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VANADIUM-CATALYZED ASYMMETRIC EPOXIDATIONS OF ALLYLIC ALCOHOLS
AND RADICAL CYCLIZATION/FRAGMENTATION EN ROUTE TO AN EIGHTMEMBERED RING
Madison McCrea-Hendrick
B.S., California State University, Chico, 2007
THESIS
Submitted in partial satisfaction of
the requirements for the degree of
MASTER OF SCIENCE
in
CHEMISTRY
at
CALIFORNIA STATE UNIVERSITY, SACRAMENTO
FALL
2011
© 2011
Madison McCrea-Hendrick
ALL RIGHTS RESERVED
ii
VANADIUM-CATALYZED ASYMMETRIC EPOXIDATIONS OF ALLYLIC ALCOHOLS
AND RADICAL CYCLIZATION/FRAGMENTATION EN ROUTE TO AN EIGHTMEMBERED RING
A Thesis
by
Madison McCrea-Hendrick
Approved by:
__________________________________, Committee Chair
James Miranda
__________________________________, Second Reader
Jacqueline Houston
__________________________________, Third Reader
Jeffrey Mack
____________________________
Date
iii
Student: Madison McCrea-Hendrick
I certify that this student has met the requirements for format contained in the University format
manual, and that this thesis is suitable for shelving in the Library and credit is to be awarded for
the thesis.
__________________________, Graduate Coordinator
Susan Crawford
Department of Chemistry
iv
___________________
Date
Abstract
of
VANADIUM-CATALYZED ASYMMETRIC EPOXIDATIONS OF ALLYLIC ALCOHOLS
AND RADICAL CYCLIZATION/FRAGMENTATION EN ROUTE TO AN EIGHTMEMBERED RING
by
Madison McCrea-Hendrick
Part one of this thesis describes the catalytic activity of Schiff base ligands and
vanadium towards the asymmetric epoxidation of allylic alcohols. Currently, the ligands
used for the vanadium-catalyzed epoxidation are hydroxamic acids. However, vanadium
catalyzed reactions employing Schiff bases as ligands have been reported by various
groups. We investigated these Schiff base ligands for enantioselectivity of epoxidation
reactions. While Schiff bases are an alternative to the use of hydroxamic acids,
enantioselectivity using the former was no greater than 10% ee.
v
Part two of this thesis describes the efforts towards the synthesis of an eightmembered carbocycle through a radical mediated cyclization/fragmentation pathway.
Previous methods for the construction of eight-membered rings include olefin metathesis
and transition-metal catalyzed cycloadditions. Molander1 has also formed eightmembered rings through various radical cascade reactions initiated by SmI2. Our efforts
towards an eight-membered ring using SmI2 concentrated on a vinyl cyclopropane as a
radical trap were unsuccessful.
_______________________, Committee Chair
James Miranda
_______________________
Date
1
Molander, G.; Harris, C.; Chem. Rev. 1996, 96, 307-338.
vi
ACKNOWLEDGEMENTS
To family and friends. Past, present, and future.
To the professors who have helped guide me along the path I need to take.
To Andrea Bailey and Chris Stains who helped work with me on these projects.
vii
LIST OF ABBREVIATIONS
(COCl)2 = oxalyl chloride
Bn = benzyl
CDCl3 = deuterochloroform
CHP = cumene hydroperoxide
DCM = dichloromethane
DMSO = dimethylsulfoxide
EDA = ethyl diazoacetate
EDP = ethyl diazopyruvate
HMPA = hexamethylphosphoramide
i-
Pr = iso-propyl
LAH = lithium aluminum hydride
m-CPBA = meta-chloroperbenzoic acid
Ph = phenyl
PhH = benzene
PhMe = toluene
SmI2 = samarium(II) iodide
TBHP = tert-butylhydroperoxide
TFA = trifluoroacetamide
TMS = tetramethylsilane
TrOOH = trityl hydroperoxide
Ts = p-toluenesulfonyl
viii
V(acac)3 = vanadium(III) acetylacetonate)
VO(acac)2 = oxyvanadyl bis(acetylacetonate)
VO(OiPr)3 = vanadium(V) oxytriisopropoxide
VOCl3 = vanadium(V) oxytrichloride
VOSO4 = vanadyl sulfate
ix
TABLE OF CONTENTS
Page
Acknowledgements ........................................................................................................... vii
List of Abbreviations ....................................................................................................... viii
List of Tables .................................................................................................................... xii
List of Figures .................................................................................................................. xiii
List of Schemes ..................................................................................................................xv
Part One: Investigation of Schiff bases for the vanadium-catalyzed asymmetric
epoxidation of allylic alcohols. ............................................................................................1
Chapter
1. INTRODUCTION ......................................................................................................... 1
1.1 Vanadium epoxidation background ...................................................................... 1
1.2 Schiff bases and vanadium.................................................................................. 16
1.3 Mosher’s ester method for determination of enantiomeric excess ..................... 21
2. RESULTS AND DISCUSSION .................................................................................. 24
2.1 Vanadium source ................................................................................................ 24
2.2 Solvent study....................................................................................................... 27
2.3 Ligand study........................................................................................................ 28
2.4 Temperature Study .............................................................................................. 33
2.5 Products and plausible mechanisms.................................................................... 34
3. CONCLUSION ............................................................................................................ 43
4. FUTURE WORK ......................................................................................................... 44
5. EXPERIMENTAL SECTION ..................................................................................... 45
References ......................................................................................................................... 54
Part Two: Investigation of a monoradical cyclization and fragmentation: Access to an 8membered ring. ..................................................................................................................57
Chapter
1. INTRODUCTION ....................................................................................................... 57
2. BACKGROUND ......................................................................................................... 58
x
3. RESULTS AND DISCUSSION .................................................................................. 70
4. CONCLUSION ............................................................................................................ 78
5. FUTURE WORK ......................................................................................................... 79
6. EXPERIMENTAL SECTION ..................................................................................... 81
References .......................................................................... Error! Bookmark not defined.
Appendix A NMR spectra ................................................................................................ 88
Bibliography ................................................................................................................... 176
xi
LIST OF TABLES
Page
1. Table 1: Vanadium epoxidation using binapthol derived hydroxamic acid ligand 8 ... 4
2. Table 2: Substrate scope using tert-leucine derived hydroxamic acid 13 ..................... 6
3. Table 3: Results of small allylic alcohol epoxidation ................................................... 8
4. Table 4: Cinnamyl alcohol substrates. Reactions performed at -20 C over 2-3 days. 8
5. Table 5: Enantioselectivities and yields of homoallylic alcohol epoxidations ............. 9
6. Table 6: Results for epoxidations in various solvents using ligand 24. ...................... 11
7. Table 7: Results of ligands 24 and 26 for the epoxidation of 1 and 17. ..................... 12
8. Table 8: Substrate scope for epoxidations in water. ................................................... 16
9. Table 9: Results of vanadium source and conversion of cinnamyl alcohol to epoxy
alcohol .............................................................................................................................. 26
10. Table 10: Conversion to oxidation products in solvents. .......................................... 28
11. Table 11: Ligands tested for enantioselectivity with nerol at 0 C in CH2Cl2. ......... 33
12. Table 12: Temperature study and enantioselectivity. Reaction quenched after 8
hours. Conversion determined by 1H NMR integration of crude reaction mixture. ....... 34
xii
LIST OF FIGURES
Page
1. Figure 1: Camphoric hydroxamic acid ligand and substrates for vanadium
epoxidations ....................................................................................................................... 2
2. Figure 2: Binapthol Derived hydroxamic acids ............................................................ 3
3. Figure 3: Peptide based hydroxamic acid ligands. ....................................................... 5
4. Figure 4: Yamamato’s bishydroxamic acid ligand. ...................................................... 7
5. Figure 5: Tosyl amide hydroxamic acid ligands used for vanadium-catalyzed
epoxidations ..................................................................................................................... 11
6. Figure 6: Proline derived hydroxamic acid ligands .................................................... 13
7. Figure 7: Ligand used for the asymmetric sulfoxidation of tert-butyl disulfide. ........ 17
8. Figure 8: Ligands for the kinetic resolution of ethyl mandalate (racemic) ................. 18
9. Figure 9: Ligands used in Jacobsen’s Epoxidation ..................................................... 20
10. Figure 10: Tridentate Schiff base for chromium(III) catalyzed Diels-Alder reactions.
Adamantyl substituent shown on the right. ...................................................................... 20
11. Figure 11: 1-Adamantyl substituted Schiff base ligands .......................................... 21
12. Figure 12: Diastereomers formed through Mosher esterification. ............................ 23
13. Figure 13: Exo and endo structures of camphor derived vanadium Schiff base
complex ............................................................................................................................ 29
14. Figure 14: Postulated structures of vanadium Schiff base complexes used in this
study ................................................................................................................................. 30
15. Figure 15: Tetradentate vanadium Schiff base complexes ....................................... 30
16. Figure 16: Postulated exo and endo isomers that could be used for vanadium
catalyzed reactions ........................................................................................................... 31
17. Figure 17: Oxo-vanadium complexed with Jacobsen’s ligand. ................................ 32
xiii
18. Figure 18: Postulated intermediate in vanadium-catalyzed reaction explaining poor
enantioselectivity ............................................................................................................. 32
19. Figure 19: Substrates used during this study. ........................................................... 35
20. Figure 20: Concerted reaction mechanism. Ligand omitted for clarify. .................. 35
21. Figure 21: Proposed mechanism of vanadium epoxidation by Sharpless and Malkov.
Ligand omitted for clarity. ............................................................................................... 40
22. Figure 22: Yamamoto’s proposed intermediate for the vanadium-catalyzed
asymmetric oxidation using bishydroxamic acid ligand. ................................................. 41
23. Figure 23: Proposed tetradentate coordinated bishydroxamic acid ligand with bound
allylic alcohol and tert-butylhydroperoxide. .................................................................... 41
24. Figure 24: Proposed dinuclear vanadium catalyzed epoxidation. ............................ 42
25. Figure 25: Anti-cancer drug paclitaxel (1) and dactylol (2). .................................... 57
26. Figure 26: Spriocyclic byproducts obtained enroute to 6-, 7- and 8-membered ring 62
27. Figure 27: By products in the radical cascade reaction. ........................................... 66
28. Figure 28: Unsubstituted vinyl group on test substrate ............................................ 80
xiv
LIST OF SCHEMES
Page
1. Scheme 1: Synthesis of hydroxamic acid ligands for epoxidations in water.............. 14
2. Scheme 2: Synthesis and diastereomeric resolution of Mosher’s carboxylate ........... 22
3. Scheme 3: Analysis of solvent and epoxidation ......................................................... 27
4. Scheme 4: Epoxidation of nerol for temperature study. ............................................. 33
5. Scheme 5: Concerted epoxidation followed by subsequent oxidation of metal and
hydrolysis of epoxy alcohol. Ligand omitted for clarity. ................................................. 36
6. Scheme 6: Postulated mechanism for the epoxidation of trans-cinnamyl alcohol.
Ligand is omitted for clarity. ........................................................................................... 37
7. Scheme 7: Postulated mechanism for the formation of cis-epoxy alcohol through a
five-membered intermediate. ........................................................................................... 37
8. Scheme 8: The third possible pathway for the formation of cis and trans epoxy
alcohols through a five membered intermediate. ............................................................. 38
9. Scheme 9: Mechanistic pathway of vanadium-catalyzed epoxidation proceeding
through a six-membered ring. Ligand omitted for clarity. ............................................... 39
10. Scheme 10: Formation of cis-epoxy alcohol through a six-membered ring. ............ 40
11. Scheme 11: Deuterium study to determine where the proton source originates ....... 59
12. Scheme 12: Reaction sequence for the formation of bicyclic rings containing an eight
membered ring ................................................................................................................. 61
13. Scheme 13: Samarium mediated radical cyclization in natural product synthesis. .. 65
14. Scheme 14: 13-exo-trig cyclization using a radical cyclization of a vinyl
cyclopropane .................................................................................................................... 66
15. Scheme 15: Synthesis of vinyl cyclopropane 54. ..................................................... 67
xv
16. Scheme 16: Synthesis of vinyl cyclopropane with electron-withdrawing group
repositioned. ..................................................................................................................... 69
17. Scheme 17: Retrosynthesis of 8-membered carbocycle ........................................... 70
18. Scheme 18: Synthesis of vinylcyclopropane substrate. ............................................ 72
19. Scheme 19: Postulated 7-endo-trig mechanism to an 8-memberd ring. ................... 74
20. Scheme 20: 6-exo-trig cyclization of 51 ................................................................... 75
21. Scheme 21: Postulated mechanism to relieve strain of trans-bicyclo[4.1.0]heptane 76
22. Scheme 22: 6-exo cyclization followed by Gassman type fragmentation to yield 71
and 73 ............................................................................................................................... 77
23. Scheme 23: Diastereomeric synthesis of chrysamthenal substrate ........................... 80
xvi
1
Chapter 1
PART ONE: INVESTIGATION OF SCHIFF BASES FOR THE VANADIUMCATALYZED ASYMMETRIC EPOXIDATION OF ALLYLIC ALCOHOLS
INTRODUCTION
Vanadium has been used as a catalyst for polymerization1, oxidation of alcohols2,
sulfides3, and more importantly, allylic alcohols. Epoxides are useful building blocks for
natural product synthesis and medicinal chemistry because new functional groups can
easily be introduced by nucleophilic addition of cyanides,4 azides,5 and organometallic
reagents.6 The epoxidation of a prochiral alkene introduces two chiral centers. In
medicinal chemistry, epoxidations must be stereoselective as the incorrect enantiomer of
a product may not be bioactive. More importantly, the wrong enantiomer may cause
death, as opposed to the other optically active isomer that would promote healing.
1.1 Vanadium epoxidation background
In 1973, K.B. Sharpless and R. C. Michaelson reported the epoxidation of allylic
alcohols using vanadium (IV) acetoacetonate and molybdenum hexacarbonyl using tertbutylhydroperoxide (TBHP) as a stoichiometric oxidant.7 Using geraniol, VO(acac)2 and
TBHP in refluxing benzene for four hours led to complete conversion of the starting
material (equation 1).
After the allylic alcohol had been completely consumed, the epoxy acetate was
formed in situ from acetic anhydride and pyridine. The epoxy acetate of geraniol was
2
produced in a 93% overall yield with a 98:2 regioselectivity of the 2,3-epoxide over the
6,7-epoxide.
VO(acac)2, TBHP
1
7
3 2
6
OH
O
OH
PhH, reflux 4 h
1
(eqn. 1)
2
Sharpless and Michaelson noted using vanadium for epoxidations of an allylic
alcohol was selective for the 2,3-epoxide over the 6,7-epoxide. The electron deficient
alkene (2,3) was epoxidized with vanadium whereas the electron rich alkene (6,7) was
epoxidized using a peroxyacid such as m-CPBA.
During the work of Sharpless and Michaelson’s epoxidations, the best
enantiomeric excess for asymmetric epoxidations was only 25% ee. Since epoxides are
useful building blocks for synthesis, further progress towards higher enantioselective
epoxidations was required. Before Sharpless began work on the more popular titanium
catalyzed epoxidations8, he synthesized hydroxamic acids as ligands for asymmetric
epoxidations with vanadium.9 Sharpless was able to produce an asymmetric epoxidation
with 50% ee using the camphorylhydroxamic acid ligand 3 (Figure 1).
O
Ph
N
OH
3
Ph
HO
Ph
4
OH
5
Figure 1: Camphoric hydroxamic acid ligand and substrates for vanadium epoxidations
Although Sharpless and Michaelson never published their results, tartrate esters
were tested as ligands for asymmetric vanadium epoxidations and gave very low
3
enantioselectivity (10% ee). Sharpless turned his efforts toward studying the titaniumcatalyzed epoxidations using tartrate ligand. Hisashi Yamamato, who worked for
Sharpless, however, continued developing the methodology for the vanadium-catalyzed
epoxidations of allylic alcohols.
Yamamoto began studying vanadium epoxidations using binapthol derived
hydroxamic acid ligands shown below in (Figure 2). 10
OMe
O
OMe
O
N
OH
6
N
OH
OMe
O
Ph
Ph
7
N
OH
Ph
8
Figure 2: Binapthol Derived hydroxamic acids
The method development began by testing trans-2-phenylcinnamyl alcohol with
vanadium(IV) acetoacetonate (5 mol%), ligand (15 mol%) and cumene hydroperoxide
(CHP) in toluene. Each epoxidation was tested using these three ligands; however, 8
proved to have both the highest enantioselectivity (65% ee) and fastest reaction time (19
hours). Epoxidations with the other two ligands were reacted for six and eight days for 6
and 7 respectively. Despite the extended reaction times, the enantioselectivities were
25% ee and 54% ee for 6 and 7 respectively.
The second part to this method development was changing the vanadium source
to vanadium(V) oxytriisopropoxide and test three different peroxide sources, including
4
CHP, tert-butylhydroperoxide (TBHP) and triphenylmethyl hydroperoxide (Trityl
hydroperoxide, TrOOH). Trityl hydroperoxide provided the best enantioselectivity of
86% ee, followed by CHP with 66% ee and TBHP with 44% ee. Although TrOOH was
the best peroxide for epoxide formation, the authors did not keep the temperature or
reaction time constant during this methodology study. It was also noted that vanadium
epoxidations could use dichloromethane as a solvent instead of toluene, however, the
enantioselectivity dropped significantly from 86% ee to 62% ee.
Having successfully developed a vanadium catalyzed epoxidation reaction, the
authors tested several substrates using vanadyl oxytriisopropoxide (5 mol %), ligand 8
(7.5 mol %), TrOOH, toluene at -20 C. The epoxides yielded between 14-96% with
enantioselectivities between 38-94% (Table 1).
9
Yield (%)
ee (%)
87
41
14
71
OH
Ph
OH
10
Table 1: Vanadium epoxidation using binapthol derived hydroxamic acid ligand 8
With the promising results of the binapthol-based ligand for vanadium
epoxidations, Yamamoto wanted to change the ligand design to improve stereoselectivity
and yield during the reaction.11 He next went on to develop a peptide based hydroxamic
acid (11) that yielded epoxides in as high as 95% (Figure 3). However, the
5
enantioselectivity was only 11% ee, whereas using the phthalimide based hydroxamic
acid (12) had an enantioselectivity of 62% ee and a yield of 91%. Based on these
preliminary results, Yamamoto et al. synthesized a library of chiral hydroxamic acids
using -amino acids as the source of chirality. The library began by varying the source
of chirality from 10 amino acids. Tert-leucine proved to give the highest
enantioselectivity of 80% ee. The second change in the ligand was the imido group.
Ph
Ph
O
HN
O
H
N
N
H
O
O
O
Ph
N
OH
Ph
Ph
11
O
N
Ph
N
OH
Ph
O
12
Figure 3: Peptide based hydroxamic acid ligands.
After changing the imido portion of the ligand to 1,8-napthlenedicarbonyl, the
enantioselectivity rose to 87% ee. The final change to the hydroxamic acid was the
phenyl groups near the hydroxamic acid moiety. When the phenyl groups were changed
to the 1-napthyl derivative, the enantioselectivity was over 95% ee. Even though this
ligand did not give the highest enantioselectivity from the ligand library, it was still
successful for a variety of epoxidation substrates.
6
The epoxidations of various allylic alcohols using the newly formed tert-leucine
based hydroxamic acid (13) produced epoxides in yields ranging from 58-99% and
enantioselectivities 76-96% ee (Table 2).
O
O
N
N
OH
O
13
Yield (%)
ee (%)
96
95
93
96
99
86
98
91
95
81
Ph
HO
Ph
4
OH
1
Table 2: Substrate scope using tert-leucine derived hydroxamic acid 13
Yamamoto subsequently went on to develop homoallylic epoxidations using the
hydroxamic acid ligands.12 Yields of the reactions ranged between 24-89% with
enantioselectivities ranging from 36-91% ee. The results from homoallylic alcohol
7
epoxidations shows that the reactivity of the catalyst differs from that of allylic alcohol
due to proximity of the olefin to the alcohol.
Because the monohydroxamic acid ligand can bind to the transition metal more
than once causing a ligand deceleration effect, Yamamato developed a new
bishydroxamic acid ligand, (14, Figure 4), for the vanadium catalyzed epoxidation of
allylic alcohols.13 The thought process towards the construction of this new ligand was
that only one equivalent of the ligand would bind to the metal due to steric interactions
regardless of the ratio of catalyst to ligand.
O
R
R=
OH
N
OH
N
R
O
14
Figure 4: Yamamato’s bishydroxamic acid ligand.
The test substrates of the newly designed bishydroxamic acid ligand ranged
between small allylic alcohols, medium allylic alcohols, and homoallylic alcohols. The
yields of the small allylic alcohols (reaction run in dichloromethane with CHP as oxidant)
were between 50-78% (Table 3). The enantiomeric excess of these molecules ranged
from 92-97%.
8
Yield (%)
ee (%)
78
97
68
95
OH
15
OH
16
Table 3: Results of small allylic alcohol epoxidation
The medium sized allylic alcohols (reaction run in dichloromethane with TBHP
as oxidant) all were produced with an enantiomeric excess of greater than 95%.
However, the yields of these substrates had ranged between 24-84% (Table 4).
Ph
Yield (%)
ee (%)
OH
84
97
OH
53
97
17
Ph
10
Table 4: Cinnamyl alcohol substrates. Reactions performed at -20 C over 2-3 days.
To further test the substrate scope of the new hydroxamic acid ligand, homoallylic
alcohols were tested for reactivity. The solvent of choice for this reaction was changed
from dichloromethane to toluene to prevent formation of the tetrahydrofuran product
(Table 5).
9
Ph
Yield (%)
ee (%)
85
99
85
93
O
HO
18
O
OH
19
Table 5: Enantioselectivities and yields of homoallylic alcohol epoxidations
With the successful epoxidation of homoallylic alcohols, Yamamoto decided to
develop the kinetic resolution of both allylic (equation 2) and homoallylic alcohols
(equation 3).14 The solvent for the allylic and homoallylic alcohol kinetic resolution was
dichloromethane and toluene for the reason previously stated about tetrahydrofuran
cyclization.
OH
Ph
()-20
1 mol % VO(OiPr)3
2 mol % 14
TBHP (70% aq.)
CH2Cl2, 0 °C
51% conversion
0.5 mol% VO(OiPr)3
HO
()-22
1.0 mol % 14
0.7 equiv CHP
PhMe, rt, 30 h
OH
HO
Ph
+
Ph
(eqn. 2)
O
(+)-20
21
95% ee
93% ee
O
HO
+
HO
(eqn. 3)
(-)-22
23
95%ee
51% yield
95%ee
48% yield
10
Yamamoto has continued to use the bishydroxamic acid ligand for the asymmetric
epoxidation of homoallylic and bishomoallylic alcohols by zirconium and hafnium.15 He
has also developed an asymmetric molybdenum epoxidation of olefins and sulfoxidation
of sulfides.16 These reactions that use the same ligand but different transition metal show
the versatility of Yamamoto’s bishydroxamic acid.
Andrei Malkov at the University of Glasglow in Scotland has also worked on the
vanadium-catalyzed epoxidation of allylic alcohols. He has also used the hydroxamic
acid moiety for the ligand design; however, they have added a tosyl amide to the ligand.17
The thought process for this is to allow the alcohol to coordinate to the ligand through
hydrogen bonding to the tosyl moiety. This would displace a ligand bonded to the
transition metal – either an epoxy alcohol or isopropoxide ligand.
These tosyl hydroxamic acid ligands are derived from the readily available amino
acids, valine (iPr), phenylalanine (Bn), phenylglycine (Ph) and tert-leucine (t-Bu). The
phenylglycine derivative showed the highest stereoselectivity over the other amino acids
synthesized (Figure 5).
11
Ph
O
Ts NH
Ph
Ph
N OH
O
Ph
Ts N
Ph
N
HO
24
25
O
Ph
Ts NH
Ph
Ph
Ph
O
S NH
O Ph
N OH
Ph
O
N OH
Ph
26
27
Figure 5: Tosyl amide hydroxamic acid ligands used for vanadium-catalyzed epoxidations
The best reaction conditions were 1.0 mol % VO(OiPr)3 and 1.8 mol % 24 in
toluene at -20 C (Table 6).
Entry
Solvent
Yield (%)
ee (%)
1
PhMe
98
64
2
CH2Cl2
96
47
3
CHCl3
96
55
4
MeCN
95
37
5
MeOH
<5
39
Table 6: Results for epoxidations in various solvents using ligand 24.
The reaction conditions from Table 6 were used to test the ligands for
enantioselectivity. The ligands from Figure 5 were tested for enantioselectivity using
12
geraniol and 2-methylcinnamyl alcohol as test substrates. Ligand 24 was the proved the
out of all of the ligands in both yield and enantioselectivity (Table 7).
OH
OH
1
17
Entry
Ligand
Yield (%)
ee (%)
Yield (%)
ee (%)
1
24
95
64
90
62
2
26
87
32
-
-
Table 7: Results of ligands 24 and 26 for the epoxidation of 1 and 17.
The tosyl amide hydroxamic acid 24 was tested on 12 substrates for reactivity.
The yields ranged between 32-95% and the enantioselectivity was between 20-70%.
Sharpless had originally used a proline derived hydroxamic acid ligand for the
vanadium catalyzed epoxidation of allylic alcohols, however, only one substrate showed
good enantioselectivity.18 Having successfully synthesized a variety of hydroxamic acid
ligands for the vanadium-catalyzed epoxidation of allylic alcohols, Malkov synthesized
several new proline derived hydroxamic acids to test for enantioselectivity in this metal
catalyzed process.
13
Malkov previously used several amino acids as sources of chirality for the
hydroxamic acid ligand synthesis; however, he did not use proline as a source of
chirality. He went on to develop a series of proline derived hydroxamic acids for ligands
in the vanadium-catalyzed epoxidation of allylic alcohols.19 Again, the sulfonamide (28)
moiety was tested for enantioselectivity along with a trifluoroacetamide (29)
functionality. Both of these functional groups proved necessary, due to electronic
interactions, for selectivity in epoxidation reactions (Figure 6).
O
Ph
N
OH
N
Ts
28
Ph
HO
N
N
O
TFA
29
Figure 6: Proline derived hydroxamic acid ligands
Several ligands, including 28 and 29 were screened for selectivity in epoxidations
of 2-phenylcinnamyl alcohol using 1.0 mol % VO(OiPr)3 and 3.0 mol % ligand. The
reaction was conducted in toluene at -20 C. The yields ranged between 28-90% and
enantioselectivity between 5-78%.
Of the ligands tested, the trifluoroacetamide derived proline hydroxamic acid (29)
proved to be best in both yield and enantioselectivity. This ligand was used to screen
several substrates for reactivity, which proved to be variable in reactivity with yields
ranging from 5-91% and enantioselectivities between 10-78%. This ligand proved
14
unsuitable for the vanadium-catalyzed epoxidation of allylic alcohols due to the large
range of yields and stereoselectivity.
Malkov went on to synthesize a new hydroxamic acid ligands for the vanadiumcatalyzed epoxidation of allylic alcohols. These ligands were synthesized from
commercially available diamines in five steps. The synthesis began by tosylating one
amine followed by an SN2 reaction with bromoacetonitrile. Oxidation of the amine to a
nitrone was achieved using mCPBA; which was subsequently transformed to the
hydroxylamine using hydroxylamine hydrochloride. The hydroxylamine was then
acetylated using an acid chloride (Scheme 1).
H2N
NH2
1.1eq. TsCl
Et3N
DCM
86%
BrCH2CN
iPr
TsHN
30
TsHN
N
H
CN m-CPBA
DCM
75%
32
TsHN
NH2
31
NH2OH
CN
TsHN
33
NH
HO
35
O
Ph
Cl
34 Ph
67%
2EtN
MeCN
99%
N
O
MeOH
84%
O
TsHN
N
HO
Ph
Ph
36
Scheme 1: Synthesis of hydroxamic acid ligands for epoxidations in water.
These newly synthesized ligands were tested for epoxidation using 2phenylcinnamylalcohol as a test substrate. This time, however, the reactions were run in
15
a combination of water and organic solvent (CH2Cl2 or PhMe). In an organic solvent, too
much ligand causes a ligand deceleration affect, hampering the reaction rate and
stereoselectivity. However, in water, an excess of ligand has the opposite affect. Since
water is a major component of the solvent mixture, the authors decided to change the
vanadium source from the expensive VO(OiPr)3 to the relatively cheap vanadyl sulfate.
The aqueous epoxidation reactions provided products in excellent
enantioselectivity, however, the reaction times varied between 48-60 hours for complete
conversion. The long reaction times can be explained because several of the substrates
and ligands were solids at room temperature and did not readily dissolve in the polar
protic solvent. Adding a small amount of organic solvent, either dichloromethane or
toluene, increased the rate of epoxidation by allowing the reactants to be more soluble.
Although both solvents proved to increase reaction times, the stereoselectivity observed
with dichloromethane as a cosolvent was diminished, whereas toluene increased
enantioselectivity. The mixed solvent system for epoxidation had yields between 40-97%
and enantioselectivity between 26-94% with the majority of enantioselectivity greater
than 80% (Table 8).
The catalyst to ligand ratio was 5/5.5 mol % and all reactions were run in water at
0 C. The yields ranged between 42-98% with enantioselecitivty between 56-94%
(Table 8).
16
Yield (%) ee (%)
Ph
OH
98
90
42
70
17
37
OH
Table 8: Substrate scope for epoxidations in water.
1.2 Schiff bases and vanadium
Jacobsen’s ligand, 1,2-diaminocyclohexane condensed with two equivalents of
3,5-di-t-butylsalicylaldehyde, forms a tetradentate Schiff base ligand that is used as a C2
symmetric source of chirality. Jacobsen developed the catalyst for the manganesecatalyzed epoxidations of olefins with aqueous bleach providing great enantioselectivities
with a variety of substrates.20 With such promising results, Jacobsen went on to develop
other transition metal catalyzed reactions using this ligand; such as Diels-Alder21
(chromium), 1,4-conjugate additions22 (aluminum) and aziridations23 (copper), kinetic
resolution of epoxides (cobalt).24 Vanadium has been used with Jacobsen’s ligand for the
addition of trimethylsilylcyanide25 to aldehydes. The conversions to the TMS protected
cyanohydrins range between 76-99% with enantioselectivities between 76-96%. To date
there has been no report on the asymmetric epoxidation of allylic alcohols with vanadium
using Jacobsen’s ligand nor any other salen or salen-like chiral ligand. However, there
have been reports of asymmetric catalyzed oxidations using the combination of vanadium
17
and salen or tridentate salen-like ligands. At the University of California Berkeley,
Ellman and Toste reported vanadium-catalyzed oxidations (38, Figure 7).
N
OH
OH
38
Figure 7: Ligand used for the asymmetric sulfoxidation of tert-butyl disulfide.
Ellman’s contributions to vanadium oxidations are primarily concerned with the
development of tert-butylsulfonamide as a single enantiomer.26 The key step of the
synthesis is the first step which introduces the chiral center on a sulfur atom from ligand
38. This stereocenter is generated using vanadayl acetoacetonate, a tridentate Schiff base
derived from (1R, 2S)-cis-1-amino-2-indanol and aqueous hydrogen peroxide (30%) with
acetone as the solvent (equation 4).
S
39
S
5 mol % 38
5 mol % VO(acac)2
30% H2O2
Acetone
O
S
S
40
85%ee
(eqn. 4)
18
The subsequent step in the reaction is aminolysis of the disulfide bond producing
the sulfonamide. The sulfoxidation product is produced in 85% ee, however the
sulfonimide can reach 99% enantiomeric excess after recrystallization.
Dean Toste has published results on vanadium-catalyzed oxidations for the kinetic
resolution of -hydroxy esters. The best ligand for chiral induction was with the use of
ligand (41; Figure 8). However, ligand 42 was also tested for the efficacy of this
vanadium-catalyzed reaction (Figure 8). The kinetic resolution of -hydroxy esters was
tested with seven different ligands using ethyl mandalate as the test substrate.
When these -substituted esters contain a bishomoallylic moiety, the substrates
are epoxidized and cyclize to either a tetrahydropyran or tetrahydrofuran ring.27 To
control the chirality of these reactions, tetradentate or tridentate Schiff base ligands are
used in combination with various vanadium sources.
Ph
Ph
N
OH
N
OH
41
OH
OH
42
Figure 8: Ligands for the kinetic resolution of ethyl mandalate (racemic)
The best ligand for the kinetic resolution of ethyl mandalate was with a tridentate
Schiff base with chirality derived from tert-leucine. The results show a 50 % conversion
and an 86% enantiomeric excess. The vanadium source was then tested for the best
stereoselectivity of these oxidations. The authors found that vanadium(IV) isopropoxide
19
was the best choice for this reaction. Vanadyl acetoacetonate, a precatalyst for
oxidations, was tested for its reactivity, however the results were not as successful as with
the isopropoxide variant. By changing the solvent from acetonitrile to acetone and the
catalyst/ligand loading to 5/5.5 mol percent respectively gave the best results for the
oxidation of ethyl mandalate (43; equation 5).
OH
OH
O
OEt
5 mol%
VO(OiPr)3
O
O
5.5 mol% 41
Acetone, 1 atm O2
O
OEt
)-43
(-)-43
(eqn. 5)
OEt
44
99% ee
49% yield
With the success of Ellman and Toste’s vanadium catalyzed oxidations using
Schiff base ligands, the epoxidations of allylic alcohols using these types of ligands as a
source of chirality needs to be investigated.
These ligands were originally used for the manganese catalyzed enantioselective
epoxidation of olefins. The methodology was developed out of the Jacobsen lab at
Harvard University.28 These ligands differ by the bridge of the salen complex, one bears
trans phenyl groups (46) and the other contains a cyclohexane ring (45; Figure 9).
20
Ph
N
Ph
N
N
N
OH HO
OH HO
45
46
Figure 9: Ligands used in Jacobsen’s Epoxidation
Since the development of these ligands, the substituents on the salicylaldehyde
precursor have been changed, including adamantyl groups. The Jacobsen lab has further
developed29 an enantioselective catalytic chromium(III) hetero-Diels-Alder reaction
using 3-(1-adamantyl)-5-methylsalicyladehyde and (1R,2S)-aminoindanol (47) to
produce the newer tridentate Schiff base (Figure 10).
N
OH
OH
1-adamantyl
1-adamantyl
47
Figure 10: Tridentate Schiff base for chromium(III) catalyzed Diels-Alder reactions. Adamantyl
substituent shown on the right.
21
The bulkier adamantyl substituent can greatly influence how a substrate can
interact with a metal center. Jacobsen has reported 99% ee for the chromium(III)
catalyzed oxo-Diels-Alder reaction.
This new salicylaldehyde allows for new ligands to be created. Toste has used
diphenylethanediamine (48) to test for the kinetic resolution of -hydroxy carbonyl
compounds (Figure 11). The cyclohexane bridged version of the bulkier Schiff base (49)
has not yet been made nor tested for enantioselectivities. Also, the tridentate Schiff base
with chirality from diphenylaminoethanol (50) has also not been made.
Ph
Ph
N
N
N
OH HO
1-adamantyl 1-adamantyl
49
Ph
N
OH
OH
OH HO
1-adamantyl 1-adamantyl
48
N
Ph
1-adamantyl
50
Figure 11: 1-Adamantyl substituted Schiff base ligands
1.3 Mosher’s ester method for determination of enantiomeric excess
What is now considered Mosher’s carboxylic acid is a chiral derivatizing reagent
used to determine enantiomeric excess of chiral molecules from asymmetric reactions.30
The carboxylic acid contains a quaternary chiral center, which is non-enolizable. This
allows for enantiomeric excess to be determined by comparing the integration of 1H or
19
F NMR peaks of the derivatized complex.
22
The synthesis of Mosher’s carboxylic acid begins with nucleophilic addition of
sodium cyanide to trifluoromethylacetophenone (51). The sodium alkoxide intermediate
is trapped with dimethyl sulfate to form the methylated cyanohydrin (52). Hydrolysis of
the nitrile to a carboxylic acid provides the racemic form of Mosher’s acid (53).
Diastereomeric recrystallization with (+) or (-) - -phenylethylamine affords the
enantiomerically pure carboxylic acid. The acid can than undergo coupling with a variety
of substrates, alcohols, acids or amines, for example, for analysis of enantiomeric excess.
The carboxylic acid may also be transformed to the acyl chloride prior to derivatization
(Scheme 4).
O
1. NaCN
CF3
2. Me2SO4
51
(+) or (-) 1-phenylethylamine
OMe
CN
CF3
OMe
COOH
CF3
hydrolysis
()-52
()-53
O

O
NH3
MeO CF3
(-)-53 (+)-1-phenylethylamine
Scheme 2: Synthesis and diastereomeric resolution of Mosher’s carboxylate
For the purpose of the study of enantioselective catalytic asymmetric epoxidations
by vanadium, the Mosher’s ester is used to determine the enantiomeric excess. An
example of a derivatized epoxy ester is shown below in Figure 12.
23
O
O
O
O
O
F3C
MeO Ph
54a
O
F3C
MeO Ph
54b
Figure 12: Diastereomers formed through Mosher esterification.
24
Chapter 2
RESULTS AND DISCUSSION
2.1 Vanadium source
The source of vanadium is very important for epoxidation of allylic alcohols. In
the literature the two most common sources of vanadium are vanadium(IV)
acetylacetonate and vanadium(V) oxytriisopropoxide. However, these are not the only
possible sources of vanadium. Several other sources of vanadium were also screened for
the reactivity of allylic alcohol epoxidation including vanadium(III) acetylacetonate31,
vanadium(V) oxytrichloride and vanadyl sulfate.
These vanadium sources were screened with cinnamyl alcohol as the substrate
and Jacobsen’s ligand. The reaction was carried out by allowing the vanadium source
and ligand to stir as a 0.02 M solution in dichloromethane for 15 minutes at ambient
temperature. Cinnamyl alcohol was added and the solution cooled 0 C with an ice bath.
Tert-butylhydroperoxide was then added to the reaction which was then allowed to warm
to room temperature. The reaction was stirred for 24 hours before being quenched with a
saturated solution of sodium thiosulfate. The crude products were then identified by 1H
NMR.
Vanadium(IV) acetylacetonate is one of the more common sources for vanadiumcatalyzed oxidations. However, due to the air and light sensitivity of the precatalyst, it
was necessary to recrystallize VO(acac)2 prior to each use. While the conversion of
cinnamyl alcohol to the epoxy alcohol was 100%, the yield of the epoxy alcohol after
silica chromatography averaged between 50-65% over ten trials.
25
Vanadium(V) oxytriisopropoxide is one of the more notably used precatalysts for
vanadium-catalyzed asymmetric oxidations. VO(OiPr)3 has been used by Yamamoto,
Malkov and Toste for vanadium oxidations. They have found that the enantiomeric
excess and isolated yields of oxidation reactions are far superior with this reagent over
other vanadium sources.
Vanadium(III) acetylacetonate was tested for epoxidation reactivity. Conversion
of cinnamyl alcohol was complete within 24 hours. Although slightly more stable than
VO(acac)2, V(acac)3 still has similar issues regarding air and light sensitivity and was
required to be recrystallized prior to use.
Vanadium(V) oxytrichloride was tested for its efficacy of epoxidation.
Purification of this liquid should be lemon yellow in color.32 An orange color indicates
the presence of vanadium(IV) chloride and chlorine gas; although it is more likely impure
with vanadium(V) pentoxide due to hydrolysis. This impure material was tested for
epoxidation reactivity. However, only starting material was recovered after the reaction
was done.
Vanadyl sulfate has been used as a vanadium source for forming metal complexes
and for biphasic epoxidation reactions; however, the screening of this vanadium source
was found to be insufficient due to the lack of solubility in dichloromethane. Vanadyl
sulfate was not further tested for epoxidation reactivity.33
26
OH
O
5 mol % VO(OiPr)3
5.5 mol % Jacobsen's Ligand
TBHP, CH2Cl2, RT
OH
55b
10
Entry
Vanadium Source
Conversion (%)
1
VO(acac)2
100
2
V(acac)3
100
3
VOCl3
0
4
VOSO4
0
5
VO(OiPr)3
100
Table 9: Results of vanadium source and conversion of cinnamyl alcohol to epoxy alcohol
27
2.2 Solvent study
OH
5 mol % VO(OiPr)3
O
5.5 mol % Jacobsen's Ligand
TBHP, solvent, RT
OH
55b
10
Scheme 3: Analysis of solvent and epoxidation
While literature data of vanadium epoxidations has been run in non-coordination
solvents such as dichloromethane and toluene, other vanadium-catalyzed reactions, such
as sulfoxidation and kinetic resolution of hydroxy alcohols have used acetone or
acetonitrile. The epoxidation reactions were tested with dichloromethane, toluene and
acetone. Using tetradentate Schiff base ligands (trans-cyclohexanediamine or
diphenylethanediamine), the primary product in all three solvents was the epoxide.
However, with acetone as a solvent, a small amount (~10%) of the crude product was
alcohol oxidation. Using tridentate Schiff base ligands (1-aminodiphenylethanol or 1amino-2-indanol) and acetone, the primary product was alcohol oxidation over alkene
epoxidation. It should be noted however, that the tridentate Schiff bases solely produce
alkene epoxidation over alcohol oxidation in non-coordinating solvents. Because of the
influence of solvent over chemoselectivity of this oxidation reaction, dichloromethane
was chosen as a solvent to screen ligands for enantiomeric excess (Table 10).
28
Conversion
Entry
Solvent
1
CH2Cl2
100
0
2
PhMe
100
0
3
Acetone
90
10
epoxy alcohol (%)
aldehyde (%)
Table 10: Conversion to oxidation products in solvents.
2.3 Ligand study
The ligands that were initially screened toward the asymmetric epoxidation of
allylic alcohols were Jacobsen’s ligand and the analog where the trans-cyclohexanebridged tetradentate Schiff base was replaced with a trans-diphenyl bridge. The
preliminary screening of these ligands used dichloromethane and VO(acac)2 for
epoxidation. The ligands and precatalyst were stirred as a 0.02 M solution for 15 minutes
followed by addition of substrate and stoichiometric oxidant. The resulting enantiomeric
excess values obtained after purification and subsequent Mosher ester formation were
4.8% and 6.0% for the trans-cyclohexane and trans-diphenyl bridged Schiff bases
respectively. The low enantiomeric excess results were most likely due to slow
formation of the active chiral catalyst. To overcome this dilemma, VO(OIPr)3 and chiral
ligand were stirred as a 0.1 M solution in dichloromethane for eight hours to allow for
sufficient formation of the active catalyst.
This study concluded that it was unnecessary to mix the vanadium and ligand for
eight hours. The active coordination complex rapidly forms at low concentrations in 15-
29
30 minutes as indicated by qualitative color change of the yellow salen solution to the
forest green complex of the active vanadium-catalyst. The comparison between
enantiomeric excess for the formation of the active catalyst had a negligible difference.
To explain the almost racemic mixture cis-tridentate vanadium-complex, the endo
and exo isomers of the V(IV)-oxo must be examined. X-Ray crystal structures of a
Schiff base complex derived from camphor with an exo (56a) and endo (56b) V=O bond
are shown below (Figure 13).34
N
O
V O
O
OEt
56a
EXO
N
V O
O
O OEt
56b
ENDO
Figure 13: Exo and endo structures of camphor derived vanadium Schiff base complex
In order for the tridentate ligands to induce the best asymmetry for the
epoxidation of allylic alcohols, it is necessary for the V=O to be in the exo position. In
this manner, the allylic alcohol can coordinate from the bottom face of the active catalyst
where chirality can have the greatest influence. However, if the V=O bond were in an
endo (57b) fashion, the alcohol would coordinate from the top and the ligand would not
be able to induce chirality as well as the exo isomer 57a (Figure 14).
30
O
N
O
V O
N
V O
O
O
57a
57b
EXO
ENDO
Figure 14: Postulated structures of vanadium Schiff base complexes used in this study
In contrast, the C2-symmetric trans-tetradentate salen ligands could have the V=O
in either the endo or exo position. Regardless of the orientation of the V=O bond,
because the ligand is C2 symmetric, the endo and exo isomers would be identical.
N O N
V
O
O
N
N
V
O
O O
58a
58b
EXO
ENDO
Figure 15: Tetradentate vanadium Schiff base complexes
Because the trans substituted ligands induce more chirality than the cis-it might be
worth testing a trans tridentate Schiff base for the induction of asymmetry. The
orientation of the endo vs. exo isomer of the V=O bond should induce more chirality in
31
the trans tridentate than the cis tridentate ligands. The exo and endo V=O isomers of one
diastereomer of the trans-1-aminodiphenylethanol is shown in Figure 16.
N O
V O
O
N
V O
O O
59a
59b
EXO
ENDO
Figure 16: Postulated exo and endo isomers that could be used for vanadium catalyzed reactions
The reaction times for the tert-butyl substituted tridentate ligands was
approximately six hours for complete conversion while the reaction time for the
tetradentate ligands required eight hours for complete conversion. In contrast, the
adamantyl substituted Jacobsen’s catalyst required only six hours for consumption of
starting material.
An alternate explanation for the low enantioselectivities could be the coordination
of the vanadium complex. While in the solid state, the vanadium complex 60 could exist
as in Figure 17. It is plausible that some of the metal-ligand bonds are broken in solution
in order for the epoxidation to take place.
32
N
O
N
V
O
O
60
Figure 17: Oxo-vanadium complexed with Jacobsen’s ligand.
One side of the ligand could become labile so the allylic alcohol and peroxide can
coordinate. As such, the chirality around the transition metal could prove insufficient for
enantioselectivity to take place. This proposed intermediate (61) is shown in Figure 18.
N
O
O O
N V O
O
OH
Ph
61
Figure 18: Postulated intermediate in vanadium-catalyzed reaction explaining poor enantioselectivity
33
Entry
Ligand
Conversion (%)
ee (%)
1
38
100
2.1
2
42
100
4.2
3
45
100
10
4
46
100
7
5
48
100
10
6
49
100
7
Table 11: Ligands tested for enantioselectivity with nerol at 0 C in CH2Cl2.
2.4 Temperature Study
5 mol % VO(OiPr)3
OH
5 mol % Jacobsen's Ligand
TBHP, CH2Cl2 0 °C
62
O
OH
63
Scheme 4: Epoxidation of nerol for temperature study.
As Jacobsen’s ligand was found to be the superior ligand for the epoxidation of
allylic alcohols, a study to see the effect of temperature on enantiomeric excess was done.
The room temperature (25 C) epoxidation of nerol yielded a 5% enantiomeric excess of
the epoxy alcohol. Lowering the temperature with the aid of an ice bath (0 C) yielded an
increase in enantiomeric excess to 9-10%. Most other epoxidation reactions in the
literature have a reaction temperature of -20 C. The epoxidation of nerol was done at
34
-20 C using an ice/NaCl bath, however, the results were identical to that of the reaction
at 0 C. An additional data point was taken at -78 C using a dry ice/acetone bath. It was
expected that there would be a prolonged reaction time, and as such, the catalyst and
ligand loading were raised to 20-mol % each. It was observed by Yamamoto that
lowering the temperature for enantioselective reactions improves the enantiomeric excess
of the product, this experiment proved unsuccessful (Table 12). The temperature study
at -78 C should be repeated with extended reaction times. However, the prolonged
reaction times at cold temperatures would require a better system to consistently keep the
reaction mixture at the appropriate temperature.
Entry
Temperature (°C)
Conversion (%)
ee (%)
1
23
100
5.5
2
0
100
10
3
-20
70
9.5
4
-50
60
9.8
5
-78
40
10
Table 12: Temperature study and enantioselectivity. Reaction quenched after 8 hours. Conversion
determined by 1H NMR integration of crude reaction mixture.
2.5 Products and plausible mechanisms
One of the other problems associated with the epoxidation of the test substrates
was the formation of multiple products. The two substrates that were chosen for the
method development were trans-cinnamyl alcohol (10) and nerol (62). These allylic
35
alcohols were chosen because both compounds have been used as substrates in previous
allylic alcohol epoxidations in the literature (Figure 19).
OH
OH
10
62
Figure 19: Substrates used during this study.
Using cinnamyl alcohol as a substrate and Jacobsen’s ligand as the ligand a
mixture of two products was obtained in approximately a 1:1 ratio of cis and trans
isomers. The products demonstrate that the mechanism of epoxidation is stepwise as
opposed to concerted. If the mechanism of epoxidation were concerted, the major
diastereomer would form based on the geometry of the substrate.
Ph
O
O
O
V
O
64
Figure 20: Concerted reaction mechanism. Ligand omitted for clarify.
Another possible concerted reaction mechanism would not involve the
stoichiometric oxidant. Instead, the V=O would donate the oxygen atom to the olefin and
then the oxidant would oxidize the metal and hydrolyze the epoxy alcohol (Scheme 5).
36
Ph
O
V
TBHP
O
65
O
O HO
V
O
66
Ph
O
O
V O
67
OH
Ph
55b
Scheme 5: Concerted epoxidation followed by subsequent oxidation of metal and hydrolysis of epoxy
alcohol. Ligand omitted for clarity.
The stepwise mechanism, which is how the epoxidation is thought to proceed by,
has several possible pathways. The first step in one pathway is the coordination of the
allylic alcohol to the catalyst. In this step, the vanadium center is oxidized from +4 to +5.
The second step of epoxidation is probably a radical bond forming reaction. This
proceeds by breaking the V=O where one electron reduces the transition metal and the
other forms a single bond with an electron from the olefin forming a five-membered ring.
Then a single electron transfer breaks the V-O bond. Here, the vanadium center is further
reduced to an oxidation state of +3 while the benzylic radical forms a C-O bond with the
oxygen radical completing the formation of the epoxide ring. Subsequent hydrolysis of
the vanadium-alkoxide bond followed by oxidation with tert-butylhydroperoxide restores
the active catalytic species. The product of this pathway would be a trans-epoxy alcohol
(Scheme 6).
37
Ph
5 mol % VO(OiPr)3
5.5 mol % Jacobsen's ligand
TBHP, CH2Cl2, RT
OH
10
V
O
O
O
O V
Ph
Ph
69a
68
V
O
O
Ph
hydrolysis
O
OH
Ph
70b
55b
Scheme 6: Postulated mechanism for the epoxidation of trans-cinnamyl alcohol. Ligand is omitted
for clarity.
A second pathway for the formation of the epoxide is through a similar fivemembered intermediate. This time, the benzylic radical intermediate that forms could
rotate about a carbon-carbon bond changing the orientation from trans to cis. All parts of
this pathway would be identical to that described in the previous paragraph, except this
product would be a cis-epoxy alcohol as opposed to the trans version (Scheme 7).
Ph
V
O
5 mol % VO(OiPr)3
5.5 mol % Jacobsen's ligand
TBHP, CH2Cl2, RT
OH
10
O
bond
rotation
O
O V
Ph
Ph
69a
68
Ph
O V
O
O
Ph
69b
70a
V
O
O
hydrolysis
OH
Ph
55a
Scheme 7: Postulated mechanism for the formation of cis-epoxy alcohol through a five-membered
intermediate.
38
A third possible mechanism for the formation of the epoxy alcohol through the
five-membered intermediate is through the single electron transfer that breaks the V-O
bond. This intermediate contains a benzylic and alkoxide radical which is free to rotate
about a carbon-carbon bond forming either the trans or cis epoxide (Scheme 8).
Ph
O
O V
O
69a
O
V
Ph
O
71
OH
O
OH
or
Ph
55a
Ph
55b
Scheme 8: The third possible pathway for the formation of cis and trans epoxy alcohols through a
five membered intermediate.
The next possibility for the mechanism for the epoxidation of allylic alcohols is
through a six-membered intermediate. In this pathway, the V=O bond is heterolytically
broken to a V-O single bond. The alkene is also heterolytically broken and the
homobenzylic radical reacts with the alkoxide radical forming a six membered ring. A
second heterolytic V-O bond is broken reducing the vanadium to a +3 oxidation state
while forming the trans epoxide. Subsequent hydrolysis of the intermediate forms the
trans-epoxy alcohol (Scheme 9).
39
V
O
5 mol % VO(OiPr)3
Ph
OH
5 mol % Jacobsen's Ligand
TBHP, CH2Cl2, rt
10
O
O
Ph
70b
V hydrolysis
O
O
Ph
Ph
72
68
O
V
O
OH
Ph
55b
Scheme 9: Mechanistic pathway of vanadium-catalyzed epoxidation proceeding through a sixmembered ring. Ligand omitted for clarity.
In order to explain the formation of the cis epoxy alcohol through the sixmembered intermediate, the V-O bond would have to heterolytically break. Prior to
coupling of the homobenzylic radical and the alkoxide radical, rotation about a C-C bond
would take place to change the orientation. From here the homobenzylic radical and
alkoxide radical would form a single bond producing the cis epoxy alcohol after
hydrolysis (Scheme 10).
40
O
V
O
O
V
O
72
74
73
O
O
Ph
V
O
Ph
Ph
Ph
O
O
hydrolysis
V
OH
Ph
70a
55a
Scheme 10: Formation of cis-epoxy alcohol through a six-membered ring.
When Sharpless originally reported the vanadium-catalyzed asymmetric
epoxidation of allylic alcohols; he used hydroxamic acid ligands to induce chirality. He
proposed a mechanism (75) as shown in Figure 20. Malkov’s work on asymmetric
vanadium-catalyzed epoxidations of allylic alcohols shows a similar mechanism (Figure
21).
O
O
V O
O
75
Figure 21: Proposed mechanism of vanadium epoxidation by Sharpless and Malkov. Ligand omitted
for clarity.
However, Yamamoto, who worked with Sharpless while pioneering the early
work of vanadium epoxidations, decided to use a bishydroxamic acid. Yamamoto
proposes that the bishydroxamic acid binds through the hydroxylamine (Figure 22).
41
R
O
N
R
O O
O
V O
N O O
O
76
Figure 22: Yamamoto’s proposed intermediate for the vanadium-catalyzed asymmetric oxidation
using bishydroxamic acid ligand.
Following the accepted work of Sharpless, the bishydroxamic acid should bind in
a similar manner (Figure 23). To date, there is no reported X-Ray crystal structure of
hydroxamic acid ligands bound to vanadium to prove how the ligand is coordinated to the
transition metal.
N
R
N O
O V O
O O O
R
O
H
77
Figure 23: Proposed tetradentate coordinated bishydroxamic acid ligand with bound allylic alcohol
and tert-butylhydroperoxide.
The multiple coordination sites of the bishydroxamic acid ligand could provide a
possible dinuclear vanadium complex that catalyzes the epoxidation of allylic alcohols.
Although the ratio of ligand to catalyst might argue against the dinuclear catalyst it
42
should still be considered, since the structure would follow the accepted transition state
proposed by both Sharpless and Malkov (Figure 24).
R
R
N
O O
O V O
N
O O O
O
O V
O
O
O
78
Figure 24: Proposed dinuclear vanadium catalyzed epoxidation.
43
Chapter 3
CONCLUSION
Four known 3,5-di-tert-butyl substituted Schiff bases as well as two 3-adamantyl5-methyl substituted Schiff bases were tested for the selectivity in the vanadiumcatalyzed enantioselective epoxidation of allylic alcohols. Jacobsen’s ligand was shown
to provide the best chiral induction at 9-10% ee, with the adamantyl-substituted version
complementary in enantiomeric excess. This proves that the steric effect on the
salicylaldehyde portion of the ligand is not as important as the source of chirality.
44
Chapter 4
FUTURE WORK
To assess the future of Schiff base ligands towards the vanadium-catalyzed
epoxidation of allylic alcohol, the next step should be reaction kinetics. Kinetics should
help clarify the mechanism of epoxidation. In addition, to reaction kinetics, a
computational study would be helpful to investigate the mechanistic pathway. Both of
these methods should help in the design of new Schiff base ligands for the vanadiumcatalyzed epoxidation of allylic alcohols.
Once kinetics is completed, new chiral ligands should be synthesized to test for
enantioselectivity. A concept not yet explored in the vanadium-catalyzed epoxidation of
allylic alcohols is the electronics of the catalyst for induction of chirality. Should these
Schiff bases have a larger steric effect around the chiral center(s) or should the
electronics of the ligands be augmented to enhance selectivity?
45
Chapter 5
EXPERIMENTAL SECTION
1
H NMR and 13C NMR spectra were recorded at ambient temperature at 500 MHz and
125 MHz, respectively, using a Bruker Avance spectrometer. All chemical shifts are
reported in ppm relative to TMS or CDCl3 on the δ scale, multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet), coupling
constants in Hz. Infrared (IR) spectra were obtained using a Perkin Elmer RX-1. All
reactions were performed under nitrogen atmosphere in oven-dried glassware using
standard syringe/septa techniques. Unless otherwise stated, all reagents were used
unpurified from the supplier. Solvents were used as received from commercial suppliers.
MgCl2, VO(acac)2, VOSO4, VOCl3, t-cinnamyl alcohol, 2-(1-adamantyl)-4methylphenol, (1R, 2S)-2-amino-1,2-diphenylethanol, (1R, 2R)-cyclohexanediamine and
Jacobsen’s ligand were purchased from Aldrich. V(acac)3, 3,5-di-tbutylsalcicylaldehyde, VO(OiPr)3, (CH2O)n and tert-butylhydroperoxide were obtained
from Alfa Aesar. (1S, 2R)-cis-1-amino-2-indanol and (1S, 2S)-1,2-dipheny-1,2ethanediamine were purchased from Acros. Dri-Solv THF, CH2Cl2 and Et3N were
obtained from EMD. Nerol was purchased from TCI-EP. V(acac)3 and VO(acac)2 were
recrystallized from CH2Cl2 prior to use. Trans-cinnamyl alcohol was purified by column
chromatography (20% EtOAc/Pet Ether). Chemicals were obtained from commercial
suppliers and used as received unless otherwise noted.
46
O
OH
MeOH
N
+
H2N
79
OH
reflux
OH
OH
80
38
(1S, 2R)-1-[(2-Hydroxy-3,5-di-tert-butylbenzylidene)amino]indan- 2-ol (38): To a
solution of (1S, 2R)-cis-1-amino-2-indanol (0.77 g, 5.17 mmol) in MeOH (20 mL) was
added 3,5-di-tert-butyl salicylaldehyde (1.21 g, 5.16 mmol). The mixture was heated to
reflux for 12 hours then cooled to 23 C. The product was extracted with
dichloromethane (3 x 30 mL), washed with brine (25 mL), dried over Na2SO4 and solvent
concentrated in vacuo. The resulting yellow oil was purified by column chromatography
(10% EtOAc/PetEther). The yellow oil was dissolved in dichloromethane and
concentrated in vacuo. The procedure was repeated twice producing a yellow foam
which was ground into a yellow solid (1.70 g, 90%) using a mortar and pestle. 1H NMR
identical to literature data.
47
O
MeOH
N
N
OH
H 2N
NH2
reflux
OH HO
81
79
46
6,6'-(1E,1'E)-((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(azan-1-yl-1ylidene)bis(methan-1-yl-1-ylidene)bis(2,4-di-tert-butylphenol) (46): To a solution of
(1S, 2S)-diphenylethanediamine (0.100 g, 0.471 mmol) in methanol (10 mL) was added
3,5-di-t-butylsalicylaldehyde (0.220 g, 0.942 mmol). After refluxing for 12 hours, the
reaction mixture was cooled to 23 C producing a solid that was isolated by vacuum
filtration (0.288 g, 95%). 1H NMR identical to literature data.35
O
MeOH
N
OH
reflux
H2N
OH
82
OH
OH
42
79
2,4-di-tert-butyl-6-((E)-((1S,2R)-2-hydroxy-1,2-diphenylethylimino)methyl)phenol
(42): To a solution of (1R, 2S)-diphenylaminoethanol (0.075 g, 0.352 mmol) in methanol
(10 mL) was added 3,5-di-t-butylsalicylaldehyde (0.082 g, 0.352 mmol). After refluxing
for 12 hours the reaction mixture was cooled to 23 C. The product was crystallized by
48
the slow evaporation of methanol. The resulting yellow solid was isolated by vacuum
filtration (0.150 g, 95%). 1H NMR identical to literature data.
MgCl2, Et3N
OH
1-adamantyl
83
(CH2O)n, THF
reflux
O
OH
1-adamantyl
84
3-(1-adamantyl)-5-methylsalicylaldehyde (84): To a solution of MgCl2 (0.571 g, 6.0
mmol) and Et3N (0.560 mL, 4.0 mmol) in THF (10 mL) was added 2-(1-adamantyl)-4methylphenol (0.500 g, 2.0 mmol). After stirring for 10 minutes paraformaldehyde
(0.180 g, 6.0 mmol) was added and the mixture heated to reflux. After 12 hours of
stirring, the reaction mixture was cooled to 23 C and quenched by the addition of 1M
HCl (10 mL). The solution was extracted with EtOAc (3 x 20 mL). The combined
organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and solvent
concentrated in vacuo. The resulting yellow oil was purified by column chromatography
(2 % EtOAc/PetEther) to afford (0.265 g, 49%) as a white solid. 1H NMR identical to
literature data.36
49
O
OH
1-adamantyl
84
MeOH
+
reflux
H2N
OH
82
N
OH
1-adamantyl
OH
47
2-((E)-((1S,2R)-2-hydroxy-1,2-diphenylethylimino)methyl)-3-(1-adamantyl)-5methylphenol (47): To a solution of (1R,2S)-diphenylaminoethanol (0.150 g, 0.703
mmol) in MeOH (10 mL) was added 3-(1-adamantyl)-5-methylsalicylaldehyde (0.189 g,
0.700 mmol). The reaction mixture was heated to reflux for 12 hours and then cooled to
23 C. The solvent was concentrated in vacuo to 1 mL and the resulting precipitate
isolated by vacuum filtration to afford the product (0.295 g, 87%) as a yellow solid.
1H
NMR (500 MHz, CDCl3): 13.4 (s, 1H); 8.07 (s, 1H); 7.45-7.20 (m, 10H); 5.10 (dd, J1
=2.2Hz, J2 = 7.0Hz, 1H); 4.50 (d, J= 7Hz, 1H); 2.28 (s, 3H); 2.24 (br, 6H); 2.21 (d, J =
2.7Hz, 2H); 2.17 (br, 3H); 1.88 (q, J =12 Hz).
13C
NMR (125 MHz, CDCl3): 166.9, 158.4, 140.4 139.7, 137.4, 130.9, 129.9, 128.8,
128.3, 128.2, 128.1, 127.3, 126.8, 118.4, 80.6, 78.4, 40.4, 37.4, 37.1, 29.3, 20.8.
FT-IR (thin film, cm-1): 3426, 2904, 2849, 1629, 1453, 700.
50
O
2
OH
1-adamantyl
84
EtOH
+
H2N
NH2
reflux
85
N
N
OH HO
1-adamantyl 1-adamantyl
49
6,6'-(1E,1'E)-(1S,2S)-cyclohexane-1,2-diylbis(azan-1-yl-1-ylidene)bis(methan-1-yl-1ylidene)bis(2-(1-adamantyl)-4-methylphenol) (49): To a solution of (1R, 2R)cyclohexane-1,2-diamine (0.100 g, 0.878 mmol) in EtOH (10 mL) was added 3-(1adamantyl)-5-methylsalicylaldehyde (0.474 g, 1.76 mmol). The reaction mixture was
heated to reflux for 12 hours before being cooled to 23 C. To the solution was added
brine (5 mL) and Et2O (5 mL). The layers were separated and the aqueous layer
extracted with Et2O (3 x 10 mL). The combined organic phases were washed with brine
(2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting yellow
oil was purified by column chromatography (2% EtOAc/Pet Ether) to afford the product
(0.144 g, 25%) as a yellow solid.
1H
NMR (500 MHz, CDCl3): 13.5 (br, 2H); 8.23 (s, 2H); 6.99 (d, J = 2 Hz, 2H); 6.77
(d, J = 2 Hz, 2H); 3.30 (dd, J1 = 4 Hz, J2 = 6 Hz, 1H); 2.21 (s, 4H); 2.15 (s, 8H), 2.08 (s,
4H) 1.96 (d, 1H), 1.88 (br, 1H), 1.79 (q, 10H).
13C
NMR (125 MHz, CDCl3): 165.9, 158.4, 137.2, 130.4, 129.8, 126.7, 118.5, 40.5,
37.4, 37.0, 33.3, 29.3, 24.6, 20.8.
FT-IR (thin film, cm-1): 3422, 2905, 2850, 1631, 1453, 739.
51
Ph
O
2
OH
1-adamantyl
Ph
N
EtOH
N
+
H2N
84
NH2
OH HO
reflux
81
1-adamantyl 1-adamantyl
48
6,6'-(1E,1'E)-(1R,2R)-diphenylethane-1,2-diylbis(azan-1-yl-1-ylidene)bis(methan-1yl-1-ylidene)bis(2-(1-adamantyl)-4-methylphenol) (48): To a solution of (1S, 2S)-1,2diphenyl-1,2-ethanediamine (0.100 g, 0.471 mmol) in EtOH (10 mL) was added 3-(1adamantyl)-5-methylsalicylaldehyde (0.254 g, 0.942 mmol). The reaction mixture was
refluxed for 12 hours then cooled to room temperature. The precipitate was isolated by
vacuum filtration and washed with cold EtOH (2 x 5 mL) to afford (0.330 g, 98%) as a
yellow solid.
1H
NMR (500 MHz, CDCl3): 13.4 (s, 2H); 8.31 (s, 2H); 7.24-7.16 (m, 10H); 6.99 (d, J =
1.75 Hz, 2H); 6.76 (d, J = 1.4 Hz, 2H); 4.69 (s, 2H); 2.18 (s, 3H); 2.14 (s, 6H); 2.09 (br,
3H); 1.80 (q, J = 7 Hz, 6H).
13C
NMR (125 MHz, CDCl3): 167.3, 158.4, 139.7, 137.2, 130.8, 130.1, 128.4, 128.3,
127.6, 126.8, 118.5, 80.3, 40.4, 37.4, 37.0, 29.3, 20.8.
FT-IR (thin film, cm-1): 3422, 2904, 2849, 1627, 1453, 733, 696.
52
General procedure for the epoxidation of allylic alcohols.
Jacobsen’s ligand (0.030 g 0.0055 mmol) was dissolved in CH2Cl2 (2.5 mL) followed by
the addition of VO(OiPr)3 (0.0116 mL, 0.005 mmol). The solution was stirred for 30
minutes at 23 C before the addition of trans-cinnamyl alcohol (0.134 g, 1.0 mmol). The
reaction was cooled with an ice bath and a 70% aqueous solution of tertbutylhydroperoxide (0.200 mL, 1.5 mmol) was added dropwise. The reaction mixture
was warmed to 23 C and stirred for 12 hours before being quenched with a saturated
aqueous solution of Na2S2O3 (3 mL). The layers were separated and the aqueous layer
extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were washed with brine
(5 mL), dried over Na2SO4, filtered and solvent concentrated in vacuo. The resulting
green oil was purified by column chromatography (30% EtOAc/Pet Ether) to afford the
product (0.0975 g, 65%) as a colorless oil Spectroscopic data identical to literature data.
53
Mosher Esterification
O
O
O
OH
55b
Ph
O
OMe
CF3
86
((2R,3R)-3-phenyloxiran-2-yl)methyl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
(86): To a solution of (3-phenyloxiran-2-yl)methanol (0.0975 g, 0.649 mmol) in CH2Cl2
(1.0 mL) was added pyridine (10 drops) and (R)-Mosher’s Acid Chloride (0.067 mL,
0.36 mmol). The reaction mixture was stirred for 24 hours before being quenched by 1M
HCl (5 mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (3
x 5 mL). The combined organic phases were washed with brine (10 mL), dried over
Na2SO4 and solvent concentrated in vacuo. The resulting oil was used without
purification and diastereomeric excess measured by 19F. See appendix for a sample 19F
NMR.
54
REFERENCES
1) Wu, J-Q.; Pan, L.; Hu, N-H.; Li, Y-S.; Organometallics 2008, 27, 3840-3848.
2) Toste, F. D.; Musich, C.; Radosevich, A. T.; J. Am. Chem. Soc. 2005, 127, 10901091.
3) Bolm, C.; Bienwlad, F.; Angew. Chem. Int. Ed. Engl. 1995, 34, 2640-2642.
4) Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004.
5) Kumaraswamy, G.; Ankamma, K.; Pitchaiah, A.; J. Org. Chem. 2007, 72, 98229825.
6) Reiss, T.; Breit, B.; Org. Lett. 2009, 11, 3286-3289.
7) Sharpless, K.B.; Michaelson, R.C; J. Am. Chem. Soc. 1973, 95, 6136-.
8) Sharpless, K.B.; Katsuki, T.; J. Am. Chem. Soc. 1980, 102, 5976-5978.
9) Michaelson, R.C.; Palermo, R. E.; Sharpless, K.B.; J. Am. Chem. Soc. 1977, 99,
1990-1991.
10) Yamamoto, H.; Murase, N.; Hoshino, Y.; Oishi, M.; J. Org. Chem. 1999, 64, 338339.
11) Yamamato, H.; Hoshino, Y.; J. Am. Chem. Soc. 2000, 122, 1042-1045.
12) Yamamoto, H.; Hoshino, Y.; Makita, N.; Angew. Chem. Int. Ed. 2003, 42, 941943.
13) Yamamoto, H.; Hoshino, Y.; Kosugi, Y.; Basak, A.; Zhang, W.; Angew. Chem.
Int. Ed. 2005, 117, 4463-4465.
14) Yamamoto, H.; Zhang, W.; J. Am. Chem. Soc. 2007 129, 286-287.
15) Yamamoto, H.; Li, Z.; J. Am. Chem. Soc. 2010 132, 7878-7880.
55
16) Yamamoto, H.; Barlan, A.; Zhang, W.; Tetrahedron Lett. 2007, 63, 6075-6087.
17) Malkov, A.; Bourhani, Z.; Kocovsky, P.; Org. Biolmol. Chem. 2005, 3, 31943200.
18) Sharpless, K.B.; Verhoeven, T. R.; Aldrichimica Acta (1979) 12, 63-74.
19) Malkov, A.; Bourhani, Z.; Synlett 2006, 20, 3525-3528.
20) Jacobsen, E.; Zhang, W.; J. Org. Chem. 1991, 56, 2296-2298.
21) Jacobsen, E.; Branalt, J.; Schaus, S.; J. Org. Chem. 1998 63, 403-405.
22) Jacobsen, E.; Myers, J. J. Am. Chem. Soc. 1999, 121, 8959-8960.
23) Jacobsen, E.; Conser, K. R.; Li, Z.; J. Am. Chem. Soc. 1993, 115, 5326-5327.
24) Jacobsen, E. et al.; J. Am. Chem. Soc. 2002, 124, 1307-1315.
25) Khan, Noor-ul H. et al.; Tetrahedron: Asymmetry 2006, 17, 2659-2666.
26) Ellman, J.; Weix. D. J.; Org. Synth. 2005, 82, 157-165.
27) Toste, F.D.; Blanc, A.; Angew. Chem. Int. Ed. 2006, 45, 2096-2099.
28) Brandes, B.; Jacobsen, E.; J. Org. Chem. 1994, 59, 4378-4380.
29) Jacobsen, E.N.; Chavez, D.; Org. Synth. 2005, 82, 34-42.
30) Dale, J.; Mosher, H. S.; J. Am. Chem. Soc. (1973) 95, 512-519.
31) Martin, E. J. Racemic and diastereoselective epoxidation reactions: synthesis,
characterization and application of chiral oxovanadyl(IV) salen. M.S. Thesis,
CSU Sacramento, Sacramento, CA, 2008.
32) Armarego, W. L. F.; Chai, Christina Li Lin; Purification of Laboratory
Chemicals. Butterworth-Heinemann. 2009.
33) Smith, K.; Olmstead, M.; Borer, L.; Inorg. Chem. 2003, 42, 7410-7415.
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34) Kureshy, R.; Prathap, K. J.; Agrawal, S.; Khan, N. H.; Abdi, S. H. R.; Jasra, R.
V.; Eur. J. Org. Chem. 2008, 3118-3128.
35) Belokon, Y. N.; Hunt, J.; North, M.; Synlett 2008, 14, 2150-2154.
36) Skattebøl, L.; Vidar Hansen, T.; Org. Synth. 2005, 82, 64-68.
57
Chapter 1
PART TWO: INVESTIGATION OF A MONORADICAL CYCLIZATION AND
FRAGMENTATION: ACCESS TO AN 8-MEMBERED RING.
INTRODUCTION
Some very important natural products, such as paclitaxel (1) and dactylol (2),
contain 8-membered ring carbocycles (Figure 25). These medium sized rings are
difficult to construct because the ends of the alkyl chain are less than likely to find each
other in solution owing to enthalpic and entropic factors.1 One such means of producing
the skeletal structure is through radical cyclizations initiated by azobisisobutyronitrile2
(AIBN) or from the lanthanide complex SmI2.
AcO
O
OH
Ph
HO
O
NH
O
Ph
H
OH O OAc
Ph
O
O
OH
O
1
Figure 25: Anti-cancer drug paclitaxel (1) and dactylol (2).
2
58
Chapter 2
BACKGROUND
H. Kagan was the first to use SmI2 for the reduction of carbonyls to a ketyl
radical.3 These radicals were reacted with alkyl halides to produce secondary or tertiary
alcohols based on the starting material. Although Kagan was the first to develop these
samarium promoted radical reactions, G. Molander is the pioneer in samarium radical
chemistry.
In 1994, Molander and McKie4 were able to synthesize cyclooctanols from
unsaturated ketones, samarium diiodide, HMPA and tert-butyl alcohol from an 8-endo
trig cyclization. The initial studies began with 8-nonen-2-one, samarium diiodide and
tert-butyl alcohol in THF; however, the only isolated product was the reduced ketone.
Addition of HMPA prevented quenching of the ketyl radical, promoting cyclization.
Cyclooctanol 4 was isolated in 54% yield along with 32% of reduced starting material 5
(equation 1).
Molander and McKie speculated the source of hydrogen atom abstraction was
either THF or the alcohol. When 1,1,1,3,3-pentadeuterio-non-8-en-2-one, t-BuOD and
THF were used for the cyclization deuterium was incorporated in both cyclized product 7
and reduced ketone 6. However, using tert-butanol and deuterated THF produced
59
cyclized product 4 and reduced ketone 5 without deuterium incorporation (Scheme 11).
This proved that hydrogen atom abstraction did not originate from the solvent.
O
SmI2, t-BuOD, HMPA
D3C
THF
D D
6
D3C
D
D
OH
D OH
D
+
D3C
D D
31%
54%
7
SmI2, t-BuOH, HMPA
O
8
HO
+
OH
d8-THF
3
29%
52%
4
5
Scheme 11: Deuterium study to determine where the proton source originates
When the ketone substituent at C3 is larger than a methyl group, the cyclization
rate is dramatically decreased forming the reduced ketone as the major product.
Substrates to test the enhancement of cyclization were placed with an allylic heteroatom.
The cyclization proceeded based on the alkene product formed by-elimination after
samarium cyclization. A second manner to increase cyclization is to stabilize the radical
at the olefinic position through electron withdrawing or electron donating groups. A
phenyl substituent forms a stable benzylic radical favoring cyclization to the
cyclooctanol. When phenyl groups were positioned on the olefin, the cyclized product
was anti with respect to the alcohol and phenyl substituents.
60
In 1995, Molander and Harris published their work on acyl substitution/Barbier
cyclizations for the formation of bicyclic and tricyclic systems, including some
cyclooctanol products.5 Formations of these polycyclic frameworks are important in
natural products such as paclitaxel (1) and dactylol (2; Figure 25).6
The initial studies began with dihalide substituted lactones or esters and two
equivalents of samarium diiodide. The samarium reduces the halide in the order of most
reactive (iodide) to least reactive (chloride). Diiodide substrates reacted completely in an
hour while a chloride and iodide substrate required six hours. When a substrate had both
iodide and bromide as halides, samarium was indiscriminate in which halide to first
reduce. Molander and Harris decided either to have substrates with diiodide or two
different halides, chloride and iodide. (Scheme 12, equation 3).
61
Scheme 12: Reaction sequence for the formation of bicyclic rings containing an eight-membered ring
In 1998, Molander and Sono7 published the conjugate addition of ketyl radicals to
,-unsaturated systems. The products of these reactions were bicyclic rings composed
of mostly 5 and 7 membered rings and a few 5 and 8 membered ring systems. The
majority of the products were ketones (23) or hemiketals (24; equation 4).
62
However, some of the products were from conjugate addition followed by
lactonization. These spirobicyclic lactones could contain either a halogen substituent or
hydrogen atom, depending upon how far the molecule had been reduced. These
spirocyclic lactones (25a, 25b) were the sole product when the n-alkyl chain on the
ketones contained more than 3 carbon atoms (Figure 26).
Figure 26: Spriocyclic byproducts obtained enroute to 6-, 7- and 8-membered rings
When ethyl acrylate 26 and 2-(3-chloropropyl)-cyclopentanone 27 were subjected to 4
equivalents of samarium diiodide, hemiketal 28 was isolated in 34% (equation 5).
In early 1999, Molander expanded the work that was published in 1998.8 These
cyclizations were for the formation of medium sized rings between 8-10 carbons in
length. The reaction conditions were very similar to the work of the preceding paper;
however, the coupling partner, in the more recent sequenced reaction, changed from an
acrylic ester to a saturated 3-iodopropanoate (equation 6).
63
In 2001, Molander was able to produce eight membered carbocycles through a
samarium(II) iodide radical cyclization followed by a Grob fragmentation. 9 The initial
approach of the study was a Barbier-type radical cyclization of -dicarbonyl compounds
(30). The product of this radical-mediated process led to a -hydroxy ketone (31) in a
bicyclic system (equation 7).
If a mesylate were  to the ketone prior to cyclization, an eight membered
carbocycle would be formed post-cyclization. The first step of the process would be the
formation of the bicyclic system as in equation 7. However the added leaving group
would induce a Grob fragmentation of the bicyclic ring system to an eight-membered
carbocycle (equation 8). The reaction occurs because the iodide is more labile than the
64
mesylate, which does not undergo addition or elimination until after the samarium
reaction has taken place.
In early 2001, Molander used a samarium-mediated cyclization for the formation
of the eight-membered ring in variecolin (40).10 Using a model substrate, the authors
were successfully able to form the tricyclic fragment using (Scheme 13).
65
Scheme 13: Samarium mediated radical cyclization in natural product synthesis.
Pattenden, at the University of Nottingham, constructed a steroid framework
through a radical cascade reaction using an aryl vinylcyclopropane and a phenylseleno
ester.11 When the starting material was refluxed under dilute conditions in benzene, a 13endo-trig macrocyclization followed by a 5-exo-trig and a 6-exo-trig cyclization
produced the tetracyclic system (Scheme 14).
66
PhSe
nBu SnH
3
O
AIBN
13-exo-trig
O
42
41
5-exo-trig
6-exo-trig
O
O
44
43
H
H
H·
H
O
H
45
H
O
H
46
Scheme 14: 13-exo-trig cyclization using a radical cyclization of a vinyl cyclopropane
The radical cascade reaction produced several products including a 25% yield of a
1:1 mixture of methyl epimers (46), which was determined by 2D NMR. One of the
byproducts was a dienone (47) intermediate produced by a 12-endo-trig cyclization. Four
minor byproducts (48a-b, 49a-b) were the alkyl vinylcyclopropane and the aldehyde
vinylcyclopropane along with the 1,2-dioxolane species (Figure 27).
Figure 27: By products in the radical cascade reaction.
67
Previous work toward the SmI2 mediated radical cyclization of vinyl
cyclopropanes to 8-membered rings was investigated by Little. Synthesis of the substrate
was accomplished in 4 steps from allylcyclopentanone. The initial step was installation
of the cyclopropane ring using ethyl diazoacetate catalyzed by rhodium acetate.
Reduction of the carbonyl groups was accomplished using lithium aluminum hydride to
form diol 52. Chromatography allowed for the separation of cis and trans diastereomers
with respect to the cyclopropane ring. Subsequent oxidation to the dicarbonyl (was
accomplished using the method of Parikh-Doering.12 Aldehyde 53 was transformed into
,-unsaturated ester (54) using a stabilized Wittig reagent (Scheme 15).
Scheme 15: Synthesis of vinyl cyclopropane 54.
68
When vinyl cyclopropane 54 was added to a solution of SmI2 in THF, a 6-exo-trig
cyclization took place (55, equation 9). The 6-exo-trig cyclization was favored over the
7-endo-trig cyclization because of the position of the electron withdrawing substituent on
the olefin. The 6-exo-trig cyclization pathway took place because the -carbon was
activated by the electron-withdrawing group favoring conjugate addition.
Little then changed the position of the electron-withdrawing group so the favored
conjugate addition pathway would provide the requisite 7-endo-trig cyclization. The
synthesis of vinyl cyclopropane (59) was similar to that of vinyl cyclopropane (54). In
this case, the allyl cyclopentanone was protected as a ketal (56) and cyclopropanation
was accomplished using ethyl diazopyruvate instead of ethyl diazoacetate. After
cyclopropane 57 was formed, a Wittig reaction was used to install the ,-unsaturated
ester (58). Subsequent deprotection of the ketone afforded the test substrate (59; Scheme
16).
69
Scheme 16: Synthesis of vinyl cyclopropane with electron-withdrawing group repositioned.
The addition of vinyl cyclopropane (59) to a solution of SmI2 in THF afforded
reduction of the ketone to secondary alcohol 60 with a yield of 43% (equation 10).
Although no further attempts to furnish 7-endo-trig cyclization took place, changing the
reaction conditions to include a more sterically hindered alcohol (tert-butanol) and the
addition of HMPA as a cosolvent could facilitate cyclization over carbonyl reduction.
70
Chapter 3
RESULTS AND DISCUSSION
The goal of this project is to construct an eight-membered carbocycle via a
radical-mediated cyclization with a vinyl cyclopropane. Our 8-membered carbocycle 61
would arise through a 7-endo-trig radical cyclization from vinyl cyclopropane followed
by radical fragmentation. The test substrate (62) would be constructed through an aldol
reaction between aldehyde 63 and p-methoxyacetophenone (64; Scheme 17). The hydroxy ketone was alluring because it could be prepared from simple reactions and the
alcohol would coordinate to the lanthanide during the key step.
Scheme 17: Retrosynthesis of 8-membered carbocycle
Reduction of ethyl chrysanthemate using lithium aluminum hydride in refluxing
THF afforded the primary alcohol in quantitative yield. Swern oxidation afforded
71
cyclopropylcarbaldehyde 63.13 Upon column chromatography, there was a product in the
first several fractions that began to crystallize. Although the identity of this product was
not investigated, the most likely explanation is the acidic opening of the cyclopropane
ring to either aldehyde 65 or 66 (equation 11).14
The acid sensitive cyclopropane became a problem throughout the remainder of
the synthesis of the substrate. During the Swern oxidation, if the addition of base is done
dropwise, a mixture of products was obtained. However, if the base is added all at once,
the sole product is aldehyde 63. Due to the acidic nature of purification media,
triethylamine is used as a co-solvent in the eluent to prevent the acidic ring opening of the
cyclopropane.15
Once the aldehyde was formed, para-methoxyacetophenone was installed via an
aldol reaction to incorporate a-hydroxy ketone moiety (Scheme 18). However, the
carbon NMR of the purified product showed four diastereomers via the chemical shift of
the carbonyl carbon.
72
Scheme 18: Synthesis of vinylcyclopropane substrate.
Preliminary studies showed that the samarium cyclization could not be run under
a nitrogen atmosphere. The nitrogen atmosphere either was wet causing the SmI2 to
quench as it was formed or the samarium complex was reducing nitrogen. Order of
addition of the products was also important; the substrate must be added to the
samarium(II) iodide solution. If the samarium solution was added to the substrate,
carbonyl reduction took place (equation 12). Addition of a coordinating co-solvent such
as HMPA was also necessary to facilitate cyclization over carbonyl reduction.
73
Switching the atmosphere to argon and using HMPA as a cosolvent afforded a
complex mixture of products. The mixture was carefully chromatographed and fractions
were collected with a single spot and identical retention factors. Even though fractions
that were thought to be pure were collected, the 1H NMR showed a complex mixture of
products as indicated by overlapping aromatic hydrogens.
The mixture of products arises not only from the starting material, which has a
mixture of four diastereomers, but also from the numerous possible products that could
be formed from the radical cyclization.
There are two possible pathways that the radical cyclization could proceed; a 6exo-trig or a 7-endo-trig cyclization. Ideally, the mixture of these complex products can
be minimized to either alcohols or alkenes through either a neutral or acidic workup
respectively. Since the goal of this project is to use a radical cyclization to form an eightmembered carbocycle, the preferred reaction pathway is through a 7-endo-trig
cyclization.
74
The pathway that would give an eight-membered ring as the product is depicted in
Scheme 19. The initial step in the mechanism is reduction of the carbonyl to a ketyl
radical. The second step is cyclization of the ketyl-radical onto the olefin. Due to the
ring strain of the cyclopropane ring, it should open forming a new alkene and a secondary
radical. The termination of the cyclization followed by acidic workup would afford diol
61 as a single diastereomer (Scheme 19).
Scheme 19: Postulated 7-endo-trig mechanism to an 8-memberd ring
Since the 1H NMR of the purified products contain peaks for cyclopropanes one
can conclude that a 7-endo-trig cyclization did not take place. The rate constant for a
vinyl cyclopropane to open up is 1.3 x 108 s-1.16 The lack of formation for the 7-endo-trig
75
cyclization could be explained because of the steric interaction of the geminal dimethyl
groups on the olefin, which would be a disfavored pathway for cyclization.
If a 6-exo-trig cyclization were to take place, the ketyl-radical would cyclize onto
C-6 forming tertiary radical at C-7 (Scheme 20). From here hydrogen atom abstraction
or elimination could take place.
Scheme 20: 6-exo-trig cyclization of 51
While a cis-bicyclo[4.1.0]heptane looks more stable than its trans counterpart due
to the high strain of a trans-bicyclo[4.1.0]heptane, they are both stable molecules.
Gassman investigated the thermal isomerization of trans bicyclo[4.1.0]heptane rings
using NMR as a tool to calculate rate constants.17 While the trans bicyclic cyclopropane
rings do isomerizes to their cis isomer, the rate constant in d8-toluene at 130 C is only
76
2.7x10-5 s-1 (equation 13). The room temperature rate constant was extrapolated to be
2.5x10-10 s-1 from the series of higher temperature rate constants.
Because of the relative instability of the trans bicyclo[4.1.0]heptane ring, it is
postulated that radical fragmentation could continue as shown in Scheme 21. The bond
adjacent to the cyclopropane ring would fragment heterolytically creating an alkene and a
cyclopropane carbinyl radical. From here, the cyclopropane could open into an alkene
and a tertiary radical which would then quench upon hydrogen abstraction.
Scheme 21: Postulated mechanism to relieve strain of trans-bicyclo[4.1.0]heptane
77
An alternate postulated pathway, for the continued fragmentation of the transbicyclo[4.1.0]heptane ring goes through a triple radical intermediate. Although this
pathway is energetically unfavorable, it follows the intermediate in the study by
Gassman. In this mechanism, the cyclopropane ring fragments expanding the bicyclic
ring to a cycloheptane ring containing a triyl radical. From here, the cis cyclopropane
ring could form, or a bicyclo[5.1.0]octane ring could form. It is also possible that upon
formation of the cycloheptane ring that the radicals would quench (Scheme 22).
Scheme 22: 6-exo cyclization followed by Gassman type fragmentation to yield 71 and 73
78
Chapter 4
CONCLUSION
A -hydroxy p-methoxyacetophenone derivative containing a vinyl cyclopropane
was synthesized and subjected to a samarium(II) iodide radical cyclization. While the
crude material was purified, the 1H NMR contained a complex mixture of products. The
mixture was unable to be purified making product identification impossible. However, in
all such cases, there is a proton signal for a cyclopropane peak indicating that if
cyclization occurred, a bicyclic product would have formed from a 6-exo-trig cyclization.
79
Chapter 5
FUTURE WORK
The best decision for any future radical cyclizations pertaining to this project
would be to synthesize a substrate as one diastereomer. Limiting the number of
stereocenters will greatly diminish the number of diastereomers that can form during the
radical cyclization step. This would allow for an easier task of discerning the identity of
cyclization products. If the ethyl chrysanthemate derived substrate is going to be used to
continue this study, it should be made in an asymmetric fashion. The synthesis of the
substrate should also be checked for enantiopurity and diastereoselectivity after each
reaction. Using this synthesis, both cis and trans diastereomers can be synthesized and
tested for the efficacy of the samarium-mediated radical cyclization.
The synthesis of the diastereomerically pure substrate would begin with ethyl
diazoacetate (85) and 2,5-dimethyl-2,5-hexadiene (86). Reduction followed by oxidation
to aldehyde (63) and aldol reaction will yield diastereomerically pure product (62). To
further add stereoselectivity, an asymmetric aldol reaction can be used to form the hydroxy ketone moiety as a test substrate (Scheme 23).
80
Scheme 23: Diastereomeric synthesis of chrysamthenal substrate
If the geminal dimethyl groups on the olefin prevent 7-endo-trig cyclization,
unsubstituted alkene 87 could be synthesized (Figure 28). The reduced sterics of vinyl
cyclopropane 87 should favor 7-endo-trig cyclization over vinyl cyclopropane 62.
Figure 28: Unsubstituted vinyl group on test substrate
81
Chapter 6
EXPERIMENTAL SECTION
1
H NMR and 13C NMR spectra were recorded at ambient temperature at 500 MHz and
125 MHz, respectively, using a Bruker Avance spectrometer. All chemical shifts are
reported in ppm relative to TMS or CDCl3 on the δ scale, multiplicity (br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet), coupling
constants in Hz. Infrared (IR) spectra were obtained using a Perkin Elmer RX-1. All
reactions were performed under nitrogen atmosphere in oven-dried glassware using
standard syringe/septa techniques. Unless otherwise stated, all reagents were used
unpurified from the supplier. Solvents were used as received from commercial suppliers.
SmI2, LAH and (COCl)2 were purchased from Alfa Aesar. THF, Et3N, Ethyl
Chyrsamthenate and DMSO were purchased from EMD. HMPA and pmethoxyacetophenone were obtained from Aldrich. NaH (60% dispersion in minral oil)
was purchased from Acros. Reactions were performed under an inert atmosphere of N2
or Argon (in the case of Samarium cyclizations). Chemicals were used without
purification unless otherwise stated.
82
O
OEt
LAH
OH
THF, reflux
100%
67
68
(2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl)methanol (68): To a solution of
lithium aluminum hydride (2.10 g, 55.4 mmol) in THF (100 mL) was added ethyl
chrysanthemate (8.0 mL, 36.9 mmol) dropwise. After heating to reflux for 24 hours the
reaction mixture was cooled to 0 C. H2O was added to the solution until precipitation
ceased. The solid was removed using a medium fritted funnel. The filtrate was dried
over MgSO4, filtered and solvent concentrated in vacuo to afford the product (5.618 g,
100%) as colorless oil. 1H NMR was identical to literature data.18
OH
(COCl)2, DMSO
O
Et3N, CH2Cl2
99%
68
H
63
2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarbaldehyde (63): To a solution
of oxalyl chloride (1.13 mL, 12.9 mmol) in CH2Cl2 (80 mL) at -78 C was added DMSO
(1.75 mL, 25.9 mmol) dropwise. The reaction mixture stirred for 10 minutes and a
solution of (2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl)methanol (1.00 g, 6.48
mmol) in CH2Cl2 (17.2 mL) was added dropwise. After one hour of stirring, Et3N (7.23
mL, 51.86 mmol) was quickly added using a syringe. The temperature was warmed to 23
83
C and the reaction mixture stirred for 12 hours before being quenched with H2O (30
mL). The layers were separated and the aqueous phase extracted with CH2Cl2 (4 x 75
mL). The combined organic phases were washed with 1M HCl (2 x 20 mL), H2O (30
mL), a saturated aqueous solution of NaHCO3 (30 mL), brine (30 mL), dried over
MgSO4, filtered and solvent concentrated in vacuo to afford the product (0.978 g, 99%)
as a mixture of 2 diastereomers. The resulting red oil was used without further
purification. 1H NMR was identical to literature data.19
O
O
O
+
H
63
OH
NaH
OMe
THF
-78 °C --> RT
27%
88
62
OMe
3-(2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl)-3-hydroxy-1-(4methoxyphenyl)propan-1-one: To a solution of NaH (washed with 3 x 15 mL hexanes)
(0.214 g, 5.35 mmol) in THF (10 mL) at 0 C was added p-methoxyacetophenone (0.804
g, 5.35 mmol) in THF (5 mL) dropwise. The reaction mixture was warmed to 23 C and
stirred for 1 hour before the temperature was lowered to -78 C. To the reaction mixture
was added 2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarbaldehyde (0.895 g,
5.88 mmol) in THF (10 mL) dropwise. The reaction mixture was stirred for 12 hours
before being quenched with H2O (15 mL). The solution was extracted with Et2O (3 x 20
mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4,
84
filtered and solvent concentrated in vacuo. The resulting yellow oil was purified by
column chromatography (1 % EtOAc/1% Et3N/ 98 % Hexanes) to afford (0.437 g, 27%)
as a colorless oil and a mixture of 4 diastereomers.
Spectroscopic data is for all 4 diastereomers.
1H
(500 MHz, CDCl3): 8.03 (m, 4H), 7.96 (m, 4H), 6.93 (m, 8H), 4.83 (dt, J = 9.4 Hz,
4H), 4.71 (dt, J = 8.6 Hz, 4H), 3.80 (s, 12H), 3.40 (dd, J1 = 6.6 Hz, J2 = 15 Hz, 4H), 3.26
(dddd, J1 = 7.1 Hz, J2 = 15 Hz, J3 = 22 Hz, 12H), 3.10 (dd, J1 = 8.4 Hz, J2 = 15.7 Hz,
4H), 2.96 (dt, J1 = 6.2 Hz, J2 = 15.8 Hz, 8H), 2.80 (dd, J1 = 6.2 Hz, J2 = 14.8 Hz, 4H),
2.72 (dd, J1 = 6.2 Hz, J2 = 14.9 Hz, 4H), 2.45 (m, 8H), 1.69 (t, J = 12.8 Hz, 8H), 1.64 (s,
12H), 1.63 (s, 12H), 1.62 (s, 12H), 1.55 (s, 4H), 1.52 (s, 12H), 1.30 (t, J = 9 Hz, 8H),
1.00 (s, 12H), 0.915 (s, 12H), 0.911 (s, 12H), 0.81 (s, 12H), 0.60 (dd, J1 = 5.55 Hz, J2 =
10.7 Hz, 4H).
13C
(125 MHz, CDCl3): 198.9, 198.7, 198.6, 198.5, 163.6, 163.5, 163.4, 1339, 132.0,
130.82, 130.78, 130.70, 130.67, 130.64, 130.55, 124.3, 120.3, 113.87, 113.83, 113.78,
113.75, 68.1, 55.6, 53.6, 44.2, 43.74, 43.73, 42.8, 38.7, 34.7, 34.6, 30.9, 30.1, 29.2, 26.7,
26.1, 25.8, 25.7, 23.7, 22.9, 21.8, 21.3, 18.4, 18.3, 16.1.
FT-IR (thin film, cm-1): 3427, 2965, 1673, 1510, 1259, 1031, 838, 737.
85
OH
O
SmI2, HMPA
THF
-78 °C --> RT
?
OMe
62
To a solution of SmI2 (42 mL, 4.2 mmol) in THF was added HMPA (7.30 mL, 42
mmol). The reaction mixture was cooled to -78 C before the addition of 3-(2,2)dimethyl-3-(2-methylprop-1-enyl)cyclopropyl)-3-hydroxy-1-(4-methoxyphenyl)propan1-one (0.183 g, 1.2 mmol) in THF (20 mL) dropwise. The reaction mixture was allowed
to warm to 23 C and stirred for 12 hours before being quenched with 1M HCl (20 mL).
The solution was extracted with Et2O (3 x 20 mL). The combined organic phases were
washed with brine, dried over Na2SO4, filtered and solvent concentrated in vacuo. The
resulting yellow oil was purified by column chromatography (2% EtOAc/Pet Ether  10
% EtOAc/Pet Ether) to afford a mixture of inseparable compounds.
86
REFERENCES
1)
Illuminati, G.; Mandolini, L.; Acc. Chem. Res. 1981, 14, 95-102.
2)
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3)
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4)
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5)
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87
APPENDICES
88
APPENDIX A
NMR spectra
N
OH
OH
89
90
91
92
93
N
N
OH HO
94
95
96
97
98
N
OH
OH
99
10
0
10
1
10
2
10
3
O
OH
10
4
10
5
10
6
N
OH
OH
10
7
10
8
10
9
11
0
11
1
11
2
11
3
11
4
N
N
OH HO
11
5
11
6
11
7
11
8
11
9
12
0
N
N
OH HO
12
1
12
2
12
3
12
4
12
5
12
6
O
OH
12
7
12
8
12
9
O
OH
13
0
O
OH
13
1
13
2
13
3
13
4
O
O
Ph
O
CF
OMe 3
13
5
OH
13
6
13
7
13
8
13
9
14
0
O
14
1
14
2
14
3
14
4
14
5
14
6
14
7
OH
O
OMe
14
8
14
9
15
0
15
1
15
2
15
3
15
4
15
5
15
6
OH
O
OMe
SmI2 reaction
15
7
15
8
15
9
16
0
16
1
16
2
Fractions 44-70
16
3
16
4
16
5
16
6
16
7
16
8
Fractions 71-83
16
9
17
0
17
1
17
2
Fractions 84-91
17
3
17
4
17
5
176
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