Cationic cyclizations of iron tricarbonyl diene complexes

with pendant alkenes and arenes

by

Victor P. Ghidu

Submitted in partial fulfillment of the requirements

for the degree of Doctor of Philosophy

Thesis advisor: Dr. Anthony J. Pearson

Department of Chemistry

CASE WESTERN RESERVE UNIVERSITY

January, 2005 CASE WESTERN RESERVE UNIVERSITY

SCHOOL OF GRADUATE STUDIES

We hereby approve the dissertation of

______

candidate for the Ph.D. degree *.

(signed)______(chair of the committee)

______

______

______

______

______

(date) ______

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

In memoriam Emilian Ghidu.

TABLE OF CONTENTS

List of Tables………………………………………………………………………..……vi

List of Figures………………………………………………………………...………….vii

Acknowledgments……………………………………………………………………....viii

List of Abbreviations…………………………………………………………………...... ix

Abstract……………………………………………………………………………...……xi

Chapter 1. Iron tricarbonyl diene complexes - general introduction……………...…1

1.1 Preparation of iron tricarbonyl diene complexes…………………………………...…3

1.2 Synthetic relevance of iron tricarbonyl diene complexes……………………………..5

1.3 Literature cited…………………………………………………...……………………9

Chapter 2. Cationic cyclizations of iron tricarbonyl diene complexes with pendant alkenes and arenes……………………………………….....16

2.1 Introduction. Stabilized acyclic iron tricarbonyl pentadienyl cations……………….17

2.2 Cyclization reactions of iron tricarbonyl pentadienyl cation with pendant nucleophiles……………………………………………………………….…….25

2.3 Studies on pendant alkenes with an increased substitution pattern………………….34

2.4 A new method for the cationic cyclizations of iron tricarbonyl stabilized pentadienyl carbocation with pendant alkenes and arenes…………………………...….37

2.5 Conclusions…………………………………………………………………………..49

2.6 Experimental section…………………………………………………………………50

2.7 Literature cited……………………………………………………………………….64

iv Chapter 3. Iron tricarbonyl pentadienyl cation as initiator for cascade polycyclization reactions……………………………………………………...70

3.1 Introduction to tandem bicyclizations. Biosynthetic relevance……………………...71

3.2 Polyene bicyclizations using iron tricarbonyl stabilized pentadienyl carbocation as initiator – a new method…………………………………………………76

3.2.1 Synthesis of polyene substrates…………………………………………....77

3.2.2 Cyclization studies……………………………………………………...….80

3.2.3 Stereochemistry assignment using 1D and 2D 1H-NMR…………………..87

3.3 Conclusions…………………………………………………………….…………….92

3.4 Experimental section…………………………………………………………………92

3.5 Literature cited………………………………………………………...……………103

Appendix. NMR Spectra of new compounds……………………………………..…111

Bibliography…………………………………………………………………………...150

v List of Tables

Table 2.1 Substrates with a pendant olefinic nucleophile…………………….………41

Table 2.2 Substrates with a pendant aromatic / heteroaromatic nucleophile…………46

Table 3.1 Demetallation of double cyclization products...……………………………86

Table 3.2 Diagnostic hydrogen resonances for compound 3.50d………………….....91

vi List of Figures

Figure 1.1 Zeise’s salt………………………………………………………………….….2

Figure 1.2 Enantiomerically pure iron tricarbonyl diene complexes obtained as such from enantiomerically pure diene precursors………………………………….….4

Figure 1.3 Iron tricarbonyl group restricts access to a neighboring group…………..……7

Figure 1.4 Iron atom can stabilize a neighboring cation……………………………….….8

Figure 2.1 Ψ-endo/exo diastereoisomers………………………………………………...21

Figure 2.2 Two key intermediates in the total synthesis of (+)-Ikarugamycin…………..25

Figure 2.3 A possible explanation for preferred

6- over 5-membered ring cyclization………………………………………………….…31

Figure 2.4 Poor economy due to low selectivity of the Grignard addition ……………...38

Figure 2.5 1H-NMR stereochemistry assignment for compound 2.103b………………...43

Figure 3.1 Diagnostic hydrogen resonances for the bicyclization product stereochemistry assignment………………………………………87

Figure 3.2 Overlapping resonances of interest in the metal complex …………………...88

Figure 3.3 Diagnostic cross peaks for H1-H5’ and H1’-H2’ interactions ….……………...89

Figure 3.4 Diagnostic cross peaks for H2’-H3’, H3’-H4’ and H4’-H5’ interactions …...…...89

Figure 3.5 Diagnostic cross peaks for H1-H4a, H1-H10a and H4a-H10a interactions…..…...90

vii Acknowledgments

I thank Professor Anthony Pearson for giving me the chance to work under his patient guidance, for sharing with me and my colleagues his, apparently, infinite knowledge of chemistry, for his everyday example of professionalism and work ethic.

I thank my best friend Titus for encouraging me to take this step and for so many other things, it would take another tome to tell the story. I thank Eugen for his generous help and encouragement during my first two years at Case.

Many thanks to all the group members, past and present, for sharing with me their knowledge of chemistry and for making this period fun and interesting. Special thanks to

Wenjing for tolerating me and my stupid music so well, Sheng (no, you are so smart!),

Jin Bum (the loading dock was so empty after you left!!!), Brian for being my American friend.

I thank the “Romanian community” for all their help and support. Thanks Simona and Attila for being my family away from my family and for keeping your door always open for me.

I thank my little sister, Rodica, for supporting my decision and for filling in for me while I’m away.

I thank my parents for their encouragement (you only cried a little when I left and that helped a lot), for overcoming so many difficulties and offering me and my sister the best childhood ever. I got here only because of you.

viii List of Abbreviations

Ac acetyl

9-BBN 9-borabicyclo[3.3.1]nonane borsm based on reacted starting material

CAN cerium ammonium nitrate cat. catalytic

COSY correlation spectroscopy

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

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de diastereomeric excess

DIBAL-H diisobutylaluminum hydride

DMF N,N-dimethylformamide eq. equation equiv. equivalent

Et ethyl

GC-MS gas chromatography- mass spectroscopy

HRMS high resolution mass spectroscopy

IR infrared

Me methyl

MHz megahertz mL milliliter m.p. melting point

ix n normal

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

Nu- nucleophile

[ox] oxidation

PCC pyridinium chlorochromate ppm parts per million psi pounds per square inch

Py pyridine

Rf retention factor

rt room temperature

s singlet

s-cis single cis

SN nucleophilic substitution

s-trans single trans

TBAF tetrabutylammonium fluoride

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilane pTs para toluenesulfonyl

UV ultraviolet

x Cationic cyclizations of iron tricarbonyl diene complexes

with pendant alkenes and arenes.

Abstract

by

Victor P. Ghidu

A new method for cationic cyclization of iron tricarbonyl diene complexes with

pendant alkenes and arenes is presented, improving an earlier method developed in the

Pearson laboratory, both in terms of economy and reactivity. Previously reported dehydroxylation of diastereomeric alcohols is replaced by regiospecific protonation of a double bond adjacent to the iron tricarbonyl diene moiety (both processes occur with anchimeric assistance from the iron atom).

(OC)3Fe (OC)3Fe (OC)3Fe OH H+ / Lewis acid Nu or Nu Nu

(OC)3Fe (OC)3Fe H+ Nu Nu

The method was tested in a simple synthetic application: bicyclization of polyene

substrates toward octahydrophenanthrene derivatives. Complete diastereoselectivity and

adherence to the Stork-Eschenmoser postulate was observed.

R R

(OC)3Fe (OC)3Fe R H+ [ox]

xi

Chapter 1.

Iron tricarbonyl diene complexes - general introduction.

- 1 -

In 1825 Danish chemist William Christopher Zeise reported that on adding KCl to

a concentrated solution of PtCl4 in ethanol, beautiful lemon-yellow crystals are obtained.

Along with considerations on the physical and chemical properties of this substance, he noted that it has a “metallic, astringent and long lasting taste”! It would take about 35 years for this compound to be confirmed as an adduct of platinum and ethylene (Fig. 1.1), and another 100 years for the first X-ray structure. Despite disagreement by some major

- Cl Cl Pt Cl K+

H2CCH2

Fig. 1.1 Zeise’s salt names of the day (Justus Liebig among others), Zeise suggested he had prepared a compound of PtCl2 and “olefiant gas”. He must be therefore credited with the first organometallic compound ever to be synthesized.1

Organometallic chemistry has come a long way since those days, in terms of compound variety, preparation methods, end uses and characterization methods. It is today mainstream chemistry, with numerous compounds used on industrial scale or in research, catalytically as well as stoichiometrically. The work described in this thesis belongs to the field of stoichiometric applications of organometallic complexes in organic synthesis,2,3 iron tricarbonyl diene complexes in particular.4 Hereafter we are going to present some basic concepts related to these complexes, in preparation for a detailed account of a new synthetic method to be presented in Chapters 2 and 3.

- 2 -

1.1 Preparation of iron tricarbonyl diene complexes.

Under various conditions, poly-carbonylated iron complexes, such as Fe(CO)5

and Fe2(CO)9 can react with an acyclic (1.1) or cyclic (1.3) diene, to afford iron tricarbonyl diene complexes (Scheme 1.1). These are Fe(0) complexes with an 18e-

count.5

(OC)3Fe Fe (CO) R2 x y R1 R1 R2 1.1 1.2 (OC)3Fe Fex(CO)y

R3 R3 1.4 1.3 x = 1, y = 5 x = 2, y = 9

Scheme 1.1

Of particular interest to us is the iron tricarbonyl complex of sorbaldehyde, 1.6.

We found the recent method for its preparation shown in eq. 1.1 to be highly appealing in terms of economy, ease of setup and workup.6

Fe2(CO)9 on silicagel 85°C, 2h (OC)3Fe O (1.1) 1.5 CHO 73% 1.6

Most of the diene precursors of these complexes are enantiotopic compounds, and

the product of the complexation reaction is a racemic mixture (eq. 1.2). It is the ultimate goal of using this methodology to employ enantiomerically pure complexes.

O O O O O O Fe (CO) Fe Fe (1.2) X 2 9 + 1.7 X X 1.8 1.9

- 3 -

A number of methods are employed to prepare enantiomerically pure iron

tricarbonyl diene complexes, including: complexation of optically pure ligands (Fig.

1.2),7-10 chromatographic separation of diastereomeric complexes,11,12 kinetic

resolution,13-15 or desymmetrization of meso complexes.16-19

(OC)3Fe O BzO Fe(CO) 3 Fe(CO)3 O N O HO CO2Et 1.10 1.12 1.11 Ph Ph

Fig. 1.2 Enantiomerically pure iron tricarbonyl diene complexes obtained

as such from enantiomerically pure diene precursors.

Iron tricarbonyl complexes of cyclic dienes such as 1.13 (Scheme 1.2), are one of the main groups of these compounds. On treatment with trityl cation they afford stable compounds 1.14 which on treatment with a nucleophile afford compounds 1.15.

Numerous studies have been devoted to this type of chemistry, and a number of reviews are available.20-22

(OC) Fe (OC)3Fe (OC)3Fe 3 - + - - Nu Ph3C X X - - - X = BF4 , PF6 Nu 1.13 1.14 1.15

Scheme 1.2

The chemistry of iron tricarbonyl cyclic diene complexes is fascinating and it has

found its way into organic synthesis in numerous ways.4 The Pearson group in particular

developed a very interesting iron carbonyl mediated olefin/diene coupling reaction,23-27 and a cyclocarbonylation reaction to afford cyclopentadienones,28-30 both reactions with

very promising synthetic applications. However, as we proceed to discuss a few more

- 4 -

generalities on iron tricarbonyl diene complexes, the focus will be on acyclic complexes

(except for two examples), as these are the focus of the research described later.

1.2 Synthetic relevance of iron tricarbonyl diene complexes.

There are several ways to use these complexes in organic synthesis:

- protecting groups for conjugated dienes;

- activation of dienes toward nucleophile addition;

- stabilization of reactive dienes (relevant mainly for antiaromatic cyclic dienes);

- to direct a chemical transformation at a center adjacent to the diene moiety by

means of a) steric hindrance and/or b) electronic participation;

As a protecting group, the iron tricarbonyl group is unreactive toward a variety of reagents. As long as a high yielding, selective complexation/decomplexation sequence can be performed on the diene of interest, unprotected olefinic moieties in the same molecule can be selectively transformed. Representative transformations include hydroboration and dihydroxylation (Scheme 1.3).4,31

(OC)3Fe

1) BH3 2) H O , NaOH (OC)3Fe 2 2 1.17 OH

1.16

OsO (OC)3Fe 4 OH

1.18 OH

Scheme 1.3

- 5 -

Complexation to zerovalent iron lowers the electron density in a diene, increasing

its reactivity toward nucleophiles. Complex 1.19 of butadiene reacts with 2-lithio-

isobutyronitrile, followed by acid mediated demetallation to afford new carbon-carbon

bonds in a fairly selective manner (eq. 1.3).32,33

CMe2CN

CMe2CN (OC)3Fe 1.22 6% 1) LiCMe CN 1.20 89% 2 (1.3) + 2) H CMe CN 1.19 2 CMe2CN 1.21 4% 1.23 1%

On the other hand, complexation to iron stabilizes highly reactive, antiaromatic dienes such as cyclobutadiene and cyclopentadienone (Scheme 1.4).34-36

Cl Cl Fe(CO)3 Fe2(CO)9

1.24 1.25

TMS Fe(CO)5, CO 100 psi, TMS toluene, 125-130 °C O TMS (OC) Fe TMS 1.26 3 1.27

Scheme 1.4

It is the use of the iron tricarbonyl diene moiety as a stereochemical controller,

however, which established it as a powerful synthetic tool. Depicted in a schematic way

in Fig. 1.3 is the hypothesis behind this application. Reaction center “C=X”, adjacent to

the iron tricarbonyl diene moiety, should be accessible only from the direction opposite to

the iron tricarbonyl group with respect to the diene plane. If “C=X” is a diastereotopic

group, such as an aldehyde or ketone, then the reaction is expected to occur with

- 6 -

diastereoselectivity. If the starting complex is enantiomerically pure (see eq. 1.2), then the reaction on adjacent center “C=X” is expected to occur enantiospecifically. Once the stereospecific transformation is accomplished, the iron tricarbonyl group can be removed, typically by an oxidative protocol.

Y

O O O O new stereocenter O O Fe Fe H H Y [ox] H Y X X X

Y

Fig. 1.3 Iron tricarbonyl group restricts

access to a neighboring group.

Shown below is an example of stereocontrol achieved by using an iron tricarbonyl group. Cyclocondensation of 1-methoxy-3-trimethylsilyloxy-1,3-butadiene 1.28 with iron tricarbonyl dienylimine complex 1.29, afforded dehydropiperidone 1.30 in > 95% de

(Scheme 1.5).37,38 In the absence of the iron tricarbonyl group, a mixture of enantiomers

(1.32 + 1.33) is obtained.

- 7 -

new stereocenter

OTMS

(OC)3Fe O (OC)3Fe 1.29 H OMe N NO 1.30 1.28 LiClO4 > 95% de

O

O O

H H O N N

N 1.32 + 1.33 1.31

O O

Scheme 1.5

Sometimes the stereochemical outcome of a reaction at the center adjacent to the iron tricarbonyl diene moiety is complicated by the conformations that a particular functionality may adopt (s-cis / s-trans). More examples and a detailed discussion can be found in Chapter 2.

The crucial concept to be addressed in the discussion of the new synthetic methodology we are proposing in this work is that of stabilization of carbocations by neighboring group participation. It is documented that a successful group may be a transition metal, in our case iron, which stabilizes the carbocation by means of a filled d orbital (Fig. 1.4).39-42

(OC)3Fe H

X

Fig. 1.4 Iron atom can stabilize a neighboring cation.

- 8 -

A detailed discussion on neighboring group participation / anchimeric assistance and reactivity implications will follow in Chapter 2.

As already shown in Fig.1.3, liberation of the diene ligand may be effected by means of an oxidant. Useful reagents for this transformation are: FeCl3, CuCl2,

43-46 (NH4)2Ce(NO2)6 [CAN], Me3NO, DDQ.

In the following chapters we are going to present a more detailed account of the chemistry of iron tricarbonyl stabilized pentadienyl cations, earlier contributions of our laboratory to this chemistry and finally, a new method for cyclizations of iron tricarbonyl stabilized pentadienyl cations with pendant alkenes and arenes.

1.3 Literature cited.

(1) Seyferth, D. "[(C2H4)PtCl3](-), the anion of Zeise's salt,

K[(C2H4)PtCl3]·H2O." Organometallics 2001, 20, 2-6.

(2) Harrington, P. J. Transition Metals in Total Synthesis; John Wiley and

Sons, Inc.: New York, 1990.

(3) Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic

Molecules; Second ed.; University Science Books: Mill Valley, CA, 1994.

(4) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press

Inc.: San Diego, CA, 1994.

(5) The Organic Chemistry of Iron; Academic Press: New York, 1978.

- 9 -

(6) Docherty, G. F.; Knox, G. R.; Pauson, P. L. "A rapid and convenient

method for the formation of (diene)Fe(CO)3 complexes." J. Organomet. Chem. 1998,

568, 287-290.

(7) 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, 6326-6343.

(8) Schmalz, H. G.; Hessler, E.; Bats, J. W.; Durner, G. "An Approach to

Chiral η-4-Butadiene-Fe(Co)3 Complexes Via Diastereoselective Complexation of

Nonracemic 2-Alkoxy-4-Vinyl- 2,5-Dihydrofuran Derivatives." Tetrahedron Lett. 1994,

35, 4543-4546.

(9) Pearson, A. J.; Chang, K.; McConville, D. B.; Youngs, W. J. "Chiral-

Auxiliary-Directed Asymmetric Tricarbonyliron Complexation of Dienes."

Organometallics 1994, 13, 4-5.

(10) Salzer, A.; Schmalle, H.; Stauber, R.; Streiff, S. "Optically-Active

Transition-Metal Complexes .1. Iron, Cobalt and Rhodium Complexes of the Optically-

Active Diolefin (+)- Nopadiene and Its Derivatives - the Crystal-Structure of

C5me5rh(Nopadiene)." J. Organomet. Chem. 1991, 408, 403-424.

(11) Franck-Neumann, M.; Briswalter, C.; Chemla, P.; Martina, D. "An

Efficient and Simple Synthesis of Functionalized and Unfunctionalized Enantiomerically

Pure Diene-Iron Tricarbonyl Complexes." Synlett 1990, 637-640.

- 10 -

(12) Nakanishi, S.; Kumeta, K.; Nakanishi, J.; Takata, T. "Preparation and

Resolution of η-4-1,3-Dienecarboxylic Acid)Fe(CO)3 Complexes." Tetrahedron:

Asymmetry 1995, 6, 2097-2100.

(13) Uemura, M.; Nishimura, H.; Yamada, S.; Hayashi, Y.; Nakamura, K.;

Ishihara, K.; Ohno, A. "Kinetic Resolution of Hydroxymethyl-Substituted

(Arene)Cr(CO)3 and (Diene)Fe(CO)3 by Lipase." Tetrahedron: Asymmetry 1994, 5,

1673-1682.

(14) Howell, J. A. S.; Palin, M. G.; Jaouen, G.; Top, S.; Elhafa, H.; Cense, J.

M. "Asymmetric Biochemical Reduction, Acylation and Hydrolysis in the

(Diene)Fe(CO)3 Series - Experimental Results and Molecular Modeling Studies."

Tetrahedron: Asymmetry 1993, 4, 1241-1252.

(15) Alcock, N. W.; Crout, D. H. G.; Henderson, C. M.; Thomas, S. E.

"Enzymatic Resolution of a Chiral Organometallic Ester - Enantioselective Hydrolysis of

2-Ethoxycarbonylbuta-1,3- Dienetricarbonyliron by Pig-Liver Esterase." J. Chem. Soc.-

Chem. Commun. 1988, 746-747.

(16) Tanaka, K.; Watanabe, T.; Shimamoto, K.; Sahakitpichan, P.; Fuji, K.

"Asymmetric olefination of metallic arene or diene complexes to form planar chiral complexes." Tetrahedron Lett. 1999, 40, 6599-6602.

(17) Takemoto, Y.; Baba, Y.; Noguchi, I.; Iwata, C. "Asymmetric synthesis of

(diene)Fe(CO)3 complexes via catalytic enantioselective alkylation with dialkylzinc."

Tetrahedron Lett. 1996, 37, 3345-3346.

(18) Donaldson, W. A.; Shang, L.; Rogers, R. D. "Reactivity of

Tricarbonyl(Pentadienyl)Iron(1+) Cations - Preparation of an Optically Pure

- 11 -

Tricarbonyl(Diene) Iron Complex Via 2nd-Order Asymmetric Transformation."

Organometallics 1994, 13, 6-7.

(19) 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, 4707-4710.

(20) Knölker, H. J. "Iron-Mediated Synthesis of Heterocyclic Ring-Systems and Applications in Alkaloid Chemistry." Synlett 1992, 371-387.

(21) Birch, A. J.; Kelly, L. F. "Tricarbonyliron Methoxycyclohexadiene and

Dienyl Complexes - Preparation, Properties and Applications." J. Organomet. Chem.

1985, 285, 267-280.

(22) Pearson, A. J. "Tricarbonyl(Diene)Iron Complexes - Synthetically Useful

Properties." Acc. Chem. Res. 1980, 13, 463-469.

(23) 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, 3739-3746.

(24) 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, 7513-7515.

(25) 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, 638-639.

- 12 -

(26) 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, 13326-13327.

(27) Pearson, A. J.; Wang, X. L.; Dorange, I. B. "Intramolecular iron-mediated

diene/olefin cyclocoupling: Formation of carbon spirocycles." Org. Lett. 2004, 6, 2535-

2538.

(28) Pearson, A. J.; Kim, J. B. "Silicon-tethered cyclocarbonylation of alkynes." Org. Lett. 2002, 4, 2837-2840.

(29) Pearson, A. J.; Kim, J. B. "Conjugate additions of carbon nucleophiles to cyclopentadienones." Org. Lett. 2003, 5, 2457-2459.

(30) Pearson, A. J.; Kim, J. B. "Cyclopentadienones as intermediates for the synthesis of highly functionalized biaryls." Tetrahedron Lett. 2003, 44, 8525-8527.

(31) Bell, P. T.; Dasgupta, B.; Donaldson, W. A. "Remote diastereoselective control via organoiron methodology: Stereoselective preparation of 4,6-, 5,7- and 6,8- dien-2-ol (tricarbonyl)iron complexes." J. Organomet. Chem. 1997, 538, 75-82.

(32) Semmelhack, M. F. "Nucleophilic-Addition to Diene and Arene-Metal

Complexes." Pure Appl. Chem. 1981, 53, 2379-2388.

(33) Semmelhack, M. F.; Herndon, J. W. "Scope of Anion Addition to η-4-1,3-

Cyclohexadiene Tricarbonyliron(0)." Organometallics 1983, 2, 363-372.

(34) Pearson, A. J.; Shively, R. J.; Dubbert, R. A. "Iron Carbonyl Promoted

Conversion of Alpha,Omega-Diynes to (Cyclopentadienone)Iron Complexes."

Organometallics 1992, 11, 4096-4104.

- 13 -

(35) Pearson, A. J.; Dubbert, R. A. "Intramolecular Alkyne-Alkyne and

Alkyne-Alkene Couplings Promoted by Iron Carbonyls." J. Chem. Soc.-Chem. Commun.

1991, 202-203.

(36) Emerson, G. F.; Watts, L.; Pettit, R. "Cyclobutadiene- and

Benzocyclobutadiene-Iron Tricarbonyl Complexes." J. Am. Chem. Soc. 1965, 87, 131-

133.

(37) Takemoto, Y.; Ueda, S.; Takeuchi, J.; Nakamoto, T.; Iwata, C.

"Diastereoselective [4+2]-Type Cycloaddition of 1-Azatriene Iron-Tricarbonyl Complex

- Asymmetric-Synthesis of a Piperidine Alkaloid." Tetrahedron Lett. 1994, 35, 8821-

8824.

(38) Takemoto, Y.; Takeuchi, J.; Iwata, C. "Absolutely Diastereoselective 1,2-

Nucleophilic Addition of Organometallic Reagents to Imines Using Diene-Iron

Tricarbonyl Chirality." Tetrahedron Lett. 1993, 34, 6069-6072.

(39) Donaldson, W. A. "Preparation and reactivity of acyclic

(pentadienyl)iron(1+) cations: Applications to organic synthesis." Aldrichimica Acta

1997, 30, 17-24.

(40) Donaldson, W. A. "Stoichiometric applications of acyclic π-organoiron complexes to organic synthesis." Curr. Org. Chem. 2000, 4, 837-868.

(41) Clinton, N. A.; Lillya C. P. "Tricarbonyl (trans-π-pentadienyl) iron

Cations. Solvolysis of Complexed Dienyl Dinitrobenzoates and Protonation of

Complexed Dienones." J. Am. Chem. Soc. 1970, 92, 3065-3075.

(42) Clinton, N. A.; Lillya C. P. "Conformational Analysis of Tricarbonyl

(diene) iron Compounds." J. Am. Chem. Soc. 1970, 92, 3058-3064.

- 14 -

(43) Grée, D. M.; Kermarrec, C. J. M.; Martelli, J. T.; Grée, R. L.; Lellouche, J.

P.; Toupet, L. J. "The first enantiocontrolled synthesis of E,E conjugated dienes with a

fluorine atom in the allylic position." J. Org. Chem. 1996, 61, 1918-1919.

(44) Legall, T.; Lellouche, J. P.; Beaucourt, J. P. "An Organoiron Mediated

Chiral Synthesis of (+)-(S)-[6]-Gingerol." Tetrahedron Lett. 1989, 30, 6521-6524.

(45) Laabassi, M.; Grée, R. "Total Synthesis of (-) Verbenalol and (-)

Epiverbenalol." Tetrahedron Lett. 1988, 29, 611-614.

(46) Monpert, A.; Martelli, J.; Grée, R.; Carrie, R. "Synthesis of Optically-

Active Hemicaronaldehydes Using Chiral Butadiene-Iron Tricarbonyl Complexes."

Nouveau Journal De Chimie-New Journal of Chemistry 1983, 7, 345-346.

- 15 -

Chapter 2.

Cationic cyclizations of iron tricarbonyl diene complexes

with pendant alkenes and arenes.

- 16 -

2.1 Introduction. Stabilized acyclic iron tricarbonyl pentadienyl cations.

The focus of this chapter is on acyclic iron tricarbonyl diene complexes. We will

address respectively:

- generation of stabilized iron tricarbonyl pentadienyl cations;

- their reactivity toward external or pendant nucleophiles;

- a new method to generate these cations and its synthetic relevance.

Unlike their cyclic counterparts, hydride abstraction is not the method of choice

for the preparation of these complexes. The reason lies in the fact that there is a required

conformation (cisoid) for this reaction to occur, whereas for a simple substitution pattern

the complexation reaction produces a transoid geometry (2.3, Scheme 2.1). Even if

(OC)3Fe (OC)3Fe Fe(CO)5 Fe(CO)5 X

2.1 2.2 2.3

Scheme 2.1 the starting material 2.2 has a Z substituted double bond, the only observable product of complexation is 2.3, which has an E substituted double bond. Treatment of 2.3 with trityl

+ cation (Ph3C ) does not yield the expected iron tricarbonyl pentadienyl cation. This can only be achieved for substrates where the Z to E isomerization does not affect the result of the complexation reaction (Scheme 2.2). For example, treatment of 2.5 with trityl

Fe(CO)3 Fe(CO)3 Fe2(CO)9 Ph3CBF4

- BF4 2.4 2.5 2.6

Scheme 2.2

- 17 -

cation affords the expected iron tricarbonyl pentadienyl cation.1

However, a more convenient method was discovered, employing oxygenated diene substrates. Pettit et al.2,3 first showed that protonation of an iron tricarbonyl

pentadienol complex will induce dehydroxylation and subsequently generate an iron

tricarbonyl pentadienyl cation, in this case as the cation of a salt with the conjugate base

of the acid used for protonation (Scheme 2.3). We will return to this later, with a more

detailed discussion of the dehydroxylation reaction.

Fe(CO)3 (OC)3Fe OH 4 - R X 4 R R + - 1 H X R 5 1 X- = BF -, PF -, ClO - R R R 5 4 6 4 R 2.7 2.10

H+

(OC)3Fe (OC) Fe H H R 3 + O 4 R 1 4 R R R 1 -H O R 2 R5 5 R 2.8 2.9

Scheme 2.3

Although NMR studies of these salts reveal mostly the cisoid form 2.10, it is believed that both the cisoid and the transoid configuration 2.9 may coexist in solution.

This fact is mostly indicated by the results of nucleophilic addition to these complexes, as addition to the cisoid or transoid form will result in different stereochemistry of the product. The insertion point is usually at the termini of the pentadienyl system (Scheme

2.4: C-1 and/or C-5; adducts at C-2 or C-4 were observed, never at C-3). Once the addition occurs, the stereochemistry of the product matches that of the starting cation

(with the cisoid cation 2.11 affording cisoid (E,Z) product 2.12 and/or 2.13, and the

- 18 -

transoid cation 2.14 affording transoid (E,E) 2.16 and/or 2.17. A delicate balance of

stability vs. reactivity plays an important role in the outcome

Fe(CO) (OC)3Fe Fe(CO)3 3 (OC)3Fe Nu - C - Nu 3 Nu 1 C4 C2 C3 C1 1 R C4 C2 R C C 5 1 5 5 1 1 R R R R C5 5 Nu R5 R 2.11 2.14 2.16 2.12 Nu- Fe(CO) 3 (OC) Fe (OC)3Fe 3 1 R1 Nu- R R5 R1 Nu Nu 2.13 5 R5 2.15 R 2.17

Scheme 2.4 of the reaction. As a general rule, the cisoid cation is more stable and less reactive than the transoid cation, which is why nucleophile insertion on the transoid isomer is often the major observed pathway. For the cisoid isomer to become more prone toward nucleophile addition, electron withdrawing substituents can be used, since these destabilize the cation

1 5 and make it more reactive. This is usually the case when R or R = CO2Me. As already

Fe(CO)3 (OC)3Fe Fe(CO)3 - NaCH(CO Me) PF6 2 2 +

THF, 53% CH(CO2Me)2 2.18 CH(CO2Me)2 2.19 1 : 1.8 2.20

Fe(CO)3 (OC)3Fe - H O CH(OH)Me BF4 2

2.22 2.21

Scheme 2.5 noted for cyclic iron tricarbonyl dienyl cations, nucleophilic attack occurs on the face of the diene opposite to the iron tricarbonyl group, for both the cisoid and the transoid

- 19 -

isomers. A number of reactions with nucleophiles have been reported, from which we

show a few examples (Scheme 2.5).4-7

Shown in Scheme 2.6 are two recent examples of reactions from the Donaldson laboratory, dealing with reactivity of acyclic iron tricarbonyl pentadienyl cations towards

weak carbon nucleophiles, of relevance to the results we are going to present later in this

work.8 We shall note here the results of the reaction of compound 2.23 with furan to

afford 2.25.

(OC)3Fe

CH2Cl2, 70% TMS

Fe(CO)3 2.24 - PF6 O (OC)3Fe 2.23 O CH2Cl2, 69%

2.25

Scheme 2.6

We will see later a different trend for an in situ generated transoid cation, albeit under different circumstances. We will further concentrate on the chemistry of the transoid form of the iron tricarbonyl pentadienyl stabilized carbocation, which is of interest to our study.

In two publications that became classical references for work in the area of acyclic iron tricarbonyl pentadienyl cations,9,10 Clinton and Lillya addressed stereochemistry and reactivity issues incumbent to the existence of a stereocenter next to the iron tricarbonyl diene moiety. They showed that there is a preferred conformation along the C1-C2 bond (Fig. 2.1), namely the iron tricarbonyl group will be in a

- 20 -

O O O Fe (CO)3Fe H3 H1 X H1 C C Ψ−endo 2 1 R H2 H3 H2 X R

O O O Fe (CO)3Fe H3 H1 R H1 Ψ−exo C2 C1 X H2 H3 H2 R X

Fig. 2.1 Ψ-endo/exo diastereoisomers.

staggered conformation relative to the substituents on C1, with the most sterically

demanding substituents on C1 (R and X – usually an oxygenated functionality) pointing away from the iron tricarbonyl group. Obviously, the least demanding group (H in this example) will occupy the most hindered position, between the iron tricarbonyl group and the diene plane. They named this conformations with the Greek letter Ψ (psi), with “exo” being the conformation where the functional group (X) is more exposed (it points away

from the iron tricarbonyl diene moiety) whereas “endo” has the functional group partially

eclipsed by the iron tricarbonyl group.

In a pivotal experiment Clinton and Lillya have further shown the reactivity

implications of having a functional group in any of the two given conformations. The

experiment deals with the solvolysis of diastereomeric dinitrobenzoate derivatives of

tricarbonyl-(hepta-3,5-dien-1-ol)-iron complex. These reactions proceed by a SN1 mechanism (inferred from salt and common ion effects on the reaction rate), in neutral media (Scheme 2.7). The striking differences in rate for the three reactions was explained by the effect of the iron tricarbonyl group on the rate limiting step, the dissociation of the

- 21 -

krel (CO) Fe (CO)3Fe (CO)3Fe H 3 H CH H O H 3 2 2.7 CH CH3 3 ODNB H Ψ−endo OH Ψ−endo 2.27 2.26 2.28

H2O 4.0 2.29 ODNB 2.30 OH

(CO) Fe (CO)3Fe (CO)3Fe 3 H H H H2O 250 ODNB OH CH Ψ−exo CH3 CH3 Ψ−exo 3 2.31 2.32 2.33 NO2 O ODNB = O

NO2 Scheme 2.7

leaving group. The iron atom can offer anchimeric assistance to the leaving group

provided that the latter is anti to the iron tricarbonyl group with respect to the diene

plane. While the leaving group in the Ψ-exo isomer is in a favorable position to receive

anchimeric assistance from the iron atom, on the other side of the diene plane, the Ψ-

endo isomer has to undergo a rotation along C1-C2 bond for the leaving group to receive assistance, placing the methyl substituent in a hindered position. As a matter of fact, the relative rate for the uncomplexed substrate suggests that there is no assistance at all in the case of the Ψ-endo isomer. As we shall see later in this chapter, the lower reactivity of the

Ψ-endo complex and the steric encumbrance inherent in this isomer will play an important role in the further development of chemistry based on acyclic iron tricarbonyl pentadienyl cation.

Putting aside for a moment the Ψ-endo / Ψ-exo reactivity issues, we have to emphasize the most important feature of this methodology, which is the high degree of

- 22 -

stereochemical control. The fact that ionization of the oxygenated functionality and

subsequent nucleophile insertion occurs with retention of configuration makes this

methodology highly interesting to the synthetic organic chemist. The chemical literature

already provides a significant number of methodology examples for carbon-carbon bond

formation.11-13 Without being exhaustive, we present here a classical example of using

this methodology toward a natural product synthesis. In 1994 Roush and Wada reported

an asymmetric synthesis of the as-indacene unit of ikarugamycin,14 a formal total synthesis. The first three key steps take full advantage of the iron tricarbonyl diene moiety, by using it three times in enantiocontrol at both ends of the unit, along with only one enantiomerically pure reagent. Starting with meso complex 2.34 (eq. 2.1),

CO2iPr O (CO) Fe B CO2iPr 3 (CO)3Fe O OH 2.35 OHC (2.1) OHC CHO (S,S)-2. , 4Å mol. sieves 2.34 toluene, -78°C, 90% 2.36 , Ψ−exo, >98% e.e.

crotylboration using reagent 2.35, not only distinguished between the enantiotopic ends

of the complex, but afforded only the Ψ-exo alcohol diastereoisomer (Fig. 2. , >98% e.e.),

which is as we already mentioned the most reactive toward nucleophiles. They continued

with condensation of the remaining carbonyl with Meldrum’s acid, followed by a 1,4-

addition to the resulting double bond, also directed anti by the iron tricarbonyl group

(Scheme 2.8). As the reaction of alcohols of type 2.38 is reportedly sluggish with carbon-

- 23 -

(CO)3Fe (CO)3Fe OR OH O O CH2=CHMgBr O O THF, -78°C to 0°C, O O O O 83-88% 2.38 R = H 2.37 2.39 R = Ac

1) Ac2O, DMAP, Meldrum's acid Py, CH2Cl2 69-75% Py, 92% 2.36 2) Et3Al, CH2Cl2, -20°C to 23°C

(CO)3Fe

1) FeCl3, CH3CN, -15°C O 2) H2O, 3-pentanone reflux; CH N O O O 2 2 O MeO 2.40 2.41 70%

Scheme 2.8

based Lewis acids,11 they chose to convert 2.38 into acetate 2.39, and then treat it with

Et3Al to afford nucleophile substitution product 2.40, with complete retention of configuration. The iron tricarbonyl group was then removed by treatment of 2.40 with

FeCl3, followed by hydrolysis and decarboxylation of the Meldrum’s acid residue, and

esterification to afford 2.41.

Several extra synthetic steps afforded the indacene unit 2.42, which constitutes a

formal total synthetis of ikarugamycin, already reported from the same key intermediate

(Figure 2.2).15 Elaboration of compound 2.40, the product of nucleophilic substitution on

Ψ-exo alcohol 2.38, all the way into the indacene unit 2.42, which was also synthesized by alternate routes, constitute the first experimental proof of retention of configuration in the case of the aforementioned nucleophilic substitution for the particular case discussed

(carbon nucleophile – alkylation).

- 24 -

O O

O MeO 2.41 O 2.42

H N

O OH

HN O O (+)-Ikarugamycin

Fig. 2.2 Two key intermediates in the total synthesis of (+)-Ikarugamycin.

2.2 Cyclization reactions of iron tricarbonyl pentadienyl cation with pendant

nucleophiles.

It is logical that at some point this methodology found its way into cyclization

reactions. The high degree of stereoselectivity already achieved could, in principle, only

be improved by bringing into play the entropic advantage. Research in this area followed

the same trend as the reactions of the in situ generated iron tricarbonyl stabilized

pentadienyl carbocation with external nucleophiles. Initial reports include pendant heteroatom nucleophiles (oxygen, sulphur), followed by carbon pendant nucleophiles, albeit of a different nature than those used for nucleophile addition on the cisoid dienyl

complexes (neutral species as opposed to negatively charged organometallic type of

reagents).

- 25 -

In 1991 Grée et al. reported a new method for the synthesis of optically active

tetrahydropyrans and tetrahydrofurans, based on trapping the iron tricarbonyl pentadienyl

stabilized carbocation by a pendant oxygen nucleophile (Scheme 2.9; only Ψ-exo shown,

similar results for the Ψ-endo alcohol).16 As already mentioned early in this chapter,

(CO)3Fe (CO) Fe (CO)3Fe HBF 3 OH 4 HO O E E E OH 2.45 2.43 2.44 2.5 : 1

(CO)3Fe (CO)3Fe E = COOMe E E O OH

2.47 2.46

(CO)3Fe (CO)3Fe OH HBF4 O E O E 2.49 2.48

Scheme 2.9 the presence of an electron withdrawing substituent (E in Scheme 2.9) on the diene frame destabilizes the cisoid cation, resulting in the formation of 2.47 cisoid product, along with

the expected 2.45. However, it appears that for the formation of a 5-membered ring, only

the transoid product is obtained, suggesting kinetic control. Paquette et al. reported

leakage of stereochemistry during a homologous 5-membered ring cyclization of a diol

substrate (the major pathway however is the expected retention of configuration - eq.

2.2).17 Loss of the labeled oxygen provides further support for the reaction mechanism,

- 26 -

(CO)3Fe (CO)3Fe (CO)3Fe O18H HBF4 O (2.2) E OH E + E 2.50 2.51 2.52 O 1.7-1.9 : 1.0 namely it is the hydroxyl next to the iron tricarbonyl pentadiene moiety that is being protonated and removed to afford a carbocation (no residual label could be detected in the resulting THF ring). Use of a pendant thiol group resulted in cyclization to afford tetrahydrothiopyrans, with very good stereoselectivity for the Ψ-exo substrates and with

almost complete loss of stereochemistry when the Ψ-endo substrate was used (55:45

expected product vs. its diastereoisomer).18 To conclude this short excursion into iron tricarbonyl pentadienyl stabilized carbocation mediated cyclization with pendant heteroatom nucleophiles, we will present an interesting variation reported in 1996 by

Lellouche et al. (Scheme 2.10)19 Acid mediated dehydroxylation of diol-ether 2.53 (note the selectivity between the hydroxyl adjacent to the iron tricarbonyl that can

(CO) Fe 3 Amberlyst (CO)3Fe O O OH (acid form) OH HO 2.53 2.54

(CO)3Fe (CO)3Fe O HO

O O 2.56 2.55

Scheme 2.10

receive anchimeric assistance and the one at the distal end of the molecule) triggers a 1,2

migration of the complexation site, to transfer the electrophilic center to the end of the

diene opposite from where it was generated. Capture of the pendant nucleophile afforded

trans-2,3-disubstituted 1,4-dioxanes with very good stereoselectivity.

- 27 -

In 1998 Pearson et al. would be the first research group to take advantage of this

methodology and apply it toward an all-carbon cyclization, by using pendant olefinic and

aromatic nucleophiles.20,21 Franck-Neumann et al. followed shortly with a similar account that includes some additional observations.22 As this reaction is the starting point of our current efforts we will provide a more detailed account, starting with the preparation of the starting materials, followed by reactivity studies and mechanistic considerations.

Grignard addition to the iron tricarbonyl sorbaldehyde complex 2.57 afforded a mixture of diastereomeric alcohols Ψ-endo and Ψ-exo, Scheme 2.11. It is believed that

the sorbaldehyde complex has a preferred s-trans conformation about the diene-aldehyde

bond, thus affording the Ψ-endo isomer 2.58 in excess over the Ψ-exo isomer 2.59, in

accord with results of Howell et al.23 The coexistence of both s-trans and s-cis

(CO)3Fe (CO)3Fe

major (1.6) O OH MgBr Ψ−endo 2.57 2.58 THF

(CO)3Fe (CO)3Fe O OH minor (1)

Ψ−exo 2.59

Scheme 2.11 conformers of the aldehyde was also confirmed by NOE studies,24 showing a slight

preference for the s-trans isomer, once again in concordance with the results of the

nucleophile addition. The two diastereoisomers are easily separable by flash

chromatography, as they have a striking difference in Rf values on silica gel. If we recall

the projections in Fig. 2.1, we can observe that for the Ψ-endo isomer the hydroxy group

- 28 -

is in a relatively hindered position, making the molecule less polar than the Ψ-exo

diastereoisomer, which has the hydroxy group pointing away from the iron tricarbonyl group, much more exposed for external interactions.

Treatment of the Ψ-exo alcohol 2.59 with three equivalents of BF3·OEt2 in

dichloromethane at -78 °C, with subsequent warming to room temperature afforded a

mixture of diastereomeric fluorides 2.62 and 2.63, Scheme 2.12.20,21 The

diastereoisomerism is not the result of the cyclization step itself, but of the second step.

(CO)3Fe (CO)3Fe F (CO)3Fe F OH BF3·OEt2 + CH Cl Ψ−exo 2 2 2.62 2.63 2.59 57% 35%

BF3-OEt2

(CO)3Fe (CO)3Fe

2.61 2.60

Scheme 2.12

To summarize the mechanism: the dehydroxylation is triggered by the Lewis acid, with anchimeric assistance from the iron, the Ψ-exo isomer having the conformation required for this step; the pendant nucleophile (a double bond in this case) will attack the stabilized carbocation from the face opposite to the iron tricarbonyl group, affording a new stereocenter with complete diastereoselectivity; the resulting secondary carbocation

- is captured by the external nucleophile (HOBF3 ) – given the high reactivity of the external nucleophile, the result is a mixture of diastereoisomers, with a 1.5 to 1 preference for the equatorial one. The Ψ-endo alcohol follows a similar pathway, affording a mixture of fluorides, equatorial 2.64 and axial 2.65 (eq. 2.3). Notably, Ψ-

- 29 -

endo homologues carrying different pendant nucleophiles were not as successful as the

simple compound.

(OC) Fe 3 (OC)3Fe (OC)3Fe BF3·OEt2 + (2.3) OH CH2Cl2, 89% 2.58 2.64 F 2.7 : 1 2.65 F

Compound 2.63 that resulted from cyclization of the Ψ-exo alcohol, and also the

mixture of 2.64 and 2.65 from the Ψ-endo alcohol cyclization, reportedly contain traces

of an unidentified, inseparable axial fluoride, consistent with the work of Franck-

Neumman et al. which for the same reaction reports the presence of minor

(CO)3Fe F (CO)3Fe F

(CO)3Fe 2.62 2.63 OH BF3·OEt2 65% 24% (2.4) 2.59 (CO)3Fe (CO)3Fe

F 2.65 2.66 4% F 7%

diastereoisomers 2.65 and 2.66 (eq. 2.4; similar for the Ψ-endo alcohol, not shown here).

Pearson et al. presumed the unidentified compound to be 2.69, Scheme 2.13, which may be explained by a transoid to cisoid isomerization of the iron tricarbonyl pentadienyl stabilized carbocation. The isomerization of 2.67 to the more stable 2.68 is also highly probable, being fairly common in the chemistry of the cisoid cations.3 It also accounts for

the presence of the same compound in the cyclization of both Ψ-exo and Ψ-endo alcohols.

- 30 -

(OC)3Fe (OC)3Fe OH Ψ−exo Ψ−endo 2.59 2.58 OH

(OC)3Fe (OC)3Fe H H

Fe(CO)3

Fe(CO)3 H

H (OC)3Fe F

2.69 2.67 2.68 Scheme 2.13

However, this mechanism cannot account for the presence of 2.66 (eq. 2.4), which is a

product of external nucleophile insertion at position 4 in the cyclohexane ring. Given our recent experience with similar compounds, which we are going to present later in this work, it is likely that a 1,2 hydride migration may be the explanation for compound 2.66

as well as for compound 2.65 (eq. 2.4), followed by external nucleophile insertion at the newly formed carbocation.

Both Pearson and Franck-Neumann reported the formation of only six membered rings, presumably attributable to the greater stability of the secondary carbocation as compared to that of primary carbocation (Fig. 2.3).

(CO) Fe (CO) Fe 3 (CO)3Fe 3 X OH

Fig. 2.3 A possible explanation for preferred

6- over 5-membered ring cyclization.

- 31 -

In an effort to diversify the outcome of the reaction, Pearson et al. carried out the

reaction in the presence of an added nucleophile. While a 1:1 mixture of BF3·OEt2 and

TMSN3 afforded only the previously reported fluorides, a large excess of TMSN3

(OC) Fe 3 BF3·OEt2 (OC)3Fe F (OC)3Fe N3 OH TMSN3 + (2.5) CH2Cl2 2.59 2.62 and 2.63 2.70 (8%) (66% combined)

afforded azide 2.70, but in only 8% yield, with the diastereomeric fluorides still being the major products of the reaction (eq. 2.5). We should note however that the azide was obtained only as an equatorial isomer, a fact that may be accounted for by the low reactivity / high selectivity of the TMSN3 nucleophile.

(OC)3Fe (OC)3Fe

F OR (OC)3Fe 2.64 and 2.65 2.71 R = H (23%) BF3·OEt2 (18% combined) 2.72 R = Ac (37%) (2.6) OH EtOAc (OC) Fe (OC) Fe 2.58 3 3

2.73 2.74 (15% combined) Carrying out the reaction in EtOAc afforded an even more complicated product

mixture (eq. 2.6). The presence of EtOAc may account for the outcome of the reaction, as

per Scheme 2.14; intermediate 2.76 may suffer loss of proton and ethylene to afford

acetate 2.78 or capture a hydroxy group to afford hemiester 2.77 which can afford then

alcohol 2.79 or acetate 2.78 in an acid catalyzed conversion. However, it is the

- 32 -

(OC)3Fe

2.75

EtOAc

(OC) Fe (OC)3Fe 3 - [HOBF3]

2.76 2.77 O OO O H OH F- - HF, CH CH 2 2 (OC)3Fe

(OC)3Fe

2.79 OH 2.78 OAc

Scheme 2.14 elimination products 2.73 and 2.74 (eq. 2.6) which are diagnostic for further efforts directed toward developing this methodology, as with increased substitution of the olefinic pendant nucleophile, a higher tendency for elimination reactions was observed, albeit in the absence of any added nucleophiles.

Finally, aromatic pendant nucleophiles were employed to afford cyclization products, with relatively little success. Only one successful cyclization was reported, that employing Ψ-exo alcohol 2.80, bearing the most favorable activating substituent

(methoxy group para to the cyclization position), affording the six membered ring tetrahydronaphthalene derivative 2.81 (eq. 2.7). All the Ψ-endo substrates were

OMe

(OC) Fe (OC)3Fe 3 BF3·OEt2 OH (2.7) CH Cl OMe 2 2 2.80 2.81

- 33 -

completely unreactive, whereas Ψ-exo alcohols with a less favorable activation pattern or

unactivated underwent a rearrangement reaction (eq. 2.8 - migration of the carbocation

across the diene is not an uncommon reactivity pattern and is synthetically useful,

Scheme 2.10.).19,25

(OC)3Fe (OC)3Fe OH BF3·OEt2 HO R (2.8) R CH2Cl2

2.82 R = (CH2)3Ph 2.83 R = (CH2)4-4-OMe-Ph 2.84 R = (CH2)2-3-OMe-Ph

2.3 Studies on pendant alkenes with an increased substitution pattern.

In continuation of these first reported cyclizations of in situ generated iron

tricarbonyl pentadienyl stabilized carbocation with pendant alkenes and arenes20-22,26, the

(OC)3Fe (OC)3Fe F OH BF3·OEt2 2.88 2.85 Ψ−endo/exo F (OC) Fe 3 (OC)3Fe OH BF3·OEt2

2.86 Ψ−endo/exo 2.89 (OC) Fe 3 (OC)3Fe OH F BF3·OEt2 2.87 Ψ−endo/exo 2.90

Scheme 2.15

current work has tried to assess the behavior of more highly substituted pendant olefins,

in an attempt to generate additional stereocenters. Several substrates were prepared by the

same Grignard addition we have already described. Scheme 2.15 depicts their expected

- 34 -

cyclization products. Unfortunately, with a few exceptions, the cyclizations were all

plagued by one major problem, competition between “cyclization / nucleophile insertion”

and “cyclization / elimination” reaction pathways, affording extremely inconsistent and

most of the time irreproducible results. We shall present two examples that provided

enough experimental data in order to assess the reaction outcome. Both belong to the Ψ-

exo alcohol series; following a common reactivity pattern, which we have already seen in previous sections, Ψ-endo alcohols were completely unsuccessful, affording only complex mixtures of elimination products.

Ψ-Exo alcohol 2.85, upon treatment with BF3·OEt2, afforded cyclization product

2.88, albeit in modest yield (eq. 2.9). Remarkably, the terminal methyl group is able

(OC)3Fe (OC)3Fe F OH BF3·OEt2 (2.9) CH2Cl2 2.85 55% 2.88 to control the external nucleophile insertion step, only the equatorial fluoride being observed along with a nonpolar mixture of inseparable elimination products. It appears that a more highly substituted center next to the carbocation formed upon cyclization

triggers the elimination reactions. The following is an even better example for this type of

result (Scheme 2.16). Substrate 2.86 was designed in order to push the cyclization reaction toward formation of a 5-membered ring product. The geminal dimethyl group was deemed to provide the necessary steric hindrance at the distal terminus of the double bond. Also after the initial cyclization event, intermediate 2.91 contains a tertiary carbocation, which was considered to be more favorable (unlike the primary

- 35 -

(OC) Fe 3 (OC) Fe OH BF3·OEt2 3

CH2Cl2 2.86

(OC)3Fe (OC)3Fe (OC)3Fe

2.93 2.92 2.91 X

F (OC)3Fe (OC)3Fe (OC)3Fe

2.95 2.94 2.89 2 : 1 30% combined

Scheme 2.16 carbocation intermediate in Fig. 2.3). This was indeed the case; however, a “cyclization / elimination” pathway was observed and a mixture of at least two cyclization products could be isolated and partially characterized. We should also note that the elimination reactions in this example are not only low yielding and nonspecific, but one of the main goals of the reaction, that is creation of a new stereocenter, is not accomplished. Franck-

Neumann et al. coincidentally reported successful cyclization reactions using a protic

(OC) Fe OCHO 3 (OC)3Fe OH HCOOH (2.10) CH2Cl2 2.86 73% 2.96 acid.27 Using a protic acid gave better results (eq. 2.10); however, elimination products were still observed. This is the point in our research where we decided to examine a completely fresh approach to these types of cyclization reactions toward formation of carbocycles.

- 36 -

2.4 A new method for the cationic cyclizations of iron tricarbonyl stabilized

pentadienyl carbocation with pendant alkenes and arenes.

In the previous two sections we have described methodology for cationic cyclizations of acyclic iron tricarbonyl stabilized pentadienyl carbocation with pendant alkenes and arenes, and we have discussed briefly some difficulties that were encountered in the process of assessing the scope of the reaction with respect to the degree of substitution of the pendant olefinic nucleophile. While the Ψ-exo isomer has some reactivity issues, the Ψ-endo isomer is actually even less successful. If we recall that in the process of making these substrates by Grignard addition to the iron tricarbonyl sorbaldehyde complex Ψ-endo is the major isomer (Scheme 2.11), then we may say that the methodology is plagued by a major problem when it comes to its economy, in spite of its good diastereoselectivity. Although most of the work in this area is being done employing racemic starting materials, the ultimate goal is to be able to use this methodology in an enantioselective fashion, starting with enantiopure materials and conserving that enantiopurity throughout the transformations to which they are subjected.

Let us assume we start with enantiopure iron tricarbonyl sorbaldehyde complex

(Fig. 2.4 - numerous studies have been dedicated to asymmetric complexation and resolution of racemates in order to obtain enantiopure complexes; see Chapter 1).28 If one sets out to synthesize the stereocenter in B, it would be necessary to use the Ψ-exo alcohol, therefore losing the material that leads to Ψ-endo; of course one may start with

- 37 -

the other enantiomer of the starting iron tricarbonyl sorbaldehyde complex to go through

the resulting Ψ-endo isomer, but remember, Ψ-endo is less reactive than Ψ-exo. Going

(OC)3Fe

CHO optically pure

Grignard addition

(OC)3Fe (OC)3Fe OH

OH Ψ−endo Ψ−exo major minor Lewis / protic acid Lewis / protic acid diastereoisomers, separable

(OC)3Fe (OC)3Fe X

diastereoisomers X demetallation demetallation

XX enantiomers AB

Figure 2.4 Poor economy due to low selectivity of the Grignard addition. back for a moment to the literature, iron tricarbonyl dienone complexes have an advantage over dienal complexes in the Grignard addition, that is the result is diastereoselective. Unlike the aldehydes that show an equilibrium between a s-trans and s-cis conformations, ketones like 2.97 have a preferred s-cis conformation, therefore affording only one diastereoisomer upon addition of Grignard reagent (Scheme 2.17).29

- 38 -

However, in the resulting tertiary alcohol 2.98, there is less discrimination between the fairly equally sized three substituents at the hydroxyl bearing carbon in terms of steric

(OC)3Fe (OC)3Fe O MgBr OH

2.97 CH3 2.98

BF3·OEt2 CH2Cl2

(OC)3Fe F (OC)3Fe minor fluoride + + insertion isomers

2.99a 73% 2.99b 11% F

Scheme 2.17 preference, and therefore no more Ψ endo / exo conformations. That translates in turn into a decrease in stereoselectivity for the cyclization reaction. While there is an obvious preference for compound 2.99a, which is the result of anchimeric assistance from the iron, a small amount of compound 2.99b is also obtained, most probably as a result of indiscriminate dehydroxylation (in the next chapter we will present slightly better results for related cyclization of tertiary alcohols).27

Although there are reports in the literature for isomerization of the Ψ-endo diastereoisomer to the Ψ-exo counterpart,3 we present herein a new way to circumvent the problems encountered in creating a new tertiary stereocenter by means of cationic cyclization of an iron tricarbonyl stabilized pentadienyl carbocation and pendant carbon nucleophiles (Ψ endo / exo separation and reactivity differences).

Starting with the same material (iron tricarbonyl sorbaldehyde complex 2.100) we propose that the precursor for the cyclization reactions be prepared by a Wittig olefination instead of the Grignard addition. Our proposal envisions that the newly

- 39 -

created double bond, although being a mixture of Z and E isomers, will adopt a unique s-

trans conformation with respect to the diene moiety and will be protonated in a

+ - R PPh3] Br (OC)3Fe (OC)3Fe 2.101 CHO R 2.100 base H+ 2.102 Z / E mixture

HX

(OC)3Fe R X (OC)3Fe R (OC)3Fe R

2.103

Scheme 2.18 regiospecific manner, with anchimeric assistance from the iron to afford the stabilized cation, identical with that generated from the homologous Ψ-exo alcohol (Scheme 2.18).

To our knowledge there is only one example of similar reactions reported in the

(OC)3Fe (OC)3Fe HPF6 H (2.11)

R CH2Cl2, 0°C R - 2.103 PF6 2.104 literature (eq. 2.11), dealing however with very different substrates (cyclic iron tricarbonyl diene complexes, affording a stable cyclic iron tricarbonyl pentadienyl carbocation).30 There are also reports on functionalization of double bonds adjacent to an iron tricarbonyl acyclic diene moiety, but they are mainly concerned with OsO4 mediated dihydroxylation.31

Several substrates were prepared, which to our great satisfaction proved our envisioned methodology to work with complete diastereoselectivity and good yields.

- 40 -

Substrates in Table 2.1 were prepared following a literature procedure,31 using in house prepared phosphonium salts.32 All yields are for the unoptimized reactions (detailed

Table 2.1 Substrates with a pendant olefinic nucleophile.

Phosphonium Salts Yield Iron Tricarbonyl Triene yield

2.101a-e Complexes 2.102a-e

(Z / E mixtures)

+ - PPh ] Br 91% (OC)3Fe 53% (75% 3 borsm)

+ - PPh ] Br 18% (OC)3Fe 55% (75% 3

borsm)

+ - PPh3] Br 17% (OC)3Fe 51% (81%

borsm)

+ - PPh3] Br 29% (OC)3Fe 76% (79%

borsm)

44% (OC)3Fe 76% + - PPh3] Br

experimental procedures can be found in the experimental section at the end of this chapter). The respective bromides were either commercially available or prepared from the homologous alcohols by literature procedures as per Scheme 2.19.33

MeSO2Cl LiBr ROOH RBSO2Me R r NEt3, THF THF

Scheme 2.19

- 41 -

Although a literature procedure suggests that dehydration of tertiary alcohol 2.105

should afford diene 2.106 in high yield (Scheme 2.20),34 several attempts on our part

were unsuccessful, with the only result being a complex mixture of inseparable

compounds (the high viscosity of the mixture suggests polymerization products).

dehydration 1) hydroboration X OH 2) oxidation OH (benzene reflux, cat. pTsOH, 2.106 2.108 2.105 Dean-Stark trap)

benzene 50-70°C, 1) 9-BBN cat. pTsOH, 5-10 eq. MgSO4 - 2) H2O2, HO

+

2.106 2.107 1.4 : 1

Scheme 2.20

We therefore developed a milder dehydration method, which upon optimization afforded

a mixture of the desired diene 2.106 with the product of exocyclic dehydration,

conjugated diene 2.107 (inseparable by conventional flash chromatography techniques;

the ratio was estimated from GC-MS experiments). Fortunately, the mixture could be

subjected to a hydroboration / oxidation sequence,35 without any prior separation, as the conjugated diene was 2.107 completely unreactive.

Simple substrates 2.102a and 2.102b cyclized successfully and in good yields

(Scheme 2.21).36 After several unsuccessful attempts in various solvents (pentane, dichloromethane), we examined the use of neat formic acid. Upon mild heating of the reaction mixture, the desired cyclization products were finally observed. After anchimerically assisted protonation of the double bond at the distal end, the

- 42 -

(OC)3Fe (OC)3Fe R HCOOH neat R 50°C 2.102a R = H 2.102b R = CH3 Z / E mixtures

(OC)3Fe R OCHO HCOOH / HCOO- (OC)3Fe R

2.103a R = H 72% 2.103b R = CH3 70%

Scheme 2.21 iron stabilized carbocation is captured by the pendant nucleophile from the face opposite to the iron tricarbonyl group, selectively affording a new stereocenter. Assignment of

stereochemistry was straightforward (Fig. 2.5): the proton geminal to the formyloxy

(OC) Fe H3a 3 H1a H3a H3C δ 4.55 ppm OCHO H4e J = 10.3, 4.6 Hz H2a H 4a 2.103b

Fig. 2.5 1H-NMR stereochemistry assignment for compound 2.103b. group appears as a triplet of doublets. The large coupling constant (triplet, 10.3 Hz) is consistent with two axial-axial couplings, while the small constant (doublet, 4.6 Hz) corresponds to one axial-equatorial interaction, hence hydrogen H3 has to be axial itself.

Extrapolating, H2 is also axial and thus the methyl substituent at position 2 in the

cyclohexane ring is in an equatorial position, consistent with the proposed mechanism.

While we can expect the methyl group to control the insertion of the external nucleophile

in a selective fashion for 2.103b, remarkably, we observed the same selectivity for

- 43 -

compound 2.103a (only one diastereoisomer was observed – analysis of the resonance

assigned to the hydrogen geminal to the formyloxy group, indicate two axial-axial

interactions, J =10 Hz, and two axial-equatorial interactions, J = 4.4 Hz). We believe that

this high selectivity is due to the low reactivity of the external nucleophile. Thus, since

the reaction is being performed in neat formic acid, it is likely that the external

nucleophile is not the conjugate base (HCOO-) but formic acid itself.

Substrate 2.102c, designed to assess the reactivity of a pendant cis double bond,

performed very poorly (eq. 2.12). Less than 5% of the supposed cyclization product could

be isolated and partially characterized. We believe that the terminal methyl in the cis

(OC)3Fe (OC)3Fe OCHO HCOOH (2.12) 50°C 2.102c 2.103c , <5% Z / E mixture pendant olefin severely hinders the approach of the double bond to the carbocation.

Alternatively, the reaction could have produced a 5-membered ring, but we could not isolate any compound consistent with this reaction path. Compound 2.102d was designed specifically to afford a 5-membered ring cyclization product (eq. 2.13),

(OC) Fe OCHO 3 HCOOH neat (OC)3Fe X (2.13) 50°C 2.102d 2.103d Z / E mixture by means of terminal geminal dimethyl substitution for the pendant double bond. Once again, from a very complex mixture (since the initial ionization definitely occurs) we could not isolate any of the desired cyclization products. As we have noticed later for a

related substrate (to be presented in Chapter 3), the basicity of the double bond adjacent

- 44 -

to the iron tricarbonyl diene moiety is very close to that of the pendant trisubstituted

double bond. It is likely that competing protonation of the pendant double bond diverts

material along reaction paths other than the desired one.

We did not observe competing protonation of the trisubstituted double bond in

2.102e. However, we did not observe the expected cyclization product either (Scheme

2.22), but instead a cyclization – elimination product, which is consistent with the

(OC)3Fe (OC)3Fe HCOOH neat

50°C 2.102e 2.103e' 70% Z / E mixture

(OC) Fe (OC)3Fe HCOOH 3 OCHO

2.102e' 2.103e not observed

Scheme 2.22 relatively hindered nature of the cation resulting from cyclization, which cannot capture the external nucleophile. Alternatively, it may just be a classical example of thermodynamic control: the external nucleophile may be captured but then released in an equilibrium which favors the stable tertiary carbocation, which eventually loses a proton to afford 2.103e’.

Two attempts were made to employ triple bond pendant nucleophiles, toward 5 and 6 membered ring formation (eq. 2.14), with neither of them affording any expected

- 45 -

(OC)3Fe (OC) Fe HCOOH neat 3 OCHO (2.14) ( )n X 50°C ( )n 2.102 2.103 Z / E mixtures f : n = 1 f: n = 1 g: n = 2 g: n = 2 cyclization products whatsoever. Most probably the inherently unstable vinyl cationic intermediate could not be generated under the given reaction conditions.

Table 2.2 Substrates with a pendant aromatic / heteroaromatic nucleophile.

Phosphonium Salts yield Iron Tricarbonyl Triene Complexes yield

2.101h-m 2.102h-m

(Z / E mixtures)

91% (OC)3Fe 53% + - PPh3] Br

84% (OC)3Fe 91% PPh ]+Br- MeO 3 OMe

+ - MeO PPh3] Br 71% (OC)3Fe OMe 30%

(OC) Fe + - 88% 3 62% MeO PPh3] Br OMe

44% (OC)3Fe 67% + - O O PPh3] Br

36% (OC)3Fe 98% O + - O PPh3] Br

- 46 -

We have continued our efforts with a number of aromatic and heteroaromatic

pendant nucleophiles (Table 2.2).The first two substrates cyclized in very good yield for

2.102i, carrying an activated pendant phenyl ring, and in somewhat modest yield for the

pendant unactivated phenyl ring 2.102h (eq. 2.15).36 We need to mention however that for the unactivated substrate this was a marked improvement, as the analogous Ψ- exo / endo alcohols with a similar pendant unactivated phenyl ring did not afford any cyclization products (details in the previous section).20,21

R

(OC)3Fe (OC) Fe HCOOH neat 3 (2.15) R 50°C 2.102h R = H 2.103h R = H 25% 2.102i R = OMe 2.103i R = OMe 92%

Also an improvement over the previously reported cyclizations of analogous alcoholic substrates is the cyclization of substrate 2.102j toward a 5-membered ring,

OMe (OC)3Fe (OC) Fe HCOOH neat 3

OMe 50°C 2.102j 2.103j 17% Z / E mixture

(OC) Fe 3 (OC)3Fe

OMe OMe

inseparable mixture of products

Scheme 2.23 albeit in low yield (Scheme 2.23). The proximity of the benzylic position may promote carbocation rearrangement by means of successive 1,2-hydride shifts, followed by

- 47 -

indiscriminate capture by the external nucleophile. While this would account for the low

yield of 2.103j, we were unable to isolate and characterize products that support this

proposition.

Substrate 2.102k, designed to test a spirocyclization did not afford any cyclization

product (eq. 2.16 – similar results for the analogous alcohols). While the use of a better

O

(OC) Fe (OC)3Fe 3 HCOOH neat (2.16) OMe X 50°C 2.102k 2.103k Z / E mixture

leaving group may be the next step in trying to push this reaction to fruition, the steric

demand on the cyclization can be assessed as being very high.

Two substrates bearing a heteroaromatic (furan) pendant nucleophile were also

(OC)3Fe O (OC)3Fe O HCOOH neat

50°C 2.103l 30% 2.102l

(OC)3Fe O

(OC)3Fe O HCOOH neat 2.103m X 50°C O 2.102m (OC)3Fe

2.103m'

Scheme 2.24 prepared and their suitability for this reaction was assessed, with surprising results

(Scheme 2.24). While compound 2.102l afforded cyclization product 2.103l, albeit in a

- 48 -

modest yield, its homologue 2.102m failed to deliver any of the two products we may

expect from this reaction. This is a surprising result considering that 2.102m has both α

and β positions open for electrophilic attack, with the more reactive α position being

expected to afford product 2.103m. The complex mixture of products that resulted from

this reaction prevented us from drawing any reasonable conclusion as to the fate of the

substrate under the given reaction conditions.

2.5 Conclusions.

A method for cationic cyclization for iron tricarbonyl stabilized pentadienyl

cations with pendant alkenes and arenes, previously reported from our laboratory, is

improved in terms of economy and reactivity. Dehydroxylation of diastereomeric

diastereomeric alcohols - require separation; for enantioselective synthesis only one can be used.

(OC)3Fe (OC)3Fe (OC)3Fe OH H+ / Lewis acid Nu or Nu Nu

(OC)3Fe (OC)3Fe H+ Nu Nu

Z/E mixtures - will generate the same product upon protonation.

Scheme 2.25 alcohols is replaced by protonation of a double bond (Scheme 2.25 - both processes occur with anchimeric assistance from the iron atom), thus eliminating one separation step and

- 49 -

providing the possibility for channeling the entire starting material in one direction only

(important in the case of enantioselective synthesis).

In terms of reactivity the new method is more successful: cyclization products that

could not be obtained from the alcoholic substrates, were obtained from the analogous

trienes.

2.6 Experimental section.

General Procedures. All reactions were performed under argon atmosphere, in

freshly distilled (under nitrogen) solvents. Analytical thin-layer chromatography was

performed on aluminum plates precoated with Merck F254 silica gel. Visualization was done either with UV light and/or with phosphomolybdic acid (solution in EtOH). Flash- chromatography was performed with hexanes-ethyl acetate mixtures on silica gel with mesh 170-400, under nitrogen pressure. NMR spectra were recorded on a Varian Gemini

200 (200 MHz) spectrometer. Mass spectra were recorded in-house using a Kratos

MS25A instrument. IR spectra were recorded on a Nicolet Impact 400 spectrometer. The melting points were measured on a Thomas Hoover apparatus and are uncorrected.

(OC)3Fe (±)-Tricarbonyl((2S,6R)-2-5-η-11-methyl-(2E,4E)- OH 2,4,10-dodecatrien-6-ol)iron (2.86), was prepared following a literature procedure[21], in 30% yield. yellow oil, TLC Rf 0.22

1 (EtOAc:Hexanes 1:4); H NMR (200 MHz, CDCl3) δ (ppm) 5.21 (dd, J = 8.2, 4.4 Hz,

1H), 5.02-5.16 (2H), 3.36-3.48 (m, 1H), 1.95-2.08 (3H), 1.69 (d, J = 0.7 Hz, 3H), 1.61 (s,

- 50 -

3H), 1.45-1.60 (4H), 1.41 (d, J = 6.2 Hz, 3H), 1.15-1.29 (m, 1H), 0.98 (t, J = 8.2 Hz, 1H);

13 C NMR (50 MHz, CDCl3) δ (ppm) 212.0, 131.8, 124.2, 86.3, 82.1, 74.1, 64.8, 58.2,

-1 38.2, 27.7, 25.7, 25.6, 19.1, 17.7; IR (CHCl3, cm ) 2971, 2927, 2902, 2865, 2044, 1975,

+ 1454, 1379, 1072; HRMS(EI) M calcd. for C16H22O3Fe 318.0918, found 318.0867.

OCHO (±)-Tricarbonyl((2S)-2-5-η-5-((1’S,2’S)-2’-((2”-formyloxy)- (OC)3Fe isopropyl)-cyclopent-1’-yl)-(2E,4E)-pentadiene)iron (2.96).

To a solution of 9 (48.9 mg, 0.146 mmol) in pentane (2 mL), was added dropwise 0.017 mL (3equiv) of formic acid 95-97% at 0°C. After 2 hours of stirring at 0 °C, the reaction

was quenched at room temperature with a saturated solution of NaHCO3 (5 mL). The organic layer was separated, diluted with diethyl ether (50 mL), washed with saturated aq. NaHCO3 (2 x 10 mL) and with water (10 mL), and dried over Na2SO4. The solvent

was then removed under reduced pressure, and the crude product was purified by flash-

chromatography (EtOAc:Hexanes 1:15) to give 10 as a yellow solid (38.5 mg, 73%

1 yield), m.p. 81-83°C, TLC Rf 0.24 (EtOAc:Hexanes 1:15); H NMR (200 MHz, CDCl3)

δ (ppm) 8.02 (s, 1H), 5.09 (ddd, J = 8.8, 4.9, 0.9 Hz, 1H), 4.94 (dd, J = 8.7, 4.8 Hz, 1H),

2.24-2.35 (m, 1H), 1.45-1.90 (7H), 1.53 (s, 3H), 1.46 (s, 3H), 1.38 (d, J = 6.2 Hz, 3H),

13 0.98-1.19 (2H); C NMR (50 MHz, CDCl3) δ (ppm) 160.6, 86.2, 84.2, 83.4, 71.2, 57.6,

-1 56.3, 46.0, 38.1, 29.5, 26.0, 24.6, 23.1, 19.1; IR (CHCl3, cm ) 2042, 1962, 1723, 1459,

+ 1386, 1202, 1128; HRMS(EI) M -3CO calcd. for C17H22O5Fe 278.0969, found 278.0969.

- 51 -

Experimental procedure for the Wittig olefination toward substrates 2.102a-

m. Phosphonium salts were dried overnight in vacuo. Under Ar atmosphere, dry THF

was added via syringe. n-BuLi (2.5M in hexanes, 1.5 - 2 equiv) was added dropwise at -

78 °C. The mixture was stirred for 30 min at -78 °C. A solution of iron tricarbonyl

sorbaldehyde complex 2.100 in dry THF was transferred by cannula into the reaction flask. Stirring was continued for 30 min at -78 °C, the cold bath was removed and the reaction flask was allowed to warm to room temperature. Reaction progress was monitored by TLC. The reaction was quenched by addition of saturated NH4Cl solution.

The organic phase was diluted with diethyl ether, washed with saturated NaHCO3 solution, water, brine, and dried (MgSO4). Removal of the solvent under reduced pressure and flash chromatography separation afforded polyene compounds 2.102a-m as yellow oils. 1H NMR spectra are reported for the Z/E mixtures; as the Z isomer is the major one, it is assumed that the resolved signals belong to it – whenever possible signals attributable to the minor E isomer are reported separately. Whenever possible, 2 sets of

13C NMR are reported; major signals are again assumed to belong to the major Z isomer.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E)-2,4,6,10-

undecatetraene)iron, inseparable mixture of 6Z and 6E

isomers (2.102a). According to the general procedure 564 mg (1.37 mmol) of

phosphonium salt 2.101a in 15 mL dry THF was treated with 0.4 mL n-BuLi (2.5M in

hexanes, 1 mmol). Addition of 227 mg complex 2.100 (0.96 mmol) in 5 mL dry THF

afforded 146 mg of 2.102a as a yellow oil, 53% yield (75% borsm). TLC Rf 0.76

1 (Hexanes); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 5.28-5.48 (2H), 5.14

- 52 -

(ddd, J = 8.7, 4.8, 0.8 Hz, 1H), 4.94-5.10 (2H), 2.03-2.27 (3H), 1.93 (dt, J = 8.6, 0.9 Hz,

1H), 1.41 (s, 3H); E isomer (minor): 5.71-5.93 (2H), 4.95-5.09 (3H), 2.03-2.27 (3H), 1.79

13 (t, J = 9.6 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.4, 138.0,

131.0, 130.3, 114.9, 85.3, 82.2, 56.9, 56.6, 33.2, 27.3, 19.2; E isomer (minor): 212.6,

-1 137.9, 131.9, 131.3, 114.9, 84.7, 81.0, 62.1, 56.7, 32.0; IR (CHCl3, cm ) 2041, 1970;

+ HRMS(EI) M calcd. for C14H16O3Fe 288.0449, found 288.0451.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E,10E)-2,4,6,10-

dodecatetraene)iron, inseparable mixture of 6Z and

6E isomers (2.102b). According to the general procedure 518 mg (1.21 mmol) of phosphonium salt 2.101b in 10 mL dry THF was treated with 0.48 mL n-BuLi (2.5M in

hexanes, 1.2 mmol). Addition of 210 mg complex 2.100 (0.89 mmol) in 5 mL dry THF

afforded 147 mg of 2.102b as a yellow oil, 55% yield (75% borsm). TLC Rf 0.52

1 (Hexanes); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 5.32-5.48 (4H), 5.14

(dd, J = 8.8, 5.5 Hz, 1H), 4.97-5.07 (1H), 2.01-2.20 (4H), 1.94 (t, J = 11.4 Hz, 1H), 1.64-

1.66 (m, 3H), 1.41 (s, 3H); E isomer (minor): 5.32-5.48 (4H), 4.97-5.17 (2H), 2.01-2.20

(4H), 1.80 (t, J = 4.6 Hz, 1H), 1.64-1.66 (m, 3H), 1.39 (s, 3H); 13C NMR (50 MHz,

CDCl3) δ (ppm) Z isomer (major): 212.4, 130.8, 130.5, 125.5, 85.3, 82.2, 56.9, 56.8,

32.1, 28.0, 19.2, 17.9; E isomer (minor): 212.6, 131.8, 131.7, 130.5, 130.4, 125.4, 84.7,

-1 + 81.0, 62.3, 56.6, 32.7, 29.7; IR (CHCl3, cm ) 2043, 1970; HRMS(EI) M calcd. for

C15H18O3Fe 302.0605, found 302.0604.

- 53 -

(OC)3Fe (±)-Tricarbonyl[(2S)-2-5-η-(2E,4E,10Z)-2,4,6,10-

dodecatetraene]iron, inseparable mixture of 6Z and 6E isomers (2.102c). According to the general procedure 372 mg (0.87 mmol) of phosphonium salt 2.101c in 10 mL dry THF was treated with 0.6 mL n-BuLi (1.6M in hexanes, 0.96 mmol). Addition of 160 mg complex 2.100 (0.68 mmol) in 5 mL dry THF afforded 104 mg of 2.102c as a yellow oil, 51% yield (81% borsm). TLC Rf 0.6

1 (Hexanes). H NMR (200 MHz, CDCl3) δ (ppm) 5.53-5.32 (4H), 5.14 (dd, J = 9.0, 4.8

Hz, 1H), 5.03 (dd, J = 8.2, 5.1 Hz, 1H), 2.23-2.03 (4H), 1.94 (t, J = 9.1 Hz, 1H), 1.61 (d,

13 J = 5.2 Hz, 3H), 1.45-1.32 (4H); C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major):

212.4, 130.9, 130.7, 129.6, 124.5, 85.3, 82.2, 56.9, 56.7, 27.8, 26.5, 19.2, 12.8; E isomer

(minor): 131.8, 131.7, 130.8, 129.5, 124.3, 84.7, 81.0, 62.2, 56.7; IR (film, cm-1) 2045,

+ 1966; HRMS (FAB) M calcd. for C15H18O3Fe 302.0605, found 302.0612.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-11-methyl-(2E,4E)-

2,4,6,10-dodecatetraene)iron, inseparable mixture of

6Z and 6E isomers (2.102d). According to the general procedure 510 mg (1.16 mmol) of phosphonium salt 2.101d in 5 mL dry THF was treated with 0.46 mL n-BuLi (2.5M in hexanes, 1.16 mmol). Addition of 213 mg complex 2.100 (0.90 mmol) in 5 mL dry THF afforded 218 mg of 2.102d as a yellow oil, 76% yield (79% borsm), TLC Rf 0.76

1 (Hexanes); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 5.33-5.39 (2H), 5.14

(dd, J = 8.9, 4.8 Hz, 1H), 4.99-5.17 (2H), 1.71-2.20 (6H), 1.70 (s, 3H), 1.61 (s, 3H), 1.41

13 (s, 3H); E isomer (minor): 5.42-5.47 (2H), 4.99-5.19 (3H); C NMR (50 MHz, CDCl3) δ

(ppm) Z isomer (major): 212.4, 132.1, 131.0, 130.8, 123.8, 85.3, 82.2, 56.8, 28.2, 27.7,

- 54 -

25.7, 19.2, 17.7; E isomer (minor): 132.4, 132.3, 131.0, 126.8, 84.7, 80.32, 56.9, 34.4,

-1 + 19.1; IR (CHCl3, cm ) 2038, 1965; HRMS(EI) M calcd. for C16H20O3Fe 316.0762, found 316.0750.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-9-cyclohex-1’-enyl-(2E,4E)-

2,4,6-nonatriene)iron, inseparable mixture of 6Z and

6E isomers (2.102e). According to the general procedure 1.18 g (2.53 mmol) of phosphonium salt 2.101e in 7 mL dry THF was treated with 1 mL n-BuLi (2.5M in hexanes, 2.53 mmol). Addition of 402 mg complex 2.100 (1.7 mmol) in 5 mL dry THF

1 afforded 442 mg of 2.102c as a yellow oil, 76% yield, TLC Rf 0.56 (Hexanes); H NMR

(200 MHz, CDCl3) δ (ppm) Z isomer (major): 5.34-5.42 (3H), 5.13 (dd, J = 8.4, 4.8 Hz,

1H), 5.02 (dd, J = 7.9, 5.3 Hz, 1H), 1.56-2.04 (12H), 1.41 (s, 3H), 1.30-1.39 (2H); E

isomer (minor): 5.27-5.46 (3H), 4.94-5.16 (2H), 1.47-2.26 (12H), 1.43 (s, 3H); 13C NMR

(50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.4, 137.1, 131.1, 130.5, 121.3, 85.3,

82.1, 56.9, 56.8, 37.3, 28.3, 26.2, 25.2, 23.0, 22.5, 19.2; E isomer (minor): 212.6, 136.9,

-1 132.3, 131.4, 121.4, 84.6, 81.0, 62.5, 56.6, 37.5, 31.0; IR (CHCl3, cm ) 2039, 1966;

+ HRMS(EI) M calcd. for C18H22O3Fe 342.0918, found 342.0922.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E)-2,4,6-undecatrien-

9-yne)iron, inseparable mixture of 6Z and 6E isomers

(2.102f). According to the general procedure 440 mg (1.08 mmol) of phosphonium salt

2.101f in 10 mL dry THF was treated with 0.43 mL n-BuLi (2.5M in hexanes, 1.08 mmol). Addition of 212 mg complex 2.100 (0.9 mmol) in 5 mL dry THF afforded 89 mg

- 55 -

of 2.102f as a yellow oil, 63% yield (based on recovered starting material). TLC Rf 0.56

1 (EtOAc:Hexanes = 1:15); H NMR (200 MHz, CDCl3) δ (ppm) 5.67-5.30 (2H), 5.15 (dd,

J = 8.6, 4.7 Hz, 1H), 5.07-4.97 (m, 1H), 3.00-2.80 (2H), 1.90-1.76 (4H), 1.46-1.36 (4H);

13 C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.1, 132.1, 125.2, 85.7, 82.2,

75.9, 57.2, 55.1, 19.2, 17.6, 3.5; E isomer (minor): 132.7, 125.9, 85.0, 81.2, 75.7, 60.8,

57.0, 29.7, 22.1, 3.5.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E)-2,4,6-dodecatrien-

10-yne)iron, inseparable mixture of 6Z and 6E isomers

(2.102g). According to the general procedure 474 mg (1.12 mmol) of phosphonium salt

2.101g in 20 mL dry THF was treated with 0.45 mL n-BuLi (2.5M in hexanes, 1.12 mmol). Addition of 192 mg complex 2.100 (0.81 mmol) in 10 mL dry THF afforded 219

1 mg of 2.102g as a yellow oil, 90% yield. TLC Rf 0.6 (EtOAc:Hexanes = 1:9); H NMR

(200 MHz, CDCl3) δ (ppm) 5.76-5.30 (2H), 5.15 (dd, J = 8.6, 5.1 Hz, 1H), 5.08-4.98 (m,

1H), 2.35-2.11 (4H), 1.91 (t, 8.7 Hz, 1H), 1.78-1.76 (3H), 1.45-1.39 (4H); 13C NMR (50

MHz, CDCl3) δ (ppm) Z isomer (major): 212.3, 131.7, 129.2, 85.4, 82.2, 78.5, 76.0, 57.0,

56.3, 27.5, 19.2, 18.6, 3.5; E isomer (minor): 132.5, 130.3, 84.8, 81.1, 78.3, 76.1, 61.7,

+ 56.8, 32.2, 18.7, 3.4; HRMS(EI) M calcd. for C15H16O3Fe 300.0449, found 299.9902.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-9-phenyl-(2E,4E)-2,4,6-

nonatriene)iron, inseparable mixture of 6Z and 6E isomers (2.102h). According to the general procedure 553 mg (1.2 mmol) of phosphonium salt 2.101h in 5 mL dry THF was treated with 0.48 mL n-BuLi (2.5M in

- 56 -

hexanes, 1.2 mmol). Addition of 224 mg complex 2.100 (0.95 mmol) in 3 mL dry THF

afforded 171 mg of 2.102h as a yellow oil, 53% yield (78% borsm), TLC Rf 0.36

1 (Hexanes); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 7.14-7.34 (5H), 5.34-

5.42 (2H), 5.13 (dd, J = 8.6, 4.9 Hz, 1H), 5.04 (dd, J = 7.9, 5.3 Hz, 1H), 2.59-2.77 (2H),

2.38-2.50 (2H), 1.87 (t, J = 8.7 Hz, 1H), 1.41 (s, 3H), 1.17-1.39 (1H); E isomer (minor):

7.14-7.34 (5H), 5.61-5.76 (1H), 5.44-5.48 (1H), 4.94-5.19 (2H), 2.54-2.80 (2H), 2.25-

13 2.34 (2H), 1.78 (t, J = 9.1 Hz, 1H), 1.17-1.44 (4H); C NMR (50 MHz, CDCl3) δ (ppm)

Z isomer (major): 212.4, 141.7, 131.2, 130.0, 128.4, 128.3, 125.9, 85.4, 82.2, 57.0, 56.4,

35.4, 29.8, 19.1; E isomer (minor): 141.5, 132.1, 131.1, 130.0, 128.3, 125.8, 84.7, 81.0,

-1 + 61.9, 56.7, 53.0, 35.6, 34.5, 30.1, 14.5; IR (CHCl3, cm ) 2039, 1966; HRMS(EI) M -

3CO calcd. for C18H18O3Fe 254.0758, found 254.0758.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-9-(3’-methoxy)-

OMe phenyl-(2E,4E)-2,4,6-nonatriene)iron, inseparable mixture of 6Z and 6E isomers (2.102i). According to the general procedure

333 mg (0.68 mmol) of phosphonium salt 2.101i in 5 mL dry THF was treated with 0.3 mL n-BuLi (2.5M in hexanes, 0.75 mmol). Addition of 133 mg complex 2.100 (0.56 mmol) in 3 mL dry THF afforded 176 mg of 2.102i as a yellow oil, 91% yield. TLC Rf

1 0.4 (EtOAc:Hexanes 1:15); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 7.16-

7.21 (1H), 6.71-6.82 (3H), 5.36-5.42 (2H), 5.13 (ddd, J = 8.6, 4.9, 0.7 Hz, 1H), 5.02 (ddd,

J = 8.4, 5.6, 0.7 Hz, 1H), 3.80 (s, 3H), 2.56-2.75 (2H), 2.26-2.49 (2H), 1.83-1.92 (m, 1H),

1.41 (s, 3H), 1.33-1.44 (1H); E isomer (minor): 7.15-7.25 (1H), 6.70-6.81 (3H), 5.61-5.76

(1H), 5.31-5.48 (1H), 4.94-5.15 (2H), 3.80 (s, 3H), 2.52-2.81 (2H), 2.22-2.50 (2H), 1.77

- 57 -

13 (t, J = 8.9 Hz, 1H), 1.43 (s, 3H), 1.28-1.36 (1H); C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.4, 159.6, 143.3, 131.2, 129.9, 129.3, 120.8, 114.2, 111.2, 85.4, 82.2,

57.0, 56.4, 55.1, 35.4, 29.7, 19.1; E isomer (minor): 212.5, 143.2, 132.1, 131.1, 129.2,

-1 120.9, 111.1, 84.7, 81.0, 61.9, 56.7, 35.6, 34.4; IR (CHCl3, cm ) 2039, 1966, 1604, 1492,

+ 1460, 1269; HRMS(FAB) M calcd. for C19H20O4Fe 340.0762, found 340.0760.

(OC)3Fe OMe (±)-Tricarbonyl((2S)-2-5-η-8-(3’-methoxy)-phenyl-

(2E,4E)-2,4,6-octatriene)iron, inseparable mixture of

6Z and 6E isomers (2.102j). According to the general procedure 630 mg (1.32 mmol) of

phosphonium salt 2.101j in 8 mL dry THF was treated with 0.48 mL n-BuLi (2.5M in

hexanes, 1.2 mmol). Addition of 168 mg complex 2.100 (0.71 mmol) in 5 mL dry THF

afforded 67 mg of 2.102j as a yellow oil, 30% yield (based on recovered started

1 material). TLC Rf 0.46 (EtOAc:Hexanes 1:15); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 7.24-7.16 (1H), 6.81-6.69 (3H), 5.87-5.41 (2H), 5.20 (dd, J = 8.6, 4.8 Hz,

1H), 5.09-4.96 (m, 1H), 3.80 (s, 3H), 3.44 (d, J = 5.5 Hz, 2H), 1.99 (t, J = 8.5 Hz), 1.45-

1.30 (4H); E isomer (minor): 3.79 (s, 3H), 3.28 (d, J = 6.9 Hz, 3H), 1.81 (t, J = 9.4 Hz,

13 1H); C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.3, 159.7, 141.7, 131.7,

129.4, 128.9, 120.8, 114.0, 111.5, 85.6, 82.4, 57.2, 56.0, 55.1, 34.1, 19.2; E isomer

(minor): 159.7, 141.6, 133.1, 130.0, 129.3, 120.9, 113.9, 111.8, 85.0, 81.2, 61.4, 56.9; IR

-1 + (CHCl3, cm ) 2039, 1966, 1604, 1499, 1446, 1262; HRMS(FAB) M calcd. for

C19H20O4Fe 354.0554, found 354.0487.

- 58 -

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-10-(4’-methoxy)-

OMe phenyl-(2E,4E)-2,4,6-decatriene)iron, inseparable mixture of 6Z and 6E isomers (2.102k). According to the general procedure 350 mg (0.69 mmol) of phosphonium salt 2.101k in 5 mL dry THF was treated with 0.28 mL n-BuLi (2.5M in hexanes, 0.7 mmol). Addition of 136 mg complex 2.100

(0.58 mmol) in 5 mL dry THF afforded 137 mg of 2.102k as a yellow oil, 62% yield

1 (92% borsm). TLC Rf 0.44 (EtOAc:Hexanes 1:15); H NMR (200 MHz, CDCl3) δ (ppm)

Z isomer (major): 7.11-6.80 (unresolved AB quartet, 4H), 5.75-5.35 (2H), 5.13 (ddd, J =

8.7, 4.9, 0.9 Hz, 1H), 5.02 (dd, J = 8.4, 5.3 Hz, 1H), 3.79 (s, 3H), 2.58 (t, J = 7.6 Hz, 2H);

13 C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.4, 157.7, 134.4, 131.0, 130.9,

129.3, 113.7, 85.3, 82.1, 56.9, 56.7, 55.2, 34.5, 31.1, 27.4, 19.2; E isomer (minor): 134.4,

-1 132.0, 131.8, 84.7, 81.0, 62.3, 34.3, 32.1, 31.0, 19.2; IR (CHCl3, cm ) 2039, 1966, 1519,

+ 1249; HRMS(FAB) M -3CO calcd. for C17H22OFe 298.1020, found 298.1024.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-9-furan-2-yl-(2E,4E)-2,4,6- O nonatriene)iron, inseparable mixture of 6Z and 6E

isomers (2.102l). According to the general procedure 538 mg (1.19 mmol) of

phosphonium salt 2.101l in 20 mL dry THF was treated with 0.44 mL n-BuLi (2.5M in

hexanes, 1.1 mmol). Addition of 174 mg complex 2.100 (0.74 mmol) in 10 mL dry THF

afforded 162 mg of 2.102l as a yellow oil, 67% yield. TLC Rf 0.36 (EtOAc:Hexanes

1 1:24); H NMR (200 MHz, CDCl3) δ (ppm) Z isomer (major): 7.30 (s, 1H), 6.29-6.27

(m, 1H), 6.02-5.97 (m, 1H), 5.74-5.29 (2H), 5.14 (dd, J = 8.6, 4.9 Hz, 1H), 5.03 (dd, J =

8.1, 5.3 Hz, 1H), 2.85-2.60 (2H), 2.50-2.25 (2H), 1.88 (t, J = 8.9 Hz, 1H), 1.45-1.28

- 59 -

13 (4H); E isomer (minor): 1.76 (t, J = 9.1 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.3, 155.3, 140.9, 131.6, 129.4, 110.1, 105.1, 85.4, 82.2, 57.0, 56.2,

27.5, 26.4, 19.2; E isomer (minor): 212.5, 155.3, 140.8, 132.3, 130.5, 110.0, 105.1, 84.8,

-1 + 81.0, 61.7, 56.7, 31.1, 27.7; IR (CHCl3, cm ) 2033, 1962; HRMS(FAB) M calcd. for

C16H16O4Fe 328.0398, found 328.0395.

(OC)3Fe (±)-Tricarbonyl((2S)-2-5-η-9-furan-3-yl-(2E,4E)-2,4,6- O nonatriene)iron, inseparable mixture of 6Z and 6E isomers (2.102m). According to the general procedure 316 mg (0.7 mmol) of phosphonium salt 2.101m in 20 mL dry THF was treated with 0.96 mL n-BuLi (1.6M in

hexanes, 1.54 mmol). Addition of 138 mg complex 2.100 (0.58 mmol) in 10 mL dry THF

1 afforded 186 mg of 2.102m as a yellow oil, 98% yield. TLC Rf 0.36 (Hexanes); H NMR

(200 MHz, CDCl3) δ (ppm) Z isomer (major): 7.36-7.34 (1H), 7.25-7.22 (1H), 6.29 (dd,

J = 1.7, 0.8 Hz, 1H), 5.75-5.30 (2H), 5.14 (ddd, J = 8.6, 4.8, 0.7 Hz, 1H), 5.03 (dd, J =

8.4, 5.0 Hz, 1H), 2.57-2.19 (4H), 1.89 (t, J = 8.6 Hz, 1H), 1.45-1.31 (4H); E isomer

13 (minor): 7.21-7.20 (1H), 6.25 (dd, J = 1.8, 0.9 Hz, 1H); C NMR (50 MHz, CDCl3) δ

(ppm) Z isomer (major): 212.4, 142.7, 138.9, 131.3, 130.0, 124.4, 110.9, 85.4, 82.2, 57.0,

56.4, 28.4, 24.4, 19.1; E isomer (minor): 212.5, 142.6, 138.9, 132.2, 131.1, 124.2, 84.8,

-1 81.0, 61.9, 56.7, 33.1, 24.5; IR (CHCl3, cm ) 2039, 1966.

General procedure for the cyclization reactions. The respective substrates were stirred with 1 mL formic acid 95-97% at 50 °C for 3 to 6 hours. The reaction was

- 60 -

monitored by TLC and quenched with a saturated solution of NaHCO3 (5mL) at room

temperature. The mixture was diluted with diethyl ether (100 mL), the organic layer was

separated, washed twice with saturated solution of NaHCO3 (2 x 50 mL) and dried over

Na2SO4. The solvent was then removed under reduced pressure, and the product was purified by flash-chromatography.

(OC)3Fe OCHO (±)-Tricarbonyl((2S)-2-5-η-5-((1’S,3’R)-3’-formyloxy-

cyclohex-1’-yl)-(2E,4E)-pentadiene)iron (2.103a).

According to the general procedure 59.5 mg (0.21 mmol) of 2.102a afforded 49.6 mg

1 (0.15 mmol) 2.103a as a yellow oil, 72% yield. TLC Rf 0.36 (EtOAc: Hexanes 1:9); H

NMR (200 MHz, CDCl3) δ (ppm) 8.01 (d, J = 0.9 Hz, 1H), 5.04 (d, J = 4.1 Hz, 1H), 4.99

(d, J = 4.4 Hz, 1H), 4.80 (tt, J = 10, 4.4 Hz, 1H), 1.70-2.14 (4H), 1.39 (d, J = 6.2 Hz, 3H),

13 1.01-1.33 (6H), 0.78 (dd, J = 8.8, 7.2 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm)

212.6, 160.6, 85.4, 82.2, 72.4, 68.8, 57.5, 41.6, 41.5, 33.7, 31.2, 23.7, 19.1; IR (CHCl3,

-1 + cm ) 2039, 1970, 1727, 1460, 1387, 1183; HRMS(EI) M calcd. for C15H18O5Fe

334.0504, found 334.0488.

(OC)3Fe OCHO (±)-Tricarbonyl((2S)-2-5-η-5-((1’S,2’R,3’R)-2’-methyl-3’-

formyloxycyclohex-1’-yl)-(2E,4E)-pentadiene)iron

(2.103b). According to the general procedure 41.1 mg (0.14 mmol) of 2.102b afforded 31

mg (0.09 mmol) 2.103b as a yellow solid, m.p. 112-114°C, 70% yield. TLC Rf 0.3

1 (EtOAc:Hexanes 1:9); H NMR (200 MHz, CDCl3) δ (ppm) 8.08 (d, J = 1.0 Hz, 1H),

5.02 (d, J = 4.6 Hz, 1H), 4.97 (d, J = 3.5 Hz, 1H), 4.55 (dt, J = 10.1, 4.4 Hz, 1H), 1.70-

- 61 -

2.05 (4H), 1.40 (d, J = 6.2 Hz, 3H), 1.10-1.38 (4H), 1.02 (d, J = 6.4 Hz, 3H), 0.65-0.96

13 (2H); C NMR (50 MHz, CDCl3) δ (ppm) 160.8, 84.0, 83.8, 77.3, 68.7, 57.8, 47.8, 43.4,

-1 35.9, 31.7, 23.8, 19.1, 15.6; IR (CHCl3, cm ) 2045, 1966, 1729, 1466, 1387, 1190;

+ HRMS(EI) M -CO calcd. for C16H20O5Fe 320.0711, found 320.0745.

(±)-Tricarbonyl((2S)-2-5-η-5-((1’S)-1’,2’,3’,4’,5’,6’,7’,8’- (OC)3Fe octahydronaphthalen-1’-yl)-(2E,4E)-pentadiene)iron (2.103e’).

According to the general procedure 34.1 mg (0.1 mmol) of 2.102e afforded 23.8 mg (0.07

1 mmol) 2.103e as a yellow oil, 70% yield. TLC Rf 0.68 (Hexanes); H NMR (200 MHz,

CDCl3) δ (ppm) 5.11 (ddd, J = 8.8, 4.8, 0.9 Hz, 1H), 4.98 (dd, J = 8.8, 4.9 Hz, 1H), 1.45-

2.35 (15H), 1.39 (d, J = 6.3 Hz, 1H), 1.02-1.17 (m, 1H), 0.96 (t, J = 9.7 Hz, 1H); 13C

NMR (50 MHz, CDCl3) δ (ppm) 129.7, 129.5, 84.1, 83.9, 70.3, 57.3, 44.3, 33.6, 31.1,

-1 + 30.9, 28.6, 23.4, 22.9, 20.3, 19.1; IR (CHCl3, cm ) 2039, 1966; HRMS(EI) M calcd. for

C18H22O3Fe 342.0918, found 342.0905.

(±)-Tricarbonyl((2S)-2-5-η-5-((1’S)-1’,2’,3’,4’-tetrahydro- (OC)3Fe naphthalen-1’-yl)-(2E,4E)-pentadiene)iron (2.103h). According

to the general procedure 79.7 mg (0.24 mmol) of 2.102h afforded 19.8 mg (0.06 mmol)

1 2.103h as a yellow oil, 25% yield. TLC Rf 0.44 (Hexanes); H NMR (200 MHz, CDCl3)

δ (ppm) 7.34-7.40 (m, 1H), 7.01-7.19 (3H), 5.33 (ddd, J = 8.9, 5.1, 0.9 Hz, 1H), 5.06 (dd,

J = 8.6, 4.9 Hz, 1H), 2.77 (t, J = 5.9 Hz, 2H), 2.44-2.65 (m, 1H), 1.66-2.10 (4H), 1.40 (d,

13 J = 6.1 Hz, 3H), 1.05-1.22 (2H); C NMR (50 MHz, CDCl3) δ (ppm) 139.9, 136.5,

- 62 -

129.2, 128.4, 126.1, 125.7, 84.7, 83.4, 70.5, 57.9, 43.2, 33.1, 29.7, 20.8, 19.2; IR (CHCl3,

-1 + cm ) 2039, 1966; HRMS(FAB) M calcd. for C18H18O3Fe 338.0605, found 338.0632.

OMe (±)-Tricarbonyl((2S)-2-5-η-5-((1’S)-6’-methoxy-1’,2’,3’,4’-

(OC) Fe 3 tetrahydronaphthalen-1’-yl)-(2E,4E)-pentadiene)iron

(2.103i). According to the general procedure 60.5 mg (0.16 mmol) of 2.102i afforded 55.6 mg (0.15 mmol) 2.103i as a yellow solid, m.p. 58 °C, 92%

1 yield. TLC Rf 0.36 (EtOAc:Hexanes 1:15); H NMR (200 MHz, CDCl3) δ (ppm) 7.28 (d,

J = 7.7 Hz, 1H), 6.71 (dd, J = 8.6, 2.8 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 5.30 (ddd, J =

8.8, 4.8, 0.9 Hz, 1H), 5.05 (dd, J = 8.8, 4.8 Hz, 1H), 3.76 (s, 3H), 2.75 (t, J = 5.7 Hz, 2H),

2.43-2.55 (m, 1H), 1.63-2.08 (4H), 1.39 (d, J = 6.2 Hz, 3H), 1.09-1.20 (2H); 13C NMR

(50 MHz, CDCl3) δ (ppm) 157.8, 137.7, 132.1, 129.4, 113.5, 112.1, 84.6, 83.4, 70.9,

-1 57.8, 55.2, 42.5, 33.3, 30.1, 20.9, 19.2; IR (CHCl3, cm ) 2039, 1966, 1262; HRMS(FAB)

+ M calcd. for C19H20O4Fe 368.0711, found 368.0729.

OMe (±)-Tricarbonyl((2S)-2-5-η-5-((1’S)-5’-methoxyindan-1’- (OC)3Fe yl)-(2E,4E)-pentadiene)iron (2.103i). According to the general procedure 28.7 mg (0.08 mmol) of 2.102j afforded 4.9 mg (0.014 mmol) 2.103j

1 as a yellow solid, m.p. 83-85 °C, 17% yield. TLC Rf 0.36 (EtOAc:Hexanes 1:15); H

NMR (200 MHz, CDCl3) δ (ppm) 7.12 (d, J = 7.7 Hz, 1H), 6.74-6.69 (2H), 5.26 (ddd, J

= 8.5, 4.9, 0.9 Hz, 1H), 5.11 (dd, J = 8.6, 4.9 Hz, 1H), 3.78 (s, 3H), 2.96-2.77 (3H), 2.46-

2.31 (m, 1H), 1.86 (m, 1H), 1.41 (d, J = 6.2 Hz, 3H), 1.21-1.10 (m, 1H), 0.99 (t, J = 9.3

13 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm) 159.1, 145.6, 138.7, 124.1, 112.2, 109.9,

- 63 -

-1 85.7, 83.0, 67.5, 57.7, 55.4, 49.6, 35.9, 31.6, 19.2; IR (CHCl3, cm ) 2039, 1966, 1262;

+ HRMS(EI) M -CO calcd. for C17H18O3Fe 326.0605, found 326.0603.

(±)-Tricarbonyl((2S)-2-5-η-5-((4’S)-4’,5’,6’,7’-tetrahydro- (OC)3Fe O benzofuran-4’-yl)-(2E,4E)-pentadiene)iron (2.103l). According

to the general procedure 19 mg (0.06 mmol) of 2.102l afforded 5.7 mg (0.017 mmol)

1 2.103l as a yellow oil, 30% yield. TLC Rf 0.40 (EtOAc:Hexanes 1:24); H NMR (200

MHz, CDCl3) δ (ppm) 7.23 (dd, J = 1.9, 1.0 Hz, 1H), 6.31 (d, J = 1.8 Hz, 1H), 5.21 (ddd,

J = 8.6, 4.9, 0.9 Hz, 1H), 5.08 (dd, J = 8.8, 5.2 Hz, 1H), 2.57-2.51 (2H), 2.41-2.28 (m,

1H), 2.05-1.91 (2H), 1.81-1.62 (m, 1H), 1.56-1.45 (m, 1H), 1.40 (d, J = 6.2 Hz, 3H),

13 1.18-1.04 (m, 1H), 0.89 (td, J = 9.3, 0.9 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm)

212.5, 150.2, 140.4, 120.7, 109.4, 85.5, 82.7, 68.5, 57.7, 38.6, 32.5, 23.0, 22.0, 19.2; IR

-1 + (CHCl3, cm ) 2037, 1958; HRMS(EI) M calcd. for C16H16O4Fe 328.0398, found

328.0385.

2.7 Literature cited.

(1) Pearson, A. J.; Ray, T.; Richards, I. C.; Clardy, J.; Silveira, L. "Conjugate

Phenylselenolactonization Coupled with Allylic Selenoxide Rearrangement for

Functionalizing Dienylacetic Acids." Tetrahedron Lett. 1983, 24, 5827-5830.

(2) Mahler, J. E.; Petit, R. "Organo-Iron Complexes. II. π-Pentadienyl- and π-

1,5-Dimethylpentadienyliron Tricarbonyl Cations." J. Am. Chem. Soc. 1963, 85, 3955.

- 64 -

(3) Mahler, J. E.; Petit, R. "Organo-Iron Complexes. III. Reactions of the syn-

1-Methylpentadienyliron Tricarbonyl Cation." J. Am. Chem. Soc. 1963, 85, 3959.

(4) Bayoud, R. S.; Biehl, E. R.; Reeves, P. C. "Reactions of unsymmetrically

substituted pentadienyliron tricarbonyl cations with water." J. Organomet. Chem. 1978,

150, 75-83.

(5) Bayoud, R. S.; Biehl, E. R.; Reeves, P. C. "Reaction of pentadienyliron

tricarbonyl cations with hydride donors." J. Organomet. Chem. 1979, 174, 297-303.

(6) Donaldson, W. A.; Ramaswamy, M. "(η-5-1-Substituted-Pentadienyl)

(Tricarbonyl)Iron(+1) Cations - Reactivity with Malonate Nucleophiles." Tetrahedron

Lett. 1988, 29, 1343-1346.

(7) Maglio, G.; Palumbo, R. "Stereochemistry of the reaction between amines and the pentadienyliron tricarbonyl cation." J. Organomet. Chem. 1974, 76, 367-371.

(8) Hossain, M. A.; Jin, M. J.; Donaldson, W. A. "Reactivity of acyclic

(pentadienyl)iron(1+) cations with weak carbon nucleophiles." J. Organomet. Chem.

2001, 630, 5-10.

(9) Clinton, N. A.; Lillya C. P. "Conformational Analysis of Tricarbonyl

(diene) iron Compounds." J. Am. Chem. Soc. 1970, 92, 3058-3064.

(10) Clinton, N. A.; Lillya C. P. "Tricarbonyl (trans-π-pentadienyl) iron

Cations. Solvolysis of Complexed Dienyl Dinitrobenzoates and Protonation of

Complexed Dienones." J. Am. Chem. Soc. 1970, 92, 3065-3075.

(11) Roush, W. R.; Wada, C. K. "Highly Stereoselective Substitution-

Reactions of Functionalized η-4-[3(E),5(E)-Heptadien-2-Ol]Iron Tricarbonyl

Complexes." Tetrahedron Lett. 1994, 35, 7347-7350.

- 65 -

(12) Wada, C. K.; Roush, W. R. "Highly Stereoselective 1,4-Addition

Reactions of Alkylidene Malonate Substituted η-4-(1,3-Butadienyl)Iron(Tricarbonyl)

Complexes." Tetrahedron Lett. 1994, 35, 7351-7354.

(13) Uemura, M.; Minami, T.; Yamashita, Y.; Hiyoshi, K.; Hayashi, Y.

"Regiospecific and Stereospecific Carbon Carbon Bond Formation of η-4-(Trans-

Dienol)Fe(CO)3 Complexes." Tetrahedron Lett. 1987, 28, 641-644.

(14) Roush, W. R.; Wada, C. K. "Application of η-4-Diene Iron Tricarbonyl

Complexes in Acyclic Stereocontrol - Asymmetric-Synthesis of the as-Indacene Unit of

Ikarugamycin (a Formal Total Synthesis)." J. Am. Chem. Soc. 1994, 116, 2151-2152.

(15) Boeckman, R. K.; Weidner, C. H.; Perni, R. B.; Napier, J. J. "An

Enantioselective and Highly Convergent Synthesis of (+)- Ikarugamycin." J. Am. Chem.

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(19) Braun, A.; Toupet, L.; Lellouche, J. P. "The η-4-dienyl tricarbonyliron moiety in heterocyclic synthesis. A rare 1,2-migration of the complexation site as a key step for a novel stereoselective preparation of trans-2,3- disubstituted 1,4-dioxanes." J.

Org. Chem. 1996, 61, 1914-1915.

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Kirschbaum, K. "Stereocontrolled cyclization of unactivated alkene onto cationic dienyl iron tricarbonyl systems." Tetrahedron Lett. 1998, 39, 5919-5922.

(21) Pearson, A. J.; Alimardanov, A. R.; Kerber, W. D. "Cationic cyclizations of (diene)iron tricarbonyl complexes with pendant alkenes and arenes." J. Organomet.

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(22) Franck-Neumann, M.; Geoffroy, P.; Hanss, D. "Cyclization and fluorination of 5-hexenols with boron trifluoride etherate. Stereoselective synthesis of

(optically active) fluorinated cyclohexane derivatives by cyclization of omega-pentenyl pentadienol tricarbonyl iron complexes." Tetrahedron Lett. 1999, 40, 8487-8490.

(23) Howell, J. A. S.; Squibb, A. D.; Bell, A. G.; McArdle, P.; Cunningham,

D.; Goldschmidt, Z.; Gottlieb, H. E.; Hezronilangerman, D.; Gree, R. "Resolution,

Racemization, and Epimerization in Acyclic (Diene)Fe(CO)2L and [(Dienyl)Fe(CO)2L]X

Complexes (L=Phosphine, Phosphite)." Organometallics 1994, 13, 4336-4351.

(24) Ley, S. V.; Burckhardt, S.; Cox, L. R.; Meek, G. "1,5-Asymmetric induction of chirality: diastereoselective addition of organoaluminium reagents and allylstannanes into aldehyclie groups in the side-chain of π-allyltricarbonyliron lactone complexes." J. Chem. Soc.-Perkin Trans. 1 1997, 3327-3337.

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(25) Takemoto, Y.; Yoshikawa, N.; Baba, Y.; Iwata, C.; Tanaka, T.; Ibuka, T.;

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Regio- and stereocontrolled functionalization of acyclic diene ligands." J. Am. Chem.

Soc. 1999, 121, 9143-9154.

(26) Alimardanov, A. R., Case Western Reserve University, 1998.

(27) Franck-Neumann, M.; Geoffroy, P.; Hanss, D. "Highly stereoselective

biomimetic polyene cyclizations using chiral pentadienol tricarbonyliron complexes."

Tetrahedron Lett. 2002, 43, 2277-2280.

(28) Knölker, H. J. "Efficient synthesis of tricarbonyliron-diene complexes -

Development of an asymmetric catalytic complexation." Chem. Rev. 2000, 100, 2941-

2961.

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Diastereoselective Reactions of Optically-Active Dienone-Iron Tricarbonyl Complexes -

Synthesis of Tertiary Alpha-Hydroxyaldehydes and Gamma-Hydroxycrotonaldehydes as

Pure Enantiomers of Known Absolute-Configuration." Synlett 1990, 641-642.

(30) Anson, C. E.; Hudson, R. D. A.; Osborne, S. A.; Smyth, D. G.;

Stephenson, G. R. "η(4) to η(5): Stereocontrolled reactivation of exocyclic triene iron complexes." Tetrahedron Lett. 1998, 39, 7603-7606.

(31) Bell, P. T.; Dasgupta, B.; Donaldson, W. A. "Remote diastereoselective control via organoiron methodology: Stereoselective preparation of 4,6-, 5,7- and 6,8- dien-2-ol (tricarbonyl)iron complexes." J. Organomet. Chem. 1997, 538, 75-82.

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model compounds." J. Org. Chem. 2000, 65, 4923-4929.

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Organoaluminum Cyclization Reaction." J. Org. Chem. 1966, 31, 3419-3422.

(35) Gream, G. E.; Serelis, A. K.; Stoneman, T. I. "The 9-Decalyl and Related

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4069-4071.

- 69 -

Chapter 3.

Iron tricarbonyl pentadienyl cation as initiator for

cascade polycyclization reactions.

- 70 - 3.1 Introduction to tandem bicyclizations. Biosynthetic relevance.

In 2002 Franck-Neumann et al. reported a very interesting use for the cyclizations of iron tricarbonyl pentadienyl stabilized cations with pendant alkenes and arenes,1 that is

initiation of a double cyclization to afford a decalin framework (Scheme 3.1). The cation

is generated by the previously reported formic acid mediated dehydroxylation of

(OC)3Fe (OC) Fe Li 3 O OH

3.1 Et2O, -78°C, 42% 3.2

HCOOH, pentane 0°C to 20°C, 53%

OH OCHO

(OC)3Fe 1) MeOH, H2O, NaHCO3, 88% H H 2) CAN, acetone, -78°C, 84%

3.4 3.3 Scheme 3.1

tertiary alcohols with anchimeric assistance from the iron. Interestingly, only one

diastereomer was isolated from the cyclization reaction (3.3), while for a similar simple

cyclization employing a tertiary alcohol a minor diastereomer could be detected. This

suggests a leakage of stereochemistry in the cyclization step, although the

dehydroxylation was triggered in that case by a Lewis acid – BF3·OEt2 – (Section 2.4,

Scheme 2.17,2 – for the polyene substrates, treatment with the same Lewis acid afforded

only a complex inseparable mixture of “cyclization – elimination” products). Hydrolysis

of the formyloxy substituent and CAN mediated demetallation afforded highly

functionalized decalin 3.4 in very good yield.

- 71 - Similar substrates bearing aromatic nucleophilic cyclization terminators, both activated and unactivated, afforded clean cyclizations upon treatment with either formic acid or boron trifluoride etherate (eq 3.1). Diastereoselectivity was also observed in both cases, no minor diastereoisomer being reported. Cyclizations of secondary alcohols of the type Ψ exo / endo,3,4 have also been reported, however no experimental or structural data

was provided.

R (OC)3Fe R (OC)3Fe OH i H (3.1)

3.5 R = H i = HCOOH 3.6 R = H 69% 3.7 R = OMe i = BF3·OEt2 3.8 R = OMe 90%

This type of tandem reaction has deep roots in previous efforts from numerous research groups in biomimetic polycyclization of polyenic substrates toward steroidal and polycyclic terpenoid frameworks.

H

HO H squalene lanosterol

C D

AB HO sterols

Scheme 3.2

From a synthetic standpoint, biosynthesis of sterols (Scheme 3.2) is one of the most interesting reactions Nature has managed to develop over some billion years of

- 72 - evolution. While biochemists managed to establish squalene as the precursor of lanosterol, which in turn is converted into other sterols, the intricate process by which this transformation takes place remained an enigma for a very long time. If we take a closer look at squalene, we can see that the future stereochemistry of the sterols is encoded in a succession of E double bonds. While they can afford no less than 128 different stereochemical products upon polycyclization, only one is formed during the natural process.

The natural process is an enzymatic one, and the initial view was that the enzyme holds the substrate in place, with the olefinic bonds properly aligned to afford just one stereoisomer. One cannot however but wonder: what if the course of the reaction is actually set by the intrinsic susceptibility of this particular “all-E” isomer of the polyolefin to go one way and only one?! This hypothesis was formulated independently by Stork and Eschenmoser (and therefore is known today as the “Stork-Eschenmoser postulate”),5,6 and may be graphically illustrated as in Scheme 3.3. Essentially it states that protonation of the epoxide ring in 3.9 (product of epoxidation of squalene at the 2,3 position, also shown to be one of the intermediates of the biosynthesis) will afford

- Y Y R R R O OH OH 3.9 3.10 3.11

Scheme 3.3 tertiary carbocation 3.10. The cation is then captured by the neighboring double bond, affording another tertiary carbocation, to be attacked by the next double bond, and so on.

The addition along the median double bond in this particular example goes in a trans

- 73 - fashion, to afford a trans fused double cycle. If the median double bond has a cis stereochemistry as in 3.12, the addition still goes in trans fashion, to a afford a cis fused

(3.2) OH OH Y- Y 3.12 3.13 double cycle (eq. 3.2). In either case, Y may be an external nucleophile, or the next double bond; for the latter case the process is repeated in a similar manner, and the same outcome is expected.

Initial experiments, however, failed to verify the hypothesis. Both cis and trans

polyolefinic precursors resulted in trans fused cyclization products, presumably because

of a stepwise mechanism that involved a common monocyclic intermediate, cyclization-

XXX + 1) H H+ Nu

2) -H+ H 3.14 3.15 3.16

X X Nu X H 3.17 3.18

Scheme 3.4 elimination product 3.15, containing a double bond that is reprotonated (Scheme 3.4).7,8

This was ultimately ruled out as not being biomimetic, because when the enzymatic process was carried out in presence of D2O, no deuterium incorporation was detected in

the cyclized products (reprotonation of a hypothetical intermediate would have to include

some deuterium).9,10

- 74 - In 1968 W. S. Johnson reported the first experimental results that supported the

Stork-Eschenmoser postulate, under very particular circumstances (acidic cleavage of a sulfonate ester instead of protonation of double bonds or epoxides, and initial use of only disubstituted olefinic bonds; Scheme 3.5).11

H HH OH OH H+ +

H H OSO C H NO 2 6 4 2 3.20 3.21 3.19

H H OH OH H+ +

H H OSO2C6H4NO2 3.23 3.24 3.22

Scheme 3.5

This methodology evolved in time into a valuable synthetic tool, with numerous variations and end uses.12-44 Equation 3.3 depicts the last step of a concise total synthesis

of (+)-α-onocerin by Corey et al.45 The bicyclization is triggered by opening of an

O H OH

TMS

1) MeAlCl2, CH2Cl2, -94 °C, 15 min. (3.3) 2) TBAF, 1h. TMS

HO O H 3.25 3.26, (+)-α-Onocerin epoxide ring, mediated however by a Lewis rather than protic acid, while the termination step is elimination of a TMS group rather than nucleophile insertion.

- 75 - 3.2 Polyene bicyclizations using iron tricarbonyl stabilized pentadienyl

carbocation as initiator - a new method.

The previous chapter presented a new method to generate iron tricarbonyl stabilized carbocations, that are captured in situ by olefinic or aromatic pendant

nucleophiles to selectively afford cyclization products containing one or more new

stereocenters.46 As this method presents significant advantages in some cases over the previously reported Lewis / protic acid mediated cyclization of diastereomeric alcohols, assessing its suitability for polycyclization reactions was considered worthwhile. This study deals with cyclization reactions terminated by an aromatic nucleophile to afford substituted octahydrophenanthrene derivatives. We envisioned this reaction to proceed under acidic conditions by the following formal steps (Scheme 3.6):

1) anchimeric assistance from the iron atom will promote regiospecific protonation of the disubstituted double bond adjacent to the iron tricarbonyl diene group;

R1

R (OC)3Fe 1 (OC)3Fe + R2 H R2

3.27 3.30

+ H - H+

R1 R1

(OC) Fe (OC)3Fe 3 R R2 2

3.28 3.29 R1 = OMe, various substitution patterns R2 = H, Me

Scheme 3.6

- 76 - 2) nucleophilic attack of the pendant double bond on the newly created cation, anti to the iron tricarbonyl group, will stereoselectively afford a 6 membered ring 3.29;

3) the terminal aromatic nucleophile will capture the second carbocation to afford a trans decalin derivative, 3.30 (an octahydrophenanthrene), consistent with the Stork-

Eschenmoser postulate.

Several substrates were prepared that cyclized in various yields and with complete diastereoselectivity. We will discus respectively: preparation of substrates, studies on the cyclization reaction and NMR based stereochemistry assignment.

3.2.1 Synthesis of polyene substrates.

Substrates were prepared by a linear sequence of reactions which was deemed to be the most reliable, although a few surprising results were encountered along the way.

We started with commercially available cinnamic acid derivatives 3.31a-d, Scheme 3.7.

Fischer esterification was followed by conjugate reduction to afford alcohols 3.33a-d,47 that were oxidized to aldehydes 3.34a-d.

COOH COOMe CH2OH CHO

CH3OH, H2SO4 LiAlH4 PCC

90-99% 90-95% 70-85% (c: 18%) R R R R 3.31a-d 3.32a-d 3.33a-d 3.34a-d a: unsubstituted b: R = 3-OMe c: R = 4-OMe d: R = 2,3-di-OMe

Scheme 3.7

- 77 - For the para-methoxy substituted methyl cinnamate 3.32c however, the results of in situ conjugate reduction with LiAlH4 were rather poor and an alternate three step route had to

be employed: hydrogenation of the double bond48 of the cinnamic acid, then esterification followed by reduction of the ester group (Scheme 3.8). This sequence is only one step longer than that in Scheme 3.7.

COOH COOMe CH2OH

1) H2, Pd/C 2) CH3OH, H2SO4 LiAlH4, 92%

93% over 2 steps OMe OMe OMe 3.31c 3.35c 3.33c

Scheme 3.8

The required pendant double bond was then constructed by means of the Roush-

Masamune modification of the Horner-Wadsworth-Emmons olefination reaction,49,50 with exclusive E selectivity (eq. 3.4), except for compound 3.36b’, which was obtained as a mixture of E : Z = 5 : 1. As we shall discuss later, for the purpose of the cyclization studies, we used the 3.36b’ E/Z mixture.

OOEt CH O 3 OEt R2 2 (OEt)2(O)PCH(R )COOEt O + (3.4)

DBU, LiCl, CH3CN 75-90% R1 OMe R1 3.34a-d 3.36a-d, b' Z-3.36b' (all E) a : unsubstituted b : R1 = 3-OMe, R2 = H 1 2 b': R = 3-OMe, R = CH3 c : R1 = 4-OMe, R2 = H 1 2 d : R = 2,3-di-OMe, R = H

- 78 - DIBAL-H reduction of α,β-unsaturated esters 3.36 afforded allylic alcohols 3.37 in very good yields. Mesylation,51 dimethyl sodiomalonate addition and

decarboxylation52,53 afforded esters 3.39, also in very good yields (Scheme 3.9).

OMe OMe

O OH O O R2 R2 R2 OEt 1) MeSO2Cl, Et3N, THF DIBAL-H, CH2Cl2 2) CH2(COOMe)2, NaH, THF

Ar 85-90% Ar 55-85% combined yield Ar 3.36a-d,b' 3.37a-d,b' 3.38a-d,b'

NaCl, H2O, DMF 80-90% Br OH OMe

O R2 R2 2 1) MeSO2Cl, Et3N, THF R 2) LiBr, THF, reflux LiAlH4, THF

85-95% combined yield 90-100% Ar Ar Ar 3.41a-d,b' 3.40a-d,b' 3.39a-d,b'

a : unsubstituted b : R1 = 3-OMe, R2 = H 1 2 b': R = 3-OMe, R = CH3 c : R1 = 4-OMe, R2 = H 1 2 d : R = 2,3-di-OMe, R = H

Scheme 3.9

The allylic mesylate of alcohol 3.37b, when left overnight on the vacuum pump reacted to afford a complex mixture of cyclization/oligomerization products. Thus, all the mesylates we prepared subsequently were used immediately in the malonate addition step. Finally, LiAlH4 reduction of esters 3.39, followed by mesylation and nucleophilic

introduction of bromide,51 afforded bromides 3.41.

- 79 - As in the previous studies (Chapter 2) phosphonium salts were prepared in good yield by a literature procedure,54 and used in Wittig olefination55 with the iron tricarbonyl sorbaldehyde complex 3.43 to afford target substrates 3.44, as inseparable Z/E mixtures at the double bond adjacent to the iron tricarbonyl diene moiety (Scheme 3.10). As established in the preceding chapter, the stereochemistry of this double bond is irrelevant for the purpose of this methodology.

1 R1 R

PPh3, neat, 110°C 2 R2 R 80-100% - + Br Br [Ph3P

3.41a-d,b' 3.42a-d,b'

Fe(CO)3

1 R CHO 3.43 (OC)3Fe nBuLi, -78°C to rt, THF R2 55-83%

3.44a-d,b' (Z/E) a : unsubstituted b : R1 = 3-OMe, R2 = H 1 2 b': R = 3-OMe, R = CH3 c : R1 = 4-OMe, R2 = H 1 2 d : R = 2,3-di-OMe, R = H

Scheme 3.10

3.2.2 Cyclization studies.

We began our studies on the double cyclization reaction with substrate 3.44b, which was deemed to bear the best terminator for the double cyclization, that is a

- 80 - methoxy group para to the cyclization position. This substrate was subjected to the reaction conditions we have successfully used for simple cyclizations: neat HCOOH, 50

°C – disappointingly, only 35% of the expected cyclization product could be isolated from a complex mixture of products (eq. 3.5).

OMe OMe

(OC) Fe HCOOH, neat (OC) Fe 3 50 °C 3 (3.5)

35%

3.44b, Z/E 3.45b

Obviously, the neat formic acid approach is not appropriate anymore, and we will explain why. As we have seen in the previous chapter, for a simple cyclization of a pendant olefinic substrate, the formic acid plays a double role: a) it protonates the double bond adjacent to the diene moiety; b) it acts as an external nucleophile to capture the cation that is produced upon cyclization (Scheme 2.21). For the simple pendant aromatic substrates, the acid is only needed as proton source, and performs well as long as only one ring is being formed (eq. 2.15 - as a nucleophile, it provides little competition to the pendant aromatic nucleophile, which has the entropic advantage). However, returning to the double cyclization reaction, unlike the simple cyclizations, this reaction goes through two cationic intermediates (Scheme 3.6), therefore the chances for side reactions are higher. Since in this case (pendant aromatic nucleophile, both simple and double cyclizations) the proton is ultimately being regenerated, a catalytic amount of acid should suffice for the reaction to take place. Ideally, an acid without nucleophilic properties should be used.

- 81 - After several attempts to utilize a catalytic amount of acid (we have tried HCOOH with very little success; HPF6 – moderate; pTsOH – no success at all; HBF4 – most promising), we established HBF4·OEt2 complex to be the best reagent, in CH2Cl2, at 0 °C.

When substrate 3.44b was subjected to the new reaction conditions, a very clean

cyclization reaction occurred, affording a mixture of regioisomers, 3.45b and 3.46b, in

OMe

(OC) Fe OMe 3 3.45b, 53%

(3.6) (OC) Fe 3 HBF4, ~ 0.25 equiv. + 3.46b, 30% 0 °C, CH2Cl2 (OC)3Fe 3.44b, Z/E OMe

83% combined yield (eq. 3.6). The regioisomers were easily separable by flash chromatography and/or preparative TLC, with 3.46b having a higher Rf value, possibly because the polar methoxy substituent is in a more hindered position. NMR analysis proved to be quite difficult because of extensive overlap of the resonances of interest.

Ultimately, the stereoselectivity of the cyclization reaction and its adherence to the Stork

– Eschenmoser postulate was established by extensive NMR analysis of the demetallated

products (see later).

The next substrate in the series, 3.44b’, was designed with a number of goals in

mind. First of all, most of the natural products in the steroidal / polycyclic terpenoids

series have angular methyl substituents, both at the A/B and C/D ring junctions (Scheme

3.2). The presence of the methyl substituent on the pendant double bond was deemed to

afford a more stable carbocation upon the first cyclization and eliminate possible minor

- 82 - pathways that may involve 1,2 hydride migration and/or loss of proton (elimination reactions), and thus improve the yield. Finally, the methyl should provide regiocontrol of

the 3-methoxy substituted aromatic terminator, to afford only one regioisomer, unlike

3.44b (Scheme 3.11). Unfortunately, as mentioned earlier, the substrate was obtained

OMe

(OC) Fe OMe 3 3.45b'

(OC)3Fe H+ X 3.46b' (OC)3Fe 3.44b', Z/E OMe

Scheme 3.11 as a mixture of 4 diastereoisomers (Z/E mixture at the double bond adjacent to the diene moiety – irrelevant for the cyclization reaction, and a E : Z = 5 : 1 mixture at the remote double bond). Before attempting any optimization for the olefination, and/or separation, for the purpose of the method, this mixture was used to asses the outcome of the proposed cyclization. Unfortunately, none of the desired products (eq. 3.7) were detected among a rather complex mixture of products. As mentioned in the previous chapter (eq.

2.13), we suspect that there is a very close basicity between the double bond adjacent to the iron tricarbonyl diene moiety and the trisubstituted pendant double bond, that leads to competing protonation. This hypothesis was tested by examining the reaction of

- 83 - OMe

(OC) Fe OMe 3

+ (OC)3Fe H + 3.45 b' OMe (3.7)

(OC)3Fe 3.44 b', Z/E - Z/E

3.47 b' compound 3.41b’ with HBF4·OEt2, in methylene chloride at 0 °C (eq. 3.8), which

afforded a nearly quantitative mixture of cyclization products, 3.48 and 3.49. Further

studies and optimization of this methodology are needed at this point in order to employ a

trisubstituted double bond as a pendant nucleophile.

OMe OMe MeO

HBF4·OEt2 Br + (3.8)

Br CH2Cl2, 0 °C Br 3.48 2 : 1 3.49 3.41b' (app. quantitative)

The following three substrates were prepared in order to test respectively:

3.44a: suitability of an unactivated phenyl ring as a cyclization terminator;

3.44c: unambiguous cyclization by means of a C2 symmetric aromatic terminator;

3.44d: unambiguous cyclization by blocking one possible cyclization site on the aromatic terminator, while providing extra activation.

All three performed as expected, once again with complete diastereoselectivity being observed, with yields that correlate with the nucleophilicity of the aromatic terminator (Scheme 3.12). In the case of substrate 3.44a, bearing an unactivated aromatic

- 84 - (OC)3Fe (OC)3Fe a) 35% (83% borsm) b) 50% (+45% 3.50a)* 3.45a 3.44a, Z/E

OMe OMe (OC)3Fe (OC)3Fe a) 58% (88% borsm) 3.45c 3.44c, Z/E MeO OMe MeO OMe

(OC)3Fe (OC)3Fe a) 85% 3.45d 3.44d, Z/E

a) HBF4, ~ 0.25 equiv., 0 °C, CH2Cl2, 4h. b) stoichiometric HBF4, 0 °C, CH2Cl2, 4h. *) 3.50a: demetallated counterpart of 3.45a ;see Table 3.1. borsm: based on recovered staring material.

Scheme 3.12 terminator, extension of the reaction time did not improve the yield, but rather afforded more demetallated compounds, both starting material and cyclized.

While 13C-NMR and HRMS analysis showed that the cyclization products were single compounds, stereochemical analysis by 1H-NMR spectroscopy proved to be quite difficult due to extensive overlap of the resonances, and removal of the iron tricarbonyl group was examined, in an effort to provide the necessary split in the 1H-NMR spectra

(details in section 3.2.3). This is the ultimate fate of the iron tricarbonyl group anyway, once it has provided the means to carry out a particular chemical reaction.

- 85 - Table 3.1 Demetallation of double cyclization products.

(OC)3Fe 78%a 3.45a OMe 3.50a

OMe

(OC)3Fe 30%b

3.45b 3.50b

(OC)3Fe OMe 79%a OMe 3.46b 3.51b OMe (OC)3Fe OMe 82%a 3.45c 3.50c MeO OMe OMe OMe (OC)3Fe

90%a 3.45d 3.50d a) 10-30 equiv. Me3NO, acetone, rt, overnight. b) satd. CuCl2 in ethanol.

Two particular demetallation procedures were used (Table 3.1). While a is the method of choice for acyclic iron tricarbonyl diene complexes, b is in fact more cost effective. While method a afforded the expected demetallated products in good yields,

method b afforded compound 3.50b in only 30% yield along with a complex mixture of

unseparable compounds (this method has originally been reported for cyclic iron

tricarbonyl diene complexes – we did not make a direct comparison with method a in this

- 86 - study). NMR analysis of the crude mixture shows multiple overlapped signals in the 3.4 –

3.7 ppm region of the spectrum, indicative for OH neighboring protons (most probably due to oxidation of the diene moiety).

3.2.3 Stereochemistry assignment using 1D and 2D H-NMR.

Provided the cyclizations occur by the proposed mechanism (Scheme 3.6), according to the Stork-Eschenmoser postulate, we expect an all-trans decalinic framework upon cyclization. We should note here that upon the first cyclization step, the iron tricarbonyl diene group will be equatorial due to its considerable size. Provided that this is the case, hydrogen atoms H1, H4a and H10a, should exhibit resonances and coupling constant patterns characteristic of axial angular positions (Fig. 3.1; the aromatic ring and the rest of the hydrogen atoms are omitted for clarity).

H1 H4a (CO)3Fe

H10a

Fig. 3.1 Diagnostic hydrogen resonances for the

bicyclization product stereochemistry assignment.

The resonances for these hydrogens were assigned using COSY experiments. The following are our results on compound 3.45d, and demetallated counterpart 3.50d, which provided the best quality spectra of the series; all other compounds however showed the exact same trend.

- 87 - Starting with the methyl group at the distal end of the pentadiene group, easily identifiable as a doublet at δ 1.42 ppm (J = 6.0 Hz, CDCl3), the terminal hydrogen of the

MeO OMe

(OC)3Fe 3.45 d

H1 H5'

Fig. 3.2 Overlapping resonances of interest in the metal complex. diene, H5’, was identified as a triplet at δ 0.81 ppm (J = 9.0 Hz; Fig. 3.2). Subsequently,

the hydrogen atom of ultimate interest, angular H1, was also identified, unfortunately as

an overlapped resonance with another aliphatic proton. Experiments in C6D6 did not resolve the situation, with the same degree of overlap being observed.

Demetallation was performed as described in the previous section, and the hydrogen of interest resonance, H1, was moved downfield, as expected, due to its

proximity to the conjugated diene moiety. Herein is a detailed account of the 1D and 2D

1H-NMR spectra of 3.50d.

Once again the terminal methyl group proves to be the best starting point in the deconvolution of the COSY spectrum. Working our way through the diene moiety, we identified H2’, the first hydrogen in the conjugated diene (Fig. 3.3), followed by the remaining diene hydrogens (H3’-H5’, Fig. 3.4), which led us to the first hydrogen

resonance of interest in establishing the stereochemistry, angular H1 of the

octahydrophenanthrene (Fig. 3.3). Unlike in the analog iron complex 3.45d, where the

- 88 - same resonance overlapped another aliphatic proton, in the case of 3.50d, it was clearly separated from any neighboring resonances as a quartet of doublets at δ 1.83 ppm.

Fig. 3.3 Diagnostic cross peaks for H1-H5’ and H1’-H2’ interactions.

Fig. 3.4 Diagnostic cross peaks for H2’-H3’, H3’-H4’ and H4’-H5’ interactions.

The next two resonances of interest are H4a and H10a (Fig. 3.5). H1 has two major crosspeaks. One of them is with a group of overlapped hydrogen resonances, of which at least two appear to have large (>12 Hz) coupling constants, which were considered to be geminal couplings in a CH2 group. The other is with a quartet of doublets at δ 1.05 ppm,

perfectly consistent with H10a. Moreover, the same resonance assigned as H10a has a very strong crosspeak with the resonance at δ 2.29 ppm, which is unambigously assigned to

benzylic hydrogen H4a (Fig. 3.5).

- 89 -

Fig. 3.5 Diagnostic cross peaks for H1-H4a, H1-H10a and H4a-H10a interactions.

Summarized in Table 3.2 are all these resonances and that of terminal hydrogen of

the diene, H5’. The latter appears as a doublet of doublets: the large coupling constant

13.2 Hz is due to the neighboring diene hydrogen H4’ and the 9.0 Hz coupling constant is

consistent with an axial-axial interaction with axial H1 of the octahydrophenathrene. The diene group must be locked in a transoid conformation.

H1 appears as a quartet of doublets: the large coupling constant 10.4 Hz is an

average of the interactions it has with H5’ of the diene, and neighboring axial H10a and axial H2. The small J value (3.6 Hz) is consistent with the axial-equatorial interaction

with equatorial H2.

H4a has a chemical shift of δ 2.29 ppm, consistent with its benzylic position. It appears as a triplet of doublets: the interactions with axial H10a and axial H4 are

- 90 - responsible for the coupling constant of 11.4 Hz, while interaction with equatorial H4 is reflected in the small coupling constant of 3.0 Hz.

Finally, H10a appears as a quartet of doublets: three axial neighboring protons, H1,

H4a and axial H10 induce an average coupling constant of 10.8 Hz and the equatorial H10

is reflected in a small coupling constant of 2.4 Hz.

Table 3.2 Diagnostic hydrogen resonances for compound 3.50d

H5’ H1 H4a H10a

5.40 ppm 1.83 ppm 2.29 ppm 1.05 ppm

J = 13.2, 9.0 Hz J = 10.4, 3.6 Hz J = 11.4, 3.0 Hz J = 10.8, 2.4 Hz

The all-trans relationship between the bridgehead hydrogens H4a and H10a on one hand, and H1 on the other, clearly demonstrates that the bicyclization reactions adhere to the Stork-Eschenmoser hypothesis, that is the median trans double bond in the polyenic precursor translates into a trans ring junction in the product.

- 91 - 3.3 Conclusions.

A new method for polycyclization of polyene substrates, carrying aromatic terminators, has been developed and tested on a number of substrates.

The triggering event of the cascade reaction is generation of an iron tricarbonyl stabilized pentadienyl carbocation, by anchimerically assisted regiospecific protonation of a double bond adjacent to the iron tricarbonyl diene moiety. Pendant disubstituted double bonds cyclized in good yields and with complete diastereoselectivity.

Trisubstituted pendant double bonds failed to cyclize due to protonation that competes with the double bond adjacent to the iron tricarbonyl diene moiety.

While 13C-NMR confirmed the result of the polycyclizations to be single products, 1H-NMR spectra showed extensive overlapping. Two mild demetallation methods were employed to afford the final octahydrophenanthrene derivative products.

1H-NMR showed very good separation for the diagnostic resonances, confirming all-trans

fused bicyclic products, thus confirming polycyclization conforms with the Stork-

Eschenmoser postulate.

3.4 Experimental section.

Experimental procedure for the Wittig olefination toward the polyene

substrates 3.44a-d,b’. Phosphonium salts were dried overnight in vacuo. Under Ar

atmosphere, dry THF was added via syringe. n-BuLi (2.5M in hexanes, 1.5 - 2 equiv) was added dropwise at -78 °C. The mixture was stirred for 30 min at -78 °C. A solution of

- 92 - iron tricarbonyl sorbaldehyde complex 3.43 in dry THF was transferred by cannula into the reaction flask. Stirring was continued for 30 min at -78 °C, the cold bath was removed and the reaction flask was allowed to warm to room temperature. Reaction progress was monitored by TLC. The reaction was quenched by addition of saturated

NH4Cl solution. The organic phase was diluted with diethyl ether, washed with saturated

NaHCO3 solution, water, brine, and dried (MgSO4). Removal of the solvent under reduced pressure and flash chromatography separation afforded polyene compounds

3.44a-d,b’ as yellow oils. 1H NMR spectra are reported for the Z/E mixtures; as the Z isomer is the major one, it is assumed that the resolved signals belong to it. Whenever possible, 2 sets of 13C NMR signals are reported; major signals are assumed to belong to the major Z isomer.

(±)-Tricarbonyl((2S)-2-5-η-(2E,4E,10E)-13-phenyltrideca-

(OC)3Fe 2,4,6,10-tetraene)iron, inseparable mixture of 6Z and 6E

isomers (3.44a). According to the general procedure 500 mg

(0.97 mmol) of phosphonium salt 3.42a in 15 mL dry THF was treated with 0.78 mL n-

BuLi (2.5M in hexanes, 1.94 mmol). Addition of 128 mg complex 3.43 (0.54 mmol) in

10 mL dry THF afforded 170 mg of 3.44a as a yellow oil, 80% yield. TLC Rf 0.4

1 (Hexanes). H NMR (200 MHz, CDCl3) δ (ppm) 7.35-7.15 (5H), 5.51-5.29 (4H), 5.15

(dd, J = 8.6, 5.1 Hz, 1H), 5.04 (dd, J = 7.7, 5.0 Hz, 1H), 2.68 (dd, J = 9.4, 7.1 Hz, 2H),

2.37-2.27 (2H), 2.17-2.03 (4H), 1.94 (t, J = 9.1 Hz, 1H), 1.50-1.30 (4H); 13C NMR (50

MHz, CDCl3) δ (ppm) Z isomer (major): 212.5, 142.2, 130.9, 130.7, 130.2, 130.1, 128.5,

128.3, 125.8, 85.4, 82.3, 57.0, 56.9, 36.1, 34.5, 32.2, 28.0, 19.3; E isomer (minor): 131.8,

- 93 - 131.7, 130.1, 128.4, 125.8, 84.8, 81.1, 62.3, 56.8, 32.8; IR (film, cm-1) 3027, 2923, 2855,

+ 2037, 1966; HRMS (EI) M -2CO calcd. for C20H24OFe 336.1177, found 336.1172.

OMe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E,10E)-13-(3-

methoxyphenyl)trideca-2,4,6,10-tetraene)iron, (OC)3Fe inseparable mixture of 6Z and 6E isomers (3.44b),

According to the general procedure 215 mg (0.39 mmol) of phosphonium salt 3.42b in 15 mL dry THF was treated with 0.74 mL n-BuLi (1.6M in hexanes, 1.182 mmol). Addition of 93 mg complex 3.43 (0.40 mmol) afforded 115 mg of 3.44b as a yellow oil, 69% yield.

1 TLC Rf 0.4 (EtOAc:Hexanes = 1:24). H NMR (200 MHz, CDCl3) δ (ppm) 7.20 (dd, J =

8.8, 7.5 Hz, 1H), 6.81-6.70 (3H), 5.50-5.25 (4H), 5.14 (ddd, J = 8.8, 5.1, 0.6 Hz, 1H),

5.03 (ddd, J = 8.2, 5.4, 0.7 Hz, 1H), 3.80 (s, 3H), 2.65 (dd, J = 10.0, 7.2 Hz, 2H), 2.38-

2.23 (2H), 2.22-2.00 (4H), 1.93 (t, J = 8.72 Hz, 1H), 1.45-1.35 (4H); 13C NMR (50 MHz,

CDCl3) δ (ppm) Z isomer (major): 212.4, 159.5, 143.8, 130.8, 130.6, 130.1, 130.0, 129.1,

120.9, 114.2, 111.0, 85.3, 82.2, 56.8, 56.7, 55.1, 36.1, 34.3, 32.1, 27.9, 19.2; E isomer

(minor): 131.7, 84.7, 81.0, 62.2, 56.7, 36.0, 34.2, 29.5; IR (film, cm-1) 2039, 1967;

+ HRMS (FAB) M calcd. for C23H26O4Fe 422.1180, found 422.1166.

OMe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E)-10-methyl-13-(4-

methoxyphenyl)trideca-2,4,6,10-tetraene)iron, (OC)3Fe inseparable mixture of 4 diastereoisomers: 6Z/ 6E, and

5:1=10E:10Z (3.44b’), According to the general procedure 560 mg (1.0 mmol) of phosphonium salt 3.42b’ in 15 mL dry THF was treated with 0.68 mL n-BuLi (2.5M in

- 94 - hexanes, 1.7 mmol). Addition of 354 mg complex 3.43 (1.5 mmol) afforded 240 mg of

3.44b’ as a yellow oil, 55% yield. TLC Rf 0.4 (EtOAc:Hexanes = 1:30). The mixture of 4 diastereoisomers was purified by flash chromatography. While H-NMR confirmed the identity of the product (see Appendix), no further characterization was performed.

(±)-Tricarbonyl((2S)-2-5-η-(2E,4E,10E)-13-(4- OMe (OC)3Fe methoxyphenyl)trideca-2,4,6,10-tetraene)iron,

inseparable mixture of 6Z and 6E isomers (3.44c),

According to the general procedure 406 mg (0.75 mmol) of phosphonium salt 3.42c in 15 mL dry THF was treated with 0.6 mL n-BuLi (2.5M in hexanes, 1.5 mmol). Addition of

215 mg complex 3.43 (0.9 mmol) afforded 161 mg of 3.44c as a yellow oil, 51% yield.

1 TLC Rf 0.36 (EtOAc:Hexanes = 1:25). H NMR (200 MHz, CDCl3) δ (ppm) 7.10

(unresolved AA’ quartet, 2H), 6.82 (unresolved AA’ quartet, 2H), 5.50-5.25 (4H), 5.14

(dd, J = 8.8, 4.8 Hz, 1H), 5.03 (ddd, J = 7.8, 5.3, 0.5 Hz, 1H), 3.79 (s, 3H), 2.61 (dd, J =

9.8, 7.3 Hz, 2H), 2.35-2.00 (6H), 1.93 (t, J = 9.3 Hz, 1H), 1.45-1.30 (4H); 13C NMR (50

MHz, CDCl3) δ (ppm) Z isomer (major): 212.5, 157.7, 134.3, 130.9, 130.8, 130.3, 130.0,

129.4, 113.7, 85.4, 82.3, 57.0, 56.9, 55.3, 35.2, 34.8, 32.2, 28.0, 19.3; HRMS (FAB) M+ calcd. for C23H26O4Fe 422.1180, found 422.1095.

MeO OMe (±)-Tricarbonyl((2S)-2-5-η-(2E,4E,10E)-13-(2,3-

dimethoxyphenyl)trideca-2,4,6,10-tetraene)iron, (OC)3Fe inseparable mixture of 6Z and 6E isomers (3.44d),

According to the general procedure 490 mg (0.85 mmol) of phosphonium salt 3.42d in 15

- 95 - mL dry THF was treated with 0.68 mL n-BuLi (2.5M in hexanes, 1.7 mmol). Addition of

360 mg complex 3.43 (1.52 mmol) afforded 320 mg of 3.44d as a yellow oil, 83% yield.

1 TLC Rf 0.35 (EtOAc:Hexanes = 1:10). H NMR (200 MHz, CDCl3) δ (ppm) 6.98 (dd, J

= 8.5, 7.3 Hz, 1H), 6.77 (d, J = 8.0 Hz, 2H), 5.60-5.25 (4H), 5.13 (dd, J = 8.6, 4.9 Hz,

1H), 5.02 (ddd, J = 8.1, 4.7, 0.8 Hz, 1H), 3.86 (s, 1H), 3.82 (s,1H), 2.68 (dd, J = 10.0, 5.7

Hz, 2H), 2.34-2.22 (2H), 2.17-2.00 (4H), 1.94 (t, J = 8.9 Hz, 1H), 1.50-1.30 (4H); 13C

NMR (50 MHz, CDCl3) δ (ppm) Z isomer (major): 212.4, 152.7, 147.1, 136.0, 130.8,

130.7, 130.5, 129.7, 123.6, 121.9, 110.0, 85.3, 82.1, 60.6, 56.9, 56.8, 55.6, 33.7, 32.1,

+ 30.0, 27.9, 19.2; HRMS (FAB) M -3CO calcd. for C20H28O2Fe 368.1439, found

368.1399.

Experimental procedure for the cyclization reactions. To complexes 3.44 in

CH2Cl2, under Ar at 0 °C, was added HBF4·OEt2 (85% in diethyl ether). While stirring at

0 °C, conversion was monitored by TLC. The reaction was quenched after 4 hours by addition of water. The organic phase was diluted with diethyl ether, then washed with sat. aq. NaHCO3 solution, water and brine. Evaporation of solvents under reduced pressure

and recrystallization using dichloromethane / pentane, afforded complexes 3.45a-d and

3.46b.

(±)-Tricarbonyl((2S)-2-5-η-5-((1R,4aR,10aR)-

(OC)3Fe 1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)-(2E,4E)-

pentadiene)iron (3.45a). According to the general procedure,

1 drop of HBF4·OEt2 (approx. 5 mg, 0.03 mmol) was added to 34.5 mg (0.088 mmol) of

- 96 - complex 3.44a in 0.5 mL CH2Cl2 to afford 11.95 mg 3.45a as a yellow solid, m.p. 173

1 °C, 35% yield (83% yield borsm). TLC Rf 0.38 (Hexanes). H NMR (200 MHz, CDCl3)

δ (ppm) 7.35-7.30 (1H), 7.20-7.06 (3H), 5.03 (unresolved AB quartet, 2H), 1.43 (d, J =

13 6.2 Hz, 3H); C NMR (50 MHz, CDCl3) δ (ppm) 140.1, 136.7, 128.9, 126.1, 125.8,

125.6, 84.3, 83.9, 70.3, 57.6, 48.3, 46.8, 43.2, 37.0, 31.4, 30.1, 26.9, 26.7, 19.2; IR (KBr pellet, cm-1) 2946, 2925, 2911, 2865, 2853, 2837, 2035, 1968; HRMS (EI) M+ calcd. for

C22H24O3Fe 392.1075, found 392.1115.

OMe (±)-Tricarbonyl((2S)-2-5-η-5-((1R,4aR,10aR)-7-

methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1- (OC)3Fe yl)-(2E,4E)-pentadiene)iron (3.45b). According to the general procedure, 2 drops of HBF4·OEt2 (approx. 10 mg, 0.06 mmol) were added to 42.9 mg (0.10 mmol) of complex 3.44b in 0.5 mL CH2Cl2 to afford 22.8 mg (53% yield)

1 3.45b as a yellow solid, m.p. 170 °C. TLC Rf 0.28 (EtOAc:Hexanes = 1:25). H NMR

(200 MHz, CDCl3) δ (ppm) 7.21 (d, J = 8.5 Hz, 1H), 6.71 (dd, J = 8.6, 2.7 Hz, 1H), 6.60

(d, J = 2.6 Hz, 1H), 5.02 (unresolved AB quartet, 2H), 3.77 (s, 3H), 2.85-2.73 (2H), 2.48-

2.20 (3H), 1.99-1.85 (2H), 1.62-1.49 (3H), 1.41 (d, J = 6.2 Hz, 3H), 1.36-1.27 (2H), 1.19-

13 0.93 (3H); C NMR (50 MHz, CDCl3) δ (ppm) 157.4, 137.9, 132.4, 127.0, 113.4, 111.8,

84.2, 83.8, 70.3, 57.5, 55.2, 48.1, 46.9, 42.6, 37.0, 31.5, 30.3, 26.9, 26.5, 19.1; IR (KBr

-1 + pellet, cm ) 2039, 1967, 1953; HRMS (FAB) M calcd. for C23H26O4Fe 422.1180, found

422.1168.

- 97 - (±)-Tricarbonyl((2S)-2-5-η-5-((1R,4aR,10aR)-5-

(OC)3Fe OMe methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-

yl)-(2E,4E)-pentadiene)iron (3.46b), obtained along with

1 3.45b as a yellow oil, 30% yield. TLC Rf 0.50 (EtOAc:Hexanes = 1:25). H NMR (200

MHz, CDCl3) δ (ppm) 7.07 (t, J = 8.0 Hz, 1H), 6.74-6.64 (2H), 5.08-4.94 (2H), 3.78 (s,

13 3H), 1.42 (d, J = 6.1 Hz, 3H); C NMR (50 MHz, CDCl3) δ (ppm) 158.8, 139.8, 128.9,

126.1, 121.5, 108.1, 84.2, 84.1, 70.3, 57.4, 55.0, 49.8, 48.7, 42.7, 37.8, 31.8, 31.7, 27.3,

25.9, 19.2.

(±)-Tricarbonyl((2S)-2-5-η-5-((1R,4aR,10aR)-6- OMe (OC)3Fe methoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-

1-yl)-(2E,4E)-pentadiene)iron (3.45c). According to the general procedure, 1 drop of HBF4·OEt2 (approx. 5 mg, 0.03 mmol) was added to

64.3 mg (0.15 mmol) of complex 3.44c in 0.8 mL CH2Cl2 to afford 37.5 mg (58% yield;

88% yield borsm) 3.45c as a yellow solid, m.p. 169 °C. TLC Rf 0.24 (EtOAc:Hexanes =

1 1:25). H NMR (200 MHz, CDCl3) δ (ppm) 7.00 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.4 Hz,

1H), 6.69 (dd, J = 8.3, 2.6 Hz, 1H), 5.03 (unresolved AB quartet, 2H), 3.79 (s, 3H), 1.42

13 (d, J = 6.2 Hz, 3H); C NMR (50 MHz, CDCl3) δ (ppm) 157.8, 141.4, 129.7, 128.9,

111.6, 111.3, 84.3, 83.9, 70.3, 57.6, 55.3, 48.3, 46.8, 43.4, 37.0, 31.4, 29.3, 27.1, 26.7,

19.2; IR (KBr pellet, cm-1) 2944, 2915, 2851, 2835, 2035, 1956; HRMS (FAB) M+ calcd. for C23H26O4Fe 422.1180, found 422.1128.

- 98 - MeO OMe (±)-Tricarbonyl((2S)-2-5-η-5-((1R,4aR,10aR)-7,8-

dimethoxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1- (OC)3Fe yl)-(2E,4E)-pentadiene)iron (3.45d). According to the general procedure, 1 drop of HBF4·OEt2 (approx. 5 mg, 0.03 mmol) was added to 45.5 mg (0.10 mmol) of complex 3.44d in 1 mL CH2Cl2 to afford 39 mg (85% yield) 3.45d as

1 a yellow solid. TLC Rf 0.26 (EtOAc:Hexanes = 1:10). H NMR (600 MHz, CDCl3) δ

(ppm) 7.02 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.03 (unresolved AB quartet,

2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.03 (dd, J = 17.4, 4.2 Hz, 1H), 2.55 (ddd, J = 18.0, 12.6,

6.0 Hz, 1H), 2.41-2.38 (2H), 2.28 (t, J = 9.0 Hz, 1H), 1.96-1.89 (2H), 1.48 (qt, J = 13.2,

3.6 Hz, 1H), 1.42 (d, J = 6.0 Hz, 3H), 1.33-1.23 (2H), 1.19-1.11 (2H), 1.01-0.95 (2H),

13 0.81 (t, J = 9.0 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm) 150.2, 146.1, 133.6, 131.2,

121.2, 109.8, 84.2, 83.8, 70.3, 59.8, 57.5, 55.7, 48.1, 46.3, 42.6, 36.9, 31.5, 26.5, 26.4,

+ 24.0, 19.2; HRMS (EI) M -CO calcd. for C23H28O4Fe 424.1337, found 424.1323.

Experimental procedure for the demetallation reactions. Trimethylamine-N-

oxide was added to solutions of complexes 3.45a,c,d, and 3.46b in acetone, or acetone/ethanol (1:1). While the reaction was stirred at room temperature for 24 h, reaction progress was monitored by TLC. The reaction mixture was filtered through a

Celite plug and evaporated. Recrystallization from dichloromethane/pentane and/or preparative TLC afforded compounds 3.50a,c,d, 3.51 b.

- 99 - (±)-(1R,4aR,10aR)-1-((1E,3E)-Penta-1,3-dienyl)-

1,2,3,4,4a,9,10,10a-octahydrophenanthrene (3.50 a).

According to the general procedure 30 equiv of Me3NO was added to 11.3 mg complex

3.45a in 0.5 mL acetone to afford 5.7 mg (78% yield) of 3.50a as a pale yellow oil. TLC

1 Rf 0.50 (Hexanes). H NMR (600 MHz, CDCl3) δ (ppm) 7.31 (d, J = 7.8 Hz, 1H), 7.14

(tm, J = 7.2 Hz, 1H), 7.11 (tm, J = 7.5 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.09-6.01 (2H),

5.65-5.59 (1H), 5.43-5.39 (1H), 2.80 (dd, J = 8.4, 3.6 Hz, 2H), 2.48-2.46 (1H), 2.38 (td, J

= 12.0, 3.0 Hz, 1H), 2.05-2.01 (1H), 1.93 (dquint, J = 13.8, 3.0 Hz, 1H), 1.90-1.84 (1H),

1.77-1.74 (1H), 1.53 (qt, J = 13.2, 4.2 Hz, 1H), 1.34-1.19 (3H), 1.14 (qd, J = 10.8, 2.4

13 Hz, 1H); C NMR (50 MHz, CDCl3) δ (ppm) 140.5, 137.2, 136.3, 131.8, 130.3, 129.0,

127.2, 125.6, 125.5, 47.6, 44.7, 43.2, 33.7, 30.9, 30.0, 27.7, 26.1, 18.1; IR (film, cm-1)

+ 3014, 2919, 2854; HRMS (EI) M calcd. for C19H24 252.1878, found 252.1875.

OMe (±)-(1R,4aR,10aR)-7-Methoxy-1-((1E,3E)-penta-

1,3-dienyl)-1,2,3,4,4a,9,10,10a-octahydro-

phenanthrene (3.50b). Complex 3.45b (22.8 mg) was stirred overnight in 3 mL sat. CuCl2/ethanol solution. The reaction mixture was filtered

through a Celite plug, diluted with Et2O and washed with water and brine. The solvent

was removed under reduced pressure. Preparative TLC afforded 4.7 mg (30% yield) of

1 3.50b as a off-white solid, m.p. 64 °C. TLC Rf 0.34 (EtOAc:Hexanes = 1:25). H NMR

(600 MHz, CDCl3) δ (ppm) 7.14 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 9.0, 3.0 Hz, 1H), 6.53

(d, J = 3.0 Hz, 1H), 6.01-5.93 (2H), 5.57-5.51 (1H), 5.33 (dd, J = 13.8, 9.0 Hz, 1H), 3.70

(s, 3H), 2.72-2.68 (2H), 2.35 (dd, J = 12.6, 3.0 Hz, 1H), 2.24 (t, J = 11.4 Hz, 1H), 1.94

- 100 - (dm, J = 12.6 Hz, 1H), 1.84 (dquint, J = 13.2, 3.0 Hz, 1H), 1.78 (qd, J = 10.4, 3.6 Hz,

1H), 1.68 (d, J = 7.8 Hz, 3H), 1.44 (qt, J = 13.2, 3.6 Hz, 1H), 1.03 (qd, J = 10.8, 3.0 Hz,

13 1H); C NMR (50 MHz, CDCl3) δ (ppm) 157.4, 138.5, 136.4, 132.8, 131.8, 130.3,

127.1, 126.6, 113.6, 111.7, 55.2, 47.5, 44.9, 42.7, 33.7, 31.1, 30.3, 27.8, 26.0, 18.1; IR

-1 + (KBr pellet, cm ) 2926, 2855; HRMS (FAB) M calcd. for C20H26O 282.1984, found

282.1975.

(±)-(1R,4aR,10aR)-5-Methoxy-1-((1E,3E)-penta-1,3-

dienyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthrene OMe

(3.51b). According to the general procedure 60 equiv of Me3NO was added to 2.7 mg complex 3.46b to afford 1.4 mg (79% yield) of 3.51b as a pale yellow oil. TLC Rf 0.42

1 (Pentane). H NMR (600 MHz, CDCl3) δ (ppm) 7.06 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 7.8

Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.08-5.98 (2H), 5.64-5.56 (1H), 5.43 (dd, J = 15.0, 9.6

Hz, 1H), 3.79 (s, 3H), 2.92 (d, J = 12.6 Hz, 1H), 2.77 (td, J = 14.7, 4.8 Hz, 1H), 2.66 (dq,

J = 16.2, 2.2 Hz, 1H), 2.49 (t, J = 10.5 Hz, 1H), 1.98 (qd, J= 10.4, 4.2 Hz, 1H), 1.89

(dquint, J = 12.6, 2.4 Hz, 1H), 1.86-1.77 (2H), 1.75 (d, J = 6.6 Hz, 3H), 1.60 (qt, J =

13.2, 4.2 Hz, 1H), 1.09 (qd, J = 12.6, 4.2 Hz, 1H), 0.97 (qd, J = 12.0, 3.0 Hz, 1H); 13C

NMR (50 MHz, CDCl3) δ (ppm) 158.9, 140.2, 136.7, 131.8, 130.0, 129.1, 127.0, 126.1,

121.7, 108.1, 55.0, 48.0, 47.8, 43.0, 34.6, 31.9, 31.5, 26.9, 26.5, 18.1; IR (film, cm-1)

+ 2923, 2855; HRMS (FAB) M calcd. for C20H26O 282.1984, found 282.1984.

- 101 - (±)-(1R,4aR,10aR)-6-Methoxy-1-((1E,3E)-penta-

OMe 1,3-dienyl)-1,2,3,4,4a,9,10,10a-octahydro- phenanthrene (3.50c). According to the general procedure 30 equiv of Me3NO were

added to 20.8 mg complex 3.45c to afford 11.4 mg (82% yield) of 3.50c as a off-white

1 solid, m.p. 93 °C. TLC Rf 0.36 (EtOAc:Hexanes = 1:25). H NMR (600 MHz, CDCl3) δ

(ppm) 6.98 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.68 (dd, J = 7.8, 1.8 Hz, 1H),

6.07-5.99 (2H), 5.64-5.58 (m, 1H), 5.40 (dd, J = 13.8, 9.0 Hz, 1H), 3.78 (s, 3H), 2.74-

2.71 (2H), 2.43-2.40 (m, 1H), 2.34 (t, J = 12.0 Hz, 1H), 2.01 (dm, J = 12.6 Hz, 1H), 1.92

(dquint, J = 13.2, 3.6 Hz, 1H), 1.85 (qd, J = 10.2, 3.0 Hz, 1H), 1.74 (d, J = 6.6 Hz, 3H),

1.52 (qt, J = 13.2, 3.6 Hz, 1H), 1.30-1.19 (3H), 1.11 (qd, J = 11.0, 2.4 Hz, 1H); 13C NMR

(50 MHz, CDCl3) δ (ppm) 157.7, 141.8, 136.3, 131.8, 130.3, 129.7, 129.4, 127.1, 111.4,

111.1, 55.3, 46.6, 44.7, 43.4, 33.7, 31.0, 29.2, 27.9, 26.1, 18.1; IR (KBr pellet, cm-1)

+ 3015, 2917, 2853; HRMS (FAB) M calcd. for C20H26O 282.1984, found 282.1979.

OMe (±)-(1R,4aR,10aR)-7,8-Dimethoxy-1-((1E,3E)- OMe penta-1,3-dienyl)-1,2,3,4,4a,9,10,10a-octahydro-

phenanthrene (3.50d). According to the general procedure 30 equiv of Me3NO were added to 30 mg complex 3.45d to afford 18.7 mg

(90% yield) of 3.50d as a off-white solid, m.p. 124 °C. TLC Rf 0.36 (EtOAc:Hexanes =

1 1:10). H NMR (600 MHz, CDCl3) δ (ppm) 7.01 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz,

1H), 6.08-5.99 (2H), 5.64-5.57 (1H), 5.40 (dd, J = 13.2, 9.0 Hz, 1H), 3.84 (s, 3H), 3.78

(s, 3H), 2.93 (ddd, J = 17.4, 5.4, 1.8 Hz, 1H), 2.58 (ddd, J = 18.0, 12.0, 6.0 Hz, 1H), 2.41

(m, 1H), 2.29 (td, J = 11.4, 3.0 Hz, 1H), 2.05 (ddt, J = 12.6, 6.0, 2.4 Hz, 1H), 1.90

- 102 - (dquint, J = 13.2, 3.0 Hz, 1H), 1.83 (qd, J = 10.4, 3.6 Hz, 1H), 1.75-1.71 (4H), 1.50 (qt, J

= 13.2, 4.2 Hz, 1H), 1.26-1.14 (3H), 1.05 (qd, J = 10.8, 2.4 Hz, 1H); 13C NMR (50 MHz,

CDCl3) δ (ppm) 150.2, 146.2, 136.3, 134.0, 131.7, 131.6, 130.2, 127.1, 120.9, 109.7,

59.8, 55.7, 47.4, 44.3, 42.7, 33.6, 31.1, 27.2, 25.9, 23.9, 18.0; IR (KBr pellet, cm-1) 3013,

+ 3002, 2924, 2855, 2833; HRMS (FAB) M calcd. for C21H28O2 312.2089, found

312.2093.

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- 110 -

Appendix

NMR spectra of new compounds.

- 111 -

(OC)3Fe OH

2.86 Ψ-exo

- 112 -

(OC)3Fe (OC)3Fe +

2.94 + 2.95

- 113 -

OCHO (OC)3Fe

2.96

- 114 -

(OC)3Fe

2.102a

- 115 -

(OC)3Fe

2.102b

- 116 -

(OC)3Fe

2.102c

- 117 -

(OC)3Fe

2.102d

- 118 -

(OC)3Fe

2.102e

- 119 -

(OC)3Fe

2.102f

- 120 -

(OC)3Fe

2.102g

- 121 -

(OC)3Fe

2.102h

- 122 -

(OC)3Fe

OMe 2.102i

- 123 -

(OC)3Fe OMe

2.102j

- 124 -

(OC)3Fe

OMe

2.102k

- 125 -

(OC)3Fe O

2.102l

- 126 -

(OC)3Fe O

2.102m

- 127 -

(OC)3Fe OCHO

2.103a

- 128 -

(OC)3Fe OCHO

2.103b

- 129 -

(OC)3Fe

2.103e’

- 130 -

(OC)3Fe

2.103h

- 131 -

OMe

(OC)3Fe

2.103i

- 132 -

OMe (OC)3Fe

2.103j

- 133 -

(OC)3Fe O

2.103l

- 134 -

(OC)3Fe

3.44a

- 135 -

OMe

(OC)3Fe

3.44b

- 136 -

OMe (OC)3Fe

3.44c

- 137 -

MeO OMe

(OC)3Fe

3.44d

- 138 -

(OC)3Fe

3.45a

- 139 -

OMe

(OC)3Fe

3.45b

- 140 -

(OC)3Fe OMe

3.46b

- 141 -

OMe (OC)3Fe

3.45c

- 142 -

MeO OMe

(OC)3Fe

3.45d

- 143 -

3.50a

- 144 -

OMe

3.50b

- 145 -

OMe 3.51b

- 146 -

OMe

3.50c

- 147 -

OMe OMe

3.50d

- 148 -

OMe OMe

3.50d - COSY

- 149 -

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