development of thermally stable versions of the burgess ... · figure 47-rice's synthesis of...
TRANSCRIPT
Development of Thermally Stable Versions of the Burgess Reagent. Approaches to the Chemoenzymatic Total Synthesis of Morphine
Thomas A. Metcalf
Department of Chemistry
Submitted in partial fulfillment of the requirements for the degree of
Master of Science
Faculty of Mathematics and Science, Brock University St. Catharines, Ontario
© December 2010
Abstract
The present studies describe our recent work on expanding the use of the Burgess
reagent and its reaction with oxiranes. Several new variants of the Burgess reagent and its
chiral auxiliary version were evaluated for their thermal stability by NMR spectroscopy.
Three new versions of the reagent were synthesized and their stability was determined.
The reactivity of all five Burgess reagents was compared in a dehydration reaction and
reactions with epoxides and diols.
Progress toward a chemoenzymatic synthesis of morphine is also included in this
report. The synthesis began with the whole cell oxidation of bromobenzene by
Escherichia coli JMI09(pDTG601). The preparation of several precursors for a key step
involving the lohnson-Claisen rearrangement and progress toward the total synthesis are
described.
-11-
i
Acknowledgements
There are many people to whom I am very indebted to for all of their help and
support. First, I would like to thank my advisor, Dr. Tomas Hudlicky for allowing me the
opportunity to work with him and for all of his patience and unwavering interest in my
progress and development as a chemist.
I would like to thank the members of my graduate committee Dr. Georgi
Nikonov, Dr. Tony Yan, Dr. Tomas Hudlicky, Dr. Heather Gordon, and the external
examiner Dr. James Green of the University of Windsor. Thanks are also due to Dr.
Stuart Rothstein, Chris Skorski and Beulah Alexander for making sure I had all of the
necessary paperwork turned in and helping me navigate the administrative bureaucracy.
Razvan Simionescu and Tim Jones are greatly appreciated for their help in both
acquiring and interpreting NMR and mass spectra. Thanks are due to Gary McDonnell at
the Electronics Shop, Steve Crumb at the Machine Shop and John and Jordan Vandenhoff
at the Glass Shop for keeping our lab running smoothly.
I have had the opportunity to work with many talented chemists in my time at
Brock University. Dr. Robert Carroll, Dr. Mohammed Haque, Dr. Hannes Leisch,
Elisabeth Kloser, Dr. Bradford Sullivan, Dr. Jon Collins, Dr. Ales Machara, Dr. Lukas
Werner, Mrs. Martina Wernerova, Dr. Jan Duchek, Amy English, Melissa Drouin,
Jacqueline Gilmet, Vigi George, Ignacio Carrera, Leon Sun, Tyler Bissett, Robert
Giacometti, David Ilceski, David Adams, Sergey Vshyvenko, Graeme Piercey, Vimal
Varghese, Christian Aichinger, Vladislav Semak, Yasmeen Albalawi, Hollich Ho and Jon
- 111 -
Scattalon. Thanks are also due to Brock University and the National Science and
Engineering Research Council of Canada (NSERC) for funding my studies.
Finally, I am grateful to my parents, my brother Benjamin, my sisters Lynn and
Anna and the rest of my family.
-tv -
Table of Contents
Abstract u
Acknowledgements 111
List of figures Vll
List of tables xu
List of abbreviations Xlll
1. Introduction 01
2. Historical 03
2.1 Burgess reagent 03
2.1.1 Development of the Burgess reagent and dehydration reactions 03
2.1.2 Alternative reactions of the Burgess reagent 08
2.1.3 Variants of the Burgess reagent 16
2.1.4 Applications of the Burgess reagent in total synthesis 20
2.2 Morphine 26
2.2.1 Historical uses, isolation and biosynthesis 26
2.2.2 Notable syntheses of morphine 31
2.3 Microbial Oxidation of Arenes 43
2.3.1 History of microbial oxidation ofarenes 43
2.3.2 Isolation and characterization of toluene dioxygenase (TDO) 45
2.3.3 Substrate scope and specificity 46
2.3.4 Use of microbial oxidation in synthesis 48
2.4 Claisen rearrangement 52
-v-
2.4.1 Variations of the Claisen rearrangement
2.4.2 Use ofthe Claisen rearrangement in organic synthesis
3. Discussion
3.1 Introduction
3.2 New Burgess reagents
3.3 Stability studies
3.4 Synthesis of morphine C-ring fragment
3.5 Coupling of A-ring fragment
3.6 Synthesis of CIa is en substrates
3.7 Claisen rearrangement
3.8 Biotransformations
4. Conclusions and future work
5. Experimental section
5.1 General
5.2 Preparation of new Burgess reagents
5.3 Stability studies
5.4 Intermediates in morphine synthesis
5.5 Biotransformations
6. Selected Spectra
7. References
8. Vita
53
57
60
60
61
65
71
72
74
76
78
81
83
83
84
91
92
100
104
126
132
- VI-
List of Figures
Figure I-Design of new Burgess reagents 01
Figure 2-Retrosynthetic analysis for morphine 02
Figure 3-Burgess' sulfonylamine preparation 03
Figure 4-Generation of N-sulfonylamines 03
Figure 5-Electrophilic addition to N-(triethylammoniumsulfonyl)carbamate
inner salt 04
Figure 6-Dehydration reactions of secondary and tertiary alcohols
with Burgess reagent 04
Figure 7-Reaction of Burgess reagent with n-hexanol 05
Figure 8-Formation of diene or urethane from an allylic alcohol
with Burgess reagent 05
Figure 9-Mechanism of dehydration by Burgess reagent 06
Figure 10-Dehydration of alcohols with stabilized carbocation intermediates 06
Figure II-Dehydration of ami des to nitriles with Burgess reagent 07
Figure I2-Conversion of cis-aldoximes to nitriles with Burgess reagent 07
Figure 13-Synthesis ofisocyanides from formamides 07
Figure I4-Barvian's preparation of carbodiimides from ureas 08
Figure 15-Dehydration of nitro alkanes with Burgess reagent 08
Figure I6-Cyc1odehydration of P-hydroxy-a-amino acids with Burgess reagent 09
Figure I7-Formation ofthiazoline rings under various conditions 10
Figure I8-Formation of p-amino alcohols from styrene derived diols 11
Figure 19-5ynthesis of sulfamides from amino alcohols 11
- Vll-
Figure 20-Nicolaou's synthesis of (1- and ~-glycosylamines 12
Figure 21-Formation ofsulfilimines from sulfoxides 13
Figure 22-Preparation of acyl ureasand amides from carboxylic acids 14
Figure 23-Formation of 5- and 7-membered sulfamidates from epoxides 15
Figure 24- Hudlicky's proposed mechanism for the formation of
cis-cyclic sulfamidates
Figure 25-Correction of the structure of 76
Figure 26-Formation of symmetrical disulfides from thiols
Figure 27-Burgess reagents utilized by Nicolaou
Figure 28-Wipfs preparation of PEG linked Burgess reagent 118
Figure 29-Brain's synthesis of 1,3,4-oxadiazoles with
PEG supported Burgess reagent
Figure 30-Montero's sulfamoylating reagent
Figure 3l-Masui's one pot preparation of sulfamides
15
16
16
17
17
18
18
19
Figure 32-Reaction of Hudlicky's chiral auxilIary Burgess reagent with epoxides 19
Figure 33-Dehydration of steroidal alcohols by Burgess reagent 20
Figure 34-Application of Burgess reagent in Stork's ketosteroid synthesis 21
Figure 35-Rigby's use of the Burgess reagent in the syntheses
of cedrene and narciclasine 21
Figure 36-Use of the Burgess reagent in Kita's synthesis offredericamycin A 22
Figure 37-Use of the Burgess reagent in Ciufolini's studies
toward the synthesis of sordarin 22
- V111-
Figure 38-Application of Burgess cyclodehydration in the synthesis
of (+ )-curacin A 23
Figure 39-Raghavan's syntheses of (-)-deoxocassine and (+)-desoxoprosophylline24
Figure 40-Hudlicky's enantiodivergent formal synthesis ofbalanol 25
Figure 41-Structure of morphine and related alkaloids 27
Figure 42-Biosynthesis of morphine 30
Figure 43-Altemate pathway for the conversion of thebaine to morphine 31
Figure 44-Gates' synthesis of intermediate 177 32
Figure 45-C-14 epimerization 33
Figure 46-Final transformations in Gates' synthesis of morphine 34
Figure 47-Rice's synthesis of cyclization precursor 190 35
Figure 48- Final transformations in Rice's formal synthesis of morphine 36
Figure 49-Hudlicky's synthesis of intermediate 200 37
Figure 50-Hudlicky's transformation of 200 to ent-codeine 38
Figure 51-Hudlicky's synthesis of the natural enantiomer of codeine 39
Figure 52-Chida's synthesis of intermediate 218 40
Figure 53-Chida's cascade and sequential Johnson-Claisen rearrangements 41
Figure 54-Final steps in Chida's formal synthesis of morphine 42
Figure 55-Gibson's proposed mechanism for diol and catechol.formation
by P. putida 43
Figure 56-Metabolism of p-chlorotoluene by P. putida 44
Figure 57-Proof of relative stereochemistry of P. putida metabolites 44
Figure 58-Proof of absolute stereochemistry of P. putida metabolite 236 45
-IX -
Figure 59-Boyd's model for the prediction of stereoselectivity of
TDO dihydroxylations 46
Figure 60-Boyd's expanded model for the stereoselectivity of
TDO dihydroxylations 46
Figure 6 I-Oxidation of o-halostyrenes by TDO 47
Figure 62-Metabolism of benzoate esters by TDO 48
Figure 63-Preparation ofpolyphenylene from 230 48
Figure 64-Ley's synthesis of(±)-pinitol 49
Figure 65-Hudlicky's synthesis of prostaglandin synthon 259 50
Figure 66-Landmark syntheses employing microbial dihydroxylation 51
Figure 67-The Claisen rearrangement 52 I
"j
Figure 68-Chair and boat transition states for the Claisen rearrangement 53
Figure 69-The Reformatskii-Claisen rearrangement 53
Figure 70-The retro-Claisen rearrangement 54
Figure 71-The Ireland-Claisen rearrangement 55
Figure 72-The Kazmaier-Claisen rearrangement 55
Figure 73-The lohnson-Claisen rearrangement 56
Figure 74-Hudlicky's general method for the synthesis oflinear and
non-linear triquinanes 58
Figure 75-Hudlicky's preparation of unnatural amino acids via a
Kazmaier-Claisen rearrangement 59
Figure 76-Chida's cascade and sequential lohnson-Claisen rearrangements 59
Figure 77-Burgess reagents employed in this study 61
- x-
Figure 78-Preparation of Burgess reagents 62
Figure 79-Possible mechanisms for the formation of 322 65
Figure 80-Decomposition of Burgess reagents at 50 DC in THF-d8
as a function of time 66
Figure 81-Decomposition of Burgess reagents at reflux in THF -d8
as a function of time 67
Figure 82-Decomposition of 1 at 50 DC and at reflux 68
Figure 83-Decomposition of124 at 50 DC and at reflux 68
Figure 84-Decomposition of312 at 50 DC and at reflux 69
Figure 85-Decomposition of313 at 50 DC and at reflux 69 I I
Figure 86-Decomposition of314 at 50 DC and at reflux 70 I
oj
I Figure 87-Synthesis of the C-ring fragment of morphine 71 I
Figure 88-Separation of diastereomers and recycling of331 72
Figure 89-Preparation of A-ring fragment 8 73
Figure 90-Suzuki coupling of 8 and 9 74
Figure 91-Synthesis of alcohol 338 75
Figure 92-Preparation of Cia is en substrate 340 75
Figure 93-Preparation of cyclic carbamate 6 75
Figure 94-Attempted 10hnson-Claisen rearrangement 76
Figure 95-Chida's intermediate compared to Claisen substrates
prepared in this thesis 81
Figure 96-Proposed cycloaddition strategy for the completion ofthe synthesis
of morphine 82
- XI-
List of Tables
Table I-Reactivity trends of the new Burgess reagents in dehydration,
reactions with oxiranes, and with styrene diol 64
Table 2-0ptimization of epimerization conditions 72
Table 3-0ptimization of Suzuki coupling 74
Table 4-Substrates and conditions attempted in Johnson-Claisen rearrangement 77
Table 5-Metabolism of halogen substituted benzoate esters by TDO 80
- Xll-
List of Abbreviations
2,4DNP 2,4-dinitrophenyl hydrazine
Ac acetyl
Boc tert-butyloxycarbonyl
(BochO di-tert-butyl dicarbonate
Cbz carboxybenzyl
CDCh deutero-chlorofornn
CDCh chlorofornn
conc. concentrated
CSA camphorsulfonic acid
CSI chlorosulfonyl isocyanate
DAST diethylaminosulfur trifluoride
DBU 1,8-Diazabicyclo[ 5 .4.0]undec-7 -ene
DCC dicyclohexylcarbodiimide
DCE 1,2 dichloroethane
DCM dichloromethane
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIPEA diisopropylethylamine
DMAP dimethylamino pyridine
DME dimethoxyethane
DMF N,N-dimethylfornnamide
DMSO dimethyl sulfoxide
- X111 -
dppf
dr
EDG
EI
eq.
er
Et20
Et3N
EtOAc
EWG
FAB
h
HATU
HCI
HMBC
Hz
IBX
i-Pr
IPTG
IR
J
LAH
1,1 ' -bis-( diphenylphosphino )ferrocene
diastereomeric ratio
electron donating group
electron ionization
equivalent(s)
enantiomeric ratio
diethyl ether
triethylamine
ethyl acetate
electron withdrawing group
fast atom bombardment
hour(s)
2-(1H-7-azabenzotriazol-I-yl)--1,1,3,3-tetramethyl uronium
hexafluorophosphate methanaminium
hydrochloric acid
heteronuclear multiple bond correlation
Hertz
2-iodoxybenzoic acid
isopropyl
~-isopropylthiogalactopyranoside
infrared spectroscopy
coupling constant
lithium aluminum hydride
- XIV-
LDA
M*
MeCN
mm
mp
MS
n-BuLi
NADH
NADPH
NBA
NMR
p-Tol
PAD
PBU3
PEG
PhH
PhMe
PMB
PMP
PPh3
ppm
quant.
rt
lithium diisopropyl amide
menthyl
acetonitrile
minute(s)
melting point
mass spectroscopy
n-butyllithium
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide phosphate
N -bromo acetamide
nuclear magnetic resonance
p-tolyl
potassium azodicarboxylate
tributyl phosphine
poly( ethylene glycol)
benzene
toluene
p-methoxybenzyl
p-methoxyphenyl
triphenyl phosphine
parts per million
quantitative
room temperature
- xv-
TBAF tetrabutylammonium fluoride
TBS tert-butyldimethylsilyl
TDS thexyldimethylsilyl
t-Bu tert-butyl
TDO toluene dioxygenase
TFA trifluoroacetic acid
THF tetrahydrofuran
TIBAL tri-isobutyl aluminum
TLC thin layer chromatography
TMS tetramethylsilane
W Watt(s)
- XVI-
I. Introduction
This thesis is presented in two parts. In the first part, the design of new variants of
type 2 of the Burgess reagent 1 and their thermal stability is to be investigated. The
second part is concerned with progress toward the total synthesis of morphine 3 with the
key steps being biooxidation of bromobenzene 4 and a Claisen rearrangement to set the
C-13 quaternary center.
The Burgess reagent 1 is a useful tool for performing a variety of transformations
in organic synthesis. However, it is unstable at high temperatures and in the presence of
acids. We investigate new variants of the reagent to overcome this instability and then
evaluate the stability and reactivity by NMR techniques. The methoxy portion of the
carbamate will be replaced with the more electron withdrawing 2,2,2-trifluoroethanol to
better stabilize the negative charge. The triethylamine portion will be replaced with the
more electron donating N-methylpiperidine to stabilize the positive charge (Figure 1).
EDG EWG 2
Figure i-Design of new Burgess reagents
Morphine (3) is a commonly used analgesic with a complex structure. Its use by
mankind has spanned centuries. Our proposed synthetic route, shown in Figure 2, begins
with the dihydroxylation of bromobenzene (13) with Escherichia coli JM109
(pDTG601). Reduction of the distal double bond and coupling with Boc glycine will
provide 11 which will be subjected to a Kazmaier-Claisen rearrangement. Subsequent
methylation and separation of the diastereomers will give the C-ring fragment 9 which is
to be coupled to A-ring fragment 8. The coupled intermediate will be further elaborated
- 1 -
to the substrate for the second Claisen rearrangement 6. Subsequent closure of the B- and
D-rings and further elaboration should provide morphine (Figure 2).
Connected to the biooxidation of bromobenzene (13) to diol 12 was the
investigation of several halogen substituted benzoate esters that were tested as substrates
for the enzyme toluene dioxygenase (TDO). The yields and physical and spectral
properties of the new metabolites will be presented.
Br C02Me Br C02Me /o~
.~ NHBoc <~~ === .~NHBOC + 'O~ <~~ === TDSO" V TDSO" V B(OHh
10 9 8 I
B 0
cxo~NHB" 11 OTDS
--""",> LOH
UOH 12
----;I> 6 13
Figure 2-Retrosynthetic analysis for morphine
- 2-
2. Historical
2.1 Burgess reagent
2.1.1 Development of Burgess reagent and dehydration reactions
The fIrst reported synthesis of an alkyl N-(triethylammoniumsulfonyl)carbamate
inner salt was in 1968 when Edward Burgess and George Atkins studied the reactivity of
N-sulfonylamines. 1 Inner salt 15 was an intermediate that was subjected to fragmentation
to prepare N-sulfonylamine 16 (Figure 3).
0" ,9 ~ Et3N ... S'N ............. O./'-......
(±) e 15
Figure 3-Burgess' sulfonylamine preparation
+
16
In their previous work 16 was generated in-situ by treating 14 with one equivalent
of triethylamine and intercepting the unstable sulfonylamine with a nucleophile such as
aniline (17).1 The more reactive benzoyl sulfonylamine 19 was also generated in the
presence of ethyl-vinyl ether (21) to form cycloadduct 22 (Figure 4).
0 -78°C Et3N 0 Qo 0 0 0" ~O )l 0, )l H2NPh (17)
Cr· ... S'N O~ .. 'S=N O~ ~ N~S~N)lO~ - Et3NHCI "
.. H 0 H H 14 16 18
0 0 ~O~
o 0
o"p~ -78°C Et3N 0, ~ o~g ~ Cr ... ·S'N ~ .. ~S=N I: 21 q I: H 1 b
- Et3NHCI .. OEt
19 20 22
Figure 4-Generation of N-sulfonylamines l
Burgess and Atkins reported several electrophilic additions to 15 (Figure 5).2 The
reaction of 15 with aniline gave 17 in 92 % yield. The addition of N-vinylpyrrolidinone
- 3 -
(23) to 15 gave 24 in 50 % yield and the addition of isopropanol to 15 gave 26 in low
yield.
o 0 0 .... II II
o~~SY"OEI OH
A 25
V 24
Figure 5-Electrophilic addition to N-(triethylammoniumsulfonyl)carbamate inner salf
In 1970, Burgess prepared the methyl variant of the inner salt 1, which would
later be named the Burgess reagent. This compound was found to be a very mild
dehydrating agent for secondary and tertiary alcohols (Figure 6).3
OH
A ~ 25 .. 27
0 b OH d? O~-,/O )l Et N ... S .... N 0/ 28
3Et:) e .. 29
1
>r0H
A 30 .. 31
Figure 6-Dehydration reactions of secondary and tertiary alcohols with Burgess reagene
When primary alcohols were treated with the Burgess reagent, dehydration did
not occur. Instead, primary urethane 32 was formed via an SN2 pathway (Figure 7).3
-4-
n-hexanol
90%
o ~N)lO/
32 H
Figure 7-Reaction of Burgess reagent with n-hexanoe
Depending on reaction conditions, allylic alcohols were shown to either undergo
dehydration reactions or form urethanes via an SN2 pathway rearrangement (Figure 8).3
~
35,70 %
triglyme OIl(
+
1
OH
~ 33
1. neat, 80 DC ,.
36, >90 %
Figure 8-Formation of diene or urethane from an allylic alcohol with Burgess reagene
In the 1970 full paper, isotope studies were presented that showed that the
elimination of an alcohol by 1 was a syn-elimination.3 Erythro and threo-2 deutero-l,2-
diphenyl ethanol (37 and 38 respectively) were treated with Burgess reagent. The former
yielded only trans-stilbene (39) while the latter yielded only protio-trans-stilbene (40).
The rate limiting step was shown to be the formation of an ion pair 42 followed by a fast
cis-p-proton transfer (Figure 9).
- 5 -
O}- / O}- /
° 0 o 0
O~s-Ne O~s-Ne H Ph HO 0 1 slow
eq ) fast
prH H'H"Ph I
)Do )Do )Do 0 0 (!)
H'H"Ph " 0 Ph H -Et3NH f£< 37 Ph H H'" "'Ph 39
41 Ph H
42
H Ph HO H 1
pro '''H''Ph )Do
(!) Ph 0 -Et3NH
38 40
Figure 9-Mechanism of dehydration by the Burgess reagent
When the carbocation intermediate in a dehydration reaction is highly stabilized,
rearrangements can occur thus making olefin formation less predictable, as in the case of
46 (Figure 10).3
00H 1 ~ ~ )0
43 44 (2.4) 45 (1)
>f-H 1 ~ )0-
46 47
-j-{H 1 h >=< H )0-
49 (1) 50 (3) 51 (1.5)
48
Figure 10-Dehydration of alcohols with stabilized carbocation intermediates (product ratio)
Following Burgess' work on dehydration reactions with 1, several other reactions
were reported. In 1988, Claremon and Phillips reported the dehydration of primary
amides to nitriles with the Burgess reagent (Figure 11).4
- 6-
o 0
0 OH [ O~S'-N)lo/] R)lNH2
"'" RANH
1 LO G) ... .. A"H R N'
-----l .. ~ R-C=N
52 53 54 55
Figure ll-Dehydration of amides to nitriles with the Burgess reagent4
Prathapan and co-workers reported the synthesis of nitriles from cis-aldoximes
with the Burgess reagent in 2000 (Figure 12).5
H
~N,OH U
56
1,3 eq . ...
58,66 %
Figure 12-Conversion of cis-aldoximes to nitriles with the Burgess reagentS
McCarthy and co workers used the Burgess reagent to convert formamides to
isocyanides (Figure 13).6
59
1, 1.5 eq ... DCM, reflux
60,80 %
Figure 13-Synthesis of isocyanides from formamides6
Building on the work of Claremon, Barvian and co-workers used the Burgess
reagent to dehydrate ureas to carbodiimides in up to 91 % yield. These reactions were
often clean enough not to require chromatography of the products (Figure 14).7
- 7 -
1,2.1 eq
DCM, rt, 20 hrs
Ph_N=C=N~OMe
~OMe 62,91 %
Figure 14-Barvian's preparation of carbodiimides from ureas7
As part of a research project on milder conditions for the dehydration of primary
nitroalkanes, Mioskowski and co-workers reported that the Burgess reagent worked
under mild conditions (Figure 15).8 However, they found diethylaminosulfur trifluoride
(DAST) to be the best reagent for the dehydration of nitroalkanes.
3 eq. 1, 5 eq Et3N •
PhMe, 50 DC ~C~~e V 0
~nC4H9 ~nC4H9 ----~~~ V N-d
64 65
Figure 15-Dehydration of nitroalkanes with Burgess reagent8
Burgess dehydrations are often milder than standard acid catalyzed dehydrations.
Often, the Burgess reagent can effect a dehydration at temperatures lower than 70 DC.
2.1.2 Alternative reactions of the Burgess reagent
Since the 1990s reactions employing the Burgess reagent have been greatly
expanded to include cyclodehydration reactions and non-dehydration reactions including
the formation of heterocycles and various functional group interconversions.
Wipf and co-workers employed the Burgess reagent in a cyclodehydration
reaction. ~-Hydroxy-a-amino acids of type 66 were treated with Burgess reagent (1) to
yield 4,5-dihydrooxazolines 68 (Figure 16).9 When Mitsunobu conditions were used for
this reaction, there were often side products, such as aziridines, formed. to
- 8 -
1, THF lit
66
j
DCM, DoC
69 70 Figure 16-Cyclodehydration of P-hydroxy-a-amino acids with the Burgess reagent9
Wipf also applied this methodology to the formation of thiazoline peptide analogs
(Figure 17) .11 The Burgess reagent gave the desired thiazolines in 96 % yield with 97:3 dr
in about 10 minutes. The same reaction under other conditions, such as TsClIEt3N,
SOClz/pyridine or Mitsunobu conditions, was lower yielding and led to extensive
epimerization at the C-2 position.
- 9-
+
72
Conditions Yield [%J Ratio 72:73
TsCI, Et3N, DCM, 42°C, 1 hr 40 1 :1
1. SOCI2, 0 °C, 2 hr; 2. pyridine, THF, O°C, 15 min 49 1: 1
Ph3P, DIAD, DCM, -78 to 22°C, 30 min 80 78:22
Burgess reagent (1), THF, 65°C, 10 min 96 >97:3
Figure 17-Fonnation ofthiazoline rings under various conditionsll
Li employed the Burgess reagent as a cyclodehydration agent in the preparation of
a series of N-bridged 5,6-bicylic pyridines. 12
The Nicolaou group employed the Burgess reagent in the synthesis of several
sulfone containing heterocycles.13 In 2002, Nicolaou and co workers reported that the
Burgess reagent could be used to synthesize sulfamidates from chiral 1,2 diols with
excellent regio- and stereoselectivity.14 The diols were prepared from styrene by the
Sharpless asymmetric dihydroxylation and then treated with excess Burgess reagent
yielding the cyclic sulfamidates. The sulfamidates were then hydrolyzed under acidic
conditions to yield p-amino alcohols (Figure 18). The minor product was originally
assumed to be regioisomer 76 but was later proven to be misassigned (See pages 15-16
for discussion ofthe structure correction).
- 10-
OH
~OH V
2.5 eq 1, THF
reflux,1 hr
74
o " II 0 O~ 1
51-0
N- -- \ ~ 0
V
o 110
0-5-:::' - \ 0 + ~ N-f VO-
75 major 76 minor (assumed structure)
I Hel, 4 M I Hel, 4 M t H20:dioxane (1 : 1) t H20:dioxane (1: 1 )
o 'o..J<
NH ::- OH
V 77 78
Figure IS-Formation of ~-amino alcohols from styrene derived diols14
Nicolaou expanded on this methodology using the Burgess reagent to synthesize
5,6, and 7-membered sulfamides from amino alcohols (Figure 19).15
1
79
1
81
1
83 84
Figure 19-5ynthesis of sulfamides from amino alcohols15
- 11 -
Nicolaou and co-workers applied their methodology to the synthesis of (l- and
~-glycosylamines (Figure 20).16 The Burgess reagent was well suited to this chemistry
because regio- and stereo selectivity are very predictable. For the preparation of (l-
glycosylamines 88, 3,4,6-protected sugars 85 were treated with the Burgess reagent. The
resulting sulfamidate 87 was then subjected to nucleophilic attack. ~-Glycosylamines 92
were prepared from 2,3,4,6-protected sugars 89. This reaction followed an SN2 pathway
similar to Burgess' early disclosures.
RO
RO~-O OH RO~
OH 85
RO
RO~-O OH RO~
OR
89
2.5 eq 1
86
2.5 eq 1 l R:~ -0 0_S~~-C02R] .,.. .. <==~ -------...... RO~ II 0 OR 0
90
Figure 20-Nicolaou's synthesis of (1- and ~-glycosylamines16
While attempting the dehydration of the alcohol moiety in 93, Raghavan and co-
workers discovered that Burgess reagent reacts preferentially with sulfoxides to give
sulfilimines 95 (Figure 21).17 Initial reactions carried out at 60°C in THF gave only
- 12-
about 30 % yield. The reaction was optimized and was found to be high yielding when
performed in benzene at room temperature. By varying the alkyl component of the
Burgess reagent 98, Raghavan was able to prepare several sulfi1imines 97.
e o I
e o I
e NC02Me I
/~l P-TOl o 1, THF ... )( /~*c p-Tol l)H 1, THF /~*c p-Tol l)H 94 93
000 "II II
Et N .... S'N/'-OR 3@ e
98a-d
PhH, rt
a:R = Me b:R = Bn c:R = Allyl d:R = CH2CCI3
e NC02R I
R1-~'R2 97
Figure 21-Formation of sulfilimines from sulfoxides 17
95
Makara and co-workers treated a series of carboxylic acids with Burgess reagent
to give mixed sulfcarboxyanhydrides of type 100 (Figure 22).18 The mixed anhydrides
could then be treated with amines to form amides 101 or acyl ureas 103. Makara found
that excess 1 was required with slow reactions due to decomposition of the Burgess
reagent. The conversion of an acid to an amide or acyl urea could be completed in one
pot as long as excess Burgess reagent was destroyed to prevent the formation of
sulfamidates. This was accomplished by heating the reaction mixture to 80°C for 15
minutes before the addition of the amine. The ratio of amide to acyl urea could be
controlled by adjusting the temperature and employing microwaves as a heat source.
- 13 -
1.4 eq 1, MeCN, 1.5 eq DIPEA
5 min rt then 15 min 80 DC
13.0 eq R2R3NH
80 DC (f.lW)
o
R)lNR2R3
101
150 DC (f.lW), 8 min
Figure 22-Preparation of acyl ureas and amides from carboxylic acids18
Until 2001, it was believed that the Burgess reagent was inert to epoxides. In his
review in 2000 Lamberth stated, "The compatibility of the Burgess reagent with many
functionalities, e.g. halogens, epoxides, alkenes, alkynes, aldehydes, ketones, acetals,
esters, secondary ami des, makes it an attractive technique for the introduction of C-C
double bonds into highly functionalized molecules".19 However, in 2003 Hudlicky and
co-workers showed that the Burgess reagent reacted with epoxides to form cyclic
sulfamidates. Lamberth cannot be blamed for the statement however, because several
dehydration reactions had been performed on molecules containing epoxides with
dehydration taking place preferentially to sulfamidate formation.3,20
In 2003, Hudlicky and co-workers showed that the Burgess reagent reacts with
epoxides to form five or seven membered cyclic sulfamidates.21 It was discovered that
aliphatic epoxides formed only five membered sulfamidates while benzylic epoxides
formed mostly seven membered sulfamidates with five membered sulfamidates being
produced in about 2 % (Figure 23).
- 14-
I
[ o::x~l 00 1===0 104 o .. \
+
o
~ 106
105 10 . (assumed structure) 7, major
Figure 23-Formation of 5- and 7-membered sulfamidates from epoxides21
o '\. II 0
O-'\. 181-0
N- -
~b 75, minor
During subsequent work it was shown by Hudlicky that the five membered
sulfamidate 105 which was initially thought to have a trans-stereochemistry was actually
cis 109?2 A mechanism was proposed to account for the cis stereochemistry.22
Hudlicky's proposed mechanism requires two equivalents of Burgess reagent and is
similar to the mechanism Nicolaou proposed for the reaction of Burgess reagent with
diols (Figure 24).14
2 eq 1
104 109
Figure 24-Hudlicky's proposed mechanism for the formation of cis-cyclic sulfamidates
Hudlicky also noted that the seven membered sulfamidate 107 formed from
styrene oxide (106) was spectroscopically identical to Nicolaou's minor product (76,
page 11, Figure 18) in the reaction of Burgess reagent with styrene diol 74.14 An X-ray
crystal structure was acquired which proved that Nicolaou's minor product was indeed
seven membered sulfamidate 107.21 A mechanism with degenerate pathways that
accounts for the formation of both five and seven membered sulfamidates was proposed.
- 15 -
o \I 0
o-S~ - \ 0
~N-L
76, proposed structure 107, actual structure
Figure 25-Correction of the structure of76
In another case of unexpected reactivity, Hudlicky and co-workers showed that
when treated with Burgess reagent, thiols form disulfides (Figure 26).23 Hudlicky had
been attempting to expand the scope of Burgess dehydration and urethane formation to
primary, secondary and tertiary thiols. However, when decane-l-thiol (104) was treated
with Burgess reagent under standard conditions, disulfide 105 was isolated in nearly
quantitative yield (Figure 26).
(ySH
CI~ 112
~SH
V 114
1, PhH
rt,2 hr
1, PhH
rt,2 hr
1, PhH
rt,2 hr
..
..
)Ir
CH3(CH2)gS-S(CH2)gCH3
111
~CI
(ys'sN M CI 113
115
Figure 26-Forrnation of symmetrical disulfides from thiols23
2.1.3 Variants of the Burgess reagent
Several researchers have modified the alkyl or amine portions of the Burgess
reagent for improved reaction characteristics or to incorporate different alkyl groups into
their products. The Nicolaou group prepared variants of the Burgess .reagent with
- 16-
different alkoxy groups 98a-e in their sulfamidate and sulfamide syntheses. 14-15 The
methyl, benzyl, allyl, trichloroethyl, and o-nitro benzyl versions 98a-e were employed in
the synthesis of sulfamidates and the methyl, benzyl and allyl versions 98a-c were used
in sulfamide preparation. Raghavan employed Nicolaou's new Burgess reagents 98a-d in
his preparation of sulfilimines from sulfoxides. 17
a:R = Me b:R = Bn c:R = Allyl d:R = CH2CCI3 e:R = o-N02Bn
Figure 27-Burgess reagents utilized by Nicolaou
Over the course of their studies of cyclodehydrations, the Wipf group noticed that
the Burgess reagent decomposed upon exposure to moisture and oxidative conditions and
that they obtained the best yields with freshly prepared Burgess reagent.24 To improve the
stability of the reagent, ease of handling and ease of purification of the products, Wipf
developed a poly(ethylene glycol) (PEG) (116) linked version of the Burgess reagent 118
(Figure 28). They found that yields of oxazolines and thiazolines were 10-20 % higher
when the PEG supported reagent was used in place of 1. Upon completion of the
reaction, filtration through a plug of silica often led to pure product as unreacted 118 and
by-products remained absorbed in the PEG matrix or on silica gel.
Ho~~0o~OMe) y
PEG 116
2.2 eq Et3N
Figure 28-Wipfs preparation of PEG linked Burgess reagent 118
Brain and co-workers employed Wipfs PEG supported Burgess reagenr4 in the
synthesis of 1,3,4-oxadiazoles 120 from 1,2-diacylhydrazines 119 under microwave
- 17 -
conditions (Figure 29).25 Reaction times from two to four minutes under 100 W
microwave conditions were noted. Building on Brain's work, Li and Dickson developed a
one pot procedure for the synthesis of 1,3,4-oxadiazoles that proceeded in moderate to
excellent yield at room temperature.26
o 0
R)lN-NAR2
H H 119
118
~LW, THF
Figure 29-Brain's synthesis of 1,3,4-oxadiazoles with PEG supported Burgess reageneS
While looking to develop a stable and efficient sulfamoylating reagent, Montero
and co-workers developed reagent 121 (Figure 30).27 Montero had been using
chlorosulfonyl isocyanate (117) as a sulfamoylating reagent but found it was often too
reactive. In order to reduce the reactivity, they treated it with tert-butanol and then
DMAP. This led to Burgess type reagent 121. Reagent 121 was shown to be an efficient
sulfamoylating reagent giving products in moderate to high yields under mild conditions.
Figure 30-Montero's sulfamoylating reagene7
At the same time as Nicolaou was developing variants of the Burgess reagent for
the formation of sulfamidates and sulfamides 14-15 the group of Wood independently
developed the benzyl version of the Burgess reagent 98b for a one step conversion of
primary alcohols to Cbz protected amines.28
Masui and co-workers prepared a variant of the Burgess reagent by treating 117
with isopropanol and pyridine in a one pot procedure?9 The reagent could then be treated
- 18-
with dry or aqueous amines to form sulfamides (Figure 31). The advantage to Masui's
methodology was that sulfamides could be produced from aqueous amines such as
ammonia or methylamine at room temperature where traditional methods required
anhydrous amines and low temperatures (either because of the low boiling point of the
amine or exothermic reactions).
0" /9 1. i-PrOH l O~sP ~ I 1 '8' -----...... ON" 'N..A-..O~ aq or dry amine
CI/ 'N==C=O 2. pyridine ~ I ® e --'------"--......
117 122
Figure 31-Masui's one pot preparation of sulfamides29
As part of their research in synthesizing sulfamidates from epoxides the Hudlicky
group attempted to use C2 symmetric Lewis acid catalysts to form chiral sulfamidates of
type US which could then be used to access chiral amino alcohols.22 These attempts were
unsuccessful and it was rationalized that the Lewis acid and the Burgess reagent could
not coordinate simultaneously to an epoxides for steric reasons. Hudlicky then turned his
attention toward creating a chiral auxiliary version of the Burgess reagent 124. When
cyclohexene oxide (104) was treated with 124 a 1: 1 mixture of diastereomeric
sulfamidates 12Sa-b was produced (Figure 32). The mixture was separable by column
chromatography and the diastereomeric sulfamidates could be treated to form cis or
trans-amino alcohols in both enantiomeric series, the latter group of compounds
produced by the reaction of cis-sulfamidates with ammonium benzoate.3o
+ 00 104
THF, reflux .. (X0,,,,o
,S~ N
ero \
M*
125a
+
M* = menthyl
Figure 32-Reaction ofHudlicky's chiral auxiliary Burgess reagent with epoxides22
- 19-
2.1.4 Applications of the Burgess reagent in total synthesis
The Burgess reagent has proven to be very useful in synthesis as a dehydrating
agent due to its mild reaction conditions. The Burgess reagent is soluble in a wide variety
of organic solvents and many reactions can be performed at room temperature at neutral
pH. Its wide range of reactivity has led to its use in the syntheses of many complex
natural products.
The first reported use of the Burgess reagent in synthesis was by Crabbe
who reported the dehydration of several steroidal alcohols (Figure 33).31 Caspi and co
workers also reported the dehydration of several steroidal alcohols to their corresponding
0lefIns.32
o o 1
PhH, rt, 75 %
126 127
Figure 33-Dehydration of steroidal alcohols by Burgess reagene1
Stork employed the Burgess reagent in his general method for the synthesis of
ll-oxygenated steroids (Figure 34).33-35 The Burgess reagent was used to dehydrate 128
which then underwent an intramolecular Diels-Alder reaction. By this general method,
Stork synthesized cortisone, adrenosterone, l1-ketoprogesterone, and 11-
ketotestosterone. Dehydration of 128 with Burgess reagent led to the desired Diels-Alder
precursor 129a as well as the regio-isomer 129b, which did not undergo cyclization and
was therefore easily separated from the mixture. Further transformations of 130 led to
131, which was identical to an authentic sample of silylated ll-ketotestosterone.
- 20-
1
128
131
129a major
1 intramolecular Diels-Alder
130
+
129b minor
Figure 34-Application of Burgess reagent in Stork's ketosteroid synthesis
Rigby employed the Burgess reagent as a dehydrating agent in his syntheses of
p-cedrene (134)36 and (+)-narciclasine (136) (Figure 35).37
~H 1 stf .. ~ .. .. 132 133 134
OAe OAe
TBSO". 0)( 0)( 1. F-, THF
<0 ° .. <0 ° 2. 1, PhH, reflux
° ° OAe ° OAe °
135 136
Figure 35-Rigby's use of the Burgess reagent in the syntheses of cedrene and narciclasine36-37
In the Kita group's synthesis of both enantiomers of the complex natural product
fredericamyein A (139), a key step was the dehydration of alcohol 138 (Figure 36).38 Kita
first employed an anti-elimination under acidic conditions which was successful but only
- 21 -
in 51 % yield. They then attempted a Chugaev elimination which was unsuccessful. The
Burgess reagent however, gave a clean elimination in quantitative yield.
1
THF, reflux
137 138
139
Figure 36-Use of the Burgess reagent in Kita's synthesis of fredericamycin A 38
Recently, Ciufolini and co-workers have employed the Burgess reagent in their
synthetic studies toward the terpenoid core of sordarin and analogs thereof.39 Alcohol 140
was treated with Burgess reagent yielding Diels-Alder precursor 141 in 54 % (Figure 37).
However, attempts at the Diels-Alder cyclization were unsuccessful and another route
was followed.
fdiC02Me
OH
TBSO ==--
CNCN
140
1
54% ~:2Me
TBSO ==--
CNCN
141
heat )( ..
142
Figure 37-Use of the Burgess reagent in Ciufolini's studies toward the synthesis of sordarin39
Wipfs synthesis of (+)-curacin A (146) employed both the Burgess reagent (1)
and PEG supported reagent 11824 in an elegant oxazoline-thiazoline conversion (Figure
38).40-41 Deprotection of the silyl group of143 proceeded in nearly quantitative yield. The
resulting alcohol was subjected to cyclodehydration with Burgess reagent to give
oxazoline 144. Thiolysis followed by cyclodehydration with Burgess reagent (1) gave the
natural product 146. When PEG supported Burgess reagent 118 was employed In
thiazoline formation, a modest increase in yield was observed.
- 22-
OMe ~R TBSO
1. HF, pyridine, 91 % .. NH 2.1, THF, 71 % 0)J
O?v<H 143 H" "H
144
1 H,S, MeOH, Et3N, 66 %
?'" OMe ~R 1, THF, 54 %
HO NH ... N or
S?v<H S)J 118, THF, 63 %
H" "H 146 145
Figure 38-Application of Burgess cyclodehydration in the synthesis of (+)-curacin A 41
Wipf also employed Burgess cyc1odehydrations and oxazoline-thiazoline
conversions in the first total synthesis of (-)-thiangazole 42 and the complex marine natural
product lissoc1inamide 7.43 Wipfs Burgess cyc1odehydration methodology was also
employed in Ino' s synthesis of yersiniabactin 44, Wipf s syntheses of westiellamide 45 and
hennoxazole A 46, and Miller's synthesis ofthe peptide fragment ofpseudobactin.47
Raghavan and co-workers demonstrated the synthetic utility of their sulfilimine
formation methodology with benzyl Burgess reagent 98b by applying it to the total
syntheses of (-)-deoxocassine (150) and (+)-desoxoprosophylline (151).48-49 Sulfoxide
147 was treated with the benzyl Burgess reagent 98b to yield sulfilimine 148. The
sulfilimine was then used as an internal nuc1eophile to give common intermediate 149
which was transformed to natural products 150 and 151 (Figure 39).
- 23-
g8 OTBS 98b S~ ..
p-Tol/@ PhH, O°C-rt
147
149
CbzN 8 OTBS 1. TBAF, THF ~ , ~ ..
p-TOI/~~ 2. NBS, H20, PhMe
148
N~: ~~~ H H (-)-deoxocassine (150)
H
(f"OH
~~~ H OH
(+ )-desoxoprosophylline (151)
149
Figure 39-Raghavan's syntheses of (-)-deoxocassine and (+)-desoxoprosophyUine48-49
Hudlicky and co-workers employed their chiral auxiliary Burgess reagent 12422 in
an enantiodivergent formal synthesis of the fungal metabolite (+)- and (-)-balanol
(155).30,50 The key step was a regioselective opening of epoxide 152 (Figure 40).22 The
resulting diastereomeric sulfamidates 153a and 153b were separated by column
chromatography and opened with benzoate to give the trans-amino alcohol moiety. These
were then further elaborated to formal intermediates of (-)- and (+ )-balanol, 154a and
154b respectively.
+
152
OH
balanol (155)
THF, reflux )0
36 % +
M* = menthyl
~! HoD ,~-pDBO
NBn 0
154a (-)-balanol 154b (+)-balanol intermediate intermediate
Figure 40-Hudlicky's enantiodivergent fonnal synthesis ofbalano13o •
- 24-
Since its discovery the Burgess reagent (1) has been widely used for dehydration
reactions in the synthesis of complex natural products. Burgess dehydrations are usually
high yielding and side reactions are rare. Renewed interest in the Burgess reagent over
the last twenty years has led to the development of new reactions as well as new versions
of the reagent further expanding the versatility of this already useful reagent.
- 25-
2.2 Morphine
2.2.1 Historical uses, isolation, and biosynthesis
Morphine (3) has been used by humans as an analgesic, antitussant and
recreational drug for thousands of years. The first recorded use of opium was by the
Sumerians in about 3400 BC.51-52 Opium poppies (Papaver somniferum) appeared in
Egyptian artwork and the Greek and Roman gods of sleep were often depicted with
poppies. The Swiss physician Paracelsus developed a preparation of opium and other
ingredients in wine and sold it as a remedy and sleep aid. In Great Britain, several
tinctures of opium in alcohol were marketed as cough suppressants and sleep aids which
were frequently administered to children to quiet them. These remedies were sold under
names such as Street's Infants' Quietness, Atkinson's Infants' Preservative, and Mrs.
Winslow's Soothing Syrup.
The British East India company was brought back from the verge of bankruptcy
by sales of Indian opium to China. The Chinese attempted to prohibit the sales and use of
Opium in 1839. However, smugglers and American ships still supplied Indian opium to
China. In 1839, Chinese officials took several British ships hostage and confiscated over
20,000 chests (1,600 tons). This led British foreign secretary Lord Palmerston to initiate
war. The goals of the British Crown were to obtain reparations for the insults suffered by
captured British sailors and officials, to recover the lost revenue from the opium· seized
by the Chinese and assure the security of British merchants in China. The British easily
defeated the Chinese and the treaty ending the war opened up four ports to British
merchants and ceded Hong Kong to Queen Victoria. The first Opium War, however, did
not fully resolve the dispute over opium trade. Throughout the 1840's and early 1850's
- 26-
the British sought to legalize the opium trade under the pretense that the Chinese could
not regulate the illicit opium trade as effectively as the British. The second Opium war,
also known as the Arrow war, began when Chinese officials boarded the British
registered ship Arrow whose crew was accused of smuggling and piracy in 1856. The
war ended with a treaty legalizing the import oflndian opium in 1858. At the time of the
Arrow war, a strong anti-opium trade movement was growing in England. In the late
nineteenth and early twentieth century, British India became less dependent on opium
revenue and an anti-opium movement began to take hold in China. This led to a series of
reductions in opium shipment to China and in 1913, the Indian government stopped all
opium shipments to China. 52-53 While use of raw opium continues today, most illicit
opium is converted to heroin which is less bulky, thus facilitating transport.54
In 1805, the German pharmacist Serturner isolated morphine from raw opium.55-56
The name morphine comes from Morpheus, the Greek god of dreams. The structure of
morphine eluded scientists for over one hundred years and its elucidation was reviewed
by Butora and Hudlicky.57 The correct structure of morphine (Figure 41) was reported in
1925 by Robinson and Gulland58 and was confirmed by Gates when he published the first
total synthesis of morphine in 1952.59
morphine (3) thebaine (157)
Figure 41-Structure of morphine and related alkaloids
- 27-
Opium is isolated from poppies by scoring the unripe seed pods of P. somniferum
approximately 98 days after germination. The latex oozes out and is collected. A single
seed pod can be harvested several days in a roW.52 The timing of the opium harvest is
important because morphine alkaloids are produced for only a short time. As the seed pod
ripens, alkaloid production stops and the alkaloids are broken down. 52 While this method
is still used in places with more primitive farming techniques, most modern commercial
poppy farms simply harvest the entire plant which is then sold to manufacturers as opium
straw from which the alkaloids are extracted on a large scale.52 The highest concentration
of alkaloids is found in the seed pods but thebaine can be found in significant quantities
in the roots of the opium poppy.52,60
The biosynthesis of morphine and related alkaloids has been elucidated (Figure
42). All carbon atoms present come from two molecules of the naturally occurring amino
acid tyrosine (158). Nature provides an elegant solution to the synthesis of these complex
molecules that is unrivalled by even the most efficient laboratory synthesis.
In the first stage of biosynthesis, one molecule of tyrosine is converted to
dopamine (159) by the action of tyrosine decarboxylase and phenol oxidase. A second
molecule of (158) is converted to 4-hydroxyphenylacetaldehyde (160). Dopamine (159)
and 4-hydroxyphenylacetaldehyde (160) are then condensed to form (S)-norcoclaurine
(161) by the action ofnorcoclaurine synthase. Subsequent methylation and oxidation give
(S)-reticuline (162a) which is then epimerized to (R)-reticuline (162b) via the 1,2-
dehydroreticulinium ion (163). A microsome bound cytochrome P450 containing enzyme
then couples carbon atoms 12 and 13 forming salutaridinol (164).61 The ketone at the C-7
position of salutaridinol is then reduced and acetylated. The free hydroxy group on C-4
- 28-
then attacks, displacing the acetate in a SN2' reaction to give thebaine (157). Thebaine is
then demethylated by thebaine 6-0-demethylase to neopinone (165)62 which exists in an
equilibrium with codeinone (166). Reduction of the C-6 ketone by codeine reductase63-64
yields codeine (156) which is then demethylated by codeine-O-demethylase to morphine
(3).62
- 29-
~C02H
HO~ NH2
L-tyrosine (158)
Me0:(A I~
HO 12
(0'NMe ..
MeO~ OH
(R)-reticuline (162b)
1 MeO
HO
MeO
o salutaridinol (164)
HO
HO'"
(-)-morphine (3)
HO~
,-----i~ HO~ NH2
dopamine (159)
~CHO HO~
4-hydroxyphenylacetaldehyde (160)
)II
MeO
HO
HO
MeO
1,2-dehydroreticulinium ion (163)
MeO
MeO
HO'"
(-)-codeine (156)
Figure 42-Biosynthesis of morphine
..
HO
HO
HO
(S)-norcoclaurine (161)
1 MeO
HO
MeO
(S)-reticuline (162a)
MeO
0 neopinone (165)
II
o codeinone (166)
Thebaine (157) can also be converted to morphine (3) by an alternate pathway
that accounts for the formation of trace amounts of oripavine (167) found in opium
- 30-
(Figure 43).62 In this alternate pathway, thebaine is converted to oripavine by the action
of codeine-O-demethylase. Thebaine 6-0-demethylase then converts oripavine to
morphinone (168) which is in tum converted to morphine by codeine reductase.
M~~ HO~ HO~ HO~ 1.0 1.0 1.0 1.0 q Q. ~ q ~ q . 1 NMe ~ '. 1 NMe . NMe . NMe
MeO ::::,... MeO ::::,... o .0 HO"> .0 thebaine (157) oripavine (167) morphinone (168) (-)-morphine (3)
Figure 43-Altemate pathway for the conversion of thebaine to morphine62
2.2.2 Notable syntheses of morphine
Gates (1952i9
Gates published the first total synthesis of morphine (3) in 1952 thus confirming
the structure proposed by Robinson and Gulland twenty seven years earlier. 58 Gates
prepared both enantiomers of morphine via a resolution of intermediate 176. Gates'
synthesis was achieved in twenty four steps from 2,6-dihydroxynapthalene (169) with an
overall yield of 0.01 %. As shown in Figure 44, an iterative nitrosation / reduction /
oxidation procedure was used to transform 2,6-dihydroxynapthalene (169) into
intermediate 172. The nitrogen atom was installed by a Michael type addition of ethyl
cyanoacetate to 172. This was followed by base hydrolysis and decarboxylation to give
173. The C-ring of the morphine skeleton was installed by a Diels-Alder reaction
between 173 and butadiene. The D-ring was completed by a reductive cyclization
yielding keto-Iactam 175. Reduction of 175 followed by methylation of the nitrogen atom
gave 176 which contains all of the carbon atoms in morphine. At this stage a resolution
was performed by crystallization of the tartrate salts of 176. The C-6 position was
hydroxylated in dilute sulfuric acid. Treatment with potassium hydroxide led to the
- 31 -
demethylation of the ether at C-4. The C-6 hydroxyl group was then oxidized to ketone
177.
HO~
~OH 169
MeO
MeO
174
27 atm H2 150 DC lEtOH
CuO/Cr20 50%
MeO
1. BzCI 2. NaN02
3. Pd/C 4. FeCI3 56%
)Iro
HOAc, heat 50%
BZOW"-'::: 1. S02 BZOW"-'::: "-'::: I )Iro.o .0
.0 0 2. (MeOhS02 OMe 170 0 78% 171 OMe
1. KOH 13. Pd/C 2. NaN02 4. FeCI3
69% o
OW 1. NC""C02Et wO
~ I .0 OMe ...... I---N-Et-3-- 0 ~ I ~ 2. K3FeCN6 .......... // OMe
NC OMe 3. KOH, EtOH 172 OMe 173 82%
MeO
MeO o 1. N2H4/KOH MeO ---=----'-----J)Iro~
175
2. Mel/NaH NH 3. LAH
76% NMe 2. KOH,
"'H (HOCH2CH2hO 3. KOt-Bu/Ph2CO
176 14% 177
Figure 44-Gates' synthesis of intermediate 17759
After the tartrate resolution of 176, the stereochemistry was correct at positions
C-9 and C-13 but epimeric at C-14. Compound 177 was treated with bromine in acetic
acid. Elimination of HBr gave an a,~-unsaturated ketone which was converted to its
hydrazone 179a. Hydrazone 179a then equilibrated to the more stable cis fused ring
system 179b (Figure 45).
- 32-
MeO
2,4 DNP HO
AcOH ..
177 Br 178 ArHNN
11 MeO MeO
HO "
Hel HO
ArHNN ArHNHN 181 180
Figure 45-C-14 epimerization59
After the epimerization at C-14 was complete, hydrogenation of a.,~-unsaturated
ketone 181 gave the precursor for the closure of the C-4,C-5 dihydrobenzofuran ring 182.
Repetition of the conditions for the epimerization of C-14 allowed for the closure of the
furan ring and installed the C-7, C-8 unsaturation. Acid hydrolysis of phenylhydrazone
183 followed by reduction with lithium aluminum hydride gave codeine (156) in 27 %
over two steps. Demethylation using Rappoport's conditions65 gave morphine (3) in 35 %
yield (Figure 46).
- 33 -
MeO
1. Br2. AcOH )Ir
2.2,4 DNP 26%
ArHNN 182
1 Hel Acetone
HO MeO MeO Br
Py-HCI 1. LAH oil[
34% 2. H2. Pd/C
HO'" HO'" 0 (-)-morphine (3) codeine (156) 184
Figure 46-Final transformations in Gates' synthesis of morphine59
Rice 198066
Rice's formal synthesis of morphine (3) in 1980 is noteworthy as it is the shortest
and the highest yielding synthesis to date. Rice's synthesis allows for the synthesis of
both the natural and unnatural enantiomers of hydrocodone. The route is biomimetic and
involves the isolation of only six intermediates, requires no chromatography and the final
yield of formal intermediate hydrocodone (185) is an amazing 29 %.
The synthesis begins with the condensation of amine 186 and acid 187 followed
by a Bischler-Napieralski reaction to give 188. Intermediate 188 was then resolved with
(8)-(-)-a-methylbezyl isocyanate. Birch reduction of the more electron deficient aromatic
ring followed by formylation, protection and bromination gave cyclization precursor 190.
- 34-
Meo~
V NH2 +
186
MeO
1. 200°C (95 %) 2. POCI3, MeCN HO .. 3. NaCNBH4 (86 %)
MeO
1. ethylene glycol, MeS03H, THF .... 2. NBA88 %
Figure 47-Rice's synthesis of cyc1ization precursor 190
MeO
HO
MeO
188
1. Li, NH3, THF, tBuOH (90 %)
2.PhOCHO, EtOH (94 %)
189
Hydrolysis of 190 with formic acid followed by a hydrogen fluoride mediated
Grewe-type cyclization gave the skeleton of morphine in 60 % yield. Acid hydrolysis of
formamide 191 gave l-bromo-nordihydro-thebainone (192). I-Bromo-nordihydro-
thebainone (192) was then converted to hydrocodone (185) by a four step sequence that
proceeded in 79 % yield. The bromine at C-l was removed by hydrogenation, the
dihydrobenzofuran ring was closed by alpha bromination of the ketone and base-induced
ring closure. Removal of the aryl bromide and methylation of the nitrogen atom were
achieved by hydrogenation over palladium on carbon in the presence of acetic acid and
formaldehyde. When 192 was subjected to hydrogenation without the addition of
formaldehyde, norhydrocodone (193) was isolated.
- 35 -
Meo&~ Sr
HO b
NH
o 192
Meo~~ Sr
HO b
NH
o 192
1. HC02H, H20, (90 %)
2. NH4F, HF, CF3S03H, (60 %)
)Do
Meo~~ Sr
HO b
NCHO
o
(92%)
Meo~~ Sr
HCI, MeOH HO b -~---i"'~
NH
o 192
1. H2, Pd/C, AcOH, HCHO 2. Sr2, AcOH
3. NaOH, CHCI3 4. H2, Pd/C, AcOH, HCHO
1. H2, Pd/C, AcOH, HCHO 2. Sr2, AcOH
3. NaOH, CHCI3 4. H2, Pd/C, AcOH
191
Meo~ 'b q
". NMe
o 185
Meo~ 'b 0,
'. NH
o 193
Figure 48-Final transformations in Rice's formal synthesis of morphine
Hudlicky 200967
Hudlicky's 2009 enantiodivergent synthesis of codeine (156) is based in part on
Parker's strategy used in the synthesis of morphine68-69 and employs a Heck coupling
similar to Trost's synthesis.70-71 Hudlicky's synthesis (Figure 49) begins with the
enzymatic dihydroxylation of p-bromoethyl benzene (194) to diol 195. Diol 195 was
subjected to diimide reduction and the hydroxyl groups were acetate protected. Protected
diol 196 was treated with methylamine and potassium carbonate to give a secondary
amine which was protected as a Boc carbamate 197 without purification. The distal
hydroxyl group was protected as a silyl ether. A Mitsunobu reaction between alcohol 198
and bromoisovanillin (199) gave intermediate 200 which was the substrate for the first
Heck reaction.
- 36-
E. coli JM109 (pDTG601)
10 gIl
194
/OYil ~O
o Br
~NMeBOC TBSO"'U
200
I ° /O~ HO:::::"" ..-::
Br 199
198
1. PAD, AcOH/MeOH 60 % .. 2. AO£O, Et3N, DMAP, 79%
Figure 49-Hudlicky's synthesis of intermediate 20067
197
The intramolecular Heck reaction gave cyclized product 201 in 82 % yield. A
Wittig reaction was used to convert the aldehyde to a vinyl bromide. Bromide 202 was
subjected to a second intramolecular Heck reaction to complete the phenanthrene core of
codeine. The C-6 stereochemistry was inverted by a desilylation followed by an
oxidation/reduction procedure. Deprotection of the Boc carbamate gave 204, the
enantiomer of Trost's intermediate.7o Hudlicky attempted to repeat Trost's
hydroamination procedure but was unsuccessful. To convert Trost's intermediate to
codeine, Hudlicky used an oxymercuration procedure which gave ent-156 in 18 % yield
(Figure 50).
- 37-
/O~ ::::,.. I ...,;0 Pd(OAc)2, A92C03
o Br .. 0
'-'::: NMeBoc 82 %
PPh3CH2Br2, t-BuOK
"'\ .. 0 . NM B THF, -60 cC, 49 % I e oc X)1 dppf, PhMe, 110 cC,
TB80'" TB80'" 200 201
TB80'" 202
/O~ /O~ I 1 TFNDCM (1 '4) I 1. TBAF, THF ::::,.. 88 % "::::,.. ... 2. IBX, DMF
o .",-~ -; H (OA) Et N 0 .",-""\ 3. NaBH4' CoCI3 H20, " 'NMe . g. C 2, ~ " NMeBoc MeOH 'H then LIAIH4 (18 Yo) 'H 72 % over 3 steps .
HO h- HO h- TB80" ent-1S6 204
Figure 50-Hudlicky's transformation of200 to ent-codeine67
j Pd(OAch, A92C03, dppp, PhMe, 107 cC, 44 %
203
Originally, Hudlicky's strategy for the synthesis of the natural isomer of codeine
was to perform two sequential Mitsunobu reactions despite low yields in a similar
sequence.72 The first Mitsunobu reaction would invert the C-5 stereochemistry and the
second reaction would invert again and couple the A-ring fragment (199). This strategy
was found to be very low yielding so an alternate path was taken. Hudlicky performed a
Mitsunobu reaction on 197 using Banwell' s procedure.73 The distal hydroxyl group was
then converted to tosylate 206. Hydrolysis of the ester, followed by displacement of the
tosylate, gave epoxide 207. The epoxide was then opened with the potassium salt of
bromoisovanillin (208). The hydroxyl group was protected as a silyl ether to give the
enantiomer of 200. The procedure shown in Figure 50 was then followed to convert
ent-200 to the natural isomer of codeine (156) (Figure 51). Hudlicky's 2009 synthesis is
noteworthy in that it can be used to synthesize both the natural and unnatural isomers
from a single starting material without a resolution. This overcomes one of the criticisms
of the use of enzymatic reactions to produce synthons in that only one enantiomer is
- 38 -
produced thus limiting chemists to the synthesis of only one enantiomer of a natural
product.
NMeBoc
DIAD, PPh3, THF .. &OPN02
82
197
/0Y') ~O
Q Br
~NMe80C HO 209
1 TBSCI, imidazole, DCM, 61 %
/0Y') ~O
Q Br
;"""~NMeBoc
TBsoN
OH 205
/O~ I 0 KO ~ h
Br 208
DME/DMF (1:1), 18-crown-6, 75 %
HO'"
TsCI, Et3N, DMAP .. DCM, 73 %
207
NMe
ent-200 (-)-codeine (156)
NMeBoc
&OPN0282
OTs 206
1 NaOMe, MeOH, THF, 88 %
J~e8OC 0·,(0
207
Figure 51-Hudlicky's synthesis of the natural enantiomer of codeine67
Chida 200874
Chida's formal synthesis of morphine employed a cascade lohnson-Claisen
rearrangement to set the C-13 quaternary center. The Claisen rearrangement was
catalyzed by 2-nitrophenol and is similar to a rearrangement he employed in his synthesis
of the Amaryllidaceae alkaloid galanthamine.75
Chida's synthesis begins with tri-O-acetyl-D-glucal (210) which is deacetylated
and reprotected in a sequence with a yield of 45 % over three steps. Cleavage of the
- 39-
I
I
p-anisaldehyde acetal and replacement of the alcohol gave iodide 212. Elimination of the
iodide to an olefin gave the substrate for a Ferrier's carbocyc1ization, 213. The
cyc1ization was followed by ~-e1imination to give cyc1ohexenone 214 and proceeded in
91 %. L-Se1ectride® was employed for a 1,4 reduction and the resulting enolate was
trapped as a vinyl triflate 215. Suzuki coupling to A-ring fragment 8 and subsequent
deprotection gave Claisen rearrangement substrate 218.
1. NaOMe, MeOH CH20Ac
ACO".~~ 2. p-anisaldehyde dimethylacetal PPTS, DMF
PMP".S)0
0". 0
ACoN 210
3. TBSCI, imidazole, DMF
1. L -Selectride
,.. TBSO .0
211
OTt
PMBOD 2. Com in's reagent
o PMBO".))
TBsoN 214
TBSO 215
'0.0 aq Na2C03 /0:Q"-'::: j Pd(OAch, Ph3P
1,4 dioxane 8 B(OHh
::~: PMBO". "-'::: DCM/H20
TBSO
DDQ
216
/O~ I '0 .0
HO". "-':::
TBSO
TBAF
THF
217
1. DIBAL, PhMe 2. Ph3PHBr, MeOH NaBr, DME
3. 12, imidazole, Ph3P, THF
1. Hg(OCOCF3), (20 mol%), acetonel acetate buffer
2. MsCI, Et3N, DMAP, DCM
/O~ I '0 ..0
HO". "-':::
HO 218
Figure 52-Chida's synthesis of intermediate 218
I
PMBO" i~ TBSOUoMe
212
!t-BUOK THF
PMBO',.~O TBsoMoMe
213
A cascade Claisen rearrangement was used to set the stereochemistry at both C-13
and C-14. The cascade rearrangement proceeded in 36 % yield. A sequential
rearrangement from 217 was also explored.
- 40-
/0
'0
HO
2-nitrophenol (150 mol%)
JIIr triethylorthoacetate
(36 %)
218 219
222
EtC02H (45 mol%) '0 JIIr
triethylorthoacetate (87 %)
TBSO
2-nitrophenol (5 mol%)
221
JIIr triethylorthoacetate
(57 %)
C02Et
TBAF JIIr
C02Et THF (97 %)
/0
'0
220
/0
'0 JIIr
/0
'0
HO
220
222
Figure 53-Chida's cascade and sequential Johnson-Claisen rearrangements 74
C02Et
Following the Claisen rearrangement, the furan ring was completed by
epoxidation of the olefin and subsequent intramolecular nucleophilic opening of the
epoxide. Protection of the alcohol followed by reduction of the ethyl esters gave a
dialdehyde. Friedel-Crafts closure of the B-ring followed by dehydration gave a mixture
of 224a-b. The mixture was subjected to silylation conditions to give 224a. A reductive
amination sequence gave (-)-dihydroisocodeine (227). Spectroscopic data for tosylamide
226 and dihydroisocodeine was matched to that reported by Parker. 69
- 41 -
"""'O~ ....... I ~ 1. mCPBA, DCM, (74 %) o C~B ~
CO Et 2. TBSCI, Imidazole, I 2 DMF, (99 %)
"""'O~ I ~ 1. DIBAL (2 eq) C02Et ~
Q, CO Et 2. Montmorillonite . 2 K10
TBSO 220 223
"""'O~ I~ Q,. ICHO
RO 224a,b a:R= TBS b:R= H
TBSOTf, DCM, 2,6-Lutidine
(75 % over 3 steps)
~ O~ O~ ....... I -.;;:::: 1. MeNH2, MeNH3CI,""'" 1-';;::::
THF, then LiBH4 ~ ~ ~
o I CHO 2. TsCI, DMAP, 0 I ". pyridine ". NMe
3.TBAF,THF +s TBSO (86 % over 3 steps) HO
Li, t-BuOH """'O~: ..
225 226
Figure 54-Final steps in Chida's formal synthesis ofmorphine74
- 42-
2.3 Microbial Oxidation of Arenes
2.3.1 llistory of microbial oxidation of arenes
The metabolism of arenes by soil bacteria was first reported by Stormer in 1908.
In 1968, Gibson and co-workers reported that a strain of Pseudomonas putida grew on
toluene as its sole carbon source.76-77 Cell extracts from this organism oxidized benzene,
toluene and ethyl benzene at equal rates. Propylbenzene and butylbenzene were
metabolized slowly while benzenes with larger substituents (pentyl, heptyl, octyl) were
not oxidized. Cell extracts were incubated with proposed intermediates for the
degradation of benzene. Phenol and trans-dihydrobenzene glycol were metabolized at a
much slower rate than catechol and cis-dihydrobenzeneglycoL When cell extracts were
incubated in the presence of benzene (228), catechol (231), and cis-dihydrobenzene
glycol (230), catechol was observed to be the only product. This led Gibson to propose
the mechanism shown in Figure 55 for the oxidation of benzene to catechoL
01" Cfl dioxygenase [ 0:9 ] ~ .. (X0H ~ V .. ~ 0 ~ OH
dihydrocatechol o:~ OH dehydrogenase ..
o OH
228 229 230 231
Figure 55-Gibson's proposed mechanism for diol and catechol formation by P. putida 76
Incubation of P. putida with p-chlorotoluene (232) yielded two metabolites
(+ )-cis-4-chloro-2,3-dihydroxy-l-methylcyclohexa-4,6-diene (233) and 4-chloro-2,3-
dihydroxy-l-methylbenzene (234),77 providing further evidence of a cis-dihydrodiol
intermediate in the metabolism of aromatic substrates (Figure 56).
- 43-
¢ CI
232
P. putida 391D .. ¢::: CI
233
+ (vOH ~OH
CI 234
Figure 56-Metabolism ofp-chlorotoluene by P. putida77
180 labeled oxygen was used to confirm that the hydroxyl groups of the catechols
originated in molecular oxygen.78 A mutant strain of P. putida was isolated that did not
have the requisite enzymes to process cis-cyc1ohexadiene diols.79 This allowed for the
isolation of several diols in sufficient quantity for stereochemical proof.
Gibson was able to isolate (+ )-cis-2,3-dihydroxy-l-methyl-4,6-cyc1ohexadiene
(236) produced by the action of the enzyme toluene dioxygenase and confirmed the
relative stereochemistry was indeed cis.79 Determination of a cis relationship between
the hydroxyl groups could not be established by NMR analysis of the free diol. In order
to get a clearer picture of the relationship of the two hydroxyl groups, a more rigid
structure was needed.79 Diol 236 was protected as a diacetate and condensed with maleic
anhydride. The resulting Diels-Alder adduct 237 was then hydrogenated and the fully
saturated tricycle 238 was analyzed by NMR spectroscopy to prove the cis relationship
(Figure 57). The relative and absolute stereochemistry were later confirmed by X-ray
diffraction. 80
235
o ::
Cc 0»
' OAc OH 1. AC20
P. putida 39/" ~ JO
~ OH 2. maleic OAc anhydride 0
236 237
Pd/C °M~ ~a OAc ----JO~ 0
H2 ~bOAc o
238 Figure 57-Proof of relative stereochemistry of P. putida metabolites79
Proof of the absolute stereochemistry of 236 was published by Gibson in 1973.81
Hydrogenation of the diol yielded diastereomeric diols 239a-b that were. separable as
- 44-
their monobenzoates. Dio1239b was then oxidized with Jones reagent to (-)-2-(R)-adipic
acid (240) which proved the absolute stereochemistry was lS,2R (Figure 58).
1. H2 Pd -
HO~OH Ce°H 2. BzCI ex:: C( Jones oxidation )Do + 3. separation .-
~ OH 4. hydrolysis OH 0 236 239a 239b (R)-(-)-methyladipic acid
(240) Figure 58-Proof of absolute stereochemistry of P. pUlida metabolite 23681
2.3.2 Isolation and characterization of toluene dioxygenase (TDO)
In 1977, Gibson was able to isolate the enzyme responsible for the oxidation of
aromatic compounds to cis-diene diols. He named this enzyme toluene dioxygenase or
TDO.82 TDO was discovered to be a three component enzyme composed of a
flavoprotein and two non-heme iron containing proteins. These proteins required
electrons from NADH. Further study led to a reliable purification method.83
Through the study of mutant strains of P. putida, Gibson and Zylstra were able to
determine the nucleotide sequence of the genes encoding TDO.84 The genes were then
expressed in a strain of E. coli JM109(pDTG601). The use of E. coli for
biotransformations of aromatic compounds has many advantages over mutant P. putida
strains. E. coli has been studied very thoroughly and its growth conditions have been well
optimized. P. putida requires an aromatic inducer to express TDO, usually toluene or
chlorobenzene. Because the inducer is also a substrate, it must be separated from the
metabolite. The recombinant organism, however, uses ~-isopropylthiogalactopyranoside
(IPTG) as an inducer. The plasmid incorporated into E. coli also contains multiple copies
of the genes responsible for TDO allowing much greater expression and thus higher
yields of diols.
- 45-
2.3.3 Substrate scope and specificity
Dihydroxylations by TDO have been found to occur in a fairly predictable manner
with respect to regio-, stereo-, and enantioselectivity. After screening a number of
1,4-disubstituted benzenes, Boyd developed a model to account for and predict the regio
and stereo selectivity ofTDO oxidations.85 According to Boyd's model, dihydroxylations
proceed as shown in Figure 59. When the difference in relative size between the two
substituents (S and L) is greater, the diol is obtained in higher er.
OH
OH
Figure 59-Boyd's model for the prediction of stereoselectivity of TDO dihydroxylations85
Boyd later expanded his model to include larger, more conformationally flexible
substituents 86-87 and determined the absolute stereochemistry of the metabolites reported
in his 1993 publication.88 Boyd's model has also proven to be fairly accurate at prediction
the regio- and stereochemistry of ortho- and meta- as well as para'- substitution on
benzene rings (Figure 60).89
TDO. OH
OH
Figure 60-Boyd's expanded model for the stereoselectivity ofTDO dihydroxylations89
- 46-
Benzenes substituted with charged or very polar functional groups are often not
metabolized.89 These substituents include phenols, sulfoxides and sulfones, carboxylic
acids and amines. When these substrates are metabolized it is usually through pathways
other than TDO. Nitrobenzene was originally thought to be among the substrates not
metabolized by TDO but was later shown to be metabolized to a diol which was then
degraded by other enzymes present in the bacterial cells.90-91
An ongoing component of the research program in the Hudlicky group is the
isolation and structural determination of new metabolites ofTDO. In 1992, Hudlicky and
co-workers isolated several metabolites derived from ortho-chlorostyrene (241).92 This
was followed a year later by a similar study on ortho-bromostyrene (242).93 Oxidation of
these substrates led to mixtures of products, as shown in Figure 61.
Br .... tAOH U OH
246 (1)
;)
0 OH
Br '-':::
I~ 247 (4)
P. putida 39/D III(
242, x=Br
P. putida 391D )II
241, x=CI
Figure 61-0xidation of o-halostyrenes by TDO (ratio )92-93
CI ... tAOH U OH
243 (1)
;SOH
CI '-':::
I~ 244 (1.8)
CI
~OH U OH
245 (trace)
Recently, Hudlicky and co-workers tested several benzoate esters 248 as possible
substrates of TDO.94 Methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl benzoate
- 47-
esters were tested as substrates to determine the role of steric bulk in oxidation by TDO.
Methyl, ethyl, allyl and prop argyl benzoate were all metabolized and their corresponding
diols were isolated in approximately I giL yield. The diols resulting from the oxidation of
n-Pr and i-Pr benzoate were isolated in trace amounts. n-Bu and t-Bu benzoate were not
metabolized.
°OOR ~I ~
248
E. coli JM109(pDTG601) .. R = Me, Et, allyl, propargyl, n-Pr, i-Pr
02XOR
~ OH
~ OH 249
Figure 62-Metabolism of benzoate esters by TD094
2.3.4 Use of microbial oxidation in synthesis
There are over 400 known metabolites of TDO, however, relatively few have
been exploited in synthesis. The majority of TDO metabolites used in synthesis are the
diols derived from benzene, toluene and monosubstituted halobenzenes.95
The first use of cis-dihydrodiols was a preparation of polyphenylene (251)
reported by researchers at Imperial Chemical Industries (lCI) in 1983.96 Diol 230 was
derivatized as a carbamate or ester 250 and then heated to initialize the formation of
polyphenylene (Figure 63).
(X0H
~ OH
230 251
Figure 63-Preparation of polyphenylene from 230
The first application of a TDO metabilite in natural product synthesis was
reported by Ley and co-workers in the racemic synthesis of (±)-pinitol (255) in 1987
- 48-
(Figure 64).97 Ley's synthesis began with diol 230 which was protected as its benzoate
252. Treatment with mCPBA gave a diastereomeric mixture of epoxides 253a-b in 14 %
and 73 % respectively. Epoxide 253b was opened with methanol in camphorsulfonic acid
(CSA) to give 254 in 88 % yield. Dihydroxylation with osmium tetroxide followed by
deprotection gave (±)-pinitol.
(X0H
~ OH 230
C:;", OBz
(XOBZ 253b
BzCI, DMAP, .. pyridine
MeOH
(+)-CSA
(X0BZ
~ OBz 252
mCPBA, DCE .. phosphate buffer
pH 8
(x0BZ +
253a OBz
0, (:(BZ 253b OBz
QH Me0yY0Bz
~OBZ 254
1. OS04, NMO tBuOH/TH F IH20 (10:3:1) ..
2. Et3N/MeOH/H20 (1:5:1)
Figure 64-Ley's synthesis of (±) pinito197
OH
Me0yYoH
HO"'~OH OH
(±)-pinitol (255)
The fIrst use of diols by the Hudlicky group involved the preparation of
prostaglandin synthon 259 in 1989.98 This synthesis was the fIrst example of an
enantioselective synthesis using diols (Figure 65). The diol resulting from the oxidation
of toluene was protected as its acetonide 256 and then subjected to ozonolysis.
Hemiacetal 257 was then carefully dehydrated on neutral alumina to 258 which can be
transformed to prostaglandin E2a 260 by the method of Johnson and Penning.99
- 49-
235
1. P. putida 39/D )10
2. DMP, TsOH
Neutral Alumina )10
DME, reflux [ ::XJ< 1 258
o
CC>< o 259
[ ~ 1 O~,O>< HO 257 0
o Neutral Alumina
DME, reflux CC>< o 259
o
"\\~C02H .0
-OH
260
Figure 65-Hudlicky's synthesis of prostaglandin synthon 25998
Hudlicky and co-workers have shown that diols are extremely useful starting
materials in the synthesis of terpeneslOO-lOl, sugars 102-103, pseudosugars, 104 cyclitols
105, aza-sugars 106, sphingosines 107-108, and alkaloids of the pyrrolizidine109,
amaryllidaceaellO-1l8, and morphine67,1l9-120 families.
Several landmark syntheses, including syntheses of conduritols121 ,
Amaryllidaceae alkaloidsllO-lll ,ll3, heliotridanes109, and triquinanes122
, are shown in
Figure 66. Several recent reviews contain more exhaustive lists of syntheses
employing microbial dihydroxylation.89,95,123-125
- 50-
Starting material Product Author (year) Reference number
9H OH
(X0H HOCOH Ho"·6··,OH
~ OH ~ ·"OH Ley (1990) 121
~ OH
230 (+)- and (-)-conduritol F (263)
9H
Br <o~:: C(" Hudlicky (1992) 110
~ OH o h- NH
12 0
Iycoricidine (264)
CI HilioH HO H rOH ((H HO"·· HOO Hudlicky (1990) 109
N N
~ OH (+)- and (-)-trihydroxyheliotridane (265)
261
9H
~OH Br
((" (0 I ~ .: OH Hudlicky (1995) 111
~ OH o h- NH
12 OH 0 pancratistatin (266)
9H
Br t~:: nOH Hudlicky (1999) 113
Br ~ OH o h- NH
262 OH 0 narciclasine (267)
C(" ~ Banwell (2004) 122
~ OH H
236 (-)-hirsutene (268)
Figure 66-Landmark syntheses employing microbial dihydroxylation95
- 51 -
2.4 Claisen rearrangement
In 1912, Ludwig Claisen reported a [3,3] sigmatropic rearrangement of allyl vinyl
ethers or their nitrogen or sulfur analogs 269.126 In his seminal disclosure, Claisen
described the transformation of phenyl allyl ether (271) to 2-allylphenol (273) and the
transformation of O-allylated acetoacetate (274) to its C-allyl isomer 275 (Figure 67).
The Claisen rearrangement quickly became a widely used reaction in organic synthesis.
l 6 heat
271
x~
V heat
269 x = 0, N, S
272
heat
() 270
273
yC02Et 275
Figure 67-The Claisen rearrangement
The Claisen rearrangement is generally thought to proceed through a chair- or
boat-like transition state (277 or 279 respectively) (Figure 68).127 Early kinetic studies of
the Claisen rearrangement of allyl vinyl ether (276), the simplest structure that can
undergo Claisen rearrangement, were performed by Schuler who found the kinetics to be
first order and the energy of activation to be 30.6 kcallmol.128 Since the rearrangement is
highly exothermic, the Hammond-Leffler postulateI29-130 predicts that the transition state
is closer in character to the starting material than the product. l3l Gajewski and
McMichael published kinetic isotope studies back to back and both detenhined that the
- 52-
i
"I
transition state had a certain amount of radical character. l3l-132 However, there is still
some disagreement on the exact nature of the transition state.133
/f.-.-:q 0
-... [ b::(f ] -... ;;;:--g 276 277 278
~~ ---... [~~)l ---... \\--} 0 '---0' 0
276 279 278
Figure 68-Chair and boat transition states for the Claisen rearrangement
2.4.1 Variations of the Claisen rearrangement
In the ninety-eight years since the discovery of the Claisen rearrangement there
has been many variations of the rearrangement published. Martin Castro provided an
excellent overview of the variations of the Claisen rearrangement in her 2004 review. 134
In 1973, Baldwin reported the Claisen rearrangements of zinc enolates 281
dubbed the Reformatskii-Claisen rearrangement. 135 The Reformatskii-Claisen
rearrangement proceeds under neutral conditions. Lang reported a variation of the
Reformatskii-Claisen rearrangement of chlorodifluoroacetates 283 in the presence of
chlorotrimethylsilane (Figure 69).136
0 [5Br
]
OlnBr
Br~o In dust 6 .. .. 0 PhH, heat
280 281 282
0 [ OSiMe,] OH
CIF2CA O In, Me3SiCI
FCAO F2CA O .. .. 0 PhH, heat 20 V 283 284 285
Figure 69-The Refonnatskii-Claisen rearrangement135-136
- 53 -
Because of the greater thermodynamic stability of the C-O double bond relative to
the C-C double bond, Claisen rearrangements are usually irreversible. However,
retro-Claisen rearrangements can occur if the reaction reduces strain in the molecule.
Boeckman showed that bridged bicyclic systems 286 will undergo retro-Claisen
rearrangements to reduce torsional strain at the bridgehead 137 and Rhoads performed
retro-Claisen rearrangements on vinylcyclopropane carboxaldehydes 288 (Figure 70).138
While Rhoads referred to the conversion of 288 to 289 a retro-Claisen rearrangement, it
is really an oxodivinyl Cope rearrangement.
H
--'W H C02CH3
287
Hi) o o ... .. 288 289
Figure 70-The retro-Claisen rearrangement137-138
In 1972, Ireland reported the Claisen rearrangement of the lithium enolates of
allyl esters 291 and the trimethylsilyl enolates of allyl esters 293 (Figure 71 ).139 These
reactions proceeded at low temperatures and often without the formation of side products.
Stereoselective enolate formation can be employed to control the stereochemistry of
Ireland-Claisen rearrangements. 140
- 54-
o 0y ° 290
[~]~ !TMSCI H~
[Q]/ 2~2 OTMS
293
Figure 71-The Ireland-Claisen rearrangement
In 1994, Uli Kazmaier reported a variation of the Ireland-Claisen rearrangement
(often referred to as the Kazmaier-Claisen rearrangement) that used a metal to chelate the
enolate formed by the deprotonation of an ester (Figure 72).141-142 This method was
applied to the synthesis of several unnatural amino acids of type 297. The
Kazmaier-Claisen rearrangement proceeds through a boat-like transition state 295 rather
than a chair-like transition state 296 and is often highly diastereoselective.142 The use of a
chelating agent allows for reactions at higher temperatures than Ireland-Claisen
rearrangements as the chelated enolates are much more stable than lithium enolates.
o o
O~NHPG LDA, ZnCI2
THF
294
PG = Boc L = coordinating solvent
~~~ PG ,L ! " N::'--Zn ';' / "L :L'---:y--o
o 295 chair
~c:s:J , , L Nft:: \ /: l ,!--I /Zn--......eG 0
L.: 0 296 boat
Figure 72-The Kazmaier-Claisen rearrangement
- 55 -
10hnson described the Claisen rearrangement of allylic alcohols in an excess of
triethyl orthoacetate (298) and a catalytic amount of acid, usually propionic acid. 143
Under acidic conditions, triethyl orthoacetate loses ethanol to form ketene diethyl acetal
(299). An allylic alcohol 300 adds to ketene diethyl acetal and then undergoes another
loss of ethanol to generate a mixed ketene acetal 302. The mixed acetal then rapidly
undergoes a [3,3] sigmatropic rearrangement (Figure 73). The 10hnson-Claisen
rearrangement is advantageous because only one operation is required as opposed to
vinyl ether formation followed by pyrolysis. Daub reported 10hnson-Claisen
rearrangements with trimethyl orthoacetate.144 McGeary and Cosgrove developed a
method of generating mixed orthoesters and and a triisobutylaluminum catalyzed
10hnson-Claisen rearrangement that proceeds at room temperature.145-146
301
[ OEt 1
~OEt 299
302
Figure 73-The Johnson-Claisen rearrangement143
rlI'R1 EtOAO ~R2
303
There have been several other variations of the Claisen rearrangement published
including chiral auxiliary and catalytic reactions. Variants of the Claisen· rearrangement
not covered here and several syntheses employing Claisen rearrangements are covered in
Martin Castro's review. 134
- 56-
2.4.2 Use of the Claisen rearrangement in organic synthesis
The Claisen rearrangement has also been featured in the synthesis of many
complex natural products including Ireland's synthesis of lasalocid A147, Paquette's
synthesis of basmane diterpenesl48, Kim's synthesis of pancratistatin149 and
Mioskowski's synthesis of halomon. 150
The Claisen rearrangement has been used extensively by the Hudlicky group. A
Johnson-Claisen rearrangement is featured in Hudlicky's general method for the
preparation of linear and non-linear triquinanes (Figure 74).151 In the synthesis of linear
triquinanes 307a, a vinyl unit is added to the carbonyl of 304 and the Johnson-Claisen
rearrangement takes place on the less substituted olefin to give (306a). To synthesize
non-linear triquinanes 307b, an alkynyl unit is added to the carbonyl of 304 and the
cyclic olefin participates in the rearrangement to give 306b.
- 57 -
linear triquinanes 307a
«/ ~H~
305b TMS
1
306b II 1 1MS
stfo non-linear triquinanes 307b
Figure 74-Hudlicky's general method for the synthesis oflinear and non-linear triquinanes151
In 1997, Hudlicky reported the synthesis of several unnatural amino acids 310a-d,
and 31la-d.152 The key step of the synthesis was a Kazmaier-Claisen rearrangement of
309a-d to 310a-d and 31la-d (Figure 75). This sequence is the basis for our synthesis of
the C-ring of morphine (3) described in this thesis.
- 58 -
R R 0 ex 1. diimide ex II NHBoc R C02H R C02H ~ OH 2. TDSCI, imidazole O~ L ( ) cr (( ______ .... ~ DA, 2.2 eq ., ::::,... 3. Boc-Gly, DCC ZnCI2 (1.2 e9).. ~ NHBoc + ~ 'NHBoc
308 OH OTDS TDSO'" TDSO'"
a: R = Ph 309 310 311
b: R= Me c: R=CI d: R = o-melhoxyphenyl
Figure 75-Hudlicky's preparation of unnatural amino acids via a Kazmaier-Claisen rearrangement
Chida's synthesis of morphine (3), described in section 2.2.2 employed a cascade
lohnson-Claisen rearrangement as the key step that set the stereochemistry at the C-13
quaternary center and at C-14. The cascade Claisen rearrangement of 218 to 220
proceeded in 36 %. A stepwise procedure starting from protected diol 217 gave the
rearranged product in 48 % yield over three steps (Figure 76).
218
222
2-nitrophenol (150 mol%) ,.
triethylorthoacetate 36%
....... 0
EtC02H (45 mol%) '0 ,. triethylorthoacetate
87%
TBSO
2-nitrophenol (5 mol%)
221
,. triethylorthoacetate
57%
TBAF C02Et THF (97 %)
....... 0
'0
220
Figure 76-Chida's cascade and sequential Iohnson-Claisen rearrangements
220
- 59-
3. Discussion
3.1 Introduction
The first part of the present studies describes the efforts to develop a thermally
stable version of the Burgess reagent that retains the reactivity of the original reagent.
Such a reagent would be useful to synthetic chemists who are employing the Burgess
reagent in reactions at elevated temperatures. At high temperatures, the original Burgess
reagent is unstable and its decomposition leads to reduced yields. A more stable reagent
would also require less care in handling and could be stored for longer periods of time.
The second part of this thesis details the progress toward the total synthesis of
morphine beginning with the enzymatic dihydroxylation of bromobenzene. As pointed
out in the Historical Section, the ultimate goal of our synthetic studies of morphine is to
develop a route efficient enough to compete with isolation of morphine from natural
sources. Progress toward this goal is discussed herein.
In addition, the characterization of several new metabolites of toluene
dioxygenase provides new chiral materials that can be utilized in total synthesis by
academic and industrial chemists. The characterization of new metabolites helps us to
better understand the nature of toluene dioxygenase and its strengths and limitations.
Hopefully, more chemists will realize the environmental benefits of enzymatic reactions
and be encouraged to incorporate enzymatic reactions into their total synthesis efforts.
- 60-
3.2 New Burgess reagents
Three new Burgess reagents were synthesized for this study. Also included were
the original Burgess reagent (1) and the menthyl chiral auxiliary Burgess reagent 124
(Figure 77). The goal was to stabilize the negative and positive charges with electron
withdrawing and donating groups respectively as shown in Figure 1 (page I). For the
electron withdrawing group, we chose trifluoroethanol and for the electron donating
group we replaced triethylamine with N-methyl piperidine. Although 1 is commercially
available from Sigma-Aldrich, the commercial reagent is expensive and often contains
impurities.13 The Burgess reagent was prepared as described in Burgess' Organic
Syntheses paper.153 Menthyl Burgess reagent 124 was prepared by the method described
by Hudlicky.22
313
Figure 77-Burgess reagents employed in this study
Reagent 313 was prepared by Burgess' method with the substitution of
triethylamine with N-methylpiperidine. Fluorinated reagents 312 and 314 required more
modification of Burgess' procedure to synthesize. Chlorosulfonyl isocyanate (117) was
treated with 2,2,2-trifluoroethanol in benzene to give carbamate 316. Carbamate 316
proved to have very limited solubility in benzene, therefore, the solvent wa,s switched to
- 61 -
THF. Treatment of 316 with 2.2 equivalents of triethylamine yielded reagent 312 and
treatment of316 with N-methylpiperidine gave 314 (Figure 78).
0,/9 's'
CI ..... 'N=C=O
117
MeOH PhH, r.t.
PhH,O°C
N-methylpiperidine (2.2 eq)
PhH,O°C 313
N-methylpiperidine 0" /P ~ (2.2 eq) G'S'N/"-....O ............... CF ------l..... E!:l" e 3
THF, 0 °c 314
Figure 78-Preparation of Burgess reagents
The reactivity of the new Burgess reagents was compared to the original Burgess
reagent and the menthyl reagent 124 in a series of reactions. 154 The results are shown in
Table 1. Each reagent was tested in a dehydration reaction, reactions with epoxides, and
with styrene dioL Yields of the dehydration of317 to 318 were about 30 % higher when
the new Burgess reagents were employed. In the reaction with cyclohexene oxide (104)
the N-methylpiperidine reagent gave a 16 % improvement in yield over that observed
with the original reagent 1. The fluorinated reagents however, gave a significant decrease
in yield. We believe that this is because the nitrogen atom bearing the negative charge is
too stable and not nucleophilic enough to open the epoxide. When the more activated
allylic epoxide 152 was treated with our Burgess reagents we did see higher yields of
sulfamidates compared to the opening of 104. The fluorinated reagents 312 and 314 were
- 62-
nucleophilic enough to open epoxide 152 and gave sulfamidate 324 in modest yield. In
the reaction of reagents 1 and 313 we obtained yields similar to those reported by
Nicolaou.13-14 Reagents 312 and 314 gave only sulfonation of the alcohol, which is
consistent with the mechanism for the formation of sulfamidates from diols proposed by
Nicolaou. 13-14 The formation of dicarbamate 322 was quite surprising. However this can
also be rationalized by invoking a bis-sulfonated intermediate 325, which, for steric
reasons, may not undergo intramolecular displacement at the benzylic position. A less
sterically demanding intramolecular displacement may take place yielding sulfamidate
326, which then could be substituted at the benzylic position by the carbamate anion 327,
created by the displacement of the second equivalent of 124. Another option is an
intramolecular SN2 type reaction similar to the mechanism· described by Burgess for the
formation of carbamates from primary alcohols (Figure 79).3
- 63-
Table I-Reactivity trends of the new Burgess reagents in dehydration, reactions with oxiranes, and with
styrene diol
OH
0) 0 0 0 0 OH
Starting material Ph~OH 317 104 152 74
Reagent Product(s)
CXO\~O CXO\~O o 0 MeO
CO Meo,J(N-S~O )::N 0 ' ~ ~ N' ''0 N 0 o ~
Me~O Me~O Ph~O ~/~ Ph 0 0
57 113
318 (63 %) 109 (40 %) 319 (30 %) 75:107 (77 %) (98:2)
CXO~O CXO~O 0
CO RO)lNH H ' " ~ NU 124 N 0
R~O R~O Ph~NnOR 0
318 (60 %) 320 (35 %) 321 (36 %) 322 (70 %) R=Menthyl R=Menthyl R=Menthyl
CO CXO~O CXO~O , ~
~ N' U 312 N 0 sulfonation only
F3CH2C~0 ~O F3CH2CO
318 (93 %) 323 (12 %) 324 (53 %)
CXO~O CXO~O o 0 MeO
CO MeO,J( S~O )=N 0
313 ' " ~ N' ''0 N- \ 0 ~ N 0 ~O ~/"
Me~O Me~O Ph Ph 0 0 75 113
318 (94 %) 109 (56 %) 319 (57 %) 57:107 (82 %) (95:5)
CO CXO~O CX°'s~O , ~ ~ N'U 314 N 0 sulfonation only
~O F3CH2C~0 F3CH2CO
318 (93 %) 323 (17 %) 324 (45 %)
- 64-
O2 (0-S.o2 OH 0~S'N~C02R
~OH 124 00 9 otN-Co,R 1-":::: ~ •
1.0 • .0 C 0'S~~'C02R e
74 325 O2 326 NHC02R
327
R=menthyl or O2 0 Cy~S'N~C02R
RO)lNH H o?O -..:::: .. 1 e Ph~NnOR
.0 CO'S~N,CO R o 2 0
325 2 322
Figure 79-Possible mechanisms for the formation of322
3.3 Stability studies
To determine the thermal stability of the reagents, we chose to follow their
decomposition in THF-ds at 50°C and at reflux by monitoring the content of the sample
by 13e NMR. Originally, we sought to use IH NMR but as the reagent decomposed, there
was quite a bit of signal broadening and the signals arising from the decomposition
products often overlapped the reagent signals. A timed series of 13e NMR spectra were
recorded for each reagent. For each spectrum the peak area of the carbamate 13e signal
(around 157 ppm) was determined by direct integration and calibration against solvent
Be signal corresponding to THF-ds at 64.6 ppm. The magnitude of the carbamate 13e
signal in the fIrst spectrum was set at 100%.154 The results are shown in Figures 80 and
81 and are compared with those obtained for the original Burgess reagent as well as its
menthyl chiral auxiliary version. [The plots shown are the actual decays with percent
content illustrated on the left.]
As seen in Figure 80, all reagents are stable at 50°C for several hours. The
original Burgess reagent (1) and menthyl reagent 124 decompose at the fastest rate and
have half-lives of216 and 198 minutes respectively. The fluorinated reagent 312 shows a
- 65-
modest increase in stability. The N-methylpiperidine reagents 313 and 314 are stable at
50°C for over 12 hours. At reflux, the half1ives of 1 and 124 drop dramatically to 19 and
13 minutes respectively and are undetectable after one hour. Again, reagent 312 shows an
increase in stability. The N-methylpiperidine reagents 313 and 314 are the most stable
and decomposition is negligible for over three hours at reflux in THF (Figure 81).
1
0) c ·c ro E Q) .... 4-' C Q) u .... Q)
D....
100
80
60
40
20
O~~--'-~--~-'--~-'--~~--~~--~~r-~~
o 100
124 312
200 300 400
Time (min)
313 .314
500 600 700
Figure 80-Decomposition of Burgess reagents at 50°C in THF-ds as a function oftime
- 66-
1
80
0) c c 60 ro E QJ '-...... C QJ 40 u '-QJ
a..
20
o
124
20
312
40 60 80 100 120 140 1 60 180
Time (min)
313 .314
Figure 81-Decomposition of Burgess reagents at reflux in THF -dg as a function of time
- 67-
Figures 82-86 show the decomposition of each reagent at both 50°C and at reflux
to illustrate the relative rates of decomposition at reflux than at 50 °Co Reagents 1, 124,
and 312, decompose much more rapidly at reflux than at 50°C. The more stable
N-methyl piperidine reagents 313 and 314, do not show as much of a decrease in stability
at refluxo
0) 80 c
c 70 om E 60 ~ 50 - 40 c Q)
30 (2 Q) 20 a.
10 0
0
100 90
0) 80 c
c 70 om 60 E
~ 50 - 40 c Q)
30 e Q) 20 a.
10 0
0
200 400
Time (min)
.. 600
.. Decomposition at 50°C
l1li Decomposition at reflux
800
Figure 82- Decomposition of 1 at 50°C and at reflux
..
200 400
Time (min)
600 800
.. Decomposition at 50°C
II Decomposition at reflux
Figure 83- Decomposition of 124 at 50 °C and at reflux
- 68-
100 90
0') c:: c:: 70 "m E 60 ~ 50 +-'
40 c:: Q)
30 ~ Q) 20 c..
10 0
100
0') 90
c:: 80 c:: 70 m E 60 ~ 50
+-' 40 c::
Q) 30 ~
Q) 20 c.. 10 0
0
0
200 400
Time (min)
600 800
.. Decomposition at 50°C
.. Decomposition at reflux
Figure 84- Decomposition of 312 at 50°C and at reflux
200 400
Time (Min)
600 800
.. Decomposition at 50°C
liD Decomposition at reflux
Figure 85- Decomposition of 313 at 50°C and at reflux
- 69-
100 90
Q) 80 c:
c: 70 ·ro E 60 ~ 50 - 40 c: CI)
30 ~ CI) 20 a..
10 0
0 200 400
Time (min)
600
• Decomposition at 50°C
IIiI Decomposition at reflux
800
Figure 86- Decomposition of 314 at 50°C and at reflux
The rapid decomposition of reagents 1 and 124 explain why yields of
sulfamidates from epoxides are often low compared to the yields of sulfamidates from
1,2-diols. The decomposition studies as well as the reactivity profiles show that reagents
312 and 313 are likely the most useful to synthetic chemists. The minor increase in
stability of reagent 314 does not offer any advantages in reactivity at least in the cases
involving oxiranes.
-70 -
3.4 Synthesis of morphine C-ring fragment
The synthesis of the C-ring of morphine (3), as outlined in the Introduction on
page 2, began with the microbial oxidation of bromobenzene (13) to diol 12.
Fermentation took place III a 15 L Biostat fermentor (12 L working volume).
Approximately 20 gIL diol was isolated from the fermentation. Diol 12 was then
subjected to diimide reduction of the distal double bond to give diol 328. The distal
hydroxyl group was then protected as a silyl ether 329. The proximal hydroxyl group was
then coupled to Boc-protected glycine. A Kazmaier-Claisen rearrangement was then
performed to give amino acid 330. The crude amino acid was then methylated with
diazomethane to give the C-ring fragment as a mixture of diastereomers 10 (Figure 82).
Br
6 E. coli JM109 (pDlG601) ~OH
13
Br aDH
OTDS 329
68 % over 2 steps
-20 gIL
BocGlyOH, DCC • DMAP, DCM, 70 %
UOH 12
Br C02Me
.»-'NHBOC
lDSO"V 10
Br PAD, AcOH, MeOH .. ~OH lDSCI, imidazole ..
DMF, _8°C, 3 days 90 % o °C, 72 %
UOH 328
LDA (2 eq)
ZnCI2, DCM
Br C02H
.»-'NHBOC
TDSO"V 330
Figure 87-Synthesis of the C-ring fragment of morphine
Diastereomeric mixture 10 was separated by column chromatography to give
C-ring fragment 9 and its diastereomer 331 in a 1:4 ratio. The undesired diastereomer 331
was then recycled by epimerization and separation (Figure 83).
- 71 -
epimerization conditions
! Br C02Me Br C02Me
.~NHBOC ------o .. ~ .N·"NHBoC
TDSO" U TDSO" U 10 331
Br C02Me
+ .~NHBOC TDSO"U
9
Figure 88-Separation of diastereomers and recycling of 331
The original epimerization conditions took five days to complete and gave a 2:1
ratio of331:9. This became a significant bottleneck in the synthesis of9, so we undertook
an optimization of the epimerization (Table 2). In Table 2, the yield refers to the total
recovery of both diastereomers. Changing the solvent from THF to DME (entries 2-4)
. allowed the time to be decreased from five to three days. Increasing the equivalents of
DBU helped to improve the ratio of331:9 but led to slightly lower recovery (entries 3-4).
A neat reaction in DBU led to major decomposition (entry 5). This data led us to
determine that the optimal conditions, were 0.5 eq DBU in DME for three days (entry 4).
These conditions gave us a good dr, shorter reaction times than the original conditions,
and low decomposition.
Table 2-0ptimization of epimerization conditions of 331
Entry Solvent eq DBU Temperature Time Yield of 10 Ratio
(OC) (d) (%) 331:9 1 THF 0.1 66 5 80 2:1 2 DME 0.1 85 3 85 2:1 3 DME 1 85 3 70 1 :1 4 DME 0.5 85 3 80 1:1 5 neat excess 120 2 20 1 :1
3.5 Coupling of A-ring fragment
With the C-ring fragment 9 in hand, we went on to explore the preparation of the
A-ring fragment 8 and the coupling of 8 and 9. Our original preparation of 8 involved a
-72 -
three step sequence starting from guaiacol (332). This sequence however gave 8 in only
30 % yield and unreacted guaiacol was difficult to remove. A search of the literature
yielded a one step preparation of 8 by Snieckus 155. Snieckus' procedure involves a
directed ortho metalation of 1,2-dimethoxybenzene (335) followed by quenching with
trimethylborate (Figure 84). This one-pot procedure gave 8 in 85 % yield and was easily
performed on a multi-gram scale.
/0X) Br2 /OJQ .. HO :::::,...
HO :::::,... Br
332 333
1. nBuLi, TMEDA
2. B(OMeh 3. HCI
335
Mel /OJQ ." '0 :::::,...
/0Y) 'O~
B(OHh 8, (85 %)
Br 334
1. nBuLi, B(OMeh .. 2. HCI
Figure 89-Preparation of A-ring fragment 8
/OJQ '0 :::::,...
B(OHh 8, (30 %
over 3 steps)
The A-ring (8) and C-ring (9) fragments were then joined by a Suzuki coupling
(Figure 85). The initial conditions employed a biphasic reaction in benzene and water.
However, the yields were not always reproducible and we worried about hydrolysis of the
methyl ester. The conditions were optimized as shown in Table 3. The palladium
tetrakis(triphenylphosphine) varied between batches and seemed to have an effect on
yields and was therefore replaced with Pd( dppf)2. The use of Pd( dppf)2Ch and CsOAc in
THF gave reproducible reactions in good yield. Substituting CsOAc for CS2C03
improved the yield by a further 19 %.
- 73 -
/OY/l 'O~
B(OHh
8
Entry
1
2
3
+
Br C02Me
.~NHBOC TDSO"V
9
Conditions
Figure 90-Suzuki coupling of 8 and 9
Table 3-Optimization of Suzuki coupling
'0
TDSO'"
Solvent Catalyst Base Phase transfer
<ment
benzene Pd(PPh3)4 Na2C03 TBAB (aq)
THF Pd(dppfhCl2 CsOAc none
THF Pd(dppfhCl2 CS2C03 none
3.6 Synthesis of Claisen substrates
NHBoc
7
Yield 1%1 60-75
70
89
Several substrates for the 10hnson-Claisen rearrangement were synthesized from
intermediate 7. The first substrate synthesized was alcohol 338. This was done by
removing the silyl ether of 7 followed by a Mitsunobu reaction to invert the
stereochemistry of the alcohol. Deprotection proceeded smoothly and the product of the
Mitsunobu reaction 337 was obtained in good yield. Hydrolysis of the benzoate ester in
methanol gave 338 in 85 % yield (Figure 86).
-74 -
/0
'0
TOSO'"
NHBoc
7
337
TBAF, THF '0 .. 95%
85%
326
PBU3, DEAD '0 .. PhC02H, THF,
NHBoc 82 %
BzO
338
Figure 91-Synthesis of alcohol 338
NHBoc
337
The next substrate synthesized for the Claisen rearrangement was acetate 340.
This was prepared by simultaneously removing the benzyl ester and Boc protecting
groups of 337 to give free amine 339 and then re-protecting the amine as its acetate
(Figure 87).
337
, TFA/MeOH (4:1) 0 ..
36%
339
/0
pN02PhOAc '0 .. Et3N, MeOH,
60% HO
Figure 92-Preparation of CIa is en substrate 340
NHAc
340
The final Claisen substrate prepared was cyclic carbamate 6. Diester 337 was
reduced with lithium aluminum hydride to give alcohol 341. Treatment of 341 with two
equivalents of sodium hydride gave carbamate 6 in 80 % yield (Figure 88).
/0» /O~ /O~ '0 I .0 C02Me LiAIH4, THF '0 1.0 OH NaH, DMF '0 1.0 0 .. .. )=0
~ NHBoc 91 % ~ NHBoc 80 % ~ N
H
BzO HO HO 337 341 6
Figure 93-Preparation of cyclic carbamate 6
-75 -
3.7 Claisen rearrangement
All attempts at performing the planned Johnston-Claisen rearrangement failed to
yield the desired rearranged product of type 342 (Figure 89). The results· of several
attempts are shown in Table 4.
conditions Substrate )( .
R
342
Figure 94-Attempted Iohnson-Claisen rearrangement
The first substrate tested in the Claisen rearrangement was 338. The substrate was
subjected to the conditions employed in Chida's synthesis of morphine.74 Unfortunately
the high temperature and acidic conditions led to the loss of the Boc protecting group.
The only product isolated was acetamide 340 in a very low yield. We then attempted the
rearrangement on 340 but after three days only starting material was isolated. We then
turned our attention to cyclic carbamate 6. Our rationale was that the C-13 (morphine
numbering) position would be more accessible without the steric bulk of the methyl ester
and amine. Unfortunately, repeating Chida's conditions on 6 led only to decomposition.
We then subjected 6 to more traditional Johnson-Claisen conditions, using propionic acid
and triethyl orthoacetate. These conditions also lead to decomposition. In the final
attempt at the rearrangement, we used McGreary and Cosgrove's TIBAL catalyzed
Johnson-Claisen rearrangement. 145 This reaction led only to the elimination of the
hydroxyl group to a diene (Table 4). At this point, it is believed that the nitrogen atom
must have some effect that prevents the rearrangement as the presence of nitrogen is the
only major difference between our Claisen substrates and Chida's.
-76 -
Table 4-Substrates and conditions attempted in Iohnson-Claisen rearrangement
Substrate Conditions Product
......... 0
........ 0 trimethyl orthoacetate, o-Nitrophenol (10 mol %),
NHAc NHBoc 140 ac, 3 days
HO 338 340, -5 %
......... 0
trimethylorthoacetate, o-Nitrophenol (10 mol %),
NHAc 140 ac, 3 days NHAc
HO 340
HO 340,60 %
......... 0
........ 0 0 triethyl orthoacetate, )=0 o-Nitrophenol (10 mol %), decomposition
N 140 ac, 3 days H
HO 6
........ 0 0 triethyl orthoacetate, )=0 propionic acid (10 mol %), decomposition
N 160 ac, 3 days H
HO 6
......... 0 ......... 0
........ 0 0 1. Diethyl ketene acetal, ........ 0 0 )=0 neat, rt, 2 hours )=0
N 2. TIBAL (1 eq), rt, 14 N H hours H
HO 6 40%
-77 -
3.8 Biotransformations
A series of halogen substituted benzoate esters were tested as substrates of TDO.
The substrates were first tested in Fernbach shake flasks. Approximately 100 mg was
incubated with E. coli JMI09(pDTG601) at 35 DC for 6 hours. The appearance of
metabolites was followed by TLC. In the event that the ester was metabolized, cells were
separated from the broth by centrifugation and the supernatant was extracted with EtOAc
and a preliminary NMR spectrum was acquired. A large scale fermentation was then
performed with the particular substrate and the metabolites were characterized. As shown
in Table 5, all meta- and para-substituted benzoates were not metabolized. Ortho
substituted benzoates were found to be substrates although the metabolites were produced
in relative low yields compared to the 1.3 giL yield of unsubstituted methyl benzoate. 94
Fluoro-substituted benzoate 343 yielded only one metabolite while chI oro- and bromo
substituted benzoates 347 and 351 gave a mixture of diols. Iodo- substituted methyl
benzoate 355 gave only a single metabolite. This trend is in accordance with Boyd's
model for predicting the regio-chemistry of dihydroxylation by TDO.89 In the case of
343, the ester directs the regiochemistry of dihydroxylation. The increasing steric bulk of
chlorine and bromine lead to a mixture of metabolites and in the case of iodine
substituted benzoate 355 the iodine atom directs dihydroxylation. At the time of this
writing, the absolute stereochemistry of the isolated metabolites has not yet been
determined. The relative stereochemistry of all metabolites was determined by 2D NMR
(H,H COSY, HSQC, and HMBC). The physical and spectral properties of344 have been
fully characterized and preliminary characterization has been achieved for metabolites
348, 349, 352, 353, and 356. It was found that like the diols isolated from the
-78 -
fermentation of unsubstituted benzoate esters (249), metabolites where dihydroxylation
occurred adjacent to the ester (344, 348, and 352) were stable at room temperature and
amenable to purification by column chromatography. Metabolites that possessed
dihydroxylation adjacent to the halogen atom (349, 353, and 355) were much less stable
and upon chromatography, would re-aromatize to give phenols.
-79 -
Table 5-Metabolism of halogen substituted benzoate esters by TDO
Starting material Products (Yield)
15M. ~ct F -..::::: F ~ OH
1.0 ~ OH
343 344 (0.05 gIL)
15M
• 1-"::::: No conversion
F .0 345
QM. 1-":::::
.0 No conversion
F 346
'8M. u· M.~~H CI -..::::: CI ~ OH
1.0 ~ OH ~ OH
347 348 (0.47 gIL) 349 (.035 gIL)
15M
• No conversion
CI .0 350
15M
• '5. M.O'C~H Br -..::::: Br ~ OH
1.0 ~ OH ~ OH
351 352 353
QM. No conversion
Br 354
15M. I -..::::: M.~C~H 1.0
~ OH 355 356
- 80-
4. Conclusions and future work
We have developed the synthesis for and measured the stability of several
Burgess reagents and tested their reactivity towards epoxides, diols and in dehydration
reactions. We found that reagents 312 and 313 are likely to be the most useful to
synthetic chemists in terms of stability and reactivity towards alcohols, epoxides, and
diols. Other variants of the Burgess reagents such as Nicolaou's reagents 98a-e and
Wipfs PEG supported reagent 118 may benefit from increase in stability by replacing the
triethylamine portion of the reagent with N-methylpiperidine.
Our proposed synthesis of morphine (3) proceeded to the Johnson-Claisen
rearrangement step which was ultimately unsuccessful. As shown in Figure 90, the
Johnson-Claisen substrates described in this thesis differ only slightly from Chida's
intermediate 219. The presence of a carbamate may prevent the reaction from proceeding
as envisioned. The carbamate may also impart lower stability on our substrates thus
leading to the decomposition observed in several of our reactions.
....... 0 .......0
'0 0 FO '0
C02Et N NHBoc NHAc H
HO HO 219 6 338 340
Figure 95-Cbida's intennediate compared to Claisen substrates prepared in this thesis
Another strategy would be the preparation of a diene of type 357 followed by a
cycloadditions of a ketene acetal. Methylation of the nitrogen atom to produce 360 may
prevent the problems encountered in performing the Johnson-Claisen rearrangement
(Figure 91). Work on the completion of the synthesis is currently being undertaken by
Mr. Vimal Varghese.
- 81 -
....... 0 ....... 0 R°Ir°R
....... 0
'0 ----.- '0 '0 ------.- ------------.- or
R R R NHBoc
RO HO
RO 359 338 357 358
....... 0 ....... 0
'0 0 '0 o '0 0 )=0 -------.- )=0 ---------.- )=0
N N Et02C N H \ \
Me Me HO HO
6 360 361 Figure 96-Proposed cyc1oaddition strategy and methylated Claisen substrate for the completion of the
synthesis of morphine
Several new metabolites of toluene dioxygenase have been discovered. More
complete characterization, proof of absolute stereochemistry and optimization of the
fermentation procedure need to be undertaken by future workers in this area.
- 82-
5 Experimental section
5.1 General
All non-hydrolytic reactions were carried out under an inert atmosphere. Glassware used
for moisture-sensitive reactions was flame-dried under vacuum and subsequently purged
with inert gas. THF, toluene and benzene were distilled from sodiumlbenzophenone.
DCM, triethylamine, and N-methylpiperidine were distilled over calcium hydride. Flash
column chromatography was performed using Silicyde Siliaflash P60 230-400 mesh
silica gel. Analytical thin-layer chromatography was performed using EMD Chemicals
TLC Silica Gel 60 F254 plates. Melting points were measured on a Thomas-Hoover
melting point apparatus and are reported uncorrected. IR spectra were obtained on a
Perkin-Elmer FT-IR 1600 Series Spectrum One instrument. IH and l3C NMR spectra
were obtained on either a 300 MHz Broker or a 600 MHz Bruker instrument. Mass
spectra were acquired on a Kratos Concept 1 S High Resolution EIB mass spectrometer.
Ionization methods were either electron impact (EI) or fast atom bombardment (FAB) on
a N-bromo-acetamide (NBA) matrix. Specific rotation measurements are given in deg.
cm3 g-l dm-l and were recorded on a Perkin-Elmer 341 Polarimeter. Large scale
fermentation was performed in a 15 L Sartorius (formerly B. Braun) Biostat C fermentor.
Combustion analyses were performed by Atlantic Microlabs, Norcross, GA, U.S.A.
- 83 -
5.2 Preparation of new Burgess reagents
2,2,2-Trifluoroethyl chlorosulfonylcarbamate (316)
2,2,2-Trifluoroethanol (3.36 mL, 46 mmol) in dry benzene (10 mL) was added dropwise
to chlorosulfonyl isocyanate (4.0 mL, 46 mmol) in 15 mL of dry benzene at room
temperature. When the addition was complete, the reaction mixture was stirred for 30
min. The product, 2,2,2-trifluoroethyl chlorosulfonylcarbamate (316), was precipitated
with cold hexanes as white crystals (10.25 g, 42 mmol, 92%); mp 80-82 °c (C6H6); IH
NMR(CDCh, 300 MHz) (5 8.44 (m, IH), 4.66 (q, J= 7.9 Hz, 2H) ppm; BC NMR (CDCh,
75 MHz) (5 147.7, 122.0 (q, J= 278.8 Hz), 62.9 (q, J= 38.6 Hz) ppm; IR (KBr) v 3167.6,
2931.6, 2637.9, 1750.3, 1483.9, 1396.8, 1166.0 em-I; LRMS (FAB+NBA matrix) mJz
242, 149 (18.9), 99 (41.3), 73 (25.9), 59 (80.8), 49 (100.0); HRMS calcd. for
N ,N-Diethyl-N-[(2,2,2-trifluoroethyloxycarbonyl)amino] sulfonyl-ethanaminium,
inner salt (312)
2,2,2-Trifluoroethyl chlorosulfonylcarbamate (316) (2.0 g, 8.3 mmol) in 50 mL dry THF
was added dropwise to triethylamine (2.90 mL, 20.8 mmol) in 20 mL dry THF in an ice
bath. Once the addition was complete, the reaction was stirred for additional two hours.
Triethylammonium chloride salt was filtered and the solvent removed i1} vacuo. The
- 84-
product (312) was recrystallized twice from dry THF (1.91 g, 6.2 mmol, 75 %); mp 77-79
°C (THF); IH NMR (CDCh, 300 MHz) 84.48 (d, J= 8.6 Hz, 2H) 3.84 (q, J= 7.8 Hz, 6H)
1.44 (t, J= 9.5 Hz, 9H) ppm; 13C NMR (THF(ds) , 150 MHz) 8 155.4, 123.8 (q, J= 277.4
Hz), 60.1 (q, J= 35.8 Hz), 50.6, 8.5 ppm; IR (KBr) v 3167.6, 2986.1, 2931.6, 2676.8,
2637.9, 2107.9, 1750.3, 1691.2 cm-I; LRMS (FAB+NBA matrix) mlz 307, 239 (30.8),
102 (100.0),86 (20.0); HRMS calcd. for C9HISF3N204S: 307.0934, found: 307.0930.
N-Methyl-N-[(methyloxycarbonyl)amino] sulfonyl piperidinamininm, inner salt
(313)
Methyl chlorosulfonylcarbamate (315) (6.83 g, 39 mmol) in benzene (30 mL) was added
dropwise to N-methylpiperidine in benzene (20 mL) cooled in an ice bath. Once the
addition was complete, the reaction was stirred for additional two hours. N-Methyl
piperidinium chloride salt was filtered off and the solvent was removed in vacuo. The
product was recrystallized two times from dry THF to yield 313 (6.6 g, 28 mmol, 71 %);
mp 87-90 °C (THF); IH NMR (CDCh, 300 MHz) 8 3.72 (s, 3H), 3.60 (m, 2H), 3.45 (m,
2H) 3.14 (s, 3H) 1.81-2.00 (m, 6H) ppm; 13C NMR (CDCh, 75 MHz) 8 158.2,54.7,53.3,
40.1,21.6,20.6 ppm; IR (KBr) v 3206.4,2951.4,2869.3,2686.4,2110.2,1704.5,1470.7
cm-\ LRMS (FAB+NBA matrix) mlz 237,205 (34.3), 100 (100.0), 70 (11.2).
- 85 -
N-Methyl-N-[(2,2,2-trifluoroethyloxycarhonyl)amino]sulfonyl-piperidinaminium,
inner salt (314)
2,2,2-Trifluoroethyl chlorosulfonylcarbamate (316) (4.0 g, 17 mmol) in 30 mL dry THF
was added dropwise to N-methylpiperidine (3.80 g, 38 mmol) in 20 mL dry THF at 0 CC.
Once the addition was complete, the reaction was stirred for an additional two hours.
N-Methylpiperidinium chloride salt was filtered off and the solvent removed in vacuo.
The product was recrystallized two times from dry THF to yield 314 (2.4 g, 7.9 mmol, 48
%); mp 79-81 cc (THF); IH NMR (CDCh, 300 MHz) D 4.48 (q, J= 8.5 Hz, 2H), 3.63 (m,
2H), 3.45 (m, 2H), 3.15 (s, 3H), 1.82-1.99 (m, 6H) ppm; 13C NMR (CDCh , 150 MHz) D
156.1, 123.2 (q, J= 277.8 Hz), 61.7 (q, J= 36.0 Hz), 54.8, 40.2, 21.4, 20.6 ppm; IR (KBr)
v 3425.3, 2964.1, 2872.7, 2716.4, 2127.0, 1712.9, 1470.3 em-I; LRMS (FAB+ NBA
matrix) mlz 305, 205 (26.7), 137 (3.9), 100 (100.00); HRMS calcd. for C9HI5F3N204S:
305.0783, found: 305.0764.
- 86-
General procedure for dehydration of 1,2,3,4 tetrahydro-l-naphthol with Burgess
reagents
1,2,3,4-Tetrahydro-l-naphthol (1.83 mmol) and Burgess reagent (2.10 mmol) were
dissolved in dry benzene (5 mL) at room temperature, the reaction mixture was brought
to reflux temperature and monitored by TLC. Reactions were stopped after 2 hours.
General procedure for reactions of Burgess reagents with oxiranes
The appropriate Burgess reagent inner salt (9.2 mmol) was added to a stirred solution of
the oxirane (4.0 mmol) in THF (20 mL) at room temperature in a single portion. The
resulting reaction mixture was brought to reflux immediately by submerging it into a
preheated oil bath (80°C). The reaction mixture was stirred until complete consumption
of the oxirane (TLC), then cooled to room temperature and filtered through a plug of
silica. The reaction mixture was concentrated, and the resulting residue was purified by
flash column chromatography using an appropriate solvent gradient to yield the
sulfamidate product(s).
General procedure for reactions of Burgess reagents with diols
l-Phenyl-l,2-ethanediol (3.7 mmol, 1.0 equiv) was dissolved in anhydrous THF (10 mL)
and Burgess reagent (9.3 mmol, 2.5 equiv) was added. The resulting solution was
warmed to reflux (using an oil bath preheated to 80°C) and stirred for 2 to 8 hours until
the diol was completely consumed (TLC). The reaction was quenched with a saturated
solution ofNH4CI (5 mL) and the mixture was extracted with CH2Cb (3 x 50 mL). The
combined organic layers were then washed with water (50 mL), dried over Na2S04 and
concentrated. The resultant yellow oil was purified by flash column chromatography
(silica gel) using an appropriate solvent system.
- 87-
319
Methyl cis-tetrahydro-3H-1,2,3-benzoxathiazole-3-carboxylate 2,2-dioxide (319)
Eluent: hexanes-ethyl acetate, 4:1; Rj 0.42 (2:1 Hex:EtOAc); mp 145-147 °C (EtOAc);
IH NMR (CDCh, 600 MHz) 8 6.12 (m, IH), 5.81 (d, J= 10.32 Hz, IH), 5.21 (s, IH), 4.80
(s, IH), 3.93 (s, 3H), 2.35 (m, IH), 2.30 (m, IH), 2.15 (m, IH), 1.92 (m, IH) ppm; l3C
NMR (CDCh, 150 MHz) 8 150.5, 131.6, 120.7, 77.8, 55.5, 54.6, 24.0, 18.5 ppm; IR
(KBr) v 3438.9, 3010.2, 2963.5, 2853.3, 2544.9, 1725.9 em-I; LRMS (FAB+NBA
matrix) mlz 234, 214 (13.5), 156 (27.4), 79 (40.3); HRMS calcd. for CsH12N04S
234.0436, found: 234.0394. Anal. calcd for CsHuN05S: C 41.20, H 4.75. Found: C
41.32, H 4.75.
322
Bis-«lR,2S,SR)-2-isopropyl-S-methylcyclohexyl) 1-phenylethane-1,2-diyldicarba-
mate (322)
RjO.75 (1:1 Hex:EtOAc); mp 173-175 °C (EtOAc); IH NMR (CDCh, 300 MHz) 8 7.36
(m, 2H), 7.29 (m, 3H), 5.72 (m, IH), 4.82 (m, 2H), 4.56 (m, 2H), 3.52 (s, 2H), 2.01 (m,
4H), 1.69 (m, 5H), 1.51 (s, 3H), 1.32 (m, 2H) 0.95 (m, 24H); l3C NMR (CDCh, 150
MHz) 8 128.7, 127.7, 126.3,.75.0, 74.8, 56.4, 47.3, 41.4, 34.3, 31.4, 26.3, 23.5, 22.0,
- 88 -
20.9, 16.4; IR (KBr) v 1015.2, 1148.8, 1291.1, 1455.0, 1533.1, 1685.8, 2956.1, 3364.2
em-I; LRMS (FAB+NBA matrix) mlz, 501(11.3), 319 (22.1), 225 (24.3), 181 (69.9), 120
(38.0),83 (100.0); Anal. ealed for C30H48N204: C 71.96, H 9.66, N 5.59, found: C 71.70,
H 9.78, N 5.60.
2,2,2, Triflooroethyl cis-hexahydro-3H-l,2,3-benzoxathiazole-3-carboxylate 2,2-
dioxide (323)
Eluent: hexanes-ethyl acetate, 2:1; Rf 0.45 (2:1 Hex:EtOAe); mp 83-85 DC (EtOAe); IH
NMR (CDCh, 600 MHz) 5 5.07 (d, J= 3.1 Hz, IH), 4.69 (m, IH), 4.61 (m, IH), 4.27 (m,
IH), 2.38 (m, IH), 2.33 (m, IH), 1.90 (m, IH), 1.81 (m,2H), 1.69 (m, IH), 1.55 (m, IH),
1.27 (m, IH); BC NMR (CDCh, 150 MHz) 5 148.3, 122.3 (q, J= 278.8 Hz), 80.0, 62.5
(q, J = 37.6 Hz), 58.4, 26.9, 21.8, 18.8; IR (KBr) v 3031.7, 2947.2, 2871.5, 1755.5,
1623.1 em-I; LRMS (FAB+NBA matrix) mlz 304,258 (5.5),224 (43.3), 136 (30.7), 81
(100.0); HRMS ealed. for C9HI3F3N05S: 304.0512, found: 304.0467; Anal. ealed for
C9H I2F3N05'S: C 35.65, H 3.99, found: C 35.74, H 3.98.
- 89-
2,2,2-Trlfluoroethyl cis-tetrahydro-3H-l,2,3-benzoxathiazole-3-carboxylate 2,2-
dioxide (324)
Eluent: hexane8-ethyl acetate, 2: 1; Rj 0.46 (2: 1 Hex: EtOAc ); mp 70-72 DC (EtOAc); IH
NMR (CDCh, 300 MHz) 8 6.15 (m, IH), 5.79 (d, J= 10.2 Hz, IH), 5.24 (8, IH), 4.85 (8,
IH), 4.65 (m, 2H), 2.29 (m, 2H), 2.09 (m, IH), 1.85 (m, IH); 13C NMR (CDCh, 75 MHz)
8 148.6, 132.3, 122.3 (q, J= 277.7 Hz), 120.1, 78.1, 62.5 (q, J= 37.6 Hz), 55.7, 27.1, 23.9,
18.5; IR (KBr) v 3492.1, 3044.8,2982.3, 2933.8,2853.8, 1766.9 cm-I; LRMS (EI) mlz
301, 221 (33.5),220 (18.4), 216 (14.2), 120 (21.5), 94 (30.0), 78 (100.0); HRMS calcd.
for C9HlOF3NOsS: 301.0232, found: 301.0229; Anal. calcd for C9HlOF3NOsS: C 35.88, H
3.35, found: C 35.98, H 3.24.
- 90-
5.3 Stability studies
NMR data collection protocol
The Be NMR spectra were acquired on a Broker Avance AV600 spectrometer equipped
with a BBO-Z grad probe and VT accessory. A series of Be NMR spectra were recorded
for each reagent using a power gated proton decoupling pulse sequence from the Bruker
library with a 30 degree flip angle and a 2 s relaxation delay. Each spectrum was acquired
using 256 transients, 16K data points with a spectral width of238 ppm, a line broadening
of 1Hz and zero filled to 32K points. The acquisition time for each spectrum was 11
minutes. All spectra were processed and analyzed using Broker Topspin2.1 PL4 software
running on a Windows XP workstation.
Decomposition study of Burgess reagents at 50°C
100 mg of Burgess reagent was dissolved in 0.75 mL d8_ THF in an NMR tube. Be
proton decoupled spectra were acquired at 12 minute intervals on the 600 MHz
spectrometer. The integral of the carbonyl peak was compared to that of the solvent peak
at 64.6 ppm to determine the percentage of reagent remaining in each spectrum.
Decomposition study of Burgess reagents at 78°C
Six identical reactions were set up in microreactor vials. 100 mg of Burgess reagent was
dissolved in 0.75 mL d8_ THF. The reaction vials were placed in a pre-heated
microreactor block. At 12 minute intervals, one vial was removed, cooled in liquid
nitrogen and transferred to a dried NMR tube and a Be proton decoupled NMR spectrum
was acquired. The percentage of intact Burgess reagent remaining was determined by
comparing the integral of the carbonyl peak to that of the solvent peak at 64.6 ppm.
- 91 -
5.4 Intermediates in morphine synthesis
B 0
c:(~NHBOC OTDS
11
A solution of Boc-glycine (12.0 g, 70 mmol), DCC (18.5 g, 90 mmol) and DMAP (85
mg, 7 mmol) in DCM (200 mL) was cooled to 0 °C and a solution of TDS protected diol
329 (15.0 g, 45 mmol) in DCM (200 mL) was added slowly over a period of 10 min. The
reaction mixture was stirred for 14 hours warming to rt. The solution was diluted with
Et20 (200 mL) and filtered through a plug of silica to remove dicyclohexyl urea. The
solvent was removed under reduced pressure and chromatographed on silica gel with
hexanes:ethyl acetate 9: 1 as the eluent. The product 11 was isolated as a colorless oil
(15.4 g, 31.5 mmol, 70 %). Rf 0.7 (4:1 Hex:EtOAc); [a]D20 -64.0 (c = 1.0, MeOH); IH
NMR CDCh, 300 MHz) 8 6.27 (dd, J= 5.2, 3.1 Hz, IH), 5.59 (d, J= 3.9 Hz, 1H), 5.00
(bs, 1H), 3.97 (m, 3H), 2.39-2.19 (m, IH), 2.15-2.09 (m, IH), 1.85-1.62 (m, 2H), 1.43 (s,
9H), 0.84 (s, 3H), 0.82 (s, 3H), 0.77 (d, J = 1.9 Hz, 6H), 0.07 (d, J = 4.6 Hz, 6H) ppm;
13C NMR (CDCh, 75 MHz) 8 169.6, 155.3, 134.8, 117.0, 79.6, 73.9, 69.2, 42.3, 34.0,
28.2, 25.5, 24.7, 22.6, 20.0, 18.5, -3.1, -3.15 ppm; IR (film) v 3445, 2958, 1755, 1715,
1511 cm-I; LRMS (EI) mlz 171 (7), 157 (9), 136 (34), 121 (9), 79 (10), 28 (100); HRMS
calcd. for C2IH39NSiBrOs(M+H): 492.1781, found: 492.1806; Anal. calcd. for
C2IH3SNSiBrOs: C 51.21, H 7.78, found: C 51.41, H 7.75.
- 92-
Br C02Me
,~NHBOC TDSO"V
10
Glycine ester 11 (6g, 11.8 mmol) was dissolved in THF (100 mL). A solution ofZnCh in
THF (1.0 M, 19 mL, 19.0 mmol) was added and the mixture was cooled to -78°C. A
solution ofLDA (2.2 M, 8.6 mL, 19.0 mmol) in THF was added dropwise. The reaction
was stirred for 16 hours warming to room temperature. The reaction mixture was then
acidified to a pH of approximately 2.5 with 1M HCI. The resulting solution was then
extracted with Et20 (3 x 100 mL), washed with brine (20 mL), and dried over Na2S04.
The solvent was removed under reduced pressure to give amino acid 330 as a mixture of
diastereomers. The unpurified acid was then treated with excess diazomethane. The
resulting diastereomeric mixture of esters 10 was then chromatographed on silica gel with
hexanes:ethyl acetate 20: 1 to give enantiopure esters 9 and 321 in a ratio of 1:4 with a
combined yield of 68 % over 2 steps.
Br C02Me
~NHBOC TDSoN
9
Yield 3.25 g (1.6 mmol); Rf 0.65 (4:1 Hex:EtOAc); [a]n20 -27.7 (c = 1.0, CHCL3); IH
NMR (CDCh, 300 MHz) 8 6.27 (dd, J= 5.6, 1.3 Hz, IH), 4.81 (m, 2H), 4.12 (m, IH),
4.11 (m, IH), 3.71 (s, 3H), 2.96 (bs, IH), 1.86-1.76 (m, IH), 1.63-1.50 (m, 3H), 1.40 (s,
9H), 0.86 (d, J = 6.9 Hz, 6H), 0.80 (s, 6H), 0.06 (d, J = 5.3 Hz, 6H) ppm; BC NMR
(CDCb, 75 MHz) 8 171.7, 155.4, 135.5, 127.9, 79.7, 65.4, 55.2, 52.2, 43.7, 34.1, 29.5,
28.2,24.8,20.2, 19.9, 18.5, -2.6, -3.0 ppm; lR (KEr) v 3443,2956,2868, 1749, 1715 cm
I; LRMS (El) mlz 370 (13), 366 (38), 364 (37), 348 (16), 346 (15),231 (24),229 (24),
- 93-
162 (95), 75 (100); HRMS calcd. for C22H4INSiBr05(M+H): 506.1920, found:
506.1937; Anal. calcd. for C22H4oNSiBr05: C 52.16, 7.96, found: C 52.34, 8.0l.
Br C02Me
N"'NHBOC
TDsoN 331
Yield 13.0 g (6.4 mmol); Rf 0.7 (4:1 Hex:EtOAc); [a]D20 -55.7 (c = 1.0, CHCL3); IH
NMR (CDCh, 300 MHz) 0 6.30 (dd, J = 5.6, l.3 Hz, 1H), 5.21 (d, J = 8.6 Hz, 1H), 4.68
(dd, J = 8.7, 2.3 Hz, 1H), 4.11 (m, 1H), 3.71 (s, 3H), 3.05 (bs, 1H), 1.86-1.78 (m,2H),
1.63-1.50 (m, 2H), 1.43 (s, 9H), 0.84 (d, J= 6.9 Hz, 6H), 0.80 (s, 6H), 0.05 (d, J= 5.3
Hz, 6H) ppm; l3C NMR (CDCh, 75 MHz) 0 171.9, 155.4, 136.3, 125.5, 80.0, 66.7, 55.9,
52.3,45.1,34.2,29.2,28.3,25.8,24.7,23.4,20.2, 18.6, -2.7, -2.9 ppm; IR (KBr) v 3439,
2955,2867, 1753, 1720 cm-I; HRMS calcd. for C22~INSiBr05(M+H): 506.1920, found:
506.1937; Anal. calcd. for C22~oNSiBr05: C 52.16, 7.96, found: C 52.28, 8.06.
Procedure for recycling 331 to diastereomeric mixture 10.
The undesired diastereomer of the C-ring fragment 331 (13.0 g, 6.4 mmol) was dissolved
in DME (50 mL). DBU (0.49 g, 3.2 mmol) was added and the solution was brought to
reflux and was stirred at reflux for 3 days. The mixture was then diluted with Et20 (100
mL) and washed with a 10 % citric acid solution to remove DBU, washed with brine (2 x
20 mL) and dried over Na2S04. The solvent was removed under reduced pressure to give
diastereomeric mixture 10. The mixture was then chromatographed as described above to
give 9 and 331 (1: 1 ratio) in 80 % combined yield.
- 94-
/0
'0
TDSO'\'
NHBoc
7
To a flame-dried flask containing Pd(dppf)2Clz (104 mg, 0.090 mmol) was added methyl
ester 9 (456.4 mg, 0.901 mmol) in degassed THF (7 mL). Boronic acid 8 (328 mg, l.802
mmol) was then added, along with CS2C03 (89 mg, 0.270 mmol). The resulting mixture
was then stirred at reflux overnight. The reaction mixture was then filtered through a plug
of silica with EtOAc, and concentrated to give 569 mg of brown oil. The oil was then
chromatographed on Si02 using 4:1 hexanes : ethyl acetate as the eluent. The coupled
product 7 (448 mg, 0.794 mmol, 88%) was obtained as a clear and colorless oil. Rf 0.8
(1:1 Hex:EtOAc); IH NMR (300 MHz, CDCh) 8 6.97 (t, J= 7.91 Hz, IH), 6.82 (dd, J=
8.29, l.1 Hz, IH), 6.66 (d, J = 7.65 Hz, IH), 5.77 (dd, J = 3.93, l.54 Hz, IH), 5.71 (d, J
= 9.72 Hz, IH), 4.33 (dd, J = 9.72, 2.28 Hz, IH), 4.24 (m, IH), 3.85 (s, 6H), 3.23 (s,
IH), 1.74 (m, 2H), 1.74 (q, J = 6.86 Hz, IH), 1.55 (bs, 4H), 1.42 (s, 9H), 0.91 (dd, J =
6.84,0.93 Hz, 6H), 0.85 (s, 7H), 0.10 (s, 6H) ppm; BC NMR (CDCh, 75 MHz) 8 172.6,
155.2,152.3, 146.2, 139.5, 134.6, 132.5, 124.1, 122.0, 11l.8, 79.3, 63.4, 60.6, 55.7, 54.7,
52.1,38.4,34.4,30.1,28.4,24.9,20.5, 18.7, 17.9, -2.3, -2.8 ppm; IR (neat) v 3449,3019,
2956,2401, 1748, 1716 cm-I; LRMS (FAB + NBA matrix) mlz 404 (10.0), 375 (17.1),
287 (68.2), 227 (54.9); HRMS calcd. for C30H49N07Si: 506.2574, found: 506.2538.
/0
'0
336
NHBoc
- 95-
To a stirred solution ofsilyl ether 7 (448 mg, 0.794 mmol) in distilled THF (10mL) was
added tetra-n-butylammonium fluoride (0.87 mL, 0.873 mmol, 1M solution in THF)
dropwise at 0 °C. The resulting solution was allowed to warm to r.t. and stir for 20 hrs.
The reaction was diluted with distilled water (20 mL) and THF was removed under
reduced pressure. The aqueous residue was then extracted with ethyl acetate (3x 10 mL).
The combined organic layers were rinsed with distilled water (10 mL), brine (10 mL) and
dried over sodium sulfate. The resulting mixture was filtered and concentrated to give
free alcohol 336 (271 mg, 0.644 mmol, 81%) as a colorless oil. RI 0.3 (1:1 Hex:EtOAc);
[a]n20 34.65 (c = 0.2, CHCh); IH NMR (CDCh, 300 MHz) 0 6.98 (t, J = 7.9 Hz, 1H),
6.83 (dd, J = 8.2, 1.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 5.89 (dd, J = 3.9, 1.40 Hz, 1H),
5.56 (d, J = 9.7 Hz, IH), 4.3 (dd, J = 9.7, 2.5 Hz, IH), 4.28 (m, IH), 3.86 (s, 3H), 3.84
(s, 3H), 3.47 (q, J = 7.03, IH), 3.37 (bs, IH), 3.30 (s, 3H), 1.92 (m, 4H), 1.42 (s, 9H)
ppm; 13C NMR (CDCh, 75 MHz) 0 172.7, 155.2, 152.2, 146.1, 141.7, 134.4, 131.0,
124.0, 122.1, 112.0, 76.6, 63.5, 60.6, 55.8, 54.9, 52.1, 39.1, 30.0, 28.3, 18.8 ppm; IR
(neat) v 3354,3015,2938, 1709, 1523 em-I; LRMS (EI) mlz 303 (13.4),216 (100.0), 200
(24.3), 185 (8.7); HRMS calcd.for C22H31N07: 421.2101, found: 421.2077. Anal. calcd
for C22H31N07: C 62.69, H 7.41, found: C 62.65, H 7.46.
NHBoc
BzO 337
To a stirred solution of alcohol 336 and benzoic acid in dry THF was added a solution of
the Mitsunobu reagent, prepared by the addition of diethyl azodicarboxylate (DEAD) to
- 96-
PBU3 in THF at 0 °c. The reaction mixture was allowed to warm to room temperature
over three hours and stirred for another three hours. The solvent was removed under
reduced pressure and the resulting oil was chromatographed on silica gel (Hex: EtOAc
4: 1). The pure product slowly solidified overnight in the freezer and was recrystallized
from EtOAc. Rj 0.27 (2:1 Hex:EtOAc); mp 102-105 °c (EtOAc); IH NMR (CDCb, 300
MHz) 8 8.02 (d, J=7.2 Hz, 2H), 7.54 (t, J=7.4 Hz, IH), 7.42 (t, J= 5.6 Hz, 2H), 6.98 (t,
J= 7.9 Hz, 1H), 6.83 (dd, J= 1.5, 8.01 Hz, IH) 6.70 (dd, J= 1.1, 7.2 Hz, 1H) 5.9 (s, 1H)
3.87 (s, 3H), 3.86 (s, 3H), 3.53 (s, IH), 3.26 (s, 3H), 2.22 (m, 2H), 1.86 (m, 2H), 1.55 (s,
2H), 1.45 (s, 9H) ppm; BC NMR (CDCh, 150 MHz) 8: 171.8, 166.3, 156.2, 152.8, 146.2,
139.2, 135.1, 133.0, 129.7, 128.4, 123.8, 122.2, 112.1,61.4, 56.0, 51.8,40.9,28.5,26.9,
24.8 ppm; LRMS (EI) mlz 525, 403 (8.4), 303 (20.8), 260 (50.4), 216 (100); HRMS
calcd. for C29H3SNOs: 525.2363, found: 525.2369 .
......... 0
'0
HO 339
To a stirred solution of benzoyl ester 337 (148 mg, 0.282 mmol) in distilled DCM (1 mL)
was added distilled TFA (0.25 mL) at r.t. The reaction was allowed to stir for 24 hr. and
was then diluted with DCM (10 mL) and washed with NaHC03 (2 x 3 mL). The aqueous
layer was extracted with DCM (1 x 5 mL). Combined organic layers were rinsed with
distilled water (5 mL) and brine (5 mL) and dried over Na2S04. The organic layer was
then filtered and concentrated to give a yellow oil. The crude mixture was purified by
FCC (98:2 DCM:MeOH) to give 339 as a clear oil (33 mg, 0.103 mmol, 36%).
- 97-
RfO.3 (95:5 DCM:MeOH), [a]D20= 128.1 (c=0.29, CHCh, 95% CI); IH NMR (300 MHz,
CDCh) 8: 6.96 (t, J=7.94 Hz, IH), 6.81 (d, J= 7.23 Hz, IH), 6.65 (d, J= 7.53 Hz, IH),
6.58 (d, J=5.13 Hz, IH), 3.85 (s, 3H), 3.73 (s, 4H), 3.46 (s, 3H), 3.40 (s, IH), 3.40 (s,
IH), 2.30 (s, IH), 2.01 (m, IH), 1.82 (m, IH), 1.69 (m, IH), 1.41 (m, IH), 1.25 (s, IH),
0.86 (m, IH) ppm; l3C NMR (150 MHz, CDCh) 8: 152.9, 146.8, 138.7, 134.4, 132.6,
124.0, 121.0, 111.6, 60.5, 58.5, 55.9, 52.1, 47.1, 38.8, 26.4, 23.1, 21.2, 14.3 ppm; mlz
(EI) 303 (M - H20, 21.2) 272 (9.5) 244 (7.4) 216 (100) HRMS calcd for C17H23N05:
303.1471 (M+ -H20); found 303.1469 (M+ -H20)
OH
NHBoc
341
Diester 337 (0.848 g, 1.6 mmol) was dissolved in 10 mL dry THF and cooled in an
ice/water bath~ Lithium aluminum hydride (0.153 g, 4.0 mmol) was added in one portion.
The mixture was stirred for 2 hours warming to room temperature. The reaction was
quenched by successively adding 0.15 mL water, 0.30 mL NaOH (15%), and 0.45 mL
water. The aluminum salts were filtered off and the resulting oil was concentrated and
chromatographed (1:2 Hex:EtOAc) yielding alcohol 341 (0.586 g, 1.5 mmol, 94 %) as a
thick colorless oil. Rf0.26 (1:2 Hex:EtOAc); [a]2oD 86.91 (MeOH); IH NMR (DMSO tf,
600 MHz) 8 6.89 (s, 2H), 6.54 (dd, J = 604, 1.8 Hz, IH), 6.00 (d, J = 8.7 Hz, IH), 5.56 (s,
IH), 4.70 (d, J = 5.3 Hz, IH), 4.54 (t, J = 5.4 Hz, IH), 4.18 (d, J = 3.7 Hz, IH), 3.78 (s,
3H), 3.68 (s, 3H), 3.16 (m, 4H), 1.97 (m, IH), 1.74 (m, IH), 1.32 (s, 9H), 1.12 (s, 2H)
ppm; l3C NMR (DMSO tf, 150 MHz) 8 155.5, 152.1, 146.0, 139.9, 136.6,.135.4, 124.0,
- 98-
122.3, 111.7, 77.7, 66.0, 61.5, 60.2, 56.0, 53.0, 37.1, 32.0, 28.7, 20.2 ppm; IR (film) v
3384,2938, 1696, 1577, 1472 cm-\ LRMS (EI) mlz 375 (m- H20), 321 (5.5),264 (20.2),
244 (14.9), 216 (100.0); HRMS calcd. for C2IH29NOs: 375.2046, found: 375.2039. Anal.
calcd. for C2IH3IN06 C 64.10, H 7.94, found: C 63.83, H 8.24.
/0
'0 0 )=0
N H
HO 6
To a solution of alcohol 341 (0.311 g, 0.79 mmol) in THF (10 mL) was added NaH
(0.019 g, 0.79 mmol). The mixture was stirred at room temperature for 10 hours. The
reaction was quenched with citric acid solution (10 % w/w, 5 mL). The aqueous phase
was separated and extracted with ether (2x20 mL). The crude material (271 mg) was
chromatographed on Si02 and chromatographed with 1: 1 hexanes/ethyl acetate as the
eluent. The product 6 (0.201 g, 0.63 mmol, 80 %) was isolated as a colorless oil.
RjO.2 (1:2 Hex:EtOAc); IH NMR (CDCh, 300 MHz) 0: 7.06 (t, J= 7.92 Hz, IH), 6.89
(d, J= 8.22 Hz, IH), 6.67 (dd, J= 7.65,1.17 Hz, IH), 5.87 (m, IH), 4.41 (m, IH), 4.16
(m, IH), 3.89 (s, 3H), 3.82 (s, 3H), 3.55 (t, J= 4.74 Hz, IH), 2.76 (bs, IH), 2.27 (m, IH),
1.67 (m, IH), 1.59 (m, IH), 1.40 (m, IH) ppm. BC NMR (CDCh, 75 MHz) 0 159.3,
152.9, 145.7, 134.7, 124.8, 121.0, 111.7, 71.6, 71.1, 67.3, 67.0, 61.9, 61.4, 55.8, 53.3,
42.1, 31.7, 31.2, 19.3, 14.2 ppm; IR (neat) v 3368,2936, 1747, 1576 cm-I; LRMS (EI)
mlz 301 (3.9),216 (49.1), 200 (14.1), 87 (87.3); HRMS calcd. for C17H2INOs: 301.1314,
found: 301.1310.
- 99-
5.5 Biotransformations
General procedure for small scale fermentation with E. coli JMI09(pDTG601)
Growth of colonies.
Agar plates consisted ofbactotryptone (10 giL), yeast extract (5 gIL), NaCl (5 gIL), agar
(30 giL), and ampicillin (100 mglL). E. coli JM109(pDTG60l) cells were streaked onto a
plate and incubated at 35 DC for 24 hours. A single colony was isolated for the preculture
preparations described in the following section.
Preculture.
Luria Bertani (LB) media consisted ofbactotryptone (10 gIL), yeast extract (5 gIL), NaCl
(5 giL), and ampicillin (100 mg/L). Three mL ofLB media was inoculated with a single
colony of E. coli JM 1 09 (pDTG60 1) and grown at 35 DC in an orbital shaker.
Fernbach shake flask.
Luria Bertani (LB) media consisted ofbactotryptone (10 gIL), yeast extract (5 gIL), NaCl
(5 giL), and ampicillin (100 mglL). A 3 L Fernbach shake flask was charged with 500
mL LB media and then inoculated with 1 mL of E. coli JMl09(pDTG60l) preculture
media. The inoculum was grown for 12 hours at 35 DC in an orbital shaker. The contents
of the shake flask were added to a 15 L Sartorius Biostat C fermentor and grown
according to literature procedure for 24 hours. 156
Substrate addition
500 mL of cell broth was- drained from the fermentor and the cells were separated by
centrifugation. The supernatant was drained off and the cells were re-suspended in 500
mL phosphate buffer (0.1 M) containing 2 gIL glucose. The substrate (200-400 gIL) was
- 100-
added neat or as a solution in isopropanol. Product formation was monitored by TLC
(hexane/EtOAc, 1: 1).
Product isolation
After 5 hours of incubation, the pH of the media was adjusted to 8.5 with NaOH (1 M)
and the supernatant was separated from the cells by centrifugation. The supernatant was
then extracted with EtOAc (3x500 mL). The extract was washed with saturated Na2C03
(100 mL) and brine (100 mL) and dried over anhydrous Na2S04. Ethyl acetate was
removed under reduced pressure and the crude material was purified by crystallization
(EtOAc/pentane) or flash colum chromatography.
Large scale fermentations
Large scale fermentations were performed according to literature procedure. 156
methyl 2-fluoro-5,6-dihydroxycyclohexa-l,3-dienecarboxylate (344):
Rf 0.15 (1:1 Hex:EtOAc); mp 74-76 °C (EtOAc); [at2o = +73.2 (c 1.05, MeOH); IH
NMR (CDCh, 600 MHz) 8 6.33 (m, IH), 5.94 (ddd, J = 10.2, 8.3,2.6 Hz, IH), 4.71 (t, J
= 6.2 Hz, IH), 4.55 (m, IH), 3.83 (s, 3H), 3.17 (bs, IH), 3.09 (brs, IH) ppm; l3C NMR
(CDCh, 150 MHz) 8 166.0 (d, J = 2.2 Hz), 163.2 (d, J = 281.0 Hz), 143.1 (d, J = 12.1
Hz), 119.6 (d, J = 36.2 Hz), 106.2 (d, J = 2.2 Hz), 69.0, 67.0 (d, J = 6.6 Hz), 52.2 ppm;
I9F NMR (CDCh, 282 MHz) 8 -92.6 (s) ppm; IR (film) 3558, 3025, 1694, 1439, 1401,
1040 cm-I; LRMS (EI) mlz 188 (15), 133 (44), 119 (49), 102 (100), 91 (37),90 (46), 86
(28), 74 (16), 46 (27); HRMS calcd. for CgH9F04 (Ml: 188.0485, found: 188.0484;
Anal. calcd. for CgH9F04: C, 51.07; H, 4.82, found: C, 51.18; H, 4.76.
- 101 -
C02Me
CI~OH
UOH 348
methyl 2-chloro-5,6-dihydroxycyclohexa-l,3-dienecarboxylate (348):
Rf 0.25 (1:1 Hex:EtOAe); mp 107-109 °c (EtOAe); [a]D20 = +86.6 (e 1.0, CHCh); IH
NMR (CDCh, 600 MHz) () 6.35 (d, J= 9.8 Hz, IH), 6.03 (dd, J= 9.8,3.0 Hz, IH), 4.44
(m, IH), 4.31 (d,J= 6.0 Hz, IH), 3.83 (s, 3H), 2.50 (bs, 2H) ppm; BC NMR (CDCh, 150
MHz) () 164.8, 140.5, 127.8, 125.1, 124.0, 72.5, 67.4, 52.3 ppm; IR (KBr) 3422, 2959,
1721, 1578, 1444, 1270, 758 em-I; LRMS (EI) mlz [M-H20t: 188 (15), 186 (43), 157
(32), 155 (100), 99 (14); HRMS ealed. for CsH9CI04 [M-H20t 188.0084, found:
188.0077.
CI
Me02C~OH
UOH 349
methyl 2-chloro-3,4-dihydroxycyclohexa-l,5-dienecarboxylate (349):
Rf 0.18 (1:1 Hex:EtOAe); mp 107-109 °c (pentane-,-ethyl acetate); [a]D 20 = +36.9 (e 1.0,
CHCh); IH NMR (CDCh, 300 MHz) () 6.18 (ddd, J= 10.0,2.4, 1.2 Hz, IH), 6.01 (dd, J
= 10.0, 2.4 Hz, IH), 4.64 (ddd, J = 6.0, 4.7, 1.2 Hz, IH), 4.52 (ddt, J = 8.7, 6.0, 2.4 Hz,
IH), 3.86 (s, 3H), 2.76 (d, J = 9.6 Hz, IH), 2.60 (d, J = 4.7 Hz, IH) ppm; BC NMR
(CDCh, 150 MHz) () 166.3, 138.8, 138.5, 127.5, 123.8, 68.6, 67.7, 52.3 ppm; IR (KBr)
3398, 3459, 1698, 1317, 1057, 762 em-I; LRMS (EI) mlz: 204 (14), 173 (23), 172 (54),
155 (50), 146 (32), 145 (36), 144 (100), 143 (80), 139 (27), 99 (27), 81 (41),53 (25),51
(21); HRMS ealcd. for CsH9CI04: 204.0189, found: 204. 0190.
- 102-
C02Me
Br~OH
U OH 352
methyl 2-bromo-5,6-dihydroxycyclohexa-l,3-dienecarboxylate (352):
Rf 0.18 (1:1 Hex:EtOAe); mp 106-109 °c (CHCh); IH NMR (CDCh, 600 MHz) 8 6.17
(dd, J = 10.0, 2.5 Hz, IH), 6.04 (ddd, J = 10.0, 2.5, 1.3 Hz, IH), 4.57 (m, IH), 4.49 (m,
IH), 3.85 (s, 3H), 3.00 (d, J = 7.9 Hz, IH), 2.97 (bs, IH) ppm; I3C NMR (CDCh, 150
MHz) 8 166.6, 137.5, 130.0, 128.0, 127.3, 68.4, 68.1, 52.3 ppm; IR (KBr) 3402, 1703,
1437, 1314, 1234, 1048 em-I; LRMS mlz: 248 (9), 218 (38),216 (47), 190 (82), 189 (53),
188 (85), 187 (48), 109 (71), 108 (31), 81 (100),65 (79), 59 (45), 53 (54); HRMS ealed.
for CSH9Br04: 247.9684, found: 247.9679.
methyl 3,4-dihydroxy-2-iodocyclohexa-l,5-dienecarboxylate (356):
IH NMR (600 MHz, CDCh) 8 6.19 (d, J= 9.8 Hz, IH), 6.11 (dd, J= 9.8, 3.8 Hz, IH),
4.42 (m, IH), 4.36 (t, J= 6.6 Hz, IH), 3.83 (s, 3H), 3.12 (brd, J= 7.6 Hz, IH), 2.59 (brd,
J = 7.2 Hz, IH) ppm; BC NMR (151 MHz, CDCb) 8 166.0, 134.3, 129.3, 123.9, 111.20,
67.2, 52.4 ppm; LRMS I: 296 (12), 278 (83), 264 (38), 247 (90), 231 (31), 137 (100), 109
(95), 92 (43), 81 (89), 63 (35), 59 (38), 53 (62); HRMS ealed for CsH9I04: 295.9546,
found: 295.9538.
- 103 -
6 Selected Spectra
I
°1 I
- 104-
ID proton
9.0 8.5 8.0 7.5
I~I ID carbon with proton
, 170 160
~ "" ~
150
7.0 6.5
decoupling
, 140
m co ,..: ~
I 130
I
6.0
a; O"i ~
I
~ ci ~
I
I 120
5.5
'" ... a;j
I
5.0
I 110
4.5
!~~
I 100
4.0
90
3.5 3.0
80
2.5 2.0 1.5 1.0 0.5 0.0 ppm
IJ')v"::::l"('t) (D~CO"r
criCV;NN co (0 co co
~I/
70 60 50 40 ppm
- 105 -
>-' o 0'1
.... !XI o
.... ..... o
....
." o
.... g:
.... ~
.... w o
.... N o
.... .... o
.... 8
!XI o
CI
g
(II o
~ o
~
-155.40
_126.56 -124.72 -122.88 -121.04
~67.21
66.90 66.69 66.54 66.40 66.25 66.10
'
61.43 61.19 60.96 60.72
...,-50.59 .......... 50.48
-46.37
~25.35
24.76 24.56 24.43 24.29 24.16 24.03
__ 8.46 ---a.05
f-' P.
" Pl
" tr 0 i:l :;: .... rt i:l"
'0
" 0 rt 0 i:l
P. ro
" 0 .g f-' .... .E
to <:>
ex>
'" ex> <:>
:-J
'" :-J 0
'" '" g:
- ... ~'"
... <:>
--'" ~'"
'" <:>
., '" ., <:>
o
'" o <:> "0 "0 3
Co) ..... N
m -'" e z 0 Of I ~ (Dz 0
)=0 0
) "T1 '"
/"4.523 ,?---4.494 ~4.466
'-4.437
/"3.521 ,?---3.497
~~::~~
./1.463 "-1.439
1.414
f-' t:J
'0
" 0 rt 0 i:l
ID proton
I 9.0 8.5 8.0 7.5
ID carbon with proton
I 180
I 170
'" cO ~
I
I 160
I 150
7.0 6.5
decoupling
I 140
I 130
6.0
I 120
5.5
I 110
5.0
I 100
I 4.5
....
I 90
I 4.0 3.5 3.0
~l~~) (~)~ vNNO> vNOIO r--:r--:r-.:cd ,...."'''' .....
"V/
I 80
I 70
2.5 2.0
I~( r--r--to'" -¢ct>
"'''' \/
[. t
60 50
1.5
ci
" I
I 40
1.0
I 30
I 0.5 0.0 ppm
"'''' """ "--:0
"'''' \/
"n
20 10 ppm
- 107-
-o 00
.... C:I .... 8 .... g
.... .... C>
.... to! C>
... ~
.... .... C>
.... 8
'" C>
co C>
..... C>
en C>
g
~
to! C>
1:1 1:1 3
-156.14
___ 125.92 _124.08 -122.24 --120.40
.L... 77 . 31 ~77.10
76.89
{
62.0B 61.84 61.60 61.36
_55.61 --......54.84
-40.18
£22.64 21.41
,$-21.37
\
20.58 20.54 20.49 20.44
,.... p,
() IlJ '"! IT 0 ~
:;: /-'. rt p-
'0 '"! 0 rt g P, CD ()
~ I-' /-' . ~
lQ
'" b
0)
'" O)
b
.."
'" .." b
'" '" '" b
'" '" '" b
~~
... b
llL", 2.00 '"
~w IQ£=
b
'" '" ~~ ~
1:19:-" ~'"
b
p
'" o b
~
G /z, ~O ~
Co) coz 0 ~ )=0
0
> C1 ""Tl
W
,.... t:J
'0 '"! 0 rt 0 ~
;
4.518 4.489 4.461
-4.433
13.753
1'-3.666 3.623 3.614
~3.581
~3.569
\"\..3.466 ~3.422
3.147 -2.818
12.015 1.961 1.928 1.915 1.903
~1.862
~~:~~~ 1.826 1.818 1.519 1.479
.... f-'
~I Q f-'
'" P. P.
CI () W ..... '0 III " .... a. cg 0
CO rT
CI 0 0 i:l _°'rrZ ° i:l
.... " ..... 1-' • 'en' CI rT ° (f ''0 P'
.... '0
'" " CI 0 ;l rT
I t::li 0 .... i:l ... -150.51 p., 6.119 CI CD 6.112 ()
~ 0 6.103
CI .§ rr5.824 f-' ... 1-'.
.... -131.60 tE 1][:: en Co> CI __ 0
0.98 A 4.798 .... 3.933 N -120.73 !" 3.921 CI en
1.01 2.403 .... 2.395 .... !" 2.388 CI
__ 0
0.98 2.378 .... .... 2.370 0 CI ... 2.363
2.356
:g-l I ~: 2.351 2.347 2.342
g:-l I .£.77.83 !" 2.337 en
~77.2B 2.333 77.07 2.325 76.86 Co> 2.322 Cl-l I 0 2.317
1.21'-- t: 2.312
g-j t 2.307 0.91,,- 2.303
_55.45 .1J!Ir N
r'" -54.61
g:-l I 1.07 0 2.294 2.165
.... 2.156
;!;-l I ... 2.147
2.137 .... 2.135
~-l I 0 2.126
2.117 0 1.944
-23.99 ... ~-l t 1.941
-18.53 1.934 1.930
Q1 I "C 1.925 "C 1.922 3
"C "tI ...... 3
0 \0
--o
.... :g .... '" co
.... .... CO
.... :!l .... g: .... ~ .... ~
.... ~ .... .... CO
.... 8 CD CO
'" CO
~
... CO
g:
~
... CO
N ,CO
.... CO
1:1 1:1 3
I'=-
f----
I-' 0-
n Pl
~ ,. ,... (1"
~
'" ... '" ...
'0 .... ~ 2.52'-- ... (1"---
o~ P
~ n
~ >-' ,...
.... ... !" UI
.____128.71 S -127.66
... ... -----'
1.00 ~UI ...
---126.30
L77 • 26 77.04 76.83
~75.02 "-74.81
-56.35
........-47.34 ""'C 46 • 32
46.11 -41.37
/34.27 ../£31.40 y:. 31. 37
--.;;
26.27 26.14
,.,. /23.52 ~22.13
~;;:~i
1:20,87 20.79 20.76 16.44
0:92~ 1.15
~,. ________ UI
,. CO
2.iiiI !" --·UI
... ... N ...
~!" 1.87 co
~ .... 2.96 ... =--~ 2.55 .... 18.64 ... 6.25;::
~CO ... 1:1 1:1 3
Co.)
~ ZI
o==(
)=0 Z I
-6,,<
I-' 0-7.371
7.359 '0 7.347 'i 7.304 7.288 7.283 7.276 4.580 4.574 4.562 4.556 3.524 2.064 2.044 2.025 1.913 1. 906 1.902 1. 895 1. 891 1.883 1. 696 1. 678 1.659 1.512 1. 507 1. 502 1.497 1.482 1.477 1.445 1.319 1.303 1.290 1. 278 1.081 1.064 1. 060 1. 043 1. 027 0.991 0.980 0.961 0.953 0.930 0.918 0.903 0.891 0.881
,;V~:~i~ 0.806 0.795 0.733 0.725
o (1"
g
f-' P.
~ Q 7.283 t:;:
Cl 5.069 ~
'" 5.063 'll ~
g~ I 0 fd 5.058 ~ i:l Co) "-°lrZ °
4.708 g
" 4.700 ,... '(J{ 4.694 ct
P' ° 0/'0 4.687
'" CO 4.673
~11 " 0 4.621 ct 0 4.607 i:l 4.600 p. 4.284 ro
i11 Cl .... 4.274 0 .§ 4.266
f-' 4.258 ,... 4.248
-148.33 S 2.392
~11 2.388
'" 2.365 2.361 2.326
___ 125.04
~HF _123.20
f"" -121.36 1.873 ----119.52 :iE:", 1.868
1.04'-1.860 1.854
811 ~ 1.850
1.01 1.805 1.791
.j>. 1.785 1.782
~-j t .........-79.98 1.777 ~77.25
77.04 1.773 76.83 1.764
{62 .• 3 too 1. 759
62.58 1.752 gH I 62.33
-............. 62.08 1. 751
58.38 1. 740 1.17'- 1. 735 .!!!1r 1. 701
~-j I 1.07\.. N 1. 697
2.iii'- 1. 678
Hb= 1. 674
<27.11 ~ I r'" 26.93 1.08 1.559
~H I -21.76 r -lB.75 11.553 1.542 1.537 1.286 1.281
co -l if
i1 l r· 276 1.264
I "tI II 1.259
"tI >-' 3
1.254 3
>-' .......
...... ...... tv
cO o
~
~
'" o
~
~
iil
~
o
8
~
~
Cl
'" o
~
... o
'" o
~
o
o :g 3
... 0-----
....
-148.61
-132.25 _127.78 .___124.10
< 120.42 120.11
........... 116.74
~78.06 77.47 77.25 77.04 76.62
/"63.27 ,?--62.77 ~62.28
"-61.78 ........... 55.74
-27.07 -23.86
-18.45
f-' t!
Cl III I-j tr 0 ::t
0;: f-'. (""t
::r 'd I-j 0 ct 0 ::t
f5' Cl
~
~ 0
!'" '" co
'" ....,
'" ....,
'" f-' '" 1-'" 0, ::t to "i(i() _._.'"
'" 0.98
1][::: '" '" '" IE='"
2.12 ~ ...
'" ... '" '" '" '" '"
~!" 2.11 '" =-1.06 ='" 1.&L '"
'" '" o
'" o
'" :g 3
"T1 Q ~CCJ ,all. '-0 )-Z .. ,0
O ",}"" o 0
6.180 6.163 6.160 6.146 6.129 5.802 5.768 5.251 5.240 5.229 4.834 4.830 4.775 4.748 4.733 4.721 4.706 4.694 4.679 4.675 4.652 4.647 4.631 4.620 4.605 4.593 4.578 4.551 2.431 2.417 2.384 2.356 2.347 2.339 2.332 2.324 2.315 2.305 2.296 2.287 2.278 2.270 2.204 2.187 2.171 2.130 1.989 1.982 1.968 1.952 1.946 1.940 1.933
f-' t!
'd I-j o ct g
ID proton
B 0
ecr ~NHBOC
~ 0
OTDS 11
f i I I I I I I I I I I I I I I I I 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm
I~~ (~I l~! l~! !§ll~! 1~~~r~II~1 ~l;1 (~I
- 113 -
I
...... ...... ,.!:::.
_____ ~<oo< oo~ ___ O<_
'" o o
f-' ex> o
f-' en o
f-' .. o
f-'
'" o
f-' o o
ex> o
en o
.. o
'" o
o
~
!-
t--
t---
f-
~
~
~ f--
F=-
I,-
f-' 0. (J DJ
tJ. g .: 1-" rt ::r 'd Ii o rt o
-171.94 i:l 0. CD (J o .§
-155.48 f-' 1-"
-136.38
-125.57
J~~:~: 77.03 76.82
1'/74.03 :/,69.35 .y;66.74
l~~~~g 1/[4l.45
~34'21 34.10
~29.20
28.33 25.61
~;::~!
!"-;~:;;
20.22 20.14
lH:H 18.47 14.14 -1. 46
.g
1.00;::
0.98-
1.01 -
1.19=
3.47=
0.99 w
~t\J 1":57"-
1. 70
~ ~
~ ... 11. 41::=
~
~ ~o
~
--I o en
Qq" ~ OJ e.g ...
(')
o Z N
::r: s:: OJ (1) o ()
7.284 6.318 6.313 6.310 6.305 6.218 6.213 5.629 5.623 5.261 5.247 4.731 4.728 4.717 4.713 4.168 4.161 4.154 4.146 4.046 4.038 4.018 4.009 3.977 3.971 3.964 3.958 3.952 3.754 3.097 1. 930 1.924 1. 913 1. 902 1. 850 1. 841 1. 836 1. 833 1. 827 1. 818 1. 809 1.716 1. 710 1.702 1. 694 1. 688 1. 680 1. 671 1. 665 1. 647 1. 636 1.625 1. 614 1. 602 1. 591
"'\
-1.579 ''-1.570
1.475
lO.924 0.913 0.889 0.878
~UH 0.819 O. B12 0.153 0.122 0.107 0.089
f-' 0.
'd Ii o rt g
.......
....... Ul
w o
~
'"' o
~
~
;---f---
r--
t--
~
!---
~
-155.22
-152.28
-146.24
-139.51
-134.55 -132.50
-124.11 -121.95
-111.83
./79.29 ~77.25 "-.77.03
76.82
-63.37 -60.58
__ 55.73 --54.?3 -52.05
-38.44
-34.44
./30.09
......... 28.36 ---28.00 -24.93
....... 20.47 ~20.45
"'= i~:~!
f-' P,
0 III
~ ~ 0
"' " .... :"' IT ::r
'<:I
8 rt~;..J g 1.07;:: a
g.0.97;::: o '" o . .g I-'
~·O.98;::: ~ LQ 0
'" '"
'" 0.96 0
in 1.14
"1.l2'-- ~ 3.08'\::: 0
3.03C
~w ~.
'"
0,
'" '"
!" 2.26 3.96 'i":"'2"6'= .... 9.06==i.n
1. 45:=
6.fi9'.... !"' 7.27/ a
?
~
.....
-I o CJJ 0-:.
Z I OJ o (")
/7.283
-;
6.980 6.967 6.954
<6.861 6.848
~6.639 6.638 6.627 6.625
<5.974 5.967
If ::m
J~4.282
~4.019
4.012 4.006 3.999 3.886 3.873 ~~:~~~
.........3.704 -3.683
"\
3.542 3.533 3.526 1.820 1. 802 1. 797 1.785 1. 729 1.722 1.711 1.705 1. 700 1. 693 1. 682 1. 670 1. 658 1. 650 1.555 1.544 1. 539 1. 534 1. 528 1.404 1.273 1. 216 0.975 0.969 0.963 0.958 0.940
f-' P,
'<:I
" o IT g
lD proton
......... 0
'0
NHBoc
336
I I I I I 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
!§~!§~!~~ !~~ !~~ ~~! (~~ ~I~ ~1~1 I~I lD carbon with proton decoupling
Oi ~co co "''''''' NO I'-01'- N ... "' ... <Xl'" 0 (\Jm,.... ....... UJ UJC\I V 0> co 0 ~I'-~
t:: cON cD cxhocv) (Y')N ~ I";Lr.!ct:!~"":"!~""':~"": "": ~ ... ~ "'"' ~ ~~~ ~~ Olt-- ............. COUJ'I"'""(Olt)"I"'"" 0 cieri"":
...... ,.... ............. r.....CO(OLOUJUJ ... NNN
\ I I \ \ / \/ ",\V \ \ \// I \1/
.,., ,J, .J. hi, 1 J l.u 1,,1 ,">L .11,
" "n .". .'", " " 'I II"
I I I I I I I I I I I I I I I I I I I I I I I 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 .10 o ppm
- 116-
---....l
'" 6
'" o o
I-'
~
I-'
'" o
I-'
;; I-'
'" o
I-'
'" o
I-'
~
:;: o
::; o
I-' I-' o
I-' o o
~
'" o
.., o
g:
g:
... o
w o
'" o
I-' o
~
I-' P. o III
~ o
-J
U1
::> -J
~~~ rT·~ P"~
'O~'" Ii . o U1 rT o ::> '" ft~;" 0---........o
-157.97,g U1
-152.38 ~ 1I1
::> -146.11 lO -I lJ1
-140.69 0.94 -135.28 ~ a -132.46
124.41 If!:.,
"::::::::124.19 ~ U1 -""""'121.68 ~
-111.72
./79.64 ~77.25 ",,=77.04
76.83
__ 66.65 __ 63.33 -60.56 ../""55.75 -54.84
138.41 34.44 34.33
l~u~ "'.f::.28.38 ./"24.93
L 20 . S1
~~~u~
18.68 18.65 17.23
~15.29 ,,'-1.03
\:-2.20 -2.86
... ~;" ~ 1.02.c: LV
~u, ~ ~
LV
o
tv
U1
tv
o 2.49
~I-' 9.03 == U1
6.03\.-- I-'
6.78r ;"
2.91\.....
o U1
3.01r 0
o
~
~ U)
Z I
'"
i~:~~~ 6.977 6.964
!/;6.864 6.851
",;6.622 y6.609
A5 . 993 5.984
f4.836 4.828 4.295 4.291 4.287 3.871 3.760 3.716 3.702 3.605 3.601 3.587 3.583
11
3 . 410
~~jg 1.806 1.803 1.780 1.711 1.700 1.688 1.677 1.666 1.654
f1.449 1.415
It~H 0.954 0.933
1[0.930 -0.920 0.919 0.909 0.902 0.891 0.885 0.875
,
0.188 0.156 0.142 0.135 0.126 0.088
I-' P.
'0 Ii o rT
g
f~ >-'
~~ 6.987 t:l
U ... U jJ 6.969 'd
" 6.961 Ii 0
6.943 ("t
~~ ¥.6.849
0
~~l ~ t:J
6.845
1J2l-Jt.:6.822
iill'-6.818
~~ r'" '" z f? 6.709
I :s:: 6.689
» CD 6.684
~~ r 0 6.659 6.655 6.634 6.629 6.572
t::~ ~6.567 6.552
~6.547 5.295
g:~ r3.863 3.852 3.779 3.743
~~
~:~: 2.764
'j t 2.077
~o 2.065
~ 2.054
~ 2.047
~'" 2.033
~'" 2.023 1.920 1.912 1.907
ld(:l ~ roo 1.879 1.870 1.857
r 1.848 1.838 1.825
1.05 ~1 } f1.761
__ 0 1.748
1dL 1.720
1.03 1.708 ~1.696
Ji~ll 1.463
- ;] I 1.432
- '{1.422
00 1.251 0.917 0.892
--\D
'" .... a
'" g
,
~
t"--
!'---~
~
I-' 0-
n
'" 8-g >1 1-'. rt P"
'0 .... o rt g r; n o
<C o
co
'" co o
.....
'" 5 5 . 4 6.§ 1.00""'"" :-"' 52. 21 ~.lQ!.,... 0
46.00Jj 0.92 C>
139.89 136.55 135.37
124.01 122.33
-111. 74
__ 79.64 -77.69
ji;65.98
~61.51
60.59 60.20
-/"55.95
~.//"~~:~i '/"40.39
40.25 40.12 39.98
~~~:~~ 39.56
~37.05 32.02
~28.74
28.24 20.24
'"
'" '" '" o
0.72 ....
1.02 '"
3.13'- b ~ ~ 3.10 !'"
----'" 1.00
0.74 ~
1.01
'" '" --'" .1QLo
2.20 ~
9.31 '"
o
~
~
Z I OJ o (")
\ o
17.024 6.998
~6.972
,6.881
"\
6.857 6.678 6.654
-5.886
-4.567 -4.386
l ~::~=======================================-__ ~3.877 -3.805 ~3.564
""'- 3.498 3.477
---3.239 -2.991
};~:~~~ 2.204
J'l1:~~! ;;"1.926
,k1:~~~
,H~i 1.565 1.534 1.402
I-' tl
'0 .... o rt
g
g -11
f-' p,
()
III
~ -11
~ ...., g IJl
:c \ f::: "
0
f-'
f-'.
P,
;'1.00:= -..]
o 7.061 '0 ..,
~-11-
'00:98""'-;;'
~;:::: 0
en
rr
at"j-K
g
8" 0. 7Or
i::: i:I '"
/r159.33 P,
IJl
6.677
CD
6.666
~ -It
~HUl ()
0
l:~: '§Q.2I""""-'"
~135.53
f-''''''''---<::: •
4.414
~.~O 135.27 lQ
4.284
E-1 t-
134.70 0.66 ~
4.254
¥ri;~:~!
4.239
IJl
4.224
l124.81
4.142
~121.17
4.130
IJl
4.120
~H I
121.04
~111.72
0
4.112
111. 68
4.105
77.25 ~ ...
4.097
77.04
3.894
t 76 . 83 DK'"
3.850
~ -II
r71. 68 o:'i'l""=
3.819
l.35"" I;1K'!'"
3.785 3.780
67.30
~o
3.753
f1Ur 67.20
0.92f..
3.750
~-I~
66.95 1.55
3.745
65.90 0. 85T ~
3.738
~64.01
0.87 IJl
~3.559
~61.88
3.551
~61.39 w
3.544
1: 61.17 0
\3.508
60.74 0.69:::
3.497
60.42
3.486
tv
2.062 2.038 2.034 2.025 2.016
55.79 '" 2.007
~~r-
~-I~
"\\\L55.74 55.65
0.82
~~ 53.26
~o
~~\L42. 09 1.17----
2.003
- ;11
31. 73 1.34,..- f-'
f'" N
31.16
1.622
0
29.59 ~'"
1.604
21. 07 0.65~
1.593
f''' ~:
1.579
19.29
~1.413
16.85
__ 0
1.400
14.20
~1.388
13.92
1.287
'0
1.275
'0 S
~1.263 0.955 0.942 0.930
ld proton
~ ~~~~~~:ri~~~~~~~~~~ N f"lf"lf"lf"lI"'lI""lf"'lMMf"lO'\O\O\O\O'\O\O'\
I I I I I 8.5 8.0 7.5 7.0 6.5 6.0 5.5
1:( 15( ld carbon with proton decoupling
I 190 180 170
.. .-i" O.-iN
", .. N
"''''''' .-i.-i.-i
\1/
Il L
160 150
ON N.-i
"'''' ~~
V
140 I
130
~~ mm .-i.-i .-i.-i
V
120
I
\O\OLfllllr-lLfl o;fIMNr-r-u> r-r-r-IOLOLO
~1P
I 5.0 4.5
I:~:( ... "! ~ .-i
I
110 100 90
'" I
I I 4.0 3.5 3.0
I~I ~~I " .. '" mo", NO'" m.-iO
"' ...... r-r-r- \0\01.0
\V \V
80 70 60
I 2.5
... N
:;:
I
I 50
I 2.0
I 40
1.5 1.0 ppm
30 20 ppm
- 121 -
ID proton
I 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
I~~~( )~~§! I~( I~~~! 1d carbon with proton decoupling
'" roro ,....., '" ..,.., NN ,...,...'" ro,... N '" ri riM riri ,...,...,...
"'''' ltl N
I V I I \V \/ I I
I I I I I I I I I I I I I I I I I I I I I
200 190 1S0 170 160 150 140 l30 120 110 100 90 SO 70 60 50 40 30 20 10 ppm
- 122-
ld proton
I I 8.5 8.0 7.5
lJ1 CD
'" " I
I 7.0
O(Ylo;;flO'lCO(Y1 COI..OI..OLI1o;;11'<;11 M(010000
I I 6.5 6.0
1:11:1 ld carbon with proton decoupling
0 0
'" "! .. 0
~ :':
I I
I l
I 5.5 5.0
OM" "'rlO
<- on ..
'" '" '" rl rl rl
\\/
co 0'\ 0'\ N 1..0 r-- r-- L!l I..OMN LfltnM 00'\ '<tlMM 0'10000 LI1o;;f1
0;;11'<;11 '<:;fI MrTlM MM
\ V \\1 V
I I I 4.5 4.0 3.5
I:~:I ~:( !!'J o:t' N r-I 0 NO 0:) 10 ""
r-- L""- \0 N 1"-t'"- t'"- t'"- t"- \0
"VII
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70
I 3.0
<-M
'" on
I
60 50
I 2.5
40
lJ1 en rl
'" I
30
I 2.0
20
I
MOO["-oLn l'MN..--i NC\lNC'\l
ri..--lr-lrl
"'-,\1/
I 1.5 1.0
10
ppm
ppm
- 123 -
Id proton
I I I I I I I I I I I I I I I I 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
I:I:~ (:1:1 lsi I~( Id carbon with proton decoupling
~ '" .-l,..'"
'" 00," I.fI.;IIMr-Il:"- N NOa)'<ttrl '" ,..
0"'''' '" r--r:--\OCOIXl ~ '" '" ~~~ .-l .-l r--r--r--\OI.O '" I I \\1 \V V I
I I I f I I I 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm
- 124-
1d proton
:ri N
" I
I
Me02C~OH
UOH 356
8.5 8.0 7.5 7.0
[,-r-Io:fr--COr-l r-IOo:fr""lNN NNr-Irlrlrl
\0\0\0 \D \D\D
'\\)//
I 6.5 6.0
(:l~ 1d carbon with proton decoupling
<I' <I' 0 01
'" <I'
'" 01 ri ri
I I
1. I I I I
200 180 160 140
I 5.5 5.0
01 ri tIl 01 '" '" '" 01 ri
'" '" ri ri ri ri
I I I
1. I
120
\OOOOI.OLtl """ MO """ ~ " ""'''<jIcncor-- "'., .,,, '"'0 ;:; "''''''MMf'l "'OO '"''"' """ <:11"'..,<:1' .... MM MM NN N '"' "\\1" II \I V I I
I I I I I 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm
EI~ !~~ 1:1 1:1
['U)<qI(TlOO <Xl NooommN ... r--r--I..OI.I)Ii'lt"'- '" r--r--r--r--r--I..D tIl
~r/ I
I I I I I I
100 80 60 40 20 0 ppm
- 125 -
7 References
5224.
(1) (2) (3)
Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1967,89,2502. Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968,90,4744. Burgess, E. M.; Penton, H. R; Taylor, E. A. J. Am. Chem. Soc. 1970, 92,
(4) (5)
30, 1509
Claremon, D. A.; Phillips, R T. Tetrahedron Lett. 1988,29,2155. Jose, R; Sulatha, M. S.; Pillai, P. M.; Prathapan, S. Syn. Commun. 2000,
(6) M. Creedon, S.; Kevin Crowley, H.; G. McCarthy, D. J. Chem. Society. Perkin Trans. 11998, 1015.
(7) Barvian, M. R; Showalter, H. D. H.; Doherty, A. M. Tetrahedron Lett. 1997,38,6799.
1547. (8) Maugein, N.; Wagner, A.; Mioskowski, C. Tetrahedron Lett. 1997, 38,
(9) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992,33,907. (10) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992,33,6267. (11) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994,35,5397. (12) Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.;
Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, R; Chen, R-C. Org. Lett. 2008,10,2897.
(13) Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X. Chem.- Eur. J. 2004, 10, 5581.
(14) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. R; Bella, M.; Reddy, M. V. Angew. Chem. Int. Ed. 2002, 41, 834.
(15) Nicolaou, K. C.; Longbottom, D. A.; Snyder, S. A.; Nalbanadian, A. Z.; Huang, X. Angew. Chem. Int. Ed. 2002,41,3866.
(16) Nicolaou, K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D. A. J. Am. Chem. Soc. 2004, 126, 6234.
(17) Raghavan, S.; Mustafa, S.; Rathore, K. Tetrahedron Lett. 2008,49,4256. (18) Wodka, D.; Robbins, M.; Lan, P.; Martinez, R L.; Athanasopoulos, J.;
Makara, G. M. Tetrahedron Letters 2006, 47, 1825. (19) Lamberth, C. J. Prakt. Chem. 2000,342. (20) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26. (21) Rinner, D.; Adams, D. R.; dos Santos, M. L.; Abboud, K. A.; Hudlicky, T.
Synlett 2003,2003, 1247. (22) Leisch, H.; Saxon, R; Sullivan, R; Hudlicky, T. Synlett 2006,2006,445. (23) Banfield, S. C.; Omori, A. T.; Leisch, H.; Hudlicky, T. J. Org. Chem.
2007, 72,4989. (24) Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996,37,4659. (25) Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett. 1999,
40,3275. (26) (27)
Li, C.; Dickson, H. D. Tetrahedron Lett. 2009,50, 6435. Toupet, L.; Barragan, V.; Dewynter, G.; Montero, J.-L. Org. Lett. 2001, 3,
2241. (28) Wood, M. R; Kim, J. y.; Books, K. M. Tetrahedron Lett. 2002,43, 3887. (29) Masui, Y.; Watanabe, H.; Masui, T. Tetrahedron Lett. 2004,45, 1853.
- 126-
346. (30) Sullivan, B.; Gilmet, J.; Leisch, H.; Hudlicky, T. J. Nat. Prod. 2008, 71,
(31) Crabbe, P.; Leon, C. J. Org. Chem. 1970,35,2594. (32) Moreau, J. P.; Aberhart, D. 1.; Caspi, E. J. Org. Chem. 1974,39,2018. (33) Stork, G.; Clark, G.; Shiner, C. S. J. Am. Chem. Soc. 1981,103,4948. (34) Stork, G.; Sherman, D. J. Am. Chem. Soc. 1982,104,3758. (35) Stork, G.; Saccomano, N. A Tetrahedron Lett. 1987,28,2087. (36) Rigby, J. H.; Kirova-Snover, M. Tetrahedron Lett. 1997,38,8153. (37) Rigby, 1. H.; Mateo, M. E. J. Am. Chem. Soc. 1997,119, 12655. (38) Kita, Y.; Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagaki, S.; Ueda, K.; Akai,
S.; Fujioka, H. J. Am. Chem. Soc. 2001, 123, 3214. (39) Schule, A; Liang, H.; Vors, 1.-P.; Ciufolini, M. A J. Org. Chem. 2009,
74, 1587. (40) Wipf, P.; Miller, C. P.; Venkatraman, S.; Fritch, P. C. Tetrahedron Lett.
1995, 36, 6395. (41) Wipf, P.; Xu, W. J. Org. Chem. 1996,61,6556. (42) Wipf, P.; Venkatraman, S. J. Org. Chem. 1995,60, 7224. (43) Wipf, P.; Fritch, P. C. J. Am. Chem. Soc. 1996,118, 12358. (44) Ino, A; Murabayashi, A Tetrahedron 2001, 57, 1897. (45) Wipf, P.; Miller, C. P. J. Am. Chem. Soc. 1992,114, 10975. (46) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995,117,558. (47) Okonya, 1. F.; Kolasa, T.; Miller, M. 1. J. Org. Chem. 1995,60, 1932. (48) Raghavan, S.; Mustafa, S. Tetrahedron 2008,64, 10055. (49) Raghavan, S.; Mustafa, S. Tetrahedron Lett. 2008,49,5169. (50) Leisch, H.; Sullivan, B.; Fonovic, B.; Dudding, T.; Hudlicky, T. Eur. J.
Org. Chem. 2009, 2009, 2806. (51) Goodman, L. S.; Gilman, A The Pharmacological Basis o/Therapeutics:
A Textbook on Pharmacology; 3 ed.; MacMillan: New York, 1965. (52) Booth, M. Opium: A History; St. Martin's Press: New York, 1998. (53) Owen, D. E. British Opium Policy in China and India; Yale University
Press: New Haven, 1934. (54) Kalant, H. Addiction 1997, 92, 267. (55) Serturner, F. W. Trommsdorff J. Pharm. 1805,13,234. (56) Serturner, F. W. Trommsdorff J. Pharm. 1806,14,47. (57) Butora, G.; Hudlicky, T. In Organic Synthesis: Theory and Applications;
Hudlicky, T., Ed.; JAI Press: Stamford, CT, 1998; Vol. 4. (58) Robinson, R; Gulland, J. M. Mem. Lit. Phil. Soc. Manchester 1925, 69,
79. (59) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109. (60) Kapoor, L. D. Opium Poppy: Botany, Chemistry, and Pharmacology;
Food Products Press: Binghamton, NY, 1995. (61) Zenk, M. H.; Gerardy, R; Stadler, R. J. Chem. Soc. Chem. Commun.
1989, 1725. (62) (63) (64)
Hagel, J. M.; Facchini, P. 1. Nat. Chem. BioI. 2010, 6,273. Lenz, R; Zenk, M. H. Tetrahedron Lett. 1995,36,2449. Unterlinner, B.; Lenz, R.; Kutchan, T. Plant J. 1999, 18, 465:
- 127-
(65) Rapoport, H.; Lovell, C. H.; Tolbert, B. M. J. Am. Chem. Soc. 1951, 73, 5900.
(66) Rice, K. C. J. Org. Chem. 1980,45, 3135. (67) Leisch, H.; Omori, A T.; Finn, K. J.; Gilmet, J.; Bissett, T.; Ilceski, D.;
Hudlick)!, T. Tetrahedron 2009, 65, 9862. (68) Parker, K. A; Fokas, D. J. Am. Chem. Soc. 1992,114,9688. (69) Parker, K. A; Fokas, D. J. Org. Chem. 2005, 71,449. (70) Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002,124, 14542. (71) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,14785. (72) Butora, G.; Hudlicky, T.; Fearnley, S. P.; Stabile, M. R.; Gum, A. G.;
Gonzalez, D. Synthesis 1998, 1998, 665. (73) Banwell, M. G.; Edwards, A 1.; Loong, D. T. J. Arkivoc 2004, x, 53. (74) Tanimoto, H.; Saito, R; Chida, N. Tetrahedron Lett. 2008, 49, 358. (75) Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett. 2007,48,6267. (76) Gibson, D. T.; Koch, 1. R; Kallio, R E. Biochemistry 1968,7,2653. (77) Gibson, D. T.; Koch, J. R; Schuld, C. L.; Kallio, R E. Biochemistry 1968,
7,3795. (78) Gibson, D. T.; Cardini, G. E.; Maseles, F. C.; Kallio, R. E. Biochemistry
1970,9, 1631. (79) Gibson, D. T.; Hensley, M.; Yoshioka, H.; Mabry, T. J. Biochemistry
1970,9, 1626. (80) Kobal, V. M.; Gibson, D. T.; Davis, R E.; Garza, A J. Am. Chem. Soc.
1973, 95, 4420. (81) Ziffer, H.; Jerina, D. M.; Gibson, D. T.; Kobal, V. M. J. Am. Chem. Soc.
1973, 95, 4048. (82) Yeh, W. K.; Gibson, D. T.; Liu, T.-N. Biochem. Biophys. Res. Commun.
1977, 78,401. (83) Subramanian, V.; Liu, T.-N.; Yeh, W. K.; Gibson, D. T. Biochem.
Biophys. Res. Commun. 1979,91, 1131. (84) Zylstra, G. 1.; Gibson, D. T. J. BioI. Chem. 1989,264, 14940. (85) Boyd, D. R.; Sharma, N. D.; Hand, M. V.; Groocock, M. R; Kerley, N.
A; Dalton, H.; Chima, J.; Sheldrake, G. N. J. Chem. Soc. Chem. Commun. 1993,974. (86) Boyd, D. R; Sharma, N. D.; Byrne, B. E.; Haughey, S. A; Kennedy, M.
A.; Allen, C. C. R. Org. Biomol. Chem. 2004,2,2530. (87) Boyd, D. R; Sharma, N. D.; Bowers, N. I.; Dalton, H.; Garrett, M. D.;
Harrison, J. S.; Sheldrake, G. N. Org. Biomol. Chem. 2006,4, 3343. (88) Boyd, D.; Sharma, N.; Coen, G.; Gray, P.; Malone, J.; Gawronski, J.
Chem.- Eur. J. 2007, 13, 5804. (89) R. Boyd, D.; N. Sheldrake, G. Nat. Prod Rep. 1998,15,309. (90) Jung, K. H.; Lee, 1. Y.; Kim, H. S. Biotechnol. Bioeng. 1995, 48, 625. (91) Haigler, B. E.; Spain, 1. C. Appl. Environ. Microbiol. 1991,57,3156. (92) Hudlicky, T.; Boros, E. E.; Boros, C. H. Synlett 1992,1992,391. (93) Konigsberger, K.; Hudlicky, T. Tetrahedron: Asymmetry 1993, 4, 2469. (94) Fabris, F.; Collins, J.; Sullivan, B.; Leisch, H.; Hudlicky, T. Org. Biomol.
Chem. 2009, 7,2619. (95) Hudlicky, T.; Reed, J. W. Synlett 2009,2009,685.
- 128 -
(96) Ballard, D. G. H.; Courtis, A.; Shirley, 1. M.; Taylor, S. C. J. Chem. Soc. Chem. Commun. 1983, 954.
(97) Ley, S. V.; Sternfeld, F.; Taylor, S. Tetrahedron Lett. 1987,28,225. (98) Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc.
1988,110,4735.
4053.
(99) Johnson, C. R; Penning, T. D. J. Am. Chem. Soc. 1986, 108, 5655. (100) Hudlicky, T.; Seoane, G.; Pettus, T. J. Org. Chem. 1989,54,4239. (101) Hudlicky, T.; Natchus, M. J. Org. Chem. 1992,57,4740. (102) Hudlicky, T.; Luna, H.; Price, 1. D.; Rulin, F. Tetrahedron Lett. 1989,30,
(103) Hudlicky, T.; Price, J. D. Synlett 1990,1990, 159. (104) Entwistle, D. A.; Hudlicky, T. Tetrahedron Lett. 1995,36,2591. (105) Hudlicky, T.; Price, J. D.; Luna, H.; Andersen, C. M. Synlett 1990, 309. (106) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994,
116,5099.
4683.
3643.
(107) Hudlicky, T.; Nugent, T.; Griffith, W. J. Org. Chem. 1994,59, 7944. (108) Nugent, T. C.; Hudlicky, T. J. Org. Chem. 1998,63,510. (109) Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. J. Org. Chem. 1990, 55,
(110) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992, 114, 9694. (111) Tian, X.; Hudlicky, T.; Koenigsberger, K. J. Am. Chem. Soc. 1995, 117,
(112) Hudlicky, T.; Tian, X.; Konigsberger, K.; Maurya, R; Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996,118, 10752.
(113) Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999, 40, 3077.
(114) Rinner, U.; Siengalewicz, P.; Hudlicky, T. Org. Lett. 2001,4, 115. (115) Tian, X.; Maurya, R.; Konigsberger, K.; Hudlicky, T. Synlett 1995, 1995,
1125. (116) Akgiin, H.; Hudlicky, T. Tetrahedron Lett. 1999,40,3081. (117) Hudlicky, T.; Rinner, u.; Gonzalez, D.; Akgun, H.; Schilling, S.;
Siengalewicz, P.; Martinot, T. A.; Pettit, G. R J. Org. Chem. 2002, 67, 8726. (118) Collins, J.; Rinner, u.; Moser, M.; Hudlicky, T.; Ghiviriga, 1.; Romero, A.
E.; Kornienko, A.; Ma, D.; Griffin, c.; Pandey, S. J. Org. Chem. 2010, 75, 3069. (119) Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R;
Abboud, K. Tetrahedron Lett. 1996, 37, 8155. (120) Omori, A. T.; Finn, K. J.; Leisch, H.; Carroll, R J.; Hudlicky, T. Synlett
2007,2007,2859. (121) Ley, S. V.; Redgrave, A. J. Synlett 1990,1990,393. (122) Banwell, M. G.; Edwards, A. J.; Harfoot, G. 1.; Jolliffe, K. A. Tetrahedron
2004, 60, 535. (123) Johnson, R. A. In Organic Reactions; John Wiley and Sons, Inc.: New
York, 2004; Vol. 63, p 117. (124) Hudlicky, T.; Gonzales, D.; Gibson, D. T. Aldrichim. Acta 1999, 32, 35. (125) Carless, H. A. 1. Tetrahedron: Asymmetry 1992, 3, 795.
- 129-
3157. (126) Claisen, L. Berichte der deutschen chemischen Gesellschaft 1912, 45,
(127) E. Doering, W. v.; Roth, W. R Tetrahedron 1962, 18, 67. (128) Schuler, F. W.; Murphy, G. W. J. Am. Chem. Soc. 1950, 72,3155. (129) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334. (130) Leffler, J. E. Science 1953, 117, 340. (131) Gajewski, J. J.; Conrad, N. D. J. Am. Chem. Soc. 1979,101,2747. (132) McMichael, K D.; Korver, G. L. J. Am. Chem. Soc. 1979,101,2746. (133) Meyer, M. P.; DelMonte, A J.; Singleton, D. A J. Am. Chem. Soc. 1999,
121,10865.
3291.
4359.
2868.
(134) Martin Castro, AM. Chem. Rev. 2004,104,2939. (135) Baldwin,1. E.; Walker, 1. A J. Chem. Soc. Chem. Commun. 1973, 117. (136) Greuter, H.; Lang, R W.; Romann, A 1. Tetrahedron Lett. 1988, 29,
(137) Boeckman, R K; Flann, C. J.; Poss, K M. J. Am. Chem. Soc. 1985, 107,
(138) Rhoads, S. J.; Cockroft, R D. J. Am. Chem. Soc. 1969,91,2815. (139) Ireland, R E.; Mueller, R H. J. Am. Chem. Soc. 1972,94, 5897. (140) Ireland, R E.; Mueller, R. H.; Willard, A K J. Am. Chem. Soc. 1976,98,
(141) Kazmaier, U. Angew. Chem. Int. Ed. 1994,33,998. (142) Kazmaier, U. Tetrahedron 1994, 50, 12895. (143) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.
T.; Faulkner, D. J.; Petersen, M. R J. Am. Chem. Soc. 1970,92, 741. (144) Daub, G. W.; Teramura, D. H.; Bryant, K E.; Burch, M. T. J. Org. Chem.
1981,46, 1485. (145) Cosgrove, K L.; McGeary, R P. Synlett 2009,2009, 1749. (146) Cosgrove, K L.; McGeary, R P. Tetrahedron 2010,66,3050. (147) Ireland, R. E.; Anderson, R C.; Badoud, R; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,105, 1988. (148) Kang, H. J.; Paquette, L. A J. Am. Chem. Soc. 1990,112,3252. (149) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002,4, 1343. (150) Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A; Falck, J. R;
Mioskowski, C. Angew. Chem. Int. Ed 1998,37,2085. (151) Hudlicky, T.; Kwart, L. D.; Tiedje, M. H.; Ranu, B. C.; Short, R. P.;
Frazier,1. 0.; Rigby, H. L. Synthesis 1986, 1986, 716. (152) Gonzalez, D.; Schapiro, V.; Seoane, G.; Hudlicky, T.; Abboud, K J. Org.
Chem. 1997, 62, 1194. (153) Burgess, E. M.; Penton, H. R. J.; Taylor, E. A; Williams, W. M. Org. Syn.
1977,56,40. (154) Metcalf, T. A; Simionescu, R; Hudlicky, T. J. Org. Chem. 2010, 75,
3447. (155) Nerdinger, S.; Kendall, C.; Cai, X.; Marchart, R.; Riebel, P.; Johnson, M.
R; Yin, C. F.; Eltis, L. D.; Snieckus, V. J. Org. Chem. 2007, 72, 5960. (156) Endoma, M. A; Bui, V. P.; Hansen, J.; Hudlicky, T. Org. Process Res.
Dev. 2002,6,525. .
- 130-
- 131 -
8 Vita Thomas A. Metcalf was born in Albion, NY on December 18, 1984. He and his
three siblings Lynn, Benjamin, and Anna were raised by their parents, Michael and Kay
Metcalf on their family farm. He attended Albion High School and graduated with the
second highest GPA in the class of 2003. During his high school years, Thomas was a
member of the Albion Cross Country and Albion Track and Field teams. The highlight of
his running career was a second place finish in the Western New York steeple chase
finals in 2002. Throughout school, he was active in the Boy Scouts of America and
attained the rank of Eagle Scout in 2002. After graduation from high school, he attended
the University of Guelph in Guelph, Ontario, Canada. He completed a BSc. in Biological
Chemistry in 2007. In 2007, he completed an undergraduate thesis under the direction of
Dr. Adrian Schwan. Upon completion of his BSc., Thomas moved to Brock University in
St. Catharines, Ontario, Canada to pursue graduate studies under the direction of Dr.
Tomas Hudlicky. He is presently working towards a Master's degree in Organic
Chemistry. His research interests include developing more stable versions of the Burgess
reagent and the application ofbiotransformations in the synthesis of natural products.
- 132-