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Dissertation FINAL Post-Revisions

Dissertation FINAL Post-Revisions

ALL– ENE–TYPE CYCLIZATIONS FROM CYCLOHEXADIENE-

TRICARBONYLIRON DERIVATIVES

by

KEITH B. BEACH

Submitted in partial fulfillment of the requirements for the degree of

DOCTOR OF PHILOSOPHY

Thesis Advisor

ANTHONY J. PEARSON, PH.D.

Department of Chemistry

CASE WESTERN RESERVE UNIVERSITY

August 2016 CASE WESTERN RESERVE UNIVERSITY

SCHOOL OF GRADUATE STUDIES

We hereby approve the thesis/dissertation of

Keith B. Beach

candidate for the degree of Doctor of Philosophy.

Committee Chair

Robert G. Salomon, Ph.D.

Committee Members

Gregory P. Tochtrop, Ph.D.

Rajesh Viswanathan, Ph.D.

Yanming Wang, Ph.D.

Date of Defense

02 May 2016

*We also certify that written approval has been obtained for any proprietary material

contained therein. For my Grandfather, my Father and Clara Cree TABLE OF CONTENTS

Table of Contents iv List of Equations vii List of Schemes viii List of Figures ix List of Tables xi Acknowledgements xii List of Abbreviations xiv Abstract xv

Chapter 1. General Introduction: –Tricarbonyliron Complexes 1 1.1 General Properties and Applications 2 1.1.1 Scope of Diene-Tricarbonyliron Complexes 3 1.1.1.1 Iron Carbonyl Reagents Used for Complexation 3 1.1.1.2 Preparation of Diene-Tricarbonyliron Complexes 5 1.1.1.3 Liberation of Diene Ligands from Iron Complexes 10 1.1.2 General Applications of Diene-Tricarbonyliron Complexes 12

1.1.2.1 Fe(CO)3 Moiety used as a Protecting Group 12

1.1.2.2 Fe(CO)3 Moiety used as a Stabilizing Group 15

1.1.2.3 Fe(CO)3 Moiety used as a Stereodirecting Group 17 1.2 Application Towards Stereogenic Quaternary-Carbon Formation 19

1.2.1 From Dienyl-Fe(CO)3 Substrates 20 1.2.1.1 Preparation 20 1.2.1.2 General Reactivity/Selectivity towards Nucleophilic Additions 21 1.2.1.3 Application: Synthesis of Trichodermol and Derivatives 23

1.2.1.4 Limitations of using Dienyl-Fe(CO)3 Complexes in Trichodermol 24 Analogue Synthesis

1.2.2 [6+2] Ene-Type Cyclizations 25

1.2.2.1 Progression towards Cyclizations from Diene-Fe(CO)3 Substrates 25 1.2.2.2 Scope of Ene-Type Cyclizations 28 1.2.2.2.1 Derivatives 28 1.2.2.2.2 and Derivatives 33

1.2.2.2.3 Stereoelectronic Considerations 35

– iv – 1.2.2.3 Transition to All-Carbon Cyclizations 37

1.3 References 40 Chapter 2. All-Carbon [6+2] Ene-Type Cyclizations of (Cyclohexadiene)-Tricarbonyl 47 Iron Derivatives 2.1 Background: All-Carbon Spirocyclizations 48 2.1.1 Acyclic Substrates 48 2.1.2 Cyclic Substrates 50

2.2 Project Aim: Cyclizations from α- Derivatives 51 2.3 Single Cyclizations 54

2.3.1 Unsubstituted (Cyclohexa-1,3-diene)-Fe(CO)3 Substrates 54

2.3.2 3-Methoxy Substituted (Cyclohexa-1,3-diene)-Fe(CO)3 Substrates 60

2.4 Attempts at Tandem Double Cyclizations from Alcohol Derivatives 65 2.4.1 Mono-Cyclization Attempts with Di-Substituted Pendant Olefin 65 2.4.2 Tandem Double Cyclization Attempts 69

2.5 Conclusions 71 2.6 Experimental Section 72 2.7 References 89 Chapter 3. Generality of Stereocontrol During Grignard Additions to 92 (Cyclohexa-1,3-dienylcarbaldehyde)-Tricarbonyl Iron

3.1 Introduction: Additions to Carbonyl-Functionalized Diene-Fe(CO)3 Derivatives 93 3.1.1 Explanation of Stereochemical-Descriptor Terminology 93 3.1.2 Alkyl Additions to Acyclic Complexes 94

3.1.2.1 Experimental Observations of Alkylations of Complexed 94 Dienylcarbaldehydes & Dienones

3.1.2.2 Accepted Model for Alkyl Additions to Dienylcarbaldehyde-Fe(CO)3 97 Complexes 3.1.3 Additions to Cyclic Derivatives 98

3.2 Grignard Additions to Cyclohexa-1,3-dienylcarbaldehyde Complexes 99 3.2.1 Observed Selectivities en route to Spirocyclic Complexes 99

3.2.1.1 Additions to Dienylcarbaldehyde-Fe(CO)3 Derivatives 100 3.2.1.2 Determination of Configuration at α-Carbon via NOE Studies 103 3.2.1.3 Comparison of Results to Acyclic Series 105 3.2.2 Observed Selectivities from Generic Grignard Additions 106

– v – 3.3 Conclusions 109 3.4 Experimental Section 110 3.5 References 113 Chapter 4. Future Works and Concluding Remarks 116 Appendix 120 Bibliography 142

– vi – LIST OF EQUATIONS

1.1: Isomerization of 1,4- to form conjugated diene-Fe(CO)3 complexes 5

1.2: Stereoselective iron complexation 9

1.3: Formation of ()-Fe(CO)3 15

1.4: Complexation of reactive o-quinodimethane 15

1.5: Addition of tetrafluoroethane to (cyclohexa-1,3-diene)-Fe(CO)3 28

1.6: Ene-type spirocyclizations of amide derivatives 28

1.7: Thermal stability of (methyl 3-methoxycyclohexa-1,3-dienecarboxylate)-Fe(CO)3 31

1.8: Formation of enone from mixture of spirocycle complexes 31

1.9: Double cyclization of an amide-derived complex 33

1.10: Spirocyclization of ester derivatives 33

2.1: Spirocyclizations from derivatives without direct connection to a 51

2.2: Spirocyclizations of dienecarbinol derivatives 53

2.3: Addition of 3-buten-1-ylmagnesium bromide to 2.42 58

2.4: Addition of 3-butenyl-1-ylmagnesium bromide to aldehyde 2.52 61

2.5: Cyclization attempt of acetyl-protected alcohol 2.58 under photothermal conditions 64

2.6: Attempted addition of (E/Z)-2.67 to aldehyde 2.42 66

2.7: Addition of Z-2.67 to aldehyde 2.42 67

2.8: Subjection of (4Z)-2.62 to cyclization under photothermal conditions 67

2.9: Addition of dienyl Grignard 2.72 to aldehyde 2.42 69

2.10: Unsuccessful attempt at tandem double cyclization of 2.69 70

3.1: Sodium borohydride reduction of acyclic ketone 3.5 96

3.2: Alkyllithium additions so acyclic ketone 3.7 96

3.3: Conformational equilibrium of acyclic ketone 3.9 96

3.4: Addition of 3-buten-1-ylmagnesium bromide to aldehyde 3.18 100

3.5: Addition of 3-buten-1-ylmagnesium bromide to aldehyde 3.24 102

3.6: Reaction of spirocycles 3.26 with CuCl2 104

– vii – LIST OF SCHEMES

Scheme 1-1: Difference between reaction of Me3NO and other reagents with methoxy- 11 substituted cyclohexadiene.

Scheme 1-2: Total synthesis of trichodermol. 24

Scheme 1-3: Proposed synthesis of verrucarol via dienyl-Fe(CO)3 complex 1.100. 25

Scheme 1-4: Proposed mechanism for cyclization of 1.109a. 32

Scheme 2-1: Sketched approach to Verrucarol from ester 2.22. 52

Scheme 2-2: Alkyl and alkoxide additions to aldehyde 2.23. 52

Scheme 2-3: Synthesis towards methyl ester 2.34 via Michael-Wittig route. 55

Scheme 2-4: Synthetic route to ester 2.34 from benzoic acid. 56

Scheme 2-5: Attempt of formation of ester 2.34 via direct complexation of 2.37. 56

Scheme 2-6: Preparation of aldehyde 2.42 via Mukiayama oxidation. 57

Scheme 2-7: Conversion of regioisomers to aldehyde 2.42 under thermal conditions. 57

Scheme 2-8: Retrosynthetic approach to enone 2.48. 60

Scheme 2-9: Synthetic route to aldehyde 2.52 via Birch reduction of m-anisic acid. 61

Scheme 2-10: Conversion to conjugated and 2.50 from mixture of isomers under basic 61 conditions. Scheme 2-11: Possible depiction for the formation of ketone 2.56 63

Scheme 2-12: Protection of alcohol 2.54 with acetic anhydride and methyl iodide. 64

Scheme 2-13: Synthetic scheme towards synthesis of Grignard reagent (E/Z)-2.67. 65

Scheme 2-14: Synthesis of Grignard reagent 2.67 from cis-2.65. 66

Scheme 2-15: Synthetic scheme towards conjugated diene Grignard 2.72. 69

Scheme 4-1: Retrosynthetic approach to all-carbon spirocycle 4.1 117

– viii – LIST OF FIGURES

Figure 1-1: Examples of reactions involving iron carbonyl derivatives. 2

Figure 1-2: General examples of an acyclic and cyclic η4-(diene)tricarbonyliron derivatives. 2

Figure 1-3: Structures of Fe(CO)5, Fe2(CO)9 and Fe3(CO)12. 3

Figure 1-4: Examples of diene-rearrangements using Fe(CO)5 to form conjugated diene 4 complexes.

Figure 1-5: Iron complexations using Fe2(CO)9 and Fe3(CO)13. 6

Figure 1-6: Examples of heterodiene-Fe(CO)3 complexes. 6

Figure 1-7: Iron complexations utilizing transfer agents. 7

Figure 1-8: Asymmetric iron complexations utilizing heterodiene-Fe(CO)3 derivatives as 8 transfer agents.

Figure 1-9: Demetallations achieved with different oxidizing agents. 10

Figure 1-10: Reactions on diene-Fe(CO)3 substrates that demonstrate the protecting 13 capability of the Fe(CO)3 group.

Figure 1-11: Diene protection from additions. 13

Figure 1-12: Friedel-Crafts acylations of diene-Fe(CO)3 complexes. 14

Figure 1-13: Stabilization of reactive diradicals and carbocations via Fe(CO)3 16 complexation.

Figure 1-14: Stereoselective additions to diene-Fe(CO)3 complexes. 18

Figure 1-15: Stereoselective Diels-Alder using diene-Fe(CO)3 complexes as 19 a source of diene or dienophile.

Figure 1-16: Preparation of dienyl-Fe(CO)3 complexes via hydride abstraction. 20

Figure 1-17: Generic example of cyclohexadienyl-Fe(CO)3 complex. 21

Figure 1-18: Nucleophilic additions to generic methoxycyclohexadienyl-Fe(CO)3 22 derivatives.

Figure 1-19: Product from reaction of 1.91 with strongly basic . 23

Figure 1-20: dimerizations of dienyl-Fe(CO)3 complexes. 26

Figure 1-21: Mechanism of radical dimerization. 26

Figure 1-22: Attempts of intramolecular radical cyclocoupling reactions from dienyl-Fe(CO)3 27 substrates.

Figure 1-23: Spirocyclization of amide diene-Fe(CO)3 complexes with pendant 29 substitution.

Figure 1-24: Pre- and post-cyclization rearrangements of diene-Fe(CO)3 complexes. 30

– ix – Figure 1-25: Cyclization attempts of thioester derivatives under various conditions. 34

Figure 1-26: Primary and secondary electronic effects of different conformations of 36 and . Figure 1-27: Primary and secondary electronic effects of different conformations of . 37

Figure 1-28: Preparation of diene-Fe(CO)3 complexes containing a ketone functionality. 38

Figure 2-1: Cyclizations of acyclic diene-Fe(CO)3 complexes under photothermal 49 conditions. Figure 2-2: Cyclizations of ketone derivatives under thermal and photothermal conditions. 50

Figure 2-3: Acorane sesquiterpenes that are potential targets using diene-Fe(CO)3 53 cyclization chemistry. Figure 2-4: Examples of angular triquinanes – potential targets via tandem double 54 cyclizations. Figure 2-5: 1H-NMR spectrum of unpurified 2.44 from reaction under photothermal 59 conditions.

Figure 2-6: 1H-NMR of mixture of spirocycles 2.68 in CDCl3, highlighting the formation of a 68 methyl-triplet.

Figure 2-7: 1H-NMR of crude mixture of spirocycles 2.68 in C6D6, highlighting the 68 separation of two methyl-triplets. Figure 3-1: Depiction of atom arrangement on a carbon attached directly to a terminus of 94 the diene-Fe(CO)3 complex.

Figure 3-2: Consistent relative Rf - values between Ψ-exo/endo diastereomers of different 96 dienylcarbinol-Fe(CO)3 complexes Figure 3-3: Two possible conformation of complexed dienones. 97

Figure 3-4: Accepted model used to explain the observed diastereoselectivities. 98

Figure 3-5: Nucleophilic additions to dienone-Fe(CO)3 complexes. 99

Figure 3-6: Grignard additions to aldehyde 3.20 that afford cyclization substrates. 100

Figure 3-7: 1H-NMR of crude alcohol 3.21. 101

Figure 3-8: 1H-NMR spectra of crude and purified alcohol 3.25. 103

Figure 3-9: Expanded NOESY of enone 3.27, highlighting the cis relationship of the α- 104 proton and methine proton.

Figure 3-10: Assumed relative configurations at the α-carbon of the major isomers 3.25, 105 3.21, and 3.22.

Figure 3-11: Gaussian calculations for the two lowest-energy aldehyde conformations. 108

– x – LIST OF TABLES

Table 2-1: Cyclization of alcohol 2.30 under thermal or photothermal conditions 59

Table 2-2: Cyclization of alcohol 2.54 (major) under thermal and photothermal conditions 62

Table 3-1: Yields and selectivities of different alkylating reagent additions to acyclic 95 dienylcarbaldehyde-Fe(CO)3 complexes.

Table 3-2: Observed selectivities of Grignard additions to aldehyde 3.20 based on the 1H- 106 NMR of the crude products.

– xi – ACKNOWLEDGEMENTS

The number of people who deserve acknowledgement during my tenure at Case Western

Reserve University is extensive, but I will do my best to make sure credit is given where it is due.

First and foremost, I would like to give my utmost gratitude to my advisor, Dr. Anthony J. Pearson, for being a great mentor and advisor during my graduate studies. Not only were his insights and advice greatly applicable in the classroom and the lab, but also in regards to outside of Millis hall. The atmosphere he provided allowed me to grow academically and intellectually without judgement or prejudice — certainly a culture that epitomized educational growth in the most effective manner. For all of the “chalk-talks” on frontier molecular orbitals, reaction mechanisms, and discussions on teaching methods and the joys of home ownership, I am truly grateful. I would also like to extend my sincere gratitude to lab mates Aaron Mulheren and Minxue Huang for their work with the general Grignard-addition studies and the preparation of hexa-3,5-dien-1-yl magnesium bromide, respectively. They both are great chemists and have bright futures ahead of them.

For assistance with Gaussian calculations, much appreciation to Dr. Thomas Gray is well- deserved. He really came in the clutch in the eleventh hour, and I cannot thank him enough for that.Many thanks to Prashansa Agrawal is also necessary, as she did a great job helping me with my 2D-NMR experiments.

I would also like to acknowledge Kathryn Howard, Jim Sill, Jim Faulk, Matthew Evans, Suzi

Mason, June Ilhan, Dave Carrino, Rehka Srinivasan, Raul Juarez and the rest of my graduate friends for their assistance in my day-to-day duties/activities. In regards to teaching, the insight provided by Dr. Sri and Dr. Juarez was priceless and I cannot thank them enough for that. For all other miscellaneous needs and random discussions, I thank the rest of the aforementioned people, as many of my work- and social-related interests were made very pleasant and enjoyable because of your help.

I would like to give a special thank-you to Dr. Forrest Etheridge and Jon Flikkema — my greatest friends during my time at Case. As the saying goes, “time with a friend is time well- spent”, and I would not have enjoyed my five years in graduate school if it were not for these fine

– xii – gentlemen. Whether it was talking chemistry, watching movies, or enjoying a quality cigar with whisky while discussing life in general, it was certainly time well-spent.

To my family I am the most grateful. I would not be where I am today if it were not for the incredible strength of my mother and support of my brothers. The odds we overcame were great, and it was because of each other we made it to where we are now.

And last but not least, I would like to thank my truly amazing wife and my beautiful baby girl,

Clara. The internal drive to be the best man I can be is most certainly fueled by the flames you ignite within me. For your love and support I am truly blessed.

– xiii – LIST OF ABBREVIATIONS acac acetylacetonate q quartet

ADD 1,1’-(azadicarbonyl)-dipiperidine Rf retention factor Ar aryl group rt room temperature BOC t-butoxycarbonyl s singlet CAN ceric t triplet cat. catalytic TBDPS t-butyldiphenylsilyl CO tBuOK t-butoxide d doublet THF DBU 1,8-diazabicyclo[5.4.0]undec-7-ene TLC thin layer chromatography DIBAL di-i-butylaluminum hydride Δ heat/reflux Et ethyl δ chemical shift

Et2O diethyl EtOAc ethyl acetate EtOH HRMS high-resolution mass spectrometry hν UV-light i-Pr i-propyl LAH lithium aluminum hydride LDA m multiplet Me methyl

Me2SO4 dimethyl sulfate n-Bu2O n-butyl ether Nu OMe p-TsOH p-toluenesulfonic acid

Ph3PO triphenylphosphine oxide

PPh3 triphenylphosphine

– xiv – ABSTRACT

All–Carbon Ene–Type Cyclizations from Cyclohexadiene-tricarbonyliron Derivatives

by

KEITH B. BEACH

Diene-tricarbonyliron chemistry has found great utility in organic synthesis. One area of particular interest utilizes an iron-promoted ene-type reaction to facilitate spirocyclization or tandem double-cyclization when a pendant alkene or diene is available, respectively. Previously in the Pearson lab, spirocyclizations as well as double-cyclizations have been reported starting from compounds containing a heteroatom (O, S, NPh) within the tethered side chain. The work herein focuses on the preparation of cyclization products containing an all-carbon backbone, such as 1. The intriguing aspect of this fundamental research is that synthesis of potential natural product-derivatives may be achieved, in particular those of the angular triquinane class.

Investigations of the generality of stereocontrol during Grignard additions used in the formation of

2 will also be described.

– xv – CHAPTER ONE

GENERAL INTRODUCTION: DIENE–TRICARBONYLIRON COMPLEXES Chapter 1 General Introduction

1.1 General Properties and Applications

Since the late 19th century, iron carbonyl in its many forms has commonly and effectively been used to carry out a vast number of organic transformations. Ranging from alkene isomerizations to deoxygenations, iron carbonyl has provided a relatively simple yet efficient approach to such conversions while also proving to be a cheaper alternative compared to its other transition-metal counterparts (Figure 1-1).1-7 The focus of this dissertation, however, is not

Figure 1-1: Examples of reactions involving iron carbonyl derivatives. to be directed towards the broad scope of general iron carbonyl chemistry, but to a set of derivatives that stem from the reaction of iron carbonyl with a diene ligand (Figure 1-2).

Figure 1-2: General examples of an acyclic and cyclic η4-(diene)tricarbonyliron derivatives.

The use of such a moiety in organic synthesis has presented great advantages for those who have employed it in their research. Not only is the formation of diene-tricarbonyliron substrates achieved under relatively mild conditions, the removal of the metallic group is easily

– 2 – Chapter 1 General Introduction accomplished as well, doing so without any harm inflicted on the rest of the . The primary benefits of using these types of “functional groups”, however, are better realized when the diene-tricarbonyliron moiety is used as a protecting group, stabilizing group and/or stereodirecting group, which will be discussed in the subsequent sections.7-14

1.1.1 Scope of Diene-Tricarbonyliron Complexes

1.1.1.1 Iron Carbonyl Reagents Used for Complexation

Before elaborating on the applications of diene-tricarbonyliron functionalities in organic synthesis, introduction to the formation of such compounds is beneficial. Preparation of these diene-iron complexes can be achieved relatively easily using a variety of iron carbonyl reagents and conditions.6-7,15 The most common and applicable of said iron carbonyls are [Fe(CO)5], [Fe2(CO)9] and [Fe3(CO)12], which are the only known neutral-stable carbonyls of iron (Figure 1-3).6-7,16

Figure 1-3: Structures of Fe(CO)5, Fe2(CO)9 and Fe3(CO)12.

Of the three, Fe(CO)5 is the most widely used, most likely due to the low commercial cost compared to the other iron carbonyls.2,6 Being a with a low vapor pressure and low reactivity with at room temperature makes Fe(CO)5 the primary choice of metallating reagent, as solubility in organic solvents is easily accommodated. Preparation of complexes using

6-7 Fe(CO)5 can be achieved from a wide range of diene-containing substrates. One regard that makes Fe(CO)5 superior to the other iron carbonyls (Fe2(CO)9, specifically) is its ability to form the iron complex from non-conjugated diene substrates in a relatively straight forward fashion (Fig

1-4).13,17-21

Complexation using Fe2(CO)9 or Fe3(CO)12 reagents can be achieved under less-extreme reaction conditions, predominately due to their increased reactivity. Although the ability to make these complexes under milder conditions is beneficial, this higher reactivity makes storage of the

– 3 – Chapter 1 General Introduction

Figure 1-4: Examples of diene-rearrangements using Fe(CO)5 to form conjugated diene complexes. reagents increasingly difficult over time. Both solid reagents slowly oxidize and are less thermally stable at room temperature (Fe3(CO)12 more so than Fe2(CO)9), which leads to degradation to produce pyrophoric iron byproducts.6 Solubility is also a bigger issue for these particular compounds then for Fe(CO)5, which also limits their use. However, even with handling and solubility issues these iron carbonyl derivatives have found broad application in forming diene- iron complexes and other reactions.7-8,15,20

– 4 – Chapter 1 General Introduction

1.1.1.2 Preparation of Diene-Tricarbonyliron Complexes

As mentioned previously, the most common metallating reagents used to form these complexes are Fe(CO)5, Fe2(CO)9, and Fe3(CO)12, with Fe(CO)5 being the reagent of choice.

Given an organic ligand containing a conjugated or non-conjugated diene, the respective metal complex can be prepared by simply refluxing said diene and Fe(CO)5 in n-butyl ether, or via

7-8,10,16,21-22 ultraviolet irradiation in refluxing . (see Figure 1-4). Even though Fe(CO)5 is able to effectively complex to non-conjugated dienes such as the dihydro derivative 1.8, a mixture of diene-iron complexes 1.9 and 1.10 (see Figure 1-4, previous page) is typically obtained owing to their greater stability. In general, a mixture of regioisomers such as 1.9 and 1.10 can usually be separated via chromatography, however it can be problematic if higher yields are desired.7 This can be circumvented by conjugating the diene prior to iron-complexation via treatment with catalytic p-toluenesulfonic acid to give predominately the 1,3-isomer 1.15 (Eq. 1.1).

22-23

(1.1)

When the formation of diene-iron complexes is desired under milder conditions, either

Fe2(CO)9 or Fe3(CO)12 can be heated with the diene-containing ligand at much lower

24-27 temperatures than required for Fe(CO)5 to give the desired product (Fig. 1-5). A potential draw-back of forming a complex with a more reactive metallating reagent and hence under milder conditions is thermodynamic diene rearrangement is less likely to occur. So it is best to use these types of iron carbonyls with conjugated dienes.

Where Fe2(CO)9 finds its greatest utility, however, is in its ability to form complexes with heterodienes (Fig. 1-6). These unique heterodiene complexes function as highly-efficient transfer

7,13,21,28 agents by essentially transporting a Fe(CO)3 group to a diene substrate. What makes them so effective at transferring the Fe(CO)3 group is the inherent weaker interaction of the heterodiene with the metal; the migration from the weakly-bound ligand to a diene is thus a thermodynamically favored process.29 A simple example was demonstrated by Brookhart and

– 5 – Chapter 1 General Introduction

Nelson, in which they were able to utilize the benzylideneacetone-iron complex 1.27 to form the iron-complex of sorbic aldehyde 1.28 (Fig. 1-7).30

Figure 1-5: Iron complexations using Fe2(CO)9 and Fe3(CO)13.

Figure 1-6: Examples of heterodiene-Fe(CO)3 complexes.

– 6 – Chapter 1 General Introduction

Figure 1-7: Iron complexations utilizing transfer agents.

Heterodiene-Fe(CO)3 complexes can also be formed in situ, where the heterodiene can be used in catalytic quantities in the presence of stoichiometric amounts of the diene substrate and the iron carbonyl, typically Fe(CO)5 or Fe2(CO)9, as shown in Fig. 1-7 with the formation of the phenylsulfonyl-substituted diene-iron complex 1.31.13,31 In many cases, this is the preferred method due to the lability of heterodiene-Fe(CO)3 complexes. Purification is also facilitated as a result of the decreased presence of another (the heterodiene).

Besides high yields and ease of purification, preparation of complex organic structures with retention of configuration or formation of new stereocenters is highly desired. The beauty of using a diene as the ligand in these Fe(CO)3 complexes is that they are prochiral and afford planar chirality. Depending on the substitution pattern of the diene-substrate, Fe(CO)3 transfer agents can add the iron moiety to the diene in a stereoselective manner, in which the metallic group adds to the less hindered face of the diene (Fig. 1-8).32-34 The typical iron carbonyl derivatives can indeed achieve stereoselective complexations as well, but the added dimension of the transfer agents achieving higher selectivity is embodied in their capability of using chiral heterodienes if desired. Noteworthy examples of this were developed by Knölker et al. as well as the Birch group.

Knölker and Birch were able to prepare optically active diene-Fe(CO)3 complexes originating from transfer agents benzylideneimine 1.36 and the benzylideneacetone analogues 1.38 and 1.39 in

– 7 – Chapter 1 General Introduction

Figure 1-8: Asymmetric iron complexations utilizing heterodiene-Fe(CO)3 derivatives as transfer agents.

– 8 – Chapter 1 General Introduction moderate to good yields (Fig. 1-8, previous page).35-37

Dienes having containing stereogenic centers can also be used for the synthesis of optically active complexes. Synthesis of the -derived complex 1.33 can be achieved simply by direct reaction with Fe2(CO)9, but yields are much lower than when using transfer agent

1.27 (Fig. 1-8).33 Nonetheless, given the intricate structure of the steroid backbone, stereoselective iron-complexation does occur.

Another example is the stereoselective complexation of the cyclohexadiene 1.41 (Eq 1.2).38

In this case, by using greater than two (2) equivalents of Fe2(CO)9 yields can be increased to

85%. It is argued by Tsai and co-workers that the ketone in the stereogenic side-chain captures a

Fe(CO)4 fragment liberated from Fe2(CO)9, which would help direct the organometallic group to give the observed stereoselectivity.

(1.2)

With the examples presented, it is easy to observe that the formation of optically active and inactive diene-Fe(CO)3 compounds can be produced via a wide variety of methods. The scope of preparation of diene-containing substrates is indeed considerable as well, where the diene starting materials do not always have to begin in the conjugated 1,3-isomeric positions. In addition, the conditions for such reactions range from relatively mild to that of a thermally more extreme nature, and the metallating reagents also have a similar range with respect to their reactivity. Preparation of these complexes consequently is achieved in a desirable fashion, making the use of this class of compounds acceptable in organic synthesis.

– 9 – Chapter 1 General Introduction

1.1.1.3 Liberation of Diene Ligands from Iron Complexes

The formation of diene-Fe(CO)3 complexes can be performed with relative ease (see Section

1.1.1.2). However, the use of such complexes would not make much sense from a synthetic standpoint if one was unable to liberate the free diene-ligand from its respective oranometallic

Figure 1-9: Demetallations achieved with different oxidizing agents.

– 10 – Chapter 1 General Introduction complex. There is a vast amount of literature that suggests that this is in fact not the case, and the free diene can be obtained using a variety of different reagents and conditions.33,39-46

For the most part, these decomplexations are usually executed under oxidizing conditions– some more extreme than others. Typical oxidizing reagents used for these reactions include ferric chloride (FeCl3), (CAN), trimethylamine N-oxide (Me3NO), cupric chloride

21 (CuCl2) and peroxide/ (H2O2/NaOH) (Fig. 1-9, previous page). In general, all of these reagents are sufficiently effective at removing the Fe(CO)3 group, however the lability of the free diene’s functional groups needs to be considered, as the majority of these reagents produce an acidic medium.7

In light of this, substrates containing a vinyl ether functionality, for example, can afford different products depending on the oxidizing reagent used (Scheme 1-1). The great advantage of using Me3NO is that it is the only reagent that does not produce acidic or extremely basic conditions. As shown in Scheme 1-1, subjecting methoxy-substituted diene-Fe(CO)3 complexes

1.53 to oxidizing conditions using Me3NO produces the free diene 1.55 without further reaction. In contrast, reaction of 1.53 with CuCl2, FeCl3 or CAN in the presence of produces the enone

1.54 as a result of vinyl ether hydrolysis.7

Scheme 1-1: Difference between reaction of Me3NO and other reagents with methoxy-substituted cyclohexadiene.

– 11 – Chapter 1 General Introduction

Overall, liberation of the free diene from its respective iron complex can be easily achieved.

When acid-sensitive functionalities are present on the diene, Me3NO proves to be the superior

21 reagent for demetallation. The ability to successfully remove the Fe(CO)3 group from dienes under mild conditions further enhances the great potential for using this type of chemistry in organic synthesis.

1.1.2 General Applications of Diene-Tricarbonyliron Complexes

As mentioned previously, η4-(diene)tricarbonyliron derivatives have numerous uses in organic synthesis, their greatest roles emanating from their ability to act as a for diene protection, stereodirection of proximal additions, as well as molecule activation and/or stabilization.7-12,14 A brief review of these applications will be presented in this section.

1.1.2.1 Fe(CO)3 Moiety used as a Protecting Group

A significant advantage of having a tricarbonyliron group complexed to a diene is in its ability to protect the diene “functional group”.5,7,47 While coordinated to iron, the diene functionality is in turn resistant to conditions to which it would otherwise be reactive in its free form.

Hydroborations, and hydrogenations, for example, have been shown to have no effect on the iron-complexed diene and hence react elsewhere on the molecule (Fig.1-10).3,33,48-49 Mild reducing or oxidizing conditions also do not affect the complexed-diene functionality. There are examples where reagents such as tert-butyl (tBuOOH) have promoted decomposition of Fe(CO)5, but decomposition is not observed when it is reacted with diene-

48 Fe(CO)3 complexes.

Other reactions of diene-Fe(CO)3 complexes with reagents that would normally attack alkene/ diene-containing have shown amelioration as well.7,21 Michael additions, osmylations, acidic halogenations and organocuprate additions have no effect on the protected diene. The

Fe(CO)3 group has also demonstrated some protection of dienes from carbene additions when a pendant alkene is present (Fig. 1-11).50-51 Depending on the substrate, diene protection is indeed efficient even when subjected to reactions with metal catalysts such as rhodium.

– 12 – Chapter 1 General Introduction

Figure 1-10: Reactions on diene-Fe(CO)3 substrates that demonstrate the protecting capability of the Fe(CO)3 group.

Figure 1-11: Diene protection from carbene additions.

– 13 – Chapter 1 General Introduction

Figure 1-12: Friedel-Crafts acylations of diene-Fe(CO)3 complexes.

However, it is important to note that these complexes are not completely unreactive towards the typical reagents used for reaction with free olefins.21 The best example of this is provided by the Friedel-Crafts acylations of complexes 1.56 and 1.1 (Fig. 1-12). When a pendant alkene is present as a on a diene-Fe(CO)3 complex (1.56), it is observed that this is the olefin that undergoes reaction with the acylium intermediate. It may be concluded that this is because the diene is totally protected from reaction. But this is not the case, as a complex without a pendant olefin (1.1) can react with the acylium intermediate to form the acylated product. The same can be seen with nucleophilic additions, where attack tends to predominate at the 2- position given no other sites of nucleophilic attack.7 This does suggest that diene reactivity is lowered, which is the case since the coordination of the iron would expectedly affect the electronic structure of the diene system.

Nonetheless, the Fe(CO)3 moiety does in fact function as an efficient protecting group for a diene functionality. Under relatively mild oxidizing, reducing, acidic or basic conditions, the protected diene survives. Due to the decreased reactivity as a result of complexation to iron, the respective reactions of olefins can be directed elsewhere in the molecule when other functional groups are present.

– 14 – Chapter 1 General Introduction

1.1.2.2 Fe(CO)3 Moiety used as a Stabilizing Group

The capability of the Fe(CO)3 group to protect a diene may not initially seem to be an obvious compliment for the moderation of diene reactivity. Thus far, arguments have been presented that demonstrate the extent of which zero-valent iron can protect a diene that would normally be thermodynamically and relatively kinetically stable as a free ligand. However, an argument has not been presented herein demonstrating the ability of the iron moiety to protect and stabilize a diene that is normally very reactive in its uncomplexed form.

(1.3)

One of the best-known examples of stabilization of a reactive diene is the synthesis of

52-53 cyclobutadiene-Fe(CO)3 (Eq. 1.3). Being the simplest antiaromatic compound coupled with a large amount of ring-strain, cyclobutadiene has attracted the attention of organic chemists

(especially in the 1970’s and 1980’s) primarily because of its synthetic challenge as well as its theoretical interest. To date, isolation of cyclobutadiene at normal temperatures has not been achieved and formation as an intermediate has only been observed. However, iron-complexed cyclobutadiene 1.69 has been prepared by Emerson et al. by reaction of dichlorocyclobutene

52 1.68 with Fe2(CO)9. The dehalogenation reaction followed by iron complexation provided complex 1.69 as yellow crystals.

The literature reporting iron-complexation to reactive dienes rapidly expanded after the isolation of complex 1.69. One such class of molecules that is interesting to note here due to their highly reactive nature is that of o-quinodimethanes (1.71). These types of compounds are derived

(1.4)

– 15 – Chapter 1 General Introduction from their corresponding dibromoxylene derivatives (1.70) and their extremely reactive character causes them to instantly undergo reaction in the presence of dienophiles to give Diels-Alder

54 products. Upon reaction of derivatives such as 1.70 with Fe2(CO)9, however, these reactive intermediates can be “trapped” and isolated as their iron-complexes, such as 1.72

(Eq. 1.4).

Use of the Fe(CO)3 group for stabilization has also been enlisted in the isolation of carbocations (Fig. 1-13).8,53 An interesting illustration of this is the complexation to (1.74) because it is a four π-electron ligand, yet does not contain a diene.

Prior to obtaining the iron-complex of trimethylenemethane, no other method was available by

Figure 1-13: Stabilization of reactive diradicals and carbocations via Fe(CO)3 complexation. which it could be studied, leaving only investigations by theoretical means. Using the same procedure used to prepare complex 1.69, Emerson and coworkers were able to obtain iron- complex 1.74 in reasonable yield.55

Acyclic and cyclic dienyl iron-complexes have also been isolated, and their chemistry continues to be investigated.56 These particular complexes are generally produced by hydride abstraction from a diene-Fe(CO)3 complex (Fig. 1-13). There is usually some regioselectivity with

– 16 – Chapter 1 General Introduction these abstractions with mono-substituted dienes, as seen with the cyclic derivative 1.77 being the major isomer of hydride abstraction of complex 1.10.

Although only a few examples are presented here, the application of the Fe(CO)3 group for compound stabilization is well-founded. The chemistry of such compounds requiring stabilization would otherwise be difficult to investigate without the use of these complexes. This in turn amplifies the significance of using the Fe(CO)3 functionality not only for organic synthesis, but investigations of highly reactive intermediates.

1.1.2.3 Fe(CO)3 Moiety used as a Stereodirecting Group

By far the largest utilization of diene-Fe(CO)3 complexes in organic synthesis is the ability of the organometallic moiety to function as a stereodirecting group.5,7,10-11,13,15,21,57 The amount of three-dimensional space the Fe(CO)3 group occupies is relatively large and would indeed persuade additions to sites in close proximity to the metal to proceed at the face anti to the metal

(Fig. 1-14).42,58-61 Simple nucleophilic additions exemplified by the formation of complex 1.80 demonstrate this perfectly, in which the major diastereomer was obtained in yields greater than

81% and was subsequently used in a total syntheses of the neuraminidase inhibitor Tamiflu and the neurotransmitter gabaculine.60-61 Similar results were observed during hydride addition to the proximal ketone of complex 1.78 to give alcohol 1.45 in 93% yield (See also Fig. 1-9). The importance of this is that the similar reduction of the free ketone corresponding to 1.78 would give almost quantitatively the other epimer of the alcohol (corresponding to 1.45).

For these two examples, it is easy to identify that these additions occur from the anti-face of

Fe(CO)3 group. Depending on the addition site, this observation may not be as easy to recognize for other complexes. Additions to or directly attached to the diene-Fe(CO)3 functionality, for example, may at first seem a bit ambiguous, as demonstrated by the nucleophilic additions to complexes (+)-1.81 and (–)-1.81 (Fig. 1-14). For cases such as these, it is presumed that the ketone/aldehyde substituents assume a preferred conformation with respect to the protected diene, on which the additions would still occur anti to the metal. A more detailed discussion of this subject will be presented in Chapter 3.

To give a slightly different perspective, further demonstration of the stereodirecting ability of

62 the Fe(CO)3 group can be seen with examples of their use in Diels-Alder reactions. Whether

– 17 – Chapter 1 General Introduction

Figure 1-14: Stereoselective additions to diene-Fe(CO)3 complexes. there is a pendant diene or dienophile present, both can undergo stereoselective cyclizations with an intermolecular dienophile or diene, respectively (Fig. 1-15). Both additions are directed to the face anti to the metal, giving the expected endo-products.

As mentioned previously, stereodirection by the organoiron moiety in these complexes is an important aspect in this field of organic chemistry. Although the examples presented are a small selection, the research is substantial not just for intermolecular nucleophilic additions, but for intramolecular processes as well. What has been of significant interest is to use these inter- and

– 18 – Chapter 1 General Introduction intramolecular operations in the formation of stereogenic quaternary , which will be elaborated in the following section.

Figure 1-15: Stereoselective Diels-Alder cycloadditions using diene-Fe(CO)3 complexes as a source of diene or dienophile.

1.2 Application Towards Stereogenic Quaternary-Carbon Formation

The focus of the Pearson group over the past few decades has been to explore the formation of quaternary stereogenic carbons using dienyl- and diene-Fe(CO)3 chemistry. Their initial work was to investigate intermolecular nucleophilic additions to the iron complexes of cationic dienyl substrates, which eventually resulted in an efficient synthesis of (±)-trichodermol.

When attempting to expand their reach into the total synthesis of other trichothecenes, new synthetic methodology had to be engineered, where the use of intramolecular annulations from neutral diene-Fe(CO)3 analogs became the compass for where to proceed on this new path.

Herein, this path will be introduced briefly as a means to demonstrate how the focus of this dissertation – all-carbon cyclizations of diene-Fe(CO)3 complexes – came to be of interest.

– 19 – Chapter 1 General Introduction

1.2.1 From Dienyl-Fe(CO)3 Substrates

1.2.1.1 Preparation

Preparation of dienyl-Fe(CO)3 salts can be achieved with relative ease and usually results in almost quantitative yields.7,15,57 The most common methods to date involve a hydride abstraction from the respective diene-Fe(CO)3 complex using the triphenylmethyl (trityl) cation in the form of its tetrafluoroborate or hexafluorophosphate salt (Fig. 1-16, see also Fig. 1-13).63 Typically,

Figure 1-16: Preparation of dienyl-Fe(CO)3 complexes via hydride abstraction.

formation of the dienyl-Fe(CO)3 hexafluorophosphate salt tends to be more efficient and produces cleaner crystals upon workup, although the corresponding tetrafluoroborate salts are acceptable.

The selectivity of these hydride abstractions is also worth mentioning. Depending on the location and nature of a substituent on the diene, the trityl cation will selectively abstract a hydride from the complex based on steric and/or electronic factors (Fig. 1-16). Steric considerations tend to take precedence over electronic stabilization, unless the steric environment at both available hydride-abstraction sites is balanced, as shown with the formation of the dienyl-Fe(CO)3 complex

– 20 – Chapter 1 General Introduction

1.91 which results in formation of the electronically more stable complex. Whereas hydride abstraction from complex 1.9 is predominantly sterically driven, formation of complex 1.91 is electronically driven, as the abstraction sites have approximately equal steric congestion.

A full discussion of the factors controlling hydride abstraction regiochemistry is given in the references cited, and only a brief summary is presented here. The directing effects during hydride abstraction are primarily the result of orbital interactions between the developing dienyl cation and

7 the Fe(CO)3 group. When the interacting HOMO/LUMO orbitals are close in energy, the interaction will be the greatest. This interaction is thus best accommodated with orbitals corresponding to less stable dienyl ligands, which are closer in energy to the d-orbitals of the iron.

As such, the resulting dienyl ligand that forms the iron complex results from what seems to be an inverse selectivity compared to the stabilities of free dienyl ligands.

In summary, dienyl-Fe(CO)3 complexes can be easily obtained via hydride abstraction from the parent diene-Fe(CO)3 complexes. The site of hydride abstraction is governed by electronic and steric considerations. As it turns out, the selectivity/reactivity of nucleophilic additions to these cationic iron-complexes are also controlled by similar factors, which will be discussed briefly in the next section.

1.2.1.2 General Reactivity/Selectivity towards Nucleophilic Additions

Section 1.1.2.3 touched on the stereodirecting ability of the Fe(CO)3 moiety with regard to additions elsewhere on the molecule, where these additions occur anti to the metal. The same scenario is indeed witnessed when nucleophilic additions occur directly on the dienyl-Fe(CO)3 system. This, as with additions to pendant functional groups, makes reactions of this sort stereospecific in nature.

Figure 1-17: Generic example of cyclohexadienyl-Fe(CO)3 complex.

– 21 – Chapter 1 General Introduction

What may not be as obvious is the regioselectivity of such nucleophilic additions, since the positive charge as a result of the hydride abstraction is delocalized over five carbons, all of which present a possible site for addition (Fig. 1-17). However, due to molecular orbital considerations, additions at carbons other than the terminal positions are not observed on cyclohexadienyl substrates.7 As with the selectivities presented for hydride abstraction of the parent diene-

Fe(CO)3 complexes, the presence of substituents also affects the selectivities of nucleophilic

15 additions via electronic effects. For example, dienyl-Fe(CO)3 complexes containing a C2- methoxy group undergo nucleophilic addition to the C5-terminus (Fig. 1-18). The electron- donating ability of the methoxy substituent results in greater electron density at the C1-terminus, so the electrophilic character at this site is decreased relative to the other terminal carbon.

Figure 1-18: Nucleophilic additions to generic methoxycyclohexadienyl-Fe(CO)3 derivatives.

For additions to methoxycyclohexadienyl-Fe(CO)3 1.90, the scope and nature of nucleophiles is large. As it turns out, there really is no limitation as to what type of nucleophiles add to these substrates — Grignard reagents, alkyllithiums, enolates, alkoxides, , allylsilanes, etc. Even weak nucleophiles such as or activated aromatics are able to add to these complexes with relative ease.7

Additions to complex 1.91 are interesting because the nucleophile reacts at the more substituted dienyl terminus, clearly a result of powerful electronic control by the methoxy group.

Given that the terminus at C5 has more steric congestion, the electronic deactivation at C1 still

– 22 – Chapter 1 General Introduction dominates, giving 1.94 as the sole product. Unfortunately, the range of nucleophiles that add to

1.90 is not as broad as additions to 1.91. With a adjacent to a cationic dienyl

4 system, deprotonation can also occur to form the neutral η -triene-Fe(CO)3 complex 1.95 when strongly basic nucleophiles are used (Fig. 1-19). Therefore, the typical reagents used for carbon-

Figure 1-19: Product from reaction of 1.91 with strongly basic nucleophiles. carbon bond formation — Grignard reagents and akyllithiums — cannot be employed. However, stabilized enolates and relatively soft tin-enolates undergo smooth addition, and provide efficient and useful routes to interesting synthetic targets.15,57,64-67

The interesting chemistry of complex 1.91 has been exploited by the Pearson group, as an efficient method for forming quaternary carbon centers, allowing the total syntheses of a variety of natural products, such as trichodermol, discussed in the following section.

1.2.1.3 Application: Synthesis of Trichodermol and Derivatives

Although dienyl-Fe(CO)3 chemistry has been used in the total synthesis of other natural products,68-71 those syntheses have not proven to be the most efficient routes nor have they offered significant advantages over other synthetic approaches. The most intriguing aspect of using dienyl-Fe(CO)3 complex 1.91 as a precursor in the total synthesis of trichodermol (1.98) and other trichothecene derivatives is that it is crucial in the formation of three stereogenic carbon centers in one step (Scheme 1-2).20,48,67,72-76 Reaction of 1.91 with tin-enolate 1.96 gives the diene-Fe(CO)3 complex 1.97 with two newly-formed stereogenic quaternary carbons at the site of addition with the excellent stereoselectivity and regioselectivity.

– 23 – Chapter 1 General Introduction

Scheme 1-2: Total synthesis of trichodermol.

1.2.1.4 Limitations of using Dienyl-Fe(CO)3 Complexes in Trichodermol Analogue Synthesis

The use of the previously mentioned method to synthesize analogues of trichodermol has been well-established using complex 1.91 as a synthon. However, attempts to make compounds like verrucarol (1.101) via dienyl-Fe(CO)3 complexes such as 1.100 were unsuccessful. For unknown reasons, the presence of an electron-withdrawing substituent at the C5-position makes the corresponding diene-Fe(CO)3 complex resistant to hydride abstraction (Scheme 1-3).

As a result of this problem, the Pearson group shifted focus from dienyl- to diene-Fe(CO)3 complexes as a means to circumvent the issue of stereogenic quaternary carbon formation using complexes containing substituents having electron-withdrawing character. Introduction to the novel iron-mediated [6+2] ene-type reactions that were thus discovered, and that are the focus of my own record will be presented.

– 24 – Chapter 1 General Introduction

Scheme 1-3: Proposed synthesis of verrucarol via dienyl-Fe(CO)3 complex 1.100.

1.2.2 [6+2] Ene-Type Cyclizations

1.2.2.1 Progression towards Cyclizations from Diene-Fe(CO)3 Substrates

At the time of learning of their predicament involving preparation of complexes such as 1.100, the Pearson group focused their efforts towards methods of carbon-carbon bond formation based

77-80 on radical dimerization and cyclocoupling reactions of dienyl-Fe(CO)3 substrates. Work presented by the Pettit group demonstrated that dimerization of pentadienyl-Fe(CO)3 (1.76) can be achieved by reaction with zinc dust, which proceeds via a radical mechanism (Fig. 1-20, Fig.

1-21). In order to investigate if similar coupling reactions could occur with electron-deficient dienyl-Fe(CO)3 complexes, the Pearson group subjected complex 1.103 to the same conditions and indeed observed the head-to-head dimerization product 1.104 as the major product. This was

– 25 – Chapter 1 General Introduction encouraging, as it presented a means by which quaternary carbon-carbon bond formation was possible as well as the potential for a way around the issues previously discussed.

Figure 1-20: Radical dimerizations of dienyl-Fe(CO)3 complexes.

Figure 1-21: Mechanism of radical dimerization.

– 26 – Chapter 1 General Introduction

Initially, intramolecular coupling reactions were investigated using the simple ester derivative

1.105 (Fig. 1-22).80 Products of reactions using ester substrates were of interest because the plausible subsequent reactions could produce substitution that is desirable for synthesis of compounds such as verrucarol (see Scheme 1-3). However, no intramolecular cross-coupling reaction was observed, reasons for which will be discussed in the next section. Cyclocoupling of amide derivative 1.106, however, does produce the desired cyclized product 1.107, albeit in very low yields. These results were promising in the sense that formation of a quaternary carbon spirocenter with adjacent electron-withdrawing groups could be achieved. However, attempts to increase the yields using this zinc-initiated coupling reaction proved fruitless.

Figure 1-22: Attempts of intramolecular radical cyclocoupling reactions from dienyl-Fe(CO)3 substrates.

Green and co-workers had earlier reported the addition of tetrafluoroethene to

81-82 (cyclohexa-1,3-diene)-Fe(CO)3 (1.2) under UV-irradiation (Eq. 1.5). This type of addition appears to resemble an incomplete ene-type reaction, where the final metal-facilitated hydride transfer required to reductively eliminate the CF2 group from the iron is yet to occur. Due to the electron-deficiency of the tetrafluoroethyl group, the resulting complex 1.108 is relatively stable and cleavage of the Fe–CF2 therefore does not occur.

It was proposed that an intermediate σ-complex such as 1.108 with less electron-withdrawing character might be more likely to undergo the final hydride transfer/reductive elimination step. By directing attention towards an intramolecular process, the desired quaternary carbon formation

– 27 – Chapter 1 General Introduction

(1.5)

might be achieved. Much of the subsequent work in the Pearson lab has focused on these intramolecular ene-type reactions. The scope of these unique reactions will now be discussed.

1.2.2.2 Scope of Ene-Type Cyclizations

1.2.2.2.1 Amide Derivatives

The Pearson group over the past couple of decades has thoroughly investigated the scope of these iron-mediated ene-type cyclizations on both cyclic and acyclic substrates.27,82-96 The cyclic variations were of greater interest for organic synthesis and thus were studied more thoroughly.

Given the initial success of the cyclocoupling of amide derivative 1.106 under radical conditions,

82,84 these were the substrates that were initially investigated. The reaction of diene-Fe(CO)3 complexes with simple pendant alkene substitution 1.109a-d in refluxing butyl ether under an atmosphere of carbon monoxide gave the expected cyclization products 1.110a-d with yields greater than 80% (Eq. 1.6). These results prompted the group to examine reactions of pendant cyclic olefins (Fig. 1-23). Cyclization adducts that contained two spirocenters (1.112 and 1.116)

(1.6)

were produced in yields greater than 85%. However, cyclizations of complexes 1.113 (X = H) and

– 28 – Chapter 1 General Introduction

1.117 both produced yields lower than 58%, suggesting there is greater ring-strain in the bicyclic intermediate.84

Electron donating substituents on the diene were observed to slow down the cyclization.

Complex 1.109e was subjected to the same thermal conditions, albeit longer reaction times to give acceptable yields of the spiro adduct, however the yields were not as good as the unsubstituted complex (see Eq. 1.6). Similar observations were made for the cyclization of 1.113

Figure 1-23: Spirocyclization of amide diene-Fe(CO)3 complexes with pendant alkene substitution.

– 29 – Chapter 1 General Introduction

(X = OMe); however, the reaction produced only trace amounts of cyclization products (Fig. 1-23).

It may be noted that throughout this dissertation, methoxy-substituted diene-Fe(CO)3 complexes are observed to give poorer yields and more sluggish reactions.

That being said, attaching a methoxy group to the diene-Fe(CO)3 complex at the 3-position can be of great use. In the above examples of cyclizations using the amide systems, the fact that there is an equilibrating rearrangement of the diene complex pre- and post-cyclization was not presented. The nature of these rearrangements is outlined in Figure 1-24.86 By introducing a methoxy group at the 3-position, these rearrangements can be masked.

Figure 1-24: Pre- and post-cyclization rearrangements of diene-Fe(CO)3 complexes.

– 30 – Chapter 1 General Introduction

(1.7)

As seen in Eq. 1.7, 3-methoxy-substituted ester 1.123 subjected to heating in butyl ether gives no change in structure. The means to control the post-cyclization rearrangement after cyclization was to convert both cyclization adducts into a single product. Even with the methoxy group positioned in the 3-position, some post-cyclization rearrangement does indeed occur.

However, by subjecting the mixture of adducts to demetallation conditions using Me3NO in benzene, the resulting free ligands can be then subjected to acidic conditions to hydrolyze the vinyl ether functionality (Eq. 1.8).86 Both isomeric vinyl afford the same enone 1.125, as the thermodynamic product.

(1.8)

With the large amount of data that was collected from these cyclizations, a mechanism could be proposed (Scheme 1-4). Under the conditions presented, the thermal energy provided by refluxing butyl ether is sufficient to cause dissociation of a CO ligand to form a 16-electron metal species and thus an open coordination site, to which the pendant olefin coordinates (1.126). The spirocyclization reaction is then able to occur, forming the iron complex 1.127. With an endo- hydrogen at the 5-position, a hydride migration to the iron occurs to re-establish the diene. The final spirocyclic product 1.110a is then obtained after reductive elimination of the methyl group followed by association of another carbon monoxide ligand.

– 31 – Chapter 1 General Introduction

Scheme 1-4: Proposed mechanism for cyclization of 1.109a.

Based on the success of these cyclization studies, it was proposed that a tandem double cyclization might occur if a pendant diene is employed. This second olefin would be in the correct orientation to undergo another cyclization to then form a tricyclic species (see 1.130 vs. 1.110a).

This was indeed the case using an amide substrate with a hydrogen or methoxy group at the 3- position of the diene (Eq. 1.9).88 Both substrates 1.131 (R = H or OMe) were prepared in good yield, and similar to previous observations, 1.131 (R = OMe) was slower reacting and lower yielding. Attempts to increase the yield of the double-cyclization by using an electron deficient olefinic intermediate such as 1.130 (R = CO2Me) proved useful only when there was no substitution at the 3-position (54%). Yields were much lower when the diene had a 3-methoxy group.

– 32 – Chapter 1 General Introduction

(1.9)

Overall, the scope of these ene-type cyclizations with amide derivatives proves to be quite robust. Varying degrees of substitution at the pendant olefin shows little hindrance in the cyclization reactions using an unsubstituted and a more electron-rich diene-Fe(CO)3 complex. For the most part, these reactions proceed under thermal conditions with relative ease. Only in limited cases were photothermal conditions necessary for reaction. However, the results presented for these amide derivatives differ greatly compared to the ester and thioester analogs, discussed in the next section.

1.2.2.2.2 Ester and Thioester Derivatives

Achieving cyclizations containing an ester or thioester functionality may have been of greater interest than those of the amide analogs primarily because of their potential to be more applicable towards the synthesis of molecules such as verrucarol.85 Unfortunately, the cyclizations of these analogs are not as well-behaved as the amide complexes. The simplest diene-Fe(CO)3 ester

1.133a — comparable to amide 1.109a — produces 1.134a under thermal conditions with a yield of 84%.82 Initially, these complexes appeared promising; however, increasing substitution on the

(1.10)

– 33 – Chapter 1 General Introduction pendant olefin even by the simplest modifications decreased the yields to less than 15% (Eq.

1.10).

The thioester derivatives gave similar results. Reaction of simple thioester 1.135 under thermal conditions (A) gives the expected spirocyclization product 1.136, although in lower yields

(21%) compared to the cyclization of the simple ester derivative 1.133a (Fig. 1-25). It was initially unclear why these reactions with a thioester functionality were so ineffective. But optimization of the reaction conditions proved to be a good starting point to increase the yields, as ligand dissociation from metal carbonyls can also be induced photochemically.97 Cyclization in refluxing

Figure 1-25: Cyclization attempts of thioester derivatives under various conditions.

– 34 – Chapter 1 General Introduction benzene under 350 nm UV-irradiation was examined (B), but good yields were obtained only for the simple ester 1.135 (95%). By adding a methyl group to the terminal carbon of the pendant olefin (1.137), a maximum yield of 45% was observed upon reaction. Cyclization attempts using

1.139, and 1.141 only led to recovery of starting material. It appears that these reactions are thwarted on a steric basis, however, derivative 1.143 undergoes spirocyclization under photothermal conditions albeit in low yields (Fig. 1-25).

1.2.2.2.3 Stereoelectronic Considerations

Initially, it was unclear as to why the amide diene-Fe(CO)3 complexes undergo cyclization more easily than ester and thioester derivatives. Both sets of substrates had the same pendant chain length and have similar electron-withdrawing functionalities (carbonyl) attached directly to the diene-Fe(CO)3. Could the transition from a direct amide linkage to an ester or thioester really affect the reactivity of the metal complex?

Indeed, the effect of the α-functionality does play the primary role in the reactivity of these complexes; however, not by deactivating the metal. For the general ester or thioester functionality, the preferred conformation is the Z-form, unless the general substrate restricts it and only leaves room for the E-conformation. Examples of this include small-ring lactones.

The reasons for this preferred conformation are based primarily on stereoelectronic effects, which have been investigated thoroughly by Deslongchamps.98 For an ester or related functionality there are two types of stereoelectronic effect, which are referred to as the primary and secondary effects (Fig. 1-26). The primary effect (designated by the BLUE orbitals) represents the delocalization of the electrons between the carbonyl oxygen and ether/thioether atom.

The secondary effects correlate to what is observed in the anomeric effect seen with , which involves a n-σ* interaction. These interactions are indicated by the red orbitals in Figure

1-26. For the E-conformation, a lone pair of electrons on the carbonyl oxygen can interact with a

σ* orbital of the C–X σ bond, which is made possible since this lone pair of electrons is positioned antiperiplanar with the C–X bond. The same primary and secondary interactions are seen for the

Z-conformation as well; however, an additional secondary electronic effect is observed, in which a

– 35 – Chapter 1 General Introduction

Figure 1-26: Primary and secondary electronic effects of different conformations of esters and thioesters. lone pair of electrons on the ether/thioether atom can interact with a different σ* orbital on the carbon atom positioned antiperiplanar to carbonyl bond.

Thus, the Z-conformation is more stable as it contains two secondary effects, whereas the E- conformation only has one. To tie this into the aforementioned ene-type cyclizations, the thermodynamic preference for the Z-conformation causes the pendant olefin not to be in close proximity to the iron, which is necessary for the cyclization to occur.

For comparison, the electronic effects for amide functionalities are shown in Figure 1-27.

Amide functionalities exhibit the same primary and secondary effects shown for the E- conformation of the ester analogs. The difference, however, is there is no electron pair on the that can be arranged to be antiperiplanar to the carbonyl C–O bond, which could then interact with a σ* orbital on the carbon. Therefore, what makes the amide derivatives unique and in turn such excellent substrates for these iron-mediated ene-type reactions is that their conformation can be dictated by steric compression. As seen in Figure 1-27, by making one of the

R-groups on the nitrogen relatively sterically demanding, a pendant olefin can be induced into close proximity to the iron, thereby favoring coordination and cyclization.

– 36 – Chapter 1 General Introduction

Figure 1-27: Primary and secondary electronic effects of different conformations of amides.

1.2.2.3 Transition to All-Carbon Cyclizations

Throughout this section (Section 1.2.2), much has been focused the ene-type cyclizations on substrates which would contain heteroatoms in the overall backbone of the molecule after cyclization. It has in some cases been painstakingly reiterated that the use of esters and thioesters was of interest for the synthesis of molecules like verrucarol. Be that as it may, it became obvious that the formation of said spirocycles proved to be problematic. The results of the amide cyclizations were nevertheless intriguing — excellent yield, little limit to pendant olefin substitution, and relative consistency in reaction conditions. Unfortunately, the applications towards natural products and other synthetic targets are limited. Another possible application of this type of chemistry is in the synthesis of all-carbon spirocycles.

(1.11)

– 37 – Chapter 1 General Introduction

Some work has been done concerning all-carbon cyclizations on acyclic and cyclic substrates.86,90,99-100 Investigations on substrates similar to those already mentioned were carried out by Wang and Dorange, where their focus was directed towards ketone and unsubstituted analogs (Eq 1.11). Although cyclization of ketones 1.145 afforded the respective spirocyclic products 1.146 with high yields (>90%), issues similar to the ester analogs were observed when spirocycles resulting from increased substitution on the pendant olefin were desired.99 Another issue that made matters difficult from a practical standpoint was the preparation of the ketone functionality itself (Fig. 1-28).

Figure 1-28: Preparation of diene-Fe(CO)3 complexes containing a ketone functionality.

Initial attempts to form the ketone via acyl chloride 1.147 proved to be cumbersome, as strenuous precautions were required to ensure no oxygen was present. Otherwise, at least half of the crude mixtures would contain oxidized organocuprate adduct 1.149. It also turned out that

1.147 was more difficult to handle than other analogs, as it had to be generated under inert anhydrous conditions. An effort to produce the ketone from methanesulfonyl mixed anhydride

1.150 proved to be more efficient from a yield perspective, but a similar issue compared with handling of the acyl chloride derivative was experienced. Aside from the expected issues with moisture, complexes 1.150 also appeared to be less stable and decomposed readily, precluding isolation and purification prior to reaction with the Grignard reagent.

– 38 – Chapter 1 General Introduction

All in all, the difficulties of ketone preparation represent a considerable challenge.

Investigations towards all-carbon cyclizations using new, more practical methods are desired since the potential application of such substrates is more robust. Thus, the focus of this dissertation is to continue the work on forming these all-carbon substrates from a different perspective, and then to investigate how they behave when subjected to cyclization conditions to form their respective spiro- and tricyclic products. During the course of these investigations, diastereoselectivity was observed during Grignard additions to dienecarbaldehyde-Fe(CO)3 complexes, and this led to a secondary objective in determining the scope of this procedure as well as developing an understanding of the stereodirecting capability of the diene-Fe(CO)3 moiety.

– 39 – Chapter 1 General Introduction

1.3 References

1. Alper, H.; Edward, J. T., Reactions of Iron Pentacarbonyl with Some Steroid Dienes. J. Organomet. Chem. 1968, 14 (2), 411-415.

2. Alper, H., Organic Syntheses with Iron Pentacarbonyl. In Organic Syntheses Via Metal Carbonyls, Wender, I.; Pino, P., Eds. Interscience Publishers: New York,, 1968; pp 545-593.

3. Banthorpe, D. V.; Fitton, H.; Lewis, J., Isomerization and Addition-Reactions of Some Monoterpene-Tricarbonyliron Complexes. J. Chem. Soc. Perkin Trans. 1. 1973, (19), 2051-2057.

4. Trost, B. M.; Ziman, S. D., Desulfurization of Episulfides - Sulfurane Reaction. J. Org. Chem. 1973, 38 (5), 932-936.

5. King, R. B., Diene Iron Complexes. In The Organic Chemistry of Iron, Koerner von Gustorf, E. A.; Grevels, F.-W.; Fischler, I., Eds. Academic Press: New York, 1978; Vol. 1, pp 525-625.

6. Shriver, D. F.; Whitmire, K. J., Iron Compounds without Ligands. In Comprehensive : The Synthesis, Reactions, and Structures of Organometallic Compounds, 1st ed.; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds. Pergamon Press: Oxford Oxfordshire ; New York, 1982; Vol. 4, pp 243-650.

7. Pearson, A. J., Iron Compounds in Organic Synthesis. Academic Press: London ; San Diego, 1994; p xiv, 201 pages.

8. Pearson, A. J., Organoiron Compounds in Stoichiometric Organic Synthesis. In Comprehensive Organometallic Chemistry : The Synthesis, Reactions, and Structures of Organometallic Compounds, 1st ed.; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds. Pergamon Press: Oxford Oxfordshire ; New York, 1982; Vol. 8, pp 939-1012.

9. Pearson, A. J., Natural-Products Synthesis Using Organoiron Complexes. Pure. Appl. Chem. 1983, 55 (11), 1767-1779.

10. Gree, R., Acyclic Iron Tricarbonyl Complexes in Organic-Synthesis. Synthesis- Stuttgart 1989, (5), 341-355.

11. Cox, L. R.; Ley, S. V., Tricarbonyliron Complexes: An Approach to Acyclic Stereocontrol. Chem. Soc. Rev. 1998, 27 (5), 301-314.

12. Knölker, H. J., Transition Metal Complexes in Organic Synthesis. Part 47.1 Organic Synthesis Via Tricarbonyl(η4-Diene)Iron Complexes. Chem. Soc. Rev. 1999, 28 (3), 151-157.

13. Knölker, H. J., Efficient Synthesis of Tricarbonyliron-Diene Complexes - Development of an Asymmetric Catalytic Complexation. Chem. Rev. 2000, 100 (8), 2941-2961.

14. Bauer, I.; Knölker, H. J., Iron Complexes in Organic Chemistry. In Iron Catalysis in Organic Chemistry: Reactions and Applications, Plietker, B., Ed. Wiley-VCH: Weinheim, 2008; pp 1-24.

15. Pearson, A. J., Tricarbonyl(Diene)Iron Complexes - Synthetically Useful Properties. Acc. Chem. Res. 1980, 13 (12), 463-469.

16. Pettit, R.; Emerson, G. F., Diene-Iron Carbonyl Complexes and Related Species. In Advances in Organometallic Chemistry, Stone, F. G. A.; West, R., Eds. Academic Press.: New York, 1964; Vol. 1, pp 1-46.

– 40 – Chapter 1 General Introduction

17. Cais, M.; Maoz, N., Organometallic Studies. Part 16. Iron Pi-Complexes of Beta-Ionone and Other Model Compounds for Vitamin A. J. Organomet. Chem. 1966, 5 (4), 370-383.

18. Alper, H.; Leport, P. C.; Wolfe, S., Mechanism of Formation of Conjugated Diene-Iron Tricarbonyl Complexes from Nonconjugated Dienes. J. Am. Chem. Soc. 1969, 91 (26), 7553-7554.

19. Birch, A. J.; Pearson, A. J., Organometallic Complexes in Synthesis. Part 9. Tricarbonyliron Derivatives of Dihydroanisic Esters. J. Chem. Soc. Perkin Trans. 1. 1978, (6), 638-642.

20. Pearson, A. J., Organoiron Complexes in Organic Synthesis. Part 3. An Approach to the Synthesis of Spirocyclic Compounds from Tricarbonyldieneiron Complex Intermediates. J. Chem. Soc. Perkin Trans. 1. 1979, 1255-1260.

21. Pearson, A. J., Metallo-Organic Chemistry. Wiley: Chichester West Sussex ; New York, 1985; p xi, 398 pages.

22. Birch, A. J.; Cross, P. E.; Lewis, J.; White, D. A.; Wild, S. B., Chemistry of Co-Ordinated Ligands. Part 2. Iron Tricarbonyl Complexes of Some Cyclohexadienes. J. Chem. Soc. A. 1968, (2), 332-340.

23. Birch, A. J.; Dastur, K. P., Reactions of Cyclohexadienes. Part 13. Catalytic Conversion of 1-Methoxycyclohexa-1,4-Dienes into 1-Methoxycyclohexa-1,3-Dienes. J. Chem. Soc. Perkin Trans. 1. 1973, (15), 1650-1652.

24. Graf, R. E.; Lillya, P., Reactivity of Dienetricarbonyliron Compounds in Friedel-Crafts Acylation. J. Organomet. Chem. 1979, 166 (1), 53-62.

25. Howell, J. A. S.; Bell, A. G.; Oleary, P. J.; Mcardle, P.; Cunningham, D.; Stephenson, G. R.; Hastings, M., Access to Homochiral Acyclic (Diene)Fe(Co)3 Complexes Containing Electron- Donor Substituents. Organometallics 1994, 13 (5), 1806-1812.

26. Yamada, H.; Aoyagi, S.; Kibayashi, C., Stereoselective Total Synthesis of Natural (+)- Streptazolin Via a Palladium-Catalyzed Enyne Bicyclization Approach. J. Am. Chem. Soc. 1996, 118 (5), 1054-1059.

27. Pearson, A. J.; Alimardanov, A., Studies on Intramolecular Coupling of Tricarbonyl(Diene)Iron Systems with Pendant Olefinic Groups: Configurational Requirements for Reactions of Acyclic Diene Complexes and Mechanistic Implications. Organometallics 1998, 17 (17), 3739-3746.

28. Knolker, H. J.; Baum, E.; Gonser, P.; Rohde, G.; Rottele, H., 1,4-Diaryl-1-Azabuta-1,3- Diene-Catalyzed Complexation of Cyclohexa-1,3-Diene by the Tricarbonyliron Fragment: Development of Highly Efficient Catalysts, Optimization of Reaction Conditions, and Proposed Mechanism. Organometallics 1998, 17 (18), 3916-3925.

29. Knolker, H. J.; Ahrens, B.; Gonser, P.; Heininger, M.; Jones, P. G., Transition Metal Complexes in Organic Synthesis. Part 57: Synthesis of 1-Azabuta-1,3-Dienes and Application to Catalytic Complexation of Buta-1,3-Dienes and Cycloalkadienes by the Tricarbonyliron Fragment. Tetrahedron 2000, 56 (15), 2259-2271.

30. Brookhart, M.; Nelson, G. O., Reaction of Benzylideneacetoneiron Tricarbonyl with Dienes - Measurement of Relative Reactivities Using Competition Experiments. J. Organomet. Chem. 1979, 164 (2), 193-202.

31. Chou, S. S. P.; Liu, S. H., Nucleophilic Additions of Phenylsulfonyl-Substituted Tricarbonyl(1,3-Cyclohexadiene)Iron Complexes. J. Organomet. Chem. 1998, 555 (2), 227-236.

– 41 – Chapter 1 General Introduction

32. Evans, G.; Johnson, B. F. G.; Lewis, J., Synthetic Studies Relation to Acetylergosterol(Tricarbonyl)Iron. J. Organomet. Chem. 1975, 102 (4), 507-510.

33. Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.; Patin, H.; Widdowson, D. A.; Worth, B. R., Synthetic Uses of Steroidal Ring B Diene Protection: 22,23-Dihydroergosterol. J. Chem. Soc. Perkin Trans. 1. 1976, (8), 821-826.

34. Paley, R. S.; deDios, A.; Estroff, L. A.; Lafontaine, J. A.; Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura, M. P.; Weers, H. L.; delaPradilla, R. F.; Castro, S.; Dorado, R.; Morente, M., Synthesis and Diastereoselective Complexation of Enantiopure Sulfinyl Dienes: The Preparation of Sulfinyl Iron(0) Dienes. J. Org. Chem. 1997, 62 (18), 6326-6343.

35. Birch, A. J.; Raverty, W. D.; Stephenson, G. R., Chirality Transfer in the Coordination Sphere of Iron. Organometallics 1984, 3 (7), 1075-1079.

36. Birch, A. J.; Kelly, L. F., Tricarbonyliron Methoxycyclohexadiene and Dienyl Complexes - Preparation, Properties and Applications. J. Organomet. Chem. 1985, 285 (1-3), 267-280.

37. Knolker, H. J.; Hermann, H.; Herzberg, D., Photolytic Induction of the Asymmetric Catalytic Complexation of Prochiral Cyclohexa-1,3-Dienes by the Tricarbonyliron Fragment. Chem. Comm. 1999, (9), 831-832.

38. Tsai, M. S.; Rao, U. N.; Hsueh, P. Y.; Yeh, M. C. P., Completely Diastereoselective Tricarbonyliron Complexation Reactions of Chiral Dienes. Organometallics 2001, 20 (2), 289-295.

39. Holmes, J. D.; Pettit, R., Synthesis and Properties of Homotropone. J. Am. Chem. Soc. 1963, 85 (16), 2531-2532.

40. Emerson, G. F.; Pettit, R.; Kochhar, R.; Mahler, J. E., Organo-Iron Complexes. Part 4. Reactions of Substituted Dienes with Iron Pentacarbonyl. J. Org. Chem. 1964, 29 (12), 3620-3624.

41. Shvo, Y.; Hazum, E., Simple Method for Disengagement of Organic Ligands from Iron Complexes. J. Chem. Soc. Chem. Comm. 1974, (9), 336-337.

42. Barton, D. H. R.; Patin, H., Chemistry of Tricarbonyliron Complexes of Calciferol and Ergosterol. J. Chem. Soc. Perkin Trans. 1. 1976, (8), 829-831.

43. Thompson, D. J., Reaction of Tricarbonylcyclohexadieneiron Complexes with Cupric Chloride. J. Organomet. Chem. 1976, 108 (3), 381-383.

44. Franck-Neumann, M.; Heitz, M. P.; Martina, D., A Simple Method of Freeing Organic- Ligands from Their Iron Carbonyl-Complexes. Tetrahedron Lett. 1983, 24 (15), 1615-1616.

45. Luh, T. Y., Trimethylamine N-Oxide - a Versatile Reagent for Organometallic Chemistry. Coord. Chem. Rev. 1984, 60 (Nov), 255-276.

46. Knolker, H. J.; Goesmann, H.; Klauss, R., Transition Metal Complexes in Organic Synthesis, Part 48. A Novel Method for the Demetalation of Tricarbonyliron-Diene Complexes by a Photolytically Induced Ligand Exchange Reaction with . Angewandte Chemie- International Edition 1999, 38 (5), 702-705.

47. Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Comprehensive Organometallic Chemistry II : A Review of the Literature 1982-1994. 1st ed.; Pergamon: Oxford ; New York, 1995.

– 42 – Chapter 1 General Introduction

48. Pearson, A. J.; Ong, C. W., Organoiron Complexes in Organic-Synthesis. Part 15. Stereocontrolled Approach to Trichothecane Derivatives Via Tricarbonylcyclohexadieneiron Complexes - Synthesis of a Key Intermediate. Tetrahedron Lett. 1980, 21 (48), 4641-4644.

49. Nunn, K.; Mosset, P.; Gree, R.; Saalfrank, R. W., Conjugate Reduction Vicinal to Butadiene Tricarbonyl Iron Complexes - Application to the Synthesis of (+/-)-6,7-Dihydro-Ltb4 Methyl-Ester. J. Org. Chem. 1992, 57 (12), 3359-3364.

50. Taylor, G. A., Dichlorocarbene Addition to Tricarbonyliron Complexes of Polyenes. J. Chem. Soc. Perkin Trans. 1. 1979, (7), 1716-1719.

51. Franck-Neumann, M.; Geoffroy, P.; Gassmann, D.; Winling, A., Inter- and Intramolecular Carbene Reactions of Diazoketones Tethered to Tricarbonyliron Coordinated Acyclic Dienes. New Tricarbonyliron Complexes of Cyclohexa-2,4-Dienone and Cyclopent-2-Enone. Tetrahedron Lett. 2004, 45 (28), 5407-5410.

52. Emerson, G. F.; Watts, L.; Pettit, R., Cyclobutadiene- and Benzocyclobutadiene-Iron Tricarbonyl Complexes. J. Am. Chem. Soc. 1965, 87 (1), 131-133.

53. Landesberg, J. M., Stabilizing of Unstable Species with Carbonyliron. In The Organic Chemistry of Iron, Koerner von Gustorf, E. A.; Grevels, F.-W.; Fischler, I., Eds. Academic Press: New York, 1978; Vol. 1, pp 627-651.

54. Segura, J. L.; Martin, N., O-Quinodimethanes: Efficient Intermediates in Organic Synthesis. Chem. Rev. 1999, 99 (11), 3199-3246.

55. Emerson, G. F.; Ehrlich, K.; Giering, W. P.; Lauterbur, P. C., Trimethylenemethaneiron Tricarbonyl. J. Am. Chem. Soc. 1966, 88 (13), 3172-3173.

56. ten Broeke, M.; Khan, M. A.; Kociok-Kohn, G.; Kann, N.; Lewis, S. E., Tricarbonyliron(0) Complexes of Bio-Derived η4 Cyclohexadiene Ligands: An Approach to Analogues of Oseltamivir. J. Organomet. Chem. 2015, 799-800, 19-29.

57. Pearson, A. J., Diene and Dienyl Complexes of Iron - Reactivity and Synthetic Utility. Trans. Met. Chem. 1981, 6 (2), 67-78.

58. Nunn, K.; Mosset, P.; Gree, R.; Saalfrank, R. W., Short, Highly Enantioselective Synthesis of a Key Intermediate for the Preparation of Leucotriene B-4 and Its 14,15-Didehydro Derivative. Angew. Chem. Int. Ed. 1988, 27 (9), 1188-1189.

59. Roush, W. R.; Park, J. C., Asymmetric Allylborations of Diene Aldehyde Fe(CO)3 Derivatives - Efficient Kinetic Resolution of Racemic Complexes and the Highly Enantiotopic Group and Face Selective Allylboration of a Meso Substrate. Tetrahedron Lett. 1990, 31 (33), 4707-4710.

60. Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N., An Iron Carbonyl Approach to the Influenza Neuraminidase Inhibitor Oseltamivir. Chem Commun (Camb) 2007, (30), 3183-3185.

61. Khan, M. A. Use in Synthesis of Microbial Arene Oxidation Products. University of Bath, Bath, UK, 2012. Ph.D.

62. Benvegnu, T.; Martelli, J.; Gree, R.; Toupet, L., Diels-Alder Reactions on Linear Polyenes, Selectively Protected as Their Tricarbonyl-Iron Complexes. Tetrahedron Lett. 1990, 31 (22), 3145-3148.

– 43 – Chapter 1 General Introduction

63. Birch, A. J.; Chamberlain, K. B.; Haas, M. A.; Thompson, D. J., Organometallic Complexes in Synthesis. Part 4. Abstraction of Hydride from Some Tricarbonylcyclohexa-1,3- Dieneiron Complexes and Reactions of Complexed Cations with Some Nucleophiles. J. Chem. Soc. Perkin Trans. 1. 1973, (17), 1882-1891.

64. Pearson, A. J., Novel-Approach to Formation of Quaternary Centers and Introduction of Angular Substituents by Using Tricarbonyldieneiron Complexes. J. Chem. Soc. Perkin Trans. 1. 1977, (18), 2069-2074.

65. Pearson, A. J., New Approach to Introduction of Functionalized Angular Substituents Via Tricarbonyldieneiron Complex Intermediates. J. Chem. Soc. Chem. Comm. 1977, (10), 339-340.

66. Pearson, A. J.; Mincione, E.; Chandler, M.; Raithby, P. R., Organoiron Complexes in Organic-Synthesis. Part 7. Regio-Chemistry and Stereo-Chemistry of Ring Connection Reactions Relevant to Steroid and Terpene Synthesis - X-Ray Crystal-Structure Determination of Tricarbonyl(Methyl 1-[2-5-Eta-4-Methoxy-1-Methylcyclohexa-2,4-Dienyl]-3-Hydroxymethyl-3- Methyl-2-Oxocyclohexanecarboxylate)Iron. J. Chem. Soc. Perkin Trans. 1. 1980, (12), 2774-2780.

67. Pearson, A. J.; Raithby, P. R., Organoiron Complexes in Organic-Synthesis. Part 4. Direct Ring Connection between Highly Substituted Centers - Potential Approach to Trichothecane Synthesis. J. Chem. Soc. Perkin Trans. 1. 1980, (2), 395-399.

68. Pearson, A. J.; Rees, D. C., Organoiron Complexes in Organic-Synthesis. Part 11. New Synthetic Approaches to Aspidosperma Alkaloids with Functionalized C(20) Substituents - Some Key Intermediates Via Diene-Fe(Co)3 Complexes. Tetrahedron Lett. 1980, 21 (40), 3937-3940.

69. Pearson, A. J.; Rees, D. C., Total Synthesis of (+/)-Limaspermine Derivatives Using . J. Am. Chem. Soc. 1982, 104 (4), 1118-1119.

70. Pearson, A. J.; Rees, D. C., Organoiron Complexes in Organic-Synthesis. Part 22. Total Synthesis of (+/-)-Limaspermine and Formal Synthesis of (+/-)-Aspidospermine Using Organoiron Complexes. J. Chem. Soc. Perkin Trans. 1. 1982, (10), 2467-2476.

71. Pearson, A. J.; Fang, X. Q., A Synthesis of (+/-)-Stemodinone: An Application of Organoiron Chemistry to the Construction of Sterically Congested Quaternary Carbon Centers. J. Org. Chem. 1997, 62 (16), 5284-5292.

72. Pearson, A. J.; Ong, C. W., Organoiron Complexes in Organic-Synthesis.Part 13. Synthesis of 6,6-Disubstituted "Tricarbonyl(Cyclohexadienylium)Iron Salts, and Their Conversion into 4,4-Disubstituted Cyclohexa-2,5-Dienones. J. Chem. Soc. Perkin Trans. 1. 1981, (6), 1614-1621.

73. Pearson, A. J.; Chen, Y. S., Organoiron Approach to 3,14-Dihydroxytrichothecenes. J. Org. Chem. 1986, 51 (11), 1939-1947.

74. Pearson, A. J.; Hsu, S. Y., Ester-Directed Alkene Functionalization - a Potential Approach to Trichothecene Synthesis. J. Org. Chem. 1986, 51 (13), 2505-2511.

75. Obrien, M. K.; Pearson, A. J.; Pinkerton, A. A.; Schmidt, W.; Willman, K., A Total Synthesis of (+/-)-Trichodermol. J. Am. Chem. Soc. 1989, 111 (4), 1499-1501.

76. Pearson, A. J.; Obrien, M. K., Trichothecene Synthesis Using Organoiron Complexes - Diastereoselective Total Syntheses of (+/-)-Trichodiene, (+/-)-12,13-Epoxytrichothec-9-Ene, and (+/-)-Trichodermol. J. Org. Chem. 1989, 54 (19), 4663-4673.

– 44 – Chapter 1 General Introduction

77. Bond, A.; Lewis, B.; Lowrie, S. F. W.; Green, M., Reaction of Fluoro-Olefins with Tricarbonyl(Buta-1,3-Diene, Trimethylenemethane, or )Iron. Journal of the Chemical Society D-Chemical Communications 1971, (19), 1230-1231.

78. Bond, A.; Green, M., Oxidative Reaction of Fluoro-Olefins with Tricabonyl(Cyclobutadiene)-Iron Complexes. J. Chem. Soc. Dalton. Trans. 1972, (6), 763-768.

79. Sapienza, R. S.; Riley, P. E.; Davis, R. E.; Pettit, R., Synthesis of Cyclic Via Intramolecular Coupling of Bis-Pentadienyl Iron Tricarbonyl Cations. J. Organomet. Chem. 1976, 121 (2), C35-C40.

80. Pearson, A. J.; Chen, Y. S.; Daroux, M. L.; Tanaka, A. A.; Zettler, M., Free-Radical Coupling Reactions of Organoiron Complexes - Electrochemical Studies and Preliminary Cross Coupling Experiments. J. Chem. Soc. Chem. Comm. 1987, (3), 155-157.

81. Bond, A.; Lewis, B.; Green, M., Reactions of Coordinated Ligands .5. Addition of Tetrafluoroethylene to Tricarbonyl(Diene)Iron, Tricarbonyl(Trans-Cinnamaldehyde)Iron, and Tricarbonyl(Ortho-Styryldiphenylphosphine)Iron Complexes. J. Chem. Soc. Dalton. Trans. 1975, (12), 1109-1118.

82. Pearson, A. J.; Zettler, M.; Pinkerton, A. A., Intramolecular Ene-Type Reaction between a Diene-Fe(Co)3 Complex and Alkene Units. J. Chem. Soc. Chem. Comm. 1987, (4), 264-266.

83. Pearson, A. J.; Zettler, M. W., Control of Absolute Stereochemistry During Ene-Type Coupling between Diene-Fe(CO)3 Groups and . J. Chem. Soc. Chem. Comm. 1987, (16), 1243-1245.

84. Pearson, A. J.; Zettler, M. W., Intramolecular Coupling between Tricarbonyl(Diene)Iron Complexes and Pendant Alkenes. J. Am. Chem. Soc. 1989, 111 (11), 3908-3918.

85. Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A., Intramolecular Coupling Reactions of Allylic Thioesters with Diene Iron Tricarbonyl Systems. J. Org. Chem. 1998, 63 (19), 6610-6618.

86. Pearson, N. J.; Dorange, I. B., Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling. J. Org. Chem. 2001, 66 (9), 3140-3145.

87. Pearson, A. J.; Wang, X. L., Intramolecular Coupling between Cyclohexadiene-Fe(CO)(3) Complexes and Pendant Alkenes: Formation of Azaspiro[5,5]Undecane Derivatives. Tetrahedron Lett. 2002, 43 (42), 7513-7515.

88. Pearson, A. J.; Wang, X. L., Double Cyclization Via Intramolecular Coupling between Cyclohexadiene-Fe(CO)(3) Complexes and Pendant Conjugated Dienes. J. Am. Chem. Soc. 2003, 125 (3), 638-639.

89. Pearson, A. J.; Wang, X. L., A Convenient One-Pot Procedure to Afford Bicyclic Molecules by Stereospecific Iron Carbonyl Mediated [6+2] Ene-Type Cyclization: A Possible Approach to Gelsemine. J. Am. Chem. Soc. 2003, 125 (44), 13326-13327.

90. Pearson, A. J.; Wang, X. L.; Dorange, I. B., Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling: Formation of Carbon Spirocycles. Org. Lett. 2004, 6 (15), 2535-2538.

91. Pearson, A. J.; Wang, X. L., Dynamic Kinetic Resolution During Iron Carbonyl Promoted [6+2] Ene-Type Reactions. Tetrahedron Lett. 2005, 46 (17), 3123-3126.

– 45 – Chapter 1 General Introduction

92. Pearson, A. J.; Wang, X. L., A Stereospecific Intramolecular [4 Pi+4 Pi] Cycloaddition Reaction between Tricarbonyliron-Complexed Cyclohexadiene and Pendant Dienes. Tetrahedron Lett. 2005, 46 (28), 4809-4811.

93. Pearson, A. J.; Sun, H., An Iron-Promoted Aldehyde-Diene Cyclocoupling Reaction. J. Org. Chem. 2007, 72 (20), 7693-7700.

94. Pearson, A. J.; Sun, H. K.; Wang, X. L., Dynamic Diastereoselectivity During Iron Carbonyl Mediated Spirocyclization Reactions. J. Org. Chem. 2007, 72 (7), 2547-2557.

95. Pearson, A. J.; Kim, E. H.; Sun, H., A Synthetic Pathway to Diquinane and Angular Triquinane Systems Via an Iron Carbonyl Promoted Tandem [6+2] Ene Type Reaction. Tetrahedron 2010, 66 (27-28), 4943-4946.

96. Pearson, A. J.; Zhang, S.; Sun, H. K., Stereocontrolled Intramolecular Iron-Mediated Diene/Vinyl Ether Cyclocoupling Reactions. J. Org. Chem. 2012, 77 (19), 8835-8839.

97. Wrighton, M., Photochemistry of Metal-Carbonyls. Chem. Rev. 1974, 74 (4), 401-430.

98. Deslongchamps, P., Stereoelectronic Effects in Organic Chemistry. 1st ed.; Pergamon Press: Oxford Oxfordshire ; New York, 1983; p xi, 375 pages.

99. Dorange, I. B. Stereocontrolled Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling. Thesis, Case Western Reserve University, 2002. Ph.D.

100. Kim, E. H. A New Synthetic Pathway for Diquinane and Angular Triquinane Systems. Dissertation, Case Western Reserve University, 2010. Ph.D.

– 46 – CHAPTER TWO

ALL-CARBON [6+2] ENE-TYPE CYCLIZATIONS OF (CYCLOHEXADIENE)-TRICARBONYL IRON DERIVATIVES Chapter 2 All-Carbon Ene-Type Cylizations

2.1 Background: All-Carbon Spirocyclizations

It has been demonstrated that intramolecular ene-type cyclizations of diene-Fe(CO)3 complexes containing a pendant olefin can be achieved from a variety of functionalities α- to the diene system. Amide derivatives proved to be the ideal substrates for investigations of these particular cyclizations, whereas the ester and thioester derivatives had potentially more synthetic applications towards natural product synthesis. Even so, potential targets resulting from the formation of these heterocycles prove to be limited. Natural products containing all-carbon bicyclic or spirocyclic backbones are more common, and hence require more thorough investigation into methods for obtaining applicable synthons for their construction. A brief summary of previously performed all-carbon cyclizations will be detailed herein, prior to moving towards the focus of this dissertation.

2.1.1 Acyclic Substrates

Given the many examples of iron-mediated ene-type cyclizations utilizing cyclohexadiene derivatives presented in Chapter 1, some less extensive yet informative investigations have been carried out on acyclic substrates.1-3 Cyclizations of complexes 2.1-2.4 containing the simplest pendant olefin were attempted under both thermal and photothermal conditions. Cyclized products were obtained only under UV-irradiation (Fig. 2-1).1 When subjected to thermal conditions, various side reactions occur presumably due to the decreased rigidity of the iron- complexed diene compared to cyclohexadiene derivatives. Isomerization and racemization of the diene-Fe(CO)3 moiety commonly transpires, as the added thermal energy can induce the formation of an alkene-Fe(CO)3 intermediate that allows for s-cis to s-trans conversion of the diene.4-6 Although these side reactions are also observed under photothermal conditions, it appears that the decreased temperature allows the cyclizations to take place albeit in low yields.

It is interesting that ketone 2.3 produced only trace amounts of cyclized product, while both amide

2.1 and ester 2.2 undergo cyclization. Nonetheless, it is apparent that the ability for acyclic dienes to rotate about the σ-bond increases the probability of epimerized product mixtures, whereas cyclic dienes restrict the diene to a s-cis conformation. Also, in the context of the current investigation, it is worth noting that the alcohol substrate 2.4 undergoes cyclization, albeit in low yield, while the corresponding ketone 2.3 does not.

– 48 – Chapter 2 All-Carbon Ene-Type Cylizations

Figure 2-1: Cyclizations of acyclic diene-Fe(CO)3 complexes under photothermal conditions.

– 49 – Chapter 2 All-Carbon Ene-Type Cylizations

2.1.2 Cyclic Substrates

All-carbon cyclizations of cyclohexadiene-Fe(CO)3 derivatives accomplished in the Pearson laboratory have mostly focused on ketone derivatives, all with slight modifications to either the pendant olefin or to the diene subunit.7-10 The difficulties concerning the preparation of the iron- complexed ketones have already been mentioned (see Chapter 1, Section 1.2.2.3), so only the scope of their cyclization will be discussed hereinafter.

Subjecting ketones 2.12-2.14 (X = H) to cyclization conditions afforded results similar to the ester and thioester derivatives (Fig. 2-2).11-12 Ketone 2.12, having the simplest substitution on the pendant olefin, produced spirocycle 2.15 in excellent yield under thermal conditions. It is interesting, however, that the reaction produced only trace amounts of cyclized product under photothermal conditions since the yields of the thioester analogs were greatly improved under similar circumstances (see Fig. 1-29). Increased substitution on the pendant olefin as in ketones

2.13 and 2.14 led to only trace amounts of cyclized product when subjected to thermal conditions;

Figure 2-2: Cyclizations of ketone derivatives under thermal and photothermal conditions. yields were not improved with added UV-irradiation. Cyclization attempts for ketones 2.12-2.14 (X

= OMe) showed analogous results under thermal and photothermal conditions.7

– 50 – Chapter 2 All-Carbon Ene-Type Cylizations

Investigations of cyclizations from all-carbon analogs not containing an α-keto functionality were also pursued. Reaction of iron complexes 2.18 under thermal conditions produces the expected mixture of regioisomers 2.19, which are formed after isomerization of the diene (Eq.

2.1).8-9 Utilizing a substrate with less electron-withdrawing character at the α-position (i.e. 2.18,

(2.1)

R = CH2OTBDPS) gives more insight into how the electronic structure of the diene-Fe(CO)3 complex can have an effect on the cyclization. What is also particularly interesting is that it seems a steric effect similar to what is seen with the amide derivatives may also persuade the cyclization reaction to occur. Substrates containing substituents at the β-position with respect to the diene-

Fe(CO)3 group were also investigated; however, no cyclization products were observed.

2.2 Project Aim: Cyclizations from α-Alcohol Derivatives

The majority of the ene-type cyclizations presented thus far have used substrates containing an α-carbonyl functionality. To reiterate, the purpose of this was based on the potential synthetic application of using ester/thioester derivatives towards natural product synthesis, i.e. verrucarol

(Scheme 2-1; see also Scheme 1-3). The scope of these cyclizations was thus directed towards similar potential targets. As the exploration of such reactions was reaching a close, attention was then given to different all-carbon substrates, such as those introduced in the preceding section.

Preliminary work concerning α-alcohol substrates was done by Eun Hoo Kim in the Pearson group. One of the main reasons for switching to these derivatives was to find an alternative to using ketones in the formation of all-carbon spirocycles. As mentioned previously, the preparation

– 51 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-1: Sketched approach to Verrucarol from ester 2.22 of the ketones from acyl chloride or acyl methanesulfonic mixed anhydride substrates proved to be rather troublesome. To circumvent this issue, a switch from an acyl derivative to an aldehyde substrate such as 2.23 would create a reversible addition in the presence of alkoxides, whereas a

Grignard addition would be irreversible (Scheme. 2-2).10 Gratifyingly, the aldehyde substrates are also much easier to handle and fairly stable compared to their acyl counterparts, which is another advantage compared to the ketone synthesis. In addition, as mentioned earlier, alcohol substrates were better behaved during cyclization of acyclic diene-Fe(CO)3 complexes (see Fig.

2-1). It is also interesting to note that the Grignard addition to aldehyde 2.23 as in Scheme 2-2

Scheme 2-2: Alkyl and alkoxide additions to aldehyde 2.23. produced a ~6:1 diastereoselectivity — a topic that will be investigated more thoroughly in

Chapter 3.

– 52 – Chapter 2 All-Carbon Ene-Type Cylizations

The goal of this dissertation was to further investigate all-carbon cyclizations from α-alcohol substrates (Eq. 2.2). Although Kim was able to achieve a spirocyclization from 2.26, the scope of such reactions was not fully explored. What is intriguing about using alcohol derivatives to form the all-carbon backbone is (1) the change in electronegativity at the α-carbon with respect to the iron-complexed diene; (2) the switch to a sp3 center from a sp2 center at the α-position; and

(3) the potential for sterically-demanding protecting groups on the alcohol to place the pendant olefin in an orientation more suitable for the cyclization reaction. How do these subtle changes to the compound affect the cyclization overall?

It was mentioned in the previous chapter that the cyclizations of all-carbon systems are of greater interest due to the availability of potential synthetic targets. Single-cyclized products — more specifically spirocyclized products — are still being extracted from natural sources and have found medicinal application. New and known acorane sesquiterpenes have been isolated from

Acorus tatarinowii by Yao and co-workers in order to expand on Chinese herbal medicinal techniques to treat Alzheimer’s disease, all of which contain the backbone structure that has been

Figure 2-3: Acorane sesquiterpenes that are potential targets using diene-Fe(CO)3 cyclization chemistry. obtained from the iron-mediated ene-type spirocyclizations produced in the Pearson lab (Fig.

2-3).13

It was also previously mentioned that tandem double cyclizations were achieved using amide derivatives (see Chapter 1, Section 1.2.2.2.1). The tricyclic backbone produced from these reactions mimics that of angular triquinane derivatives (Fig. 2-4). These naturally occurring terpenoids, such as pentalenene and isocomene, have been of considerable interest due to their complex structure and medicinal properties.14-18 In this chapter, the focus will be directed towards

– 53 – Chapter 2 All-Carbon Ene-Type Cylizations the construction of spirocyclic and tricyclic compounds that can be potentially used as intermediates towards synthetic targets such as those shown in Figure 2-3 and Figure 2-4.

Figure 2-4: Examples of angular triquinanes — potential targets via tandem double cyclizations.

2.3 Single Cyclizations

2.3.1 Unsubstituted (Cyclohexa-1,3-diene)-Fe(CO)3 Substrates

The most logical starting point to investigate cyclizations from α-hydroxy diene-Fe(CO)3 complexes was the simplest alcohol 2.30, which contains no additional substitution on the iron- complexed diene or on the pendant olefin. The first approach was to use a route that utilized an

important Michael-Wittig addition to form the conjugated diene 2.33 (Scheme 2-3).19-20 This approach was beneficial as it required only two (2) steps to obtain the diene ligand that would directly form iron complex 2.34.21 The first step in the synthesis resulted in quantitative yields of alkyl phosphonium bromide 2.32 from methyl 4-bromocrotonate with no need for purification.

Formation of methyl ester 2.33 was achieved rather smoothly via reaction of 2.32 with

– 54 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-3: Synthesis towards methyl ester 2.34 via Michael-Wittig route. and saturated sodium bicarbonate. However, an issue arose during purification of 2.33 from large scale reactions, as the triphenylphosphine oxide (Ph3PO) byproduct proved to be quite difficult to remove. Attempts to crystallize the Ph3PO from the crude mixture via trituration in hexanes or cold diethyl ether (Et2O) were fruitless, as only a brown gum would form which consisted of a

1 mixture of the desired ester 2.33 and Ph3PO based on H-NMR. A workup procedure using and hexanes was also employed, with the intent of dissolving the Ph3PO in the acid and removal from hexanes by means of a separatory funnel.22 But it turns out that ester 2.33 is more readily miscible in acetic acid than in hexanes, and thus a mixture still remained. Removal of

Ph3PO could indeed be accomplished via flash chromatography, although large amounts of solvent as well as multiple rounds of purification were needed which proved to be wasteful and impractical. Therefore, a different approach towards the synthesis of iron-complexed ester 2.34 was desired.

The formation of 1,4-cyclohexadienes via aromatic acid reduction by alkali metal in liquid

21,23 and subsequent metal complexation with Fe(CO)5 has been well documented. The same approach was used as an alternative method to secure ester 2.34 (Scheme 2-4). By subjecting benzoic acid (2.35) to Birch reduction conditions using sodium or lithium metal, the corresponding 1,4-diene 2.36 was obtained. It is important to note that unless an overhead mechanical stirrer is used, lithium wire is the preferred choice in this reaction. When using sodium the resulting salts tend to be less soluble in the liquid ammonia, which makes it more difficult to

– 55 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-4: Synthetic route to ester 2.34 from benzoic acid. achieve full conversion to the 1,4-diene derivative. The corresponding lithium salts are more soluble, and a mere froth is observed.

Carboxylic acid 2.36 was then methylated and the diene was subsequently rearranged under basic conditions to give methyl ester 2.38. After reaction with Fe(CO)5 and then acid-catalyzed rearrangement of the diene, the desired methyl ester 2.34 was afforded in 63% overall yield

(compared to 28% overall yield using Michael-Wittig route). It has been reported that direct complexation of 2.37 using Fe(CO)5 followed by diene rearrangement under acidic conditions can afford methyl ester 2.34 in quantitative yields (Scheme 2-5).21 After many attempts, however, only one trial produced a ~1:1 mixture of 2.34 and 2.39, which could not be reproduced. Therefore, pre-complexation diene rearrangement under basic conditions to form conjugated diene 2.38

Scheme 2-5: Attempt of formation of ester 2.34 via direct complexation of 2.37. proved advantageous, as subsequent iron complexation followed by rearrangement produced the desired complex 2.34 in reproducibly good yield.

From this point, the goal was to produce aldehyde 2.42. The optimized procedure obtained by

Kim required full reduction to alcohol 2.41 followed by Mukaiyama oxidation to give 2.42 (Scheme

2-6). Previously in the Pearson lab, direct conversion from ester to aldehyde would occur uncleanly, wherein mild reducing agents were only able to produce low yields of aldehyde

– 56 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-6: Preparation of aldehyde 2.42 via Mukiayama oxidation.

Scheme 2-7: Conversion of regioisomers to aldehyde 2.42 under thermal conditions.

2.42.7,10 Moreover, attempts to oxidize alcohol 2.41 to aldehyde 2.42 using Swern oxidation, for example, led to extensive decomposition of the iron complex.1

It is also worth mentioning certain observations concerning aldehyde 2.42. During one synthesis of ester 2.34, it was observed that incomplete conversion of 2.39 to 2.34 (see Scheme

2-6) occurred, and the mixture was carried through towards the formation of aldehyde 2.42

(Scheme 2-7). It had previously never been attempted to thermally re-arrange a diene-iron complex containing an α-carbaldehyde substituent. To our satisfaction, complete conversion of the mixture of 2.42 and 2.43 to 2.42 could be achieved quantitatively. It is also important to note that these two isomers are separable via chromatography, and conversion of pure 2.43 to 2.42 also proceeds in high yield.

Alcohol 2.30 was secured by the reaction of 3-buten-1-ylmagnesium bromide with aldehyde

2.42. The Grignard addition gave excellent yields, and interestingly with a diastereomeric ratio of

8:1 (Eq. 2.3). A more general investigation of the generality of this selectivity will be presented in

Chapter 3.

(2.3)

– 57 – Chapter 2 All-Carbon Ene-Type Cylizations

The major isomer of alcohol 2.30 was then used to investigate the all-carbon ene-type cyclization (note that, at this point, the stereochemistry of this isomer was undefined). By reaction of 2.30 under thermal conditions (CO, n-Bu2O, reflux), the expected mixture of regioisomers

(~3:2) was obtained with a crude yield of 48% (Table 2-1). Given the similar polarities of the regioisomers, they could not be separated via flash chromatography and were isolated as a mixture. By switching the conditions to refluxing benzene in a Rayonet UV reactor (350 nm), the cyclization was achieved relatively smoothly and produced 2.44 (~3:2 ratio) in 98% crude yield with no need for further purification. Besides the high yield, the use of photothermal conditions also appears to give a much cleaner reaction with fewer byproducts.

Although the two cyclization products were obtained as a mixture, evidence that supports their actual formation is demonstrated by the presence of the signature methyl doublets in the aliphatic region of the 1H-NMR spectrum (Fig. 2-5). Peaks corresponding to the iron-complexed diene protons are also present.

Table 2-1: Cyclization of alcohol 2.30 under thermal or photothermal conditions.

Purified Yield Conditions (Yield) (mixture of isomers)

thermal (CO, n-Bu2O, Δ) 45% (48%)

photothermal (CO, 350 nm, benzene, Δ) n/a (98%)

– 58 – Chapter 2 All-Carbon Ene-Type Cylizations

Figure: 2-5: 1H-NMR spectrum of unpurified 2.44 from reaction under photothermal conditions.

2.3.2 3-Methoxy Substituted (Cyclohexa-1,3-diene)-Fe(CO)3 Substrates

With the success of achieving an all-carbon cyclization under both thermal and photothermal conditions, we were curious about the diastereoselectivity observed in the Grignard addition to aldehyde 2.42 to give alcohols 2.30 (see Eq. 2.3). However, this would be difficult to determine with unsubstituted diene-iron complexes 2.44, as the mixture of regioisomers cannot be adequately separated via flash chromatography or preparative TLC. In order to obtain a single product, a substrate with a 3-OMe group (2.45) is a useful option, as this type of methodology has worked well with complexes similar to 2.46 and 2.47 (Scheme 2-8).7,9,24-28 Preparation of enone

2.48 will be discussed further in Chapter 3.

– 59 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-8: Retrosynthetic approach to enone 2.48.

The synthetic approach to produce complexes 2.46 and 2.47 was very similar to that for unsubstituted alcohol 2.44. Birch reduction of m-anisic acid afforded 2.50 in 82% yield (Scheme 2-9). A unique characteristic of this particular reaction is that a conjugated diene can be obtained under appropriate workup conditions.29 The key is to maintain the temperature of the crude reaction mixture at 0 °C during acidification to pH = 4. Otherwise, a mixture of 2.50 and the 1,4-isomer 2.53 is collected (Scheme 2-10). The mixture, however, can be treated with DBU in refluxing benzene after to afford the thermodynamically more stable isomer 2.74 in good yields.

Scheme 2-9: Synthetic route to aldehyde 2.52 via Birch reduction of m-anisic acid.

Scheme 2-10: Conversion to conjugated and 2.50 from mixture of isomers under basic conditions.

After methylation and subsequent reaction with Fe(CO)5, the desired iron complex 2.51 is obtained, which is the most thermodynamically stable isomer. This is convenient, since this

– 60 – Chapter 2 All-Carbon Ene-Type Cylizations rearrangement does not always occur directly for these types of reactions and an acidic diene- rearrangement reaction is usually required (see Scheme 2-4). Subjection of ester 2.51 to DIBAL reduction followed by Mukiayama oxidation gave aldehyde 2.52.

Addition of butenylmagnesium bromide to aldehyde 2.52 to give alcohols 2.54 produced similar results to that of unsubstituted aldehyde 2.42 (Eq. 2.4). There was a noticeable difference

(2.4)

in diastereoselectivity, but determination of the actual ratio via 1H-NMR proved to be much more difficult in comparison to the analysis of crude 2.30. This is not too concerning, however, as the two isomers were completely separated via flash chromatography and the ratio of the recovered amounts was ~22:1. This will be discussed in more detail in Chapter 3.

Table 2-2: Cyclization of alcohol 2.54 (major) under thermal and photothermal conditions.

Conditions Yield Yield

A: CO, n-Bu2O, 9% 4% Δ, 16 h

B: CO, benzene, recovered SM recovered SM 350 nm, Δ, 10 h

C: CO, , 16% 2% 350 nm, Δ, 10 h

D: CO, xylenes, 350 nm, Δ, 4h 11% n/a

Subjecting the major isomer of 2.54 to thermal cyclization conditions produced disappointing yet interesting results (Table 2-2). Unlike cyclized products 2.44, these complexes are separable via flash chromatography or preparative TLC (see Table 2-1). The crude yield was difficult to

– 61 – Chapter 2 All-Carbon Ene-Type Cylizations determine, but upon purification spriocycles 2.55a and 2.55b were obtained in 9% and 4% yield, respectively. This was surprising since the crude NMR demonstrated near-complete consumption of starting material. However, a byproduct isolated in considerable amount during purification was identified as ketone 2.56 (Scheme 2-11). It is believed that this is formed by an iron-mediated olefin isomerization of alcohol 2.54 to 2.57, which would then tautomerize to give ketone

2.56. This is problematic for the cyclization, since the tautomerization is irreversible and thus consumes the starting material unproductively.

Scheme 2-11: Possible depiction for the formation of ketone 2.56.

A switch to photothermal conditions for the cyclization of 2.54 (major), however, produced a

40% crude yield of what appeared to be solely 2.55a. We speculate that this may occur due to the decreased thermal energy produced from the refluxing toluene versus butyl ether, leaving a smaller likelihood of diene rearrangement. Despite the high crude yield, collection of complex

2.55a after purification produced low yields. On a positive note, it was observed that the presence of ketone 2.56 was significantly lower and was never isolated in any of the fractions collected during purification.

Although photothermal conditions increased the overall yield of the spirocyclization product with minimal ketone 2.56 byproduct, we were still curious about other ways which would increase the yields under the same conditions. One approach would be to protect the alcohol, which would potentially do two things: (1) make the isomerization of the pendant olefin reversible and (2) add steric bulk at the α-position to induce the pendant olefin to be in closer proximity to the Fe(CO)3

– 62 – Chapter 2 All-Carbon Ene-Type Cylizations moiety. Initially, protection of the alcohol functionality by forming a methyl ether was attempted; however, the reaction afforded only starting material (Scheme 2-12). It should be noted that the alkoxide is sterically hindered and therefore a poor substrate for an SN2 reaction. Attempts to form acetate 2.58 were much more successful and proceeded rather smoothly. This could very well be due to an easier approach of the alkoxide of 2.54 to the sp2 center of the acetic anhydride versus the sp3 center of the methyl iodide, but this has not been thoroughly investigated at this time.

Scheme 2-12: Protection of alcohol 2.54 with acetic anhydride and methyl iodide.

Although the formation of acetate 2.58 was achieved with relative ease, an attempt to cyclize the substrate under photothermal conditions proved to be dismal (Eq. 2.5). The 1H-NMR of the crude product showed a very messy mixture of products, which consisted of some demetallated materials, isomerized-olefin, and minimal cyclization products. It appeared that cyclization was not the preferred course of reaction and that olefin isomerization was more likely to occur,

(2.5)

indicated by the presence of a methyl-triplet instead of a methyl-doublet in the aliphatic region of the 1H-NMR spectrum. Since the reaction was run under photothermal conditions, the possibility

– 63 – Chapter 2 All-Carbon Ene-Type Cylizations of fragmentation of the acetate group is also likely which leaves an increased probability for side reactions to occur.

Overall, the substrates with a 3-OMe functionality tend to be rather sluggish towards cyclization. A previous graduate student Ismet Dorange observed decreased IR frequencies of the CO-ligands on the iron that are attributable to electron donation by the methoxy group attached to the diene. The results we observe do indeed support this phenomenon, as the added electron density on the iron would result in a lower propensity for a pendant olefin to interact with the metal. Therefore, the occurrence of side reactions would be more likely — another phenomenon that is also observed.

2.4 Attempts at Tandem Double Cyclizations from Alcohol Derivatives

The next phase in the examination of these all-carbon cyclizations was to explore the possibility of a double cyclization. As mentioned previously, the yields of cyclization products from ketone-derived iron complexes were dramatically reduced when a higher level of substitution was present on the pendant olefin.7-8 Accordingly, an investigation of the mono cyclization of an alcohol substrate containing a di-substituted pendant olefin was considered necessary before attempting a double cyclization.

2.4.1 Mono-Cyclization Attempts with Di-Substituted Pendant Olefin

The simplest choice of substrate to investigate increased olefin substitution was alcohol 2.62, which contains an added methyl group. A synthesis of this substrate similar to that of the previous alcohol-containing iron complexes, required preparation of the Grignard reagent needed to form

2.62 and this requires a synthesis of the corresponding bromopentene. Starting from 2-pentenoic acid (2.63), the unconjugated acid 2.64 was obtained via reaction with two equivalents

– 64 – Chapter 2 All-Carbon Ene-Type Cylizations

Scheme 2-13: Synthetic scheme towards synthesis of Grignard reagent (E/Z)-2.67. of LDA followed by kinetically-controlled protonation in 83% yield (Scheme 2-13). After reduction to alcohol 2.65, alkenyl bromide 2.66 is afforded by reaction with PBr3. This reaction consistently gave crude yields no higher than 25%, and significant material loss occurred during purification.

The use of as a solvent may be a possibility for improvement; however, the potential for

E2 elimination could be a major side reaction. Trials on a similar substrate by previous graduate students Minxue Huang and Eun Hoo Kim were examined using the CBr4/PPh3 method, during which it was discovered that some cyclopropyl byproducts were formed due to intermediate carbene formation from the CBr4. However, they were successful in the purification of a similar alkyl bromide, for which vacuum distillation was the method of choice. The issue with my reaction scheme was that there was never an adequate amount of crude product to distill. The purification method that was therefore employed was filtration through a silica plug, which produced what was assumed to be a mixture of geometric isomers. However, attempts to form (E/Z)-2.62 by reacting aldehyde 2.42 with Grignard reagent 2.67 prepared from bromide 2.66 produced unsatisfactory results, as ~60% of the crude reaction mixture was recovered starting material (Eq.

2.6).

(2.6)

– 65 – Chapter 2 All-Carbon Ene-Type Cylizations

To circumvent this problem, synthesis of a single isomer of 2.66 was executed via commercially available cis-3-penten-1-ol ((Z)-2.65, Scheme 2-14). Bromination of (Z)-2.65 gave

(Z)-2.66 in higher yield (21%) after purification. Formation of Grignard (Z)-2.67 also proceeded

Scheme 2-14: Synthesis of Grignard reagent 2.67 from (Z)-2.65. more smoothly, since alcohol (Z)-2.62 was isolated in 52% yield as a mixture of diastereomers and unreacted aldehyde 2.42 was obtained (Eq. 2.7).

(2.7)

Thus, the major isomer was subjected to the optimized cyclization conditions of refluxing benzene in a Rayonet UV-reactor under carbon monoxide atmosphere to give an isolated 5% yield of spirocycles 2.68 as an inseparable mixture (Eq. 2.8). However, TLC of the crude product

(2.8)

mixture indicated that the spirocyclization products constitute most of the mixture. Since spirocycles 2.68 could not be separated, a clean 1H-NMR spectrum could not be obtained. So what is important to observe is the formation of a triplet corresponding to the CH3CH2 group in the aliphatic region (Fig. 2-6). Using CDCl3 as NMR solvent did not allow separation of the methyl triplet corresponding to the regioisomers, but they were resolved in C6D6 solution (Fig. 2-7). With spirocycles 2.68 identified, a double cyclization could now be attempted.

– 66 – Chapter 2 All-Carbon Ene-Type Cylizations

Figure 2-6: 1H-NMR of mixture of spirocycles 2.68 in CDCl3, highlighting the formation of a methyl- triplet.

Figure 2-7: 1H-NMR of crude mixture of spirocycles 2.68 in C6D6, highlighting the separation of two methyl-triplets.

– 67 – Chapter 2 All-Carbon Ene-Type Cylizations

2.4.2 Tandem Double Cyclization Attempts

I n r e g a r d s t o achieving an all-carbon double cyclization, the goal was to utilize the same methodology employed in the synthesis of the aforementioned spirocycles and using starting material such as alcohol 2.69. The same process executed for the preparation of pentenyl

Grignard 2.67 was employed for Grignard reagent 2.72 (Scheme 2-15). A previous Masters’ student Minxue Huang was able to supply alcohol 2.70, which was then subjected to reaction with

PBr3 to give a 19% yield of dienyl bromide 2.71. Bromide 2.71 was typically purified via distillation

Scheme 2-15: Synthetic scheme towards conjugated diene Grignard 2.72.

in the trials which Minxue attempted, but elution through a silica plug with 6:1 hexanes:Et2O seemed to be adequate for smaller scale preparations. Formation of Grignard 2.72 was successful as only a minimal amount of aldehyde 2.42 was recovered after reaction to afford alcohol 2.69 (Eq 2.9). However, there seemed to be significant amounts of cyclopropyl byproducts as indicated by high-field absorptions in the crude 1H-NMR spectrum, which has also been noted in the literature for this particular Grignard reagent.30 Nonetheless, alcohol 2.69 was obtained in relatively high purity after chromatographic separation and appeared to be only one

(2.9)

– 68 – Chapter 2 All-Carbon Ene-Type Cylizations diastereomer; no other diastereomer was observed or collected. It is assumed that this major diastereomer had stereochemistry analogous to the earlier Grignard reaction products, which will be discussed in Chapter 3.

Alcohol 2.69 was then subjected to cyclization conditions; first under thermal conditions and then a different attempt under photothermal conditions (Eq. 2.10). When reacted in refluxing butyl ether under carbon monoxide atmosphere, the crude product mixture consisted mostly

(2.10)

of aromatized material and residual starting material. In some respects, this was expected as we had determined through the course of our earlier work that thermal conditions are less productive.

Under photothermal conditions, the starting material was indeed consumed and only minimal aromatic byproducts were observed. The crude 1H-NMR spectrum of the crude product showed a very complex mixture of compounds, from which it was difficult to discern if the desired methyl- doublet was present. Purification attempts were fruitless, as the bands extracted from preparative

TLC were difficult to characterize because the amount of material was very small. Therefore, no definite conclusions can be made whether or not a double cyclization was achieved. It is encouraging that the starting material was completely consumed and that there are some peaks in the olefinic region of the NMR spectrum which may correspond to a diene-Fe(CO)3 complex.

However, much more work will need to be done in order to properly determine if a tricyclic product is formed under these conditions.

– 69 – Chapter 2 All-Carbon Ene-Type Cylizations

2.5 Conclusions

In summary, it has been established by the work herein that all-carbon spirocyclizations can be achieved using the diene-Fe(CO)3 methodology. Spirocyclizations afforded from an unsubstituted diene substrate or with 3-OMe substitution work relatively well with a pendant terminal olefin. Spirocycles resulting from unsubstituted-diene substrates with higher substitution on the olefin were obtainable albeit in in low yields, something that was also a concern with the ketone derivatives. Yields were decreased even further upon purification.

These cyclizations also appear to be optimized by the use of photothermal conditions for 6-7 hours rather than using thermal conditions. Ismet Dorange investigated the scope of ketone- derived cyclizations using both sets of conditions, but never explored using the photothermal conditions for periods longer than 2.5 hours. I speculate that the cyclizations of the ketone derivatives may afford higher yields with longer reaction time, but this is yet to be determined.

The cyclization of the 3-OMe derivatives are much more sluggish and the Grignard addition to aldehyde 2.52 is also slower than for unsubstituted complexes. As mentioned previously,

Dorange determined using IR that the effect of the methoxy group resonates through the iron to the carbon monoxide ligands rather than the carbonyl functionality attached to the diene. It is therefore unclear why the 3-OMe substitution would affect the Grignard additions, but more studies would need to be implemented in order to understand this phenomenon.

No definite conclusions can be made at this time in regards to whether a double cyclization can be achieved. Preliminary evidence suggests the possibility of at least some cyclization products, but this is all that can be said. The diagnostic methyl-doublets in the NMR spectrum were difficult to observe and product purification was also difficult to achieve in order to determine identity of the major products of the reaction. The synthesis of the cyclization substrate 2.69 will need to be optimized, especially in view of the propensity for cyclopropanation during formation of the Grignard reagent from bromide 2.71.

– 70 – Chapter 2 All-Carbon Ene-Type Cylizations

2.6 Experimental Section

(4-Methoxy-4-oxobut-2-en-1-yl) phosphonium bromide (2.32).20,31

Triphenylphosphine (17.6 g, 66.9 mmol) was added to a round-

bottomed flask and was dissolved in toluene (100 mL). Methyl 4-

bromocrotonate (9.50 mL, 68.7 mmol, 85% purity) was then added

dropwise to the solution. The reaction flask was then stoppered and allowed to stir for two (2) days at room temperature. The reaction mixture was then vacuum- filtered with multiple washings of toluene and ether, after which the precipitate was placed under vacuum in a desiccator to remove the residual solvent to produce 2.32 (30.3 g, 68.6 mmol,

99.9%) as an off-white powder. 1H-NMR (400 MHz, CDCl3) δ 7.92 – 7.75 (m, 9H), 7.72 – 7.65 (m,

6H), 6.71 (m, 1H), 6.48 (dd, J = 15.4, 4.8 Hz, 1H), 5.22 (dd, J = 16.4, 7.6 Hz, 2H), 3.66 (s, 3H).

Methyl cyclohexa-1,3-dienylcarboxylate (2.33).19-20 Phosphonium bromide

2.32 (22.6 g, 51.2 mmol) was dissolved in chloride (360 mL) in a

three-necked round-bottomed flask containing a magnetic stir bar and a reflux

condenser. To this solution was then added acrolein (3.60 mL, 53.9 mmol) and sat. NaHCO3 (287 mL) under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 3 days. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (290 mL). The combined organic extract was washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The product was separated from the solid Ph3PO via recrystallization with hexanes and the resulting suspension was rotary evaporated to give a crude oil. This oil was then purified by flash chromatography (5:95

MeOH:CH2Cl2) to give a clear, colorless oil (3.97 g, 28.7 mmol, 56.1%) with a minty scent. Rf =

1 0.34 (1:1 hexanes:CH2Cl2). H-NMR (400 MHz, CDCl3) δ: 6.97 (d, J = 5.4 Hz, 1H), 6.13 (dtd, J =

9.0, 4.3, 1.0 Hz, 1H), 6.05 (ddt, J = 9.0, 5.4, 1.6 Hz, 1H), 3.74 (s, 3H), 2.44 (ddt, J = 10.5, 9.0, 1.6

Hz, 2H), 2.23 (m, 2H).

1,4-Dihydrobenzoic Acid (2.36).32 To a 1-L three-necked round-bottomed

flask containing a magnetic stir bar was added benzoic acid (2.35, 10 g, 82.3

mmol) and ethanol (100 mL). The flask was then stoppered and ammonia

– 71 – Chapter 2 All-Carbon Ene-Type Cylizations

(500 mL) was condensed into the flask using a CO2/ condenser. Small pieces of lithium wire (3 g, 421 mmol)) was then added to the reaction flask piece-by-piece. A deep-blue color was maintained for ~5 minutes and ammonium chloride (1:1 with metal) was carefully added to the flask once the color dissipated. The reflux condenser was then removed and the ammonia was allowed to evaporate overnight through the fume hood. To the resulting white solid in the reaction flask was then added ice-cold water (500 mL) and the solution was made distinctly acidic (pH = 1) using conc. HCl. The reaction mixture was then extracted with CH2Cl2 (5 x 100 mL) and the combined organics were rotary evaporated and concentrated further using a mechanical pump to

1 give a clear oil (10.2 g, 81.5 mmol, 99%). H-NMR (400 MHz, CDCl3) δ: 10.81 (bs, 1H), 5.92 (dtd,

J = 10.6, 3.2, 1.9 Hz, 2H), 5.83 (ddt, J = 10.6, 3.8, 2.0 Hz, 2H), 3.82 – 3.69 (m, 1H), 2.69 (dtt, J =

9.0, 3.5, 1.5 Hz, 2H).

Methyl cyclohexa-2,5-dienylcarboxylate (2.37).33 To a 1-L three-necked

round-bottomed flask fitted with a reflux condenser containing a magnetic stir

bar was added 1,4-Dihydrobenzoic acid (10.7 g, 83.2 mmol), acetone (300

mL) and anhydrous K2CO3 (35 g, 250 mmol). The flask was then stoppered and flushed with nitrogen. Dimethyl sulfate (8.60 mL, 90.7 mmol) was then added to the reaction flask and the mixture was allowed to reflux for one (1) hour at 70-75 °C.

The reaction flask was allowed to cool to room temperature, the reaction mixture was vacuum-filtered and the filtrate was concentrated on the rotary evaporator. The resulting oil was diluted with diethyl ether (200 mL) and was then washed thoroughly with 2 M ammonium hydroxide (5 x 100 mL) to destroy unreacted dimethyl sulfate. The ether layer was then dried over sodium sulfate and concentrated to give the crude product as a clear colorless oil (8.77 g, 63.5

1 mmol, 76%). H-NMR (400 MHz, CDCl3) δ: 5.88 (dtd, J = 10.4, 3.2, 1.8 Hz, 2H), 5.84 – 5.77 (m,

2H), 3.80 – 3.71 (m, 1H), 3.70 (s, 3H), 2.72 –2.64 (m, 2H).

Methyl cyclohexa-1,5-dienecarboxylate (2.38).34-35In a 250-mL three-

necked round-bottomed flask containing a magnetic stir bar was dissolved

ester 2.37 (9.50 g, 68.7 mmol) in anhydrous benzene (100 mL). DBU (11 mL) was added to the flask, which was then fitted with a reflux condenser and nitrogen bubbler and

– 72 – Chapter 2 All-Carbon Ene-Type Cylizations heated to reflux for 9 hours. After allowing the reaction flask to cool, the reaction mixture was washed with 2% HCl (3 x 100 mL) followed by brine (100 mL). The organics were then dried over

Na2SO4 and the solvent was removed in vacuo to give 2.38 as a clear, slightly yellow oil (8.92 g,

1 64.6 mmol, 94%). H-NMR (500 MHz, CDCl3) δ: 6.93 (t, J = 4.6 Hz, 1H), 6.36 (d, J = 9.4 Hz, 1H),

5.90 (dt, J = 9.4, 4.0 Hz, 1H), 3.76 (s, 3H), 2.33 (td, J = 9.9, 4.6 Hz, 2H), 2.20 – 2.13 (m, 2H).

(Methyl cyclohexa-2,4-dienylcarboxylate) tricarbonyliron (2.40).

36-37 Ester 2.37 (6.54 g, 47.4 mmol)) was dissolved in dibutyl ether

(250 mL) in a three-necked round-bottomed flask fitted with a reflux

condenser, which was then stoppered and flushed with nitrogen. Iron pentacarbonyl (16.0 mL, 119 mmol) was the added to the reaction flask via syringe. The reaction mixture was then heated to reflux for two (2) days under nitrogen atmosphere.

The reaction mixture was then vacuum-filtered with diethyl ether over a pad of Celite, which the filtrate was concentrated via rotary evaporation to give the diene-Fe(CO)3 derivative in 94% yield as a crude mixture (12.4 g).The black precipitate was kept wet with solvent through the entirety of the filtration process due to its pyrophoric nature. Once the product was completely filtered though the funnel, the black precipitate was washed with 15% HCl followed by H2O for

1 neutralization. H-NMR (400 MHz, CDCl3) δ: 5.34 (ddd, J = 6.6, 4.0, 1.2 Hz, 1H), 5.25 (ddd, J =

6.6, 4.0, 1.3, 1H), 3.75 – 3.65 (m, 4H), 3.36 (ddd, J = 6.5, 1.3, 0.9 Hz, 1H), 3.24 (dddd, J = 6.3,

3.7, 2.6, 1.3 Hz, 1H), 2.51 (ddd, J = 8.1, 4.9, 1.8 Hz, 1H), 2.19 (ddd, J = 15.6, 4.9, 3.6 Hz, 1H),

1.89 (ddd, J = 15.6, 8.1, 2.4 Hz, 1H).

(Methyl cyclohexa-1,3-dienecarboxylate) tricarbonyliron (2.34).

21 From (methyl cyclohexa-2,4-dienecarboxylate)-Fe(CO)3 (2.40): To a

three-necked round-bottomed flask containing a magnetic stir bar

and 2.40 (3.34 g, 12.0 mmol) was added 10% (v/v) H2SO4 (20 mL) in

MeOH (200 mL). The flask was placed under nitrogen and the reaction mixture was allowed to reflux (~85 °C) overnight. The reaction flask was removed from heat and allowed to cool to room temp, and the contents were then added to ice-cold brine (200 mL). The solution was then extracted with EtOAc (200 mL) followed by diethyl ether (2 x 200 mL), and the combined organics

– 73 – Chapter 2 All-Carbon Ene-Type Cylizations

were dried over MgSO4 (3x) and concentrated under vacuum to give a crude 2.34 yellow oil

(0.862 g, 3.10 mmol, 26%).

From (methyl cyclohexa-1,5-dienecarboxylate)-Fe(CO)3: To a 2-L round-bottomed flask containing a magnetic stir bar was added methyl ester 2.39 (13.98 g, 50.28 mmol) and 10% (v/v)

H2SO4 (100 mL) in MeOH (1 L). The flask was equipped with a Findenser and nitrogen bubbler and was then heated to reflux for 24 hours. The reaction flask was then removed from heat and allowed to cool to room temperature. The reaction mixture was then transferred to a 3-L separatory funnel containing ice water (1 L) and Et2O (500 mL). The organics were then extracted with Et2O (3 x 500 mL) and the combined Et2O layers were washed with brine (500 mL) and dried over Na2SO4 (2x). Once the solvent was removed, some residual water still remained, so the crude product was dissolved in toluene (250 mL) and the solution was concentrated once more via rotary evaporation and vacuum pump to give a clear, yellow-orange oil (12.74 g, 91%) which did not further purification.

From methyl cyclohexa-1,3-dienecarboxylate: Ester 2.33 (1.61 g, 11.7 mmol) was added to a three-necked round-bottomed flask fitted with a reflux condenser containing a magnetic stir bar and was flushed with nitrogen. The carboxylate was then dissolved with n-butyl ether (80 mL), added via syringe. Fe(CO)5 (4.00 mL, 29.7 mmol) was then added to the reaction flask and the reaction mixture was heated under reflux (~142-145 ℃) for 2 days. The reaction mixture was then vacuum-filtered with Et2O over a pad of Celite. The black precipitate was kept wet with solvent through the entirety of the filtration process due to its pyrophoric nature. The filtrate was concentrated via rotary evaporation to give a red-brown oil. The oil was then purified by filtration through a silica plug (9:1 hexanes:ethyl acetate) to give a yellow oil (2.58 g, 9.59 mmol) after

1 removal of the solvent. H-NMR (400 MHz, CDCl3) δ: 6.04 (d, J = 4.4, 1H), 5.36 (t, J = 5.5, 1H),

3.70 (s, 3H), 3.37-3.33 (m, 1H), 2.18 (ddd, J = 15.4, 11.7, 3.7 Hz, 1H), 1.92 (ddt, J = 15.4, 11.7,

3.7 Hz, 1H), 1.75-1.66 (m, 1H), 1.43 (ddd, J = 15.5, 8.9, 3.7 Hz, 1H).

[(Cyclohexa-1,3-dienyl)] tricarbonyliron (2.41).21 Methyl

ester 2.34 (2.58 g, 9.26 mmol) was dissolved in methylene chloride (70

mL) in a dry three-necked round-bottomed flask and was flushed with

nitrogen. DIBAL in toluene (24.0 mL, 28.8 mmol) was then added

– 74 – Chapter 2 All-Carbon Ene-Type Cylizations dropwise to the reaction flask at -42 ℃ and the mixture was allowed to stir at this temperature for

40-60 minutes. MeOH (7 mL) was then added to the reaction mixture to destroy the excess

DIBAL. 15% HCl (70 mL) was then added to the reaction flask and the mixture was allowed to stir at room temperature for 2 hours. The organics were extracted with methylene chloride (3x60 mL), washed with brine (150 mL) and dried over anhydrous Na2SO4. After concentration via rotary evaporation and removal of residual solvent under reduced pressure, the alcohol was produced as an oil. which was then purified by flash chromatography (8:2 hexanes:EtOAc) to give a yellow

1 oil (1.92 g, 8.19 mmol, 88%). Rf = 0.49 (8:2 hexanes: EtOAc). H-NMR (400 MHz, CDCl3) δ: 5.40

(d, J = 4.3 Hz, 1H), 5.22 (dd, J = 6.2, 4.3 Hz, 1H), 3.85, 3.81 (ABq, J = 12.0 Hz, 2H), 3.25 – 3.18

(m, 1H), 1.94 – 1.78 (m, 1H), 1.63 (m, 1H), 1.59 (d, J = 12.7, 1H), 1.50 (t, J = 5.8 Hz, 1H).

(Cyclohexa-1,3-dienecarbaldehyde) tricarbonyliron (2.42). The

crude alcohol 2.41 (2.24 g, 8.96 mmol) was dissolved in freshly-distilled

THF (30 mL) in a 100-mL three-necked round-bottomed flask under

nitrogen atmosphere. Isopropylmagnesium bromide (3.50 mL, 10.5

mmol, 3M in 2-Me-THF) was then added dropwise to the flask at 0 ℃ and was allowed to stir at this temperature for 10 minutes. 1,1’-(Azadicarbonyl)-dipiperidine

(ADD) (2.29 g, 9.08 mmol) dissolved in freshly-distilled THF (20 mL) was then added dropwise to the reaction flask via syringe at 0 ℃ and the reaction mixture was allowed to stir for 50 minutes.

The reaction mixture was then quenched with brine (45 mL) and 15% (v/v) HCl (35 mL), and the organics were extracted with diethyl ether (3 x 50 mL). The combined organic layers were then washed with 15% HCl (100 mL) and brine (100 mL) and dried over Na2SO4. After removal of the solvent via rotary evaporation followed by a low-pressure mechanical pump, the crude aldehyde was produced as a red-orange solid. Purification via flash chromatography (1:9 EtOAc:hexanes)

1 afforded an orange-yellow oil (1.70 g, 6.83 mmol, 76%). Rf = 0.63 (7:3 hexanes:EtOAc). H-NMR

(400 MHz, CDCl3) δ: 9.17 (s, 1H), 5.85 (d, J = 4.2 Hz, 1H), 5.43 (d, J = 5.2 Hz, 1H), 3.58 (dt, J =

6.9, 3.2 Hz, 1H), 2.11 (ddd, J = 14.4, 11.6, 2.9 Hz, 1H), 2.01 (ddt, J = 15.2, 11.6, 3.4, 1H), 1.89 –

13 1.77 (m, 1H), 1.35 (ddd, J = 14.4, 8.5, 3.2 Hz, 1H). C-NMR (100 MHz, CDCl3) δ: 209.65,

– 75 – Chapter 2 All-Carbon Ene-Type Cylizations

+ 195.51, 88.66, 86.95, 74.50, 65.50, 25.89, 20.09. HRMS (m/z) M calculated for C10H8O4Fe,

247.9772; found 247.9775.

[1-(Cyclohexa-1,3-dienyl)pent-4-en-1-ol] tricarbonyliron

(2.30). To a dry 125-mL three-necked round-bottomed flask

was added magnesium turnings (0.5886 g, 24.21 mmol) and

freshly distilled Et2O (50 mL). The flask was then equipped

with glass stoppers and a reflux condenser containing a nitrogen bubbler, via which the apparatus was flushed with nitrogen. 4-Bromo-1-butene (1.0 mL,

9.9 mmol) and a chip of iodine were then added to the flask and the reaction mixture was heated to reflux for one (1) hour. To a 250-mL three-necked round-bottomed flask containing a magnetic stir bar was added aldehyde 2.42 (0.5590 g, 2.25 mmol) and freshly distilled Et2O (7 mL). The flask was equipped with glass stoppers and an addition funnel, upon which the apparatus was flushed with nitrogen at 0 °C. After 10 minutes, the Grignard solution (~50 mL, ~9.9 mmol) was transferred to the addition funnel, which was then set to a slow steady drip into the reaction flask.

Once the addition was complete, the reaction was allowed to stir at 0 °C for 45 minutes. The reaction mixture was then quenched with saturated NH4Cl (50 mL). Water (50 mL) and some

NaCl was added to the mixture and the phases were separated. The aqueous phase was then extracted with Et2O (2 x 50 mL) and the combined organics were washed with brine (100 mL) and dried over Na2SO4. The solvent was removed in vacuo to give an opaque yellow oil (0.6319 g,

93%). The crude product was then purified via flash chromatography (2:8 EtOAc:hexanes) to give

1 a yellow oil (0.4506 g, 66%). Major diastereomer: Rf = 0.82 (3:7 EtOAc:hexanes). H-NMR (400

MHz, CDCl3) δ: 5.85 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.39 (d, J = 4.3 Hz, 1H), 5.21 (t, J = 5.5 Hz,

1H), 5.08 (dq, J = 17.1, 1.7 Hz, 1H), 5.01 (d, J = 9.9 Hz, 1H), 3.57 (td, J = 6.8, 3.6 Hz, 1H), 3.19

(q, J = 4.2, 3.6 Hz, 1H), 2.25, 2.15 (ABqm, J = 14.6, 7.5 Hz, 2H), 1.97 – 1.78 (2H), 1.76 – 1.65

13 (3H), 1.45 (d, J = 3.6 Hz, 1H), 1.37 (td, J = 10.3, 9.8, 4.7 Hz, 1H). C-NMR (100 MHz, CDCl3) δ:

212.04, 138.04, 115.22, 87.27, 86.04, 82.16, 77.35, 62.06, 35.71, 30.79, 24.46, 21.19. HRMS (m/

+ z) M calculated for C14H16O4Fe, 304.0398; found 304.0395.

– 76 – Chapter 2 All-Carbon Ene-Type Cylizations

(4-methylspiro[4.5]deca-6,8-dien-1-ol)

tricarbonyliron (2.44). Thermal conditions: In a 50-

mL round-bottomed flask was dissolved alcohol

2.30-major (96.8 mg, 0.318 mmol) in distilled n-

Bu2O (20 mL). The reaction flask was fitted with a reflux condenser and the joint was sealed with Teflon tape. The apparatus was degassed with nitrogen followed by carbon monoxide. The top of the condenser was then sealed with a rubber septum and a balloon filled with carbon monoxide was fitted through the septum via needle. The reaction was the heated to reflux for 16 hours. The flask was then removed from heat and allowed to cool to room temperature. The reaction mixture was vacuum-filtered through a pad of

Celite with washings of CH2Cl2 and the resulting filtrate was concentrated via rotary evaporation at 70 °C to give a yellow oil. The product was then purified via flash chromatography (2:8

EtOAc:hexanes) to give a yellow oil in 45% yield (43.4 mg).

Photothermal conditions: Alcohol 2.30 (33.4 mg, 0.11 mmol) was dissolved in benzene (10 mL) in a 25-mL round-bottomed flask containing a magnetic stir bar, which was then fitted with a reflux condenser with a Teflon-tape seal for the joint. The apparatus was then flushed with nitrogen followed by carbon monoxide. The tope of the condenser was then sealed with a rubber septum, through which a balloon filled with carbon monoxide was fitted. The apparatus was then placed into a Rayonet UV reactor (350 nm) and the reaction was heated to reflux while under UV- irradiation for 6.5 hours. The apparatus was then removed from the Rayonet system to cool. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give a brown

1 oil which did not require further purification (32.8 mg, 98%). Rf=0.50 (3:7 EtOAc:hexanes). H-

NMR (400 MHz, CDCl3) Major isomer - δ: 5.50 (ddd, J = 6.1, 4.0, 1.5 Hz, 1H), 5.34 – 5.26 (2H),

3.35 – 3.30 (m, 1H), 3.14 – 3.08 (3H), 2.00 (ddt, J = 13.4, 8.8, 7.0 Hz, 1H), 1.14 (d, J = 7.0 Hz,

3H). Minor isomer - δ: 5.40 – 5.34 (m, 1H), 5.34 – 5.26 (2H), 3.59 – 3.49 (2H), 3.29 – 3.21 (m,

1H), 3.07 (s, 1H), 2.65 (dd, J = 6.4, 1.5 Hz, 1H), 1.33 (tdd, J = 13.2, 5.4, 3.0 Hz, 1H), 1.27 – 1.18

(m, 1H), 1.01 (d, J = 6.4 Hz, 3H). Aliphatic Envelope: δ: 1.92 – 1.69 (8H), 1.65 (dt, J = 6.3, 3.2 Hz,

2H), 1.61 (dd, J = 7.9, 3.1 Hz, 3H), 1.52 (d, J = 2.7 Hz, 1H), 1.50 – 1.40 (3H). 13C-NMR (100

MHz, CDCl3) δ: 212.15, 211.98, 87.55, 86.25, 85.31, 83.55, 83.04, 80.63, 70.41, 63.90, 63.21,

– 77 – Chapter 2 All-Carbon Ene-Type Cylizations

61.14, 52.12, 50.54, 44.45, 44.01, 41.47, 32.81, 30.58, 30.43, 29.49, 29.00, 18.35, 16.71. HRMS

+ (m/z) M calculated for C14H16O4Fe, 304.0398; found 304.0404.

5-Methoxy-3,4-dihydrobenzoic acid (2.50).29 In a 1-L three-necked

round-bottomed flask containing a magnetic stir bar was dissolved m-

anisic acid (9.05 g, 59.5 mmol) in EtOH (100 mL). The flask was then

fitted with a dry ice/acetone condenser and two rubber septa, one of which contained a balloon for back pressure. The reaction flask was then partly submerged into a dry ice/acetone bath and ammonia (~300 mL) was condensed into the flask over a one hour period. The dry ice/acetone bath was removed and small pieces of sodium metal (5.85 g, 254 mmol) were then added carefully. Once the addition was complete, the flask was re-stoppered and allowed to reflux until the blue color dissipated (~5 minutes). The reaction mixture was then cautiously quenched with saturated NH4Cl (15 g) and the condenser was removed to allow the ammonia to evaporate overnight. The resulting off-white solid was then dissolved in ice water

(300 mL) and the solution was saturated with ice. The mixture was then acidified to pH = 4 with

15% HCl (50 mL) and the organics were extracted with CH2Cl2 (3 x 200 mL). The combined organics were then dried over Na2SO4 and the solvent was removed to produce an off-white solid

1 (6.63 g, 72%). H-NMR (400 MHz, CDCl3) δ: 11.93 (s, 1H), 6.75 (tt, J = 4.8, 1.2 Hz, 1H), 5.43 (dt,

J = 2.2, 1.1 Hz, 1H), 3.67 (s, 3H), 2.55-2.39 (m, 2H), 2.38 – 2.22 (m, 2H).

Methyl 5-Methoxycyclohexa-1,5-dienylcarboxylate.36 In a 500-mL

three-necked round-bottomed flask containing a magnetic stir bar was

dissolved 5-methoxy-3,4-dihydrobenzoic acid (6.63 g, 43.0 mmol) in acetone (250 mL). Potassium carbonate (18.3 g, 132 mmol) and Me2SO4 (4.10 mL, 43.2 mmol) were added to the flask, which was then fitted with a reflux condenser and nitrogen bubbler. The reaction was then heated to reflux for two hours. The reaction flask was then removed from heat and allowed to cool. The reaction mixture was then vacuum-filtered and the filtrate was concentrated in vacuo. The resulting residue was diluted with Et2O (200 mL) and the organics were washed with 2 M NH4OH (5 x 100 mL) to destroy unreacted dimethyl sulfate and then dried over Na2SO4 (2x). Concentration of the organics via rotary evaporation produced a yellow oil

– 78 – Chapter 2 All-Carbon Ene-Type Cylizations

1 (6.15 g, 85%). H-NMR (400 MHz, CDCl3) δ: 6.48 (td, J = 4.7, 1.0 Hz, 1H), 5.33 (q, J = 1.0 Hz,

1H), 3.65 (s, 3H), 3.54 (s, 3H), 2.35 – 2.27 (m, 2H), 2.19 – 2.12 (m, 2H).

(Methyl 3-methoxycyclohexa-1,3-dienylcarboxylate)

tricarbonyliron (2.51).36 In a 250-mL three-necked round-bottomed

flask containing a magnetic stir bar was added methyl 5-

methoxycyclohexa-1,5-dienecarboxylate (4.58 g, 27.2 mmol) and anhydrous n-Bu2O (140 mL) followed by Fe(CO)5 (9.0 mL, 66.8 mmol). The reaction flask was then fitted with a reflux condenser and glass stoppers, and the joints were sealed with Teflon tape. The reaction was then heated to 142-150 °C for two (2) days. The reaction mixture was removed from heat and allowed to cool to room temperature. The black reaction mixture was then slowly vacuum-filtered through a pad of Celite, being careful to keep the black precipitate wet with solvent. The filter was washed multiple times with Et2O until all of the yellow compound had passed through. The filtrate was then rotary evaporated at 70 °C and concentrated via mechanical pump to give a yellow oil (5.35 g, 65%). The pyrophoric black precipitate on the filter

1 pad was then destroyed using 15% HCl. H-NMR (400 MHz, CDCl3) δ: 5.70 (d, J = 1.5 Hz, 1H),

3.72 (s, 3H), 3.69 (s, 3H), 2.08 (ddd, J = 14.6, 11.5, 3.3 Hz, 1H), 1.91 (ddt, J = 15.1, 11.5, 3.9 Hz,

1H), 1.85 – 1.72 (m, 1H), 1.35 (ddd, J = 14.6, 8.3, 3.9 Hz, 1H).

[(3-Methoxycyclohexa-1,3-dienyl)methanol] tricarbonyliron.

Ester 2.51 (1.35 g, 4.37 mmol) was dissolved in freshly distilled

CH2Cl2 (30 mL) in a 100-mL three-necked round-bottomed flask containing a magnetic stir bar. The flask was then placed in an ice bath and flushed with nitrogen.

DIBAL (11 mL, 13 mmol, 1.2 M in toluene) was added dropwise to the reaction mixture. Once the addition was complete, the reaction was left to stir at 0 °C under nitrogen atmosphere for one (1) hour. The reaction mixture was then quenched with MeOH (8 mL) and 15% HCl (30 mL). Once the bubbling ceased, the layers were separated and the organics were extracted with CH2Cl2 (3 x

30 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4 and then concentrated in vacuo to give an oil (1.18 g), which was purified via flash chromatography (2:8

1 EtOAc:hexanes) to give a clear yellow oil (1.08 g, 88%). Rf = 0.30 (3:7 EtOAc:hexanes). H-NMR

– 79 – Chapter 2 All-Carbon Ene-Type Cylizations

(400 MHz, CDCl3) δ: 5.21 (d, J = 2.2 Hz, 1H), 3.87 (bs, 2H), 3.62 (s, 3H), 3.45 (q, J = 2.7 Hz,

1H), 1.88 – 1.80 (m, 2H), 1.68 (ddd, J = 14.4, 10.4, 4.0 Hz, 1H), 1.59 – 1.46 (2H), 1.25 (bs, 1H).

13 C-NMR (100 MHz, CDCl3) δ: 211.21, 138.14, 69.73, 69.34, 69.24, 55.16, 54.45, 25.44, 25.34.

+ HRMS (m/z) M calculated for C11H12O4Fe (-CO, -H2O), 235.04; found 233.9993.

(3-Methoxycyclohexa-1,3-dienecarbaldehyde) tricarbonyliron (2.52).

In a 100-mL three-necked round-bottomed flask containing a magnetic

stir bar was dissolved 2.51 (2.05 g, 7.30 mmol) in freshly distilled THF

(20 mL). The flask was then equipped with rubber septa and was

flushed with nitrogen while cooling in an ice bath. i-Propylmagnesium bromide (2.90 mL, 8.70 mmol, 3 M in 2-Me-THF) was added dropwise to the reaction mixture, which was then allowed to stir at 0 °C for 10 minutes. A solution of 1,1’-

(azadicarbonyl)dipiperidine (1.92 g, 7.61 mmol) in freshly distilled THF (20 mL) was was then added dropwise to the reaction flask and the mixture was left to stir at 0 °C under nitrogen for one

(1) hour. The reaction was quenched with brine (50 mL) and the organics were then extracted with Et2O (3 x 50 mL). The combined organics were then washed with 15% HCl (2 x 100 mL) and brine (100 mL) and were then dried over Na2SO4. The solvent was removed to give a crude yellow residue, which was purified via flash chromatography (15:85 EtOAc:hexanes) to give a

1 yellow oil (1.85 g, 91%). Rf = 0.62 (3:7 EtOAc:hexanes). H-NMR (400 MHz, CDCl3) δ: 9.24 (s,

1H), 5.48 (d, J = 2.2 Hz, 1H), 3.73 – 3.68 (m, 1H), 3.66 (s, 3H), 2.03 – 1.86 (m, 3H), 1.32 – 1.20

13 (m, 1H). C-NMR (100 MHz, CDCl3) δ: 196.54, 166.80, 139.86, 68.25, 65.60, 57.42, 54.80,

+ 26.68, 20.32. HRMS (m/z) M calculated for C11H10O4Fe, 277.9877; found 277.9881.

[1-(3-methoxycyclhexa-1,3-diene)pent-4-en-1-ol]

tricarbonyliron (2.54). Aldehyde 2.52 (0.65 g, 2.3 mmol) was

dissolved in freshly distilled Et2O (8 mL) in a 100-mL three-necked

round-bottomed flask containing a magnetic stir bar. The flask was then equipped with an addition funnel and rubber septa, through which the apparatus was flushed with nitrogen while the flask was being cooled in an ice bath. Freshly prepared 3-buteni1- ylmagnesium bromide (45 mL, 24 mmol, in Et2O) was then transferred to the addition funnel and

– 80 – Chapter 2 All-Carbon Ene-Type Cylizations was set to a slow steady drip. Once the addition was complete, the reaction mixture was left to stir at 0 °C under nitrogen for 1.5 hours. The reaction was then quenched with saturated NH4Cl

(36 mL). Water (20 mL) and 15% HCl (5 mL) were added, upon which the organics were extracted with CH2Cl2 (2 x 50 mL). The combined organics were then washed with brine (100 mL), dried over Na2SO4 and the solvent was removed to give a yellow oil, which was purified via flash chromatography (2:8 EtOAc:hexanes) to give a yellow solid for the major diastereomer (0.45 g, 58%) and a yellow oil for the minor diastereomer (0.093 g, 12%). Major isomer: Rf = 0.73 (3:7

1 EtOAc:hexanes). H NMR (400 MHz, CDCl3) δ: 5.83 (d, J = 6.8 Hz, 1H), 5.19 (s, 1H), 5.06 (d, J =

17.1 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H), 3.59 (s, 3H), 3.57 – 3.51 (m, 1H), 3.40 (d, J = 2.7 Hz,

1H), 2.24, 2.14 (ABqm, J = 14.3, 7.2 Hz, 2H), 1.87 – 1.62 (5H), 1.51 (s, 1H), 1.24 (d, J = 6.9 Hz,

13 1H). C NMR (100 MHz, CDCl3) δ: 211.41, 138.34, 137.72, 115.40, 77.32, 76.01, 69.08, 54.98,

+ 54.46, 36.13, 31.09, 25.40, 21.55. HRMS (m/z) M calculated for C15H18O5Fe, 334.0504; found

1 334.0524. Minor diastereomer: Rf = 0.31 (3:7 EtOAc:hexanes). H NMR (400 MHz, CDCl3) δ: 5.86

(dq, J = 16.6, 7.9 Hz, 1H), 5.21 (s, 1H), 5.10 (d, J = 16.9 Hz, 1H), 5.01 (d, J = 10.2 Hz, 1H), 3.65

(s, 1H), 3.62 (s, 3H), 3.43 (d, J = 3.6 Hz, 1H), 2.23 (ddt, J = 39.6, 17.1, 8.4 Hz, 2H), 1.91 – 1.75

(m, 3H), 1.72 (s, 1H), 1.69 – 1.42 (m, 3H).

(7-Methoxy-4-methylspiro[4.5]deca-6,8-dien-1-ol) tricarbonyliron

(2.55a). Thermal conditions: In a 50-mL round-bottomed flask was

dissolved alcohol 2.54-major (76 mg, 0.23 mmol) in distilled n-Bu2O (15

mL). The reaction flask was fitted with a reflux condenser and the joint

was sealed with Teflon tape. The apparatus was degassed with nitrogen followed by carbon monoxide. The top of the condenser was then sealed with a rubber septum and a balloon filled with carbon monoxide was fitted through the septum via needle. The reaction was the heated to reflux for 16 hours. The flask was then removed from heat and allowed to cool to room temperature. The reaction mixture was vacuum-filtered through a pad of Celite with washings of Et2O and the resulting filtrate was concentrated via rotary evaporation at 60 °C to give a yellow oil (~2:1 with other regioisomer). The product was then purified via preparative TLC

(2:8 EtOAc:hexanes) to give a yellow residue in 8% yield (6.1 mg).

– 81 – Chapter 2 All-Carbon Ene-Type Cylizations

Photothermal conditions: Alcohol 2.54-major (197 mg, 0.11 mmol) was dissolved in toluene (50 mL) in a 25-mL round-bottomed flask containing a magnetic stir bar, which was then fitted with a reflux condenser and the joint was sealed with Teflon tape. The apparatus was then flushed with nitrogen followed by carbon monoxide. The top of the condenser was then sealed with a rubber septum, through which a balloon filled with carbon monoxide was fitted. The apparatus was then placed into a Rayonet UV reactor (350 nm) and the reaction was heated to reflux while under UV- irradiation for 10 hours. The apparatus was then removed from the Rayonet system to cool. The reaction mixture was filtered through a pad of Celite and the solvent was removed, and the product was then purified via preparative TLC (2:8 EtOAc:hexanes) to give a yellow oil (32 mg,

1 16%). Rf = 0.31 (2:8 EtOAc:hexanes). H-NMR (400 MHz, CDCl3) δ: 5.03 (dd, J = 6.7, 2.2 Hz,

1H), 3.66 (s, 3H), 3.36 (d, J = 2.2 Hz, 1H), 3.33 (d, J = 4.7 Hz, 1H), 2.62 (dt, J = 6.7, 3.0 Hz, 1H),

1.90 – 1.72 (m, 3H), 1.68 (d, J = 3.0 Hz, 1H), 1.66 – 1.56 (m, 1H), 1.51 – 1.42 (m, 1H), 1.40 (dd, J

13 = 5.7, 2.9 Hz, 2H), 1.16 (d, J = 6.2 Hz, 3H). C-NMR (101 MHz, CDCl3) δ: 211.50, 139.04, 86.05,

67.53, 56.76, 54.65, 53.92, 49.37, 44.18, 43.84, 33.06, 30.66, 18.62. HRMS (m/z) M+ calculated for C15H18O5Fe, 334.0504; found 334.0504.

(7-methoxy-4-methylspiro[4.5]deca-7,9-dien-1-ol) tricarbonyliron

1 (2.55b). (3 mg, 2%). Rf = 0.25 (2:8 EtOAc:hexanes). H-NMR (400 MHz,

CDCl3) δ: 5.28 (d, J = 4.5 Hz, 1H), 4.97 (dd, J = 6.4, 4.5 Hz, 1H), 3.53 (s,

1H), 3.49 (s, 3H), 2.39 (d, J = 6.4 Hz, 1H), 2.26 (d, J = 15.2 Hz, 1H), 1.91

(d, J = 15.2 Hz, 1H), 1.80 (3H), 1.36 – 1.12 (3H), 1.04 (d, J = 6.5 Hz, 3H).

3-Pentenoic Acid (2.64).38 To a 1-L three-necked round-bottomed flask

containing a magnetic stir bar was added diisopropylamine (60 mL, 430

mmol) and distilled THF (160 mL). The flask was then equipped with an addition funnel and glass stoppers, and the apparatus was then flushed with nitrogen at 0 °C. n-

BuLi (190 mL, 430 mmol in hexanes) was then added to the addition funnel, which was then set to a slow steady drip into the reaction flask. Once the addition was complete, 2-pentenoic acid

(2.63, 20 mL, 200 mmol) in distilled THF (100 mL) was then added to the addition funnel, which was also set to slowly drip into the reaction flask. The ice bath was removed and the reaction was

– 82 – Chapter 2 All-Carbon Ene-Type Cylizations allowed to stir at room temperature under nitrogen for two (2) hours. The reaction mixture was then quenched and acidified to pH = 1 with 15% HCl (400 mL). The organics were extracted with

EtOAc (2 x 200 mL) and the combined organics were washed with H2O (200 mL), brine (200 mL)

1 and dried over Na2SO4. The solvent was removed to give a clear oil (16.4 g, 83%). H-NMR (500

MHz, CDCl3) δ: 10.73 (s, 1H), 5.66 (dq, J = 13.8, 7.3 Hz, 1H), 5.55 (tq, J = 13.2, 6.2, 5.3 Hz, 1H),

3.11 (d, J = 7.1 Hz, 2H), 1.62 (d, J = 7.0 Hz, 3H).

3-Penten-1-ol (2.65).39 A 250-mL three-necked round-bottomed flask

containing a magnetic stir bar was fitted with a Claisen head, a Findenser

and an addition funnel, and the flask was flushed with nitrogen. LAH (5.48 g, 144 mmol) and dry Et2O (80 mL) were then added to the flask and stirred until the LAH was well-suspended. Carboxylic acid 2.64 (8.40 g, 84 mmol) dissolved in dry Et2O (40 mL) was transferred to the addition funnel and set to a steady drip into the reaction flask. Once the addition was complete, the reaction mixture was heated to reflux under nitrogen for 12 hours. The reaction flask was then removed from heat and was quenched with H2O (50 mL) after placing the flask into an ice bath. 1.0 M H2SO4 (300 mL) and Et2O (100 mL) were added to the mixture, which was then extracted with Et2O (3 x 100 mL). The combined organics were washed with brine (200 mL), dried over Na2SO4 and the solvent was removed to give a clear, slightly yellow oil (6.49 g, 90%).

1 H-NMR (500 MHz, CDCl3) δ: 5.62 (p, J = 8.5 Hz, 1H), 5.42 – 5.33 (m, 1H), 3.63 (d, J = 7.3 Hz,

2H), 2.32 (q, J = 7.0 Hz, 2H), 1.63 (d, J = 6.9 Hz, 3H).

5-Bromo-2-pentene (2.66).40 Alcohol 2.65 (6 g, 70 mmol) was dissolved in

anhydrous Et2O (50 mL) in a 500-mL three-necked round-bottomed flask

containing a magnetic stir bar. The reaction flask was equipped with a fractionating column and a bubbler, and then placed into an ice bath and flushed with nitrogen.

After 10 minutes, PBr3 (6.0 mL, 64 mmol) was added dropwise, the ice bath was then removed and the reaction was allowed to stir at room temperature under nitrogen for 6 hours. The reaction flask was then placed into an ice bath and the reaction was quenched with ice-cold H2O (50 mL).

Et2O (50 mL) was added, the layers were separated and the organics were washed with 2.0 M

NaOH (3 x 50 mL) followed by brine (50 mL). The ether solution was then dried over Na2SO4 and

– 83 – Chapter 2 All-Carbon Ene-Type Cylizations the solvent was removed to give an oil. The crude product was then purified via silica plug (100% hexanes) to give a clear colorless oil (0.29 g, 3%). Rf = 0.99 (5:1 hexanes:Et2O, visualized with

1 KMnO4). Major isomer: H-NMR (500 MHz, CDCl3) δ: 5.65-5.55 (m, 1H), 5.39 (m, 1H), 3.36 (t, J =

7.3 Hz, 2H), 2.61 (q, J = 7.3 Hz, 2H), 1.62 (d, J = 7.0 Hz, 3H). Minor isomer: 1H-NMR (500 MHz,

CDCl3) δ: 5.52 (q, J = 7.2 Hz, 1H), 3.40 (dd, J = 8.5, 6.3 Hz, 2H), 2.52 (q, J = 7.4 Hz, 2H), 1.66

(d, J = 6.3 Hz, 3H). One of the olefin peaks is embedded with the peaks of the major isomer.

Z-5-Bromo-2-pentene ((Z)-2.66).40 cis-Alcohol 2.65 (2.2 g, 25 mmol) was

dissolved in anhydrous Et2O (30 mL) in a 50-mL three-necked round-

bottomed flask containing a magnetic stir bar. The reaction flask was equipped with a fractionating column and a bubbler, then placed into an ice bath and was flushed with nitrogen. After 10 minutes, PBr3 (2.0 mL, 21 mmol) was added dropwise, after which the ice bath was removed and the reaction was allowed to stir at room temperature under nitrogen for six

(6) hours. The reaction flask was then placed into an ice bath and the reaction was quenched with ice-cold H2O (100 mL). Et2O (15 mL) was added, the layers were separated and the organics were washed with 2.0 M NaOH (3 x 50 mL) followed by brine (30 mL). The ether layer was then dried over Na2SO4 and the solvent was removed to give an oil. The crude product was purified via filtration through a silica plug (5:1 hexanes:Et2O) to give a clear colorless oil (0.78 g, 21%). Rf =

1 0.99 (5:1 hexanes:Et2O, visualized with KMnO4). H-NMR (500 MHz, CDCl3) δ: 5.60 (p, J = 8.8

Hz, 1H), 5.37 (q, J = 8.6 Hz, 1H), 3.35 (q, J = 7.3 Hz, 2H), 2.61 (d, J = 7.3 Hz, 2H), 1.62 (d, J =

6.8 Hz, 3H).

[Z-1-(cyclohexa-1,3-dienyl)hexa-4-en-1-ol] tricarbonyliron

((Z)-2.62). In a 50-mL three-necked round-bottomed flask

containing a magnetic stir bar was dissolved bromide (Z)-2.66

(0.78 g, 5.2 mmol) in anhydrous Et2O (30 mL), and the flask was then flushed with nitrogen. Magnesium turnings (0.35 g, 14 mmol) and a chip of iodine were added to the reaction flask and the mixture was heated to reflux under nitrogen for one (1) hour.

Aldehyde 2.42 (0.17 g, 0.67 mmol) was dissolved in freshly distilled Et2O (15 mL) in a 100-mL three-necked round-bottomed flask containing a magnetic stir bar. The flask was then equipped

– 84 – Chapter 2 All-Carbon Ene-Type Cylizations with an addition funnel and rubber septa, after which the apparatus was then flushed with nitrogen while being cooled in an ice bath. The freshly-made Grignard reagent (30 mL, 5.2 mmol, in Et2O) was then transferred to the addition funnel and was set to a slow steady drip. Once the addition was complete, the reaction mixture was left to stir at 0 °C under nitrogen for 40 minutes.

The reaction was then quenched with saturated NH4Cl (50 mL), upon which the organics were extracted with Et2O (3 x 30 mL). The combined organics were then washed with brine (50 mL), dried over Na2SO4 and the solvent was removed. The crude product was then purified via preparative TLC (2:8 EtOAc:hexanes) to give a yellow residue (44 mg, 21%). Rf = 0.74 (2:8

1 EtOAc:hexanes). H-NMR (500 MHz, CDCl3) δ: 5.51 (p, J = 7.2 Hz, 1H), 5.20 (dd, J = 5.8, 5.2 Hz,

1H), 3.56 (dt, J = 8.4, 4.0 Hz, 1H), 3.21 – 3.15 (m, 1H), 1.64 (d, J = 6.9 Hz, 3H), 1.48 (d, J = 3.3

Hz, 1H), 1.41 – 1.34 (m, 1H). 13C-NMR (126 MHz, CDCl3) δ: 212.06, 129.59, 128.33, 125.01,

87.45, 86.04, 82.15, 62.01, 36.42, 24.47, 24.00, 21.24, 12.85. HRMS (m/z) M+-2(CO) calculated

+ for C13H18O2 , 262.0656; found M -2(CO), 262.0664.

(4-Ethylspiro[4.5]deca-6,8-dien-1-ol)

tricarbonyliron (2.68). Alcohol (Z)-2.62 (20 mg,

0.063 mmol) was dissolved in benzene (12 mL) in a

25-mL round-bottomed flask containing a magnetic

stir bar, which was then fitted with a reflux condenser and the joint was sealed with Teflon tape. The apparatus was then flushed with nitrogen followed by carbon monoxide. The top of the condenser was then sealed with a rubber septum, through which a balloon filled with carbon monoxide was fitted. The apparatus was then placed into a

Rayonet UV reactor (350 nm) and the reaction was heated to reflux while under UV-irradiation for

10 hours. The apparatus was then removed from the Rayonet apparatus to cool. The reaction mixture was filtered through a pad of Celite, the solvent was removed, and the residue was then purified via preparative TLC (2:8 EtOAc:hexanes) to give a yellow oil (1.5 mg, 7.5%). Rf = 0.23

1 (2:8 EtOAc:hexanes) Major isomer: H-NMR (500 MHz, CDCl3) δ: 5.48 (ddd, J = 6.3, 4.1, 1.5 Hz,

1H), 5.31 (tdd, J = 7.9, 4.6, 1.4 Hz, 1H), 3.30 (s, 1H), 3.10 (ddd, J = 6.4, 3.1, 1.5 Hz, 1H), 3.07

(dd, J = 6.6, 1.3 Hz, 1H), 2.04 – 1.97 (m, 1H), 1.91 – 1.68 (3H), 1.68 – 1.57 (2H), 1.52 – 1.45

1 (3H), 1.43 (d, J = 5.5 Hz, 1H), 0.91 (t, J = 6.8 Hz, 3H). Minor isomer: H-NMR (500 MHz, CDCl3)

– 85 – Chapter 2 All-Carbon Ene-Type Cylizations

δ: 5.39 – 5.34 (m, 1H), 3.52 (s, 1H), 3.26 (dp, J = 4.5, 2.1 Hz, 1H), 0.90 – 0.88 (m, 3H), other

13 protons are engulfed in an envelope of peaks from 2.0-1.25 ppm. C-NMR (100 MHz, CDCl3) δ:

211.96, 99.98, 86.12, 85.26, 83.20, 63.64, 61.02, 52.53, 52.22, 44.53, 32.86, 27.46, 25.26, 13.11.

+ HRMS (m/z) M calculated for C15H18O4Fe, 318.0554; found 318.0556.

3,5-Hexadien-1-yl bromide (2.71).30 Alcohol 2.70 (2.4 g, 24 mmol) was

dissolved in anhydrous Et2O (40 mL) in a 250-mL three-necked round-

bottomed flask containing a magnetic stir bar. The reaction flask was equipped with a fractionating column and a bubbler, then placed into an ice bath and flushed with nitrogen. After 10 minutes, PBr3 (2.0 mL, 21 mmol) was added dropwise to the reaction mixture, upon which the ice bath was removed and the reaction was allowed to stir at room temperature under nitrogen for 6 hours. The flask was then placed into an ice bath and the reaction was quenched with ice-cold H2O (50 mL). Et2O (100 mL) was added, the layers were separated and the organics were washed with 2.0 M Na2CO3 (3 x 50 mL). The ether layer was then dried over

Na2SO4 and the solvent was removed to give a crude product which was then purified via filtration through a silica plug (6:1 hexanes:Et2O) to give a clear colorless oil as a mixture of

1 isomers (0.74 g, 19%). Rf = 0.99 (6:1 hexanes:Et2O). H-NMR (500 MHz, CDCl3) δ: 6.32 (dt, J =

16.9, 10.3 Hz, 1H), 6.14 (dd, J = 15.3, 10.4 Hz, 1H), 5.79 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H), 5.67

(dt, J = 14.6, 7.0 Hz, 1H), 5.58 – 5.44 (m, 2H), 5.44 – 5.28 (m, 2H), 5.17 (dd, J = 16.9, 1.5 Hz,

1H), 5.09 – 4.94 (m, 2H), 3.41 (q, J = 6.8 Hz, 6H), 3.37 (td, J = 7.1, 1.5 Hz, 1H), 2.70 – 2.58 (m,

2H), 2.25 – 1.98 (m, 5H), 1.97 – 1.80 (m, 5H), 1.65 (tt, J = 7.0, 1.5 Hz, 5H), 1.58 – 1.49 (m, 3H),

1.02 – 0.94 (m, 1H), 0.92 – 0.82 (m, 4H).

[1-(cyclohexa-1,3-dienyl)hepta-4,6-dien-1-ol]

tricarbonyliron (2.69). In a 100-mL three-necked round-

bottomed flask containing a magnetic stir bar was dissolved

bromide 2.71 (0.74 g, 4.6 mmol) in anhydrous Et2O (20 mL), and the flask was then flushed with nitrogen. Magnesium turnings (0.23 g, 9.5 mmol) and a chip of iodine were added to the reaction flask and the mixture was heated to reflux under nitrogen for one (1) hour. Aldehyde 2.42 (0.09 g, 0.36 mmol) was dissolved in freshly distilled Et2O (13 mL) in

– 86 – Chapter 2 All-Carbon Ene-Type Cylizations a 100-mL three-necked round-bottomed flask containing a magnetic stir bar. The flask was then equipped with an addition funnel and rubber septa, after which the apparatus was then flushed with nitrogen while being cooled in an ice bath. The freshly-made Grignard reagent (20 mL, 4.6 mmol, in Et2O) was then transferred to the addition funnel and was set to a slow steady drip.

Once the addition was complete, the reaction mixture was left to stir at 0 °C under nitrogen for 40 minutes. The reaction was then quenched with saturated NH4Cl (50 mL), upon which the organics were extracted with Et2O (3 x 50 mL). The combined organics were then washed with brine (100 mL), dried over Na2SO4 and the solvent was removed. The crude product was then purified via flash chromatography (1:10 EtOAc:hexanes) to give a yellow residue (46 mg, 10%). Rf = 0.66

1 (1:10 EtOAc:hexanes). H-NMR (500 MHz, CDCl3) δ: 6.31 (dt, J = 16.9, 10.2 Hz, 1H), 6.11 (dd, J

= 15.3, 10.4 Hz, 1H), 5.72 (dt, J = 14.6, 6.9 Hz, 1H), 5.38 (d, J = 4.5 Hz, 1H), 5.23 – 5.19 (2H),

5.11 (dd, J = 17.1, 1.6 Hz, 1H), 4.99 (dd, J = 10.2, 1.6 Hz, 1H), 3.56 (ddd, J = 8.2, 5.4, 2.7 Hz,

1H), 3.22 – 3.15 (m, 1H), 2.29 (dq, J = 14.8, 7.5 Hz, 1H), 2.18 (dq, J = 15.0, 7.6 Hz, 1H), 1.95 –

1.79 (2H), 1.79 – 1.68 (2H), 1.45 (d, J = 3.5 Hz, 1H), 1.42 – 1.32 (m, 1H). 13C-NMR (100 MHz,

CDCl3) δ: 212.07, 136.97, 134.01, 131.72, 124.40, 115.42, 87.21, 86.23, 86.03, 82.21, 82.16,

77.51, 76.97, 62.10, 36.38, 36.06, 33.66, 29.71, 29.63, 28.86, 26.64, 26.41, 24.83, 24.47, 21.24,

+ 21.05, 17.93. HRMS (m/z) M calculated for C16H18O4Fe, 330.0554; found 330.0556.

– 87 – Chapter 2 All-Carbon Ene-Type Cylizations

2.7 References

1. Pearson, A. J.; Alimardanov, A. Studies On Intramolecular Coupling of Tricarbonyl(Diene)Iron Systems with Pendant Olefinic Groups: Configurational Requirements for Reactions Of Acyclic Diene Complexes and Mechanistic Implications. Organometallics 1998, 17 (17), 3739-3746.

2. Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Fouchard, D. M.; Kirschbaum, K. Stereocontrolled Cyclization of Unactivated Alkene onto Cationic Dienyl Iron Tricarbonyl Systems. Tetrahedron Lett. 1998, 39 (33), 5919-5922.

3. Pearson, A. J.; Alimardanov, A. R.; Kerber, W. D. Cationic Cyclizations of (Diene)Iron Tricarbonyl Complexes with Pendant Alkenes And Arenes. J. Organomet. Chem. 2001, 630 (1), 23-32.

4. Markezic.Rl; Whitlock, H. W. Synthesis and Interconversion of 2 Diastereoisomieric Polyene-Bis(Iron Tricarbonyl) Complexes. J. Am. Chem. Soc. 1971, 93 (20), 5291-&.

5. Whitlock, H. W.; Markezic.Rl, Shift Isomerization and Racemization of Some Polyene- Tretrahaptoiron Tricarbonyl Complexes. J. Am. Chem. Soc. 1971, 93 (20), 5290-&.

6. Whitesides, T. H.; Neilan, J. P. Thermolysis of Diene Iron Tricarbonyl Complexes - Cis- Trans Isomerization and Hydrogen Scrambling Reactions in Cyclic and Acyclic Complexes. J. Am. Chem. Soc. 1976, 98 (1), 63-73.

7. Dorange, I. B. Stereocontrolled Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling. Thesis, Case Western Reserve University, 2002. Ph.D.

8. Pearson, A. J.; Wang, X. L.; Dorange, I. B. Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling: Formation of Carbon Spirocycles. Org. Lett. 2004, 6 (15), 2535-2538.

9. Wang, X. Iron Carbonyl Mediated Cyclizations and Their Potential Application in Synthesis. Thesis, Case Western Reserve University, Cleveland, OH, 2005. Ph.D.

10. Kim, E. H. A New Synthetic Pathway for Diquinane and Angular Triquinane Systems. Thesis, Case Western Reserve University, 2010. Ph.D.

11. Pearson, A. J.; Zettler, M. W. Intramolecular Coupling between Tricarbonyl(Diene)Iron Complexes and Pendant Alkenes. J. Am. Chem. Soc. 1989, 111 (11), 3908-3918.

12. Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. Intramolecular Coupling Reactions of Allylic Thioesters with Diene Iron Tricarbonyl Systems. J. Org. Chem. 1998, 63 (19), 6610-6618.

13. Feng, X. L.; Yu, Y.; Gao, H.; Mu, Z. Q.; Cheng, X. R.; Zhou, W. X.; Yao, X. S. New Sesquiterpenoids from the Rhizomes of Acorus Tatarinowii. RSC. Adv. 2014, 4 (79), 42071-42077.

14. Paquette, L. A.; Han, Y. K., Total Synthesis of (+/-)-Isocomene, a Naturally-Occurring Triquinane. J. Am. Chem. Soc. 1981, 103 (7), 1835-1838.

15. Mehta, G.; Srikrishna, A. Synthesis of Polyquinane Natural Products: An Update. Chem. Rev. 1997, 97 (3), 671-719.

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16. Seemann, M.; Zhai, G. Z.; de Kraker, J. W.; Paschall, C. M.; Christianson, D. W.; Cane, D. E. Pentalenene Synthase. Analysis of Active Site Residues by Site-Directed Mutagenesis. J. Am. Chem. Soc. 2002, 124 (26), 7681-7689.

17. Pallerla, M. K.; Fox, J. M. Enantioselective Synthesis of (-)-Pentalenene. Org. Lett. 2007, 9 (26), 5625-5628.

18. Odeleye, O. M.; Oyedeji, A. O.; Opoku, A. R. Antimicrobial activity of Berkheya Bergiana leaves Extracts. Afr. J. Biotechnol. 2011, 10 (24), 4941-4946.

19. Bohlmann, F.; Zdero, C. New Synthesis of Cyclohexadiene Derivatives. Chem. Ber. Recl. 1973, 106 (12), 3779-3787.

20. Graden, H.; Hallberg, J.; Kann, N.; Olsson, T. Iron Carbonyl-Mediated Parallel Solution- Phase Synthesis of Cyclohexadienoic Acid Amides. J. Comb. Chem. 2004, 6 (5), 783-788.

21. Birch, A. J.; Williamson, D. H. Organometallic Complexes in Synthesis. Part V. Some Tricarbonyliron Derivatives of Cyclohexadienecarboxylic Acids. J. Chem. Soc. Perkin Trans. 1. 1973, 1892.

22. Fukumoto, T.; Yamamoto, A. Workup of Wittig Reaction Products. EP0630877A1, 1994.

23. Kuehne, M. E.; Lambert, B. F. The Reduction of Aromatic Acids and Amides by Sodium in Liquid Ammonia. J. Am. Chem. Soc. 1959, 81 (16), 4278-4287.

24. Pearson, A. J.; Dorange, I. B. Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling. J. Org. Chem. 2001, 66 (9), 3140-3145.

25. Pearson, A. J.; Wang, X. L. Intramolecular Coupling between Cyclohexadiene-Fe(CO)(3) Complexes and Pendant Alkenes: Formation of Azaspiro[5,5]Undecane Derivatives. Tetrahedron Lett. 2002, 43 (42), 7513-7515.

26. Pearson, A. J.; Wang, X. L. Double Cyclization via Intramolecular Coupling Between Cyclohexadiene-Fe(Co)(3) Complexes and Pendant Conjugated Dienes. J. Am. Chem. Soc. 2003, 125 (3), 638-639.

27. Pearson, A. J.; Wang, X. L. A Stereospecific Intramolecular [4 Pi+4 Pi] Cycloaddition Reaction between Tricarbonyliron-Complexed Cyclohexadiene and Pendant Dienes. Tetrahedron Lett. 2005, 46 (28), 4809-4811.

28. Pearson, A. J.; Zhang, S.; Sun, H. K. Stereocontrolled Intramolecular Iron-mediated Diene/Vinyl Ether Cyclocoupling Reactions. J. Org. Chem. 2012, 77 (19), 8835-8839.

29. Biffin, M. E. C.; Moritz, A. G.; Paul, D. B. Re-Examination of Sodium and Liquid-Ammonia Reduction of Meta Methoxybenzoic Acid. Aust. J .Chem. 1972, 25 (6), 1329.

30. Howden, M. E. H.; Maercker, A.; Burdon, J.; Roberts, J. D. Small-Ring Compounds. XlV. Influence of Vinyl and Phenyl Substituents on Interconversion of Allylcarbinyl-Type Gringnard Reagents. J. Am. Chem. Soc. 1966, 88 (8), 1732.

31. Lang, R. W.; Kohlmines, E.; Hansen, H. J. Synthesis of Alkenyl-Substituted Allenecarboxylates. Helv. Chim. Acta. 1985, 68 (8), 2249-2253.

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32. Kuehne, M. E.; Lambert, B. F. 1,4-Dihydrobenzoic Acid. Org. Synth. 1963, 43, 22.

33. Meyer, W. L.; Brannon, M. J.; Burgos, C. D.; Goodwin, T. E.; Howard, R. W. Annulation of Alpha-Formyl Alpha,Beta-Unsaturated Ketones by a Michael Addition-Cyclization Sequence - a Versatile Synthesis of Alicyclic 6-Membered Rings. J. Org. Chem. 1985, 50 (4), 438-447.

34. Crimmins, M. J.; Ohanlon, P. J.; Rogers, N. H. The Chemistry of Pseudomonic Acid. Part 8. Electrophilic Substitutions at C-2 and C-15 of the Pseudomonic Acid Nucleus by Means of Lithium Dienolates. J. Chem. Soc. Perkin Trans. 1. 1985, (3), 549-555.

35. Bhaskar, K. V.; Rao, G. S. R. S. Vinyl Radical Induced Michael Additions - Total Synthesis of (+/-)-Seychellene. Tetrahedron Lett. 1989, 30 (2), 225-228.

36. Birch, A. J.; Pearson, A. J. Organometallic Complexes in Synthesis. Part 9. Tricarbonyliron Derivatives of Dihydroanisic Esters. J. Chem. Soc. Perkin Trans. 1. 1978, (6), 638-642.

37. Bandara, B. M. R.; Birch, A. J.; Chauncy, B.; Kelly, L. F. Tricarbonyliron Complexes of Some Blocked Cyclohexadienes. J. Organomet. Chem. 1981, 208 (2), C31-C35.

38. Linstead, R. P.; Noble, E. G.; Boorman, E. J. Investigations of the Olefinic Acids. Part VII. The Preparatton of Delta (-Beta) -Acids. J. Chem. Soc. 1933, 557-561.

39. Kim, W. Y.; Kim, B. G.; Kang, T.; Lee, H. Y. Unexpected Formation of a trans-syn-Fused Linear Triquinane from a Trimethylenemethane (TMM)-Diyl-Mediated [2+3] Cycloaddition Reaction. Chem. Asian J. 2011, 6 (8), 1931-1935.

40. Hornyanszky, G.; Rohaly, J.; Novak, L. Facile synthesis of mill moth's sex pheromone components. Syn. Comm. 2008, 38 (10), 1533-1540.

– 90 – CHAPTER THREE

GENERALITY OF STEREOCONTROL DURING GRIGNARD ADDITIONS TO (CYCLOHEXA-1,3-DIENYLCARBALDEHYDE)– TRICARBONYL IRON Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

3.1 Introduction: Alkyl Additions to Carbonyl-Functionalized Diene-Fe(CO)3 Derivatives

The use of diene-Fe(CO)3 complexes in organic synthesis has been well-documented, and the scope covers a large array of reactions and transformations.1-3 Previous discussions presented herein outlined the reactivity/selectivity of alkyl additions to various iron complexes

(see Section 1.1.2.3 and 1.2.1.2). An area of great interest as it pertains to this chapter concerns the selectivity of alkyl additions to iron complexes bearing a carbaldehyde functionality, such as

3.1. In contrast the substantial amount of literature documenting the reactions of acyclic diene-

Fe(CO)3 complexes, investigations of such reactions on the analogous cyclic substrates are not as well-studied. A brief overview of alkyl additions to acyclic complexes will be presented prior to discussing the investigations of alkyl additions to aldehydes 3.1.

3.1.1 Explanation of Stereochemical-Descriptor Terminology

Before we begin, it is pertinent to understand the terminology used to describe the relative stereochemistry of the complexes resulting from either alkyl (R) or hydride (H) addition (3.2). The

stereochemical descriptors used to describe the two different spacial arrangements of the alcohol

4 group relative to the Fe(CO)3 moiety are Ψ-endo and Ψ-exo. Given a generic diene-Fe(CO)3 complex as seen in Fig. 3-1, position “c” is the most sterically-crowded if a staggered conformation is achieved on the carbon directly attached to the diene. Therefore, if one imagines that the smallest atom — hydrogen in this case — occupies this position, the less crowded positions “a” and “b” are then left to be occupied by either the hydroxy or alkyl groups; The Ψ- endo configuration would occur when the hydroxy and alkyl groups occupy the “a” and “b”

– 92 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes positions, respectively, and vice versa for the Ψ-exo configuration. The accepted explanation pertaining to how these configurations are afforded will be discussed in more detail later in this chapter.

a – slightly crowded

b – uncrowded

c – severely crowded

Figure 3-1: Depiction of atom arrangement on a carbon attached directly to a terminus of the diene-Fe(CO)3 complex.

3.1.2 Alkyl Additions to Acyclic Complexes

3.1.2.1 Experimental Observations of Alkylations of Complexed Dienylcarbaldehydes & Dienones

4 5 The stereodirecting capability of the Fe(CO)3 group in η -diene and η -dienyl complexes has

5-12 found great utility in organic synthesis, and alkyl additions to diene-Fe(CO)3 complexes bearing a carbaldehyde functionality represent a specific class of reactions that embody such an ability.13-19 A large amount of work with these types of reactions has been achieved in the Grée laboratory and the results are illustrated in Table 3-1.15 Grignard and alkyllithium reagents lead to the Ψ-exo isomer as the major diastereomer. Additions from alkylating reagents with a metal containing higher Lewis-acidic character (i.e. Al, Ti), however, produce a mixture of alcohols where the Ψ-endo isomer is the major diastereomer.

These diastereomers are usually readily separated by chromatography, where the Ψ-endo

4,15 isomer typically has the higher Rf-value on TLC. This phenomenon can be explained by the alcohol of the Ψ-endo isomer being sterically “protected” by the Fe(CO)3 group, while the

– 93 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Table 3-1: Yields and selectivities of different alkylating reagent additions to acyclic dienylcarbaldehyde-Fe(CO)3 complexes.

R1 R2M Yield (%) (exo/endo)

CO2Me CH3MgI 80 60 : 40

CO2Me CH3Li 85 80 : 20

CH3 CH3MgI 57 53 : 47

CO2Me PhLi 94 66 : 34

CH3 PhMgBr 91 75 : 25

CO2Me EtO2CCH2Li 88 86 : 14

CO2Me t-BuO2CCH2Li 94 66 : 34

CO2Me PhSCH2Li 88 72 : 28

CO2Me H3C(H2C)≡CLi 96 70 : 30

CO2Me LiO2C(H2C)2C≡CLi 42 60 : 40

CO2Me BrMgO(H2C)2C≡CMgBr 87 70 : 30

CO2Me H3CTi(OPr-i)3 94 25 : 75

CO2Me HC≡CCH2Al2/3Br 94 25 : 75

CO2Me H2C=C=(Al2/3Br)(CH2)4CH3 80 43 : 57 increased polarity of the Ψ-exo isomer is accounted for by the alcohol being more exposed.4

These observations are also in good agreement with the Ψ-endo/exo diastereomers of different iron complexes 3.3 and 3.4 (Fig. 3-2).4,20-21

Examples of alkyl additions to the corresponding ketone derivatives are fewer in number, but such reactions still afford products highly enriched with one diastereomer. In fact, reduction of ketone 3.5 gives the Ψ-endo isomer 3.6 as the sole product (Eq. 3.1). Additions of alkyllithium reagents to ketones 3.7 similarly afford alcohols 3.8 stereoselectively (Eq. 3.2). As free ligands, dienones 3.9 (R1 = Ph, Me) exhibit multiple IR-stretching frequencies due to the population of the s-cis and s-trans conformations (Eq. 3.3).22 However, the respective complexed dienones show a single carbonyl stretch, implying that one conformation is strongly preferred or the two

– 94 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Figure 3-2: Consistent relative Rf – values between Ψ-exo/endo diastereomers of different dienylcarbinol-Fe(CO)3 complexes

(3.1)

(3.2)

(3.3)

conformations have very similar stretching frequencies. Clinton and Lillya made the argument that the former is more likely for a few reasons.4 As one might expect, what makes the ketones unique compared to the aldehyde derivatives is the additional steric factor of the alkyl group attached to the carbonyl. Populating the s-trans conformation (3.10b) would produce unfavorable steric interactions with the residues of the diene and the proximal CO ligand on the iron (Fig. 3-3). The s-cis conformation (3.10a) was also argued to be favored due to a stabilizing interaction that saturated aliphatic aldehydes exhibit when eclipsed with the neighboring alkyl group (if smaller

– 95 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Figure 3-3: Two possible conformations of complexed dienones.

1 23,24 than t- butyl) based on H-NMR coupling constants. Since diene-Fe(CO)3 complexes uniquely demonstrate an increased sp3-character at the terminal positions, the same stabilizing interaction was presumed to be likely.

However, there are some issues with this rationalization. Firstly, Clinton and Lillya are making the assumption that the diene-Fe(CO)3 moiety is not as sterically-demanding as a t-.

Secondly, the argument concerning a stabilizing interaction for an eclipsed conformation corresponds to aldehydes, not ketones. Having an additional alkyl group attached to the carbonyl functionality will have a much different effect on the rotameric energies than when a hydrogen is attached. Nonetheless, population of the s-cis conformation agrees with the experimental evidence of Ψ-endo isomer 3.6 being the sole product as a result of hydride reduction of ketone

3.5 (see Eq. 3.1). Crystallographic evidence has also been obtained suggesting that the s-cis conformation is preferred.18,25

3.1.2.2 Accepted Model for Alkyl Additions to Dienylcarbaldehyde-Fe(CO)3 Complexes

Given the overview of alkyl additions to iron-complexed dienones and dienylcarbaldehydes presented in the previous section, it is easy to see that these types of reactions have been thoroughly investigated. That being said, obtaining a model that would best describe the results that were observed was inevitable. It has been well-established that the steric implications of

– 96 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

having a Fe(CO)3 group coordinated to a diene will induce additions to occur at the face anti to the metal (see Section 1.1.2.3). Since there is evidence suggesting a preferred conformation in the ketone derivatives, the observed diastereoselectivities for the aldehyde analogs would thus be determined by which preferred conformation the aldehyde adopts. Therefore, additions to the s-cis and s-trans conformers would give predominantly the Ψ-exo and Ψ-endo isomers, respectively (Fig. 3-4).15,18

Figure 3-4: Accepted model used to explain the observed diastereoselectivites.

3.1.3 Additions to Cyclic Derivatives

The literature concerning nucleophilic additions to cyclic diene-Fe(CO)3 complexes bearing a carbonyl functionality is not nearly as extensive as for the acyclic derivatives. However, there are some examples of additions to cyclic dienone-Fe(CO)3 complexes that can be used for comparison. When methyl ketone 3.11 is reacted with alkyllithium reagents, the expected stereoselectivity is observed with the Ψ-exo isomer (3.12, 3.15, 3.16) being the major product

(Fig. 3-5).26,27 Interestingly, addition of methyl lithium to ethyl ketone 3.13 gives Ψ-endo 3.14 in a stereospecific fashion. Although addition to 3.13 affords an adduct with a different stereodescriptor than those from additions to 3.11, the selectivities indicate that the nucleophiles add to a ketone that adopts a s-cis conformation. Similarly, the same is observed for hydride addition to ketone 3.11, from which the Ψ-endo isomer 3.17 is obtained with high stereoselectivity.

– 97 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Similar reactions using aldehyde substrates have not been explored up to this point. In the following sections, discussions on selective additions to (cyclohexa-1,3-dienylcarbaldehyde)-

Fe(CO)3 using Grignard reagents will be presented.

Figure 3-5: Nucleophilic additions to dienone-Fe(CO)3 complexes.

3.2 Grignard Additions to Cyclohexa-1,3-dienylcarbaldehyde Complexes

3.2.1 Observed Selectivities en route to Spirocyclic Complexes

During our investigations of ene-type cyclizations from diene-Fe(CO)3 complexes, we made some interesting observations en route to their preparation. As mentioned in Chapter 2, Eun Hoo

– 98 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Kim noticed a ~ 6:1 diastereoselectivity from reaction of 3-buten-1-ymagnesium bromide with aldehyde 3.18 (Eq. 3.4) during his investigations to find a better route to the all-carbon cyclization substrates (see Section 2.2).28 Since the main goal of obtaining 3.19 was to

(3.4)

eventually oxidize the mixture to the ketone, no further analysis of the diastereoselectivity was conducted. Nonetheless, similar observations were made throughout my own research, and the focus of this chapter is to provide more information on the generality of these Grignard additions.

3.2.1.1 Additions to Dienylcarbaldehyde-Fe(CO)3 Derivatives

During my investigations of all-carbon ene-type cyclizations with no additional substitution on the diene, three different cyclization substrates were prepared via Grignard addition to aldehyde

3.20 (Fig. 3-6). Due to purification difficulties in preparation of the Grignard reagent

Figure 3-6: Grignard additions to aldehyde 3.20 that afford cyclization substrates.

– 99 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes used to prepare alcohol 3.23, observation of the diastereoselectivity via 1H-NMR was not feasible, as there was always a mixture of geometric isomers. However, during the preparation of alcohol

3.21, 8:1 diastereoselectivity was observed consistently by 1H-NMR analysis. The main distinction between the two diastereomers is the proton α- to the in the 1H-NMR spectrum, as can be seen in Fig. 3-7. These peaks are also confirmed after purification by means of flash chromatography or preparative TLC, where the α-proton corresponding to the major isomer is shifted to higher field relative to that of the minor isomer. Moreover, the major isomer demonstrates a higher Rf value than the minor isomer on TLC, suggesting a Ψ-endo configuration.

~ 8:1

Figure 3-7: 1H-NMR of crude alcohol 3.21.

It is difficult to determine the diastereoselectivity during the formation of alcohol 3.22 based on the 1H-NMR spectrum of the crude product mixture, since there are some overlapping peaks in the 3-4 ppm range, some of which correspond to unidentified byproducts. The best approximation for diastereoselectivity is based on the weights of individual isomers after chromatographic purification, which corresponded to a 5:1 ratio. However, it is important to note

– 100 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes that the diastereoselectivity followed similar patterns observed for the butenyl Grignard addition:

(1) the major diastereomer had a higher Rf on TLC and (2) the peak corresponding to the proton

α- to the alcohol was shifted further upfield in the 1H-NMR spectrum compared to that of the minor diastereomer.

Addition of 3-buten-1-ylmagnesium bromide to aldehyde 3.24 to give alcohols 3.25 produced results similar to that for unsubstituted aldehyde 3.20 (Eq. 3.5). There was a noticeable difference in diastereoselectivity, but determination of the actual ratio via 1H-NMR proved to be much more difficult in comparison to the analysis of crude 3.21 (see Fig. 3-7). The primary reason for this is

(3.5)

the presence of the methoxy-protons in the same location as the α-proton corresponding to the alcohol (Fig. 3-8). However, one can still see that there is a noticeable shift of the α-proton when comparing the spectra of the isolated diastereomers: a shift downfield for the minor isomer and a shift upfield for the major. What makes this ambiguous, however, is the resolution of the α-proton of the minor isomer, which appears broadened and is also difficult to observe in the 1H-NMR spectrum of the crude product mixture. Further examination of the aliphatic region of the spectra illustrates differing characteristics between the major and minor diastereomers, where a 1H- doublet is present for the major isomer and not for the minor around 1.5 ppm. It is likely that this corresponds to the alcohol proton, as a similar grouping is seen in the 1H-NMR spectrum of the major isomer of alcohol 3.21. In contrast, a set of multiplets is present in the minor isomer around

1.6 ppm, but not in the major, which is also observed for the unsubstituted alcohol 3.21.

Inspection of the NMR spectrum of the mixture reveals a very minor amount of this particular isomer, but a quantitative evaluation is very difficult. This is not too concerning, however, as the two isomers were completely separated via flash chromatography and the ratio of the recovered amounts was ~22:1. The TLC data for the two diastereomers of alcohol 3.25 is also comparable to that of 3.21 and 3.22, where the major isomer has a higher Rf - value relative to the minor isomer.

– 101 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Minor Diastereomer

Major Diastereomer

Crude Product

Figure 3-8: 1H-NMR spectra of crude and purified alcohol 3.25.

3.2.1.2 Determination of Configuration at α-Carbon via NOE Studies

After Eun Hoo Kim’s and my first observations of diastereoselctivity from the butenyl addition to aldehydes 3.18 and 3.20, repectively, our curiosity about the configuration of the alcohol stereogenic center was piqued. While we were able to obtain the crystalline major diastereomer of 3.25, efforts to secure an x-ray structure were fruitless. Consequently we sought to determine the stereochemistry of this compound by NMR methods. The resulting spirocycles 3.26 obtained after cyclization could be used to form a single enone product, which then might be used to determine the configuration at the α-carbon. Subjecting the mixture of spirocycles 3.26 to demetallation conditions with cupric chloride in ethanol produced enone 3.27 in 34% yield (Eq.

3.6). Initially, demetallation was attempted using Me3NO in benzene, but this gave very low crude yields of diene products, which were nearly impossible to carry through to enone 3.27. The recovery of starting material was also very low. It is unclear at this time why this occurs. Although

– 102 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

previous graduate student Eun Hoo Kim reported demetallation of similar complexes resulting

from alcohol 3.19 (see Eq. 3.4) using only cupric chloride in ethanol, I can only speculate that he

also observed poor results when using Me3NO in benzene.

(3.6)

With enone 3.27 in hand, 2D-NMR studies were carried out in order to determine the

configuration at the carbon α- to the OH relative to that at the methyl-substituted carbon. After the

protons were assigned via COSY NMR experiments, a NOESY experiment was conducted, for

which the spectrum is shown in Figure 3-9. A NOE is observed between the α-proton of the

alcohol and the methine proton (see highlighted structure 3.27, Fig. 3-9), which indicates that they

are cis with respect to each other.

KBB-05-70-1-D2O_NOE-16ns-2 5 1 C:\Bruker\TopSpin3.2\data\kbb28\data\kbb28\nmr F1 [ppm] 1 2 3

3.0 2.5 2.0 1.5 1.0 0.5 F2 [ppm]

Figure 3-9: Expanded NOESY of enone 3.27, highlighting the cis relationship of the α-proton and methine proton.

– 103 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Since it was determined that the alcohol and the methyl group are cis to each other, it can be deduced that the major diastereomer resulting from the Grignard addition to aldehyde 3.24 is the

Ψ-endo isomer 3.25 (Fig. 3-10), since the configuration of methine-carbon relative to the Fe(CO)3

Figure 3-10: Assumed relative configurations at the α-carbon of the major isomers 3.25, 3.21, and 3.22. group has already been established from spirocyclization products related to 3.26.29 Recall that there is general agreement of TLC observations between various carbinol-iron complexes, where the Ψ-endo isomers have a higher Rf - value than the Ψ-exo isomer (see Section 3.1.2.1). That information coupled with the observations made on the Grignard additions to aldehyde 3.20 suggests that the major isomers of alcohols 3.21 and 3.22 also have the Ψ-endo configuration.

3.2.1.3 Comparison of Results to Acyclic Series

Comparing the results obtained from the alkyl additions to acyclic substrates reported by

Grée (see Table 3-1), some interesting observations are made. Of the few reactions involving

Grignard reagents in Table 3-1, all of them show modest stereoselectivity with a slight preference for the Ψ-exo isomer. Based on the accepted model outlined in Section 3.1.2.2, the observed results would suggest that a s-cis conformation is adopted. Our observed stereochemistry for the cyclohexadienylcarbaldehyde reaction suggests that the aldehyde substrates prefer s-trans conformation. This is intriguing for a couple of reasons: (1) the steric interaction of the added methylene residues of the cyclohexadiene appears to greatly shift the conformation equilibrium of the aldehyde; and (2) Grignard additions to the cyclic analogs also show an increased selectivity overall, compared with the acyclic derivatives which are less pronounced. The following section will discuss these observations in more detail.

– 104 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

3.2.2 Observed Selectivities from Generic Grignard Additions

At this point, it seems clear that Grignard additions to cyclic carbaldehyde derivatives do not afford the same stereochemistry seen with the acyclic substrates. The argument presented by

Clinton and Lillya concerning the energetic reasons why an eclipsed conformation of the aldehyde would be preferred does not seem to be appropriate for these substrates.

Consequently, we decided to investigate reactions of aldehyde 3.20 with a broader selection of commercially-available Grignard reagents in order to determine if this trend is characteristic of all

Grignard additions to cyclic substrates (Table 3-2).

Table 3-2: Observed selectivities of Grignard additions to aldehyde 3.20 based on the 1H-NMR of the crude products.

Product R Selectivity at 0 °Ca Selectivity at -78 °Cb

3.21 3-Buten-1-yl 8:1 94:6

3.28a Phenyl 4:1 7:1

3.28b Benzyl 15:2 6:1

3.28c Vinyl 7:2 4:1

3.28d Allyl 4:1 4:1

3.28e Methy n/ac n/ac

3.28f i-Propyl 2:1 n/a

a45 minute reaction time; b120 minute reaction time; csee text

Initially, the Grignard reactions were carried out at 0 °C in order to keep the conditions consistent with the additions conducted previously to aldehyde 2.30 en route to the all-carbon spirocycles (see Fig. 3-6). At lower temperature, only a modest improvement was observed in some cases. Nonetheless, the reactions did prove to be reasonably selective, and for the majority of alcohols 3.28 the selectivities were easily observed by analysis of the crude product 1H-NMR.

In many respects, analysis of the crude alcohols 3.28 was easier than for the alcohols from butenylmagnesium bromide addition, since there were more diagnostic peaks present to assist in

– 105 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes diastereomer identification, especially for alcohols 3.28a-d. The methyl alcohol 3.28e was the only Grignard adduct for which it was difficult to measure the selectivity by NMR. Unlike the other alcohols, the two diastereomers of 3.28e do not have a noticeable difference in the shift of their α- proton or of other protons. After separation, the only noticeable difference was between the methyl groups of each diastereomer, but this was insufficient for analysis of the mixture. The best approximation of the selectivity is therefore the mass ratio obtained after separation, which is

~5:1.

Given that characteristic peaks are observed in the 1H-NMR spectrum of the crude products, there are indeed similarities between alcohols 3.28 and the cyclization substrates 3.21, 3.22 and

3.25. Firstly, the major isomer in the crude mixture has an upfield shift of the proton α- to the alcohol compared to the minor isomer. The TLC data also demonstrates that the major isomers of

3.28 have the higher Rf - value, indicating that they all identify as Ψ-endo isomers.

The results obtained for the additions to cyclic dienylcarbaldehyde complexes are indeed compelling. It is interesting that the presence of two extra methylene groups in the cyclic derivatives in contrast to the acyclic complexes can change the outcome of reaction so dramatically. Even more so, the stereoselectivity is completely inverted rather than just enhanced.

Calculations using Gaussian ’09 show that the s-trans conformation is 0.54 kcal/mol lower in energy than the s-cis conformer, which is consistent with the selectivities that are observed (Fig.

3-11).30-31 It is well-established that additions to functionalities in close proximity to the diene-

Fe(CO)3 moiety occur preferentially at the anti-face of the complex, a concept that is not disputed.

However, it seems that further experimental investigations (such as NOE studies) of the aldehyde during these types of additions is required to establish their preferred conformations.

– 106 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

s-Trans (-1223497.97804166 kcal/mol) Bottom-Up View OHC–C=C View

s-Cis (-1223497.43700915 kcal/mol) Bottom-Up View OHC–C=C View

Figure 3-11: Gaussian calculations for the two lowest-energy aldehyde conformations.

– 107 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

3.3 Conclusions

In summary, it appears that as some questions have been answered, more have been raised.

The model that has been used to describe the selectivities we observe from alkyl additions to acyclic dienylcarbaldehyde-Fe(CO)3 complexes does not fit the observation for cyclohexadiene systems. A complete inversion of stereoselectivity is observed for the Grignard additions to the cyclic complexes compared to the acyclic substrates. The stereoselectivity is more pronounced for the cyclic derivatives, a phenomenon that also differs greatly from the acyclic complexes which had only moderate selectivities. While one might have expected a difference between these two systems because of the presence of methylene groups in the cyclic diene, such residues might have been expected to lead to additional that produce a lower favorability for one aldehyde conformer over the other. However, this does not appear to be the case and it is clear that more detailed considerations of such conformational preferences need to be made in future work.

– 108 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

3.4 Experimental Section

1-hydroxy-4-methylspiro[4.5]dec-7-en-8-one (3.27). In a 25-mL round-

bottomed flask containing a magnetic stir bar was added regioisomeric

spiroadducts 2.55 (17 mg, 0.052 mmol) and 100% EtOH (2 mL). Once

dissolved, CuCl2 (excess) was added to the reaction flask, which was then

capped with a glass stopper and was left to stir at room temperature for 20 hours. The reaction flask was then removed from stirring and H2O (2 mL) was added. The organics were then extracted with Et2O (3 x 3 mL) and the combined organic layers were washed with brine (9 mL) and dried over Na2SO4. The solvent was removed to give a clear colorless residue, which was purified via preparative TLC (2:3 EtOAc:hexanes) to afford enone 2.61 in 34%

1 yield (3 mg). Rf = 0.32 (2:3 EtOAc:hexanes). H-NMR (500 MHz, C6D6) δ: 6.15 (dt, J = 10.1, 4.0

Hz, 1H), 6.01 (dt, J = 10.2, 2.2 Hz, 1H), 3.33 (t, J = 7.4 Hz, 1H), 2.44 (d, J = 16.3 Hz, 1H), 2.08 (d,

J = 16.3 Hz, 1H), 1.76 – 1.47 (2H), 1.42 – 1.22 (3H), 1.22 – 1.02 (2H), 0.70 (d, J = 6.7 Hz, 3H),

0.55 (s, 1H). 13C-NMR (126 MHz, C6D6) δ: 198.07, 146.11, 130.12, 80.54, 48.81, 41.49, 37.90,

+ 35.63, 30.41, 28.37, 15.77. HRMS (m/z) M calculated for C11H16O2, 180.1150; found 180.1151.

General procedure for Grignard additions: In a 50-mL three-necked round-bottomed flask containing a magnetic stir bar was dissolved aldehyde 3.20 (75-100 mg, 0.3-0.4 mmol) in anhydrous Et2O (15 mL). The flask was then placed into an ice bath (or CO2/acetone bath) and was flushed with nitrogen for 10 minutes. The Grignard reagent (1.1-1.5 eq.) was then added dropwise to the reaction mixture, which was left to stir at 0 °C for 30 minutes (or -78 °C for 2 hours). The reaction was then quenched with saturated NH4Cl (20 mL) and the aqueous phase was extracted with Et2O (3 x 20 mL). The combined organics were washed with brine (50 mL) and dried over Na2SO4. The solvent was evaporated in vacuo to give a yellow oil, which was purified by preparative TLC.

[1-(Cyclohexa-1,3-dienyl)benzyl alcohol]-Fe(CO)3 (3.28a). 10.6 mg

1 (11%). Rf = 0.54 (9:1 hexanes:EtOAc). H-NMR (500 MHz, CDCl3) δ:

7.42 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (d, J = 7.5 Hz,

– 109 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

1H), 5.62 (d, J = 4.3 Hz, 1H), 5.26 – 5.20 (m, 1H), 4.73 (s, 1H), 3.19 (dt, J = 6.3, 3.1 Hz, 1H), 1.94

– 1.83 (2H), 1.78 (ddt, J = 15.2, 11.6, 3.5 Hz, 1H), 1.61 – 1.52 (m, 1H), 1.04 (ddd, J = 14.4, 8.5,

13 3.2 Hz, 1H). C-NMR (100 MHz, CDCl3) δ: 211.95, 142.54, 128.27, 127.56, 125.68, 86.74, 86.23,

+ 82.56, 79.19, 62.38, 24.21, 21.27. HRMS (m/z) M calculated for C16H14O4Fe, 326.0241; found

326.0243.

[1-(Cyclohexa-1,3-dienyl)-2-phenylethanol]-Fe(CO)3 (3.28b). 36

1 mg (26%). Rf = 0.81 (8:2 hexanes:EtOAc). H-NMR (500 MHz,

CDCl3) δ: 7.34 (t, J = 7.4 Hz, 2H), 7.30 – 7.20 (3H), 5.24 (d, J = 4.4

Hz, 1H), 5.14 (dd, J = 6.4, 4.4 Hz, 1H), 3.79 (ddd, J = 7.7, 4.9, 2.0

Hz, 1H), 3.17 (dt, J = 6.4, 3.0 Hz, 1H), 3.01 (dd, J = 13.5, 4.8 Hz, 1H), 2.84 (dd, J = 13.5, 8.7 Hz,

1H), 2.03 (ddd, J = 14.5, 11.5, 3.0 Hz, 1H), 1.87 (ddt, J = 15.2, 11.5, 3.7 Hz, 1H), 1.74 (ddd, J =

13 15.2, 8.4, 3.0 Hz, 1H), 1.51 (ddd, J = 14.5, 8.4, 3.7 Hz, 1H). C-NMR (100 MHz, CDCl3) δ:

212.13, 138.23, 129.31, 128.74, 126.73, 85.93, 85.53, 82.05, 78.20, 61.68, 43.55, 24.47, 21.91.

+ HRMS (m/z) M calculated for C17H16O4Fe, 340.0398; found 340.0402.

[1-(Cyclohexa-1,3-dienyl)-2-propen-1-ol]-Fe(CO)3 (3.28c). 14.0 mg

1 (17%). Rf = 0.64 (8:2 hexanes:EtOAc). H-NMR (500 MHz, CDCl3) δ:

5.93 (ddd, J = 17.0, 10.3, 6.7 Hz, 1H), 5.49 (d, J = 4.3 Hz, 1H), 5.28 (d,

J = 17.0 Hz, 1H), 5.24 – 5.16 (2H), 4.14 (dd, J = 6.7, 2.6 Hz, 1H), 3.17

(dt, J = 6.8, 2.9 Hz, 1H), 1.89 – 1.73 (m, 2H), 1.72 – 1.62 (m, 1H), 1.59

13 (d, J = 3.3 Hz, 1H), 1.41 – 1.34 (m, 1H). C-NMR (100 MHz, CDCl3) δ: 212.10, 139.79, 115.97,

+ 85.01, 84.60, 82.09, 77.81, 61.59, 24.09, 22.57. HRMS (m/z) M calculated for C12H12O4Fe,

276.0085; found 276.0076.

[1-(Cyclohexa-1,3-dienyl)-3-buten-1-ol]-Fe(CO)3 (3.28d). 23.9 mg

1 (27%). Rf = 0.51 (8:2 hexanes:EtOAc). H-NMR (500 MHz, CDCl3)

δ: 5.84 (dddd, J = 17.9, 9.9, 8.0, 6.4 Hz, 1H), 5.42 (d, J = 4.4 Hz,

1H), 5.23 – 5.17 (2H), 5.16 (s, 1H), 3.61 (ddd, J = 7.4, 4.4, 2.3 Hz,

– 110 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

1H), 3.20 – 3.14 (m, 1H), 2.49 (dt, J = 12.8, 5.5 Hz, 2H), 2.31 (dt, J = 12.8, 8.3 Hz, 2H), 1.91

(ddd, J = 13.8, 11.4, 2.6 Hz, 1H), 1.83 (ddt, J = 15.1, 11.4, 3.3 Hz, 1H), 1.71 (ddt, J = 12.0, 8.4,

2.6 Hz, 1H), 1.65 (d, J = 2.3 Hz, 1H), 1.38 (ddd, J = 13.8, 8.4, 3.3 Hz, 1H). 13C-NMR (100 MHz,

CDCl3) δ: 212.07, 134.78, 118.45, 85.96, 85.79, 82.08, 75.97, 61.76, 41.63, 24.43, 21.72. HRMS

+ (m/z) M calculated for C13H14O4Fe, 290.0241; found 290.0242.

[1-(cyclohexa-1,3-dienyl)ethanol]-Fe(CO)3 (3.28e). 23.0 mg (29%). Rf

1 = 0.47. H-NMR (500 MHz, CDCl3) δ: 5.42 (d, J = 4.4 Hz, 1H), 5.20 (dd,

J = 6.6, 4.4 Hz, 1H), 3.85 (q, J = 6.4 Hz, 1H), 3.21 – 3.14 (m, 1H), 1.93 –

1.78 (2H), 1.76 – 1.65 (m, 1H), 1.47 – 1.39 (2H), 1.37 (d, J = 6.4 Hz,

13 3H). C-NMR (100 MHz, CDCl3) δ: 212.18, 88.39, 85.38, 81.97, 72.74,

+ 61.80, 24.23, 23.27, 21.60. HRMS (m/z) M calculated for C11H12O4Fe, 264.0085; found

290.0078.

[1-(Cyclohexa-1,3-dienyl)-2-methyl-1-propanol]-Fe(CO)3 (3.28f).

1 10.0 mg (11%). Rf = 0.63 (8:2 hexanes:EtOAc). H-NMR (500 MHz,

CDCl3) δ: 5.34 (d, J = 4.5 Hz, 1H), 5.21 (dd, J = 4.5, 1.1 Hz, 1H), 3.19

(ddd, J = 6.4, 4.3, 2.5 Hz, 1H), 2.95 (dd, J = 9.5, 2.3 Hz, 1H), 1.96

(ddd, J = 14.6, 11.4, 3.1 Hz, 1H), 1.84 (ddt, J = 15.1, 11.5, 3.6 Hz, 1H),

1.74 (ddt, J = 15.4, 11.9, 7.6 Hz, 2H), 1.47 (d, J = 2.7 Hz, 1H), 1.31 (ddd, J = 14.8, 8.4, 3.5 Hz,

13 1H), 1.05 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H). C-NMR (100 MHz, CDCl3) δ: 211.94,

88.01, 87.47, 84.08, 81.99, 62.39, 31.96, 24.79, 20.50, 20.33, 19.27. HRMS (m/z) M+ calculated for C13H16O4Fe, 292.0398; found 292.9826.

– 111 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

3.5 References

1. Pearson, A. J., Organoiron Compounds in Stoichiometric Organic Synthesis. In Comprehensive Organometallic Chemistry : The Synthesis, Reactions, and Structures of Organometallic Compounds, 1st ed.; Wilkinson, G.; Stone, F. G. A.; Abel, E. W., Eds. Pergamon Press: Oxford Oxfordshire ; New York, 1982; Vol. 8, pp 939-1012.

2. Pearson, A. J., Metallo-Organic Chemistry. Wiley: Chichester West Sussex ; New York, 1985; p 1-398.

3. Pearson, A. J., Iron Compounds in Organic Synthesis. Academic Press: London ; San Diego, 1994; p 1-201.

4. Clinton, N. A.; Lillya, C. P., Conformational Analysis of Tricarbonyl(Diene)Iron Compounds. J. Am. Chem. Soc. 1970, 92 (10), 3058-&.

5. Banthorpe, D. V.; Fitton, H.; Lewis, J., Isomerization and Addition-Reactions of Some Monoterpene-Tricarbonyliron Complexes. J. Chem. Soc. Perkin Trans. 1. 1973, (19), 2051-2057.

6. Barton, D. H. R.; Patin, H., Chemistry of Tricarbonyliron Complexes of Calciferol and Ergosterol. J. Chem. Soc. Perkin Trans. 1. 1976, (8), 829-831.

7. Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.; Patin, H.; Widdowson, D. A.; Worth, B. R., Synthetic Uses of Steroidal Ring B Diene Protection: 22,23-Dihydroergosterol. J. Chem. Soc. Perkin Trans. 1. 1976, (8), 821-826.

8. Pearson, A. J.; Ong, C. W., Organoiron Complexes in Organic-Synthesis. Part 15. Stereocontrolled Approach to Trichothecane Derivatives Via Tricarbonylcyclohexadieneiron Complexes - Synthesis of a Key Intermediate. Tetrahedron Lett. 1980, 21 (48), 4641-4644.

9. Bandara, B. M. R.; Birch, A. J.; Raverty, W. D., Organo-Metallic Compounds in Organic- Synthesis. Part 14. Tricarbonyliron as Lateral Control-Group in the Selective Alkaline-Hydrolysis of Some Cyclohexa-1,3-Diene Carboxylic Esters. J. Chem. Soc. Perkin Trans. 1. 1982, (8), 1763-1769.

10. Benvegnu, T.; Martelli, J.; Grée, R.; Toupet, L., Diels-Alder Reactions on Linear Polyenes, Selectively Protected as Their Tricarbonyl-Iron Complexes. Tetrahedron Lett. 1990, 31 (22), 3145-3148.

11. Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N., An Iron Carbonyl Approach to the Influenza Neuraminidase Inhibitor Oseltamivir. Chem Commun (Camb) 2007, (30), 3183-3185.

12. ten Broeke, M.; Khan, M. A.; Kociok-Kohn, G.; Kann, N.; Lewis, S. E., Tricarbonyliron(0) Complexes of Bio-Derived Eta(4) Cyclohexadiene Ligands: An Approach to Analogues of Oseltamivir. J. Organomet. Chem. 2015, 799-800, 19-29.

13. Gree, R.; Laabassi, M.; Mosset, P.; Carrie, R., Enantioselective Synthesis of E,E-Diene Alcohols and Ethers. Tetrahedron Lett. 1984, 25 (34), 3693-3696.

14. Lellouche, J. P.; Breton, P.; Beaucourt, J. P.; Toupet, L.; Gree, R., Synthesis in the Butadiene-Iron Tricarbonyl Series. Tetrahedron Lett. 1988, 29 (20), 2449-2452.

15. Grée, R., Acyclic Butadiene Iron Tricarbonyl Complexes in Organic-Synthesis. Synthesis- Stuttgart 1989, (5), 341-355.

16. Roush, W. R.; Park, J. C., Asymmetric Allylborations of Diene Aldehyde Fe(CO)3 Derivatives - Efficient Kinetic Resolution of Racemic Complexes and the Highly Enantiotopic

– 112 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Group and Face Selective Allylboration of a Meso Substrate. Tetrahedron Lett. 1990, 31 (33), 4707-4710.

17. Benvegnu, T. J.; Toupet, L. J.; Gree, R. L., Stereoselective Synthesis of Macrolactin A Analogues. Part 1. The C-7-C-20 Fragment. Tetrahedron 1996, 52 (36), 11811-11820.

18. Cox, L. R.; Ley, S. V., Tricarbonyliron Complexes: An Approach to Acyclic Stereocontrol. Chem. Soc. Rev. 1998, 27 (5), 301-314.

19. Takemoto, Y.; Yoshikawa, N.; Baba, Y.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H., Utility of a Diene-Tricarbonyliron Complex as a Mobile Chiral Auxiliary: Regio- and Stereocontrolled Functionalization of Acyclic Diene Ligands. J. Am. Chem. Soc. 1999, 121 (39), 9143-9154.

20. Hill, E. A.; Richards, J. H., Carbonium Ion Stabilization by Metallocene Nuclei. Part 3. Evidence for Metal Participation. J. Am. Chem. Soc. 1961, 83 (20), 4216-4221.

21. Kuhn, D. E.; Lillya, C. P., Tricarbonyl(Trans-Pi-Pentadienyl)Iron Cations - Solvolysis Stereochemistry. J. Am. Chem. Soc. 1972, 94 (5), 1682-1688.

22. Erskine, R. L.; Waight, E. S., Stereochemistry and Infrared Spectra of Α--Beta- Unsaturated Ketones. J. Chem. Soc. 1960, (Sep), 3425-3431.

23. Karabats, G. J.; Hsi, N., Structural Studies by Nuclear Magnetic Resonance. Part X. Conformations of Aliphatic Aldehydes. J. Am. Chem. Soc. 1965, 87 (13), 2864-2870.

24. Eliel, E. L., Conformational Analysis. Interscience Publishers: New York,, 1965; pg 19-22.

25. Ley, S. V.; Cox, L. R.; Meek, G.; Metten, K. H.; Pique, C.; Worrall, J. M., 1,5-Asymmetric Induction of Chirality: Highly Diastereoselective Addition Reactions of Organoaluminium Reagents into Ketone Groups in the Side-Chain of Pi-Allyltricarbonyliron Lactone Complexes. J. Chem. Soc. Perkin Trans. 1. 1997, (22), 3299-3313.

26. Anson, C. E.; Attwood, M. R.; Raynham, T. M.; Smyth, D. G.; Stephenson, G. R., More Efficient Iterative Uses of Tricarbonyliron Complexes are Possible by Diastereoselective Formation of Eta(5)-Cyclohexadienyl Complexes. Tetrahedron Lett. 1997, 38 (4), 505-508.

27. Jablonski, C. R.; Sorensen, T. S., Acid-Catalyzed Rearrangements of Structurally Constrained Tricarbonyl(Trans-Pentadienyl)Iron Cations. Can. J. Chem. 1974, 52 (11), 2085-2097.

28. Kim, E. H. A New Synthetic Pathway for Diquinane and Angular Triquinane Systems. Thesis, Case Western Reserve University, 2010. Ph.D.

29. Pearson, A. J.; Zettler, M.; Pinkerton, A. A., Intramolecular Ene-Type Reaction between a Diene-Fe(Co)3 Complex and Alkene Units. J. Chem. Soc. Chem. Comm. 1987, (4), 264-266.

30. Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E., Optimization of Gaussian-Type Basis-Sets for Local Spin-Density Functional Calculations .1. Boron through Neon, Optimization Technique and Validation. Can. J. Chem. 1992, 70 (2), 560-571.

31. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;

– 113 – Chapter 3 Grignard Additions to Dienylcarbaldehyde Complexes

Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision E.01, Gaussian, Inc., Wallingford CT, 2009.

– 114 – CHAPTER FOUR

CONCLUSIONS AND FUTURE WORK Chapter 4 Conclusions and Future Works

4.1 Conclusions

The ene-type cyclization reaction from diene-Fe(CO)3 complexes has proven to be very effective in the formation of stereo-defined spiro- and tricyclic frameworks. However, formation of such frameworks containing an all-carbon backbone has proven to be more difficult, as the respective cyclizations have only been successful from substrates containing a simple pendant olefin. One possible explanation for this observation is the electronic nature of the diene-Fe(CO)3 system is changed just enough in the alcohol derivatives (compared to the amide analogs) to the point where the cyclization reaction is much slower, allowing side reactions to compete. Another possible explanation could be since there is probably free rotation about the bond linking the diene-Fe(CO)3 complex to the ketone or the alcohol, the pendant olefin may not prefer to be in close proximity to the iron on a steric basis. If one could increase the steric substitution at the carbon beta- to the diene-Fe(CO)3 complex or on the alcohol by means of a protecting group, perhaps cyclization could be induced as a result of conformational change as observed with the amide derivatives.

Alkyl additions to cyclohexadienylcarbaldehyde-Fe(CO)3 complexes have also proven to give interesting results, which suggest that the cyclic dienylcarbaldehyde systems deviate from the selectivities observed in the acyclic derivatives. Evidence suggests that the cyclohexa-1,3- dienylcarbaldehyde complexes prefer an s-trans conformation of the aldehyde, whereas the acyclic substrates prefer a s-cis conformation. However, as Grée has mentioned, the observed selectivities depend on multiple variables — temperature, the nature of the metal counter cation and the presence (or absence) of Lewis acids.1 More work is needed in order to determine if the observed selectivities are indeed due to a preferred aldehyde conformation or not.

4.2 Future Work

In regards to the ene-type cyclizations from diene-Fe(CO)3 complexes, a couple of other synthetic routes could still be investigated. A spirocycle without any functionality at the α-position may be obtained by using 4-phenylbutyric acid (4.4) as a substrate (Scheme 4-1). Thus, the cyclization of a diene-Fe(CO)3 complex such as 4.2 would be interesting since there is no electron-withdrawing functionality directly attached to the diene system. Investigating similar systems with a higher-substituted pendant olefin may also provide insight into whether or not the

– 116 – Chapter 4 Conclusions and Future Works

Scheme 4-1: Retrosynthetic approach to all-carbon spriocycle 4.1.

electronic nature of the diene-Fe(CO)3 complex is an important factor for the cyclization reaction to occur.

Another possible substrate that could be used to investigate the iron-mediated ene-type cyclizations is phenylhydrazone 4.5. Having the phenylhydrazone group present still offers another means to investigate a different class of an all-carbon cyclization while also providing the capability of post-cyclization functional group transformation. It may also provide some insight into the electronic effect of having a less electron-withdrawing substituent attached to the diene terminus. The preparation of 4.5, however, could be difficult, as it has been demonstrated with the alcohol derivatives that the carbon alpha- to the diene-Fe(CO)3 system is in a sterically congested region.

To compliment the work done on the Grignard additions to (cyclohexa-1,3-dienyl- carbaldehyde)-Fe(CO)3, it would be interesting to do a full comparison with Grée’s work on the acyclic series by studying additions using alkyllithium reagents. Using alkylating reagents that contain a metal with increased Lewis-acidic character (i.e. aluminum, titanium, etc.) would also be of great interest.

– 117 – Chapter 4 Conclusions and Future Works

4.3 References

1. Grée, R., Acyclic Butadiene Iron Tricarbonyl Complexes in Organic-Synthesis. Synthesis- Stuttgart 1989, (5), 341-355.

– 118 – APPENDIX

NMR & IR SPECTRA Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 120 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 121 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 122 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 123 – Appendix NMR and IR Spectra

– 124 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 125 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 126 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 127 – Appendix NMR and IR Spectra

Infrared Spectrum

– 128 – Appendix NMR and IR Spectra

1 H-NMR (400 MHz, CDCl3)

13 C-NMR (100 MHz, CDCl3)

– 129 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 130 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 131 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 132 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, C6D6)

13 C-NMR (125 MHz, C6D6)

– 133 – Appendix NMR and IR Spectra

COSY (500 MHz, C6D6)

NOESY (500 MHz, C6D6)

– 134 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 135 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 136 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 137 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 138 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 139 – Appendix NMR and IR Spectra

1 H-NMR (500 MHz, CDCl3)

13 C-NMR (125 MHz, CDCl3)

– 140 – BIBLIOGRAPHY Bibliography

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