Synthesis of Nitrogen-Containing Heterocycles Via Carbenoid Insertion/Ring-Closing

Home , Enyne metathesis, Insertion reaction

Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing

Metathesis Sequence

A dissertation presented to

the faculty of

the College of Arts and Sciences of Ohio University

In partial fulfillment

of the requirements for the degree

Doctor of Philosophy

Oksana M. Pavlyuk

June 2011

2 This dissertation titled

Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing

Metathesis Sequence

OKSANA M. PAVLYUK

has been approved for

the Department of Chemistry and Biochemistry

and the College of Arts and Sciences by

Mark C. McMills

Associate Professor of Chemistry and Biochemistry

Benjamin M. Ogles

Dean, College of Arts and Sciences 3 ABSTRACT

PAVLYUK, OKSANA M., Ph.D., June 2011, Chemistry and Biochemistry

Synthesis of Nitrogen-Containing Heterocycles via Carbenoid Insertion/Ring-Closing

Metathesis Sequence

Director of Dissertation: Mark C. McMills

A series of five- to nine-membered nitrogen-containing heterocycles were prepared via a general and efficient sequence featuring rhodium-catalyzed insertions of !- diazocarbonyls into the N-H or C-H bonds of a series of tert-butoxy-(Boc)-protected amines, followed by ring-closing metathesis catalyzed by ruthenium benzylidene complexes. The newly developed methodology allows easy and convenient access to highly functionalized azacycloalkenes in good yields and excellent selectivities.

Vinyl diazoacetoacetate and styryl diazoacetate were found to undergo exceptionally chemoselective carbenoid insertions into the N-H bonds of a series of Boc- protected amines in good yields; however, no stereoselectivity was observed for this process. In contrast, diastereo- and enantioselective C-H insertions and cyclopropanations were observed for the decomposition of styryl diazoacetate catalyzed by the same rhodium catalyst. Based on these findings, reactivity trends of rhodium carbenoids derived from styryl diazoacetate were postulated.

Approved: ______

Mark C. McMills

Associate Professor of Chemistry and Biochemistry 4

To my husband, Dr. Joe Slocik 5 ACKNOWLEDGEMENTS

I would like to thank my Ph.D. advisor, Professor Mark Chad McMills for agreeing to oversee my doctoral work. Under Professor McMills’ supervision, I have grown both as a scientist and as a person. During my time in Professor McMills’ group I have acquired invaluable knowledge, and for this priceless experience I will be eternally grateful. I feel that the skills I have learned during my time with Professor McMills have prepared me for the future and the world outside of Athens.

I would also like to thank my former undergraduate supervisor, Professor Tomá!

Hudlick" for introducing me to the field of organic chemistry and encouraging me to pursue the highest academic degree attainable.

I am very thankful to all the present and past group members in Professor

McMills’ lab. I would like to gratefully acknowledge Dr. Jason Stengel, who has helped me tremendously when I first joined the group; as well as the future graduates, John

Bougher and Alicia Frantz. I would like to thank all the undergraduate research associates, including Ross Humes, Katie Castor, Austin Doyle and John Feltenberger. It has been fun to have the German exchange students and I would really like to thank

Henrik Teller and Daniel Becker, with whom I was fortunate to work with. I am grateful to my friends and colleagues, Shannon Cook and Dr. Crina Orac, for sharing our graduate experience together.

I would never be able to graduate without my committee members, and I am very grateful they have guided me through my journey. I appreciate advice given by Professor

Stephen Bergmeier, as well as various reagents and solvents borrowed from his lab over 6 the years. I am very grateful to Professor Shawn Chen for his valuable discussions and suggestions. I am thankful for Professor Glen Jackson’s patience and understanding.

I am very appreciative of the Department and all the people who work here, including Carolyn Khurshid, Marlene Jenkins, Rollie Merriman and many others.

My family has always been there for me and I am very thankful for their continuours love and support.

Last but not least, I would like to thank my husband, Dr. Joe Slocik. His love and support give meaning to my undertakings and his professional expertise does not hurt either. Joe has always been insistent on me getting my work done during our trips to

Panera and although at the time I thought it was ruining our weekends, I know now that my dissertation would not have been written otherwise.

I would like to acknowledge Ohio University and Biomolecular Innovation and

Technology (BMIT) Group for financial support. 7 TABLE OF CONTENTS

Page

Abstract...... 3

Dedication...... 4

Acknowledgments ...... 5

List of Abbreviations ...... 10

List of Figures...... 11

List of Schemes ...... 13

List of Tables ...... 15

Chapter 1: Introduction...... 16

1.1 Olefin Metathesis...... 18

1.1.1 General Aspects of Olefin Metathesis ...... 18

1.1.2 Historical Perspective ...... 19

1.1.3 Mechanism and Catalytic Cycle ...... 22

1.1.4 Methodological Studies and Applications in Synthesis ...... 27

1.1.4.1 Synthesis of 5- to 7-membered Azacycles via RCM...... 28

1.1.4.2 Synthesis of 8- and 9-membered Azacycles via RCM ...... 33

1.2 Diazocarbonyl Chemistry ...... 36

1.2.1 General Aspects of Diazocarbonyl Chemistry ...... 36

1.2.2 Historical Perspective ...... 42

1.2.3 Mechanism and Catalytic Cycle ...... 44

1.2.3.1 Cyclopropanation Mechanism...... 46

8 Page

1.2.3.2 C-H Insertion Mechanism ...... 48

1.2.3.3 N-H Insertion Mechanism ...... 48

1.2.4 Methodological Studies and Applications in Synthesis ...... 49

1.2.4.1 Cyclopropanations ...... 50

1.2.4.2 C-H Insertions...... 52

1.2.4.3 N-H Insertions ...... 54

Chapter 2: Results and Discussion ...... 57

2.1 Synthetic Strategy...... 57

2.2 Synthesis of N-containing Heterocycles via N-H Insertion/RCM Sequence ...... 59

2.2.1 Preparation of Substrates ...... 59

2.2.2 Intermolecular N-H Insertions...... 61

2.2.2.1 Acceptor/acceptor-substituted Diazocarbonyls ...... 65

2.2.2.2 Acceptor/donor-substituted Diazocarbonyls ...... 67

2.2.3 RCM of N-H Insertion Products...... 69

2.2.3.1 Synthesis of 6- to 9-membered N-containing Heterocycles...... 70

2.2.3.2 Synthesis of 5- to 8-membered N-containing Heterocycles...... 72

2.2.4 One-pot Carbenoid N-H Insertions/RCM...... 74

2.3 Synthesis of N-containing Heterocycles via C-H Insertion/RCM Sequence ...... 79

2.3.1 Preparation of Substrates ...... 79

2.3.2 Intermolecular C-H Insertions and Cyclopropanations ...... 79

2.3.3 RCM of C-H Insertion Products...... 85

9 Page

2.4 Summary and Outlook...... 87

Experimental...... 90

References and Notes ...... 128

Appendix: Selected NMR Spectra...... 138

10 LIST OF ABBREVIATIONS

Ac acetyl ADMET acyclic diene metathesis Bn benzyl Boc tert-butoxycarbonyl Cbz carbobenzyloxy CM cross metathesis Cp cyclopropane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane DCM dichloromethane EDA ethyl diazoacetate Et ethyl iPr isopropyl LAH lithium aluminium hydride LDA lithium diisopropylamide mCPBA m-chloroperoxybenzoic acid Me methyl Mes mesityl Ms methanesulfonyl (mesyl) NHC N-heterocyclic carbene NMR nuclear magnetic resonance Ns p-nitrobenzenesulfonyl OiPr iso-propoxy p-ABSA p-acetamidobenzenesulfonyl azide p-DBSA p-dodecylbenzenesulfonyl azide PMB p-methoxybenzyl ppm parts per million RCM ring-closing metathesis ROCM ring-opening cross metathesis ROM ring-opening metathesis ROMP ring-opening metathesis polymerization TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butylsilyl TES triethylsilyl TFA trifluoroacetic acid TLC thin layer chromatography TMS trimethylsilyl TOF turnover frequency TON turnover number Ts toluenesulfonyl (tosyl) 11 LIST OF FIGURES

Page

Figure 1. Nitrogen-containing heterocycles ...... 16

Figure 2. Olefin metathesis catalysts...... 21

Figure 3. Chauvin mechanism for ring-closing metathesis ...... 23

Figure 4. Olefin metathesis types ...... 26

Figure 5. Classification of carbenoid intermediates ...... 36

Figure 6. Common precursors to carbenoids in order of increasing reactivity ...... 37

Figure 7. Diazo transfer reagents...... 39

Figure 8. Dirhodium catalysts ...... 40

Figure 9. Comparison of Rhodium (II) Carboxylates I, II and III...... 42

Figure 10. Chiral copper catalysts for asymetric cyclopropanations...... 44

Figure 11. General catalytic cycle of diazocarbonyl decomposition...... 45

Figure 12. Davies model for asymmetric cyclopropanations ...... 47

Figure 13. Davies model for asymmetric C-H insertions...... 48

Figure 14. N-H insertion mechanism ...... 49

Figure 15. Reactivity profile of acceptor/donor-substituted rhodium carbenoids...... 50

Figure 16. C-H insertions as surrogates of classic reactions ...... 54

Figure 17. Enantioselective transformations proceeding through the ylide Mechanisms.64

Figure 18. Carbamate resonance structures...... 69

Figure 19. Influence of the olefin substitution on RCM...... 73

Figure 20. Reactivity trend of vinyldiazoacetate 2...... 83

Page

Figure 21. Mechanistic implications of the observed product distributions...... 84 13 LIST OF SCHEMES

Page

Scheme 1. Ring-closing metathesis to form simple azacycles ...... 29

Scheme 2. Rutges synthesis of azacycles ...... 30

Scheme 3. Synthesis of sterically crowded cyclic amines...... 31

Scheme 4. Synthesis of azasugars via RCM...... 32

Scheme 5. Synthesis of bicyclic lactams via RCM ...... 32

Scheme 6. Synthesis of Ala-Gly dipeptide by Grubbs ...... 33

Scheme 7. Martin’s approach to fused bicyclic heterocycles...... 33

Scheme 8. Simple alkaloid synthesis via RCM...... 34

Scheme 9. RCM/Ring fragmentation strategy ...... 34

Scheme 10. (+)-Australine synthesis via an eight-membered ring...... 35

Scheme 11. Diastereoselectivity of the cyclopropanations with vinyldiazoacetate ...... 51

Scheme 12. Enantioselectivity of the cyclopropanations with vinyldiazoacetate ...... 51

Scheme 13. Selectivity of the C-H insertions with aryldiazoacetate...... 53

Scheme 14. Effect of ring size on N-H insertion...... 55

Scheme 15. General strategy for the synthesis of 5-10-membered heterocycles ...... 58

Scheme 16. General strategy for the synthesis of 4-9-membered heterocycles ...... 58

Scheme 17. Synthesis of acceptor/acceptor-substituted diazocarbonyl 1 ...... 59

Scheme 18. Synthesis of acceptor/donor-substituted diazocarbonyl 2...... 60

Scheme 19. Synthesis of N-H insertion substrates 5a-d...... 61

Scheme 20. Catalytic asymmetric N-H insertions with copper ferrocene bipyridine ...... 62

Page

Scheme 21. Catalytic asymmetric N-H insertions with copper spirobisoxazoline...... 63

Scheme 22. Intermolecular N-H insertions with acceptor/acceptor diazocarbonyl 1 ...... 66

Scheme 23. Intermolecular N-H insertions with acceptor/donor diazocarbonyl 2...... 68

Scheme 24. Ring-closing metathesis of N-H insertion products 6a-d...... 70

Scheme 25. Ring-closing metathesis of N-H insertion products 7a-d...... 72

Scheme 26. Two-step, three component tandem transformation ...... 75

Scheme 27. CM and carbonyl ylide formation/intramolecular cycloaddition strategy.....76

Scheme 28. Carbenoid N-H insertion/RCM strategy ...... 77

Scheme 29. Synthesis of N-Boc ethyl alkenyl amines 11a-d ...... 79

Scheme 30. Rh2(S-DOSP)4-catalyzed decomposition of vinyl diazoacetate 2 ...... 80

Scheme 31. Ring-closing metathesis of C-H insertion products 13a-d...... 85

Scheme 32. Regioselectivity of styryl diazoacetate ...... 89

15 LIST OF TABLES

Page

Table 1. Intermolecular N-H insertions with diazo ketoester 1...... 67

Table 2. Intermolecular N-H insertions with styryl diazoacetate 2...... 69

Table 3. Ring-closing metathesis of dienes 6a-d...... 71

Table 4. Ring-closing metathesis of dienes7a-d...... 74

Table 5. Comparison of the two-step process and the one-pot approach ...... 78

Table 6. Enantioselective cyclopropanation of 11a-d with 2 ...... 81

Table 7. Enantioselective C-H insertions of styryl diazoacetate 2 ...... 82

Table 8. Ring-closing metathesis of dienes 13a-d...... 87

16 CHAPTER 1: INTRODUCTION

Heterocyclic systems of the general type shown in Figure 1 are common structural motifs present in a variety of alkaloids. For example, piperidine and pyrrolidine subunits are found in naturally occurring alkaloids such as coniine and kainic acid, importance of which lies in their biological activity. Coniine is a powerful neurotoxin found in hemlock and carnivorous yellow pitcher plant and it is the very same toxin that poisoned Greek philosopher Socrates in 399 BC.1 Interestingly, this molecule was the first alkaloid to be synthesized by a German chemist Albert Ladenburg in 1886.2 Marine alkaloid kainic acid is isolated from the seaweed off the shore of Okinawa and is a potent central nervous system stimulant, which makes it useful in the study of epilepsy and

Alzheimer’s disease.3 Since these and many other alkaloids serve as the primary source of pharmaceuticals and compounds used in the studies of many biological systems, the development of new methods for their synthesis is of considerable interest to organic and medicinal chemists. A number of approaches for the synthesis of nitrogen-containing heterocycles have been developed, most leading to the formation of five- and six- membered ring systems, while the construction of seven-membered and larger heterocycles is still quite limited.4-6

Figure 1. Nitrogen-containing heterocycles 17 A great number of the existing ring-forming methodologies rely on metal- catalyzed processes4 and over the last few decades chemical catalysis has become a valuable addition to the naturally found catalysts or as they are more widely known in the scientific community, enzymes. One of the advantages of chemical catalysis over existing methodologies or enzymatic transformations is that it is more efficient than reactions requiring one or more stoichiometric equivalents of a reagent.

When it comes to catalyst design, several factors need to be considered, including catalyst activity and efficiency, which is characterized by its turnover number (TON) and turnover frequency (TOF).7 Turnover number reflects the catalyst’s resistance to consumption or decomposition during the course of the reaction, while turnover frequency effectively measures the rate of productive catalysis, i.e. the formation of products while leaving the catalyst chemically intact to react in another catalytic cycle.

Additionally, substrate scope and selectivity of any catalytic process reflect its efficiency, i.e. the extent of functional group tolerance by the catalyst as well as reaction chemo-, regio- and stereoselectivity. Finally, for any catalytic process to be industrially viable, two goals must be met: a) the catalyst should be easily recovered and re-used and b) catalyst contamination of the product should be minimal. For example, in the production of fine chemicals metal impurities are unacceptable because they can promote undesired side reactions in the subsequent reaction steps or can be incompatible in therapeutic use.

The pharmaceutical industry generally limits the acceptable contamination levels to less than 10ppm.7 Therefore, removal of metal impurities and catalyst recycling is of utmost importance to any catalytic process. 18 1.1 Olefin Metathesis

1.1.1 General Aspects of Olefin Metathesis

The unusual rearrangement of the carbon skeleton characterized by a direct and neutral scission of a double bond is known in organic chemistry as olefin metathesis.7-54

The term metathesis is derived from a Greek word “transposition” and the process itself refers to a metal-catalyzed exchange of the alkylidene moieties of two olefins.35

This simultaneous cleavage and formation of new carbon-carbon bonds has become one of the most powerful transformations utilized in organic synthesis for several reasons. First, many of the olefinic substrates are easily accessible through chemical synthesis or available from natural sources. The metathesis reaction transforms the easily prepared olefins into tri- or tetrasubstituted alkenes that are more difficult to access.35

Second, metathesis is a catalytic process that is also highly atom economic, where the re- arranged olefins are the only products and the newly formed alkenes can be isolated and utilized in synthesis. Molecules with double bonds are routinely used by organic chemists, because they are both stable and reasonably reactive in the sense that the olefinic products can be further structurally elaborated via a number of synthetic transformations including hydrogenation, epoxidation, dihydroxylation or cycloaddition.41 Finally, high yields, mild conditions and relatively short reaction times are characteristic of metathesis transformations.41

For the reasons listed above, it is not surprising that olefin metathesis has been used as a key step in the total synthesis of natural products,55 as well as in the synthesis of other synthetically useful compounds such as crown ethers,56, 57 aza sugars,58, 59 #- lactams60-64 and amino acids.65 19 1.1.2 Historical Perspective

At the dawn of olefin metathesis technology, the process was applied almost exclusively in polymer chemistry.7 Heterogeneous Ziegler-Natta type catalysts were easily obtained, but they were poorly defined with respect to the oxidation state of the metal and the nature of the ligands, as well as the actual active catalytic components.42

Additionally, their use was limited owing to long initiation periods, harsh reaction conditions and sensitivity to air and moisture.7 Although these heterogeneous catalysts found their use in several industrial processes, their high reactivity at the expense of poor compatibility with polar functional groups made them less attractive in the synthesis of advanced organic intermediates and restricted their use to the synthesis of unfunctionalized polymers.45

The opportunities for employing olefin metathesis for the synthesis of low molecular weight carbo- and heterocycles have grown considerably in the late 1980s- early 1990s with the development of structurally defined, functional group tolerant catalysts of tunable reactivities.7 This progress was in part due to the elucidation of the metathesis catalytic cycle by Chauvin et al., who postulated that the reaction mechanism proceeds via a metallacyclobutane intermediate.66 Subsequently, well-defined and highly active metal alkylidenes were developed by Richard R. Schrock67-69 and Robert H.

Grubbs.70-73

Molybdenum complex (S I, Figure 2) developed by Schrock and co-workers67-69 was employed in most metathesis reactions until the development of ruthenium alkylidenes by Grubbs et al.70-73 In terms of ease of synthesis, stability and conditions required for long-term storage, molybdenum alkylidenes are inferior to the ruthenium 20 catalysts.52 Nevertheless, although the Mo catalyst is extremely sensitive to air and moisture, it exhibits significantly higher metathesis activity than Grubbs first generation

Ru catalyst (G I, Figure 2). Examples of transformations that cannot be carried out with

G I include ring-closing metathesis to form tri- and tetrasubstituted cycloalkenes and cross metathesis of sterically hindered or electronically deactivated olefins.34

Major progress in the ruthenium metathesis catalyst design was made when N- heterocyclic (NHC) carbenes were used as ligands, thus leading to a development of second generation Grubbs catalysts (G II, Figure 2). These non-labile, sterically demanding NHC ligands with strong $-donor and poor %-acceptor properties stabilize the

14-electron reactive intermediates, resulting in greater overall activity of the ruthenium catalysts.54 Subsequently, Hoveyda and co-workers have discovered that the substitution of an OiPr group on the ruthenium phenylcarbene unit stabilizes the complex in its resting state; this reversible binding, however, opens up a coordination site in the presence of the substrate.45 This observation has led to the development of phosphine- free Hoveyda-Grubbs complexes (H-G II, Figure 2). In comparison to the phosphine- containing G II, H-G II complex exhibits improved thermal stability and is more tolerant to oxygen and moisture.18 However, the less labile benzylidene ether ligand results in a decreased initiation rate of this complex. Grubbs third generation complexes (G III,

Figure 2) are known to exhibit the fastest initiation rates among the five- or six- coordinated ruthenium complexes.18 In 2004, Piers and co-workers reported a series of

14-electron ruthenium complexes which are isoelectronic with the active methylidene species.54 Labile ligand dissociation is circumvented in these complexes and as a result, the olefin substrate can coordinate faster to the catalyst which in turn results in higher 21 catalytic activity. Incorporation of quaternary ammonium ion ligands in the ruthenium complexes gave rise to a water-soluble metathesis catalysts.54 Finally, the design of chiral molybdenum and ruthenium complexes for asymmetric metathesis has been successful to a certain degree.54

Figure 2. Olefin metathesis catalysts (iPr = isopropyl, Mes = mesityl)

The activities of Mo and Ru catalysts are, to a large degree, complementary due to the different nature of their metal-substrate interactions.35 Specifically, the Mo center acts as a Lewis acid that chelates the Lewis basicity of an olefin, but in Ru catalysts it is the alkene substrate that serves primarily as a % Lewis acid.35 Additionally, the Schrock Mo catalyst appears to be tolerant of functional groups containing “soft” electron pairs such as sulfides and amines, which has been attributed to the greater steric hindrance surrounding the molybdenum atom.52 As a result, Mo-based catalysts are catalytically active in the presence of phosphines, thioethers and primary amines, the same functionalities that decompose Grubbs first generation catalyst.54 Ruthenium catalysts, particularly the second generation and phosphine-free complexes are active in the 22 presence of carboxylic acids, amides, ketones, aldehydes and alcohols, which generally decompose molybdenum catalysts.54

1.1.3 Mechanism and Catalytic Cycle

In the classic metathesis mechanism described by Chauvin (Figure 3), olefin metathesis is thought to proceed via an intermolecular [2+2] cycloaddition between the alkylidene ligand on the ruthenium catalyst and the olefinic substrate, followed by the intramolecular cycloreversion.45 Thus, the catalytic cycle consists of a series of [2+2]- cycloadditions, metallacyclobutane intermediate formation followed by cycloreversion to give olefins with a substitution pattern different from that of the starting materials. Since all the steps of the catalytic cycle are reversible, an equilibrium mixture of olefins is obtained. Therefore, the stereochemistry of the double bond formations is difficult to control and mixtures of E and Z isomers are often obtained. Regioselectivity can be controlled to a certain extent by using 1,2-disubtituted olefins, resulting in the formation of regioisomeric metallacyclobutane intermediates, and thus leading to mixtures of differently substituted products. In reality, however, there are two reaction pathways, the minor one not involving any ligand loss from the ruthenium center. In the major reaction pathway, one of the two phosphine ligands of G I catalyst dissociates from the metal center prior to the formation of metallacyclobutane intermediate. Specifically, in the first step of the cycle one of olefins coordinates to Ru and the resulting 18-electron species suffers from severe strain and dissociates one of the phosphine ligands to re-generate the initial 16-electron complex.43 The subsequent rate-determining step is formation of the metallacyclobutane through a 90º rotation about the formal Ru-olefin bond to obtain the required co-linearity of the orbitals.43 Ring-opening of the metallacyclobutane leads to a 23 ruthenium carbene intermediate which coordinates intramolecularly to the second olefin followed by release of a volatile by-product, usually ethylene. Subsequent formation of a new metallacyclobutane and its ring-opening results in the product formation.

Figure 3. Chauvin mechanism for ring-closing metathesis (RCM)

A 14-electron ruthenium complex is believed to be the catalytically active species following the loss of phosphine from the initiating ruthenium pre-catalyst.34 Thus, the 24 catalyst precursor is converted into the true active catalyst upon the completion of the first catalytic cycle. Consequently, in the first turn of the catalytic cycle, the volatile by- product depends on the ruthenium alkylidene, while in the second and subsequent catalytic cycles it depends on the olefinic substrate.

Catalytic activity strongly depends on the catalyst structure and the nature of its ligands. The 5-coordinate, 16-electron Grubbs catalysts are based on a ruthenium atom surrounded by five ligands: two neutral electron-donating entities (e.g., trialkylphosphines, for the purpose of generalization denoted as L; or N-heterocyclic carbenes denoted as L'), two monoanionic groups (e.g., halides, X) and one alkylidene moiety (e.g., unsubstituted or substituted methylidenes).34 Ruthenium catalyst are divided into two categories based on the nature of the neutral ligand: L2X2Ru=CHR were the initial complexes developed and are referred to as first generation Grubbs catalysts (G I); while LL'X2Ru=CHR complexes were developed later and are referred to as the second generation Grubbs catalysts (G II).

The steric bulk of the phosphine ligand certainly plays a key role. When the size of the labile phosphine ligand is increased from PCy3 to PPh3, its dissociation rate is also increased and the overall catalyst initiation rate is also increased.34 The opposite size effect is observed with the halogen ligands. Small and electron-withdrawing halogens trans to the olefin substrate promote stronger olefin coordination, resulting in a more facile metallacyclobutane formation.

Since the steric and electronic properties of the residual neutral ligand in the catalytically active intermediates formed after the phosphine dissociation are decisive for the performance of the catalyst, it should be evident that more basic and sterically 25 demanding ligands than PPh3 would be important in order to increase the catalyst’s lifetime and reactivity.45 The kinetically inert and electron-donating N-heterocyclic carbine (NHC) in combination with coordinatively labile PPh3 results in the desired synergistic effect.45 This NHC ligand exhibits a significantly stronger bonding to Ru than

PPh3 due to its short Ru-NHC bond, which is formally represented as “single” bond since the ligand acts as a $-donor and has almost no %-acceptor properties.

Several different types of olefin metathesis have been classified to-date (Figure

4) and the outcome of the metathesis reaction depends not only on the type of the catalyst used, but also classified by the type of substrate undergoing metathesis. For example, the release of ring strain of a small molecule such as a cyclobutene is the driving force for ring-opening metathesis polymerization (ROMP), while the ring strain of the ring-closing metathesis (RCM) product determines the reaction outcome.50 That is, the formation of the strained eight-membered ring will be less likely than the formation of the conformationally stable six-membered cyclohexene. Therefore, ROMP is governed by enthalpic factors, while RCM is entropically driven. As with all ring-forming reactions,

RCM of the medium-sized rings is also controlled by the kinetics of ring closure and competing acyclic diene metathesis polymerization (ADMET).50 26

Figure 4. Olefin metathesis types: RCM – Ring-Closing Metathesis; ROM – Ring- Opening Metathesis; ROMP – Ring-Opening Metathesis Polymerization; ADMET – Acyclic Diene Metathesis; ROCM – Ring-Opening Cross Metathesis; RRM – Ring Rearrangement Metathesis; EM – Enyne Metathesis; CM – Cross Metathesis.

Competition between RCM and ADMET reactions can be controlled to some extent by adjusting the dilution of the reaction mixture. Specifically, dilute solutions disfavor ROMP of the RCM product, because such reaction proceeds only above the critical concentration of the cyclic compound.48 In a homogeneous series of reactions this critical concentration becomes progressively lower as the ring size of the product and thus the unfavorable interactions increase.48 Additionally, the influence of the pre- existing conformational constraints in the substrate also affects the outcome of the metathesis. That is, rotation about the bonds separating the two olefins undergoing RCM is restricted by a number of factors: normal rotational barriers around single bonds, presence of other double or triple bonds, presence of rings and hydrogen bonds.48 These 27 pre-existing conformational restraints sometimes favor RCM by bringing the reacting olefins closer together, and sometimes disfavor RCM by holding those olefins apart, especially in the formation of the smaller rings.

1.1.4 Methodological Studies and Applications in Synthesis

Olefin metathesis, particularly RCM, has become a method of choice for the synthesis of a myriad of nitrogen-containing heterocycles including various piperidine and pyrrolidine derivatives. Many of the synthetic targets obtained via RCM are used as key intermediates for the synthesis of azasugars and alkaloids. However, olefinic substrates employed in the synthesis of azacycles containing free amines are generally incompatible with ruthenium metathesis catalysts, thus limiting the scope of metathesis.

Although most ruthenium catalysts are compatible with less basic amines such as anilines, enamines and substituted pyridines, free amines inhibit catalyst activity by chelation of the basic nitrogen with the alkylidene metal compound.40 Fortunately, several strategies29 have been developed to prevent coordination of the electron pair on the nitrogen atom with metal alkylidene complexes. Unsaturated amines can be protected by conversion into a carbamate, sulfonamide or amide. In this way, poisoning of the ruthenium catalyst by the amino group is avoided by the presence of the electron- withdrawing group which decreases the electron density on the nitrogen atom. The disadvantage of such a strategy is the additional steps involving protecting group manipulations, which can reduce the efficiency of the whole synthetic sequence.

Formation of the unproductive metallacycle by chelation of metal complexes by the carbonyl oxygen of the protecting group may also occur. Protonation of the free amine and employing the corresponding ammonium salt in the subsequent metathesis may help 28 to avoid catalyst inhibition. However, this approach may not be suitable when acid- sensitive substrates are used. Finally, steric hindrance of the amine function in the olefinic substrate may prevent the coordination of the amino group to the catalyst’s metal center.

1.1.4.1 Synthesis of 5- to 7-membered Azacycles via RCM

In the early 1990s, the application of olefin metathesis shifted from the formation of defined polymers to the synthesis of low molecular weight carbo- and heterocycles. It is now generally accepted that due to the ring strain associated with small rings, three- and four-membered rings cannot be easily accessed via RCM. Instead, the olefinic substrates polymerize rapidly resulting in complex mixtures of cross-metathesis products.

On the other hand, ring-opening of small rings is a thermodynamically favorable process, and so these highly strained molecules are excellent substrates for ROMP processes.

Cyclization reactions that lead to five-, six- and seven-membered carbo- and heterocycles are known to proceed with relative ease and high efficiency.

In early reports, Grubbs and co-workers described the synthesis of 5- to 7- membered simple azacycles with Schrock molybdenum complex and Grubbs first generation ruthenium complexes as catalysts (Scheme 1).70,74

Scheme 1. Ring-closing metathesis to form simple azacycles

Six- and seven-membered lactams and azacycles were synthesized by Rutjes and co-workers (Scheme 2).75 Interestingly, the yields of the RCM-derived tetrahydropyridines shown in Scheme 2 were dependent on the nature of the protecting group R on the nitrogen. Without protection (R = H), ring closure was not observed, while Boc protection resulted in an excellent yield of product. Also, the introduction of a methyl substituent & to the carboxyl group resulted in a marked increase in the ease of

RCM. This increase in the rate of cyclization may be attributed to the so-called “Thorpe-

Ingold effect”, where increasing the size of two substituents on a tetrahedral quaternary center leads to enhanced proximity and thus reactivity between the remaining two substituents. 30

Scheme 2. Rutges synthesis of azacycles

Ring-closing metathesis of sterically crowded amines bearing an N-&- methylbenzyl protecting group showed that the efficiency of ring closure increases with the steric hindrance around the amino group (Scheme 3).76-78 Since the amine functionality is not easily accessible for binding by the ruthenium metal, olefins are the sole substrates that coordinate to the catalyst. 31

Scheme 3. Synthesis of sterically crowded cyclic amines

Facile synthesis of an azasugar scaffold has been reported by Blechert and co- workers.58,59 Ring-closing metathesis of glycine derivative, followed by a stereoselective oxidation of the newly formed double bond gave the desired azasugar derivatives in good yields (Scheme 4).

Scheme 4. Synthesis of azasugars via RCM

1.1.4.2 Synthesis of 8- and 9-membered Azacycles via RCM

Although five- to seven-membered heterocyclic rings are readily formed by

RCM, the synthesis of eight- and nine-membered rings appears to be more difficult due to enthalpic (increasing ring strain) and entropic (probability of two chain ends meeting) factors. Therefore, many of the syntheses of medium-sized rings reported in the literature tend to be on dienes attached to or fused to other ring systems. In other words, the acyclic diene precursor is “pre-organized” into a conformation that favors cyclization.

For example, attachment of the olefinic side chains to lactams promotes the RCM cyclization (Scheme 5).64

Scheme 5. Synthesis of bicyclic lactams via RCM

Grubbs and co-workers have reported the applications for their ruthenium catalyst in the synthesis of cyclic amino acids (Scheme 6).79 In this study, the synthesis of an eight- 33 membered dipeptide was accomplished using the Grubbs first generation ruthenium carbene.

Scheme 6. Synthesis of Ala-Gly dipeptide by Grubbs

Martin and co-workers have reported the synthesis of a series of bicyclic rings systems as shown in Scheme 7. Thus, it was demonstrated that RCM can be used to prepare a number of fused nitrogen heterocycles, including pyrrolizidine, indolizidine and quinolizidine alkaloid scaffolds.80

Scheme 7. Martin’s approach to fused bicyclic heterocycles 34 RCM-induced ring cyclizations to form the bicyclic heterocycles has been applied in the synthesis of simple alkaloids, such as (-)-coniceine and (S)-pyrrolam A (Scheme 8).81

Additionally, an example of a nine-membered ring synthesis was described in this report.

Scheme 8. Simple alkaloid synthesis via RCM

An interesting example of a nine-membered carbocycle synthesis using RCM as a key step was reported by Mascarenas et al.83 In this study, the overall strategy was to install a temporary one-atom internal tether to decrease the activation barrier of the ring closure.

Subsequent cleavage of the bridging tether of the resulting bicycle led to the formation of

8- or 9-membered carbocycles (Scheme 9).

Scheme 9. RCM/Ring fragmentation strategy

35 An elegant synthesis of (+)-australine, utilizing RCM as the key step to form an eight- membered ring, has been reported by White and co-workers (Scheme 10).82

Scheme 10. (+)-Australine synthesis via an eight-membered ring

In summary, olefin metathesis is a viable cyclization method for the synthesis of carbo- and heterocycles. As discussed above, diene metathesis is a method of choice for 36 the construction of biologically active molecules and is often used as a key step in many syntheses.

1.2 Diazocarbonyl Chemistry

1.2.1 General Aspects of Diazocarbonyl Chemistry

Diazocarbonyl compounds are versatile reactive intermediates capable of undergoing numerous carbon-carbon and carbon-X (X = N, O, S, halides) bond-forming transformations.84 In organic syntheses, &-diazocarbonyl compounds serve as the source of high energy species referred to as carbenoids, a term used to describe a transition metal-bound carbenes.85 Based on their structure and reactivity profile, carbenoid intermediates can be classified into three major groups: acceptor-, acceptor/acceptor- and acceptor/donor-substituted &-diazocarbonyls.105 The terms “acceptor” and “donor” refer, respectively, to the withdrawal and donation of the electron density by the functional groups flanking the carbenoid (Figure 5). Generally, an acceptor substituent makes the carbenoid species more electrophilic and more reactive, whereas a donor group makes the carbenoid more stable and thus more selective.105

Figure 5. Classification of carbenoid intermediates

Additionally, the degree of electrophilicity bestowed upon the carbenoid species is dependent on the nature of acceptor and donor group. For example, carbenoids derived 37 from diazoketones are usually more reactive than the carbenoids derived from diazoacetates, whereas the carbenoids derived from diazoacetamides are the least reactive

(Figure 6).105 Diazocarbonyls with two electron withdrawing groups tend to be indefinitely stable at room temperature, while most vinyldiazocarbonyls are stored at

-20ºC. Finally, depending on the stability of the diazocarbonyl, different amount of energy is required for its decomposition, and usually higher temperature is required for the decomposition of an acceptor/acceptor diazocarbonyl than for acceptor/donor.

Figure 6. Common precursors to carbenoids in order of increasing reactivity

38 The applications of the diazocarbonyls in syntheses followed closely the development of new methodologies for their synthesis. Generally, most of the diazocarbonyl compounds are prepared via a diazo transfer procedure, which refers to the transfer of a complete diazo group from a donor (sulfonyl azide) to an acceptor (a carbonyl derivative).84 Transfer of the diazo moiety to the &-methylene position of a carbonyl compound requires the presence of a base of sufficient strength to deprotonate the substrate. For acceptor/acceptor-substituted diazo precursors, triethylamine is strong enough to deprotonate the &-methylene prior to diazo transfer, and for acceptor/donor- substituted precursors, the non-nucleophilic base 1,8-diazobicyclo[5.4.0]undec-7-ene

(DBU) is normally used.84

Different diazo transfer donors are available to chemists, but all of them are

84 invariably sulfonyl azides. Methanesulfonyl azide (MsN3, Figure 7) is the most hazardous diazo transfer reagent, because it exhibits the highest specific heat of decomposition and the highest shock sensitivity. However, it is also superior than toluenesulfonyl (tosyl) azide for diazo transfer, its main advantage being the greater ease with which the sulfonamide by-product is removed from the reaction mixture by washing with 10% aqueous NaOH solution.84 The sulfonamide by-product of p- dodecylbenzenesulfonyl azide (p-DBSA) is an oil and this diazo transfer reagent is used when the diazocarbonyl product is a solid. Conversely, if the diazocarbonyl product is an oil, then the crystalline p-acetamidobenzenesulfonyl azide (p-ABSA) is employed in the diazo transfer since its sulfonamide by-product is a solid. 39

Figure 7. Diazo transfer reagents

Effective catalysts for diazocarbonyl decomposition are Lewis acidic transition metal complexes. Their catalytic activity depends on coordinative unsaturation at the metal center, which enables them to react as electrophiles with diazocarbonyls.84 Late transition metals in the 3rd and 4th periods such as copper, cobalt, iron, palladium, rhodium and ruthenium fit these requirements and it comes as no surprise that copper bronze was the first heterogeneous catalyst used in the decomposition of &- diazocarbonyls. Because of the coordination unsaturation of the active metal catalysts,

Lewis bases such as amines, sulfides and nitriles can associate with the metal and inhibit diazo decomposition. Halogenated hydrocarbons such as DCM and DCE are not known to coordinate with catalytically active transition metal complexes and this is why they are typically used as solvents in the diazocarbonyl chemistry.

The advent of rhodium (II) catalysts in the 1970s has provided an alternative to copper catalysts and greatly expanded the field of diazocarbonyl chemistry. Rhodium catalysts proved to be more reactive and selective than complexes derived from copper or palladium.84 Based on the ligand type, there are two major classes of rhodium catalysts – dirhodium (II) carboxylates and dirhodium (II) carboxamidates (Figure 8). Dirhodium

(II) tetraacetate was the first rhodium catalyst introduced for diazo decomposition and it can be prepared from RhCl3·xH2O via the standard Wilkinson protocol, which involves 40 refluxing rhodium (II) chloride hydrate in acetic acid containing acetic anhydride.84 Other carboxylate analogues are prepared from Rh2(OAc)4 by refluxing in a large excess of the replacing acid together with its anhydride.

Figure 8. Dirhodium catalysts

The dirhodium (II) acetate D4h symmetrical complex consists of a dinuclear core surrrounded by four bridging ligands and two axial ligands.98 The core is held together by a rhodium-rhodium single bond and each rhodium is considered to have octahedral geometry. The axial ligands are labile and so they occupy the catalytically active sites of the paddlewheel complex. However, the overall lantern structure is considered to remain intact during the catalysis. One interesting hypothesis concerning the dinuclear catalyst is that only one of the two rhodium centers serves as a carbene-binding site, while the second rhodium atom assists the diazo decomposition by serving as an “electron sink” to enhance the electrophilicity of the carbene. Another interesting suggestion is that the binding at one rhodium atom weakens the binding at the other site via the trans effect. 41 Unfortunately, it is difficult to design a mechanistic experiment to support these suggestions.

The dirhodium (II) carboxylates such as the D2 symmetrical dirhodium tetraprolinates are kinetically more active than dirhodium (II) carboxamidates due to their electron deficient character.98 Rhodium carboxamidates, on the other hand, are very electron rich due to the basicity of the carboxamide ligands and therefore catalytically less active than dirhodium carboxylates.98 The dirhodium carboxamidates are limited to complexes with overall C2-symmetry. This is because the preferred alignment of the carboxamidate ligands is cis-(2,2) configuration in which two nitrogen and two oxygen atoms are attached to each Rh in a cis fashion (Figure 8).98

It is well established that the electrophilicity of the metal carbenoid intermediate has a great influence on the selectivity of the reaction. That is, in addition to the electronic, steric and conformational effects of the substrate which reacts with metal carbenoid, the outcome of the reaction can be influenced by the nature of the metal- stabilized carbene itself. The nature of the diazocarbonyl has a marked effect on the electrophilicity of the carbenoid species as described above. In addition, the reactivity of the carbenoid can be modulated by using rhodium catalysts of different reactivity, which in turn is governed by the nature of its ligands. Electron withdrawing ligands will increase the electrophilicity of the catalyst, making it more reactive towards diazo decomposition and thus resulting in a more electrophilic and more reactive metal carbenoid. As illustrated in Figure 9, the more electron withdrawing carboxylate ligands result in a more kinetically active rhodium catalyst. However, an increased electron withdrawal by the ligands on the metal generates a more reactive carbenoid that 42 undergoes bond formation with the substrate through an earlier transition state, resulting in reduced selectivity.

Figure 9. Comparison of Rhodium (II) Carboxylates I, II and III

1.2.2 Historical Perspective

Diazocarbonyl compounds were known to chemists for more than a century now, and the first synthesis of ethyl diazoacetate (EDA) from glycine was recorded in 1883.123

Almost thirty years later, Wolff discovered the silver-catalyzed rearrangement that now bears his name.124 The Wolff rearrangement involves the reactive ketene intermediate generated from the transient carbene species, which can subsequently react with a number of nucleophiles. An extension of Wolff rearrangement is the well-known Arndt and Eistert homologation of the carboxylic acids, which became a method of choice for the synthesis of #-amino acids from the corresponding &-amino acids.125 43 However, it was not until the 1960s when the chemistry of olefin cyclopropanation with diazocarbonyls has taken off. Thus, the first report of a homogeneous chiral copper (II) catalyst used for the asymmetric cyclopropanation was published by Nozaki and co-workers in 1966.86,126 However, their initial results with copper-ligated chiral salicylaldimines showed low enantiomeric excess. Extensive efforts in chiral ligand design by Aratani have resulted in the development of chiral salicylaldimine-copper catalysts.127-129 Unfortunately, these catalysts exhibited narrow reaction scope and could only be used with certain substrates.

The next major breakthrough in the development of chiral catalysts for enantioselective cyclopropanations with diazocarbonyls came from the reports of Pfaltz and co-workers on their synthesis of chiral semicorrin copper (II) complexes.130-136

Finally, C2-symmetric bis-oxazolines were introduced as alternatives to semicorrins which have further improved the enantioselectivity of copper-catalyzed cyclopropanations.137,138

Figure 10. Chiral copper catalysts for asymmetric cyclopropanations

Introduction of dirhodium tetraacetate by Teyssié and co-workers139-142 as a homogeneous catalyst for decomposition of ethyl diazoacetate in 1973 has revolutionized the field and led to the development of many other effective rhodium catalysts. Thus, rhodium carboxamidates (pyrrolidinones, oxazolidinones, imidazolidinones or azetidinones) developed by Doyle and co-workers102,111,112,117,121,122 have emerged as effective catalysts for the transformations of acceptor- and acceptor/acceptor-substituted diazocarbonyls. Simultaneously, rhodium tetraprolinates developed by McKervey115,118 and utilized extensively by Davies92,100,101,103-106,108-110,114 proved to be the catalysts of choice for the transformations of acceptor/donor-substituted diazocarbonyls.

1.2.3 Mechanism and Catalytic Cycle

Chemists who deduce reaction mechanisms agree that it is difficult to obtain mechanistic data for the reactions of the carbenoid intermediates, because the rate 45 determining step – the loss of the nitrogen – occurs before the carbenoid has been formed.110 Consequently, information about the mechanism is obtained from the relative rates of reactions of different substrates and the product distribution that is obtained.

However, the general consensus exists where it is believed that the metal-catalyzed decomposition of the diazocarbonyl compounds proceeds via a metal carbenoid complex formed as a result of electrophilic addition of the metal catalyst to the diazocarbonyl compound (Figure 11). The loss of the nitrogen is the driving force for the transformation. It is believed that the reaction between the substrate and the carbenoid occurs without prior coordination of this substrate to the metal and so the outcome of the carbenoid transformations is governed in part by the mode of the substrate approach to the carbenoid complex.110 Transfer of the electrophilic carbene entity to an electron-rich substrate regenerates the catalytically active metal complex and completes the catalytic cycle.

Figure 11. General catalytic cycle of diazocarbonyl decomposition 46

This general mechanism, however, does not account for the chemo-, regio- and stereoselectivity trends exhibited by metal carbenoids, which depend to a great extent on the substrate, as well as on the type of the catalyst and diazocarbonyl compound. For instance, due to their low bond polarity, C-H insertions differ mechanistically from N-H insertions, which can be better described as ylide transformations. As a result, it would make sense to discuss the mechanism of each transformation separately.

1.2.3.1 Cyclopropanation Mechanism

The mechanism for the vinylcarbenoid cyclopropanations has been adequately described by Davies and is found to be consistent with the distinctive features of the vinylcarbenoid chemistry.110 First, the carbenoids derived from vinyldiazoacetates do not participate readily in the intermolecular cyclopropanations of trans 1,2-disubstituted olefins, but they react extremely well with 1,2-disubstituted, 1,1-disubstituted and 1- substituted alkenes. Second, the diastereoselectivity of the rhodium prolinate-catalyzed cyclopropanations is very high, suggesting a very specific substrate-rhodium carbenoid interactions. Third, the presence of bulky electron-withdrawing groups significantly decreases enantioselectivity and even can cause the vinylogous position of the vinylcarbenoid to become the active electrophilic site.

To account for the diastereoselectivity of the cyclopropanation, this process is explained to occur in a concerted non-synchronous mode, where the alkene approaches the vinylcarbenoid on the side of the electron withdrawing group with bulky functionality of the alkene pointing away from the face of the rhodium complex (Figure 12).110 A trans alkene is not very reactive, because it is unable to avoid having a substituent 47 pointing directly toward the rhodium surface. As the reaction proceeds, the alkene rotates outwards to form the cyclopropane ring where the substituent R1 on the alkene ends up on the same side as the vinyl group, leading to the observed stereochemistry.

Figure 12. Davies model for asymmetric cyclopropanations

The distinction between the electron donating group (vinyl or phenyl) and electron withdrawing group (carbonyl) on the carbenoid appears to be crucial, because if one of these substituents is absent as in the case of acceptor- and acceptor/acceptor- substituted carbenoids, the same level of diastereoselectivity is not observed.

To account for the enantioselectivity of the cyclopropanation, one of the two

“faces” of the D2-symmetrical catalyst must be considered. Assuming that the alkene approaches side-on over the electron withdrawing group, the attack from the back is inhibited by the arylsulfonyl group. The effect of the arylsulfonyl group would be greatest when the transition state requires close approach of the alkene to the carbenoid and this would be consistent with the observation that electron rich alkenes result in lower enantioselectivity as these substrates would be expected to have earlier transition states. Presumably, non-polar solvents would favor less charge separation and a later transition state and this is consistent with the significantly enhanced enantioselectivity when pentane is used as a solvent instead of DCM. Finally, increasing the size of the 48 ester group causes unfavorable steric interactions between the ester group and the sulfonyl group explaining why the bulky ester groups result in significantly lower enantioselectivity.

1.2.3.2 C-H insertion Mechanism

Similar to cyclopropanation, intermolecular vinylcabenoid C-H insertions catalyzed by rhodium prolinates are thought to occur in a concerted non-synchronous manner with buildup of positive charge at the carbon of the C-H bond undergoing insertion (Figure 13).108 Approach of the substrate is thought to occur over the electron withdrawing group with the C-H bond approaching side-on in the same plane as the large group L which is pointing up in the least sterically demanding position. The medium group M faces away from the catalyst while the small group S faces into the catalyst.

Figure 13. Davies model for asymmetric C-H insertions (L = Large, M = Medium, S = Small Substituent)

1.2.3.3 N-H Insertion Mechanism

Although the outcome of the N-H insertion reaction is an insertion product of a carbene into the N-H bond, mechanistically many processes are possible. These range from unanalyzed electrophilic attack of a free carbene of the diazocarbonyl as in the case of photolysis or thermolysis to a metal-stabilized ylide formation as in the case of metal catalysis.84 The general agreement is that the insertion into the N-H bond is a stepwise 49 process, where nucleophilic attack by the amine occurs on the electrophilic metal carbene to form a nitrogen ylide, which then undergoes a 1,2-rearrangement to transfer a proton from nitrogen to carbon with regeneration of the catalyst (Figure 14).

Figure 14. N-H insertion mechanism

1.2.4 Methodological Studies and Applications in Synthesis

Electrophilic vinyl carbenoids are capable of undergoing a variety of transformations (Figure 15), which makes them extremely versatile intermediates in organic synthesis. Some of these transformations, namely cyclopropanations, C-H insertions and N-H insertions are described in more detail in the paragraphs below. 50

Figure 15. Reactivity profile of acceptor/donor-substituted rhodium carbenoids

1.2.4.1 Cyclopropanations

Traditionally, cyclopropanations using diazoacetates and copper bis-oxazolines or rhodium carboxamidates were one of the most widely accepted methods for cyclopropane formation.121,122 Unfortunately, intermolecular cyclopropanations via this methodology are not very diastereoselective unless very bulky ester groups are used.114 Additionally,

Doyle’s rhodium (II) carboxamidates are not reactive enough to decompose vinyl- or aryldiazomethanes, thus limiting the scope of this methodology. Interestingly enough,

McKervey’s rhodium prolinates exhibit limited enantiocontrol in intermolecular cyclopropanations with diazoacetates, but they show exceptional diastereo- and enantioselectivity in the intermolecular cyclopropanations with Davies’ vinyl- or 51 aryldiazoacetates. Thus, vinylcarbenoid structure appears to be crucial for the high levels of stereoselectivity observed with rhodium carboxylates (Scheme 11).114

Scheme 11. Diastereoselectivity of the cyclopropanations with vinyldiazoacetate

Moreover, vinyldiazoacetate/prolinate combination is exceptional for asymmetric cyclopropanation (Scheme 12).109 As is typical of vinyldiazoacetate cyclopropanations, the E/Z ratio for the reaction in Scheme 12 was greater than 50:1. Much higher enantioselectivity was observed when pentane was used as a solvent. Rh2(S-DOSP)4 was found to be soluble in hydrocarbons at -78ºC yielding the corresponding cyclopropane in high enantiomeric excess.

Scheme 12. Enantioselectivity of the cyclopropanations with vinyldiazoacetate 52 1.2.4.2 C-H Insertions

A major advantage of carbenoid C-H activation over traditional C-H activation is a catalytic cycle which is extremely favorable, because the carbenoid rather than the metal inserts into the C-H bond.108 Traditionally, the catalysts used for diazocarbonyl decomposition were copper based, but the resulting copper carbenoids showed little tendency towards C-H insertions, much rather preferring cyclopropanations. Thus, it is clear that selective functionalization of unactivated C-H bonds is difficult, because the carbenoid must be reactive enough to cleave the strong C-H bonds but also selective and controllable enough to favor C-H insertions over other processes. Rhodium carbenoids have a greater tendency to undergo C-H insertion reactions compared to copper catalysts.

Significant progress has been made in the intramolecular C-H insertions of acceptor- and acceptor/acceptor-substituted diazocarbonyls catalyzed by Doyle’s rhodium carboxamidates. In general, five-membered ring formation is preferred in the absence of other factors, and tertiary C-H bonds exhibit greater preference for C-H insertions over the secondary and primary ones. Electron-donating substituents such as methoxy activate the adjacent C-H bonds towards insertion, while electron-withdrawing substituents such as acetoxy are deactivating. Unfortunately, intermolecular C-H insertions with these systems produce multiple products and generally require highly elecrophilic catalysts

(Scheme 13). In contrast, donor/acceptor-substituted carbenoids are very effective at intermolecular C-H insertions. These carbenoid species are still sufficiently reactive to undergo C-H insertion but are much more selective than traditional carbenoids (Scheme

13). 53

Scheme 13. Selectivity of the C-H insertions with aryldiazoacetate

Carbon-hydrogen insertions are used as surrogates for some of the classic C-C bond-forming reactions such as aldol, Michael, Mannich and Claisen rearrangement

(Figure 16).105

Figure 16. C-H insertions as surrogates for classic reactions

1.2.4.3 N-H Insertions

Although the history of N-H insertions parallels closely that of O-H insertions, this methodology attracted little attention from synthetic chemists until its use as a key step in the synthesis of thienamycin by Merck in 1978.143-145 Since then intramolecular N- 55 H insertion has become a method of choice for the synthesis of bicyclic #-lactams from

2-azetidinones.

In general, N-H bonds of amides, carbamates and aromatic amines undergo facile insertions with all diazocarbonyl types, while unprotected primary amines tend to inhibit rhodium catalysts, resulting in diazocarbonyl dimerization. Competition studies show that amides and lactams are more reactive than carbamates.146,147

Rapoport and co-workers have performed an investigation of the effect of ring size on N-H insertions.148 They have constructed a series of substrates of the general type shown in Scheme 14 where the carbamate N-H bond undergoing insertion is tethered to an &-diazo #-ketoester with carbon chains of various lengths.

Scheme 14. Effect of ring size on N-H insertion 56

In this study, cyclizations to 4- and 5-membered heterocycles occurred efficiently and effectively under rhodium catalysis. Interestingly, when an opportunity existed to form a 5-membered ring via C-H insertion or a 6-membered ring via N-H insertion, the 6- membered ring was a major product. Thus, N-H insertion was faster than C-H insertion leading to a 5-membered ring. However, when the opportunity existed to form a 5- or 6- membered ring via C-H insertion or a 7-membered ring via N-H insertion, the 5- membered ring was the major product. In this case, kinetic preference for 5-membered ring formation was preferred over the 7-membered ring formation. 57 CHAPTER 2: RESULTS AND DISCUSSION

2.1 Synthetic Strategy

We envisioned synthesis of nitrogen heterocycles of various ring sizes by combining the diazocarbonyl insertion and ring-closing metathesis technologies as shown in Scheme 15 and Scheme 16. Specifically, by utilizing the ability of diazocarbonyls to undergo N-H and C-H insertions, a variety of diolefinic substrates can be synthesized which can then be used in ring-closing metathesis to construct a series of structurally diverse heterocycles. To this end, variation in the carbenoid source was achieved by employing two different diazocarbonyl substrates, acceptor/acceptor diazoketoester 1 and acceptor/donor styryl diazoester 2. Additionally, two different trapping agents were used in the carbenoid insertion studies, 2o and 3o amines 5a-d and 11a-d, respectively. Thus, five- to ten-membered polyoxygenated heterocycles can be synthesized by employing the vinyl diazoketoester 1 (Scheme 15). Potentially, using styryl diazoester 2, four- to nine- membered azacycles can be constructed via this general synthetic strategy (Scheme 16).

Scheme 15. General strategy for the synthesis of 5-10 membered heterocycles

Scheme 16. General strategy for the synthesis of 4-9 membered heterocycles 59

2.2 Synthesis of N-containing Heterocycles via N-H Insertion/ RCM Sequence

2.2.1 Preparation of Substrates

The requisite acceptor/acceptor-substituted diazocarbonyl 1 (Scheme 17) was prepared in a straightforward manner, starting from simple, commercially available materials according to published protocols.149,150 Aldol condensation involving ethyl acetate and crotonaldehyde followed by Jones oxidation resulted in the formation of the

!,"-unsaturated ketoester as a mixture of keto-enol tautomers. Diazo transfer with triethylamine and p-ABSA gave the corresponding !-diazo-"-ketoester 1, which was stable enough to be purified by column chromatography. Isolated vinyl ketoester 1 could be stored as a 0.1 M solution in DCE for extended periods of time without any noticeable carbene dimerization.

Scheme 17. Synthesis of acceptor/acceptor-substituted diazocarbonyl 1

Styryl diazoester 2 was prepared by Fischer esterification of the commercially available trans-styryl acetic acid to give the corresponding methyl ester, which was then transformed into the !-diazocarbonyl constituent with p-ABSA as a diazo transfer agent and DBU as a base in accordance to the published procedure (Scheme 18).151 However, the work-up procedure was modified to avoid purification by column chromatography. 60 After the removal of acetonitrile, the crude reaction mixture was re-dissolved in a 4:1 mixture of hexanes:ethyl acetate, and the insoluble sulfonamide by-product was removed by filtration. Freshly prepared vinyl diazoacetate was used immediately in the N-H insertion reactions to prevent its electrocyclization to the corresponding 1H-pyrazole.152

Scheme 18. Synthesis of acceptor/donor-substituted diazocarbonyl 2

Protection of the commercially available allyl- and butenylamines 3a and 3b, respectively, as their Boc-derivatives produced the corresponding carbamates 5a and 5b in excellent chemical yields (Scheme 19).153,154 Pentenyl- and hexenylamines were prepared from the corresponding nitriles 4a and 4b via LAH reduction,153,154 followed by their conversion into N-Boc protected alkenyl amines 5c and 5d.

Scheme 19. Synthesis of N-H insertion substrates 5a-d

2.2.2 Intermolecular N-H Insertions

Rhodium carboxylate catalyzed decomposition of substituted !-diazocarbonyl olefins 1 and 2, in the presence of a series of N-Boc-protected amines 5a-d (Scheme 22 and 23), resulted in an efficient carbenoid insertions of the carbamate N-H bond.

Commercially available inexpensive rhodium acetate II (Figure 9) was used initially for this transformation; however, most of the reactions were performed with chiral rhodium prolinate I, because the yields were comparable to dirhodium tetraacetate-catalyzed insertions and it was interesting to see if asymmetric induction was possible. This was a reasonable expectation since some evidence exists for the enantioselective carbenoid insertions into the N-H bonds of amines and carbamates.155-157 For example, Fu and co- workers have reported on the use of chiral copper ferrocene bipyridine catalyst in the coupling of aryl &-diazo esters with Boc- or Cbz-protected primary amines (Scheme

20).153 In this study, it was found that stereoselectivity decreases as the steric bulk of the ester decreases, and silver salt such as AgSbF6 is required to remove the bromine from the copper prior to the formation of the active catalyst. 62

Scheme 20. Catalytic asymmetric N-H insertions with copper ferrocene bipyridine

In another study, copper spirobisoxazoline-catalyzed enantioselective N-H insertions were performed with a series of aromatic amines and &-diazoesters providing

&-amino acid derivatives in high yields and excellent enantioselectivities (Scheme 21).154

One of the shortcomings of this transformation is the limited substrate scope with respect to the N-H component, which had to be an aromatic amine, as well as the diazo component, which was limited to diazopropanoate. 63

Scheme 21. Catalytic asymmetric N-H insertions with copper spirobisoxazoline

In addition to the enantioselective N-H insertion studies (vide supra), reports by Hodgson and co-workers verify that asymmetric induction is possible for the transformations proceeding via an ylide-like mechanisms.158-161 Specifically, Hodgson et al. have reported enantioselective rhodium-catalyzed tandem carbonyl ylide formation-cycloaddition of diazocarbonyls (Figure 17), arguing that the rate of cycloaddition was faster than the rate of catalyst decomplexation from the ylide intermediate thus resulting in the observed asymmetric induction. Since the mechanism of the N-H insertion is thought to proceed through the ylide-like intermediates, asymmetric induction was expected. In our studies, however, N-H insertion products were not optically active, suggesting either “free” ylide intermediates or a very early transition state where the bond formation takes place too far away from the catalyst-associated ylide.

a) Asymmetric ylide formation/cycloaddition

b) Asymmetric N-H insertion

Figure 17. Enantioselective transformations proceeding through the ylide mechanisms

On the other hand, exceptional chemoselectivity was observed in the intermolecular N-H insertions. Reactive rhodium carbenoids are known to undergo a number of significant synthetic transformations (Figure 15), and in the current study, intermolecular C-H insertions or cyclopropanations were possible reactions in addition to the anticipated N-H insertions. However, N-H insertion was the only observed process under the reaction 65 conditions employed, suggesting that a nucleophilic attack by nitrogen at the electrophilic rhodium carbenoid is faster than the other processes. The unique chemoselectivity observed with this system allowed the utilization of the pendant olefins in the subsequent ring-closing metathesis (vide infra).

Interestingly, simple substrates such as allylamine were found to be unsuitable for the N-H insertion reaction. It appears that the rhodium catalyst was poisoned, as evidenced by the change of the color of the reaction mixture from green to pink, likely an oxidation state change for rhodium metal. Moderation of the reactive nitrogen via formation of the trifluoroacetamide was thought to increase the overall reaction yields due to greater polarization of the N-H bond undergoing insertion, but no insertion products were isolated. It is likely that the trifluoroacetamide derivative moderated the reactivity of the nitrogen too severely to react with the rhodium carbenoid. Fortunately, formation of the tert-butoxycarbonyl protecting group provided the necessary degree of nucleophilicity of the nitrogen without any attendant catalyst poisoning, providing the N-

H insertion products in reasonable chemical yields.

2.2.2.1 Acceptor/acceptor-substituted diazocarbonyls

Substitution of the diazocarbonyl compound with two electron withdrawing groups makes this chemical species rather stable (vide supra); indeed, diazo ketoester 1 did not dimerize at room temperature for extended periods of time. Moreover, decomposition of 1 with rhodium catalyst required elevated temperatures, and all reactions with this compound were carried out at reflux. The corresponding rhodium carbenoid, however, is highly reactive as a result of its pronounced elecrophilicity which is the consequence of the substitution pattern. This reactivity was evidenced by the fact 66 that only 1.5 equivalents of the N-Boc alkenylamine were required to trap the highly electrophilic rhodium carbenoid. Diazocarbonyl compound 1 (5 mL of 0.2 M solution in

DCE) was added drop wise over a period of 0.5 h to the solution of rhodium catalyst and

N-Boc alkenyl amine at reflux and was consumed immediately as indicated by TLC of the reaction mixture. The reaction remained green throughout, good evidence of the regeneration of the rhodium catalyst.

Scheme 22. Intermolecular N-H insertions with acceptor/acceptor diazocarbonyl 1

The yields of the N-H insertion products decreased slightly as the length of the carbon chain increased in the N-Boc alkenyl amine substrates (Table 1).

Table 1. Intermolecular N-H insertions with diazo ketoester 1

Entry N-H insertion product % Yielda

1 78

2 79

3 72

4 73

aIsolated yields after chromatography

2.2.2.2 Acceptor/donor-substituted Diazocarbonyls

In contrast to vinyl diazoketoester 1, decomposition of styryl diazoacetate 2

(Scheme 23) was accomplished at room temperature. Functionally, the reaction required a dilute solution (10 mL of 0.1 M in DCE) and a slow addition rate (0.1 mL/min) for effective diazo decomposition. Moreover, the reaction required more than 3 equivalents 68 of the trapping agent to ensure the effective capture of the rhodium-stabilized carbenoid intermediate.

Scheme 23. Intermolecular N-H insertions with acceptor/donor diazocarbonyl 2

Rapid addition (0.2 mL/min or greater) of the diazocarbonyl solution to the carbamate substrate caused the reaction solution to become yellow (catalyst poisoning as evidenced by the change of the oxidation state of the metal) and resulted in very low isolated yields of the insertion products. Changing reaction conditions by using a slow addition rate (0.1 mL/min) produced the best yield for this diazocarbonyl system (Table 2, entry 1). This marked difference in reactivity can be explained by the decreased electrophilicity of the rhodium carbenoid derived from the acceptor/donor-substituted diazocabonyl. That is, acceptor/donor diazocarbonyl is less stable and will decompose readily in the presence of rhodium catalyst at room temperature; however, the corresponding rhodium carbenoid is less electrophilic and therefore less reactive towards insertion substrate.

Broadening of the 1H NMR signals was observed for 7a-d and this is thought to be due to restricted rotation about the amide bond of the bulky tert-butoxycarbonyl group

(Figure 18). Similarly, multiple 13C signals were observed for the carbons in close proximity to the carbamate nitrogen. Assignment of the spectra for all compounds 69 containing the carbamate group was difficult because of this signal broadening and multiplicity.

Figure 18. Carbamate resonance structures

Table 2. Intermolecular N-H insertions with styryl diazoacetate 2

Entry Product % Yielda Entry Product % Yielda

1 55 3 45

2 51 4 50

aIsolated yields after chromatography

2.2.3 RCM of N-H insertion Products

Rhodium carbenoid N-H insertion reactions have provided a series of substrates with olefinic tethers that are strategically positioned for a ring-closing metathesis reaction to form rings of 5-9 atoms. Interestingly, two different sets of reaction conditions were developed for each substrate type. Specifically, for dienes 6a-d, 2nd generation Grubbs catalyst (G II) in dichloromethane were found to give the best results, whereas for dienes 70 7a-d, Hoveyda-Grubbs 2nd generation (H-G II) in dichloroethane provided the best results. Thus, a more active catalyst, higher temperatures and greater catalyst loading

(Scheme 24 and 25) were required to cyclize substrates 7a-d.

2.2.3.1 Synthesis of 6- to 9-membered N-containing Heterocycles

Ring-closing metathesis of dienes 6a-d in the presence of Grubbs 2nd generation catalyst resulted in the formation of a series of substituted azacycles as shown in Scheme

24. Surprisingly, it appears from spectroscopic data that azacycles 8a and 8b were isolated when n = 1 and 2, both 8c and 9a were isolated when n = 3 and 9b only was isolated when n = 4. Formation of azacycles 8a-c could not be rationalized easily, as the azacycles have seemingly undergone some reduction process and although tautomerization of the initial RCM product is likely, reduction of the resulting enamine moiety is unlikely.

Scheme 24. Ring-closing metathesis of N-H insertion products 6a-d

Azacycles 9a,b were present as complex mixtures of amide conformers and flexible conformers as evidenced by their 1H NMR spectra. The difficulty of forming eight- and nine-membered rings is reflected in the dramatically lower chemical yields found for azacycles 9a and 9b (Table 3, entry 4 and 5). 71 Table 3. Ring-closing metathesis of dienes 6a-d

Entry RCM product % Yielda

1 85

2 96

3 <5

4 54

5 56

aIsolated yields after chromatography 72

2.2.3.2 Synthesis of 5- to 8-membered N-containing Heterocycles

Cyclization of dienes 7a-d in the presence of Hoveyda-Grubbs 2nd generation led to the formation of azacycles 10a-d as shown in Scheme 25. Although numerous examples of RCM with substrates similar to dienes 7a-d exist in the literature,162-165 one potential problem with this type of system was the formation of stable six- or five- membered chelates between the ester carbonyl group and the Lewis acidic metal of the intermediate alkylidene carbene (Figure 19).39 In our case, formation of the five- membered chelate was avoided by using differently substituted olefins and thus directing the initial cyclobutane formation at the mono-substituted double bond in the carbon chain tethered to the nitrogen. Therefore, due to the different reactivity of the two olefins, i.e. less sterically crowded mono-substituted alkene reacting faster with the ruthenium catalyst, the catalytic cycle was controlled by forming regiospecific metallacyclobutane intermediates (Figure 19). As a result, the formation of the five-membered chelate was avoided as evidenced by the excellent chemical yields of the RCM products (Table 4).

Scheme 25. Ring-closing metathesis of N-H insertion products 7a-d

a) Metal chelates unreactive in RCM

b) Regiospecific RCM

Figure 19. Influence of the olefin substitution on RCM

Cyclized azacycles 10a-d were isolated as complex mixtures of amide rotamers and flexible conformers as evidenced by the multiple signals in their 1H and 13C spectra.

Eight-membered azacycle 10d was isolated in 65% yield (Table 4, entry 4) and although the yield is moderate, such decreased cyclization efficiency is characteristic in the formation of 8- and 9-membered rings, which is mainly due to angle and torsional strain associated with the formation of the medium-sized rings.

74 Table 4. Ring-closing metathesis of dienes 7a-d

Entry RCM product % Yielda

1 88

2 94

3 80

4 65

aIsolated yields after chromatography

2.2.4 One-pot Carbenoid N-H Insertions/RCM

Once the sequential intermolecular N-H insertions of 1 and 2 with N-Boc alkenyl amines 5a-d followed by RCM proved to be viable reactions, the development of one-pot process was needed to provide a more efficient manner of generating azacycles.166

Tandem reactions are especially applicable to industrial processes. As the tandem process 75 is highly atom economical transformation, the extension of the stepwise methodology toward the one-pot process was particularly appealing.

Many examples of tandem processes are known in the literature.167-172 For example, Davies and co-workers have developed an enyne metathesis/Rh-catalyzed [4+3] cycloaddition coupling strategy for the enantioselective synthesis of highly functionalized cycloheptadienes (Scheme 26).173 In this two-step, three-component coupling strategy, the first step is based on the enyne metathesis between alkynes and vinyl ethers to form

3-substituted-1-alkoxy-1,3-dienes. The second step in the sequence is the is the Rh2(S-

DOSP)4-catalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes. The success of this two-step, three-component coupling depends on the selectivity of rhodium vinylcarbenoid, i.e. its ability to undergo cyclopropanation at the 1,1-disubstituted double bond in preference to the trans-substituted olefin.

Scheme 26. Two-step, three component tandem transformation 76 In another example, Hodgson and co-workers have performed one-pot cross metathesis in tandem with carbonyl ylide formation/intramolecular cycloaddition of unsaturated &-diazo-#-keto esters (Scheme 27).174-176 It was found that olefin cross metathesis can proceed in the presence of dicarbonyl-stabilized diazo functionality, which will allow for the generation of a large number of unsaturated diazo compounds.

The diazo functionality left intact during the cross metathesis reaction can subsequently be used for carbonyl ylide formation, which can ultimately undergo intramolecular cycloaddition with the newly formed olefin.

Scheme 27. CM and carbonyl ylide formation/intramolecular cycloaddition strategy

Encouraged by the viability of the aforementioned one-pot examples, we have combined the carbenoid N-H insertion and RCM reactions in a one-pot procedure for the construction of nitrogen-containing heterocycles of varying sizes and functionality166 77 (Scheme 28). To ensure the success of our chosen tandem process, several factors were considered. For example, the initial N-H insertion had to be chemoselective at low catalyst loadings with minimal equivalents of the trapping agent to avoid side reactions.

Also, the reaction conditions of each step in the sequence had to be tuned carefully in order to minimize the formation of byproducts and to avoid the suppression each subsequent step in the sequence.

Scheme 28. Carbenoid N-H insertion/RCM strategy

In the case of the vinyldiazoacetate 2, the one-pot procedure was quite successful, resulting in the formation of aza-heterocycles 10a-d in yields comparable or better than the sequential process (Table 5). 1 mol% of rhodium catalyst was determined to be optimal for diazo decomposition and 1.5 molar equivalent of N-Boc alkenyl amine (based on methyl styryl diazoacetate 2) was found to give the best results. The progress of the N- 78 H insertion reaction was monitored by TLC for the disappearance of 2, followed by the addition of Grubbs catalyst to the reaction mixture. Unfortunately, under these conditions no metathesis products were isolated, suggesting inhibition of the ruthenium catalyst by the rhodium metal. In order to minimize exposure of the Grubbs catalyst to the rhodium metal, the products of the insertion reaction were slowly added to a solution of metathesis catalyst. Thus, N-H insertion products 7a-d were added via cannula to a solution of the

Grubbs catalyst at reflux and the reaction mixture continued to be heated at reflux until the disappearance of compounds 7a-d by TLC.

Table 5. Comparison of the two-step process and the one-pot approach

a a Compound Two-Step (yield %) One-Pot (yield %) 10a 48 % 42 %

10b 47 % 57 % 10c 36 % 31 %

10d 32 % 30 % aIsolated yield after chromatography

Unfortunately, the same tactic was not successful for the compounds 6a-d, suggesting the inhibition of the ruthenium catalyst by the rhodium metal before the RCM with this particular system could be initiated. One possible solution would be to modify the olefinic substrates by making the alkenes more electron-rich and thus more reactive towards metathesis. 79 2.3 Synthesis of N-containing Heterocycles via C-H Insertion/RCM Sequence

2.3.1 Preparation of Substrates

The requisite substrates 11a-d (Scheme 29) were prepared by N-alkylation of the

N-Boc protected amines 5a-d according to a published procedure.177 Ease of synthesis and excellent overall yields for the preparation of these substrates is one of the attractive features of this study. This structural modification of the N-H insertion substrates 5a-d eliminated the highly polarized N-H bond and presented rhodium carbenoid with electronically activated C-H bonds.

Scheme 29. Synthesis of N-Boc ethyl alkenyl amines 11a-d

2.3.2 Intermolecular C-H Insertions and Cyclopropanations

Substrates 11a-d were subsequently used as trapping agents in the rhodium- catalyzed reactions with vinyldiazoacetate 2. Regioselective C-H activation & to the nitrogen atom was first reported by Davies et al., where the authors described unprecedented selective carbenoid insertion into the C-H bond of a methyl group over the electronically favored allylic site.178 Based on this seminal study, we decided to test the chemo- and regioselectivity of the acceptor/donor carbenoid derived from vinyldiazoacetate with a series of simple N-Boc-protected ethyl amines 11a-d. 80 Specifically, we wanted to see which of the two methylene C-H bonds, & to the nitrogen would be prone to activation.

Similar reaction conditions as in the case of N-H insertions were employed in the current study. A dilute solution of vinyldiazoacetate 2 was slowly added to the mixture of

1mol% Rh2(S- or R-DOSP)4 and excess trapping agent, maintaining a green solution throughout the reaction period. Completion of the reaction was monitored by the disappearance of 2 by TLC.

Interestingly, cyclopropanation products 12a-d were found in addition to the C-H insertion products 13a-d, obtained in a 2:1 ratio (Scheme 30). The chemoselectivity of this reaction was unaffected by the choice of the rhodium catalyst (Rh2(OAc)4, Rh2(pfb)4,

Rh2(TFA)4, Rh2(TPA)4) or solvent (hexanes, benzene). Acceptor/acceptor-substituted diazoketoester 1 did not participate in the intermolecular C-H insertions, resulting in the recovery of starting materials 11a-d.

Scheme 30. Rh2(S-DOSP)4-catalyzed decomposition of vinyl diazoacetate 2

Thus, 100% consumption of the vinyl diazoacetate 2 resulted in the combined chemical yields of 82-96%, with both the cyclopropanes and the C-H insertion products formed predominantly as single diastereomers with high enantioselectivities (Table 6 and 81 Table 7). Relative stereochemistry of the isolated products was determined by NOE correlation experiments and was tentatively assigned according to Davies stereochemical model (Figure 12 and Figure 13). Enantiomeric excess of both the C-H insertion and cyclopropane products were determined by chiral stationary phase HPLC on the (R,R)

Whelk-O 1 column. Utilization of the opposite catalyst antipode resulted in the formation of the opposite enantiomer.

Table 6. Enantioselective cyclopropanation of N-Boc alkenyl amines 11a-d with styryl diazoacetate 2

Entry Cp product Yield %a de %b ee %c

1 64 95 96

2 61 98 92

3 59 98 95

4 55 98 92

aIsolated yield after chromatography bDetermined by 1H NMR of crude material cDetermined by chiral HPLC on a (R,R)-Whelk-O 1 column

Table 7. Enantioselective C-H insertions of styryl diazoacetate 2 into C-H bond of N- Boc alkenyl amines 11a-d

Entry C-H ins. product Yield %a de %b ee %c

1 32 90 92

2 30 94 90

3 28 98 85

4 27 98 83

aIsolated yield after chromatography bDetermined by 1H NMR of crude material cDetermined by chiral HPLC on a (R,R)-Whelk-O 1 column

83 Interestingly, no C-H insertion reaction occurred at the methylene C-H bonds of the alkenyl side chain, resulting in highly regioselective C-H activation of the ethyl methylene. Since the two methylenes & to the nitrogen are somewhat similar on the electronic grounds, the exclusive activation of the ethyl methylene may be a result of the acceptor/donor rhodium carbenoid’s steric demand as described by Davies and co- workers.178 No C-H insertions was observed at the methyl position of the ethyl substituent, likely a result of C-H bonds # to the nitrogen not being electronically activated.

Considering the fact that no cyclopropanation was observed with substrates 5a-d and that the product distribution with substrates 11a-d shows the 2:1 ratio of cyclopropanes to C-H insertion products, it becomes evident that N-H insertion is a faster process, followed by cyclopropanation and then insertion into an electronically activated

C-H bond (Figure 20).

Figure 20. Reactivity trend of vinyldiazoacetate 2

Additionally, employing the same vinyldiazoacetate/chiral catalyst system, no asymmetric induction was observed in the case of N-H insertion, while C-H insertion and cyclopropanation products were obtained in greater than 90% enantiomeric excess. This observation leads to speculation that N-H insertions are mechanistically different 84 processes from C-H insertions and cyclopropanations. N-H insertions can be thought to proceed via ylide-like intermediates, where decomplexation of the chiral catalyst from the active intermediates is likely (Figure 21a). Alternatively, this transformation may proceed through an early transition state, where bond formation between the reacting species may occur at greater distances from each other, and little or no influence of the chiral catalyst is observed. This early transition state may be a result of greater polarization of the N-H bond in comparison to the C-H bond. Therefore, nitrogen is a better nucleophile and competing processes such as cyclopropanation are suppressed resulting in a highly chemoselective transformation.

a) Stepwise N-H insertion process

b) Concerted C-H insertions and cyclopropanations

Figure 21. Mechanistic implications of the observed product distributions 85 In contrast, C-H insertion and cyclopropanation reactions can be viewed as concerted 3-bond processes (Figure 21b). As a result of lower bond polarity, C-H bonds and olefins are weaker nucleophiles, thus the presence of the neighboring electron- donating groups is necessary to stabilize the positive charge buildup. However, this low bond polarity may result in a later transition state allowing the chirality transfer from the catalyst to the newly forming bond of the reacting species. This transfer of chiral information is possible if the bond breaking and new bond formation with carbene carbon proceeds at the same time as the ligated rhodium catalyst dissociates.158-161

2.3.3 RCM of C-H Insertion Products

The C-H insertion products 13a-c were treated with Hoveyda-Grubbs second generation catalyst in refluxing DCE, resulting in a rapid intramolecular metathesis reaction to produce the corresponding azacycloalkenes 14a-c (Scheme 31) as a mixture of conformers/rotamers in 95-98% isolated chemical yields, with 92-95% enantioselectivity (Table 8).179

Scheme 31. Ring-closing metathesis of C-H insertion products 13a-d

Unfortunately, no nine-membered ring was isolated when 13d was subjected to the RCM conditions described above. Milder reaction conditions (Grubbs I or Grubbs II catalysts, 86 DCM, r.t.) did not change the reaction outcome and decomposition products were the only products isolated in each case.

The one-pot protocol developed for the carbenoid N-H insertions/RCM was attempted in this study, but unfortunately only complex mixtures of products were obtained, with no metathesis products isolated. This may be due to the competing cyclopropanation which complicates the subsequent metathesis step by allowing cross- metathesis and polymerization processes to take place in addition to the desired intramolecular metathesis process. 87 Table 8. Ring-closing metathesis of dienes 13a-d

Entry RCM product Yield %a de %b ee %c

1 98 >98 93

2 96 >98 95

3 95 >98 92

4 – d – d – d

aIsolated yield after chromatography bDetermined by 1H NMR of crude material cee was determined by chiral HPLC on a (R, R)-Whelk-O 1 column dNot isolated

2.4 Summary and Outlook

A general synthetic strategy has been developed that allows easy access to nitrogen-containing heterocycles of varying ring sizes. A series of five- to nine- 88 membered azacycloalkenes were prepared via an efficient two-step sequence featuring chemoselective rhodium catalyzed insertion of an &-diazocarbonyl into the N-H bond of the Boc-protected amines with subsequent ring-closing metathesis catalyzed by ruthenium benzylidene complex. In addition, a one-pot, two-component coupling was developed for the synthesis of five- to eight-membered azacycles 10a-d. The isolated yields of the one-pot process are comparable or better in one case to those of the sequential reaction series and thus, this protocol can be utilized in the construction of biologically relevant heterocycles on an industrial scale.

A series of six- to eight-membered nitrogen-containing heterocycles was synthesized by employing the aptitude of the vinyl &-diazocarbonyls to insert into activated C-H bonds in a highly regio-, diastereo- and enantioselective fashion. In addition to regioselective C-H insertions, cyclopropanes 12a-d were obtained in good chemical yield and high enantiomeric excess. Subsequent ring-closing metathesis of the

C-H insertion products allowed easy access to the highly functionalized azacycloalkenes

14a-c.

Interesting chemoselectivity trends of the acceptor/donor rhodium carbenoid species were observed. In contrast to the N-H insertion, where no cyclopropanation products were detected, alkene addition is a predominant process when given a choice between it and the C-H insertion reaction. Finally, while no enantioselectivity is observed for the N-H insertion, the identical combination of the rhodium catalyst and acceptor/donor carbenoid yields cyclopropanation and C-H insertion products in high enantiomeric excess. Given these findings, the synthetic task becomes to modify the existing methodology in a way that would allow for the synthesis of nitrogen 89 heterocycles in both chemo- and stereoselective fashion. For example, a series of tertiary amines could be synthesized with a substitution pattern shown in Scheme 32. Utilizing this type of alkenyl amines as trapping agents in the styryl diazoacetate decomposition, regioselectivity of this transformation could be re-examined. Namely, would the C-H activation occur at the sterically crowded methine site or the methylene site & to the nitrogen? Finally, to address the stereoselectivity of the intermolecular N-H insertions, chiral copper catalysts (Scheme 20 and Scheme 21) need to be considered as alternatives to rhodium prolinates.

Scheme 32. Regioselectivity of styryl diazoacetate 90 EXPERIMENTAL

General materials and methods:

All reactions were carried out under an argon atmosphere and anhydrous conditions unless otherwise noted. Dichloroethane (DCE) and acetonitrile (MeCN) were dried over

CaH2 and then distilled. Dichloromethane (DCM) and tetrahydrofuran (THF) were dried using Solv-Tek, Inc. column purification/drying system, which uses low pressure nitrogen or argon gas to force solvents through various filter materials that remove moisture and impurities from the solvents. Reagents purchased from commercial sources were used without further purification unless noted otherwise. Analytical TLC was performed on 0.25 mm silica gel (60 F254) plates purchased from EMD Chemicals, Inc.

UV light and potassium permanganate solution (1.5 g KMnO4, 10 g K2CO3, 1.25 mL

10% NaOH in 200 mL H2O) as visualizing agents. Flash column chromatography was carried out using Merck silica 60 (230-400 mesh). 1H NMR spectra were recorded at 300

MHz on a Bruker AVANCE-300 spectrometer. 13C NMR spectra were recorded at 75

MHz. Chemical shifts (') are quoted in parts per million (ppm) downfield from tetramethylsilane (TMS). Multiplicities are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet or overlap of non-equivalent resonances; br, broad.

Infrared spectra were obtained on a Shimadzu FTIR-8400 spectrometer as neat oils. GC analyses were performed on a HP-5890 gas chromatograph fitted with a RTX-OPP capillary column (30 m x 0.25 mm x 0.25 µm); flow rate: 1 mL/min. MS analyses were performed on a 5971 Single Quad mass spectrometer using 70 eV electron impact (EI) ionization. Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA.

Melting points (mp) were recorded on a capillary melting point apparatus and are uncorrected. 91

(E)-ethyl 2-diazo-3-oxohex-4-enoate (1).

Freshly distilled diisopropylamine (15.7 mL, 112.2 mmol) in 202 mL anhydrous THF was cooled to 0ºC and n-butyllithium (74.8 mL, 112.2 mmol) was added via the syringe.

The reaction was stirred at 0ºC for 15 min and then cooled to -78ºC. Freshly distilled ethyl acetate (10 mL, 102 mmol) was added dropwise so that the internal temperature did not exceed -65ºC. When the addition of ethyl acetate was complete, the reaction was stirred at -78ºC for 1h. A 2 M solution in THF of freshly distilled crotonaldehyde (8.4 mL, 102 mmol) was added via cannula and reaction mixture was stirred at -78ºC for another hour. Reaction mixture was quenched with 50 mL saturated NH4Cl solution and extracted 3x50mL Et2O. Combined organic layers were washed with brine, dried over

Na2SO4, concentrated and crude yellow oil was used in the next step.

Crude aldol product was dissolved in 204 mL acetone and cooled to 0ºC. Jones reagent

(12 g CrO3, 11 mL conc. H2SO4 in 80 mL dist. H2O) was added via a dropping funnel and reaction mixture was allowed to warm up to room temperature overnight. Methanol

(10 mL) was added to quench the excess Jones reagent and reaction mixture was extracted 3x100 mL Et2O. Combined organic layers were washed with brine, dried over

Na2SO4 and concentrated under reduced pressure.Vacuum distillation gave 10.5 g (66%) of pure product as a yellow oil.

92 To the solution of (E)-ethyl 3-oxohex-4-enoate (780 mg, 5.0 mmol) and p- acetamidobenzenesulfonyl azide (p-ABSA) (1.3 g, 5.5 mmol) in 25 mL anhydrous MeCN at 0ºC was added dropwise freshly distilled (CaH2) triethylamine (0.8 mL, 5.5 mmol).

Reaction mixture was allowed to warm up to room temperature and then it was diluted with 50 mL of 4:1 Hex:EtOAc. White sulfonamide was removed by filtration through a short SiO2 plug, and crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 850 mg (94%) of the title compound as a yellow oil. IR (NaCl disc) 2983, 2939, 2912, 2135, 1716, 1612 cm-1; 1H NMR (300 MHz,

CDCl3): ' [ppm] 1.33-1.38 (t, 3H, J=7.1 Hz), 1.94-1.97 (dd, 3H), 4.29-4.36 (q, 2H, J=7.1

13 Hz), 7.04-7.13 (m, 1H), 7.18-7.25 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 14.34,

18.37, 61.42, 76.58, 126.61, 143.35, 161.40, 181.66.

(E)-methyl 2-diazo-4-phenylbut-3-enoate (2).

Concentrated H2SO4 (0.5 mL, 9 mmol) was added to the solution of trans-styryl acetic acid (6 g, 37 mmol) in 15 ml methanol and the reaction mixture was heated at reflux overnight. Reaction mixture was diluted with 50 mL ethyl acetate, and washed once with

10 mL saturated NaHCO3. Organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (4:1 hexanes:ethyl acetate) gave 6 g (92%) of title compound as a yellow oil.

93 To the solution of (E)-methyl 4-phenylbut-3-enoate (704 mg, 4.0 mmol) and p- acetamidobenzenesulfonyl azide (p-ABSA) (1.06 g, 4.4 mmol) in 10 mL anhydrous

MeCN at 0ºC was added dropwise 0.5 M solution of 1,8-diazabicyclo[5.4.0]undec-7-ene

(DBU) (670 mg, 4.4 mmol in 8.8 mL MeCN). Reaction mixture was stirred at 0ºC under argon for 1h. Acetonitrile was removed under reduced pressure and residue was re- dissolved in 4:1 Hex:EtOAc (20mL). White sulfonamide was removed by filtration through a short SiO2 plug to give 750 mg (93%) of the title compound as a red oil. IR

(NaCl disc) 3082, 3060, 3028, 2954, 2082, 1708, 1438, 1247 cm-1; 1H NMR (300 MHz,

CDCl3): ' [ppm] 3.73 (s, 3H), 6.06-6.12 (d, 1H, J=16.3 Hz), 6.35-6.40 (d, 1H, J=16.3

13 Hz), 7.09-7.26 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 52.30, 77.32, 111.30,

123.12, 125.88, 127.11, 128.71, 136.82, 165.56.

tert-Butyl allylcarbamate (5a).

To the solution of allylamine (5.0 g, 87.7 mmol) and freshly distilled (CaH2) triethylamine (26.8 mL, 192.9 mmol) in anhydrous DCM (100 mL) at 0ºC was added

Boc2O (21.1 g, 96.5 mmol) in two portions. Reaction mixture was allowed to warm up to room temperature overnight. Solvent was removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 13 g (95%) of the title compound as a white solid. IR (NaCl disc) 2979, 2931, 2358,

-1 1 1680, 1521 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.38 (s, 9H), 3.66 (s, 2H), 4.66 94 13 (br s, 1H), 5.07 (m, 2H), 5.78 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 28.37,

43.06, 79.33, 115.64, 134.92, 155.77; m/z (relative intensity) 57(100), 41(92), 28(31).

tert-Butyl but-3-enylcarbamate (5b).

To the solution of 3-butenylamine hydrochloride (2.5 g, 23.2 mmol) and freshly distilled

(CaH2) triethylamine (7.1 mL, 51.04 mmol) in anhydrous DCM (80 mL) at 0ºC was added Boc2O (5.58 g, 25.5 mmol) in two portions. Reaction mixture was allowed to warm up to room temperature overnight. Solvent was removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography

(hexanes:EtOAc 4:1) to give 3.91 g (98%) of the title compound as a clear oil. IR (NaCl

-1 1 disc) 3006, 2979, 2931, 2360, 2341, 1697, 1508, 1172 cm ; H NMR (300 MHz, CDCl3):

' [ppm] 1.39 (s, 9H), 2.22-2.29 (m, 2H), 3.18-3.24 (m, 2H), 4.55 (br s, 1H), 5.07-5.14 (m,

13 2H), 5.73-5.78 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 25.99, 26.98, 32.79, 83.74,

115.62, 133.92, 154.48; m/z (relative intensity) 57(100), 41(94), 29(30).

tert-Butyl pent-4-enylcarbamate (5c).

To the stirred suspension of LAH (835 mg, 22 mmol) in 20 mL dry ether was added dropwise 4-pentenenitrile (811.1 mg, 10 mmol) at room temperature. Reaction mixture 95 was heated at reflux overnight, and then it was cooled to 0ºC in an ice bath. Reaction mixture was quenched with 1 mL H2O, 1 mL 15% NaOH and 2 mL H2O. Reaction mixture was extracted 3x50 mL ether, washed with 10 mL of brine, dried over Na2SO4 and ether was removed under atmospheric pressure to give 700 mg (82%) of title compound as a clear colorless oil.

To the solution of 4-pentenylamine (930 mg, 10.9 mmol) and freshly distilled (CaH2) triethylamine (3.3 mL, 23.98 mmol) in anhydrous DCM (30 mL) at 0ºC was added

Boc2O (2.62 g, 11.99 mmol) in two portions. Reaction mixture was allowed to warm up to room temperature overnight. Solvent was removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc

4:1) to give 1.98 g (98%) of the title compound as a clear oil. 1H NMR (300 MHz,

CDCl3): ' [ppm] 1.42 (s, 9H), 1.53-1.58 (m, 2H), 2.03-2.10 (m, 2H), 3.08-3.14 (m, 2H),

13 4.49 (br s, 1H), 4.94-5.04 (m, 2H), 5.71-5.81 (m, 1H); C NMR (75 MHz, CDCl3): '

[ppm] 28.43, 29.25, 30.98, 40.12, 79.09, 115.10, 137.86, 155.95; m/z (relative intensity)

57(100), 41(83), 29(30).

tert-Butyl hex-5-enylcarbamate (5d).

To the stirred suspension of LAH (835 mg, 22 mmol) in 20 mL dry ether was added dropwise 5-hexenenitrile (951.4 mg, 10 mmol) at room temperature. Reaction mixture was heated at reflux overnight, and then it was cooled to 0ºC in an ice bath. Reaction 96 mixture was quenched with 1 mL H2O, 1 mL 15% NaOH and 2 mL H2O. Reaction mixture was extracted 3x50 mL ether, washed with 10 mL of brine, dried over Na2SO4 and ether was removed under atmospheric pressure to give 860 mg (87%) of title compound as a clear colorless oil.

To the solution of 5-hexenylamine (523 mg, 5.27 mmol) and freshly distilled (CaH2) triethylamine (1.6 mL, 11.6 mmol) in anhydrous DCM (18 mL) at 0ºC was added Boc2O

(1.3 g, 5.8 mmol) in two portions. Reaction mixture was allowed to warm up to room temperature overnight. Solvent was removed under reduced pressure and the crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to

1 give 0.9 g (90%) of the title compound as a clear oil. H NMR (300 MHz, CDCl3): '

[ppm] 1.41 (br m, 11H), 2.00-2.07 (m, 2H), 3.05-3.11 (m, 2H), 4.45 (br s, 1H), 4.90-5.00

13 (m, 2H), 5.69-5.82 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 26.02, 27.40, 28.41,

29.51, 33.33, 85.15, 114.66, 138.49, 146.73; m/z (relative intensity) 57(100), 41(91),

29(40).

tert-Butyl (E)-1-(ethoxycarbonyl)-2-oxopent-3-enylallylcarbamate (6a).

To the solution of tert-butyl allylcarbamate (235 mg, 1.5 mmol) and Rh2(S-DOSP)4 (18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.2 M solution of ethyl

3-oxohex-2-diazo-4-enoate (5 mL, 1.0 mmol). Reaction mixture was heated at reflux 97 under argon for 1h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 242 mg (78%) of title compound as a colorless oil. IR (NaCl disc) 3083, 2979, 2939, 1738, 1697, 1434,

-1 1 1367, 1245, 1147 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.14-1.19 (t, 3H, J=7.1

Hz), 1.41 (s, 9H), 1.65-1.67 (d, 3H, J=5.3 Hz), 4.05-4.12 (q, 2H, J=7.1), 4.20-4.27 (m,

2H), 4.82-4.85 (d, 1H, J=7.5), 5.02-5.13 (m, 2H), 5.64-5.74 (m, 3H); 13C NMR (75 MHz,

CDCl3): ' [ppm] 13.05, 17.09, 26.83, 45.61, 56.64, 60.20, 82.45, 115.41, 122.61, 130.28,

131.89, 151.77, 168.10, 169.49; m/z (relative intensity) 182(4), 138(5), 99(9), 82(13),

57(100), 41(41), 29(21).

tert-Butyl (E)-1-(ethoxycarbonyl)-2-oxopent-3-enylbut-3-enylcarbamate (6b).

To the solution of tert-butyl but-3-enylcarbamate (256 mg, 1.5 mmol) and Rh2(S-DOSP)4

(18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.2 M solution of ethyl 3-oxohex-2-diazo-4-enoate (5 mL, 1.0 mmol). Reaction mixture was heated at reflux under argon for 1h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 256 mg (79%) of title compound as a colorless oil. IR (NaCl disc) 3020, 2979, 2939, 1753,

-1 1 1693, 1369, 1217, 1147 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.19-1.24 (t, 3H,

J=7.2 Hz), 1.48 (s, 9H), 1.70-1.72 (d, 3H, J=4.9 Hz), 2.23-2.31 (m, 2H), 3.71-3.75 (m,

2H), 4.09-4.17 (q, 2H, J=7.2 Hz), 4.85-4.87 (d, 1H, J=7.1 Hz), 4.99-5.05 (m, 2H), 5.68- 98 13 5.75 (m, 3H); C NMR (75 MHz, CDCl3): ' [ppm] 14.08, 18.12, 27.91, 32.90, 44.01,

57.70, 61.20, 83.39, 116.81, 123.66, 131.25, 135.01, 152.91, 169.17, 170.78; m/z

(relative intensity) 99(10), 82(14), 57(100), 41(38), 29(31).

tert-Butyl(E)-1-(ethoxycarbonyl)-2-oxopent-3-enylpent-4-enylcarbamate 6c.

To the solution of tert-butyl pent-4-enylcarbamate (244 mg, 1.32 mmol) and Rh2(S-

DOSP)4 (15.8 mg, 0.009 mmol) in 5 mL of anhydrous DCE was added dropwise 0.2 M solution of ethyl 3-oxohex-2-diazo-4-enoate (4.4 mL, 0.9 mmol). Reaction mixture was heated at reflux under argon for 1h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give

215 mg (72%) of title compound as a colorless oil. IR (NaCl disc) 2979, 2937, 2920,

-1 1 1735, 1693, 1446, 1369, 1147 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.18-1.22 (t,

3H, J=7.2 Hz), 1.47 (s, 9H), 1.51-1.63 (m, 2H), 1.69-1.71 (d, 3H, J=4.9 Hz), 1.99-2.06

(m, 2H), 3.62-3.70 (m, 2H), 4.08-4.15 (q, 2H, J=7.1 Hz), 4.84-4.86 (d, 1H, J=7.4 Hz),

13 4.91-5.02 (m, 2H), 5.67-5.81 (m, 3H); C NMR (75 MHz, CDCl3): ' [ppm] 14.08, 18.14,

27.43, 27.93, 31.01, 44.31, 57.71, 61.20, 83.32, 114.96, 123.67, 131.25, 137.80, 153.01,

169.19, 170.79; m/z (relative intensity) 128(21), 100(37), 82(64), 69(15), 53(61), 41(88),

29(100).

tert-Butyl(E)-1-(ethoxycarbonyl)-2-oxopent-3-enylhex-5-enylcarbamate 6d.

To the solution of tert-butyl hex-5-enylcarbamate (299 mg, 1.5 mmol) and Rh2(S-

DOSP)4 (18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.2 M solution of ethyl 3-oxohex-2-diazo-4-enoate (5 mL, 1.0 mmol). Reaction mixture was heated at reflux under argon for 1h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give

258 mg (73%) of title compound as a colorless oil. IR (NaCl disc) 2977, 2937, 2858,

-1 1 1735, 1697, 1446, 1369, 1147 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.22-1.24 (t,

3H, J=7.0 Hz), 1.27-1.44 (m, 2H), 1.51-1.58 (m, 11H), 1.73-1.75 (d, 3H, J=4.8 Hz), 2.04-

2.11 (m, 2H), 3.66-3.74 (m, 2H), 4.13-4.20 (q, 2H, J=7.1 Hz), 4.88-4.90 (d, 1H, J=7.4

13 Hz), 4.97-5.04 (m, 2H), 5.71-5.81 (m, 3H); C NMR (75 MHz, CDCl3): ' [ppm] 12.88,

16.91, 24.91, 26.68, 26.75, 32.16, 43.41, 56.50, 59.98, 82.06, 113.43, 122.56, 129.98,

137.33, 151.90, 168.00, 169.59; m/z (relative intensity) 128(25), 100(43), 82(52), 67(15),

55(70), 41(100), 29(88).

tert-Butyl (E)-1-(methoxycarbonyl)-3-phenylallylallylcarbamate (7a). 100 To the solution of tert-butyl allylcarbamate (235 mg, 1.5 mmol) and Rh2(S-DOSP)4 (9 mg, 0.005 mmol) in 2 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate (5 mL, 0.5 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 91 mg (55%) of title compound as a pale yellow oil. IR (NaCl

-1 1 disc) 3005, 2996, 1743, 1691, 1217 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.28 (s,

9H), 3.58 (s, 3H), 3.68 (br m, 1H), 3.93 (br m, 1H), 4.40 (br m, 0.5H), 4.98 (br m, 2.5H),

13 5.69 (m, 1H), 6.25-6.32 (m, 2H), 7.08-7.23 (m, 5H); C NMR (75 MHz, CDCl3): '

[ppm] 28.32, 40.97, 52.26, 52.94, 80.74, 123.35, 126.63, 128.04, 128.33, 128.36, 128.58,

128.61, 134.79, 136.28, 171.18; m/z (relative intensity) 216(9), 190(86), 172(24), 158(9),

130(33), 115(66), 7(5), 5(100), 41(54).

tert-Butyl (E)-1-(methoxycarbonyl)-3-phenylallylbut-3-enylcarbamate (7b).

To the solution of tert-butyl but-3-enylcarbamate (308.23 mg, 1.8 mmol) and Rh2(S-

DOSP)4 (8.1 mg, 0.0045 mmol) in 2 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate (4.5 mL, 0.45 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 80 mg (51%) of title compound as a pale yellow oil. IR (NaCl 101 -1 1 disc) 3020, 2979, 1745, 1691, 1217 cm ; H NMR (300 MHz, CDCl3): '[ppm] 1.38 (s,

9H), 2.27 (br m, 2H), 3.21 (br m, 1H), 3.39 (br m, 1H), 3.68 (s, 3H), 4.48 (br m, 0.5H),

4.91-5.00 (m, 2.5H), 5.70 (m, 1H), 6.30-6.51 (m, 2H), 7.10-7.34 (m, 5H); 13C NMR (75

MHz, CDCl3): '[ppm] 19.04, 25.93, 38.56, 49.89, 50.55, 78.12, 114.06, 123.98, 124.23,

125.69, 125.82, 126.23, 126.63, 133.05, 133.84, 168.78; m/z (relative intensity) 230(6),

186(7), 144(24), 115(92), 9(6), 57(100), 41(29).

tert-Butyl (E)-1-(methoxycarbonyl)-3-phenylallylpent-4-enylcarbamate (7c).

To the solution of tert-butyl pent-4-enylcarbamate (556 mg, 3.0 mmol) and Rh2(S-

DOSP)4 (18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 168 mg (45%) of title compound as a yellow oil. IR (NaCl disc)

-1 1 2975, 2950, 2933, 1743, 1689, 1251 cm ; H NMR (300 MHz, CDCl3): '[ppm] 1.48 (s,

9H), 1.67-1.72 (m, 2H), 2.04 (br m, 2H), 3.20 (br m, 1H), 3.40 (br m, 1H), 3.74 (s, 3H),

4.48 (br m, 0.5H), 4.92-5.02 (m, 2.5 H), 5.76 (m, 1H), 6.43-6.50 (m, 2H), 7.24-7.39 (m,

13 5H); C NMR (75 MHz, CDCl3): '[ppm] 28.35, 28.93, 31.03, 40.97, 52.31, 52.97,

80.50, 114.96, 126.64, 126.72, 128.07, 128.36, 128.59, 128.63, 136.27, 138.02, 171.24; m/z (relative intensity) 144(16), 115(54), 91(21), 57(100), 41(81). 102

tert-Butyl (E)-1-(methoxycarbonyl)-3-phenylallylhex-5-enylcarbamate (7d).

To the solution of tert-butyl hex-5-enylcarbamate (597 mg, 3.0 mmol) and Rh2(S-DOSP)4

(18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10:1 hexanes:EtOAc) to give 186 mg (50%) of title compound as a yellow oil. IR (NaCl disc)

-1 1 2975, 2931, 1747, 1689, 1164 cm ; H NMR (300 MHz, CDCl3): '[ppm] 1.37 (s, 11H),

1.49-1.54 (m, 2H), 1.94-2.01 (m, 2H), 3.13 (br m, 1H), 3.33 (br m, 1H), 3.67 (s, 3H),

4.43 (br m, 0.5H), 4.83-4.93 (m, 2.5H), 5.63-5.74 (m, 1H), 6.37-6.43 (m, 2H), 7.18-7.33

13 (m, 5H); C NMR (75 MHz, CDCl3): '[ppm] 26.08, 28.35, 28.93, 33.36, 40.97, 52.27,

52.96, 80.42, 114.55, 126.39, 126.64, 128.05, 128.36, 128.58, 128.61, 136.30, 138.63,

171.24; m/z (relative intensity) 144(20), 130(41), 115(76), 91(36), 57(51), 41(100).

(Z)-tert-butyl 2-(ethoxy(hydroxy)methylene)-3-hydroxy-5,6-dihydropyridine-1(2H)- carboxylate (8a). 103 To the solution of Grubbs 2nd generation catalyst (8.5 mg, 0.01 mmol) in 2 mL anhydrous

DCM at gentle reflux was added dropwise 0.1 M solution of 6a (0.10 mmol in 1.0 mL of anhydrous DCM). Reaction mixture was heated at reflux for 2 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2-isocyanoacetate

(0.05 mmol in 0.24 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 23 mg (85%) of the title compound as a yellow oil. IR (NaCl disc) 2979, 2937, 2906, 1731, 1456, 1257, 1145 cm-

1 1 ; H NMR (300 MHz, CDCl3): ' [ppm] 1.25-1.30 (t, 3H, J=7.1 Hz), 1.49 (s, 9H), 2.45-

2.51 (m, 2H, J=4.4 Hz, J=6.3 Hz), 3.81-3.85 (t, 2H, J=6.3 Hz), 4.21-4.28 (q, 2H, J=7.1

13 Hz), 7.42-7.45 (t, 1H, J=4.3 Hz); C NMR (75 MHz, CDCl3): ' [ppm] 14.14, 24.73,

28.03, 43.03, 61.47, 83.54, 130.86, 148.53, 152.65, 160.02, 164.03; m/z (relative intensity) 271(1), 124(27), 97(64), 85(20), 68(49), 53(67), 39(95), 29(100). Anal.Calcd. for C13H20NO5: C, 57.76; H, 7.46; O, 29.60. Found: C, 57.00; H, 7.07; O, 30.15.

(5E,7Z)-tert-butyl 7-(ethoxy(hydroxyl)methylene)-6-hydroxy-3,4-dihydro-2H- azepine-1(7H)-carboxylate (8b). 104 To the solution of Grubbs 2nd generation catalyst (17 mg, 0.02 mmol) in 5 mL anhydrous

DCM at gentle reflux was added dropwise 0.1 M solution of 6b (0.25 mmol in 2.5 mL of anhydrous DCM). Reaction mixture was heated at reflux for 2 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2-isocyanoacetate

(0.12 mmol in 0.6 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 5:1) to give 69 mg (96%) of the title compound as a yellow oil. IR (NaCl disc) 3022, 2981, 2933, 2906, 1770, 1735, 1697,

-1 1 1506, 1394, 1369, 1249, 1147, 1026 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.24-

1.29 (t, 3H, J=7.1 Hz), 1.50 (s, 9H), 1.85-1.94 (m, 2H), 2.33-2.40 (m, 2H), 3.69-3.74 (t,

2H, J=6.2 Hz), 4.19-4.26 (q, 2H, J=7.1 Hz), 7.25-7.30 (t, 1H, J=7.6 Hz); 13C NMR (75

MHz, CDCl3): ' [ppm] 14.15, 23.02, 25.38, 28.04, 43.07, 61.43, 83.40, 99.99, 133.41,

144.14, 151.74, 164.05; m/z (relative intensity) 284(1), 210(6), 184(59), 166(20), 154(6),

138(38), 109(18), 81(12), 57(100), 41(49), 29(37). Anal.Calcd. for C14H21NO5: C, 59.35;

H, 7.47; O, 28.24. Found: C, 58.85; H, 7.56; O, 28.80.

(Z)-1-tert-butyl 2-ethyl 3-oxo-2,3,7,8-tetrahydroazocine-1,2(6H)-dicarboxylate (8c) and (2Z,3E)-tert-butyl 2-(ethoxy(hydroxy)methylene)-3-hydroxy-5,6,7,8- tetrahydroazocine-1(8H)-carboxylate (9a).

To the solution of Grubbs 2nd generation catalyst (86 mg, 0.1 mmol) in 50 mL anhydrous

DCM at gentle reflux was added dropwise 0.1 M solution of 6c (1.0 mmol in 10 mL of anhydrous DCM). Reaction mixture was heated at reflux for 4h, then it was cooled down 105 to room temperature and quenched with 0.2 M solution of potassium 2-isocyanoacetate

(0.6 mmol in 3 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 13 mg (4.4%) of 8c as a yellow oil and 160 mg (54%) of 9a as a white solid.

Compund 8c: yellow oil. IR (NaCl disc) 2977, 2916, 1766, 1720, 1367, 1278, 1238, 1145

-1 1 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.24-1.28 (t, 3H, J=7.1 Hz), 1.52 (s, 9H),

1.68 (m, 2H), 1.78 (m, 2H), 2.39-2.41 (m, 2H), 3.78 (m, 2H), 4.17-4.24 (q, 2H, J=7.1

13 Hz), 7.11-7.16 (t, 1H, J=7.0 Hz); C NMR (75 MHz, CDCl3): ' [ppm] 14.12, 20.45,

28.04, 28.55, 28.88, 45.56, 61.50, 83.26, 129.62, 145.63, 152.07, 164.38, 166.94; m/z

(relative intensity) 151(100), 123(44), 85(84), 53(43), 41(45), 29(79). Anal.Calcd. for

C15H23NO5: C, 60.59; H, 7.80; O, 26.90. Found: C, 60.89; H, 7.67; O, 26.76. 106

Compund 9a: white solid, mp 115-117 ºC. IR (NaCl disc) 2979, 2935, 2871, 1728, 1681,

-1 1 1446, 1369, 1147, 914, 732 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): '

[ppm] 1.17-1.24 (m, 3H), 1.40-1.68 (m, 11H), 1.93-2.05 (m, 2H), 3.52-3.58 (m, 1H),

3.79-3.95 (m, 1H), 4.04-4.16 (m, 2H), 4.70-4.86 (dd, 0.7H), 5.10-5.13 (d, 0.3H), 5.56-

13 5.73 (m, 2H); C NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm] 14.08, 14.19,

21.03, 22.20, 27.93, 27.98, 28.00, 29.77, 43.78, 44.08, 56.61, 57.01, 60.37, 61.26, 83.45,

83.50, 123.22, 123.39, 135.87, 136.33, 152.98, 153.05, 168.64, 169.08, 169.18, 171.04,

171.12, 171.87; m/z (relative intensity) 57(15), 44(61), 28(100). Anal.Calcd. for

C15H23NO5: C, 60.59; H, 7.80; O, 26.90. Found: C, 61.21; H, 7.80; O, 25.83.

(Z)-1-tert-butyl 2-ethyl 3-oxo-2,3,6,7,8,9-hexahydroazonine-1,2-dicarboxylate (9b).

To the solution of Grubbs 2nd generation catalyst (26 mg, 0.033 mmol) in 6 mL anhydrous DCM at gentle reflux was added dropwise 0.1 M solution of 6d (0.42 mmol in

4.2 mL of anhydrous DCM). Reaction mixture was heated at reflux for 2h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2- isocyanoacetate (0.18 mmol in 0.9 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with 107 DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 73 mg (56%) of the title compound as a white solid, mp 123-126 ºC. IR (NaCl disc) 3020, 2981, 2935,

-1 1 2858, 1733, 1689, 1369, 1147, 908, 756 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): ' [ppm] 1.15-1.20 (m, 3H), 1.32-1.38 (m, 2H), 1.40-1.48 (m, 11H), 1.92-

2.16 (m, 2H), 3.36-3.60 (m, 1H), 3.71-3.86 (m, 1H), 4.07-4.16 (m, 2H), 4.80-4.90 (dd,

13 1H), 5.47-5.53 (m, 1H), 5.63-5.71 (m, 1H); C NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm] 14.07, 14.10, 25.55, 27.39, 27.91, 27.96, 32.31, 44.22, 44.63,

57.42, 61.15, 61.26, 83.33, 83.35, 123.57, 124.15, 128.31, 128.33, 135.68, 135.74,

152.84, 152.94, 169.27, 170.53; m/z (relative intensity) 57(94), 41(43), 29(100).

Anal.Calcd. for C16H25NO5: C, 61.72; H, 8.09; O, 25.69. Found: C, 61.63; H, 8.02; O,

25.45.

(Z)-1-tert-butyl 2-methyl 2H-pyrrole-1,2(5H)-dicarboxylate (10a).

To the solution of Grubbs 2nd generation catalyst (12 mg, 0.014 mmol) in 3 mL anhydrous DCM at gentle reflux was added dropwise 0.1 M solution of 7a (0.18 mmol in

1.8 mL of anhydrous DCM). Reaction mixture was heated at reflux for 1.5 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2- isocyanoacetate (0.086 mmol in 0.43 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with 108 DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 36 mg (88%) of the title compound as a yellow oil. IR (NaCl disc) 3018, 2977, 2867, 1758, 1701,

-1 1 1689, 1402, 1172 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): ' [ppm]

1.39-1.44 (d, 9H), 3.69-3.70 (d, 3H), 4.14-4.24 (m, 2H), 4.91-5.00 (m, 1H), 5.65-5.72 (m,

13 1H), 5.88-5.96 (m, 1H); C NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm]

28.28, 28.41, 52.16, 53.26, 66.57, 80.22, 124.64, 124.77, 129.27, 129.41, 155.23, 171.13; m/z (relative intensity) 126(40), 112(17), 69(53), 57(100), 41(86), 29(22).

(Z)-1-tert-butyl 2-methyl 5,6-dihydropyridine-1,2(2H)-dicarboxylate (10b).

To the solution of Grubbs 2nd generation catalyst (12 mg, 0.014 mmol) in 3 mL anhydrous DCM at gentle reflux was added dropwise 0.1 M solution of 7b (0.17 mmol in

1.7 mL of anhydrous DCM). Reaction mixture was heated at reflux for 2.5 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2- isocyanoacetate (0.084 mmol in 0.42 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with

DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 39 mg (94%) of the title compound as a yellow oil. IR (NaCl disc) 3008, 2977, 2931, 1758, 1708,

-1 1 1681, 1406, 1170, 1062 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): ' 109 [ppm] 1.36-1.41 (d, 9H), 1.97-2.03 (m, 1H), 2.16-2.17 (m, 1H), 2.89-3.05 (m, 1H), 3.66

(s, 3H), 3.95-4.13 (m, 1H), 4.76-4.91 (d, 1H), 5.68-5.78 (m, 1H), 5.88-5.92 (m, 1H); 13C

NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm] 24.58, 28.28, 28.37, 37.65,

39.02, 52.11, 54.72, 55.86, 80.29, 121.61, 122.29, 122.30, 127.71, 128.15, 154.91,

155.20, 170.99, 171.26; m/z (relative intensity) 140(28), 126(19), 80(85), 57(100),

41(66), 29(10).

(Z)-1-tert-butyl 2-methyl 6,7-dihydro-2H-azepine-1,2(5H)-dicarboxylate (10c).

To the solution of Hoveyda-Grubbs 2nd generation catalyst (11.7 mg, 0.016 mmol) in 3 mL anhydrous DCM at gentle reflux was added dropwise 0.1 M solution of 7c (0.2 mmol in 2.0 mL of anhydrous DCM). Reaction mixture was heated at reflux for 3.5 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2- isocyanoacetate (0.096 mmol in 0.5 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with

DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 41 mg (80%) of the title compound as a yellow oil. IR (NaCl disc) 2977, 2952, 2933, 1747, 1677,

-1 1 1413, 1166, 910 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): ' [ppm]

1.42-1.47 (d, 9H), 1.62-1.66 (m, 1H), 1.84-1.93 (m, 1H), 2.09-2.12 (m, 1H), 2.22-2.27

(m, 1H), 3.23-3.51 (m, 1H), 3.69-3.80 (m, 4H), 5.09-5.51 (d, 1H), 5.76-5.84 (m, 2H); 13C 110 NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm] 24.34, 25.06, 25.14, 25.52,

28.29, 28.43, 44.14, 44.75, 52.27, 52.35, 59.24, 59.60, 80.13, 80.36, 125.72, 126.05,

130.10, 131.15, 154.84, 155.76, 171.32, 171.44; m/z (relative intensity) 154(15), 140(38),

96(67), 80(20), 67(100), 41(56), 29(45). Anal.Calcd. for C13H21NO4: C, 61.16; H, 8.29;

O, 25.07. Found: C, 61.13; H, 8.44; O, 25.25.

(Z)-1-tert-butyl 2-methyl 5,6,7,8-tetrahydroazocine-1,2(2H)-dicarboxylate (10d).

To the solution of Hoveyda-Grubbs 2nd generation catalyst (17.5 mg, 0.028 mmol) in 14 mL of anhydrous DCM at gentle reflux was added dropwise 0.1 M solution of 7d (0.28 mmol in 2.8 mL of anhydrous DCM). Reaction mixture was heated at reflux for 3.0 h, then it was cooled down to room temperature and quenched with 0.2 M solution of potassium 2-isocyanoacetate (0.168 mmol in 0.84 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give

48 mg (65%) of the title compound as a colorless oil. IR (NaCl disc) 2975, 2937, 1747,

-1 1 1689, 1402, 1367, 1161 cm ; H NMR (300 MHz, CDCl3, mixture of conformers): '

[ppm] 1.37-1.43 (q, 9H), 1.53-1.61 (m, 1H), 1.75-1.85 (m, 2H), 2.00-2.06 (m, 1H), 2.19-

2.26 (m, 1H), 2.98-3.17 (m, 1H), 3.57-3.68 (m, 5H), 5.07-5.38 (d, 1H), 5.58-5.63 (m,

13 1H), 5.71-5.82 (m, 1H); C NMR (75 MHz, CDCl3, mixture of conformers): ' [ppm]

25.39, 25.54, 27.35, 27.83, 28.33, 28.45, 44.95, 45.00, 52.21, 52.30, 57.85, 58.46, 58.81, 111 59.24, 80.13, 80.24, 123.60, 124.14, 134.02, 134.40, 154.98, 156.23, 172.04, 172.18; m/z

(relative intensity) 154(70), 110(67), 57(100), 41(40), 29(15). Anal.Calcd. for

C14H23NO4: C, 62.43; H, 8.61; O, 23.76. Found: C, 62.62; H, 8.73; O, 23.81.

Typical one-pot N-H insertion/RCM protocol:

To the solution of Rh2 (S-DOSP)4 (18 mg, 0.01 mmol) and N-Boc alkenylamine (1.5 mmol) in 5 mL dry DCE at r.t. under argon was added dropwise 0.1M solution of !- diazo-"-ketoester in DCE (10 mL, 1.0 mmol). Reaction mixture was stirred at r.t. under argon until the diazo substrate disappeared by TLC (4:1 Hex:EtOAc). Reaction mixture was then added via cannula to the 2x10-3 M solution of Hoveyda-Grubbs 2nd generation

(63 mg, 0.1 mmol) in dry DCE (50 mL) at reflux. Reaction mixture was heated at reflux

2-3 h, then it was cooled down to r.t. and quenched with 0.2 M solution of potassium 2- isocyanoacetate (74 mg, 0.6 mmol in 3 mL of methanol). After stirring at room temperature for 30 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (Hex:EtOAc 9:1, then

Hex:EtOAc 4:1) to give the title compound as a colorless oil. 112

tert-Butyl allyl(ethyl)carbamate (11a).

Sodium hydride (768 mg of 60% dispersion in mineral oil, 19.2 mmol) was washed twice with 15 mL portions of hexane and suspended in 15 mL anhydrous THF. Reaction mixture was cooled to 0ºC and tert-butyl allylcarbamate (1.0 g, 6.4 mmol) was added dropwise. Reaction mixture was warmed up to room temperature and stirred under argon for 30 min. Reaction mixture was cooled to 0ºC and freshly distilled ethyl iodide (1.02 mL, 12.8 mmol) was added dropwise. Reaction mixture was allowed to warm up to room temperature overnight, and it was then cooled to 0ºC and quenched with saturated ammonium chloride solution. The layers were separated and aqueous layer was extracted with Et2O. Organics were combined and washed with saturated NaCl solution, dried over

MgSO4 and concentrated under reduced pressure. Crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 1.0g (85%) of the title compound as a colorless oil. IR (neat) 3083, 3010, 2979, 2933, 2249, 1682 cm-1; 1H

NMR (300 MHz, CDCl3): ' [ppm] 1.03-1.07 (t, 3H, J=7.1 Hz), 1.42 (s, 9H), 3.20 (br m,

13 2H), 3.77 (br m, 2H), 5.05-5.11 (m, 2H), 5.68-5.81 (m, 1H); C NMR (75 MHz, CDCl3):

' [ppm] 12.59, 27.55, 40.39, 48.19, 78.31, 115.10, 133.67, 154.46; m/z (relative intensity) 185(1), 129(25), 112(9), 84(10), 70(30), 57(100), 41(65), 29(25). Anal.Calcd. for C10H19NO2: C, 64.83; H, 10.34; O, 17.24. Found: C, 64.67; H, 10.60; O, 17.31.

113

tert-Butyl but-3-enyl(ethyl)carbamate (11b).

Sodium hydride (583 mg of 60% dispersion in mineral oil, 14.6 mmol) was washed twice with 16 mL portions of hexane and suspended in 16 mL anhydrous THF. Reaction mixture was cooled to 0ºC and tert-butyl but-3-enylcarbamate (830 mg, 4.85 mmol) was added dropwise. Reaction mixture was warmed up to room temperature and stirred under argon for 30 min. Reaction mixture was cooled to 0ºC and freshly distilled ethyl iodide

(0.78 mL, 9.7 mmol) was added dropwise. Reaction mixture was allowed to warm up to room temperature overnight, and it was then cooled to 0ºC and quenched with saturated ammonium chloride solution. The layers were separated and aqueous layer was extracted with Et2O. Organics were combined and washed with saturated NaCl solution, dried over

MgSO4 and concentrated under reduced pressure. Crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 900 mg (93%) of the title compound as a colorless oil. IR (neat) 3078, 2976, 2932, 2871, 1685 cm-1; 1H NMR (300

MHz, CDCl3): ' [ppm] 1.04-1.09 (t, 3H, J=7.1 Hz), 1.42 (s, 9H), 2.20-2.27 (m, 2H), 3.19

13 (br m, 4H), 4.95-5.06 (m, 2H), 5.67-5.81 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm]

11.58, 26.45, 31.25, 39.90, 44.32, 77.01, 114.33, 133.62, 153.36; m/z (relative intensity)

199(1), 158(5), 102(8), 57(100), 41(70), 29(52). Anal.Calcd. for C11H21NO2: C, 66.29; H,

10.62; O, 16.06. Found: C, 66.07; H, 10.66; O, 15.95.

114

tert-Butyl ethyl(pent-4-enyl)carbamate (11c).

Sodium hydride (602 mg of 60% dispersion in mineral oil, 15.06 mmol) was washed twice with 15 mL portions of hexane and suspended in 15 mL anhydrous THF. Reaction mixture was cooled to 0ºC and tert-butyl pent-4-enylcarbamate (930 mg, 5.02 mmol) was added dropwise. Reaction mixture was warmed up to room temperature and stirred under argon for 30 min. Reaction mixture was cooled to 0ºC and freshly distilled ethyl iodide

(0.80 mL, 10.04 mmol) was added dropwise. Reaction mixture was allowed to warm up to room temperature overnight, and it was then cooled to 0ºC and quenched with saturated ammonium chloride solution. The layers were separated and aqueous layer was extracted with Et2O. Organics were combined and washed with saturated NaCl solution, dried over MgSO4 and concentrated under reduced pressure. Crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 1.1 g (96%) of the title compound as a colorless oil. IR (neat) 2975, 2931, 2873, 1681 cm-1; 1H NMR (300

MHz, CDCl3): ' [ppm] 1.08-1.13 (t, 3H, J=7.08 Hz), 1.47 (s, 9H), 1.60-1.68 (m, 2H),

2.02-2.09 (m, 2H), 3.16-3.24 (br m, 4H), 4.96-5.08 (m, 2H), 5.76-5.90 (m, 1H); 13C NMR

(75 MHz, CDCl3): ' [ppm] 13.63, 27.75, 28.43, 31.01, 41.72, 46.19, 78.89, 114.72,

138.04, 155.37; m/z (relative intensity) 213(1), 157(12), 102(15), 57(100). Anal.Calcd. for C12H23NO2: C, 67.57; H, 10.87; O, 15.00. Found: C, 66.97; H, 10.86; O, 15.57.

115

tert-Butyl ethyl(hex-5-enyl)carbamate (11d).

Sodium hydride (503 mg of 60% dispersion in mineral oil, 12.6 mmol) was washed twice with 20 mL portions of hexane and suspended in 20 mL anhydrous THF. Reaction mixture was cooled to 0ºC and tert-butyl hex-5-enylcarbamate (836 mg, 4.2 mmol) was added dropwise. Reaction mixture was warmed up to room temperature and stirred under argon for 30 min. Reaction mixture was cooled to 0ºC and freshly distilled ethyl iodide

(0.70 mL, 8.4 mmol) was added dropwise. Reaction mixture was allowed to warm up to room temperature overnight, and it was then cooled to 0ºC and quenched with saturated ammonium chloride solution. The layers were separated and aqueous layer was extracted with Et2O. Organics were combined and washed with saturated NaCl solution, dried over

MgSO4 and concentrated under reduced pressure. Crude reaction mixture was purified by flash column chromatography (hexanes:EtOAc 4:1) to give 900 mg (94%) of the title compound as a colorless oil. IR (neat) 2975, 2931, 1693 cm-1; 1H NMR (300 MHz,

CDCl3): ' [ppm] 1.02-1.06 (t, 3H, J=7.11 Hz), 1.29-1.40 (m, 2H), 1.45 (s, 9H), 1.47-1.50

(m, 2H), 1.98-2.06 (m, 2H), 3.09-3.14 (br m, 4H), 4.88-4.99 (m, 2H), 5.67-5.81 (m, 1H);

13 C NMR (75 MHz, CDCl3): ' [ppm] 13.57, 26.03, 27.98, 28.41, 33.40, 41.59, 46.36,

78.80, 114.46, 138.53, 155.36; m/z (relative intensity) 227(1), 171(10), 128(20), 102(24),

57(100). Anal.Calcd. for C13H25NO2: C, 68.68; H, 11.08; O, 14.08. Found: C, 68.42; H,

10.89; O, 14.36.

116

(E)-Methyl 2-((tert-butoxycarbonyl)methyl)-1-styrylcyclopropanecarboxylate (12a).

To the solution of ethyl tert-butyl allylcarbamate (740 mg, 4.0 mmol) and Rh2(R-DOSP)4

(18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 228 mg (64%) of title compound as yellow oil. HPLC analysis indicated 96% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 95:5, 1.0 mL min-1, 254

25 nm; Rt = 21.0 min (minor, 4% ee), 26.0 min (major, 96% ee); [&]D = +101.7 (c=1.0,

-1 1 CHCl3); IR (NaCl disc) 2975, 2952, 2931, 2875, 1728, 1677 cm ; H NMR (300 MHz,

CDCl3): ' [ppm] 0.90-0.95 (t, 3H, J=7.1 Hz), 1.17-1.21 (m, 1H), 1.31 (s, 9H), 1.51-1.54

(m, 1H), 1.76-1.82 (m, 1H), 2.97-3.04 (m, 2H), 3.11-3.18 (m, 2H), 3.58 (s, 3H), 6.23-

6.29 (d, 1H, J=16.05 Hz), 6.49-6.54 (d, 1H, J=16.05 Hz), 7.11-7.29 (m, 5H); 13C NMR

(75 MHz, CDCl3): ' [ppm] 11.79, 16.03, 26.71, 27.97, 28.60, 39.78, 43.26, 50.58, 77.62,

121.94, 124.59, 125.91, 126.83, 130.61, 134.90, 153.51, 172.41; m/z (relative intensity)

259(12), 228(3), 200(7), 168(68), 129(25), 91(9), 71(100), 52(35). Anal.Calcd. for

C21H29NO4: C, 70.17; H, 8.13; O, 17.80. Found: C, 70.18; H, 8.20; O, 17.88. 117

(E)-Methyl 2-(2-(tert-butoxycarbonyl(ethyl)amino)ethyl)-1- styrylcyclopropanecarboxylate (12b).

To the solution of tert-butyl but-3-enyl(ethyl)carbamate (796 mg, 4.0 mmol) and Rh2(R-

DOSP)4 (18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 229 mg (61%) of title compound as yellow oil. HPLC analysis indicated 92% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 95:5, 1.0 mL min-1, 254

25 nm; Rt = 23.0 min (minor, 8% ee), 26.2 min (major, 92% ee); [&]D = +89.8 (c=1.0,

-1 1 CHCl3); IR (neat) 3013, 2976, 2926, 1721, 1683 cm ; H NMR (300 MHz, CDCl3): '

[ppm] 0.91-0.96 (t, 3H, J=7.05Hz), 1.06-1.09 (m, 1H), 1.34 (s, 9H), 1.38-1.45 (m, 2H),

1.53-1.61 (m, 2H), 2.97-3.21 (br m, 4H), 3.61 (s, 3H), 6.23-6.28 (d, 1H, J=16 Hz), 6.57-

13 6.62 (d, 1H, J=16 Hz), 7.12-7.33 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 12.43,

18.02, 26.27, 27.41, 27.77, 29.34, 40.76, 45.03, 51.19, 78.05, 123.13, 125.28, 126.49,

127.52, 131.00, 135.81, 154.22, 173.58; m/z (relative intensity) 371(1), 141(4), 115(11),

91(19), 57(100). Anal.Calcd. for C22H31NO4: C, 70.75; H, 8.37; O, 17.14. Found: C,

70.70; H, 8.54; O, 17.23.

118

(E)-Methyl 2-(3-(tert-butoxycarbonyl(ethyl)amino)propyl)-1- styrylcyclopropanecarboxylate (12c).

To the solution of tert-butyl ethyl(pent-4-enyl)carbamate (547 mg, 2.4 mmol) and Rh2(R-

DOSP)4 (10.8 mg, 0.006 mmol) in 3 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (6 mL, 0.6 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 142 mg (59%) of title compound as yellow oil. HPLC analysis indicated 95% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 95:5, 1.0 mL min-1, 254

25 nm; Rt = 25.2 min (minor, 5% ee), 29.2 min (major, 95% ee); [&]D = +74.60 (c=1.5,

25 CHCl3, Rh2(R-DOSP)4), [&]D = -56.16 (c=1.25, CHCl3, Rh2(S-DOSP)4); IR (neat) 3005,

-1 1 2974, 2949, 2932, 2865, 1722, 1688 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 0.93-

0.98 (t, 3H, J=7.05 Hz), 1.01-1.06 (m, 1H), 1.16-1.24 (m, 2H), 1.31 (s, 9H), 1.44-1.62

(m, 4H), 3.04 (br m, 4H), 3.60 (s, 3H), 6.22-6.27 (d, 1H, J=16.02 Hz), 6.53-6.59 (d, 1H,

13 J=15.99 Hz), 7.13-7.32 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 12.53, 18.30,

24.31, 24.60, 27.38, 29.51, 30.08, 40.52, 45.18, 51.14, 77.91, 123.22, 125.26, 126.43,

127.50, 130.93, 135.87, 154.33, 173.68; m/z (relative intensity) 115(10), 91(20), 57(100).

Anal.Calcd. for C23H33NO4: C, 71.29; H, 8.58; O, 16.51. Found: C, 71.14; H, 8.69; O,

16.74.

119

(E)-Methyl 2-(4-(tert-butoxycarbonyl(ethyl)amino)butyl)-1- styrylcyclopropanecarboxylate (12d).

To the solution of tert-butyl ethyl(hex-5-enyl)carbamate (2.56 g, 11.2 mmol) and Rh2(S-

DOSP)4 (50.4 mg, 0.028 mmol) in 14 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (28 mL, 2.8 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 623 mg (55%) of title compound as yellow oil. HPLC analysis indicated 92% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 95:5, 1.0 mL min-1, 254

24 nm; Rt = 22.4 min (major, 92% ee), 27.7 min (minor, 8% ee); [&]D = +53.9 (c=1.0,

24 CHCl3, Rh2(R-DOSP)4), [&]D = -46.9 (c=1.0, CHCl3, Rh2(S-DOSP)4); IR (neat) 3082,

-1 1 3058, 2975, 2933, 2860, 1724, 1689 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.03-

1.08 (t, 3H, J=7.08 Hz), 1.12-1.15 (m, 1H), 1.34 (br m, 4H), 1.44-1.51 (m, 11H), 1.61-

1.65 (m, 2H), 3.15 (br m, 4H), 3.70 (s, 3H), 6.31-6.36 (d, 1H, J=16.02 Hz), 6.63-6.69 (d,

13 1H, J=15.99 Hz), 7.23-7.41 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 13.71, 19.28,

26.65, 26.70, 27.95, 28.47, 30.53, 31.51, 41.71, 46.53, 52.16, 78.90, 124.46, 126.28,

127.43, 128.55, 131.80, 136.99, 155.42, 174.81; m/z (relative intensity) 402(1), 345(9),

328(8), 301(25), 210(22), 115(30), 91(36), 57(100). Anal.Calcd. for C24H35NO4: C,

71.79; H, 8.79; O, 15.94. Found: C, 71.80; H, 8.98; O, 16.13.

120

(E)-Methyl 2-(1-(tert-butoxycarbonyl)ethyl)-4-phenylbut-3-enoate (13a).

To the solution of ethyl tert-butyl allylcarbamate (740 mg, 4.0 mmol) and Rh2(R-DOSP)4

(18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 115 mg (32%) of title compound as yellow oil. HPLC analysis indicated 92% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min-1, 254

24 nm; Rt = 8.0 min (minor, 8% ee), 8.6 min (major, 92% ee); [&]D = +95.5 (c=1.0,

-1 1 CHCl3); IR (neat) 2975, 2952, 2933, 1728, 1674 cm ; H NMR (300 MHz, CDCl3): '

[ppm] 1.26-1.28 (d, 3H, J=6.8 Hz), 1.36 (s, 5H), 1.50 (s, 4H), 3.52-3.61 (br m, 2H), 3.72

(s, 3H), 3.76-3.80 (br m, 1H), 4.11-4.43 (br m, 0.4H), 4.46-4.48 (br m, 0.6H), 5.07-5.22

(m, 2H), 5.73-5.84 (br m, 1H), 6.15-6.27 (br m, 1H), 6.44-6.50 (d, 1H, J=15.8 Hz), 7.28-

13 7.38 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 28.26, 28.50, 44.78, 52.04, 53.98,

55.06, 79.60, 115.85, 125.61, 126.38, 127.57, 128.45, 133.57, 135.70, 136.72, 155.29,

172.94; m/z (relative intensity) 286(4), 184(25), 128(100), 84(91), 57(51). Anal.Calcd. for C21H29NO4: C, 70.17; H, 8.13; O, 17.80. Found: C, 70.15; H, 8.24; O, 17.85. 121

(E)-Methyl 2-(1-(but-3-enyl(tert-butoxycarbonyl)amino)ethyl)-4-phenylbut-3-enoate

(13b).

To the solution of tert-butyl but-3-enyl(ethyl)carbamate (796 mg, 4.0 mmol) and Rh2(R-

DOSP)4 (18 mg, 0.01 mmol) in 5 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (10 mL, 1.0 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 111 mg (30%) of title compound as yellow oil. HPLC analysis indicated 90% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min-1, 254

25 nm; Rt = 8.1 min (minor, 10% ee), 8.6 min (major, 90% ee); [&]D = +62.0 (c=1.0,

-1 1 CHCl3); IR (neat) 3013, 2977, 2931, 1732, 1685 cm ; H NMR (300 MHz, CDCl3): '

[ppm] 1.33-1.36 (dd, 3H, J=6.7 Hz), 1.43-1.45 (d, 4H), 1.55-1.57 (d, 5H), 2.25-2.47 (br m, 2H), 3.04-3.30 (br m, 2H), 3.60-3.67 (m, 1H), 3.74-3.75 (d, 3H), 4.22-4.40 (br m, 1H),

5.07-5.17 (m, 2H), 5.76-5.88 (m, 1H), 6.19-6.31 (m, 1H), 6.50-6.58 (dd, 1H, J=15.8 Hz),

13 7.29-7.46 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 15.94, 27.06, 33.19, 44.09,

50.62, 53.06, 53.56, 78.05, 114.96, 124.10, 124.95, 126.16, 127.03, 132.13, 134.09,

135.27, 153.91, 171.62; m/z (relative intensity) 128(2), 98(12), 57(100), 41(39), 29(25).

Anal.Calcd. for C22H31NO4: C, 70.75; H, 8.37; O, 17.14. Found: C, 67.73; H, 8.39; O,

16.68. 122

(E)-Methyl 2-(1-(tert-butoxycarbonyl(pent-4-enyl)amino)ethyl)-4-phenylbut-3- enoate (13c).

To the solution of tert-butyl ethyl(pent-4-enyl)carbamate (547 mg, 2.4 mmol) and Rh2(R-

DOSP)4 (10.8 mg, 0.006 mmol) in 3 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (6 mL, 0.6 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 67 mg (28%) of title compound as yellow oil. HPLC analysis indicated 85% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min-1, 254

25 nm; Rt = 7.5 min (minor, 15% ee), 8.2 min (major, 85% ee); [&]D = +82.40 (c=0.5,

25 CHCl3, Rh2(R-DOSP)4), [&]D = -75.5 (c=0.4, CHCl3, Rh2(S-DOSP)4); IR (neat) 3024,

-1 1 3003, 2975, 2930, 2870, 2857, 1732, 1692 cm ; H NMR (300 MHz, CDCl3): ' [ppm]

1.17-1.19 (d, 3H, J=6.8 Hz), 1.26-1.28 (d, 5H), 1.38 (s, 4H), 1.51 (br m, 2H), 1.89-1.96

(br m, 2H), 2.82-3.03 (br m, 2H), 3.17-3.59 (m, 1H), 3.69 (s, 3H), 4.22 (br m, 1H), 4.86-

4-98 (m, 2H), 5.62-5.78 (m, 1H), 5.98-6.15 (m, 1H), 6.34-6.39 (d, 1H, J=15.8 Hz), 7.13-

13 7.26 (m, 5H); C NMR (75 MHz, CDCl3): ' [ppm] 16.30, 27.32, 27.47, 30.25, 44.45,

51.03, 53.49, 53.91, 78.32, 113.91, 124.57, 125.36, 126.58, 127.44, 132.47, 135.70,

136.91, 154.37, 172.14; m/z (relative intensity) 285(4), 115(6), 91(14), 57(100). 123 Anal.Calcd. for C23H33NO4: C, 71.29; H, 8.58; O, 16.51. Found: C, 70.82; H, 8.82; O,

16.10.

(E)-Methyl 2-(1-(tert-butoxycarbonyl(hex-5-enyl)amino)ethyl)-4-phenylbut-3-enoate

(13d).

To the solution of tert-butyl ethyl(hex-5-enyl)carbamate (2.56 g, 11.2 mmol) and Rh2(S-

DOSP)4 (50.4 mg, 0.028 mmol) in 14 mL of anhydrous DCE was added dropwise 0.1 M solution of methyl styryldiazoacetate in DCE (28 mL, 2.8 mmol). Reaction mixture was stirred at room temperature under argon for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (8:1 hexanes:EtOAc) to give 302 mg (27%) of title compound as yellow oil. HPLC analysis indicated 82% ee ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min-1, 254

24 nm; Rt = 10.2 min (major, 82% ee), 11.4 min (minor, 18% ee); [&]D = +51.2 (c=0.5,

24 CHCl3, Rh2(R-DOSP)4), [&]D = -92.2 (c=0.9, CHCl3, Rh2(S-DOSP)4); IR (neat) 3026,

-1 1 2972, 2933, 2858, 1733, 1695 cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.17-1.19 (d,

3H, J=6.78 Hz), 1.26-1.39 (m, 13H), 1.91-1.98 (m, 2H), 2.84-3.03 (m, 2H), 3.53-3.59 (m,

1H), 3.62 (s, 3H), 4.16 (br m, 1H), 4.84-4.96 (m, 2H), 5.61-5.75 (m, 1H), 6.01-6.14 (m,

13 1H), 6.34-6.39 (d, 1H, J=15.8 Hz), 7.13-7.26 (m, 5H); C NMR (75 MHz, CDCl3): '

[ppm] 16.04, 25.06, 27.08, 28.20, 32.12, 44.59, 50.78, 53.31, 53.63, 77.99, 113.35,

124.34, 125.10, 126.29, 127.19, 132.21, 135.48, 137.26, 154.11, 171.94; m/z (relative 124 intensity) 170(9), 143(8), 115(30), 91(5), 57(100). Anal.Calcd. for C24H35NO4: C, 71.79;

H, 8.79; O, 15.94. Found: C, 71.82; H, 8.87; O, 16.08.

(Z)-1-tert-Butyl 3-methyl 2-methyl-2,3-dihydropyridine-1,3-(6H)-dicarboxylate

(14a).

To the solution of Hoveyda-Grubbs 2nd generation catalyst (5 mg, 0.0085 mmol) in 8.5 mL of anhydrous DCE at gentle reflux was added dropwise 0.05 M solution of 11a (0.17 mmol in 3.4 mL of anhydrous DCE). Reaction mixture was heated at reflux for 1 h, then it was cooled down to room temperature and quenched with 0.1 M solution of potassium

2-isocyanoacetate (6.3 mg, 0.051 mmol in 0.5 mL of methanol). After stirring at room temperature for 5 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give

42 mg (98%) of the title compound as a colorless oil. HPLC analysis indicated 93% ee

-1 ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min , 254 nm; Rt = 3.4 min

23 (major, 93% ee), 5.2 min (minor, 7% ee); [&]D = -165.8 (c=0.8, CHCl3); IR (NaCl disc)

2975, 2952, 2933, 2840, 1739, 1685, 1413, 1363, 1174 cm-1; 1H NMR (300 MHz,

CDCl3): ' [ppm] 1.08-1.10 (d, 3H, J=6.9 Hz), 1.39 (s, 9H), 2.85 (br s, 1H), 3.40-3.47 (br d, 1H), 3.61 (s, 3H), 4.18-4.25 (br d, 1H), 4.75-4.83 (m, 1H), 5.68-5.73 (m, 1H), 5.77-

13 5.81 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 16.65, 27.39, 38.40, 45.19, 45.20, 125 51.07, 78.63, 118.88, 125.32, 153.51, 171.40; m/z (relative intensity) 155(17), 124(10),

96(46), 80(30), 57(100). Anal.Calcd. for C13H21NO4: C, 61.16; H, 8.29; O, 25.07. Found:

C, 61.19; H, 8.26; O, 25.32.

(Z)-1-tert-Butyl 3-methyl 2-methyl-2,3-dihydro-1H-azepine-1,3(6H, 7H)- dicarboxylate (14b).

To the solution of Hoveyda-Grubbs 2nd generation catalyst (5.6 mg, 0.009 mmol) in 9 mL of anhydrous DCE at gentle reflux was added dropwise 0.05 M solution of 13b (0.18 mmol in 3.6 mL of anhydrous DCE). Reaction mixture was heated at reflux for 1 h, then it was cooled down to room temperature and quenched with 0.1 M solution of potassium

2-isocyanoacetate (6.3 mg, 0.054 mmol in 0.5 mL of methanol). After stirring at room temperature for 5 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give

46 mg (96%) of the title compound as a colorless oil. HPLC analysis indicated 95% ee

-1 ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min , 254 nm; Rt = 3.3 min

27 (major, 95% ee), 5.2 min (minor, 5% ee); [&]D = -185.0 (c=0.8, CHCl3); IR (NaCl disc)

-1 1 2975, 2929, 2837, 1740, 1692, 1455, cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.07-

1.11 (t, 3H), 1.38 (s, 9H), 2.12-2.18 (br m, 1H), 2.49-2.56 (br m, 1H), 3.10-3.15 (m, 1H),

3.29-3.38 (br m, 1H), 3.51-3.58 (m, 1H), 3.66 (s, 3H), 4-34-4.59 (m, 1H), 5.39-5.45 (m, 126 13 1H), 5.56-5.63 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 18.67, 19.03, 28.48, 29.20,

29.61, 38.54, 38.91, 50.36, 50.76, 52.20, 52.57, 53.89, 79.31, 79.72, 124.40, 124.94,

130.51, 130.80, 155.31, 173.32, 173.78; m/z (relative intensity) 169(29), 154(14),

110(35), 82(32), 57(100). Anal.Calcd. for C14H23NO4: C, 62.43; H, 8.61; O, 23.76.

Found: C, 62.64; H, 8.71; O, 23.49.

(Z)-1-tert-Butyl 3-methyl 2-methyl-2,3,7,8-tetrahydroazocine-1,3(6H)-dicarboxylate

(14c).

To the solution of Hoveyda-Grubbs 2nd generation catalyst (6.2 mg, 0.01 mmol) in 10 mL of anhydrous DCE at gentle reflux was added dropwise 0.05 M solution of 13c (0.2 mmol in 4 mL of anhydrous DCE). Reaction mixture was heated at reflux for 1 h, then it was cooled down to room temperature and quenched with 0.1 M solution of potassium 2- isocyanoacetate (7.4 mg, 0.06 mmol in 0.6 mL of methanol). After stirring at room temperature for 5 min, reaction mixture was passed through a short silica plug and washed with DCM. Crude reaction mixture was then concentrated under reduced pressure and residue was purified by flash column chromatography (hexanes:EtOAc 4:1) to give

54 mg (95%) of the title compound as a colorless oil. HPLC analysis indicated 92% ee

-1 ((R,R) Whelk-O 1, hexane/isopropyl alcohol 90:10, 1.0 mL min , 254 nm; Rt = 3.4 min

25 (major, 92% ee), 5.3 min (minor, 8% ee); [&]D = -112.5 (c=0.8, CHCl3); IR (NaCl disc)

-1 1 2972, 2952, 2861, 1729, 1699, 1463, cm ; H NMR (300 MHz, CDCl3): ' [ppm] 1.03- 127 1.07 (dd, 3H), 1.36 (s, 9H), 1.44-1.54 (m, 1H), 1.77 (br m, 1H), 2.02-2.08 (m, 2H), 2.63-

2.72 (m, 1H), 3.13-3.23 (m, 1H), 3.45-3.64 (m, 1H), 3.65 (s, 3H), 4.25-4.52 (m, 1H),

13 5.46-5.62 (m, 1H), 5.75-5.84 (m, 1H); C NMR (75 MHz, CDCl3): ' [ppm] 15.09, 24.25,

24.43, 26.11, 26.32, 41.01, 48.59, 48.78, 49.82, 50.35, 77.16, 77.35, 124.81, 125.23,

130.62, 131.56, 152.86, 153.36, 171.24, 171.72; m/z (relative intensity) 210(7), 183(9),

168(36), 152(6), 124(41), 71(12), 57(100), 41(24). Anal.Calcd. for C15H25NO4: C, 62.58;

H, 8.89; O, 22.58. Found: C, 63.81; H, 8.97; O, 22.71. 128 REFERENCES AND NOTES

(1) Hughes, B. The Hemlock Cup: Socrates, Athens and the Search for the Good Life. Alfred A. Knopf, New York, 2011.

(2) Ladenburg, A. Chem. Soc. Abstr. 1886, 19, 2579.

(3) Farwick, A.; Helmchen, G. Org. Lett. 2010, 12, 1108–1111.

(4) Yet, L. Chem. Rev. 2000, 100, 2963-3007.

(5) Mehta, G.; Sing, V. Chem. Rev. 1999, 99, 881-930.

(6) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131-9166.

(7) Deshmukh, P. H.; Blechert, S. Dalton Trans. 2007, 2479-2491.

(8) Lozano-Vila, A. M.; Monsaert, S.; Bajek, A.; Verpoort, F. Chem. Rev. 2010, 110, 4865-4909.

(9) Mori, M. Materials 2010, 3, 2087-2140.

(10) Basset, J.-M.; Coperet, C.; Soulivong, D.; Taoufik, M.; Cazat, J. T. Acc. Chem. Res. 2010, 43, 323-334.

(11) Hoveyda, A. H.; Malcolmson, S. J.; Meek, S. J.; Zhugralin, A. R. Angew. Chem. Int. Ed. 2010, 49, 34-44.

(12) Takao, K.; Tadano, K. Heterocycles 2010, 81, 1603-1629.

(13) Majumdar, K. C.; Chattopadhyay, B.; Ray, K. Curr. Org. Synth. 2010, 7, 153- 176.

(14) Nolan, S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305-3316.

(15) Burke, A. J.; Marinho, V. R.; Furtado, O. M. R. Curr. Org. Synth. 2010, 7, 94- 119.

(16) Tori, M.; Mizutani, R. Molecules 2010, 15, 4242-4260.

(17) Aljarilla, A.; Lopez, J. C.; Plumet, J. Eur. J. Org. Chem. 2010, 6123-6143.

(18) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746-1787.

(19) Gulajski, L.; Mauduit, M.; Grela, K. Pure Appl. Chem. 2009, 81, 2001-2012. 129

(20) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817-3858.

(21) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783-3816.

(22) Samojlowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708-3742.

(23) Diesendruck, C. E.; Tzur, E.; Lemcoff, N. G. Eur. J. Inorg. Chem. 2009, 4185- 4203.

(24) Boeda, F.; Clavier, H.; Nolan, S. P. Chem. Commun., 2008, 2726-2740.

(25) Szadkowska, A.; Grela, K. Curr. Org. Chem. 2008, 12, 1631-1647.

(26) Reymond, S.; Ferrie, L.; Guerinot, A.; Capdevielle, P.; Cossy, J. Pure Appl. Chem., 2008, 80, 1683-1691.

(27) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716- 5726.

(28) Michrowska, A.; Grela, K. Pure Appl. Chem. 2008, 80, 31-43.

(29) Compain, P. Adv. Synth. Catal. 2007, 349, 1829-1846.

(30) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919-3952.

(31) Villar, H.; Frings, M.; Bolm, C. Chem. Soc. Rev. 2007, 36, 55-66.

(32) Kotha, S.; Lahiri, K. Synlett, 2007, 2767-2784.

(33) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 6786-6801.

(34) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40, 45-52.

(35) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243-251.

(36) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem. Int. Ed. 2006, 45, 2664- 2670.

(37) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490- 4527.

(38) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140. 130

(39) Dieters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199-2238.

(40) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712.

(41) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003, 42, 1900-1923.

(42) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592-4633.

(43) Jorgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.; Wrodnigg, T. M. Curr. Org. Chem. 2000, 4, 565-588.

(44) Roy, R.; Das, S. K. Chem. Commun. 2000, 519-529.

(45) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012-3043.

(46) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75-89.

(47) Wright, D. L. Curr. Org. Chem. 1999, 3, 211-240.

(48) Ivin, K. J. J. Mol. Catal. A: Chemical 1998, 133, 1-16.

(49) Randall, M. L.; Snapper, M. L. J. Mol. Catal. A: Chemical 1998, 133, 29-40.

(50) Noels, A. F.; Demonceau, A. J. Phys. Org. Chem. 1998, 11, 602-609.

(51) Pariya, C.; Jayaprakash, K. N.; Sarkar, A. Coord. Chem. Rev. 1998, 168, 1-48.

(52) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371-388.

(53) Schmalz, H.-G. Angew. Chem. Int. Ed. 1995, 34, 1833-1836.

(54) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 2036-2056.

(55) In February 2011, there were 758 references found in SciFinder containing the concept “total synthesis” and “metathesis”.

(56) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108-2109.

(57) Konig, B.; Horn, C. Synlett 1996, 1013-1014.

(58) Huwe, C. M.; Blechert, S. Tet. Lett. 1995, 36, 1621-1624.

(59) Huwe, C.M.; Blechert, S. Synthesis 1997, 61-67. 131

(60) Barrett, A. G. M.; Baugh, S. P. D.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1996, 2231-2232.

(61) Barrett, A. G. M.; Baugh, S. P. D.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155-156.

(62) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett 1997, 1179-1180.

(63) Grossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999, 1660-1662.

(64) Diedrichs, N.; Westermann, B. Synlett 1999, 1127-1129.

(65) Hammer, K.; Undheim, K. Tetrahedron 1997, 53, 2309-2322.

(66) Herisson, P. J.-L.; Chauvin, Y. Macromol. Chem. 1971, 141, 161-176.

(67) Schaverien, C. J.; Dewan, J. C.; Schrock, R. R. J. Am. Chem. Soc. 1986, 108, 2771-2773.

(68) Schrock, R. R.; DePue, R. T.; Feldman, J.; Schaverien, C. J.; Dewan, J. C.; Liu, A. H. J. Am. Chem. Soc. 1988, 110, 1423-1435.

(69) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886.

(70) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856-9857.

(71) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 3974- 3975.

(72) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. 1995, 34, 2039-2041.

(73) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100-110.

(74) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324-7325.

(75) Rutjes, F. P. J. T.; Schoemaker, H. E. Tet. Lett. 1997, 38, 677-680.

(76) Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J. Org. Chem. 2003, 756-760.

(77) Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Synlett 2002, 1146-1148. 132

(78) Pachamuthu, K.; Vankar, Y. D. J. Organomet. Chem. 2001, 624, 359-363.

(79) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606- 9614.

(80) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Patzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251-7264.

(81) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa, M. Synlett 1997, 1179-1180.

(82) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359- 7360.

(83) Rodriquez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2000, 2, 3209-3212.

(84) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides. Wiley- Interscience, New York, 1998.

(85) Yates, P. J. Am. Chem. Soc. 1952, 74, 5376-5381.

(86) Nozaki, H.; Moriuti, S.; Takaya, H. Tetrahedron Lett. 1966, 5239-5244.

(87) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704-724.

(88) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681-6705.

(89) Zhang, Y.; Wang, J. Coord. Chem. Rev. 2010, 254, 941-953.

(90) Maas, G. Angew. Chem. Int. Ed. 2009, 48, 8186-8195.

(91) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072-3081.

(92) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061-3071.

(93) Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350-5361.

(94) Honma, M.; Takeda, H.; Takano, M.; Nakada, M. Synlett 2009, 1695-1712.

(95) Zhang, Y.; Lu, Z.; Wulff, W. D. Synlett 2009, 2715-2739.

(96) Whited, M. T.; Grubbs, R. H. Acc. Chem. Res. 2009, 42, 1607-1616.

133 (97) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577-6605.

(98) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545-555.

(99) Diaz-Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379-3394.

(100) Davies, H. M. L.; Hedley, S. J. Chem. Soc. Rev. 2007, 36, 1109-1119.

(101) Davies, H. M. L. Angew. Chem. Int. Ed. 2006, 45, 6422-6425.

(102) Doyle, M. P. J. Org. Chem. 2006, 71, 9253-9260.

(103) Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176-4187.

(104) Davies, H. M. L.; Loe, O. Synthesis 2004, 2595-2608.

(105) Davies, H. M. L.; Beckwith, E. J. Chem. Rev. 2003, 103, 2861-2903.

(106) Davies, H. M. L. J. Mol. Catal. A: Chemical 2002, 189, 125-135.

(107) Timmons, D. J.; Doyle, M. P. J. Organomet. Chem. 2001, 617-618, 98-104.

(108) Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001, 617-618, 47- 55.

(109) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459-2469.

(110) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463-488.

(111) Doyle, M. P. Pure & Appl. Chem. 1998, 70, 1123-1128.

(112) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911-935.

(113) Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron: Asymmetry 1998, 9, 3145-3169.

(114) Davies, H. M. L. Aldrichimica Acta 1997, 30, 107-114.

(115) Doyle, M. P.; McKervey, M. A. Chem. Commun. 1997, 983-989.

(116) Calter, M. A. Curr. Org. Chem. 1997, 1, 37-70.

(117) Doyle, M. P. Aldrichimica Acta 1996, 29, 3-11.

(118) Ye, T.; McKervey, A. Chem. Rev. 1994, 94, 1091-1160. 134

(119) Padwa, A.; Austin, D. J. Angew. Chem. Int. Ed. 1994, 33, 1797-1815.

(120) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765-1808.

(121) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348-356.

(122) Doyle, M. P. Chem. Rev. 1986, 919-939.

(123) Curtius, T. Ber. Dtsch. Chem. Ges. 1883, 16, 2230-2231.

(124) Wolff, L. Ann. 1912, 394, 23-59.

(125) Arndt, F.; Eistert, B.; Partale, W. Ber. Dtsch. Chem. Ges. 1927, 60, 1364-1370.

(126) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655- 3669.

(127) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1975, 1707-1710.

(128) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977, 2599-2602.

(129) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1982, 23, 685-688.

(130) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Angew. Chem. Int. Ed. 1986, 25, 1005- 1006.

(131) Fritschi, H.; Leutenegger, U.; Siegmann, K.; Pfaltz, A. Helv. Chim. Acta 1988, 71, 1541-1552.

(132) Fritschi, H.; Leutenegger, U.; Pfaltz, A. Helv. Chim. Acta 1988, 71, 1553-1565.

(133) Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232- 240.

(134) Leutenegger, U.; Umbricht, G.; Fahrni, C.; von Matt, P.; Pfaltz, A. Tetrahedron 1992, 48, 2143-2156.

(135) Pfaltz, A. Acc. Chem. Res. 1993, 26, 339-345.

(136) Mazet, C.; Kohler, V.; Pfaltz, A. Angew. Chem. Int. Ed. 2005, 44, 4888-4891.

(137) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc. 1991, 113, 726-728.

135 (138) Evans, D. A.; Woerpel, K. A.; Scott, M. J. Angew. Chem. Int. Ed. 1992, 31, 430- 432.

(139) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1973, 2233-2236.

(140) Paulissen, R.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1974, 607- 608.

(141) Hubert, A. J.; Noels, A. F.; Anciaux, A. J. Teyssie, P. Synthesis 1976, 600-602.

(142) Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.; Teyssie, P. Tetrahedron 1982, 38, 2733-2739.

(143) Cama, L. D.; Christensen, B. G. Tetrahedron Lett. 1978, 4233-4236.

(144) Melillo, D. G.; Shinkai, L. T. Tetrahedron Lett. 1980, 21, 2783-2786.

(145) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6163-6165.

(146) Osipov, S. N.; Sewald, N.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. Tetrahedron Lett. 1996, 37, 615-618.

(147) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. Slawin, A. M. Z. Synlett 1996, 825-826.

(148) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985, 50, 5223-5230.

(149) Zibuck, R.; Streiber, J. Org. Syn. 1998, 9, 432-435.

(150) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.; Baum, J. S. Org. Syn. 1998, 9, 422-426.

(151) Davies, H. M. L.; Clark, T. J.; Smith, H. D. J. Org. Chem. 1991, 56, 3817-3824.

(152) Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696-5700.

(153) Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737-1739.

(154) Taillier, C.; Hameury, T.; Bellosta, V.; Cossy, J. Tetrahedron 2007, 63, 4472- 4490.

(155) Lee, E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066-12067.

136 (156) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 5834-5835.

(157) Moody, C. J. Angew. Chem. Int. Ed. 2007, 46, 9148-9150.

(158) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett. 1997, 38, 6471- 6472.

(159) Hodgson, D. M.; Stupple, P. A.; Pierard, F. Y. T. M.; Labande, A. H.; Johnstone, C. Chem. Eur. J. 2001, 7, 4465-4476.

(160) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50-61.

(161) Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Castro, M. A. E. J. Org. Chem. 2003, 68, 6153-6159.

(162) Taillier, C.; Hameury, T.; Bellosta, V.; Cossy, J. Tetrahedron 2007, 63, 4472- 4490.

(163) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.; Smethurst, C. A. P.; Smith, A. D.; Solla-Rodriguez, H. Tetrahedron 2003, 59, 3253-3265.

(164) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677-680.

(165) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606- 9614.

(166) Pavlyuk, O.; Teller, H.; McMills, M.C. Tetrahedron Lett. 2009, 50, 2716-2718.

(167) Pellissier, H. Tetrahedron 2006, 62, 2143-2173.

(168) Pellissier, H. Tetrahedron 2006, 62, 1619-1665.

(169) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195-206.

(170) Tietze, L. F. Chem. Rev. 1996, 96, 115-136.

(171) Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.

(172) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. 1993, 32, 131-161.

(173) Deng, L.; Giessert, A. J.; Gerlitz, O. O.; Dai, Z.; Diver, S. T.; Davies, H. M. L. J. Am. Chem. Soc. 2005, 127, 1342-1343.

137 (174) Hodgson, D. M.; Angrish, D. Chem. Eur. J. 2007, 13, 3470-3479.

(175) Hodgson, D. M.; Angrish, D. Adv. Synth. Catal. 2006, 348, 2509-2514.

(176) Hodgson, D. M.; Angrish, D.; Labande, A. H. Chem. Commun. 2006, 627-628.

(177) Hunt, J. C. A.; Laurent, P.; Moody, C. J. J. Chem. Soc., Perkin Trans. 1 2002, 2378-2389.

(178) Davies, H. M. L.; Venkataramani, C. Angew. Chem. Int. Ed. 2002, 41, 2197-2199.

(179) Pavlyuk, O.; Humes, R.; McMills, M.C. Tetrahedron Lett. 2011, submitted.

138

APPENDIX

SELECTED NMR SPECTRA 139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187 188

189

190

191

192

193

194