rh NH P O R2 4

R1OOC NHCOR2

COOR1 H P S P Rh ! Rh ! NH P S P H O R 3 5 2

R1OOC ! NHCOR2

H S COOR1 S P ! ! Rh NH P S H O R2 S = Solvent 6 Scheme 1.4 Catalytic cycle for Rh-catalyzed hydrogenation of N-acylated dehydroamino esters.

In 1979 Crabtree developed an iridium catalyst that was highly active for the hydrogenation of alkenes.44 However, the limitation of Crabtree’s catalyst was the competitive deactivation in the presence of hydrogen to form inactive hydride-bridged trinuclear complexes. In 1997, Pfaltz and co- workers modified the Crabtree catalyst with chiral PHOX ligands45 and later - - replaced the PF6 anion with the weakly coordinating and bulky BArF coun- terion,46 which overcame the deactivation problem. These catalysts have shown excellent enantioselectivities in the hydrogenation of a wide range of unfunctionalized olefins. Iridium-catalyzed asymmetric hydrogenation has been successfully applied to various olefins and excellent results have been achieved. There are many studies on the mechanism of the iridium-catalyzed asymmetric hydrogenation, however the details of the exact mechanism are uncertain. In 2003, Brandt, Hedberg, and Andersson conducted a DFT and kinetic study of the mechanism of iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins.47 Based on the results from this study, a mechanism was proposed, proceeding via an Ir(III)/Ir(V) pathway (Scheme 1.5). Burgess and co-workers also reported a DFT study of iridum-catalyzed hydrogenation reactions of trisubstituted arylalkenes via the Ir(III)/Ir(V) pathway.48 Their results show that the predicted configuration of the hydrogenation product by calculations are in agreement with the experimental result. In 2004, Chen and Dietiker reported the gas-phase hydrogenation of sty- rene by means of electrospray ionization tandem mass spectrometry and

18 using a catalyst developed by the Pfaltz group.49 Their results strongly sug- gest that the mechanism is likely to follow a Ir(I)/Ir(III) pathway (Scheme 1.5). Both the Ir(I)/Ir(III) and Ir(III)/Ir(V) cycles start from the active catalyst 7. In the Ir(I)/Ir(III) cycle, the olefin coordinates to 7 by solvent dis- placement to give intermediate 8. Then the olefin does a migratory insertion to give intermediate 9. Subsequently, 9 undergoes reductive elimination to release the hydrogenated product. In the Ir(III)/Ir(V) cycle, the olefin and H2 coordinate to 7 by solvent displacements to give intermediate 11. Then the olefin undergoes migratory insertion into the Ir-H bond while the H2 undergoes an oxidative addition onto iridium generating intermediate 12. The last step is a reductive elimination to release the hydrogenated product.

H H 2S H2 H H N P N P Ir Ir S S H H H H 10 13

S S S H H N P N P N P N P Ir(I)/Ir(III) Ir(III)/Ir(V) Ir Ir Ir Ir S H S H H H H H H S 7 7 H 9 12

S HH H S N P 2 N P Ir Ir H H H H S 8 2S 11 S = Solvent Scheme 1.5 Two possible catalytic cycles for the N,P-ligated iridium hydrogenation of olefins.

Due to the differences in iridium catalysts, substrates and conditions used in the experimental and computational study of iridium-catalyzed asymmetric hydrogenation, it is difficult to draw definitive conclusions on the mechanism.

19 2 Research Performed in this Thesis

Former group members have focused their research on the development of chiral N,P-ligated iridium catalysts. For example, iridium catalysts with oxa- zoline, imidazole or thiazole ligands have been synthesized50-55 and evaluated in the asymmetric hydrogenation of a number of standard substrates (Scheme 2.1).

P(o-tol)2 PPh2

NN NN PPh2 P(o-tol)2 N N Ph N Ph N Ph Ph O Ph S

BAr P(o-tol)2 F P(o-tol)2 N R P N N 2 Ir N N Ph O S

P(o-tol)2 PPh2 N N N Ph PPh2 O PPh2 O S N N Ph Ph O S Scheme 2.1 Chiral N,P-ligated iridium catalysts developed in our group

The aims of this thesis are to further study and expand the substrate scope. Chiral N-heterocyclic compounds and chiral sulfones are two important classes of compounds in medicinal and organic chemistry. Chiral N-heterocyclic compounds have shown important biological activity and chiral sulfones are useful synthetic intermediates for the preparation of natural products and pharmaceutical compounds.

As a result, we have expanded the substrate scope of our iridium catalysts into N-hetercocylic compounds and unsaturated sulfones.

20 Summary of the work performed in this thesis: The substrate scope has been expanded to various N-heterocyclic olefins and unsaturated sulfones with different ring sizes and substituents, and the new substrate scope has been hydrogenated by our chiral N,P-ligated iridium catalysts. The Ramberg-Bäcklund reaction was explored as a novel route to convert chiral sulfones to chiral allylic and homoallylic compounds.

21 3 Asymmetric Hydrogenation of N- Heterocyclic Olefins.

3.1 Introduction Chiral N-heterocycles, such as pyrrolidines, piperidines and azepanes,16,56 are important sub-units of many natural products and pharmaceutically active compounds (Figure 3.1).57,58 For example the natural alkaloid (-)- lobeline, isolated from Lobelia inflate (Indian tobacco), has been shown to exhibit a variety of biological activities, including an emetic and a tobacco cessation properties.59 (+)-Dexmethylphenidate, sold as Focalin XR by No- vartis, is a central nervous system stimulant and is used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children.60 MK-482761 and Veliparib (ABT-888)62 are inhibitors of poly- (ADP-ribose) polymerase (PARP) and are used for cancer treatment.

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

(-)-Lobeline (-)-Spectaline (+)-Dexmethylphenidate

H H N Me N N HN H2N N N O HO N O

H2N MK-4827 Preclamol Veliparib (ABT-888) Figure 3.1 Biologically active chiral N-heterocycles compounds

Therefore, preparation of chiral N-heterocyclic compounds has received much attention from researchers and pharmaceutical companies. Of the top 200 highest selling drugs in 2010, eighteen possess chiral N-heterocyclic fragments.63 One of the most common routes to access chiral N-heterocyclic compounds is by hydrogenation of heterocyclic compounds. In 1987 Murata and co-workers reported the first example of asymmetric hydrogenation of heterocyclic compounds,64 using Rh[(S,S)-DIOP]H as the catalyst: 2- methylquinoxaline was hydrogenated to 2-methyl-1,2,3,4- tetrahydroquinoxaline in 3% ee (Scheme 3.1). However, asymmetric hydro-

22 genation of heteroaromatic compounds has many limitations. The high sta- bility of heterocyclic olefins usually requires higher temperatures and pres- sures. Therefore, asymmetric hydrogenation of N-heterocyclic olefins has become an important focus. In 2009, Zhou and co-workers developed chiral iridium complexes of spiro-phosphoramidites for asymmetric hydrogenation of N-heterocycles olefins, however only five-membered N-heterocycles were hydrogenated in good to excellent enantioselectivities (up to 97% ee) while six membered N-heterocycles resulted in poorer enantioselectivity (21% ee, Scheme 3.1). 65 In this initial study, N,P-ligated iridium catalysts were applied to the asymmetric hydrogenation of five-, six-, and seven-membered N- heterocyclic olefins. H H N N O Rh(S,S-DIOP)H / EtOH PPh2 H (7 atm), r.t. N 2 N O PPh2 H H Murata, 1987 ee: 3% (S,S)-DIOP

R2 R2 N N R1 R1 Ph * O [Ir(COD)Cl]2 / L* P N up to 97% ee O I2, H2 (1 atm), THF, r.t. N Ph N Ph Ph * L Zhou and co-workers, 2009 ee: 21%

R1 R1 N N

* n R2 n R2 n=0,1,2 [Ir(COD)Cl]2 / L* n=0,1,2 H ,CH Cl , r.t. Ts Ts 2 2 2 Ts N N N

* R R R This work, 2010 Scheme 3.1 Examples of chiral N-heterocyclic compounds prepared from asymmetric hydrogenation

23 3.2 Synthesis of N-Heterocyclic Olefins The N-heterocyclic olefins were readily prepared using ring-closing metathesis (RCM).66 For five- and six-membered N-heterocyclic olefins, cou- pling of the respective allyl bromide with the corresponding sulfonamide resulted in various substitution patterns of N-protected aminodienes. For the preparation of seven-membered N-heterocyclic olefins, mesylates were used to supply the acyclic sulfonamide dienes after treatment of the mesylates with the sulfonamide and NaH in DMF. Using the same conditions as reported by Nolan and Clavier,66 ring-closing metathesis of the acyclic sulfonamide dienes produced the corresponding N-heterocyclic substrates. The five-membered N-heterocyclic olefins (Table 3.1, entries 1-8) were obtained in good yields at room temperature using Grubbs 2nd generation catalyst67,68 (Scheme 3.2) regardless of the protecting group. The six-membered rings were also isolated in good to excellent yields (entries 9-21). However lower yields were obtained for the seven-membered ring substrates. A contributing factor to the poor yields is the isomerization of the double bond producing significant amounts of six-membered ring compounds. R' R R' N Br + HN n K R Acetonitrile2 CO 3 m=1, n=0 R' R' Grubbs 2nd N N n m 4 mol% CH Cl R 2 2 R m=1, n=1 R' R' R' NaH N N R R' DMF N OMs + HN m n R R R m=1,n=2 m=2,n=1 m=3,n=0 NN R = Alkyl or aryl Cl R' = Ts or Cbz Ru Cl Ph P

nd Grubbs 2 Generation Catalyst Scheme 3.2 RCM approach to N-heterocyclic olefins

24 Table 3.1 Synthesis of five-, six- and seven-membered N-heterocyclic olefins by RCMa entry substrate product R yieldb (%)

1 14a 15a Me 70 Ts Ts 2 14b N 15b N Bu 75 3 14c 15c Bn 53 R 4 14d 15d R Ph 92 Cbz Cbz N N 5 16 17 Ph 90

R R 6 18a 19a Me 89 7 18b 19b i-Pr 87 8 18c 19c Bu 62 9 18d 19d Bn 82

10 18e Ts 19e C6H5 86 Ts N 11 18f 19f N 4-MeC6H4 77

12 18g 19g 3-MeC6H4 98 R R 13 18h 19h 4-MeOC6H4 52

14 18i 19i 3-MeOC6H4 87

15 18j 19j 4-F3CC6H4 91

16 18k 19k 4-ClC6H4 72

17 18l 19l 4-BrC6H4 82 Ts Ts N N 18 20 21 Ph 52 R R

Ts Ts N N 19 22 23 Ph 60

R R Ts Ts N N 20 24 25 Ph 55 R R a b Reaction conditions: 4% mmol catalyst loading, 0.1M substrate in CH2Cl2, r.t. Isolated yields.

25 3.3 Hydrogenation of N-Heterocyclic Olefins The six-membered N-heterocyclic substrates 19e and 19a possessing phenyl and methyl substituents respectively, were chosen as model substrates. We screened our library of iridium complexes (p 7) A1, A5, B, C, D2, E2 and F against 19e and 19a in the hydrogenation. The results are presented in Table 3.2. Good to excellent results were obtained with most catalysts. Notably, thiazole catalysts C and F displayed excellent enantioselectivities in the reduction of 19e (>99% ee, entries 4 and 7). However, only catalyst F gave full conversion, whilst catalyst C was observed to be less active (27% conv., entry 4). Bicyclic oxazole catalyst A5 was found to have the best performance in the hydrogenation of 19a (conv.>99%, 97% ee, entry 2).

Table 3.2 Screening of catalysts for asymmetric hydrogenation of six membered N-heterocyclic olefins with methyl and phenyl substituentsa Ts Ts N N Catalysts, H2 CH Cl !! R 2 2 R 19a R=Me 26a R=Me 19e R=Ph 26e R=Ph entry catalysts R conv.b (%) eec (%) Ph 93 61(–) 1 A1 Me >99 79(–) Ph 95 57(–) 2 A5 Me >99 97(–) Ph 99 91(–) 3 B Me >99 88(–) Ph 27 >99(–) 4 C Me 43 84(–) Ph >99 91(–) 5 D2 Me >99 91(–) Ph 81 97(–) 6 E2 Me 97 70(–) Ph >99 >99(+) 7 F Me 65 85(+) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

26 Table 3.3 Asymmetric hydrogenation of six-membered N-heterocyclic olefins with different substituentsa

Ph Ts Ts Ph P BAr N N Ir F Catalyst F, H2 !! N R CH2Cl2 R Ph S 19a-m 26a-m F entry substrate R conv.b (%) eec (%) 1 19a Me 65 85(+) 2 19b i-Pr 96 30(+) 3 19c Bu 93 41(+) 4 19m CH2OH 25 81(+) 5 19d Bn 49 93(+) 6 19e C6H5 >99 >99(+) 7 19f 4-MeC6H4 >99 >99(+) 8 19g 3-MeC6H4 97 97(+) 9 19h 4-MeOC6H4 >99 99(+) 10 19i 3-MeOC6H4 60 98(+) 11 19j 4-F3CC6H4 19 87(+) 12 19k 4-ClC6H4 57 87(+) 13 19l 4-BrC6H4 68 94(+) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

Encouraged by these excellent results, catalyst F was further evaluated with a variety of six membered N-heterocyclic olefins bearing different aliphatic and aromatic substituents. Excellent enantioselectivities (97-99% ee, Table 3.3, entries 6-10) were obtained with aryl groups bearing electron-donating substituents. However, alkyl and aryl groups having electron-withdrawing substituents were transformed with either lower enantioselectivity or lower conversion (entries 1-5, 11-13). From Table 3.2, it follows that catalyst A5 performed well against substrate 19a; hence, A5 was tested with other alkyl-substituted heterocycles. To our delight, A5 had superior activity and selectivity over F for the alkyl substituted substrates (Table 3.4, entries 1-5). Even when the double bond is shift- ed by one carbon to the vinylic position, the enantioselectivity remained high (90% conv, 89% ee, entry 6).

27 Table 3.4 Asymmetric hydrogenation of six-membered N-heterocyclic olefins with alkyl substituentsa entry R catalyst conv.b (%) eec (%)

1 19a Me A5 >99 97(–)(S)

2 19b i-Pr A5 >99 68(–) Ts 3 19c Bu A5 >99 81(–) N

4 19m CH2OH A5 >99 97(–) R 5 19d Bn A5 96 92(–)

Ts N 6 27 Me A5 90 89(+)(R) R a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

Catalyst D2, which had performed well for both model substrates 19a and 19e (Table 3.2, entry 5), was tested in the hydrogenation of the substrates bearing aryl units having electron-impoverished aryl groups. The results for catalyst D2 (74-94% conv., 96-98% ee, Table 3.5, entries 1-3) show great improvement in both conversion and enantionselectivity over catalyst F (19- 68% conv., 87-94% ee, Table 3.3, entries 11-13).

Table 3.5 Asymmetric hydrogenation of six-membered N-heterocyclic olefins with election-withdrawing substituentsa

Ph Ts Ts Ph P Ir BArF N N Catalyst D2, H2 ! D2 N CH2Cl2 R R N Ph 19j-l 26j-l entry substrate R conv.b (%) eec (%) 1 19j 4-F3CC6H4 74 96(–) 2 19k 4-ClC6H4 94 98(–) 3 19l 4-BrC6H4 92 98(–) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

The five-membered N-heterocyclic compounds 15a and 15d were also screened using our catalysts (p 7). Catalyst E2 was observed to hydrogenate 15d in full conversion and in good enantioselectivity (85% ee, Table 3.6, entry 6). However, all other catalysts performed poorly against 15a (21-44% ee, Table 3.6).

28 Table 3.6 Screening of catalysts for asymmetric hydrogenation of five- membered N-heterocyclic olefins with methyl and phenyl substituentsa Ts Ts

N Catalysts, H2 N

CH2Cl2 !! R R 15a R=Me 28a R=Me 15d R=Ph 28d R=Ph entry catalysts R conv.b (%) eec (%) Ph >99 31(+) 1 A1 Me –d –d Ph >99 20(+) 2 A5 Me >99 24 Ph >99 79(–) 3 B Me >99 44 Ph 75 71(–) 4 C Me >99 31 Ph >99 57(+) 5 D1 Me –d –d Ph >99 85(–) 6 E2 Me >99 21 Ph 97 74(+) 7 F Me >99 27 a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses. d Not analyzed.

Catalyst E2 was chosen to hydrogenate a variety of five-membered N- protected heterocyclic olefins having different substituents. Poor enantioselectivity was obtained for substrates bearing alkyl substituents (12-37% ee, Table 3.7, entries 1-3). When the protecting group was changed from Tosyl to Cbz, an improvement in selectivity was observed for the phenyl substitution (85% for entry 4 vs 99% ee for entry 5).

29 Table 3.7 Asymmetric hydrogenation of five-membered N-Heterocyclic olefins with different substituentsa

R' R' Ph Ph N Catalyst E2, H2 N P N Ir BArF CH2Cl2 ! E2 R R N 15a-d 28a-d Ph 17 29 S entry R conv.b (%) eec (%) entry R conv.b (%) eec (%)

1 15a Me >99 21 Ts Cbz 15b Bu >99 12 2 N N 5 17 Ph 78 99(+) 3 15c Bn >99 37 R R 4 15d Ph >99 85(+) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

Several catalysts (A5, B, C, E2, F) were evaluated with various seven- membered N-heterocyclic substrates with phenyl substitution. We found that catalyst E2 obtained the best enantioselectivity (98% ee, Table 3.8, entry 4) with full conversion. Seven-membered substrates with different double bond positions were screened against catalyst E2, which resulted in full conversions and excellent ee’s (90-96%, entries 6 and 7).

Table 3.8 Screening of catalysts for asymmetric hydrogenation of seven- membered N-heterocyclic olefins with phenyl substituentsa entry substrate catalysts conv.b (%) eec (%) 1 A5 >99 24(+) 2 Ts B >99 73(–) N 3 21 C >99 90(–) Ph 4 E2 >99 98(–) 5 F >99 94(+)

Ts N 6 23 E2 >99 96(–)

Ph Ts N 7 25 E2 >99 90(+)

Ph a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. c Determined by chiral HPLC analyses.

30 To demonstrate the utility of this asymmetric hydrogenation of N- heterocyclic olefins, we applied it for the synthesis of 3-PPP (Preclamol, Scheme 4.3). Preclamol is the first selective D2-like dopamine autoreceptor agonist.69,70 There are many related 3-phenylpiperidines71,72 that have shown dopaminergic activity and proven useful in the treatment of various central nervous system disorders. The hydrogenation of N-heterocyclic olefin 19i was performed using 1 mol % of catalyst F under standard conditions. The chiral compound 26i was generated in 98% ee. The enantiomeric excess was increased to >99% by recrystallization from Et2O. The deprotection of amine 26i with sodium naphthalenide, furnished compound 30 in 85% yield and without any loss in enantiomeric excess. Preclamol can be prepared by N- alkylation and removal of the methyl group of compound 30.70 Ts Ts N catalyst F N

O 50 bar H2,CH2Cl2 O

19i 26i 98% ee (93% yield, >99% ee, recrystal.)

H + - N N [Na] [C10H8] lit. O HO

30 Preclamol 85% yield, >99% ee Scheme 3.3 Enantioselective synthesis of Preclamol precursor compound 30

3.4 Conclusions The successful construction of a variety of five-, six- and seven-membered N-heterocyclic olefins was demonstrated using a straightforward synthetic protocol utilizing RCM. The five- and six-membered N-heterocyclic olefins were obtained in good to excellent yields with modest yields being achieved for the seven-membered heterocycles from RCM. These N-heterocyclic olefins were screened in the hydrogenation against a library of N,P-ligated iridium catalysts developed in our group. Extremely high activity and enantioselectivity (both up to >99%) were achieved for most substrates using different catalysts.

31 4 Asymmetric Hydrogenation of Unsaturated Sulfones

4.1 Introduction In recent years chiral sulfones have attracted considerable attention in both organic chemistry and medicinal chemistry.73-75 In medicinal chemistry, chiral sulfones are present in many biologically active compounds (Figure 4.1).76-79 In organic chemistry, chiral sulfones are synthetically useful compounds and are used in reductive desulfonylation, alkylative desulfonylation, oxidative desulfonylation, Julia olefinations, and Ramberg-Bäcklund reactions.80 The Julia reaction and the Ramberg-Bäcklund reaction are extensive- ly used for preparing C=C bonds in organic chemistry.

a, R= H2C H O H O S OH H O O O H H S N N N S N N b, R= H2C N O O H O O RO OR HO Ph O N NH2 H N HO OH c, R= H2C S Tazobactam HIV-1 protease inhibitor HIV-1 protease inhibitor

O O O H H O S S O OH N N O O O H N S S N H H H H N N S N N O O 2 H O O O OH HN O O NH N

MK-0507 (Trusopt) Remikiren Hepatitis C Virus NS3/4A protease inhibitor Figure 4.1 Biologically active compounds with chiral sulfone moieties.

However, despite the immense importance of chiral sulfones in many areas of chemistry, the development of methods for the preparation of chiral sulfones remains a challenge. Some compounds employing asymmetric catalysis are shown in Scheme 4.1.

32 CN Pfaltz and Misun(1996) O O O O S NaBH4,EtOH/diglyme * S N N R R H CoCl2, ligand O R = Me 66% ee Si R = Ph 40% ee Yuasa and co-workers(1998) ligand

CO2H CO2H Ru2Cl4[(S)-p-tolyl-Binap]2Et3N P(p-Tol)2 40 atm H2, 80 °C, MeOH:H2O SO2tBu SO2tBu P(p-Tol)2 84% ee

(S)-p-tolyl-Binap Carretero and co-workers

O O Rh(acac)(C2H4)2 O O PPh2 S (S,S)-chiraphos S in 2004 Ar1 Ar1 Ar-B(OH)2 PPh2 R H R Ar dioxane:H2O,100 °C (S,S)-chiraphos Ar1 = Ph, conv.<2% Ar1 = 2-Py, 76-92% ee

O O PhSiH3 O O S CuCl / tBuONa S PPh in 2007 Ar Ar 2 (R)-Binap * PPh2 R1 R2 toluene, r.t. R1 R2 Ar = Ph, conv. 0% Ar = 2-Py, 70-94% ee (R)-Binap

Charette and Desrosiers(2007) H3C

O O PhSiH3 O O P S S Ph CuF2.H2O Ph O CH3 Me-DuPhos(O) CH3 R1 R2 aq. NaOH,Benzene,r.t. R1 R2

90-99% ee H3C Me-DuPhos(O)

This Work ! m R O O O O S S R1 Ramberg-Bäcklund m Iridium-catalyzed ! reactionAsymmetric synthesis * R R R asymmetric hydrogenation m R buliding block of 2 n renin inhibitors O O O O m=1,2, n=0,1 R S R S 1 R 1 R n * n * R R2 R2 m=0-2, n=0,1 SO2

Scheme 4.1 Chiral sulfones prepared by asymmetric catalysis

In 1996, Pfaltz and Misun, used ‘semicorrin’ cobalt catalysts and sodium borohydride to reduce vinyl phenyl sulfones with modest enantioselectivities.81 Later, Yuasa and co-workers reported a Ru-Binap complex to hydrogenate an unsaturated sulfone in 84% ee in the presence of triethylamine.82 In 2004, Carretero and co-workers reported rhodium-catalyzed enantioselective addition of arylboronic acids to β-substituted α,β-unsaturated sulfones

33 with good to excellent enantioselectivities.83 Furthermore in 2007, both Car- retero’s84 and Charette’s85 groups reported copper-catalyzed conjugate reduction of β,β-disubstituted α,β-unsaturated sulfones with outstanding enantioselectivities. However, to the best of our knowledge, there is no existing asymmetric catalytic method to prepare chiral cyclic sulfones. Development of a new methodology, expanding the substrate scope for acyclic sulfones and also the preparation of chiral cyclic sulfones is therefore highly desirable. In this initial study, five-, six- and seven-membered cyclic and several acyclic unsaturated sulfones with different substituents were hydrogenated by chiral N,P-ligated iridium catalysts.

4.2 Synthesis of Unsaturated Sulfones The unsaturated cyclic and acyclic sulfones were prepared using different procedures. The acyclic vinyl sulfones 35 were prepared from previously reported α-thioketones 31 (Scheme 4.2).86 First, α-thioketones 31 were oxidized with mCPBA in CH2Cl2 at 0 °C to produce sulfones 32 (Scheme 4.2). Alkylation of the phenyl-substituted ketone was first attempted with MeMgCl, unfortunately, no reaction occurred. However, when the α- thioketones were treated with MeMgCl, alkylation occurred, though, slug- gishly, affording alcohols 33 in poor yields. When CeCl3 was incorporated to the reaction the yields improved dramatically. Sulfides 33 were oxidized to sulfones 34 in good yield. Sulfones 34 were treated with TFAA in the presence of DMAP and Et3N to form the desired products 35. A variety of dialkyl and aryl-alkyl substrates were prepared using organocuprates. Several alkynyl sulfides 36 were prepared as reported in the literature. The alkynyl sulfides were oxidized to their corresponding sulfoxides 37 using 1.0 equiva- lent of mCPBA at 0 °C. Vinyl sulfoxides 38 were prepared via addition of organocuprates to the alkynyl sulfides. Oxidation of sulfoxides 38 afforded the sulfones 39 in good yield. O O S Ph MeMgCl

mCPBA Ar O 32 O O O O S Ph S Ph MeMgCl mCPBA S Ph DMAP,Et3N S Ph OH CeCl3 OH TFAA Ar O Ar Ar Ar 31 33 34 35 O O O O mCPBA LiR, CuI S mCPBA S R" S R' R" S R' R' R' or RMgBr,CuBr,LiBr R R" R R" 36 37 38 39 Scheme 4.2 Preparation of unsaturated acyclic vinyl sulfones

34 Allylic alcohol 40 (Scheme 4.3) was brominated using phosphorus tribro- mide in Et2O to produce bromide 41. Bromide 41 was coupled with a selection of thiol compounds using sodium methoxide as the base in THF to give the sulfides 42, which were used directly in the next step without further purification. The sulfides 42 were oxidized with mCPBA in CH2Cl2 at 0 °C to produce sulfones 43.

Me Me Me Me PBr3 R-SH mCPBA R R Ph S Ph OH Ph Br Ph S O O 40 41 42 43 Scheme 4.3 Preparation of unsaturated acyclic allylic sulfones

For the preparation of seven-membered cyclic sulfone 48 and 49a PhMgBr/CeCl3 was used to alkylate the ketone and produce alcohol 45 (Scheme 4.4). Ketone 44 was prepared using a method obtained from literature.87 The selectivity between formation of the vinylic 46 and allylic 47 positions was found to be temperature dependent. Treatment of alcohol 45 with TFA at room temperature resulted in elimination to give predominantly vinylic sulfide 46. If the reaction was carried out at -78 °C, the allylic sulfide 47 was found to be the major product. Oxidation of vinyl sulfide 46 or allylic sulfide 47 using mCPBA afforded the desired unsaturated seven-membered sulfones 48 and 49a. Six-and seven-membered unsaturated sulfones with different substituents were prepared following this procedure. O O S S mCPBA

n Ar n Ar S S ArMgBr TFA 33 35 OH CeCl3 O O n O n S S Ar mCPBA 31 32 n Ar n Ar 34 36 n=1,2 Scheme 4.4 Preparation of unsaturated cyclic sulfones

4.3 Hydrogenation of Unsaturated Sulfones The seven-membered cyclic sulfone with phenyl substituent, 49a, was chosen as the model substrate for hydrogenation using our iridium catalyst library (A1, A3, B, D1, E1, F). Thiazole catalysts exhibited excellent enantioselectivities (96%-97% ee, Table 4.1, entries 3, 5, 6). However, only the thiazole catalyst B with a bulky backbone obtained full conversion.

35 Table 4.1 Catalyst screening for asymmetric hydrogenation of cyclic unsaturated sulfone 49aa O O O O S S Catalysts, H2 Ph CH2Cl2 * Ph 49a 50a entry catalysts conv.b (%) eec,d (%) 1 A1 25 14 (S) 2 A3 30 87 (R) 3 B >99 96 (R) 4 D1 >99 83 (S) 5 E1 42 97 (S) 6 F 49 96 (S) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses. d Absolute configuration determined from the corresponding alkenes obtained from Ramberg-Bäcklund reaction.

Seven-membered cyclic sulfones with aliphatic and aromatic substituents were subjected to hydrogenation by catalyst B. The results are summarized in Table 4.2. Generally, decent to outstanding enantioselectivities were achieved for most substrates (Table 4.2, entries 1-8). Substrates with methyl substituents were the exception. It was discovered that A3 was the most efficient catalyst for the hydrogenation of the sulfone with methyl substituents, and resulted in full conversion with 96% ee (Table 4.2, entry 10). From Ta- ble 4.2, it follows that electron-donating or electron-withdrawing substituents on the phenyl ring had very little effect on enantioselectivities of the reaction. Meta-substituted aryl substrates showed slightly higher enantioselectivity than the para-substituted substrates (Table 4.2, entries 3 vs 4). The ortho-substituted aryl substrates resulted in slightly lower enantioselectivity and poorer reactivity compared to the para-substituted substrate, possibly due to the steric hindrance (Table 4.2, entry 2 vs 4).

36 Table 4.2 Asymmetric hydrogenation of β-substituted β,γ-unsaturated seven-membered cyclic sufonesa

o-Tol o-Tol O O O O o-Tol BArF o-Tol BArF S S P Ir P Ir Catalysts, H2 N N CH2Cl2 * N N R R Ph Ph Ph 49a-i 50a-i S O B A3 entry substrate catalyst conv.b (%) eec,d (%) 1 49a Ph B >99 96 (-)(R) 2 49b 2-MeC6H4 B 23 93 (-) 3 49c 3-MeC6H4 B >99 98 (-) 4 49d 4-MeC6H4 B >99 96 (-)(R) 5 49e 4-MeOC6H4 B >99 97 (-) 6 49f 4-FC6H4 B 91 95 (-) 7 49g 4-ClC6H4 B >99 90 (-) e 8 49h CH2OH B >99 92 (-) 9 49i Me B >99 43 10 49i Me A3 >99 96 (-)(S) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses. d Absolute configuration determined by analogy with the corresponding alkenes obtained from Ramberg-Bäcklund reaction. e Determined by chiral GC after conversion to 1-(2-cyclohexenyl)methanol and then into its acetate, 1-(2- cyclohexenyl)methyl ethanoate.

Encouraged by the excellent results in the hydrogenation of the seven- membered unsaturated sulfones with different substitutions, a variety of substitution patterns and ring sizes were evaluated using catalyst B. The R group on the six-membered cyclic sulfones had no obvious influence on the enantioselectivity (Table 4.3, entries 1-3), but the reactivity was lower for the substrate with phenyl substituent. The seven-membered ring substrates with vinylic, allylic and homoallylic C=C were hydrogenated with catalyst B in good to excellent enantioselectivities and full conversions (89-93% ee, entries 4-7). The substrate with a methyl substituent 54c (entry 8), however, did not give good results with catalyst B. Catalyst A3 offered good enantioselectivity and full conversion (90% ee, entry 8). Catalyst A1 has proved to be the best catalyst for the five-membered cyclic sulfone and achieved 87% ee (entry 9).

37 Table 4.3 Asymmetric hydrogenation of cyclic unsaturated sulfones having five-, six- and seven-membered ringsa entry substrate R catalyst conv. (%)b ee (%)c,d

1 51a O O Ph B 43 90 (!)(R) S 2 51b CH2OH B >99 93 (!)f 3 51c R Me B >99 85 (!)(S)e O O S 4 52 Ph B >99 93 (+)(S) R O O S 5 53 Ph B >99 89 (!)

R O O 6 54a S Ph B >99 89 (+)

7 54b CH2OH B >99 90 (!)(S)g 8 54c Me A3 >99 90 (+)(S) R O O S 9 55 Ph A1 78 87 (!) R a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses. d Absolute configuration determined by analogy with the corresponding alkenes obtained from Ramberg-Bäcklund reaction. e Determined by comparing the optical rotation with a literature value.88 f Determined by GC after conversion to the corresponding acetate. g Determined by GC after conversion to 1-(3- cyclohexenyl)methanol.

Having obtained good results for cyclic sulfones, we evaluated the acyclic sulfones. First, we chose 35a as the model substrate to hydrogenate with our iridium catalysts (A1, A3, B, D1, E1, F). These results are presented in Ta- ble 4.4. Catalyst B proved to be the most efficient for the model substrate giving full conversion and excellent enantioselectivity (96% ee, Table 4.4, entry 3). Next, a variety of acyclic trans sulfones that have different aliphatic and aromatic substituents at sulfur were studied. Catalyst B was used for the asymmetric hydrogenation of these compounds.

38 Table 4.4 Catalyst screening for asymmetric hydrogenation of acyclic unsaturated sulfones 35aa O O O O S Ph Catalysts, H2 S Ph CH Cl 2 2 * Ph Ph 35a 56a entry catalyst conv.b (%) eec,d (%) 1 A1 45 76 (S) 2 A3 24 41 (S) 3 B >99 96 (S) 4 D1 >99 27 (R) 5 E1 27 50 (R) 6 F 90 75 (R) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses. d Absolute configuration determined by compar- ison with the corresponding alkenes obtained from Ramberg-Bäcklund reaction.

It was found that the R group on sulfur had very little influence on the enantioselectivities and the activities (91-96% ee, Table 4.5, entries 1-4). When the acyclic trans-sulfones were changed to cis-sulfones, the enantiose- lecitvity remained similar, but the reactivity was lower. This means that the same catalyst can be used to hydrogenate the trans- and/or cis-sulfones to produce either the (R)- or (S)-enantiomer with similar enantioselectivities.

Table 4.5 Asymmetric hydrogenation of acyclic unsaturated sulfones with different substituents at sulfura

o-Tol O O O O o-Tol S Catalyst B S P Ir BArF R R N !! B H2,CH2Cl2 N Ph Ph Ph (E) / (Z) S entry R conv.b (%) eec (%) entry R conv.b (%) eec (%) 1 57a n-Bu >99 91 (-) O O O O S S 2 R 57b Cy >99 94 (-) R 5 58 Bn 61 96 (R) 3 Ph 35a Bn >99 96 (S) Ph (E) (Z) 4 57d Ph >99 94 a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses.

The acyclic trans-sulfones with a benzyl group on sulfur and different substituents on the β-position were also studied. Here as well catalyst B was

39 used for the asymmetric hydrogenation. The results are presented in Table 4.6.

Table 4.6 Asymmetric hydrogenation of acyclic trans-sulfones with different substituentsa

o-Tol O O O O o-Tol S Ph S Ph P Ir BArF Catalyst B, H2 N CH2Cl2 B !! N Ph R1 R2 R1 R2 (E) S b c,d entry R1 R2 conv. (%) ee (%) 1 59a n-Bu Me >99 93 (+)(R) 2 59b Cy Me >99 86 (+) 3 35a C6H5 Me >99 96 (+)(S) 4 35b 4-MeC6H4 Me >99 90 (+) 5 35c 4-MeOC6H4 Me >99 92 (+) 6 35d 4-ClC6H4 Me >99 96 (+) 7 35e 4-BrC6H4 Me >99 96 (+) 8 35f 4-CF3C6H4 Me >99 95 (+) 9 60 C6H5 n-Bu >99 91 (+) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses. d Absolute configuration determined by analogy with the corresponding alkenes obtained from Ramberg-Bäcklund reaction.

Generally, all the products were obtained in good to excellent enantioselectivities with full conversion (86-96% ee, Table 4.6, entries 1-9). The substrates with the electron-withdrawing substituent displayed slightly higher enantioselectivities than those with the electron-donating ones (entries 6-8 vs 4-5, respectively). When the R2 of the substrate changed from the Me to the n-Bu group, the result revealed that the size of the R2 group had very little influence on the enantioselectivity (Table 4.6, entry 9 vs 3). Next, the focus moved to the study of the acyclic cis-sulfones with different substituents in the asymmetric hydrogenation. In this case the size of R1 had remarkable influence on the enantioselectivities and reactivities. It was established that a long chain in the R1 position resulted in decreased enantioselectivities (Table 4.7, entry 3).

40 Table 4.7 Asymmetric hydrogenation of acyclic cis-sulfones with different of substituentsa

o-Tol O O O O o-Tol S Ph S Ph P Ir BArF Catalyst B, H2 N CH2Cl2 B !! N Ph R1 R2 R1 R2 (Z) S b c entry substrate R1 R2 conv. (%) ee (%) 1 61 Me n-Bu >99 93 (-)(S) 2 58 Me Ph 61 96 (-)(R) 3 62 n-Bu Ph 50 74 (-) a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses.

Motivated by the results achieved for the acyclic vinyl sulfones, the study of the acyclic allylic sulfones continued. A selection of substituents at the sulfur for acyclic allylic sulfones was explored. Substrates with aliphatic substituents at sulfur can be used in the Ramberg-Bäcklund reaction to form the C=C double bond. Substrates with aromatic substituents at sulfur, like ben- zothiazo-2-yl groups (Table 4.8, entry 1), 2-pyridyl groups (Table 4.8, entry 2) and phenyl groups (Table 4.8, entry 3), can be used in the Julia olefination to form a high ratio of the trans C=C double bond. The asymmetric hydrogenation of these substrates with a variety of substitutions on the sulfur atom, using catalyst B, was studied. The results are summarized in Table 4.8. Un- fortunately, the substrates bearing heteroaromatic substituents showed no reactivity. This is possibly due to coordination to the iridium complex deac- tivating the catalyst. However excellent enantioselectivities were achieved for the substrates having aliphatic and phenylic substituents (96-99% ee, Table 4.8, entries 3-10).

41 Table 4.8 Asymmetric hydrogenation of γ,γ-disubstituted allylic sulfonesa

O O O O S Catalyst B,H2 S o-Tol o-Tol R CH2Cl2 R P Ir BArF * N B N Ph Ph Ph 63a-j 64a-j S entry R conv.b (%) eec (%) entry R conv.b (%) eec (%)

N 1 63a -d – 6 63f >99 97 (-) S N d 2 63b - – 7 63g n-Bu >99 98 (-)

>99 96 (-) 8 63h >99 98 (-) 3 63c t-Bu

4 63d >99 99 (-) 9 63i i-Pr >99 97 (-)

5 63e C >99 97 (-) 10 63j MeOOCH2C >99 97 (-) H2 a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Conversion, determined by 1H NMR spectroscopy. No side products were detected. c Determined by chiral HPLC or GC analyses.

4.4 Application

4.4.1 Preparation of Chiral Allylic and Homoallylic Compounds via the Ramberg-Bäcklund Reaction In 1940, Swedish chemists Ludwig Ramberg and Birger Bäcklund (Scheme 4.5) discovered that an α-bromo sulfone (1-bromo-1- ethanesulfonyl ethane) can be converted to an alkene: (Z)-2-butene (major product) and (E)-2-butene (minor product).89 This was achieved at high temperature in aqueous KOH solution. Since then, several modifications based on Ramberg and Bäcklund’s original findings have broadened the substrates scope of the reaction. For example, in 1969 Meyers and co-workers reported an efficient one-pot procedure.90 This allowed an in situ generation of α-halo sulfones in the presence of KOH with CCl4, to convert the sulfones directly into an alkene. This procedure, however, had a limited substrate scope. It was successfully applied to substrates with benzylic sulfones only. Non- benzylic sulfones behave differently and form the alkenes as well as the alkene-dichlorocarbene adducts. In 1994, Chan and co-workers modified 91 Meyers’ procedure by using CBr2F2 instead of CCl4. The acyclic benzylic and non-benzylic sulfones were converted to the corresponding alkenes with

42 good to excellent yields by this method. This method is widely applied to form C=C bonds in organic chemistry. Chiral olefins, especially chiral allylic and homoallylic compounds, are valuable intermediates for the preparation of biologically active compounds and natural products. Currently no method has been developed that can prepare both chiral allylic and homoallylic compounds. For example, asymmetric allylic substitution is widely used in the preparation of chiral allylic compounds,92-94 but it cannot be used to prepare homoallylic chiral compounds. Ramberg and Bäcklund (1940) O O H3C S CH3 2N KOH (aq.) H C CH CH 3 3 + H C 3 90-100 °C,85% 3 Br major minor

KOH-CCl -tBuOH O O 4 Meyers' modification (1969) R1 R3 R1 S R3 R R R2 R4 Chan's modification (1994) 2 4 KOH/Al2O3-CBr2F2-tBuOH Scheme 4.5 Developments and modifications of the Ramberg-Bäcklund reaction

In this study, we converted cyclic and acyclic chiral sulfones, which were obtained from the iridium-catalyzed asymmetric hydrogenation, to the corresponding chiral alkenes via Ramberg-Bäcklund reaction. We chose to em- ploy Chan’s method to perform the reaction. It was found that the reaction required microwave heating at 60 °C for 1.5 hours to go to completion. We found that chiral seven-membered cyclic sulfones were fully converted to chiral olefins in high yield under these conditions (Table 4.9, entries 2-9). It was observed that the six-membered cyclic sulfone was not fully converted to the five-membered alkene, even at a higher temperature of 80 °C in the microwave reactor. Only a mere 30% yield was obtained, possibly due to the inherent ring strain in the formation of the five-membered ring (entry 1). Acyclic chiral sulfones with aromatic substitutions at the β-position were easily converted to corresponding chiral alkenes with very mild conditions: 0 °C for 2 hours produced a good yield and only trans isomers (entries 10-12). When acyclic chiral sulfones, with dialkyl substitution at the β-position, were reacted overnight at 60 °C, a good yield and only the trans isomers were obtained. For 64f, when tBuOK was used as the base only the trans isomer was produced (entry 14). However, when KOH was used as the base a mixture of cis and trans isomers was obtained. From these results, we concluded that the enantioselectivities of chiral olefins was similar to the corresponding chiral sulfones, that is, no decrease of enantiometric excess was observed during the Ramberg-Bäcklund reaction of the substrates tested.

43 Table 4.9 Transformation of chiral sulfones to chiral allylic and homoallylic compounds by the Ramberg-Bäcklund reaction O O O O S S R * R * * * KOH / Al O R 2 3 Ph R O O O O CBr2F2, tBuOH / CH2Cl2 S Ph S * * R * * R R R O O Ph S Ph tBuOK

R CCl4, tBuOH * R *

entry substrate product R yield (%)a ee (%)b

O O S 1 65 68 Ph 30 90 ( )(S)c R ! R 2 50i 69a Me >99d 96 (!)(S)c,e 3 50a O O 69b Ph 88 96 (!)(S)c S c 4 50d 69c R 4-MeC6H4 85 96 (!)(S) R 5 50e 69d 4-MeOC6H4 90 97 (!)

6 50h 69e CH2OH 82 92 (!) O O 7 66a S 70a Me >99d 90 (!)(S)c,e 8 66b 70b Ph 90 89 (!) c 9 66c 70c R CH2OH 80 90 (!)(S) R 10 56a 71a Ph 91f 96 (+)(R)c O O Ph f 11 56e S Ph 71b 4-BrC6H4 94 96 (+) f 12 56c 71c 4-MeOC6H4 93 92 (+) R R 13 67 71d n-Bu 78f 93 (+)(S)c O O Ph S Ph 14 64f 72 Ph 75f >97 (!) R R a Isolated yields. b Determined by chiral HPLC or GC analyses. c Absolute configuration determined by comparing the optical rotation with a literature value. d Not an isolated yield but a conversion determined by GC. e ee determined from the chiral sulfone. See Supporting Information for reaction conditions. f Only the trans (E) isomer was observed.

4.4.2 Asymmetric Synthesis of Chiral Building Blocks for Renin Inhibitors Renin inhibitors are important classes of compounds that block the renin- angiotensin aldosterone system (RAAS), which is known to play an important role in the regulation of blood pressure. Thus renin inhibitors have been considered as drugs for the treatment of hypertension. In the past dec-

44 ade, many renin inhibitors have been designed, such as Remikiren (Ro 42- 5892) which has been selected for clinical development.95 The key intermediate of this renin inhibitor was prepared from enzymatic hydrolysis (Scheme 4.6) of racemate 73.96 However preparation of the intermediate 73a from this method resulted in a yield of less than 50%. In this study, we applied the iridium-catalyzed asymmetric hydrogenation to the preparation of a key intermediate 73a of the renin inhibitor Remikiren.

O OH H N 2 OH H2N OH NH + N +

O O OH O O H O O H S N S N OH O O N S OH H O O OH NH O NH N 74 N 75 Remikiren

4 enzyme O O SO O O S OEt 1) NaOH,2 EtOH S OEt 2) H O O hydrolysis 73 73a enzymatic hydrolysis of racemate >99% ee, 41 - 46% yield

O O S OH

O O O O S OEt S OEt O O O !! O S OH This work O

O O O O S Iridium-catalyzed S asymmetric hydrogenation OH OH

Scheme 4.6 Synthetic strategy for key intermediate for the preparation of Remikiren

The synthetic route is shown in Scheme 4.7. The key intermediate was synthesized from benzaldehyde 77. The first step involves the Baylis-Hillman reaction with benzaldehyde 77 and ethyl acrylate 76 in DABCO at room temperature for 5 days to give 78 in 60% yield. Then treatment of compound 78 with lithium bromide and concentrated sulfuric acid produced allylic bromide 79 (yield 80%). The allylic bromide 79 was coupled with tert-

45 butylthiol, using K2CO3 as the base in acetonitrile, overnight reaction at room temperature resulted in sulfide 80 in 85% yield. Sulfide 80 was oxidized with mCPBA at 0 °C for 3 hours to provide sulfone 81 in 90% yield. Sulfone 81 was reduced to alcohol 82 by using DIBAL-H in 85% yield.

O OH O O O OEt a b c + OEt OEt OEt O Br S d 76 77 78 79 80

OH OH O O !! OEt !! f e f OEt

SO2 SO2 SO2 SO2

83 82 81 73 a Condition: (a) DABCO, r.t.; (b) LiBr, conc. H2SO4, CH2Cl2, r.t.; (c) tBuSH, K2CO3, CH3CN, r.t.; (d) mCPBA, CH2Cl2, 0°C; (e) DIBAL-H, THF,-78°C; (f) iridium catalyst, H2, CH2Cl2, r.t. Scheme 4.7 Preparation of chiral sulfones 73 and 83a

With two sulfone substrates 81 and 82, we began to evaluate the substrates with our different iridium catalysts (A1, A3, B, C, D1, E1, and F). The results are shown in Table 4.10. We found all the catalysts gave poor enantioselectivities for the sulfone with ester substituent 81. However, when the ester group 81 was reduced to an alcohol group 82 with DIBAL, higher enantioselectivities in the hydrogenation were observed for all catalysts. Cata- lyst F achieved the best enantioselectivities for both substrates (55% and 85%, Table 4.10, entries 7 and 14).

46 Table 4.10 Asymmetric hydrogenation of key intermediates in the synthesis of Remikirena Ph catalysts Ph O O O O !! S H2, CH2Cl2 S R R

entry substrate catalyst eeb (%) entry substrate catalyst eeb (%)

1 A1 29% 8 A1 44%

2 A3 rac. 9 A3 74% Ph Ph 3 82% O O B 17% 10 O O B S OEt S 4 C 58% 11 C 72% O OH 5 81 D1 7% 12 82 D1 63%

6 E1 47% 13 E1 61%

7 F 55% 14 F 85% a Reaction conditions: 0.25 mmol substrate, 0.5 mol% catalyst, 2 mL CH2Cl2, 50 bar H2, 17 h, r.t. b Determined by chiral HPLC analyses.

In conclusion, we have prepared the key intermediate in the synthesis of Remikiren. However, the results were not as good as expected. We are in the progress of attempting to prepare other vinyl sulfones that may improve the enantioselectivity in the asymmetric hydrogenation.

4.4.3 Selectivity Model Brandt and Andersson have proposed an IrIII/IrV catalytic cycle of iridium- catalyzed asymmetric hydrogenation based on their DFT calculations.47 Both Brandt and Andersson, and Burgess and Hall, developed a general selectivity model for the iridium-catalyzed asymmetric hydrogenation of olefins.48,97,98 This model can predict the absolute configuration of products from the asymmetric hydrogenation of non-chelating olefins based on the IrIII/IrV cycle.

For example, bicyclic phosphine-thiazole catalyst B hydrogenated the unsaturated sulfones, including six- and seven-membered cyclic sulfones as well as the acyclic vinyl sulfones. The thiazole catalyst is represented both as ⌒ + a 3-D model and as a simplified cation, [(N P)Ir(H2)(olefin)] in Scheme 4.8, (a). When the selectivity model is applied to the catalyst (Scheme 4.8, (a)) two of the quadrants are occupied by the steric bulk of the ligand with quadrant 2 fully occupied.47,99,100 Quadrant 4 is partially occupied by the ortho- tolyl. Quadrants 1 and 3 are relatively free of steric bulk. In the most stable configuration, the smallest substituent of the sulfone-olefin, a hydrogen, should be pointing towards the most hindered quadrant (2, Scheme 4.8, (a)). Then according to the IrIII/IrV catalytic cycle, the olefin undergoes migratory

47 insertion to the Ir-H bond. The H2 will undergo oxidative addition to the Ir and then reductive elimination releasing the hydrogenation product. The results of the predicted and observed absolute configurations for the chiral sulfone from the hydrogenation by catalyst B are summarized in Table 4.11. The selectivity model successfully predicts the correct absolute configuration observed in the experiment. Thus the model proved to be a useful and convenient method for predicting the stereoselectivity of the hydrogenation of an unsaturated sulfonated olefin by iridium catalysts.

Ir N P N S

(a)

X HH N P Ir H H

Hindered Open

H H H Ph S Ph S O O O O (R) Open Semi-Hindered (b)

Hindered Open

O O O O H S Ph H S Ph H Ph Me Ph Me (S) Open Semi-Hindered

Scheme 4.8 Selectivity model applied in predicting the absolute configuration of the products from the asymmetric hydrogenation

48 Table 4.11 Predicted and observed product absolute configurations in the hydrogenation of unsaturated sulfones by catalyst Ba substrate entry R predicted observed substrate entry R predicted observed

Hindered Open

1 Me S S Hindered Open S O R O 2 Ph R R O S Open Semi-Hindered 7 CH2OH S S R O Hindered Open O O Open Semi-Hindered S 3 Ph S S R Hindered Open

Open Semi-Hindered O O S Ph 8 n-Bu R R Hindered Open

4 Me S S R 9 Ph S S

5 Ph R R Open Semi-Hindered R S O O 6 4-MeC6H4 R R Open Semi-Hindered a Absolute configuration observed from experiment, see Table 4.9.

4.5 Conclusions Unsaturated cyclic sulfones, of various ring sizes with different substituents and acyclic sulfones have been prepared. The unsaturated sulfones were used for asymmetric hydrogenation with chiral N,P-ligated iridium catalysts. Cy- clic and acyclic sulfones gave up to 99% ee. The Ramberg-Bäcklund reaction has been successfully applied, for the preparation of chiral allylic and homoallylic olefins with high yield. This method was also useful in the synthesis of the key intermediate of a renin inhibitor with good enantioselectivity.

49 5 Conclusion and Outlook

The aim of this study, as presented in Chapter 2, was to expand the substrate scope of the asymmetric hydrogenation using chiral N,P-ligated iridium complexes. In Chapter 3, the synthesis of the five-, six- and seven-membered N-heterocyclic olefins by ring-closing metathesis is described. The N- heterocyclic olefins of different ring sizes and bearing various substitutions were subjected to asymmetric hydrogenation with chiral N,P-ligated iridium catalysts. Good to excellent conversions and enantioselectivities (up to 99% conv. and >99% ee) were achieved by using different iridium catalysts. Six- membered N-heterocyclic olefins with phenyl and electronically enriched aromatic substituents were hydrogenated to give excellent enantioselectivities using catalyst F. Six-membered N-heterocyclic olefins bearing electron impoverished aromatic substituents were hydrogenated to give excellent enantioselectivities with catalyst D2. Catalyst E2 showed better enantioselectivities for the hydrogenation of five- and seven-membered N- heterocyclic olefins (up to 99% ee). This method was also successfully applied to prepare a key intermediate 26i (in 98 % ee) in the synthesis of Pre- clamol using catalyst F. We have successfully expanded the substrate scope for the asymmetric hydrogenation to include N-heterocyclic olefins. The synthesis of the five-, six- and seven-membered unsaturated cyclic sulfones with different substituents is explained in Chapter 4. The unsaturated sulfones were hydrogenated with iridium catalysts developed in this group. Bicyclic thiazole iridium catalyst B showed good to excellent enantiose- lecitvities for most unsaturated sulfones. The hydrogenation products, chiral sulfones, were converted to chiral allylic and homoallylic olefins through the Ramberg-Bäcklund reaction. To test the applicability of this method we employed it to prepare key intermediates of in the synthesis of renin inhibitors and achieved modest enantioselectivity (up to 85% ee).

The results in this study are potentially useful for the preparation of biologically active compounds and natural products that contain the chiral N- heterocyclic sub-unit and chiral sulfones. For example, the application that we are curently working on is the preparation of the biologically active natural compound Imperanene. Iridium-catalyzed asymmetric hydrogenation will be used to create the chiral center and a Ramberg-Bäcklund reaction to convert the chiral sulfone to a C=C bond as illustrated in Scheme 5.1.

50 Iridium-catalyzed Asymmetric Hydrogenation

O ∗ OH OH imperanene O SH Ramberg-BŠcklund Rearrangement OP PO O O H PO O S + O O HO O O O OEt OH Vanillin PO Br P = protecting group O Iridium-Catalyzed Asymmetric Hydrogenation

OH OH Imperanene O SH Ramberg-Bäcklund Reaction OP PO O O H PO O S + O O HO O O O OEt OH Vanillin PO Br P = protecting group O Scheme 5.1 Strategy for the synthesis of Imperanene

51 Acknowledgements

I would like to express my sincere gratitude to my supervisor Prof. Pher G. Andersson for accepting me as a Ph.D. student in his research group and providing me with many thought-provoking research projects. I am very thankful for his patience, support and the freedom he gave me to carry out my research.

I would like to thank my co-supervisor Prof. Lars Baltzer for his help and advice.

I would like to thank the China Scholarship Council for the fellowship that supported me during my study in Sweden.

I would like to thank the present members of the PGA group:

Johan J. Verendel, You are my colleague as well as my teacher in the lab. I’m really glad that I could share a lab and work with you during these four years. Jia-Qi Li, It was fun to be with you and to travel around Europe. By- ron Peters, Naming reactions is a piece of cake for you. I’m glad that we worked together on the sulfones project. Xu Quan, You are the ‘legend’ in the PGA group. Alban Cadu, Thank you for sharing your knowledge with me. You will be the next generation of “King of cakes”. Vijay Singh, It was good to work with you in the same lab. Dr. Alexander Paptchikhine You are such a good chemist. Dr. Janjira Rujirawanich, I’m glad that you have joined the group. Dr. Thishana Singh, Thank you for the time spent in cor- recting my thesis. Jian-Guo Liu, Welcome to the PGA group.

Thanks to all the present members in the PGA group who have helped me correct my thesis, especially Byron Peters, Alban Cadu, Thishana Singh and my supervisor Prof. Pher G. Andersson.

I would like to thank Dr. Tamara L.Church for the careful reading of my manuscripts.

I also would like to thank a few other people in the department:

52 Prof. Adolf Gogoll, For your help with the NMR and other instruments. Jo- seph Samec and Peter Dinér, For the Name Reaction Course: a really useful course. Supaporn Sawadjoon, For all the help with chemistry. Maxim Gal- kin, I enjoyed our discussions about chemistry and also thanks for the deli- cious Russian food. Xiaojiao Sun, Jie Yang, Huan Ma, Ruisheng Xiong Thank you for being such good friends throughout my studies. Christian Dahlstrand, as Alex says, ‘You are a wise man’. I have gained a lot from our discussions. Jia-Fei Poon, I am glad to have worked with you in the department. Hao Huang, It was always fun having you around and thanks for your help with the NMR. Sara Norrehed, For teaching me how to use the NMR. Johanna Johansson, For helping me with administrative issues. Gunnar Svensson, For help with the chemicals.

Thank you to everyone else in the department.

I also would like to thank my previous supervisor Prof. Bochu Wang at CQU for his help and advice.

And a special thanks to my parents for their love and support throughout my life.

Taigang

Uppsala, October 2012

53 Summary in Swedish

Kiralitet är ett av de mest fantastiska fenomenen i naturen. Precis som våra hander, finns det många molekyler som existerar i två former och som är spegelbilder av varandra (en vänster och en höger hand) Detta gör att de inte är överlagringsbara på sin spegelbild och denna egenskap kallas kiralitet. Även om kirala molekyler är mycket lika varandra, kan de bägge spegelbilderna av dem ha olika egen- skaper, såsom enantiomererna (spegelbilderna) av karvon har olika lukt, (R)-karvon luktar mint, (S)-karvon luktar kummin. De bägge enantiomererna av naproxen har olika biologisk aktivitet, (S)- naproxen ett anti-inflammatoriskt läkemedel, men (R)-naproxen orsa- kar leverskador. Många av de molekyler som utgör byggstenar levande celler (socker, aminosyror, proteiner, DNA och RNA) är alla kirala molekyler. Livet självt är således en kiral miljö, vilket gör att olika enantiomerer av en molekyl kan ha stor skillnad i sin inverkan på kirala molekyler i levande celler. Detta kan förklara olika enantiomerer av naproxen kan ha olika biologisk aktivitet i vår kropp.

O O

H H

(R)-Karvon (S)-Karvon

OH HO

O O O O

(R)-Naproxen (S)-Naproxen År 1992 utfärdade Food and Drug Administration (FDA) i USA en policyförklaring för utveckling av nya kirala läkemedel. Det visar hur viktigt kiralitet har kommit att bli vid utveckling och produktion av enantiomert rena kirala läkemedel. Vanligtvis används kirala metallkomplex, såsom koppar, järn, rodi- um, rutenium och iridium komplex, som katalysatorer för att möjliggöra framställning av endast den ena av två möjliga spegel-

54 former av en förening. Denna metod har använts i stor utsträckning inom läkemedelsindustrin. Till exempel har Knowles med flera använt kirala rodiumkomplex för att producera läkemedlet L-DOPA i indus- triell skala, och han belönades med Nobelpriset i kemi 2001 för sitt utomordentliga arbete. I denna avhandling använder vi kirala metallkomplex av iridium för att producera kirala heterocykliska föreningar och kirala sulfoner. Denna metodik har gjort det möjligt att framställa kväveinnehållande föreningar och kirala sulfoner enantiomert rena (upp till 99% ee). Kirala heterocykliska föreningar kan användas för framställning av biologiskt aktiva föreningar i medicinsk kemi, t.ex. läkemedlet preclamol. Kirala sulfoner är användbara mellanprodukter i organisk kemi. Vi har framgångsrikt tillämpat denna metod för framställning av kirala allyliska och homoallylic föreningar som i sin tur är viktiga byggstenar i syntesen av flera läkemedel.

55 References

(1)Flack, H. Acta Crystallographica Section A 2009, 65, 371. (2)Fischer, E. Chem. Ber. 1894, 27, 2985. (3)Lin, G.-Q.; Zhang, J.-G.; Cheng, J.-F. In Chiral Drugs; John Wiley & Sons, Inc.: 2011, p 3. (4)Donald, T. H.; Bingyun, L. In Encyclopedia of Chemical Processing; Taylor & Francis: 2007, p 449. (5)Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.; Zelinski, T. Angewandte Chemie International Edition 2004, 43, 788. (6)http://www.drugs.com/stats/top100/2011/sales,(Accessed 01-09- 2012). (7)Blaser, H. U. Chemical Reviews 1992, 92, 935. (8)Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chemical Reviews 1995, 95, 1677. (9)Farina, V.; Brown, J. D. Angew. Chem., Int. Ed. 2006, 45, 7330. (10)Crabtree, R. H. In Handbook of Green Chemistry; Wiley-VCH: Weinheim, 2009, p 173. (11)Fujima, Y.; Ikunaka, M.; Inoue, T.; Matsumoto, J. Organic Process Research & Development 2006, 10, 905. (12)Kamal, A.; Khanna, G. B. R.; Ramu, R.; Krishnaji, T. Tetrahedron Letters 2003, 44, 4783. (13)Buitrago, E.; Lundberg, H.; Andersson, H.; Ryberg, P.; Adolfsson, H. ChemCatChem 2012, n/a. (14)Träff, A.; Lihammar, R.; Bäckvall, J.-E. J. Org. Chem. 2011, 76, 3917. (15)Adolfsson, H. In Modern Reduction Methods; Wiley-VCH Verlag GmbH & Co. KGaA: 2008, p 339. (16)Yu, J.; Shi, F.; Gong, L.-Z. Accounts of Chemical Research 2011, 44, 1156. (17)Adolfsson, H. Angewandte Chemie International Edition 2005, 44, 3340. (18)Ward, T. R. Accounts of Chemical Research 2010, 44, 47. (19)Zhu, Y.; Burgess, K. Accounts of Chemical Research 2012, 45, 1623. (20)Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis, 1999; Vol. 1–3. (21)Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. (22)Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions, 2004. (23)Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272. (24)Church, T. L.; Andersson, P. G. Coord. Chem. Rev. 2008, 252, 513. (25)Xie, J. H.; Zhu, S. F.; Zhou, Q. L. Chem. Rev. 2011, 111, 1713.

56 (26)Cadu, A.; Andersson, P. G. Journal of Organometallic Chemistry 2012, 714, 3. (27)Shultz, C. S.; Krska, S. W. Accounts of Chemical Research 2007, 40, 1320. (28)Imwinkelried, R. CHIMIA International Journal for Chemistry 1997, 51, 300. (29)Blaser, H. U.; Spindler, F. Topics in Catalysis 1997, 4, 275. (30)Stinson, S. C. Chemical & Engineering News Archive 1997, 75, 38. (31)Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J. Chem. Soc. (A) 1966, 1711. (32)Knowles, W. S.; Sabacky, M. J. J. Chem. Soc., Chem. Commun. 1968, 1445. (33)Horner, L.; Siegel, H.; Buthe, H. Angew. Chem., Int. Ed. 1968, 7, 942. (34)Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc. 1972, 94, 6429. (35)Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, O. J. J. Am. Chem. Soc. 1977, 99, 5946. (36)Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (37)Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. (38)Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (39)Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (40)Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (41)Halpern, J. Acc. Chem. Res. 1982, 15, 332. (42)Halpern, J. Science 1982, 217, 401. (43)Kitamura, M.; Tsukamoto, M.; Bessho, Y.; Yoshimura, M.; Kobs, U.; Widhalm, M.; Noyori, R. J. Am. Chem. Soc. 2002, 124, 6649. (44)Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331. (45)Schnider, P.; Koch, G.; Prétôt, R.; Wang, G.; Bohnen, F. M.; Krüger, C.; Pfaltz, A. Chem.—Eur. J. 1997, 3, 887. (46)Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897. (47)Brandt, P.; Hedberg, C.; Andersson, P. G. Chem.—Eur. J. 2003, 9, 339. (48)Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B. J. Am. Chem. Soc. 2004, 126, 16688. (49)Dietiker, R.; Chen, P. Angew. Chem., Int. Ed. 2004, 43, 5513. (50)Trifonova, A.; Diesen, J. S.; Andersson, P. G. Chem.—Eur. J. 2006, 12, 2318. (51)Hedberg, C.; Källström, K.; Brandt, P.; Hansen, L. K.; Andersson, P. G. J. Am. Chem. Soc. 2006, 128, 2995. (52)Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P. G. J. Am. Chem. Soc. 2007, 129, 4536. (53)Kaukoranta, P.; Engman, M.; Hedberg, C.; Bergquist, J.; Andersson, P. G. Adv. Synth. Catal. 2008, 350, 1168. (54)Li, J.-Q.; Paptchikhine, A.; Govender, T.; Andersson, P. G. Tetrahedron: Asymmetry 2010, 21, 1328. (55)Li, J.-Q.; Quan, X.; Andersson, P. G. Chem.-Eur. J. 2012, 18, 10609.

57 (56)Minakata, S. Accounts of Chemical Research 2009, 42, 1172. (57)Alexandre-Moreira, M. S.; Viegas, J. C.; Miranda, A. L. P.; Bolzani, V. S.; Barreiro, E. J. Planta Med. 2003, 69, 795. (58)Viegas, J. C.; Silva, D. H. S.; Pivatto, M.; de Rezende, A.; Castro- Gambôa, I.; Bolzani, V. S.; Nair, M. G. Journal of Natural Products 2007, 70, 2026. (59)Kesting, J. R.; Tolderlund, I.-L.; Pedersen, A. F.; Witt, M.; Jaroszewski, J. W.; Staerk, D. Journal of Natural Products 2009, 72, 312. (60)Chavan, A. B.; Gundecha, S. S.; Kadam, P. N.; Maikap, G. C.; Gurjar, M. K. Organic Process Research & Development 2010, 14, 1473. (61)Wang, L.; Mason, K.; Ang, K. K.; Buchholz, T.; Valdecanas, D.; Mathur, A.; Buser-Doepner, C.; Toniatti, C.; Milas, L. Invest New Drugs 2011, 1. (62)Clark, C. C.; Weitzel, J. N.; O'Connor, T. R. Molecular Cancer Therapeutics 2012, 11, 1948. (63)http://www.drugs.com/top200.html; (Accessed 01-09-2012). (64)Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26, 763. (65)Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366. (66)Clavier, H.; Nolan, S. P. Chem.– Eur. J. 2007, 13, 8029. (67)Grubbs, R. H. Tetrahedron 2004, 60, 7117. (68)Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (69)Liljefors, T.; Wikström, H. J. Med. Chem. 1986, 29, 1896. (70)Wikström, H.; Sanchez, D.; Lindberg, P.; Hacksell, U.; Arvidsson, L. E.; Johnsson, A. M.; Thorberg, S. O.; Nilsson, J. L. G.; Svensson, K. J. Med. Chem. 1984, 27, 1030. (71)Hansson, L. O.; Waters, N.; Holm, S.; Sonesson, C. J. Med. Chem. 1995, 38, 3121. (72)Macchia, M.; Cervetto, L.; Demontis, G. C.; Longoni, B.; Minutolo, F.; Orlandini, E.; Ortore, G.; Papi, C.; Sbrana, A.; Macchia, B. J. Med. Chem. 2003, 46, 161. (73)Kelly, S. E.; Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis, 1991; Vol. 1. (74)Prilezhaeva, E. N. Russ. Chem. Rev. 2000, 69, 367. (75)Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563. (76)Fischlli, W.; Clozel, J. P.; el Amrani, K.; Wostl, W.; Neidhart, W.; Stadler, H.; Branca, Q. Hypertension 1991, 18, 22. (77)Ghosh, A. K.; Liu, W. J. Org. Chem. 1995, 60, 6198. (78)Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada, Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington, J. M.; Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W. J. Med. Chem. 1996, 39, 3431. (79)Velázquez, F.; Sannigrahi, M.; Bennett, F.; Lovey, R. G.; Arasappan, A.; Bogen, S. p.; Nair, L.; Venkatraman, S.; Blackman, M.; Hendrata, S.; Huang, Y.; Huelgas, R.; Pinto, P.; Cheng, K. C.; Tong, X.; McPhail, A. T.; Njoroge, F. G. J. Med. Chem. 2010, 53, 3075. (80)Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357.

58 (81)Misun, M.; Pfaltz, A. Helvetica Chimica Acta 1996, 79, 961. (82)Yuasa, Y.; Yuasa, Y.; Tsuruta, H. Can. J. Chem. 1998, 76, 1304. (83)Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195. (84)Llamas, T.; Arrayás, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 3329. (85)Desrosiers, J. N.; Charette, A. B. Angew. Chem., Int. Ed. 2007, 46, 5955. (86)Perez, D. I.; Palomo, V.; Pérez, C. n.; Gil, C.; Dans, P. D.; Luque, F. J.; Conde, S.; Martínez, A. J. Med. Chem. 2011, 54, 4042. (87)Hamon, J.; Espaze, F.; Vignon, J.; Kamenka, J.-M. Eur. J. Med. Chem 1999, 34, 125. (88)Sliwka, H. R.; Hansen, H. J. Helv. Chim. Acta 1984, 67, 434. (89)Ramberg, L.; Bäcklund, B. Chem. Abstr. 1940, 34, 4725. (90)Meyers, C. Y.; Malte, A. M.; Matthews, W. S. J. Am. Chem. Soc. 1969, 91, 7510. (91)Chan, T. L.; Fong, S.; Li, Y.; Man, T. O.; Poon, C. D. J. Chem. Soc., Chem. Commun. 1994, 15, 1771. (92)Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (93)Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796. (94)Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. (95)Himmelmann, A.; Bergbrant, A.; Svensson, A.; Hansson, L.; Aurell, M. Am J Hypertens 1996, 9, 517. (96)Doswald, S.; Estermann, H.; Kupfer, E.; Stadler, H.; Walther, W.; Weisbrod, T.; Wirz, B.; Wostl, W. Bioorganic & Medicinal Chemistry 1994, 2, 403. (97)Church, T. L.; Andersson, P. G. Coordination Chemistry Reviews 2008, 252, 513. (98)Church, T. L.; Rasmussen, T.; Andersson, P. G. Organometallics 2010, 29, 6769. (99)Church, T. L.; Rasmussen, T.; Andersson, P. G. Organometallics 2010, 29, 6769. (100)Hopmann, K. H.; Bayer, A. Organometallics 2011, 30, 2483.

59 Acta Universitatis Upsaliensis Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 983 Editor: The Dean of the Faculty of Science and Technology

A doctoral dissertation from the Faculty of Science and Technology, Uppsala University, is usually a summary of a number of papers. A few copies of the complete dissertation are kept at major Swedish research libraries, while the summary alone is distributed internationally through the series Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology.

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