A NEW SYNTHETIC PATHWAY FOR DIQUINANE AND ANGULAR
TRIQUINANE SYSTEMS
by
Eun Hoo Kim
Submitted in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Thesis Advisor: Prof. Anthony J. Pearson
Department of Chemistry
CASE WESTERN RESERVE UNIVERSITY
May 2010 CASE WESTERN RESERVE UNIVERSITY
SCHOOL OF GRADUATE STUDIES
We hereby approve the dissertation of
Eun Hoo Kim
candidate for the Ph.D. degree*.
(signed) Prof. Michael, Zagorski (Chair of the Committee, Department of
Chemistry, CWRU)
Prof. Anthony J. Pearson (Department of Chemistry, CWRU)
Prof. Robert G. Salomon (Department of Chemistry, CWRU)
Prof. Geneviève Sauvé (Department of Chemistry, CWRU)
Prof. Bin Su (Department of Chemistry, Cleveland State University)
Date: 26st Februray 2010
*We also certify that written approval has been obtained for any propriety material contained therein.
To my family & my teachers
Table of Contents
List of Tables ……………………………………………………………………..……vi
List of Figures ………………………………………………………………………….. vii
List of Schemes …………………………………………………………………….…….ix
Acknowledgements ……………………………………………………….…..…….…xii
List of Abbreviations…………………………………………………….……………xiii
Abstract …………………………..…………………………………………………..…xvi
CHAPTER 1. Background: Iron Carbonyl Chemistry And Synthesis of Triquinane
Natural Products ………………………………………………………………………...... 1
1.1 Background : Fe(0) chemistry .…………………………………………………..2
1.2 Synthesis of triquinane natural products………………………………..………14
1.2.1. Diquinanes …………………………………………………………………..…15
1.2.2. Triquinanes ………………………………………………………………….…16
1.2.3 Syntheses of pentalenene ………………………………………………….….18
1.3 References …………………………………………………………………….…27
CHAPTER 2. Synthesis of Azatriquinane System………………………………………30
2.1 Introduction …………………………………………………………………...…31
2.2 Synthesis of a model compound ……………………………………………..…36
2.2.1. Synthesis of iron complexed structure/demetallated structure ...... ……..36
iv 2.2.2. Oxidative cleavage of double bonds to give carbonyl compounds………47
2.3.4. Studies of aldol condensation conditions………………………………...54
2.3 Conclusions ……………………………………………………………………...57
2.4 Experimental section ……………………………………………………….……58
2.5 References ……….………………………………………………………………68
CHAPTER 3. Studies Directed Towards Synthesis of All-Carbon Triquinane Systems .71
3.1 Introduction ………………………………………………………………...... 72
3.2 Single cyclization ………………………………………………………………..77
3.3 Double cyclization .……………………………………………………………...93
3.4 Conclusions ………………………………………………………………..….…97
3.5 Experimental section ………………………………………………………….....98
3.6 References ……………………………………………………………………...108
APPENDIX ..…………………………………………………………………………..110
BIBLIOGRAPHY ……………………………………………………………………...143
v List of Tables
Table 1.1. Double cyclization of amide complexes 1.34 ……………………………...11
Table 2.1. Cyclization of amide complexes 2.32 ………………………….…………….43
Table 2.2. Dematallation of the iron complex 2.33 ……………………………………..45
Table 2.3. Ozonolysis of the compound 2.14 …………………………………………...48
Table 2.4. OsO4/NaIO4 oxidation of the compound 2.14 ………………………….……51
Table 2.5. RuO4 oxidation of the compound 2.14 ………………………………………52
Table 2.6. Intramolecular aldol cyclization to afford model compound 2.16 …………..55
vi List of Figures
Figure 1.1. Z/E conformations of esters (thioesters) …………………………………...... 4
Figure 1.2. Orbital interactions for amides, esters, and thioesters ………………………..4
Figure 1.3. Conformational preferences for amides ...... 4
Figure 1.4. Comparison of cis vs trans h3-metallacyle intermediate ……………………..6
Figure 1.5. NOE effects …………………………………………………………………12
Figure 1.6. Polyquinane carbocyclic skeletal …………………………………………...14
Figure 1.7. Diquinanes ……………………………………………………………….….15
Figure 1.8. Three major forms of triquinanes …………………………………………...17
Figure 1.9. Pentalenene pentalenic acid and pentalenolactone H system ……………….17
Figure 2.1. 1H NMR spectrum of iron complexed methyl ester 2.37 …………………...39
Figure 2.2. 1H NMR spectrum of iron complexed methyl ester 2.38 …………...………40
Figure 2.3. 1H NMR spectrum of iron complexed acid 2.39 ……………………………41
Figure 2.4. 1H NMR spectrum of iron complexed acid 2.32 ……………………………43
Figure 2.5. 1H NMR spectrum of cyclized product 2.33 ………………………………..45
Figure 2.6. 1H NMR spectrum of demetallated product 2.14 …………………………...46
Figure 2.7. 1H NMR spectrum of cleaved cyclized product 2.15 ……………………….53
Figure 2.8. 1H NMR spectrum of aldol reaction product 2.16 ………………….……….56
Figure 3.1. 1H NMR spectrum of cleavage product 3.37 ………………………………..79
Figure 3.2. 1H NMR spectrum of cleavage product 3.39 ………………………………..83
Figure 3.3. Four possible isomers from the Grignard reaction and cyclization …………87
Figure 3.4. 1H NMR spectrum of cleavage product 3.51 and 3.52 ………………….….89
Figure 3.5. 1H NMR spectrum of oxidation product 3.66 ………………………………91
vii Figure 3.6. 1H NMR spectrum of oxidation product 3.67 ……………………..………..91
viii List of Schemes
Scheme 1.1. Intramolecular coupling of olefin with diene-Fe(CO)3 moiety …………….2
Scheme 1.2. Proposed mechanism of the spirocyclization ……………………………....5
Scheme 1.3. The stereochemistry of intermediates ………………………………………7
Scheme 1.4. Racemization due to precyclization rearrangement ………………………..8
Scheme 1.5. The use of methoxy group at 3-positon …………………………………….9
Scheme 1.6. Steroselective tandem double cyclization ………………………………….9
Scheme 1.7. Consideration of the mechanism …………………………………………..10
Scheme 1.8. Proposed mechanism for double cyclization under thermal conditions …...12
Scheme 1.9. Formation of the trans-fused diquinane system …………………………...16
Scheme 1.10. The first synthesis of epi-pentalenene ……………………………………19
Scheme 1.11. [3+2]-Annulation strategy to pentalenolactone-E methyl ester ………….20
Scheme 1.12. Stereospecific pathway to pentalenolactone ……………………………..21
Scheme 1.13. Stereospecific pathway to pentalenic acid ……………………………….22
Scheme 1.14. New rapid assembly method using cascade pathway ……………………23
Scheme 1.15. Stereospecific pathway to pentalenolactone ……………………………..24
Scheme 1.16. The formation of pentalenene from farnesyl diphosphate ……………….24
Scheme 1.17. Two pathways to pentalenene and intermediates ………………………...25
Scheme 2.1. Iron promoted [6+2] ene type of spirocyclization …………………………31
Scheme 2.2. Cyclization of dienyl amide complex with 3-position substitution ………..32
Scheme 2.3. A new pathway to triquinane systems ……………………………………..33
Scheme 2.4. 6- to 5-membered ring contraction pathway ………………………………34
Scheme 2.5. Aldol reaction in total synthesis of silphinene …………………………….35
ix Scheme 2.6. Proposed synthesis of model compound 2.21 ……………………………..36
Scheme 2.7. Synthesis of iron-complexed acid 2.39 ……………………………………37
Scheme 2.8. Direct iron complexation of 1,4-diene compound 2.35 …………………...38
Scheme 2.9. Preparation of amine 2.41 …………………………………………………39
Scheme 2.10. Ozonolysis to cleave double bonds of complex molecules ………………47
Scheme 2.11. OsO4 oxidative cleavage reactions ……………………………………….49
Scheme 2.12. OsO4 oxidation used in preparing natural product stephaoxocane 2.56 …49
Scheme 2.13. OsO4/NaIO4 cleavage and aldol reactions applied to aphidicolin and
phytuberin intermediates ………………………………………………………………...50
Scheme 2.14. Mild conditions of intramolecular aldol reaction for tricyclic structure …54
Scheme 3.1. Single cyclizations of esters from iron-complexed acid ………………….62
Scheme 3.2. Single cyclizations of amides and thioesters from iron-complexed acid ….63
Scheme 3.3. Proposed mechanism of the cyclization …………………………………...63
Scheme 3.4. Optimization of single cyclization ………………………………………...74
Scheme 3.5. Proposed mechanistic rationale for the cyclization ………….…………….75
Scheme 3.6. Proposed synthesis of an all-carbon angular triquinane ..………………….76
Scheme 3.7. Intramolecular iron-mediated diene/olefin cyclocoupling ………………...77
Scheme 3.8. Preparation of pendant ene compound …………………………………….78
Scheme 3.9. Undesired nucleophilic addition product ………………………………….78
Scheme 3.10. Formation of mesylate and anhydride ……………………………………80
Scheme 3.11. Generation of alkoxide in Grignard reaction ……………………………..81
Scheme 3.12. Alternative Grignard reaction using aldehyde 3.41 …………...…………84
Scheme 3.13. Preparation of the iron-complexed aldehyde 3.41 ……………………....85
x Scheme 3.14. Overall comparison of the synthetic methods of aldehyde 3.41 …………86
Scheme 3.15. The result of single cyclization reaction ……………………………..….90
Scheme 3.16. Proposed scheme to construct a triquinane system ………………..…….94
Scheme 3.17. Preparation of bromide 3.73 for Grignard reaction ………………………95
xi Acknowledgements
I would like to express my sincere appreciation and thanks to Prof. Anthony J.
Pearson for his support and understanding throughout my thesis. With his patience and knowledge, I was encouraged to finish this long journey. His mentorship and understanding has helped me tremendously in achieving my goal. Without him this thesis would not have been completed.
I would like to thank the Department of Chemistry, Case Western Reserve
University and National Science Foundation for financial contributions.
I would like to thank my committee members, Dr. Michael Zagorski, Dr. Robert
Salomon, Dr. Geneviève Sauvé, and Dr. Bin Su for their help and advice. I would also like to thank Dr. Kee-Jung Lee for introduction to organic chemistry at Hanyang
University in South Korea.
I would like to thank my friends and colleagues from the Pearson group, especially to Huikai Sun who gave a lot of advice and worked with me in the laboratory.
All the lab members made my stay worth remembering.
Finally, I would like to thank my parents and family for supporting me throughout all my studies.
xii List of Abbreviations
ADDP Azodicarbonyl dipiperidine AIB Anisyl isoborneol Atm Atmosphere(s) BMPA Bis(4-methyl-1-piperazinyl)aluminum hydride Bn Benzyl br Broad (for NMR listings) CCS 13C NMR chemical shift COSY Correlation spectroscopy Cp Cyclopentadienyl d Doublet DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC N,N’-Dicyclohexylcarbodiimide DCE 1,2-dichloroethane dd Doublet of doublets DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone de Diastereomeric excess DIBAl Di-isobutylaluminum hydride DIPEA Diisopropylethylamine DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide DMS Dimethyl sulfide DMSO Dimethyl sulfoxide ee Enantiomeric excess EI HRMS Electron impact high resolution mass spectrometry FAB HRMS Fast atom bombardment high resolution mass spectrometry FT-IR Fourier transform infra-red (spectroscopy) h Hour(s) HMPA Hexamethylphosphoric triamide
xiii HMQC Hetero molecular quantum correlation (spectroscopy) HOMO Highest occupied molecular orbital HSQC Hetero quantum correlation (spectroscopy) iPr Isopropyl LDA Lithium di-isopropylamide LDBB Lithium 4,4’-di-tert-butylbiphenylide LUMO Lowest unoccupied molecular orbital m Multiplet
Me CH3 min Minute(s) mp Melting point MM2 Molecular mechanics MO Molecular orbital Ms Mesyl (methanesulfonyl) MS Molecular sieves NMR Nuclear magnetic resonance NOE Nuclear overhauser effect PCC Pyridinium chlorochromate PLC Preparative thin layer chromatography ppm Parts per million PPTS Pyridinium p-toluenesulfonate PtlA Pentalenene synthase q Quartet rt Room temperature
Rf Retention factor S Singlet satd Saturated t Triplet tert Tertiary TBAF Tetrabutylammonium fluoride TBDMS Tert-butyldimethylsilyl
xiv THF Tetrahydrofuran TLC Thin-layer chromatography TMS Tetramethylsilane (NMR standard) or trimethylsilyl (substituent) Ts Tosyl = 4-methylphenylsulfonyl TS Transition State UV Ultra violet (light) V/V Volume ratio
xv
A New Synthetic Pathway for Diquinane And Angular Triquinane Systems
Abstract
by
Eun Hoo Kim
A new application for intramolecular double cyclization methods using cyclohexadiene-Fe(CO)3 complexes and pendant conjugated dienes is described in this thesis. An azatriquinane system and an all-carbon system were studied using the iron- promoted double cyclization followed by ozonolysis and intramolecular aldol reaction, which is potentially useful for synthesis of various diquinane and angular triquinane natural products.
xvi Control of the stereochemical outcome of these cyclization reactions has been
previously reported and confirmed in our group. The present work represents the first applications of this methodology to the synthesis of triquinane structures. During the investigation of an all carbon system, a stereoselective Grignard addition was observed. It is the first example for the iron complexed cyclic diene structure. This study can be applied and expanded to synthesize pentalenene natural products.
Fe(CO)3 Fe(CO)3 Fe(CO)3
H COOH O OH
(OC)3Fe
hv CuCl2, EtOH
O HO HO
xvii
CHAPTER 1
Background : Iron(0) Chemistry And Synthesis of Triquinane Natural Products
1 1.1 Background : Fe(0) chemistry
Iron carbonyls have been widely used in organic synthesis, acting as catalysts to isomerize double bonds, activation groups, stereodirecting groups, protective groups for
conjugated dienes, and transition metal complexes to mediate stereoselective functional
group transformations.1,2,3,4,5
Green and co-workers6 introduced a new reaction in which complexes such as 1.1
and electron-deficient olefins 1.2 combine under photochemical conditions to furnish π-
allyl complex 1.3 (eq 1.1).
(CO)3 Fe(CO)3 CF2=CF2 Fe 1.2 CF2 (1.1) CF h 2 1.1 1.3
Based upon these results, Pearson and co-workers developed an intramolecular
reaction under thermal (CO atmosphere, n-butyl ether, reflux)6 or photothermal (CO,
benzene, 80 C, 350 nm) conditions to form spirolactones, spirothiolactones and
spirolactams as outlined in Scheme 1.1. 7,8,9
The best substrates for these intramolecular cyclocouplings were found to be the amide derivatives. The cyclization of ester derivatives was limited to a low degree of substitution on the pendant olefin and often required photothermal conditions, whereas the cyclization of the analogous amide derivatives proceeded in good yields under standard thermal conditions.
2 (OC) Fe (OC) Fe n-Bu O 3 3 2 X = NPh 95% CO X = O 88% X 142 oC X = S 90%
O O X 1.4 1.5
(OC)3Fe (OC)3Fe n-Bu2O CO X = NPh 90% o X = O 40% X 142 C X = S 45% O O X 1.6 1.7
(OC)3Fe (OC)3Fe n-Bu2O CO N O 142 oC O Ph 85% O N O Ph 1.8 1.9
Fe(CO)3 (OC) Fe n-Bu2O 3 CO 142 oC N Ph 58% O N O Ph 1.10 1.11
Scheme 1.1. Intramolecular coupling of olefin with diene-Fe(CO) moiety 3
The greater reactivity of amides vs esters or thioesters can be understood from the following considerations. In the case of the Z conformation, and only in the case of the Z conformation for carboxylic acid derivatives, there is secondary orbital interaction between the lone pair of the ester oxygen or of the thioester sulfur (oriented
antiperiplanar to the CO bond) and the * orbital of the C-O carbonyl bond which
stabilizes the Z conformation over the E conformation (Figure 1.2, A vs B). As a result,
esters and thioesters adopt preferentially the Z conformation.
3 O O R R X X R R
Z-conformation E-conformation
Figure 1.1. 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 1.2. Orbital interactions for amides, esters, and thioesters
(OC)3Fe (OC)3Fe
N N O 1.12 1.13 O
Figure 1.3. Conformational preferences for amides
Amides display a similar primary electronic effect (Figure 1.2, C), delocalization
of the nitrogen lone pair through the carbonyl oxygen, but there is only one secondary electronic effect present, i.e., interaction of the lone pair of the carbonyl oxygen antiperiplanar to the C-N bond with the * orbital. The other interaction that is observed for esters is lacking because there is only one lone pair on nitrogen. Therefore, amides
4 adopt preferentially the less sterically hindered conformation as exemplified in Figure
1.3. Thus N-phenyl-N-allyl amide complex 1.12/1.13 adopts preferentially the conformation of 1.13, which places the olefinic group closer to the iron and therefore is the more favorable conformation for cyclization. Since esters or thioesters adopt preferentially the Z conformation, a higher energy barrier must be overcome to bring together the reactive sites. Because there is an increase in the energy barrier due to more steric interactions on substitution of the pendant olefin, why esters or thioesters are much less reactive compared to amides.
The mechanism and stereoselectivity of this reaction were probed by labeling and
X-ray crystallographic studies (Scheme 1.2).1
(OC)3Fe (OC)2Fe (OC)2Fe
X or h X X O CO O O 1.14 1.15 1.16
H
(CO)2Fe (CO)2Fe (CO)2Fe CH3 H H H 4 H X X O X O O 1.17 1.18 1.19
(CO)3Fe CH3 CO H X = O, NPh, CH2 O X 1.20
Scheme 1.2. Proposed mechanism of the spirocyclization
5 One CO ligand is ejected from complex 1.14 under thermal or photothermal conditions to create a vacant coordination site, which is then stabilized by coordination of the pendant olefin to the metal (see 1.16). Cyclization leads to metallacycle 1.17 which, after hydrogen migration (1.18) followed by reductive elimination, furnishes 1.19. The
16-e complex then recaptures one CO ligand to produce spirocomplex 1.20. The net result is equivalent to a [6 + 2] ene reaction.
As indicated in Scheme 1.2 the cyclization reaction from 1.16 to 1.17 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 metallabicyclooctane 1.17, the cis junction is exclusively formed, fixing the C(4) position stereochemistry (Figure 1.4).
Favored metallacycle LnFe H LnFe H 4 O X X O Highly strained H metallacycle LnFe H LnFe
O X = O, NPh, CH2 X X O
3 Figure 1.4. Comparison of cis vs trans h -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
enantiopurity, when chiral nonracemic starting material was used (Scheme 1.3). Partial
6 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.11 The detailed sequence of precyclization rearrangement is shown in Scheme 1.4. The formation of epimers is a result of rearrangement of the diene-
Fe(CO)3 by hydride 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
Diastereoisomers Enantiomers Racemization Enantiomers
(OC)3Fe (OC)3Fe Me Me Cyclization Rearrangement N Ph O N (OC)3Fe O N O Ph Ph
Scheme 1.3. The stereochemistry of intermediates
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 1.3 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.10
7 Fe(CO)3 Fe(CO)3 1.21 R R R H Fe(CO)3 H 1.14
H H
(OC)3Fe R H R 1.22 R H Fe(CO)3 Fe(CO)3 1.21'' 1.21'
H
R = CO·XCH CH=CH (OCH)3Fe R 2 2 R Fe(CO)3
1.23 ent-1.14
Scheme 1.4. Racemization due to precyclization rearrangement
When a methoxy group is introduced at the 3-position of the complex, cyclization
followed by demetalation and hydrolysis gives a single enone diastereomer as product (X
= NPh, Scheme 1.5).8 Unfortunately, the reaction is very sensitive to substitution on the
pendant double bond, which makes the reaction very slow under thermal cyclization
conditions.
8 OMe OMe OMe O (OC)3Fe (OC)3Fe 3 Fe(CO)3 i)Demetallation 4 2 + + X n-Bu O ii) H3O 5 1 2 6 CO X X X O 142 oC O O O
1.24 1.25 1.26 1.27 X = O, NPh, CH2
Scheme 1.5. The use of methoxy group at 3-positon
This methodology has also been applied to the synthesis of all-carbon spirocyclic
9 molecules (X = CH2, Scheme 1.5), but only a few successful examples were presented.
Recently, Pearson and Wang reported an intramolecular double cyclization using cyclohexadiene-Fe(CO)3 complexes and pendant conjugated dienes under thermal conditions. Further development of this reaction resulted in stereospecific tandem coupling reactions, e.g. 1.30 was obtained as a single diastereomer (Scheme 1.6).12
Me3NO,PhH
n-Bu2O (OC)3Fe Fe(CO)3 CO + 142 oC N Ph O O N O N Ph Ph
1.28 1.29 1.30
Scheme 1.6. Stereoselective tandem double cyclization
9 Examination of the mechanism (Scheme 1.2) shows that the formal [6+2] ene
cyclization requires a 5-endo hydrogen (see structure 1.31 for numbering) to be
transferred within the cyclohexadiene ring. The cyclization products 1.32a and 1.32b both fulfill this requirement (H10-endo in 1.32a and 1.32b). If another pendant double bond is aligned in the proper position, a second cyclization might occur. If R = vinyl,
1.32a can give 1.33 by coupling of C(12) and C(6) followed by hydrogen transfer. The same C(12)-C(6) coupling in 1.32b would be too strained, since C(12) and C(6) are on opposite sides of the lactam ring. As 1.32a and 1.32b are in equilibrium under the cyclization conditions, a single diastereomerically pure tricyclic product 1.33 should be produced exclusively after two successive cyclizations.
R Fe(CO) n-Bu O 3 (OC) Fe 7 (OC)3Fe 3 Fe(CO) 2 R 3 in situ 3 CO 8 6 4 2 cyclization o 9 5 1 N 142 C Ph 10 H5 N N 1.32a O O O N O Ph Ph epimerization R = vinyl Ph of product 1.31 1.33 13 (OC) Fe 3 R (OC)3Fe 9 11 10 12 8 Conditions not met 7 4 5 3 for cyclization 6 1 2 N N 1.32b O O Ph Ph
Scheme 1.7 Consideration of the mechanism
The reaction proceeded as predicted. Amide compounds in anhydrous n-Bu2O
(0.02 mol/L) under carbon monoxide atmosphere yielded a single diene-Fe(CO)3 complex 1.35a in 75% yield. No other diastereomers were detected in the 1H NMR
10 spectrum of the reaction mixture. The only side products detected appear to be isomers of the starting material (<2% yield) and in some cases the demetallated product 1.36.
6 Demetalation of 1.35a using Me3NO in benzene produced 1.36a almost quantitatively.
Table 1.1. Double cyclization of amide complexes 1.34
R2 Me3NO PhH R1 R2 R1 R2 R1 n-Bu2O Fe(CO)3 CO (OC) Fe + 142 oC 3 N Ph O O O N N Ph Ph 1.34 1.35 1.36
1 2 a b c Reactant R , R Time Product [c] Yield 1.36/%
1.28 H, Me 10 1.29 0.02 75
1.34b OMe, Me 24 1.36b 0.004 54
1.34c H, CO2Me 12 1.36c 0.004 51
1.34d OMe, CO2Me 24 1.36d 0.004 34
a Reaction time for cyclization step. b Concentration(mol/L) of reactant 1.34. c Overall yield from 1.34 after demetalation, two steps.
The stereochemistry of 1.35a was determined by 2D COSY and 2D NOESY
experiments (Figure 1.35).13 The detailed proposed mechanism is shown in Scheme 1.8.
11 H11 R1 11 H11 6 H5a 7 H 5a 5 5 4 (OC)3Fe 10 8 9 3a H3a NOE 1 H9 3 O N 2 H3 Ph NOE
1.35
Figure 1.5. NOE effects
(OC)2Fe Fe(CO) 3 Fe(CO)2 (OC)2Fe - CO H N N H Ph N Ph Ph N O O O O Ph 1.34a 1.37 1.38 1.39
(OC) Fe (OC)3Fe (OC)2Fe H 2
H H 1.43 1.39 H N N O O O N Ph Ph Ph 1.40 1.41 + CO H
(OC)2Fe (OC)3Fe 1.44 (OC)2Fe H O H N N O Ph Ph N O Ph 1.42 + CO + CO 1.40'
(OC)3Fe H (OC)3Fe
N O 1.35a Ph O N 1.42' Ph
Scheme 1.8. Proposed mechanism for double cyclization under thermal conditions.
12 The previous work in our group proposed CO dissociation of compound 1.34a
under thermal conditions,6 followed by iron coordination with one of the pendant double
bonds to generate intermediate 1.38. Eventually, the compound 1.34a undergoes two successive ene-like reactions to compound 1.35a. Also both newly generated C-C bonds are endo to the iron atom, which gives a single diastereomer. Thermal rearrangement of
1.40 to 1.40’ is not problematic as 1.40’ cannot undergo cyclization. Its reversion to 1.40
allows the reaction to proceed along a single pathway through 1.41.13
13 1.2 Synthesis of triquinane natural products
Polyquinane natural products represent a rapidly growing subgroup among the terpenes. The word “poly+quin+ane”, quin (meaning five), indicates that the molecule is composed entirely of fused five-membered rings.14 Polyquinane natural products have been known since the first determination of the structure of hirsutic acid-C in 1966. Four main skeleta represent the fused five-membered ring systems (Figure 1.6).
Diquinane Linear triquinane
Angular triquinane Angular tetraquinane
Figure 1.6. Polyquinane carbocyclic skeleta
The polyquinane natural products are structurally challenging and evoked great interest due to wide-ranging biological activities and synthetic challenges. Therefore, the synthesis of polyquinane natural products has continued to be an active and exciting area of research in organic chemistry since the 1970s. The remainder of this chapter will outline some of the broad background information about diquinanes and triquinanes, as a prelude for the proposed application of the aforementioned iron mediated double cyclization to the construction of angular triquinanes.
14 1.2.1. Diquinanes
Diquinane structures, e.g. albane,15 gymnomitrane,16 cedrane,17 have been known
for a while, but only recently were isolated directly from natural products. Xestenone18 and chloriolin19 are representative ring systems and interesting structures considered
more popular targets by synthetic chemists over the years.
Albane 1.44 Cedrane 1.46 Gymnomitrane 1.47
H OH H HO
Cl H OH O O
Xestenone 1.48 Chloriolin-A 1.49
Figure 1.7. Diquinanes
Cohen and co-workers generated the trans-fused diquinane skeleton through the
use of intramolecular addition of an alkylithium, formed by reductive lithiation of a
tertiary alkyl thiophenyl ether to an alkene. The cyclization is favored by the accelerating effect of a neighboring oxyanionic group. Due to the fused ring strain, a trans-fused diquinane is energetically less favorable than a cis-fused diquinane. Allylic lithium
oxyanionic groups on the alkenes greatly enhace the stereoselectivity of cyclization and also
15 lead to increase rate of cyclization. Relatively inaccessible trans-bicyclo[3.3.0]octanes
were prepared by this method.20
H OH H OH 1. n-BuLi
SPh 2. LDBB, - 78 °C, 1h D H H 3. CD3OD
1.50 1.51
Scheme 1.9. Formation of the trans-fused diquinane system
1.2.2. Triquinanes
Triquinanes consist of three types of skeletal carbon structures: Linear triquinane,
angular triquinane, and propeller shaped propellanes. Hirsutene 1.50 and Capnellene
1.51 are well-known simpler linear triquinanes. Hirsutene21 has antibiotic and antitumor
properties and was one of the first polyquinanes to be synthesized by chemists.
Capnellene,22 synthesized in 1978 for the first time, is the parent hydrocarbon23 and presumed biosynthetic precursor of the Capnellanes. Its derivatives24-27 were presumably
developed as chemical defense systems during the growth of microorganisms.28
Isocomene 1.55 29 is a sesquiterpene hydrocarbon belonging to the angular triquinanes.30
Pentalenene 1.54 31 is also an angular triquinane and is a potential target molecule related
to our model studies described in chapters 2 and 3. Modhephene 1.5632 is the first
16 carbocyclic [3,3,3]propellane to be isolated from nature. Since then many chemists have developed creative syntheses of this interesting propeller skeleton structure.32, 33, 34
H H H
H Hirsutene Capnellene Pentalenene Isocomene Modhephene
1.52 1.53 1.54 1.55 1.56 propeller linear angular shaped
Figure 1.8. Three major forms of triquinanes
1.2.3. Syntheses of Pentalenene
(+)-Pentalenene (1.54), isolated from Streptomyces griseochromogenes, has been studied because of its promising bioactivities and its biogenesis through the humulene cyclization cascade.30, 35 Both pentalenene and pentalenic acid (Figure 1.9) are key compounds of the pentalenolactone family of antibiotics. Since these compounds are potentially accessible using the tandem-ene cyclization reactions discussed in this thesis, earlier total syntheses will be briefly described here. Several new syntheses of 1.54 have followed the first two syntheses by Paquette36 and Matsumoto37 in the early 1980s.38
17 H
1.54
O O HO O H H 1.55 CO2H 1.57 CO2Me
HO H
Pentalenolactone H system. Pentalenic Acid
Figure 1.9. Pentalenene, pentalenic acid and pentalenolactone H system
Paquette and Annis (Scheme 1.10) started with silyl enol ether 1.58, prepared
from 4,4-dimethyl-2-cyclopentenone, which was condensed with dichloroketene to
furnish cyclobutanone 1.59.39 After further manipulation through hemiketal 1.60, the
cyclopentanone 1.62 resulted from treatment of 1.61 with diazomethane.40,41 The conjugated compound 1.63 was obtained by Zn/CH3COOH reduction of 1.62, and
further lithium bis(3-butenyl)cuprate addition provided pendant ene-compound 1.64.42
Grignard reaction led to intermediate 1.65. The third cyclopentane ring was generated
(Scheme 1.10) via acetal 1.66, 1.6743 and aldehyde 1.6844 that anchor Prins cyclization,
PCC oxidation of either the exo or endo alcohol that is produced by cyclization of 1.68
delivered ketone 1.69. Kinetically controlled selenation of ketone 1.69 and selenoxide elimination generated 1.70. Further conjugate addition of lithium dimethylcuprate led to
1.71 and Wolff-Kishner reduction with hydrazine hydrate and potassium carbonate in
18 triethylene glycol completed the first synthesis of epi-pentalenene 1.72 in 1982.36 The main difficulty experienced in this synthesis was controlling the stereochemistry of the cuprate addition, which gave predominantly the incorrect stereochemistry for the natural product.
HO Cl Et3SiO Cl OSiEt3 Cl CHCOCl 2 Cl CH3OH Cl (C2H5)3N H+ OCH3 pentane O OH 1.58 1.59 1.60
HO Cl Cl CH N HO Cl p-TsOH, CH3OH, THF Cl 2 2 O O 1.61 1.62
Cl Cl Cl Zn 2CuLi CH3MgBr CH O 3 AcOH O THF THF OH
1.63 1.64 1.65 O O 1. O3, (CH3)2S Cl O Na O CH3 HO NH3 2. p-TsOH, OH OH
1.66 1.67 O O CHO Ts-Pyr 1. SbCl4·C6H6 1. LDA, PhSeCl
acetone 2. PCC 2. H2O2
1.68 1.69 1.70
epimer to 1.54
R2 O R1 Me2CuLi Wolff-Kishner
1.71 a, R1 = CH3, R2 = H 1.72 1.71 b, R1 = H, R2 = CH3
Scheme 1.10. The first synthesis of epi-pentalenene
19
Marino and co-workers explored a formal [3+2]-annulation strategy toward a
synthesis of pentalenolactone-E methyl ester 1.77 (Scheme 1. 11).47
OTMS OTMS O 1. TMSCl, NEt3 CO2Et
2. N2CHCOOEt, CuSO4 t COOtBu COO Bu 1.73 1.74 1.75
H SPh
+ - CO2Me CH2=C(SPh) - P Ph3·BF4 , KF H CO Et O 2 O COOtBu 1.77 1.76 Pentalenolactone E methyl ester
Scheme 1.11. [3+2]-Annulation strategy to pentalenolactone-E methyl ester
In 1984, Cane and co-workers successfully synthesized (±)-pentalenolactone over
twenty steps.30 Until the late 1980s, published synthetic routes to these target molecules
mostly were rather long and used traditional methods. In 1987, Hua and co-workers
reported an efficient enantioselective synthesis of pentalenolactone-E methyl ester 1.77
(Scheme 1.12).48 The key steps for the synthesis were intramolecular Pauson-Khand
bicyclization of 1.78 and a regio- and stereospecific 1,4-addition of sulfinylallyl anion to enone 1.79.
20
H Co2(CO)8, CO 1. n-BuLi O O 2. CH2=CHCH2S(O)Tol OR OR OR 1.79 1.78 R = TBDMS S(O)Tol 1.80 H H H 1. NaBH4 1. O3 OAc O CO2Me 2. AcCl, py 2. HF H H 3. Zn, AcOH OR O O MeO O S(O)Tol 1.77 1.81 1.82 Pentalenolactone E methyl ester
Scheme 1.12. Stereospecific pathway to pentalenolactone
Negishi and Agnel (Scheme 1.13) used zirconium-promoted stereoselective enyne bicyclization-carbonylation and allyl phosphonate Michael addition as key steps to generate the triquinane systems.49 Cyclopentannulation via hydroboration-aldol sequence
(1.83 to 1.86) and palladium-catalyzed carbonylation of the enol triflate-derived from the
triquinane ketone 1.87 led to (±)-pentalenic acid 1.88.
21 TMS TMS BuLi, ZrCp2Cl2, CO O
HO H 1.83 1.84
P(O)(OEt) >98% 2
MeCH=CH-CH2-P(O)(OEt)2
TBAF O
HO H 1.85
CHO 1. PPTS + 1. (CH2OH)2, H H O 2. MsCl, NEt3 2. (a) BH (b) H O /OH- O 3 2 2 3. DBU O 3. NaHCO3 4. H , Pd-C HO H 2 HO H
1.86 1.87
H 1. LDA, PhNTf2/Pd(OAc)2/CO COOH 2. DDQ 3. NaOH HO H
1.88 (±)-Pentalenic acid
Scheme 1.13. Stereospecific pathway to pentalenic acid
The synthetic routes for pentalenene have been diversified in recent years.
Paquette and Geng developed a new approach to pentalenene using the sequential addition of 5-methylcyclopentyllithium and propynyllithium to diisopropyl squarate 1.89
(Scheme 1.14).50 In this synthesis, a triquinane system was generated from the starting material through three steps.
22 i-PrO Oi-Pr -O O- i-PrO O 1. Li i-PrO -O O- i-PrO O i-PrO 2. Li
1.89 1.90 1.91
i-PrO Oi-Pr i-PrO Oi-Pr i-PrO Oi-Pr - - - O O -O O H+ -O O H H
1.92 1.93 1.94
i-PrO OH O
i-PrO i-PrO
O i-PrO OH
1.95 1.96
O O O
Ac2O Li, NH Li, NH R i-PrO 3 i-PrO 3 DMAP MeOH PhCOONa R i-PrO OAc 1.99 1.97 1.98 R = H KOt-Bu, MeI R = Me
RO Na Li, NH3 R = H Ac2O, DMAP R = Ac HMPA
1.100 1.101
Scheme 1.14. New rapid assembly method using cascade pathway
Cane and co-workers also modified their synthetic approach to pentalenene structures in 2006 (Scheme 1.15).51 Unlike the same group’s work in 1984, which used
intramolecular carbene insertions of α-diazocarbonyl substrates as a strategy for the
23 construction of polycyclic ring systems, biosynthetic approaches were used.52
PtlA(Pentalenene synthase) and several oxidation reactions afforded 1-deoxypentalenic acid 1.104 and pentalenolactone 1.108.
O PtlA COOH
PPO
1.102 1.54 1.104 O
O COOH O COOH O COOH
O O O O O O O
1.105 1.106 1.107
COOH O
O O O 1.108
Scheme 1.15. Stereospecific pathway to pentalenolactone
In 2006, Tantillo and Gutta studied the mechanism of the formation of
pentalenene from farnesyl diphosphate 1.109, an isoprene oligomer (Scheme 1.16).53
Pyrophosphate, H+ O O O O P P O O O
1.109 1.54 Farnesyl diphosphate Pentalenene
Scheme 1.16. The formation of pentalenene from farnesyl diphosphate
24 PtlA generates not only pentalenene but also other byproducts based upon the regulation timing and location of proton removal (Scheme 1.17).
H 1.114 Protoilludene H
H
H H 1.110 1.111 1.113
Farnesyl diphosphate 1.112 1.109 Humulene
H
H
1.110' 1.111' 1.115
H
H
1.116 Asteriscadiene
H H H H
1.117 1.118 1.52 Pentalenene
Scheme 1.17. Two pathways to pentalenene and intermediates
25 Thousands of polycyclic fused molecule structures are produced by specific enzymes in nature which have active sites promoting a simple hydride shift and intramolecular cyclizations. New approaches for this popular angular triquinane are still desirable and the objective of this thesis is to provide an account of a new synthetic approach for angular triquinane systems as well as potential applications in natural products synthesis. Iron mediated chemistry previously developed in the Pearson laboratory was applied for the model studies and Chapter 2 describes the synthesis of an aza-triquinane system. Chapter 3 describes progress on the all-carbon systems.
26 1.3. References
(1) Pearson, A. J. Acc. Chem. Res 1980, 13, 463-469.
(2) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press: London, 1994.
(3) Pearson, A. J. Pure and Appl. Chem. 1983, 55, 1767-1779.
(4) Pearson, A. J. Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds; Pergamon Press: Oxford, 1995; Vol. 12, pp 637.
(5) Pearson, A. J. Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds; Pergamon press: Oxford, 1982; Vol. 8, pp 939.
(6) Bond, A.; Lewis, B.; Green, M. J. Chem. Soc., Dalton Trans. 1975, 1109-1118.
(7) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908-3918.
(8) Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. J. Org. Chem. 1998, 63, 6610-6618.
(9) Pearson, A. J.; Dorange, I. B. J. Org. Chem. 2001, 66, 3140-3145.
(10) Dorange, I. B. Ph. D. Thesis, Case Western Reserve University, Cleveland, OH, 2001.
(11) Alper, H.; LePort, P. C.; Wolfe, S. J. Am. Chem. Soc. 1969, 91, 7553-7554.
(12) Pearson A. J.; Wang. X. J. Am. Chem. Soc. 2003, 125, 638-639.
(13) Wang, X. Ph. D. Thesis, Case Western Reserve University, Cleveland, OH, 2004.
(14) Mehta, G.; Srikrishna, A. Chem. Rev. 1997, 97, 671-719.
(15) Paquette, L. A.; Doherty, A. M. Recent Synthetic Developments in Polyquinane Chemistry, Springer-Verlag; New York, 1987.
(16) Hudlicky, T.; Price, J. D. Chem. Rev. 1989, 89, 1467-1486.
(17) Northcote, P. T.; Andersen, R. J. Tetrahedron Lett. 1988, 29, 4357-4360.
(18) Lansbury, P. T.; Boden, R. M. Tetrahedron Lett. 1973, 5017-5020.
(19) Curran, D. P.; Chem, M. –H. J. Am. Chem. Soc. 1987, 109, 6558-6560.
(20) Deng, K. Ph.D. Thesis, University of Pittsburgh, Pittsburgh, PA, Oct. 2004.
27
(21) Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron Lett. 1976, 195-198.
(22) Ayanoglu, E.; Gebreyesus, T.; Beecham, C. M.; Djerassi, C. Tetrahedron Lett. 1978, 1671-1674.
(23) Kaisin, M.; Sheikh, T. M.; Durham, L. J.; Djerassi, C.; Tursch, B.; Daloze, D.; Braekman, J. C.; Losman, D.; Karlsson, R. Tetrahedron Lett. 1974, 2239-2242.
(24) Sheikh, Y. M.; Singy, G.; Kaisin, M.; Eggert, H.; Djerassi, C. D.; Braekman, J. C. Tetrahedron 1976, 32, 1171-1178.
(25) Sheikh, Y. M.; Djerassi, C.; Braekman, J. C.; Daloze, D.; Kaisin, M.; Karlsson, R. Tetrahedron 1977, 33, 2115-2117.
(26) Karlson, R. Acta Crystallogr. Sect. B. 1976, 32, 2609-2614.
(27) Kaisin, M.; Tursch, B.; Declercq, J. P.; Germain, G.; van Meer R. K. Chim. Belg. 1979, 88, 253-258.
(28) Burkolder, P. R.; Burkolder, L. M. Science, 1958, 127, 1174-1175
(29) Bohlmann, F.; Le Van, N.; Pickardt. J. Chem. Ber. 1977, 110, 3777-3781.
(30) Cane, D. E.; Abell, C.; Tillman, A. M. Bioorg. Chem, 1984, 12, 312-328.
(31) Zalkow, L. H.; Harris, R. N.; Van Derveer, D. J. Chem. Soc., Chem. Commun. 1978, 420.
(32) Smith, A. B.; Jerris, P. J. J. Am. Chem. Soc. 1981, 103, 194.
(33) Karpf, M.; Dreiding, A. S. Tetrahedron Lett. 1980, 4569.
(34) Paquette, L. A.; Schostarez, H. J. Am. Chem. Soc. 1981, 103, 722.
(35) Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.; Shuda, P. J. Am. Chem. Soc. 1978, 100, 6536.
(36) Paquette, L. A.; Annis, G. D. J. Am. Chem. Soc. 1982, 104, 4504.
(37) Misumi, S.; Ohtsuka, T.; Ohfune, Y.; Sugita, K.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett. 1979, 31.
(38) Baldwin, J. E.; Barden, T. C. J. Org. Chem. 1983, 48, 625.
(39) Exon, C.; Nobbs, M.; Magnus, P. Tetrahedron 1981, 37, 4515.
28
(40) Greene, A. E.; Deprb, J.-P. J. Am. Chem. Soc. 1979, 101, 4003.
(41) Depres, J.-P.; Greene, A. E. J. Org. Chem. 1980, 45, 2036.
(42) Cunico, R. F.; Han, Y.-K. J. Organomet. Chem. 1979, 174, 247.
(43) Barluenga, J.; Yus, M.; Bernad, P. J. Chem. Soc. Chem. Commun. 1978, 847.
(44) Sterzycki, R. Synthesis 1979, 724.
(45) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97, 5434.
(46) Hansen, H.-J.; Sliwka, H.-R.; Hug, W. Helv. Chim. Acta 1979, 62, 1120.
(47) Marino, J. P.; Silveira, C.; Comasseto, J.; Petragnani, N. J. Org. Chem. 1987, 52, 4139.
(48) Hua, D. H. J. Am. Chem. Soc. 1986, 108, 3835.
(49) Agnel, G.; Negishi, E.; J. Am. Chem. Soc. 1991, 113, 7424.
(50) Paquette, L. A.; Geng, F. Org. Lett. 2002, 4, 4547.
(51) Cane D. E.; Quaderer R.; Omura S.; Ikeda H.; J. Am. Chem. Soc 2006, 128, 13036.
(52) You Z.; Omura S.; Ikeda H.; Cane E. E. J. Am. Chem. Soc 2006, 128, 6566.
(53) Gutta P.; Tantillo, L. J. Am. Chem. Soc. 2006, 128, 6172.
29
CHAPTER 2
Synthesis of an Azatriquinane System
30 2.1. Introduction
Previous research from the Pearson laboratory have investigated spirocyclization of cyclohexadiene-Fe(CO)3 complexes with pendant alkenyl groups, especially amides
(Scheme 2.1),1,2 or with a pendant all-carbon olefin (eq. 2.1).3
(OC)3Fe (OC)3Fe
N Ph O N O 84% Ph 2.1 2.2
(OC)3Fe (OC)3Fe
N N Ph 90% O O Ph 2.3 2.4
(OC)3Fe (OC)3Fe
N Ph 70% O N O Ph 2.5 2.6
Scheme 2.1. Iron promoted [6+2] ene type of spirocyclization
31 (OC)3Fe (OC) Fe (OC) Fe n-Bu2O (OC)3Fe 3 3 CO (2.1) 142 °C + 68%
2.7 2.8 2.9a 2.9b
In general, only mono-substituted olefins undergo all-carbon spirocyclization with
the iron-complexed ring in satisfactory yields. The diene double bond migration under cyclization conditions is a necessary step for the conversion shown in eq. 2.1. Substrate
2.7 can not directly undergo cyclocoupling and needs to be converted to intermediate 2.8, which then cyclizes to afford products 2.9a, 2.9b with formation of a five-membered ring.
Pearson and Wang synthesized a compound in which the 3-position of the six- membered ring was methoxy-substituted (Scheme 2.2). Hydrolysis of methoxycyclohexadiene 2.12 gave enone 2.13 in 75% yield4,5 (eq. 2.2). The demetallated
organic compounds 2.12 and 2.13 are 6,5,5-membered fused-ring systems which were
not studied further at that time.
OMe OMe n-Bu2O OMe CO (OC)3Fe Me3NO Fe(CO)3 142 oC PhH O N N Ph O N Ph O Ph Overall 54%
2.10 2.11 2.12
Scheme 2.2. Cyclization of dienyl amide complex with 3-position substitution
32
OMe O
oxalic acid (2.2) O H2O, MeOH O N N Ph Ph 2.12 2.13
The possibility of substitution at the diene 3- position during [6+2] ene-type cyclization provides a potential alternative synthetic approach.11 If a methyl group is at the 3-position of the six-membered ring instead of methoxy group, ozonolysis followed by intramolecular aldol reaction would convert the 6,5,5-membered fused-ring to an angular triquinane structure (Scheme 2.3).
O O O3 aldol O O O O X X X
X = NPh or CH2
2.14 2.15 2.16
Scheme 2.3. A new pathway to triquinane systems
Kwart and co-workers reported oxidative cleavage of the conjugated diene in a 6- membered ring to afford a 1,4-dicarbonyl system. Prostaglandin intermediate 2.21 was prepared by a controlled ozonolysis reaction followed by intramolecular aldol reaction
(Scheme 2.3).6 Ozonolysis conditions were varied to allow isolation of intermediate 2.18
33 or to give direct conversion to 2.19. Basic alumina in benzene was used for the intramolecular aldol reaction to give the target molecule 2.21 (Scheme 2.4). However, in some cases, direct ozonolysis of diene compounds led to undesired rearrangement products of the allylic ozonide.7-10
EtOAc, -60 °C, excess O3
O OH O O3 O O3 O OHC O O CH2Cl2 O CH2Cl2 O -78 °C -78 °C HO 2.17 2.18 2.19
O O Al2O3 O Al2O3 O PhH PhH OHC O O
2.20 2.21
Scheme 2.4. 6- to 5-membered ring contraction pathway
The potential for applications of this approach in the syntheses of complex molecules makes research on all-carbon double cyclization reactions more compelling.
The tricyclic framework as shown in compound 2.16 can be found in many natural product molecules as all-carbon systems (X = CH2), among which angular triquinanes are
most attractive.
Aldol approaches have been applied to synthesize angular triquinane natural
products from diquinanes.12,13 Banks and co-workers used potassium hydroxide to cyclize
5-membered fused ring system from diquinane compound 2.26 (Scheme 2.5). (±)-
34 Silphinene (2.30) was synthesized efficiently through intramolecular Diels-Alder reaction and aldol condensation. These two key steps transformed compound 2.24 to the angularly fused triquinane skeleton. Based on this precedent, we concluded that the combination of ozonolysis and intramolecular aldol reaction would allow production of azatriquinane
2.16 from our model compound 2.14 (Scheme 2.3).
CHO
R 2.22 2.23 2.24
KOH CHO CHO MeOH CHO rt O O
2.25 2.26 2.27
O O (±) Silphinene
2.28 2.29 2.30
Scheme 2.5. Aldol reaction in total synthesis of silphinene
35 2.2. Synthesis of a model compound
2.2.1. Synthesis of iron complexed structure/demetallated structure
Synthesis of an azatriquinane model compound 2.16 was designed by using m-
toluic acid as the starting material. The methyl group on the resulting diene ring might
allow an ozonolysis and intramolecular aldol reaction to deliver the five-membered ring
of 2.21 (Scheme 2.6). The complex 2.32 was prepared in six steps from m-toluic acid.1,14
(OC) Fe n-Bu2O 3 Fe(CO)3 CO 142 oC COOH N O Ph N O Ph 2.31 2.32 2.33
O O Me NO O 3 3 O aldol PhH O O O N N N Ph Ph Ph
2.19 2.20 2.21
Scheme 2.6. Proposed synthesis of model compound 2.21
m-Toluic acid 2.31 was selected as the starting material with a view toward the possibility of ring contraction. Several conditions for Birch reduction were tried to prepare the compound 2.34 (Scheme 2.7). Sodium was used for initial reactions.
36 However, agitation of the solution for a large scale reaction required motorized overhead stirring, especially in cases where 2.31 was reduced in more than a 10 g scale owing to formation of insoluble sodium salts of the acids. To avoid this, using lithium instead of sodium diminished the amount of precipitate, resulting in cleaner and more complete reactions on large scale. Moreover, the use of lithium with methanol as proton source gave 100% conversion. Both Na and Li methods were used to perform this Birch reduction.
The next step was esterification of 2.34 using methanol under Fischer esterification conditions. The purpose of this functional group interconversion is to promote a more favorable complexation reaction with pentacarbonyl iron. In general, iron complexation on dienyl acid compounds gives poor yields. Ester compounds react more smoothly with
Fe(CO)5. Methanol with concentrated H2SO4 as acid catalyst was used to generate 2.35 quantitatively.
Li, NH3 ; MeOH, c. H2SO4
COOH MeOH COOH COOMe -78°C 2.31 2.34 2.35
DBU Fe(CO)5 Fe(CO)3 PhH n-Bu O COOMe 2 COOMe 2.36 2.37 56% over 3 steps 52%
Fe(CO)3 Fe(CO)3 MeOH / H2SO4 30% KOH(aq) Dioxane COOH 88% COOMe 78% 2.38 2.39
Scheme 2.7. Synthesis of iron-complexed acid 2.39
37 Compound 2.36 is a regioisomer of 2.35 and a more favorable form of conjugated
diene for iron complexation. Direct iron complexation of 2.35 generated diene rearranged
product 2.37 and 2.38 in addition to 2.41 (the major product, Scheme 2.8).
Fe(CO)3 Fe(CO)3 Fe(CO)5 Fe(CO)3 + + n-Bu O COOMe 2 COOMe COOMe COOMe 2.35 2.38 2.41 overall 52% 2.37
Scheme 2.8. Direct iron complexation of 1,4-diene compound 2.35
However, the two-step method in Scheme 2.7 gave a higher overall yield of 2.37
and easier purification for metal complexation. Column chromatography separation of
isomers 2.37, 2.38, and 2.41 is not effective due to their similar Rf values. While
seperation is not necessary for the next step, it does hamper characterization of the
products.
The iron complexation reaction of 2.36 was carried out under Ar. n-Bu2O was
filtered through basic alumina before use to remove any peroxides that would cause
oxidation of Fe(CO)5. The reaction mixture was refluxed for 2 days and then cooled to rt.
The reaction solution was filtered through Celite and the filter pad was washed with fresh
n-Bu2O. This work-up process is a necessary step to purify the product from iron
byproducts or other impurities. All the iron complexed compounds in this series of
reactions were subjected to Celite filtration after each reaction.
38 The complexation is confirmed by analysis of 1H NMR data of compound 2.37
(Fig. 2.1).
Fig. 2.1. 1H NMR spectrum of iron complexed methyl ester 2.37
1H NMR spectrum of compound 2.36 has two vinyl hydrogens around 5.7-6.8 ppm, which is the expected range. However, iron complexed structure 2.37 shows one of those vinyl hydrogens upfield in the 1H NMR spectrum. This is because the iron shields the terminal diene hydrogen strongly to move the peak upfield (δ 3.64). This is a key feature that helps to identify iron complexed diene structures.
The rearrangement reaction of 2.37 to compound 2.38 was carried out under acidic conditions. The conversion is expected because 2.38 is a more stable linear conjugated system than 2.37. The 1H NMR spectrum of 2.38 shows small differences in vinyl hydrogen peaks compared to 2.37. The main structural indicator is the lower field signal
39 of the methyl singlet of 2.38 (δ 2.09) vs 2.37 (δ 1.66) which is typical for C-2 vs C-1 substitution for these complexes. Similarly the CO2Me group resonance is at slightly
lower field for 2.37 (δ 3.81) compared with 2.38 (δ 3.71).
Fig. 2.2. 1H NMR spectrum of iron complexed methyl ester 2.38
The key intermediate iron-complexed acid 2.39 was prepared by hydrolysis of 2.38 with 30% aqueous KOH solution in dioxane. Hydrolysis with NaOH in methanol was also an effective method to obtain acid 2.39. This compound is quite stable in the refrigerator over several years. The 1H NMR spectrum of 2.39 shows a broad terminal
vinyl hydrogen peak at 3.40 ppm and the internal hydrogen as a singlet at 5.96 ppm.
40
Fig. 2.3. 1H NMR spectrum of iron complexed acid 2.39
1. 3M H2SO4 / THF H O N Ph 2. PhNH2 / MeOH 2.40 2.41 3. NaBH4 Overall 56% + Ph N
2.42
Scheme 2.9. Preparation of amine 2.41
41 To synthesize iron complexed diene amide 2.32, secondary amine 2.41 was reliably obtained from sorbic aldehyde by reductive amination (Scheme 2.9).15 The double addition of aldehyde generated side product 2.42 which was easily separated by chromatography.
2.41 Fe(CO) H Fe(CO)3 3 N Ph + CH3SO2Cl / DIPEA N (2.3) COOH CH2Cl2 Ph 87% O 2.39 2.32
Conversion of acid to amide was carried out in two steps in a one-pot process (eq.
2.3). First acid 2.39 was dissolved in CH2Cl2 with DIPEA as base. Methanesulfonyl chloride (CH3SO2Cl) was added and the mixture stirred for 1 h, and then the solution was evaporated to dryness using a rotary evaporator. After drying, 2 equiv of 2,4- hexadienylamine 2.41/DIPEA in CH2Cl2 was added to afford the amide 2.32 in 87 % overall yield.
The 1H NMR spectrum of 2.32 shows vinyl hydrogen peaks in the six-membered ring separated from four new vinyl hydrogen peaks from the diene side chain.
42
Fig. 2.4. 1H NMR spectrum of iron complexed amide 2.32
Table 2.1 Cyclization of amide complex 2.32
(OC)3Fe Fe(CO)3 hv
N CO, 8 h O N Ph Conversion = 70% O Ph 2.32 2.33
a b Heating Time (h) Yield (%)
thermal 24 65
thermal 48 54
photothermal 8 74
photothermal 12 55 a Reaction time for cyclization step. b Yield based on the recovered starting material.
43
Double cyclization of 2.32 was studied using two methods, thermal and photothermal reaction. Photothermal reaction has been found to reduce the reaction time because harsh conditions might decompose the starting material or products. Heating
2.32 under a CO atmosphere gave 2.33 in 70% conversion and the isolated yield was
74%, along with 5% of unreacted starting material (Table 2.1). Other minor compounds were not assigned due to unclear 1H NMR chart. Unfortunately, longer reaction time resulted in decomposition of the starting material and the product.
The 1H NMR spectrum of compound 2.33 is dramatically different from that of
2.32. It is clear that methyl, ethyl, and phenyl group proton peaks are easily identified.
The two hydrogens in the 4-position appear as a multiplet at 1.99 ppm, which is slightly higher value than normal sp3 C-H. In this case, the fused rigid ring system influences the coupling constants and peak position of the hydrogens. Two hydrogens at C3 are at lower field (δ 2.95 and δ 4.06) due to the direct connection of the CH2 to nitrogen. The hydrogen on C5a was split to a doublet and vinyl hydrogens on the iron complexed diene are found at δ 5.34 (H7), 5.15 (H8) and 2.38 (H9). The high field location of the resonance for H-9 is caused by a combination of its location on the terminal carbon of the diene-Fe(CO)3 system and its projection into the shielding cone of the neighboring amide carbonyl. The stereochemistry of the similar structures (2.11/2.12, see Scheme 2.2) were confirmed previously by Xiaolong Wang in the Pearson lab.11
44
Fig. 2.5. 1H NMR spectrum of cyclized product 2.33
Table 2.2 Demetallation of the iron complex 2.33
(OC)3Fe demetallation
O O N N Ph Ph 2.33 2.14
Methods Time (h) Yield (%)
Me3NO/PhH/heat 3 62
Me3NO/PhH/heat 5 61
CuCl2/EtOH/rt 24 60
CuCl2/EtOH/rt 12 54
45 Compound 2.33 was demetallated by treatment with Me3NO or CuCl2 (Table 2.2).
Me3NO in purified benzene is a commonly used reagent for demetallation of iron
carbonyl complexes. The mechanism of this reaction is still uncertain.16 Both methods
gave similar yield of 2.14.
According to 1H NMR, three vinyl hydrogens are in the expected 5.38-5.94 ppm
range. A hydrogen at C9 of 2.33 is shifted from 2.38 ppm to 5.4 ppm due to the absence of iron carbonyl coordination, but is still at relatively high field due to the effect of the neighboring amide carbonyl (vide supra).
Fig. 2.6. 1H NMR spectrum of demetallated product 2.14
46 2.2.2. Oxidative cleavage of double bonds to give carbonyl compounds
The combination of the oxidative cleavage and base-catalyzed aldol condensation
of the keto aldehyde to provide spirocyclopentenone structures has been used widely in
natural product synthesis.21-24
Among those methods, along with small molecules described in Scheme 2.4,
ozonolysis has been used a great deal for cleavage of double bonds of complex molecules
and drug candidates in many syntheses.21,25,26
O β O H 3 O 2 R N α H N 2 N N NH 2 o R H N (1) O3, -78 C t-BuOK, t-BuOH H N H 3 3 O β o (2) Me2S α 0 C to rt O O O
O
2.43 2.44 2.45
CHO H O , CH Cl H 3 2 2 H
H H pyridine H H O 95% O
2.46 2.47
Scheme 2.10. Ozonolysis to cleave double bonds of complex molecules
With compound 2.14 in hand, its transformation to aldehyde 2.15 was
investigated. Gaseous ozone was passed through a -78 C, CH2Cl2 solution of 2.14 until the distinctive blue color of excess ozone persisted. Ozone addition was then terminated,
47 the solution was allowed to warm to 0 C, then rt, whereupon neat Me2S was added dropwise. After 2 h, the mixture was purified by PLC after normal work-up. The yield was not promising using ozonolysis at the first attempt. The 1H NMR spectrum of the crude compound showed only a trace of aldehyde peak at 9.98 ppm. The yields obtained from ozonolysis under the conditions examined was rather poor (Table 2.3). Therefore, other oxidation methods were examined.
Table 2.3 Ozonolysis of the compound 2.14
O [O] O O O N N Ph Ph
2.14 2.15
[O] Temp (C) Time (h) Yield (%)
O3 / Me2S / CH2Cl2 -78 C to rt 2 < 5*
O3 / Me2S / CH2Cl2 -78 C to rt 4 < 10*, decomposed
O3 / Me2S / Ethyl Acetate -78 C to rt 2 No reaction
O3 / Me2S / Ethyl Acetate -78 C to rt 8 decomposed
* This is measured by crude 1H NMR peak ratio relative to the starting material unreacted. No isolated yield was measured.
In the presence of catalytic amounts of osmium tetraoxide, sodium periodate
(NaIO4) is reported to afford aldehydes in good yields from acyclic alkenes and
27, 28 cyclohexenes (eq. 2.4, 2.5). The OsO4 can be used in catalytic amounts for efficient
48 conversion of alkene to diol, as it is regenerated by oxidizing agents, such as H2O2, or N-
17,29,30 methylmorpholine N-oxide and K3Fe(CN)6. Jorgensen and co-workers studied
17 OsO4 with various co-solvents to oxidize alkene compounds. NaIO4 treatment of the
resultant diol led to complete cleavage to the carbonyl compound.31
cat. OsO4, NaIO4 C10H21 C10H21 O aq. dioxane, rt (2.4) 68 % 2.48 2.49
O cat. OsO4, NaIO4 H H ether, H2O, rt (2.5) O 77 %
2.50 2.51
OPMB PMBO OH PMBO O cat. OsO , NMO NaIO4 H C 4 H C OH H C 3 3 3 H THF,acetone, THF, H2O, rt CH CH 3 3 H2O, rt CH3 CH3 CH3 CH3
2.52 2.53 2.54
Scheme 2.11. OsO4 oxidative cleavage reactions
Scheme 2.12. OsO4 oxidation used in preparing stephaoxocane 2.56
49 These reaction conditions oxidize cyclopentene to glutaraldehyde in good yield
(eq. 2.5). However, 1-methycyclohexene is oxidized very slowly, unlike cyclohexene, and surprisingly, uncharacterized carbonyl compound is obtained. This result shows that
NaIO4-cat. OsO4 method can be used for the cleavage of unhindered alkenes more effectively than hindered ones. Applications of the product dicarbonyl compounds in aldol reactions are smooth, e.g. in syntheses of aphidicolin22 and phytuberin (Scheme
2.13).23
O
cat. OsO4, NaIO4
O H aq. dioxane, rt O 86 % 2.57 O O O NaH, benzene H O aphidicolin O trace t-pentyl alcohol, reflux H H O O 95 %
2.58 2.59
cat. OsO4, NaIO4
O aq. dioxane, rt H OAc 86 %
2.60
10 % aq. NaOH O O MeOH, rt H OAc H OAc 90 % O
2.61 2.62
50 Scheme 2.13. OsO4/NaIO4 cleavage and aldol reactions applied to aphidicolin and phytuberin intermediates.
Therefore, these conditions were applied to compound 2.14 in an effort to secure better yield of 2.15 (Table 2.4).
Table 2.4 OsO4/NaIO4 oxidation of the compound 2.14
O [O] O O O N N Ph Ph
2.14 2.15
[O] Time (h) Yield (%)
17 5 mol% OsO4 / excess NaIO4 (Et2O/H2O) reflux, 4 < 3*
17 a OsO4 / NMO (Acetone:H2O/1:2) rt, 12 No reaction
17 OsO4 / NMO (Acetone:H2O:t-BuOH/3:2:2) rt, 12 No reaction
OsO4 / NMO (Acetone:H2O:t-BuOH/3:2:2) reflux, 5 decomposed
OsO4/pyridine reflux, 3 decomposed
OsO4, H2O2, t-BuOOH rt, 8 decomposed
17 OsO4, 75% dioxane, NaIO4 rt, 16 decomposed
* : This is measured by crude 1H NMR peak ratio relative to the starting material unreacted. Not isolated. a : 80 % of the starting material 2.14 was recovered. Crude 1H NMR spectra of the reaction mixture showed small amount of multiple broad peaks which seem alcohol peaks (δ 2-5).
51 Since ozonolysis and OsO4 catalyzed oxidation were problematic for the
transformation of compound 2.14, other methodology was investigated. The use of RuO4
18,32 was examined to improve the yield of cleavage. RuO4 generated in situ from RuCl3
33 and NaIO4 has been used to cleave double bonds to yield carbonyl products directly.
R R'' RuCl3, NaIO4 R O (2.6) R' R''' DCE/H2O (1:1) R' 2.63 2.64
However, the results were again not promising, possibly due to the complexity of
the molecule and the extra carbonyl group in amide moiety.
Table 2.5. RuO4 oxidation of the compound 2.14
[O] Time (h) Yield (%)
18 RuO4, (CCl4:H2O/1:1) rt, 8 decomposed
18 RuO4, (CCl4:CH3CN:H2O/2:2:3) rt, 4 decomposed
At this point, it became apparent that ozonolysis is the only reaction producing
any of the keto aldehyde. Therefore, modified reaction conditions were investigated in an
effort to improve the yield. Eventually, 50% yield of the desired keto aldehyde was
obtained using the following protocol, and no unreacted starting material was recovered.
The temperature of the reaction solution was maintained at -78 C for 1h with the
blue/purple color of the CH2Cl2 solution under a O2/O3 stream indicating excess O3. After
52 addion of dimethyl sulfide at -10 C, the reaction mixture was warmed to rt and stirred
for an additional 3 h. Since scale up of the reaction produced poorer yield, the combined product from repetition of the small scale procedure was used for the subsequent intramolecular aldol reaction step.
Aldehyde 2.15 was identified by 1H NMR spectroscopy (Fig. 2.7). Methyl
hydrogens on C11 and aldehyde proton on C9 are signature peaks for successful
oxidation. Other hydrogen peaks in the azadiquinane structure are not changed
significantly from the starting material.
Fig. 2.7. 1H NMR spectrum of cleavage product 2.15
53 2.2.3. Studies of aldol condensation conditions
Finally, target molecule 2.16 was prepared by an intramolecular aldol/dehydration
reaction from keto aldehyde 2.15. Several reaction conditions were applied to obtain
maximum yield. One of the common methods for intramolecular aldol reaction uses an
amine as a base.37,38 Unfortunately, treatment of 2.15 with DBU,39 which is a mild
condition, did not generate the desired tricyclic structure 2.16 (Table 2.6). Aldehyde 2.15
has three carbonyl groups and a somewhat rigid structure. Therefore, intramolecular aldol conditions previously applied to related structures such as 2.67 (Scheme 2.15) were studied.19,20,22,23,25,26
O TMS O TMS m-CPBA, CH2Cl2 O
76 % H H 2.65 2.66
O 5 % KOH CHO HCO2H THF, Et O O 2 H n-Bu4NOH H
2.67 2.68 26 % from 2.64
Scheme 2.14. Mild conditions of intramolecular aldol reaction for tricyclic structure
Treatment with KOH(aq) in methanol was easy to set up at rt and purification of
the product was convenient. Therefore, multiple trials were performed. However, NaOMe
54 in THF showed the highest yield. Short reaction time and easy purification was also advantageous for the reaction (Table 2.6).
Table 2.6. Intramolecular aldol cyclization to afford model compound 2.16
O O conditions O O O N N Ph Ph 2.15 2.16
Aldol reaction conditions Time (h) Yield (%)
DBU / THF39 rt, 2 15
5 % KOH / (Et2O/H2O) rt, 4 30
5 % KOH / THF, ether rt, 6 50
KOH, MeOH12 rt, 12 33
t-BuOK / tBuOH reflux, 4 decomposed
NaOMe / MeOH / THF19 rt, 6 71
20 Tridentate bis(oxazolinyl)pyridyl (pybox)3 Cu(II)/THF rt, 1 21
20 Tridentate bis(oxazolinyl)pyridyl (pybox)3 Cu(II)/THF rt, 6 27
55
Fig. 2.8. 1H NMR of aldol reaction product 2.16
The aldol reaction was carried out best using NaOMe/THF to yield azatriquinane
2.16. The NMR spectrum showed the pendant ethyl group around δ 0.85 (CH3) and δ
1.22 (CH2). The vinyl hydrogens are at δ 6.25 and 6.73, typical of an α,β-unsaturated
ketone and the two hydrogens on C-11 are at δ 3.59 and 3.95. Furthermore, FT-IR
spectrum also showed two carbonyl groups at 1675 cm-1 for the enone and 1640 cm-1 for the lactam. Yields of the last three steps will hopefully be improved with future modifications.
56 2.3. Conclusions
In conclusion, intramolecular double cyclization between a diene-Fe(CO)3 complex and a pendant diene provides a complex tricyclic molecule with excellent stereocontrol from a relatively simple and easily available starting material. Ozonolysis and subsequent aldol reaction gave an angular azatriquinane system. The schemes use accessible and standard organic reactions. However, there are a few steps with moderate yields (iron complexation, demetallation and ozonolysis). These need to be improved for better conversions of those intermediates to secure higher overall yield. This approach is the first example of application of organo iron chemistry to the synthesis of an angular azatriquinane system and might be expanded to all carbon systems, as will be discussed in Chapter 3.
57 2.4. Experimental Section
General Methods
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 immediately prior to use. Organic solvents/reagents were purified prior to use as
follows: THF, diethyl ether, toluene 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. All other solvents were used as purchased.
Column chromatography was performed on flash grade silica gel (0.04-0.063 mm).
Eluting solvents are reported as V/V percent mixture. 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 on Varian Gemini XL200 (200 MHz), Varian Gemini 300 (300 MHz), or
Varian Inova 400 (400 MHz) spectrometers using CDCl3 or C6D6 in solvent, and
referenced to the solvent or to TMS as an internal standard. Chemical shifts (δ) are
reported in ppm downfield from tetramethylsilane. Infrared spectra were recorded for
solutions in CHCl3 using NaCl cell, or as a KBr pellet on a MIDAC M2000 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.
58
3-Methylcyclohexa-2,5-diene-1-carboxylic acid (2.34)
Method A: m-Toluic acid 2.31 (13.6 g, 100 mmol) was
reduced with sodium (9g) in 400 mL of liquid ammonia and 100
COOH mL of anhydrous THF to afford the dihydro acid 2.34 in 90 %
yield. Method B: Lithium metal (2.43 g, 350 mmol) was added to
a stirred mixture of m-toluic acid 2.31 (13.6 g, 100 mmol) in dry THF (150 mL) and
anhydrous liquid ammonia (700 mL) until the blue color persisted. After the mixture had
been stirred for 30 min, excess of lithium was destroyed by addition of methanol until it
became colorless. After the ammonia had been allowed to evaporate, the residue was
dissolved in water and the solution washed with ether to remove impurities. It was then
acidified with 5% aqueous HCl solution and extracted with ether. The ether extract was
washed with brine, dried with Na2SO4 and evaporated to yield 2.34 (13.12 g, 95%) yield.
40 1 m.p. 78.8-80 C (literature 79.5-82.5 C). H NMR (CDCl3, 400 MHz, δ, ppm) 1.7 (s,
3H), 2.5 (d, 2H, J = 8 Hz), 3.6 (m, 1H), 5.4 (m, 1H), 5.8 (m, 2H), 11.5(s, 1H).
Methyl 3-methylcyclohexa-2,5-diene-1-carboxylate (2.35)
3-Methylcyclohexa-2,5-diene-1-carboxylic acid 2.34
(1.14g, 8.26 mmol) in 25 mL of MeOH was mixed with COOMe MeOH/conc. H2SO4 (15 mL/1 mL) and refluxed for 12 h. The
excess methanol was removed by rotary evaporation and the residue was taken up in
ether and the solution washed with aqueous NaHCO3, brine, dried with Na2SO4 and
59 evaporated under reduced pressure. Flash chromatography afforded the methyl ester 2.35
1 as an oil. H NMR (CDCl3, 400 MHz, δ, ppm) 1.7 (s, 3H), 2.62-2.65 (m, 2H), 3.65 (s,
3H), 3.7 (m, 1H), 5.36 (m, 1H), 5.60-5.65 (m , 2H).41
(Methyl 3-methylcyclohexa-2,6-diene-1-carboxylate (2.36)
Ester 2.35 (100 mg, 0.66 mmol) was dissolved in 2 mL of
benzene. DBU (0.01 mL, 0.06 mmol) was added and the mixture
COOMe was refluxed for 10 h. After cooling to rt, the mixture was washed
with 2% aqueous HCl solution and brine, then dried with Na2SO4 and evaporated. Flash
1 chromatography afforded the conjugated diene ester 2.36 in 99% yield. H NMR (CDCl3,
400 MHz, δ, ppm) 1.7 (s, 3H), 2.15 (m, 2H), 2.17 (m, 2H), 3.76 (s. 3H), 5.68 (s, 1H), 6.8
(t, 2H, J = 4.2 Hz ).40
Tricarbonyl(Methyl 5-methylcyclohexa-1,5-dienecarboxylate)iron (2.37).
Ester 2.36 (288 mg, 1.89 mmol) was dissolved in 3.5 mL
Fe(CO)3 of n-Bu2O, and 0.41 mL of iron pentacarbonyl (594 mg, 3.03
COOMe mmol, 1.6 equiv) was added. The reaction mixture was refluxed
under Ar for 43 h, then cooled to rt. The reaction mixture was
filtered through Celite and the filter pad was rinsed with fresh n-Bu2O. Evaporation of n-
Bu2O, followed by flash chromatography purification (silica gel, Hex:EA/10:1) afforded
1 complex 2.37 (277 mg, 52% yield) as a yellow oil. Rf = 0.5 (Hex:EA/15:1); H NMR
(CDCl3, 400 MHz, δ, ppm) 1.53-1.60 (m, 1H), 1.66 (s, 3H), 1.67-1.72 (m, 1H), 1.83-1.95
60 13 (2H), 3.64 (t, 1H, J = 8Hz), 3.81 (s, 3H), 6.00 (s, 1H); C NMR (CDCl3, 100 MHz, δ,
ppm) 12.5, 22.9, 25.5, 33.4, 39.8, 43.5, 55.1, 120.2, 133.6, 208.7; HRMS-FAB (m/z) (M-
+ H)Na2 calcd for C12H11O5FeNa2, 336.9751; found 336.9751.
Tricarbonyl(methyl 3-methylcyclohexa-1,3-dienecarboxylate)iron (2.38).
Ester 2.37 (190 mg, 0.65 mmol) degassed with Ar for 1
Fe(CO)3 minute was dissolved in 1.5 mL of MeOH and 1.5 mL of conc.
COOMe H2SO4 and refluxed for 24 h. The reaction mixture was extracted
with CH2Cl2 (2 x 20 mL) after filtering through Celite and was
treated with saturated NaHCO3(aq) solution. Flash column chromatography (silica gel,
Hex:EA/5:1) afforded rearranged ester 2.38 as a yellowish oil in 88% yield. Rf = 0.49
1 (Hex:EA/15:1); H NMR (CDCl3, 400 MHz, δ, ppm) 1.35-1.42 (m, 1H), 1.65-1.78 (m,
1H), 1.89-1.98 (m, 1H), 2.07-2.18 (m, 1H), 2.09 (s, 3H), 3.35 (t, 1H, J = 8Hz), 3.71 (s,
13 3H), 5.93 (s, 1H); C NMR (CDCl3, 100 MHz, δ, ppm) 13.5, 29.2, 35.5, 46.6, 49.9,
+ 123.2, 128.9, 209.9; HRMS-FAB (m/z) (M-H)Na2 calcd for C12H11O5FeNa2, 336.9751;
found 336.9748.
Tricarbonyl[3-methylcyclohexa-1,3-dienecarboxylic acid] (2.39).
To a solution of (methyl 3-methylcyclohexa-1,3- Fe(CO) 3 dienecarboxylate)tricarbonyliron (2.38) (130mg, 0.45 mmol) in a
COOH
61 mixture of dioxane (0.7 mL) and methanol (0.7 mL) which was purged with Ar for 10
min, was added 30% aqueous KOH solution (0.36 mL) which was also bubbled with Ar
for 10 min before addition. After the reaction solution was stirred under Ar at rt for 24 h,
2N HCl was added to adjust to pH = 2-3. The aqueous solution was extracted with
CH2Cl2 (3 mL x 3). The combined organic layer was filtered through Celite, washed with
brine (2 mL x 2), dried (Na2SO4), filtered and concentrated in vacuo. Flash
chromatography (Hex:EA/2:1) afforded acid 2.39 (90 mg, 78%). Rf = 0.19 (Hex:EA/2:1);
MP 182-185 C; 1H NMR (DMSO, 400 MHz, δ, ppm) 1.28-1.35 (m, 1H), 1.60-1.70 (m,
1H), 1.80-1.90 (m, 1H), 1.90-2.00 (m, 1H), 2.07 (s, 3H), 3.40 (br, 1H), 5.96 (s, 1H),
13 12.30-12.15 (br, 1H); C NMR (CDCl3, 100 MHz, δ, ppm) 22.0, 23.3, 26.0, 63.9, 67.4,
+ 89.1, 103.5, 174.0, 211.6; HRMS-FAB (m/z) MH calcd for C11H11O5Fe, 278.9956;
found, 278.9952.
N-((2E, 4E)-Hexa-2,4-dienyl)benzenamine (2.41).
Sorbaldehyde 2.40 (0.47g, 4.9 mmol) was H N Ph dissolved in 4.4 mL of THF, followed by addition of
1.2 mL of 3M H2SO4. The solution was mixed with
aniline (0.396 g, 4.25 mmol) in THF/MeOH (22 mL/7 mL) co-solvent at 0 C. The mixture was treated with NaBH4 (0.287 g, 7.6 mmol) and raised to rt. The reaction was
stopped after 3 hours. The mixture was treated with NaHCO3 and extracted with CH2Cl2.
Flash chromatography (Hex:EA/5:1) afforded the known amine 2.41 in 60% yield.15 1H
62 NMR (CDCl3, 400 MHz, δ, ppm) 1.7 (d, 3H), 3.7 (m, 2H), 4.0 (br, 1H), 5.61-6.15 (m,
4H), 6.4-7.05 (5H).
Tricarbonyl[1-4-η-3-methylcyclohexa-1,3-dienecarboxylic acid (N-phenyl)hexa-2,4- dienyl amide]iron (2.32).
Acid 2.39 (69 mg, 0.248 mmol) and 80 mg of 4 Å
molecular sieves in 2 mL of CH2Cl2 was treated with 82 μL
Fe(CO)3 of DIPEA (0.496 mmol, 2 equiv), followed by 0.12 mL of
N Ph CH3SO2Cl (0.323 mmol, 1.3 equiv) dropwise over 5 minutes O and the mixture was stirred at 0 C for 1 h under argon. A
degassed CH2Cl2 (2 mL) solution containing 110 μL of 2,4-hexadienyl-(phenyl)amine
(0.496 mmol, 2 equiv) and 110 μL of DIPEA was added and the mixture was stirred at rt
for 24 h. The product mixture was diluted with diethyl ether, washed with 2N aqueous
HCl, water, dried over MgSO4, and concentrated under vacuum. Flash chromatography
on silica gel (Hex:EA/5:1) afforded 87 mg (81% yield) of the title compound 2.32 as a
light brown oil, along with 5 mg of recovered acid complex after chromatography. Based
1 on the recovered starting material, the yield was 87%. Rf = 0.34 (Hex:EA/9:1); H NMR
(CDCl3, 400 MHz, δ, ppm) 1.26-1.29 (2H), 1.56-1.65 (m, 2H) 1.70 (d, J = 8 Hz, 3H),
1.73-1.84 (m, 2H), 1.89 (s, 3H), 3.25 (1H), 4.13 (dd, 1H, J = 14, 6.6 Hz), 4.45 (dd, 1H, J
= 14, 6.4 Hz), 5.44 (s, 1H), 5.53-5.63 (m, 1H), 5.91-6.01 (m, 1H), 7.18 (dd, 2H, J = 8.4,
13 1.2 Hz), 7.32 (m, 1H), 7.40-7.43 (m, 2H); C NMR (CDCl3, 100 MHz, δ, ppm) 18.3,
22.0, 25.0, 26.7, 54.2, 66.2, 68.2, 87.1, 101.5, 125.2, 125.6, 128.0, 129.6, 129.8, 131.1,
63 + 133.9, 143.8, 173.0; MALDI_TOF (m/z) MH calcd for C23H24NO4Fe, 434.1055; found,
433.10.
Tricarbonyl(6-9-η-6-methyl-5-ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-2-
azacyclopenta[c]inden-1-one)iron (2.33).
The amide 2.32 (36 mg, 0.083 mmol) was dissolved
(OC)3Fe in 15 mL of freshly distilled di-n-butyl ether under argon in a
glass round bottomed flask. The air in the solution was O N Ph removed by freeze-pump-thaw method three times, followed
by bubbling with Ar for 10 minutes and then with CO for
another 10 minutes. The reaction flask connected with a reflux condenser was put into an
oil bath heated to the boiling point of the solvent (142 C) being used and irradiated in a
Rayonet reactor with a 350 nm light source, with magnetic stirring for 8 h under balloons
of CO(g). The cooled product mixture was diluted with ether, filtered through Celite,
dried over MgSO4, and concentrated. Flash chromatography or preparative TLC
separation yielded 22.3 mg of the title compound 2.33 (74%) as a pale yellow viscous oil
along with 6.48 mg of recovered starting material and a trace amount of demetallated
1 product 2.14 after PLC. Rf = 0.63 (Hex:EA/4:1); H NMR (CDCl3, 400 MHz, δ, ppm)
0.87-0.94 (m, 2H), 0.97 (t, 3H J = 7.2 Hz), 1.37-1.51 (m, 1H), 1.62 (s, 3H), 1.89-1.99 (m,
2H), 2.38 (d, 1H, J = 8 Hz), 2.69 (dd, 1H, J = 9.4, 1 Hz), 2.95 (dd, 1H, J = 7.4, 1.6 Hz),
3.44 (d, 1H, J = 6.6 Hz), 4.06 (dd, 1H, J = 9.6, 7.2 Hz), 5.15 (d, 1H, J = 4.2 Hz), 5.34 (dd,
13 1H, J = 6.8, 4.2 Hz), 7.13-7.64 (5H); C NMR (CDCl3, 100 MHz, δ, ppm) 16.3, 17.8,
64 19.1, 25.6, 31.2, 52.3, 60.4, 62.2, 73.7, 115.4, 120.0, 126.4, 129.5 139.3, 155.9, 158.4
+ 160.6, 165.0; HRMS-FAB (m/z) MH calcd for C23H24NO4Fe, 434.1055; found,
434.1048.
6-Methyl-5-ethyl-2-phenyl-2,3,3a,4,5,5a-hexahydro-2-azacyclopenta[c]inden-1- one)iron (2.14).
Method A, using Me3NO : A solution of complexed
intermediate 2.33 (12 mg, 0.027 mmol) in dried benzene was
added to a mixture of Me3NO (40mg, 0.55 mmol) and 2 mL of O N dried benzene. The reaction mixture was then heated at 40-50 C Ph for 3 h, then filtered through Celite and concentrated in vacuo.
Purification by PLC (Hex/EA, 5:1) afforded 4.9 mg of the title compound 2.14 as a
1 colorless viscous oil (62 %). Rf = 0.18 (Hex:EA/9:1); H NMR (CDCl3, 400 MHz, δ,
ppm) 0.85-0.88 (t, 3H, J = 7.2 Hz), 0.92-1.02 (m, 2H), 1.23-1.30 (m, 1H), 1.33-1.41 (m,
1H), 1.82 (s, 3H), 2.0 (dd, 1H, J = 12.0, 5.4 Hz), 2.35-2.39 (m, 1H), 2.61-2.70 (m, 1H),
2.97 (d, 1H, J = 6.8 Hz), 3.60 (d, 1H, J = 6.8 Hz), 4.11 (dd, 1H, J = 10, 7.4 Hz), 5.40 (d,
1H, J = 6.5 Hz), 5.77 (d, 1H, J = 9.4 Hz), 5.92 (dd, 1H, J = 9.4, 6,5 Hz), 7.13-7.75 (5H);
13 C NMR (CDCl3, 100 MHz, δ, ppm) 12.3, 21.2, 25.1, 26.5, 39.1, 41.3, 42.2, 51.6, 52.3,
119.5, 121.6, 123.5, 124.4, 129.0, 133.9, 141.7, 153.3, 174.0. Method B. using CuCl2,
EtOH : To a small vial was added the iron carbonyl complex (0.1 mmol) and sat. CuCl2 solution in EtOH (2.5 mL). The solution was stirred at rt for 12-24 h under Ar, then filtered through Celite and concentrated in vacuo. After water (4 mL) was added to the residue, the mixture was extracted with ether (3 mL x 3). The organic layer was washed
65 with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude products were purified by preparative TLC or flash chromatography.
4-Acetyl-5-ethyl-octahydro-3-oxo-2-phenylcyclopenta[c]pyrrole-3a-carbaldehyde
(2.15).
Ozone was bubbled through a solution of compound
2.14 (6.9 mg, 0.024 mmol) in dichloromethane (1.2 mL) -78 O O C until the distinct blue color of ozone appeared. Bubbling O N Ph was stopped immediately and dimethyl sulfide (0.3 mL) was
then added, dropwise, at -78 C. The resultant mixture was
warmed to rt and stirred for 3 h, and then the solvent was removed under reduced
pressure. PLC of the crude product and concentration in vacuo gave 3.5 mg (50%) of the
1 title compound 2.15 as a colorless oil, purified by PLC. Rf = 0.35 (Hex:EA/5:1). H
NMR (CDCl3, 400 MHz, δ, ppm) 0.94 (t, 3H, J = 7.2 Hz), 1.29-1.37 (m, 1H), 1.40-1.47
(m, 1H), 1.74-1.77 (m, 1H), 2.02 (s, 3H), 2.30-2.39 (m, 1H) 2.82 (d, 1H, J = 3.8 Hz),
3.24 (d, 1H, J = 8 Hz), 3.80 (dd, 1H, J = 8, 3.8 Hz), 7.02-7.68 (5H), 9.98 (s, 1H); 13C
NMR (CDCl3, 100 MHz, δ, ppm) 11.9, 16.7, 25.2, 28.6, 34.6, 39.8, 46.1, 51.3, 67.1,
121.5, 124.0, 128.1, 170.2, 200.3, 203.6.
5-Ethyl-2,3,3a,4,5,5a-hexahydro-2-phenylpentaleno[1-c]pyrrole-1,6-dione (2.16).
66 A solution of aldehyde 2.15 (3.5 mg, 0.0117 mmol)
O in 1 mL of MeOH-THF (5:1) solution was prepared at 0 C.
The solution was stirred for 5 minutes, then NaOMe (15 mg, O N 1.3 mmol) was added to the solution. The resulting solution Ph was stirred for 2 h, warmed to rt and stirred 4 h more. The
mixture was washed with aqueous NH4Cl solution (1 mL x 2) and extracted with Et2O.
The organic fractions were washed with brine, dried with MgSO4, concentrated under
reduced pressure and then purified by PLC. The title compound 2.16 was acquired as a
1 viscous pale yellow oil (71%). Rf = 0.15 (Hex:EA/9:1). H NMR (C6D6, 400 MHz, δ,
ppm) 0.93 (t, 3H, J = 7.4 Hz ), 1.26 (m, 2H), 1.32 (m, 1H), 1.49-1.53 (m, 1H), 1.75-1.78
(m, 1H), 2.21-2.28 (m, 1H), 2.36-2.43 (m, 1H), 3.48 (d, 1H, J = 8.1 Hz), 3.92 (dd, 1H, J
= 8.1, 3.8 Hz), 6.25 (d, 1H, J = 9.1 Hz), 6.73 (d, 1H, J = 9.1 Hz), 7.15-7.61 (5H) ; 13C
NMR (CDCl3, 100 MHz, δ, ppm) 12.5, 22.9, 25.5, 33.4, 39.8, 43.5, 49.9, 55.1, 120.2,
123.2, 128.9, 133.6, 142.8, 150.2, 207.7.
67 2.5. References
(1) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908-3918.
(2) Pearson, A. J.; Wang, X. Tetrahedron Lett., 2002, 43, 7513-7515.
(3) Pearson, A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6, 2535-2538.
(4) Pearson, A. J.; Dorange, I. B. J. Org. Chem. 2001, 66, 3140-3145.
(5) Olah, G. A.; Husain, A.; Balaram Gupta, B. G.; Narang, S. C. Angew. Chem. Int. Ed. 1981, 20, 690-710.
(6) Hudlicky, T.; Luna, H,; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110, 4735-4741.
(7) Bailey, P. S. Chem. Rev. 1958, 58, 925-1010.
(8) Heldeweg, R. F.; Hogeveen, H.; Schudde, E. P. J. Org. Chem. 1978, 43, 1912-1916.
(9) Pelletier, S. W.; Iyer, K. N.; Chang, C. W. J. J. Org. Chem. 1970, 35, 3535-3538.
(10) Odinokiv, V. N.; Nkhunova, V. R.; Bakeeva, R. S.; Galeeva, R. I.; Semenovskii, A. V.; Moiseenkov, A. M.; Tidsikov, G. A. Zh. Org. Khim. 1986, 22, 281.
(11) Wang, X. Ph. D. Thesis, Case Western Reserve University, Cleveland, OH, 2004.
(12) Banks, B. A.; Sternbach, D. D.; Hughes, J. W.; Burdl, D. F. J. Am. Chem. Soc. 1985, 107, 2149-2153.
(13) Sha, C. -K.; Santhosh K. C.; Lih, S. H. J. Org. Chem. 1998, 63, 2699-2704.
(14) Pearson, A. J.; Zettler, M.; Pinkerton, A. A. J. Chem. Soc. Chem. Commun. 1987, 264-266.
(15) Verardo G.; Giumanini A. G.; Strazzolini P.; Poiana M. Synthesis 1993, 121-125.
(16) (a) Shvo, Y.; Hazum, E. Chem. Commun. 1974, 336-337. (b) Eekhof, J. H.; Hogeveen, H.; Kellogg, R. M. Chem. Commun. 1976, 16, 657- 659.
(17) Jorgensen, K. B.; Nakata, T.; Suenaga, T. Tetrahedron Lett. 1999, 40, 8855-8858.
(18) Sharpless, K. B.; Martin, V. S.; Katsuki, T.; Carlsen, Per H. J. J. Org. Chem, 1981, 46(19), 3936-3938.
68 (19) Mukaiyama, T.; Shiina, I; Iwadare, H.; Sakoh, H.; Tani, Y; Masatoshi, H.; Saitoh, K. Chem. Lett. 1997, 1139-1140.
(20) Evans, D. A.; Kozlowski, M. C.; Burger, C. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893-7894.
(21) Fisher, M. H.; Wyvratt, M. J.; Schmatz, D. M.; Galuska, S.; Allocco, J. J.; Darkin- Rattray S. J.; Dulski, P. M.; Gurnett, A. M.; Myers, R. W.; Doss, C. G.; Collectti, S. L.; Meinke, D. T. J. Med. Chem. 2000, 43, 4919-4922.
(22) McMurry, J. E.; Andrus, A.; Ksander, G. M.; Musser, J. H.; Johnson, M. A. J. Am. Chem. Soc. 1979, 101, 1330-1332.
(23) Kido, F.; Kitahara, H.; Yoshikoshi, A. J. Org. Chem. 1986, 51, 1478-1481.
(24) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113- 120.
(25) Van Ornum, S. G.; Pariza, R.; Champeau, R. M. Chem. Rev. 2006, 106, 2990-3001.
(26) Shepard, D. A.; Donia, R. A.; Campbell, J. A.; Johnson, B. A.; Holysz, R. P.; Slomp, G., Jr.; Stafford, J. E.; Pederson, R. L.; Ott, A. C. J. Am. Chem. Soc. 1955, 77, 1212-1215. (b) Slomp, G., Jr. J. Org. Chem. 1957, 22, 1277-1279. (c) Slomp, G., Jr.; Johnson, J. L. J. Am. Chem. Soc. 1958, 80, 915-921. (d) Boddy, I. K.; Boniface, P. J.; Cambie, R. C.; Craw, P. A.; Huang, Z.-D.; Larsen, D. S.; McDonald, H.; Rutledge, P. S.; Woodgate, P. D. Aust. J. Chem. 1984, 37, 1511- 1529. (e) Haag, T.; Luu, B.; Hetru, C. J. Chem. Soc., Perkin Trans. 1 1988, 2353- 2363.
(27) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21, 478-479.
(28) Cantor, S. E.; Tarbell, D. S. J. Am. Chem. Soc. 1964, 86, 2902-2909.
(29) Ogino, Y.; Chen, H.; Kwong, H.; Sharpless, K. B. Tetrahedron Lett. 1992, 32(32), 3965-3968.
(30) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.; Sheidt, K. A. J. Org. Chem. 2002, 67, 4275-4283.
(31) Bianchi, D. A.; Kaufman, T. S. Can. J. Chem. 2000, 78, 1165-1169.
(32) Yang, D.; Zhang, C. J. Org. Chem., 2001, 66, 4814-4818.
(33) Cotton, S. A. Chemistry of Precious Metals, Chapman and Hall: London, 1997.
69 (34) Kulkarni, M. G.; Davawala, S. I.; Doke, A. K.; Pendharkar, D. S. Synthesis 2004, 17, 2919-2926.
(35) Stoltz, B. M.; McFadden, R. M. J. Am. Chem. Soc. 2006, 128, 7738-7739.
(36) Sha, C. -K; Santhosh, K. C.; Lih, S. J. Org. Chem. 1998, 63, 2699-2704.
(37) Mahrwald, R. Modern Aldol Reactions, Vol. 2: Metal Catalysis. WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2004.
(38) Bode, J. W.; Struble, J. R. Tetrahedron 2009, 65, 4957-4967.
(39) Fukuyama, T.; Waizumi, N.; Itoh, T. J. Am. Chem. Soc. 2000, 122, 7825-7826.
(40) Kaliappan, K.; Subba Rao, G. S. R. . J. Chem. Soc., Perkin Trans. 1 1997, 3387- 3392.
(41) Bhaskar, Vijaya.; Subba Rao, G. S. R. J. Chem. Soc., Perkin Trans. 1 1993, 2333- 2337.
70
CHAPTER 3
Studies Directed Toward Synthesis of an All-carbon Triquinane System
71 3.1. Introduction
Mono-cyclization reactions of iron-complexed dienes bearing a pendant alkene
were studied previously in the Pearson laboratory. In 1989, Zettler and Pearson found an
interesting iron-mediated cyclization reaction under thermal or photothermal conditions.1
Various esters, amides, and thioesters were prepared from tricarbonyl(1,3-cyclohexadiene carboxylic acid)iron 3.1 by conversion to the acid chloride and further nucleophilic addtions.2,3 (Scheme 3.1, Scheme 3.2)
This work was motivated by Green and co-workers4 who described a novel
photochemically induced coupling reaction between polyhalogenated or polycyano-
substituted alkenes and diene-Fe(CO)3 complexes. The new methodology developed
makes it straightforward to construct sterically congested quaternary carbon centers.5
(OC)3Fe Fe(CO)3 Fe(CO)3 n-Bu2O (1) (COCl) ,CH Cl R1 2 2 2 CO R2 OH OR o (2) ROH, pyridine, PhH 142 C R3 O O O O 3.1 3.2 3.3
(a) R =CH ,R =R =H (a) R = CH2CH=CH2, 1 3 2 3 (b) R =Et,R =R =H (b) R = CH2CH=CHMe, 1 2 3 (c) R =R =Me,R =H (c) R = CH2CMe=CH2, 1 2 3 (d) R =R =Me,R =H (d) R = CHMeCH=CH2 1 3 2
Scheme 3.1. Single cyclizations of esters from iron-complexed acid
72 n-Bu O (OC)3Fe Fe(CO)3 2 CO R1 R R2 N 142 oC Ph O O N Ph 3.4 3.5
(a) R = CH2CH=CH2, (a) R1 =CH3,R2 =H (b) R = CH2CH=CHMe, (b) R1 =Et,R2 =H (c) R = CH2CMe=CH2, (c) R1 =R2 =Me (d) R = CH2CH=CHPh (d) R1 =CH2Ph, R2 =H (OC)3Fe Fe(CO)3 n-Bu2O S CO 142 oC O O S 3.6 3.7
Scheme 3.2. Single cyclizations of amides and thioesters from iron-complexed acid
The reaction is carried out under carbon monoxide atmosphere (balloon pressure) to ensure the conversion of electron-deficient diene-Fe(CO)2 complex 3.12 to the product
3.13. The probable mechanism of this reaction is shown below (Scheme 3.3).
(OC)2Fe Fe(CO)3 Fe(CO)2
O O O
O O O 3.2a 3.8 3.9 H (OC) Fe (OC) Fe (OC)2Fe 2 2 Me
O O O O O O 3.12 3.11 3.10
(OC)3Fe Me CO
O O 3.13
Scheme 3.3. Proposed mechanism of the cyclization
73
Later, the 3-position was substituted by a methoxy group and the reaction afforded spirocycle 3.13/3.14 (Scheme 3.4).6 So far the Pearson group has developed a
novel coupling reaction between a diene-Fe(CO)3 complex and a pendant alkene and
modified the reaction conditions.1,3,5,6,7,8
OMe OMe OMe (OC)3Fe 3 (OC)3Fe (OC) Fe o 3 4 2 Bu2O, 140 C Me Me Bu2O 1 5 X o 1 atm, CO 140 C 6 O O X O X 3.14 3.15 3.16
X = CH2 or NPh O Me CuCl2, EtOH
O X
3.17
Scheme 3.4. Optimization of single cyclization
The thermal reaction, through the rearrangement of the diene-Fe(CO)3 system, via a hydride shift, affords a mixture of regioisomers 3.15 and 3.16 under the reaction conditions. After removal of the metal using saturated CuCl2/EtOH solution, with in situ
hydrolysis of the mixture, the reaction afforded a single stereoisomer of enone 3.17
(Scheme 3.4). The stereochemistry was studied and rationalized by the proposed
rearrangement-cyclization steps (Scheme 3.5).9
74
Fe(CO)3 Fe(CO)3 Nucleophile - R = H, Alkyl + PF6 R 3.18 3.19
(OC)3Fe Fe(CO)3 Rearrangement Cyclization
R R
3.20 3.21
Scheme 3.5. Proposed mechanistic rationale for the cyclization
By nucleophile addition, complex 3.19 is easily accessed from cyclohexadienyliron cation 3.18. Under cyclization reaction conditions, complex 3.20 is generated from 5-exo isomers 3.19 by in situ rearrangement. The required substrate, 1- substituted cyclohexadiene-Fe(CO)3 complex 3.20 then undergoes cyclization to form the
spirocyclic carbon skeleton 3.21.
The proposed scheme for constructing angular triquinanes is shown below
(Scheme 3.6). The ketone functionality might need to be protected prior to the ozonolysis due to its potential involvement in the later steps.
75 (OC)3Fe Fe(CO)3 Fe(CO)3 hv
O COOH O 3.22 3.23 3.24
O O O Me3NO 3 NaOMe O PhH THF O O O Triquinane
3.25 3.26 3.27
Scheme 3.6. Proposed synthesis of an all-carbon angular triquinane
76 3.2. Single cyclization
Previous students, Dorange and Wang succeeded in developing short and
convenient diastereoselective syntheses of all-carbon spirocyclic molecule (Scheme 3.4
and 3.7).5
A 3-methyl substituted cyclohexadiene iron carbonyl and substrate 3.22 (Scheme
3.6), derived from m-toluic acid, is a potential starting material as seen in chapter 2 for a new methodology to construct diquinane and angular triquinane systems. Before attempting a double cyclization reaction to generate a potential precursor of angular triquinanes, a simpler spirocyclic structure was studied for optimization of reaction conditions.
The compound 3.22 is quite stable on the laboratory shelf over a period of several years. Grignard addition via an acyl mesylate derivative was envisioned for the alkylation of various iron-complexed acids.1,10 This methodology was applied and optimized
77 previously for the non-substituted iron-complexed acid and 3-methoxy substituted iron-
complexed acid 3.32 (R = H or OMe) (Scheme 3.8).11
R R R Fe(CO)3 Fe(CO)3 Fe(CO)3 MsCl, Et3N MgBr 3.34 o OSO Me COOH CH2Cl2, 0 C 2 Et O, 0 oC O 2 O 3.32 3.33 3.35
(a) R = H , 75% over two steps (b) R = OMe, 60% over two steps
Scheme 3.8. Preparation of pendant ene compound
Attempted conversion of 3.22 to ketone 3.36 using this approach did not afford the desired product according to 1H NMR analysis. Instead, ester peaks were detected, and compound 3.37 was isolated in 80% yield.
3.34 Fe(CO)3 Fe(CO) Fe(CO)3 3 MgBr MsCl, Et3N
CH Cl , 0 oC OSO2Me CH Cl COOH 2 2 2 2 O O 3.22 3.39 3.36
Fe(CO)3
O
O
3.37
Scheme 3.9. Undesired nucleophilic addition product
78 The peaks at δ = 4.02 ppm and δ = 4.18 ppm were assigned for hydrogens next to
the oxygen in ester group. They occur at lower field than expected for a ketone α-CH2 group (close to δ = ~ 2 ppm) in 3.36.
Figure 3.1. 1H NMR spectrum of ester product 3.37
This is not the desired result but it is not totally unexpected. Previous studies by
Dorange showed that formation of the ester is due to oxidation of the Grignard reagent by adventitious oxygen to form butenoxide which then reacts with the acyl mesylate. The resulting ester is too unreactive to react with Grignard reagent.
79 Another problem with this approach lies in the possibility that acid anhydride
formation can occur during the reaction of 3.22 with methanesulfonyl chloride (Scheme
3.10).
O Fe(CO)3 Fe(CO)3 Fe(CO) S Cl 3 DIPEA O O OH O O S Me CH2Cl2 O O O O
3.22 3.38 3.39
+
(OC)3Fe Fe(CO) (OC) Fe Fe(CO)3 3 3 O Me S O O O O O O O O Traces
3.40
Scheme 3.10. Formation of mesylate and anhydride
If a nucleophile is strong enough to attack the carbonyl, iron complexed pendant alkene compounds are generated easily.
Fe(CO)3 (OC)3Fe Fe(CO) 3 Nu attack O (3.1) OSO2Me O O O possible Nu attack
3.39 3.40
80 However, the prepared Grignard reagent might be an aggregate and therefore
hindered sterically. In result, the major product of the Grignard addition was not the
expected ketone 3.36, but the ester 3.37.
Fe(CO)3 Fe(CO)3 (OC)3Fe Fe(CO)3 O MgBr O S Me + O (3.2) CH Cl O 2 2 O O O O
3.39 3.40 3.36
Another rationale is that the alkoxide anion generated from Grignard reagent 3.34
and oxygen presented in the system prevented the addition and consumed most of
mesylate 3.39 (Scheme 3.11). Therefore, ester 3.37 was isolated as a major product.
MgBr + O2 O + MgBr
3.34 3.34'
3.34' Fe(CO)3 Fe(CO)3 O
OSO2Me O CH2Cl2 O O 3.39 3.37
Scheme 3.11. Generation of alkoxide in Grignard reaction
Former research by Dorange in the Pearson group showed similar observation of the reaction when acid chlorides were used (eq 3.3).1,10,11 The pure reagent 3.1 with
81 copper iodide conditions led to a 1:1 mixture of ketone 3.35a and butenyl ester 3.41.11
Thorough degassing of the solvents favored formation of the desired product 3.35a.
However, the reaction conditions could not be improved to afford only the ketone compound. Changes in reagent amount or other reaction conditions did not affect to the outcome of the reaction. In the case of complex 3.33 (R = OMe), the electron donating effect of the methoxy substituent is also a potential problem because the acyl halide is less electrophilic. The formation of tricarbonyl(cyclohexadienyl)ketone iron complexes via acyl mesylate derivatives was also studied by Dorange. The acyl mesylate method was the best to obtain 3.35a composed to using other reagents and different conditions
(eq. 3.3). Ester compound 3.41 which was observed via acid chloride formation, was eliminated when he used the acyl mesylate method.
Fe(CO) Fe(CO)3 3 Fe(CO)3 (a) (COCl)2, pyr, CH2Cl2 + o O COOH (b) CuI, THF, 0 C (3.3) MgBr O O
3.1 3.34 45% 45%
3.35a 3.41
The same reaction condition could not be applied to the 3-methyl substituted iron-
complexed acid 3.32 intermediate, maybe because of the difference in electron donating
effect of the methyl group in the iron complexed system. A slightly more electron rich
diene by methyl group in conjunction with iron tricarbonyl group might generate this problem.12 This results in the difficulties observed for Grignard addition to 3.32.
82 To further analyze the situation, in an attempt to optimize the reaction, the carboxylic methanesulfonic anhydride intermediate 3.39 was isolated. The 1H NMR spectrum of the major product, resumed to be 3.39, showed some differences in peak positions compared with 3.22, and the mesylate CH3 appears at δ 2.59 ppm. This means the anhydride formation proceeded as expected, but the Grignard addition step failed. At this point, it is clear that allylic amines react with this intermediate easily,1, 5, 13 therefore, addition of Grignard reagent is a challenge of this step.9
Figure 3.2. 1H NMR spectrum of mesylate 3.39
83 In order to circumvent this frustrating problem bearing in mind that the goal of
this study is to build angular triquinane systems, a new approach for attaching the
pendant alkene was investigated. We decided to utilize an aldehyde intermediate instead
of the acyl mesylate 3.39, since this substrate would not be as sensitive to the presence of alkoxides that are formed by oxidation of the Grignard reagent 3.34. The reasoning
behind this choice is that aldehyde 3.41, reacts with alkoxide 3.34’ reversibly, but with
Grignard reagent 3.34 irreversibly, while acyl mesylates 3.39 react essentially irreversibly with alkoxide 3.34’ to form esters 3.37 (Scheme 3.12).
Fe(CO)3 3.34'
O O
O Fe(CO) reversible 3 3.37
H
O 3.34 Fe(CO) MgBr Fe(CO)3 3 3.41
O OH 3.36'
Scheme 3.12. Alternative Grignard reaction using aldehyde 3.41
84 o Fe(CO)3 1) (COCl)2, DMF, 0 C Fe(CO)3 o CH2Cl2, Pyr, -30 C
OH t H 2) LiAlH(OBu )3 o O cat. CuI, -78 C O THF, 20% 3.22 3.41
BMPA OMe H
O 10 hr, 72% O 3.42 3.43
CHO DIBAl-H Mn2O CO Et 2 CH2OH Fe(CO) 3 Fe(CO)3 Fe(CO)3 3.44 3.45 3.46 i-PrMgBr
O O N C N N C N CH2OMgBr CHO Fe(CO)3 Fe(CO)3 71% 3.47 3.49
Scheme 3.13. Preparation of the iron-complexed aldehyde 3.41
The first approach to aldehyde 3.41 employed methods used by Dorange, which gave low yield of the aldehyde and only 15% of the starting material was recovered. Also, the experiment requires a long time and a few steps. The second method was developed by Mukaiyama and co-workers14 to transform various esters to their corresponding
aldehydes in one step. Two equivalents of bis(4-methyl-1-piperazinyl)aluminum hydride
under thermal conditions transform methyl benzoate to benzaldehye directly in good
yield. The last method, the so-called Mukaiyama oxidation, is mild enough to use for
85 iron-complexed compounds, such as 3.47 as shown by Mukaiyama and Muraki (Scheme
3.13).14
Two procedures were employed successfully for the preparation of aldehyde 3.41,
and these are summarized in Scheme 3.14.14-16
i-PrMgBr Fe(CO) Fe(CO)3 DIBAl-H Fe(CO)3 3 O O H COOMe CH2OH N C N N C N O 3.50 3.48 3.41 Overall 61%
Fe(CO)3 Fe(CO)3 BMPA H COOMe THF, 10 hr O 3.50 3.41
42%
Scheme 3.14. Overall comparison of the synthetic methods of aldehyde 3.41
Both conditions were examined to secure the iron-complexed aldehyde 3.41 from ester 3.50. Mukaiyama’s oxidation method through alcohol intermediate 3.48 gives the highest yield without difficult handling techniques during the experiment and workup.
86 3.34
Fe(CO)3 Fe(CO)3 Fe(CO)3 MgBr H + Et O, 3hr (3.4) O 2 OH OH 72% 3.41 3.51 3.52
Figure 3.3. 1H NMR spectrum of the crude product 3.51 and 3.52
The Grignard reagent 3.34 was freshly prepared from 4-bromobut-1-ene and Mg turnings in ethyl ether. The iron-complexed alcohols 3.51 and 3.52 were obtained in 72 % combined yield. The reaction was expected generate both diastereomers of the alcohol product. Surprisingly, the ratio of the major versus minor product was roughly 6:1.
87
Similar stereoselectivity was also observed during studies by Asaf Alimardanov,3 a former Pearson group member. Alcohols 3.54 and 3.55 were obtained as a 2:1 mixture of diastereomers (eq. 3.5). The more rigid structure 3.56 produced higher diasteromeric ratio (5:1 between 3.57a/3.57b).
Fe(CO)3 MgBr O
3.54 (3.5)
Fe(CO)3 Fe(CO)3 OH OH +
3.55a 3.55b ( 2 : 1 )
Fe(CO) 3 MgBr O
3.56 (3.6)
Fe(CO)3 Fe(CO)3 OH OH +
3.57a 3.57b ( 5 : 1 )
As noted above, aldehyde 3.41, a cyclic structure, generated a 6:1 ratio between
3.51 and 3.52. At this stage, the mixture 3.53 is clean enough to use in the next step. We
88 did not determine which diastereomer is the major product, although 3.51 seems the
major product by analogy with reactions in eq. 3.5 and eq. 3.6.
Fe(CO)3 (OC) Fe o 3 (OC)3Fe Bu2O, 142 C Me Me + (3.7) 1 atm, CO OH HO HO
3.53(= 3.51 + 3.52) 3.58 3.59
Cyclization of 3.53 afforded the expected mixture of regioisomers 3.58 and 3.59.
This regio-isomerism will not be an impediment for the proposed double cyclization which requires iron coordination to 3,5-diene position in the six membered ring, not 2,4- diene position (Chapter 1, Scheme 1.8), because the regioisomers are in equilibrium.
Thus, cyclization of the mixture of diastereomers 3.51 and 3.52 is expected to yield four compounds as a result of thermal rearrangement of the initial product 3.58 to give regioisomer 3.59 (Eq. 3.7). We expected to obtain compounds 3.60, 3.61, 3.62 and
3.63, but given the 6:1 ratio of diastereomeric alcohols 3.53, two of these products would be very minor.
(OC)3Fe (OC) Fe (OC)3Fe (OC) Fe Me 3 Me Me 3 Me + + +
HO HO HO HO
3.60 3.61 3.62 3.63
Figure 3.4. Four possible isomers from the Grignard reaction and cyclization
89
The Fe(CO)3 group was removed by treatment with saturated copper(II) chloride solution in ethanol, and the hydroxyl group in the cyclized products 3.58 and 3.59 was oxidized with sodium dichromate under acidic conditions to afford ketones 3.66 and 3.67
(Scheme 3.15).20 The ratio of the regioisomers is 75 % and 25 % (3:1) by 1H NMR with
3.66 as the major component.
(OC) Fe 3 (OC)3Fe Me Me Me Me CuCl , EtOH + 2 +
HO HO HO HO
3.58 3.59 3.64 3.65
Me Me Na2Cr2O7, H2SO4, H2O +
O O
75 % 25 %
3.66 3.67
Scheme 3.15. The result of single cyclization reaction
The major 1H NMR spectral differences between 3.66 and 3.67 are shown in
Figure 3.5 and Figure 3.6. Comparing hydrogens on sp2 carbons, both structures are assigned clearly. For 3.66, H-6 is a singlet, H-8 is a doublet and H-9 is a multiplet (Figure
3.5). However, for 3.67, H-8 is a doublet, H-10 is a doublet, and H-9 is dd (Figure 3.6).
90
Figure 3.5. 1H NMR spectrum of oxidation product 3.66
Figure 3.6. 1H NMR spectrum of oxidation product 3.67
91 The preponderance of regioisomer 3.66 in the product mixture which corresponds to the iron complexes (3.58 / 3.59) that result directly from the ene cyclization reaction
suggests that the thermodynamically more stable diene complexes have the methyl group
at C-2 of the diene. This observation should be investigated more thoroughly in the future.
92 3.3. Double Cyclization
In the previous sections, we have shown examples of making molecules including spirolactam structures diastereoselectively by an iron carbonyl mediated [6+2] ene-like cyclization, initially developed in the Pearson laboratory. A previous student, Xiaolong
Wang, successfully demonstrated that this methodology can be applied to prepare double cyclization products, although only a few examples were presented (eq. 3.8). During the study, he also observed a different cyclization mode involving the pendant diene corresponding to a [4+4] cycloaddition (eq. 3.9). Our focus in the present study is to examine the double cyclization using an all-carbon substrate.
Me3NO PhH
n-Bu2O (OC)3Fe Fe(CO)3 CO + 142 oC N O Ph 71% O N N (3.8) O Ph Ph
3.68 3.69 3.70
7 8 10 6 Fe(CO) 11 3 Me3NO 9
12 5 (3.9) MeCN 1 4 N 13 2 3 Ph N O O Ph
3.68 3.71
93 Application of this strategy to the synthesis of a carbocyclic triquinane is
preposed in Scheme 3.14. Double cyclization requires that Grignard reagent 3.72 be
coupled with aldehyde 3.41 to append the diene side chain in substrate 3.73. The
preparation of the required precursor 6-bromohexa-1,3-diene, will now be discussed.
Fe(CO) Fe(CO)3 3 MgBr o Bu2O, 140 C 3.72 (OC)3Fe H
O OH HO
3.41 3.73 3.74
O O aldol CuCl2, EtOH 3 O O
HO HO HO
3.75 3.76 3.77
Scheme 3.16. Proposed scheme to construct a triquinane system
Ethyl hexa-3,5-dienoate (3.79) was prepared in 85% yield by the deconjugation of ethyl sorbate (3.78).18,19 The rearranged ester was reduced to an alcohol maintaining the
terminal vinyl group by LAH. Reaction of alcohol 3.80 with Ph3P/CBr4 under standard
conditions18 afforded the desired bromide 3.81.
94 1) LDA, n-BuLi, THF, -78 oC O diisopropylamine, HMPA O
O 2) acetic acid O
3.78 3.79
LiAlH4 PPh3, CBr4 OH Br
ether, 15h 3.80 ether, 15h 3.81
Scheme 3.17. Preparation of bromide 3.81 for Grignard reaction
The bromide 3.81 is unstable and decomposed in the freezer after 1-2 weeks.
Consequently, the alcohol 3.80 was used as the storage material, and this was converted to bromide 3.81 when needed for the preparation of the Grignard reagent. The addition of the Grignard reagent 3.72 derived from 3.81 to aldehyde 3.41 was tried several times but the desired product 3.82 was not obtained.
Fe(CO)3 MgBr Fe(CO)3 3.72 H (3.10)
O OH
3.41 3.82
At this time it appears that the difficult step is preparation of the Grignard reagent
3.72. One possible explanation for this is that bromide 3.81 is very susceptible to E2 elemination, owing to the presence of the neighboring diene. Thus as Grignard reagent is
95 formed, it could act as a base to promote this elimination (eq 3.11). In result, hexatriene
3.84 might be generated to stop the Grignard reaction.
R MgBr H Br (3.11) + RH + MgBr2
3.83 3.84
96 3.3. Conclusion
In conclusion, intramolecular double cyclization reactions between alkene and diene-Fe(CO)3 moieties to produce all-carbon triquinane system was not accomplished.
But, single cyclization with pendant monoalkene was successful. A new approach via tricarbonyliron(cyclohexadienyl)alcohol formation was developed. This route proved to be the most effective for the 3-methyl substituted complex. The alternative pathway using aldehyde 3.41 was stereoselective. This is potentially useful for future applications of cyclic iron complexed diene chemistry. The main problem encountered during the attempted double cyclization approach to angular triquinanes was the preparation and storage of bromide 3.73, and its conversion to Grignard reagent 3.64. A Barbier reaction or preparation of a Grignard reagent with chloride might be applied to this problem. A new student in the Pearson laboratory is currently evaluating an alternate route to substrates related to 3.74 in order to test the proposed tandem double [6+2] ene reaction on an all-carbon system.
97 3.4. Experimental Section
General experimental and spectroscopic methods are as described in Chapter 2.
General procedure for the thermally induced cyclization. The appropriate
amide was dissolved in freshly distilled di-n-butyl ether under argon. The solution was
purged with CO for 5 min, and then refluxed under a balloon of CO for 8-16 h. The
cooled product mixture was diluted with ether, filtered through Celite, and concentrated.
Flash chromatography or preparative TLC separation yielded the desired product.
Tricarbonyl[1-4-η-1-{3-butenyl(3-methyl-1,3-cyclohexadiene-1-carboxylate)}]iron
(3.37).
12 Formation of the Grignard reagent: 140 mg of Mg 11
3 Fe(CO)3 in 5 mL of anhydrous Et2O was treated with 4-bromobutene 10 4 2 9 1 5 7 O 8 according to the general procedure. Formation of ester 6 O complex: 300 mg of acid 3.22 in 5 mL of anhydrous CH2Cl2 was mixed with 0.4 mL of anhydrous Et3N and 0.55 mL of methanesulfonyl chloride is a
flask immersed in an ice bath for 1 h. Then, the reaction mixture was rotary evaoporated
to yield 600 mg of mixed anhydride as a brown oil. anhydrous Et2O (2 mL) was added to
this oil and then the solution was added dropwise over 30 min to the Grignard reagent
freshly prepared in 5 mL of anhydrous Et2O. The reaction mixture was refluxed for
98 additional 2 h. to yield 288 mg (80%) of the title compound as a light brown oil, along
1 with 20 mg of recovered acid complex 3.37. Rf = 0.33 (Hex:EA/4:1); H NMR (CDCl3,
400 MHz, δ, ppm) 1.35 (ddd, J = 14.2, 8.2, 3.0 Hz, 1H, H6), 1.62 (m, 1H, H5), 1.83 (dt, J
= 14.8, 3.2 Hz, 1H, H5’), 2.03 (s, 3H), 2.04 (ddd J = 14.2, 11.5, 3.2 Hz, H6’), 2.18 (m,
2H), 3.28 (s, 1H, H2), 4.01 (dt, J = 10.8, 6.6 Hz, 1H, H10), 4.19 (dt, J = 10.8, 6.6 Hz, 1H,
H10’), 5.01 (br d, J = 10.2 Hz, 1H, H12), 5.08 (br d, J = 16.5 Hz, 1H, H12’), 5.75 (ddt, J
13 = 16.5, 10.2, 6.6 Hz, 1H, H11), 5.86 (t, J = 3.2Hz, 1H, H4). C NMR (CDCl3, 100 MHz,
δ, ppm): 19.4, 22.2, 25.2, 33.7, 63.2, 64.0, 65.1, 84.4, 89.0, 116.5, 134.0, 172.6; HRMS-
+ FAB (m/z) M calcd for C15H16FeO5, 332.0347; found, 332.0348.
(Methansulfonyl 3-methylcyclohexa-2,5-dienecarboxylate)tricarbonyliron (3.39).
The acid 3.22 (1.14g, 4.12 mmol) in 25 mL of CH2Cl2 Fe(CO)3 was treated with 0.68 mL of DIPEA (8.24 mmol, 2 equiv), OSO2Me
O followed by 0.4 mL of CH3SO2Cl (5.356 mmol, 1.3 equiv)
dropwise for 5 minutes and stirred at 0 C for 1 h. The solution was evaoporated and
Flash chromatography afforded the mesylate 3.39 as an brown oil. Rf = 0.43
1 (Hex:EA/2:1); H NMR (CDCl3, 400 MHz, δ, ppm) 1.61 (m, 1H), 1.79 (m, 1H), 2.01 (m,
1H), 2.11 (m, 1H), 2.12 (s, 3H), 2.59 (s, 3H), 3.35 (br, 1H), 6.08 (s, 1H); 13C NMR
(CDCl3, 100 MHz, δ, ppm) 22.0, 24.4, 26.0, 36.6, 113.5, 121.5, 130.9, 140.4, 174.0;
+ HRMS-FAB (m/z) M calcd for C12H12FeO7S, 355.9653; found, 355.9650.
99 Tricarbonyl[1-4-η-1-{3-butenyl(3-methyl-1,3-cyclohexadiene-1-carbaldehyde)}]iron
(3.41).
Formation by Mukaiyama’s method with DIBAl-H: To
Fe(CO)3 a solution of the ester complex 3.50 (292 mg, 1 mmol) in dry ether
H (20 mL) was added dropwise DIBAl-H (0.4 mL, 2.3 mmol) in dry O ether (5 mL) at -50 °C. After the solution was stirred an additional
30 min at the same temperature, the excess DIBAl-H was destroyed by addition of ether and water. Cold 15% tartaric acid (4.5 mL, 4.5 mol) was added, and the resulting mixture was stirred for 2 h at rt. The organic layer was extracted with ether followed by standard workup to afford the crude alcohol 3.48. To a solution of the residue in dry THF (10 mL) was added diisopropylmagnesium bromide (0.38 M ether solution, 1.9 mL, 1.23 mmol) at
0 °C. After the solution was stirred for 10 min, a solution of azodicarbonyldipiperidine
(300 mg, 0.70 mmol) in dry THF (4 mL) was added at 0 °C, and the resulting mixture was stirred for an additional 20 min. The reaction was quenched with brine (20 mL), and then the organics were extracted with ether (3 x 30 mL), and dried with MgSO4. After solvent evaporation, the crude product was purified by column chromatography
(ether:hexane =1:4) to afford the aldehyde 3.41 (160 mg, 61%) as a yellow oil. For characterization, see below. Formation by direct conversion with aminoaluminum hydride: N-Methylpiperazine (40 mg, 0.4 mmol) was added to a 0.64M solution of aluminum hydride in THF (1 mL, 0.46 mmol) over 3 minutes at 0 °C under Ar and the solution was stirred at rt for additional 1 h. A solution of iron-complexed ester (26 mg,
0.1 mmol) in THF (1 mL) was added to the cooled solution of the reducing agent and the mixture was then refluxed for 4 h. The cooled (0 °C) solution was quenched with distilled
100 water (10 mL, 0.6 mmol). The suspension was warmed to 65 C and filtered off using
THF for washing solvent. The combined filtrate was rotary evaporated in a round bottom
flask. The residue was dissolved in ether, washed with water, 5% H2SO4 and dried with
MgSO4. A crude oil was produced after removal of solvent. The brown oil was purified
by PLC to afford iron-complexed aldehyde 3.41 (11 mg, 42%). Rf = 0.69 (Hex:EA/2:1);
1 H NMR (CDCl3, 400 MHz, δ, ppm) 1.38 (m, 1H), 1.42 (m, 1H), 1.90 (m, 1H), 1.99 (m,
13 1H), 2.07 (s, 3H), 3.48 (s, 1H), 5.62 (s, 1H), 9.13 (s, 1H); C NMR (CDCl3, 100 MHz, δ,
ppm) 21.5, 22.4, 26.9, 65.1, 69.0, 130.5, 139.6, 197.7; HRMS-FAB (m/z) M+ calcd for
C11H10FeO4, 261.9929; found, 261.9927.
Tricarbonyl[1-4-η-1-(3-methyl-1,3-cyclohexadiene-4-penten-1-ol)]iron (3.51, 3.52).
Formation of the Grignard reagent: Mg was kept at 100 Fe(CO) 3 C (oven) for 3h before reaction. A flame dried 3 neck flask
equipped with a flame dried condenser was assembled while hot OH and allowed to cool to rt under a flow of Ar. The flask was then
charged with 1.2 equiv of Mg (32 mg), followed by addition of the 5 mL of diethyl ether
under Ar. 4-Bromo-1-butene (150 mg, 1.1 mmol) was the added via syringe such that the
reaction mixture gently refluxed for 1 h until most pieces of Mg turning disappear.
Formation of alcohol complex 3.51/ 3.52: 78.6 mg of aldehyde 3.41 in 2 mL of
anhydrous CH2Cl2 was reacted with 0.4 mL of Grignard reagent in 1 mL of anhydrous
Et2O to yield 75 mg of the crude compound as a light brown oil. Flash chromatography
purification (silica gel, Hex:EA/10:1) afforded complex 3.51/3.52 (68.7 mg, 72% yield)
101 1 as a yellow oil. Rf = 0.3 (Hex:EA/5:1); H NMR (CDCl3, 400 MHz, δ, ppm) 1.21 (m, 1H),
1.63 (m, 1H), 1.75 (m, 1H), 2.01 (s, 3H), 2.07 (m, 1H), 3.11(s, 1H), 3.49 (dd, 1H, J = 8.9,
2.1 Hz), 4.82 (d, 1H, J = 10.3 Hz), 4.90-5.03 (m, 2H), 5.21 (d, 1H, J = 15.3 Hz), 5.79 (t,
13 1H, J = 3.3 Hz); C NMR (CDCl3, 100 MHz, δ, ppm) 18.2, 19.3, 23.2, 26.1, 33.2, 38.9,
+ 54.9, 79.1, 118.6, 120.2, 133.4, 170.1; HRMS-FAB (m/z) M calcd for C15H18FeO4,
318.0555; found, 318.0559.
Tricarbonyl(6-9-η-4,7-Dimethylspiro[4,5]dec-6,8-en-1-ol)iron (3.58)/ Tricarbonyl(7-
10-η-4,7-Dimethylspiro[4,5]dec-7,9-en-1-ol)iron (3.59).
A 6:1 mixture of alcohols 3.51/3.52 (OC) Fe 3 (OC)3Fe Me Me (63.6 mg, 0.2 mmol) dissolved in 12 mL of + anhydrous n-Bu2O was refluxed for 7 h HO HO according to the general procedure to afford, after preparative TLC (Hex:EA/10:1, multiple development), a mixture of two inseparable spirocycles (ratio≈7:2) 38 mg (60%), and another mixture of two inseparable
spirocycles, which were produced in very small amount due to the composition of the
starting mixture of 3.51 and 3.52. Traces of demetallated spiroalcohols were also
1 observed. Rf = 0.50 (Hex:EA/5:1); first mixture, major compound 3.58; H NMR (CDCl3,
400 MHz, δ, ppm) 0.97 (d, 3H, J = 7.2 Hz), 1.22-2.40 (series of m, 8H), 2.04 (s, 3H),
3.01 (s, 1H), 3.48 (t, 1H, J = 6.9 Hz), 5.60 (d, 1H, J = 6.6 Hz), 5.72 (m, 1H); 13C NMR
(CDCl3, 100 MHz, δ, ppm) 16.8, 22.5, 28.4, 29.9, 38.8, 40.0, 70.0, 76.3, 80.5, 125.4,
+ 210.1, 214.9; HRMS-FAB (m/z) M calcd for C15H18FeO4, 318.0555; found, 318.0556.
102 1 Second mixture, minor compound 3.59; H NMR (CDCl3, 400 MHz, δ, ppm) 1.12 (d, 3H,
J = 7.2 Hz), 1.40-2.26 (series of m, 8H), 2.01 (s, 3H), 3.19 (d, 1H, J = 6.6 Hz), 3.5 (t, 1H,
13 J = 7.2 Hz), 5.67 (d, 1H, J = 6.6 Hz), 5.78 (m, 1H); C NMR (CDCl3, 100 MHz, δ, ppm)
16.9, 22.2, 28.2, 29.5, 38.0, 40.1, 68.5, 75.8, 80.1, 123.2, 209.9, 212.2.
4,7-Dimethylspiro[4,5]dec-6,8-en-1-ol (3.64) / 4,7-Dimethylspiro[4,5]dec-7,9-en-1-ol
(3.65).
A mixture of complexes 3.54/ 3.55
Me Me (32 mg, 0.1 mmol) was added to 2 mL of + saturated CuCl2/EtOH solution . The reaction HO HO mixture was stirred at rt for 24 h to afford
10.6 mg (60% yield) of the title compound
3.64/ 3.65 as a colorless viscous oil, purified by PLC. Rf = 0.28 (Hex:EA/9:1); first
1 mixture, major compound 3.64; H NMR (CDCl3, 400 MHz, δ, ppm) 0.96 (d, 3H, J = 6.6
Hz), 1.4-2.4 (series of m, 7H), 2.03 (s, 3H), 2.22 (br, 1H), 3.26 (dd, 1H, J = 8.9, 2.2 Hz),
5.60 (d, 1H, J = 1.6 Hz), 5.80 (dd, 1H, J = 8.9, 1.6 Hz), 5.90 (dt, 1H, J = 8.9, 4.5 Hz); 13C
NMR (CDCl3, 100 MHz, δ, ppm) 17.8 18.2, 21.3, 22.0, 24.5, 25.0, 26.8, 27.7, 53.9, 54.2,
66.2, 68.2, 122.5, 122.8, 124.8, 125.0, 128.0, 129.6, 131.1, 132.1, 132.9, 133.9, 143.8,
1 144.5; Second mixture, minor compound 3.65; H NMR (CDCl3, 400 MHz, δ, ppm) 1.04
(d, 3H, J = 6.6 Hz), 1.3-2.3 (series of m, 7H), 2.00 (s, 3H), 2.05 (br, 1H), 3.47 (dd, 1H, J
= 8.9, 2.2 Hz), 5.48 (dd, 1H, J = 9.6, 1.6 Hz), 5.78(dd, 1H, J = 8.9, 4.5 Hz), 5.96 (dd, 1H,
+ J = 9.6, 8.9 Hz); HRMS-EI (m/z) M calcd for C12H18O, 178.1358; found.
103 4,7-Dimethylspiro[4,5]dec-6,8-en-1-one (3.66) and 4,7-Dimethylspiro[4,5]dec-7,9-en-
1-one (3.67).
10 mg. of alcohol 3.64/3.65 and 1 mL of Me Me water were placed in a small vial and cooled in ice
water. To this was added gradually 0.2 mL of conc. O O
3.66 3.67 sulfuric acid. Sodium dichromate (Na2Cr2O7, 20 mg) was dissolved in a solution of 0.2 mL of conc. sulfuric acid in 1mL of water. The chromic acid solution was added to the solution of 3.64/3.65 over 30 minutes with vigorous
stirring. Then, after 1h, the solution was heated at 90 °C in a water-bath for 2 h, cooled,
ether (2 x 2 mL) extracted, and the combined extract dried with Na2SO4. preparative TLC
1 separation afforded 5 mg of ketone 3.66, and 1.7 mg of 3.67. 3.66: H NMR (CDCl3, 400
MHz, δ, ppm) 0.99 (d, 3H, J = 6.6 Hz), 1.3-2.4 (series of m, 7H), 2.02 (s, 3H), 5.61 (s,
13 1H), 5.82 (m, 1H), 5.91 (d, 1H, J = 10.6 Hz); C NMR (CDCl3, 100 MHz, δ, ppm) 16.9,
22.2, 28.2, 29.5, 38.0, 40.1, 68.5, 75.8, 80.1, 123.2, 209.9, 212.2; HRMS-EI (m/z) M+
1 calcd for C12H16O, 176.1201; found. 3.67: H NMR (CDCl3, 400 MHz, δ, ppm) 1.06 (d,
3H, J = 6.5 Hz), 1.4-2.2 (series of m, 6H), 1.98 (s, 3H), 2.41 (d, 1H, J = 10.7 Hz), 5.61 (d,
1H, J = 7.0 Hz), 5.81 (d, 1H, J = 10.7 Hz), 5.92 (dd, 1H, J = 10.1, 6.9 Hz); 13C NMR
(CDCl3, 100 MHz, δ, ppm) 17.5, 22.5, 25.6, 28.5, 36.7, 39.5, 64.9, 118.4, 121.5, 132.8,
+ 148.6; HRMS-EI (m/z) M calcd for C12H16O, 176.1201; found.
104 Ethyl Hexa-3,5-dienoate (3.71).
A solution of lithium diisopropylamide (LDA) O in THF was prepared by the slow addition of n-BuLi O (55 mmol, 2.2 M in hexane) in 25 mL of hexane to a
solution of diisopropylamine (5.6 g, 0.27 mol) in 100 mL of dry THF under Ar. The
solution was cooled to -78 °C, and dry hexamethyl phosphoramide (1.74 g, 65 mmol)
was added dropwise and the mixture allowed to stir 0.5 h. Ethyl sorbate (3.70) (6.3 g, 45
mmol) was added to the cold solution over 2 h. Stirring was continued an additional hour
at -78 °C, then the dark-red mixture was siphoned into a rapidly stirred solution of acetic
acid (9 g, 0.15 mol) in 150 mL of H2O. The resultant solution was extracted with pentane
(5 x 20 mL), and the combined extracts were washed with water, 1 N NaHCO3, dried
(Na2SO4), and concentrated by rotary evaporation. The residue was distilled to give the
19 1 known compound, pure diene 3.70 (4.8 g, 76 %); H NMR (CDCl3, 400 MHz, δ, ppm)
1.25 (t, 3H), 3.10 (d, 2H), 4.14 (q, 2H), 4.9-6.7 (series of m, 5H).
Hexa-3,5-dien-1-ol (3.72).
A solution of ethyl hexa-3,5-dienoate (3.71)
OH (3.1 g, 22 mmol) in anhydrous ether (3 mL) was added dropwise to a suspension of lithium aluminum hydride
(1.1 g, 29 mmol) in anhydrous ether (20 mL). After the addition was completed, the reaction mixture was heated at reflux for 15 h; The flask in an ice bath, was cooled and water was carefully added dropwise to destroy the excess hydride until hydrogen evolution ceased. After 2 N H2SO4 (10 mL) was added to dissolve the white solid, the
105 layers were separated, and the aqueous layer was extracted with ether (3 x 30 mL). The
combined organic extracts were washed with saturated NaHCO3 (10 mL) and dried
(MgSO4). After removal of solvent under reduced pressure, the crude material was vacuum distilled to give 1.8 g (83.5 %) of pure alcohol 3.72: bp 71-73 °C (19 mm). 1H
NMR (CDCl3, 400 MHz, δ, ppm) 2.32 (q, 2H), 3.00 (br s, 1H), 3.63 (t, 2H), 4.8-6.7
(series of m, 5H).19
6-Bromo-1,3-hexadiene (3.73).
3,5-Hexadien-1-ol (1.8 g, 18 mmol) in 3 mL of
Br diethyl ether was slowly added to a solution of
tetrabromomethane (10.8 g, 32.4 mmol) and
triphenylphosphine (8.46 g, 32.4 mmol) in 40 mL of diethyl ether. The mixture was
heated at reflux for 1 h. After addition of 50 mL of pentane, the mixture was filtered.
After evaporation of the solvents, 1.98g (69% yield) of the bromide 3.73 was recovered
by distillation; 1H NMR 2.62 (dt, 2H), 3.37 (t, 2H), 4.98 (d, lH), 5.11 (d, lH), 5.75 (dt, lH),
6.12 (dd, lH), 6.31 (dt, 1H).21
Attempted preparation of 3,5-hexadiene-1-magnesiumbromide (3.64).
Mg (79.0 mg, 3.25 mmol) was kept at 100 C
(oven) for 3h before raction. A flame dried 3 neck flask MgBr equipped with a flame dried condenser was assembled while hot and allowed to cool to rt under a flow of Ar. The flask was then charged with
79 mg of Mg (1.3 equiv), followed by addition of 15 mL of diethyl ether under Ar.
106 Bromide 3.73 (0.14 g, 2.5 mmol)was added dropwise via syringe such that the reaction mixture gently refluxed. The mixture was heated to reflux for one more hour after the completion of addition. Then, compound 3.41 (262 mg, 1 mmol) in 5 mL of anhydrous ether was added dropwise for the Grignard reaction. After the usual work, no desired
product 3.82 was isolated.
107 3.5. References
(1) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908-3918.
(2) Pearson, A. J.; Zettler, M.; Pinkerton, A. A. J. Chem. Soc. Chem. Commun.1987, 264- 266.
(3) Alimardanov, A. . Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 1998.
(4) Bond, A.; Green, M. J. Chem. Soc. 1971, 12. Bond, A.; Green, M.; Taylor, S. H. J. Chem. Soc., Chem. Commun. 1973, 112. Bond, A.; Lewis, B.; Green, M. J. Chem. Soc., Dalton Trans. 1975, 1109.
(5) Pearson, A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6, 2535-2538.
(6) Pearson, A. J.; Wang, X. Tetrahedron Lett., 2002, 43, 7513-7515.
(7) Pearson A. J.; Wang. X. J. Am. Chem. Soc. 2003, 125, 638-639.
(7) Yang, N. C.; Elliott, S. P.; Kim, B. J. Am. Chem. Soc. 1969, 91, 7551-7553.
(9) (a) Pearson, A. J. Acc. Chem. Res 1980, 13, 463-469. (b) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic Press: London, 1994.
(10) Zettler, M. W. Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 1988.
(11) Dorange, I. B. Ph.D. Thesis, Case Western Reserve University, Cleveland, OH, 2001.
(11) McMurry, J.; Castellion, M.; Ballantine, D. Fundamentals of General, Organic, and Biological Chemistry, Fifth Edition, Pearson Prentice Hall: New Jersey, 2006.
(13) Pearson, A. J.; Alimardanov, A.; Pinkerton, A. A.; Parrish, D. A. J. Org Chem. 1998, 63, 6610-6618.
(14) Mukaiyama, T.; Muraki, M. Chem. Lett. 1975, 215-218.
(15) Wada, A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K,; Ito, M. J. Org Chem. 1997, 62, 4343-4348.
(16) Fujisawa, T.; Mori, T.; Tsuge, S.; Sato, T. Tetrahedron Lett. 1983, 24, 1543-1546.
(17) Saigo, K.; Morikawa, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1976, 49, 1656-1658.
108 (18) Martin, S. F.; Tu, C.; Chou, T. J. Am. Chem. Soc. 1980, 102, 5274-5279.
(19) Stevens, R. V.; Cherpeck, R. E.; Harrison, B. L.; Lai, J.; Lapalme, R. J. Am. Chem. Soc. 1976, 98, 6317-6321.
(20) Kendall, E. C.; Osterberg, A. E.; J. Am. Chem. Soc. 1920, 42, 2616-2626.
(21) Jousseaume, B.; Lahcini, M.; Rascle, M. Organometallics 1995, 14, 685-689.
109
APPENDIX
1H and 13C NMR Spectra of New Compounds
110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142
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