TANDEM ISOMERIZATION REACTION OF ALKYNES:
TOTAL SYNTHESIS OF ALPHA-YOHIMBINE
FENGWEI
NATIONAL UNIVERSITY OF SINGAPORE
2012
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TANDEM ISOMERIZATION REACTIONS OF
ALKYNES: TOTAL SYNTHESIS OF
ALPHA-YOHIMBINE
FENG WEI (BSc., Nankai University)
A THESIS SUBMITTED
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
DEPARTMENT OF CHEMISTRY
NATIONAL UNIVERSITY OF SINGAPORE
To my family
For their love, support, and encouragement
Acknowledgements
First and foremost, I would like to take this opportunity to thank my supervisor,
Associate Professor Tan Choon-Hong, for his guidance and encouragement
throughout my PhD research and study.
I would like to thank all my labmates for creating such a harmonious,
encouraging, and helpful working environment. My special thanks go to Mr. Liu
Hongjun for his pioneering work on the isomerization project.
I thank Dr Wu Jien, Mdm Han Yanhui for their assistance in NMR analysis, and
Mdm Wong Lai Kwai and Mdm Lai Hui Ngee for their assistance in Mass analysis as
well. I also owe my thanks to many other people in NUS chemistry department, for
their help and assistance from time to time.
Last but not least, I thank all my friends in Singapore who helped me settle down
at the beginning. Singapore is a great place and I enjoy the life here.
Table of Contents
Summary
List of Schemes
List of Tables
List of Figures
List of Abbreviations
Chapter 1
Introduction to allenes
1.1 General introduction to allenes--------------------------------------------------------- 2
1.2 Intramolecular conjugate addition to allenes----------------------------------------- 3
1.3 Intramolecular Diels-Alder reaction of allenes-------------------------------------- 11
1.4 Summary--------------------------------------------------------------------------------- 22
Chapter 2
Brønsted-base catalyzed tandem isomerization-aza-Michael reactions
2.1 Different approaches for the preparation of piperidines and lactams ----------- 28
2.2 Tandem isomerisation-aza-Michael reaction of alkynylamines and
alkynylamides--------------------------------------------------------------------------- 35
2.3 Summary--------------------------------------------------------------------------------- 45
Chapter 3
Total synthesis of alpha-yohimbine via intramolecular-Diels-Alder reaction
3.1 Introduction to the synthesis of alpha-yohimbine---------------------------------- 48
3.2 Tandem-isomerization intramolecular-Diels-Alder reactions of alkynoates: total
synthesis of alpha-yohimbine -------------------------------------------------------- 54
3.3 Summary--------------------------------------------------------------------------------- 71
Chapter 4
Experimental
4.1 General information-------------------------------------------------------------------- 74
4.2 Preparation and characterization of compounds for the Michael reaction ----- 75
4.3 Preparation and characterization of compounds for the IMDA reaction-------- 83
4.4 Procedures to (+)-alpha-yohimbine and characterization of compounds----- 100
Appendix-------------------------------------------------------------------------------------- 116
Summary
The aim of this study is to apply the highly enantioselective alkyne isomerization
reactions that is developed in our group to construct complex and usefull molucules
towards natural product synthesis.
We have found that a Brønsted-base catalyzed tandem isomerization-aza-Michael
reaction can be used to form useful heterocycles under mild conditions. This efficient
method was applied to the synthesis of various functionalized heterocycles with
excellent yields. Tandem isomerization-aza-Michael reaction with alkynyl-amines,
alkynyl-amide led to interesting piperidines and lactams. Asymmetric version of
tandem isomerization-aza-Michael reaction using alkynyl-amide was tested to give
high ee using a chiral bicyclic guanidine as a catalyst. Effort to synthesize larger ring
sized lactams was carried out although failed.
We have also found that chiral bicyclic guanidine could catalyze a tandem
isomerisation intramolecular-Diels-Alder (IMDA) reaction. Interesting and useful
hydroisoquinolines were obtained with moderate to high ees. The chirality was
generated at the stage of alkyne isomerisation and transferred efficiently at the [4+2]
cyclization step. We have also successfully finished the first catalytic enantioselective
synthesis of alpha-yohimbine starting from the IMDA products.
List of Schemes
Scheme 1.1.1 Natural products containing allene structure
Scheme 1.1.2 Two addition models of allenes
Scheme 1.2.1 Intramolecular Michael addition of alcohol to allene sulphoxide
Scheme 1.2.2 Cyclic vinyl sulfoxide and sulfone formation via intramolecular
Michael addition of alcohol to allenic sulphoxide and allenic
sulfone
Scheme 1.2.3 Intramolecular oxa-Michael reaction of allenyl phosphonates
Scheme 1.2.4 Intramolecular Michael addition to allenotes
Scheme 1.2.5 Intramolecular Michael addition to allenic ketones, example1
Scheme 1.2.6 Intramolecular Michael addition to allenic ketones, example 2
Scheme 1.2.7 Intramolecular Michael addition to allenic ketones, example 3
Scheme 1.2.8 Intramolecular conjugate addition of nitrogen to allenes
Scheme 1.3.1
Intromolecular Diels-Alder reaction between allenic ketone and
furan toward the synthesis of Periplanone B
Scheme 1.3.2 Intramolecular Diels-Alder reaction between allene and bezene
Scheme 1.3.3 Intramolecular Diels-Alder reaction of allenic amide, example 1
Scheme 1.3.4 Intramolecular Diels-Alder reaction of allenic amide, example 2
Scheme 1.3.5 Intramolecular Diels-Alder reaction of sulfonyl allene
Scheme 1.3.6 Total synthesis of hippadine via intramolecular Diels-Alder reaction
of allenic carbonate
Scheme 1.3.7 Intramolecular Diels-Alder reaction of allenyl ether
Scheme 1.3.8 Euryfuran synthesis via IMDAreaction of alkoxyallene
Scheme 1.3.9 Total synthesis of Forskoin via intramolecular Diels-Alder reaction
of allenyl ether
Scheme 1.3.10 Total synthesis of tirkentrins via Hetero-Diels-Alder reaction of
allene
Scheme 1.3.11 Proposal of the Intramolecular Diels-Alder reaction of vinylallene
toward the total synthesis of esperamicin A
Scheme 1.3.12 IMDA reaction of vinylallene toward the total synthesis of
cis-Dehydrofukinone
Scheme 1.3.13 IMDA reaction of vinylallene toward the total synthesis of
(+)-Compactin
Scheme 2.1.1 Piperidine formation via amine-ketone condensation
Scheme 2.1.2 Piperidine formation via ring closing metathesis
Scheme 2.1.3 Piperidine formation via intramolecular electrophilic addition of
amine to allene
Scheme 2.1.4 Piperidine formation via ruthenium catalysis
Scheme 2.1.5 Piperidine formation via radical cyclization
Scheme 2.1.6 Pyrrolidine formation via oxidative cyclization
Scheme 2.1.7 Pyrrolidine formation via cobalt mediated cyclization
Scheme 2.1.8 β–lactam synthesis via [2+2]-cycloaddition
Scheme 2.1.9 5-membered lactam formation via gold catalysis
Scheme 2.1.10 6-membered lactam formation via aza-oxy-carbanion relay
Scheme 2.2.1 Alkynyl amine synthesis
Scheme 2.2.2
Brønsted-base catalyzed tandem isomerization-aza-Michael
reaction of alkynyl-amines 141
Scheme 2.2.3 Proposed mechanism for tandem isomerization-aza-Michael
reaction of 141
Scheme 2.2.4 Synthesis of the chiral bicyclic guanidine 149
Scheme 2.2.5 Synthesis of alkynyl amide 150
Scheme 2.2.6 Synthetic schemes to different alkynyl amides and carbonates
Scheme 2.2.7 Enantioselective isomerization of alkynes to allenes
Scheme 3.1.1 Total synthesis of alpha-yohimbine, route1
Scheme 3.1.2 Total synthesis of alpha-yohimbine, route 2
Scheme 3.1.3 Total synthesis of alpha-yohimbine, route 3
Scheme 3.1.4 Total synthesis of alpha-yohimbine, route 4
Scheme 3.2.1 Initial plan for the construction of hydroisoquinoline derivative,
core sutructure of yohimbines
Scheme 3.2.2 Synthesis of IMDA substrates containing opening diene
Scheme 3.2.3 Synthesis of IMDA substrates containing cyclic diene
Scheme 3.2.4
X-ray structures of the compounds 208ba, 208ca and the X-ray
structure of the hydrogenation product of compound 208bb.
Scheme 3.2.5 Intramolecular-Diels-Alder reaction of substrate 208g and
manipulation on the IMDA product 208ga
Scheme 3.2.6 Attempt on the total synthesis starting with compound 208ca
Scheme 3.2.7 Ring opening of compound 217 with triflic acid
Scheme 3.2.8 Protection of alcohol group in compound 221
Scheme 3.2.9 Total synthesis of alpha-yohimbine 170 starting from 208ca
Scheme 3.2.10 Total synthesis of alpha-yohimbine starting from 208ha and 208hb
List of Tables
Table 1.3.1 Intramolecular [4+2] cycloaddition of allenic acid and ester
Table 2.1 Solvent effect on asymmetric tandem isomerization-aza-Michael
reaction of alkynyl amine 141c
Table 2.2 Bicyclic guanidine catalyzed enantioselective tandem
isomerization-aza-Michael reaction
Table 3.1 Solvent effect on IMDA reaction
Table 3.2
Solvent and concentration effect on the IMDA reaction of 208b
Table 3.3 Intramolecular-Diels-Alder (IMDA) reaction of 208
Table 3.4 Oxabicyclic ring opening of IMDA product 208ca
Table 3.5 Optimization of reductive oxabicyclic ring opening of IMDA product
208ca
Table 3.6 Optimization of hydrogenation of compound 222
List of Figures
Figure 1.1 Allene models
Figure 2.1 Piperidine or pyridine containing natural products
Figure 2.2 Enantioselectivity step (Gibbs free energy difference given in
kcal/mol)
Figure 2.3 Different alkyne substrates for the isomerization reaction.
Figure 2.4 Asymmetric synthesis of allenic ketones 94 and 95a-b.
List of Abbreviations
AcOH acetic acid
Ac acetyl
[] optical rotation
aq. aqueous
Ar aryl
Bn benzyl
Boc tert-Butyloxycarbonyl
iBu iso-butyl
tBu tert-butyl
c concentration
cat. catalyst
mCPBA meta-Chloroperoxybenzoic acid
Cbz Carbobenzyloxy
oC degrees (Celcius)
chemical shift in parts per million
DCM dichloromethane
DFT density functional theory
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulfoxide
dd doublet of doublet
dr diastereomeric ratio
ee enantiomeric excess
EI electron impact ionization
ESI electro spray ionization
Et ethyl
Et3N triethylamine
Eoc ethoxycarbonyl
FAB fast atom bombardment ionization
FTIR fourier transformed infrared spectroscopy
g grams
ΔG Gibbs free energy
h hour(s)
HPLC high pressure liquid chromatography
HRMS high resolution mass spectroscopy
Hz hertz
i.d. internal diameter
IR infrared
J coupling constant
LRMS low resolution mass spectroscopy
Me methyl
MeCN acetonitrile
MeOH methanol
mg milligram
MHz megahertz
min. minute(s)
ml milliliter
l microliter
mmol millimole
MS mass spectroscopy
MeNO2 nitromethane
NMR nuclear magnetic resonance
NOE nuclear overhauser effect
NIS N-iodosuccinimide
ppm parts per million
iPr isopropyl
Ph phenyl
rt room temperature
rac racimic
T kelvin
TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
THF tetrahydrofuran
TLC thin layer chromatography
TS transition state
TsCl para-toluenesulfonyl chloride
Ts para-toluenesulfonyl
TsOH para-toluenesulfonic acid
Ns 2-nitrobenzensulfonyl
M mol∙l-1
mM mmol∙l-1
Chapter 1
1
Chapter 1
Introduction to Allenes
Introduction
2
1.1 General introduction to allene
Allenes are three-carbon functional groups possessing a 1, 2-diene moiety and
they are potential precursors in the synthesis of highly complex and strained target
molecules of biological and industrial importance. Allenes were first synthesized
in 1887,1 However, the structures were confirmed only in 1954.2 Surprisingly,
van’t Hoff, in 1875, was able to predict that unsymmetrically substituted allenes
should be chiral and exist in two enantiomeric forms.3 The initial development of
allene chemistry was severely impeded by limited synthetic methods and also the
false notion that such a 1, 2-diene functional group would be highly unstable.
Since the development of modern analytical technologies, especially IR and
Raman spectroscopy, allene chemistry is drawing more and more attention from
organic chemists. A lot of natural products with interesting biological activities
have been found containing the allene moiety (Scheme 1.1.1).4
Scheme 1.1.1 Natural products containing allene structure
Chapter 1
3
As a class of unique compounds, allenes have two π-orbitals perpendicular to
each other. They have been shown to demonstrate nice reactivities as well as
selectivities, which can usually be tuned by electronic or steric effects or the
nature of the catalysts involved. They are ready to undergo either electrophilic
addition or nucleophilic addition (Scheme 1.1.2). Electrophilic addition may
afford terminal attack and central attack products. The regio- and stereoselectivity
depends on the steric and electronic effects of the substituents on the allene, the
nature of the electrophile and solvent effects. However, nucleophilic addition
usually occurs at the central carbon atom with few exceptions.
Electrophilic addition
Nucleophilic addition
Scheme 1.1.2 Two addition models of allenes
Allenes have also been shown to be great precursors for cycloaddition reactions.5
They are able to afford many complex and interesting molecules via various
cycloaddition reactions, such as [2+2], [3+2] and [4+2].5 Furthermore,
intramolecular type cycloaddition usually affords more complex and interesting
structures which may be synthetically useful in natural product synthesis.
This chapter will review the progress on intramolecular conjugate addition and
intramolecular Diels-Alder cycloaddition of allenes.
1.2 Intramolecular conjugate addition to allenes
Introduction
4
In 1987, the first example of intramolecular addition of alcohols to 1, 2-allenyl
sulfoxides was reported by Parsons et al.6 This offered an efficient route for the
preparation of hydropyrans and spiroketals, which are widely distributed in nature
and are found in molecules possessing a diverse range of biological activity.7
Scheme 1.2.1 Intramolecular Michael addition of alcohol to allene sulphoxide
When alcohol 5 was treated with sodium hydride in dry THF, 5-methyl
-6-(phenylsulfinylmethyl)-3, 4-dihydro-2H-pyran (6) was obtained in 97% yield
(Scheme 1.2.1). Similarly, when alcohol 7 was treated with sodium hydride in dry
THF, nucleophilic Michael addition occurred. After removal of the silyl protecting
group with HF in MeOH, an electrophilic addition was promoted when treating 8
with catalytic amount of CSA in DCM, which afforded the (4, 5)-spiroketal 9
(Scheme 1.2.1). An interesting compound 12 of a bicyclic pyran structure was
also obtained (Scheme 1.2.1). When diol 10, the deprotection product of 7, was
treated with PTSA in benzene, an electrophilic addition took place to produce 11
Chapter 1
5
in 88% yield. After treatment of 11 with sodium hydride in THF, the bicyclic
pyran 12 was obtained in 50% yield. However, the diastereoisomers are
inseparable.
Another investigation on 1, 2-allenyl sulfoxide cyclization was reported in 2001
by Mukai et al (Scheme 1.2.2).8 When alcohol 13 was subjected to the basic
condition tBuOK/tBuOH, nucleophilic addition to allene followed by double bond
migration occurred. Cyclic vinyl sulfoxides of different sizes, five to seven, were
formed in good yields. However, eight member ring product cannot be obtained
from the corresponding allenic sulfoxide.
Scheme 1.2.2 Cyclic vinyl sulfoxide and sulfone formation via intramolecular Michael
addition of alcohol to allenic sulphoxide and allenic sulfone
Allenic sulfonyl derivatives 15 were also successfully transformed into oxacycle
16 of different sizes (Scheme 1.2.2). Five membered to eight membered cyclic
vinyl sulfones were all achieved in good yields. When a substituent group was
attached to the other side of allene, substrates 17 and 18 were also smoothly
cyclized to form the eight membered oxacycles 19 and 20 without double bond
migration.
Introduction
6
Several examples of cyclizations of allenic alcohols to prepare 2,
5-dihydrofurans9 and furans10 have also been reported. Application of this
approach to phosphorus-containing allenes can pave the way to phosphorylated
furans and dihydrofurans. However, relatively little work have been performed on
the synthesis and study of intramolecular cyclization of phosphorylated allenic
carbinols.
In 2001, Brel reported an intramolecular oxa-Michael reaction of allenyl
phosphonates (Scheme 1.2.3).11 The glycols 21a–i were easily prepared from
Scheme 1.2.3 Intramolecular oxa-Michael reaction of allenyl phosphonates
propargylic alcohols and obtained as a mixture of two diastereomers (31P NMR
spectral data, in 1:1–1.4 ratio) resulting from the chirality of the allenic group.
They are stable compounds and can be handled at ambient temperature. However,
under basic conditions, they were cyclized to 2, 3-dihydrofurans via nucleophilic
addition of the terminal alcohol to the central carbon atom of the allene system.
Dihydrofurans 22a-f were obtained in good yields and high diastereoselectivities.
Treated under acidic condition, compounds 22a-f were easily transformed into
alpha-substituted furans 23a-f, which is a system that occurs in a number of
Chapter 1
7
natural products.12
Besides allenyl sulfoxides, allenyl sulfones and allenyl phosphonates, allenoates
and 1, 2-allenic ketones are also good Michael acceptors. In 1994, Nagao found
that treatment of diethyl (acetylamino)ethynylmalonate 24 with 1M KOH
afforded trisubstituted oxazole 26 (Scheme 1.2.4) via a new mode of 5-endo
cyclization of the resultant acetylaminoallenic ester intermediate 25.13 The
intermediate was generated from hydrolysis of the ethyl ester followed by
decarboxylation. Then the amide was enolized under basic condition and attack of
the oxygen to the central carbon of the allenoate afforded the final oxazole 26.
Scheme 1.2.4 Intramolecular Michael addition to allenotes
In the same paper, an electrophilic Michael addition of carbon atom to allenyl
ketone was also reported (Scheme 1.2.5).13 Allenyl aryl ketones 28a-g were easily
prepared via the nucleophilic attack of propargylmagnesium bromide to amides
27a-g. Under the treatment of a Lewis acid BF3-OEt2, 1, 2-allenyl ketones 28
undergoes 5-endo mode cyclization to benzocycloketones 29 and 30. In this
reaction, the presence of electron donating group on the aromatic moiety seems to
be essential. The regioselectivity was controlled by the steric interaction between
the aromatic substituents and the allenic moiety.
Introduction
8
Scheme 1.2.5 Intramolecular Michael addition to allenic ketones, example 1
It was also found that allenyl aryl ketones are good substrates for the
construction of medium sized rings. Compounds 32, 33, 34, containing six, seven,
eight membered rings respectively, were all successfully achieved by tuning the
length of the tether connecting the aryl group and the carbonyl group.14 The
location of the C=C double bond in the products depended on the length of the
tether. This reaction proceeded through a cationic intermediate 35 which was
produced from the interaction of the Lewis acid with the carbonyl group. The
cationic intermediate 35 would attack the aromatic ring as an electrophile to
afford the 5-endo mode cyclization products.
Chapter 1
9
In these reactions, the authors also found that the cyclization mode was
determined by the substitution pattern of the aryl ring.15 For example, if one or
both ortho-positions are occupied by a methoxy group like compound 36, the
spiro-endo mode cyclization product 37 was obtained (Scheme 1.2.6).
Scheme 1.2.6 Intramolecular Michael addition to allenic ketones, example 2
One limitation of the above reaction is that at least two methoxy groups are
required on the phenyl ring. In 1998, Hashimi et al found that when
4-methoxybenzyl-1,2-propadienyl ketone 38 was treated with 1 mol% of
Hg(ClO4)2 in MeCN and water, the spiro-endo cyclization product 39 was formed
in good yields (Scheme 1.2.7).16 They also found that the presence of water was
important. The reason for the high efficiency of Hg(II) was believed to be the high
coordination capability of Hg(II) ion to both the carbonyl oxygen and the terminal
double bond.
Scheme 1.2.7 Intramolecular Michael addition to allenic ketones, example 3
Introduction
10
For the intramolecular Michael reactions of allenes, both oxygen and carbon
atoms have been involved as nucleophiles. However, no examples of aza-Michael
reaction of allenes have been reported. This is probably due to the difficulty in
obtaining such a substrate. Instead, intramolecular conjugate additions of nitrogen
atom to allenes have been well developed. These reactions are usually
electrophilic additions and catalyzed by metals, especially silver ion. Products of
these reactions are usually pyrrolines,17 pyrroles,18 piperidines19 or pyridines,20
which are all biologically important heterocycles (Scheme 1.2.8).
When the amino allenes 42a and 42b were treated with a catalytic amount of
AgNO3 in acetone (25 °C, in the dark), 3-pyrrolines were obtained in good to
excellent yields.21 The reaction readily formed both simple and annulated
3-pyrrolines (43a and 43b). The procedure was very reliable and tolerant to a
wide range of substitution patterns. As expected, the reaction showed little
diastereoselectivity in the reaction of 42b.
Chapter 1
11
Scheme 1.2.8 Intramolecular conjugate addition of nitrogen to allenes
The piperidine structure has also been achieved via intramolecular conjugate
addition of amine to allene.22 When the chiral allene 44 was treated with AgNO3,
the piperidine 45 was obtained in good yield and the natural product
(R)-(-)-Coniine was achieved in two more steps. The axial chirality of allene was
fully transferred to the central chirality of the product.
1.3 Intramolecular Diels-Alder reactions of allenes
Hydrogenation of one carbon-carbon double bond of allene will release an
enthalpy of 41 kcal/mol. This is 12 kcal/mol greater than the enthalpy of
hydrogenation of an ordinary alkene which is 29 kcal/mol. Accumulation of two
carbon-carbon double bonds imparts extra reactivity to the allene, which makes it
a remarkably active component participating in cycloaddition reactions.
Cycloaddition reactions are categorized according to assembly modes, such as
[m+n]-cycloaddition, where the variables m and n simply denote the number of
atoms that each component contributes to the ring construction. Among these
cycloaddition reactions, the [4+2] Diels-Alder reaction is the most important and
useful in natural product synthesis.23 Because it leads to increasing molecular
complexity, especially for intramolecular cyclization. As a result, the
intramolecular Diels-Alder reaction of allene (either as dienophile or part of diene)
has been drawing greater attention from organic chemists.
1.3.1 Intramolecualr Diels-Alder reaction with allenes as dienophiles
Introduction
12
Allenes participate in the Diels-Alder type [4+2]-cycloaddition mostly as an
electron-deficient dienophile. The LUMO energy level of an allene is lowered by
the introduction of an electron-withdrawing unsaturated substituent. The largest
LUMO coefficient is located on the central carbon (C2) and the next largest is on
the substituted carbon (C1). Thus, Diels-Alder reaction of activated allenes takes
place at the internal carbon-carbon double bond of the allene (Figure 1.1).
Figure1.1 Allene models
When the allenic acid 46a and the allenic ester 46b were heated in refluxing
toluene, intramolecular [4+2] cycloaddition between the diene and the internal
double bond of allene ouccurred to give two bicyclic compounds with exo-isomer
predominating (table 1.3.1).24 When a Lewis acid was used as a promoter, the
[4+2] cycloaddition can occur at 0 oC in DCM with an inverse in stereoselectivity
favouring the endo isomer.
R R’ conditions Yield(%) endo:exo
H Me Toluene, 110 oC 87 35:65
Me Et Toluene, 110 oC 83 34:66
Chapter 1
13
H Me Et2AlCl, DCM, 0 oC 65 87:13
Me Et Et2AlCl, DCM, 0 oC 49 87:13
Table 1.3.1 Intramolecular [4+2] cycloaddition of allenic acid and ester
In the approach to synthesize Periplanone B developed by Cauwberghs and De
Clercq in 1988, an allene-furan substrate 49 was synthesized as intramolecular
Diels-Alder reaction substrate (Scheme 1.3.1).25 Upon treated in refluxing
benzene, compound 49 underwent an IMDA reaction to afford the expected exo
products 50 and 51 and an endo product (not identified). The transition states
leading to the IMDA products were proposed and it was found that compound 50
should be more thermally stable than compound 51 because of the equatorial
isopropyl group. Under thermal dynamic control in refluxing mesitylene, the less
stable compound 51 was found to cyclorevert to 50 and the ratio of 50:51 changed
from 5:4 to 2:1. The IMDA product 50 was converted to 52 via a series of
synthetic manipulations, which constituted a formal total synthesis of periplanone
53.
A benzene ring can act as the diene in intramolecular [4+2] cycloaddition with
an activated allene. Aryl allene carboxylates 54 gave tricyclic lactons 55 in
moderate yields in xylene at reflux (Scheme 1.3.2).26 Allenyl amides were also
explored in the intramolecular Diels-Alder reaction. Aromatic rings and furans
were used as the dienes and the allene acted as the dienophile.
Introduction
14
Scheme 1.3.1 Intromolecular Diels-Alder reaction between allenic ketone and furan toward
the synthesis of Periplanone B
Scheme 1.3.2 Intramolecular Diels-Alder reaction between allene and bezene
In Harwood’s investigation towards the synthesis of a morphinan skeleton
(Scheme 1.3.3),27 the allenic amide 56 was designed as an intramolecular
Diels-Alder substrate and it was found that on standing at room temperature, 56
slowly underwent cycloaddition. However, the IMDA reaction was most
conveniently carried out in refluxing toluene, in which the reaction will be
finished in less than 2 h. Analysis of the crude material by NMR showed the
presence of single cycloadduct, the stereochemistry of which was initially
Chapter 1
15
assigned to be the desired diastereoisomer 57 on the basis of coupling constants
and NOE difference studies.
Scheme 1.3.3 Intramolecular Diels-Alder reaction of allenic amide, example 1
When compound 57 was treated with n-BuLi, the amino alcohol 58 was obtained
and its structure was confirmed by X-ray crystallographic analysis, which further
confirmed the structure and stereochemistry of compound 57.
Scheme 1.3.4 Intramolecular Diels-Alder reaction of allenic amide, example 2
In 1982, Himbert developed allenyl carboxanilides 59, of which the aromatic
rings acted as the diene to furnish the tricyclic lactams 60 in moderate to good
yields (Scheme 1.3.4).28 The tendency to form tricyclic lactams 60 was attributed
to the following factors: relatively easy formation of five-membered lactams,
partial activation of the benzene ring by the amino group, increased
energy-content of allene-systems relative to olefins, and comparatively high
rigidity in the allene and carboxamide moieties.
A furyl-substituted sulfonylallene readily undergoes a [4+2] cycloaddition to
give the IMDA adduct (Scheme 1.3.5). When the sulfonylallene 61 was heated in
Introduction
16
refluxing benzene, the intramolecular Diels-Alder reaction proceeded smoothly to
afford compound 62 in high yield.29 The rigid furyl diene was essential for the
Diels-Alder reaction to occur. When the furan ring was changed to an open diene,
under the same condition, compound 63 was transformed into 64 via a [2+2]
cycloaddition.
Scheme 1.3.5 Intramolecular Diels-Alder reaction of sulfonyl allene
Nitrogen containing heterocycles are common and important constituents of a lot
of natural products. Considering the efficiency of IMDA reactions of allene in
constructing complex molecules, allenic amides and allenic carbonates have great
potential in natural product synthesis. In 1986, Kanematsu and co-workers
prepared alkynyl diene carbonate 65 and subjected it to Crabbe’ homologative
allenylation. The allenic diene carbonate 66 was thus formed, and it underwent
intramolecular Diels-Alder reaction spontaneously to afford the tetrahydroindole
67. Upon dehydrogenation with DDQ, 67 was oxidized to indole 68. Differently
substituted indoles can be synthesized via this sequence.30 The natural product
hippadine 69 was successfully synthesized (Scheme 1.3.6).31
Chapter 1
17
Scheme 1.3.6 Total synthesis of hippadine via intramolecular Diels-Alder reaction of allenic
carbonate
Alkoxyallene is another type of allene that has been extensively studied. They
are usually generated from base-catalyzed isomerisation of propargyl ether to
allenyl ether. This kind of substrates usually generates furan rings after
cycloaddition. Treatment of the propargyl ether 70 with tBuOK in refluxing
tBuOH caused an intramolecular Diels-Alder reaction of the resulted intermediate
allenyl ether 71 to afford the tricyclic compounds 72, which isomerized to 73
spontaneously (Eq 1, Scheme 1.3.7).32 An asymmetric synthesis of benzofuran
lactone 74 was achieved by an analogous procedure (Eq 2,Scheme 1.3.7).33
Eq 1
Eq 2
Introduction
18
Scheme 1.3.7 Intramolecular Diels-Alder reaction of allenyl ether
An example of natural product synthesis involving allenyl ethers was reported by
Kanematsu and Soejims in 1991(Scheme 1.3.8).34 They managed to synthesize
euryfuran 80, which is a natural product possessing a synthetically challenging
structure of 3,4-disubstituted furan ring, via a furan ring transfer reaction with the
intramolecular Diels-Alder reaction of allenyl ether as the key step. Compound 75,
when heated with potassium tert-butoxide, afforded the isomerisation product 76.
This allene underwent a spontaneous intramolecular Diels-Alder reaction in
tert-butanol at reflux to give compound 77. Deprotonation of α position of the
furan oxygen initiated a ring opening of the oxybridge in 77 to give the furan
transfer product 78. Repeating this process via the intermediate 79 led to the final
target euryfuran 80.
Scheme 1.3.8 Euryfuran synthesis via IMDA reaction of alkoxyallene
An asymmetric synthesis of the intermediate 84 of forskolin by Nagashima in
1990 also employed intramolecular Diels-Alder reaction of allenyl ether (Scheme
1.3.9).35 Treatment of propargyl ether 81 with potassium tert-butoxide in refluxing
Chapter 1
19
tert-butanol affords 83 as a single stereoisomer via the allenyl ether intermediate
82. Further transformation of compound 83 led to the intermediate 84, which was
readily transformed to forskolin.
Scheme 1.3.9 Total synthesis of Forskoin via intramolecular Diels-Alder reaction of allenyl
ether
As a dienophile, an allene is able to cyclise not only with carbon dienes but also
heterodienes. Both intermolecular36 and intramolecular hetero-Diels-Alder
reactions of allenes have been developed.
An example of intramolecular hetero-Diels-Alder reaction of allene was reported
by Boger in 1991during their work toward the total synthesis of trikentrin 87
(Scheme 1.3.10).37 Treatment of 85 with acetic anhydride at 160 oC provided
indole derivatives via a cascade reaction, N-acylation followed by [4+2]
cycloaddition cascade followed by release of N2. Finally, deacetylation of 86 led
to the natural products, cis and trans (±) trikentrins 87.
Introduction
20
Scheme 1.3.10 Total synthesis of tirkentrins via Hetero-Diels-Alder reaction of allene
1.3.2 Intramolecular Diels-Alder reaction with allenes as dienes
Vinylallenes are commonly used as the diene component in Diels-Alder
reactions, and thus they are ubiquitously used in natural product synthesis,
especially their intramolecular Diels-Alder reaction. The natural compound 90
Esperamicin A has been found to show great DNA binding and damaging
properties which are traced to the bicyclic core structure equipped with an
enediyne bridge. Vinylallene 88 was proposed by Schreiber and Kiessling to be a
biogenetic intermediate for the synthesis of the skeleton of esperamicin A
(Scheme 1.3.11).38 Although the proposed transformation (88–>89) was not really
tested, the synthetic approach to esperamicin A was modeled in which an
intramolecular Diels-Alder reaction was employed to synthesize the highly
unsaturated bicyclic core of 90.
Scheme 1.3.11 Proposal of the intramolecular-Diels-Alder reaction of vinylallene toward the
total synthesis of esperamicin A
Siloxyvinylallenes, which have been prepared by Reich et al in two ways, have
proved to be good candidates for Diels-Alder reaction in which the
siloxyvinylallenes act as the diene components.39 They are readily prepared by
addition of vinyllithium to α-chloroacylsilane followed by a Brook rearrangement.
Chapter 1
21
The vinylallene 91 was reported to be unstable and was subjected to a Lewis acid
directly after preparation. It underwent intramolecular Diels-Alder reaction to
afford the adduct 92 in 51% yield (Scheme 1.3.12). Both Lewis acid catalysis and
thermal conditions proved to be successful for the Diels-Alder reaction. The
cycloadduct 92 was subsequently converted to the natural product 93.
Scheme 1.3.12 Intramolecular Diels-Alder reaction of vinylallene toward the total synthesis
of cis-Dehydrofukinone
(+)-Compactin 97 was synthesized by Keck and Kachensky via an
intramolecular Diels-Alder reaction which used a vinylallene as the diene
(Scheme 1.3.13).40 This work was done at a time when there was little literature
precedent on the use of vinylallenes as dienes. Model study figured that the
transition state for the Diels-Alder reaction of 94 would adopt a conformation to
give only the exo cycloaddition product. Thus, the intramolecular Diels-Alder
reaction perfectly constructed the bottom bicyclic structure. When compound 94
was heated at 140 oC for one hour in toluene in the presence of BHT, it afforded
the intermediate 95, which was immediately subjected to L-selectride to reduce
the ketone to alcohol to avoid the formation of a conjugated enone. The resulting
alcohol 96 was obtained as a 1:1 mixture of diastereomers in 84% yield. Although
the two diastereomers could be separated, their stereochemistry was unknown at
this point and both diastereomers were not separated until the end of the total
Introduction
22
synthesis of (+)-compactin. One of these compounds matched the spectral data of
97 exactly.
Scheme 1.3.13 IMDA reaction of vinylallene toward the total synthesis of (+)-Compactin
1.4 Summary
As an efficient and powerful tool for the construction of complex structures,
especially regarding natural product synthesis, intramolecular cyclization
reactions have been attracting more and more attention. As a class of reactive and
interesting compounds, allenes have been well employed in different kinds of
cyclizations. Excellent reactivity and selectivity have been achieved in these
reactions. Most of the enantioselective examples are based on chiral auxiliaries or
chiral starting materials. Some are developed under transition metal catalysis
using a chiral ligand. However, there are few examples of organocatalyst
catalyzed enantioselective intramolecular cyclization of allenes until now. The use
of chiral allenes in intramolecular cyclizations is rarely reported as well. Thus
Chapter 1
23
catalytic enantioselective formation of allene towards natural product synthesis is
quite attractive. The following chapters will describe our recent work on chiral
allene formation followed by intramolecular Michael reaction and intramolecular
Diels-Alder reaction. The first catalytic enantioselective total synthesis of
α–yohimbine based on the intramolecualr Diels-Alder reaction will also be
decribed.
Introduction
24
References:
(1) Burton, B. S.; Pechman, H. V. Chem. Ber. 1887, 20, 145.
(2) Tius, M. A.; Cullingham, J. M.; Ali, S. J. Chem.Soc., Chem. Commun. 1989, 13, 867.
(3) van’t Hoff, J. H. La Chimie dans I’Espace; Bazendijk: Rotterdam, 1875, 29.
(4) Hoffman-Röder, A.; Krause, N. Angew. Chem. Int. Ed. 2004, 43, 1196.
(5) Ma, S. M. Chem. Rev. 2005,105, 2829.
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1718.
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M.; Voie E. J. L.; Branfman A. R.; Fei B. Y.; Brigh,W. M.; Bryan R. F. J. Am. Chem. SOC.,
1977, 99, 3199. c) Kato Y.; Fusetani N.; Matsunaga S.; Hashimoto K.; Fugita S.; Furiya T. J.
Am. Chem. SOC., 1986, 108, 2780. d) Baker R.; Herbert R.; House P. E.; Jones O. T.; Francke
W.; Reith W. J. Chem. Soc., Chem. Commun., 1980, 2, 52. e) Tachibana K.; Scheuer P. J.;
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Soc., 1981, 103, 2469
(8) Mukai C.; Yamashita H; Hanaoka M. Org. Lett. 2001, 3, 3385.
(9) (a) Claesson, A.; Olsson, L.-I. In The Chemistry of Allenes, Vol. 2; Landor, S. R. Ed.;
Academic Press: London, 1982, 369. (b) Nikam, S. S.; Chu, K.-H.; Wang, K. K. J. Org.Chem.
1986, 51, 745. (c) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387. (d) Marshall, J. A.; Yu , B.-C.
J. Org. Chem. 1994, 59, 324. (e) Hormuth, S.; Reissig, H.-U. J. Org. Chem. 1994, 59, 67.
(10) (a) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5967. (b) Marshall, J. A.; Bartley, G.
S.; Wallace, E. M. J.Org. Chem. 1996, 61, 5729.
(11) Brel V. K. Synthesis, 2001, 10, 1539.
(12) Marshall, J. A.; Bart ley, G. S.; Wallace, E. M. J.Org. Chem. 1996, 61, 5729.
(13) Nagao, Y.; Lee, W.-S.; Kim, L. Chem. Lett. 1994, 23, 389.
(14) Nagao, Y.; Lee, W.-S.; Komaki, Y.; Sano, S.; Shiro, M. Chem. Lett. 1994, 23, 597.
(15) Nagao, Y.; Lee, W.-S.; Jeong, I.-Y.; Shiro, M. Tetrahedron Lett.1995, 36, 2799.
(16) Hashimi, A. S. K.; Schwarz, L.; Bolte, M. Tetrahedron Lett.1998, 39, 8969.
Chapter 1
25
(17) Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995, 36,
1401.
(18) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621.
(19) Hall, H.K. J. Am. Chem. Soc. 1957, 79, 5441.
(20) Pearson, R. G.; Williams, F. V. J. Am. Chem. Soc, 1953, 75, 3073.
(21) Dieter R. K.; Yu H. Y. Org. Lett. 2001, 3, 3385.
(22) Lathbury D.; Gallagher T. J. Chem.Soc., Chem. Commun. 1986, 2, 114.
(23) Corey E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.
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1449.
(25) Cauwberghs S. G.; Clercq P. J. D. Tetrahedron Lett. 1988, 29, 6501.
(26) Himbert, G.; Fink, D. Tetrahedron Lett. 1985, 26, 4363.
(27) Finch H.; Harwood L. M.; Robertson G. M.; Sewellb R. C. Tetrahedron Lett. 1989, 30, 2585.
(28) Himbert, G.; Henn, L. Angew. Chem. Int. Ed. 1982, 21, 620.
(29) Padwa, A.; Filipkowski, M. A.; Meske, M.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1993,
115, 3776.
(30) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1986, 27, 1837.
(31) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895.
(32) Hayakawa, K.; Yodo, M.; Ohsuki, S.; Kanematsu, K. J. Am. Chem.Soc. 1984, 106, 6735.
(33) Hayakawa, K.; Nagatsugi, F.; Kanematsu, K. J. Org. Chem. 1988, 53, 860.
(34) Kanematsu, K.; Soejima, S. Heterocycles, 1991, 32, 1483.
(35) a)Nagashima, S.; Kanematsu, K. Tetrahedron Asymm. 1990, 1, 743. b) Zieg ler, F. E.; Jaynes,
N. H.; Saindane, M. T. J. Am. Chem. Soc. 1987, 109, 8115.
(36) a) Tamura, Y.; Tsugoshi, T.; Nakajima, Y.; Kita, Y. Synthesis 1984, 11, 930. b) Bos, H. J.
T.; Slagt, C.; Boleij, J. S. M. Recl. Trav. Chim. Pays-Bas. 1970, 89, 1170.
(37) Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230.
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Introduction
26
(40) Keck, G. E.; Kachensky, D. F.; J. Org. Chem. 1986, 51, 2487.
Chapter 2
27
Chapter 2
Brønsted-Base Catalyzed Tandem
Isomerization-aza-Michael Reactions
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
28
2.1 Different approaches for the preparation of piperidines and
lactams
2.1.1 Piperidines and Lactams in natural products
Azacycles are important heterocyclic systems which are commonly found in
natural products and valuable fine chemicals.1 In particular, functionalized
piperidines and pyridines are present in a variety of pharmacologically active
natural products including most of the alkaloids (Figure 2.1).2 The naturally
occurring cinchonine alkaloids, which are known for their highly enantioselective
catalytic activity in organic synthesis, have attracted increasing interest. These
piperidine containing natural products are synthetically challenging, because they
usually have several asymmetric centers present. Meanwhile, the most important
step in the synthesis of these natural products is usually the ring-closing step to
obtain the piperidine rings. A lot of attentions have been paid to the development
of piperidine formation methods resulting in great advancements being made in
this field.
Figure 2.1 Piperidine or pyridine containing natural products
2.1.2 Synthetic methods for piperidines and lactams
In 1971, Edwarlde Ete reported an efficient synthesis of 2-alkylidenepiperidines
Chapter 2
29
(Scheme 2.1.1).2 Compound 102, the open chain form of compound 103, was
prepared from 101 via enzymatic transamination. Asymmetric hydrogenation of
compound 103 led to the natural alkaloid (+)-coniine 98. Hydroxylation of
compound 103 led to hydroxyl imine 104, which was hydrogenated to afford the
natural alkaloid 105 conhydrine.
Scheme 2.1.1 Piperidine formation via amine-ketone condensation
Another method to prepare piperidine was developed in 2000 by Kunio
Ogasawara (Scheme 2.1.2).3 This method employed ring closing metathesis (RCM)
to form the heterocycle. When the N-protected secondary amine 106 was
subjected to ring closing metathesis condition and then hydrogenation, the
N-protected piperidine 107 was achieved in 89% yield over two steps, which is
part of the natural product 100 (+)-febrifugine.
Scheme 2.1.2 Piperidine formation via ring closing metathesis
Intramolecular electrophilic addition of an amine to allene is another way to
construct piperidine rings. Cha and co-workers reported one example in 1999
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
30
(Scheme 2.1.3).4 When the diastereomerically pure aminoallene 108 was
subjected to a silver salt, silver nitrate, heterocyclization occurred via two
transition states 109 and 110. The desired products quinolizidine 111 and 112,
both possessing the desired E double bond geometry, were achieved in a ratio of
7:1. From the proposed transition states, we can see that 109 is more favored than
110 due to the steric repulsion between the silyl ether group and the allene tail.
Compound 111 was successfully converted to the target natural products
clavepictine A (113) and B (114).
Scheme 2.1.3 Piperidine formation via intramolecular electrophilic addition of amine to
allene
Trost B. M. and co-workers developed another route to synthesize piperidine in
2000 (Scheme 2.1.4).5 A ruthenium catalyst (10%) and a co-catalyst CH3AlCl2
were used. When allenyl amine 115 was subjected to a methyl vinyl ketone in the
presence of ruthenium and aluminum catalyst, compound 117 was achieved in
Chapter 2
31
67% yield. It was found that both the Ru catalyst and the CH3AlCl2 co-catalyst are
essential for the formation of the product. To achieve better yield, quenching with
pyrrolidine was required, which is believed to dissociate the coordination between
the product and the Ru catalyst. Both piperidines and pyrrolidines have been
achieved using this method.
Scheme 2.1.4 Piperidine formation via ruthenium catalysis
In the same year, Lee E. and co-workers developed a radical process to
synthesize such cyclic amines (Scheme 2.1.5).6 A protected secondary amine 118
was chosen as the substrate for the radical cyclization. The radical precursor can
be alkyl bromide or alkyl selenium. When compound 118 was subjected to the
radical initiator AIBN and the hydride reductant, a mixture of diastereoisomers
119 and 120 was achieved. The reaction tolerates both alkyl and aryl R
substituents. Pyrrolidines can be formed as well. Compound 121 (-)-indolizidine
223AB was synthesized employing two consecutive radical cyclization reactions
of aminoacrylate substrates.
Conversely, the cyclization of allenyl amides can occur under oxidative
condition as developed in 2000 by Jonasson and co-workers (Scheme 2.1.6).7
When the allenyl amide 122 was subjected to palladium catalyst and LiBr, an
intermediate of π-allyl palladium complex 124 was formed. After an
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
32
intramolecular nucleophilic addition of the nitrogen to the π-allyl palladium
system, the pyrrolidine product 123 was formed and Pd(II) was reduced to Pd(0),
which was reoxidized by copper acetate.
Scheme 2.1.5 Piperidine formation via radical cyclization
Scheme 2.1.6 Pyrrolidine formation via oxidative cyclization
In fact, this transformation can be achieved via cobalt mediated
acylation-cyclization of allenes as well (Scheme 2.1.7).8 When compound 125 was
subjected to the acetyltetracarbonylcobalt and the base diisopropylethylamine, the
five membered ring product 126 can be achieved via the intermediate 127.
Chapter 2
33
Scheme 2.1.7 Pyrrolidine formation via cobalt mediated cyclization
Although first synthesized in 1907 by Staudinger, β- lactams were recognized in
organic chemistry only until Fleming’s discovery of penicillin in 1929.9 The
resulting recognition of the β- lactam moiety as the key pharmacophoric
component of the penam antibiotics initiated a flurry of synthetic activity.10 Today,
β-lactam rings are found in thousands of chiral compounds. Due to their high
efficacy and safe toxicological profiles, penicillin and its derivatives are still the
most commonly used antibiotics. The asymmetric synthesis of β- lactams usually
employs a [2+2] cycloaddition10 and one example is shown below (Scheme 2.1.8).
Scheme 2.1.8 β–lactam synthesis via [2+2]-cycloaddition
When an acid chloride 128 and an imine 129 were treated with the combination
of a cinchona alkaloid derivative such as benzoylquinine (BQ) and a
non-nucleophilic amine base, β- lactam products 130 were achieved in very high
ee and dr. Varieties of acid chlorides were tolerated in this process.
[2+2]-cyclization can lead to β–lactam only, 5-membered and 6-membered
lactams are formed via different methods.
In 2007, Che reported an intramolecular addition of β-ketoamide to unactivated
alkenes under gold catalysis, which led to the formation of 5-membered lactams
(Scheme 2.1.9).11 The reaction proceeded in toluene under mild condition. When
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
34
the β-ketoamide 131 was treated with the combination of a gold salt and a silver
salt, the alkene was activated by the gold and attacked by the enolate leading to
the formation of a 5-membered lactam 132.
Scheme 2.1.9 5-membered lactam formation via gold catalys is
Wei Ying and co-workers developed a convenient method for the synthesis of
6-membered lactams in 2010 (Scheme 2.1.10).12 Deprotonation of the starting
material 134 with a strong base NaH results in an aza-Michael reaction followed
by an electrophilic ring opening of the cyclopropane. After a double bond shift,
carbon anion 138 forms and condenses with an aldehyde to give the final product
135.
Scheme 2.1.10 6-membered lactam formation via aza-oxy-carbanion relay
2.1.3 Summary
Chapter 2
35
In summary, a lot of natural products and synthetic compounds with medical
potential are found containing heterocycles like piperidines and lactams. A great
number of methods have been developed towards the formation of such systems.
For the piperidine formation, either metal or harsh conditions were required. A
mild organo-catalytic method will thus be much more attractive. Furthermore, the
organo-catalytic enantioselective synthesis of six membered lactams is not
available. We are pleased to report our work on piperidine and axial chiral lactam
formation via organo-catalysis.
2.2 Tandem isomerisation-aza-Michael reaction of alkynylamines
and alkynylamides
2.2.1 Synthesis of alkynyl amines and chiral bicyclic guanidine catalyst.
Alkynyl amines 141a-141c were synthesized as outlined in scheme 2.2.1.
Standard amide formation protocol between different anilines and pent-4-ynoic
acid afforded different alkynyl amides 139 in around 70% yield, which were then
Scheme 2.2.1 Alkynyl amine synthesis
reduced to alkynyl amines 140 with LiAlH4. After a well-established coupling
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
36
between the alkyne moiety and diazo compounds,13 the desired compounds
141a-141c were obtained.
Treatment of alkynyl amines 141a-c with a brønsted base TBD formed the
products 142a-c in good yields (Scheme 2.2.2). Slightly long reaction time (24
hours) was required to ensure that the reaction proceeded to completion as the
products 142a-c were non-separable from their corresponding alkynyl-amines
141a-c.
Scheme 2.2.2 Brønsted-base catalyzed tandem isomerization-aza-Michael reaction of
alkynyl-amines 141. a Isolated yield
Since the reaction is base catalyzed and the starting material itself is a base, we
doubt whether self-catalyzed reaction is possible. For better understanding of
Scheme 2.2.3 Proposed mechanism for tandem isomerization-aza-Michael reaction of 141
the reaction, we subjected alkynyl-amine 141 to the same reaction conditions for
Chapter 2
37
one day without the presence of the base, TBD. The starting material was fully
recovered and no other product was obtained. Hence, the self-catalyzed reaction
mechanism was excluded. Therefore, we believe that the tandem isomerization-
aza-Michael reaction goes through the proposed pathway in Scheme 2.2.3.
Since we have been interested in the brønsted base, bicyclic chiral guanidine 149,
catalyzed asymmetric transformations, we expected that alkynyl amine 141c may
afford 142c with axial chirality when the reaction was catalyzed by our chiral
guanidine. The chirality was generated from the restricted rotation of the C-N
bond connecting the piperidine ring and the phenyl ring.
The chiral bicyclic guanidine was prepared by the well-established procedure
published by our lab.14 N-Tosyl aziridine 146 was readily prepared from its
Scheme 2.2.4 Synthesis of the chiral bicyclic guanidine 149
corresponding commercially available α-amino alcohol 145 via a two-step process.
Triamine unit 147 was easily obtained by treating N-tosyl aziridine 146 in MeOH
saturated with NH3 gas in a sealed vessel. After removing the solvent, the residue
was dissolved in MeCN and refluxed for 3 days. The subsequent removal of tosyl
groups was conducted in liquid ammonia in the presence of sodium. After the
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
38
final cyclization step, the triamine intermediate was cyclized to give the chiral
bicyclic guanidine149 and basified with 5 M KOH aqueous solution or solid
K2CO3 (Scheme 2.2.4).
The alkynyl amine 141c was treated with bicyclic guanidine 149 in different
solvents and the results are summarized in Table 2.1. The reaction proceeded
fastest in DCM and reached completion in 24 hous, however, no enantioselectivity
was observed (Entry 1). Toluene gave 0% ee as well and a non-complete reaction
(Entry 2). Pleasingly, hexane gave 7 % ee and the best ee achieved was 27% in
THF. However, the starting material cannot be completely consumed in hexane
and THF even after 3 days. Since the starting material and the product cannot be
separated and the reaction cannot proceed to completion, no further study was
conducted.
Table 2.1 Solvent effect on asymmetric tandem isomerization-aza-Michael reaction of
alkynyl amine 141c
entry solvent time conversion (%)a ee(%)
b
1 DCM 24 h 100 0
2 Toluene 24 h 70 0
3 Hexane 32 h 50 7
4 THF 3 d 60 27
adetermined by
1H NMR
b determined by HPLC
2.2.2 Bicyclic guanidine catalyzed enantioselective tandem isomerisation-
aza-Michael reaction of alkynyl amides to the synthesis of lactams.
Chapter 2
39
Based on our discovery of the tandem isomerization-aza-Michael reaction,
especially the asymmetric reaction performed on alkynyl amine141C, We were
keen to achieve a high enantioselectivity by tuning the substrates. We have
demonstrated that 3-Alkynoates bearing a tButyl ester will afford highly
enantioselective allenes when treated with bicyclic guanidine. It is believed that
the axial chirality of the piperidine 142c was transferred from the chiral allene
which was generated in situ. The poor ee of 142c is probably due to the low
energy level that is required for the rotation of the C-N bond. We expected that the
energy level could be increased by adding hindering substituents. Thus we
synthesized the alkynyl amide 150 from 139b by alkyne and diazo compound
coupling (Scheme 2.2.5). We expected that the extra carbonyl group would help to
restrict the rotation.
Scheme 2.2.5 Synthesis of alkynyl amide 150
The alkynyl amide 150 was then treated with bicyclic guanidine 149 in different
solvents. Two cyclized products were detected, which were assigned as 151 and
152 by 1H NMR. The ratio between 151 and 152 on TLC was about 4:1.
Subsequently, by passing the reaction mixture through a silica gel column slowly,
cyclic compound 151 can be fully converted to lactam 152.
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
40
Optimization results are summarized in Table 2.2. Similarly, the fastest reaction
was observed in DCM, full conversion was observed after stirring at rt for 4 days
as indicated by TLC analysis. However, only moderate yield was obtained after
separated by column chromatography with 60% ee (Entry 1). The best
enantioselectivity was obtained in ether type solvents (Entry 3 and 5). Different
ethers were tested as well but THF still gave the best result (Entry 5, 8 and 9).
With THF as solvent, different concentrations were tested and it was found that
dilution led to very slow reaction time (Entry 6) while concentrated reaction
afforded much lower ee (Entry 7).
Table 2.2 Bicyclic guanidine catalyzed enantioselective tandem isomerization-aza-Michael
Reaction
entry solevnt concentration(M) time(d) yield(%)a ee(%)
b
1 DCM 0.1 4 68 60
2 Toluene 0.1 3 60 81
3 Ether 0.1 2 75 85
4 Hexane 0.1 2 74 65
5 THF 0.1 3 67 89
6 THF 0.01 6 <10 nd
7 THF 0.5 2 60 73
Chapter 2
41
8 TBDME 0.1 4 70 72
9 Phenylmethyl ether 0.1 4 60 67
a isolated yield
b determined by HPLC
Having achieved the axial chiral lactam 152 with high enantiomeric purity, we
encountered some difficulty with the establishment of its absolute configuration.
Difficulty in obtaining single crystals for 152, together with the lack of heavy
atoms in 152 impeded absolute configuration determination via single crystal
X-ray diffraction.15 As a result, we had to derive the absolute configuration via
theoretical approaches. Reliable specific optical rotation can be calculated from
density functional theory (DFT) by considering thermally accessible
conformations and with judicious choice of basis set and functional coupled with
solvation model to account for solvent effects.16 The specific optical rotation for
152-Sa configuration calculated is -57.8, which agrees well with the -64.1
obtained experimentally.
In addition, we have investigated the mechanism via DFT calculation. The
enantioselective step is postulated to be the intramolecular Michael reaction. The
activation barriers for the relevant pathways are given in figure 2.2. Based on this
mechanism, the formation of Sa product is predicted to be more favourable than
the Ra product. The Gibbs free energy of activation difference (∆G‡) of the
pathways leading to the Sa lactam is 3.4 kcal/mol lower in Gibb free energy than
the pathway leading to the Ra lactam, which is consistent with the high ee
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
42
observed experimentally.
Figure 2.2: Enantioselectivity step (Gibbs free energy difference given in
kcal/mol)
As an interesting axial chiral lactam, compound 152 is also a potentially useful
intermediate in organic synthesis. It will be extremely interesting if different ring
sized lactams, especially larger rings, can be achieved with similar axial chirality.
Different alkynyl amides and carbonates that might lead to larger rings were
synthesized as outlined in Scheme 2.2.6.
Chapter 2
43
eq 1
eq 2
eq 3
eq 4
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
44
eq 5
Scheme 2.2.6 Synthetic schemes to different alkynyl amides and carbonates
However, efforts to prepare atropisomeric lactams with different ring sizes were
not too successful. Upon exposure to bicyclic guanidine 149, alkynes 153-157
were unable to complete the intramolecular Michael reactions and provided the
corresponding enantio-enriched allenes, whose absolute configurations were
determined by the Lowe-Brewster rule (Scheme 2.2.7) .17
Scheme 2.2.7 Enantioselective isomerization of alkynes to allenes
Chapter 2
45
The observation of allenes when 153, 154, 155, 156 and 157 were used as
reactants suggests that the formation of 152 from 150 proceeds via an allene
intermediate.
2.3 Summary
In conclusion, we have found that a Brønsted-base catalyzed tandem
isomerization-aza-Michael reaction can be used to form useful heterocycles under
mild conditions. This efficient method was applied to the synthesis of
functionalized piperidine with good yields. Enantioselective tandem
isomerization-aza-Michael reaction of alkynyl-amide led to an axially chiral
lactam of high enantioselectivity when a chiral guanidine was used as the catalyst.
Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions
46
References:
1. (a) Progress in Heterocyclic Chemistry; Suschitzky, H.; Scriven, E. F. V. Eds.; Pergamon:
Amsterdam, 1998; Vol. 5–7. For reviews on azacycles, see: (e) Boger, D. L.; Boyce, C. W.;
Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997, 97, 787. (f) Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 48, 15031. (g) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J.
2009, 15, 1300.
2. Leete, E. Acc. Chem. Res., 1971, 4, 100.
3. Taniguchi T.; Ogasawara, K. Org. Lett. 2000, 2, 3193.
4. Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.
5. Trost B. M.; Pinkerton A. B.; Kremzow D. J. Am. Chem. Soc. 2000, 122, 12007.
6. Lee E.; Jeong E. J.; Min S.; Hong S. k.; Lim J.; Kim S. K.; Kim H. J.; Choi B. G.; Koo K. C.
Org. Lett. 2000, 2, 2169.
7. Jonasson, C.; Karstens, W. F. J.; Hiemstra, H.; Bäckvall, J.-E. Tetrahedron Lett. 2000, 41,
1619.
8. Bates, R. W.; Rama-Devi, T.; Ko, H.-H. Tetrahedron 1995, 51, 12939.
9. Morin, R. B.; Gorman, M., Eds. Chemistry and Biology of â-Lactam Antibiotics, Academic
Press: New York, 1982, Vols. 1-3.
10. For a review on lactam synthesis see: France S.; Weatherwax A.; Taggi A. E.; Lectka T. Acc.
Chem. Res. 2004, 37, 592.
11. Zhou C.-Y.; Che C.-M. J. Am. Chem. Soc. 2007, 129, 5828.
12. Liang F.; Lin S.; Wei Y. J. Am. Chem. Soc. 2011, 133, 1781.
13. Suárez, A.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 3580.
14. Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett.
2006, 47, 1007.
15. Flack, H. D.; Bernardinelli, G. Chirality, 2008, 20, 681.
16. Kwit, M.; Rozwadowska, M. D.; Gawroński, J.; Grajewska, A. J. Org. Chem. 2009, 74, 8051.
17. a) Lowe, G. Chem. Commun. 1965, 17, 411; b) Brewster, J. H. Top. Stereochem. 1967, 2, 1.
Chapter 3
47
Chapter 3
Total Synthesis of alpha-Yohimbine via
Intramolecular-Diels-Alder Reaction
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
48
3.1 Introduction to the Synthesis of alpha-Yohimbine
Alpha-Yohimbine, also known as isoyohimbine, rauwolscine, and orynanthidine,
is an alkaloid found in various species within the genera Rauwolfia and
Pausinystalia (formerly known as Corynanthe).1 It is a stereoisomer of yohimbine.
Alpha-Yohimbine is a central nervous system stimulant, a local anesthetic and a
vague aphrodisiac.1 It acts predominantly as a α2-adrenergic receptor antagonist.2 It
has also been shown to function as a 5-HT1A receptor partial agonist and 5-HT2A,
5-HT2B receptor antagonist.3 Due to its important pharmacological effect and
synthetically challenging structure, chemists have paid considerable attention to the
synthesis of alpha-yohimbine. However, only limited numbers of successful
synthetic routes have been developed until now. There is no enantioselective total
synthesis available before this report.
During nineteen seventies, Tökel and co-workers did a lot of study on the
synthesis of yohimbines.4 During their work toward the total synthesis of
alloyohimbines, they found that alpha-yohimbine 170 was formed via
epimerization at C3 (Scheme 3.1.1).4c The synthesis started with the cyclization of
N-formyl tryptamine 160 using POCl3 under thermal condition, which delivered
compound 161 containing the A, B, C rings of the pentacyclic structure in
yohimbine bases. A Mannich reaction followed by an aza-Michael reaction
between 161 and 162 in refluxing EtOH formed the D ring with the necessary
Chapter 3
49
substituents for further manipulation, affording the compound 163. Upon
condensation with diethyl cyanomethylphosphonate 164, a cyano group was
introduced to form the nitrile ester 165. Pd/C catalyzed hydrogenation afforded
two products 166a and 166b. The major product 166a is a trans isomer which was
transformed into yohimbine. The minor product 166b is a cis isomer which is a
potential candidate for allo-type yohimbines. Treatment of 166b with a strong
base, potassium tert-butyloxide in DMSO, afforded the pentacyclic compound
167 which contained nitrile and ketone moieties. Reduction of the ketone using
sodium boron hydride afforded two alcohols 168a and 168b in a ratio of 2:3.
Scheme 3.1.1 Total synthesis of alpha-yohimbine, route 1
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
50
As a final step in the synthesis, the nitrile group was converted to methyl ester by
first converting the nitrile in 168b to acid amide using hydrogen peroxide in
alkaline methanol. Subsequent refluxing with aqueous HCl afforded the free acid,
which was converted to methyl ester using diazomethane to afford the
3-epi-alpha-yohimbine 169 and certain amount of alpha-yohimbine 170. The
alpha-yohimbine was believed to have formed via the epimerization at C3 during
hydrolysis with aqueous HCl. Since the alpha-yohimbine was formed from a
minor isomer of the hydrogenation step, the yield was extremely low.
Following the work above, the same group developed a new route that gave
better yield for the synthesis of alloyohimbines (Scheme 3.1.2).4d The readily
available compound 163 was condensed with methyl cyanoacetate 171 in
triethylammonium acetate in the presence of phosphrous pentaoxide to form
compound 172. It was found that an epimerization at C20 occurred. Reduction
with sodium boron hydride in MeOH at 0 oC afforded the compound 173, which
was then converted to diacid 174 by hydrolysis and acidification. Decarboxylation
via boiling in DMF and esterification with methanolic HCl afforded the diester
175. The condensation between the two ester groups required highly dry condition
and as expected yielded 176 (36%) and 177 (30%) in similar yields. Reduction of
the ketone 177 with sodium boron hydride afforded a mixture of alloyohimbines,
but alpha-yohimbine 170 was obtained in only 6% yield.
Although route 2 is optimized and obtained much better yield as compared to
Chapter 3
51
Scheme 3.1.2 Total synthesis of alpha-yohimbine, route 2
route 1, alpha-yohimbine is still produced as a minor product and poor selectivity
is still obtained in several steps. These reasons result in the extremely low overall
yield for alpha-yohimbine.
Another contribution was made by Wenkert E. et al in 1979 (Scheme 3.1.3).5
They constructed a structure of indoloquinolizidine with necessary functional
groups in a quite efficient way. Condensation between nicotinaldehyde and
malonic acid under piperidine catalysis afforded an unsaturated acid which was
transformed into ester 180 with acidic MeOH. Alkylation of the ester with
tryptophyl bromide yielded the desired pyridinium salt 181, which was attacked
by dimethyl sodiomalonate at the γ-position to afford the tetracycle 182. Since
only two ester groups were required, iodide- induced demethylation was
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
52
Scheme 3.1.3 Total synthesis of alpha-yohimbine, route 3
performed on 182, and the diester 183 was obtained in good yield. Reduction of
the diene moiety was done with sodium boron hydride which afforded a mixture
of 184, 185 and 186. Hydrogenation converted 184 to 185 and 186 in almost the
same yields. Direct hydrogenation of 183 would similarly lead to formation of
185 and 186, however, the yield for 186 is considerably low. Then compound 186
was epimerized via mercury acetate oxidation and NaBH4 reduction to 175, which
had been transformed to alpha-yohimbine in Scheme 3.1.2.
Until date, Martin S. F. and coworkers developed the most efficient method
toward the synthesis of alpha-yohimbine.6 They employed an intramolecular-
Diels-Alder (IMDA) reaction as the key step to construct the D, E rings and ring
Chapter 3
53
C was formed via mercury catalyzed oxidative cyclization.
Scheme 3.1.4 Total synthesis of alpha-yohimbine, route 4
As shown in Scheme 3.1.4, the amide 192 required for intramolecular-Diels-
Alder reaction was conveniently prepared in six direct steps. Subsequent
thermolysis of 192 in xylene at reflux proceeded smoothly to afford the
cycloadduct 193. The next stage is to set the functionality on the ring E.
Regioselective epoxidation and subsequent epoxide opening installed the required
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
54
alcohol that was present in the final product (193-195). The MOM protected
alcohol was then deprotected and oxidized. The following esterification afforded
the methyl ester group that was present in alpha-yohimbine (196-197). Under H2
in the presence of Pd(OH)2, the benzyl protecting was removed together with the
side chain of ester which was used as a nucleophile to open the epoxide. With the
free amine, the indole moiety was installed by alkylation to afford compound 200.
Finally, an oxidative cyclization and reduction sequence led to the final product
alpha-yohimbine 170.
In conclusion, as a pharmacologically and synthetically important natural
compound, alpha-yohimbine has attracted considerable attention of chemists.
Most of the present synthetic routes are developed during the synthesis of other
yohimbines and the overall yields are quite low. The route by Martin S. F. was the
most direct completing the synthesis in 19 steps, which is considerably reasonable.
There has been no reports on enantioselective synthesis of alpha-yohimbine. We
would like to introduce our work on bicyclic guanidine catalyzed
intramolecular-Diels-Alder reaction of alkynoates: the first enantioselective
synthesis of alpha-yohimbine, which was achieved via a shorter and more
efficient route.
3.2 Tandem isomerisation intromolecular-Diels-Alder (IMDA)
reaction of alkynoates: total synthesis of (+)-alpha-yohimbine
Our initial plan was based on the work of tandem isomerisation
Chapter 3
55
intramolecular-aza-Michael reaction of alkynoates (Eq 1, Scheme 3.2.1). We were
interested to develop an intramolecular-Diels-Alder reaction using the in-situ
generated chiral allenes, which will produce hydroisoquinoline derivatives (Eq 2,
Scheme 3.2.1).
Scheme 3.2.1 Initial plan for the construction of hydroisoquinoline derivative - core
structure of yohimbines
3.2.1 Synthesis of intramolecular-Diels-Alder (IMDA) reaction substrates
First, some Diels-Alder substrates were synthesized with open dienes (Scheme
3.2.2). Alkynyl amide 201 was then synthesized via amide coupling between (2E,
4E)-hexa-2, 4-dienoic acid and propargyl amine followed by coupling between
terminal alkyne and diazo compound. Alkynyl amide 202 was synthesized in
similar way as previously mentioned. The two compounds were both obtained
together with small amount of allenes. Since the amide and allene are inseperable,
they were not characterized and were treated with TBD in DCM together.
However, no cyclization occurred and only allene was obtained. Further thermal
treatment of the allene in toluene under reflux did not result in any reaction.
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
56
Scheme 3.2.2 Synthesis of IMDA substrates containing opening diene
As such, we begin to focus on alkynyl amides with cyclic diene moiety.
Substrates with a furan ring and an alkyne can be easily obtained by the protocol
as outlined in Scheme 3.2.3.
Scheme 3.2.3 Synthesis of IMDA substrates containing cyclic diene
The synthesis begins with an SN2 substitution between furfuryl amine and
propargyl bromide in the presence of 1 eq lithium hydroxide. To minimize the
production of disubstituted product 205, 3 eq of furfuryl amine was used.
Chapter 3
57
However, compound 205 was still formed in 10% yield. The desired product 206
was obtained in 80% yield. Then the secondary amine 206 was protected with an
amine protecting group (Table 3.1), such as Pivaloyl. Majority of this protecting
step uses the condition as described in Scheme 3.2.3. However, there are a few
substrates, which employ conditions that are different and can be found in chapter
4. Amides 207 are obtained in considerably good yields. Finally coupling between
terminal alkyne and diazo compounds afforded the desired IMDA subsrates 208.
In our previous cases,7 the coupling step always produced some allene as
inseperable by-products. However, we did not observe any allene and isolated
only the intramolecular-Diels-Alder cycladdition products.
3.2.2 Optimization study of the intramolecular-Diels-Alder reaction
These new substrates were subjected to our catalyst, bicyclic guanidine.
Pleasingly, guanidine was found to promote the intramolecular-Diels-Alder
(IMDA) reaction and the IMDA products were obtained in good yields, moderate
dr, and moderate to good ee.
During our initial study, we screened different solvents for this IMDA reaction
using 208a as a model substrate (Table 3.1). The reaction is generally a bit slow.
Chlorinated solvent (DCM) led to very low enantioselectivity (Entry 3) although
the reaction was a bit faster. Toluene, hexane and ether type solvents (THF and
diethyl ether) resulted in ees of same level. However, all of the ees were only
moderate. From prior experience, we postulated that the size of the ester group
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
58
could affect the enantioselectivity thus we changed the ethyl ester to a tert-Butyl
ester as shown in Table 3.2.
Table 3.1 Solvent effect on IMDA reaction
entry solvent time
(day)
conversiona
(%)
drb
(208aa:208ab)
eec
(208aa %/208ab %)
1 THF 2 100% 3:1 55%/56%
2 Toluene 2 100% 3:1 59%/59%
3 DCM 2 100% 7:3 38%/38%
4 Et2O 4 90% 4:1 60%/63%
5 Hexane 4 90% 4:1 60%/60%
Reactions were run on a 0.01 mmol scale with 10 mol% bicyclic guanidine in 0.5 ml solvent. a Conversion is determined
by crude 1H NMR.
b determined by crude
1H NMR.
c determined by chiral HPLC analysis.
The ee was increased by about 20% in Hexane (Entry 5, Table 3.1 vs Entry 6,
Table 3.2) and diethyl ether (Entry 4, Table 3.1 vs Entry 7, Table 3.2) giving the
best ee so far. Other ether-type solvents were screened as well, and TBME gave
similar enantioselectivity (Entry 10). Preliminary screening with various
concentrations indicated that a change in concentration would lead to a drop in ee
(Entry 10-12). We also attempted to lower the temperature but the reaction
became extremely slow and the ee was not increased. Different catalyst loadings
were also screened but the enantioselectivitives were not improved as well.
Finally, we decided to choose hexane as reaction solvent because it is cheap and
not as volatile as diethyl ether. Substrates bearing different protecting groups were
Table 3.2 Solvent and concentration effect on the IMDA reaction of 208b
Chapter 3
59
entry solvent concen-
tration(M)
time
(day)
conversiona
(%)
drb
(208ba:208bb)
eec
(208ba %/208bb %)
1 THF 0.02 4 80% 3:1 68/70
2 EA 0.02 3 80% 4.5:1 73/75
3 MeCN 0.02 2 100% 1.7:1 21/21
4 Tol 0.02 2 80% 4:1 72/75
5 DCM 0.02 2 100% 4:1 46/50
6 Hexane 0.02 4 80% 4:1 79/80
7 Ether 0.02 4 90% 4.5:1 77 /78
8 0.02 3 100% 7:1 60/62
9 PhOMe 0.02 3 90% 7:1 71/73
10 TBME 0.02 4 85% 4:1 79 /80
11 TBME 0.01 4 90% 7:3 60/35
12 TBME 0.005 4 50% 4:1 72/62
13 nBu2Od 0.02 7 0 nd nd
14 1,4-dioxaned 0.02 7 0 nd nd
Reactions were run on a 0.01 mmol scale with 10 mol% bicyclic guanidine in 0.5 ml solvent. a
Conversion is determined by
crude 1H NMR.
b determined by crude
1H NMR.
c determined by HPLC analysis.
d not determined
subjected to the optimal condition which employs hexane as solvent under room
temperature condition with a concentration of 0.02M and 10 mol% catalyst
loading.
Different N protecting groups led to slightly different reaction rates and ees
(Entry 2-8). The best result was achieved with the Boc protecting group, when a
triethyl methyl type ester was employed (Entry 9). When the nitrogen atom was
protected using tosyl group, the reaction rate increases probably due to the strong
electron withdrawing ability of sulfonyl group, but the ee obtained was bad.
Majority of the two diastereoisomers can be separated via chromatography on
silica gel. The IMDA products of 208e and 208g can be obtained only as
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
60
diastereoisomer mixtures. We confirmed the IMDA products 208ba and 208ca by
X-ray analysis (Scheme 3.2.3) and 1H NMR and 13C NMR analysis. We failed to
obtain any X-ray structure of the cis IMDA product, instead we obtained the X-ray
structure of the hydrogenation product of compound 208bb, which can also help
to determine the structure of the cis compound.
Table 3.3 Intramolecular-Diels-Alder (IMDA) reaction of 208
entry 208x(PG, R) time(d) conv(%)a yield(%)
b dr(10Xa/10Xb)
c ee(%/%)
d
1 208a(Piv, Et) 4 87.5 88.5 3:1 60/60
2 208b(Piv, tBu) 4 80 75 4:1 83/83
3 208c(Boc, tBu) 7 84 91 3.3:1 79/77
4 208d(Cbz, tBu) 7 76 89 4:1 77/77
5 208e(Ts, tBu)e 3 100 80 2:1 76.5/80
6 208f(4-bromo
Benzoyl, tBu )
7 84 83.3 2.5:1 65/65
7
208g( ,tBu)e
7 77 72 4:1 68/69
8 208h(Boc, CEt3) 8 85.3 80 4:1 87/87.5
9 208i (Piv, CEt3) 5 86% 80 3:1 87/88
Reactions were run on a 0.2 mmol scale with 10 mol% bicyclic guanidine in 10 ml hexane at room
temperature. a based on recovered starting material.
b isolated yield (10xa+10xb) based on
conversion. c determined by
1H NMR.
d determined by HPLC analysis.
e the reaction was run in
THF due to low solubility.
Other DA products were confirmed by comparing the 1H, 13C NMR data with
that of 10ba and 10bb. Due to the lack of heavy atoms in the molecule, the
absolute configurations of products 10ca and 10cb were determined via DFT
calculation on optical rotation to be (5S, 6S, 9R) and (5R, 6S, 9R) respectively.8
Chapter 3
61
Compound 208ba
Compound 208ca
Hydrogenation product of compound 208bb
Scheme 3.2.4 X-ray structures of the compounds 208ba, 208ca and the X-ray structure of the
hydrogenation product of compound 208bb.
3.2.3 Enantioselective total synthesis of (+)-alpha-yohimbine
To achieve the synthesis of the natural product alpha-yohimbine 170, we
designed the substrate 208g. The indole moiety was installed as a protecting group
to facilitate the IMDA reaction. The IMDA products contain all the elements that
are required in alpha-yohimbine. The natural product synthesis can be completed
in a few steps with first cyclization to form the ring C, followed by amide
reduction, olefin hydrogenation and transesterification. We proceeded to attempt
the total synthesis with 208ga according to the route as discussed (Scheme 3.2.5).
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
62
Scheme 3.2.5 Intramolecular-Diels-Alder reaction of substrate 208g and manipulation on the
IMDA product 208ga
We first attempted to cyclise the IMDA product 208ga via oxidative cyclization
which has been used to form the ring C by the oxidation of tertiary amine to
iminium.6 However, the amide oxidation did not work. As such, we decided to
reduce the amide instead. IMDA products are generally not stable probably due to
the double bonds. Hydrogenation of 208ga gave 210 in good yield. The amide
210 was subjected to kinds of conditions for tertiary amide reduction, like borane,
sodium boron hydride in the presence of Lewis acid, Hantzsch ester in the
presence of Tf2O, Silane in the presence of zinc acetate. But all of these
conditions did not work. Compound 210 was either recovered or decomposed.
The strong reducing reagents LiAlH4 did reduce the amide to amine, however, the
ester was reduced together, which results in a very polar compound. The change
Chapter 3
63
in oxidation state of the compound made the route not appealing.
Manipulation on other IMDA products was then planed. Deprotection of the
nitrogen atom followed by alkylation or reductive amination should install the
indole moiety without an oxidation state change. Compound 208ca was selected
to be the desired starting point due to the easy removal of Boc group as well as its
high ee (Scheme 3.2.6).
Scheme 3.2.6 Attempt on the total synthesis starting with compound 208ca
IMDA product 208ca was hydrogenated to afford two compounds 211 and 212
in a ratio of 1:4 in quantitative yield. Then the main product 212 was treated with
TFA in DCM to remove the Boc protecting group. Temperature and amount of
TFA have been screened. It was found that the reaction in a mixture of TFA and
DCM (volume ratio of 1:4) at 0 oC for 10 minutes, gave the free amine 213 in the
best yield (80%). Less TFA resulted in a longer reaction time. Longer reaction
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
64
time and high temperature resulted in the reaction of tert-butyl ester with TFA.
The tert-butyl ester was changed to carboxylic acid resulting in a lower yield of
the amine.
Secondary amine 213 was not purified and used directly after quenching and
extraction. Alkylation of the amine with tryptophyl bromide in DMF or MeCN in
the presence of K2CO3, afforded compound 214 in quite low yield (around 20%).
The reason is probably the oxa-bridge reduced the nucleophilicity of the nitrogen
atom. Then reductive amination using 2-(1-H-indol-3-yl)-acetaldehyde was
carried out. The condition was reported by Eric. N. Jacobsen during their
synthesis of yohimbine.9 Compound 214 was obtained in 60% yield. The
transesterification proceeded smoothly in the presence of 1 eq of CSA in refluxing
MeOH and the methyl ester 215 was achieved in 80% yield. Then the oxidative
cyclization using mercury acetate followed by NaBH4 reduction was employed to
form the ring C. Two products 216 and 217 were achieved in same yield (30%).
Compound 217 was the desired product.
In order to attain the hydroxyl group at C-18, the oxa-bridge has to be opened.
Initially Lewis acid, such as ZrCl4, and BF3 were attempted, but these were not
strong enough, only the starting material 217 was recovered. Stronger Lewis acid
BCl3 led to a messy reaction at -20 oC, and no product could be isolated. The
temperature was lowered to -78 oC but there was no reaction. Brønsted acids such
as HCl and HBr were used in EA and in toluene respectively but these did not
Chapter 3
65
work as well and no reaction was observed. Finally, it was found that
trifluoromethanesulfonic acid could promote the ring opening with DCM as
solvent. On closer analysis of the structure with NMR (1H, 13C, COSY, HMQC,
NOESY), we confirmed that the compound is 218. However, the hydroxyl group
was formed at C20 instead of C17. This result can be explained by the
neighboring carbonyl stabilization of the carbon cation intermediate 219 (scheme
3.2.7).
Scheme 3.2.7 Ring opening of compound 217 with triflic acid
So far, we observed that in acid catalysis, the carbon cation prefers to form at
C-17 rather than C-20 and alpha-yohimbine was not possible to achieve via this
route. As such, we decided to take a different approach and open the oxabicyclic
ring with a nucleophile before the double bonds were reduced.
Different conditions have been screened, however, in most results either no
reaction was observed or the starting material was decomposed and no isolation of
product was possible (Entry 1-8, Table 3.4). The palladium-catalyzed
hydrostannation of olefin led to 50% yield of 220, which would afford a tertiary
alcohol instead of the desired secondary alcohol after destannation (Entry 9).
Finally, the desired product 221 was obtained via nickel catalyzed reductive
oxabicyclic ring opening with DIBAL-H as hydride source (Entry 10). Due to the
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
66
low yield obtained, an optimization was done.
Table 3.4 Oxabicyclic ring opening of IMDA product 208ca
entrya condition time result
110
2 eq ZrCl4, 0.1 M in DCM 2 d Decomposition
2 TiCl4, DCM, -78 oC 1 hr Decomposition
3 2 eq SmI2, THF 24 hr No reaction
4 2 eq Red-Al, toluene, rt 24 hr No reaction
511
2 eq PhSH, 2 eq BF3-Et2O, DCM, rt 24 hr Decomposition
6 2 eq PhSH, 2 eq Et3N, DCM, rt 24 hr No reaction
7 LiNH2, -78 oC 1 hr Decomposition
812
LTBAH, Et3B, THP 24 hr No reaction
913
20 wt% Pd(OH)2, 1.5 eq Bu3SnH, THF 2 hr
220, 50% y ield
1014
0.1 eq Ni(COD)2, 0.4 eq PPh3, 1.2 eq DIBAL-H in
hexane, rt
2 hr
221, 11% yield
Reaction details see corresponding literatures. a Corresponding literatures
The reaction using Ni(COD)2 and DIBAL-H system was very fast. Catalytic
amount of Ni(COD)2 led to quite low yield (Entry 1-2, Table 3.5). Increase in the
catalyst loading gave better yield (Entry 4). Excess of DIBAL-H would decrease
the yield because of the side reaction of ester reduction (Entry 3). Actually, side
product from olefin hydroalumination was also detected via LCMS. The best yield
(50%) was achieved when 1 eq of Ni(COD)2, 4 eq of PPh3 and 1.3 eq of
DIBAL-H were used at 0 oC in this reaction (Entry 7). Decrease of temperature to
Chapter 3
67
-78 oC did not improve the result (Entry 6).
Table 3.5 Optimizat ion of reductive oxab icyclic ring opening of IMDA product 208ca
entry Ni(COD)2 PPh3 DIBAL-H temperature conversiona yield
b
1 0.1 eq 0.4 eq 1.2 eq in heptane rt 70% 11%
2 0.3 eq 1.2 eq 1.2 eq in heptane rt 90% 30%
3 0.3 eq 1.2 eq 2.3 eq in heptane rt 100% 24%
4 1 eq 4 eq 1.1 eq in heptane rt 80% 35%
5 1 eq 4 eq 1.3 eq in heptane -78 oC-rt 80% 40%
6 1 eq 4 eq 1.3 eq in toluene -78 oC-rt 80% 45%
7 1 eq 4 eq 1.3 eq in toluene 0 oC 90% 50%
8 1 eq 4 eq 1.5 eq in toluene -78 oC-rt 90% 42%
9 1 eq 4 eq 2.0 eq in toluene -78 oC-rt 100% 20%
Reaction details see chapter 7. a
based on TLC analysis b isolated yield.
Compound 221 is found to be unstable as after standing at rt or even -30 oC for
overnight, new spots were observed on TLC. Direct hydrogenation of compound
221 led to messy reaction. Thus, the alcohol was protected with acetyl group
using 1.5 eq of acetic anhydride with DMAP as catalyst in the presence of 1.5 eq
of Et3N (Scheme 3.2.8). The O-protected product 222 was obtained in 80% yield
with no ee change.
Scheme 3.2.8 Protection of alcohol group in compound 221
Having achieved compound 222, we aimed to reduce the two double bonds. It
was speculated that the bulky tert-butyl ester group would help to form the
desired product 223 during heterogeneous hydrogenation. Unfortunately, only a
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
68
mixture of two diastereoisomers that could not be separated was obtained and the
stereochemistry of the products could not be determined at this moment. To
increase the yield and the dr, an optimization was also performed (Table 3.6).
Table 3.6 Optimizat ion of hydrogenation of compound 222
entry catalyst catalyst loading temperature time ratio of 225a dr
b
1 10%Pd/C 30 wt% rt 2 d 70% 4:1
2 10%Pd/C 100 wt% rt 2 d 60% 4:1
3 20%Pd(OH)2 50 wt% rt 2 d 60% 3:1
4 10%Pt/C 100 wt% rt 2 d 50% 8:1
5 10%Pt/C 200 wt% rt 2 d 30% 5:1
6 10%Pt/C 50 wt% rt 3 d 50% 8:1
7 10%Pt/C 50 wt% 70 0C 3 d 10% 8:1
a based on crude nmr analysis and ESI mass analysis
b based on crude nmr analysis
By ESI mass analysis, it was found that there was always a monohydrogenated
product 225, which could not be isolated and its double bond could not be located.
By crude 1H NMR analysis, its ratio could be determined. The stereochemistry of
compounds 223 and 224 cannot be determined at this stage but the
stereochemistry of the major product 223 was later determined. A brief catalyst
screening indicated that Pt/C is better than Pd/C and Pd(OH)2/C in the perspective
of reaction rate and diastereoselectivity (Entry 2-4). More catalyst loading and
higher temperature increased the reaction rate significantly (Entry1-2, 6-7). When
using more Pt/C, a decrease of dr was observed (Entry 5). Finally, the condition of
Chapter 3
69
50 wt% Pt/C at 70 oC was used for the hydrogenation, which afforded the
products with 10% of compound 225 and a dr (223:224) of 8:1.
The products of this step are not separable and they were used together in the
following synthesis. With this result and our previous experience in hand, we
carried out the rest synthesis without much problem (Scheme 3.2.9).
Scheme 3.2.9 Total synthesis of (+)-alpha-yohimbine starting from 208ca
The inseparable mixture of 223 and 224 was treated with TFA in DCM at 0 oC,
which afforded an inseparable diisomer mixture of free amine 226 (dr 8:1). The
amine was confirmed via crude 1H NMR analysis and ESI mass analysis. Without
purification, the mixture 226 was used in the reductive amination step directly.
Unfortunately, the product 227 was inseparable again from the by-product
2-(1H-indol-3-yl) ethanol that was generated from the reduction of
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
70
2-(1H-indol-3-yl) acetaldehyde. The mixture of 227 and 2-(1-H-indol-3-yl)
ethanol was isolated via flushing silica gel chromatography and used together in
the transesterification step. When the mixture was treated with CSA in refluxing
MeOH in a sealed tube, the acetyl group was cleaved and the tert-butyl ester was
converted to methyl ester together, which afforded 228 in 31% yield over four
steps. An increase in ee was observed during the analysis of compound 228 with
chiral HPLC, the ee increased from 79% of IMDA product 209ca to 85% of
compound 228. The compound 228 was fully characterized and the
stereochemistry was established by NOESY analysis and also confirmed by
comparing the 1H, 13C NMR with the reported data.6 The oxidative cyclization
followed by NaBH4 reduction was subsequently carried out to finish the total
synthesis of (+)-alpha-yohimbine. The final product was also fully characterized
and confirmed by comparing the NMR data with the reported one.6
Since the ee of the starting IMDA product 208ca is 79% only, the total synthesis
was carried out starting from IMDA products 208ha and 208hb (Scheme 3.2.10).
which are inseparable. When the mixture of 208ha and 208hb was treated with
Ni(COD)2 and DIBAL-H, two products 229 and 230 were obtained. By
comparing the NMR data with that of compound 221, the trans isomer can be
identified. The synthesis was completed in the same sequence as above. However,
the ee for compound 228 was not increased and almost same as in scheme 3.2.9.
The yield dropped to 20% over the four-step sequence. This is probably due to the
Chapter 3
71
low distereoselectivity (3.5:1) at the hydrogenation step.
Scheme 3.2.10 Total synthesis of (+)-alpha-yohimbine starting from 208ha and 208hb
3.3 Summary
In conclusion, we have found that a Brønsted-base catalyzed tandem
isomerisation intramolecular-Diels-Alder reaction can be used to form useful
hydroisoquinoline derivatives under mild conditions. The IMDA products have
been obtained in moderate to high enantiomeric purity. This efficient method was
successfully applied to the catalytic enantioselective total synthesis of
(+)-alpha-yohimbine.
Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction
72
References:
1. Kohli, J. D.; De, N. N. Nature,1956, 177, 1182.
2. Perry, B. D.; ÚPrichard, D. C. European Journal of Pharmacology, 1981, 76, 461.
3. Arthur, J. M.; Casańas S. J.; Raymond J. R. Biochemical Pharmacology, 1993, 45, 2337.
4. a) Szántay, Cs.; Töke, L.; Honty, K. Tetrahedron Lett., 1965, 6, 1665 . b) Töke, L.; Honty K.;
Szántay, Cs. Chem. Ber., 1969, 102, 3248. c) Töke, L; Honty, K.; Szabó, L.; Blaskó, G.;
Szántay, C. J. Org. Chem. 1973, 38, 2496. d) Töke, L; Gábor, Z.; Blaskó, G; Honty, K.; Szabó,
L.; Tamás J.; Szántay G. J. Org. Chem. 1973, 38, 2501.
5. Wenkert, E.; Halls, T. D. J.; Kunesch, G.; Orito, K.; Stephens, R. L.; Temple, W. A.; Yadv, J. S.
J. Am. Chem. Soc. 1979, 101, 5370.
6. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109,
6124.
7. Liu, H.; Leow, D.; Huang, K.-W., Tan, C.-H., J. Am. Chem. Soc. 2009, 131, 7212.
8. Kwit, M.; Rozwadowska, M. D.; Gawroński, J.; Grajewska, A. J. Org. Chem. 2009, 74, 8051.
9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745.
10. Giovanni, V.; Stephen, B.; Jamal, E. M.; Marcella, B.; Giuseppe, Z. Tetrahedron Lett. 2002,
43, 2687.
11. Rigby, J. H.; Wilson, J. A. Z. J. Org. Chem. 1987, 52, 34.
12. Moss, R. J.; Rickborn, B. J. Org. Chem. 1985, 50, 1381.
13. Lautens, M.; Aspiotis, R.; Colucci J. J. Am. Chem. Soc. 1996, 118, 10930.
14. Lautens, M.; Ma, S.; Chiu, P. J. Am. Chem. Soc. 1997, 119, 6478.
Chapter 4
73
Chapter 4
Experimental
Experimental
74
4.1 General information
4.1.1 General procedures and methods
1H and 13C NMR spectras were recorded on a Bruker ACF300 (300MHz), Bruker
DPX300 (300MHz) or AMX500 (500MHz) spectrometer. Chemical shifts are
reported in parts per million (ppm). The residual solvent peak was used as an
internal reference. Low-resolution mass spectras were obtained on a
Finnigan/MAT LCQ spectrometer in ESI mode and a Finnigan/MAT 95XL-T
mass spectrometer in FAB mode. All high-resolution mass spectras were obtained
on a Finnigan/MAT 95XL-T spectrometer. Infrared spectras were recorded on a
BIO-RAD FTS 165 FTIR spectrometer. Enantiomeric excess values were
determined by chiral HPLC analysis on two sets: Jasco HPLC units, including a
Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980
Intelligient HPLC Pump, UV-975 Intelligient UV/VIS Detectors, and an AS-950
Intelligient Sampler; Dionex Ultimate 3000 HPLC units, including a Ultimate
3000 Pump, Ultimate 3000 variable Detectors. Optical rotations were recorded on
Jasco DIP-1000 polarimeter. Melting points were determined on a BÜCHI B-540
melting point apparatus. Analytical thin layer chromatography (TLC) was
performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness
0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040
- 0.063mm) mesh silica gel. Toluene and THF were distilled from
sodium/benzophenone and were stored under N2 atmosphere. Dichloromethane
Chapter 4
75
was distilled from CaH2 and was stored under N2 atmosphere. Other reagents and
solvents were commercial grade and were used as supplied without further
purification, unless otherwise stated.
4.1.2 Materials
All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar,
Merck, TCI, and Acros of the highest purity grade. They were used without
further purification unless specified. All solvents used, mainly hexane (Hex) and
ethyl acetate (EtOAc), were distilled. Anhydrous DCM was freshly distilled from
CaH2. Anhydrous THF was freshly distilled from Na/benzophenone. MeCN and
CHCl3 were distilled from CaH2. MeOH was distilled from Mg.
4.2 Preparation and characterization of compounds for the
Michael reaction
4.2.1 Preparation of alkynyl amines
Alkynyl amines 141a-c were synthesized according to the equation above. To a
flame-dried 50 ml rbf, pent-4-ynoic acid (2.9 mmol) and 5 ml THF were added
under N2. This is followed by DCC (3.2 mmol) and HOBT (3.2 mmol). Finally,
Experimental
76
aniline (3.4 mmol) in THF (5 ml) was added and the reaction mixture was stirred
at rt for 18 hrs. The reaction mixture was filtered and the solvent was removed
under reduced pressure. The residue was purified via flash chromatography.
Amide 139a was obtained in 70% yield.
Then in a 50 ml dry rbf equipped with a condenser, amide 139a (2 mmol) was
dissolved in 10 ml dry THF under N2, cooled to 0 oC, LiAlH4 (5 mmol) was
added. The mixture was refluxed at 70 oC overnight, and was then cooled to 0 oC,
quenched with 1ml water, stirred untill a white solid was formed. Then the solid
was filtered off and the filtrate was concentrated to afford the crude 140a.
Compound 140a was mixed together with 2 mmol of ethyl diazoacetate in 4 ml
MeCN under N2. Then 0.2 mmol of copper iodide was added. The mixture was
stirred overnight and the reaction was monitored with TLC until starting material
was consumed. After concentrated under reduced pressure, the mixture was
purified via chromatography on silco gel. Compound 141a was obtained in 60%
yield over two steps.
4.2.2 Representative procedure for Brønsted-base catalyzed tandem
isomerization-aza-Michael reaction of alkynyl-amines
Substrate 141a (0.5 mmol) was dissolved in 5 ml DCM, then TBD (0.05 mmol)
Chapter 4
77
was added and the mixture was stirred at rt for 24 hours. After concentrated, the
mixture was purified by chromatography on silco gel. Compound 142a was
obtained as pale yellow oil in 83% yield.
(E)-ethyl 2-(1-phenylpiperidin-2-ylidene)acetate (142a): Yellow oil; 83% yield;
1H NMR (300 MHz, CDCl3): δ 7.41 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H),
7.16 (d, J = 7.3 Hz, 2H), 4.34 (s, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 6.0 Hz,
2H), 3.24 (t, J = 6.4 Hz, 2H), 1.93-1.78 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3): δ 167.7, 162.2, 145.1, 128.9, 128.2, 125.8, 85.7, 57.2,
51.0, 25.3, 22.7, 19.0, 13.6 ppm; IR (film): 3020, 2977, 2896, 1556, 1422, 1216,
1137, 1046, 929 cm-1; LRMS (ESI) m/z: 268.1; HRMS (ESI) m/z:
C15H19O2N23Na1+ ([M+Na]+), Calc. 268.1308, Found 268.1302.
(E)-tert-butyl 2-(1-phenylpiperidin-2-ylidene)acetate (142b): Slight yellow
solid; 70% yield; 1H NMR (300 MHz, CDCl3): δ 7.40 (t, J = 7.6 Hz, 2H),
7.27-7.22 (m, 1H), 7.17 (d, J = 7.6 Hz, 2H), 4.32 (s, 1H), 3.44 (t, J = 6.0 Hz, 2H),
3.20 (t, J = 6.4 Hz, 2H), 1.91-1.76 (m, 4H), 1.38 (s, 9H) ppm; 13C NMR (75 MHz,
CDCl3): δ 168.8, 162.2, 146.4, 130.0, 126.8, 126.5, 89.1, 51.9, 28.6, 27.9, 26.3,
23.8, 20.3 ppm; IR (film): 3020, 2978, 2897, 1524, 1378, 1216, 1129, 1046, 929
cm-1; mp: 102.5 –103.9 °C; LRMS (ESI) m/z: 296.1; HRMS (ESI) m/z:
C17H23O2N23Na1+ ([M+Na]+), Calc. 296.1621, Found 296.1622.
Experimental
78
(E)-tert-butyl 2-(1-(2-tert-butylphenyl)piperidin-2-ylidene)acetate (142c):
White solid; 70% yield; 1H NMR (300 MHz, CDCl3): δ 7.51-7.48 (m, 1H),
7.28-7.25 (m, 2H), 7.05 (dd, J = 3.6, 5.6 Hz, 1H), 4.01 (s, 1H), 3.83-3.77 (m, 1H),
3.40-3.30 (m, 2H), 2.57-2.49 (m, 1H), 1.95-1.59 (m, 4H), 1.36-1.35 (m, 18H) ppm;
13C NMR (75 MHz, CDCl3): δ 168.6, 162.8, 146.5, 144.8, 130.1, 128.8, 127.8,
127.6, 91.9, 53.8, 35.5, 31.2, 28.6, 26.1, 23.6, 20.6 ppm; IR (film): 3020, 2977,
2896, 1524, 1424, 1218, 1129, 1046, 929 cm-1; mp: 113.5 –114.7 °C; LRMS (ESI)
m/z: 352.1; HRMS (ESI) m/z: C21H31O2N23Na1+ ([M+Na]+), Calc. 352.2247,
Found 352.2261.
4.2.3 Synthesis of alkynyl amides and procedure for Brønsted-base catalyzed
tandem isomerization-aza-Michael reaction
Compound 150 was obtained via the coupling of compound 139b with tButyl
diazoacetate, 1 To a clear and dry vial, tert-butyl 7-(2-tert-butylphenylamino)
-7-oxohept-3-ynoate (150) (36 mg, 0.1 mmol), a stirring bar and anhydrous THF
(0.9 mL) were added in this sequence. After stirring at room temperature for a
while, bicyclic guanidine 149 (2 mg, 0.01 mmol) in anhydrous THF (0.1 mL)
were added to the mixture in one portion. After the reaction was completed in 3
Chapter 4
79
days, the reaction mixture was concentrated and loaded onto a short silica gel
column, followed by flash chromatography. Product 152 (24 mg) was obtained as
white solid in 67% yield with 89% ee.
Synthesis of compounds 155,157, 159, 163, 166 follows the synthetic schemes in
Scheme 2.2.6, chapter 5. Bicyclic guanidine catalyzed isomerization of these
compounds follows the procedure above for compound 150
N-(2-tert-butylphenyl)pent-4-ynamide (139b) White solid; 62% yield; 1H
NMR (300 MHz, CDCl3): δ= 7.52 (d, J = 7.41 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H),
7.34 (s, 1H), 7.23-7.15 (m, 2H), 2.62 (d, J = 2.64 Hz, 4H), 2.03 (s, 1H), 1.41 (s,
9H); 13C NMR (75 MHz, CDCl3): δ= 169.4, 143.1, 134.8, 128.5, 126.8, 126.6,
126.4, 82.9, 69.7, 36.4, 34.6, 30.8, 14.8; LRMS (ESI) m/z: 230.2.
tert-Butyl 7-(2-tert-butylphenylamino)-7-oxohept-3-ynoate (150) colorless oil;
86% yield; 1H NMR (300 MHz, CDCl3): δ= 7.52 (d, J = 4.56 Hz, 1H), 7.47 (s,
1H), 7.42 (d, J = 4.53 Hz, 1H), 7.25-7.19 (m, 2H), 3.17 (s, 2H), 2.69-2.64 (m, 4H),
1.44 (s, 18H); 13C NMR (75 MHz, CDCl3): δ= 169.9, 167.8, 143.4, 135.1, 128.7,
126.8, 126.6, 126.5, 82.1, 81.8, 74.0, 36.8, 34.7, 30.7, 27.9, 27.1, 15.3; LRMS
(ESI) m/z: 366.1.
(E)-tert-Butyl-2-(1-(2-tert-butylphenyl)-6-oxopiperidin-2-ylidene)acetate (152)
white solid; 67% yield; 1H NMR (300 MHz, CDCl3): δ= 7.59 (d, J = 8.19 Hz, 1H),
7.40 (t, J = 7.29 Hz, 1H), 7.31 (t, J = 1.47 Hz, 1H), 6.82 (d, J = 7.89 Hz, 1H), 4.49
(s, 1H), 3.48-3.38 (m, 1H), 3.28-3.18 (m, 1H), 2.70 (t, J = 6.42 Hz, 2H), 2.02-1.94
Experimental
80
(m, 2H), 1.39 (s, 9H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3): δ= 171.2, 166.9,
156.9, 146.7, 135.5, 131.2, 129.8, 128.8, 127.6, 102.4, 79.6, 36.0, 34.0, 31.6, 28.3,
25.7, 18.4; IR (film)/cm-1 : 2970, 1690, 1605, 1281, 1219, 1134, 771, 756; mp:
145.1-146.0oC; LRMS (ESI) m/z: 366.1; HRMS (ESI): [M+Na]+ C21H29O3N23Na1,
Calc, 366.2040. found, 366.2035; [α]29D = -64.1 (c 0.1, CHCl3); HPLC analysis:
Chiralpak IA+IA column ( Hexane/IPA=90/10, 1.0ml/min, 254nm, 25oC),
11.33min(major), 12.31(minor), 89%ee. The geometry about the C=C bond was
confirmed by NOSEY.
tert-Butyl-6-(2-(2-tert-butylphenylamino)-2-oxoethoxy)hex-3-ynoate (153)
colorless oil; 46% yield; 1H NMR (300 MHz, CDCl3): δ=8.61 (s, 1H) 7.83 (d, J =
4.92 Hz, 1H), 7.39 (d, J = 4.92 Hz, 1H), 7.24 (t, J = 4.56 Hz, 1H), 7.14 (t, J = 4.56
Hz, 1H), 4.16 (s, 1H), 3.75 (t, J = 4.26 Hz, 2H), 3.11 (t, J = 1.56 Hz, 2H), 2.59 (t,
J = 5.28 Hz, 2H), 1.43 (s, 9H). 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3): δ=
167.7, 167.2, 141.4, 134.7, 126.8, 126.5, 125.9, 125.7, 81.8, 79.5, 73.9, 70.6, 69.9,
34.4, 30.5, 27.9, 27.1, 20.3; LRMS (ESI) m/z: 396.1.
tert-Butyl-5-(2-(2-tert-butylphenylamino)-2-oxoethoxy)-5-methylhex-3-ynoate
(154) colorless oil; 40% yield; 1H NMR (300 MHz, CDCl3): δ= 8.64 (s, 1H), 7.98
(d, J = 7.89 Hz, 1H), 7.38 (d, J = 7.89 Hz, 1H), 7.26-7.08 (m, 2H), 4.27 (s, 2H),
3.19 (s, 2H), 1.56 (s, 6H), 1.46(s, 9H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3):
δ= 167.6, 166.8, 140.3, 134.9, 126.8, 126.3, 125.2, 124.9, 83.7, 82.0, 78.4, 71.8,
64.3, 34.3, 30.3, 28.7, 27.9, 27.0; LRMS (ESI) m/z: 410.2.
Chapter 4
81
tert-Butyl 6-(2-tert-butylphenylcarbamoyloxy)hex-3-ynoate 155 colorless oil;
66% yield; 1H NMR (300 MHz, CDCl3): δ= 7.54 (s, 1H), 7.37 (d, J = 7.56 Hz,1H),
7.24-7.01 (m, 2H), 4.25 (t, J = 7.02 Hz, 2H), 3.17 (s, 2H), 2.60 (t, J = 7.02 Hz,
2H), 1.46 (s, 9H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3): δ= 167.8, 154.1,
135.1, 126.8, 126.4, 125.7, 81.7, 79.1, 73.9, 63.2, 34.6, 30.6, 27.9, 27.1, 19.7;
LRMS (ESI) m/z: 382.1.
tert-Butyl-5-(2-(2-tert-butylphenylamino)-2-oxoacetamido)pent-3-ynoate (156)
colorless oil; 50% yield; 1H NMR (300 MHz, CDCl3): δ= 9.56 (s, 1H), 7.98 (d, J
= 7.9 Hz, 1H), 7.88 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.29-7.15 (m, 2H), 4.59 (s, J
= 6.4 Hz,1H), 3.72 (s, 2H), 1.46-1.47 (m, 18H); 13C NMR (75 MHz, CDCl3): δ=
166.4, 160.1, 156.5, 140.9, 133.9, 126.8, 126.5, 126.0, 124.0, 119.6, 116.5, 82.1,
47.8,47.2, 34.2, 30.5, 27.8; LRMS (EI) m/z: 395.1.
(S)-tert-Butyl 5-(N-(2-(2-tert-butylphenylamino)-2-oxoethyl)acetamido)penta
-2,3-dienoate (157) colorless oil; 67% yield; 1H NMR (300 MHz, CDCl3): δ=
8.19 (s, 1H), 7.52 (d, J = 7.29 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H), 7.23-7.12 (m,
2H), 5.68-5.64 (m, 2H), 4.29-4.10 (m, 4H), 3.24 (s, 3H), 1.46-1.38(m, 18H); 13C
NMR (75 MHz, CDCl3): δ= 211.3, 172.0, 167.4, 164.0, 142.8, 134.6, 127.8, 126.7,
126.3, 93.1, 91.3, 81.7, 51.7, 47.8, 44.2, 34.5, 30.4, 28.0, 20.1. IR (film)/cm-1
3016, 2399, 1682, 1520, 1474, 1427, 1211, 925. LRMS (ESI) m/z: 423.2; HRMS
(ESI): [M+Na]+ C23H32O4N223Na1, Calc, 423.2254. found, 423.2259. [α]29
D =
+31.7 (c 0.5, CHCl3); HPLC analysis: PHENOMENEX Lux 5u Cellulose-2
Experimental
82
column ( Hexane/IPA=80/20, 1.0ml/min, 230nm, 25oC), 29.45 min(major), 50.49
min (minor), 65%ee.
(S)-tert-Butyl 5-(2-(2-tert-butylphenylamino)-2-oxoethoxy)-5-methylhexa-2,3
-dienoate (158) colorless oil; 68% yield; 1H NMR (300 MHz, CDCl3): δ= 8.69 (s,
1H), 8.02 (dd, J = 1.32, 7.89 Hz, 1H), 7.42 (dd, J =1.65, 8.07 Hz, 1H), 7.30-7.25
(m, 1H), 7.18-7.12 (m, 1H), 5.70 (d, J =6.06, 1H), 5.59 (d, J =6.24, 1H), 4.17 (d, J
=7.89, 2H), 1.52-1.48(m, 24H); 13C NMR (75 MHz, CDCl3): δ= 210.8, 167.34,
164.3, 140.1, 134.9, 126.8, 125.2, 124.8, 100.1, 92.5, 81.6, 76.0, 63.4, 34.3, 30.4,
28.1, 27.1, 26.6, 34.3, 30.4, 28.1, 26.6. IR (film)/cm-1 1959, 1697, 1527, 1288,
1219, 1141, 1288, 1219, 1141, 1087, 910; LRMS (ESI) m/z: 410.2; HRMS (ESI):
[M+Na]+ C23H33O4N123Na1, Calc, 410.2302. found, 410.2321. [α]29
D = +45.1 (c
1.2, CHCl3); HPLC analysis: Chiralpak IB column ( Hexane/IPA=90/10,
1.0ml/min, 230nm, 25oC), 5.13min(major), 9.68(minor), 87%ee.
(S)-tert-Butyl 5-(N-(2-(2-tert-butylphenylamino)-2-oxoethyl)acetamido)penta-
2,3-dienoate (159) colorless oil; 67% yield; 1H NMR (300 MHz, CDCl3): δ= 8.19
(s, 1H), 7.52 (d, J = 7.29 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H), 7.23-7.12 (m, 2H),
5.68-5.64 (m, 2H), 4.29-4.10 (m, 4H), 3.24 (s, 3H), 1.46-1.38(m, 18H); 13C NMR
(75 MHz, CDCl3): δ= 211.3, 172.0, 167.4, 164.0, 142.8, 134.6, 127.8, 126.7,
126.3, 93.1, 91.3, 81.7, 51.7, 47.8, 44.2, 34.5, 30.4, 28.0, 20.1. IR (film)/cm-1
3016, 2399, 1682, 1520, 1474, 1427, 1211, 925. LRMS (ESI) m/z: 423.2; HRMS
(ESI): [M+Na]+ C23H32O4N223Na1, Calc, 423.2254. found, 423.2259. [α]29
D =
Chapter 4
83
+31.7 (c 0.5, CHCl3); HPLC analysis: PHENOMENEX Lux 5u Cellulose-2
column ( Hexane/IPA=80/20, 1.0ml/min, 230nm, 25oC), 29.45 min(major), 50.49
min (minor), 65%ee.
4.3 Preparation and characterization of compounds for the IMDA
reaction
5.3.1 Synthesis and Characterizations of IMDA substrates
To a flame-dried 50 ml rbf, (2E,4E)-hexa-2,4-dienoic acid (2.9 mmol) and 5 ml
THF was added under N2. This is followed by DCC (3.2 mmol) and HOBT (3.2
mmol). Finally, propargyl amine (3.4 mmol) in THF (5 ml) was added and the
reaction mixture was stirred at rt for 18 hrs. The reaction mixture was filtered and
the solvent was removed under reduced pressure. The residue was purified via
flash chromatography. The resulting (2E,4E)-N-(prop-2-ynyl)hexa-2,4-
dienamide was obtained in 70% yield. The amide was then subjected to tButyl
Experimental
84
diazoacetate catalyzed by CuI to afford comound 201 together with certain
amount of inseparable allene in 60% yield.
Representative procedure for the synthesis of IMDA substrates:
Step 1: To a 200 ml rbf was added a stirring bar, 10 mmol LiOH.H2O and 10 ml
DMF (AR grade), followed by the addition of 30 mmol Furfurylamine 6. The
mixture was stirred vigorously. Then 10 mmol propargyl bromide 7 in 30 ml
DMF was added slowly during 1 hour. After stirred for another 3 hours, the
mixture was filtered through clite via sucktion and was washed thoroughly with
Diethyl Ether. The filtrate was washed four times with water. The combined
aqueous layer was extracted again with Diethyl Ether and the combined organic
layers were washed with brine and dried over sodium sulphate, concentrated via
rotary evaporation and purified by flushing silica gel chromatography
(Hexane:EA=6:1). The product 8 was obtained as pale yellow oil in 80% yield.
(Due to the low boiling point, 8 cannot be dried under vacumn and it was dried
only under rotary evaporation)
Chapter 4
85
Step 2: To a solution of 8 (8 mmol) in dry DCM (50 mL) under nitrogen
atmosphere was added Et3N (8.8 mmol, 1.1 eq). After the mixture was cooled to 0
oC, pivaloyl chloride was added dropwisely. Then the reaction mixture was
warmed to rt and stirred till full conversion indicated by TLC (usually around 1
hour). The product was obtained as colorless oil in 95% yield by flushing silica
gel chromatography purification. (Other substrates were prepared in the same way
but with different acid chlorides or anhydrides)
Step 3: (take 10a for example) Compound 9 (6 mmol) was dissolved in MeCN
(AR grade) under N2, and 0.6 mmol CuI was added to the solution. The mixture
was stirred for 10 minutes. Then ethyl diazoacetate(9 mmol) was added and the
mixture was stirred under N2 for 10 hours. Check TLC to ensure full conversion
of starting material 9 (if not, add a bit more diazo compound and stirred till
completion). Rotary evaporate to remove solvent and load the mixture to silica gel
column. After chromatography purification, the product 10a was obtained as
colorless oil in 75% yield. The IMDA products (10aa and 10ab) were obtained
together in around 10% yields. (Other IMDA substrates were prepared in the same
way but with appropriate alkynes and dizao-compounds.)
N-(furan-2-ylmethyl)prop-2-yn-1-amine (206): Pale yellow oil, 80% yield. 1H
NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 6.31 (t, J = 1.4 Hz, 1H), 6.21 (d, J = 3.15
Hz, 1H), 3.88 (s, 2H), 3.43 (d, J = 2.5 Hz, 2H), 2.22 (q, 1H). 13C NMR (125 MHz,
Experimental
86
CDCl3) δ 152.96, 142.06, 110.14, 107.48, 81.64, 71.67, 44.62, 37.16; LRMS
(ESI) m/z 174.0 (M + K+), HRMS (ESI) m/z 136.0757 ([M + H+]), calc. for
[C8H9NO+ H+] 136.0684.
N-(furan-2-ylmethyl)-N-(prop-2-ynyl)pivalamide (207a): colorless oil, 95%
yield. 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 1.25 Hz, 1H), 6.31 (q, 1H), 6.26
(d, J = 3.15 Hz, 1H), 4.72(s, 2H), 4.14 (d, J = 2.5 Hz, 2H), 2.22 (t, J = 2.5 Hz,
1H). 13C NMR (125 MHz, CDCl3) δ 177.10, 150.40, 142.39, 110.33, 108.75,
79.02, 72.00, 43.25, 38.98, 36.37, 28.55; LRMS (ESI) m/z 220.1 (M + H+),
HRMS (ESI) m/z 220.1339 ([M + H+]), calc. for [C13H17NO2+ H+] 220.1259.
tert-Butyl furan-2-ylmethyl(prop-2-ynyl)carbamate (207c): was prepared as
below: To a solution of 206 (8 mmol) in dry DCM (50 mL) under nitrogen
atmosphere was added Et3N (8.8 mmol, 1.1 eq). After the mixture was cooled to 0
oC, Boc anhydride (8 mmol) was added dropwisely. Then the reaction mixture
was warmed to rt and stirred till full conversion indicated by TLC (usually around
1 hour). The product was obtained as colorless oil in 95% yield by flushing silica
gel chromatography purification. Colorless oil, 1H NMR (500 MHz, CDCl3) δ
7.34 (t, J = 2.0 Hz, 1H), 6.30 (q, 1H), 6.22 (br, 1H), 4.50(s, 2H), 4.05 (br, 2H),
2.20 (s, 1H), 1.47 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 154.64, 151.06, 142.15,
Chapter 4
87
110.20, 108.00, 80.62, 79.18, 71.62, 42.18, 35.34, 28.27; LRMS (ESI) m/z 257.9
(M + Na+), HRMS (ESI) m/z 258.1113 ([M + Na+]), calc. for [C13H17NO3+ Na+]
258.1208.
Benzyl furan-2-ylmethyl(prop-2-ynyl)carbamate (207d): colorless oil, 90%
yield. 1H NMR (500 MHz, CDCl3) δ 7.38-7.31 (m, 6H), 6.32-6.2 (m, 2H), 5.20 (s,
2H), 4.60(s, 2H), 4.14-4.08 (m, 2H), 2.24 (s, 1H). 13C NMR (125 MHz, CDCl3) δ
155.42, 150.42, 142.42, 136.36, 128.46, 128.05, 127.87, 110.30, 108.85, 108.47,
78.71, 72.14, 67.70, 42.49, 42.20, 35.80. LRMS (ESI) m/z 292.0 (M + Na+),
HRMS (ESI) m/z 292.0947 ([M + Na+]), calc. for [C16H15NO3+ Na+] 292.1052.
N-(furan-2-ylmethyl)-4-methyl-N-(prop-2-ynyl) benzenesulfonamide (207e):
yellow solid, 85%yield. 1H NMR (500 MHz, CDCl3) δ 7.74-7.72 (d, J =8.8, 2H),
7.33 (s, 1H), 7.28 (d, J =8.2, 2H), 6.30-6.28 (m, 2H), 4.43 (s, 2H), 4.01 (d, J =1.9,
2H), 2.42 (s, 3H), 2.07(d, J = 2.5, 1H). 13C NMR (125 MHz, CDCl3) δ 148.57,
143.58, 142.91, 135.93, 129.44, 127.68, 110.35, 109.94, 76.39, 73.90, 42.65,
36.08, 21.47. LRMS (ESI) m/z 312.0 (M + Na+), HRMS (ESI) m/z 312.0673 ([M
+ Na+]), calc. for [C15H15NSO3+ Na+] 312.0773.
4-bromo-N-(furan-2-ylmethyl)-N-(prop-2-ynyl)benzamide (207f): colorless
Experimental
88
oil, 90% yield. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J =8.2, 2H), 7.43 (d, J =8.2,
2H), 7.37 (s, 1H), 6.31 (br, 2H), 4.76-4.54 (brm, 2H), 4.24-3.95 (brm, 2H), 2.31(s,
1H). 13C NMR (125 MHz, CDCl3) δ 170.05, 149.26, 142.64, 133.95, 131.59,
128.79, 124.36, 110.31, 109.27, 78.13, 72.65, 44.79, 40.61, 38.35, 34.43, 33.59,
33.33. LRMS(ESI) m/z 339.9 (M + Na+), HRMS (ESI) m/z 339.9951,341.9932
([M + Na+]), calc. for [C15H12NO2Br+ Na+] 340.00057.
N-(cyclopenta-1,3-dienylmethyl)-2-(1H-indol-3-yl)-N-(prop-2-ynyl)acetamide
(207g) was prepared as below: 206 (1 mmol) was dissolved in 5 ml dry THF
under N2, then DCC (1.1 mmol) and DMAP (0.1 mmol) were added. The mixture
was stirred at rt for 30 mins. And then 2-(1H-indol-3-yl)acetic acid (1.1 mmol)
was added and the mixture was left stirring overnight. The mixture was filtered
through clite and then was concentrated and purified via silica gel
chromatography. The product was obtained as a yellow solid in 70% yield.
1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.62-7.60 (m, 1H), 7.40-7.32 (m, 2H),
7.21-7.18 (m, 1H), 7.14-7.11 (m, 1H), 7.08-7.03 (m, 1H), 6.34-6.31 (m, 2H), 4.73
(s, 1H), 4.61 (s, 1H), 4.28 (s, 1H), 4.04 (s, 1H), 4.01 (s, 1H), 3.95 (s, 1H), 2.24 (d,
1H) . 13C NMR (125 MHz, CDCl3) δ 171.29, 150.44, 149.72, 142.74, 142.32,
136.18, 127.13, 127.09, 122.7, 122.64, 122.16, 119.60, 118.59, 111.25, 110.30,
108.92, 108.73, 108.54, 78.82, 78.30, 72.62, 71.94, 43.70, 41.40, 37.03, 34.12,
Chapter 4
89
31.33, 31.08. LRMS(ESI) m/z 293.0 (M + H+) , HRMS (ESI) m/z 315.1113 ([M +
Na+]), calc. for [C18H16N2O2+ Na+] 315.1212.
Ethyl 5-( N - ( furan -2 - ylmethyl) pivalamido) pent -3 –ynoate (208a):
colorless oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ 7.34 (s, 1H), 6.31 – 6.30
(m, 1H), 6.27 (d, J = 3.15, 1H), 4.72 (s, 2H), 4.21-4.16 (m, 4H), 3.27-3.26 (m,
2H), 1.32 (s, 9H), 1.27 (t, J =6.9, 3H). 13C NMR (125 MHz, CDCl3) δ 177.09,
168.15, 150.63, 142.30, 110.31, 108.69, 78.53, 75.97, 61.62, 43.07, 39.00, 36.80,
28.58, 26.08, 14.12. LRMS (ESI) m/z 328.15 (M + Na+), HRMS (ESI) m/z
328.1528 ([M + Na+]), calc. for [C17H23O4N + Na+] 328.1628.
tert-butyl 5-(N-(furan-2-ylmethyl)pivalamido)pent-3-ynoate (208b): colorless
oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 6.29 (d, J =1.8, 1H),
6.25 (d, J = 1.5, 1H), 4.70 (s, 2H), 4.16 (s, 2H), 3.16 (t, J =1.9, 2H), 1.44 (s, 9H),
1.31 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 177.00, 167.19, 150.69, 142.23,
110.28, 108.61, 81.87, 78.20, 76.61, 42.98, 38.96, 36.83, 28.57, 27.94, 27.08.
LRMS (ESI) m/z 356.15 (M + Na+), HRMS (ESI) m/z 356.1835 ([M + Na+]),
calc. for [C19H27O4N + Na+] 356.1940.
Experimental
90
tert-butyl 5-( tert - butoxycarbonyl (furan-2-ylmethyl) amino) pent- 3 –
ynoate (208c): colorless oil, 80% yield. 1H NMR (500 MHz, CDCl3) δ 7.31 (s,
1H), 6.27 (t, J =4.1, 1H), 6.21 (br, 1H), 4.49 (s, 2H), 4.05 (br, 2H), 3.16 (t, J =3.7,
2H), 1.44 (d, 18H). 13C NMR (125 MHz, CDCl3) δ 167.25, 154.64, 151.25,
142.01, 110.12, 107.83, 91.01, 81.72, 80.35, 78.35, 41.98, 35.59, 28.24, 27.97,
27.84. LRMS (ESI) m/z 372.20 (M + Na+), HRMS (ESI) m/z 372.1787 ([M +
Na+]), calc. for [C19H27O5N + Na+] 372.1889.
tert-Butyl -5-( (benzyloxycarbonyl) (furan -2-ylmethyl) amino ) pent -3-
ynoate (208d): colorless oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ
7.38-7.30 (m, 6H), 6.30-6.21 (m, 2H), 5.18 (s, 2H), 4.61 (s, 2H), 4.15-4.08 (m,
2H), 3.19 (s, 2H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 167.25, 154.64,
151.25, 142.01, 110.12, 107.83, 91.01, 81.72, 80.35, 78.35, 41.98, 35.59, 28.24,
27.97, 27.84. LRMS (ESI) m/z 406.20 (M + Na+), HRMS (ESI) m/z 406.1622
([M + Na+]), calc. for [C22H25O5N + Na+] 406.1733.
tert-butyl 5-(N -(furan -2 -ylmethyl) -4 -methylphenylsulfonamido)pent - 3 -
ynoate (208e) : yellow solid, 65% yield. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J
=8.2, 2H), 7.34(s, 1H), 7.28 (d, J =8.2, 2H), 6.31 (dd, J =13.2 2H), 4.43 (s, 2H),
4.02 (s, 2H), 2.94 (t, J =1.9, 2H), 2.42 (s, 3H) 1.44 (s, 9H). 13C NMR (125 MHz,
Chapter 4
91
CDCl3) δ 166.79, 148.83, 143.38, 142.90, 136.12, 129.38, 127.88, 110.38, 109.96,
81.93, 78.52, 75.78, 42.78, 36.65, 27.94, 27.02, 21.52. LRMS (ESI) m/z 426.14
(M + Na+), HRMS (ESI) m/z 426.1336 ([M + Na+]), calc. for [C21H25O5NS +
Na+] 426.1453.
tert-butyl 5-(4-bromo-N- ( furan- 2- ylmethyl) benzamido) pent- 3- ynoate
(208f) : color- less oil , 65% yield. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J =8.2,
2H), 7.48 (d, J =8.2, 2H), 7.40 (s, 1H), 6.35 (br, 2H), 4.83, 4.59 (br, 2H), 4.31,
3.99 (br, 2H), 3.24 (t, J =2.2, 2H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3) δ
170.14, 167.01, 142.66, 134.26, 131.66, 128.95, 124.37, 110.37, 109.29, 81.98,
77.57, 28.06, 27.95, 27.20. LRMS (ESI) m/z 454.10, 456.10 (M + Na+), HRMS
(ESI) m/z 454.0634, 456.0618 ([M + Na+]), calc. for [C21H22O4NBr + Na+]
454.0732, 456.0732.
tert-butyl 5- ( N - (furan -2 -ylmethyl) -2 -(1H-indol -3-yl)acetamido)pent-3-
ynoate (208g): white solid, 60% yield. 1H NMR (500 MHz, CDCl3) δ 8.52 (s,
1H), 7.63-7.59 (m, 1H), 7.39-7.7.30 (m, 2H),7.18-7.16(m, 1H), 7.11-7.09(m, 1H),
7.06-7.00(m, 1H), 6.32-6.23 (m, 2H), 4.72 (s, 1H), 4.63 (s, 1H), 4.30 (s, 1H), 4.05
Experimental
92
(s, 1H), 3.99 (s, 1H), 3.94 (s, 1H), 3.18(t, J =1.9), 1.47(d, J =13.8, 9H). 13C NMR
(125 MHz, CDCl3) δ 171.36, 171.32, 167.35, 167.13, 150.58, 149.94, 142.60,
142.20, 136.18, 127.15, 127.10, 122.94, 122.85, 122.01, 121.94, 119.46, 119.40,
118.60, 118.53, 118.49, 111.25, 111.19, 110.32, 110.29, 108.71, 108.57, 108.40,
82.05, 81.86, 78.07, 77.67, 77.25, 77.00, 76.75, 76.39, 43.53, 41.35, 37.43, 34.44,
31.36, 31.06, 27.90, 27.18, 27.09. LRMS (ESI) m/z 429.15 (M + Na+), HRMS
(ESI) m/z 429.1792 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893.
3-ethylpentan- 3 -yl 5-(tert-butoxycarbonyl(furan-2-ylmethyl)amino) pent-
3-ynoate (208h): clorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.33 (s,
1H), 6.30-6.28 (m, 1H), 6.21 (br, 1H), 4.50 (s, 2H), 4.09 (br, 2H), 3.20 (t, J
=2.2,1H), 1.82 (q, J =15.2, 7.5, 6H), 1.49 (s, 9H), 0.82 (t, J =7.5, 9H). 13C NMR
(125 MHz, CDCl3) δ 166.96, 154.68, 151.32, 142.04, 110.16, 108.31, 107.79,
89.88, 80.41, 78.33, 42.10, 41.83, 41.71, 35.84, 35.64, 35.53, 28.29, 27.05, 26.66,
7.59. LRMS (ESI) m/z 414.0 (M + Na+), HRMS (ESI) m/z 414.2265 ([M + Na+]),
calc. for [C22H33O5N + Na+] 414.2359.
3-ethylpentan-3-yl 5-(N-(furan-2-ylmethyl)pivalamido)pent-3-ynoate (208i) :
colorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J =1.9, 1H),
Chapter 4
93
6.28-6.27 (m, 1H), 6.23 (d, J =3.1, 1H), 4.68 (s, 2H), 4.15 (s, 2H), 3.18 (t, J =1.2,
2H), 1.8 (q, J =15.1, 7.5, 6H), 1.29 (s, 9H), 0.83 (t, J =7.5, 9H). 13C NMR (125
MHz, CDCl3) δ 176.90, 166.71, 150.60, 142.14, 110.18, 108.47, 89.88, 77.99,
42.87, 38.84, 36.72, 28.46, 27.23, 26.98, 26.62, 7.52. LRMS (ESI) m/z 398.1 (M
+ Na+), HRMS (ESI) m/z 398.2296 ([M + Na+]), calc. for [C22H33O4N + Na+]
398.2410.
4.3.2 Representative Procedure for Bicyclic guanidine catalyzed IMDA
reactions and Characterizations of IMDA products
Substrate 208 (2 mmol) was dissolved in 100ml distilled hexane. Then bicyclic
guanidine catalyst was added and the mixture was stirred at rt for appropriate days
when TLC showed the starting material was almost completely consumed. The
solvent was removed via rotary evaporation; further purification was completed
by flushing silica gel chromatography. The products were obtained in 72-88%
yields. The two diisomers can be separated by flushing silica gel chromatography
for most of the substrates. For 208e, 208h, 208i, the IMDA product diisomers
cannot be separated by silica gel chromatography, and the products were
characterized by checking the crude 1H NMR. The IMDA products of 208h were
characterized after reductive ring opening.
Experimental
94
208aa: colorless oil, 66%yield. 1H NMR (500 MHz, CDCl3) δ 6.39 (s, 2H), 5.74
(t, J =1.8, 1H), 5.20 (d, J =4.4, 1H), 5.08 (d, J =12.6, 1H), 4.58 (d, J =17.6, 1H),
4.12-4.06 (m, 2H), 3.73 (d, J =18.3, 1H), 3.69-3.67 (m, 1H), 3.03 (d, J =12.6, 1H),
1.3(s, 9H), 1.22 (t, J =6.9, 9H). 13C NMR (125 MHz, CDCl3) δ 177.28, 169.78,
135.73, 135.00, 134.90, 116.19, 84.27, 78.68, 60.83, 48.49, 45.47, 44.44, 38.95,
28.28, 14.07. LRMS (ESI) m/z 305.9 (M + H+), HRMS (ESI) m/z 328.1528 ([M +
Na+]), calc. for [C17H23NO4 + Na+] 328.1627. [α]29D = +129.1 (c 4.5, CHCl3);
HPLC analysis: Chiralpak Ce2 (Hex/IPA = 70/30, 0.5 mL/min, 210 nm, 23°C),
23.3, 47.3(major) min, 59.5% ee.
208ab: colorless oil, 22%yield. 1H NMR (500 MHz, CDCl3) δ 6.42-6.39 (m, 2H),
5.83-5.82 (m, 1H), 5.30 (d, J =1.9, 1H), 5.13 (d, J =12.6, 1H), 4.64-4.59 (m, 1H),
4.26-4.18 (m, 2H), 3.73 (d, J =18.3, 1H), 3.07 (d, J =12,1H), 2.99 (s, 1H), 1.31(s,
9H), 1.29 (t, J =7.6, 3H). 13C NMR (125 MHz, CDCl3) δ 177.27, 170.93, 136.67,
135.31, 134.68, 116.79, 83.39, 80.22, 61.19, 47.71, 45.69, 44.69, 38.97, 28.31,
14.21. LRMS (ESI) m/z 305.9 (M + H+), HRMS (ESI) m/z 328.1526 ([M + Na+]),
calc. for [C17H23O4N + Na+] 328.1627. [α]29D = -156.7 (c 1.5, CHCl3); HPLC
analysis: Chiralpak Ce2 (Hex/IPA = 70/30, 0.5 mL/min, 210 nm, 23°C), 37.4,
62.8 (major) min, 60% ee.
Chapter 4
95
208ba: colorless oil, 60%yield. 1H NMR (500 MHz, CDCl3) δ 6.39 (s, 2H), 5.70
(s, 1H), 5.15 (d, J =4.4, 1H), 5.07 (d, J =12.6, 1H), 4.59 (d, J =17.6, 1H), 3.72 (d,
J =18.3 1H), 3.61 (d, J =1.9, 1H), 3.04 (d, J =12.6,1H), 1.40 (s, 9H), 1.31(s, 9H).
13C NMR (125 MHz, CDCl3) δ 177.34, 169.00, 153.88, 135.70, 134.99, 115.99,
84.37, 81.30, 78.86, 49.55, 45.53, 44.64, 39.01, 28.35, 27.99. LRMS (ESI) m/z
334.1 (M + H+), HRMS (ESI) m/z 356.1826 ([M + Na+]), calc. for [C19H27O4N +
Na+] 356.1940. [α]29D = +146.1 (c 1.0, CHCl3); HPLC analysis: Chiralpak
IA+Ce1 (Hex/IPA = 80/20, 1.0 mL/min, 210 nm, 23°C), 10.8 (major), 12.0 min,
83.5% ee.
208bb: colorless oil, 15%yield. 1H NMR (500 MHz, CDCl3) δ 6.40-6.37 (m, 2H),
5.80-5.78 (m, 1H), 5.24 (d, J =1.6, 1H), 5.12 (d, J =12.5, 1H), 4.61 (d, J =18, 1H),
3.73 (d, J =17.8, 1H), 3.08 (d, J =12.6, 1H), 2.92-2.91 (m, 1H), 1.48 (s, 9H),
1.31(s, 9H). 13C NMR (125 MHz, CDCl3) δ 177.19, 170.00, 136.47, 135.36,
135.04, 116.21, 83.22, 81.34, 80.18, 48.37, 45.62, 44.66, 38.88, 29.59, 28.23,
28.06. LRMS (ESI) m/z 334.1 (M + H+), HRMS (ESI) m/z 356.1819 ([M + Na+]),
calc. for [C19H27O4N + Na+] 356.1940. [α]29D = -244.7 (c 0.3, CHCl3); HPLC
analysis: Chiralpak IA+Ce1 (Hex/IPA = 80/20, 1.0 mL/min, 210 nm, 23°C), 12.8,
20.3 min(major), 83% ee.
Experimental
96
208ca: colorless oil (white solid after standing at rt for a while), 70% yield. 1H
NMR (500 MHz, CDCl3) δ 6.38 (br, 2H), 5.67 (br, 1H), 5.11 (d, J =4.4, 1H),
4.77-4.63 (m, 1H), 4.48-4.31 (m, 1H), 3.57-3.52 (m, 2H), 3.02-2.93 (m, 1H),
1.45(s, 9H), 1.38 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 169.14, 154.39, 136.41,
135.75, 135.07, 134.59, 116.69, 116.36, 84.02, 81.26, 80.26, 78.75, 49.40, 43.99,
43.13, 42.66, 29.62, 28.36, 27.96. LRMS (ESI) m/z 372.1 (M + Na+), HRMS
(ESI) m/z 372.1770 ([M + Na+]), calc. for [C19H27O5N + Na+] 372.1188. [α]29D =
+99.2 (c 1.0, CHCl3); HPLC analysis: Chiralpak IA (Hex/IPA = 90/10, 0.5
mL/min, 210 nm, 23°C), 6.3 (major), 6.9 min, 79.3% ee.
208cb: colorless oil (white solid after standing at rt for a while), 21% yield. 1H
NMR (500 MHz, CDCl3) δ 6.39 (br, 2H), 5.79 (br, 1H), 5.24 (s, 1H), 4.84-4.70
(m, 1H), 4.53-4.38 (m, 1H), 3.62-3.52 (m, 1H), 3.13-3.04 (m, 1H), 2.92-2.90 (m,
1H) 1.49(s, 9H), 1.48 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.21, 154.55,
136.71, 135.30, 134.28, 117.15, 116.59, 82.94, 81.34, 80.32, 80.21, 78.78, 49.43,
48.31, 44.30, 43.24, 29.65, 28.39, 28.12, 27.99. LRMS (ESI) m/z 372.1 (M +
Na+), HRMS (ESI) m/z 372.1770 ([M + Na+]), calc. for [C19H27O5N + Na+]
372.1889. [α]29D = -167.5 (c 1.0, CHCl3); HPLC analysis: Chiralpak IA (Hex/IPA
= 90/10, 0.5 mL/min, 210 nm, 23°C), 10.2, 15.0(major) min, 77% ee.
Chapter 4
97
208da: colorless oil, 71% yield. 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 5H),
6.44-6.33 (m, 2H), 5.70 (d, J =23.3, 1H), 5.20-5.16 (m, 3H), 4.90-4.74 (m, 1H),
4.56-4.44 (m, 1H), 3.70-3.61 (m, 2H), 3.16-3.05 (m, 1H), 1.41(s, 9H). 13C NMR
(125 MHz, CDCl3) δ 169.09, 155.72, 155.19, 136.42, 135.27, 134.95, 134.87,
134.70, 128.56, 128.17, 128.01, 116.31, 116.88, 83.92, 83.82, 81.37, 67.54, 49.52,
43.83, 43.67, 43.52, 36.66, 31.44, 29.68, 28.01, 24.70. LRMS (ESI) m/z 406.1 (M
+ Na+), HRMS (ESI) m/z 406.1162 ([M + Na+]), calc. for [C22H25O5N + Na+]
406.1733. [α] 29D = +109.7 (c 1.2, CHCl3); HPLC analysis: Chiralpak IA
(Hex/IPA = 90/10, 0.5 mL/min, 210 nm, 23°C), 11.4 (major), 13.0 min, 77% ee.
208db:colorless oil, 18% yield. 1H NMR (500 MHz, CDCl3) δ 7.37-7.32 (m, 5H),
6.42-6.29 (m, 2H), 5.80-5.75 (m, 1H), 5.24-5.16 (m, 3H), 4.92-4.78 (m, 1H),
4.57-4.44 (m, 1H), 3.71-3.61 (m, 1H), 3.22-3.12 (m, 1H), 2.91(s, 1H), 1.48(s,
9H). 13C NMR (125 MHz, CDCl3) δ 170.04, 155.12, 153.83, 136.82, 136.45,
136.36, 135.43, 134.66, 134.35, 128.17, 128.50, 128.12, 127.94, 116.63, 116.07,
82.68, 81.35, 80.25, 67.49, 48.45, 48.31, 44.03, 43.83, 43.71, 31.57, 29.62, 28.08,
27.89. LRMS (ESI) m/z 406.1 (M + Na+), HRMS (ESI) m/z 406.1614 ([M +
Na+]), calc. for [C22H25O5N + Na+] 406.1733. [α]29D = -163.7 (c 0.3, CHCl3);
Experimental
98
HPLC analysis: Chiralpak IA (Hex/IPA = 90/10, 0.5 mL/min, 210 nm, 23°C),
27.8 (major), 30.4 min, 77% ee.
208fa: colorless oil, 60% yield. 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J =8.2,
2H), 7.35 (d, J = 8.2, 2H), 6.56-6.33 (m, 2H), 5.84-4.98 (m, 3H), 4.34-3.96 (m,
2H), 3.67-3.66 (m, 1H), 3.41-3.14 (m, 1H), 1.44(s, 9H). 13C NMR (125 MHz,
CDCl3) δ 170.17, 168.88, 136.18, 135.94, 135.68, 135.26, 135.04, 134.49, 131.83,
128.79, 124.36, 115.65, 83.99, 81.51, 78.86, 67.49, 49.53, 47.71, 42.32, 27.99.
LRMS (ESI) m/z 454.1, 456.1 (M + Na+), HRMS (ESI) m/z 454.0631, 456.0613
([M + Na+]), calc. for [C21H22O4NBr + Na+] 454.0732. [α]29D = +46.65 (c 2.0,
CHCl3); HPLC analysis: Chiralpak IA+IA (Hex/IPA = 80/20, 1.0 mL/min, 230
nm, 23°C), 22.9 (major), 26.6 min, 65% ee.
208fb: colorless oil, 23% yield. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J =7.5,
2H), 7.32 (d, J = 8.4, 2H), 6.54-6.30 (m, 2H), 5.87-5.69 (m, 1H), 5.34-4.98 (m,
2H), 4.36-3.71 (m, 2H), 3.44-3.18 (m, 1H), 2.93(d, J =1.9, 1H), 1.48(s, 9H). 13C
NMR (125 MHz, CDCl3) δ 169.92, 137.01, 136.03, 135.78, 131.86, 128.72,
124.81, 124.39, 115.92, 83.08, 81.58, 80.39, 48.47, 47.81, 42.60, 29.68, 28.12.
LRMS (ESI) m/z 454.1, 456.1 (M + Na+), HRMS (ESI) m/z 454.0612, 456.0595
Chapter 4
99
([M + Na+]), calc. for [C21H22O4NBr + Na+] 454.0732. [α]29D = -68.7 (c 0.7,
CHCl3); HPLC analysis: Chiralpak IA+IA (Hex/IPA = 80/20, 1.0 mL/min, 230
nm, 23°C), 23.7, 28.9(major) min, 68% ee.
208ga: pale yellow oil, 58% yield. 1H NMR (500 MHz, CDCl3) δ = 8.30 (dd,
J=41.8, 13.1, 1H), 7.65 (dd, J=37.5, 7.9, 1H), 7.35 (d, J=8.0, 1H), 7.20 (t, J=7.5,
1H), 7.13 (t, J=7.4, 1H), 7.04 (s, 1H), 6.41 (dd, J=18.5, 5.6, 1H), 6.04 (dd,
J=265.8, 5.6, 1H), 5.68 (d, J=47.2, 1H), 5.14 (dd, J=22.6, 4.2, 1H), 4.98 (dd,
J=396.4,12.6, 1H), 3.98 (s, 1H), 3.91 (d, J=5.0, 1H), 3.67 (dd, J=138.35, 17.8,
1H), 3.61 (dd, J=16.5, 1.9, 1H), 3.09 (dd, J=12.7, 1H), 1.41 (d, J=9.6, 9H). 13C
NMR (125 MHz, CDCl3) δ = 171.15, 171.12, 169.09, 169.00, 136.30, 136.20,
135.88, 135.30, 134.92, 134.07, 127.11, 127.01, 122.75, 122.53, 122.36, 122.27,
119.84, 119.68, 118.99, 118.65, 116.21, 115.52, 111.31, 108.71, 84.24, 83.93,
81.52, 81.48, 78.95, 78.82, 77.32, 77.07, 76.81, 49.50, 45.88, 45.67, 42.38, 41.54,
32.13, 31.89, 28.03, 28.00. LRMS (ESI) m/z 407.10 (M + H+), HRMS (ESI)
m/z 429.1780 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893. [α]29D =
+141.2 (c 2.5, CHCl3); HPLC analysis: Chiralpak AD+AD (Hex/IPA = 80/20, 1.0
mL/min, 230 nm, 23°C), 28.4 (major), 32.1 min, 68% ee.
Experimental
100
208gb: pale yellow oil, 14.5% yield. 1H NMR (500 MHz, CDCl3) δ 8.18 (d,
J=28.6, 1H), 7.66 (dd, J =35.6, 7.8, 1H), 7.37 (d, J =8.2, 1H), 7.22-7.21 (m, 1H),
7.19-7.06 (m, 2H), 6.38 (s, 1H), 6.06 (dd, J = 293, 5.5, 1H), 5.73 (d, J = 56.6,
1H), 5.01(dd, J =388, 12.7, 1H), 5.21 (d, J =23.4, 1H), 4.19 (dd, J = 678.4,19.0,
1H), 4.07 (dd, J = 494.2, 17.1, 1H), 3.15 (dd, J = 420, 12.9, 1H), 2.88-2.84 (m,
1H), 1.46 (d, J =3.7, 9H). 13C NMR (125 MHz, CDCl3) δ 170.96, 170.87, 170.03,
169.99, 136.89, 135.68, 135.54, 133.70, 127.03, 122.58, 122.47, 122.39, 122.13,
119.93, 119.76, 119.09, 118.61, 116.55, 115.68, 111.20, 109.01, 83.13, 82.80,
81.51, 81.44, 80.35, 80.26, 77.25, 77.00, 76.75, 49.48, 48.52, 48.26, 46.06, 45.68,
42.36, 41.70, 32.15, 32.01, 28.11, 28.00. LRMS (ESI) m/z 407.0 (M + Na+),
HRMS (ESI) m/z 429.1775 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893.
[α]29D = -116.2 (c 4.5, CHCl3); HPLC analysis: Chiralpak AD+AD (Hex/IPA =
80/20, 1.0 mL/min, 254 nm, 23°C), 34.7, 46.5 min(major), 70% ee.
4.4 Procedures towards (+)-alpha-yohimbine and characterization of
compounds
Compound 208ga (0.5 mmol) was dissolved in MeOH (3 ml), 10 % Pd/C (50
mg) was added and reaction vassel was evacuated and recharged with H2 using a
balloon. Stirred untill 208ga was completely consumed. Filter through clite to
Chapter 4
101
remove Pd/C, and the product 210 was obtained as pale yellow oil after
chromatography on silco gel.
210: pale yellow oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ 56(brd, J =13.25,
1H), 7.62 (t, J =8.85, 1H), 7.33 (d, J =8.15, 1H), 7.18 (t, J =7.6, 1H), 7.12(t, J
=7.6, 2H), 7.02 (d, J =11.35, 1H), 4.92 (d, J =14.5, 0.5H), 4.72-4.66 (m, 1H),
4.59(d, J =12.6, 0.5H), 4.20(d, J =15.15, 0.5H), 4.01-3.81(m, 2H), 3.34(d, J
=15.15, 0.5H ), 3.03(d, J =14.5, 0.5H), 2.94 (t, J =12.6, 0.5H), 2.67 (s, 0.5H),
2.57-2.54(m, 1H), 2.27-2.22 (m, 1H), 1.94(s, 0.5H), 1.80-1.57 (m, 4.5H), 1.48 (d,
J =6.3, 9H). 13C NMR (125 MHz, CDCl3) δ 171.17, 170.72, 136.28, 136.23,
127.33, 127.08, 122.83, 122.72, 121.95, 119.39, 118.76, 118.53, 111.30, 111.26,
109.15, 108.99, 83.82, 83.76, 81.06, 78.72, 78.43, 57.26, 57.17, 49.21, 44.60,
44.57, 42.76, 42.21, 41.24, 33.18, 33.00, 31.39, 31.14, 31.06, 30.62, 28.11, 27.07,
26.97. LRMS (ESI) m/z 433.1 (M + Na+), HRMS (ESI) m/z 433.2100, ([M +
Na+]), calc. for [C24H30O4N2 + Na+] 433.2206.
Experimental
102
Compound 208ca (1 mmol) was dissolved in MeOH (4 ml), 10 % Pd/C (100 mg)
was added and reaction vassel was evacuated and recharged with H2 using a
balloon. Stirred untill 208ca was completely consumed. Filter through clite to
remove Pd/C, and the products 211 and 212 were obtained as colorless oil in 20%
and 70% yields respectively after chromatography on silco gel. The two products
become solid after standing at rt for a while.
211: Colorless oil, 20% yield. 1H NMR (500 MHz, CDCl3) δ 4.76 (d, J =5.0, 1H),
4.29-3.96 (m, 2H), 3.07 (brs, 1H), 2.7 (d, J =8.8, 1H), 2.55 (brs, 1H), 2.17-2.12
(m, 1H), 1.76-1.73 (m, 1H), 1.55(brs, 1H), 1.47-1.22(m, 22H). 13C NMR (125
MHz, CDCl3) δ 170.78, 154.98, 81.62, 80.96, 79.67, 78.49, 53.27, 45.03, 33.06,
30.68, 28.44, 28.20, 25.28. LRMS (ESI) m/z 376.0 (M + Na+), HRMS (ESI) m/z
376.2107 ([M + Na+]), calc. for [C19H31O5N + Na+] 376.2202.
212: Colorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 4.64 (t, J =5.1, 1H),
Chapter 4
103
4.26 (brs, 1H), 4.03 (brs, 1H), 3.10-3.03 (m, 1H), 2.61 (brs, 2H), 2.19-2.15 (m,
1H), 1.76-1.71 (m, 3H), 1.64-1.56(m, 2H), 1.55-1.24(m, 19H). 13C NMR (125
MHz, CDCl3) δ 171.10, 154.80, 83.31, 80.64, 79.33, 78.28, 56.90, 42.26, 32.95,
30.54, 28.24, 27.90, 26.73. LRMS (ESI) m/z 376.0 (M + Na+), HRMS (ESI) m/z
376.2107 ([M + Na+]), calc. for [C19H31O5N + Na+] 376.2202.
The compound 212 (0.5 mmol) was dissolved in 3 ml DCM and cooled to 0 oC,
then 0.75 ml TFA was added and the reaction mixture was stirred at 0 oC for 10
mins . The reaction was monitored with TLC. After the reaction was finished, the
reaction mixture was quenched with saturated NaHCO3 and was extracted with
DCM for four times. The combined organic layers were dried over Na2SO4, and
then was concentrated and dried under vacumn. The crude product was used
directly in the next step.
213 (crude product from above), HOBz(5.0 mmol) and NaCNBH3 (3.5 mmol)
were mixed in 5 ml toluene in a 50 ml rbf under N2, the mixture was stirred for 30
minutes at rt. Then 2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl
2-(1H-indol-3-yl)acetate (2.5 mmol) via DIBAL-H reduction) in another 5 ml
toluene was added and the reaction mixture was stirred at rt overnight. Then the
reaction mixture was quenched with saturated NaHCO3 and was extracted with
DCM for four times. The combined organic layers were dried over Na2SO4, and
were concentrated and purified via silica gel chromatography to afford 214 as
colorless oil in 60% yield.
Experimental
104
214: colorless oil, 60% yield. 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.60 (d,
J =7.6, 1H), 7.33 (d, J =8.2, 1H), 7.17 (t, J =7.0, 1H), 7.10 (t, J =7.0, 1H), 7.00 (s,
1H), 4.71 (t, J =5.0, 1H), 3.35 (d, J =13.2, 1H), 3.03-2.96 (m, 3H), 2.77-2.66 (m,
3H), 2.37 (d, J =13.2, 1H), 2.13-2.10 (m, 1H), 2.00 (t, J =11.4, 1H), 1.86-1.82(m,
1H), 1.78-1.72(m, 1H), 1.65-1.59(m, 1H), 1.57-1.49(m, 3H), 1.47(s, 9H). 13C
NMR (125 MHz, CDCl3) δ 171.65, 136.21, 127.47, 121.77, 121.51, 119.06,
118.80, 114.36, 111.05, 84.39, 80.71, 78.60, 59.37, 57.52, 56.76, 52.56, 42.00,
33.72, 31.69, 28.07, 26.80, 22.83. LRMS (ESI) m/z 397.2 (M + H+), HRMS (ESI)
m/z 419.2287 ([M + Na+]), calc. for [C24H32O3N2+ Na+] 419.2413.
The compound 214 (0.25 mmol) was dissolved in 4 ml MeOH in a sealed tube,
then CSA (0.5 mmol) was added and the mixture was heated to 80 oC. After 24
hours, the mixture was cooled to rt and MeOH was evaporated away. Then the
mixture was dissolved in DCM and was quenched with 1 M NaOH. Extraction
was done with DCM for four times. The combined organic layers were dried over
Na2SO4, then was concentrated and purified via flushing silica gel
chromatography. Compound 215 was obtained as a white solid in 80% yield.
215: white solid, 80% yield. 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.60 (d, J
=8.2, 1H), 7.34 (d, J =7.55, 1H), 7.19 (dt, J =7.0, 1H), 7.10 (t, J =8.2, 1H), 7.00
(d, J =2.5, 1H), 4.76 (t, J =5.0, 1H), 3.71 (s, 3H), 3.37 (dd, J =10.0, 1.3, 1H),
3.03-2.96 (m, 3H), 2.79-2.66 (m, 3H), 2.38 (d, J =13.25, 1H), 2.20-2.15 (m, 1H),
2.05-1.98(m, 1H), 1.87-1.83(m, 1H), 1.77-1.74(m, 1H), 1.58-1.50(m, 4H). 13C
Chapter 4
105
NMR (125 MHz, CDCl3) δ 172.89, 136.20, 127.47, 121.79, 121.50, 119.07,
118.78, 114.36, 111.04, 84.37, 78.44, 59.32, 56.69, 56.50, 52.56, 52.50, 51.76,
42.34, 33.70, 31.76, 27.07, 22.85. LRMS (ESI) m/z 355.1 (M + H+), HRMS (ESI)
m/z 355.2024 ([M + H+]), calc. for [C21H26O3N2 + H+] 355.1943.
Compound 215 (0.08 mmol) was dissolved in 1.5 ml EtOH, then an aqueous
solution of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 ml of a 0.1 M solution in water,
0.24 mmol) was added. The resulting solution was heated to 85 oC and refluxed
for 3 hours. Then the mixture was cooled down to 0 oC and 2.5 ml 25% HClO4
was added and stirred at 0 oC for 10 minutes. The mixture was then extracted with
DCM (4x5 ml), the combined organic layers was washed with brine, dried over
Na2SO4 and concentrated via rotary evaporation. The residue was redissolved in
MeOH:H2O (9:1, volume ratio, 2.5 ml). The PH was adjusted to 6 using 5%
NaHCO3 solution. The mixture was cooled to 0 oC, and NaBH4 (0.6mmol, 25mg)
was added. Then the reaction was brought to rt and stirred for 1 hour. The solvents
were removed under reduced pressure, and the residue was partitioned between
cold 10%NH4OH and DCM, the aqueous layer was extracted with DCM for 4
times, and the combined organic layers were dried (Na2SO4) and evaporated under
reduced pressure. The residue was purified by flushing silco gel chromatography
(Hexane:EA 1:1, then DCM: MeOH 20:1) to afford 217 as white foam in 30%
yield.
217: white foam, 30% yield. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.47 (d,
Experimental
106
J =7.55, 1H), 7.30 (d, J =8.2, 1H), 7.14-7.07 (m, 2H), 4.83 (t, J =5.0, 1H), 3.67 (s,
3H), 3.28 (d, J =10.7, 1H), 3.24-3.20 (m, 2H), 3.11-3.07 (m, 1H), 2.99-2.94 (m,
1H), 2.79(dd, J =26.17, 10.1, 1H), 2.74-2.69 (m, 2H), 2.34-2.19(m, 3H),
2.01-1.96(m, 1H), 1.75-1.70(m, 1H), 1.63-1.52(m, 2H). 13C NMR (125 MHz,
CDCl3) δ 172.89, 136.20, 127.47, 121.79, 121.50, 119.07, 118.78, 114.36, 111.04,
84.37, 78.44, 59.32, 56.69, 56.50, 52.56, 52.50, 51.76, 42.34, 33.70, 31.76, 27.07,
22.85. LRMS (ESI) m/z 353.25 (M + H+), HRMS (ESI) m/z 353.1851 ([M + H+]),
calc. for [C21H24O3N2 + H+] 353.1787.
Compound 217 (0.1 mmol) was dissolved in dry DCM under N2 in a dry rbf,
then 0.5 eq of triflic acid was added. The mixture was stirred at rt for12 hrs untill
compound 217 was completely consumed. Purification by flushing silica gel
chromatography afforded 218 as colorless oil in 50% yield.
218: colorless oil, 50% yield. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (d,
J =7.55, 1H), 7.31 (d, J =8.2, 1H), 7.15 (t, J = 6.95, 1H), 7.10 (t, J = 6.95, 1H),
5.87 (d, J =9.45, 1H), 5.73-5.70 (m, 1H), 3.86 (s, 3H), 3.82-3.81 (m, 1H), 3.32 (d,
J = 12, 1H), 3.10-3.04 (m, 2H), 2.97-2.95 (m, 1H), 2.89 (d, J = 10.1, 1H),
2.74-2.69(m, 2H), 2.41 (d, J = 10.7, 1H), 2.40-2.21(m, 1H), 1.96 (d, J = 19.55,
1H), 1.84-1.79(m, 1H), 1.47-1.44 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 174.30,
135.99, 134.15, 127.22, 125.16, 121.51, 121.08, 119.49, 118.12, 110.82, 108.42,
Chapter 4
107
69.64, 66.70, 59.13, 52.81, 52.04, 422.61, 41.43, 33.66, 29.10, 21.88. LRMS
(ESI) m/z 353.19 (M + H+), HRMS (ESI) m/z 353.1875 ([M + H+]), calc. for
[C21H24O3N2 + H+] 353.1787.
In glovebox, to a100ml rbf was add 208ca (2 mmol), then 8 mmol of PPh3 and 2
mmol of Ni(COD)2 was added. The mixture was dissolved in 20 ml dry toluene.
After stirring in glovebox for 1 hour at rt, the rbf was sealed with a rubber septum
and taken out of the glovebox. Under protection of N2 balloon, the mixture was
cooded to 0oC. 2.5 mmol DIBAL-H (1 M in toluene) was diluted with 20 ml dry
toluene and was added to the mixture slowly during 1 hour using a syringe pump.
After addition, the reaction was monitored with TLC, if there is still a lot of
starting material (due to the inaccurate concentration) remained. A bit more
DIBAL-H should be added to ensure full conversion. After full conversion, the
reaction mixture was quenched with saturated NH4Cl solution, and was extracted
with DCM (4x50 ml), the combined organic layers were dried over Na2SO4,
concentrated and purified by flushing silica gel chromatography. 221 was
obtained as colorless oil in 50% yield.
Experimental
108
(5S,6S)-di-tert-butyl 6-hydroxy -3,5,6,7- tetrahydroisoquinoline
-2,5(1H)-dicar- boxylate (221): colorless oil, 50% yield. 1H NMR (500 MHz,
CDCl3) δ 5.54(brs, 1H), 5.48 (brs, 1H), 4.19-4.15 (m, 1H), 4.07-3.98 (t, J =16.3,
2H), 3.94(t, J =23.35, 2H), 3.19 (dd, J =8.2, 1.9, 1H), 2.56-2.50(m, 1H), 2.21(dd,
J = 17.65, 6.95, 1H), 2.06 (brs, 1H), 1.49(s, 9H), 1.45(s, 9H). 13C NMR (125
MHz, CDCl3) δ 171.26, 154.60, 129.45, 121.69, 119.90, 81.66, 79.92, 67.80,
54.38, 45.42, 43.70, 32.42, 28.40, 28.15. LRMS (ESI) m/z 374.2 (M + Na+),
HRMS (ESI) m/z 374.1940, ([M + Na+]), calc. for [C19H29O5N + Na+] 374.2046.
[α]29D = +46.2 (c 0.3, CHCl3); HPLC analysis: Chiralpak IC(Hex/IPA = 90/10,
1.0 mL/min, 230 nm, 23°C), 13.1 (major), 17.5 min, 75.6% ee.
In a dry rbf, 221 (0.6 mmol) was dissolved in 12ml dry DCM under N2, cooled
to 0oC, then Et3N (0.9 mmol) and DMAP (0.06 mmol) were added. Finally, Ac2O
(0.9 mmol) was added and the reaction mixture was brought to rt and stirred. The
reaction was monitored with TLC untill completion (usually around 10 hours).
Rotary evaporate to remove solvent and purified by flushing silica gel
chromatography. 222 was obtained as colorless oil in 80% yield.
(5S,6S)-di-tert-butyl 6- acetoxy -3,5,6,7-tetrahydroisoquinoline-2,5(1H)-
dicarboxyl- ate (222): colorless oil, 80% yield. 1H NMR (500 MHz, CDCl3) δ
5.53(br, 1H), 5.45 (br, 1H), 5.27-5.23 (m, 1H), 4.01(brs, 4H), 3.33(dd, J = 8.5,
Chapter 4
109
1.85, 1H), 2.65(dt, J =17.65, 4.4, 1H), 2.18 (dd, J =17.0, 5.1, 1H), 2.00(s, 3H),
1.44 (d, J =3.8, 18H). 13C NMR (125 MHz, CDCl3) δ 170.01, 169.89, 154.65,
129.32, 128.81, 119.13, 81.44, 79.22, 69.95, 51.17, 43.71, 29.47, 28.39, 27.95,
21.04. LRMS (ESI) m/z 416.1 (M + Na+), HRMS (ESI) m/z 416.2055, ([M +
Na+]), calc. for [C21H31O6N + Na+] 416.2151. [α]29D = +20.2 (c 5.0, CHCl3);
HPLC an alysis: Chiralpak IC(Hex/IPA = 90/10, 1.0mL/min, 254 nm, 23°C),
14.4, 21.01(major) min, 79% ee.
222(0.25 mmol, 110 mg) was dissolved in 2.5 ml EtOH in a 10 ml schlenk flask
which was equipped with an adapter attaching with a H2 balloon, and then Pt/C
(50 wt%, 55 mg) was added. The system was evacuated and charged with H2 (4
times). The reaction mixture was heated to 70 oC, and left stirred for 4 days. The
reaction was monitored by checking curde 1H NMR untill the reaction was
finished. Pt/C was filtered off and the filtrate was concentrated and used directly
in the next step without further purification. Crude 1H NMR shows that a mixture
223 of diisomers (8:1) was obtained.
The mixture 223 was dissolved in 3 ml DCM and cooled to 0 oC, then 0.75 ml
Experimental
110
TFA was added and the reaction mixture was stirred at 0 oC for 10 mins . The
reaction was monitored with TLC. After the reaction was finished, the reaction
was quenched with saturated NaHCO3 and extracted with DCM for 4 times. The
combined organic layers were dried over Na2SO4, then was concentrated and
dried under vacumn. The crude product (a mixture of diisomers 8:1 shown by
crude 1H NMR) was used directly in the next step.
226 (crude product form above), HOBz and NaCNBH3 were mixed in 5ml
toluene in a 50ml rbf under N2, the mixture was stirred for 30 minutes at rt. Then
2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl 2-(1H-indol-3-yl)
acetate via DIBAL-H reduction) in another 5ml toluene was added and the
reaction mixture was stirred at rt overnight. Then the reaction mixture was
quenched with saturated NaHCO3 and extracted with DCM for 4 times. The
combined organic layers were dried over Na2SO4, then was concentrated and
purified via silica gel chromatography. A mixture of 227 and
2-(1H-indol-3-yl)ethanol which is produced from the reduction of the aldehyde
was obtained as evidenced by crude 1H NMR. The mixture can not be separated
and was used directly in the next step.
Chapter 4
111
The mixture of 227 and 2-(1H-indol-3-yl)ethanol, obtained from above, was
dissolved in 4 ml MeOH in a sealed tube, then CSA (0.25 mmol) was added and
the mixture was heated to 80 oC. After 24 hours, the mixture was cooled to rt and
MeOH was evaporated away. Then the mixture was dissolved in DCM and was
quenched with 1 M NaOH. Extraction was done with DCM for four times. The
combined organic layers were dried over Na2SO4, then was concentrated and
purified via flushing silica gel chromatography. Compound 228 was obtained as
white foam in 31% yield over four steps.
(4S,5S,6S,8S)-methyl-(2-(1H-indol-3-yl)ethyl)-6-hydroxydecahydroisoquinoli
ne-5-carboxylate 228: white foam, 31% yield over 4 steps. 1H NMR (500 MHz,
CDCl3) δ 7.95(br, 1H), 7.60 (d, J=8.2, 1H), 7.35 (d, J=8.2, 1H), 7.18 (t, J= 7.6,
1H), 7.11(t, J= 6.9, 1H), 7.04(brs, 1H), 4.05(dt, J= 11.1, 3.8, 1H), 3.74 (s, 3H), 3.0
(brd, J=10.7, 1H), 2.93-2.89(m, 4H), 2.68-2.62(m, 1H), 2.59-2.53(m, 1H), 2.48
(dd, J=10.1, 5.5, 1H), 2.20-2.16(m, 2H), 2.10-2.05(m, 2H), 1.93(brt, J= 11.7, 2.0,
1H), 1.77-1.69(m, 2H), 1.54-1.51 (m, 1H), 1.36 (dq, J= 24.9, 11.0, 3.8, 1H),
1.21-1.18 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 174.85, 136.18, 127.57,
121.91, 121.48, 119.16, 118.82, 114.77, 111.04, 66.11, 59.35, 58.85, 54.69, 54.62,
51.73, 37.84, 36.62, 33.10, 24.56, 23.47, 22.84. LRMS (ESI) m/z 357.1 (M + H+),
Experimental
112
HRMS (ESI) m/z 357.2176, ([M + H+]), calc. for [C21H28O3N2 + H+] 357.2100.
[α] 29D = +6.7 (c 0.8, CHCl3); HPLC analysis: Chiralpak IC (Hex/IPA =
90/10(30mins)70/30, 1.0 mL/min, 254 nm, 23°C), 37.8, 40.2 (major) min,
85.3% ee.
Reported data2 : 1H NMR (CDCl3, 360 MHz) δ 8.11 (brs, 1H), 7.59 (d, J =7.5,
1H), 7.33 (d, J =7.5, 1H), 7.17 (t, J =7.5, 1H), 7.10 (t, J =7.5, 1H), 7.01 (brs, 1H),
4.04 (ddd, J =11.0 , 10.5 , 4.0 , 1H) , 3.73 (s , 3H) , 2.97 (brd , J =12.0, 1H),
2.80-2.95 (m, 4H), 2.52-2.70 (m, 2H), 2.48 (dd, J =10.5, 5.0, 1H), 1.98-2.22 (m,
4H), 1.92 (brt, J =12.0Hz, 1H), 1.65-1.80 (m, 2H), 1.51 (m, 1 H), 1.35 (dq, J =3.0,
12.0Hz, 1H), 1.20 (m, 1H); 13C NMR (CDCl3,) δ 174.6, 136.2, 127.5, 121.7,
121.6, 119.0, 118.7, 111.4, 111.0, 66.0, 59.3, 58.7, 54.6, 54.5, 51.6, 37.8, 36.6,
33.2, 24.5, 23.3, 22.7; mass spectrum, m/e 356.2092 (C21H28N2O3, requires
m/e356.2100).
228 (28 mg, 0.08 mmol) was dissolved in 1.5 ml EtOH, then an aqueous solution
of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 ml of a 0.1 M solution in water, 0.24 mmol)
was added. The resulting solution was heated to 85 oC and refluxed for 3 hours.
Then the mixture was cooled down to 0 oC and 2.5 ml 25% HClO4 was added and
stirred at 0 oC for 10 minutes. The mixture was then extracted with DCM (4x5 ml),
Chapter 4
113
the combined organic layers were washed with brine, dried over Na2SO4 and
concentrated via rotary evaporation. The residue was redissolved in MeOH:H2O
(9:1, volume ratio, 2.5 ml). The PH was adjusted to 6 using 5% NaHCO3 solution.
The mixture was cooled to 0 oC, and NaBH4 (0.6 mmol, 25 mg) was added. Then
the reaction was brought to rt and was stirred for 1 hour. The solvent was removed
under reduced pressure, and the residue was partitioned between cold
10%NH4OH and DCM, the aqueous layer were extracted with DCM for four
times, and the combined organic layers were dried (Na2SO4) and evaporated under
reduced pressure. The residue was purified by flushing silica gel chromatography
(Hexane: EA 1:1, then DCM: MeOH 20:1) to afford 1 as white foam in 30%
yield.
(+)-Alpha-Yohimbine 170: white foam, 30% yield. 1H NMR (500 MHz,
CDCl3) δ 7.74(brs, 1H), 7.46 (d, J =7.8, 1H), 7.30 (d, J =8.0, 1H), 7.13 (t, J = 7.7,
1H), 7.08(t, J = 7.6, 1H), 4.00(dt, J = 10.9, 4.3, 1H), 3.84 (s, 3H), 3.15 (brd, J
=11.2, 1H), 2.99-2.92(m, 2H), 2.84(dd, J =11.3, 1.8, 1H), 2.70-2.67(m, 2H),
2.61-2.50(m, 3H), 2.45-2.41(m, 1H), 2.10-2.04(m, 2H), 1.82 (brd, J =12.6, 1H),
1.71 (q, J = 24.5, 11.9,1H), 1.61-1.54(m, 2H), 1.41-1.33(m, 1H). 13C NMR (125
MHz, CDCl3) δ 174.71, 135.99, 134.47, 127.32, 121.44, 119.46, 118.10, 110.77,
108.48, 66.07, 60.55, 60.24, 54.73, 53.30, 51.98, 37.95, 36.56, 33.11, 27.75, 24.60,
21.73. LRMS (ESI) m/z 355.2 (M + H+), HRMS (ESI) m/z 355.2013, ([M + H+]),
calc. for [C21H26O3N2 + H+] 355.1943. [α]29D = +16.0 (c 0.25, EtOH);
Experimental
114
Reported data2 : 1H NMR(CDCl3, 500 MHz) δ 7.77 (brs, 1H), 7.45 (d, J =7.8,
1H), 7.27( brd , J =7.8, l H ) , 7.12 (dt , J =1.1, 7.8, lH ) , 7.07 (dt , J =1.1, 7.8,
1H), 3.99 (dt , J =4.4, 11.0, 1H), 3.83 (s, 3H), 3.13 (dd, J =11.2, 2.1, 1H),
2.90-3.00(m, 2H), 2.83 (dd, J =11.4, 1.9, 1H), 2.77 (brs, 1H), 2.67 (m, 1H), 2.58
(dd, J =11.4, 3.0,1H), 2.56 (dd, J =11.0, 4.5, 1H), 2.52 (m, 1 H), 2.42 (ddt, J =12.5,
3.5, 4.5, 1H), 2.09 (dq, J =13.0, 3.5, 1H), 2.04 ( dq , J =13.0, 3.5, 1H), 1.81 (m,
1H), 1.70 (dt, J =11.2, 12.5, 1H), 1.61(dt, J =12.5, 3.5, 1H), 1.54 (dq, J =13.0, 3.5,
1H), 1.35 (ddt, J =11.0, 3.5, 13.0 Hz, 1H); 13C NMR (CDCl3,) δ 174.6, 136.1,
134.6, 127.4, 121.4, 119.5, 118.1, 110.8, 108.6, 66.1, 60.6, 60.3, 54.9, 53.3,
51.8,38.1, 36.7, 33.3, 27.8, 24.7, 21.8; mass spectrum, m/e 354.1937 (C21H26N2O3
requires m/e 354.1943).
Reported optical rotation3: [α]29D = -26.0(c1.3, EtOH); [α]29
D = -15.0 (c 1.3,
pyridine)
Chapter 4
115
References:
1. Suárez, A.; Fu, G. C. Angew. Chem. Int. Ed. 2004, 43, 3580.
2. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109,
6124.
3. Stoll, von A.; Hofmann, A.; Brunner, R. Helv. Chim. Acta. 1955, 32, 270.
116
Appendix
Copies of NMR Spectra
142a 2.0
000
1.2
742
2.0
695
0.9
746
2.0
694
2.0
976
2.0
414
4.1
135
3.0
502
Inte
gra
l
7.4
314
7.4
071
7.3
808
7.2
853
7.2
600
7.2
366
7.1
753
7.1
509
4.3
420
4.0
206
3.9
963
3.9
729
3.9
495
3.4
849
3.4
655
3.4
450
3.2
570
3.2
356
3.2
142
1.9
276
1.9
062
1.8
857
1.8
662
1.8
390
1.8
175
1.7
961
1.7
766
1.6
296
1.1
737
1.1
494
1.1
260
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
nv13fdw2 1 fdw5233
16
7.7
110
16
2.1
688
14
5.1
045
12
8.8
864
12
8.1
766
12
5.7
962
85
.673
7
76
.403
175
.980
175
.557
1
57
.173
6
50
.950
2
25
.346
7
22
.665
2
19
.037
3
13
.552
3
(ppm)
-20-100102030405060708090100110120130140150160170180190200
nv13fdw1 2 fdw5233
117
142b
2.0
000
1.2
736
2.1
137
0.8
623
2.1
491
2.3
165
2.2
503
2.2
312
9.8
944
Inte
gra
l
7.4
285
7.4
032
7.3
778
7.2
736
7.2
600
7.2
493
7.2
240
7.1
811
7.1
558
4.3
186
3.4
625
3.4
431
3.4
226
3.2
171
3.1
957
3.1
742
1.9
100
1.8
896
1.8
691
1.8
019
1.7
805
1.7
610
1.6
140
1.4
669
1.3
753
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
nv14fdw 3 fdw5236B
16
8.7
549
16
2.2
465
14
6.4
255
12
9.7
707
12
6.7
821
12
6.5
165
89
.148
3
77
.408
076
.987
476
.559
4
51
.890
8
28
.557
827
.945
326
.292
423
.813
020
.278
3
(ppm)
0102030405060708090100110120130140150160170180190200210220
nv14fdw 31 fdw5236B
118
142c
1.01
04
2.41
39
1.01
00
1.00
00
1.02
64
2.13
35
1.02
18
3.19
60
1.09
76
18.4
28
Inte
gral
7.50
937.
4899
7.47
727.
2824
7.26
977.
2600
7.25
037.
0681
7.05
647.
0496
7.03
70
4.01
283.
8249
3.76
933.
7576
3.42
553.
3992
3.38
563.
3671
3.35
153.
3048
3.26
482.
5821
2.56
842.
5441
2.52
562.
5129
2.49
152.
4730
1.95
191.
9363
1.91
981.
9042
1.88
671.
8769
1.84
581.
7620
1.74
161.
7231
1.71
531.
7075
1.69
191.
6763
1.58
471.
3598
1.34
81
(ppm)
0.01.02.03.04.05.06.07.08.09.0
nv15fdw 2 fdw5236A
168.
6295
162.
8368
146.
5140
144.
7652
130.
1323
128.
7966
127.
8078
127.
5717
91.9
155
77.4
006
76.9
800
76.5
520
53.7
651
35.4
721
31.1
774
28.5
652
26.1
226
23.6
432
20.6
104
(ppm)
020406080100120140160180200220
nv15fdw 3 fdw5236A
119
139b
1.0
240
0.9
712
0.9
639
1.1
206
0.9
052
4.1
947
1.0
000
10
.214
Inte
gra
l
7.5
285
7.5
134
7.4
025
7.3
873
7.3
407
7.2
600
7.2
335
7.2
184
7.2
033
7.1
831
7.1
680
7.1
541
2.6
293
2.6
205
2.0
381
1.4
090
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw06011 1.1 fdw7119
169.
3817
143.
0534
134.
8422
128.
4565
126.
7983
126.
5801
126.
4492
82.9
348
77.4
218
77.0
000
76.5
709
69.7
197
36.3
948
34.6
057
30.7
655
14.7
867
(ppm)
020406080100120140160180200220
13C Standard AC300 ju01fdw 11.1 fdw7119
120
150
2.8
557
1.9
453
2.0
000
3.9
655
18
.910
Inte
gra
l
7.5
282
7.5
130
7.4
714
7.4
235
7.4
084
7.2
861
7.2
546
7.2
407
7.2
256
7.2
042
7.1
890
3.1
761
2.6
933
2.6
832
2.6
567
2.6
441
1.6
494
1.4
376
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw06011 3.1 fdw4234
16
9.9
213
16
7.8
444
14
3.3
807
13
5.0
803
12
8.7
112
12
6.7
800
12
6.5
614
12
6.4
594
82
.144
981
.824
2
77
.255
177
.000
076
.744
973
.961
2
36
.839
334
.653
1
30
.725
2
27
.883
127
.117
9
15
.341
5
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw06011 31.1 fdw4234
82
.144
9
81
.824
2
(ppm)
8182838485
12
8.7
112
12
6.7
800
12
6.5
614
12
6.4
594
(ppm)
125.0126.0127.0128.0129.0
121
152
1.00
00
1.04
60
1.10
08
0.94
25
0.89
06
1.04
50
1.01
15
1.89
77
2.05
69
9.03
56
8.90
62
Inte
gral
7.60
197.
5746
7.39
347.
3691
7.34
677.
3136
7.30
877.
2882
7.26
00
6.83
056.
8042
4.48
81
3.48
303.
4606
3.42
463.
4031
3.38
273.
2755
3.25
513.
2337
3.19
763.
1791
2.72
332.
7019
2.68
04
2.02
111.
9997
1.97
821.
9578
1.93
541.
5536
1.39
001.
2965
(ppm)
0.01.02.03.04.05.06.07.08.09.0
jun29fdw1 1.1 fdw5159
17
1.2
343
16
6.8
880
15
6.8
670
14
6.6
616
13
5.4
895
13
1.1
801
12
9.7
854
12
8.7
523
12
7.6
455
10
2.3
865
79
.621
777
.415
476
.994
776
.574
1
36
.025
533
.981
531
.583
228
.255
225
.694
7
18
.381
9
(ppm)
0102030405060708090100110120130140150160170180190200210220
oc19fdw 2 fdw5159
122
153
0.9
410
0.9
225
1.0
260
1.0
175
0.9
501
1.9
684
2.0
124
1.9
368
1.9
830
18
.000
Inte
gra
l
8.6
065
7.8
425
7.8
399
7.8
261
7.8
235
7.3
987
7.3
962
7.3
823
7.3
798
7.2
600
7.2
524
7.2
499
7.2
373
7.2
222
7.2
184
7.1
528
7.1
503
7.1
377
7.1
226
7.1
201
4.1
636
3.7
653
3.7
514
3.7
388
3.1
185
3.1
135
3.1
084
2.6
079
2.6
041
2.5
953
2.5
903
2.5
852
2.5
777
2.5
726
1.5
968
1.4
291
1.4
228
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw06011 2.1 fdw4231
7.8
425
7.8
399
7.8
261
7.8
235
7.3
987
7.3
962
7.3
823
7.3
798
7.2
600
7.2
524
7.2
499
7.2
373
7.2
222
7.2
184
7.1
528
7.1
503
7.1
377
7.1
226
7.1
201
(ppm)
7.17.27.37.47.57.67.77.87.9
167.
6944
167.
2071
141.
3806
134.
7113
126.
8274
126.
4710
125.
9473
125.
6637
81.7
711
79.5
165
77.4
218
77.0
000
76.5
709
73.9
526
70.6
361
69.9
525
34.4
166
30.4
673
27.9
072
27.0
708
20.2
706
(ppm)
020406080100120140160180200220
13C Standard AC300 jun02fdw 21.1 fdw4231
123
154
1.0
098
1.0
074
1.1
039
1.2
342
1.0
168
2.0
000
1.9
428
6.3
889
19
.555
Inte
gra
l
8.6
371
7.9
904
7.9
641
7.3
923
7.3
660
7.2
609
7.2
336
7.2
083
7.1
352
7.1
099
7.0
846
4.2
747
3.1
946
1.5
603
1.4
551
1.4
337
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
jun16fdw 3.1 fdw7140
16
7.5
940
16
6.8
412
14
0.2
769
13
4.9
425
12
6.7
832
12
6.3
315
12
5.1
557
12
4.9
119
83
.699
681
.978
978
.358
177
.426
077
.003
076
.580
071
.769
0
64
.298
0
34
.335
3
30
.348
828
.728
427
.896
727
.065
0
(ppm)
0102030405060708090100110120130140150160170180190200210220
jun16fdw 31.1 fdw7140
124
155
0.9
546
1.0
449
1.1
543
0.9
618
0.9
136
2.0
000
1.9
029
1.9
084
18
.122
Inte
gra
l
7.5
532
7.5
298
7.3
788
7.3
535
7.2
600
7.2
415
7.2
181
7.1
947
7.1
538
7.1
295
7.1
051
6.5
305
4.2
768
4.2
544
4.2
310
3.1
665
2.6
191
2.5
967
2.5
733
1.4
572
1.4
046
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
jun16fdw 2.1 fdw7145
16
7.7
733
15
4.0
788
13
5.1
361
12
6.8
191
12
6.4
176
12
5.6
719
81
.692
179
.118
177
.433
277
.010
276
.587
2
73
.891
3
63
.193
9
34
.550
3
30
.642
8
27
.918
227
.143
9
19
.708
8
(ppm)
0102030405060708090100110120130140150160170180190200210220
jun16fdw 21.1 fdw7145
125
156
1.00
00
1.10
74
0.78
15
1.09
95
1.27
59
0.85
58
1.75
11
1.77
75
18.1
58
Inte
gral
9.56
06
7.99
277.
9883
7.96
647.
9620
7.88
377.
4388
7.43
397.
4125
7.40
767.
2985
7.29
367.
2733
7.25
967.
2481
7.20
277.
1977
7.17
757.
1517
7.14
68
4.60
704.
5856
3.72
33
1.47
821.
4639
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
1H normal range AC300 jun08fdw 2.1 fdw5188.1
166.
4433
160.
1595
156.
4720
140.
9224
133.
8966
126.
7982
126.
4855
125.
9836
124.
0345
119.
5761
116.
4705
82.0
838
47.7
988
47.2
024
34.2
565
30.4
673
27.8
053
(ppm)
020406080100120140160180200220
13C Standard AC300 jun08fdw 21.1 fdw5188.1
126
157
0.89
17
1.02
20
1.16
22
2.05
88
4.17
95
2.00
00
3.11
29
19.1
32
Inte
gral
8.07
907.
5410
7.51
757.
3915
7.36
687.
2600
7.22
827.
2069
7.18
177.
1422
4.26
544.
2381
3.18
45
2.27
51
1.44
461.
4018
1.37
88
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H normal range AC300 jun02 3.1 fdw5207
127
158
1.03
07
1.04
67
1.18
57
0.84
39
1.00
46
1.00
00
0.95
82
2.14
50
0.09
32
25.3
61
Inte
gral
8.68
958.
0365
8.03
218.
0102
8.00
527.
4377
7.43
227.
4108
7.40
597.
2996
7.27
667.
2508
7.24
597.
1802
7.17
477.
1539
7.15
007.
1292
7.12
43
5.70
975.
6895
5.60
515.
5843
4.31
444.
2377
4.18
784.
1615
4.11
16
3.23
34
1.52
361.
5050
1.49
621.
4798
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H normal range AC300 jun07fdw1 2.1 fdw7122A
210.
8160
167.
3453
164.
3197
140.
0933
134.
9222
126.
8492
126.
3692
125.
1837
124.
8346
100.
1209
92.5
133
81.5
529
77.4
218
77.0
000
76.5
709
75.9
963
63.4
286
34.3
438
30.3
946
28.0
818
27.0
708
26.6
054
(ppm)
020406080100120140160180200220
13C Standard AC300 jun07fdw1 21.1 fdw7122A
128
159
0.9
126
0.9
814
1.1
283
2.1
407
1.8
497
4.0
000
3.1
862
19
.403
Inte
gra
l
8.1
921
7.5
356
7.5
113
7.3
964
7.3
720
7.2
600
7.2
347
7.2
113
7.1
850
7.1
480
7.1
256
5.6
822
5.6
617
5.6
442
4.2
885
4.2
651
4.2
388
4.1
920
4.1
813
4.1
511
4.1
024
2.2
782
2.2
373
2.2
042
1.4
640
1.4
299
1.3
851
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
jun18fdw 1.1 fdw7136
21
1.3
414
17
2.0
363
16
7.3
759
16
4.0
204
14
2.8
479
13
4.6
025
12
7.7
984
12
6.6
584
12
6.2
712
93
.082
091
.268
0
81
.739
377
.423
077
.000
076
.577
0
51
.740
6
47
.754
2
44
.198
0
34
.511
5
30
.718
630
.424
728
.022
8
20
.974
8
(ppm)
0102030405060708090100110120130140150160170180190200210220
jun18fdw 11.1 fdw7136
129
206
15
2.9
655
14
2.0
636
11
0.1
376
10
7.4
850
81
.636
777
.271
577
.023
876
.768
7
71
.667
6
44
.624
1
37
.161
9
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw6070.2
130
207a
1.00
00
1.03
79
1.02
19
2.15
98
2.16
55
0.96
62
9.83
82
Inte
gral
7.35
337.
3508
7.26
00
6.32
206.
3182
6.31
576.
3119
6.26
656.
2602
4.72
22
4.14
984.
1447
2.22
592.
2209
2.21
71
1.33
08
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw1223 2 fdw6087
177.
1013
150.
4003
142.
3915
110.
3344
108.
7530
79.0
205
77.2
934
77.0
384
76.7
833
72.0
028
43.2
468
38.9
837
36.3
748
28.5
482
(ppm)
020406080100120140160180200220
13C AMX500 fdw1223 21 fdw6087
131
207c
1.0
000
1.0
478
0.9
871
2.1
313
2.1
397
0.9
921
9.4
316
Inte
gra
l
7.3
422
7.3
406
7.3
381
7.2
600
6.3
051
6.3
004
6.2
972
6.2
925
6.2
245
4.4
990
4.0
484
2.1
990
1.4
699
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw10227
15
4.6
375
15
1.0
648
14
2.1
476
11
0.1
972
10
8.0
025
80
.623
879
.180
177
.320
877
.000
076
.686
571
.619
0
42
.176
9
35
.344
9
28
.272
4
(ppm)
0102030405060708090100110120130140150160170180190200210220
fdw10227
132
207d
6.39
98
2.09
32
2.24
82
2.35
24
2.33
32
1.00
00
Inte
gral
7.37
547.
3627
7.34
897.
3363
7.33
257.
3262
7.31
997.
3123
7.26
06
6.31
636.
2016
5.20
06
4.60
30
4.14
914.
0823
2.23
91
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw0617 1.1 fdw7149
155.
4194
150.
4203
142.
4187
136.
3556
128.
4634
128.
0480
127.
8731
110.
2960
108.
8531
108.
4669
78.7
052
77.2
551
77.0
000
76.7
449
72.1
393
67.7
013
42.4
943
42.1
955
35.7
972
(ppm)
020406080100120140160180200220
13C AMX500 fdw0617 11.1 fdw7149
133
207e
2.00
00
1.00
17
2.21
05
1.96
62
2.09
55
2.11
17
0.21
86
3.29
29
0.94
81
Inte
gral
7.76
477.
7470
7.36
007.
3197
7.30
33
6.32
126.
3174
6.31
36
4.45
40
4.03
804.
0342
2.44
32
2.10
402.
0990
2.09
52
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw1223 1 fdw6086
148.
6441
143.
6595
142.
9818
136.
0078
129.
5147
127.
7585
110.
4291
110.
0137
77.3
298
77.0
748
76.8
197
73.9
777
42.7
294
36.1
562
21.5
450
(ppm)
020406080100120140160180200220
13C AMX500 fdw1223 11 fdw6086
134
207f
2.16
83
2.19
52
1.05
03
2.12
92
2.36
51
2.37
33
1.00
00
Inte
gral
7.54
377.
5273
7.43
787.
4214
7.37
357.
2600
6.31
57
4.76
38
4.53
56
4.23
68
3.95
31
2.30
91
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw08101 1.1 fdw7202
170.
0452
149.
2616
142.
6446
133.
9508
131.
5897
128.
7913
124.
3606
110.
3106
109.
2758
78.1
295
77.2
551
77.0
000
76.7
449
72.6
494
(ppm)
020406080100120140160180200220
13C AMX500 fdw08101 31.1 fdw7202
135
207g
136
208a
0.8
599
0.9
002
0.8
607
1.8
961
3.8
960
1.8
975
9.0
000
3.2
652
Inte
gra
l
7.3
413
7.2
606
6.3
138
6.3
075
6.3
037
6.2
785
6.2
722
4.7
203
4.2
071
4.1
920
4.1
781
4.1
643
3.2
742
3.2
704
3.2
666
1.7
084
1.3
238
1.2
898
1.2
759
1.2
621
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw1018 1.1 fdw11023A
17
7.0
940
16
8.1
451
15
0.6
262
14
2.3
041
11
0.3
125
10
8.6
874
78
.532
377
.293
477
.045
676
.790
675
.974
4
61
.618
3
43
.071
9
38
.998
336
.797
5
28
.577
3
26
.077
8
14
.119
2
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw1018 11.1 fdw11023A
137
208b
0.9
131
0.9
809
0.9
379
2.0
858
2.0
378
2.0
000
9.5
675
9.8
028
Inte
gra
l
7.3
211
6.2
885
6.2
848
6.2
570
6.2
520
4.7
051
4.1
642
3.1
733
3.1
695
3.1
645
1.4
448
1.3
061
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500fdw1225 2 fdw6089
17
7.0
065
16
7.1
904
15
0.6
918
14
2.2
385
11
0.2
833
10
8.6
145
81
.869
978
.204
377
.322
677
.067
576
.812
476
.615
7
42
.977
2
38
.961
836
.833
9
28
.570
027
.943
3
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500fdw1225 21 fdw6089
138
208c
1.0
000
2.0
846
2.0
788
1.9
780
1.8
456
20
.551
Inte
gra
l
7.3
106
7.2
600
6.2
792
6.2
695
6.2
627
6.2
101
4.4
940
4.0
450
3.1
723
3.1
645
3.1
577
1.4
425
1.4
387
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
de17fdw 6 fdw6081
16
7.2
548
15
4.6
364
15
1.2
493
14
2.0
106
11
0.1
178
10
7.8
302
91
.005
781
.715
380
.350
178
.350
477
.420
677
.000
076
.572
0
41
.978
4
35
.588
0
28
.238
327
.972
727
.847
227
.131
5
(ppm)
0102030405060708090100110120130140150160170180190200210220
de17fdw 61 fdw6081
139
208d
5.83
72
1.90
55
1.98
16
1.94
37
2.04
04
1.92
11
9.00
00
Inte
gral
7.38
497.
3668
7.35
927.
3477
7.33
077.
3263
7.32
197.
3181
7.29
787.
2600
6.29
806.
2098
5.18
09
4.60
84
4.15
204.
1279
4.10
444.
0808
3.19
00
1.46
48
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H normal range AC300 jun19fdw 1.1 fdw7154
167.
1780
155.
3884
150.
5737
142.
2825
136.
3914
128.
3765
127.
9256
127.
7874
110.
2013
108.
7030
108.
3321
81.8
147
77.9
237
77.4
291
77.0
000
76.5
782
67.5
087
42.2
423
41.9
659
35.9
512
27.8
781
27.1
436
(ppm)
020406080100120140160180200220
13C Standard AC300 jun19fdw 11.1 fdw7154
140
208e
1.9
045
0.9
822
2.2
502
0.9
223
0.9
473
2.0
338
2.0
309
2.0
000
3.1
223
9.4
207
Inte
gra
l
7.7
485
7.7
321
7.3
362
7.2
896
7.2
732
7.2
606
6.3
238
6.3
175
6.2
961
6.2
923
4.4
302
4.0
155
2.9
413
2.9
375
2.9
337
2.4
181
1.4
423
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500fdw1225 3 fdw6090
16
6.7
896
14
8.8
263
14
3.3
826
14
2.9
016
13
6.1
171
12
9.3
763
12
7.8
823
11
0.3
781
10
9.9
627
81
.928
278
.517
777
.286
177
.031
176
.776
075
.777
6
42
.780
4
36
.651
7
27
.943
327
.017
8
21
.523
2
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500fdw1225 31 fdw6090
141
208f
2.0
104
1.8
929
1.0
000
1.8
661
2.0
528
2.1
796
1.8
405
8.9
493
Inte
gra
l
7.5
811
7.5
647
7.4
878
7.4
714
7.3
996
7.2
861
6.3
506
4.8
315
4.5
856
4.3
146
3.9
880
3.2
505
3.2
467
3.2
417
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0811
16
7.0
100
14
2.6
629
13
4.2
533
13
1.6
590
12
8.9
553
12
4.3
716
11
0.3
725
10
9.2
867
81
.980
977
.572
177
.258
777
.003
776
.748
6
28
.061
727
.952
427
.201
8
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw7203.1
142
208g 1.
1055
1.10
07
2.13
46
1.14
98
1.14
53
1.11
51
2.11
32
1.04
46
1.13
93
1.18
61
1.08
38
1.24
49
1.08
32
1.99
25
9.00
00
Inte
gral
8.51
827.
6269
7.60
807.
5903
7.38
867.
3331
7.32
567.
3180
7.30
037.
2600
7.18
567.
1717
7.15
667.
1163
7.10
627.
0923
7.05
706.
9952
6.32
716.
2855
6.25
526.
2502
6.23
126.
2262
4.71
964.
6276
4.60
24
4.30
494.
2796
4.05
273.
9884
3.94
18
3.18
913.
1853
3.18
15
1.89
31
1.48
961.
4619
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0902 1.1 fdw7229
1.10
07
2.13
46
1.14
98
1.14
53
1.11
51
2.11
32
7.62
697.
6080
7.59
037.
3886
7.33
317.
3256
7.31
807.
3003
7.26
007.
1856
7.17
177.
1566
7.11
637.
1062
7.09
237.
0570
6.99
52
6.32
716.
2855
6.25
526.
2502
6.23
126.
2262
(ppm)
6.46.66.87.07.27.47.6
1.04
46
1.13
93
1.18
61
1.08
38
1.24
49
1.08
32
Inte
gral
4.71
96
4.62
764.
6024
4.30
494.
2796
4.05
27
3.98
84
3.94
18
(ppm)
3.94.04.14.24.34.44.54.64.7
171.
3642
171.
3277
167.
3561
167.
1302
150.
5806
149.
9393
142.
6009
142.
2001
136.
1807
127.
1517
127.
1080
122.
9396
122.
8521
122.
0141
121.
9485
119.
4635
119.
4052
118.
6109
118.
5380
118.
4943
111.
2507
111.
1996
110.
3252
110.
2887
108.
7146
108.
5689
108.
4086
82.0
502
81.8
680
78.0
785
77.6
777
77.2
551
77.0
000
76.7
522
76.3
952
43.5
364
41.3
575
37.4
369
34.4
418
31.3
592
31.0
677
27.9
050
27.1
835
27.0
961
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0902 11.1 fdw7229
82.0
502
81.8
680
78.0
785
77.6
777
77.2
551
77.0
000
76.7
522
76.3
952
(ppm)
757677787980818283
143
208h
0.8
432
0.8
823
0.8
306
1.7
832
1.8
030
1.8
143
6.2
620
8.8
870
9.0
000
Inte
gra
l
7.3
281
7.2
600
6.2
943
6.2
905
6.2
880
6.2
842
6.2
136
4.4
977
4.0
867
3.2
068
3.2
030
3.1
979
1.8
464
1.8
313
1.8
162
1.8
010
1.4
594
0.8
303
0.8
152
0.8
000
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 boc eoc DA sub
16
6.9
626
15
4.6
761
15
1.3
166
14
2.0
398
11
0.1
575
10
8.3
066
10
7.7
891
89
.884
1
80
.410
578
.326
377
.255
177
.000
076
.744
9
42
.100
841
.831
141
.714
535
.840
935
.644
235
.534
928
.291
227
.045
126
.658
8
7.5
878
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0807-1 11.1 boc eoc DA sub
144
208i
0.8
760
0.9
261
0.8
579
1.9
472
1.8
915
1.9
339
6.6
961
9.0
000
9.8
348
Inte
gra
l
7.3
117
7.3
079
7.2
600
6.2
817
6.2
779
6.2
754
6.2
716
6.2
363
6.2
300
4.6
843
4.1
510
3.1
841
3.1
803
3.1
752
1.8
237
1.8
086
1.7
935
1.7
783
1.2
904
0.8
076
0.7
925
0.7
773
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0128 3 fdw6143.2
17
6.8
953
16
6.7
148
15
0.6
025
14
2.1
418
11
0.1
794
10
8.4
742
89
.884
1
77
.991
177
.247
877
.000
076
.744
976
.570
1
42
.873
2
38
.843
336
.715
4
28
.458
827
.234
526
.979
526
.615
1
7.5
222
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0128 31 fdw6143.2
145
208aa
2.00
00
1.00
36
0.99
32
1.01
40
1.07
74
2.09
49
1.04
99
1.01
78
1.00
84
9.55
91
3.39
75
Inte
gral
7.26
00
6.39
395.
7433
5.73
965.
7358
5.73
205.
2050
5.19
625.
0966
5.07
144.
5999
4.56
464.
1208
4.11
324.
1044
4.09
944.
0905
4.08
424.
0767
4.07
044.
0615
4.05
523.
7514
3.71
483.
6858
3.68
213.
6770
3.67
323.
0441
3.01
89
1.30
181.
2362
1.22
111.
2072
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw1026 1.1 fdw11026.1
177.
2815
169.
7828
135.
7289
135.
0002
134.
9055
116.
1915
84.2
728
78.6
834
77.2
551
77.0
000
76.7
449
60.8
366
48.4
918
45.4
748
44.4
473
38.9
453
28.2
766
14.0
663
(ppm)
020406080100120140160180200220
13C AMX500 fdw1026 11.1 fdw11026.1
146
208ab
2.0
000
0.9
161
0.9
011
0.9
728
1.0
542
1.9
478
1.1
545
1.0
215
0.9
103
12
.994
Inte
gra
l
7.2
600
6.4
229
6.4
115
6.3
977
6.3
863
5.8
316
5.8
278
5.8
240
5.8
202
5.8
165
5.3
033
5.2
996
5.1
508
5.1
256
4.6
352
4.6
314
4.5
986
4.5
961
4.5
923
4.2
557
4.2
481
4.2
406
4.2
330
4.2
267
4.2
191
4.2
128
4.2
053
4.1
989
4.1
914
4.1
838
4.1
775
3.7
514
3.7
148
3.0
807
3.0
567
2.9
975
2.9
937
1.3
144
1.3
081
1.2
930
1.2
791
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw1027 1.1 fdw11026.2
17
7.2
742
17
0.9
342
13
6.6
690
13
5.3
063
13
4.6
795
11
6.7
890
83
.391
080
.221
077
.255
177
.000
076
.744
9
61
.193
7
47
.712
145
.686
244
.687
8
38
.967
2
28
.305
8
14
.212
0
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw1027 11.1 fdw11026.2
147
208ba
2.0
000
1.0
029
0.9
891
1.0
341
1.0
737
1.1
568
1.0
156
1.0
308
9.6
137
9.6
677
Inte
gra
l
7.2
606
6.4
084
5.7
200
5.7
150
5.7
112
5.7
074
5.7
036
5.1
691
5.1
603
5.0
909
5.0
670
4.6
182
4.6
131
4.5
879
4.5
829
3.7
520
3.7
167
3.6
360
3.6
323
3.6
272
3.6
234
3.0
637
3.0
385
1.4
109
1.3
201
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw02061 4 fdw6229.1
17
7.3
252
16
9.0
031
13
5.6
925
13
4.9
783
11
5.9
874
84
.360
281
.299
578
.851
077
.247
877
.000
076
.744
9
49
.541
2
45
.504
044
.629
5
38
.996
3
28
.334
927
.977
8
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw02061 41 fdw6219.1
148
208bb
2.13
58
1.00
00
0.92
64
0.97
59
1.21
92
1.12
06
1.03
87
0.93
15
10.2
31
10.9
48
Inte
gral
7.26
057.
2591
6.40
266.
3912
6.38
386.
3824
6.38
116.
3710
6.36
925.
7994
5.79
625.
7925
5.78
845.
7847
5.24
065.
2374
5.13
895.
1138
4.62
964.
5935
3.75
213.
7164
3.09
213.
0669
2.91
852.
9144
2.91
072.
9071
1.47
811.
3118
(ppm)
0.01.02.03.04.05.06.07.08.09.0
fdw0802 5.1 fdw7189.3
177.
1917
170.
0059
136.
4701
135.
3573
135.
0373
116.
2148
83.2
244
81.3
407
80.1
843
77.3
697
76.9
478
76.5
260
48.3
722
45.6
230
44.6
630
38.8
809
29.5
933
28.2
333
28.0
587
(ppm)
020406080100120140160180200220
13C Standard AC300 aug02fdw 11.1 fdw7189.3
149
208ca
2.0
000
1.0
459
1.0
772
0.9
939
0.8
841
1.8
889
0.8
861
24
.217
Inte
gra
l
7.2
607
6.3
933
5.6
822
5.1
237
5.1
162
4.7
896
4.6
421
4.6
194
4.4
946
4.4
606
4.3
484
4.3
156
3.5
806
3.5
768
3.5
302
3.0
561
3.0
347
2.9
414
1.8
408
1.5
180
1.4
588
1.4
323
1.3
932
1.2
646
1.2
218
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0330 2.1 fdw6274.1
16
9.0
725
13
6.3
522
13
5.6
818
13
5.0
114
13
4.6
033
13
4.3
555
11
6.6
108
11
6.2
099
83
.934
281
.186
880
.188
578
.709
177
.251
776
.996
676
.741
5
49
.370
2
44
.021
243
.831
843
.081
242
.614
8
28
.317
027
.916
2
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500
150
208cb
2.0
952
1.0
000
0.9
506
1.1
218
1.1
258
1.1
828
1.1
256
0.9
631
19
.353
Inte
gra
l
7.2
600
6.3
939
5.7
900
5.2
365
4.8
381
4.7
045
4.5
343
4.5
028
4.3
755
3.6
178
3.6
127
3.5
560
3.5
207
3.1
311
3.0
454
2.9
155
2.9
117
2.9
067
2.9
029
1.4
972
1.4
846
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0419 5 fdw7027.2
151
208da
5.0
000
2.0
582
1.0
430
3.2
693
1.0
885
1.1
038
2.1
431
1.0
813
9.7
907
Inte
gra
l
7.3
729
7.3
615
7.3
451
7.3
338
7.3
287
7.3
237
7.3
174
7.3
098
7.2
606
6.4
437
6.4
084
6.3
983
6.3
252
5.7
263
5.6
797
5.1
994
5.1
565
4.8
955
4.8
703
4.7
694
4.7
442
4.5
627
4.5
261
4.4
782
4.4
429
3.7
054
3.6
688
3.6
512
3.6
134
3.1
582
3.1
330
3.0
801
3.0
549
1.4
172
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0425 1.1 fdw7156.1
16
9.0
924
13
6.4
231
13
6.1
900
13
5.6
434
13
5.2
645
13
4.8
709
13
4.7
033
12
8.5
601
12
8.1
738
12
8.0
135
11
6.3
100
11
5.8
800
83
.910
381
.374
378
.838
377
.329
877
.074
876
.819
7
67
.564
8
49
.521
2
43
.917
243
.829
843
.669
543
.523
736
.659
031
.441
330
.209
729
.685
028
.008
9
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0625 11.1 fdw7156.1
152
208db
4.9
799
1.9
584
0.9
843
3.0
229
1.0
087
1.0
600
1.0
649
1.0
000
0.9
279
9.4
553
Inte
gra
l
7.3
735
7.3
621
7.3
470
7.3
356
7.3
306
7.3
193
7.2
600
6.4
166
6.3
750
6.2
943
5.8
026
5.7
572
5.2
365
5.1
798
5.1
558
4.9
163
4.8
961
4.8
003
4.7
751
4.5
734
4.5
381
4.4
763
4.4
410
3.7
085
3.6
720
3.6
467
3.6
114
3.2
219
3.1
967
3.1
462
3.1
235
2.9
067
1.4
808
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0726 1.1 fdw7173.3
17
0.0
379
15
5.1
206
15
3.8
235
13
6.8
147
13
6.4
504
13
6.3
556
13
5.4
301
13
4.3
443
12
8.4
999
12
8.1
136
12
7.9
314
11
6.6
287
11
6.0
676
82
.676
981
.350
680
.250
2
77
.255
177
.000
076
.744
9
67
.482
7
48
.448
148
.309
644
.024
643
.827
943
.711
3
31
.570
529
.617
528
.072
6
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500
13
6.8
147
13
6.4
504
13
6.3
556
13
5.4
301
13
4.3
443
12
8.4
999
12
8.1
136
12
7.9
314
(ppm)
126128130132134136
11
6.6
287
11
6.0
676
(ppm)
116.0117.0118.0
48
.448
148
.309
6
44
.024
643
.827
943
.711
3
(ppm)
4244464850
31
.570
5
29
.617
5
28
.072
6
(ppm)
283032
153
208fa
2.0
000
1.9
883
1.9
513
2.9
940
1.9
417
1.0
050
1.0
207
8.8
397
Inte
gra
l
7.5
789
7.5
582
7.3
419
7.3
362
7.3
315
7.3
196
7.3
149
7.2
600
6.5
230
6.4
384
6.4
255
5.9
918
5.9
592
5.9
030
5.7
782
5.7
757
5.6
114
5.5
370
5.3
388
5.2
523
5.1
739
5.1
651
4.9
522
4.9
142
4.3
155
4.3
005
4.1
236
4.1
057
4.0
499
3.9
160
3.9
035
3.8
097
3.7
783
3.7
554
3.7
388
3.7
225
3.6
520
3.6
463
3.6
410
3.6
353
3.6
300
3.6
240
3.3
669
3.1
176
2.9
266
2.9
216
1.4
166
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw10256C.1
17
0.1
752
16
8.8
847
13
6.1
760
13
5.9
354
13
5.6
802
13
5.2
646
13
5.0
386
13
4.4
917
13
1.8
304
12
8.7
899
12
4.3
568
11
5.6
511
83
.992
3
81
.513
3
78
.859
377
.313
577
.000
076
.679
2
49
.533
847
.710
9
42
.322
7
27
.988
0
(ppm)
0102030405060708090100110120130140150160170180190200210220
fdw10256C.1
154
208fb
2.0
807
2.0
000
1.9
188
1.0
476
2.0
182
2.2
299
1.0
475
0.7
566
9.7
066
Inte
gra
l
7.5
811
7.5
660
7.3
305
7.3
136
7.2
600
6.5
350
6.4
292
6.4
195
6.3
046
5.8
745
5.6
890
5.3
437
5.2
562
4.9
846
4.3
599
4.0
489
3.9
325
3.7
113
3.4
374
3.1
796
2.9
300
2.9
263
1.4
799
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw1016 2.1 fdw10256C.2
169.
9178
169.
9032
137.
0080
136.
0315
135.
7837
131.
8558
128.
7150
124.
8089
124.
3935
115.
9183
83.0
814
81.5
802
80.3
851
77.2
515
76.9
965
76.7
414
48.4
664
47.8
033
42.6
001
29.6
796
28.1
201
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw1221 11.1 fdw10256C.2
155
208ga
1.0
052
0.9
831
0.9
699
1.0
518
1.0
518
1.0
000
1.0
343
0.4
894
0.4
725
1.0
339
0.5
688
1.0
219
0.5
205
0.5
220
0.5
603
1.0
729
1.0
090
0.5
794
1.0
184
0.5
391
0.5
197
0.5
661
10
.479
Inte
gra
l
8.3
574
8.3
263
8.2
690
8.2
475
7.6
951
7.6
795
7.6
200
7.6
044
7.3
594
7.3
434
7.2
600
7.2
169
7.2
027
7.1
867
7.1
482
7.1
327
7.1
189
7.0
434
6.4
305
6.4
191
6.3
934
6.3
825
6.3
156
6.3
041
5.7
843
5.7
728
5.7
234
5.6
290
5.3
918
5.3
670
5.1
701
5.1
614
5.1
248
5.1
165
4.8
719
4.8
348
4.5
994
4.5
738
4.3
567
4.3
219
3.9
756
3.9
161
3.9
060
3.8
222
3.7
874
3.6
275
3.6
238
3.5
945
3.5
469
3.5
093
3.3
115
3.2
858
2.8
919
2.8
672
1.6
791
1.6
604
1.4
167
1.3
975
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw1012 1.1 fdw10256A.1
171.
0800
171.
0508
169.
0176
168.
9229
136.
2245
136.
1735
136.
1297
135.
8091
135.
2334
134.
8472
133.
9945
127.
0351
126.
9404
122.
6772
122.
4586
122.
2910
122.
1963
119.
7696
119.
6093
118.
9170
118.
5745
116.
1405
115.
4482
111.
2361
108.
6418
84.1
708
83.8
574
81.4
453
81.4
089
78.8
729
78.7
490
77.2
478
77.0
000
76.7
449
49.4
246
45.8
101
45.5
987
42.3
121
41.4
668
32.0
588
31.8
256
27.9
560
27.9
341
(ppm)
020406080100120140160180200220
13C AMX500 fdw1012 21.1 fdw10256A.1
156
208gb
0.8
489
0.8
477
0.8
424
0.9
449
1.8
042
0.8
689
0.4
512
0.4
756
0.8
829
0.4
753
0.8
550
0.4
985
0.4
982
0.4
843
2.0
060
0.4
933
0.5
408
0.4
992
0.4
567
0.8
673
9.0
000
Inte
gra
l
8.1
467
8.1
041
7.7
043
7.6
887
7.6
324
7.6
168
7.3
782
7.3
621
7.2
600
7.2
330
7.2
183
7.2
110
7.2
037
7.1
954
7.1
469
7.1
322
7.0
635
6.3
820
6.2
602
6.2
492
5.7
866
5.6
734
5.6
620
5.4
138
5.3
886
5.2
374
5.1
907
4.8
903
4.8
522
4.6
379
4.6
122
4.3
315
4.2
976
3.9
976
3.9
106
3.8
377
3.8
029
3.5
332
3.4
956
3.3
751
3.3
490
2.9
542
2.9
286
2.8
883
2.8
407
2.8
374
1.5
756
1.4
657
1.4
584
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw1016 1.1 fdw10256A.2
17
0.9
525
17
0.8
723
17
0.0
270
16
9.9
905
13
6.8
913
13
6.1
844
13
5.6
743
13
5.5
358
13
3.6
994
12
7.0
315
12
2.5
789
12
2.4
696
12
2.3
894
12
2.1
271
11
9.9
263
11
9.7
587
11
9.0
955
11
8.6
073
11
6.5
522
11
5.6
777
11
1.1
960
10
9.0
098
83
.132
382
.797
181
.507
381
.441
780
.355
980
.253
877
.251
477
.003
776
.748
6
49
.479
348
.517
348
.255
046
.061
545
.682
542
.359
541
.696
3
32
.157
232
.011
428
.105
4
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw1014 11.1 fdw10256A.2
157
210
1.00
00
0.97
66
0.98
91
1.01
99
0.98
44
0.97
51
0.45
17
1.00
51
0.55
43
0.54
05
0.55
56
1.98
04
0.53
58
0.44
85
0.46
13
0.53
82
1.02
14
1.01
94
0.55
19
1.63
80
1.46
58
1.58
09
9.64
42
1.00
81
Inte
gral
8.56
838.
5418
7.63
797.
6202
7.60
267.
3428
7.32
657.
2874
7.20
047.
1853
7.17
017.
1361
7.12
107.
1058
7.03
027.
0075
4.93
234.
9033
4.71
674.
7067
4.69
664.
6827
4.67
264.
6625
4.59
954.
5743
4.21
504.
1847
4.00
823.
9767
3.85
063.
8368
3.80
523.
3539
3.32
363.
0400
3.01
102.
9669
2.94
292.
9177
2.67
442.
5710
2.54
452.
2709
2.25
832.
2495
2.22
431.
9406
1.80
451.
7818
1.77
171.
7603
1.68
971.
6721
1.65
701.
6469
1.59
901.
5876
1.57
251.
4842
1.47
16
(ppm)
0.01.02.03.04.05.06.07.08.09.0
1H AMX500 fdw0302 2.1 fdw9021
171.
1766
170.
7248
136.
2774
136.
2337
127.
3285
127.
0807
122.
8322
122.
7156
121.
9504
119.
3926
118.
7586
118.
5326
111.
2963
111.
2599
109.
1538
108.
9862
83.8
229
83.7
646
81.0
610
78.7
217
78.4
302
77.3
226
77.0
675
76.8
124
57.2
604
57.1
730
49.2
079
44.6
023
44.5
731
42.7
586
42.2
120
41.2
428
33.1
757
33.0
008
31.3
903
31.1
352
31.0
550
30.6
178
28.1
109
27.0
688
26.9
741
(ppm)
020406080100120140160180200220
13C AMX500 fdw0302 21.1 fdw9021
158
211
1.0
000
1.0
873
1.0
629
1.0
960
1.1
073
1.0
521
1.0
912
1.8
138
1.2
416
3.6
451
20
.124
0.9
238
Inte
gra
l
7.2
606
4.7
909
4.7
820
4.3
093
4.1
378
3.9
739
3.0
851
2.7
233
2.7
056
2.5
720
2.1
849
2.1
723
2.1
673
2.1
597
2.1
559
2.1
484
2.1
433
2.1
307
1.7
979
1.7
878
1.7
764
1.7
651
1.7
538
1.7
285
1.5
684
1.5
016
1.4
688
1.4
436
1.4
146
1.4
058
1.3
881
1.3
806
1.3
150
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0331 5 fdw 6280.2
17
0.7
812
15
4.9
822
81
.612
980
.964
379
.674
578
.486
677
.255
177
.000
076
.744
9
53
.265
0
45
.030
3
33
.064
430
.681
528
.444
228
.203
825
.281
5
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0301 21.1 fdw7027.2
159
212
1.0
000
1.1
496
1.0
134
1.1
466
2.0
745
1.0
336
2.9
307
2.5
305
22
.369
1.6
406
Inte
gra
l
7.2
606
4.7
203
4.6
421
4.2
613
4.0
319
3.9
777
3.0
990
3.0
674
2.6
148
2.1
925
2.1
862
2.1
799
2.1
723
2.1
635
2.1
584
2.1
509
1.7
487
1.7
449
1.7
386
1.7
348
1.7
285
1.7
248
1.7
210
1.7
147
1.7
071
1.6
352
1.6
277
1.6
176
1.6
100
1.5
924
1.5
861
1.5
684
1.5
583
1.5
457
1.5
356
1.5
281
1.5
180
1.4
953
1.4
751
1.4
714
1.4
424
1.4
058
1.4
020
1.3
793
1.3
718
1.3
541
1.3
478
1.3
226
1.3
049
1.2
810
1.2
734
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0331 3 fdw 76280.1
17
1.3
588
15
5.0
424
83
.531
480
.907
979
.596
278
.510
477
.278
877
.023
876
.768
7
57
.107
4
42
.452
5
33
.161
130
.749
028
.446
228
.395
128
.147
428
.103
626
.923
1
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500
160
214
0.9
733
1.0
000
0.9
846
1.0
293
1.0
655
1.0
249
1.0
520
1.0
375
3.1
916
3.2
210
1.0
576
1.6
853
1.2
717
1.0
954
1.1
656
1.1
616
3.4
746
9.7
978
Inte
gra
l
8.1
685
7.6
100
7.5
948
7.3
427
7.3
263
7.2
607
7.1
876
7.1
737
7.1
574
7.1
170
7.1
031
7.0
880
7.0
023
4.7
204
4.7
103
4.7
002
3.3
600
3.3
336
3.0
272
3.0
146
3.0
070
2.9
932
2.9
856
2.9
604
2.7
725
2.7
612
2.7
486
2.7
360
2.7
297
2.7
158
2.6
982
2.6
843
2.6
717
2.6
591
2.3
817
2.3
552
2.1
271
2.1
207
2.1
144
2.1
056
2.0
981
2.0
905
2.0
842
2.0
501
2.0
186
1.9
959
1.9
707
1.8
573
1.8
434
1.8
358
1.8
308
1.8
169
1.7
766
1.7
652
1.7
514
1.7
413
1.7
274
1.7
211
1.6
543
1.6
442
1.6
366
1.6
190
1.6
127
1.5
912
1.5
673
1.5
572
1.5
509
1.5
383
1.5
307
1.5
219
1.5
143
1.5
068
1.4
979
1.4
891
1.4
702
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
1H AMX500 fdw0405 1 fdw7014.3
17
1.6
484
13
6.2
099
12
7.4
723
12
1.7
736
12
1.5
113
11
9.0
627
11
8.7
931
11
4.3
551
11
1.0
539
84
.389
480
.709
378
.603
277
.255
177
.000
076
.752
2
59
.371
957
.520
956
.763
052
.558
2
42
.006
0
33
.720
331
.687
1
28
.072
626
.804
6
22
.825
7
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0405 11 fdw7014.3
161
215
1.0
000
0.9
895
0.9
624
1.0
165
1.0
271
0.9
834
1.0
060
3.0
808
1.0
511
3.0
818
3.1
678
1.0
532
1.0
544
1.1
501
1.0
977
1.0
699
4.1
561
Inte
gra
l
8.1
400
7.6
130
7.5
966
7.3
432
7.3
281
7.2
600
7.1
932
7.1
907
7.1
768
7.1
629
7.1
604
7.1
226
7.1
062
7.0
923
7.0
129
7.0
079
4.7
675
4.7
575
4.7
461
3.7
060
3.3
770
3.3
744
3.3
505
3.3
480
3.0
290
3.0
176
3.0
076
2.9
962
2.9
874
2.9
697
2.9
622
2.7
932
2.7
895
2.7
819
2.7
756
2.7
718
2.7
680
2.7
554
2.7
428
2.7
352
2.7
226
2.7
088
2.7
025
2.6
987
2.6
886
2.6
848
2.6
772
2.6
646
2.3
936
2.3
671
2.1
969
2.1
906
2.1
830
2.1
755
2.1
667
2.1
604
2.1
528
2.0
507
2.0
330
2.0
292
2.0
065
1.9
838
1.9
801
1.8
716
1.8
578
1.8
502
1.8
452
1.8
363
1.8
313
1.7
695
1.7
594
1.7
481
1.7
443
1.7
380
1.5
779
1.5
678
1.5
413
1.5
262
1.5
060
1.5
022
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0331 1.1 fdw9157
17
2.8
945
13
6.2
026
12
7.4
723
12
1.7
882
12
1.4
967
11
9.0
700
11
8.7
785
11
4.3
551
11
1.0
393
84
.367
578
.442
977
.247
877
.000
076
.744
9
59
.320
8
56
.690
156
.500
652
.499
951
.756
5
42
.341
3
33
.698
431
.760
0
27
.074
2
22
.847
5
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0331 11.1 fdw9157
162
217
0.9
733
0.9
583
0.9
852
1.0
051
0.9
767
1.0
000
2.9
261
1.0
518
2.0
519
1.0
625
1.0
588
1.0
600
2.0
976
1.0
611
2.0
922
1.0
608
1.1
176
1.2
016
0.8
827
Inte
gra
l
7.7
882
7.4
768
7.4
617
7.3
092
7.2
928
7.2
600
7.1
541
7.1
516
7.1
377
7.1
238
7.1
213
7.1
024
7.0
999
7.0
860
7.0
722
4.8
369
4.8
268
4.8
154
3.6
657
3.2
950
3.2
736
3.2
358
3.2
332
3.2
244
3.2
131
3.2
105
3.2
042
3.1
097
3.1
034
3.0
958
3.0
882
3.0
769
3.0
706
3.0
101
3.0
063
2.9
950
2.9
899
2.9
849
2.9
786
2.9
735
2.9
685
2.9
609
2.9
521
2.9
458
2.9
395
2.8
248
2.8
046
2.7
668
2.7
579
2.7
441
2.7
365
2.7
214
2.6
962
2.6
886
2.3
318
2.3
242
2.3
129
2.3
066
2.2
990
2.2
663
2.2
599
2.2
410
2.2
335
2.2
297
2.2
183
2.2
032
2.1
931
2.0
141
2.0
103
2.0
065
1.9
889
1.9
851
1.9
813
1.9
662
1.9
624
1.9
586
1.7
544
1.7
418
1.7
393
1.7
304
1.7
178
1.7
052
1.6
964
1.6
258
1.6
132
1.6
069
1.6
006
1.5
892
1.5
703
1.5
439
1.5
186
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0505 1.1 fdw10019
17
2.1
295
13
5.9
720
13
4.5
524
12
7.3
108
12
1.4
602
11
9.4
742
11
8.1
621
11
0.7
341
10
8.3
824
84
.456
6
79
.939
677
.423
077
.000
076
.577
0
62
.029
460
.767
5
54
.121
0
51
.418
0
47
.510
446
.764
8
29
.528
528
.847
327
.936
7
22
.093
3
(ppm)
0102030405060708090100110120130140150160170180190200210220
may04fdw 11.1 fdw10019
163
218
1.0
000
1.0
270
1.1
821
1.1
613
1.0
831
1.0
090
1.0
185
2.8
381
1.3
095
1.0
461
2.1
665
1.1
597
1.0
491
2.1
240
1.0
115
1.2
212
1.1
445
1.1
532
1.2
371
Inte
gra
l
7.7
050
7.4
592
7.4
441
7.2
953
7.2
789
7.1
415
7.1
390
7.1
251
7.1
112
7.1
087
7.0
898
7.0
759
7.0
621
7.0
595
5.8
619
5.8
429
5.7
043
5.6
992
5.6
904
5.6
841
5.6
778
5.6
702
5.6
639
3.8
283
3.7
955
3.7
880
3.7
804
3.3
114
3.2
887
3.0
782
3.0
693
3.0
643
3.0
479
3.0
441
3.0
378
3.0
277
3.0
151
2.9
622
2.9
584
2.9
508
2.9
433
2.9
382
2.9
332
2.9
269
2.9
180
2.9
130
2.9
067
2.9
017
2.8
764
2.8
563
2.7
163
2.7
088
2.6
924
2.6
861
2.6
709
2.3
986
2.3
772
2.2
322
2.2
234
2.2
133
2.2
070
2.1
982
2.1
881
2.1
755
1.9
473
1.9
448
1.9
145
1.9
082
1.8
099
1.8
036
1.7
960
1.7
847
1.7
771
1.7
708
1.5
539
1.4
443
1.4
203
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0505 1.1 fdw10022.1
17
4.3
612
13
5.9
859
13
4.1
495
12
7.2
192
12
5.1
569
12
1.5
059
12
1.0
759
11
9.4
946
11
8.1
173
11
0.8
226
10
8.4
251
77
.278
877
.023
876
.768
7
69
.641
7
66
.697
6
59
.126
0
52
.807
852
.035
4
42
.612
841
.425
0
33
.656
6
29
.102
0
21
.880
2
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0505 51.1 fdw10022.1
164
221
0.9
843
1.0
040
1.0
229
2.1
092
2.1
764
0.9
651
1.0
303
1.1
829
1.8
512
9.3
819
9.8
550
Inte
gra
l
7.2
600
5.5
429
5.4
849
4.1
914
4.1
813
4.1
737
4.1
636
4.1
586
4.1
485
4.1
019
4.0
741
4.0
414
3.9
859
3.9
392
3.9
090
3.2
042
3.2
005
3.1
878
3.1
841
2.5
587
2.5
487
2.5
398
2.5
234
2.5
134
2.5
045
2.2
385
2.2
246
2.2
032
2.1
893
2.0
557
2.0
330
1.4
922
1.4
493
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw10213
17
1.2
622
15
4.5
959
12
9.4
545
12
1.6
862
11
9.8
935
81
.663
979
.922
277
.255
177
.000
076
.744
9
67
.803
3
54
.380
0
45
.416
543
.704
0
32
.423
1
28
.400
528
.145
5
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw10215
165
222
1.0
031
1.0
108
1.0
000
4.1
522
0.9
767
1.0
845
1.1
454
3.0
866
21
.435
Inte
gra
l
7.2
600
5.5
303
5.4
521
5.2
668
5.2
567
5.2
517
5.2
491
5.2
391
5.2
353
5.2
252
4.0
136
3.3
454
3.3
417
3.3
278
3.3
253
2.6
785
2.6
697
2.6
596
2.6
432
2.6
344
2.6
243
2.2
045
2.1
944
2.1
704
2.1
604
2.0
015
1.4
493
1.4
417
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0824 2.1 fdw10217
17
0.0
087
16
9.8
921
15
4.6
542
12
9.3
160
12
8.8
132
11
9.1
283
81
.438
079
.922
277
.255
177
.000
076
.744
9
69
.953
1
51
.173
6
43
.711
3
29
.471
828
.385
927
.948
7
21
.040
3
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0824 21.1 fdw10217
166
227
0.9
589
0.9
461
0.9
180
0.9
525
0.9
666
0.9
293
1.0
000
1.0
005
3.8
670
1.0
268
1.0
265
0.9
986
1.9
576
2.0
819
1.0
396
2.2
465
1.2
833
1.1
653
1.0
806
Inte
gra
l
7.9
496
7.6
080
7.5
916
7.3
583
7.3
419
7.2
600
7.1
970
7.1
818
7.1
667
7.1
213
7.1
075
7.0
923
7.0
381
7.0
343
4.0
792
4.0
704
4.0
565
4.0
489
4.0
351
4.0
262
3.7
363
3.0
126
2.9
912
2.9
319
2.9
130
2.9
017
2.8
954
2.8
865
2.6
760
2.6
634
2.6
520
2.6
394
2.6
331
2.6
205
2.5
940
2.5
802
2.5
751
2.5
625
2.5
512
2.5
373
2.4
957
2.4
856
2.4
755
2.4
654
2.2
032
2.1
931
2.1
843
2.1
780
2.1
679
2.1
616
2.1
011
2.0
935
2.0
847
2.0
797
2.0
696
2.0
608
2.0
557
2.0
280
2.0
217
1.9
549
1.9
498
1.9
309
1.9
271
1.9
069
1.9
044
1.7
720
1.7
645
1.7
468
1.7
393
1.7
216
1.7
141
1.6
964
1.6
876
1.6
082
1.5
375
1.5
287
1.5
086
1.5
010
1.3
989
1.3
913
1.3
711
1.3
636
1.3
484
1.3
421
1.3
207
1.3
131
1.2
564
1.2
072
1.2
009
1.1
808
1.1
757
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
1H AMX500 fdw0922 1.1 fdw10243.3
0.9
461
0.9
180
0.9
525
0.9
666
0.9
293
7.6
080
7.5
916
7.3
583
7.3
419
7.2
600
7.1
970
7.1
818
7.1
667
7.1
213
7.1
075
7.0
923
7.0
381
7.0
343
(ppm)
7.07.27.47.6
1.0
000
Inte
gra
l
4.0
792
4.0
704
4.0
565
4.0
489
4.0
351
4.0
262
(ppm)
4.004.10
1.0
005
3.8
670
1.0
268
1.0
265
0.9
986
1.9
576
2.0
819
1.0
396
2.2
465
1.2
833
1.1
653
1.0
806
Inte
gra
l2.2
032
2.1
931
2.1
843
2.1
780
2.1
679
2.1
616
2.1
011
2.0
935
2.0
847
2.0
797
2.0
696
2.0
608
2.0
557
2.0
280
2.0
217
1.9
549
1.9
498
1.9
309
1.9
271
1.9
069
1.9
044
1.7
720
1.7
645
1.7
468
1.7
393
1.7
216
1.7
141
1.6
964
1.6
876
1.6
082
1.5
375
1.5
287
1.5
086
1.5
010
1.3
989
1.3
913
1.3
711
1.3
636
1.3
484
1.3
421
1.3
207
1.3
131
1.2
564
1.2
072
1.2
009
1.1
808
1.1
757
(ppm)
1.21.41.61.82.02.22.42.62.83.0
17
4.8
475
13
6.1
807
12
7.5
671
12
1.9
121
12
1.4
821
11
9.1
574
11
8.8
222
11
4.7
704
11
1.0
393
77
.255
177
.000
076
.744
9
66
.112
7
59
.350
058
.847
2
54
.693
454
.620
551
.727
4
37
.844
936
.620
733
.100
9
24
.560
123
.474
322
.840
3
(ppm)
-100102030405060708090100110120130140150160170180190200210220
13C AMX500 fdw0922 11.1 fdw10243.3
167
170
0.9
833
0.8
913
0.9
333
1.0
546
1.0
265
1.1
440
3.0
000
1.1
265
2.3
334
1.1
591
2.0
626
3.4
618
1.1
857
2.5
277
1.2
067
1.3
157
2.5
058
1.4
593
Inte
gra
l
7.6
772
7.4
661
7.4
505
7.3
154
7.2
994
7.2
600
7.1
482
7.1
464
7.1
322
7.1
185
7.1
162
7.0
956
7.0
933
7.0
800
7.0
658
4.0
260
4.0
173
4.0
049
3.9
962
3.9
866
3.9
774
3.8
419
3.1
631
3.1
599
3.1
420
3.1
388
2.9
858
2.9
744
2.9
661
2.9
588
2.9
542
2.9
465
2.9
396
2.9
222
2.9
171
2.9
103
2.9
052
2.8
585
2.8
558
2.8
361
2.7
051
2.6
982
2.6
671
2.6
116
2.6
052
2.5
887
2.5
823
2.5
718
2.5
622
2.5
507
2.5
416
2.5
232
2.5
150
2.5
017
2.4
884
2.4
587
2.4
504
2.4
417
2.4
330
2.4
243
2.1
523
2.1
449
2.1
248
2.1
179
2.0
987
2.0
913
2.0
730
2.0
671
2.0
552
2.0
465
2.0
396
2.0
318
1.8
394
1.8
147
1.7
478
1.7
226
1.6
988
1.6
741
1.6
054
1.5
976
1.5
797
1.5
733
1.5
509
1.5
445
1.4
226
1.4
103
1.3
929
1.3
869
1.3
681
1.3
622
1.3
425
1.3
343
(ppm)
0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6
fdw1001 1.1 fdw10248.1
17
4.7
104
13
5.9
937
13
4.4
698
12
7.3
244
12
1.4
403
11
9.4
644
11
8.1
009
11
0.7
732
10
8.4
837
77
.320
877
.000
076
.686
5
66
.070
4
60
.550
960
.237
4
54
.732
453
.303
351
.976
3
37
.947
936
.555
333
.113
8
27
.747
4
24
.597
6
21
.732
1
(ppm)
0102030405060708090100110120130140150160170180190200210220
sep26fdw 1.1 fdw10248.1
168
Chiral HPLC Chromatograms
152
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 19.0
-100
0
100
200
300
400
500
600
700
800
900062008 #151 [modified by TCH] fdw4221 UV_VIS_3mAU
min
1 - 11.3932 - 12.320
WVL:254 nm
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 19.0
-50
0
50
100
150
200
250
300
350
400062008 #152 [modified by TCH] fdw4215A UV_VIS_3mAU
min
1 - 11.380
2 - 12.313
WVL:254 nm
169
158
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
-500
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000062008 #212 [modified by TCH] fdw5189 UV_VIS_1mAU
min
1 - 5.173
2 - 9.700
WVL:230 nm
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
-200
250
500
750
1,000
1,250
1,500
1,750
2,000
2,250
2,500
2,750
3,000062008 #219 [modified by TCH] fdw5206A UV_VIS_1mAU
min
1 - 5.127
2 - 9.680
WVL:230 nm
170
159
10.0 20.0 30.0 40.0 50.0 60.0
-50
0
50
100
150
200
250
300
350
400
450
500
550
600062008 #224 [modified by TCH] fdw5212 UV_VIS_1mAU
min
1 - 29.527
2 - 49.527
WVL:230 nm
10.0 20.0 30.0 40.0 50.0 60.0
-50
100
200
300
400
500
600
700
800
900
1,000062008 #227 [modified by TCH] fdw5214A UV_VIS_1mAU
min
1 - 29.447
2 - 50.493
WVL:230 nm
171
208aa+208ab 11023A.2 Ce2 3005210
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0
-150
0
200
400
600
800
1,000Template #250 [modified by TCH]fdw11023A.2 UV_VIS_1mAU
min
1 - 23.067
2 - 36.733
3 - 47.053
4 - 62.593
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 23.07 n.a. 755.450 594.200 31.14
2 36.73 n.a. 280.832 355.800 18.65
3 47.05 n.a. 371.223 603.155 31.61
4 62.59 n.a. 165.165 355.015 18.61
Total: 1572.669 1908.171 100.00
172
208aa(11024E)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0
-150
0
200
400
600
800
1,000Template #255 [modified by TCH]fdw11024E UV_VIS_1mAU
min
1 - 23.313
2 - 47.300
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 23.31 n.a. 415.694 301.873 20.11
2 47.30 n.a. 695.470 1199.169 79.89
Total: 1111.164 1501.042 100.00
208ab(11024E)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0
-150
0
200
400
600
800
1,000Template #255 [modified by TCH]fdw11024E UV_VIS_1mAU
min
1 - 37.367
2 - 62.767
WVL:210 nm
173
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 37.37 n.a. 66.753 77.490 19.83
2 62.77 n.a. 149.742 313.194 80.17
Total: 216.496 390.684 100.00
(6098.3) I A+Ce1 2010210
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-40
50
100
150
200
250
300Template #53 [modified by TCH]fdw6098.3 UV_VIS_3mAU
min
1 - 10.807
2 - 12.020
3 - 13.060
4 - 21.180
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 10.81 n.a. 128.070 26.615 20.11
2 12.02 n.a. 111.397 27.096 20.47
3 13.06 n.a. 137.198 39.752 30.03
4 21.18 n.a. 79.010 38.913 29.40
174
208ba(6106A)
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-100
250
500
750
1,000
1,250
1,500Template #69 [modified by TCH]fdw6106A UV_VIS_3mAU
min
1 - 10.873
2 - 11.980
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 10.87 n.a. 890.852 248.318 91.80
2 11.98 n.a. 78.836 22.166 8.20
Total: 969.687 270.485 100.00
208bb(6106A)
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-100
200
400
600
800
1,000Template #69 [modified by TCH]fdw6106A UV_VIS_3mAU
min
1 - 12.793
2 - 20.340
WVL:210 nm
175
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 12.79 n.a. 12.751 3.499 8.56
2 20.34 n.a. 73.254 37.350 91.44
Total: 86.005 40.849 100.00
(6083A) IA1005210
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0
-20
50
100
150
200Template #31 [modified by TCH]fdw6083A UV_VIS_1mAU
min
1 - 5.427
2 - 6.060
3 - 9.2604 - 14.280
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 5.43 n.a. 83.255 16.165 36.42
2 6.06 n.a. 75.527 15.453 34.81
3 9.26 n.a. 21.429 6.199 13.97
4 14.28 n.a. 15.454 6.572 14.80
176
208ca(10183)
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
-400
-300
-200
-100
0
100
200Template #191 [modified by TCH]fdw10183 UV_VIS_1mAU
min
1 - 6.293
2 - 6.953
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 6.29 n.a. 356.253 100.644 89.69
2 6.95 n.a. 43.810 11.573 10.31
Total: 400.063 112.218 100.00
208cb(10183)
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
-400
-300
-200
-100
0
100
200Template #191 [modified by TCH]fdw10183 UV_VIS_1mAU
min
1 - 10.153
2 - 14.987
WVL:210 nm
177
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 10.15 n.a. 42.171 19.689 11.46
2 14.99 n.a. 234.569 152.125 88.54
Total: 276.741 171.815 100.00
(7173) IA 1005210
0.0 10.0 20.0 30.0 40.0 50.0
-100
500
1,000
1,500
2,000
2,500Template #129 [modified by TCH] UV_VIS_1mAU
min
1 - 12.2872 - 13.4803 - 28.093
4 - 35.660
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 12.29 n.a. 1663.108 1110.012 12.96
2 13.48 n.a. 1592.875 1165.708 13.61
3 28.09 n.a. 1751.224 3122.662 36.46
4 35.66 n.a. 1293.867 3165.506 36.96
Total: 6301.073 8563.888 100.00
178
208da(7176B)
0.0 10.0 20.0 30.0 40.0 50.0
-100
250
500
750
1,000
1,250
1,500Template #132 [modified by TCH]fdw7176B UV_VIS_1mAU
min
1 - 11.360
2 - 12.973
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 11.36 n.a. 829.910 483.929 88.77
2 12.97 n.a. 101.669 61.198 11.23
Total: 931.579 545.128 100.00
208db(7176B)
0.0 10.0 20.0 30.0 40.0 50.0
-100
250
500
750
1,000
1,250
1,500Template #132 [modified by TCH]fdw7176B UV_VIS_1mAU
min
1 - 27.833
2 - 36.447
WVL:210 nm
179
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 27.83 n.a. 63.142 57.022 11.42
2 36.45 n.a. 305.894 442.345 88.58
Total: 369.036 499.367 100.00
(7204A) IA+IA 2010230
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0
-30
50
100
150
200
250
300Template #142 [modified by TCH]fdw7204A UV_VIS_1mAU
min
1 - 22.573
2 - 23.767
3 - 26.140
4 - 29.953
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 22.57 n.a. 187.129 98.149 35.73
2 23.77 n.a. 64.880 40.789 14.85
3 26.14 n.a. 161.353 98.817 35.98
4 29.95 n.a. 48.909 36.911 13.44
Total: 462.271 274.666 100.00
180
208fa (7209)
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0
-30
500
1,000
1,500
2,000Template #151 [modified by TCH]fdw7209 UV_VIS_3mAU
min
1 - 22.907
2 - 26.560
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 22.91 n.a. 955.640 652.162 82.54
2 26.56 n.a. 180.696 137.934 17.46
Total: 1136.336 790.096 100.00
208fb (7209)
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0
-100
250
500
750
1,000
1,250
1,500Template #139 [modified by TCH]fdw7204C UV_VIS_2mAU
min
1 - 23.7072 - 29.807
WVL:254 nm
181
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 23.71 n.a. 15.291 6.643 10.55
2 29.81 n.a. 76.987 56.344 89.45
Total: 92.278 62.988 100.00
(7217) AD+AD 2010230
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-20
50
100
150
200
250
300Template #145 [modified by TCH]fdw7217 UV_VIS_1mAU
min
1 - 26.453
2 - 32.307
3 - 35.107
4 - 46.893
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 26.45 n.a. 253.946 269.899 36.68
2 32.31 n.a. 236.165 267.775 36.40
3 35.11 n.a. 80.771 101.649 13.82
4 46.89 n.a. 39.806 96.409 13.10
Total: 610.688 735.732 100.00
182
208ga(7218)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-20
125
250
375
500
625
800Template #146 [modified by TCH]fdw7218 UV_VIS_1mAU
min
1 - 26.407
2 - 32.080
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 26.41 n.a. 113.000 109.982 15.90
2 32.08 n.a. 520.009 581.562 84.10
Total: 633.009 691.544 100.00
208gb(7218)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-50
100
200
300
400
500
600Template #146 [modified by TCH]fdw7218 UV_VIS_1mAU
min
1 - 34.7532 - 46.533
WVL:230 nm
183
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 34.75 n.a. 2.873 1.965 5.10
2 46.53 n.a. 18.460 36.539 94.90
Total: 21.332 38.504 100.00
(10257B racemic) IA0505210
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
-150
200
400
600
800
1,000
1,200Template #258 [modified by TCH]fdw10257B racemic UV_VIS_1mAU
min
1 - 11.353
2 - 12.827
3 - 19.5874 - 30.213
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 11.35 n.a. 820.119 442.261 41.73
2 12.83 n.a. 730.318 453.532 42.80
3 19.59 n.a. 95.021 82.064 7.74
4 30.21 n.a. 53.037 81.877 7.73
Total: 1698.496 1059.734 100.00
184
208ha(Fdw10257B)
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
-150
0
200
400
600
800
1,000Template #257 [modified by TCH]fdw10257B UV_VIS_1mAU
min
1 - 11.413
2 - 12.900
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 11.41 n.a. 572.142 318.666 93.36
2 12.90 n.a. 42.654 22.660 6.64
Total: 614.796 341.327 100.00
208hb(Fdw10257B)
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
-150
0
125
250
375
500
625
800Template #257 [modified by TCH]fdw10257B UV_VIS_1mAU
min
1 - 19.673
2 - 30.173
WVL:210 nm
185
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 19.67 n.a. 6.486 5.440 5.94
2 30.17 n.a. 42.169 86.146 94.06
Total: 48.656 91.586 100.00
(6153A IC 2010210)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-20
25
50
75
100
125
150Template #77 [modified by TCH]fdw6153A UV_VIS_3mAU
min
1 - 20.627
2 - 28.367
3 - 39.233
4 - 50.380
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 20.63 n.a. 39.832 31.684 14.49
2 28.37 n.a. 72.730 78.051 35.70
3 39.23 n.a. 52.440 77.598 35.49
4 50.38 n.a. 16.231 31.316 14.32
Total: 181.232 218.649 100.00
186
208ia(6157B)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-20
100
200
300
400
500Template #82 [modified by TCH]fdw6157B UV_VIS_3mAU
min
1 - 27.027
2 - 36.867
WVL:210 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 27.03 n.a. 31.929 31.876 6.51
2 36.87 n.a. 314.382 457.704 93.49
Total: 346.311 489.580 100.00
208ib(6157B)
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0
-20
100
200
300
400
500Template #82 [modified by TCH]fdw6157B UV_VIS_3mAU
min
1 - 19.920
2 - 47.100
WVL:210 nm
187
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 19.92 n.a. 10.687 6.298 4.50
2 47.10 n.a. 73.856 133.622 95.50
Total: 84.543 139.920 100.00
208haa IC1010230 (fdw10208.2) racemic
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-20.0
-10.0
0.0
10.0
20.0
30.0
40.0
50.0Template #198 fdw10208.2 UV_VIS_1mAU
min
1 - 14.000
2 - 18.060
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 14.00 n.a. 39.723 33.897 50.06
2 18.06 n.a. 31.631 33.813 49.94
Total: 71.354 67.710 100.00
188
(11029.2) chiral
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-50
0
50
100
150
200
250
300Template #261 [modified by TCH]fdw11029.2 UV_VIS_1mAU
min
1 - 14.633
2 - 19.820
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 14.63 n.a. 248.287 253.329 91.68
2 19.82 n.a. 17.897 22.985 8.32
Total: 266.184 276.315 100.00
208hbb IC 1010230 (fdw10208.1) racemic
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
-100
0
100
200
300Template #199 fdw10208.1 UV_VIS_3mAU
min
1 - 13.167
2 - 24.540
WVL:254 nm
189
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 13.17 n.a. 175.800 135.423 49.98
2 24.54 n.a. 101.102 135.516 50.02
Total: 276.902 270.939 100.00
fdw11029.1 chiral
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
-50
200
400
600
800
1,000
1,200
1,500Template #260 [modified by TCH]fdw11029.1 UV_VIS_1mAU
min
1 - 13.773
2 - 27.327
WVL:230 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 13.77 n.a. 1185.044 1142.111 89.44
2 27.33 n.a. 80.712 134.839 10.56
Total: 1265.756 1276.951 100.00
190
221 (fdw10131) IC 1010254 racemic
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-20
0
20
40
60
80Template #204 [modified by TCH]fdw10131 UV_VIS_1mAU
min
1 - 13.173
2 - 17.687
WVL:254 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 13.17 n.a. 36.508 28.741 49.53
2 17.69 n.a. 29.468 29.285 50.47
Total: 65.976 58.026 100.00
fdw10215 chiral
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-100
200
400
600
800
1,000Template #206 [modified by TCH]fdw10215 UV_VIS_1mAU
min
1 - 13.047
2 - 17.527
WVL:254 nm
191
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 13.05 n.a. 673.317 635.175 87.81
2 17.53 n.a. 78.342 88.182 12.19
Total: 751.659 723.356 100.00
222 (fdw10130) IC1010254 racemic
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-30
0
20
40
60
80
100Template #209 [modified by TCH]fdw10130 UV_VIS_1mAU
min
1 - 14.360
2 - 21.027
WVL:254 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 14.36 n.a. 47.588 33.203 48.58
2 21.03 n.a. 32.812 35.144 51.42
Total: 80.400 68.347 100.00
192
fdw10217 chiral
0.0 5.0 10.0 15.0 20.0 25.0 30.0
-30
0
20
40
60
80
100Template #210 [modified by TCH]fdw10217 UV_VIS_1mAU
min
1 - 14.393
2 - 21.013
WVL:254 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 14.39 n.a. 10.294 7.729 10.56
2 21.01 n.a. 58.427 65.490 89.44
Total: 68.721 73.219 100.00
227 (FDW10207) AD1010(30mins)->1030230 racemic
30.0 35.0 40.0 45.0 50.0 55.0 60.0
-20
50
100
150
200Template #220 [modified by TCH]fdw10207 UV_VIS_2mAU
min
1 - 37.9332 - 40.853
WVL:230 nm
193
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 37.93 n.a. 114.622 117.133 51.08
2 40.85 n.a. 119.569 112.200 48.92
Total: 234.191 229.334 100.00
FDW10220.2 chiral
30.0 35.0 40.0 45.0 50.0 55.0 60.0
-20
100
200
300
400
500Template #221 [modified by TCH]fdw10220.2 UV_VIS_1mAU
min
1 - 37.773
2 - 40.233
WVL:254 nm
No. Ret.Time Peak Name Height Area Rel.Area
min mAU mAU*min %
1 37.77 n.a. 19.135 16.124 7.33
2 40.23 n.a. 344.631 203.987 92.67