IRON CARBONYL MEDIATED CYCLIZATIONS AND THEIR POTENTIAL
APPLICATION IN SYNTHESIS
by
Xiaolong Wang
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.
Dedicated to my wife and son.
ii TABLE OF CONTENTS
Table of Contents………………………………………………………………...….……iii
List of Equations………………………………………………………………………...... v
List of Schemes………………………………………………………………………...... vi
List of Tables…………………………………………………………………..…………ix
List of Figures…………………………………………………………………..………....x
Acknowledgements……………………………………………………………………….xi
List of Abbreviations………………………………..……..……………………………xiv
Abstract……………………………………………………………………………………ii
CHAPTER 1. Background: Introduction to Iron Carbonyls and Diene-Fe(CO)3 ...... 1
1.1 Iron Carbonyl Complexes. General Introduction, Mechanism Studies, and Preparation
of Diene-Fe(CO)3 Complexes………………………………..………………..……....2
1.1.1 Isomerization of Double Bonds by Fe(CO)5..…………………...…..…………..2
1.1.2 Preparation of Some Representative Diene-Fe(CO)3 Complexes…………...….4
1.2 Cyclic Cationic Dienyl Iron Carbonyl Complexes and Their Applications….…….....6
1.3 Diene-Fe(CO)3/Olefin Ene-Cyclization……………………………………………...12
1.4 Literature Cited……………………………………………………………….….…..20
CHAPTER 2. Formation of Six-membered Sporolactams……….….…..…………..25
2.1 Preparation of 6-Membered Spirolactams……………………………………….…..26
2.2 Conclusions…………………………………………………………………………..31
2.3 Experimental Section……………………………………………………….…….….32
2.4 Literature Cited……………………………………………………………….….…..47
iii CHAPTER 3. Double Cyclization…………….……………….....…………………....49
3.1 Double Cyclization….……………………………………………………………….50
3.2 Conclusions…………………………………………………………………………..61
3.3 Experimental Section……………………………………………………….…….….62
3.4 Literature Cited……………………………………………………………….….…..75
CHAPTER 4. Bicyclization………..………….……………….....……….…………....77
4.1 Preparation of Bicyclic Molecules by Rearrangement-Cyclization Procedure…..….78
4.2 One-Pot Cyclization………………………………………………………………….83
4.3 Conclusions…………………………………………………………………………..90
4.4 Experimental Section……………………………………………………….…….….91
4.5 Literature Cited…………………………………………………...………….….….117
CHAPTER 5. Formation of All-carbon Spirocycles……...….....……….…………..119
5.1 Preparation of All-Carbon Spirocycles…………………………………..…………120
5.2 Conclusions…………………………………………………………………………131
5.3 Experimental Section……………………………………………………….………132
5.4 Literature Cited……………………………………………………...………..…….146
CHAPTER 6. Diastereoselective Spirocyclization: Studies toward Kinetic Dynamic
Resolution during the Intramolecular Diene-Fe(CO)3/Olefin Coupling…….….....148
6.1 Diastereoselective Cyclization…………………………………….……..…………149
6.2 Conclusions…………………………………………………………………………159
6.3 Experimental Section……………………………………………………….………161
6.4 Literature Cited……………………………………………………...………..…….177
BIBLIOGRAPHY……………………………………..……………………………....178
iv LIST OF EQUATIONS
Equation 1.1………………………………………………………………………………2
Equation 1.2………………………………………………………………………………2
Equation 1.3………………………………………………………………………………2
Equation 1.4………………………………………………………………………………2
Equation 1.5………………………………………………………………………………2
Equation 1.6………………………………………………………………………………2
Equation 1.7……………………………………………………………………………..12
Equation 3.1……………………………………………………………………………...51
Equation 3.2...…………………………………………………………………….….…..56
Equation 3.3……………………………………………………………………….……..61
Equation 4.1…...…………………………………………………………………………78
Equation 4.2...……………………………………………………………………………86
Equation 5.1...……………………………………………………………………….….122
v LIST OF SCHEMES
Scheme 1.1 …………………………………………………….………………………2
Scheme 1.2 …………………………………………………….………………………3
Scheme 1.3 Preparation of Diene-Fe(CO)3 Complexes ………….……………………4
Scheme 1.4 ……………………………………………………….….………………...6
Scheme 1.5 ……………………………………………………….….……….…..……7
Scheme 1.6 Synthesis of Trichodermol Using Organoiron Chemistry ….…..…….…..9
Scheme 1.7 Unsuccessful Hydride Abstraction from p-Anisic Acid Derivatives ...….11
Scheme 1.8 Intramolecular Coupling of Olefin with Diene- Fe(CO)3 Moiety …..…..13
Scheme 1.9 Proposed Mechanism of the Spirocyclization ………….………...……...16
Scheme 1.10 ………………………………………………………….…….…………..17
Scheme 1.11 Racemization due to Precyclization Rearrangement ……………………18
Scheme 1.12 ……………………………………………………………………………18
Scheme 2.1 Proposed Mechanism for Double Cyclization …………………………..29
Scheme 2.2 ……………………………………………...... …………………….…….30
Scheme 2.3 …………………………………………………………………...……….31
Scheme 3.1 …………………...……………………………………………………….50
Scheme 3.2 …………………………………….……………………………………...53
Scheme 3.3 ………………………………….………………………………………...57
Scheme 3.4 ………………………………….………………………………………...58
Scheme 3.5 ……………………………………………….…………………………...59
Scheme 3.6 ……………………………………………………………………………60
vi Scheme 4.1 …………………...……………………………………………………….78
Scheme 4.2 …………………………………….……………………………………...82
Scheme 4.3 ………………………………….………………………………………...83
Scheme 4.4 ………………………………….………………………………………...84
Scheme 4.5 ……………………………………………….…………………………...87
Scheme 4.6 Diastereoselective Complexation ………..………………………………88
Scheme 4.7 ……………………………………………………………………………89
Scheme 5.1 All-Carbon Cyclization via Ketone Intermediate ….…………………..120
Scheme 5.2 Proposed Rearrangement-Cyclization …...…………………………….121
Scheme 5.3 Rearrangement-Cyclization ……...…………………………………….123
Scheme 5.4 Regiocontrolled Rearrangement-Cyclization ………………………….124
Scheme 5.5 ……………………………………………….………………………….125
Scheme 5.6 …………………………………………………………………………..126
Scheme 5.7 Diastereoselective Rearrangement-Cyclization ………………………..128
Scheme 5.8 …………………………………………………………………………..129
Scheme 6.1 Proposed Diastereoselective Cyclization ..……………………………..149
Scheme 6.2 Preparation of Dienamines 6.8………………………………………….151
Scheme 6.3 Diastereoselective Cyclization ...……………………………………….152
Scheme 6.4 Stepwise Diastereoselective Double Cyclization ...…………………….153
Scheme 6.5 Retrosynthetic Analysis for 18-Deoxycytochalasin H ………………....154
Scheme 6.6 Preparation of Amine …………………………………………………..156
Scheme 6.7 Kinetic Dynamic Resolution .…………………………………………..157
Scheme 6.8 …………………………………………………………………………..159
vii Scheme 6.9 Proposed Synthesis of Synthon 6.25 toward 18-Deoxycytochalasin H...160
viii LIST OF TABLES
Table 1.1 Examples of Nucleophilic Addition to Cyclohexadienyliron Complexes
……………………………………………………………..………………8
Table 2.1 Preparation of N-Butenyl Amide Complexes ……………..…………….27
Table 2.2 Cyclization of 2.2a-f………………………………………..……………28
Table 3.1 Cyclization of Amide Complexes 3.6……………………………………52
Table 3.2 Chemically Induced Cyclization of Amide Complexes 3.6a……………56
Table 4.1 Optimization of Cyclization Conditions for 4.7a………………..………79
Table 4.2 Preparation of Amide 4.7 and Its Cyclization….………………..………80
ix LIST OF FIGURES
Figure 1.1 Potential Cation Precursors to Calonectrin and Verrucarol……….……..10
Figure 1.2 Z/E Conformations of Esters (Thioesters)………………………..…...... 14
Figure 1.3 Orbital Interactions for Esters, Thioesters and Amides……………....….14
Figure 1.4 Conformational Preferences for Amides…………….……………..…....14
Figure 1.5 Comparison of cis vs trans η3-Metallacycle Intermediate……………….16
Figure 2.1 ……………………….…………………………………….……………..26
Figure 3.1 ………………...………………………………………………………….59
Figure 6.1 Intermediates Comparison during Diastereoselective Cyclization……..150
Figure 6.2 Energy Calculation of Intermediates 6.43……………………………...158
x
ACKNOWLEDGMENTS
I am very grateful to all those who helped make my graduate work at Case an enjoyable experience. I am greatly indebted to Professor Anthony J. Pearson for his patient instruction, guidance, encouragement, and beyond, an example for many to follow. His philosophy, profound understanding about chemistry, and work ethic made these four years an invaluable experience for me. I am fortunate to have him as my advisor. The financial support provided by the National Science Foundation is greatly appreciated. Case Western Reserve University and the Chemistry Department are also acknowledged for giving me the opportunity to study in such a nice environment.
I would like to express my thanks to my labmates, past and present, for a very congenial and supportive research group. I am especially grateful to Ismet B. Dorange for teaching me to do Birch reduction, to Sheng Cui for his help of some 2 D NMR experiments, to Avdhoot Velankar, my benchmate, for his helpful discussion about chemistry and life, and to Brian Servé for the discussion about America and the world.
I also want to express my gratitude to my parents without whom nothing would have been possible. Above all, I would like to thank my wife for her everyday support.
xi LIST OF ABBREVIATIONS
Ac acetyl
aq aqueous
br broad
COSY correlation spectroscopy
Cp cyclopentadienyl
d doublet
DIBALH diisobutylaluminum hydride
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EA ethyl acetate
EDCI 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide equiv equivalent(s)
Et ethyl
FTIR Fourier transform infrared
GC-MS gas chromatography-mass spectroscopy h hour(s)
Hex hexane
HMPA hexamethylphosphoramide
HOBT 1-hydroxybenzotriazole
HRMS high resolution mass spectroscopy
xii IR infrared spectroscopy
KHMDS potassium hexamethyldisilazide
LDA lithium diisopropylamide
Me methyl min minute(s)
Ms methanesulfonyl mp melting point
MS molecular sieves
NMR nuclear magnetic resonance
NOE nuclear Overhauser effect
NOESY nuclear Overhauser effect spectroscopy
Nu nucleophile
Ph phenyl
PLC preparative thin layer chromatography i-Pr isopropyl q quartet rt room temperature s singlet sat saturated sep septet t triplet
TEBAC triethylbenzylammonium chloride
TFA trifluoroacetic acid
xiii THF tetrahydrofuran
TLC thin layer chromatography
TMS tetramethylsilane
Ts p-toluenesulfonyl
xiv Iron Carbonyl Mediated Cyclizations and Their Potential Application in Synthesis
Abstract
by
Xiaolong Wang
Extension of the intramolecular coupling between a cyclohexadiene-Fe(CO)3 moiety and pendant olefins to make δ-lactam derivatives was investigated. δ-Lactams were found more difficult to form than γ-lactams, thus resulting in poorer yield and requiring longer reaction time. By introducing an ester group on the pendant olefin, increased yield was achieved.
Intramolecular double cyclization between a cyclohexadiene-Fe(CO)3 complex and a pendant diene yielded a tricyclic molecule containing a spirocenter, with defined relative stereochemistry of four contiguous carbon centers.
A convenient one-pot procedure to prepare angularly substituted bicyclic and tricyclic molecules with excellent diastereoselectivity in good yield was developed, by
Fe(CO)5 promoted cyclization. Three transformations (complexation, isomerization and cyclization) were realized in a single operation. The product of this reaction might be a potential intermediate for synthesis of the alkaloid gelsemine.
A new short protocol, rearrangement of the cyclohexadiene followed by cyclization, was discovered to give carbon spirocyclic molecules in fair to good yield.
Diastereoselective cyclizations of diastereomeric amide complexes, which were prepared from chiral amines and racemic acid complexes, were investigated to show that the chirality, originating from the amine, can dictate the stereochemistry of the
xv cyclization product by steric approach control. In one case, kinetic dynamic resolution during intramolecular coupling between the cyclohexadiene-Fe(CO)3 moiety and pendant
olefin was demonstrated, which also showed an promise of a potential enantioselective
methodology toward spriocyclic targets using racemic iron complexes.
xvi 1
CHAPTER ONE
Background: Introduction to Iron Carbonyl and Diene Iron
Tricarbonyl Chemistry
2
1.1 Iron Carbonyl Complexes. General Introduction, Mechanism Studies, and
Preparation of Diene-Fe(CO)3 Complexes
Iron carbonyl (with or without organic ligands) has been widely used in organic synthesis, and can act as a catalyst to isomerize double bonds, a protective group for conjugated dienes, a stereodirecting group, an activation group, and a transition metal complex to mediate stereoselective organic transformations.1,2,3,4,5,6
1.1.1 Isomerization of Double Bonds by Fe(CO)5
H cat. 1 cat. H R R1 N Fe(CO) N Fe(CO) 5 (1.1) OH 5 O (1.2) 2 2 O O R R
OH O D cat. Fe(CO) Cat. Fe(CO)5 5 (1.3) (1.4)
D
Fe(CO)3 Fe(CO) 5 (1.5) Fe(CO)5 Fe(CO)3 (1.6) n-Bu2O 1.1
Scheme 1.1
Pentacarbonyliron, an inexpensive, readily available industrial material, is found to
catalyze double bond migration7,8 besides its many other applications in organic
synthesis. Although other iron complexes, such as diene-Fe(CO)3, also show similar behavior, iron pentacarbonyl, the simplest form of iron carbonyls, has been the focus of extensive study. The reaction normally requires elevated temperature, sometimes light 3
irradiation, and it is often reversible. The products are generally thermodynamically more
stable than their precursors. Allylamides give enamides (eq 1.1),8 allyl alcohols give enols, which then tautomerize to form ketones or aldehydes (eq 1.2-1.3),9,10 and dienes
give conjugated dienes (eq 1.4). Conjugation of dienes can be effected equally well using
bicycloheptadiene-Fe(CO)3, cyclooctatetraene-Fe(CO)3 or hexadiene-Fe(CO)3 in place of
11 Fe(CO)5, but not cyclohexadiene-Fe(CO)3 (1.1). In contrast, no rearrangement of 1,5-
11 cyclooctadiene has been observed using Mo(CO)6, Cr(CO)6, Ni(CO)4 or W(CO)6.
Often, the presence of another olefinic group allows the eventual formation of a 1,3- diene-Fe(CO)3 complex (eq 1.4, 1.6) upon treatment with stoichiometric amount of
11 Fe(CO)5.
An allylic hydrogen abstraction mechanism has been proposed (Scheme 1.2) based
on labeling studies.12 A mixture of the deuterated diene 1.2 and iron pentacarbonyl in anhydrous benzene was irradiated with UV light to afford 1.5 in 46% yield. In this
reaction, the conjugated diene-iron tricarbonyl complex is formed by stereospecific
deuterium migration, which suggests the involvement of π-allylhydridoiron tricarbonyl
intermediate 1.4. For monoolefins, the same mechanism applies, followed by dissociation
of the iron moiety from the final product (eq 1.1-1.3). Similar evidence for stereospecific
hydrogen migration is also observed in eq 1.3 for the allylic alcohol system.13
DD DD D D D (OC) Fe Fe(CO)3 3 Fe(CO)5 Fe(CO)3
D DD DD DD DD 1.2 1.3 1.4 1.5
Scheme 1.2 4
1.1.2 Preparation of Some Representative Diene-Fe(CO)3 Complexes
Fe(CO) o 3 1 2 Fe(CO)5, n-Bu2O, 142 C 1.5a R = Me, R = CO2Me 1 2 R R R1 R2 1.5b R1 = Me, R2 = CHO or Fe2(CO)9 silica gel, 50 oC 1 3 2 1.6a R = R = H, R = CO2Me R2 2 Fe(CO)5 R 1.6b R1 = R3 = H, R2 = OMe 3 (OC) Fe 3 R n-Bu O, 142 oC 3 R 1 2 3 2 1.6c R = OMe, R = CO2Me, R = H 1 2 3 1 or Fe2(CO)9 1.6d R = OMe, R = Me, R = H R R1 o 1 2 3 Et2O, 35 C 1.6e R = OMe, R = H, R = Me 1.6f R1 = OMe, R2 = R3 = H 1.6g R1 = R2 = OMe, R3 = H Fe(CO)3 Fe(CO)5 1.1 R1 = R2 = R3 = H n-Bu2O 1.7 142 oC
(OC) Fe (OC)3Fe 3 (OC) Fe n-Bu O 3 2 CO2Me CO o 142 C 1.8 1.9 1.6a 38% + CO2Me CO Me CO Me 40% SM 2 2 8 : 1 : 1
(OC)3Fe n-Bu2O CO 142 oC 1.10 CO Me 2 CO2Me
Scheme 1.3 Preparation of Diene-Fe(CO)3 Complexes
While Fe(CO)5 is very useful in organic synthesis, diene-Fe(CO)3 complexes are found to have greater potential in synthesis among all organoiron compounds.1-6 Their preparation, therefore, becomes an important issue. Extensive work has been done in this area and a variety of diene iron complexes have been made available to organic 5
chemists.14 The conventional method is to heat or irradiate a mixture of diene (conjugated or nonconjugated) and iron carbonyl, either Fe(CO)5 or Fe2(CO)9, normally with solvent.
15,16 In some cases, an improved yield is obtained by using (dba)Fe(CO)3 or a 1-azadiene-
17 Fe(CO)3 complex as Fe(CO)3 donor, or by using iron carbonyl in the presence of a 1- azadiene as catalyst.18 Recently, a convenient procedure was reported using silica gel as the medium for the complexation, but only a few examples were given.19 Scheme 1.2
1,3 shows the preparation of some typical diene-Fe(CO)3 complexes. The precursor substituted cyclohexadienes are often prepared by Birch reduction of the corresponding arene and the diene complex can be prepared on large scale and in good to excellent yield. It should be noted that the Fe(CO)3 moiety brings chirality to the planar diene with
appropriate substitution pattern. Complexes 1.5 and 1.6 are all produced in racemic form
by the methods shown here. Enantioselective complexation of some cyclohexadienes has
been reported to give high enantiomeric excess.20 When nonconjugated cyclic dienes are used for the complexation, they tend to give a mixture of products, not only regioisomers, but also diastereomers. One example is the 5-carbomethoxycyclohexa-1,4-diene. When it
21 is reacted with Fe(CO)5, 1.8, 1.9, 1.6a are produced in a ratio of 8:1:1. The ester group is endo to the Fe(CO)3 unit in the major product 1.8. The blocked cyclohexadiene, 3-
carbomethoxy-3-methylcyclohexa-1,4-diene, gives only the endo product 1.10. It is
concluded that the ester group has directing effect toward iron carbonyls.22
6
1.2 Cyclic Cationic Dienyl Iron Carbonyl Complexes and Their Applications
Fe(CO)3 Fe(CO)3 + - Ph3C BF4 + - BF4 CH2Cl2 1.1 100% 1.11
CO Me 2 CO2Me Fe(CO) + - 3 Ph3C BF4 Fe(CO)3 + CH2Cl2 - 95% BF4 1.12 1.13 R R R Fe(CO) + - (OC)3Fe 3 Fe(CO)3 Ph C BF 3 4 + + BF - + - CH2Cl2 4 BF4
1.6a R = CO2Me 1.14a 80% 1.14b 20% 1.6b R = OMe 1.15a 94% 1.15b 6%
OMe OMe OMe (OC) Fe Fe(CO) 3 Fe(CO)3 3 Ph C+BF - 3 4 + - + + BF4 BF - CH2Cl2 4 1.6f 1.15a 20% 1.15c 80%
OMe OMe Fe(CO)3 + - Fe(CO)3 Ph3C BF4 + - CH2Cl2 BF4 95%
1.6e 1.16
Scheme 1.4
Although diene-Fe(CO)3 complexes can react with stong nucleophiles, radicals, and strong electrophiles, they are unreactive toward many organic transformations such as
DIBAL reduction, Swern oxidation, hydroboration, hydration, osmylation, hydrogenation, epoxidation, cyclopropanation, and so on, which makes Fe(CO)3 a good 7
23,3 protective group for conjugated dienes. Diene-Fe(CO)3 complexes usually are not directly employed in synthesis, rather they are transformed to the corresponding cationic dienyl complexes, especially for cyclic ones.
Many functionally substituted cyclohexadienyliron complexes have been prepared by hydride abstraction from diene-Fe(CO)3 complexes using triphenylmethyl tetrafluoroborate or hexafluorophosphate,24,25,26,27 as summarized in Scheme 1.4.
Remarkable selectivity is achieved for substituted complexes, which is determined by the
electronic nature of the substituent and the neighboring steric environment.28 Another method is the acid treatment of an iron complex of a methoxy- or hydroxy-substituted diene.29
OMe OMe Fe(CO)3 Fe(CO) 3 Fe(CO)3 1) c. H2SO4 + + - PF6 2) NH4PF6 1.11 1.6b 1.6f
OMe R Fe(CO) Fe(CO)3 3 1) c. H SO 2 4 - + PF6 2) NH4PF6 R 1.6d R = Me 1.17a 1.6g R = OMe 1.17b
Fe(CO) Fe(CO)3 3 HPF6 + PF - CH2OH 6 1.18 1.19
Scheme 1.5
The cationic dienyl complexes are very reactive electrophiles.3 Reactions of the
incoming nucleophile with the cationic complexes are stereospecific (anti to the metal) 8
and regioselective as controlled by the substituents. When carbon nucleophiles are
employed, the reaction becomes a powerful tool for carbon-carbon bond formation as
exemplified in Table 1.1.30,31,32,33,34
Table 1.1. Examples of Nucleophilic Addition to Cyclohexadienyliron Complexes
Fe(CO)3 2 Fe(CO)3 2 2 Fe(CO)3 - R R R Nu + 1 + - 1 R 1 PF6 R Nu Nu R
1.20 1.21
Entry Cation R1, R2 Nucleophile Product Yield, % Ref.
1 1.11 H, H -Me 1.20a 52 30
- 2 1.11 H, H CH(CO2Et)2 1.20b 98 31
- 3 1.11 H, H CH2CO2Et 1.20c 75 32
4 1.13 CO2Me, H -OH 1.21 35 33
- 5 1.15a H, OMe Me 1.20d 89 30
O 6 1.16 Me, OMe - 1.20e 100 34 CO2Me
The resulting complexes 1.20 have been demetallated using trimethylamine N- oxide35 to give cyclohexadiene derivatives. For the methoxy-substituted diene, acidic 9
hydrolysis of the vinyl ether gives a cyclohexenone. Both the diene and the enone serve
as useful functional groups for further transformations in synthesis.
This methodology has proven to be especially efficient for preparation of
quaternary carbon centers, and two vicinal quaternary carbon centers can be produced in excellent yield (entry 6, Table 1.1). Cation 1.16 and its derivatives have been applied to the synthesis of many natural products by treatment with different functionalized enolates. Examples include steroids,36,37,38 aspidosperma alkaloids,39,40,41 aphidicolanes,36,42 trichothecenes43,44,45 and trichothecene analogs.46,47
OSnBu3
(OC)3Fe (OC)3Fe MeO O MeO SiMe Ph - 2 + PF6
1.16 1.22 SiMe2Ph
(OC)3Fe i) LDA, -78 oC O O O OMs o MeO OMs MoOPH, -60 C CuCl2
ii) MsCl, 80% EtOH, 87%
SiMe2Ph 1.23SiMe2Ph 1.24
HH 5 steps O
O OH 1.25 (trichodermol)
Scheme 1.6 Synthesis of Trichodermol Using Organoiron Chemistry
10
One of the examples is the synthesis of trichodermol45 (Scheme 1.6), which represented the shortest and the highest overall yield synthesis of this natural product. It also illustrated the use of the Fe(CO)3 moiety as a stereodirecting group (anti addition of
the nucleophile), a protecting group (protection of the diene moiety and the vinyl ether) and an activating group, allowing the total synthesis of the natural product to be more efficient than the more traditional syntheses. However this “enone γ-cation” methodology found its limits in the synthesis of more complex trichothecenes, such as verrucarol48
1.26 and calonectrin49 1.27.
H H O X
O RO Y
1.26 verrucarol: R = X = H, Y = OH 1.27 calonectrin: R = Ac, X = OAc, Y = H
The use of cation complexes 1.28 and 1.29 (Figure 1.1) was desirable for the
synthesis of 1.26 and 1.27 using the previously discussed protocol.
(OC)3Fe (OC)3Fe
MeO PF - MeO 6 PF - + + 6
CO2Me OR 1.29 1.28 R = Me, Ac, CH2Ph
Figure 1.1 Potential Cation Precursors to Calonectrin and Verrucarol
11
Based upon the precedent that hydride abstraction of complex 1.6e and complex
1.12 occurs in excellent yields,25,27 complexes 1.28 and 1.29 were envisioned to be prepared in the same way from complexes 1.30 and 1.31. Surprisingly, hydride
abstraction from those complexes did not take place as summarized in Scheme 1.7.50 This observation eventually led to the development of a new intramolecular ene-type reaction, to be introduced in the following paragraphs.
Fe(CO)3 Fe(CO)3 MeO MeO Ph CPF 3 6 + - PF6
1.6e 1.16
Fe(CO)3 Fe(CO)3 Ph3CPF6 - + PF6 CO Me CO2Me 2 1.12 1.13
Fe(CO) Fe(CO) 3 MeO 3 MeO PF - X + 6 CO Me CO2Me 2 1.30 1.28
Fe(CO)3 MeO Fe(CO)3 MeO - X + PF6
1.31 OR 1.29 OR
R = Me, Ac, CH2Ph
Scheme 1.7 Unsuccessful Hydride Abstraction from p-Anisic Acid Derivatives
12
1.3 Diene-Fe(CO)3/Olefin Ene-Cyclization
(CO)3 Fe(CO)3 CF2=CF2 Fe 1.32 CF2 (1.7) CF hν 2 1.1 1.33
Some years ago, Green and co-workers51 introduced a new reaction in which complexes such as 1.1 and electron-deficient olefins 1.32 combine under photochemical conditions to furnish π-allyl complex 1.33 (eq 1.7).
In view of the problems discussed at the end of Section 1.2, Pearson and co- workers developed an intramolecular ene cyclization based on Green’s observations.
Allylic esters, allylic thioesters, and allylic amides attached to diene-Fe(CO)3 complexes cyclize under thermal conditions (CO atmosphere, n-Bu2O, reflux) or photothermal
conditions (CO, benzene, 80 °C, 350nm) to form spirolactones, spirothiolactones and spirolactams as outlined in Scheme 1.8.52,53
The best substrates for these intramolecular cyclocouplings were found to be the amide derivatives. Substitution on the pendant olefin decreases the yield, which was attributed to steric hindrance. The cyclization of ester and thioester derivatives are limited to a very low degree of substitution on the pendant olefin and are often performed under photothermal conditions, whereas cyclization of the analogous amide derivatives proceed in good yields under thermal conditions. This lack of reactivity of allylic esters as well as thioester derivatives was rationalized in terms of steric and stereoelectronic effects.52,53
When the pendant olefin is more substituted (1.36 vs 1.34), coordination of the olefin to 13
(OC) Fe (OC) Fe n-Bu O 3 3 2 X = NPh 95% CO X = O 88% o X 142 C X = S 90% O O X 1.34 1.35
(OC)3Fe (OC)3Fe X = NPh 90% X = O X 40% X = S 45% O O X 1.36 1.37
(OC)3Fe (OC)3Fe n-Bu2O CO N O 142 oC O Ph 85% O N O Ph 1.38 1.39
Fe(CO)3 n-Bu2O (OC)3Fe CO 142 oC N Ph 58% O N O Ph 1.40 1.41
Scheme 1.8 Intramolecular Coupling of Olefin with Diene- Fe(CO)3 Moiety
the iron in the 16e intermediate (see 1.44 in Scheme 1.9) is less favorable (steric repulsion). Moreover, esters and thioesters exist in two conformations, E and Z as represented in Figure 1.2. Both conformers benefit from delocalization of the lone pair of the ester (or thioester) through the carbonyl group, a primary electronic effect (Figure 1.3,
A and B). In addition both conformers have a lone pair on the carbonyl oxygen oriented antiperiplanar to the C-OR (or C-SR) bond and this n-σ* interaction stabilizes both conformers (secondary electronic effects, Figure 1.3, A and B).54 14
O O R R X X R R
Z-conformation E-conformation
Figure 1.2 Z/E Conformations of Esters (Thioesters)
O O RC RC X R X
X = O, S R AB
O RC N R R C Figure 1.3 Orbital Interactions for Amides, Esters, and Thioesters
(OC) Fe 3 (OC)3Fe
N N O 1.42 1.43 O
Figure 1.4 Conformational Preferences for Amides
In the case of the Z conformation of ester or thioester, there is another secondary interaction between the lone pair of the oxygen ester or the sulfur (oriented antiperiplanar to the CO bond) and the σ* orbital of the C-O carbonyl bond which makes the Z 15 conformer more stable than the E conformer (Figure 1.3, A). As a result, esters and thioesters adopt preferentially the Z conformation.
Amides display a similar primary electronic effect (Figure 1.3, C), delocalization of the nitrogen lone pair through the carbonyl oxygen, but there is only one secondary electronic effect present (e.g., interaction of the lone pair of the carbonyl oxygen antiperiplanar to the C-N bond with the σ* orbital). Therefore, amides adopt preferentially the less sterically hindered conformation as exemplified in Figure 1.4. Thus
N-phenyl-N-allyl amide complex adopts preferentially the conformation of 1.43, which is also the favorable conformation for cyclization. Since esters or thioesters adopt preferentially the Z conformation, a higher energy is required to bring together the reactive sites, and taking into consideration the increase of the energy barrier due to more steric interactions upon substitution of the pendant olefin, one can understand why esters or thioesters are much less reactive in comparison to amides.
The mechanism and stereoselectivity of this reaction were revealed by labeling and X-ray crystallographic studies.52 Under thermal or photothermal conditions one CO ligand is ejected from complex 1.34 to create a vacant coordination site, which is then occupied by coordination of the pendant olefin to the metal (see 1.45). Cyclization leads to metallacycle 1.46 which, after hydrogen migration (1.47) followed by reductive elimination, furnishes 1.48. The 16e complex then recaptures one CO ligand to produce spirocomplex 1.49. The net result is similar to a [6 + 2] ene reaction.
As indicated in Scheme 1.9 the reaction is stereospecific (the newly formed carbon-carbon bond is syn to the metal) and also fixes the stereochemistry at the C(4) position of the product (vide infra). Since the reaction occurs through a 16 metallabicyclooctane 1.46, the cis junction is exclusively formed, fixing the C(4) position stereochemistry (Figure 1.5).
(OC)3Fe (OC)2Fe (OC)2Fe ∆
X or ∆, hυ X X 1.34 O 1.44 O 1.45 O
H (CO) Fe (CO)2Fe 2 (CO)2Fe (CO)3Fe CH 3 CO CH3 H H H H 4 H X X X O O O O X 1.46 1.47 1.48 1.49
Scheme 1.9 Proposed Mechanism of the Spirocyclization
Favored metallacycle LnFe H LnFe H 4 O X X O Highly strained H metallacycle LnFe H LnFe
O X X O
Figure 1.5 Comparison of cis vs trans η3-Metallacyle Intermediate
Paradoxically, this stereospecific cyclization was accompanied by a total scrambling of the stereochemistry, leading to a mixture of epimers with partial loss of 17 enantiopurity, when chiral nonracemic starting material was used (Scheme 1.10). Partial loss of absolute stereochemistry is caused by racemization of the starting material (pre- cyclization rearrangement). It occurs through a hydrogen migration via the metal, a well- precedented phenomenon.12 Three continuous hydrogen abstractions and reductive eliminations result in precyclization rearrangement as shown in Scheme 1.11. The formation of epimers occurs similarly by hydrogen migration after cyclization.
(OC) Fe (OC) Fe 3 3 (OC)3Fe 3 Me Me 4 2 Cyclization Rearrangement 5 1 N Ph 6 O N N O O Ph Ph
DiastereoisomersEnantiomers Racemization Enantiomers
(OC)3Fe (OC)3Fe Me Me Cyclization Rearrangement N Ph O N (OC)3Fe O N O Ph Ph
Scheme 1.10
It has been shown that these rearrangements can be controlled by having a substituent at the C(5) position of the diene-Fe(CO)3 moiety (see Scheme 1.10 for numbering). Unfortunately, either these substituents limit the substitution on the pendant double bond or the substituent itself is difficult to be converted to useful groups.52
When a methoxy group is introduced at the 3 position of the complex, cyclization followed by demetalation and hydrolysis give a single diastereomer as product (X = NPh,
Scheme 1.12).55 Unfortunately, the reaction is very sensitive to substitution on the 18 pendant double bond, which makes the conversion very slow under thermal cyclization conditions.
OC CO (OC)3Fe (OC) Fe 2 H Fe ∆ X X - CO X O H O O 1.34 1.50 1.51
OC CO H Fe (OC)2Fe H X X H X (OC)2Fe O O O
1.52 1.53 1.54
OC H OC Fe + CO X X X (OC)2Fe (OC)3Fe O O O
1.55 1.56 ent-1.34
Scheme 1.11 Racemization due to Precyclization Rearrangement
R R R O (OC)3Fe (OC)3Fe R=OMe 3 Fe(CO)3 i)Demetallation 4 2 + ii)Hydrolysis X n-Bu O 5 1 2 6 CO X X X O o O O O 142 C 53 54 55 56
Scheme 1.12
19
Recently, this methodology was applied to the synthesis of all-carbon spirocyclic
56 molecules (X = CH2, Scheme 1.12), but only a few successful examples were presented.
The objective of this thesis is to provide a full account of this reaction. Methods to circumvent the pre- and post-cyclization rearrangement emerged as the two compelling topics that needed to be addressed, as well as potential applications in synthesis.
20
1.4 Literature Cited
(1) Pearson, A. J. “Tricarbonyl(Diene)Iron Complexes: Synthetically Useful Properties.” Acc. Chem. Res 1980, 13, 463-469.
(2) Pearson, A. J. “Natural Product Synthesis Using Organoiron Complexes.” Pure and Appl. Chem. 1983, 55, 1767-1779.
(3) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press: London, 1994.
(4) Pearson, A. J. “Organoiron Compounds in Stoichiometric Organic Synthesis.” In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds; Pergamon press: Oxford, 1982; Vol. 8, pp 939-1012.
(5) Pearson, A. J. “Transition Metal Alkene, Diene, and Dienyl Complexes: Nucleophilic Attack on Diene and Dienyl Complexes.” In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds; Pergamon Press: Oxford, 1995; Vol. 12, pp 637-684.
(6) Cox, L. R.; Ley, S. V. “Tricarbonyliron Complexes: An Approach to Acyclic Stereocontrol.” Chem. Soc. Rev. 1998, 23, 301-314.
(7) Uma, R.; Crevisy, C.; Grée, R. “Transposition of Allylic Alcohols into Carbonyl Compounds Mediated by Transition Metal Complexes.” Chem. Rev. 2003, 103, 27-51.
(8) Stille, J. K.; Becker, Y. “Isomerization of N–Allylamides and –imides to Aliphatic Enamides by Iron, Rhodium, and Ruthenium Complexes.” J. Org. Chem. 1980, 45, 2139- 2145.
(9) Damico, R.; Logan, T. J. “Isomerization of Unsaturated Alcohols with Iron Pentacarbonyl. Preparation of Ketones and Aldehydes.” J. Org. Chem. 1967, 32, 2356- 2358.
(10) Strauss, J. U.; Ford, P. W. “Stereochemistry and Mechanism of Iron Carbonyl- Induced Olefin Isomerization in Allylic Alcohols.” Tetrahedron Lett. 1975, 33, 2917- 2918.
(11) Arnett, J. E.; Pettit, R. “Rearrangement of Dienes with Iron Pentacarbonyl.” J. Am. Chem. Soc. 1961, 83, 2954-2955.
(12) Alper, H.; LePort, P. C.; Wolfe, S. “Mechanism of Formation of Conjugated Diene- Iron Tricarbonyl Complexes from Nonconjugated Dienes.” J. Am. Chem. Soc. 1969, 91, 7553-7554.
21
(13) Hendrix, W. T.; Cowherd, F. G.; von Rosenberg, J. L. “Mechanism of the rearrangement of Allyl Alcohol with Iron Pentacarbonyl. Evidence for a π-Allyl- Hydroirontricarbonyl Complex.” Chem. Comm. 1968, 97-98.
(14) Knölker, H. J. “Efficient Synthesis of Tricarbonyl-Diene Complexes - Development of an Asymmetric Catalytic Complexation.” Chem. Rev. 2000, 100, 2941-2961.
(15) Graham, C. R.; Scholes, G.; Brookhart, M. “Selective Trapping of Dienes by Benzylideneacetoneiron Tricarbonyl. Synthetic and Mechanistic Studies of the Reactions of 1,3,5-Cyclooctatriene and Its Derivatives with Benzylideneacetoneiron Tricarbonyl.” J. Am. Chem. Soc. 1977, 99, 1180-1188
(16) Brookhart, M.; Nelson, G. O. “The Reaction of Benzylideneacetoneiron Tricarbonyl with Dienes; Measurement of Relative Reactivities Using Competition Experiments.” J. Organomet. Chem. 1979, 164, 193-202
(17) Knölker, H. J.; Ahrens, B.; Gonser, P.; Heininger, M.; Jones, P. G. “Transition Metal Complexes in Organic Synthesis. Part 57: Synthesis of 1-Azabuta-1,3-dienes and Application to Catalytic Complexation of Buta-1,3-dienes and Cycloalkadienes by the Tricarbonyliron Fragment.” Tetrahedron 2000, 56, 2259-2271.
(18) Knölker, H. J.; Baum, E.; Gonser, P.; Rohde, G.; Rottele, H. “1,4-Diaryl-1-azabuta- 1,3-diene-Catalyzed Complexation of Cyclohexa-1,3-diene by the Tricarbonyliron Fragment: Development of Highly Efficient Catalysts, Optimization of Reaction Conditions, and Proposed Mechanism.” Organometallics 1998, 17, 3916-3925.
(19) 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.
(20) Knölker, H. J.; Hermann, H.; Herzberg, D. “Photolytic Induction of the Asymmetric Catalytic Complexation of Prochiral Cyclohexa-1,3-diene by the Tricarbonyliron Fragment.” Chem. Comm. 1999, 831-832.
(21) Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 13. Stereoselectivity of Complexation of Cyclohecadiene Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1755-1762.
(22) Bandara, B. M. R.; Birch, A. J.; Chauncy, B.; Kelly, L. F. “Tricarbonyliron Complexes of Some Blocked Cyclohexadienes.” J. Organomet. Chem. 1981, 208, C31- C35.
(23) Evans, G.; Johnson, B. F. G.; Lewis, J. “Synthetic Studies Relating to Acetylergosterol(tricarbonyl)iron.” J. Organomet. Chem. 1975, 102, 507-510.
22
(24) Fischer, E. O.; Fischer, R. D. “A Cyclohexadienyliron Tricarbonyl Cation.” Angew. Chem. 1960, 72, 919-920.
(25) Birch, A. J.; Chamberlain, K. B.; Haas, M. A.; Thompson, D. J. “Organometallic Complexes in Synthesis. IV. Abstraction of Hydride from Tricarbonylcyclohexa-1,3- Dieneiron Complexes and Reactions of the Complexed Cations with Nucleophiles.” J. Chem. Soc., Perkin Trans. 1 1973, 1882-1891.
(26) Ireland, R. E.; Brown, G. G.; Stanford, R. H.; McKenzie, T. C. “Reactions of Pentahapto-Cyclohexadienyliron Tricarbonyl Cations with Enamines.” J. Org. Chem. 1974, 39, 51-59.
(27) Birch, A. J.; Williamson, D. H. “Organometallic Complexes in Synthesis. V. Tricarbonyliron Derivatives of Cyclohexadienecarboxylic Acids.” J. Chem. Soc., Perkin Trans. 1 1973, 1892-1900.
(28) Eisenstein, O.; Butler, W.; Pearson, A. J. “Theoretical Study of the Formation and Reactivity of Substituted Cyclohexadienyliron Complexes. The Structures and Reactivities of Tricarbonyl(2-methoxycyclohexadienyl)iron Cation and Tricarbonyl(1- methyl-4-methoxycyclohexadienyl)iron Cation.” Organometallics 1984, 3, 1150-1157.
(29) Birch, A. J.; Haas, M. A. “Organometallic Complexes in Synthesis. III. Reaction of Concentrated Sulfuric Acid with Tricarbony-1,3-Cyclohexadieneiron Complexes. Preparation of Alkyltricarbonyl-π-Cyclohexadienyliron Salts.” J. Chem. Soc. (C) 1971, 2565-2467.
(30) Bandara, B. M. R.; Birch, A. J.; Khor, T.-C. “Alkylation of Tricarbonylcyclohexadienyliron Salts with Lithium Alkyls.” Tetrahedron Lett. 1980, 21, 3625-3626.
(31) Pearson, A. J.; Ong, C. W. “Organoiron Complexes in Organic Synthesis. 25. Complete Stereocontrol in the Synthesis of 4,4,5-Trisubstituted Cyclohexenones.” J. Org. Chem. 1982, 47, 3780-3782.
(32) Pearson, A. J.; Kole, S. L.; Yoon, J. “Stereocontrolled Double Functionalization of (Cyclohexadiene)- and (Cycloheptadiene)iron Complexes via Oxidative Cyclization Techniques.” Organometallics 1986, 5, 2075-2081.
(33) Birch, A. J.; Kelly, L. F.; Weerasuria, D. V. “A Facile Synthesis of (+)- and (-)- Shikimic Acid with Asymmetric Deuterium Labeling, Using Tricarbonyl Iron as A Lateral Control Group.” J. Org. Chem. 1988, 53, 278-281.
(34) Pearson, A. J.; Raithby, P. R. “Organoiron Complexes in Organic Synthesis. Part 4. Direct-Ring Connection between Highly Substituted Centers. A Potential Approach to Trichothecane Synthesis.” J. Chem. Soc., Perkin Trans. 1 1980, 395-399.
23
(35) Shvo, Y.; Hazum, E. “A Simple Method for the Disengagement of Organic Ligands from Iron Complexes.” J. Chem. Soc., Chem. Comm. 1974, 336-337.
(36) Pearson, A. J.; Heywood, G. C.; Chandler, M. “Organoiron Complexes in Organic- Synthesis. 23. New Strategies for Steroid and Aphidicolane Synthesis.” J. Chem. Soc., Perkin Trans. 1 1982, 2631-2639.
(37) Mincione, E.; Pearson, A. J.; Bovicelli, P.; Chandler, M.; Heywood, G. C. “New Approach to the Synthesis of 6-Ketosteroids via Organoiron Complexes.” Tetrahedron Lett. 1981, 22, 2929-2932.
(38) Mincione, E.; Pearson, A. J.; Bovicelli, P.; Chandler, M.; Heywood, G. C. “New Approach to the Synthesis of 6-Ketosteroids via Organoiron Complexes.” Tetrahedron Lett. 1981, 22, 2929-2932.
(39) Pearson, A. J.; Rees, D. C. “Total Synthesis of (±)-Limaspermine Derivatives Using Organoiron Chemistry.” J. Am. Chem. Soc. 1982, 104, 1118-1119.
(40) Pearson, A. J.; Rees, D. C. “Organoiron Complexes in Organic-Synthesis. 22. Total Synthesis of (±)-Limaspermine and Formal Synthesis of (±)- Aspidospermine Using Organoiron Complexes.” J. Chem. Soc., Chem. Comm. 1982, 2467-2476.
(41) Pearson, A. J.; Rees, D. C.; Thornber, C. W. “Synthetic Approaches to C-18 Oxygenated Aspidosperma Alkaloids via Organoiron Complexes.” J. Chem. Soc., Perkin Trans. 1 1983, 619-623.
(42) Pearson, A. J.; O’Brien, M. K. “Alkylation of Silyl Ketene Acetals with Dienyliron Complexes - Application in the Formation of Quaternary Carbon Centers.” Tetrahedron Lett. 1988, 29, 869-872.
(43) Pearson, A. J.; O’Brien, M. K. “Reaction of Tin Enolates with Substituted Tricarbonylcyclohexadienyliumiron Hexafluorophosphate Electrophiles - Diastereoselective Synthesis of (±)-Trichodiene.” J. Chem. Soc., Chem. Commun. 1987, 1445-1447.
(44) Pearson, A. J.; O’Brien, M. K. “Trichothecene Synthesis Using Organoiron Complexes - Diastereoselective Total Syntheses of (±)-Trichodiene, (±)- 12,13- Epoxytrichothec-9-Ene, and (±)-Trichodermol.” J. Org. Chem. 1989, 54, 4663-4673.
(45) O’Brien, M. K.; Pearson, A. J.; Pinkerton, A. A.; Schmidt, W.; Willman, K. “A Total Synthesis of (±)-Trichodermol.” J. Am. Chem. Soc. 1989, 111, 1499-1501.
(46) Pearson, A. J.; Chen, Y. S. “Organoiron Approach to 3,14- Dihydroxytrichothecenes.” J. Org. Chem. 1986, 51, 1939-1947.
24
(47) Pearson, A. J.; Ong, C. W. “Trichothecene Analogs - Total Synthesis of 12,13- Epoxy-14-Methoxytrichothecene via Organoiron Complexes.” J. Am. Chem. Soc. 1981, 103, 6686-6690.
(48) Trost, B. M.; McDougal, P. G.; Haller, K. J. “A Tandem Cycloaddition-Ene Strategy for the Synthesis of (±)-Verrucarol and (±)-4,11-Diepi-12,13-Deoxyverrucarol.” J. Am. Chem. Soc. 1984, 106, 383-395.
(49) Kraus, G. A.; Roth, B.; Frazier, K.; Shimagaki, M. “Stereoselective Synthesis of Calonectrin.” J. Am. Chem. Soc. 1982, 104, 1114-1116.
(50) Birch, A. J.; Pearson, A. J. “Organometallic Complexes in Synthesis. Part 9. Tricarbonyliron Derivatives of Dihydroanisic Esters.” J. Chem. Soc., Perkin Trans. 1 1978, 638-642.
(51) Bond, A.; Lewis, B.; Green, M. “Reactions of Coordinated Ligands. V. Addition of Tetrafluoroethylene to Tricarbonyl(diene)iron, Tricarbonyl(trans-cinnamaldehyde)iron, and Tricarbonyl(O-styryldiphenylphosphine)iron Complexes.” J. Chem. Soc., Dalton Trans. 1975, 1109-1118.
(52) Pearson, A. J.; Zettler, M. W. “Intramolecular Coupling between Tricarbonyl(diene)iron Complexes and Pendant Alkenes.” J. Am. Chem. Soc. 1989, 111, 3908-3918.
(53) Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. “Intramolecular Coupling Reactions of Allylic Thioesters with Diene Iron Tricarbonyl Systems.” J. Org. Chem. 1998, 63, 6610-6618.
(54) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Organic Chemistry Series; Pergamon Press: Oxford, 1983; Vol. 1, pp. 390.
(55) Pearson, A. J.; Dorange, I. B. “Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling.” J. Org. Chem. 2001, 66, 3140-3145.
(56) Dorange, I. B. "Stereocontrolled Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling." Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 2001.
25
CHAPTER TWO
Formation of Six-membered Sporolactams
26
2.1 Preparation of 6-Membered Spirolactams
Stereoselective construction of quaternary1,2,3 and spirocyclic4 carbon centers remains a challenging problem in synthesis and continues to attract the attention of numerous researchers. In the synthesis of 2-azaspiro[5.5]undecane alkaloids, 2- azaspiro[5.5]undecan-1-one (spiro-δ-lactam) derivatives have frequently been used as intermediates,5,6,7 which attracted our attention. Pearson et al. have previously described
an interesting and potentially useful cyclization reaction between cyclohexadiene-
Fe(CO)3 complexes and pendant alkenes to generate spiro-γ-lactams in excellent yield as
described in Chapter One, Section 1.3.
While it seems trivial to construct spiro-δ-lactams (6-membered lactam) similarly,
using this method just by addition of one more carbon in the starting material, evaluation
of the reaction mechanism (see Chapter 1, Scheme 1.9) shows that a 7-membered
metallacycle is required for the desired δ-lactam formation (6-metallacycle for γ-lactam,
Figure 2.1). Since the formation of 7-membered rings is generally much slower than 6-
membered rings,8 longer reaction times were expected to be required and side reactions may, consequently, predominate during the δ-lactam cyclization.
(OC)2Fe (OC)2Fe (OC)2Fe (OC)2Fe N N N Ph N Ph Ph Ph O O O O 5-spirolactam intermediate 6-spirolactam intermediate 6-metallacycle 7-metallacycle
Figure 2.1
27
To test the scope and limitations of the δ-lactam formation, amide complexes 2.2
were prepared in very good to excellent yield (Table 1) from acid complexes 2.1 (a R1 =
H, b R1 = OMe), and the corresponding but-3-enylanilines,9 which were prepared by heating a mixture of 4 equiv of aniline and one equiv of the but-3-enyl bromide or mesylate in benzene at 80 °C for 12 h. Complexes 2.1a and 2.1b were each prepared in six steps from benzoic acid and m-anisic acid respectively.10,11
Table 2.1 Preparation of N-butenyl amide complexes.
H 1 R 3 1 R R2 Fe(CO)3 R Fe(CO)3 i) Et3N, MeSO2Cl, CH2Cl2 OH R3 N Ph O R2 ii) PhHN , Et3N 1 O 2.1 a R = H H b R1 =OMe 85-95% 2.2
a Entry R1, R2, R3 Amide 2.2 Yield (%)
1 H, H, H 2.2a 85
2 OMe, H, H 2.2b 95
3 H, Me, H 2.2c 86
4 OMe, Me, H 2.2d 89
5 H, CO2Me, H 2.2e 89
6 OMe, CO2Me, H 2.2f 94
7 H, H, Me 2.2g 89
a Double bonds in 2.2 are all cis except trans in 2.2e.
28
Table 2.2 Cyclization of 2.2a-f (R1, R2, R3 as in Table 2.1).
H 3 2 1 1 1 R R R R R (OC) Fe 2 2 3 2 R (OC)3Fe R Fe(CO)3 3 3 R 2 R3 + N 3 Ph O N O N O Ph Ph 2.2 2.3 2.4
Entry Reactant Rxn. Cond.a Productsb Ratio (7 : 8) Yield: (7+8)/%
1 2.2a A (8h) 2.3a, 2.4a 4 : 3 70
2 2.2a B (2.5h) 0
3 2.2a C (24h) 2.3a, 2.4a 4 : 3 20
4 2.2b A (8h) 2.3b, 2.4b 5 : 2 65c
5 2.2c A (8h) 2.3c, 2.4c 1.8 : 1 35
6 2.2c B (2.5h) 0
7 2.2d A (8h) 2.3d, 2.4d 3 : 1 20
8 2.2e A (8h) 2.3e, 2.4e 3 : 2 80
9 2.2f A (8h) 2.3f, 2.4f 2 : 1 53d
10 2.2g A (8h) 2.3g, 2.4g 0 a Reaction conditions: A: n-Bu2O, CO, 142 °C; B: Rayonet, 350 nm; C: 1.7 equiv b Me3NO, benzene, then CO for 12 h. Cyclization products as inseparable mixtures, single recrystallization gave 2.3. c Including 5% demetallated product. d Including 13% demetallated product.
Heating 2.2a under a CO atmosphere gave 2.3a and 2.4a in 70% yield (Table 2.2, entry 1). The stereochemistries of 2.3a and 2.4a were determined by comparison of their
1H NMR spectra with the corresponding azaspiro[4.5]decane prepared earlier.12 Chemical shifts of H2 and H3 (for numbering, see Table 2.2, R1 = H) are both about 0.2 ppm 29
downfield in 2.3a compared to those in 2.4a. Alternative reaction conditions12 were tested to improve the yield, but without success (Table 2.2, entries 2 and 3).
The effect of substitution on the pendant double bond, and the generality of δ- lactam formation were also studied. 3-Methoxy-substituted amide complex 2.2b cyclized to give 2.3b and 2.4b in a yield comparable to that of 2.2a. Cyclization of 2.2c yielded
2.3c and 2.4c in only 35% combined yield (Table 2.2, entry 5) along with regioisomers
(2.5 and 2.6) of 2.2c from diene rearrangement. It was expected that 2.2c, 2.5, and 2.6 are
in equilibrium and extension of the reaction time would lead to eventual cyclization
(Scheme 2.1). Unfortunately, refluxing 2.5 and 2.6 in n-Bu2O for up to 24 hours produced no cyclization. Cyclization of 2.2d gave a similar result.
(OC)3Fe
2.3c/2.4c O N Ph Cyclization
Fe(CO)3 Fe(CO)3
N N N Ph Ph Ph (OC)3Fe O O O 2.5 2.2c 2.6
Scheme 2.1
Cyclization of 2.2g gave a surprising result. The only expected cyclization product was 2.3g (2.4g is actually the enantiomer of 2.3g, Table 2, entry 10), which
1 should have two singlets in its H NMR spectrum, each corresponding to one CH3 group.
The reaction (n-Bu2O, CO, 142 °C, 8 h) gave a pair of epimers as cyclization products, 30
and the 1H NMR spectrum of the major epimer showed two methyl doublets. Careful examination of its IR spectrum revealed the formation of a γ-spirolactam (1697 cm-1) instead of a δ-lactam (around 1660 cm-1), and the 1H NMR spectrum was consistent with structure 2.7. Thus isomerization of the pendant double bond, a known process,10 followed by cyclization led to 2.7a and 2.7b (ratio/2:1) in 30% yield (Scheme 2.2).
Fe(CO) (OC) Fe (OC)3Fe 3 Fe(CO)3 3 Isomerization Cyclization + N N Ph Ph N N O O O O Ph Ph 2.2g 2.7a 2.7b
Scheme 2.2
The δ-lactam formation is therefore quite sensitive to substitution on the pendant double bond, and does not compete well with diene rearrangement followed by γ-lactam formation. Iron carbonyls form more stable complexes with electron deficient olefins than with ethylene or electron rich olefins.13,14 We believed that if we add an electron withdrawing group on the pendant olefin, more efficient coordination to the intermediate diene-Fe(CO)2 might ameliorate the steric hindrance from the introduced group.
Gratifyingly, by introducing an ester group on the terminal position of pendant double bond, cyclization of 2.2e gave 2.3e, 2.4e in 80% yield (Table 2.2, entry 8) and 2.2f gave
2.3f, 2.4f in 53% yield (Table 2.2, entry 9), respectively, a great improvement over the reactions of 2.2c and 2.2d. Moreover, the ester group provides a means of introducing further functionality into the product molecules. 31
Cyclization products from 2.2b were converted to enones 2.8 in about 70% yield
(Scheme 3).11 This conversion utilized the standard demetallation procedure followed by hydrolysis of the dienol ether, as described previously.11
OMe OMe OMe OMe O (OC)3Fe (OC)3Fe Me3NO + Oxalic Acid + PhH H2O, CH3OH
O N O N O N O N O N Ph Ph Ph Ph Ph
2.3b 2.4b 2.8
Scheme 2.3
2.2 Conclusions
In this chapter, intramolecular couplings between alkene and diene-Fe(CO)3 moieties to produce 6-membered spirolactams were shown to be successful. δ-Lactams were found to be more difficult to form than γ-lactams, thus resulting in poorer yield and requiring longer reaction time. Improved yield was achieved by adding an ester group to
the olefin and stereocontrol was also demonstrated (2.8), all of which bodes well for
future applications of this chemistry. 32
2.3 Experimental Section.
General. All reactions were carried out under inert atmosphere of dry, deoxygenated argon, unless otherwise noted. All glassware used was oven dried
(overnight at 140 °C) or flame dried prior to use. Organic solvents/reagents were purified prior to use as follows: THF, ether and benzene were freshly distilled from
Na/benzophenone; CH3CN and CH2Cl2 were distilled from CaH2; acetone was distilled
from CaSO4; n-Bu2O was distilled from Na; pyridine was stored over KOH and distilled from CaH2; oxalyl chloride was distilled under Ar prior to use. All other solvents were used as purchased. Column chromatography was performed on flash grade silica gel.
Eluting solvents are reported as V/V percent mixture. Thin layer chromatography was performed on E. Merck silica gel 60 F254 0.25 mm plates and visualized with UV light,
and/or with phosphomolybdic acid. Preparative thin layer chromatography was
performed on E. Merck silica gel 60 F254 0.5 or 2 mm plates. CO was used as purchased
(Matheson Tri-Gas, C.P. Grade). 1H and 13C NMR spectra were recorded as solutions in
CDCl3 or other deuterated solvents on Varian Gemini XL200 (200 MHz), Varian Gemini
XL300 (300 MHz), or Varian Inova 600 (600 MHz) spectrometers, and referenced to the solvent or to TMS as an internal standard. Infrared spectra were recorded for solutions in
CHCl3 using NaCl cell, or as a KBr pellet on a Nicolet Impact 400 FTIR spectrometer.
Mass spectra were recorded by the Chemistry Department of CWRU on a Kratos MS25A instrument. Melting points were measured on a Thomas-Hoover melting point apparatus and are uncorrected.
33
General procedure for the preparation of butenyl amide complexes. A flame
dried round bottom flask was charged with the appropriate amount of carboxylic acid
complex, and with activated 4 Å molecular sieves (40 mg/mL of solvent), then kept
overnight under vacuum (0.5 mmHg). The vacuum was broken with Ar, and then the acid
was suspended in freshly distilled CH2Cl2 under argon. Then, 1.3 equivalents of freshly distilled (from CaH2) triethylamine were added via syringe to the suspension. The yellow
solution of alkylammonium salts (soluble in CH2Cl2) was cooled to 0 °C, then 2 equivalents of freshly distilled (from P2O5) methanesulfonyl chloride were added rapidly
via syringe. The reaction mixture was stirred at 0 °C for 1 h under argon (the reaction can
be monitored by IR). Two equivalents of amine and 2.7 equivalents of Et3N were added to the above mixture, which was stirred overnight at room temperature, then washed with
2N HCl and water, extracted three times with CH2Cl2, dried over MgSO4, and concentrated under vacuum. Flash chromatography on silica gel afforded the desired racemic amide complexes.
General procedure for the thermally induced cyclization. The appropriate amide was dissolved in freshly distilled n-Bu2O ether under argon. The solution was purged with CO for 1 min, and then refluxed under a balloon of CO for 8 h. The cooled product mixture was diluted with ether, filtered through Celite, and concentrated. Flash chromatography or preparative TLC separation yielded the desired product.
13 Note: The quaternary carbons of the Fe(CO)3 moiety were not detected by C NMR for amide complexes 2.2a-g, even when a very long pulse delay was used.
34
Arbitrary numbering system used for NMR assignments.
12 8 11 (OC)3Fe 7 12 (OC)3Fe 3 10 9 2 4 9 5 10 6 4 7 X 11 1 2 3 5 1 8 6 O X O
35
Tricarbonyl[N-but-3-enyl-N-phenyl-(1-4-η-cyclohexa-1,3-
Fe(CO)3 diene)-1-carboxamide]iron (2.2a).
N Ph O According to the general procedure, acid 2.1a (200 mg,
0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.14 mL of Et3N, followed by 0.12 mL of CH3SO2Cl, then 255 mg of 3-butenyl(phenyl)amine and 0.28 mL of Et3N to afford 268 mg (85% yield) of the title compound 2.2a as a light
brown oil, along with 6 mg of recovered acid complex 2.1a after chromatography. Rf =
0.30 (1:9/EA:Hex). IR (cm-1, neat): 2047, 1977, 1637, 1593, 1495. 1H NMR (200 MHz,
CDCl3) δ: 7.50-7.15 (5H, Ph), 5.74 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H, H11), 5.32 (dd, J =
4.6, 1.0 Hz, 1H, H2), 5.10-4.92 (3H, H12, H12’, H3), 4.00 (ddd, J = 13.2, 9.6, 6.2 Hz,
1H, H9), 3.51 (ddd, J = 13.2, 9.4, 5.6 Hz, 1H, H9’), 3.21 (m, 1H, H4), 2.50-2.20 (2H,
H10), 2.08 (m, 1H, H6-endo), 1.87 (m, 1H, H5-endo), 1.65 (m, 1H, H5-exo), 1.44 (dddd,
13 J = 14.2, 8.4, 4.0, 0.8 Hz, 1H). C NMR (50 MHz, CDCl3) δ: 172.5, 143.7, 135.4, 129.9,
127.5 (2C), 116.7, 86.1, 83.6, 72.2, 63.3, 51.0, 32.0, 26.2, 25.4. HRMS (m/z) for MH+
(C20H20FeNO4): calc: 394.0742; found: 394.0735.
OMe Tricarbonyl[N-but-3-enyl-N-phenyl-1-4-η-(3-methoxycyclohexa- Fe(CO)3 1,3-diene)-1-carboxamide]iron (2.2b). N Ph O According to the general procedure, acid 2.1b (200 mg, 0.68 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.12 mL
of Et3N, followed by 0.10 mL of CH3SO2Cl, then 230 mg of 3-butenyl(phenyl)amine and
0.24 mL of Et3N to afford 273 mg (95% yield) of the title compound 2.2b as a light
-1 brown oil after chromatography. Rf = 0.35 (1:4/EA:Hex). IR (cm , neat): 2052, 1980, 36
1 1631, 1598, 1493. H NMR (200 MHz, CDCl3) δ: 7.50-7.20 (5H, Ph), 5.85-5.64 (m, 1H,
H11), 5.41 (d, J = 2.4 Hz, 1H, H2), 5.08-4.95 (m, 2H, H12), 4.03 (ddd, J = 13.4, 9.8, 6.2
Hz, 1H, H9), 3.45 (s, 3H, H13), 3.48 (ddd, J = 13.4, 9.6, 5.6 Hz, 1H, H9’), 3.48-3.40 (m,
1H, H4), 2.45-2.12 (2H, H10), 1.75-1.60 (3H, H5, H5’, H6), 1.30-1.10 (m, 1H, H6’). 13C
NMR (50 MHz, CDCl3) δ: 173.5, 143.5, 138.2, 135.3, 129.8, 128.0, 127.6, 116.6, 68.9,
+ 60.5, 55.8, 54.1, 51.6, 32.0, 26.8, 24.4. HRMS (m/z) for MH (C21H22FeNO5): calc:
424.0848; found: 424.0848.
Tricarbonyl[N-pent-3-enyl-N-phenyl-(1-4-η-cyclohexa-1,3- Fe(CO) 3 diene)-1-carboxamide]iron (2.2c). N Ph O According to the general procedure, acid 2.1a (200 mg,
0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.14 mL of Et3N, followed by 0.12 mL of CH3SO2Cl, then 260 mg of pent-3- enyl(phenyl)amine and 0.28 mL of Et3N to afford 270 mg (86% yield) of the title compound 2.2c as a light brown oil, along with 4 mg of recovered acid complex 2.1a
-1 after chromatography. Rf = 0.37 (1:4/EA:Hex). IR (cm , neat): 2051, 1980, 1963, 1631,
1 1593, 1494. H NMR (200 MHz, CDCl3) δ: 7.50-7.18 (5H, Ph), 5.57-5.40 (m, 1H, H12),
5.34 (dd, J = 4.5, 1.3 Hz, 1H, H2), 5.40-5.24 (m, 1H, H11), 4.97 (ddd, J = 6.4, 4.5, 0.8
Hz, 1H, H3), 3.95 (ddd, J = 13.2, 9.2, 6.0 Hz, 1H, H9), 3.46 (ddd, J = 13.2, 9.2, 5.4 Hz,
1H, H9’), 3.23 (m, 1H, H4), 2.48-2.18 (2H, H10), 2.08 (ddd, J = 14.2, 11.6, 3.0 Hz, 1H,
H6-endo), 1.85 (m, 1H, H5-endo), 1.66 (m, 1H, H5-exo), 1.55 (d, J = 6.0 Hz, 3H, CH3),
13 1.36 (ddd, J = 14.2, 8.4, 3.6 Hz, 1H). C NMR (50 MHz, CDCl3) δ: 172.5, 143.7, 129.8, 37
127.5, 127.4, 126.6, 126.2, 86.2, 83.7, 72.2, 63.3, 51.1, 26.3, 25.4, 25.3, 12.9. HRMS
+ (m/z) for MH (C21H22FeNO4): calc: 408.0898; found: 408.0888.
Tricarbonyl[N-pent-3-enyl-N-phenyl-(1-4-η-3- OMe Fe(CO) 3 methoxycyclohexa-1,3-diene)-1-carboxamide]iron (2.2d). N Ph O According to the general procedure acid 2.1b (200 mg,
0.68 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.12 mL of Et3N and 0.10 mL of CH3SO2Cl, followed by 329 mg of pent-3-enyl(phenyl)amine
and 0.24 mL of Et3N to afford 264 mg (89% yield) of the title compound 2.2d as a light
-1 brown oil after chromatography. Rf = 0.45 (1:3/EA:Hex). IR (cm , neat): 2051, 1978,
1 1629, 1596, 1491. H NMR (200 MHz, CDCl3) δ: 7.50-7.20 (5H, Ph), 5.58-5.42 (m, 1H,
H12), 5.45 (d, J = 2.6 Hz, 1H, H2), 5.42-5.25 (m, 1H, H11), 3.97 (ddd, J = 13.4, 10.0, 6.2
Hz, 1H, H9), 3.47 (s, 3H, H14), 3.50-3.40 (m, 1H, H4), 3.41 (ddd, J = 13.2, 9.8, 5.4 Hz,
1H, H9’), 2.50-2.15 (series of m, 2H, H10), 1.74-1.50 (6H, H5-endo, H5-exo, H6-endo,
13 CH3), 1.30-1.11 (m, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ: 173.4, 143.6, 138.3,
129.8, 128.0, 127.5, 126.6, 126.3, 68.9, 60.5, 55.8, 54.1, 51.7, 26.8, 25.3, 24.4, 12.9.
+ HRMS (m/z) for MH (C22H24FeNO5): calc: 438.1004; found: 438.1003.
Tricarbonyl{6-[(1-4-η-3-methoxycyclohexa-1,3-dienecarbonyl)phenylamino]hexa-
2,4-dienoic acid methyl ester}iron (2.2e).
CO2Me According to the general procedure, acid 2.1a (200
Fe(CO)3 mg, 0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL
N of CH2Cl2 was treated with 0.14 mL of Et3N and 0.12 mL of Ph O 38
CH3SO2Cl, followed by 295 mg of 5-phenylamino-pent-2-enoic acid methyl ester and
0.28 mL of Et3N to afford 298 mg (89% yield) of the title compound 2.2e as a light
brown oil, along with 5 mg of recovered acid complex 2.1a after chromatography. Rf =
0.10 (1:4/EA:Hex). IR (cm-1, neat): 2053, 1986, 1724, 1640, 1596. 1H NMR (200 MHz,
CDCl3) δ: 7.50-7.12 (5H, Ph), 6.85 (dt, J = 15.8, 7.0 Hz, 1H, H11), 5.81 (dt, J = 15.8, 1.4
Hz, 1H, H12), 5.32 (d, J = 4.4 Hz, 1H, H2), 4.97 (apparent t, J = 5.6 Hz, 1H, H3), 4.05
(ddd, J = 13.2, 9.2, 6.0 Hz, 1H, H9), 3.70 (s, 3H, H14), 3.54 (ddd, J = 13.2, 9.2, 5.4 Hz,
1H, H9’), 3.22 (m, 1H, H4), 2.30-2.65 (2H, H10, H10’), 2.03 (ddd, J = 14.2, 11.6, 3.0
Hz, 1H, H6-endo), 1.82 (m, 1H, H5-endo), 1.63 (m, 1H, H5-exo), 1.32 (ddd, J = 14.0,
13 8.4, 3.6 Hz, 1H). C NMR (50 MHz, CDCl3) δ: 172.8, 166.8, 145.7, 143.4, 130.0, 127.7,
127.4, 121.6, 86.2, 83.8, 71.5, 63.5, 51.5, 50.3, 30.4, 26.2, 25.2. HRMS (m/z) for MH+
(C22H22FeNO6): calc: 452.0798; found: 452.0798.
Tricarbonyl(6-9-η-5-ethyl-2-phenyl-2,3,3a,4,5,5a- OMe CO2Me Fe(CO) 3 hexahydro-2-aza-cyclopenta[c]inden-1-one)iron (2.2f). N Ph O According to the general procedure, 2.1b (200 mg,
0.68 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.12 mL of Et3N and 0.10 mL of CH3SO2Cl, followed by 329 mg of 5-phenylamino-pent-2-
enoic acid methyl ester and 0.24 mL of Et3N to afford 308 mg (94% yield) of the title compound 2.2f as a light brown oil after chromatography. Rf = 0.17 (1:4/EA:Hex). IR
-1 1 (cm , neat): 2047, 1966, 1723, 1630, 1593, 1492. H NMR (200 MHz, CDCl3) δ: 7.50-
7.20 (5H, Ph), 6.26 (dt, J = 11.6, 7.4 Hz, 1H, H11), 5.80 (dt, J = 11.6, 1.8 Hz, 1H, H12),
5.39 (d, J = 2.2 Hz, 1H, H2), 4.09 (dt, J = 13.4, 7.6 Hz, 1H, H9), 3.61 (s, 3H, H15), 3.58 39
(dt, J = 13.4, 7.6 Hz, 1H, H9’), 3.43 (s, 3H, H14), 3.42-3.39 (m, 1H, H4), 2.88 (apparent
q, J = 7.7 Hz, 2H, H10), 1.74-1.58 (3H, H5-endo, H5-exo, H6-endo), 1.23-1.06 (m, 1H,
13 H6-exo). C NMR (50 MHz, CDCl3) δ: 173.7, 166.6, 146.6, 143.2, 138.2, 129.9, 127.9,
127.7, 120.9, 68.9, 60.3, 55.8, 54.1, 51.0, 50.7, 27.8, 26.8, 24.4. HRMS (m/z) for MH+
(C23H23FeNO7): calc: 482.0902; found: 482.0887.
Tricarbonyl[N-(3-methyl-but-3-enyl)-N-phenyl-(1-4-η-
Fe(CO)3 cyclohexa-1,3-diene)-1-carboxamide (2.2g). N Ph O According to the general procedure, acid 2.1a (200 mg, 0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.14 mL
of Et3N, followed by 0.12 mL of CH3SO2Cl, then 260 mg of (3-methyl-3- butenyl)(phenyl)amine and 0.28 mL of Et3N to afford 275 mg (89% yield) of the title compound 2.2g as a light brown oil after chromatography. Rf = 0.50 (1:4/EA:Hex). IR
-1 1 (cm , neat): 2052, 1980, 1637, 1591, 1499. H NMR (200 MHz, CDCl3) δ: 7.50-7.16
(5H, Ph), 5.30 (d, J = 4.4 Hz, 1H, H2), 4.94 (dd, J = 6.3, 4.6 Hz, 1H, H3), 4.71 (s, 1H,
H12), 4.65 (s, 1H, H12’), 3.54 (ddd, J = 13.2, 10.3, 5.7 Hz, 1H, H9), 3.54 (ddd, J = 13.2,
10.4, 5.7 Hz, 1H, H9’), 3.21 (m, 1H, H4), 2.42-2.10 (2H, H10), 2.18-2.08 (m, 1H, H6-
endo), 1.85 (m, 1H, H5-endo), 1.69 (s, 3H, CH3), 1.70-1.52 (m, 1H, H5-exo), 1.35 (dddd,
13 J = 13.6, 8.0, 3.6, 0.6 Hz, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ: 172.4, 143.7,
129.8, 127.5, 127.4, 111.5, 86.2, 83.6, 72.2, 63.3, 50.4, 35.4, 26.3, 22.6.. HRMS (m/z) for
+ MH (C21H22FeNO4): calc: 408.0898; found: 408.0891.
40
Fe(CO)3 Fe(CO)3 Tricarbonyl(7-10-η-5-methyl-2-phenyl-2-
azaspiro[5,5]undeca-7,9-dien-1-one)iron (2.3a/2.4a).
O N O N 2.3 Ph 2.4 Ph Amide complex 2.2a (100 mg, 0.25 mmol) was heated in n-Bu2O (12.5 mL) according to the general procedure. Flash chromatography
yielded 2.3a/2.4a as a 4:3 mixture of epimers (70 mg, 70% yield). A single recrystallization from EA/Hex afforded 2.3a and 2.4a, each as a white solid. Rf = 0.15
(1:4/EA:Hex). 2.3a: Mp 158-160 °C dec. IR (cm-1, film): 2043, 1960, 1647. 1H NMR
(200 MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 5.51 (ddd, J = 6.6, 4.2, 1.2 Hz, 1H, H9), 5.34
(ddd, J = 6.4, 4.0, 1.4 Hz, 1H, H8), 3.82 (apparent td, J = 12.2, 6.0 Hz, 1H, H3), 3.55
(ddd, J = 12.4, 7.2, 1.4 Hz, 1H, H3’), 3.42 (dtd, J = 6.6, 2.8, 1.4 Hz, 1H, H10), 3.34 (dd, J
= 6.4, 1.2Hz, 1H, H7), 2.54 (dddd, J = 14.0, 12.0, 7.2, 4.0 Hz, 1H, H4), 2.33 (dd, J =
14.4, 2.8Hz, 1H, H11-endo), 2.11 (qt, J = 7.0, 3.4 Hz, 1H, H5), 1.73 (dd, J = 14.4, 2.8
Hz, 1H, H11-exo), 1.70 (dddd, J = 14.0, 6.0, 3.0, 1.4 Hz, 1H, H4’) 1.08 (d, J = 7.0 Hz,
13 3H, CH3). C NMR (50 MHz, CDCl3) δ: 212.0, 174.8, 143.8, 129.1, 126.6, 126.2, 89.6,
+ 81.2, 65.1, 64.6, 48.7, 47.5, 38.2, 35.8, 25.2, 14.3. HRMS (m/z) for MH (C20H20FeNO4): calculated: 394.0742; found: 394.0723. 2.4a: Mp 154-156 °C dec. IR (cm-1, film): 2043,
1 1966, 1650. H NMR (200 MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 5.71 (ddd, J = 6.7, 4.2,
1.5 Hz, 1H, H8), 5.34 (ddt, J = 6.5, 4.2, 1.1 Hz, 1H, H9), 3.80 (apparent td, J = 12.1, 5.0
Hz, 1H, H3), 3.40 (ddd, J = 12.3, 6.4, 1.3 Hz, 1H, H3’), 3.14 (m, 1H, H10), 2.84 (dd, J =
6.7, 1.2Hz, 1H, H7), 2.10-2.00 (3H, H5, H4, H11-endo), 1.84 (dd, J = 15.2, 3.2 Hz, 1H,
13 H11-exo), 1.70 (m, 1H, H4’) 1.22 (d, J = 7.1 Hz, 3H, CH3). C NMR (50 MHz, CDCl3)
δ: 212.3, 173.7, 143.8, 129.2, 126.9, 126.3, 87.6, 85.6, 62.5, 60.9, 51.0, 47.4, 42.8, 37.6,
25.4, 15.0. 41
Tricarbonyl(7-10-η-8-methoxy-5-methyl-2-phenyl-2- OMe (OC)3Fe azaspiro[5,5]undeca-7,9-dien-1-one)iron (2.3b).
Amide complex 2.2b (100 mg, 0.24 mmol) was heated in O N Ph n-butyl ether (12 mL) according to the general procedure. Flash chromatography yielded 2.3b/2.4b as a 5:2 mixture of regioisomers (60 mg, 60% yield) along with 3.8 mg (5%) of demetallated product. Recrystallization from EA/Hex afforded
-1 2.3b as a white solid. Rf = 0.10 (1:4/EA:Hex). Mp 174-176 °C dec. IR (cm , film): 2039,
1 1957, 1643. H NMR (200 MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 5.08 (ddd, J = 6.6, 2.1,
1.0 Hz, 1H, H9), 3.86 (apparent td, J = 12.2, 5.0 Hz, 1H, H3), 3.69 (s, 3H, OCH3), 3.40
(ddd, J = 12.2, 7.0, 1.6 Hz, 1H, H3’), 3.10 (d, J = 2.1 Hz, 1H, H7), 2.69 (ddd, J = 6.4, 3.2,
2.6 Hz, 1H, H10), 2.27-2.06 (2H, H4, H5), 2.06 (ddd, J = 14.9, 2.6, 0.8 Hz, 1H, H11-
endo), 1.78-1.65 (m, 1H, H4’), 1.65 (dd, J = 14.8, 3.4 Hz, 1H, H10-exo), 1.26 (d, J = 7.2
13 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 211.7, 174.2, 143.8, 142.5, 129.2, 126.8,
126.4, 66.4, 56.6, 54.7, 52.4, 49.2, 47.5, 42.9, 36.7, 25.5, 14.9. HRMS (m/z) for MH+
(C21H21FeNO5): calculated: 424.0858; found: 424.0832.
Tricarbonyl(7-10-η-5-ethyl-2-phenyl-2-azaspiro[5,5]undeca- (OC)3Fe 7,9-dien-1-one)iron (2.3c).
O N Ph Amide complex 2.2c (100 mg, 0.24 mmol) was heated in
n-butyl ether (12 mL) according to the general procedure to yield 2.3c/2.4c as a 1.8:1
mixture of epimers (35 mg, 35% yield) along with 25 mg of 2.5 and 20 mg of 2.6.
Recrystallization from EA/Hex afforded 2.3c as a white solid. Rf = 0.14 (1:4/EA:Hex).
-1 1 Mp 170-174 °C dec. IR (cm , film): 2042, 1960, 1650. H NMR (200 MHz, CDCl3) δ: 42
7.40-7.10 (5H, Ph), 5.51 (ddd, J = 6.6, 4.2, 1.2 Hz, 1H, H9), 5.34 (ddd, J = 6.4, 4.0, 1.4
Hz, 1H, H8), 3.82 (td, J = 12.2, 6.2 Hz, 1H, H3), 3.55 (ddd, J = 12.4, 7.2, 1.4 Hz, 1H,
H3’), 3.42 (dtd, J = 6.6, 2.8, 1.4 Hz, 1H, H10), 3.38 (dd, J = 6.6, 0.8 Hz, 1H, H7), 2.43
(m, 1H, H4), 2.38 (dd, J = 15.3, 3.1 Hz, 1H, H11-endo), 1.95 (dddd, J = 14.6, 6.8, 2.8,
1.8 Hz, 1H, H4’), 1.73 (dd, J = 15.4, 3.0 Hz, 1H, H11-exo), 1.86-1.10 (3H, H5, H12),
13 1.00 (t, J = 7.4 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 212.0, 174.8, 143.8, 129.1,
126.6, 126.2, 89.8, 81.1, 65.1, 64.7, 48.4, 47.4, 43.0, 38.3, 20.1, 19.3, 12.6. HRMS (m/z)
+ for MH (C21H22FeNO4): calculated: 408.0898; found: 408.0908.
Tricarbonyl[N-pent-3-enyl-N-phenyl-(1-4-η-cyclohexa-
1,3-diene)-2-carboxamide]iron (2.5). N Ph (OC)3Fe O -1 Pale yellow oil. Rf = 0.43 (1:4/EA:Hex). IR (cm ,
1 neat): 2046, 1975, 1652. H NMR (200 MHz, CDCl3) δ: 7.45-7.17 (5H, Ph), 5.56 (dqt, J
= 12.2, 6.6, 1.4 Hz, 1H, H12), 5.53 (d, J = 6.8 Hz, 1H, H2), 3.98-3.74 (2H, H9), 3.02-
2.93 (2H, H3, H6), 2.38 (apparent q, J = 7.2 Hz, 2H, H10), 1.58 (3H, CH3), 1.74-1.16
(3H, H4-exo, H4-endo, H5-endo), 0.86-0.80 (m, 1H, H5-exo). 13C NMR (50 MHz,
CDCl3) δ: 211.0, 168.9, 143.6, 129.5, 128.3, 127.2, 126.5, 126.4, 98.9, 88.8, 63.1, 59.5,
+ 50.4, 25.4, 24.0, 23.4, 13.0. HRMS (m/z) for MH (C21H22FeNO4): calc: 408.0898; found: 408.0896.
Tricarbonyl[N-pent-3-enyl-N-phenyl-(1-4-η-cyclohexa-
(OC)3Fe N 1,3-diene)-5-carboxamide]iron (2.6). Ph O -1 Pale yellow oil. Rf = 0.23 (1:4/EA:Hex). IR (cm , 43
1 neat): 2046, 1975, 1652. H NMR (200 MHz, CDCl3) δ: 7.45-7.05 (5H, Ph), 5.56-5.42
(3H, H2, H3, H12), 5.36-5.21 (m, 1H, H11), 3.81-3.50 (2H, H9), 3.08 (ddd, J = 6.0, 4.5,
3.2 Hz, 1H, H1), 2.88-2.73 (2H, H4, H5), 2.24 (apparent q, J = 7.4 Hz, 2H, H10), 1.74-
13 1.66 (2H, H6), 1.60-1.54 (3H, CH3). C NMR (50 MHz, CDCl3) δ: 211.7, 174.2, 142.1,
129.8, 128.3, 128.2, 126.6, 126.4, 85.3, 85.5, 60.6, 60.2, 49.3, 41.4, 30.1, 25.4, 13.0.
+ HRMS (m/z) for MH (C21H22FeNO4): calc: 408.0898; found: 408.0890.
OMe Tricarbonyl(7-10-η-8-methoxy-5-ethyl-2-phenyl-2- (OC)3Fe azaspiro[5,5]undeca-7,9-dien-1-one)iron (2.3d)
O N Amide complex 2.2d (100 mg, 0.23 mmol) was heated in Ph n-butyl ether (11.5 mL) according to the general procedure. Flash chromatography yielded spirocylic complexes 2.3d/2.4d as a 3:1 mixture of regioisomers (20 mg, 20% yield). Recrystallization from EA/Hex afforded 2.3d as a white solid. Rf = 0.13
(1:3/EA:Hex). Mp 180-182 °C dec. IR (cm-1, film): 2038, 1961, 1644. 1H NMR (600
MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 5.07 (dd, J = 6.6, 1.8 Hz, 1H, H9), 3.72 (dt, J =
12.6, 5.0 Hz, 1H, H3), 3.68 (s, 3H, OCH3), 3.36 (ddd, J = 12.6, 6.0, 1.8 Hz, 1H, H3’),
3.12 (d, J = 2.4 Hz, 1H, H7), 2.68 (dt, J = 6.6, 3.0 Hz, 1H, H10), 2.06 (dd, J = 14.9, 2.6
Hz, 1H, H11-endo), 2.07-1.86 (3H, H4, H4’, H12), 1.65 (dd, J = 14.9, 3.6 Hz, 1H, H10-
13 exo), 1.40 (ddd, J = 13.8, 11.1, 7.4 Hz, 1H, H4’), 1.08 (d, J = 7.2 Hz, 3H, CH3). C
NMR (50 MHz, CDCl3) δ: 211.7, 174.3, 143.8, 142.5, 129.2, 126.8, 126.4, 66.3, 56.6,
+ 54.7, 52.7, 49.2, 47.3, 43.4, 43.3, 20.8, 20.3, 12.1. HRMS (m/z) for MH (C22H24FeNO5): calculated: 438.1004; found: 438.1013. 44
Tricarbonyl[(7-10-η-1-oxo-2-phenyl-2-azaspiro[5,5]undeca-7,9-dien-5-yl)acetic acid methyl ester]iron (2.3e).
(OC) Fe 3 CO2Me Amide complex 2.2e (100 mg, 0.22 mmol) was
heated in n-butyl ether (11 mL) according to the general O N Ph procedure. Flash chromatography yielded 2.3e/2.4e as a 3:2 mixture of epimers (80 mg, 80% yield). Recrystallization from EA/Hex afforded 2.3e as a
-1 white solid. Rf = 0.09 (1:4/EA:Hex). Mp 162-164 °C dec. IR (cm , film): 2045, 1981,
1 1735, 1650. H NMR (200 MHz, CDCl3) δ): 7.40-7.10 (5H, Ph), 5.53 (ddd, J = 6.6, 4.2,
1.2 Hz, 1H, H9), 5.35 (ddd, J = 6.4, 4.0, 1.4 Hz, 1H, H8), 3.84 (ddd, J = 12.8, 12.0, 6.0
Hz, 1H, H3), 3.77 (s, 3H, OCH3), 3.60 (ddd, J = 13.0, 7.6, 1.4 Hz, 1H, H3’), 3.42 (dtd, J
= 6.6, 2.8, 1.4 Hz, 1H, H10), 3.32 (dd, J = 6.4, 1.0Hz, 1H, H7), 2.60-2.27 (5H, H12,
H12’, H11-endo, H4, H5), 1.98-1.20 (m, 1H, H4’), 1.68 (dd, J = 15.0, 2.8 Hz, 1H, H11-
13 exo). C NMR (50 MHz, CDCl3) δ: 211.6, 173.9, 172.8, 143.4, 129.2, 126.9, 126.1,
89.8, 81.0, 64.0 (2C), 52.0, 47.7, 47.2, 38.6, 38.3, 32.9, 21.9. HRMS (m/z) for MH+
(C22H22FeNO6): calculated: 452.0808; found: 452.0787.
Tricarbonyl[(7-10-η-8-methoxy-1-oxo-2-phenyl-2- OMe (OC) Fe 3 CO2Me azaspiro[5,5]undeca-7,9-dien-5-yl)acetic acid methyl
ester]iron (2.3f). O N Ph Amide complex 2.2f (100 mg, 0.21 mmol) was heated in n-butyl ether (10 mL) according to the general procedure. Flash chromatography yielded 2.3f/2.4f as a 2:1 mixture of regioisomers (40 mg, 40% yield) along with 9.3 mg
(13%) of demetallated product. Recrystallization from EA/Hex afforded 2.3f as a white 45
-1 solid. Rf = 0.25 (1:4/EA:Hex). Mp 178-180 °C dec. IR (cm , film): 2039, 1959, 1753,
1 1645. H NMR (600 MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 5.08 (ddd, J = 6.8, 2.1, 1.0 Hz,
1H, H9), 3.84 (apparent td, J = 12.6, 5.0 Hz, 1H, H3), 3.77 (s, 3H, OCH3), 3.68 (s, 3H,
OCH3), 3.42 (ddd, J = 12.2, 6.6, 1.6 Hz, 1H, H3’), 2.89 (d, J = 2.1 Hz, 1H, H7), 2.86 (dd,
J = 13.2, 4.8 Hz, 1H, H12), 2.70 (ddd, J = 6.4, 3.2, 2.6 Hz, 1H, H10), 2.63-2.51 (m, 1H,
H5), 2.44 (dd, J = 13.2, 9.4 Hz, 1H, H12’), 2.26-2.05 (m, 1H, H4), 2.08 (ddd, J = 14.9,
2.6, 0.8 Hz, 1H, H11-endo), 1.83 (ddd, J = 14.5, 5.2, 3.2 Hz, 1H, H4’), 1.70 (dd, J = 14.8,
13 3.4 Hz, 1H, H11-exo). C NMR (50 MHz, CDCl3) δ: 211.4, 173.4, 172.7, 143.4, 142.2,
129.3, 127.0, 126.4, 66.4, 55.6, 54.8, 52.0, 51.9, 48.8, 47.5, 43.0, 39.1, 34.2, 22.8. HRMS
+ (m/z) for MH (C23H24FeNO7): calculated: 482.0902; found: 482.0887.
Tricarbonyl(4-Isopropyl-2-phenyl-2-azaspiro[4.5]deca-6,8-dien-1-one)iron (2.7a).
(OC) Fe 3 Amide complex 2.2g (100 mg, 0.24 mmol) was heated in
n-butyl ether (12 mL) according to the general procedure. Flash N O Ph chromatography yielded 2.7a/2.7b as a 1:1 mixture of epimers
(30 mg, 30% yield). Recrystallization from EA/Hex afforded 2.7a as a white solid. Rf =
0.41 (3:7/Hex:EA). Mp 170-172 °C dec. IR (cm-1, neat): 2044, 1965, 1697. 1H NMR (200
MHz, CDCl3) δ: 7.70-7.05 (5H, Ph), 5.57 (ddd, J = 6.2, 4.0, 1.4 Hz, 1H, H8), 5.30 (ddd, J
= 6.2, 4.2, 1.6 Hz, 1H, H7), 4.02 (dd, J = 10.6, 5.0 Hz, 1H, H3), 3.53 (d, J = 10.4 Hz, 1H,
H3’), 3.43 (m, 1H, H9), 3.01 (dd, J = 6.4, 1.4 Hz, 1H, H6), 2.24 (dd, J = 7.0, 2.8 Hz, 1H,
H4), 2.14 (d, J = 3.2 Hz, 2H, H10), 2.11 (m, 1H, H11), 1.00 (d, J = 6.8 Hz, 3H, CH3),
13 0.58 (d, J = 7.0 Hz, 3H, CH3),. C NMR (50 MHz, CDCl3) δ: 211.6, 176.4, 139.5, 128.9, 46
124.5, 119.6, 88.7, 82.2, 65.3, 63.4, 51.8, 47.3, 46.0, 31.8, 26.5, 21.3, 16.4. HRMS (m/z)
+ for MH (C21H22FeNO4): calculated: 408.0898; found: 408.0896.
5-Methyl-2-phenyl-2-azaspiro[5.5]undec-9-ene-1,8-dione (2.8).
O A solution of 50 mg of 2.3b/2.4b in 8 mL of C6H6 was treated
with 0.31 g (35 equiv) of Me3NO according to the general procedure. The O N Ph product was then dissolved in 5 mL of MeOH and hydrolyzed using a
solution of 0.16 g of (CO2H)2 in 1 mL of H2O to give, after flash chromatography, 2.8 as
-1 1 a colorless oil (23 mg, 70% yield). IR (cm , CH2Cl2): 2965, 1647, 1604, 1506. H NMR
(200 MHz, CDCl3) δ: 7.45-7.18 (series of m, 5H, Ph), 6.81 (ddd, J = 10.1, 4.6, 1.8 Hz,
1H, H10), 6.13 (dt, J = 10.1, 2.2 Hz, 1H, H9), 3.80 (m, 1H, H3), 3.58 (m, 1H, H3’), 3.11
(d, J = 15.8 Hz, 1H, H7), 3.05 (dt, J = 18.6, 3.2 Hz, 1H, H11), 2.66 (ddt, J = 18.8, 4.4, 1.6
Hz, 1H, H11’), 2.48 (dd, J = 16.0, 1.0 Hz, 1H, H7’), 2.42-2.20 (2H, H4, H5), 1.77 (m,
13 1H, H4’), 1.16 (d, J = 7.4 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 198.1, 173.1,
145.4, 143.2, 129.5, 129.3, 127.1, 126.3, 48.6, 47.9, 43.7, 36.1, 33.6, 25.9, 15.7. HRMS
+ (m/z) for MH (C17H20NO2): calculated: 270.1494; found: 270.1494. 47
2.4 Literature Cited
(1) Corey, E. J.; Guzman-Perez, A. “The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters.” Angew. Chem., Int. Edit. 1998, 37, 388-401.
(2) Fuji, K. “Asymmetric Creation of Quaternary Carbon Centers.” Chem. Rev. 1993, 93, 2037-2066.
(3) Martin, S. F. “Methodology for the Construction of Quaternary Carbon Centers.” Tetrahedron 1980, 36, 419-460.
(4) Sannigrahi, M. “Stereocontrolled Synthesis of Spirocyclics.” Tetrahedron 1999, 55, 9007-9071.
(5) Kim, D.; Choi, W. J.; Hong, J. Y.; Park, I. Y.; Kim, Y. B. “An Asymmetric Synthesis of (+)-Isonitramine by ‘Triple Allylic Strain-Controlled’ Intramolecular SN2’ Akylation.” Tetrahedron Lett. 1996, 37, 1433.
(6) Keppens, M.; De Kimpe, N. “Enantioselective Total Syntheses of the Nitraria Alkaloids (-)-Nitramine and (+)-Isonitramine.” J. Org. Chem. 1995, 60, 3916-3918.
(7) Fujii, M.; Kawaguchi, K.; Nakamura, K.; Ohno, A. “Stereoselective Synthesis of (±)- Isonitramine and (±)-Sibirine.” Chem. Lett. 1992, 1493-1496.
(8) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A, 3Ed, Plenum Press: New York and London, 1990, page 163.
(9) Barluenga, J.; Sanz, R.; Fananas, F. J. “Zirconium-Mediated Intramolecular Coupling Reactions of Unsaturated Anilines. Diastereoselective Synthesis of Azetidines.” J. Org. Chem. 1997, 62, 5953-5958.
(10) Pearson, A. J.; Zettler, M.; Pinkerton, A. A. “Intramolecular Ene-Type Reaction between a Diene-Fe(CO)3 Complex and Alkene Units.” J. Chem. Soc., Chem. Commun. 1987, 264-266.
(11) Pearson, A. J.; Dorange, I. B. “Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling.” J. Org. Chem. 2001, 66, 3140-3144.
(12) Pearson, A. J.; Zettler, M. W. “Intramolecular Coupling between Tricarbonyl(diene)iron Complexes and Pendant Alkenes.” J. Am. Chem. Soc. 1989, 111, 3908-3918.
48
(13) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press: London, 1994; Chapter 2, page 19-20.
(14) Green, M.; Lewis, B.; Daly, J. J.; Sanz, F. “Reactions of Coordinated Ligands. VI. Addition of Hexafluoropropene, Trifluoroethylene, and Chlorotrifluoroethylene to Tricarbonyl(Diene)Iron or Ruthenium Complexes and to Tricarbonyl(O- Styryldiphenylphosphine)Iron.” J. Chem. Soc., Dalton Trans. 1975, 1118-1127. 49
CHAPTER THREE
Double Cyclization
50
3.1 Double Cyclization
One of the problems with the diene/olefin spirocoupling reaction is that it
produces a pair of epimers as a result of thermal rearrangement of the diene-Fe(CO)3 system after the cyclization. Several attempts have focused on controlling the rearrangement by substitution on the cyclohexadiene-Fe(CO)3 moiety, which either
increases the number of the synthetic steps and/or brings restrictions and limitations to
the reaction, as discussed in Chapter 1, Section 1.3.
R Fe(CO) n-Bu O 3 (OC) Fe 7 (OC)3Fe 3 Fe(CO) 2 R 3 in situ 3 8 6 4 2 CO cyclization o 9 5 1 N 142 C H Ph 10 5 N N 3.2a N O O O O Ph Ph Ph 3.1 epimerization R = vinyl of product 3.3 13 (OC)3Fe R (OC)3Fe 9 11 10 12 8 Conditions not met 7 4 5 3 for cyclization 6 1 2 N N 3.2b O O Ph Ph
Scheme 3.1
The ideal solution would be to convert the two epimers to a single diastereomer
without any further steps before and after the cyclization, if it is possible. Examination of
the mechanism (Scheme 1.9, Chapter 1) shows that the [6+2] ene cyclization requires a 5-
endo hydrogen (see structure 3.1 for numbering) to be transferred within the
cyclohexadiene ring. The cyclization products 3.2a and 3.2b (Scheme 3.1) both fulfill
this requirement (H10-endo in 3.2a and 3.2b). If another pendant double bond is aligned 51
in the proper position, a second cyclization might occur. If R = vinyl, 3.2a can give 3.3
by coupling of C(12) and C(6) followed by hydrogen transfer. The same C(12)-C(6)
coupling in 3.2b would be too strained, since C(12) and C(6) are on opposite sides of the
lactam ring. As 3.2b and 3.2a are in equilibrium under the cyclization conditions, a single diastereomerically pure tricyclic product 3.3 should be produced exclusively after two successive cyclizations.
The cyclization substrates 3.6, derivatives of 3.1 (R = vinyl), for the cyclization were readily prepared in high yield from carboxylic acid complexes 3.4 and the
2 2 corresponding amines (3.5a R = Me, 3.5b R = CO2Me, eq 3.1). Amine 3.5a was prepared by reductive amination of sorbaldehyde and aniline according to the literature procedure.1 Amine 3.5b was prepared in about 40% yield by refluxing methyl (2E, 4E)-6- bromo-2,4-hexadienoate2 and aniline in water.
R2
1 R R1 Fe(CO)3 Fe(CO)3 i) Et3N, MeSO2Cl, CH2Cl2 (3.1) OH 2 N ii) PhHN R , Et3N Ph O O 1 2 85-95% a R = H, R = Me 3.4 3.6 b R1 = OMe, R2 = Me 1 1 2 a R = H c R = H, R = CO2Me b R1 = OMe 1 2 d R = OMe, R = CO2Me
Refluxing 3.6a in anhydrous n-Bu2O (0.02 mol/L) under carbon monoxide
atmosphere for 10 h yielded a single diene-Fe(CO)3 complex 3.7a in 75% yield (Table
3.1). No other diastereomers were detected by 1H NMR of the reaction mixture. The only 52
side products detected appear to be isomers of the starting material (<2% yield).
3 Demetallation of 3.7a using Me3NO in benzene produced 3.8a almost quantitatively.
Table 3.1 Cyclization of Amide Complexes 3.6
2 R Me NO 2 3 R2 R PhH 1 R1 R R1 n-Bu2O (OC)3Fe Fe(CO)3 CO + 142 oC N Ph N N O O O Ph Ph
3.6 3.7 3.8
1 2 a b c Reactant R , R Time Product [c] Yield 3.8/%
3.6a H, Me 10 3.8a 0.02 75
3.6b OMe, Me 24 3.8b 0.004 54
3.6c H, CO2Me 12 3.8c 0.004 51
3.6d OCH3, CO2Me 24 3.8d 0.004 34
a Reaction time for cyclization step. b Concentration of reactant 3.6. c Overall yield from 3.6 after demetalation, two steps.
H11 11 H11' H5a 6 H5 5 7 5a 4 H NOE (OC)3Fe 10 3a 8 3a 3 H 9 1 2 3 H N 9 O 3.7a Ph NOE
The stereochemistry of 3.7a was determined by 2D COSY and 2D NOESY experiments. There was a strong NOE between H3a and H9, but no effect between H3a 53 and H5 or H3a and H5a, which indicated the stereochemical relationship between each of the latter pairs is trans. Strong NOE was also observed between H3 and H5, which showed the cis relationship between H3a and 5-ethyl and confirmed the trans relationship between H3a and H5. The structure was also supported by the coupling constant between
H5 and H5a (J = 8.4 Hz).
(OC)2Fe Fe(CO)2 (OC)2Fe 3.6a - CO 10 H N N H 3a 3 Ph Ph N O 1 2 O O Ph 3.9 3.10 3.11
(OC) Fe 2 5 (OC)2Fe 5a 4 (OC)2Fe 3a H 10 3 H H N2 O 1 N N Ph O O 3.15 3.14 Ph Ph + CO3.12
(OC)3Fe
H
N (OC) Fe 6 O 2 (OC)2Fe 5a Ph 7 3.13 H 8 N O 9 N (OC) Fe Ph O 3 H 3.12' Ph + CO 3.16 N O Ph 3.13' 3.7a
Scheme 3.2 Proposed Mechanism for Double Cyclization under Thermal Conditions 54
According to the above results and previous work,3 the proposed mechanism is shown in Scheme 3.2. Under thermal conditions, dissociation of one CO ligand from complex 3.6a creates a vacant coordination site, which is then occupied by one of the
double bonds from the pendant diene (3.10). Cyclization leads to metallacycle 3.11. The
newly formed C(3a)-C(10) bond is endo to the metal, and the stability of the metallacycle
fixes the configuration of C(3a). Hydride migration and reductive elimination delivers
16e intermediate 3.12. Formation of 3.13 and 3.13’ could occur by addition of a CO ligand or rearrangement of the diene-Fe(CO)2 system, respectively. Further coordination
of 3.12 with the remaining double bond and subsequent second cyclization produces
3.15. Again, the newly formed C(5)-C(5a) bond is endo to the metal and C(5) stereochemistry is controlled by the metal in 3.15 just as for that at C(3a). Hydride migration, reductive elimination and coordination of CO ligand yields the final product
4,5 3.7a. Since H5a is exo to the Fe(CO)3 group, hydride migration to C(9) is prevented.
Encouraged by the excellent stereocontrol and good yield of this reaction, we examined the amide complex 3.6b, which has a methoxy substituent on the cyclohexadiene ring. Surprisingly, heating 3.6b in n-Bu2O for 12 hours only gave about
15% complex 3.7b and 10% demetallated product 3.8b along with some side products, none of which was starting material. Attempts to separate and unambiguously identify these side products were unsuccessful. The major product mixture was found to contain alkene protons as evidenced by 1H NMR. The IR spectrum indicated the presence of a 5-
membered lactam (1688 cm-1). Most likely analogs of 3.13 and 3.13’ are formed and the
reaction needs more time to reach completion. The second cyclization is slow, which
might be due to the steric effect of the methoxy group close to the reaction site. 55
Optimization of the reaction conditions (0.004 mol/L, 24 h) led to the formation of a 1:1
ratio (1H NMR) of 3.7b and 3.8b in 54% combined yield. Demetallation of a
6 spiromethoxycyclohexadiene-Fe(CO)3 during cyclization was also seen in earlier work.
Nevertheless, the reaction mixture was converted to 3.8b in almost quantitative yield.
The relatively lower yield is tentatively attributed to demetallation of the monocyclized product on prolonged heating.
It was shown in Chapter 2 that the cyclization gave a better yield when an ester functionality was introduced onto the pendant double bond. We therefore decided to add an ester group to the pendant diene system, hoping that it would facilitate the reaction and improve the yield. Unfortunately cyclizations of 3.6c and 3.6d were very slow and seemed to suffer from side reactions of the labile dienoate. High dilution of reactants is required, whereupon 3.8c and 3.8d were formed in 51% and 34% yields, respectively
(Table 3.1).
Photothermal and chemical cyclization conditions3 were screened in an effort to improve the yield of 3.7. When 3.6a-d were subjected to photothermal conditions
(Rayonet, 350 nm, benzene, 80 °C, 2.5-10 h), the product mixture became very complicated and gave poorer yields of the desired products. Very interestingly, treatment of 3.6a with 1.2 equivalent of Me3NO in acetonitrile for 10 h at 50 °C followed by CO bubbling in benzene, the standard chemically induced cyclization conditions, resulted in a totally different product (3.17) from 3.7a along with substantial amounts of demetalated
3.6a and 50% unreacted 3.6a (Table 3.2, entry 1). The 1H NMR spectrum of 3.17 displayed a methyl doublet at 1.10 ppm instead of triplet as in 3.7a or 3.8a. The carbon and proton spectra of 3.17 showed no evidence for a diene-Fe(CO)3 moiety. The 56
demetallated material could not be fully characterized and heating it at 60 °C did not give
3.17. Comprehensive spectroscopic studies (COESY, NOESY, HMQC, and HMBC)
excluded the Diels-Alder product (Scheme 3.3, 3.19), and 3.17 was eventually proved to
be the bis(diene) cycloaddition product. Chemical shifts for all the carbons and protons of
3.17, except H12 and H13, were assigned as listed in the experimental section. H9-H12
correlation in COSY, C8-H12, C9-H12 correlation in HMBC, and H5-H13 (or H12), H8-
H12 (or H13), H10-methyl correlation in NOESY support the structure of 3.17 (eq. 3.2).
Table 3.2 Chemically Induced Cyclization of Amide Complex 3.6aa
7 8 10 6 Fe(CO)3 Me NO 9 11 3 (3.2) 12 5 N MeCN 1 4 Ph 13 2 3 N O O Ph 3.6a 3.17
b c Entry Equivalent of Me3NO t (h) T (°C) Conversion Yield 3.17/%
1 1.2 10 50 50% 61
d 2 1.0 2 50 45% -
3d 1.0 20 50 45% -
4 1.7 15 60 - 60
5 3.0 12 25 100% 30
6e 2.0 20 25 90% 60
7e 2.2 10 25 100% 71
a b The reactions were done in CH3CN with the substrate concentration at about 0.5M. Reaction time. c d 1 e Yields based on recovered starting materials. Reaction run in CD3CN, monitored by H NMR. Me3NO was added in 4 portions every 2.5 h.
57
Fe(CO)3 Me3NO N N CH3CN Ph Ph O N O O Ph 3.6a 3.18 3.19
Scheme 3.3
A series of conditions were tested to optimize the reaction (Table 3.2). The
1 reaction was then monitored by H NMR in CD3CN using 1 equivalent of Me3NO at 50
°C, which stopped in 2 h at 45% conversion (entry 2, Table 3.2). Further conversion was not observed upon prolonged warming up to 20 h (entry 3, Table 3.2). Using 3 equiv of
Me3NO at rt for 12 h gave only 30% of 3.17, although with 100% consumption of starting material (entry 5, Table 3.2). When 2 equiv of Me3NO was used as in entry 6,
90% starting material was consumed. Finally, the optimal conditions were shown to give
71% of 3.17 with 2.2 equiv of Me3NO, added in four portions in 10 h. It appears that 2 equivalents of Me3NO is necessary for converting 3.6a to 3.17.
Similar (intermolecular) cycloadditions of conjugated dienes catalyzed by Ni,7
Ru,8 and Fe9 have been reported. The general mechanism is shown in Scheme 3.4. The metal coordinates to one molecule of butadiene as an η-4 complex 3.21, followed by coordination to another butadiene, as an η-2 ligand, to form a diene(olefin)complex 3.22.
Reductive elimination (3.23), followed by slippage of η-1 to η-3 complex, gives a bis(allyl) metal complex 3.24. A second reductive elimination and dissociation of the metal from the cycloaddition product, octa-1,5-diene, liberates the metal for the next catalytic cycle. 58
LnM LnM
3.21 3.22 +
MLn LnM 3.20
3.23
- LnM
LnM
3.25 3.24
Scheme 3.4
(CO)2Fe Fe(CO) Fe(CO)3 2 Me3NO H - CO N N 2 Ph Ph O N O O Ph 3.6a 3.9 3.11
Fe(CO)2 (CO)2Fe Me3NO H
N O N N Ph O O Ph Ph 3.19 3.27 3.26
Scheme 3.5
59
On this basis, a tentative explanation is given in Scheme 3.5. Removal of one CO from 3.6a by one equivalent of Me3NO at rt gives 3.9, which then cyclizes to produce the
allylalkyliron complex 3.11 (Scheme 3.3). The 3.11→3.26→3.27 transformation
10 resembles that of 3.23→3.24→3.25. A second equivalent of Me3NO then demetallates the 16e complex 3.27 to give 3.19, which also explains why 2 equivalents of Me3NO are needed to complete the cycloaddition. The fact that only 50% conversion was reached with 1 equivalent of Me3NO (Table 3.2, entry 3) indicated that abstraction of CO from
3.6a to form 3.9 is slow in comparison to the formation of 3.19. Attempts to isolate 3.26
or 3.27 were not successful.
4. 89, t, J = 6.0 Hz MeO C 4.94, d, J = 6.0 Hz 2 H H H (CO)2Fe H 5.13, t, J = 10.2 Hz HH3.01, d, J = 10.2 Hz H 3.83, dd, J = 10.2, 2.7 Hz O N 3.28 Ph
Figure 3.1
The reaction of 3.6c is extremely slow upon similar treatment with Me3NO at rt, and warming the reaction mixture to 50 °C gave a complex mixture of products. Among many fractions separated from the product mixture, only one could be recognized to contain a 5-membered spirolactam structure. Trace amounts (less than 1 mg, < 5% yield) of relatively “pure” material was obtained by PLC purification. Although contaminated with substantial amounts of impurity peaks, 1H NMR (600 MHz) suggested the presence 60
of a bis(allyl)iron complex (Figure 3.1, 3.28), an analogue of 3.26, while analogues of
3.19 or 3.27 were not unambiguously detected. Bis(allyl)iron complexes are known
11 species. Heating 3.28 in CH3CN at 60 °C overnight or using excess Me3NO gave a complex product mixture.
(OC)3Fe CO2Me CO2Me
CO2Me Fe(CO)3 N N O 1.3 equiv. Me3NO O Ph 30 equiv. Me3NO Ph N CH CN Bn 3 Benzene, rt (OC)3Fe O rt CO2Me CO2Me
3.29 N N 3.30 O 3.31 O Ph Ph
Scheme 3.6
It remains unclear why the thermal cyclization gave only double cyclization product and the chemical cyclization of 2.6a only led to cycloaddition product. To test whether this is because the low temperature of chemically induced reaction conditions prohibits the hydrogen transfer, diene-Fe(CO)3 amide 3.29, which has a pendant enoate
(in Chapter 2, enoate gave best results in cyclizations), was prepared and subjected to
Me3NO treatment. A pair of epimeric spiro-γ-lactams were obtained after demetallation
(Scheme 3.6). Clearly, hydrogen transfer is possible even at rt. The chemically induced bis(diene) cycloaddition therefore must be much faster than the [6+2] ene-reaction. Since our attention is mainly focused on the ene-cyclization, further studies of the cycloaddition were postponed. 61
The electron deficient conjugated diene (3.6c) showed poorer reactivity toward cylcohexadiene-Fe(CO)3 complex under both thermally and chemically induced
cyclizations than normal dienes (3.6a), which is opposite from the monoolefin
cyclizations, where the ester group on the pendant double bond facilitated the cyclization
(see Chapter 2). At present we do not have a reasonable explanation for this observation.
6 Hydrolysis of methoxycyclohexadiene 3.8b (oxalic acid, H2O, MeOH) and 3.8d
12 (MeSiCl3, CD3CN, then water) gave enone 3.32a in 75% yield and 3.32b in 68% yield
(eq. 3.2), which are expected to be more useful than the aforementioned dienes for further functionalization.
R R OMe O
(3.3)
N N O O Ph Ph 3.8b R = Me 3.32a R = Me 3.8d R = CO2Me 3.32b R = CO2Me
3.2 Conclusions
In conclusion, intramolecular double cyclization between a diene-Fe(CO)3 complex and a pendant diene provides a complex tricyclic molecule containing four contiguous chiral carbon centers, with excellent stereocontrol from relatively simple and easily available starting materials. More examples of this diastereoselective double cyclization will be discussed in Chapter 6. 62
3.3 Experimental Section.
General experimental and spectroscopic methods, general procedure for the
preparation of amide complexes, and general procedures for the thermally induced
cyclization are as described in Chapter 2. The quaternary carbons of the Fe(CO)3 moiety were not detected by 13C NMR for amide complexes 3.6a-d, even when very long pulse delay was set up.
Arbitrary numbering system used for NMR assignments.
R 13 R 7 12 11 8 6 11 (OC) Fe 6 10 Fe(CO)3 3 5 11 3 10 7 5a 4 9 4 2 9 10 8 3a 12 1 5 3 4 7 X 8 9 1 2 13 2 3 5 1 N N 6 O O O Ph Ph
63
6-Phenylaminohexa-2,4-dienoic acid methyl ester (3.5b)
Ph O N H O To a hot mixture (100 °C) of 2 mL aniline (2.04 g,
22 mmol ), 1.26 g of NaHCO3 and 0.5 mL of water, was added methyl (2E, 4E)-6-bromo-
2,4-hexadienoate (1.0 g, 5 mmol). The reaction mixture then was heated at 100 °C for 1.5 h, diluted with toluene, washed with water, dried (MgSO4), and evaporated. Aniline was removed under vacuum (50 °C/0.5 mmHg). Chromatography on silica gel gave 426 mg
(40% yield) of title compound 3.5b as brown viscous oil. Rf = 0.30 (1:4/EA:Hex). IR
-1 1 (cm , neat): 3393, 2954, 1722, 1617, 1512, 1445. H NMR (200 MHz, CDCl3) δ: 7.31
(dd, J = 15.4, 10.4 Hz, 1H, H3), 7.25-6.60 (5H, Ph), 6.41 (ddd, J = 15.4, 10.6, 0.6 Hz,
1H, H4), 6.21 (dt, J = 15.4, 4.0 Hz, 1H, H5), 5.86 (d, J = 15.4 Hz, 1H, H2), 3.95-3.85
13 (3H, H6, N-H), 3.75 (s, 3H, OCH3). C NMR (50 MHz, CDCl3) δ: 167.5, 147.7, 144.2,
+ 140.4, 129.4, 128.9, 120.7, 117.9, 113.0, 51.6, 45.7. HRMS (m/z) for MH (C13H16NO2): calc: 218.1181; found: 218.1178.
Tricarbonyl[(1-4-η-cyclohexa-1,3-dienecarboxylic acid hexa-
2,4-dienyl(phenyl)amide]iron (3.6a). (CO)3Fe
N Ph According to the general procedure, acid 3.4a (200 mg, O 0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of
CH2Cl2 was treated with 0.14 mL of Et3N, followed by 0.12 mL of CH3SO2Cl, then 262 mg of hexa-2,4-dienyl(phenyl)amine and 0.28 mL of Et3N to afford 273 mg (86% yield) of the title compound 3.6a as a light brown oil, along with 5 mg of acid complex 3.4a. Rf
= 0.60 (1:4/EA:Hex). IR (cm-1, neat): 2048, 1980, 1637, 1598, 1494. 1H NMR (200 MHz,
CDCl3) δ: 7.50-7.10 (5H, Ph), 6.05-5.85 (2H, H11, H12), 5.70-5.50 (2H, H10, H13), 5.36 64
(dd, J = 4.4, 1.0 Hz, 1H, H2), 4.96 (ddd, J = 6.4, 4.6, 1.0 Hz, 1H, H3), 4.42 (dd, J = 14.6,
6.3 Hz, 1H, H9), 4.14 (dd, J = 14.6, 7.0 Hz, 1H, H9’), 3.21 (m, 1H, H4), 2.08 (m, 1H,
H6-endo), 1.82 (m, 1H, H5-endo), 1.70 (d, J = 6.0 Hz, 3H, CH3), 1.63 (m, 1H, H5-exo),
13 1.34 (dddd, J = 14.0, 8.0, 3.6, 0.8Hz, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ: 172,4,
143.7, 133.8, 130.9, 129.7, 129.6, 127.6, 127.4, 125.3, 86.2, 83.7, 72.0, 63.4, 53.8, 26.2,
+ 25.3, 18.1. HRMS (m/z) for MH (C22H22FeNO4): calc: 420.0899; found: 420.0887.
Tricarbonyl[(1-4-η-3-methoxycyclohexa-1,3-dienecarboxylic
OMe acid hexa-2,4-dienyl(phenyl)amide]iron (3.6b). Fe(CO)3
N According to the general procedure, acid 3.4b (200 mg, Ph O 0.68mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with 0.12 mL of Et3N and 0.10 mL of CH3SO2Cl, followed by 236 mg of hexa-2,4-dienyl(phenyl)amine and 0.24 mL of Et3N to afford 284 mg (93% yield) of the title compound 3.6b as a light brown oil, along with 4 mg of acid complex 3.4b. Rf =
0.60 (1:4/EA:Hex). IR (cm-1, neat): 2047, 1979, 1620, 1591, 1493. 1H NMR (200 MHz,
CDCl3) δ: 7.50-7.15 (5H, Ph), 6.05-5.87 (2H, H11, H12), 5.68-5.55 (2H, H10, H13), 5.44
(d, J = 2.2 Hz, 1H, H2), 4.46 (dd, J = 14.4, 6.0 Hz, 1H, H9), 4.08 (dd, J = 14.4, 7.0 Hz,
1H, H9’), 4.02-3.39 (m, 1H, H4), 3.45 (s, 3H, OCH3), 1.75-1.60 (6H, H5-endo, H5-exo,
13 H6-endo, CH3), 1.30-1.10 (m, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ: 173.3, 143.5,
138.3, 133.8, 130.9, 129.7, 129.6, 128.1, 127.5, 125.3, 68.9, 60.4, 55.8, 54.3, 54.1, 26.8,
+ 24.4, 18.1. HRMS (m/z) for MH (C23H24FeNO5): calc: 450.1004; found: 450.1014.
65
Tricarbonyl{6-[(1-4-η-cyclohexa-1,3-dienecarbonyl)phenylamino]hexa-2,4-dienoic
acid methyl ester}iron (3.6c).
MeO2C According to the general procedure acid 3.4a (200 mg,
(OC)3Fe 0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of
N CH2Cl2 was treated with 0.14 mL of Et3N and 0.12 mL of Ph O CH3SO2Cl, followed by 329 mg of 6-(phenylamino)hexa-2,4- dienoic acid methyl ester and 0.28 mL of Et3N to afford 298 mg (85% yield) of the title
-1 compound 3.6c as a light brown oil. Rf = 0.20 (1:4/EA:Hex). IR (cm , neat): 2049, 1978,
1 1718, 1631, 1593, 1494. H NMR (200 MHz, CDCl3) δ: 7.50-7.11 (6H, Ph and H12),
6.18-6.10 (2H, H10, H11), 5.78 (d, J = 15.2 Hz, 1H, H13), 5.44 (d, J = 3.8 Hz, 1H, H2),
4.98 (m, 1H, H3), 4.53 (apparent dd, J = 15.2, 3.2 Hz, 1H, H9), 4.18 (apparent dd, J =
15.2, 4.1 Hz, 1H, H9’), 3.30-3.20 (m, 1H, H4), 2.12-1.53 (m, 3H, H5-endo, H5-exo, H6-
13 endo), 1.33 (ddd, J = 13.7, 8.6, 3.8 Hz, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ:
172.7, 167.4, 144.0, 143.4, 137.3, 130.9, 130.0, 127.8, 127.5, 121.1, 86.2, 84.0, 71.4,
+ 63.5, 53.5, 51.6, 26.2, 25.2. HRMS (m/z) for MH (C23H22FeNO6): calc: 464. 0797; found: 464.0799.
Tricarbonyl{6-[(1-4-η-3-methoxycyclohexa-1,3- CO2Me dienecarbonyl)phenylamino]-hexa-2,4-dienoic acid OMe Fe(CO) 3 methyl ester}iron (3.6d). N Ph O According to the general procedure acid 3.4b (200 mg, 0.68 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated with
0.12 mL of Et3N and 0.10 mL of CH3SO2Cl, followed by 295 mg of 6- 66
(phenylamino)hexa-2,4-dienoic acid methyl ester and 0.25 mL of Et3N to afford 298 mg
(89% yield) of the title compound 3.6d as a light brown oil, along with 5 mg of acid
-1 complex 3.4b. Rf = 0.10 (1:4/EA:Hex). IR (cm , neat): 2046, 1988, 1972, 1717, 1650,
1 1620, 1593, 1488. H NMR (200 MHz, CDCl3) δ: 7.50-7.10 (6H, Ph and H12), 6.16-6.11
(2H, H10, H11), 5.77 (d, J = 15.2 Hz, 1H, H13), 5.43 (d, J = 2.2 Hz, 1H, H2), 4.57 (ddd,
J = 15.3, 4.5, 2.4 Hz, 1H, H9), 4.14 (ddd, J = 15.2, 5.3, 2.6 Hz, 1H, H9’), 3.70 (s, 3H,
CO2CH3), 3.45 (s, 3H, OCH3), 3.44 (m, 1H, H4), 1.70-1.52 (3H, H5-endo, H5-exo, H6-
13 endo), 1.30-1.08 (m, 1H, H6-exo). C NMR (50 MHz, CDCl3) δ: 173.7, 167.3, 144.0,
143.3, 138.4, 137.3, 130.8, 129.9, 127.94, 127.86, 121.1, 68.7, 59.7, 55.9, 54.1, 54.0,
+ 51.6, 26.7, 24.3. HRMS (m/z) for MH (C24H24FeNO7): calc: 494.0902; found: 494.0887.
Tricarbonyl(6-9-η-5-ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-
(OC)3Fe 2-aza-cyclopenta[c]inden-1-one)iron (3.7a).
N O According to the general procedure 3.6a (100 mg, 0.24 Ph mmol) was refluxed in 12 mL n-Bu2O for 10 h to afford 75 mg
(75%) of the title compound 3.7a as a white solid. Mp 87-89 °C (dec). Rf = 0.60
(1:4/EA:Hex). IR (cm-1, film): 2044, 1965, 1688, 1597, 1496. 1H NMR (600 MHz,
CDCl3) δ: 7.70-7.05 (5H, Ph), 5.50 (dd, J = 6.4, 4.0 Hz, 1H, H7), 5.44 (dd, J = 6.2, 4.0
Hz, 1H, H8), 4.06 (t, J = 10.0 Hz, 1H, H3), 3.32 (dd, J = 10.0, 5.2 Hz, 1H, H3’), 3.05 (d,
J = 6.2 Hz, 1H, H9), 3.02 (d, J = 6.4 Hz, 1H, H6), 2.76 (m, 1H, H3a), 2.34 (dd, J = 13.2,
8.4 Hz, 1H, H5), 2.31 (d, J = 8.4 Hz , 1H, H5a), 1.97 (m, 1H, H4), 1.68 (dd, J = 13.2, 7.8
13 Hz, 1H, H4’), 1.58 (m, 1H, H11), 1.48 (m, 1H, H11’), 0.94 (t, J = 7.4 Hz, 3H, CH3). C
NMR (50 MHz, CDCl3) δ: 212.0, 175.9, 139.5, 128.9, 124.6, 119.8, 86.2, 67.9, 67.4, 67
+ 61.1, 53.6, 49.8, 43.3, 41.5. HRMS (m/z) for MH (C22H22FeNO4): calc: 420.0899; found: 420.0887.
5-Ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-2-azacyclopenta[c]inden-1-one (3.8a).
Complex 3.7a (19.8 mg, 0.047 mmol) was added to a mixture of
Me3NO (80 mg, 1.09 mmol) and 2 mL of benzene. The reaction mixture
N was then heated at 40-60 °C for 2 h to afford 13.1 mg (>99%) of the title O Ph compound 3.8a as a white solid. Mp 79-81 °C. Rf = 0.52 (1:4/EA:Hex).
-1 1 IR (cm , film): 1694, 1598, 1497, 1396. H NMR (200 MHz, CDCl3) δ: 7.75-7.10 (5H,
Ph), 6.05-5.63 (4H, H6-9), 4.17 (dd, J = 6.7, 5.2 Hz, 1H, H3), 3.45 (dd, J = 4.8, 1.5 Hz,
1H, H3’), 3.35 (m, 1H, H5a), 2.67 (m, 1H, H3a), 2.06 (m, 1H, H5), 1.70-1.25 (4H, H4,
13 H4’, H11, H11’), 0.96 (t, J = 5.0 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 177.5,
139.5, 128.9, 126.1, 125.0, 124.7, 123.4, 123.2, 119.9, 58.8, 54.0, 46.3, 45.6, 44.2, 40.2,
+ 23.6, 13.0. HRMS (m/z) for MH (C19H22NO): calc: 280.1701; found: 280.1704.
Tricarbonyl(6-9-η-6-methoxy-5-ethyl-2-phenyl-2,3,3a,4,5,5a- OMe (OC)3Fe hexahydro-2-azacyclopenta[c]inden-1-one)iron (3.7b).
N O Ph Complex 3.6b (100 mg, 0.22 mmol) was refluxed in 56 mL
n-Bu2O for 24 hours and worked up according to the general procedure to afford 27 mg (27% yield) of the title compound 3.7b as pale yellow viscous
-1 oil along with demetallated product 3.8b after PLC. Rf = 0.20 (1:9/EA:Hex). IR (cm ,
1 neat): 2052, 1992, 1966, 1703. H NMR (600 MHz, CDCl3) δ: 7.75-7.10 (5H, Ph), 5.53
(d, J = 4.4 Hz, 1H, H7), 4.94 (dd, J = 6.3, 4.4 Hz, 1H, H8), 3.82 (t, J = 9.6 Hz, 1H, H3), 68
3.48 (s, 3H, OCH3), 3.37 (d, J = 6.6 Hz, 1H, H5a), 3.26 (dd, J = 9.6, 4.6 Hz, 1H, H3’),
2.66 (dd, J = 6.4, 1.4 Hz, 1H, H9), 2.30 (m, 1H, H3a), 1.82 (m, 1H, H5), 1.77 (m, 1H,
H4), 1.65 (m, 1H, H4’), 1.61 (m, 1H, H11), 1.28 (m, 1H, H11’), 0.88 (t, J = 7.2 Hz, 3H,
13 CH3). C NMR (50 MHz, CDCl3) δ: 211.8, 175.9, 139.6, 128.9, 124.8, 120.2, 117.0,
81.7, 72.6, 62.0, 60.8, 57.2, 54.5, 50.4, 44.0, 43.9, 36.4, 23.3, 13.7. HRMS (m/z) for MH+
(C23H24FeNO5): calc: 450.1004; found: 450.0991.
OMe 6-Methoxy-5-ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-2-
azacyclopenta[c]inden-1-one (3.8b).
N O Ph Complex 3.6b (100 mg, 0.22 mmol) was refluxed in 56 mL n-
Bu2O for 24 hours and worked up according to the general procedure. The crude product
mixture was then treated with 400 mg of Me3NO in 10 mL dry benzene at 40-60 °C for 2 h to afford 37.3 mg (54% yield) of the title compound 3.8b as a colorless viscous oil,
-1 1 purified by PLC. Rf = 0.11 (1:9/EA:Hex). IR (cm , neat): 1703, 1664, 1603, 1493. H
NMR (200 MHz, CDCl3) δ: 7.75-7.10 (5H, Ph), 5.93 (dd, J = 9.4, 6.4 Hz, 1H, H8), 5.20
(d, J = 9.4 Hz, 1H, H9), 5.05 (d, J = 6.6 Hz, 1H, H7), 4.08 (dd, J = 10.0, 7.4 Hz, 1H, H3),
3.61 (s, 3H, OCH3), 3.58 (dd, J = 10.0, 1.3 Hz, 1H, H3’), 3.12 (d, J = 6.8 Hz, 1H, H5a),
2.55 (m, 1H, H3a), 2.40 (m, 1H, H5), 1.96 (ddd, J = 12.6, 7.2, 1.0 Hz, 1H, H4), 1.35 (dd,
J = 12.2, 5.8 Hz, 1H, H4’), 1.50-1.25 (m, 1H, H11), 1.00 (m, 1H, H11’), 0.87 (t, J = 7.2
13 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 176.5, 158.2, 139.9, 128.8, 124.5, 123.4,
119.9, 117.2, 92.1, 59.3, 54.5, 50.3, 48.9, 47.6, 44.4, 33.5, 20.8, 12.3. HRMS (m/z) for
+ MH (C20H24NO2): calc: 310.1807; found: 310.1805.
69
Tricarbonyl[6-9-η-(1-oxo-2-phenyl-2,3,3a,4,5,5a-hexahydro-
MeO2C 1H-2-azacyclopenta[c]inden-5-yl)acetic acid]iron (3.7c). (OC)3Fe
Complex 3.6c (100 mg, 0.22 mmol) was refluxed in 54 mL N O Ph n-Bu2O for 11 h and worked up according to the general procedure to afford >50 mg (>50%) of title compound 3.7c as light yellow viscous oil with minor
-1 impurity. Rf = 0.15 (1:4/EA:Hex). IR (cm , neat): 2050, 1975, 1738, 1693, 1600, 1500.
1 H NMR (200 MHz, CDCl3) δ: 7.70-7.10 (5H, Ph), 5.58-5.40 (2H, H7, H8), 4.06 (t, J =
9.7Hz, 1H, H3), 3.69 (s, 3H, CO2CH3), 3.38 (dd, J = 9.7, 5.1 Hz, 1H, H3’), 3.08 (dd, J =
6.2, 1.5 Hz, 1H, H9), 2.90 (dt, J = 6.6, 1.5 Hz, 1H, H6), 2.70-2.30 (5H, H3a, H5, H5a,
13 H11, H11’), 1.83-1.65 (2H, H4, H4’). C NMR (50 MHz, CDCl3) δ: 211.8, 175.4,
173.1, 139.3, 128.9, 124.8, 119.8, 86.2, 83.6, 67.7, 67.0, 60.6, 53.0, 51.8, 49.5, 41.4, 38.1,
+ 37.4, 35.0. HRMS (m/z) for MH (C23H22FeNO6): calc: 464.0797; found: 464.0792.
(1-Oxo-2-phenyl-2,3,3a,4,5,5a-hexahydro-1H-2- MeO2C azacyclopenta[c]inden-5-yl) acetic acid (3.8c).
N Complex 3.6c (100 mg, 0.22 mmol) was refluxed in 54 mL O Ph n-Bu2O for 24 h and worked up according to the general procedure,
and the crude product mixture was then treated with 400 mg of Me3NO in 10 mL benzene at 40-60 °C for 2 h to afford 35.6 mg (51% yield) of the title compound 3.8c as a viscous
-1 colorless oil, purified by PLC. Rf = 0.12 (1:4/EA:Hex). IR (cm , neat): 1734, 1699, 1684,
1 1600, 1505, 1488. H NMR (200 MHz, CDCl3) δ: 7.75-7.10 (5H, Ph), 6.08-5.95 (2H, H6,
H9), 5.75-5.62 (2H, H7, H8), 4.15 (dd, J = 10.1, 8.2 Hz, 1H, H3), 3.68 (s, 3H, CO2CH3),
3.51 (dd, J = 10.1, 2.1 Hz, 1H, H3’), 3.53 (m, 1H, H5a), 2.79-2.67 (2H, H3a, H5), 2.59 70
(dd, J = 15.4, 6.0 Hz, 1H, H11), 3.51 (dd, J = 15.4, 9.0 Hz, 1H, H11’), 1.70-1.25 (2H,
13 H4, H4’). C NMR (50 MHz, CDCl3) δ: 176.6, 173.3, 139.4, 128.9, 125.7, 124.8, 124.5,
123.5, 123.5, 123.0, 120.0, 57.8, 52.6, 51.7, 45.7, 44.2, 41.5, 38.4, 35.2. HRMS (m/z) for
+ MH (C20H22NO3): calc: 324.1600; found: 324.1597.
(6-Methoxy-1-oxo-2-phenyl-2,3,3a,4,5,5a-hexahydro-1H-2- CO2Me OMe azacyclopenta[c]inden-5-yl)acetic acid methyl ester (3.8d).
Complex 3.6d (100 mg, 0.20 mmol) was refluxed in 51 mL N O Ph n-Bu2O for 24 h and worked up according to the general procedure, then the crude product mixture was treated with 380 mg of Me3NO in 10 mL dry benzene
at 40-60 °C for 12 h to afford 24.3 mg (34% yield) of the title compound as a colorless
-1 1 oil after PLC. Rf = 0.23 (3:7/EA:Hex). IR (cm , neat): 1733, 1694, 1597, 1495. H NMR
(200 MHz, CDCl3) δ: 7.75-7.10 (5H, Ph), 5.95 (dd, J = 9.4, 6.6 Hz, 1H, H8), 5.23 (d, J =
9.4 Hz, 1H, H9), 5.08 (d, J = 6.6 Hz, 1H, H7), 4.10 (dd, J = 10.0, 7.4 Hz, 1H, H3), 3.68
(s, 3H, CO2CH3), 3.60 (s, 3H, OCH3), 3.58 (dd, J = 10.0, 1.3 Hz, 1H, H3’), 3.19 (d, J =
7.0 Hz, 1H, H5a), 3.04 (m, 1H, H5), 2.74 (m, 1H, H3a), 2.39 (dd, J = 15.4, 4.6 Hz, 1H,
H11), 2.09 (dd, J = 15.4, 11.0 Hz, 1H, H11’), 1.91 (ddd, J = 12.8, 7.2, 1.2 Hz, 1H, H4),
13 1.48 (ddd, J = 12.4, 11.6, 6.0 Hz, 1H, H4’). C NMR (50 MHz, CDCl3) δ: 175.9, 173.5,
157.1, 139.6, 128.9, 124.7, 123.3, 119.9, 117.2, 92.6, 59.3, 54.7, 51.6, 50.2, 48.0, 44.5,
+ 42.6, 35.0, 33.5. HRMS (m/z) for MH (C21H24NO4): calc: 354.1705; found: 354.1709.
8-Methyl-3-phenyl-3-azatricyclo[7.2.2.01,5]trideca-6,10-dien-2-one.
(3.17)
N O Ph
71
To amide 3.6a (10 mg, 0.04 mmol) in 0.5 mL CH3CN was added 3.5 mg (0.088 mmol) of Me3NO in four portions every 3 h over 12 h at rt. The reaction mixture was then filtered through celite and concentrated under vacuum to give 6.7 mg (71% yield) of
-1 the title compound 3.19 as white solid. Mp 85-87 °C. Rf = 0.38 (1:4/EA:Hex). IR (cm ,
1 neat): 1696, 1597. H NMR (600 MHz, CDCl3) δ: 7.70-7.10 (5H, Ph), 6.06 (dd, J = 9.0,
6.0 Hz, 1H, H10), 6.00 (d, J = 9.0 Hz, 1H, H11), 5.23 (dt, J = 13.8, 2.4 Hz, 1H, H6), 5.17
(dd, J = 13.8, 1.8 Hz, 1H, H7), 3.81 (t, J = 8.8 Hz, 1H, H4), 3.50 (dd, J = 11.2, 9.2 Hz,
1H, H4’), 3.11 (m, 1H, H5), 2.64 (m, 1H, H8), 2.55 (ddd, J = 13.6, 6.0, 3.0 Hz, 1H, H9),
2.18 (m, 1H, H12), 2.07 (m, 1H, H13’), 1.76-1.67 (2H, H12’ H13’), 1.10 (d, J = 7.2 Hz,
13 3H, CH3). C NMR (50 MHz, CDCl3) δ: 177.5, 139.4 (Ph-quaternary C), 132.9 (C6),
131.7 (C10), 130.0 (C11), 128.9 (Ph-m), 124.5 (Ph-p), 123.1 (C7), 119.8 (Ph-o), 52.2
(C4), 50.9 (C1), 46.7 (C5), 45.8 (C8), 35.9 (C9), 32.9 (C13), 23.9 (C12), 21.9 (Me).
+ HRMS (m/z) for MH (C19H22NO): calc: 280.1701; found: 280.1708.
Tricarbonyl{6-[(1-4-η-4-[Benzyl-(cyclohexa-1,3-dienecarbonyl)-amino]-but-2-enoic acid methyl ester}iron (3.29).
MeO2C According to the general procedure, acid 3.4a (200 mg, (OC)3Fe 0.76 mmol) and 80 mg of 4 Å molecular sieves in 2 mL of N Bn O CH2Cl2 was treated with 0.14 mL of Et3N and 0.12 mL of
CH3SO2Cl, followed by 295 mg of 4-benzylamino-but-2-enoic acid methyl ester and 0.28 mL of Et3N to afford 295 mg (88% yield) of the title compound 3.29 as a light brown oil
-1 after chromatography. Rf = 0.20 (1:4/EA:Hex). IR (cm , neat): 2053, 1986, 1724, 1640.
1 H NMR (200 MHz, CDCl3) δ: 7.50-7.12 (5H, Ph), 6.85 (dt, J = 15.4, 5.6 Hz, 1H, H10), 72
6.15 (d, J = 4.2 Hz, 1H, H2), 5.85 (dt, J = 15.2 Hz, 1H, H11), 4.97 (dd, J = 6.4, 4.6 Hz,
1H, H3), 5.0 (d, J = 15.2 Hz, 1H, benzyl H), 4.50-4.30 (2H, H9, benzyl H’), 4.15-3.80
(m, 1H, H9’), 3.72 (s, 3H, OCH3), 3.50-3.00 (m, 1H, H4), 2.00-1.35 (4H, H5, H5, H6,
13 H6’). C NMR (50 MHz, CDCl3) δ: 211.0, 173.7, 166.1, 143.0, 142.9, 128.9, 127.5,
126.3, 123.0, 86.3, 85.5, 82.3, 69.5, 64.5, 51.6, 30.4, 26.4, 24.0. HRMS (m/z) for MH+
(C22H22FeNO6): calc: 452.0798; found: 452.0798.
(1-Oxo-2-phenyl-2-azaspiro[4.5]deca-6,8-dien-4-yl)acetic acid methyl ester (3.31).
CO2Me Complex 3.29 (80 mg, 0.18 mmol) was treated with 8.5
mg of Me3NO in 5 mL of CH3CN at rt for 12 h. The reaction N O Bn mixture was then concentrated under vacuum, dissolved in 4
mL of benzene, bubbled with CO for 6 h, concentrated, and CO2Me filtered through Celite. The resulting oil was then stirred in 8 O N Bn mL of benzene with 850 mg of Me3NO at rt for 12 h to afford
35 mg (62% yield) of the title compound 3.31 as two (1:1) separated oily compounds,
-1 1 purified by PLC. One isomer: Rf = 0.26 (2:3/EA:Hex). IR (cm , neat): 1734, 1696. H
NMR (200 MHz, CDCl3) δ: 7.40-7.10 (5H, Ph), 6.12 (ddd, J = 10.2, 5.4, 0.8 Hz, 1H),
5.90 (dddd, J = 9.5, 5.2, 2.6, 0.8 Hz, 1H), 5.70 (ddd, J = 9.6, 5.8, 2.8 Hz, 1H), 5.60 (dt, J
= 9.5, 1.1 Hz, 1H), 4.61 (d, J = 13.6 Hz, 1H, benzyl H), 4.31 (d, J = 13.6 Hz, 1H, benzyl
H’), 3.62 (s, 3H, OCH3), 3.34 (dd, J = 10.0, 3.7 Hz, 1H, H3), 3.34 (dd, J = 10.0, 8.8 Hz,
1H, H3’), 2.69 (d, J = 15.6 Hz, 1H, H10), 2.67 (dd, J = 10.0, 8.8 Hz, 1H, H10’), 2.55-
13 2.40 (m, 1H, H4), 2.31-2.15 (2H, H11, H11’). C NMR (50 MHz, CDCl3) δ: 178.3,
172.6, 136.4, 128.8, 128.1, 127.7, 126.4, 125.9, 123.9, 123.7, 51.8, 48.0, 47.5, 40.5, 33.7, 73
1 25.8, 16.8. The other isomer: H NMR (200 MHz, CDCl3) δ: 7.40-7.20 (5H, Ph), 6.17
(ddd, J = 9.8, 3.8, 2.2 Hz, 1H), 5.90-5.80 (2H), 5.60 (dd, J = 9.8, 0.8 Hz, 1H), 4.63 (d, J =
13.6 Hz, 1H, benzyl H), 4.36 (d, J = 13.6 Hz, 1H, benzyl H’), 3.62 (s, 3H, OCH3), 3.34
(dd, J = 10.0, 7.2 Hz, 1H, H3), 3.13 (dd, J = 18.2, 0.8 Hz, 1H, H9), 2.89 (dd, J = 10.0, 8.0
Hz, 1H, H3’), 2.67 (dd, J = 17.8, 3.8 Hz, 1H, H9’), 2.55-2.40 (m, 1H, H4), 2.34-2.10
(2H, H11, H11’).
5-Ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-9H-2- O azacyclopenta[c]indene-1,6-dione (3.32a).
N Dienol ether 3.8b (10.2 mg, 0.033 mmol) was treated with a O Ph solution of 275 mg of oxalic acid in 1.6 mL of water and 4.0 mL
CH3OH for 24 h. The reaction mixture was then washed with saturated aqueous Na2CO3 solution, extracted with Et2O, dried and concentrated under vacuum. PLC afforded 7.3 mg (75% yield) of the title compound 3.32 as a viscous colorless oil. Rf = 0.22
-1 1 (3:7/EA:Hex). IR (cm , neat): 1697, 1601, 1506. H NMR (200 MHz, CDCl3) δ: 7.76-
7.12 (5H, Ph), 6.88 (ddd, J = 10.2, 5.9, 2.5 Hz, 1H, H8), 6.13 (ddd, J = 10.0, 2.6, 1.0 Hz,
1H, H7), 4.18 (dd, J = 10.2, 8.0 Hz, 1H, H3), 3.58 (dd, J = 10.2, 1.8 Hz, 1H, H3’), 3.06
(d, J = 6.6 Hz, 3H, H5a), 2.86 (dt, J = 18.5, 2.6 Hz, 3H, H9), 2.65 (m, 1H, H3a), 2.46
(ddd, J = 18.5, 5.9, 1.0 Hz, 1H, H9’), 2.15-1.30 (5H, H5, H4, H4’, H11, H11’), 0.97 (t, J
13 = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 198.0, 176.0, 145.4, 139.2, 131.9,
129.2, 125.2, 120.0, 58.6, 54.5, 53.9, 47.6, 41.0, 39.3, 30.7, 24.3, 13.6. HRMS (m/z) for
+ MH (C19H22NO2): calc: 296.1650; found: 296.1653. 74
(1,6-Dioxo-2-phenyl-2,3,3a,4,5,5a,6,9-octahydro-1H-2-
CO2Me O azacyclopenta[c]inden-5-yl)-acetic acid methyl ester (3.32b).
To dienol ether 3.8d (15.1 mg, 0.043 mmol) and 9 mg of NaI
N in a dry NMR tube was added 1 mL of CD3CN containing 9 mg of O Ph MeSiCl3. The tube was sealed and shaken. After 5-10 minutes
1 (Monitored by H NMR), the reaction mixture was poured into 1 mL CH3OH, quickly
diluted with aqueous NaHCO3, and extracted with ether. The ethereal extract was washed with aqueous solutions of Na2S2O3 and NaCl, dried and concentrated under vacuum. PLC gave 9.8 mg (68% yield) of the title compound as a colorless viscous oil. Rf = 0.11
(2:3/EA:Hex). IR (cm-1, neat): 1735, 1685, 1668, 1597, 1498. 1H NMR (200 MHz,
CDCl3) δ: 7.76-7.12 (5H, Ph), 6.91 (ddd, J = 10.2, 6.0, 2.4 Hz, 1H, H10), 6.12 (ddd, J =
10.0, 2.8, 1.0 Hz, 1H, H9), 4.19 (dd, J = 10.3, 7.9 Hz, 1H, H3), 3.58 (dd, J = 10.4, 1.4 Hz,
1H, H3’), 3.19 (d, J = 6.0 Hz, 3H, H7), 3.05-2.40 (6H, H4, H6, H11, H11’, H13, H13’),
13 1.95-1.84 (m, 1H, H5), 1.74 (dd, J = 12.4, 9.8 Hz, 1H, H5’). C NMR (50 MHz, CDCl3)
δ: 197.9, 175.5, 173.4, 146.1, 139.1, 131.4, 129.1, 125.2, 120.1, 58.5, 54.4, 53.6, 51.7,
+ 40.2, 39.0, 35.8, 30.5. HRMS (m/z) for MH (C20H22NO4): calc: 340.1549; found:
340.1546. 75
3.4 Literature Cited
(1) Verardo, G.; Giumanini, A. G.; Strazzolini, P.; Poiana, M. “Reductive N- Monoalkylation of Primary Aromatic Amines.” Synthesis 1993, 121-125.
(2) Durrant, G.; Green, R. H.; Lambeth, P. F.; Lester, M. G.; Taylor, N. R. “Synthesis of Some Aromatic Prostaglandin Analogs. Part 1.” J. Chem. Soc., Perkin Trans. I 1983, 2211-2214.
(3) Pearson, A. J.; Zettler, M. W. “Intramolecular Coupling between Tricarbonyl(diene)iron Complexes and Pendant Alkenes.” J. Am. Chem. Soc. 1989, 111, 3908-3918.
(4) Alper, H.; LePort, P. C.; Wolfe, S. “Mechanism of Formation of Conjugated Diene- Iron Tricarbonyl Complexes from Nonconjugated Dienes.” J. Am. Chem. Soc. 1969, 91, 7553-7554.
(5) Whitesides, T. H.; Neilan, J. P. “Thermolysis of Diene Iron Tricarbonyl Complexes. Cis-Trans Isomerization and Hydrogen Scrambling Reactions in Cyclic and Acyclic Complexes.” J. Am. Chem. Soc. 1976, 98, 63-73.
(6) Pearson, A. J.; Dorange, I. B. “Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling.” J. Org. Chem. 2001, 66, 3140-3144.
(7) ElAmrani, M. A.; Suisse, I.; Knouzi, N.; Mortreux, A. “Chemo and Enantioselective Butadiene-Functionalized Diene Cyclodimerization Catalyzed by Nickel Complexes.” Tetrahedron Lett. 1995, 36, 5011-5014.
(8) Itoh, K.; Masuda, K.; Fukahori, T.; Nakano, K.; Aoki, K.; Nagashima, H. “Stoichiometric and Catalytic Dimerization of Conjugated Diene with + (C5R5)Ru(diene) .” Organometallics 1994, 13, 1020-1029.
(9) Dieck, H. T.; Dietrich, J.; Wilke, G. “Diazadienes as Directing Ligands in Homogeneous Catalysis. 11. Selectivity and Mechanism of Diene Cyclodimerization on Iron (0).” Angew. Chem. 1985, 97, 795-796.
(10) Eekhof, J. H.; Hogeveen, H.; Kellogg, R. M. “Intermediate Compound in the Decomplexation of a Tricarbonyl Iron Complex Using Trimethylamine Oxide.” Chem. Comm. 1976, 657.
(11) Grosselin, J. M.; Dixneuf, P. H. “Electron-Rich, Hydrocarbon-Metal Complexes:Synthesis and Oxidation Properties of Bis(η3-allyl)iron Complexes Containing Phosphines.” J. Organomet. Chem., 1986, 314, C76-C80.
76
(12) Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. “Synthetic Methods and Rreactions. 96. Trichloromethylsilane/Sodium Iodide, A New Regioselective Reagent for Ether Cleavage.” Angew. Chem. Int. Ed. 1981, 20, 690-691. 77
CHAPTER FOUR
Intramolecular [6+2] Ene-type Reactions to Afford Non-spirocyclic
Products
78
4.1 Preparation of Bicyclic Molecules by a Rearrangement-Cyclization Procedure
In the preceding chapter, tandem double cyclization of 4.1 (3.6a in Chapter 3)
yielded a tricyclic molecule in a single step with complete diastereoselectivity (Scheme
4.1).
(OC)2Fe n-Bu2O (OC)3Fe CO Fe(CO)3 142 oC 1st Cyclization 2nd Cyclization N N N Ph O O Ph Ph O
4.1 4.2 4.3
Scheme 4.1
Looking only at the second cyclization suggests that a bicyclic structure might be formed in the absence of the lactam ring. If substrates 4.5 similar to the double cyclization intermediate 4.2 can be made (eq. 4.1), this methodology may be extended to produce a variety of bicyclic molecules.
(OC)3Fe (OC)3Fe (4.1) R = H or Substituent R R 4.4 4.5
79
Table 4.1 Optimization of Cyclization Conditions for 4.7a
(OC)3Fe (OC)3Fe
4.6 OH N O O Bn 4.9a (OC)3Fe
(OC)3Fe (OC)3Fe + N NBn N Bn O Bn O O 4.7a 4.8 4.10a
[4.7a] (M) Conditionsa Time (h) Conversion Yield Ratio (4.10a/%) (4.10a/4.8) b 0.02 A 6 50% 20 10 : 1
0.02 A 17 100% 0 ---
0.01 A 6 20% 5 10 : 1
0.004 A 6 10% 0 ---
0.02 B 6 100% 91 > 50 : 1
a b A: n-Bu2O, CO, 142 °C; B: n-Bu2O, 1.0-1.5 equiv Fe(CO)5, CO, 142 °C. Along with approximately 25% 4.7a and 25% 4.9
The cyclization reaction proceeds via coordination of a pendant double bond to Fe
(Scheme 3.2, Chapter 3), which should therefore be cis to Fe(CO)3 in 4.5. With this in mind, we began with amide complex 4.7a, which was prepared from known acid 4.61 and
N-(benzyl)allylamine (Table 4.2). The amide 4.7a showed rotamer equibrium in 1H NMR
(broad) and 13C NMR spectra, which has two sets of peaks for every carbon. Recording
13 C NMR spectrum in CD3OD at 50 °C gave only one set of peaks. Our initial plan was to make 6-membered lactam 4.8. To our surprise, refluxing 4.7a in n-Bu2O (0.02 M) under CO atmosphere for 6 h gave only traces of 4.8. The major products were enamide 80
4.9a and 5-membered lactam 4.10a. Extension of the reaction time led to decomposition
and aromatization. Varying the substrate concentration indicated a second order kinetics
for the conversion of 4.7a (within same reaction time lower [4.7a], less conversion, Table
4.1).
Table 4.2 Preparation of Amide 4.7 and Its Cyclization
R2 3 i) (COCl)2, 2 R (OC) Fe R2 R 3 Fe(CO)3 (OC)3Fe pyridine, Fe(CO)3 MS, CH2Cl2 Fe(CO) 3 5 R R3 NR1 ii) pyridine, n-Bu2O N 1 N 1 allyl amine R R O O O O OH 83-90% 4.6 4.74.9 4.10
1 3 c Entry R , R2, R Amide Lactam T Yield 4.10/%
1 Bn, H, H 4.7a 4.10a 6h 91
2 Ph, Me, H 4.7b 4. 10b 8h 72
3 Ph, H, Me 4.7c 4. 10c 8h <1
4 1 2 3 4.7d 4. 10d 8h 10 R +R = CH2, R = H
1 2 3 5 R +R = CH2CH2, R = H 4.7e 4. 10e 8h 5 6 H, H, H 4.7f 4. 10f 9h 0
7 Ph, CO2Me, H 4.7g 4. 10g 8h 0
We conclude that 6-membered lactam formation is not favored, and instead the
reaction proceeds via isomerization (catalyzed by a diene-Fe(CO)2 residue of another
4.7a molecule), followed by cyclization, also observed in Chapter 2, Scheme 2.1. Since it 81
is known that Fe(CO)5 catalyzes double bond migration (see Chapter 1, section 1.1), we
added 1-1.5 equiv of Fe(CO)5, whereupon the isomerization-cyclization proceeded cleanly in 6 h to give 4.10a in 91% yield as the sole product!
A series of derivatives 4.7b-g were prepared to test the generality of this
bicyclization. Addition of a methyl group at the terminal position of the pendant double
bond slowed the reaction a little, with some reduction of the yield (entry 2, Table 4.2).
When the methyl was appended to the inner site of the double bond (4.7c), only trace
amounts of the bicyclic lactam were obtained after 8 h, the major product being the
enamide 4.9c. This slow cyclization is probably due to the steric hindrance from the gem
dimethyl on the double bond in 4.9c. The lack of reactivity of 4.7d and 4.7e is thought to
result from the strain caused by the extra 5 or 6-membered nitrogen ring during
cyclization (entry 3 and 4). Extension of the reaction time resulted in no improvement.
Although there is no substitution on the pendant double bond, cyclization of 4.7f did not
give any desired product, which suggested that a substituent on the nitrogen is necessary
for the iron mediated ene-cyclizations. The enamides 4.9a-f were all observed during the
reaction, but only 4.9e were fully characterized. The reaction of 4.7g suffered from side
reaction of the enoate with Fe(CO)5 to give no 4.10g or 4.9g. Attempts to use a chiral auxiliary, α-methylbenzyl group, on the nitrogen of 4.7f to induce diastereoselective
cyclization failed to produce any selectivity.
The introduction of an alkyl substituent at the amide (4.7) α-position was explored, because it should push the pendant double bond toward iron and therefore promote the cyclization (Thorpe-Ingold effect).2 Alkylation (LDA, benzyl bromide or methyl iodide) of 4.7c failed to yield any α-substituted amide complex. Other bases, such 82
as NaH and KHMDS, were also tried but gave the same result. Thus this proposition could not be tested at this stage (but see later).
Coupling of acid 4.6 with benzylamine, reduction of amide 4.11 by DIBALH, and
Michael addition of the resulting amine to methyl propiolate produced enamine 4.12.
Direct cyclization of enamine iron complex 4.12 to afford 4.13, without the isomerization
step, was also realized in good yield.
(COCl)2, Fe(CO)3 CO2Me (OC)3Fe Fe(CO)3 pyridine, i) DIBALH, CH2Cl2 H Benzyl amine ii) CO Me N N 2 Bn 95% O Bn THF O OH 4.11 4.12 4.6 86%, 2 steps
(OC) Fe (OC)3Fe CO2Me 3 1-1.5 equiv. Fe(CO) 5 N Bn o NBn 4.13 CO, n-Bu2O, 142 C, 8h 4.10a O 80%
OH OH OH O N O N O several steps N N N O H O 4.14 gelsemine
Scheme 4.2
Compounds 4.13 and 4.10a have a bicyclic framework and stereochemistry identical to that in gelsemine, a hexacyclic natural product which has attracted much attention from the synthetic community because of its unique cage structure.3,4,5 If proper 83
functionality could be introduced onto 4.10a, this reaction might provide a potential
pathway to gelsemine via intermediate 4.14 or its equivalent.
4.2 One-Pot Cyclization
Fe(CO)3 Fe(CO)3 o O c O a O Fe(CO)5, 142 C CO H Hydrolysis 2 Esterificaion O Complexation OMe OH RRb R R = H R 4.15 4.16
(OC) Fe Fe(CO)3 3 Fe(CO)5 (OC)3Fe o e CO, 142 C d 7a NBn NBn Alkylation NBn Cyclization Amidation R R f O R = H O O 4.18 4.7a 4.17
Scheme 4.3
In order to generate a possible approach to the gelsemine structure or other
angularly substituted bicyclic lactams, a substituent is required at C7a (structure 4.18,
Scheme 4.3). What is more, introducing the substituent at C7a before cyclization is
expected to promote the cyclization (allowing more substitution and steric hindrance).
Investigation of our earlier protocol showed that this is problematic. If the R group (for
example Me) is introduced before step c, the ester 4.15 cannot be hydrolyzed due to steric
hindrance.6 Similar difficulties are anticipated for direct conversion of 4.16 (R ≠ H) to its
amide counterpart, even if it can be prepared. Attempts on alkylation (LDA, benzyl
bromide, step e) of 4.7a were disappointing. The same problems would exist for
alkylation of 4.17 (R = H) to give 4.18 (R ≠ H). One may think of alkylating 4.18 (R = H, 84
also 4.10a) after demetalation, but the resulting cyclohexadiene is prone to aromatization
and the regioselectivity is likely to be a problem.
This dilemma prompted us to devise an alternate strategy. Careful examination of
Scheme 4.3 shows that preparation of the iron complex (step b) and cyclization (step f) shared the same reaction conditions. We argued that these two steps might be combined, making the organic framework first, which is then treated with Fe(CO)5 in refluxing n-
Bu2O as the last step for preparing the bicyclic lactam iron complexes 4.21 (Scheme 4.4).
This last step would require selective complexation of Fe(CO)3 to the cyclohexadiene, and isomerization of the pendant double bond, followed by cyclization. In this protocol, the steric problems are circumvented by a later involvement of the Fe(CO)3 and only three operations, half the number of steps as in Scheme 4.3, are required to obtain the angularly substituted bicyclic lactam with stereochemistry matching the possible gelsemine intermediate 4.14.
R3 (COCl) , pyridine, O O 2 2 equiv. LDA amine R2 OH 1 OH RX 4 or DCC/EDCI, N R R HOBT, amine R4 O 4.19 4.20 R1 - R4 R3 see Table 4.3 2 Si Ph (OC)3Fe R Fe(CO)5 4.21g 1 N n-Bu O N R 2 Me NO 142 oC 3 4 O CO R O Benzene 4.22 4.21 OTBDPS
Scheme 4.4
85
To our delight, the transformations worked as planned. Alkylation of 1,4-
dihydrobenzoic acid7 with benzyl bromide or 2-iodoethyl TBDPS ether8 followed by
amidation with various N-allylamines delivered amides 4.20a-g, substrates that were
subjected to the Fe-mediated one-pot cyclization reaction. The allylamine for preparing amide 4.20g, [3-(Dimethylphenylsilyl)allyl]methylamine, was prepared by C-silylation9 of
N-methyl-propargylamine with chlorodimethylphenylsilane followed by partial
hydrogenation of the triple bond.
When trienes 4.20 were refluxed in n-Bu2O (0.02 mol/L) under CO atmosphere in the presence of Fe(CO)5, a single product 4.21 was obtained in good yield for all of the
substrates except 4.20c (Table 4.3). Tricyclic products were formed for 4.21a, b and f.
Table 4.3 One-Step Cyclization of 4.20 to Produce Bicycles 4.21a
Reactant R1, R2, R3, R4 Product Time (h) Yield
1 2 3 4 4.20a R + R = CH2, R = H, R = Bn 4.21a 24 92
1 2 3 4 4.20b R + R = CH2CH2, R = H, R = Bn 4.21b 36 85
4.20c R1 = Ph, R2 = H, R3 = Me, R4 = Bn 4.21c 24 81b
4.20d R1 = Me, R2 = R3 = H, R4 = Bn 4.21d 24 82c
4.20e R1 = R2 = R3 = H, R4 = Bn 4.21e 36 20
1 2 3 4 4.20f R + R = CH2, R = H, R = 4.21f 36 68
CH2CH2OTBDPS
4.20g R1 = Me, R2 = DMPS, R3 = H, R4 = 4.21g 36 63
CH2CH2OTBDPS
a b The substrates were refluxed in n-Bu2O with Fe(CO)5. Including another isomer, where iron is on the other face of the cyclohexadiene ring. c Including 21% demetalated product.
86
In 4.21f and 4.21g, a vinyl equivalent (CH2CH2OTBDPS) was introduced at the
angular position instead of a simple benzyl group (but note that a phenyl group can be
converted to carboxylic acid10). 4.21g is especially noteworthy, where the organic part
matches 4.14, not only in terms of skeleton and stereochemistry, but also functionality,
since dimethylphenylsilyl is a latent hydroxyl and TBDPS protected hydroxyethyl is a
potential vinyl group. It also showed that a vinylsilane is compatible with the reaction
conditions. This compound was chosen to demonstrate the demetallation of these diene-
Fe(CO)3 complexes, yielding the corresponding diene 4.22 quantitatively. With known chemistry to selectively functionalize conjugated cyclohexadienes,11,12 we have good reason to envision compound 4.22 as a potential gelsemine intermediate.
(OC)3Fe (OC)3Fe Ha Ha 4.20c N Ph + N Ph (4.2) Hb Hb O Bn Bn O
4.21c 4.21c'
The benzyl substituted substrate, 4.20a, reacted faster than the CH2CH2OTBDPS substituted one, 4.20f (Table 1). 4.20a also cyclized faster than 4.20b, which contains a
6-membered nitrogen ring instead of the 5-membered one in 4.20a. Surprisingly, cyclization of 4.20c gave two products, 4.21c and 4.21c’ as shown in eq 4.2. The organic frameworks were proved to be identical by NMR studies. In 4.21c, the Fe(CO)3 group is syn to the pyrrolidinone ring, while Fe(CO)3 in 4.21c’ is on the opposite side. The
deviation of Ha, Hb patterns (chemical shift and coupling constant) in the 1H NMR 87
spectrum of 4.21c’ from those of 4.12a-g provided a clue to differentiate the two isomers.
4.21c’ is thought to be produced from 4.21c under the reaction conditions (Fe(CO)5, 142
°C) after cyclization due to the steric hindrance between the isopropyl and Fe(CO)3 group. Refluxing 4.21c and Fe(CO)5 in n-Bu2O for 6 h gave a mixture of 4.21c and
4.21c’, while 4.21c’ could not be converted back to 4.21c similarly.
Comparison of Tables 4.2 and 4.3 confirms the superiority of substituents at the
angular position for the cyclization. 4.21a-c and 4.21f were all prepared in good to
excellent yield, while their analogs 4.10c-e without the angular substituent were all
obtained in very poor yield due to the slow cyclization. 4.21e was obtained in 20% yield,
but the corresponding analogue 4.10f was inaccessible. It should be noted that amides
4.20a-c, f-g were prepared selectively to test the superiority of the one-pot cyclization at
the beginning.
R2 R2 R3 3 (OC)3Fe R N 1 1 R N R a 4 R O R4 O 4.20 4.23
Fe(CO)5 c b 3 R 3 R3 R 2 2 R (OC)3Fe R R' (OC)3Fe 1 N R1 N R N R1 d 4 4 R O R O R4 O 4.24 4.25 4.21
Scheme 4.5
88
Bn R Bn R -CO -CO Fe(CO)5 Bn O O O (OC) Fe R 4 Fe(CO)4
4.26 4.27
Bn R Bn Bn R R -CO O O O
H Fe(CO)3 Fe(CO) Fe(CO)3 H H 2
4.28 4.29 4.30
Fe(CO) Bn R 3 (OC)2Fe Bn R +CO R O O Bn O Fe(CO) H 2 4.31 4.32 4.23/4.25
Scheme 4.6 Diastereoselective Complexation
Scheme 4.5 and 4.6 explain the diastereoselectivity of this one-pot cyclization.
The amide carbonyl directs Fe(CO)3 to coordinate the diene on the same side (see 4.26
→4.27, Scheme 4.6; an α-alkyl substituent is essential for 100% selectivity),13 followed by rearrangement of the allyl amide to enamide by Fe(CO)5 (steps a and b, Scheme 4.5) or vice versa (steps c and d) to give the intermediate 4.25, which then readily cyclizes to give the final product 4.21. A control experiment was done to test the explanation, which allowed us to isolate intermediates 4.23a and 4.25a (see Table 4.1 for substituents) and supported the mechanism. When 4.20a was refluxed in n-Bu2O for 8 h with 2 equiv of
Fe(CO)5, 44% of 4.23a and 22% of 4.25a were produced. It should be mentioned that 89
enamides 4.25 are difficult to make by conventional organic chemistry. The stepwise
explanation for step a or step d is presented in Scheme 4.6.
Interestingly, when N-methylpropargylamide 4.33 was subjected to the above
cyclization conditions in the presence of three equivalents of triethylsilane, 4.34 and 4.35
were produced in 53% (unoptimized) combined yield (Scheme 4.7). Here, four
transformations are realized in a single operation, but there is little or no regiocontrol during the hydrosilylation reaction (4.34:4.35/1.1:1). Direct cyclization of 4.33 without
silane did not yield any bicyclic lactam. Rearrangement of propargyl amide (4.33) by base treatment gave the allenylamide 4.36.14 The desired product from 4.36 is 4.37, which is also a synthetic equivalent of 4.14. Unfortunately, cyclization of 4.36 gave only
14% of enamide 4.38 after 24 h, which was presumably formed from the initial cyclization product, allylamide 4.37, by Fe(CO)5 promoted rearrangement.
Et3Si HSiEt (OC) Fe SiEt 3 3 3 (OC)3Fe N Fe(CO)5 N + N n-Bu O, CO O 2 R o O 142 C R R O 4.33 53% 4.34 4.35
t-BuOK R = CH2CH2OTBDPS THF C Fe(CO)5 (OC)3Fe (OC)3Fe CO N N N n-Bu2O O o R 142 C R O R O 14% 4.36 4.37 4.38
Scheme 4.7
90
As mentioned above, compound 4.7a shows the presence of rotamers in its NMR
spectra. Similar phenomena were also found in compounds 4.7d-e, 4.9e, 4.23a, 4.25a, all
of which showed broadened peaks in 1H NMR spectrum, except for 4.9e, where two
rotamers (3:1) can be distinctively recognized.
4.3 Conclusions
In conclusion, bicyclic lactams can be prepared by the intramolecular coupling
between a cyclohexadiene-Fe(CO)3 complex and a pendant double bond following a rearrangement-cyclization procedure in the presence of Fe(CO)5. The reaction was found
to be limited due to steric hindrance and a strained ring junction. A substituent on the
amide nitrogen was also found to be necessary for the cyclization. A one-pot
(complexation, isomerization and cyclization) procedure was developed to construct, with excellent diastereoselectivity, angularly substituted bicyclic and tricyclic molecules,
which are difficult to make using conventional methods (Scheme 4.3). Comparing the
one-pot cyclization (with a substituent at the amide α–position) and the conventional
rearrangement-cyclization (without a substituent at the α–position) showed that
introduction of a substituent at the angular position accelerates the cyclization for
preparing bicyclic lactams. 91
4.4 Experimental Section
General procedure for the preparation of allylic amides. The carboxylic acid
was dissolved in freshly distilled CH2Cl2 under argon in a flame dried single neck round
bottom flask. Two equivalents of freshly distilled oxalyl chloride were added via a
syringe at rt, followed by 1.1 equiv of anhydrous pyridine. The reaction mixture was
stirred at rt for 30 min under argon (the reaction was monitored by IR). The solvent was
then evaporated under reduced pressure. The resulting viscous oil was kept under high
vacuum (0.5 mm Hg) for 10 min., then dissolved in freshly distilled benzene. Anhydrous pyridine (2 equiv) was added via a syringe, followed by 2 equiv of the appropriate amine.
The reaction mixture was stirred under argon for 24 h (reaction can be monitored by
TLC). The product mixture was diluted with diethyl ether, washed with 2N aq HCl,
water, dried over MgSO4, and concentrated under vacuum. Flash chromatography on silica gel or preparative TLC separation afforded the desired allyl amide, usually as a viscous oil. Deviations from this procedure are noted in the experimental data for the
specific compound.
General procedure for the thermally induced bicyclization and one-pot
cyclization. The appropriate amide was dissolved in freshly distilled n-Bu2O under argon together with 2.5 equiv of Fe(CO)5. The solution was purged with CO for 1 min, and then
refluxed under a balloon of CO for the required time, during which 1-1.5 equivalents of
Fe(CO)5 was added every 8 h. The cooled product mixture was diluted with ether, filtered through Celite, and concentrated. Flash chromatography or preparative TLC separation yielded the desired product. 92
Numbering system used for NMR assignments.
9 3 3 8 3 8 2 7 4 2 4 4 2 8 7 7 1 9 1 5 1 5 N 5 N N 6 10 6 6 Bn 9 O BnO O 11 10 OTBDPS
9 1 2 8 2 1 (OC)3Fe (OC) Fe 4 Si Ph 9 9b 3 10 3a 3 9a 10b 3 5 8 3 9 N N 10a 4 7a 1 5a 5 4 N 6 2 7 8 6 5 6 7 O O 7 O 10 Bn Bn 11 OTBDPS
CO Me 11 2 (OC) Fe (OC)3Fe 3 3 3 10 10 2 4 9 2 4 9 7 5 7 N 1 N 1 8 Ph 8 5 6 O 6 BnO
93
Ph [3-(Dimethylphenylsilanyl)allyl]methylamine Si
N H To N-methylpropargylamine (0.5g, 7.24 mmol) in 20 mL of
THF, was added n-BuLi (2.9 mL, 2.5 M, 7.25 mmol) in hexane at -78 °C, the reaction mixture then was warmed to 0 °C over 0.5 h, and chlorodimethylphenylsilane (1.56 mL,
7.98 mmol) was added at 0 °C. The reaction mixture was then stirred for 2 h at rt, washed with water, dried and evaporated. A portion (20%) of the resulting material was then dissolved in 1 mL of methanol, hydrogenated with a hydrogen balloon for 4.5 h in the presence of 53 mg (18% by weight) of 1% palladium on carbon. A 5:4:1 mixture of alkene:alkyne:alkane was produced. The title vinylsilane (132 mg, 45% yield over two steps) was obtained after flash chromatography as a light yellow oil. Rf = 0.30 (2%
-1 1 methanol in CH2Cl2 saturated with amonia). IR (cm , neat): 2967, 1431, 1256, 1117. H
NMR (300 MHz, CDCl3) δ: 7.60-7.30 (5H, Ph), 6.48 (dt, J = 14.4, 6.6 Hz, 1H, H2), 5.81
(d, J = 14.1 Hz, 1H, H3), 3.15 (d, J = 6.6 Hz, 2H, H1), 2.26 (s, 3H, N-CH3), 0.39 (s, 6H,
13 Si-CH3). C NMR (50 MHz, CDCl3) δ: 148.4, 133.9, 129.9, 129.2, 128.1, 53.7, 36.0, -
+ 0.7. HRMS (m/z) for MH (C12H20NSi): calc: 206.1365; found: 206.1364.
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienecarboxylic acid allyl- (OC)3Fe benzylamide]iron (4.7a). N Bn O Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was
treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 223 mg of
N-allylbenzylamine and 0.28 mL of pyridine to afford 257 mg (86% yield) of the title
-1 compound as light brown oil. Rf = 0.47 (1:4/EA:Hex). IR (cm , neat): 2051, 1990, 1651,
1 1496. H NMR (200 MHz, CDCl3) δ: 7.40-7.08 (5H, Ph), 5.88-5.60 (m, 1H, H10), 5.40- 94
4.98 (4H, H2, H3, H11, H11’), 4.70-4.40 (2H, benzyl H), 4.10-3.68 (2H, H9, H9’), 3.25-
3.20 (m, 1H, H1 or H4), 3.12 (d, J = 6.4 Hz, 1H, H4 or H1), 2.57 (t, J = 7.0 Hz, 1H, H5),
13 2.32-1.83 (2H, H6, H6’). C NMR (50 MHz, CD3OD, 50 °C) δ: 212.7, 175.8, 134.5,
129.9, 129.7, 129.0, 128.7, 128.5, 127.8, 117.7, 87.9, 84.2, 64.0, 62.9, 50.2, 50.1, 49.4,
+ 36.9, 33.2. HRMS (m/z) for MH (C20H20FeNO4): calc: 394.0742; found: 394.0719.
(OC)3Fe Tricarbonyl(4-7-η-2-benzyl-3-ethyl-2,3,3a,7a-tetrahydro- N Bn isoindol-1-one)iron (4.10a). O
According to the general procedure, amide 4.7a (100 mg,
0.25 mmol) was refluxed in 13 mL of n-Bu2O for 6 h in the presence of 0.033 mL of
Fe(CO)5 (49 mg, 0.25 mmol) to afford 91 mg (91% yield) of the title compound as a pale
-1 yellow solid. Mp 130-132 °C (dec). Rf = 0.18 (1:9/EA:Hex). IR (cm , film): 2052, 1970,
1 1685, 1395. H NMR (300 MHz, CDCl3) δ: 7.38-7.18 (5H, Ph), 5.40-5.25 (2H, H5, H6),
5.27 (d, J = 15.6 Hz, 1H, benzyl H), 3.73 (d, J = 15.6 Hz, 1H, benzyl H’), 3.64 (ddd, J =
6.0, 3.0, 1.2 Hz, 1H, H7), 3.22 (ddd, J = 11.1, 7.8, 3.0 Hz, 1H, H3), 2.96 (d, J = 6.6 Hz,
1H, H4), 2.78 (dd, J = 7.8, 3.0 Hz, 1H, H7a), 2.31 (t, J = 7.8 Hz, 1H, H3a), 1.98-1.82 (m,
13 1H, H8), 1.80-1.68 (m, 1H, H8’), 0.88 (t, J = 7.5 Hz, 3H, CH3). C NMR (50 MHz,
CDCl3) δ: 210.9, 174.1, 135.7, 128.7, 128.2, 127.5, 85.0, 83.4, 62.7, 58.7, 57.6, 46.6,
+ 43.2, 32.6, 19.4, 10.9. HRMS (m/z) for MH (C20H20FeNO4): calc: 394.0742; found:
394.0737.
(OC)3Fe Tricarbonyl[(2-5-η-cyclohexa-2,4-dienecarboxylic acid N-
but-2-enyl-N-phenylamide]iron (4.7b). N Ph O 95
Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 223 mg of N-but-2-enylaniline and 0.28 mL of pyridine to afford 247 mg (83% yield) of the title compound as a light
-1 1 brown oil. Rf = 0.58 (1:4/EA:Hex). IR (cm , neat): 2052, 1995, 1653. H NMR (200
MHz, CDCl3) δ: 7.40-7.00 (5H, Ph), 5.60-5.40 (2H, H10, H11), 5.24-5.00 (2H, H2, H3),
4.30-4.00 (2H, H9, H9’), 3.25-3.10 (m, 1H, H1 or H4), 3.10 (dt, J = 6.4, 1.5 Hz, 1H, H4 or H1), 2.34 (apparent t, J = 7.0 Hz, 1H, H5), 2.00 (ddd, J = 15.2, 6.2, 2.9 Hz, 1H, H6),
13 1.62 (d, J = 4.6 Hz, 3H, CH3), 1.56-1.38 (m, 1H, H6’). C NMR (50 MHz, CDCl3) δ:
211.4, 173.1, 142.3, 129.5, 129.3, 128.9, 127.8, 125.9, 86.0, 82.4, 62.4, 52.1, 36.1, 32.4,
+ 17.8. HRMS (m/z) for MH (C20H20FeNO4): calc: 394.0742; found: 394.0739.
Tricarbonyl(4-7-η-2-phenyl-3-propyl-2,3,3a,7a-tetrahydro- (OC)3Fe
N Ph isoindol-1-one)iron (4.10b).
O According to the general procedure, amide 4.7b (100 mg, 0.25 mmol) was refluxed in 13 mL of n-Bu2O for 8 h in the presence of 0.033 mL of
Fe(CO)5 (49 mg, 0.25 mmol) to afford 72 mg (72% yield) of the title compound as a pale
-1 1 yellow oil. Rf = 0.36 (1:9/EA:Hex). IR (cm , neat): 2049, 1975, 1695. H NMR (300
MHz, CDCl3) δ: 7.48-7.18 (5H, Ph), 5.40-5.25 (2H, H5, H6), 4.15 (d, J = 8.4 Hz, 1H,
H3), 3.70 (dt, J = 5.0, 2.8 Hz, 1H, H7), 3.01 (dt, J = 5.8, 1.6 Hz, 1H, H4), 2.93 (dd, J =
8.4, 3.0 Hz, 1H, H7a), 2.53 (t, J = 8.4 Hz, 1H, H3a), 1.90-1.20 (4H, H8, H8’, H9, H9’),
13 0.94 (t, J = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 210.8, 173.1, 137.3, 128.8,
126.0, 124.5, 84.9, 83.5, 62.5, 60.2, 58.7, 47.4, 32.9, 29.6, 20.2, 14.0. HRMS (m/z) for
+ MH (C20H20FeNO4): calc: 394.0742; found: 394.0739. 96
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienecarboxylic acid N-
(OC)3Fe (2-methyl-allyl)-N-phenylamide]iron (4.7c).
N Ph Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was O treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 223 mg of N-(2-methylallyl)aniline and 0.28 mL of pyridine to afford 242 mg (81% yield) of the title compound as light brown oil. The Rf = 0.50
1 (1:4/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.40-7.00 (5H, Ph), 5.24-5.00 (2H, H2,
H3), 4.70-4.30-4.00 (2H, H9), 4.8 (s, 1H, H11), 4.7 (s, 1H, H11’), 4.30 (d, J = 15.0 Hz,
1H, H9), 4.18 (d, J = 15.0 Hz, 1H, H9’) , 3.20-3.05 (2H, H1, H4), 2.34 (t, J = 7.0 Hz, 1H,
H5), 2.03 (ddd, J = 15.0, 6.0, 0.8 Hz, 1H, H6), 1.75 (s, 3H, CH3), 1.50 (ddd, J = 15.0,
13 8.2, 2.2 Hz, 1H, H6’). C NMR (50 MHz, CDCl3) δ: 211.4, 173,4, 142.4, 141.0, 129.5,
128.5, 127.8, 113.1, 86.0, 82.4, 62.3, 61.7, 55.7, 36.2, 33.0, 20.3.
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienyl-(2,5-dihydro- (OC)3Fe pyrrol-1-yl)methanone]iron (4.7d). N
O Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was
treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 105 mg of 3-pyrroline and 0.28 mL of pyridine to afford 203 mg
-1 (85% yield) of the title compound as light brown oil. Rf = 0.23 (3:7/EA:Hex). IR (cm ,
1 neat): 2047, 1991, 1650. H NMR (200 MHz, CDCl3) δ: 5.86 (d, J = 6.6 Hz, 1H, H10),
5.75 (d, J = 6.6 Hz, 1H, H10’), 5.40-5.10 (2H, H2, H3), 4.40-4.10 (4H, H9, H9’), 3.35-
3.25 (m, 1H, H1 or H4), 3.10 (d, J = 6.4 Hz, 1H, H4 or H1), 2.43 (t, J = 7.0 Hz, 1H, H5),
2.23 (ddd, J = 15.0, 5.6, 2.8 Hz, 1H, H6), 1.95 (ddd, J = 15.0, 8.0, 2.8 Hz, 1H, H6). 13C 97
NMR (50 MHz, CDCl3) δ: 211.4, 171.8, 126.5, 124.7, 86.3, 82.5, 62.6, 60.4, 53.4, 52.9,
+ 36.7, 30.9. HRMS (m/z) for MH (C14H14FeNO4): calc: 316.0272; found: 316.0273.
Tricarbonyl(4-7-η-1,2,3,5a,9a,9b-hexahydro-pyrrolo[2,1-
(OC)3Fe a]isoindol-5-one)iron (4.10d). N
O According to the general procedure, amide 4.7d (50 mg,
0.16 mmol) was refluxed in 8 mL of n-Bu2O for 8 h in the presence of 0.022 mL of
Fe(CO)5 (33 mg, 0.16 mmol) to afford 5 mg (10% yield) of the title compound as a pale
1 yellow oil. Rf = 0.05 (3:7/EA:Hex). H NMR (200 MHz, CDCl3) δ: 5.35-5.22 (m, 2H,
H7, H8), 3.98-3.80 (m, 1H, H9b), 3.70-3.50 (2H, H3, H3’), 3.15-3.00 (2H, H6, H9), 2.85
(dd, J = 7.8, 2.0 Hz, 1H, H5a), 2.40-1.60 (4H, H1, H1’, H2, H2’). 13C NMR (50 MHz,
+ CDCl3) δ: 84.8, 82.4, 63.0, 62.9, 59.9, 51.3, 39.6, 32.8, 25.9, 24.8. HRMS (m/z) for MH
(C14H14FeNO4): calc: 316.0272; found: 316.0268.
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienyl-(3,6-dihydro-2H- Fe(CO)3 pyridin-1-yl)methanone]iron (4.7e). N
O Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 135 mg of
1,2,3,6-tetrahydropyridine and 0.28 mL of pyridine to afford 203 mg (82% yield) of the
1 title compound as light brown oil. Rf = 0.20 (1:4/EA:Hex). H NMR (200 MHz, CDCl3)
δ: 5.90-5.50 (2H, H10, H11), 5.40-5.15 (2H, H2, H3), 4.10-3.35 (4H, H9, H9’, H13,
H13’), 3.30-3.20 (m, 1H, H1 or H4), 3.10-3.00 (m, 1H, H4 or H1), 2.52 (br s, 1H, H5),
13 2.20-1.83 (4H, H6, H6’, H12, H12’). C NMR (50 MHz, CDCl3) δ: 211.2, 171.9, 127.0, 98
125.1, 124.4, 123.3, 86.3, 82.7, 62.4, 60.9, 45.0, 42.5, 42.3, 39.1, 35.7, 35.4, 31.6, 26.0,
+ 25.0. HRMS (m/z) for MH (C15H16FeNO4): calc: 330.0429; found: 330.0434.
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienyl-(3,4-dihydro-2H- Fe(CO)3 pyridin-1-yl)-methanone]iron (4.9e). N
O According to the general procedure, amide 4.7e (50 mg,
0.15 mmol) was refluxed in 7.5 mL of n-Bu2O for 8 h in the presence of 0.022 mL of Fe(CO)5 (33 mg, 0.16 mmol) to afford 5 mg (10%) of the starting material, 30 mg (60%) of the title compound as yellow oil, and 2.5 mg (5% yield)
-1 1 of 4.10e. Rf = 0.35 (1:9/EA:Hex). IR (cm , neat): 2925, 2050, 1987, 1645. The H NMR
1 showed rotamer property. H NMR (200 MHz, CDCl3) δ: 7.19 (dt, J = 8.6, 1.8 Hz, 1H,
H9, minor ratomer), 6.59 (dt, J = 8.6, 1.8 Hz, 1H, H9, major rotamer), 5.38 (t, J = 5.2 Hz,
1H, H3), 5.24 (dd, J = 6.4, 4.0 Hz, 1H, H2), 5.05 (dt, J = 8.4, 4.2 Hz, 1H, H10, minor
rotamer), 4.92 (dt, J = 8.4, 4.2 Hz, 1H, H10, major rotamer), 3.82-3.37 (m, 1H, H13),
3.69 (ddd, J = 8.6, 6.4, 5.0 Hz, 1H, H13’), 3.30 (dtd, J = 6.4, 3.2, 1.4 Hz, 1H, H1), 3.11
(dd, J = 6.4, 1.4 Hz, 1H, H4), 2.62 (t, J = 6.8 Hz, 1H, H5), 2.27 (ddd, J = 15.2, 5.6, 3.0
13 Hz, 1H), 2.10-1.70 (5H). C NMR (50 MHz, CDCl3) δ: 211.1, 170.6, 125.2, 108.1, 86.4,
82.7, 62.4, 60.4, 40.9, 25.6, 31.4, 22.0, 21.6.
Tricarbonyl(4-7-η-1,3,4,6a,10a,10b-hexahydro-2H-
(OC)3Fe pyrido[2,1-a]isoindol-6-one)iron (4.10e). N Pale yellow oil. R = 0.05 (3:7/EA:Hex). 1H NMR (200 O f
MHz, CDCl3) δ: 5.35-5.26 (2H, H8, H9), 4.12 (ddd, J = 15.0,
4.2, 2.0 Hz, 1H), 3.61 (dt, J = 4.8, 3.0 Hz, 1H), 3.90 (ddd, J = 10.6, 8.6, 5.0 Hz, 1H), 3.95 99
(dt, J = 6.0, 2.4 Hz, 1H), 2.68-2.53 (m, 1H, H), 2.35 (td, J = 8.2, 1.6 Hz, 1H), 2.10-1.30
13 (m, 4H). C NMR (50 MHz, CDCl3) δ: 211.0, 172.4, 85.1, 82.8, 62.6, 59.5, 58.0, 46.9,
+ 40.0, 34.0, 26.4, 24.0, 22.7. HRMS (m/z) for MH (C15H16FeNO4): calc: 330.0429; found: 330.0424.
Tricarbonyl[(2-5-η-cyclohexa-2,4-dienecarboxylic acid (OC)3Fe allylamide]iron (4.7f). NH
O Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was
treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 105 mg of
allylamine and 0.28 mL of pyridine to afford 203 mg (85% yield) of the title compound
1 as light brown oil. Rf = 0.13 (3:7/EA:Hex). H NMR (200 MHz, CDCl3) δ: 5.95-5.70
(2H, H8, H10), 5.40-5.15 (4H, H2, H3, H11, H11’), 3.87 (td, J = 5.6, 1.0 Hz, 2H, H9),
3.30 (dtd, J = 6.2, 3.0, 1.4 Hz, 1H, H1), 3.10 (dt, J = 6.5, 1.4 Hz, 1H, H4), 2.43 (t, J = 6.8
13 Hz, 1H, H5), 2.15-1.87 (2H, H6, H6’). C NMR (50 MHz, CDCl3) δ: 211.1, 173.2,
134.3, 116.5, 86.5, 83.0, 62.8, 60.1, 42.1, 39.7, 30.7.
Tricarbonyl[(2-5-η-4-[(cyclohexa-2,4-dienecarbonyl)phenyl- O O (OC)3Fe amino]but-2-enoic acid methyl ester]iron (4.7g).
Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was N Ph O treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 295 mg of 4-phenylamino-2-butenoic acid methyl ester and 0.28 mL of pyridine to afford 295 mg (80% yield) of the title compound as a pale brown oil. Rf =
0.42 (2:3/EA:Hex). IR (cm-1, neat): 2048, 1967, 1721, 1683, 1652. 1H NMR (200 MHz,
CDCl3) δ: 7.42-7.00 (5H, Ph), 6.90 (dt, J = 15.6, 6.0 Hz, 1H, H10), 5.84 (dt, J = 15.8, 1.6 100
Hz, 1H, H11), 5.20 (apparent t, J = 5.3 Hz, 1H, H4), 5.08 (dd, J = 6.6, 4.8 Hz, 1H, H1),
4.39 (dd, J = 6.0, 1.4 Hz, 2H, H9), 3.71 (s, 3H, OCH3), 3.14 (dtd, J = 6.2, 2.8, 1.2 Hz,
1H, H1), 3.07 (dt, J = 6.6, 1.6 Hz, 1H, H4), 2.39 (t, J = 7.2 Hz, 1H, H5), 2.01 (ddd, J =
15.0, 6.0, 2.8 Hz, 1H, H6), 1.50 (ddd, J = 15.0, 7.8, 2.8 Hz, 1H, H6’). 13C NMR (50
MHz, CDCl3) δ: 211.3, 173.6, 166.4, 143.0, 142.0, 129.8, 128.5, 128.3, 122.9, 86.0, 82.4,
62.3, 61.2, 51.7, 51.0, 36.1, 32.9.
O Tricarbonyl[2-5-η-3-(benzyl-cyclohexa-2,4-dienylmethyl- (OC)3Fe O amino)acrylic acid methyl ester]iron (4.12). N Bn
Acid 4.6 (200 mg, 0.76 mmol) in 2 mL of CH2Cl2 was
treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 200 mg of
N-benzylamine and 0.28 mL of pyridine to afford 248 mg (95% yield) of 2.11 as a pale
-1 brown oil after chromatography. Rf = 0.10 (1:4/EA:Hex). IR (cm , neat): 3200, 2051,
1 1989, 1648. H NMR (200 MHz, CDCl3) δ: 7.40-7.20 (5H, Ph), 5.86 (br s, 1H, N-H),
5.40-5.20 (2H, H2, H3), 4.58-4.32 (2H, benzyl H), 3.35-3.25 (m, 1H, H1), 3.19 (dt, J =
6.2, 1.6 Hz, 1H, H4), 2.38 (t, J = 7.0 Hz, 1H, H5), 2.20-1.90 (2H, H6, H6’). 13C NMR (50
MHz, CDCl3) δ: 211.0, 173.1, 138.3, 128.8, 127.9, 127.6, 86.5, 83.0, 62.7, 60.1, 43.8,
39.7, 30.7.
To 150 mg of 2.11 (0.42 mmol) in 6 mL of dry THF at -78 °C, was added 4 mL of
DIBAL in toluene (1.5M, 6 mmol), the reaction mixture was allowed to warm to rt after 2 hours and stirred overnight. To the solution was added ethyl acetate at 0 °C. The mixture was stirred for 0.5 h, and 0.5 mL of H2O was added. The mixture was then dried
(MgSO4), and concentrated. The concentrates were treated with 1 equiv of methyl 101
propiolate (35 mg, 0.42 mmol) in 1.3 mL of THF, stirred for 10 h, concentrated, and flash chromatographed to yield 153 mg (86%) of title compound. Rf = 0.32 (2:3/EA:Hex). IR
-1 1 (cm , neat): 2043, 1964, 1693, 1613, 1454. H NMR (200 MHz, CDCl3) δ: 7.62 (d, J =
13.2 Hz, 1H, H9), 7.40-7.15 (5H, Ph), 5.40-5.20 (2H, H2, H3), 4.70 (d, J = 13.2 Hz, 1H,
H10), 4.35 (s, 2H, benzyl H), 3.66 (s, 3H, OCH3), 3.30-2.90 (4H, H1, H4, H7), 2.10-1.90
(m, 1H, H5), 1.80 (ddd, J = 15.2, 7.6, 2.7 Hz, 1H, H6), 1.28 (ddd, J = 15.2, 5.0, 3.2 Hz,
13 1H, H6’). C NMR (50 MHz, CDCl3) δ: 211.9, 170.1, 152.4, 136.7, 128.9, 127.9, 127.3,
86.8, 85.5, 83.5, 77.3, 63.5, 62.6, 50.7, 31.7 (2C), 31.6. HRMS (m/z) for MH+
(C21H22FeNO5): calc: 424. 0847; found: 424.0849.
Tricarbonyl[4-7-η-(2-benzyl-2,3,3a,7a-tetrahydro-1H- CO Me (OC) Fe 2 3 isoindol-1-yl)acetic acid methyl ester]iron (4.13). NBn
According to the general procedure, 4.12 (100 mg,
0.24 mmol) was refluxed in 12 mL of n-Bu2O for 8 h in the presence of 0.031 mL of
Fe(CO)5 (47 mg, 0.24 mmol) to afford 86 mg (86% yield) of the title compound as a pale
-1 yellow oil after chromatography. Rf = 0.33 (1:4/EA:Hex). IR (cm , neat): 2049, 1980,
1 1732, 1436. H NMR (600 MHz, CDCl3) δ: 7.35-7.20 (5H, Ph), 5.20-5.05 (2H, H5, H6),
3.95 (d, J = 12.6 Hz, 1H, benzyl H), 3.73 (s, 3H, OCH3), 3.04 (d, J = 6.6 Hz, 1H, H1 or
H4), 3.00 (d, J = 12.6 Hz, 1H, benzyl H’), 2.95 (d, J = 6.6 Hz, 1H, H4 or H1), 2.88-2.74
(3H, H1, H1’, H3), 2.62-2.56 (m, 1H, H8), 2.45 (t, J = 6.0 Hz, 1H, H3a), 2.26-2.20 (2H,
13 H7a, H8’). C NMR (50 MHz, CDCl3) δ: 211.8, 173.1, 138.0, 129.8, 128.1, 127.0, 83.7,
83.6, 67.8, 63.6, 61.3, 59.2, 58.5, 51.8, 42.9, 38.8, 33.3. HRMS (m/z) for MH+
(C21H22FeNO5): calc: 424. 0847; found: 424.0836. 102
1-[2-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohexa-2,5- O dienecarboxylic acid (4.19b). OH
OTBDPS A solution of 1,4-dihydrobenzoic acid (2.00 g, 16.1 mmol) in 25 mL of THF was introduced into a solution of LDA (33.8 mmol) in
50 mL of THF and 14.3 mL of hexane at -10 °C over 30 min. Then 1.5 equiv of TBDPS protected 2-iodoethanol (9.53 g, 24.2 mmol) was added. The reaction mixture was stirred for 1.5 h at rt, poured into 20 mL of ice water, acidified to pH = 2 with dropwise addition of ice-cold 6M HCl, and extracted with ether (50 mL × 3) to afford 4.90 g (75%) of the title acid as a colorless solid after chromatography. Mp 78-81 °C. Rf = 0.40
-1 1 (2:3/EA:Hex). IR (cm , film): 2976, 1701, 1433. H NMR (300 MHz, CDCl3) δ: 7.78-
7.38 (10H, Ph), 5.86 (dt, J = 10.5, 2.7 Hz, 2H, H3), 5.74 (d, J = 10.5 Hz, 2H, H2), 3.69 (t,
J = 6.9 Hz, 2H, H7), 2.75-2.48 (2H, H4, H4’), 2.07 (t, J = 6.9 Hz, 2H, H6), 1.05 (s, 9H, t-
13 Bu). C NMR (75 MHz, CDCl3) δ: 181.2, 135.6, 133.7, 129.6, 127.7, 126.6, 125.9, 60.3,
+ 46.1, 41.6, 26.8, 26.0, 19.1. HRMS (m/z) for MH (C25H31SiO3): calc: 407.2042; found:
407.2043.
(1-Benzyl-cyclohexa-2,5-dienyl)(2,5-dihydropyrrol-1-yl)methanone (4.20a).
1-Benzyl-1,4-dihydrobenzoic acid (163 mg, 0.76 mmol) in 2
N mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by Bn O 0.12 mL of oxalyl chloride, then 105 mg of 3-pyrroline (1.52 mmol) and 0.28 mL of pyridine, to afford 184 mg (91% yield) of the title compound as a colorless solid after
-1 chromatography. Mp 137-139 °C. Rf = 0.50 (1:9/EA:Hex). IR (cm , neat): 1640, 1398.
1 H NMR (200 MHz, CDCl3) δ: 7.26-7.08 (5H, Ph), 5.88-5.68 (4H, H3, H8), 5.57 (d, J = 103
10.0 Hz, 2H, H2), 4.31 (s, 4H, H7), 3.16 (s, 2H, benzyl H), 2.50-1.95 (2H, H4, H4’). 13C
NMR (50 MHz, CDCl3) δ: 171.0, 137.8, 131.6, 126.9, 126.6, 126.3, 125.7, 125.6, 124.7,
+ 55.4, 53.0, 49.9, 44.4, 25.9. HRMS (m/z) for MH (C18H20NO): calc: 266.0894; found:
266.0899.
(1-Benzylcyclohexa-2,5-dienyl)(3,6-dihydro-2H-pyridin-1-yl)methanone (4.20b).
1-Benzyl-1,4-dihydrobenzoic acid (163 mg, 0.76 mmol) in 2 N mL of CH Cl was treated with 0.14 mL of pyridine and 0.12 mL of Bn O 2 2 oxalyl chloride, followed by 126 mg of 1,2,5,6-tetrahydropyridine
(1.52 mmol) and 0.28 mL of pyridine, to afford 180 mg (86% yield) of the title
-1 compound as a colorless oil after chromatography. Rf = 0.40 (1:9/EA:Hex). IR (cm ,
1 neat): 1646, 1344, 1237. H NMR (200 MHz, CDCl3) δ: 7.20-7.05 (5H, Ph), 5.83-5.55
(6H, H2, H2’, H3, H3’, H8, H9), 4.08 (t, J = 2.5 Hz, 2H, H7), 3.69 (t, J = 5.8 Hz, 2H,
H11), 3.12 (s, 2H, benzyl H), 2.34 (dt, J = 23.2, 2.7 Hz, 1H, H4), 2.07 (br. s, 2H, H10),
13 1.82 (d, J = 23.2 Hz, 1H, H4’). C NMR (50 MHz, CDCl3) δ: 172.4, 137.8, 132.1, 128.1,
+ 126.9, 125.6, 124.6, 50.0, 44.9, 25.9, 25.5. HRMS (m/z) for MH (C19H22NO): calc:
280.1701; found: 280.1708.
1-Benzylcyclohexa-2,5-dienecarboxylic acid (2-methyl-
allyl)phenylamide (4.20c) N Ph Bn O 1-Benzyl-1,4-dihydrobenzoic acid (163 mg, 0.76 mmol) in 2 mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, then 223 mg of N-(2-methylallyl)aniline and 0.28 mL of pyridine, to afford 222 mg (85% yield) of the title compound as a colorless oil after chromatography. Rf = 0.50 104
-1 1 (1:9/EA:Hex). IR (cm , neat): 1664, 1594, 1494. H NMR (200 MHz, CDCl3) δ: 7.20-
6.92 (5H, Ph), 5.44 (dt, J = 10.5, 2.0 Hz, 2H, H2), 5.19 (dd, J = 10.5, 3.4 Hz, 2H, H3),
4.77 (s, 1H, H9), 4.61 (s, 1H, H9’), 4.22 (s, 2H, H7), 3.12 (s, 2H, benzyl H), 2.00-1.90
13 (2H, H4, H4’), 1.71 (s, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 173.4, 143.2, 140.8,
137.8, 131.5, 129.2 (2C), 128.4, 127.3, 127.2, 125.9, 123.5, 112.7, 58.3, 51.3, 47.1, 25.7,
+ 20.5. HRMS (m/z) for MH (C24H26NO): calc: 344.2014; found: 344.2006.
1-Benzylcyclohexa-2,5-dienecarboxylic acid N-allyl-N-methylamide (4.20d).
1-Benzyl-1,4-dihydrobenzoic acid (163 mg, 0.76 mmol) in 2
N mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by Bn O 0.12 mL of oxalyl chloride, then 106 mg of N-methyl-N-allylamine
and 0.28 mL of pyridine to afford 175 mg (83% yield) of the title compound as a
-1 colorless oil after chromatography. Rf = 0.25 (1:9/EA:Hex). IR (cm , neat): 1642, 1495,
1 1453. H NMR (200 MHz, CDCl3) δ: 7.20-7.15 (5H, Ph), 5.80-5.55 (5H, H2, H2’, H3,
H3’, H8), 5.20-5.00 (2H, H9, H9’), 4.02 (br s, 2H, H7), 3.12 (s, 2H, benzyl H), 2.94 (br s,
13 3H, N-CH3), 2.32 (dt, J = 22.4, 2.2 Hz, 1H, H4), 1.85 (d, J= 22.4 Hz, 1H, H4’). C NMR
(50 MHz, CDCl3) δ: 137.9, 132.0, 127.9, 127.8, 127.7, 126.9, 125.8, 125.6, 52.5, 50.0,
+ 45.0, 25.9 (carbonyl was not detected). HRMS (m/z) for MH (C18H22NO): calc:
268.1701; found: 268.1694.
1-Benzyl-cyclohexa-2,5-dienecarboxylic acid allylamide (4.20e). NH Bn O 1-Benzyl-1,4-dihydrobenzoic acid (163 mg, 0.76 mmol) in 2 mL of CH2Cl2 was treated with 0.14 mL of pyridine, followed by 0.12 mL of oxalyl chloride, 105
then 87 mg of allylamine (1.52 mmol) and 0.28 mL of pyridine to afford 162 mg (84%
yield) of the title compound as a colorless oil after chromatography. Rf = 0.30
-1 1 (2:3/Hex:EA). IR (cm , neat): 1650, 1545, 1315. H NMR (200 MHz, CDCl3) δ: 7.26-
7.10 (5H, Ph), 5.92-5.68 (6H, H2, H2’, H3, H3’, H8, N-H), 5.12-4.96 (2H, H9, H9’),
3.89-3.80 (2H, H7, H7’), 3.11 (s, 2H, benzyl), 2.54 (2H, H4, H4’). 13C NMR (50 MHz,
CDCl3) δ: 173.7, 137.6, 134.3, 130.7, 128.7, 128.3, 127.7, 126.7, 126.6, 126.1, 115.9,
+ 49.9, 44.2, 42.0, 26.2. HRMS (m/z) for MH (C17H20NO): calc: 254.1545; found:
254.1549.
{1-[2-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohexa-2,5-
N dienyl}(2,5-dihydropyrrol-1-yl)methanone (4.20f). O OTBDPS According to standard peptide coupling conditions, acid 4.19b
(100 mg, 0.25 mmol) in 0.8 mL of CH2Cl2 and 0.2 mL of DMF was treated with 35 mg
of 3-pyrroline (0.49 mmol), followed by 100 mg of HOBt (0.75 mmol) and 144 mg of
EDCI (0.75 mmol), washed with 2 N HCl, followed by saturated NaHCO3, dried, concentrated and chromatographed to afford 92 mg (80% yield) of the title compound as
-1 1 a colorless oil. Rf = 0.27 (1:4/EA:Hex). IR (cm , neat): 1642, 1397. H NMR (300 MHz,
CDCl3) δ: 7.70-7.30 (10H, Ph), 5.85-5.63 (4H, H3, H3’, H8, H8’), 5.42 (d, J = 10.5 Hz,
2H, H2), 4.27 (s, 4H, H7), 3.68 (t, J = 7.5 Hz, 2H, H10), 2.58 (br. s, 2H, H4), 2.18 (t, J =
13 7.5 Hz, 2H, H9), 1.02 (s, 9H, t-Bu). C NMR (50 MHz, CDCl3) δ: 170.8, 135.7, 135.6,
134.2, 129.6, 129.5, 127.8, 127.7, 127.6 (2C), 126.5, 125.8, 124.8, 61.0, 55.6, 52.5, 47.4,
+ 40.7, 26.2, 19.2. HRMS (m/z) for MH (C29H36NSiO2): calc: 458.2515; found: 458.2511.
106
1-[2-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohexa-2,5-dienecarboxylic acid [3-
(Dimethylphenylsilanyl)allyl]methylamide (4.20g).
According to standard peptide coupling reaction conditions, Ph Si
acid 4.19b (100 mg, 0.25 mmol) in 0.8 mL of CH2Cl2 and 0.2 mL of N DMF was treated with 100 mg of [3- O
OTBDPS (dimethyl(phenyl)silanylallyl]methylamine (0.49 mmol), followed by
155 mg of DCC (0.75 mmol) and 100 mg of HOBt (0.75 mmol). The reaction mixture was stirred at rt for 24 h, washed with water, dried, concentrated and chromatographed to afford 120 mg (81% yield) of the title compound as a colorless oil. Rf = 0.36
-1 1 (1:4/EA:Hex). IR (cm , neat): 1639, 1428, 1111. H NMR (200 MHz, CDCl3) δ: 7.70-
7.30 (15H, Ph), 6.21 (dt J = 14.2, 6.2 Hz, 1H, H8), 5.84 (d, J = 14.2 Hz, 1H, H9), 5.68 (d,
J = 10.4 Hz, 2H, H2 or H3), 5.46 (d, J = 10.4 Hz, 2H, H3 or H2), 3.93 (dd, J = 6.3, 1.3
Hz, 2H, H7), 3.65 (t, J = 7.7 Hz, 2H, H11), 2.69 (br. s, 3H, N-CH3), 2.55-2.45 (2H, H4,
13 H4’), 2.12 (t, J = 7.7 Hz, 2H, H10), 1.01 (s, 9H, t-Bu), 0.39 (s, 6H, Si-CH3). C NMR
(50 MHz, CDCl3) δ: 172.5, 135.7, 134.3, 133.7, 130.3, 129.4, 129.2, 128.3, 128.2, 128.0,
127.8, 127.6, 124.5, 60.9, 51.3, 47.2, 41.5, 35.0, 26.9, 26.0, 19.2, -1.0. HRMS (m/z) for
+ + MH (C37H48NSi2O2): calc: 296.1650; found: 13.5. HRMS (m/z) for MH
(C22H22FeNO4): calc: 594.3224; found: 594.3221.
Tricarbonyl(6-9-η-5a-benzyl-1,2,3,5a,9a,9b-hexahydro-
(OC)3Fe N pyrrolo[2,1-a]isoindol-5-one)iron (4.21a).
Bn O 107
Amide 4.20a (64 mg, 0.24 mmol) was refluxed in 12 mL of n-Bu2O for 24 h in
the presence of 0.189 mL of Fe(CO)5 (282 mg, 1.44 mmol, added in portions according to the general procedure) to afford 89 mg (92% yield) of the title compound as a white
-1 solid. Mp 195-197 °C. Rf = 0.21 (1:4/EA:Hex). IR (cm , film): 2051, 1965, 1685, 1495,
1 1403. H NMR (600 MHz, CDCl3) δ: 7.26-7.10 (5H, Ph), 5.30-5.20 (2H, H7, H8), 3.55
(dt, J = 12.0, 8.4 Hz, 1H, H3), 3.45 (d, J = 6.0 Hz, 1H, H6), 3.18 (d, J = 13.2 Hz, 1H,
benzyl H), 2.92-2.82 (2H, H3’, H9b), 2.66 (d, J = 6.0 Hz, 1H, H9), 2.39 (d, J = 13.2 Hz,
1H, benzyl H’), 2.21 (d, J = 7.8 Hz, 1H, H9a), 2.24-2.16 (m, 1H, H2), 1.94-1.78 (2H,
13 H2’, H1), 1.58-1.50 (m, 1H, H1’). C NMR (50 MHz, CDCl3) δ: 210.7, 172.8, 137.9,
129.6, 128.0, 126.5, 84.1, 82.2, 68.2, 64.0, 61.4, 58.0, 46.6, 38.9, 37.3, 25.4, 24.4. HRMS
+ (m/z) for MH (C21H20NO4Fe): calc: 406.0742; found: 406.0732.
Tricarbonyl(7-10-η-6a-benzyl-1,3,4,6a,10a,10b-hexahydro-2H-
(OC)3Fe N pyrido[2,1- a]isoindol-6-one)iron (4.21b).
Bn O Amide 4.20b (67 mg, 0.24 mmol) was refluxed in 12 mL of n-Bu2O for 36 h in the presence of 0.253 mL of Fe(CO)5 (376 mg, 1.92 mmol, added in portions according to the general procedure) to afford 85 mg (85% yield) of the title compound as a colorless solid after chromatography. Mp 158-160 °C. Rf = 0.31
(2:3/EA:Hex). IR (cm-1, film): 2049, 1976, 1690, 1453, 1412, 1374. 1H NMR (200 MHz,
CDCl3) δ: 7.25-7.00 (5H, Ph), 5.35-5.20 (2H, H8, H9), 4.10-4.00 (m, 1H, H4), 3.50 (dd, J
= 6.1, 1.7 Hz, 1H, H7), 3.24 (d, J = 12.8 Hz, 1H, benzyl H), 2.75 (dt J = 6.2, 1.5 Hz, 1H,
H10), 2.26 (d, J = 12.8 Hz, 1H, benzyl H’), 2.31-1.00 (9H, H1, H1’, H2, H2’, H3, H3’,
13 H4’, H10a, H10b). C NMR (50 MHz, CDCl3) δ: 211.0, 174.4, 138.2, 129.6, 128.1, 108
126.7, 84.6, 82.8, 68.0, 58.6, 57.7, 56.8, 47.1, 39.9, 38.7, 26.1, 23.8, 22.4. HRMS (m/z)
+ for MH (C22H22FeNO4): calc: 420.0898; found: 420.0894.
(OC)3Fe Tricarbonyl(4-7-η-7a-benzyl-3-isopropyl-2-phenyl-2,3,3a,7a- N Ph tetrahydroisoindol-1-one)iron (4.21c/4.21c’). Bn O
Amide 4.20c (82 mg, 0.24 mmol) was refluxed in 12 mL (OC) Fe 3 N Ph
Bn O of n-Bu2O for 24 h in the presence of 0.189 mL of Fe(CO)5 (282 mg, 1.44 mmol, added in portions according to the general procedure) to afford 63 mg
(54% yield) of 4.21c as a colorless oil and 32 mg (27% yield) of 4.21c’ as a white solid
-1 after chromatography. 4.21c Rf = 0.48 (1:4/EA:Hex). IR (cm , film): 2051, 1981, 1689.
1 H NMR (200 MHz, CDCl3) δ: 7.40-6.80 (10H, Ph), 5.40-5.30 (2H, H5, H6), 3.66-3.58
(m, 1H, H7), 3.29 (d, J = 12.6 Hz, 1H, benzyl H), 3.05 (dt, J = 6.0, 1.8 Hz, 1H, H4), 2.86
(t, J = 7.7 Hz, 1H, H3), 2.43 (dd, J = 8.0, 1.2 Hz, 1H, H3a), 2.33 (d, J = 12.8 Hz, 1H,
benzyl H’), 2.14-1.95 (m, 1H, H8), 0.83 (d, J = 6.8 Hz, 1H, CH3), 0.67 (d, J = 7.2 Hz,
13 1H, CH3). C NMR (50 MHz, CDCl3) δ: 210.9, 176.4, 138.7, 137.8, 129.8, 128.6, 128.3,
126.9, 126.2, 125.5, 84.4, 83.4, 68.2, 63.5, 59.1, 58.7, 48.3, 38.9, 28.4, 19.9, 19.7. HRMS
+ (m/z) for MH (C27H26FeNO4): calc: 484.1211; found: 484.1201.
-1 4.21c’ Mp 153-155 °C. Rf = 0.29 (1:4/EA:Hex). IR (cm , film): 2054, 1989,
1 1684. H NMR (600 MHz, CDCl3) δ: 7.60-7.18 (10H, Ph), 5.52 (d, J = 4.2 Hz, 1H, H7),
5.33 (dd, J = 6.4, 4.2 Hz, 1H, H6), 4.36 (t, J = 2.1 Hz, 1H, H3), 3.60 (d, J = 16.2 Hz, 1H,
benzyl H), 3.50 (ddd, J = 6.4, 3.0, 1.4 Hz, 1H, H5), 3.25 (d, J = 16.2 Hz, 1H, benzyl H),
2.91 (dd, J = 8.2, 3.3 Hz, 1H, H4), 2.09 (d, J = 8.2 Hz, 1H, H3a), 1.39 (septet of d, J =
13 7.0, 2.2 Hz, 1H, H8), 0.48 (d, J = 7.0 Hz, 3H, CH3), 0.42 (d, J = 7.0 Hz, 3H, CH3). C 109
NMR (50 MHz, CDCl3) δ: 210.9, 172.8, 138.4, 137.6, 128.9, 128.8, 128.3, 126.8, 125.7,
124.2, 88.3, 81.1, 79.9, 66.2, 60.5, 48.1, 42.6, 36.7, 31.5, 18.0, 17.0. HRMS (m/z) for
+ MH (C27H26FeNO4): calc: 484.1211; found: 484.1201. Note: Compound 16c’ has very strong fluorescence under UV.
Tricarbonyl(4-7-η-7a-benzyl-3-ethyl-2-methyl-2,3,3a,7a-
(OC)3Fe tetrahydroisoindol-1-one)iron (4.21d). N
O Bn Amide 4.20d (32 mg, 0.12 mmol) was refluxed in 6 mL of n-Bu2O for 24 h in the presence of 0.079 mL of Fe(CO)5 (117 mg, 0.60 mmol, added in portions according to the general procedure) to afford 32 mg (66% yield) of the title compound 4.21d and 5 mg (16% yield) of demetallated 4.21d, each as a colorless oil
-1 after chromatography. Rf = 0.54 (2:3/EA:Hex). IR (cm , neat): 2051, 1982, 1738, 1693,
1 1683, 1495. H NMR (200 MHz, CDCl3) δ: 7.26-7.00 (5H, Ph), 5.32-5.22 (2H, H5, H6),
3.53-3.42 (m, 1H, H7), 3.21 (d, J = 12.8 Hz, 1H, benzyl H), 2.82-2.75 (m, 1H, H4), 2.57
(s, 3H, N-CH3), 2.30 (d, J = 12.8 Hz, 1H, benzyl H’), 2.20-2.10 (2H, H3a, H3), 1.70-1.50
13 (2H, H8, H8’), 0.82 (t, J = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 210.8,
176.0, 138.1, 129.6, 128.1, 126.7, 84.5, 83.4, 68.3, 61.1, 58.2, 56.0, 46.5, 37.6, 27.0, 20.0,
+ 11.0. HRMS (m/z) for MH (C21H22FeNO4): calc: 408.0898; found: 408.0885.
Tricarbonyl(4-7-η-7a-benzyl-3-ethyl-2,3,3a,7a- (OC)3Fe NH tetrahydroisoindol-1-one)iron (4.21e). Bn O Amide 4.20e (30 mg, 0.12 mmol) was refluxed in 6 mL of n-Bu2O for 36 h in the presence of 0.126 mL of Fe(CO)5 (188 mg, 0.96 mmol, added in portions according to the general procedure) to afford 9.4 mg (20% yield) of the title 110
-1 compound as a colorless oil after chromatography. Rf = 0.21 (1:4/EA:Hex). IR (cm ,
1 neat): 2052, 1981, 1693, 1454. H NMR (200 MHz, CDCl3) δ: 7.27-7.10 (5H, Ph), 5.48
(br. s, 1H, N-H), 5.32-5.20 (2H, H5, H6), 3.39 (dd, J = 6.0, 1.8 Hz, 1H, H7), 3.18 (d, J =
12.8 Hz, 1H, benzyl H), 2.77 (dt, J = 6.0, 1.8 Hz, 1H, H4), 2.57 (q, J = 7.6 Hz, 1H, H3),
2.37 (d, J = 12.8 Hz, 1H, benzyl H’), 2.26 (d, J = 7.2 Hz, 1H, H3a), 1.70-1.50 (2H, H8),
13 0.85 (t, J = 7.4 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 210.9, 178.2, 137.8, 129.8,
128.3, 126.8, 84.5, 82.8, 67.1, 58.6, 56.6, 55.4, 46.4, 40.0, 23.3, 11.4. HRMS (m/z) for
+ MH (C20H20FeNO4): calc: 394.0742; found: 394.0767.
Tricarbonyl{6-9-η-5a-[2-(tert-butyldiphenylsilanyloxy)ethyl]1,2,3,5a,9a,9b- hexahydropyrrolo[2,1-a]isoindol-5-one}iron (4.21f).
(OC)3Fe Amide 4.20f (55 mg, 0.12 mmol) was refluxed in 6 mL of n- N Bu2O for 36 h in the presence of of 0.126 mL of Fe(CO)5 (188 mg, O OTBDPS 0.96 mmol, added in portions according to the general procedure) to afford 49 mg (68% yield) of the title compound as a colorless oil after chromatography.
-1 1 Rf = 0.14 (1:4/EA:Hex). IR (cm , neat): 2054, 1989, 1694, 1433. H NMR (200 MHz,
CDCl3) δ: 7.70-7.30 (10H, Ph), 5.30-5.15 (2H, H7, H8), 3.88-3.50 (4H, H11, H11’, H3,
H9b), 3.27 (dd, J = 6.2, 1.4 Hz, 1H, H6), 3.12-2.92 (m, 1H, H3’), 2.70 (dt, J = 6.2, 1.6
Hz, 1H, H9), 2.34 (dd, J = 9.4, 0.6 Hz, 1H, H9a), 2.35-2.20 (1H), 2.10-1.80 (3H), 1.40-
13 1.50 (2H). C NMR (50 MHz, CDCl3) δ: 210.9, 173.7, 135.6, 133.5, 129.8, 127.8, 84.0,
82.4, 68.1, 61.8, 61.6, 60.7, 58.9, 42.2, 39.6, 38.2, 26.9, 25.8, 24.8, 19.2. HRMS (m/z) for
+ MH (C32H36FeNO5Si): calc: 598.1712; found: 598.1704.
111
Tricarbonyl{4-7-η-7a-[2-(tert-butyldiphenylsilanyloxy)ethyl]-3-[2-(dimethylphenyl silanyl)ethyl]-2-methyl-2,3,3a,7a-tetrahydroisoindol-1-one}iron (4.21g).
Si Ph Amide 4.20g (35 mg, 0.059 mmol) was refluxed in 3 (OC)3Fe N mL of n-Bu2O for 36 h in the presence of 0.02 mL of Fe(CO)5 O
OTBDPS (23.5 mg, 0.12 mmol), and 0.015 mL of Fe(CO)5 was added
every 8 h to afford 28 mg (63% yield) of the title compound as a colorless oil after
-1 1 chromatography. Rf = 0.40 (3:7/EA:Hex). IR (cm , neat): 2052, 1980, 1700, 1430. H
NMR (200 MHz, CDCl3) δ: 7.70-7.30 (15H, Ph), 5.28-5.17 (2H, H5, H6), 3.72-3.47 (2H,
H11, H11’), 3.40-3.20 (m, 1H, H3), 3.23 (dd, J = 6.0, 1.8 Hz, 1H, H7), 2.70-2.62 (m, 1H,
H4), 2.65 (s, 3H, N-CH3), 2.39 (d, J = 8.0 Hz, 1H, H3a), 1.90 (dt, J = 14.0, 6.0 Hz, 1H,
H10), 1.80-1.50 (3H, H8, H10’), 1.03 (s, 9H, t-Bu), 0.75-0.52 (2H, H9, H9’), 0.33 (s, 6H,
13 Si-CH3). C NMR (50 MHz, CDCl3) δ: 210.8, 176.1, 135.6, 135.5, 133.6, 133.4, 129.8,
129.3, 128.0, 127.8, 84.4, 83.3, 68.0, 62.1, 61.5, 56.7, 55.0, 41.0, 37.8, 27.1, 27.0, 21.1,
+ 19.2, 12.7, -3.2, -3.3. HRMS (m/z) for MH (C40H48FeNO5Si2): calc: 734.2420; found:
734.2409.
7a-[2-(tert-butyldiphenylsilanyloxy)ethyl]-3-[2-(dimethyl-phenyl-silanyl)ethyl]-2- methyl-2,3,3a,7a-tetrahydroisoindol-1-one (4.22).
Iron complex 4.21g (10 mg, 0.013 mmol) was treated with
Si Ph 40 mg of trimethylamine-N-oxide in 2 mL of dry benzene at rt N
O overnight. The reaction mixture was filtered through a short
OTBDPS column of silica gel, and eluted with 30% EA in Hex. Evaporation
of the solvent afforded 7.9 mg (100%) of the title compound as a colorless oil. Rf = 0.40 112
-1 1 (3:7/EA:Hex). IR (cm , neat): 1697, 1431, 1117. H NMR (300 MHz, CDCl3) δ: 7.70-
7.30 (15H, Ph), 5.90-5.70 (2H, H5, H6), 5.60 (dd, J = 9.0, 5.7 Hz, 1H, H4), 5.46 (d, J =
9.3 Hz, 1H, H7), 3.67 (t, J = 6.8 Hz, 2H, H11), 3.50-3.30 (m, 1H, H3), 3.13 (dd, J = 8.7,
5.7 Hz, 1H, H3a), 2.76 (s, 3H, N-CH3), 1.97 (dt, J = 14.4, 6.8 Hz, 1H, H10), 1.67 (dt, J =
14.4, 6.8 Hz, 1H, H10’), 1.50-1.37 (2H, H8, H8’), 1.00 (s, 9H, t-Bu), 0.62-0.50 (2H, H9,
13 H9’), 0.21 (s, 6H, Si-CH3). C NMR (75 MHz, CDCl3) δ: 176.3, 138.9, 135.8, 134.0,
133.9, 133.7, 129.7, 129.2, 127.9, 127.85, 127.80, 127.76, 124.8, 123.8, 123.0, 65.2, 60.3,
46.8, 40.9, 39.7, 28.9, 27.0, 23.8, 19.3, 13.3, -3.1, -3.2. HRMS (m/z) for MH+
(C37H48NO2Si2): calc: 594.3224; found: 594.3222.
Tricarbonyl[(2-5-η-(1-benzyl-cyclohexa-2,4-dienyl)(2,5- (OC)3Fe dihydropyrrol-1-yl)methanone]iron (4.23a). N
Ph O Amide 4.20a (64 mg, 0.24 mmol) was refluxed in 12
mL of n-Bu2O for 8 h in the presence of 0.063 mL of Fe(CO)5 (91 mg, 0.48 mmol, added in portions according to the general procedure) to afford 43 mg (44% yield) of the title compound as a white solid along with 21 mg of (22%) enamide iron complex 4.25a and
trace amount of cyclization product 4.21a. Mp 170-172 °C (dec). Rf = 0.50
-1 1 (1:4/EA:Hex). IR (cm , film): 2926, 2049, 1972, 1643. H NMR (200 MHz, CDCl3) δ:
7.30-6.95 (5H, Ph), 5.90-5.55 (2H, H10, H10’), 5.43-5.22 (2H, H2, H3), 4.50-3.78 (4H,
H9, H9’), 3.59 (dd, J = 6.6, 1.2 Hz, 1H, H4 or H1), 3.10-3.00 (m, 1H, H1 or H4), 3.00 (d,
J = 13.2 Hz, 1H, benzyl H), 2.60 (d, J = 13.2 Hz, 1H, benzyl H’), 2.53 (dd, J = 15.4, 3.4
13 Hz, 1H, H6), 1.99 (dd, J = 15.4, 2.4 Hz, 1H, H6’). C NMR (50 MHz, CDCl3) δ: 211.2,
172.5, 137.1, 129.9, 128.1, 126.6, 125.5 (2C), 124.9 (2C), 85.7, 82.6, 67.4, 59.1, 55.7,
52.9, 51.6, 49.2, 37.9. 113
Fe(CO)3 Tricarbonyl[(2-5-η-(1-benzylcyclohexa-2,4-dienyl)(2,3-
N dihydropyrrol-1-yl)methanone]iron (4.25a).
Ph O 1 4.25a: Yellow oil. Rf = 0.41 (1:4/EA:Hex). H NMR (200
MHz, CDCl3) δ: 7.30-6.95 (5H, Ph), 6.32 (br s, 1H, H9), 5.43-5.20 (2H, H2, H3), 5.15
(dt, J = 3.6, 1.8 Hz, 1H, H10), 3.95-3.75 (2H, H12), 3.52 (dd, J = 6.5, 1.0 Hz, 1H, H4 or
H1), 3.05-2.92 (m, 1H, H1 or H4), 2.96 (d, J = 13.2 Hz, 1H, benzyl H), 2.62 (d, J = 13.2
Hz, 1H, benzyl H’), 2.70-2.50 (2H, H11, H11’), 2.36 (dd, J = 15.2, 3.4 Hz, 1H, H6), 2.06
(dd, J = 15.2, 2.2 Hz, 1H, H6’).
1-[2-(tert-butyldiphenylsilanyloxy)ethyl]cyclohexa-2,5-
N dienecarboxylic acid N-methyl-N-prop-2-ynylamide (4.33).
O According to standard peptide coupling conditions, acid 4.19b OTBDPS
(100 mg, 0.25 mmol) in 0.8 mL of CH2Cl2 and 0.2 mL of DMF was treated with 35 mg
of N-methyl-N-propargylamine (0.49 mmol), followed by 100 mg of HOBt (0.75 mmol)
and 144 mg of EDCI (0.75 mmol). The reaction solution was washed with 2 N HCl,
followed by saturated NaHCO3, dried (MgSO4), and concentrated to afford 100 mg (87% yield) of the title compound as a colorless oil after chromatography. Rf = 0.28
-1 1 (1:4/EA:Hex). IR (cm , neat): 2368, 1643, 1433, 1387. H NMR (200 MHz, CDCl3) δ:
7.70-7.30 (10H, Ph), 5.76 (dt, J = 10.4, 3.4 Hz, 2H, H3), 5.53 (d, J = 10.2 Hz, 2H, H2,
H’), 4.17 (d, J = 2.4 Hz, 2H, H7, H7’), 3.67 (t, J = 7.2 Hz, 2H, H11, H11’), 3.00 (s, 3H,
N-CH3), 2.58 (br. s, 2H, H4, H4’), 2.18 (t, J = 2.4 Hz, 1H, H9, H9’), 2.15 (t, J = 7.2 Hz,
13 2H, H10, H10’), 1.03 (s, 9H, t-Bu). C NMR (50 MHz, CDCl3) δ: 172.5, 135.7, 134.2, 114
129.5, 127.9, 127.6, 124.9, 79.3, 71.7, 60.8, 47.2, 41.5, 39.1, 35.1, 26.9, 26.1, 19.2.
+ HRMS (m/z) for MH (C29H26NO2Si): calc: 458.2515; found: 458.2519.
Tricarbonyl{4-7-η-7a-[2-(tert-butyldiphenylsilanyloxy)ethyl]- 2-methyl-3-(2- triethylsilanylethyl)-2,3,3a,7a-tetrahydroisoindol-1-one}iron (4.34).
SiEt3 (OC)3Fe Amide 4.33 (55 mg, 0.12 mmol) was refluxed in 6 mL of N n-Bu2O for 36 h with 3 equivalents of HSiEt3 (0.058 mL, 42 mg, O
OTBDPS 0.36 mmol), in the presence of 0.126 mL of Fe(CO)5 (188 mg, 0.96 mmol, added in portions according to the general procedure) to afford 24 mg (28% yield) of the title compound 4.34 as a colorless oil and 21 mg (25% yield) of 4.35 after
-1 chromatography. 4.34: Rf = 0.30 (1:4/EA:Hex). IR (cm , neat): 2052, 1980, 1697, 1433,
1 1117. H NMR (600 MHz, CDCl3) δ: 7.70-7.30 (10H, Ph), 5.28 (dd, J = 5.4, 4.2 Hz, 1H,
H5 or H6), 5.22 (dd, J = 5.4, 4.2 Hz, 1H, H6 or H5), 3.65 (dt, J = 10.8, 5.7 Hz, 1H, H11),
3.55 (dt, J = 10.8, 5.7 Hz, 1H, H11’), 3.35-3.26 (m, 1H, H3), 3.25 (d, J = 6.6 Hz, 1H, H4
or H7), 2.77 (d, J = 6.6 Hz, 1H, H7 or H4), 2.69 (s, 3H, N-CH3), 2.44 (d, J = 7.8 Hz, 1H,
H3a), 1.92 (dt, J = 13.8, 6.0 Hz, 1H, H10), 1.80-1.62 (2H, H8, H8’), 1.58 (dt, J = 13.8,
6.0 Hz, 1H, H10’), 1.03 (s, 9H, t-Bu), 0.95 (t, J = 7.8 Hz, 9H, CH3), 0.56 (q, J = 7.8 Hz,
13 6H, Si-CH2Me), 0.53-0.30 (2H, H9, H9’). C NMR (50 MHz, CDCl3) δ: 210.8, 176.1,
135.6, 133.5, 129.8, 127.8, 84.4, 83.3, 68.1, 62.5, 61.5, 56.8, 55.0, 41.0, 37.8, 27.1, 26.9,
+ 21.2, 19.2, 8.5, 7.5, 3.2. HRMS (m/z) for MH (C38H52FeNO5Si2): calc: 714.2733; found:
714.2716. 115
Tricarbonyl{4-7-η-7a-[2-(tert-butyldiphenylsilanyloxy)ethyl]- 2-methyl-3-(1- triethylsilanylethyl)-2,3,3a,7a-tetrahydroisoindol-1-one}iron (4.35).
Colorless oil. R = 0.38 (1:4/EA:Hex). IR (cm-1, H f SiEt (OC) Fe 3 3 neat): 2052, 1988, 1967, 1697, 1431. 1H NMR (600 MHz, N
O CDCl3) δ: 7.65-7.58 (10H, Ph), 5.28-5.22 (m, 1H, H5 or
OTBDPS H6), 5.20-5.15 (m, 1H, H6 or H5), 3.65-3.50 (3H, H11, H8,
H8’), 3.25 (dd, J = 6.2, 1.6 Hz, 1H, H4 or H7), 2.89 (d, J = 6.9 Hz, 1H, H7 or H4), 2.77
(s, 3H, N-CH3), 2.12 (d, J = 7.5 Hz, 1H, H3a), 1.89 (dt, J = 13.8, 7.2 Hz, 1H, H10), 1.60
(dt, J = 13.8, 7.5 Hz, 1H, H10’), 1.26 (d, J = 7.5 Hz, 3H, H9), 1.28-1.20 (m, 1H, H8),
1.03 (s, 9H, t-Bu), 0.95 (t, J = 7.8 Hz, 9H, Si-CH2CH3), 0.60 (q, J = 7.8 Hz, 6H, Si-
13 CH2CH3). C NMR (50 MHz, CDCl3) δ: 210.8, 178.1, 135.6, 133.5, 129.8, 127.7, 84.9,
82.6, 66.9, 61.0, 59.6, 59.2, 54.8, 42.4, 40.3, 30.4, 26.9, 19.1, 18.7, 12.0, 7.8, 3.1. HRMS
+ (m/z) for MH (C38H52FeNO5Si2): calc: 714.2733; found: 714.2751.
1-[2-(tert-Butyldiphenylsilanyloxy)ethyl]cyclohexa-2,5- C dienecarboxylic acid N-methyl-N-propa-1,2-dienylamide (4.36). N
O Amide 4.33 (42 mg, 0.09 mmol) in 0.1 mL of THF at 0 °C
OTBDPS was added 0.1 mL of 1 M KOt-Bu in THF. After 5 min, 2 mL of ether
was added at 0 °C, followed by 1 drop of saturated aqueous ammonium chloride solution. The reaction mixture was then dried (MgSO4), and concentrated to afford 20 mg (48% yield) of the title compound as a colorless oil after
1 chromatography. Rf = 0.33 (1:9/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.80-7.10 (6H,
Ph, H7), 5.78 (dt, J = 10.4, 3.4 Hz, 2H, H3), 5.54 (d, J = 10.2 Hz, 2H, H2), 5.31 (d, J = 116
6.2 Hz, 2H, H9), 3.69 (t, J = 7.4 Hz, 2H, H10), 3.00 (s, 3H, N-CH3), 2.60 (br. s, 2H, H4),
2.17 (t, J = 7.4 Hz, 2H, H9), 1.04 (s, 9H, t-Bu).
Tricarbonyl{4-7-η-7a-[2-(tert-butyldiphenylsilanyloxy)ethyl]-3-ethylidene-2-methyl-
2,3,3a,7a-tetrahydroisoindol-1-one}iron (4.38).
(OC)3Fe Amide 4.36 (18 mg, 0.04 mmol) was refluxed in 4 mL of
N n-Bu2O for 36 h with 0.042 mL of Fe(CO)5 (62 mg, 0.32 mmol, O added in portions according to the general procedure) to afford TBDPSO 2.6 mg (14% yield) of the title compound 4.38 as a colorless oil
1 after chromatography. Rf = 0.30 (1:9/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.70-7.30
(10H, Ph), 5.30-5.20 (2H, H5 and H6) 4.63 (q, J = 7.0 Hz, 1H, H8), 3.70-3.40 (2H, H11,
H11’), 3.20-3.00 (3H, H3a, H4, and H7), 2.83 (s, 3H, N-CH3), 1.93 (dt, J = 13.8, 6.0 Hz,
1H, H10), 1.66 (d, J = 7.0 Hz, 3H, H9), 1.64-1.15 (m, 1H, H10’), 1.23 (s, 6H, Si-CH3),
13 0.99 (s, 9H, t-Bu). C NMR (50 MHz, CDCl3) δ: 210.6, 183.3, 135.6, 155.7, 133.4,
129.7, 127.7, 84.0, 83.6, 74.1, 67.2, 61.3, 59.8, 44.2, 40.7, 30.4, 29.8, 26.9, 19.1. 117
4.5 Literature Cited
(1) Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 13. Stereoselectivity of Complexation of Cyclohexadiene Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1755-1762.
(2) Kirby, A. J. “Effective Molarities for Intramolecular Reactions.” Adv. Phys. Org. Chem., 1980, 17, 183-278.
(3) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. “Total Synthesis of (±)-Gelsemine.” Angew. Chem. Int. Ed. 1999, 38, 2934-2936.
(4) Yokoshima, S.; Tokuyama, H.; Fukuyama, T. “Enantioselective Total Synthesis of (+)-Gelsemine: Determination of Its Absolute Configuration.” Angew. Chem. Int. Ed. 2000, 39, 4073-4075.
(5) Ng, F. W.; Lin, H.; Danishefsky, S. J. “Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine.” J. Am. Chem. Soc. 2002, 124, 9812-9824.
(6) Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 14. Tricarbonyliron as Lateral Control Group in the Selective Alkaline Hydrolysis of Some Cyclohexa-1,3-Diene Carboxylic Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1763-1769.
(7) Ganem, B.; Holbert, G. W.; Weiss, L. B.; Ishizumi, K. “A New Approach to Substituted Arene Oxides. Total Synthesis of Senepoxide and Seneol.” J. Am. Chem. Soc. 1978, 100, 6483-6491.
(8) Bennani, Y. L.; Hanessian, S. “The Asymmetric Synthesis of α-Substituted α-Methyl and α-Phenyl Phosphonic Acids: Design, Carbanion Geometry, Reactivity and Preparative Aspects of Chiral Alkyl Bicyclic Phosphonamides.” Tetrahedron 2000, 52, 13837-13866.
(9) Shibata, T.; Yamashita, K.; Takagi, K.; Ohta, T.; Soai, K.; “Inter- and Intramolecular Carbonylative Alkyne – Alkyne Coupling Reaction Mediated by Cobalt Carbonyl Complex.” Tetrahedron 2000, 56, 9259-9267.
(10) Mander, L. N.; Williams, C. M. “Oxidative Degradation of Benzene Rings.” Tetrahedron 2003, 59, 1105-1136.
(11) Bäckvall, J. E.; Vagberg, J.; Nordberg, R. E. “Palladium-Catalyzed 1,4-Acetoxy- trifluoroacetoxylation of 1,2-Dienes.” Tetrahedron Lett. 1984, 25, 2717-2720.
118
(12) Sato, Y.; Honda, T.; Shibasaki, M. “A Catalytic Asymmetric Synthesis of Hydrindans.” Tetrahedron Lett. 1992, 33, 2593-2596.
(13) Bandara, B. M. R.; Birch, A. J.; Chauncy, B.; Kelly, L. F. “Tricarbonyliron Complexes of Some Blocked Cyclohexadienes.” J. Organomet. Chem. 1981, 208, 332- 337.
(14) Grigg, R.; Köppen, I.; Rasparini, M.; Sridharan, V. “Synthesis of Spiro- and Fused Heterocycles by Palladium Catalysed Carbo- and Heteroannulation Cascades of Allenes.” Chem. Comm. 2001, 964-965.
119
CHAPTER FIVE
Formation of All-Carbon Spirocycles
120
5.1 Preparation of All-Carbon Spirocycles
Spirocyclic carbon systems constitute an important class of molecules owing to
their frequent occurrence in many natural products, such as spirocyclic sesquiterpenes.1,2
Although a wide range of methods directed to the synthesis of these classes of compounds are available,3-13 the stereocontrolled formation of the stereogenic spirocenter is sometimes restricted, and the cyclization yields are often poor.
In the previous chapters we have shown examples of making molecules including spirocyclic and bicyclic lactam structures, diastereoselectively, by an iron carbonyl mediated [6+2] ene cyclization, initially developed by Pearson and Zettler. A previous student, Ismet B. Dorange, successfully demonstrated that this methodology can be applied to prepare all-carbon spirocycles, although only a few examples were presented
(Scheme 5.1).14
R R R (CO) Fe Fe(CO) Fe(CO) 3 3 3 MgBr MsCl, Et3N n n o o OMs Et2O, 0 C 1 OH CH2Cl2, 0 C 72-89% ca. 83-85% O O O 5.1 a R = H 5.2 5.3 b R = OMe R = H, OMe n = 1, 2 R R O (CO)3Fe (CO)3Fe n = 1 n-Bu2O CO R = OMe o 1 n i) Me NO 142 C 1 n 3 5-7 h O ii) (COOH) /H O O 2 2 O Methanol 5.4 5.5
Scheme 5.1 All-Carbon Cyclization via Ketone Intermediate
121
Although cyclization product 5.4 can be prepared in good yield from the ketone
complex 5.3, preparation of 5.3 needs seven steps (5 steps to prepare acid complexes
5.1). In the last step, a very reactive acyl mesylate is employed to react with the Grignard
reagent. If this method is to be applied to natural product synthesis, it also requires
transformation of the 1-keto group to an alkyl group in many cases. Since it is not trivial
to manipulate a ketone next to a spirocenter, we decided to introduce the alkyl group into
the starting material. This would require a protracted synthetic route from ketones such as
5.4. A simpler and more efficient approach was therefore investigated.
Fe(CO)3 Fe(CO)3 Fe(CO)3 Cyclization Rearrangement
R R R 5.6 5.7 5.8
Fe(CO)3 nucleophile - R = H, Alkyl + PF6
5.9
Scheme 5.2 Proposed Rearrangement-Cyclization
There is evidence that, in cyclohexadiene-iron tricarbonyl complexes, the iron moiety migrates around the ring by hydride transfer under thermal cyclization conditions
(see Scheme 1.11, Chapter 1). The required cyclization substrates, 1-substituted cyclohexadiene-Fe(CO)3 complexes 5.7, might be formed from the 5-exo isomers 5.8 by in situ rearrangement prior to cyclization. Complexes 5.8 can be very easily accessed from cyclohexadienyliron cation 5.9 (1.11, Chapter 1) by nucleophile addition. It should 122
be mentioned that nucleophile additions to cation 5.9 and its derivatives have been extensively studied. A large number of substituted cations related to 5.9 are available and easily prepared (see Section 1.2). A wide range of nucleophiles can be reacted with 5.9 and its derivatives in good to excellent yield and selectivity (Table 1.1, Chapter 1).
Fe(CO)3
Fe(CO)3 Fe(CO)3 n-Bu2O CO N + Ph (5.1) o N N 142 C (OC) Fe Ph Ph 3 X X 5.10a X, X = O 5.10b X = X = H 5.11 N 5.12 Ph
Amide 5.10a was prepared from 5-exo-carboxycyclohexa-1,3-diene-Fe(CO)3 complex,15 a side product when preparing its endo isomer (4.6, Chapter 4). Complex
5.10a, an analog of 5.8, was initially subjected to cyclization conditions to test the rearrangement-cyclization transformation sequence. Only traces of cyclization product, a spirolactam, were observed after 12 h, the remaining material being unreacted 5.10a. The reluctance of 5.10a to undergo rearrangement was tentatively attributed to a difficult hydride transfer from the α-position of the carbamide to the Fe group. Based on this proposition amine 5.10b, from the DIBALH reduction of 5.10a, was subjected to spirocyclization. Spiroamine 5.12 was produced in good yield with 80% conversion upon heating for 12 h. The putative intermediate 5.11 could not be isolated from low conversion experiments. Nevertheless, the rearrangement-cyclization strategy is feasible. 123
Fe(CO)3 MgBr Fe(CO) Catalyst Fe(CO)3 3 + - Fe(CO)5 Ph3C PF6 in THF + - PF6 CH Cl Dioxane CH2Cl2 2 2 - 78 oC Reflux 100% 5.9 5.13 93% 70%
Fe(CO)3 Fe(CO)3 n-Bu2O (OC)3Fe CO + 142 oC 68% 5.14 5.15a 5.15b
Catalyst NOMe
Scheme 5.3 Rearrangement-Cyclization
Next, complex 5.13, the simplest all carbon substrate, was prepared by Grignard addition to 5.9 at -78 °C in dichloromethane,16 as shown in Scheme 5.3. Upon heating
5.13 for 12 h, 5.15a and 5.15b (ratio 1.5:1) were produced in 68% yield. Only 4 steps are required to produce spiro[4.5]decane derivatives from 1,3-cyclohexadiene (2 steps from
5.9, which is also commercially available) with good overall yield. This represents a significant improvement over our previous method.
Migration of the Fe(CO)3 in 5.13 can occur in two directions, “clockwise” and
“anticlockwise”. Clockwise rearrangement would give 5.14, while two anticlockwise
rearrangements will give ent-5.14. Both enantiomers of 5.14 cyclize to give racemic
5.15a and 5.15b. Thus, even an enantioselective alkylation of 5.9 would not allow enantioselective synthesis of 5.15.
Introducing a substituent onto the cyclohexadiene ring of 5.9 (not at the para- position) serves to control this rearrangement. Regioselective addition of Grignard 124
17 reagent to the 1-carbomethoxycyclohexadienyl-Fe(CO)3 cation 5.16 (1.13, Chapter 1) gave exo-5-(4-pentenyl)-1-carbomethoxycyclohexadiene iron tricarbonyl (5.17).
Cyclization of 5.17 revealed the effect of the ester functionality, wherein an inseparable
1:1:1:7 mixture (by integration of the terminal methyl doublets, 600 MHz 1H NMR) of
5.19a, 5.19b, 5.22a, 5.22b was formed in about 50% yield. 1H NMR and NOE difference
studies of the major isomer established its structure as 5.22b. A tentative explanation is
presented in Scheme 5.4, in which the diene-Fe(CO)3 rearranges in both directions, path a and b. Although fewer steps are required to produce 5.19 (path a), it appears that b is the major pathway where two successive diene rearrangements to give 5.21, followed by cyclization, affording 5.22. The major product, 5.22b, is thermodynamically more stable than 5.22a.18
Fe(CO)3 Fe(CO)3 60% Fe(CO)3 MgBr PF - 6 + MeO C path a MeO2C 2 MeO2C 5.16 5.17 5.18 path b
Fe(CO)3 Fe(CO)3 (OC)3Fe
MeO2C MeO2C MeO2C 5.20 5.19b 5.19a
Fe(CO)3 Fe(CO)3
MeO2C MeO2C MeO2C (OC) Fe 3 5.21 5.22a 5.22b
Scheme 5.4 Regiocontrolled Rearrangement-Cyclization
125
A number of derivatives of 5.13 were prepared to expand the scope of the
rearrangement-cyclization method. When 2-methoxycyclohexadienyl-Fe(CO)3 cation
5.23 (1.15a, Chapter 1) was treated with IZnCH2CH2CO2Et, prepared from ethyl 3-
iodopropionate, in the presence of a catalytic amount of CuI and LiCl,19 5.24 was obtained in 55% yield. α–Allylation at the ester gave 5.25 as a pair of diastereomers, which has an oxygen functionality at C(2) and an ester group at C(8). Its cyclization product 5.27 is envisioned to be more useful than the unfunctionalized 5.15.
Disappointingly, cyclization of 5.25 was very slow, although 5.27 was obtained in acceptable yield based on recovered starting material (Scheme 5.5). Cyclization of 5.26 was even worse under thermal conditions. It appears that rearrangement of these methoxy-substituted complexes is much slower than the parent or its ester derivatives.
Fe(CO) (OC)3Fe Fe(CO) 3 IZn CO2Et 3 MeO MeO CuI, LiCl MeO LDA, THF - PF + Allyl iodide 8 6 THF CO Et CO Et 60% 2 5.23 50% 2 5.24 5.25
Fe(CO)3 MgBr Fe(CO)3 MeO o in THF MeO n-Bu2O, CO, 142 C CH Cl 18 h, 40% conversion 2 2 48% yield BRSM - 78 oC 31% 5.26 5.27 CO2Et
Scheme 5.5
Regioelective deprotonation of the terminal α-hydrogen from hex-5-en-2-one,
followed by addition of cation 5.9 to the enolate, gave 5.28. DIBALH reduction of ketone
5.28 and TBDPS protection of the resulting alcohol formed 5.29. Alkylation of 5.30, 126
Fe(CO)3 Fe(CO) 3 91% Fe(CO)3 - LDA, THF i) DIBALH + PF6 8 Hex-5-en-2-one ii) TBDPSCl 8 O OTBDPS Imidazole 5.9 35% 5.28 5.29
Fe(CO) Fe(CO) Fe(CO)3 3 3 3 2 4 NaH, THF NaH, THF - CO Me 5 + PF6 2 1 6 7 Methyl Malonate Allyl iodide
100% CO2Me MeO2CCO2Me 5.9 5.30 5.31
Fe(CO) 3 Fe(CO)3 i) DIBALH Fe(CO)3 - LDA, THF ii) AllylMgBr + PF6 Methyl acetate CO2Me 8 iii) TBDPSCl OTBDPS 75% Imidazole 5.9 5.32 5.33
Fe(CO) Fe(CO)3 Fe(CO)3 3 i) BrZn CO2Et LDA, THF - CuI PF 8 + 6 ii) 6 N HCl Allyl iodide CO2Et CO2Et 5.9 5.34 5.35
Fe(CO)3 MgBr Fe(CO)3 Fe(CO)3
- in THF + PF6 CH2Cl2 6 - 78 oC MeO C CO2Me 20% CO2Me 2 5.36 5.37 5.38
Scheme 5.6
prepared from methyl sodiomalonate addition to 5.9,19 produced 5.31. Partial reduction of the known ester 5.3220 to an aldehyde by DIBALH, allyl magnesium bromide addition to the aldehyde, and silyl ether formation delivered 5.33. Zn-Cu reagent addition to 5.9 was 127
initially aimed at producing the 5-exo isomer, but the reaction yielded the 2-substituted
isomer 5.3421 after 6M HCl treatment during the workup. Allylation of 5.34 gave 5.35.
Pent-4-enylmagnesium bromide addition to cyclohexadienyl cation 5.36,22 an analogue of
5.9, generated 5.37 in poor yield, possibly due to competing deprotonation of the ester α- hydrogen to produce methyl benzoate. Complex 5.37 was expected to give a single product 5.38, which does not have a 5-endo hydrogen and therefore cannot undergo further diene rearrangemnt.
Unfortunately, none of the substrates prepared in Scheme 5.7 yielded any cyclization products. Complexes 5.28 and 5.29 might suffer from a slow 6-membered
ring formation. It remains unclear to us why 5.33, 5.35, and 5.37 did not work. We
suspect that the failure of the cyclization of 5.31 is due to the effect of the two electron-
withdrawing ester groups on the hydride transfer from their β-position, which is required
for the initial rearrangement. A similar electronic problem exists with 5.10a. The steric
environment caused by the quaternary carbon center (C5) next to the reaction site (C7)
might be another reason to prohibit the cyclization. Complex 5.39, which has one ester
group less than 5.31, was therefore prepared to test the electronic hypothesis.
Treatment of methyl 5-hexenoate with 1 equiv of LDA in THF, and subsequent
addition of 5.9 at -78 °C produced 5.39 as a 2:1 mixture of diastereomers (Scheme 5.5).20
Refluxing 5.39 in n-Bu2O for 14 hours gave the spirocycle 5.40 (142 °C, about 60%
yield) containing some inseparable side products along with about 10% of unreacted
starting material. Although cyclization of 5.39 was still slow compared to 5.13, it was a
great improvement over 5.31. Reduction of the ester 5.39 followed by TBDPS protection
gave 5.41, again as a 2:1 mixture. Since the two diastereomers of 5.41 can be 128
LDA Fe(CO)3 (OC)3Fe CO2Me 142 oC 5.9 o THF, -78 C n-Bu2O 65% CO 5.39 CO Me MeO2C 2 5.40 i) DIBALH, -78 oC 75% ii) TBDPSCl, Imidazole
Fe(CO)3 Fe(CO)3 142 oC
(+ enantiomer) (+ enantiomer) OTBDPS OTBDPS
5.41 o n-Bu2O 142 C CO 80%
Fe(CO)3
5.42a 5.42b (OC) Fe 3 CH OTBDPS CH2OTBDPS 2
NOE Fe(CO) (OC)3Fe Fe(CO)3 (OC)3Fe 7 H6 3 + 5 + 4 1 3 H10 2 OTBDPS OTBDPS NOE OTBDPS OTBDPS 5.43a 5.43b 5.43c 5.43d
i) Me3NO ii) H2/Pd/C > 95%
4.5 : 1
5.44a 5.44b OTBDPS OTBDPS
Scheme 5.7 Diastereoselective Rearrangement-Cyclization
129
interconverted during cyclization, and both can rearrange to give 5.42a and 5.42b, their stereochemistries were not fully assigned. The mixture cyclized after 12 h in 80% yield to give an inseparable mixture of four isomeric products 5.43a-d in a ratio 4.5:4:1:1. The
TBDPSOCH2 group in 5.41 is a much weaker electron-withdrawing and bulkier group
that the ester group in 5.39, implying that electronic factors seem to play a more
important role.
5.41 (2:1 mixture of diastereomers)
5.42a 5.42b
- CO - CO O O C C Fe H H 5.45b 5.45a C Fe O CH OTBDPS C 2 115.6 kcal/mol CH2OTBDPS O 120.3 kcal/mol
4.5 : 1
5.44a 5.44b OTBDPS OTBDPS
Scheme 5.8
Demetallation of 5.43 followed by hydrogenation gave a 4.5:1 mixture of 5.44a and 5.44b based on 1H NMR. The major products in 5.43 were shown to be a pair of
trans spirocycles 5.43a and 5.43b by NOE difference study on the major isomer in the 130
mixture of 5.43. When the methyl doublet was irradiated, positive enhancement was observed with H6 (5.43a, Scheme 5.5). Irradiation of the methylene hydrogens next to
oxygen of CH2OTBDPS showed a positive NOE with a doublet
(δ = 1.7 ppm, J = 15.0 Ηz), which was assigned as H10. Since H6 and H10 are on
different sides with respect to the five-membered ring, the methyl group and the TBDPS
ether group must be trans.
The preference for a trans relationship is supported by molecular mechanics strain
energy calculations using PC Spartan (Spartan′ 02, Wavefunction, Inc. Irvine, CA) on
two intermediates, 5.45a and 5.45b, which lead to the cyclization products (for
mechanism, see Scheme 1.11, Chapter 1). The trans intermediate 5.45a is lower in energy
than cis intermediate 5.45b by 4.7 kcal/mol, therefore the corresponding product from
5.45a would be the major one at 142 °C.
Good diastereoselectivity during cyclization is observed here between C1 and C4
in products 5.27. Therefore, in principle, the chirality at C1 can be utilized to control the
configuration of the final product. It is noteworthy that the major product, 5.27a, has
much of the carbon skeleton corresponding to natural terpenoids such as Cedrol23 and
Elisabethin A.24
O MeO OH
O
Elisabethin A Cedrol
131
5.2 Conclusions
In summary, we have developed a short isomerization-cyclization procedure to
prepare all-carbon spirocycles, and this preliminary work might form the basis for future studies. The full scope of this reaction: substitution effects on the cyclohexadiene ring; substitution effects on the pendant alkyl chain including the double bond; tandem double cyclization; and optimization of cyclization conditions remains to be further investigated. 132
5.3 Experimental Section
General experimental and spectroscopic methods, and general procedure for the thermally induced cyclization are as described in Chapter 2.
Arbitrary numbering system used for NMR assignments.
11 Fe(CO) 3 Fe(CO)3 7 3 11 2 4 10 8 6 9 4 5 9 1 8 5 10 3 6 7 1 2
133
Tricarbonyl(2-5-η-cyclohexa-2,4-dienecarboxylic acid N-but-2- Fe(CO)3 enyl-N-phenylamide)iron (5.10a). N Ph O Tricarbonyl(5-carboxycyclohexa-1,3-diene)iron (200 mg,
0.76 mmol) and 80 mg of 4 Å molecular sieves were dissolved in 2 mL of dry CH2Cl2, followed by sequential addition of 0.14 mL of Et3N, and 0.12 mL of CH3SO2Cl. The reaction mixture was stirred at rt for 1 h, 262 mg of N-crotylaniline and 0.28 mL of Et3N were then added at 0 °C, and the mixture was stirred at rt for 12 h, washed with water, and dried (MgSO4) to afford 273 mg (86% yield) of the title compound as a pale brown
-1 1 oil after chromatography. Rf = 0.39 (1:9/EA:Hex). IR (cm , neat): 2046, 1965, 1651. H
NMR (300 MHz, CDCl3) δ: 7.50-7.10 (5H, Ph), 5.53-5.40 (4H, H2, H3, H10, H11), 4.25-
4.00 (2H, H9, H9’), 3.07 (m, 1H, H1 or H4), 2.88-2.73 (2H, H5, H4 or H1), 1.75-1.65
13 (2H, H6, H6’), 1.62 (d, J = 5.7, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 211.7, 173.9,
142.1, 129.8, 129.6, 128.3, 128.1, 125.6, 86.3, 85.4, 60.7, 60.1, 52.1, 41.3, 30.0, 17.8.
+ HRMS (m/z) for MH (C20H20FeNO4): calculated: 394.0742; found: 394.0739.
Tricarbonyl(2-5-η-N-but-2-enyl-N-cyclohexa-2,4-dienylmethyl-
Fe(CO)3 N-phenylamine)iron (5.10b). N Ph To 100 mg (0.25 mmol) of 5.10a in 2 mL of CH2Cl2 at -78
°C was added DIBALH (2 mL, 1.5 M in toluene, 3.0 mmol). The reaction mixture was warmed to rt over 2 h, stirred for 6 h, quenched with water at 0 °C, extracted three times with CH2Cl2, dried (MgSO4), and concentrated under vacuum. Chromatography afforded
1 93 mg (93% yield) of the title amine as a pale brown oil. Rf = 0.60 (1:19/EA:Hex). H
NMR (200 MHz, CDCl3) δ: 7.25-6.60 (5H, Ph), 5.60-5.20 (4H, H2, H3, H10, H11), 3.84 134
(d, J = 4.4 Hz, 2H, H9, H9’), 3.23-3.00 (3H, H1, H4, H7), 2.91 (dd, J = 14.4, 8.6 Hz, 1H,
H7’), 2.50 (m, 1H, H6), 2.00 (ddd, J = 15.2, 10.5, 3.6 Hz, 1H, H6’), 1.65 (d, J = 5.8 Hz,
13 3H, CH3), 1.72-1.50 (m, 1H, H5). C NMR (50 MHz, CDCl3) δ: 211.9, 148.4, 129.2,
127.4, 126.4, 116.1, 112.3, 86.1, 84.8, 64.6, 59.8, 58.8, 36.7, 29.2, 17.7.
Tricarbonyl(6-9-η-4-ethyl-2-phenyl-2-azaspiro[4.5]deca-6,8-diene)iron (5.12).
A solution of 45 mg of 5.10b in 5 mL of n-Bu2O was
Fe(CO)3 Fe(CO)3 refluxed for 12 h according to the general procedure.
Spiroamines 5.12 were isolated as a 1.3:1 mixture of epimers N N Ph Ph (brown oil, 36 mg, 50%), which also contained about 20%
1 inseparable unreacted starting material. Rf = 0.60 (1:19/EA:Hex). H NMR (600 MHz,
CDCl3), mixture of epimers, δ: 7.25-6.50 (10H, Ph), 5.45-5.32 (4H, H7, H8 of both isomers), 3.54 (dd, J = 8.6, 6.6 Hz, 1H, H3 minor), 3.31 (dd, J = 9.0, 6.6 Hz, 1H, H3
major), 3.24-1.00 (series of m, 20H), 0.97 (t, J = 7.8, 3H, CH3, major), 0.94 (t, J = 7.8,
13 3H, CH3, minor). C NMR (50 MHz, CDCl3), major epimer, δ: 211.9, 147.4, 129.2,
115.4, 111.1, 86.6, 83.3, 69.3, 63.5, 61.1, 51.5, 50.0, 43.3, 35.1, 29.8, 21.8, 12.6. HRMS
+ (m/z) for MH (C20H22FeNO3): calculated: 380.0954; found: 380.0954.
Fe(CO)3 Tricarbonyl(1-4-η-5-pent-4-enylcyclohexa-1,3-diene)iron (5.13).
To 520 mg (1.43 mmol) of cation 5.9 in 10 mL of CH2Cl2 at -
78 °C, was added dropwise 4-pentenylmagnesium bromide (1.6 mL, 1.1 M solution in
Et2O) via syringe over 10 min. After being stirred for 2 h at -78 °C, the reaction was warmed to 0 °C, and quenched with 10 mL of water. The organic layer was separated, and the aqueous layer was extracted with 10 mL of CH2Cl2 and ether (2 x 10 mL). The 135
extracts were combined, dried (MgSO4), and evaporated to give 288 mg (70% yield) of the title compound as a yellow oil after flash chromatography using hexane. 1H NMR
(200 MHz, CDCl3) δ: 5.75 (ddt, J = 18.0, 10.2, 6.4 Hz, 1H, H10), 5.40-5.20 (2H, H2,
H3), 5.03-4.85 (2H, H11, H11’), 3.19-2.98 (2H, H1, H4), 2.15-1.90 (4H), 1.42-1.10 (5H).
13 C NMR (50 MHz, CDCl3) δ: 212.3, 138.8, 114.5, 85.5, 84.6, 67.2, 60.0, 39.6, 38.2,
33.9, 30.8, 32.6.
Tricarbonyl(6-9-η-4-methylspiro[4.5]deca-6,8-diene)iron (5.15). Fe(CO)3
Complex 5.13 (61 mg, 0.21 mmol) dissolved in 8 mL of n-Bu2O was heated for 12 h according to the general procedure to yield, after reverse phase PLC
(pure methanol, Rf = 0.47), 41 mg (68% yield, yellow oil) of the title product as a mixture
1 of epimers. H NMR (200 MHz, CDCl3), mixture of epimers, δ: 5.36-5.24 (4H, H7, H8 of both isomers), 3.25-2.93 (4H, H6, H9 of both isomers), 2.00-1.00 (18H), 0.92 (d, J =
13 7.0 Hz, 3H, CH3-major), 0.84 (d, J = 7.0 Hz, 3H, CH3 mainor). C NMR (50 MHz,
CDCl3), major epimer, δ: 212.5, 85.9, 82.2, 68.5, 61.7, 48.9, 44.9, 43.5, 42.0, 31.7, 22.4,
+ 17.0. HRMS (m/z) for MH (C14H17FeO3): calculated: 289.0528; found: 289.0799.
Fe(CO)3 Tricarbonyl(1-4-η-5-pent-4-enylcyclohexa-1,3-dienecarboxylic
acid methyl ester)iron (5.17). MeO2C
Cation 5.16 (211 mg, 0.5 mmol ) was treated with 1.3 equiv of Grignard reagent
according to the procedure for 5.13 to afford 103 mg (60% yield) of the title complex as a
1 pale brown oil after flash chromatography on silica gel. Rf = 0.31 (1:19/EA:Hex). H
NMR (200 MHz, CDCl3), δ 6.08 (d, J = 4.4 Hz, 1H, H2), 5.76 (ddt, J = 18.0, 10.0, 6.4 136
Hz, 1H, H10), 5.34 (dd, J = 6.4, 4.4 Hz, 1H, H3), 5.05-4.88 (2H, H11, H11’), 3.69 (s, 3H,
OCH3), 3.30 (ddd, J = 6.4, 3.5, 1.1 Hz, 1H, H4), 2.43 (dd, J = 14.6, 10.8 Hz, 1H, H6-
endo), 2.22 (m, 1H, H5), 1.65 (apparent t, J = 6.6, 2H, H9, H9’), 1.42-1.15 (4H, H7, H7’,
13 H8, H8’), 1.07 (dd, J = 14.6, 3.6 Hz, 1H, H6-exo). C NMR (50 MHz, CDCl3), δ 210.3,
172.7, 138.6, 114.7, 88.6, 84.5, 68.0, 51.6, 39.6, 39.4, 33.8, 29.7, 27.4. HRMS (m/z) for
+ MH (C16H19FeO5): calculated: 347.0582; found: 347.0566.
Tricarbonyl(7-10-η-1-methylspiro[4.5]deca-7,9-diene-7- Fe(CO)3 carboxylic acid methyl ester)iron (5.22b). MeO2C
Complex 5.17 (40 mg) dissolved in n-Bu2O (5 mL) was heated for 12 h according to the general procedure to yield the title compound as a yellow oil (20 mg, 50% yield), along with 30% of other inseparable isomers after
1 preparative TLC. Rf = 0.35 (1:19/EA:Hex). H NMR (200 MHz, CDCl3) δ: 6.09 (d, J =
4.4 Hz, 1H, H8), 5.34 (dd, J = 6.4, 4.4 Hz, 1H, H9), 3.71 (s, 3H, OCH3), 3.14 (d, J = 6.4
Hz, 1H, H10), 2.36 (d, J = 15.6 Hz, 1H, H6-endo), 1.40 (d, J = 15.6 Hz, 1H, H6-exo),
13 2.22-1.15 (7H), 0.92 (d, J = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 210.4,
90.8, 87.8, 82.3, 73.0, 51.7, 48.4, 44.5, 42.6, 35.7, 32.1, 21.0, 16.5. HRMS (m/z) for MH+
(C16H19FeO5): calculated: 347.0582; found: 347.0550.
Tricarbonyl[2-5-η-3-(4-methoxycyclohexa-2,4- Fe(CO)3 MeO dienyl)propionic acid ethyl ester]iron (5.24).
CO2Et To 394 mg (1.00 mmol) of cation 5.23 in 4 mL of
THF at -78 °C, was added dropwise zinc copper reageant (1.0 mL, 1.0 M in THF), 137
prepared according to the literature procedure as stated in the text, via a syringe over 10
min. After being stirred for 2 h at -78 °C, the reaction was warmed to 0 °C, and quenched with 10 mL of water. The title compound (183 mg, 50% yield) was obtained as a yellow oil following the same workup procedure as for 5.13 and flash chromatography. 1H NMR
(200 MHz, CDCl3) δ: 5.06 (dd, J = 6.6, 2.4 Hz, 1H, H3), 4.11 (q, J = 7.2 Hz, 2H,
CO2CH2CH3), 3.63 (s, 3H, OCH3), 3.27 (dt, J = 3.6, 2.3 Hz, 1H, H1), 2.66 (dd, J = 6.5,
13 3.4 Hz, 1H, H4), 2.20-1.26 (5H), 1.11 (t, J = 7.2 Hz, 3H, CO2CH2CH3). C NMR (50
MHz, CDCl3) δ: 211.3, 171.5, 139.8, 66.3, 60.4, 54.4, 54.3, 52.6, 37.1, 34.7, 33.2, 31.6,
14.3.
Tricarbonyl[2-5-η-2-(4-methoxycyclohexa-2,4- Fe(CO)3 MeO dienylmethyl)pent-4-enoic acid ethyl ester]iron (5.25).
CO2Et To a stirred solution of LDA (1 mmol, 0.25 mL of
2 M solution in heptane/THF) at -78 °C under Ar was added 183 mg of 5.24 in 1 mL of
THF. The mixture was stirred for 30 min at -78 °C, and 0.5 mL of allyl iodide was added.
Stirring was continued at -78 °C for 3 h, and the reaction mixture was allowed to warm to
rt over 2 h, and stirred overnight. The title compound was obtained as mixture of
diastereomers (122 mg, 60%) following the same workup procedure as for 5.13 and flash
1 chromatography using 5% EA in Hex. H NMR (200 MHz, CDCl3), mixture of diastereomers, δ: 5.81-5.58 (m, 1H, H10), 5.10-4.85 (3H, H3, H11, H11’), 4.23-4.00 (2H,
CO2CH2CH3), 3.63 (s, 3H, OCH3), 3.27 (apparent dt, 2.2, 1.2 Hz, 1H, H1), 2.76 (dd, J =
6.5, 3.4 Hz, 1H, H4 minor), 2.61 (dd, J = 6.5, 3.4 Hz, 1H, H4 major), 2.50-1.00 (8H),
1.26 (t, J = 7.2 Hz, 3H, CO2CH2CH3 minor), 1.25 (t, J = 7.2 Hz, 3H, CO2CH2CH3 138
13 major). C NMR (50 MHz, CDCl3), major isomer, δ: 211.2, 175.4, 139.7, 135.2, 117.0,
66.3, 60.3, 55.0, 54.3, 52.5, 44.8, 42.4, 37.1, 36.0, 31.4, 14.3.
Tricarbonyl(1-4-η-2-methoxy-5-pent-4-enylcyclohexa-1,3-diene)iron (5.26).
Fe(CO)3 Cation 5.23 (394 mg, 1.0 mmol) in 6 mL of CH2Cl2 was MeO treated with 1.3 equiv of Grignard reagent according to the procedure for 5.13 to afford 97 mg (31% yield) of the title compound as a yellow oil along with 1:1 mixture of an inseparable side product after flash chromatography using
1 5% EA in Hex. H NMR (200 MHz, CDCl3) δ: 5.75 (ddt, J = 18.0, 10.2, 6.4 Hz, 1H,
H10), 5.10-4.85 (3H, H3, H11, H11’), 3.63 (s, 3H, OCH3), 3.32-3.26 (m, 1H, H1), 2.71
(dd, J = 6.5, 3.5 Hz, 1H, H4), 2.15-1.90 (4H), 1.42-1.00 (5H). 13C NMR (50 MHz,
CDCl3) δ: 211.5, 138.8, 114.5, 66.6, 59.8, 55.8, 54.3, 52.9, 48.5, 39.7, 37.8, 33.8, 31.8,
27.8.
Tricarbonyl(1-4-η-8-methoxy-4-methylspiro[4.5]deca-6,8- Fe(CO)3 MeO diene-2-carboxylic acid methyl ester)iron (5.27).
CO2Me Complex 5.25 (100 mg) dissolved in n-Bu2O (10 mL)
was heated for 18 h according to the general procedure to yield 19 mg (48% yield
BORSM) of the title compound as mixture of almost equal amount of four isomers, along
with 60 mg (60% conversion) of unreacted starting material after preparative TLC. Rf =
1 0.43 (1:9/EA:Hex). H NMR (600 MHz, CDCl3), mixture of isomers, δ: 5.12-5.01 (m,
1H, H7), 4.20-4.00 (2H, CO2CH2CH3), 3.63 (s, 3H, OCH3), 3.45 (m, 1H, H9), 3.00-2.55
(m, 1H), 2.40-1.20 (7H), 1.03-0.82 (6H, CH3, CO2CH2CH3). 139
Tricarbonyl(2-5-η-1-cyclohexa-2,4-dienylhex-5-en-2-one)iron (5.28).
Fe(CO)3 To a stirred solution of LDA (1 mmol, 0.5 mL, 2 M in
heptane/THF) at -78 °C under Ar was added 0.10 mL of hex-5-en-2- O one in 1 mL of THF. The mixture was stirred for 10 min at -78 °C, and 394 mg of 5.9 was added in one portion. Stirring was continued at -78 °C for 2 h, warmed to 0 °C, and quenched with 5 mL of water. The title compound was obtained as a yellow oil (133 mg,
42%) following the same workup procedure as for 5.13 and flash chromatography using
1 5% EA in Hex. H NMR (200 MHz, CDCl3) δ: 5.75 (ddt, J = 18.0, 10.2, 6.4 Hz, 1H,
H11), 5.40-5.20 (2H, H2, H3), 5.10-4.95 (2H, H12, H12’), 3.10-2.95 (2H, H1, H4), 2.65-
13 2.00 (7H), 1.35-1.10 (2H). C NMR (50 MHz, CDCl3) δ: 211.8, 208.9, 137.0, 115.4,
86.0, 84.2, 65.6, 59.8, 52.9, 42.0, 33.3, 31.0, 27.7.
Tricarbonyl[2-5-η-tert-butyl-(1-cyclohexa-2,4-
Fe(CO)3 dienylmethylpent-4-enyloxy)diphenylsilane]iron (5.29).
8 OTBDPS To a solution of 140 mg (0.44 mmol) of complex 5.28 in
1 mL of dichloromethane at -78 °C under Ar was added 0.5 mL of DIBALH (1.5 M in toluene). The reaction mixture was stirred for 0.5 h, then warmed to 0 °C, quenched with water at 0 °C, extracted three times with CH2Cl2, dried (MgSO4), and concentrated under
vacuum to give the intermediate alcohol. The alcohol, 6.8 mg of DMAP, 55.8 mg of
imidazole, and one drop of DMF were dissolved in 0.5 mL of dichloromethane at 0 °C. t-
Butyldiphenylsilyl chloride (180 mg, 0.18 mL, 1.2 equiv) was added slowly. The reaction mixture was stirred at rt for 1 h, filtered through Celite, washed with sat. aq. NH4Cl and 140
H2O, dried (MgSO4), and evaporated. Chromatography (5% EA in Hex) gave the title
compound (166 mg, 80% over two steps) as mixture of diastereomers (colorless oil). 1H
NMR (200 MHz, CDCl3), mixture of isomers, δ: 7.75-7.30 (10H, Ph), 5.75 (m, 1H, H11),
5.20-5.00 (2H, H2, H3), 5.00-4.80 (2H, H12, H12’), 3.70-3.50 (m, 1H, H8), 3.10-2.60
13 (2H, H1, H4), 2.25-0.75 (9H), 1.08 (s, 9H, t-Bu). C NMR (50 MHz, CDCl3), major isomer, δ: 212.2, 138.6, 136.1, 134.1, 129.7, 127.6, 114.4, 85.6, 84.2, 71.2, 67.2, 59.9,
47.4, 36.4, 34.4, 31.2, 29.2, 27.1, 19.4.
Tricarbonyl(2-5-η-2-but-3-enyl-2-cyclohexa-2,4-dienyl- Fe(CO) 3 3 2 4 malonic acid dimethyl ester)iron (5.31). 5 1 6 7
MeO CCO Me 2 2 To a stirred solution of NaH (1 mmol, 24 mg) in 0.5 mL
DMF at 0 °C under Ar was added 350 mg of 5.20 in 0.5 mL of DMF. The mixture was stirred for 20 min at 0 °C, and 0.5 mL of 4-bromobutene was added at rt. The reaction mixture was stirred at 40 °C overnight. The title compound was obtained as a yellow oil
(270 mg, 67%) following the same workup procedure as for 5.13 and flash
1 chromatography using 10% EA in Hex. H NMR (200 MHz, CDCl3) δ: 5.73 (ddt, J =
18.0, 10.2, 6.4 Hz, 1H, H10), 5.40-5.20 (2H, H2, H3), 5.10-4.90 (2H, H11, H11’), 3.15-
2.98 (2H, H1, H4), 5.73 (ddt, J = 18.0, 10.2, 6.4 Hz, 1H), 2.86-2.78 (m, 1H), 2.10-1.80
13 (5H), 1.63-1.60 (m, 1H). C NMR (50 MHz, CDCl3) δ 137.4, 115.2, 85.3, 62.5, 59.6,
59.3, 52.2 (2C), 42.5, 33.5, 29.0, 27.1.
Fe(CO)3 Tricarbonyl[2-5-η-tert-butyl-(1-cyclohexa-2,4-
8 OTBDPS dienylmethylbut-3-enyloxy)diphenylsilane]iron (5.33). 141
To a solution of 260 mg (0.94 mmol) of ester 5.32 in 2 mL of ether at -78 °C under Ar was added 1.5 mL of 1.5 M DIBAL in toluene. The reaction mixture was stirred for 0.5 h, and quenched with methanol and water at -78 °C, extracted three times with
CH2Cl2, dried (MgSO4), and concentrated under vacuum to give 115 mg (76%) of the
intermediate aldehyde. The aldehyde was then dissolved in 1.5 mL CH2Cl2 at -78 °C, and
1.5 mL of allylmagnesium bromide (1.0 M in THF) was added to the reaction mixture.
After stirring at -78 °C for 20 min, t-butyldiphenylsilyl chloride (275 mg, 0.27 mL, 2 equiv) was added. The reaction mixture was stirred at rt for 1 h, washed with sat aq sodium carbonate, aq NH4Cl, and H2O, dried (MgSO4), and evaporated. Chromatography
(5% EA in Hex) gave the title compound (129 mg, 30% over two steps) as mixture of
1 diastereomers (colorless oil). H NMR (200 MHz, CDCl3) δ: 7.75-7.30 (10H, Ph), 5.75
(m, 1H, H10), 5.30-5.20 (m, 1H, H2 or H3), 5.10-4.80 (3H, H11, H11’, H3 or H2), 3.72-
3.50 (m, 1H, H8), 3.00-2.60 (2H, H1, H4), 2.26-0.87 (7H), 1.05 (s, 9H, t-Bu).
Tricarbonyl(1-2, 5-6-η-2-cyclohexa-1,5-dienylmethylpent-4- Fe(CO)3 enoic acid ethyl ester)iron (5.35). 8 CO2Et To a stirred solution of LDA (1.1 mmol, 0.55 mL, 2 M in heptane/THF) at -78 °C under Ar was added 306 mg of 5.24 in 1.6 mL of THF. The mixture was stirred for 30 min at -78 °C, and 0.45 mL (5.0 mmol) of allyl iodide was added. Stirring was continued at -78 °C for 3 h, and the reaction mixture was allowed to warm to 0 °C over 2 h, then at rt overnight. The title compound was obtained as mixture of diastereomers (190 mg, 55%) following the same workup procedure as for 5.13 and
1 flash chromatography using 10% EA in Hex. H NMR (200 MHz, CDCl3), mixture of 142
isomers, δ: 5.90-5.63 (m, 1H, H10), 5.10-4.85 (3H, H3, H11, H11’), 4.25-4.08 (2H,
CO2CH2CH3), 3.20-3.02 (2H, H1, H4), 2.80-2.25 (5H), 1.85-1.40 (5H), 1.28 (t, J = 7.2
13 Hz, 3H, CO2CH2CH3 minor), 1.27 (t, J = 7.2 Hz, 3H, CO2CH2CH3 major). C NMR (50
MHz, CDCl3), major isomer, δ: 211.9, 174.5, 134.9, 117.5, 103.6, 86.0, 65.1, 60.7, 59.5,
48.2, 39.7, 36.4, 24.6, 23.7, 14.4.
Tricarbonyl(1-4-η-6-pent-4-enylcyclohexa-2,4-dienecarboxylic Fe(CO)3 acid methyl ester)iron (5.37). 6
CO Me 2 Cation 5.36 (211 mg, 0.5 mmol ) was treated with 1.3 equiv of
Grignard reagent according to the procedure for 5.13 to afford 34 mg (20% yield) of the title complex as a light brown oil after flash chromatography on silica gel. Rf = 0.28
1 (1:19/EA:Hex). H NMR (200 MHz, CDCl3) δ: 5.71 (ddt, J = 18.0, 10.2, 6.4 Hz, 1H,
H10), 5.38-5.28 (2H, H2, H3), 5.03-4.85 (2H, H11, H11’), 3.73 (s, 3H, OCH3), 3.45-3.39
(m, 1H, H1 or H4), 3.15-3.05 (m, 1H, H4 or H1), 2.57 (dd, J = 15.8, 3.8 Hz, 1H), 1.95
(apparent q, J = 6.9 Hz, 2H, H9), 1.58 (dd, J = 15.8, 2.6 Hz, 1H), 1.58-1.10 (4H). 13C
NMR (50 MHz, CDCl3) δ: 211.3, 138.2, 114.9, 85.8, 82.5, 65.5, 60.4, 52.1, 50.8, 44.9,
35.4, 33.8, 25.7.
Tricarbonyl(2-5-η-2-cyclohexa-2,4-dienylhex-5-enoic acid methyl ester)iron (5.39).
Fe(CO) 3 To a stirred solution of LDA (1 mmol, 0.5 mL, 2 M in
heptane/THF) at -78 °C under Ar was added 130 mg of methyl 5- CO2Me hexenoate in 1 mL of THF. The mixture was stirred for 20 min, after which time the complex 5.9 (364 mg, 1 mmol) was added in one portion. Stirring was continued at -78 143
°C for 30 min, and the reaction mixture was allowed to warm to rt. The title compound
was obtained as a 2:1 mixture of diastereomers (223 mg, 65%) following the same
1 workup procedure as for 5.13 and flash chromatography. Rf = 0.31 (1:19/EA:Hex). H
NMR (200 MHz, CDCl3), mixture of epimers, δ: 5.82-5.60 (m, 1H, H10), 5.40-5.26 (2H,
H2, H3), 5.15-4.92 (2H, H11, H11’), 3.69 (s, 3H, OCH3 major), 3.65 (s, 3H, OCH3
13 minor), 3.10-2.83 (2H, H1, H4), 2.40-1.33 (8H). C NMR (50 MHz, CDCl3), major isomer, δ: 211.8, 175.2, 137.6, 115.3, 85.6, 85.1, 62.7, 59.1, 53.4, 51.5, 40.8, 31.8, 30.4,
+ 28.8. HRMS (m/z) for MH (C16H19FeO5): calculated: 347.0582; found: 347.0571.
Tricarbonyl(6-9-η-4-methylspiro[4.5]deca-6,8-diene-1-carboxylic Fe(CO)3 acid methyl ester)iron (5.40).
MeO2C Complex 5.39 (73 mg, 0.21 mmol) dissolved in 8 mL of n-Bu2O was heated for 12 h according to the general procedure to yield, after chromatography using 10% EA in Hex, 44 mg (60% yield, yellow oil) of the title product as a mixture of
1 isomers. H NMR (200 MHz, CDCl3), two major isomers, δ: 5.36-5.14 (2H, H7, H8),
3.71 (s, 3H, OCH3 one isomer), 3.69 (s, 3H, OCH3 another isomer), 3.28-2.47 (3H), 2.20-
1.13 (7H), 1.09 (d, J = 6.8 Hz, 3H, CH3 one isomer), 1.01 (d, J = 6.6 Hz, 3H, CH3
13 another isomer). C NMR (50 MHz, CDCl3), major epimer, δ: 212.1, 86.4, 82.6, 69.2,
63.9, 61.9, 57.8, 51.3, 46.4, 31.0, 30.0, 26.3, 15.7.
Tricarbonyl(2-5-η-tert-butyl-(2-cyclohexa-2,4-dienylhex-5- Fe(CO)3 enyloxy)diphenylsilane)iron (5.41).
OTBDPS To a solution of 134 mg (0.39 mmol) of complex 5.39 in 1 144
mL of dichloromethane at -78 °C under Ar was added 1 mL of 1.5 M DIBALH in toluene. The reaction mixture was stirred for 2 h, then warmed to 0 °C over 2 h, quenched with water at 0 °C, extracted three times with CH2Cl2, dried (MgSO4), and concentrated under vacuum to give the intermediate alcohol. Rf = 0.32 (1:4/EA:Hex). The alcohol, 6.8 mg of DMAP, 55.8 mg of imidazole, and one drop of DMF were dissolved in 0.5 mL of dichloromethane at 0 °C. t-Butyldiphenylsilyl chloride (135 mg, 1.2 equiv) was added
slowly. The reaction mixture was stirred at rt for 1 h, filtered through Celite, washed with
sat. aq. NH4Cl and H2O, dried (MgSO4), and evaporated. Chromatography gave the title
compound (150 mg, 75% over two steps) as a 2:1 mixture of diastereomers (colorless
1 oil). H NMR (300 MHz, CDCl3), mixture of isomers, δ: 7.75-7.66 (4H, Ph-m), 7.50-7.30
(6H, Ph-o and p), 5.82-5.67 (m, 1H, H10), 5.40-5.16 (2H, H2, H3), 5.05-4.90 (2H, H11,
H11’), 3.50 (2H, H12, H12’), 3.00 (2H, H1, H4), 2.45 (m, 1H), 2.10-1.80 (3H), 1.45-1.20
13 (4H), 1.07 (s, 9H, t-Bu). C NMR (75 MHz, CDCl3), major isomer, δ: 212.5, 139.0,
135.8, 133.9, 129.8, 127.8, 114.7, 85.6, 85.0, 65.2, 64.7, 46.8, 39.8, 32.1, 28.8, 27.7, 27.5,
+ 27.1, 19.4. HRMS (m/z) for (M-3CO) (C28H36FeOSi): calculated: 472.1885; found:
472.1868.
Tricarbonyl[6-9-η-tert-butyl-(4-methylspiro[4.5]deca-6,8-dien-1- ylmethoxy)diphenylsilane]iron (5.43).
Fe(CO) Fe(CO) Fe(CO)3 Fe(CO)3 3 3 Complex 5.41 (70 mg) dissolved 6 4 5 3 in 5 mL of n-Bu2O was heated for 12 h ab1 2 c d according to the general procedure to OTBDPS OTBDPS OTBDPS OTBDPS yield after preparative TLC (1:9/EA:Hex), the title compound (56 mg, 80% yield) as a 145
colorless oil, which contained four isomers (5.43a: 5.43b: 5.43c: 5.43d/4.5:4:1:1). 1H
NMR (600 MHz, CDCl3) δ, characteristic peaks 5.43a: 3.70 (dd, J = 10.2, 3.6 Hz, 1H,
H12), 3.32 (dd, J = 10.2, 7.8 Hz, 1H, H12’), 3.00 (m, 1H, H9), 2.66 (dd, J = 6.6, 1.2 Hz,
1H, H6), 1.04 (s, 9H, t-Bu), 0.93 (d, J = 7.2 Hz, 3H, CH3). 5.43b: 3.65 (dd, J = 10.2, 6.0
Hz, 1H, H12), 3.54 (dd, J = 10.2, 7.2 Hz, 1H, H12’), 3.08 (m, 1H, H9), 2.64 (m, 1H, H6),
1.05 (s, 9H, t-Bu), 0.83 (d, J = 7.2 Hz, 3H, CH3). tert-Butyl-(4-methylspiro[4.5]dec-1-ylmethoxy)diphenylsilane (5.44).
Complexes 5.43 (56 mg, 0.1 mmol) were treated with 30 mg of
trimethylamine-N-oxide in 1 mL of benzene. The reaction mixture was
OTBDPS stirred at 60 °C for 2 h, filtered through Celite, evaporated, and dissolved in 1 mL of methanol containing 5 mg of 10% Pd on activated carbon under a balloon of hydrogen gas. After stirring at rt overnight, the reaction mixture was filtered and concentrated to give 42 mg (>95% yield) of the title compound as a 4.5:1 mixture of
1 diastereomers (colorless oil). H NMR (200 MHz, CDCl3) δ: 7.75-7.30 (10H, Ph), 3.74
(dd, J = 9.8, 5.2 Hz, 1H, H12), 3.48 (dd, J = 10.2, 8.8 Hz, 1H, H12’), 2.10-1.00 (16H),
13 1.07 (s, 9H, t-Bu), 0.82 (d, J = 6.8 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 135.7,
134.2, 129.5, 127.6, 65.1, 46.3, 45.8, 40.0, 30.6, 30.5, 27.0, 26.8, 26.6, 25.4, 23.2, 22.9,
+ 19.3, 15.1. HRMS (m/z) for (M-t-Bu) (C24H31OSi): calculated: 363.2144; found:
363.2126. 146
5.4 Literature Cited
(1) Fraga, B. M. “Natural Sesquiterpenoids.” Nat. Prod. Rep. 1999, 16, 711-730.
(2) Fraga, B. M. “Natural Sesquiterpenoids.” Nat. Prod. Rep. 2000, 17, 483-504.
(3) Clive, D. L. J.; Huang, X. J. “Stereocontrolled Formation of Spiro Enones by Radical Cyclization of Bromo Acetals.” Tetrahedron 2001, 57, 3845-3858.
(4) Kuroda, C.; Koshio, H. “New Cyclization Reaction of 2- (Trimethylsilylmethyl)pentadienal. Synthesis of Spiro[4.5]decane Ring System.” Chem. Lett. 2000, 962-963.
(5) Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.; Hirono, Y. “Nazarov Cyclization of 4-Cycloalkylidene-5-(Trimethylsilyl)pent-1-en-3-one Derivatives. Synthesis of Spiro[4.5]Decane, Spiro[4.4]nonane, and Their Derivatives.” Tetrahedron 2000, 56, 6441-6455.
(6) Pohmakotr, M.; Bunlaksananusorn, T.; Tuchinda, P. “A General Strategy to Spiro[4.n]alk-2-ene-1,6-Diones and Spiro[5.n]alk-2-ene-1,7-diones via Intramolecular Acylation of α-Sulfinyl Carbanions.” Tetrahedron Lett. 2000, 41, 377-380.
(7) Srikrishna, A.; Kumar, P. P. “Claisen Rearrangement Based Methodology for the Spiroannulation of a Cyclopentane Ring. Formal Total Synthesis of (±)-Acorone and Isoacorones.” Tetrahedron 2000, 56, 8189-8195.
(8) Robertson, J.; Lam, H. W.; Abazi, S.; Roseblade, S.; Lush, R. K. “Radical Cascade Processes Leading to Fused- and Spiro-Bicyclic Ring Systems.” Tetrahedron 2000, 56, 8959-8965.
(9) Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.; Matsui, A.; Funakoshi, K.; Sakai, K.; Suemune, H. “Application of Rh-Catalyzed Cyclization for the Construction of Three Consecutive Chiral Carbons in 4,9- Dimethylspiro[4.4]nonane-2,7-dione.” Tetrahedron Lett. 2000, 41, 7879-7883.
(10) Biju, P. J.; Rao, G. “A New Strategy for the Synthesis of Spiro[4.5]Decanes: A Formal Total Synthesis of Acorone.” Tetrahedron Lett. 1999, 40, 2405-2406.
(11) Sattelkau, T.; Eilbracht, P. “Diastereospecific Synthesis of Spiro[4.5]decan-2-ones as Vetivane Precursor via Rhodium Catalysed Claisen Rearrangement/Hydroacylation.” Tetrahedron Lett. 1998, 39, 1905-1908.
(12) Aburel, P. S.; Undheim, K. “Synthesis of Spirosystems by Rhodium(II)-Carbenoid C-H Insertion Reactions.” Tetrahedron Lett. 1998, 39, 3813-3814. 147
(13) Molander, G. A.; Alonso-Alija, C. “Opening of Cyclopropyl Ketones with SmI2. Synthesis of Spirocyclic and Bicyclic Ketones by Intramolecular Trapping of an Electrophile.” Tetrahedron 1997, 53, 8067-8084.
(14) Dorange, I. B. "Stereocontrolled Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling." Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 2001.
(15) Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 13. Stereoselectivity of Complexation of Cyclohexadiene Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1755-1762.
(16) Grieco, P. A.; Larsen, S. D. “An Intramolecular Immonium Ion Variation of the Diels-Alder Reaction: Synthesis of (±)-Dihydrocannivonine.” J. Org. Chem. 1986, 51, 3553-3555.
(17) Pearson, A. J.; Zettler, M. W. “Control of Absolute Stereochemistry During Ene- Type Coupling between Diene-Fe(CO)3 Groups and Alkenes.” J. Chem. Soc., Chem. Commun. 1987, 1243-1245.
(18) Yeh, M. P.; Sheu, B.-A.; Fu, H.-W.; Tau, S.-I.; Chuang, L.-W. “Construction of Bridged and Fused Bicyclic Skeletons via Intramolecular Addition of Nucleophiles to 4 (η -Diene)Fe(CO)3 Complexes Bearing Functionalized Side Chains.” J. Am. Chem. Soc. 1993, 115, 5941-5952.
(19) Pearson, A. J.; Chandler, M. “Organoiron Complexes in Organic Synthesis. Part 24. Studies in the Synthesis and Reactivity of 6-Exo-substituted Cyclohexadienylium(tricarbonyl)iron Salts.” J. Chem. Soc., Perkin Trans. I 1982, 2641- 2146.
(20) Pearson, A. J.; Kole, S. L.; Yoon, J. “Stereocontrolled Double Functionalization of (Cyclohexadiene)- and (Cycloheptadiene)iron Complexes via Oxidative Cyclization Techniques.” Organometallics 1986, 5, 2075-2081.
(21) Rodríguez, J.; Brun, P.; Waegell, B. “Isomerization of Functionalized 1,5-Dienes with Pentacarbonyliron.” J. Organomet. Chem. 1989, 359, 343-369.
(22) Birch, A. J.; Williamson, D. H. “Organometallic Complexes in Synthesis. V. Tricarbonyliron Derivatives of Cyclohexadienecarboxylic Acids.” J. Chem. Soc., Perkin Trans. I 1973, 1892-1900.
(23) Rodríguez, A. D.; González, E.; Huang, S. D. “Unusual Terpenes with Novel Carbon Skeletons from the West Indian Sea Whip Pseudopterogorgia Elisabethae (Octocorallia).” J. Org. Chem. 1998, 63, 7083-7091.
(24) Corey, E. J.; Girotra, N. N.; Mathew, C. T. “Total Synthesis of dl-Cedrene and dl- Cedrol.” J. Am. Chem. Soc. 1969, 91, 1557-1559. 148
CHAPTER SIX
Diastereoselective Spirocyclization: Studies toward Kinetic Dynamic
Resolution during Intramolecular Iron-Mediated Diene/Olefin
Cyclocoupling Reactions
149
6.1 Diastereoselective Cyclization
All the reactions shown in Chapters 2-5 were investigated using racemic starting
materials, hence the products obtained were also racemic. As discussed in Scheme 1.10,
Chapter 1, even if enantiomerically pure material was employed, the reaction still gave
racemic products due to racemization of starting material before cyclization under
thermal cyclization conditions. Enantioselective synthesis using this methodology seems
to be impractical.
(OC)3Fe
6.1 R 6.2 R N N R Ph O OH (OC)3Fe Ph O (OC)3Fe HN 6.3a 6.4a O Ph + 142 oC 13 Fe(CO)3 12 when R is not 11 H, no or slow (OC) Fe OH (OC)3Fe 3 3 10 R cyclization 4 2 9 O 7 R 5 1 N 6 8 Ph N ent-6.1 O O Ph 6.3b 6.4b
Scheme 6.1 Proposed Diastereoselective Cyclization
On the other hand, the fact that the two stereoisomers of amide 6.3 are interconvertible during cyclization meets the requirement for kinetic dynamic resolution.
When R = H, 6.3a and 6.3b are enantiomers, they behave identically during cyclization.
If another chiral element is introduced in amides 6.3 at C9 (R ≠ H), 6.3a and 6.4b then 150
become diastereomers and their cyclization rates should be different. Under ideal
conditions, if we can induce one isomer to cyclize, and not the other, we would obtain a
single product utilizing the double cyclization strategy under thermal cyclization conditions where 6.3a and 6.3b can be interconverted. The selectivity of cyclization between 6.3a and 6.3b would rely on steric control of the R group and the stability of the cyclization products 6.4.
O O O O 2C C C C 2 1 R R R 1 11 R 11 Fe Fe 6.4a 6.4b 10 H H 10 H 9 R R N N H O O Ph Ph 6.5a 6.5b
6.3a 6.3b
Figure 6.1 Intermediates Comparison during Diastereoselective Cyclization
It is anticipated that cyclization of 6.3a to form the cis product 6.4a would be favored both kinetically and thermodynamically (Figure 6.1). If both isomers of 6.3 undergo cyclization, 6.3a would cyclize through intermediate 6.5a and 6.3b through 6.5b according to the ene-cyclization mechanism (Scheme 1.9, Chapter 1). Comparison of
6.5a and 6.5b reveals their relative energies. A molecular modeling study of 6.5b showed that R1, C11, C10, and R are almost coplanar and there is strong steric repulsion between
the R1 and R group, if neither the R1 nor the R group is hydrogen. Such a steric issue in
6.5a is not present, since R and R1 are far away from each other. Under certain conditions 151
where steric repulsion between R1 and R is sufficient to prevent the formation of intermediate 6.5b, formation of 6.4b would be prohibited and 6.4a might be produced exclusively. Moreover, by superimposing this steric control on a tandem double cyclization, described in Chapter 2, post-cyclization diene rearrangement is prevented and overall absolute stereocontrol should be possible.
We turned our attention to testing this idea. The chiral (racemic) dienamines 6.8 were prepared by carbon nucleophile addition to imine or oxime 6.7,1,2 which were
formed by reacting the corresponding amines with sorbaldehyde 6.6.2,3 Coupling amines
6.8a-c with acid 6.1 gave 6.9a-c, each as a 1:1 mixture of a pair of inseparable
diastereomers.
1 2 R NH2, ether R M, THF
MgSO4 M = MgBr or Li 1 O NR R2 NHR1
6.6 6.7 6.8 a R1 = Ph a R1 = Ph, R1 = Me b R1 = OBn b R1 = Ph, R2 = n-Bu 1 2 c R = OBn, R = Bn
Scheme 6.2 Preparation of Dienamines 6.8
2 Refluxing 6.9a (R = Me) in n-Bu2O for 12 h provided 6.10 and 6.11 in 2:1 ratio
in 48% yield after tandem double cyclization. Extension of the reaction time did not
improve the yield or change the ratio of products. The cis product 6.10 was shown to be
the major cyclization product (determined by chemical shift and the coupling constant of
H3). When a bulkier butyl group was introduced into 6.9b, the cyclization proceeded in 152
Fe(CO) 3 (OC)3Fe 2 i) (COCl)2, CH2Cl2 R n-Bu2O, CO OH Reflux, 12 h ii) 6.8, pyridine, N 1 benzene, reflux R O O Racemic 50-70% 1:1 mixture of diastereomers 6.1 6.9
(OC)3Fe 1 2 (OC)3Fe a R = Ph, R = Me, 48% 1 2 R2 b R = Ph, R = Bu, 46% R2 1 2 N c R = OBn, R = Bn, 33% 1 N O R O R1 6.102 : 1 6.11
Scheme 6.3 Diastereoselective Cyclization
similar yield and the same selectivity. Complex 6.9c was prepared from
benzyloxylamine. Its cyclization would give N-benzyloxylactams 6.10c/6.11c, which are
expected to be opened upon hydride reduction or nucleophile addition.4 Unfortunately, cyclization of 6.9c gave 6.10c and 6.11c in only 33% yield with partial demetallation of
the iron complex and debenzyloxylation of 6.10c and 6.11c, as evidenced by their mass
spectra.
A stepwise diastereoselective double cyclization was also investigated. Mono-N-
benzylation5 of valine methyl ester hydrochloride, followed by coupling of the resulting
amine 6.13 to the mixed anhydride prepared from acid 6.1, produced 6.14 as a 1:1
mixture of isomers. Partial reduction of the ester by DIBALH6 gave aldehyde 6.15 in
73% yield and subsequent olefination of the aldehyde gave complex 6.16 with a pendant enoate as a 1:1 mixture of diastereomers. Refluxing 6.16 in n-Bu2O for 12 h produced a 153
7:3:2:2 mixture of four spirolactams (two pairs of epimers) in 58% yield for two steps
from aldehyde 6.15. Iterative partial reduction of the ester and olefination provided the
corresponding complex 6.18 with a pendant enoate. Cyclization of 6.18 in 6 h generated a pair of double cyclization products 6.19 and 6.20 in 2.5:1 ratio, the trans product 6.19
being the major one. Thus, the selectivity was slightly improved by using a bulky
isopropyl group at C9 and stepwise double cyclization was also shown to be possible.
Fe(CO)3 (OC) Fe OSO2Me 3 MeO2C LiOH 2H2O, DMF O 9 - + Cl H3NCO2Me BnBr, 4A MS, rt BnHN CO Me Et N, CH Cl N 2 3 2 2 Bn 90% 62% O 6.12 6.13 6.14
MeO C O 2 (OC)3Fe (OC)3Fe DIBALH Ph3P CO2Me n-Bu2O, CO, Reflux
Et2O, 73% N Toluene, 110, 2 h N 58%, 2 steps Bn Bn O O 6.15 6.16
MeO2C Fe(CO)3 CO Me (OC)3Fe n-Bu O, CO 2 + epimers 2 i) DIBALH, Et2O Reflux, 6 h + epimers ii) Ph3P CO2Me 58%, 3 steps N Toluene, 110, 2 h N O O Bn Bn 4 isomers 4 isomers 2.5:2.5:1:1 6.18 6.17
CO2Me
(OC)3Fe (OC)3Fe 2.5 : 1
MeO2C N N O O Bn Bn 6.19 6.20
Scheme 6.4 Stepwise Diastereoselective Double Cyclization 154
The above diastereoselective cyclizations only gave modest selectivity and yield,
and the diastereomeric cyclization substrates 6.9 and 6.16 could not be separated. Kinetic
dynamic resolution was not unambiguously observed. As discussed earlier in this chapter
when analyzing intermediates 6.5a and 6.5b (Figure 1), to prevent the cis product
formation, R1 and R need to have strong steric repulsion. In 6.9 and 6.16, R1 = H, which exhibits less steric interaction with R group than that when R1 is not H. For R1 to be a substituent other than hydrogen, the C9-C10 double bond must either be cis (R2 = H, disubstituted) or trisubstituted (R2 ≠ H).
O PMP O O OH OAc O O H Bn H OP H OP Bn N O Bn N H O N O PMB 18-deoxycytochalasin PMB 6.22 6.23 6.21
O CO2Et Fe(CO) CO2Et Fe(CO)3 OEt 11 3 10 142 oC H 4 H H Bn 5 Bn Bn 3 6 N 1 O N O N O 2 PMB PMB PMB 6.24 6.25 6.26
EtO2C EtO C Fe(CO) (OC)3Fe 2 142 oC 3 Bn Bn HO L-PLA N NH PMB O PMB O 6.27 Rac-6.1 6.28
Scheme 6.5 Retrosynthetic Analysis of a Potential Pathway for 18-Deoxycytochalasin H
155
18-Deoxycytochalasin H (6.21), a HIV-1 protease inhibitor,7 which contains a spiro-γ-lactam structure, inspired us to use a trisubstituted pendant double bond during
the Fe(CO)3–mediated diastereoselective cyclization and directed the study toward a potential synthetic pathway for 6.21, or at least in part.
Retrosynthetic analysis showed that 6.21 might be reached from spirolactam 6.25, which can be prepared along with its epimer 6.26 (which can be rearranged to give 6.25) using the Fe(CO)3 mediated ene-cyclization. Formation of 6.25 requires the cyclization of amide 6.27, which should be accessible from racemic acid complex 6.1 and trisubstituted allyl amine 6.28. At present, our attention is mainly focused on the diastereoselectivity of cyclizing amides 6.27 (mixture of two diastereomers). Since in 6.27, a trisubstituted pendant double bond is present, kinetic dynamic resolution might be realized according to the analysis shown in Figure 6.1 and the accompanying discussion earlier in this chapter.
Boc-protected N-p-methoxybenzylaminoaldehyde 6.33 was prepared in four steps from L-phenylalanine methyl ester hydrochloride according to the literature procedure.8
Horner-Wadsworth-Emmons olefination of 6.33 with phosphonate 6.34 under conditions
9 (a) (CH3CN, LiCl, DBU) gave the E enoate 6.35 exclusively in 70% yield. When n-BuLi
(conditions b) was used as the base, a 1:4 mixture of Z (6.36) to E (6.35) olefins were
obtained.10 Deprotection of amine using TFA at 0 °C in 10 min liberated the secondary amine 6.37 in almost quantitative yield. Unfortunately, similar treatment of the cis enoate afforded lactam 6.38 without a detectable amount of 6.28.
156
Cl Bn O O Bn O LiAlH4, THF Bn -Cl+H N CO Me N CO2Me 3 2 > 95% H 98% PMBHN CO2Me O 6.29 6.31 6.30
Bn Bn Boc2O, 1,4-dioxane i) (COCl)2, DMSO Boc O a: 6.34, DBU, CH3CN, 76% Boc OH N 98% N ii) Et3N PMB or b: 6.34, n-BuLi, THF PMB - 78 oC, 74% 6.32 6.33
CO2Et Bn Bn CO2Et O Boc a: E:Z / 100:1 P Boc EtO N CO2Et N b: E:Z / 4:1 OEt PMB PMB 6.36 6.35 6.34 TFA, CH Cl > 95% 2 2 0 oC, 10 min
Bn Bn CO2Et + PMBHN CO Et Bn N O 2 PMBHN PMB 6.37 6.38 >95% 6.28 0%
Scheme 6.6 Preparation of Amine
The chiral trisubstituted amine 6.37 was then coupled to the racemic acid 6.1 to produce a pair of diastereomeric amides, 6.39a and 6.39b in 78% yield (40% conversion). The two diastereomers were separated. Complex 6.39a was also prepared from the enantiomerically pure acid and amine, which led to unambiguous structural identification of 6.39a and 6.39b. Interestingly, isomer 6.39b showed the presence of amide rotamers in its 1H NMR spectrum, while 6.39a did not. Cyclization of 6.39a gave a
1:1 mixture of epimeric spirolactams 6.40 in 75% yield (4 h, 100% conversion).
Isomerization of 6.39a to form its diastereomer 6.39b followed by cyclization to produce lactam 6.41 was not observed. Direct cyclization of 6.39b should give the same cis products 6.41. Gratifyingly, this did not happen either. Instead, upon heating, 6.39b 157 rearranged to give its diastereomer 6.39a, which then cyclized to give the same products
6.40 in 65% yield (8 h, 40% conversion). Cyclization of a 1:1 mixture of 6.39a and 6.39b gave the same pair of epimers 6.40 in 63% yield. The much slower cyclization of 6.39b than 6.39a is consistent with the proposition that complex 6.39b has to undergo rearrangement, a slower process than the spirocyclization, to form 6.39a first. The epimeric lactams were demetallated, followed by hydrogenation to give a single product
6.42.
CO2Et Fe(CO) Bn 3 CO2Et 100% conversion N 75% yield Bn PMB 4 hours (OC)3Fe O H Fe(CO)3 H 6.39a NH EtO2C EtO2C PMB (COCl)2 H H n-Bu2O 6.37 Bn Bn pyridine CO 142 oC N N 78% yield, 47% 8 hours O O (OC) Fe CO2Et PMB PMB 3 conversion 65% yield 6.40a Bn 60% conversion 6.40b HO
O N PMB Fe(CO)3 Racemic O i) Me3NO 50% ii) H /Pd/C 6.1 6.39b 2
H OEt H CO Et H CO2Et Fe(CO) 2 Fe(CO)3 3 H O H H Bn Bn Bn N 6.42 N O N O O PMB PMB PMB 6.41a 6.41b
Scheme 6.7 Kinetic Dynamic Resolution
The difference in reactivity between 6.39a and 6.39b can be explained by molecular mechanics strain energy calculations using PC Spartan. According to the 158
mechanism, 6.39a and 6.39b have to be transformed to the intermediates 6.43a and 6.43b respectively. Intermediate 6.43a is lower in energy than 6.43b by 1.8 kcal/mol, which is a significant energy difference. Formation of 6.43b from 6.39b is therefore very slow compared with its isomerization to 6.39a, which prevents the formation of the cis product. At the same time, conversion of 6.39b to 6.39a occurs easily and 6.39a then cyclizes to form the trans product through a lower energy pathway.
trans product E6.43a = 147.3 Kcal/mol E6.43b= 149.1 Kcal/mol cis product O O H CO Et H Fe(CO)3 O O 2 Fe(CO) 11 CC 3 EtO2C 10 EtO2C C C CO Et H 2 H Me Me Bn 4 5 Fe Fe Bn 3 6 N N 1 O 2 O H PMB 6.43a H H Bn 6.43b PMB Bn N N H 6.41a 6.40b O O PMB PMB
CO Et CO2Et 2 Fe(CO) Bn 3 Bn
N N PMB PMB Fe(CO)3 O O 6.39a 6.39b
Figure 6.2 Energy Calculation of Intermediates 6.43
The chirality at C9 in 6.39, originating from L-phenylalanine, dictates the stereochemical outcome of the cyclization process as envisioned in Scheme 6.8. When the diastereomeric mixture of 6.39a and 6.39b is subjected to cyclization, 6.39b does not react by itself, but rearranges to give 6.39a. Dissociation of a CO ligand from 6.39a followed by coordination of the pendant trisubstituted double bond to the 16e iron complex gives intermediate 6.43a. Cyclization gives the spirocyclic ferrocycle 6.44. The 159
configuration of C3 determines the chirality at C4 and C5. The configuration of C11 is
determined by the combination of C3 chirality and geometry of the pendant double bond.
Hydrogen abstraction from 6.44 forms 6.45, reductive elimination followed by
coordination of CO ligand produces spirolactam 6.40b, which epimerizes to form 6.40a
(post-cyclization rearrangement).
O O 6.39b O O EtO2C Fe 11 H 10 EtO2C Fe 11 6.43a H H 10 Bn 4 5 3 6 H 6.39a Bn 4 5 N 1 2 O 3 6 PMB N 2 1 O PMB 6.44 6.46
H Fe(CO) H Fe(CO) (OC)3Fe 11 2 11 3 H EtO2C 10 EtO2C 10 EtO2C H H H Bn 4 5 Bn 4 5 Bn 3 6 3 6 N N N 2 1 O 2 1 O O PMB PMB PMB 6.46 6.40b 6.40a
Scheme 6.8
6.2 Conclusions
In summary, cyclization of 6.39 shows that spirocyclic molecules can be prepared from racemic acid complex 6.1 and chiral trisubstituted allyl amine 6.37 with complete diastereoselectivity (without considering the epimerization of the product). As the two epimeric lactams (6.40) can be equilibrated under thermal cyclization conditions, the 160
reaction provides a potential enantioselective methodology toward spriocyclic molecules,
especially spirolactams. Although the proposed synthon 6.25 was not prepared, successful formation of its C11 epimer shows promise of a potential enantioselective synthesis toward 18-deoxycytochalasin H, based on Fe(CO)3-mediated ene cyclization, provided a linear synthetic pathway for preparing amides 6.27 or their equivalent can be achieved as proposed in Scheme 6.9.
Fe(CO)3 O (OC)3Fe MeO C OSO2Me 2 (OC)3Fe Bn Bn O 9 Bn DIBALH N PMBHN CO Me Et3N, CH2Cl2 Et O N 2 Bn 2 Bn O O 6.47 6.48 6.49
CO2Et O O PCOEt (OC)3Fe F3C O 2 Bn n-Bu2O, CO, Reflux F3C 6.25 + 6.26 N Bn O 6.50
Scheme 6.9 Proposed Synthesis of Synthon 6.25 toward 18-Deoxycytochalasin H
161
6.3 Experimental Section.
General experimental and spectroscopic methods, and general procedures for the
thermally induced cyclization are as described in Chapter 2.
General procedure for the preparation of amides. The carboxylic acid 6.1 was
dissolved in freshly distilled CH2Cl2 under argon in a flame dried single neck round bottom flask. Two equivalents of freshly distilled oxalyl chloride were added via a syringe at rt, followed by 1.1 equiv of anhydrous pyridine. The reaction mixture was stirred at rt for 30 min under argon (reaction was monitored by IR). The solvent was then evaporated under reduced pressure. The resulting viscous oil was kept under high vacuum (0.5 mm Hg) for 10 min., then dissolved in freshly distilled benzene. Anhydrous pyridine (2 equiv) was added via a syringe, followed by 2 equiv of the appropriate amine.
The reaction mixture was refluxed under argon for 24 h. The product mixture was diluted with diethyl ether, washed with 2N aq HCl and water, dried over MgSO4, and concentrated under vacuum. Flash chromatography on silica gel or preparative TLC separation afforded the desired amide, usually as a viscous oily 1:1 mixture of diastereomers. Deviations from this procedure are noted in the experimental data for the specific compound.
162
Arbitrary numbering system used for NMR assignments.
13 11 CO2Et 12 3 Fe(CO)3 11 Bn 10 (OC)3Fe 3 2 2 4 10 R 9 4 2 9 8 7 5 N 1 7 6 5 1 N 1 PMB 6 8 R O O
8 (OC)3Fe H 9 Fe(CO)3 7 9 3a EtO2C 11 10 8 10 H 5a 3 2 6 4 R 4 5 Bn 3 5 7 3 N 2 6 R 1 2 N 11 O R1 1 O PMB
163
N-(1-Methylhexa-2,4-dienyl)-N-phenylamine (6.8a)
Ph N H To 1.09 mL (10 mmol) of aniline and 1.01 mL (10 mmol) of benzaldehyde in 20 mL of Et2O were added 2 g of sodium sulfate and 4 g of 4
Å molecular sieves. After stirring overnight, the reaction mixture was filtered and concentrated under vacuum to produce 1.7 g of imine 6.7a (quantitative). This compound
(520 mg, 3 mmol) was dissolved in 12 mL of dry THF, and cooled to -42 °C. MeLi (6 mL, 1.0 M in Et2O, 2 equiv) was then added dropwise to the reaction mixture, which was
then stirred at the same temperature for 3 h, quenched with 0.5 mL of water, warmed to
rt, dried (MgSO4), and evaporated. Chromatography on silica gel gave 410 mg (73%
1 yield) of the title compound as a yellow oil. Rf = 0.44 (1:19/EA:Hex). H NMR (200
MHz, CDCl3) δ: 7.25-6.50 (5H, Ph), 6.40-5.95 (2H), 5.80-5.50 (2H), 4.00 (m, 1H, H1),
13 3.64 (m, 1H, NH), 1.78 (d, J = 6.6 Hz, 3H, CH3), 1.35 (d, J = 6.6 Hz, 3H, CH3). C
NMR (50 MHz, CDCl3) δ: 147.5, 134.1, 131.1, 129.8, 129.3, 129.0, 117.3, 113.4, 50.4,
22.1, 18.2.
Bu N-(1-Butylhexa-2,4-dienyl)-N-phenylamine (6.8b) Ph N H Imine 6.7a (520 mg, 3 mmol) of was dissolved in 12 mL of dry THF, cooled to -42 °C, and two equiv of n-BuLi (2.4 mL, 2.5 M in hexane) was then added dropwise. The reaction mixture was then stirred at the same temperature for 3 h, quenched with 0.5 mL of water, warmed to rt, dried (MgSO4), and evaporated.
Chromatography on silica gel gave 515 mg (75% yield) of the title compound as a yellow
1 oil. Rf = 0.47 (1:19/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.25-6.60 (5H, Ph), 6.40-
5.95 (2H), 5.80-5.60 (m, 1H), 5.50 (dd, J = 15.0, 6.6 Hz, 1H), 3.85 (m, 1H, H1), 3.65 (m,
164
1H, NH), 1.77 (d, J = 6.6 Hz, 3H, CH3), 1.70-1.30 (6H), 0.95 (t, J = 6.9 Hz, 3H, CH3).
13 C NMR (50 MHz, CDCl3) δ: 147.8, 133.2, 131.2, 130.6, 129.2, 128.8, 117.1, 113.3,
55.3, 36.1, 28.3, 22.8, 18.2, 14.2.
O-Benzyl-N-(1-benzylhexa-2,4-dienyl)hydroxylamine (6.8c)
Bn To 960 mg (10 mmol) of sorbaldehyde and 1.60 g (10 BnO N mmol) of O-benzylhydroxylamine hydrochloride in 10 mL of H
pyridine were added 3 g of dry K2CO3 and 3 g of 4 Å molecular sieves. After stirring overnight, the reaction mixture was filtered through MgSO4 (without washing), and concentrated under vacuum to produce 1.76 g (70% yield) of oxime 6.7b. This compound
(400 mg, 3 mmol) was dissolved in 5 mL of dry toluene, cooled to -78 °C, and three equivalents of BF3⋅Et2O (0.76 mL, 6 mmol) was then added slowly. The reaction mixture was then stirred at -78 °C for 15 min, after which time three equiv of BnMgCl (0.6 mL,
1M in THF) were added, and the reaction mixture was stirred at -78 °C for 2.5 h, quenched with 0.5 mL of water, warmed to rt, dried (MgSO4), and evaporated.
Chromatography on silica gel gave 400 mg (70% yield) of the title compound as a
1 viscous yellow oil. Rf = 0.28 (1:9/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.40-7.20
(5H, Ph), 6.30-5.95 (2H), 5.80-5.50 (3H), 4.76 (s, 2H, OCH2), 3.82-3.70 (m, 1H, H1),
2.96 (dd, J = 13.7, 7.0 Hz, 1H, benzylic H), 2.82 (dd, J = 13.7, 6.4 Hz, 1H, benzylic H’),
13 1.79 (dd, J = 7.2, 2.8 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 138.3, 137.9, 133.0,
131.2, 130.3, 129.5, 128.6, 128.5, 128.4, 127.9, 126.4, 76.9, 64.5, 39.2, 18.3. HRMS
+ (m/z) for MH (C20H24NO): calc: 294.1858; found: 294.1859.
165
Tricarbonyl[1-4-η-cyclohexa-1,3-dienecarboxylic acid (1-
methylhexa-2,4-dienyl)phenylamide]iron (6.9a).
(OC)3Fe According to the general procedure, acid 6.1 (60 mg, N Ph O 0.23 mmol) in 1 mL of CH2Cl2 was treated with 0.02 mL of pyridine, followed by 0.1 mL of (COCl)2, then 140 mg of 1-methylhexa-2,4- dienyl(phenyl)amine, 0.04 mL of pyridine, and 2 mL of benzene to afford 35 mg (65% yield, 55% conversion) of the title compound as a light brown oil (1:1 mixture of two
1 diastereomers) along with 27 mg of starting material 6.1. Rf = 0.60 (1:4/EA:Hex). H
NMR (200 MHz, CDCl3), mixture of diastereomers, δ: 7.50-7.00 (5H, Ph), 6.10-4.88
(7H, H10, H11, H12, H13, H2, H3, H9), 3.25-3.10 (m, 1H, H4), 2.10-1.10 (10H).
Tricarbonyl[1-4-η-cyclohexa-1,3-dienecarboxylic acid (1-
butylhexa-2,4-dienyl)phenylamide]iron (6.9b). (OC)3Fe B
N According to the general procedure, acid 6.1 (60 mg, 0.23 P O mmol) in 1 mL of CH2Cl2 was treated with 0.02 mL of pyridine, followed by 0.1 mL of (COCl)2, then 140 mg of 1-butylhexa-2,4-dienyl(phenyl)amine,
0.04 mL of pyridine, and 2 mL of benzene to afford 38 mg (70% yield, 50% conversion)
of the title compound as viscous yellow oil (1:1 mixture of two diastereomers) along with
1 30 mg of starting material 6.1. Rf = 0.65 (1:4/EA:Hex). H NMR (200 MHz, CDCl3), mixture of diastereomers, δ: 7.50-7.00 (5H, Ph), 6.10-4.88 (7H, H10, H11, H12, H13,
H2, H3, H9), 3.25-3.10 (m, 1 H, H4), 2.10-1.20 (13H), 0.98-0.80 (3H, CH3).
166
Tricarbonyl[1-4-η-cyclohexa-1,3-dienecarboxylic acid (1-benzylhexa-2,4-
dienyl)benzyloxyamide)iron (6.9c).
According to the general procedure for preparing
amides in Chapter 2, acid 6.1 (104 mg, 0.4 mmol) and 40
(OC)3Fe Bn mg of 4 Å molecular sieves in 2 mL of CH2Cl2 was treated N OBn with 0.07 mL of Et3N and 0.05 mL (1.5 equiv) of O CH3SO2Cl, followed by 1.6 equiv (200 mg) of amine 6.8c and 0.12 mL of Et3N to afford 80 mg (55% yield, 65% conversion) of the title compound as a viscous yellow oil (1:1 mixture of diastereomers) along with 35 mg of the acid 6.1.
1 Rf = 0.23 (1:9/EA:Hex). H NMR (200 MHz, CDCl3), mixture of diastereomers, δ: 7.50-
7.10 (5H, Ph), 6.25-5.50 (5H, H10, H11, H12, H13, H2), 5.25-5.16 (t, J = 5.3 Hz, 1H,
H3), 5.10-4.60 (3H, Obenzyl H, H9), 3.36-3.16 (2H, H4, benzyl H), 2.99 (dd, J = 13.7,
7.1 Hz, 1 H, benzyl H’), 2.10-1.55 (6H), 1.50-1.00 (m, 1H). HRMS (m/z) for MH+
(C30H30FeNO5): calc: 540.1473; found: 540.1453.
(OC)3Fe Tricarbonyl(6-9-η-5-ethyl-3-methyl-2-phenyl-2,3,3a,4,5,5a-
hexahydro-2-azacyclopenta[c]inden-1-one)iron (6.10/6.11a). 6.10 N O Ph According to the general procedure 6.9a (26 mg, 0.24
(OC)3Fe mmol) was refluxed in 3 mL of n-Bu2O for 15 h to afford 8.3 mg
(32%) of 6.10a and 4.2 mg (16%) of 6.11a, each as a colorless 6.11 N O oil. 6.10a: R = 0.27 (1:4/EA:Hex). 1H NMR (200 MHz, CDCl ) Ph f 3 δ: 7.42-7.13 (5H, Ph), 5.55-5.38 (2H, H7, H8), 3.68 (apparent quintuplet, J = 6.0 Hz, 1H,
H3), 3.09 (d, J = 6.4 Hz, 1H, H6 or H9), 3.01 (d, J = 6.4 Hz, 1H, H9 or H6), 2.42-2.20
167
(3H), 2.10-1.82 (1H), 1.72 (dd, J = 12.8, 6.8 Hz , 1H), 1.70-1.40 (2H), 1.24 (d, J = 6.8
13 Hz, 3H, CH3), 0.95 (t, J = 7.4 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 212.1, 137.6,
128.9, 125.9, 124.2, 86.2, 83.6, 68.1, 67.1, 61.1, 60.8, 51.7, 49.5, 43.7, 37.7, 23.3, 21.7,
+ 13.4. HRMS (m/z) for MH (C23H24FeNO4): calc: 434.1055; found: 434.1064; 6.11a: Rf
1 = 0.24 (1:4/Hex:EA). H NMR (200 MHz, CDCl3) δ: 7.42-7.13 (5H, Ph), 5.55-5.44 (2H,
H7, H8), 4.55-4.38 (m, 1H, H3), 3.15-3.07 (2H, H6, H9), 2.92-2.80 (m, 1H), 2.50-2.40
(m, 1H), 2.32-2.20 (m, 1H), 2.10-1.40 (4H), 1.10 (d, J = 6.6 Hz, 3H, CH3), 0.96 (t, J =
13 7.4 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 212.2, 176.3, 137.7, 128.9, 126.1,
124.7, 86.0, 84.3, 67.6, 66.7, 63.1, 54.5, 48.7, 46.7, 44.3, 32.0, 23.4, 15.6, 13.8.
Tricarbonyl(6-9-η-5-ethyl-3-butyl-2-phenyl-2,3,3a,4,5,5a- (OC)3Fe hexahydro-2-azacyclopenta[c]inden-1-one)iron (6.10/6.11b). Bu 6.10 N O Ph According to the general procedure, 6.9b (30 mg, 0.24
mmol) was refluxed in 3 mL of n-Bu2O for 15 h to afford 9.2 (OC)3Fe mg (31%) of 6.10b and 4.6 mg (15%) of 6.11b, each as a Bu 6.11 1 N colorless oil. 6.10b: R = 0.30 (1:4/EA:Hex). H NMR (200 O f Ph
MHz, CDCl3) δ: 7.42-7.13 (5H, Ph), 5.55-5.38 (2H, H7, H8),
3.63 (m, 1H, H3), 3.09 (d, J = 6.4 Hz, 1H, H6 or H9), 3.01 (d, J = 6.4 Hz, 1H, H9 or H6),
2.42-2.20 (3H), 2.10-1.82 (m, 1H), 1.72 (dd, J = 12.8, 6.8 Hz, 1H), 1.70-1.20 (6H), 0.94
13 (t, J = 7.2 Hz, 3H, CH3), 0.86 (t, J = 6.0 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ:
212.1, 175.6, 137.7, 128.9, 125.8, 124.1, 86.3, 83.6, 68.0, 67.2, 65.0, 61.0, 49.7, 49.1,
+ 43.6, 38.8, 34.1, 26.7, 23.3, 22.7, 14.1, 13.4. HRMS (m/z) for MH (C26H30FeNO4): calc:
1 476.1524; found: 476.1521; 6.11a: Rf = 0.26 (1:4/Hex:EA). H NMR (200 MHz, CDCl3)
168
δ: 7.42-7.13 (5H, Ph), 5.50-5.40 (2H, H7, H8), 4.30-4.12 (m, 1H, H3), 3.13 (d, J = 6.4
Hz, 1H, H6 or H9), 3.12 (d, J = 6.2 Hz, 1H, H9 or H6), 2.83 (apparent q, J = 7.4 Hz, 1H),
2.48 (d, J = 8.8 Hz, 1H), 2.10-1.20 (9H), 0.97 (t, J = 7.4 Hz, 3H, CH3) , 0.88 (t, J = 6.0
13 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 212.2, 176.8, 137.8, 128.9, 126.2, 125.1,
85.9, 84.6, 67.4, 65.8, 64.1, 58.7, 48.0, 45.8, 43.5, 31.2, 28.6, 28.1, 23.4, 22.7, 14.0 (2C).
Tricarbonyl(6-9-η-3-benzyl-2-benzyloxy-5-ethyl-2,3,3a,4,5,5a-hexahydro-2-
azacyclopenta[c]inden-1-one)iron (6.10/6.11c).
(OC)3Fe According to the general procedure, 6.9c (50 mg, 0.093
Bn 6.10 mmol) was refluxed in 5 mL of n-Bu2O for 16 h to afford 11 N O OBn mg (22%) of 6.10c and 5.5 mg (11%) of 6.11c, each as a
1 colorless oil. 6.10c: Rf = 0.20 (1:4/EA:Hex). H NMR (600 (OC)3Fe
MHz, CDCl3) δ: 7.40-7.15 (10H, Ph), 5.32 (dd, J = 6.0, 4.2 Hz, Bn 6.11 N 1H, H7), 5.17 (ddd, J = 6.0, 4.0, 1.2 Hz, 1H, H8), 5.10 (d, J = O OBn 10.8 Hz, 1H, Obenzyl H), 4.99 (d, J = 10.8 Hz, 1H, Obenzyl
H’), 3.04 (td, J = 5.4, 3.6 Hz, 1H, H3), 2.96 (dd, J = 13.5, 5.4 Hz, 1H, benzyl H), 2.80 (d,
J = 6.6 Hz, 1H, H6), 2.75 (dd, J = 13.5, 3.6 Hz, 1H, benzyl H’), 2.20 (dd, J = 8.4, 3.6 Hz,
1H, H3a), 2.00-1.90 (2H, H4, H5a), 1.64 (dd, J = 6.6, 1.2 Hz , 1H, H9), 1.49-1.32 (3H,
13 H5, H11, H11’), 1.11 (dd, J = 13.2, 7.4 Hz, 1H, H4’), 0.94 (t, J = 7.2 Hz, 3H, CH3). C
NMR (50 MHz, CDCl3) δ: 211.8, 171.4, 135.7, 135.3, 130.4, 129.8, 129.1, 128.6 (2C),
126.9, 86.2, 83.8, 66.8, 65.1, 62.8, 59.7, 48.2, 45.8, 43.2, 38.2, 38.0, 23.2, 13.2. HRMS
+ (m/z) for MH (C30H20FeNO5): calc: 540.1473; found: 540.1482; 6.10c: Rf = 0.17
1 (1:4/Hex:EA). H NMR (600 MHz, CDCl3) δ: 7.40-7.10 (10H, Ph), 5.45 (dd, J = 6.6, 4.2
169
Hz, 1H, H7), 5.40 (ddd, J = 6.0, 4.0, 1.2 Hz, 1H, H8), 4.96 (d, J = 10.2 Hz, 1H, Obenzyl
H), 4.86 (d, J = 10.2 Hz, 1H, Obenzyl H’), 3.96 (ddd, J = 9.6, 7.8, 4.8 Hz, 1H, H3), 3.10
(dd, J = 14.7, 4.8 Hz, 1H, benzyl H), 3.01 (dd, J = 6.6, 1.8 Hz, 1H, H6), 2.86 (dd, J = 6.6,
1.2 Hz , 1H, H9), 2.60-2.50 (1H), 2.55 (dd, J = 15.0, 9.6 Hz, 1H, benzyl H’), 2.31 (d, J =
8.4 Hz, 1H), 1.90-1.76 (3H), 1.50-1.30 (2H), 0.92 (t, J = 7.2 Hz, 3H, CH3). HRMS (m/z)
+ for MH (C30H20FeNO5): calc: 540.1473; found: 540.1461.
Tricarbonyl[1-4-η-cyclohexa-1,3-dienecarboxylic acid O (OC)3Fe benzyl-(1-formyl-2-methyl-propyl)amide]iron (6.15). N Bn O According to the general procedure for preparing amides in Chapter 2, acid 6.1 (400 mg, 1.51 mmol) and 100 mg of 4 Å molecular sieves in 4 mL of CH2Cl2 was treated with 0.28 mL of Et3N and 0.24 mL of CH3SO2Cl, followed by 670 mg (2 equivalent) of N-benzylvaline methyl ester and 0.56 mL of Et3N to afford 438 mg
(62% yield) of amide 6.14 as a light brown oil, a 1:1 inseparable mixture of diastereomers. This compound (330 mg, 0.71 mmol) in 2 mL of Et2O at -78 °C was treated with DIBALH (2 mL, 1.5 M in toluene, 4 equiv) for 12 min. The reaction mixture was quenched with 0.3 mL of methanol, followed immediately by 10 mL of sat aq potassium sodium tartrate, extracted with Et2O, dried (MgSO4), and concentrated under vacuum. The title compound (226 mg, 73%), a light brown oil, was obtained as a 1:1 inseparable mixture of diastereomers after flash chromatography. 1H NMR (200 MHz,
CDCl3), mixture of isomers, δ: 9.70-9.44 (m, 1H, H10), 6.22-6.04 (m, 1H, H2), 5.45-5.25
(2H, H3, benzyl H), 4.60-4.40 (1H, benzyl H’), 3.60-3.40 (m, 1H), 2.95-2.53 (2H), 2.15-
1.40 (4H), 1.14-0.85 (6H, CH3).
170
Tricarbonyl[6-9-η-(2-benzyl-3-isopropyl-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4- yl)acetic acid methyl ester]iron (6.17).
100 mg (0.23 mmol) of aldehyde 6.15 was refluxed (OC)3Fe CO2Me in 1 mL of Toluene with 280 mg of Methyl
N triphenylphosphanylideneacetate for 2 h to afford 95 mg O Bn (84%) of 6.16 as a colorless oil. According to the general
procedure 6.16 (65 mg, 0.13 mmol) was refluxed in 6 mL of n-Bu2O for 12 h to afford 45 mg (69%) of the title compound as a colorless oil, which contains a 7:3:2:2 (integration of one of the benzylic H, which are four doublets) mixture of four inseparable diastereomers. Rf = 0.10 (1:4/EA:Hex).
Tricarbonyl[6-9-η-(2-benzyl-3-isopropyl-1-oxo-2,3,3a,4,5,5a-hexahydro-1H-2-aza- cyclopenta[c]inden-5-yl)acetic acid methyl ester]iron (6.19/6.20).
(OC)3Fe 45 mg (0.71 mmol) of 6.17 in 0.4 mL of Et2O at -78
°C was treated with six equiv of DIBALH (0.4 mL, 1.5 M in MeO C 2 N O Bn toluene) for 8 min. The reaction mixture was worked up 6.19 according to the procedure used to prepare 6.15. The newly CO2Me formed aldehyde was refluxed in 1 mL of toluene with 280 (OC)3Fe mg of methyl triphenylphosphanylideneacetate for 2 h to
N O afford 6.18 as a colorless oil after flash chromatography. Bn 6.20 According to the general procedure, complex 6.18 was refluxed in 4 mL of n-Bu2O for 6 h to afford 32 mg (58% for 3 steps) of the title compound as a colorless oil, produced as a 2.5:1 inseparable mixture of two
171
1 diastereomers. Rf = 0.27 (2:3/EA:Hex). H NMR (600 MHz, CDCl3), major isomer, δ:
7.25-7.00 (5H, Ph), 5.44 (ddd, J = 6.0, 3.7, 1.2 Hz, 1 H, H8), 5.37 (m, 1H, H7), 4.98 (d, J
= 15.0 Hz, 1H, benzyl H), 3.68 (d, J = 15.0 Hz, 1H, benzyl H’), 3.60 (s, 3H, OCH3), 2.88
(dd, J = 6.0, 1.2 Hz, 1H, H9), 2.79 (dt, J = 6.6, 1.2 Hz, 1H, H6), 2.77 (t, J = 4.2 Hz, 1H,
H3), 2.46 (dd, J = 15.6, 7.2 Hz, 1H, H11), 2.31 (dd, J = 15.6, 6.6 Hz, 1H, H11’), 2.27 (d,
J = 7.8 Hz, 1H, H12), 2.26-2.15 (3H, H3a, H4, H5), 2.05-2.00 (m, 1H, H12), 1.40 (dd, J
= 12.6, 7.2 Hz, 1H, H4’), 0.79 (d, J = 7.2 Hz, 3H, CH3), 0.67 (d, J = 7.2 Hz, 3H, CH3).
13 C NMR (50 MHz, CDCl3), major isomer, δ: 212.1, 176.2, 173.1, 136.0, 129.0, 128.2,
127.7, 86.7, 84.0, 67.0 (2C), 66.2, 62.0, 52.0, 47.8, 44.2, 42.6, 35.1, 32.1, 22.9, 18.3,
+ 14.3. HRMS (m/z) for MH (C27H30FeNO6): calc: 520.1423; found: 520.1433.
4-(S)-5-(E)-4-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-2-methyl-5-phenyl- pent-2-enoic acid ethyl ester (6.35)
Method A: Ethyl 2-(diethoxyphosphoryl)propionate Bn Boc N CO2Et (700 mg, 3 mmol), 20 mL of CH3CN, and vacuum oven dried PMB LiCl (3 mmol) were placed in a flask, followed by 0.44 mL of
DBU (3 mmol). The reaction mixture was stirred at rt for 15-20 min until LiCl disappeared completely, then cooled to 0 °C. Aldehyde 6.33 (670 mg, 1.8 mmol) in 2 mL of CH3CN was added dropwise via syringe and the reaction mixture was stirred at 0 °C for 2 h (monitored by TLC). The reaction mixture was then quenched with sat aq NH4Cl
(30 mL) and extracted with Et2O (3 x 20 mL) to afford 576 mg (70% yield) of 6.35 as
viscous oil after chromatography. Method B: To a solution of 960 mg (4 mmol) of ethyl
2-(diethoxyphosphoryl)propionate in 8 mL of THF at -78 °C was added n-BuLi slowly
172
via a syringe. The reaction mixture was stirred at the same temperature for 1 h, aldehyde
6.33 (740 mg, 2 mmol) dissolved in 8 mL of THF was added, and the mixture was stirred
for 3 h at -78 °C (monitored by TLC) to afford 520 mg (58% yield) of 6.35 and 130 mg
(14% yield) of 6.36 following the workup procedure of Method A and chromatography.
1 Rf = 0.43 (1:9/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.40-6.70 (9H, Ph), 5.98-5.40
(m, 1H), 4.41-4.20 (2H), 4.14 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H, OCH3), 3.04 (dd, J = 13.4,
7.8 Hz, 1H, benzyl H), 2.77 (dd, J = 13.4, 7.6 Hz, 1H, benzyl H’), 1.65-1.30 (12H, t-Bu,
CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH3).
4-(S)-2-(Z)-4-[tert-Butoxycarbonyl-(4-methoxybenzyl)amino]-2-methyl-5-phenyl- pent-2-enoic acid ethyl ester (6.36)
1 Bn CO2Et Rf = 0.54 (1:9/EA:Hex). H NMR (200 MHz, CDCl3) δ: Boc N PMB 7.30-6.70 (9H, Ph), 6.50-6.00 (m, 1H, H3), 5.20-4.95 (m, 1H),
4.31-3.80 (2H), 4.14 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H, OCH3), 3.40-2.92 (m, 1H, benzyl
H), 2.85 (dd, J = 13.0, 5.8 Hz, 1H, benzyl H’), 1.83 (s, 3H, CH3), 1.46 (s, 9H, t-Bu), 1.25
13 (t, J = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 167.2, 158.5, 140.2, 130.9,
129.4, 129.0, 128.8, 128.7, 128.2, 127.8, 126.1, 113.6, 60.3, 55.3, 28.5, 20.6, 14.4, 14.3.
Bn 4-(S)-2-(Z)-4-(4-Methoxy-benzylamino)-2-methyl-5-
PMBHN CO2Et phenyl-pent-2-enoic acid ethyl ester (6.37)
Compound 6.36 (740 mg) was dissolved in 8 mL of dry CH2Cl2, and cooled to 0
°C. TFA (4 mL) was then added slowly to the reaction mixture, which was then stirred at
the same temperature for 10 min, quenched by slow addition of 40 mL aq sat NaHCO3
173
solution at 0 °C, extracted with CH2Cl2, dried (MgSO4), and concentrated to give 577 mg
(100% yield) of the title compound as a light yellow oil which was not further purified.
1 H NMR (200 MHz, CDCl3) δ: 7.30-6.70 (9H, Ph), 6.68-6.60 (m, 1H, H3), 4.20 (q, J =
7.0 Hz, 2H), 3.78 (s, 3H, OCH3), 3.80-3.45 (3H), 2.89-2.65 (2H), 1.63 (s, 3H, CH3), 1.30
13 (t, J = 7.2 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 168.0, 158.6, 144.0, 137.9,
132.2, 129.4, 129.3, 129.2, 128.5, 126.6, 113.8, 60.7, 56.7, 55.3, 51.0, 41.5, 14.3, 12.8.
5-Benzyl-1-(4-methoxybenzyl)-3-methyl-1,5-dihydro-pyrrol-2-one (6.38)
Compound 6.36 (90 mg) was dissolved in 1 mL of dry
CH Cl , and cooled to 0 °C. TFA (0.5 mL) was then added slowly to Bn N O 2 2 PMB the reaction mixture, which was then stirred at the same temperature for 6 min, quenched by slow addition of 10 mL aq sat NaHCO3 solution at 0 °C, extracted with CH2Cl2, dried (MgSO4), and concentrated to give 61 mg (100% yield) of
1 the title compound as a light yellow oil. Rf = 0.47 (1:19/EA:Hex). H NMR (200 MHz,
CDCl3) δ: 7.40-6.80 (9H, Ph), 6.48 (t, J = 1.6 Hz, 1H, H4), 5.14 (d, J = 15.0 Hz, 1H, N-
benzyl H), 4.11 (d, J = 15.0 Hz, 1H, N-benzyl H’), 4.00-3.85 (m, 1H, H5), 3.78 (s, 3H,
OCH3), 3.15 (dd, J = 13.2, 5.6 Hz, 1H, benzyl H), 3.48 (dd, J = 13.2, 9.3 Hz, 1H, benzyl
13 H’), 1.88 (t, J = 1.7 Hz, 3H, CH3). C NMR (50 MHz, CDCl3) δ: 171.9, 159.0, 140.2,
136.7, 134.9, 129.8, 129.3, 129.2, 128.6, 126.9, 114.1, 60.5, 55.3, 43.7, 38.0, 11.3.
174
Tricarbonyl{1-4-η-4-[(cyclohexa-1,3-dienecarbonyl)(4-methoxybenzyl)amino]-2- methyl-5-phenylpent-2-enoic acid ethyl ester}iron (6.39).
According to the general procedure, acid 6.1 (300 CO2Et Fe(CO)3 Bn mg, 1.14 mmol) in 5 mL of CH2Cl2 was treated with 0.1 mL
N PMB of pyridine, followed by 0.5 mL of (COCl)2, then 400 mg of O a amine 6.37, 0.2 mL of pyridine, and 2 mL of benzene to
CO2Et Bn afford 125 mg (38% yield, 47% conversion) of 6.39a and
N 130 mg (40% yield, 47% conversion) of 6.39b, each as a PMB Fe(CO)3 O b light brown oil, along with 160 mg of unreacted starting
1 material 6.1. 6.39a: Rf = 0.18 (3:7/EA:Hex). H NMR (200 MHz, CDCl3) δ: 7.40-6.75
(10H, Ph, H10), 5.94 (d, J = 3.8 Hz, 1H, H2), 5.20 (dd, J = 6.6, 4.6 Hz, 1H, H8), 4.99-
4.22 (3H, O-benzyl, H9), 4.14 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 3.81 (s, 3H, OCH3),
3.42-3.32 (m, 1H, H4), 3.18 (dd, J = 13.2, 5.8 Hz, 1H, benzyl H), 2.96 (dd, J = 13.2, 9.0
13 Hz, 1H, benzyl H’), 2.00-1.30 (7H), 1.26 (t, J = 7.0 Hz, 3H, CO2CH2CH3). C NMR (50
MHz, CDCl3) δ: 173.7, 167.9, 159.1, 137.7, 129.9, 129.5, 128.4 (2C), 126.5, 114.3, 84.6,
84.2, 73.5, 63.7, 60.7, 59.5, 59.4, 26.3, 24.7, 14.2, 12.4. HRMS (m/z) for M-3CO
1 (C29H33FeNO4): calc: 515.1759; found: 515.1737; 6.39b: Rf = 0.21 (3:7/Hex:EA). H
NMR (200 MHz, CDCl3) δ: 7.40-7.10 (10H, Ph), 6.30-4.55 (3H, H2, H3, O-benzyl H),
4.50-3.90 (3H, O-benzyl H’, CO2CH2CH3), 3.85-3.65 (3H, OCH3), 3.50-2.50 (3H, H4,
+ benzyl), 2.50-1.10 (10H, H5, H5’, H6, H6’, CH3, CO2CH2CH3). HRMS (m/z) for MH
(C32H34FeNO7): calc: 600.1685; found: 600.1692.
175
Tricarbonyl[6-9-η-2-[3-benzyl-2-(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-
dien-4-yl]propionic acid ethyl ester]iron (6.40).
According to the general Fe(CO) H Fe(CO)3 H 3 EtO2C EtO2C procedure, a 1:1 mixture of 6.39a H H Bn Bn and 6.39b (60 mg, 0.1 mmol) was N O N O PMB PMB a b refluxed in 5 mL of n-Bu2O for 16 h to afford 38 mg (63%) of 6.40a and 6.11c (about 1:1 ratio), as a colorless oil. Rf = 0.30
1 (2:3/EA:Hex). H NMR (300 MHz, CDCl3), mixture of isomers, δ: 7.40-6.70 (9H, Ph),
5.76 (ddd, J = 6.3, 4.1, 1.1 Hz, 1H), 5.60-5.40 (m, 2H), 5.23 (t, J = 5.1 Hz, 1H), 4.98 (d, J
= 14.3 Hz, 1H, N-benzyl H, one isomer), 4.68 (d, J = 14.3 Hz, 1H, N-benzyl H, another isomer), 4.20-3.50 (14H, N-benzyl H’, H3, OCH3, CO2CH2CH3), 3.40-2.30 (12H), 2.12-
1.83 (4H), 1.14 (t, J = 7.0 Hz, 3H, CO2CH2CH3, one isomer), 1.00 (t, J = 7.0 Hz, 3H,
CO2CH2CH3, another isomer), 0.60 (d, J = 7.0 Hz, 3H, CH3, one isomer), 0.42 (d, J = 7.0
13 Hz, 3H, CH3, another isomer). C NMR (50 MHz, CDCl3), mixture of isomers, δ: 211.4,
211.3, 177.5, 176.5, 174.6, 174.5, 159.3, 159.2, 137.6, 137.4, 134.2, 130.4, 129.8, 129.6,
129.5, 129.3, 129.1, 128.9, 128.8, 128.7, 128.5, 128.4, 128.2, 127.0, 126.7, 114.2, 114.1,
114.0, 113.9, 88.3, 86.7, 85.8, 82.3, 68.0, 62,9, 60.6, 60.5, 59.7, 59.0, 58.2, 57.7, 55.3,
50.9, 50.4, 49.8, 47.5, 45.5, 45.0, 40.8, 40.2, 39.2, 38.6, 33.8, 14.0, 13.7, 10.6, 10.4.
+ HRMS (m/z) for MH (C32H34FeNO7): calc: 600.1685; found: 600.1646.
2-[3-Benzyl-2-(4-methoxy-benzyl)-1-oxo-2-aza-spiro[4.5]dec- H OEt 4-yl]-propionic acid ethyl ester (6.42) H O Bn 20 mg (0.033 mmol) of 6.40 was dissolved in 1 mL of dry O N PMB
176
benzene, followed by 90 mg of Me3NO. The reaction mixture was then heated at 40-60
°C for 4 h, filtered through Celite and a short column of silica gel, eluted with 30 mL
20% EA/Hex solution, and concentrated under vacuum. The concentrate was then dissolved in 1 mL of methanol along with 10 mg of 10% Pd on activated carbon under a balloon of hydrogen gas. After stirring at rt overnight, the reaction mixture was then filtered and concentrated to give 8 mg (52% yield for two steps) of the title compound as
1 a colorless oil after PLC purification. Rf = 0.25 (3:7/EA:Hex). H NMR (300 MHz,
CDCl3) δ: 7.35-6.78 (9H, Ph), 4.82 (d, J = 14.3 Hz, 1H, N-benzyl H), 3.96 (d, J = 14.3
Hz, 1H, N-benzyl H’), 3.79 (s, 3H, OCH3), 3.78-3.60 (m, 1H, CO2CH2CH3) 3.60-3.48
(m, 1H, H3), 3.46-3.28 (m, 1H, CO2CH2CH3), 3.06 (dd, J = 13.5, 5.7 Hz, 1H, benzyl H),
2.71 (dd, J = 13.5, 8.5 Hz, 1H, benzyl H’), 2.55 (qd, J = 7.2, 2.1 Hz, 1H, H11), 3.48 (s,
1H), 1.90-1.10 (10H), 1.04 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 0.62 (d, J = 7.2 Hz, 3H,
13 CH3). C NMR (50 MHz, CDCl3) δ: 178.8, 174.9, 159.1, 138.0, 130.3, 129.5, 128.7,
128.6, 126.6, 113.9, 60.4, 57.8, 55.3, 46.3, 44.4, 43.5, 40.8, 38.5, 37.0, 28.5, 25.5, 22.9,
+ 22.4, 14.0, 11.1. HRMS (m/z) for MH (C29H38NO4): calc: 464.2801; found: 464.2807.
177
6.4 Literature Cited
(1) Tomioka, K.; Shioya, Y.; Nagaoka, Y.; Yamada, K. “Electronic and Steric Control in Regioselective Addition Reactions of Organolithium Reagents with Enaldimines.” J. Org. Chem. 2001, 66, 7051 -7054.
(2) Laurent, P.; Miyaji, H.; Collinson, S. R.; Proke, I.; Moody, C. J.; Tucker, J. H. R.; Slawin, A. M. Z. “Asymmetric Synthesis of Chiral -Ferrocenylalkylamines and Their Use in the Preparation of Chiral Redox-Active Receptors.” Org. Lett. 2002, 4, 4037- 4040.
(3) Knölker, H. J.; Baum, G; Foitzik, N.; Goesmann, H.; Gonser, P. “Synthesis, Molecular Structure, Fluxional Behavior, and Tricarbonyliron Transfer Reactions of (η4- 1-Azabuta-1,3-diene)tricarbonyliron Complexes.” Eur. J. Inorg. Chem. 1998, 993-1007.
(4) Paris, M.; Pothion, C.; Heitz, A.; Martinez, J.; Fehrentz, J. “Synthesis of N- and Side Chain Protected Aspartyl and Glutamyl Aldehyde Derivatives. Reinvestigation of the Reduction of Weinreb Amides.” Tetrahedron Lett. 1998, 39, 1341-1344.
(5) Cho, J. H.; Kim, B. M. “LiOH-Mediated N-Monoalkylation of α-Amino Acid Esters and a Dipeptide Ester Using Activated Alkyl Bromides.” Tetrahedron Lett. 2002, 43, 1273-1276.
(6) Rich, D. H.; Sun, E. T.; Boparai, A. S. “Synthesis of (3S,4S)-4-Amino-3-Hydroxy-6- methylheptanoic Acid Derivatives. Analysis of Diastereomeric Purity.” J. Org. Chem. 1978, 43, 3624-3626.
(7) Ondeyka, J.; Hensens, O. D.; Zink, D.; Ball, R.; Lingham, R. B.; Bills, G.; Dombrowski, A.; Goetz, M. “L-696,474, A Novel Cytochalasin as an Inhibitor of HIV-1 Protease. II. Isolation and Structure.” J. Antibiot. 1992, 45, 679-685.
(8) Dondoni, A.; Perrone, D.; Merino, P. “Chelation- and Non-chelation-Controlled Addition of 2-(Trimethylsilyl)thiazole to α-Amino Aldehydes: Stereoselective Synthesis of the β-Amino-α-hydroxy Aldehyde Intermediate for the Preparation of the Human Immunodeficiency Virus Proteinase Inhibitor Ro 31-8959.” J. Org. Chem. 1995, 60, 8074-8080.
(9) Browder, C. C.; Marmsäter, F. P.; West, F. G. “Highly Efficient Trapping of the Nazarov Intermediate with Substituted Arenes.” Org. Lett, 2001, 3, 3033-3035.
(10) Maryanoff, B. E.; Reitz, A. B. “The Wittig Olefination Reaction and Modifications Involving Phosphoryl-Stabilized Carbonanions. Stereochemistry, Mechanism, and Selected Synthetic Aspects.” Chem. Rev. 1989, 89, 863-927.
178
BIBLIOGRAPHY
179
Aburel, P. S.; Undheim, K. “Synthesis of Spirosystems by Rhodium(II)-Carbenoid C-H Insertion Reactions.” Tetrahedron Lett. 1998, 39, 3813-3814.
Alper, H.; LePort, P. C.; Wolfe, S. “Mechanism of Formation of Conjugated Diene-Iron Tricarbonyl Complexes from Nonconjugated Dienes.” J. Am. Chem. Soc. 1969, 91, 7553- 7554.
Arnett, J. E.; Pettit, R. “Rearrangement of Dienes with Iron Pentacarbonyl.” J. Am. Chem. Soc. 1961, 83, 2954-2955.
Bäckvall, J. E.; Vagberg, J.; Nordberg, R. E. “Palladium-Catalyzed 1,4-Acetoxy- trifluoroacetoxylation of 1,2-Dienes.” Tetrahedron Lett. 1984, 25, 2717-2720.
Bandara, B. M. R.; Birch, A. J.; Chauncy, B.; Kelly, L. F. “Tricarbonyliron Complexes of Some Blocked Cyclohexadienes.” J. Organomet. Chem. 1981, 208, C31-C35.
Bandara, B. M. R.; Birch, A. J.; Khor, T.-C. “Alkylation of Tricarbonylcyclohexadienyliron Salts with Lithium Alkyls.” Tetrahedron Lett. 1980, 21, 3625-3626.
Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 13. Stereoselectivity of Complexation of Cyclohexadiene Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1755-1762.
Bandara, B. M. R.; Birch, A. J.; Raverty, W. D. “Organometallic Compounds in Organic Synthesis. Part 14. Tricarbonyliron as Lateral Control Group in the Selective Alkaline Hydrolysis of Some Cyclohexa-1,3-Diene Carboxylic Esters.” J. Chem. Soc., Perkin Trans. I 1982, 1763-1769.
Barluenga, J.; Sanz, R.; Fananas, F. J. “Zirconium-Mediated Intramolecular Coupling Reactions of Unsaturated Anilines. Diastereoselective Synthesis of Azetidines.” J. Org. Chem. 1997, 62, 5953-5958.
Bennani, Y. L.; Hanessian, S. “The Asymmetric Synthesis of α-Substituted α-Methyl and α-Phenyl Phosphonic Acids: Design, Carbanion Geometry, Reactivity and Preparative Aspects of Chiral Alkyl Bicyclic Phosphonamides.” Tetrahedron 2000, 52, 13837-13866.
Biju, P. J.; Rao, G. “A New Strategy for the Synthesis of Spiro[4.5]Decanes: A Formal Total Synthesis of Acorone.” Tetrahedron Lett. 1999, 40, 2405-2406.
Birch, A. J.; Chamberlain, K. B.; Haas, M. A.; Thompson, D. J. “Organometallic Complexes in Synthesis. IV. Abstraction of Hydride from Tricarbonylcyclohexa-1,3- Dieneiron Complexes and Reactions of the Complexed Cations with Nucleophiles.” J. Chem. Soc., Perkin Trans. 1 1973, 1882-1891.
180
Birch, A. J.; Haas, M. A. “Organometallic Complexes in Synthesis. III. Reaction of Concentrated Sulfuric Acid with Tricarbony-1,3-Cyclohexadieneiron Complexes. Preparation of Alkyltricarbonyl-π-Cyclohexadienyliron Salts.” J. Chem. Soc. (C) 1971, 2565-2467.
Birch, A. J.; Kelly, L. F.; Weerasuria, D. V. “A Facile Synthesis of (+)- and (-)-Shikimic Acid with Asymmetric Deuterium Labeling, Using Tricarbonyl Iron as A Lateral Control Group.” J. Org. Chem. 1988, 53, 278-281.
Birch, A. J.; Pearson, A. J. “Organometallic Complexes in Synthesis. Part 9. Tricarbonyliron Derivatives of Dihydroanisic Esters.” J. Chem. Soc., Perkin Trans. 1 1978, 638-642.
Birch, A. J.; Williamson, D. H. “Organometallic Complexes in Synthesis. V. Tricarbonyliron Derivatives of Cyclohexadienecarboxylic Acids.” J. Chem. Soc., Perkin Trans. I 1973, 1892-1900.
Bond, A.; Lewis, B.; Green, M. “Reactions of Coordinated Ligands. V. Addition of Tetrafluoroethylene to Tricarbonyl(diene)iron, Tricarbonyl(trans-cinnamaldehyde)Iron, and Tricarbonyl(O-styryldiphenylphosphine)iron Complexes.” J. Chem. Soc., Dalton Trans. 1975, 1109-1118.
Brookhart, M.; Nelson, G. O. “The Reaction of Benzylideneacetoneiron Tricarbonyl with Dienes; Measurement of Relative Reactivities Using Competition Experiments.” J. Organomet. Chem. 1979, 164, 193-202.
Browder, C. C.; Marmsäter, F. P.; West, F. G. “Highly Efficient Trapping of the Nazarov Intermediate with Substituted Arenes.” Org. Lett, 2001, 3, 3033-3035.
Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A, 3Ed, Plenum Press: New York and London, 1990, page 163.
Cho, J. H.; Kim, B. M. “LiOH-Mediated N-Monoalkylation of α-Amino Acid Esters and a Dipeptide Ester Using Activated Alkyl Bromides.” Tetrahedron Lett. 2002, 43, 1273- 1276.
Clive, D. L. J.; Huang, X. J. “Stereocontrolled Formation of Spiro Enones by Radical Cyclization of Bromo Acetals.” Tetrahedron 2001, 57, 3845-3858.
Corey, E. J.; Girotra, N. N.; Mathew, C. T. “Total Synthesis of dl-Cedrene and dl- Cedrol.” J. Am. Chem. Soc. 1969, 91, 1557-1559.
Corey, E. J.; Guzman-Perez, A. “The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters.” Angew. Chem., Int. Edit. 1998, 37, 388-401.
181
Cox, L. R.; Ley, S. V. “Tricarbonyliron Complexes: An Approach to Acyclic Stereocontrol.” Chem. Soc. Rev. 1998, 23, 301-314.
Damico, R.; Logan, T. J. “Isomerization of Unsaturated Alcohols with Iron Pentacarbonyl. Preparation of Ketones and Aldehydes.” J. Org. Chem. 1967, 32, 2356- 2358.
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Organic Chemistry Series; Pergamon Press: Oxford, 1983; Vol. 1, pp. 390.
Dieck, H. T.; Dietrich, J.; Wilke, G. “Diazadienes as Directing Ligands in Homogeneous Catalysis. 11. Selectivity and Mechanism of Diene Cyclodimerization on Iron (0).” Angew. Chem. 1985, 97, 795-796.
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.
Dondoni, A.; Perrone, D.; Merino, P. “Chelation- and Non-chelation-Controlled Addition of 2-(Trimethylsilyl)thiazole to α-Amino Aldehydes: Stereoselective Synthesis of the β- Amino-α-hydroxy Aldehyde Intermediate for the Preparation of the Human Immunodeficiency Virus Proteinase Inhibitor Ro 31-8959.” J. Org. Chem. 1995, 60, 8074-8080.
Dorange, I. B. "Stereocontrolled Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling." Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 2001
Durrant, G.; Green, R. H.; Lambeth, P. F.; Lester, M. G.; Taylor, N. R. “Synthesis of Some Aromatic Prostaglandin Analogs. Part 1.” J. Chem. Soc., Perkin Trans. I 1983, 2211-2214.
Eekhof, J. H.; Hogeveen, H.; Kellogg, R. M. “Intermediate Compound in the Decomplexation of a Tricarbonyl Iron Complex Using Trimethylamine Oxide.” Chem. Comm. 1976, 657.
Eisenstein, O.; Butler, W.; Pearson, A. J. “Theoretical Study of the Formation and Reactivity of Substituted Cyclohexadienyliron Complexes. The Structures and Reactivities of Tricarbonyl(2-methoxycyclohexadienyl)iron Cation and Tricarbonyl(1- methyl-4-methoxycyclohexadienyl)iron Cation.” Organometallics 1984, 3, 1150-1157.
ElAmrani, M. A.; Suisse, I.; Knouzi, N.; Mortreux, A. “Chemo and Enantioselective Butadiene-Functionalized Diene Cyclodimerization Catalyzed by Nickel Complexes.” Tetrahedron Lett. 1995, 36, 5011-5014.
Evans, G.; Johnson, B. F. G.; Lewis, J. “Synthetic Studies Relating to Acetylergosterol(tricarbonyl)iron.” J. Organomet. Chem. 1975, 102, 507-510.
182
Fischer, E. O.; Fischer, R. D. “A Cyclohexadienyliron Tricarbonyl Cation.” Angew. Chem. 1960, 72, 919-920.
Fraga, B. M. “Natural Sesquiterpenoids.” Nat. Prod. Rep. 1999, 16, 711-730.
Fraga, B. M. “Natural Sesquiterpenoids.” Nat. Prod. Rep. 2000, 17, 483-504.
Fuji, K. “Asymmetric Creation of Quaternary Carbon Centers.” Chem. Rev. 1993, 93, 2037-2066.
Fujii, M.; Kawaguchi, K.; Nakamura, K.; Ohno, A. “Stereoselective Synthesis of (±)- Isonitramine and (±)-Sibirine.” Chem. Lett. 1992, 1493-1496.
Ganem, B.; Holbert, G. W.; Weiss, L. B.; Ishizumi, K. “A New Approach to Substituted Arene Oxides. Total Synthesis of Senepoxide and Seneol.” J. Am. Chem. Soc. 1978, 100, 6483-6491.
Graham, C. R.; Scholes, G.; Brookhart, M. “Selective Trapping of Dienes by Benzylideneacetoneiron Tricarbonyl. Synthetic and Mechanistic Studies of the Reactions of 1,3,5-Cyclooctatriene and Its Derivatives with Benzylideneacetoneiron Tricarbonyl.” J. Am. Chem. Soc. 1977, 99, 1180-1188
Green, M.; Lewis, B.; Daly, J. J.; Sanz, F. “Reactions of Coordinated Ligands. VI. Addition of Hexafluoropropene, Trifluoroethylene, and Chlorotrifluoroethylene to Tricarbonyl(Diene)Iron or Ruthenium Complexes and to Tricarbonyl(O- Styryldiphenylphosphine)Iron.” J. Chem. Soc., Dalton Trans. 1975, 1118-1127.
Grieco, P. A.; Larsen, S. D. “An Intramolecular Immonium Ion Variation of the Diels- Alder Reaction: Synthesis of (±)-Dihydrocannivonine.” J. Org. Chem. 1986, 51, 3553- 3555.
Grigg, R.; Köppen, I.; Rasparini, M.; Sridharan, V. “Synthesis of Spiro- and Fused Heterocycles by Palladium Catalysed Carbo- and Heteroannulation Cascades of Allenes.” Chem. Comm. 2001, 964-965.
Grosselin, J. M.; Dixneuf, P. H. “Electron-Rich, Hydrocarbon-Metal Complexes:Synthesis and Oxidation Properties of Bis(η3-allyl)iron Complexes Containing Phosphines.” J. Organomet. Chem., 1986, 314, C76-C80.
Hendrix, W. T.; Cowherd, F. G.; von Rosenberg, J. L. “Mechanism of the rearrangement of Allyl Alcohol with Iron Pentacarbonyl. Evidence for a π-Allyl-Hydroirontricarbonyl Complex.” Chem. Comm. 1968, 97-99.
Ireland, R. E.; Brown, G. G.; Stanford, R. H.; McKenzie, T. C. “Reactions of Pentahapto- Cyclohexadienyliron Tricarbonyl Cations with Enamines.” J. Org. Chem. 1974, 39, 51- 59. 183
Itoh, K.; Masuda, K.; Fukahori, T.; Nakano, K.; Aoki, K.; Nagashima, H. “Stoichiometric + and Catalytic Dimerization of Conjugated Diene with (C5R5)Ru(diene) .” Organometallics 1994, 13, 1020-1029.
Keppens, M.; De Kimpe, N. “Enantioselective Total Syntheses of the Nitraria Alkaloids (-)-Nitramine and (+)-Isonitramine.” J. Org. Chem. 1995, 60, 3916-3918.
Kim, D.; Choi, W. J.; Hong, J. Y.; Park, I. Y.; Kim, Y. B. “An Asymmetric Synthesis of (+)-Isonitramine by ‘Triple Allylic Strain-Controlled’ Intramolecular SN2’ Akylation.” Tetrahedron Lett. 1996, 37, 1433.
Kirby, A. J. “Effective Molarities for Intramolecular Reactions.” Adv. Phys. Org. Chem., 1980, 17, 183-278.
Knölker, H. J. “Efficient Synthesis of Tricarbonyl-Diene Complexes - Development of an Asymmetric Catalytic Complexation.” Chem. Rev. 2000, 100, 2941-2961.
Knölker, H. J.; Ahrens, B.; Gonser, P.; Heininger, M.; Jones, P. G. “Transition Metal Complexes in Organic Synthesis. Part 57: Synthesis of 1-Azabuta-1,3-dienes and Application to Catalytic Complexation of Buta-1,3-dienes and Cycloalkadienes by the Tricarbonyliron Fragment.” Tetrahedron 2000, 56, 2259-2271.
Knölker, H. J.; Baum, E.; Gonser, P.; Rohde, G.; Rottele, H. “1,4-Diaryl-1-azabuta-1,3- diene-Catalyzed Complexation of Cyclohexa-1,3-diene by the Tricarbonyliron Fragment: Development of Highly Efficient Catalysts, Optimization of Reaction Conditions, and Proposed Mechanism.” Organometallics 1998, 17, 3916-3925.
Knölker, H. J.; Baum, G; Foitzik, N.; Goesmann, H.; Gonser, P. “Synthesis, Molecular Structure, Fluxional Behavior, and Tricarbonyliron Transfer Reactions of (η4-1-Azabuta- 1,3-diene)tricarbonyliron Complexes.” Eur. J. Inorg. Chem. 1998, 993-1007.
Knölker, H. J.; Hermann, H.; Herzberg, D. “Photolytic Induction of the Asymmetric Catalytic Complexation of Prochiral Cyclohexa-1,3-diene by the Tricarbonyliron Fragment.” Chem. Comm. 1999, 831-832.
Kraus, G. A.; Roth, B.; Frazier, K.; Shimagaki, M. “Stereoselective Synthesis of Calonectrin.” J. Am. Chem. Soc. 1982, 104, 1114-1116.
Kuroda, C.; Koshio, H. “New Cyclization Reaction of 2- (Trimethylsilylmethyl)Pentadienal. Synthesis of Spiro[4.5]Decane Ring System.” Chem. Lett. 2000, 962-963.
Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.; Hirono, Y. “Nazarov Cyclization of 4-Cycloalkylidene-5-(Trimethylsilyl)Pent-1-en-3-one Derivatives. Synthesis of Spiro[4.5]decane, Spiro[4.4]nonane, and Their Derivatives.” Tetrahedron 2000, 56, 6441-6455. 184
Laurent, P.; Miyaji, H.; Collinson, S. R.; Proke, I.; Moody, C. J.; Tucker, J. H. R.; Slawin, A. M. Z. “Asymmetric Synthesis of Chiral -Ferrocenylalkylamines and Their Use in the Preparation of Chiral Redox-Active Receptors.” Org. Lett. 2002, 4, 4037- 4040.
Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. “Total Synthesis of (±)-Gelsemine.” Angew. Chem. Int. Ed. 1999, 38, 2934-2936.
Mander, L. N.; Williams, C. M. “Oxidative Degradation of Benzene Rings.” Tetrahedron 2003, 59, 1105-1136.
Martin, S. F. “Methodology for the Construction of Quaternary Carbon Centers.” Tetrahedron 1980, 36, 419-460.
Maryanoff, B. E.; Reitz, A. B. “The Wittig Olefination Reaction and Modifications Involving Phosphoryl-Stabilized Carbonanions. Stereochemistry, Mechanism, and Selected Synthetic Aspects.” Chem. Rev. 1989, 89, 863-927.
Mincione, E.; Pearson, A. J.; Bovicelli, P.; Chandler, M.; Heywood, G. C. “New Approach to the Synthesis of 6-Ketosteroids via Organoiron Complexes.” Tetrahedron Lett. 1981, 22, 2929-2932.
Molander, G. A.; Alonso-Alija, C. “Opening of Cyclopropyl Ketones with SmI2. Synthesis of Spirocyclic and Bicyclic Ketones by Intramolecular Trapping of an Electrophile.” Tetrahedron 1997, 53, 8067-8084.
Ng, F. W.; Lin, H.; Danishefsky, S. J. “Explorations in Organic Chemistry Leading to the Total Synthesis of (±)-Gelsemine.” J. Am. Chem. Soc. 2002, 124, 9812-9824.
O’Brien, M. K.; Pearson, A. J.; Pinkerton, A. A.; Schmidt, W.; Willman, K. “A Total Synthesis of (±)-Trichodermol.” J. Am. Chem. Soc. 1989, 111, 1499-1501.
Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. “Synthetic Methods and Rreactions. 96. Trichloromethylsilane/Sodium Iodide, A New Regioselective Reagent for Ether Cleavage.” Angew. Chem. Int. Ed. 1981, 20, 690-691.
Ondeyka, J.; Hensens, O. D.; Zink, D.; Ball, R.; Lingham, R. B.; Bills, G.; Dombrowski, A.; Goetz, M. “L-696,474, A Novel Cytochalasin as an Inhibitor of HIV-1 Protease. II. Isolation and Structure.” J. Antibiot. 1992, 45, 679-685.
Paris, M.; Pothion, C.; Heitz, A.; Martinez, J.; Fehrentz, J. “Synthesis of N- and Side Chain Protected Aspartyl and Glutamyl Aldehyde Derivatives. Reinvestigation of the Reduction of Weinreb Amides.” Tetrahedron Lett. 1998, 39, 1341-1344.
Pearson, A. J. “Natural Product Synthesis Using Organoiron Complexes.” Pure and Appl. Chem. 1983, 55, 1767-1779. 185
Pearson, A. J. “Organoiron Compounds in Stoichiometric Organic Synthesis.” In Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds; Pergamon press: Oxford, 1982; Vol. 8, pp 939-1012.
Pearson, A. J. “Transition Metal Alkene, Diene, and Dienyl Complexes: Nucleophilic Attack on Diene and Dienyl Complexes.” In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds; Pergamon Press: Oxford, 1995; Vol. 12, pp 637-684.
Pearson, A. J. “Tricarbonyl(Diene)Iron Complexes: Synthetically Useful Properties.” Acc. Chem. Res. 1980, 13, 463-469.
Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press: London, 1994.
Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. “Intramolecular Coupling Reactions of Allylic Thioesters with Diene Iron Tricarbonyl Systems.” J. Org. Chem. 1998, 63, 6610-6618.
Pearson, A. J.; Chandler, M. “Organoiron Complexes in Organic Synthesis. Part 24. Studies in the Synthesis and Reactivity of 6-Exo-substituted Cyclohexadienylium(tricarbonyl)iron Salts.” J. Chem. Soc., Perkin Trans. I 1982, 2641- 2146.
Pearson, A. J.; Chen, Y. S. “Organoiron Approach to 3,14-Dihydroxytrichothecenes.” J. Org. Chem. 1986, 51, 1939-1947.
Pearson, A. J.; Dorange, I. B. “Use of a Methoxy Substituent in Controlling the Stereochemistry of Intramolecular Iron-Mediated Diene/Olefin Cyclocoupling.” J. Org. Chem. 2001, 66, 3140-3144.
Pearson, A. J.; Heywood, G. C.; Chandler, M. “Organoiron Complexes in Organic- Synthesis. 23. New Strategies for Steroid and Aphidicolane Synthesis.” J. Chem. Soc., Perkin Trans. 1 1982, 2631-2639.
Pearson, A. J.; Kole, S. L.; Yoon, J. “Stereocontrolled Double Functionalization of (Cyclohexadiene)- and (Cycloheptadiene)iron Complexes via Oxidative Cyclization Techniques.” Organometallics 1986, 5, 2075-2081.
Pearson, A. J.; O’Brien, M. K. “Alkylation of Silyl Ketene Acetals with Dienyliron Complexes - Application in the Formation of Quaternary Carbon Centers.” Tetrahedron Lett. 1988, 29, 869-872.
Pearson, A. J.; O’Brien, M. K. “Reaction of Tin Enolates with Substituted Tricarbonylcyclohexadienyliumiron Hexafluorophosphate Electrophiles - Diastereoselective Synthesis of (±)- Trichodiene.” J. Chem. Soc., Chem. Commun. 1987, 1445-1447. 186
Pearson, A. J.; O’Brien, M. K. “Trichothecene Synthesis Using Organoiron Complexes - Diastereoselective Total Syntheses of (±)-Trichodiene, (±)- 12,13-Epoxytrichothec-9- Ene, and (±)-Trichodermol.” J. Org. Chem. 1989, 54, 4663-4673.
Pearson, A. J.; Ong, C. W. “Organoiron Complexes in Organic Synthesis. 25. Complete Stereocontrol in the Synthesis of 4,4,5-Trisubstituted Cyclohexenones.” J. Org. Chem. 1982, 47, 3780-3782.
Pearson, A. J.; Ong, C. W. “Trichothecene Analogs - Total Synthesis of 12,13-Epoxy-14- Methoxytrichothecene via Organoiron Complexes.” J. Am. Chem. Soc. 1981, 103, 6686- 6690.
Pearson, A. J.; Raithby, P. R. “Organoiron Complexes in Organic Synthesis. Part 4. Direct-Ring Connection between Highly Substituted Centers. A Potential Approach to Trichothecane Synthesis.” J. Chem. Soc., Perkin Trans. 1 1980, 395-399.
Pearson, A. J.; Rees, D. C. “Organoiron Complexes in Organic-Synthesis. 22. Total Synthesis of (±)-Limaspermine and Formal Synthesis of (±)- Aspidospermine Using Organoiron Complexes.” J. Chem. Soc., Chem. Commun. 1982, 2467-2476.
Pearson, A. J.; Rees, D. C. “Total Synthesis of (±)-Limaspermine Derivatives Using Organoiron Chemistry.” J. Am. Chem. Soc. 1982, 104, 1118-1119.
Pearson, A. J.; Rees, D. C.; Thornber, C. W. “Synthetic Approaches to C-18 Oxygenated Aspidosperma Alkaloids via Organoiron Complexes.” J. Chem. Soc., Perkin Trans. 1 1983, 619-623.
Pearson, A. J.; Zettler, M. W. “Control of Absolute Stereochemistry During Ene-Type Coupling between Diene-Fe(CO)3 Groups and Alkenes.” J. Chem. Soc., Chem. Comm. 1987, 1243-1245.
Pearson, A. J.; Zettler, M. W. “Intramolecular Coupling between Tricarbonyl(diene)iron Complexes and Pendant Alkenes.” J. Am. Chem. Soc. 1989, 111, 3908-3918.
Pearson, A. J.; Zettler, M.; Pinkerton, A. A. “Intramolecular Ene-Type Reaction between a Diene-Fe(CO)3 Complex and Alkene Units.” J. Chem. Soc., Chem. Commun. 1987, 264-266.
Pohmakotr, M.; Bunlaksananusorn, T.; Tuchinda, P. “A General Strategy to Spiro[4.n]alk-2-ene-1,6-Diones and Spiro[5.n]alk-2-ene-1,7-diones via Intramolecular Acylation of α-Sulfinyl Carbanions.” Tetrahedron Lett. 2000, 41, 377-380.
Rich, D. H.; Sun, E. T.; Boparai, A. S. “Synthesis of (3S,4S)-4-Amino-3-hydroxy-6- methylheptanoic Acid Derivatives. Analysis of Diastereomeric Purity.” J. Org. Chem. 1978, 43, 3624-3626.
187
Robertson, J.; Lam, H. W.; Abazi, S.; Roseblade, S.; Lush, R. K. “Radical Cascade Processes Leading to Fused- and Spiro-Bicyclic Ring Systems.” Tetrahedron 2000, 56, 8959-8965.
Rodríguez, A. D.; González, E.; Huang, S. D. “Unusual Terpenes with Novel Carbon Skeletons from the West Indian Sea Whip Pseudopterogorgia Elisabethae (Octocorallia).” J. Org. Chem. 1998, 63, 7083-7091.
Rodríguez, J.; Brun, P.; Waegell, B. “Isomerization of Functionalized 1,5-Dienes with Pentacarbonyliron.” J. Organomet. Chem. 1989, 359, 343-369.
Sannigrahi, M. “Stereocontrolled Synthesis of Spirocyclics.” Tetrahedron 1999, 55, 9007-9071.
Sato, Y.; Honda, T.; Shibasaki, M. “A Catalytic Asymmetric Synthesis of Hydrindans.” Tetrahedron Lett. 1992, 33, 2593-2596.
Sattelkau, T.; Eilbracht, P. “Diastereospecific Synthesis of Spiro[4.5]decan-2-ones as Vetivane Precursor via Rhodium Catalysed Claisen Rearrangement/Hydroacylation.” Tetrahedron Lett. 1998, 39, 1905-1908.
Shibata, T.; Yamashita, K.; Takagi, K.; Ohta, T.; Soai, K.; “Inter- and Intramolecular Carbonylative Alkyne – Alkyne Coupling Reaction Mediated by Cobalt Carbonyl Complex.” Tetrahedron 2000, 56, 9259-9267.
Shvo, Y.; Hazum, E. “A Simple Method for the Disengagement of Organic Ligands from Iron Complexes.” J. Chem. Soc., Chem. Commun. 1974, 336-337.
Srikrishna, A.; Kumar, P. P. “Claisen Rearrangement Based Methodology for the Spiroannulation of a Cyclopentane Ring. Formal Total Synthesis of (±)-Acorone and Isoacorones.” Tetrahedron 2000, 56, 8189-8195.
Stille, J. K.; Becker, Y. “Isomerization of N–Allylamides and –imides to Aliphatic Enamides by Iron, Rhodium, and Ruthenium Complexes.” J. Org. Chem. 1980, 45, 2139- 2145.
Strauss, J. U.; Ford, P. W. “Stereochemistry and Mechanism of Iron Carbonyl-Induced Olefin Isomerization in Allylic Alcohols.” Tetrahedron Lett. 1975, 33, 2917-2918.
Takahashi, M.; Tanaka, M.; Sakamoto, E.; Imai, M.; Matsui, A.; Funakoshi, K.; Sakai, K.; Suemune, H. “Application of Rh-Catalyzed Cyclization for the Construction of Three Consecutive Chiral Carbons in 4,9- Dimethylspiro[4.4]nonane-2,7-dione.” Tetrahedron Lett. 2000, 41, 7879-7883.
Tomioka, K.; Shioya, Y.; Nagaoka, Y.; Yamada, K. “Electronic and Steric Control in Regioselective Addition Reactions of Organolithium Reagents with Enaldimines.” J. Org. Chem. 2001, 66, 7051 -7054. 188
Trost, B. M.; McDougal, P. G.; Haller, K. J. “A Tandem Cycloaddition-Ene Strategy for the Synthesis of (±)-Verrucarol and (±)-4,11-Diepi-12,13-Deoxyverrucarol.” J. Am. Chem. Soc. 1984, 106, 383-395.
Uma, R.; Crevisy, C.; Grée, R. “Transposition of Allylic Alcohols into Carbonyl Compounds Mediated by Transition Metal Complexes.” Chem. Rev. 2003, 103, 27-51.
Verardo, G.; Giumanini, A. G.; Strazzolini, P.; Poiana, M. “Reductive N-Monoalkylation of Primary Aromatic Amines.” Synthesis 1993, 121-125.
Whitesides, T. H.; Neilan, J. P. “Thermolysis of Diene Iron Tricarbonyl Complexes. Cis- Trans Isomerization and Hydrogen Scrambling Reactions in Cyclic and Acyclic Complexes.” J. Am. Chem. Soc. 1976, 98, 63-73.
Yeh, M. P.; Sheu, B.-A.; Fu, H.-W.; Tau, S.-I.; Chuang, L.-W. “Construction of Bridged and Fused Bicyclic Skeletons via Intramolecular Addition of Nucleophiles to (η4- Diene)Fe(CO)3 Complexes Bearing Functionalized Side Chains.” J. Am. Chem. Soc. 1993, 115, 5941-5952.
Yokoshima, S.; Tokuyama, H.; Fukuyama, T. “Enantioselective Total Synthesis of (+)- Gelsemine: Determination of Its Absolute Configuration.” Angew. Chem. Int. Ed. 2000, 39, 4073-4075.