synthesis of several bisabolane sesquiterpenoids...
TRANSCRIPT
SYNTHESIS OF SEVERAL BISABOLANE SESQUITERPENOIDS FROM XANTHORRHIZOL ISOLATED FROM C. XANTHORRHIZA
NGAI MUN HONG
UNIVERSITI TEKNOLOGI MALAYSIA
SYNTHESIS OF SEVERAL BISABOLANE SESQUITERPENOIDS FROM XANTHORRHIZOL ISOLATED FROM C. XANTHORRHIZA
NGAI MUN HONG
A thesis submitted in fulfilment of the
requirements for the award of the degree of
Master of Science (Chemistry)
Faculty of Science
Universiti Teknologi Malaysia
MARCH 2005
iii
For the Lord Almighty
and my beloved family
iv
ACKNOWLEDGEMENTS
I thank God for His love and care which have kept me going forward and for
His grace that led me throughout the whole process of completing this research. I
praise His faithfulness.
I would like to express my sincere gratitude and appreciation to my research
advisor, Professor Dr. Hasnah M. Sirat, for her guidance, support, encouragement
and patient throughout the completion of this work.
Grateful acknowledgements are to Assoc. Prof. Dr. Farediah Ahmad for her
advice and support.
I am also indebted to Ibnu Sina Institute for Fundamental Science Studies for
allowing me get access to the NMR facility.
I would like to thank Prof. Dr. Nordin Lajis of the Bioscience Institute, UPM
for assistance with the optical rotation measurements.
I would also like to thank Dr. Mariko Kitajima of the Graduate School of
Pharmaceutical Sciences, Chiba University for recording the NMR spectra.
To my labmates, Pn. Shaja, Pn. Yanti, Syahrizal, Wong and Gan, thank you
for their valuable discussion and friendship.
My sincere appreciation also extends to lab assistants and others who have
provided assistance at various occasions.
I wish to thank the Ministry of Science, Technology and Innovation (MOSTI)
for awarding the National Science Fellowship.
v
PREFACE
This thesis is the result of my work carried out in the Department of Chemistry,
Universiti Teknologi Malaysia between June 2002 and September 2004 under
supervision of Prof. Dr. Hasnah M. Sirat. Part of my work described in this thesis has
been reported in the following publications:
1. M. H. Ngai and Hasnah M. Sirat. (2005). Synthesis of Several Bisabolane Type
Sesquiterpenoids from Xanthorrizol. Mal. J. Sci. 24. 177-182.
2. M. H. Ngai and Hasnah M. Sirat (2003). Chemistry of Xanthorrhizol from
Curcuma xanthorrhiza. Poster presented at the Annual Fundamental Science
Seminar 2003, Puteri Pan Pacific Hotel, Johor Bahru. 20-21 May 2003.
3. M. H. Ngai and Hasnah M. Sirat (2003). Synthesis of Several Bisabolane Type
Sesquiterpenoids from Xanthorrhizol. Poster presented at the International
Seminar & Workshop on Natural Products, University of Malaya, Kuala Lumpur.
13-16 October 2003.
4. M. H. Ngai and Hasnah M. Sirat (2004). Synthesis of Bisabolane
Sesquiterpenoids from Xanthorrhizol Isolated from C. xanthorrhiza. Oral
presentation at the 20th Annual Seminar of the Malaysian Natural Products
Society, Hilton Kuching, Kuching, Sarawak. 29-30 November 2004.
5. M. H. Ngai and Hasnah M. Sirat (2004). Synthesis of Bisabolane
Sesquiterpenoids from Xanthorrhizol Isolated from C. xanthorrhiza and Their
Bioactivities. Proceeding of the 4th Annual National Science Fellowship Seminar.
Vistana Hotel, Penang. 20-21 December 2004. 181-186.
vi
ABSTRACT
Xanthorrhizol was isolated from the essential oil of fresh rhizomes of C.
xanthorrhiza in 20.2% yield by fractionation using vacuum liquid chromatography.
Several bisabolane-type sesquiterpenoids have been synthesised from this
xanthorrhizol. Both diastereomers of 10,11-dihydro-10,11-dihydroxyxanthorrhizols,
sesquiterpenoids isolated from the Mexican medicinal plant, Iostephane
heterophylla, have been prepared in three steps from xanthorrhizol via Sharpless
asymmetric dihydroxylation as the key steps. Fremy’s salt oxidation of xanthorrhizol
gave curcuhydroquinone in 60% yield, which was successfully reduced with sodium
dithionite to curcuhydroquinone in 100% yield. Sequential acetylation and Sharpless
asymmetric dihydroxylation on curcuhydroquinone led to the diacetate derivative of
helibisabonol A. Cleavage of the diacetate esters by reduction with lithium
borohydride furnished helibisabonol A, an allelopathic agent isolated from
Helianthus annuus (sunflowers). The unexpected difficulty in deprotection of
helibisabonol A diacetate was due to acidic, basic and air-sensitive natures of
helibisabonol A. An allylic alcohol derivative of O-methylxanthorrhizol, (3S,6R)-(3-
methoxy-4-methylphenyl)-2-methylhept-1-en-3-ol, has been synthesised from
xanthorrhizol in five steps via Sharpless asymmetric dihydroxylation as the key
steps. Sharpless asymmetric dihydroxylation in all syntheses gave excellent
enantioselectivity (ee > 98%). The enantiomeric excess and the absolute
configuration of the diol was determined by the modified Mosher’s method.
vii
ABSTRAK
Xantorizol telah diasingkan daripada minyak pati rizom segar C.
xanthorrhiza sebanyak 20.2% secara pemeringkatan dengan menggunakan turus
vakum. Beberapa sebatian seskuiterpena jenis bisabolana telah disintesis daripada
xantorizol ini. Kedua-dua diastereomer 10,11-dihidro-10,11-dihidroksixantorizol
yang merupakan seskuiterpenoid yang dipisahkan daripada sejenis tumbuhan ubatan
Mexico, Iostephane heterophylla telah disediakan dalam tiga langkah daripada
xantorizol dengan menggunakan pendihidroksilan asimetri Sharpless sebagai langkah
utama. Pengoksidaan xantorizol dengan garam Fremy menghasilkan kurkukuinon
sebanyak 60%. Kurkukuinon diturunkan dengan jayanya menggunakan natrium
ditionit kepada kurkuhidrokuinon sebanyak 100%. Pengasetilan dan pendihidroksilan
asimetri Sharpless ke atas kurkuhidrokuinon menghasilkan terbitan diasetat
helibisabonol A. Penyingkiran kumpulan diasetat secara penurunan dengan litium
borohidrida menghasilkan helibisabonol A, iaitu agen alelopatik yang diasingkan
daripada Helianthus annuus (bunga matahari). Kesukaran di luar jangkaan dalam
penyahlindungan helibisabonol A diasetat adalah disebabkan oleh sifat helibisabonol
A yang terlalu peka terhadap asid, bes dan udara. Terbitan alkohol alilik O-
metilxantorizol, (3S,6R)-(3-metoksi-4-metilfenil)-2-metilhept-1-en-3-ol telah
disintesis daripada xantorizol dalam lima langkah melalui pendihidroksilan asimetri
Sharpless sebagai langkah utama. Pendihidroksilan asimetri Sharpless memberi
keenantiopilihan yang baik (ee > 98%) bagi semua sintesis. Kelebihan enantiomer
dan konfigurasi mutlak diol telah ditentukan dengan kaedah Mosher terubahsuai.
viii
TABLE OF CONTENTS
CHAPTER TITLE PAGE
DECLARATION OF THE STATUS OF THESIS
SUPERVISOR’S DECLARATION
CERTIFICATION OF EXAMINATION
TITLE PAGE i
DECLARATION OF ORIGINALITY AND EXCLUSIVENESS
ii
DEDICATION iii
ACKNOWLEDGEMENTS iv
PREFACE v
ABSTRACT vi
ABSTRAK vii
TABLE OF CONTENTS viii
LIST OF TABLES xi
LIST OF SCHEMES xii
LIST OF FIGURES xiv
LIST OF ABBREVIATIONS xvi
LIST OF APPENDICES xix
1 INTRODUCTION
1.1 General Introduction 1
1.2 Curcuma xanthorrhiza 1
1.3 Chemical Constituents of Curcuma xanthorrhiza
2
1.4 Synthesis of Xanthorrhizol (1) 7
ix
1.4.1 Rane’s Short Synthesis of Xanthorrhizol (1) [35]
8
1.4.2 Meyers’ Asymmetric Synthesis of (+)-Xanthorrhizol (35) [38]
8
1.4.3 Fuganti’s Baker’s Yeast-mediated Enantioselective Synthesis of S-(+)-Xanthorrhizol (35) [39]
10
1.4.4 Conversion of Parvifoline (36) to R-(–)-Xanthorrhizol (1) [40]
11
1.4.5 Shishido’s Enantiocontrolled Total Synthesis of R-(–)-Xanthorrhizol (1)
12
1.5 The Sharpless Asymmetric Dihydroxylation 15
1.5.1 Recent Developments in Asymmetric Dihydroxylation
22
1.5.2 Synthetic Application for 1,2-diols 23
1.5.2.1 Conversion of Diols into Halohydrin Esters and Epoxides
23
1.5.2.2 Regioselective Sulphonylation
24
1.6 Application of Sharpless AD on the Synthesis of Natural Products
25
1.6.1 Sharpless’s Asymmetric Synthesis of the C-13 Side Chain (115) of Taxol
25
1.6.2 Corey’s Total Synthesis of (–)-Ovalicin (117)
26
1.6.3 Nicolaou’s Total Synthesis of Apoptolidin (123)
27
1.6.4 Solid-Phase Synthesis of (3’R,4’R)-Di-O-cis-acyl 3-Carbonyl Khellactones
29
1.7 Xanthorrhizol as Chiral Starting Material for the Synthesis of Natural Products
30
1.8 Objectives 34
2 RESULTS AND DISCUSSION
2.1 Extraction and Isolation of Xanthorrhizol 35
2.2 Synthesis of (10R/10S)-10,11-dihydro-10,11-dihyroxyxanthorrhizols (137 and 138) from Xanthorrhizol (1)
38
x
2.3 Synthesis of Curcuquinone, Curcuhydroquinone and Helibisabonol A Diacetate from Xanthorrhizol
54
2.4 Synthesis of Allylic Alcohol Derivative of O-methylxanthorrhizol
63
2.4.1 Determination of the Absolute Configuration of Methoxydiol (168) by Mosher’s Method
66
2.5 Attempted Synthesis of 2-methyl-5-(4(S)- hydroxy-1(R),5-dimethylhex-5-enyl)phenol (134) from Acetoxydiol (149)
74
2.6 Summary of Results 77
3 EXPERIMENTAL
3.1 General Procedures 78
3.2 Extraction and Isolation 79
3.3 Synthesis of Triols (137) and (138) 80
3.4 Attempted Synthesis of Helibisabonol A (142)
83
3.5 Synthesis of Allylic Alcohol (147) 88
3.6 Attempted Synthesis of Allylic Alcohol Derivative of Xanthorrhizol
92
4 CONCLUSION 96
REFERENCES 97
APPENDICES 108
xi
LIST OF TABLES
TABLE NO. TITLE PAGE
2.1 1H and 13C NMR data of xanthorrhizol (1) 37
2.2 1H NMR and 13C NMR data of xanthorrhizyl acetate (148)
39
2.3 1H NMR and COSY data of acetoxydiols (149) and (150)
40
2.4 13C NMR data of acetoxydiols (149-150) and triols (137-138)
41
2.5 1H NMR, COSY and HMBC data of triols (137) and (138)
42
2.6 1H and 13C NMR data of curcuquinone (139) and curcuhydroquinone (140)
57
2.7 1H and 13C NMR data of curcuhydroquinone diacetate (163) and diol (164)
58
2.8 1H NMR data of helibisabonol A (142) and quinone (166)
61
2.9 1H NMR data of methoxyxanthorrhizol (167) and methoxydiol (168)
66
2.10 1H NMR data of MTPA esters (171S) and (171R)
67
2.11 1H NMR data of monoacetate (169), allylic acetate (170) and diacetate (175)
72
2.12 1H NMR data of allylic alcohol (147) 74
2.13 1H and 13C NMR data of diacetate (176) and monoacetate phenol (177)
76
2.14 Summary of results 77
xii
LIST OF SCHEMES
SCHEME NO.
TITLE PAGE
1.1 Rane’s synthesis of xanthorrhizol (1) 8
1.2 Meyers’ asymmetric synthesis of S-(+)-xanthorrhizol (35)
9
1.3 Fuganti’s Baker’s yeast-mediated enantiosynthesis of S-(+)-xanthorrhizol (35)
11
1.4 Conversion of parvifoline (36) to R-(–)-xanthorrhizol (1)
12
1.5 Shishido’s enantiocontrolled total synthesis of (–)-xanthorrhizol (1)
14
1.6 The first enentioselective dihydroxylation reactions developed by Sharpless
16
1.7 The two catalytic cycles for the Sharpless AD with NMO as a co-oxidant
17
1.8 Catalytic cycle for asymmetric dihydroxylation using potassium ferricyanide as co-oxidant.
20
1.9 The osmylation of olefins 21
1.10 Mnemonic device for the AD of olefins 21
1.11 Formation of acetoxy halides and epoxides via cyclic acetoxonium ions (104)
23
1.12 Synthesis of glyceraldehyde building block (110)
25
1.13 Sharpless’s asymmetric synthesis of the C-13 side chain (115) of taxol (116)
26
1.14 Corey’s total synthesis of (–)-ovalicin (117) 27
1.15 Nicolaou’s synthesis of apoptolidin (123) 29
1.16 Asymmetric solid-phase synthesis of (3’R,4’R)- di-O-cis-acyl 3-carbonyl khellactones (131)
30
xiii
1.17 Xanthorrhizol derivatives 32
1.18 Shishido’s synthesis of (+)-heliannuol D (141) from synthetic (–)-xanthorrhizol (1).
33
2.1 Stereoselective synthesis of (10R/10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizols (137 and 138)
38
2.2 Retrosynthetic analysis of helibisabonol A (142)
55
2.3 Nitration of xanthorrhizol (1) 55
2.4 Nitration of curcuphenol (159) 55
2.5 Elbs persulphate oxidation of xanthorrhizol (1) 56
2.6 Synthesis of helibisabonol A (142) from Xanthorrhizol (1)
56
2.7 Attempted deprotection of diol (164) 60
2.8 Deprotection of diol (164) with LiBH4 60
2.9 Attempted deacetylation of diol (164) with KCN
63
2.10 Synthesis of allylic alcohol of O-methylxanthorrhizol
64
2.11 Presumed preferred conformation of the ester linkage following derivatisation methoxydiol (168) with (S)-(+) and (R)-(–) MTPCl (172S and 172R) to form 171R (R-MTPA ester) and 171S (S-MTPA ester) respectively.
70
2.12 Reaction sequences led to the allylic acetate (170)
71
2.13 Hydrolysis of diacetate (175) 73
2.14 Route to synthesis of the allylic alcohol (134) from diacetate (176)
75
xiv
LIST OF FIGURES
FIGURES NO.
TITLE PAGE
1.1 Structure of phthalazine (90,91), pyrimidine (92,93),diphenylpyrazinopyridazine (DPP) (94,95), diphenylphthalazine (DP-PHAL) (96,97) and anthraquinone (AQN) (98,99) ligands used in the Sharpless AD and composition of AD-mix-α and AD-mix-β.
19
1.2 Isolation of xanthorrhizol (1) and transformation of xanthorrhizol (1) to several bisabolane type sesquiterpenoids.
34
2.1 Extraction and fractionation of xanthorrhizol from C. xanthorrhiza
36
2.2 HMBC correlations of (7R,10R)-triol (138) 44
2.3 1H NMR spectra of (7R,10S)-triol (137) and (7R,10R)-(138)
46
2.4 1H-1H COSY spectrum of (7R,10S)-triol (137) 47
2.5 1H-1H COSY spectrum of (7R,10R)-triol (138) 48
2.6 HMBC spectrum of (7R,10R)-triol (138) 49
2.7(a) HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 10-90 ppm, δH 0-2.8 ppm)
50
2.7(b) HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 100-160 ppm, δH 1.0-2.8 ppm)
51
2.7(c) HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 5-90 ppm, δH 6.3-7.2 ppm
52
2.7(d) HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 100-160 ppm, δH 6.0-7.5 ppm)
53
2.8 1H NMR spectra of the (S)-and (R)-MTPA esters of compound (168)
68
xv
2.9 Difference in 1H chemical shift (∆δ 1H 171S-174R) between the two Mosher esters (171S) and (171R).
69
2.10 Models of R- and S-MTPA esters (171R and 171S) of methoxydiol (168)
70
xvi
LIST OF ABBREVIATIONS
AD asymmetric dihydroxylation
amu atomic mass unit
AQN anthraquinone
ATP adenosine 5’-triphosphate
br broad
c concentration
CAL Candida antarctica lipase
CD circular dichroism
CI chemical ionisation
COSY correlated spectroscopy
d doublet
dd doublet of doublets
DEPT distortionless enhancement of polarisation transfer
DHQ dihydroquinine
DHQD dihydroquinidine
DIC 2-diisopropylaminoethyl chloride hydrochloride
DIEA diisopropylethylamine
DIPHOSBr 1,2-bis(diphenylphosphino)ethane tetrabromide
DMAP 4-(N,N-dimethylamino)pyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DPP diphenylpyrazinopyridazine
DP-PHAL diphenyl phthalazine
dr diastereomeric ratio
ee enantiomeric excess
EI electron ionisation
HMBC heteronuclear multiple bond correlation
xvii
HMPA hexamethylphosphoramide
i-Pr isopropyl
IR infrared
J coupling constant
LAE ligand acceleration effect
m multiplet
m/z mass-to-charge ratio
MCPBA m-chloroperbenzoic acid
MOM methoxyoxymethyl
MS mass spectrometry
Ms methanesulphonyl
MTPA α-methoxy-α-(trifluoromethyl)phenylacetic acid
NMM N-methylmorpholine
NMO N-methylmorpholine-N-oxide
NMR nuclear magnetic resonance
PHAL phthalazine
PMB 4-methoxybenzyl
PPL porcine pancreas lipase
PPTS pyridinium 4-toluenesulphonate
py pyridine
PYR pyrimidine
q quartet
Rf retardation factor
rt room temperature
s singlet
sext sextet
t triplet
tt triplet of triplets
TBS tert-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin-layer chromatography
Ts 4-toluenesulphonyl
VLC vacuum liquid chromatography
xviii
δ chemical shift
xix
LIST OF APPENDICES
APPENDIX TITLE PAGE
A Reprint 108
1 MS of xanthorrhizol (1) 114
2 IR spectrum of xanthorrhizol (1) 115
3 1H NMR spectrum of xanthorrhizol (1) 116
4 13C NMR spectrum of xanthorrhizol (1) 117
5 1H NMR spectrum of xanthorrhizyl acetate (148) 118
6 13C NMR spectrum of xanthorrhizyl acetate (148) 119
7 IR spectrum of xanthorrhizyl acetate (148) 120
8 MS of xanthorrhizyl acetate (148) 121
9 1H NMR spectrum of (7R,10S)-acetoxydiol (149) 122
10 13C NMR spectrum of (7R,10S)-acetoxydiol (149) 123
11 DEPT spectrum of (7R,10S)-acetoxydiol (149) 124
12 IR spectrum of (7R,10S)-acetoxydiol (149) 125
13 COSY spectrum of (7R,10S)-acetoxydiol (149) 126
13(a) COSY spectrum of (7R,10S)-acetoxydiol (149) 127
14 MS of (7R,10S)-acetoxydiol (149) 128
15 1H NMR spectrum of (S)-MTPA ester (151) 129
16 COSY spectrum of (S)-Mosher ester (151) 130
17 CIMS of (S)-Mosher ester (151) 131
18 1H NMR spectrum of (7R,10R)-acetoxydiol (150) 132
19 13C NMR spectrum of (7R,10R)-acetoxydiol (150) 133
20 DEPT spectrum of (7R,10R)-acetoxydiol (150) 134
21 IR spectrum of (7R,10R)-acetoxydiol (150) 135
22 MS of (7R,10R)-acetoxydiol (150) 136
23 1H NMR spectrum of (S)-MTPA ester (152) 137
xx
24 COSY spectrum of (S)-Mosher ester (152) 138
25 IR spectrum of (10S)-10,11-dihydro-10,11- dihydroxyxanthorrhizol (137)
139
26 13C NMR spectrum of (10S)-10,11-dihydro- 10,11-dihydroxyxanthorrhizol (137)
140
27 DEPT spectrum of (10S)-10,11-dihydro-10,11- dihydroxyxanthorrhizol (137)
141
28 MS of (10S)-10,11-dihydro-10,11- dihydroxyxanthorrhizol (137)
142
29 IR spectrum of (10R)-10,11-dihydro-10,11- dihydroxyxanthorrhizol (138)
143
30 13C NMR spectrum of (10R)-10,11-dihydro- 10,11-dihydroxyxanthorrhizol (138)
144
31 DEPT spectrum of (10R)-10,11-dihydro- 10,11dihydroxyxanthorrhizol (138)
145
32 MS of (10R)-10,11-dihydro-10,11- dihydroxyxanthorrhizol (138)
146
33 IR spectrum of 4-nitroxanthorrhizol (157) 147
34 1H NMR spectrum of 4-nitroxanthorrhizol (157) 148
35 IR spectrum of 2,4-dinitroxanthorrhizol (158) 149
36 1H NMR spectrum of 2,4-dinitroxanthorrhizol (158)
150
37 IR spectrum of curcuhydroquinone (140) prepared by Elbs persulphate hydroxylation
151
38 1H NMR spectrum of curcuhydroquinone (140) prepared by Elbs persulphate hydroxylation
152
39 IR spectrum of curcuquinone (139) 153
40 1H NMR spectrum of curcuquinone (139) 154
41 MS of curcuquinone (139) 155
42 IR spectrum of curcuhydroquinone (140) 156
43 1H NMR spectrum of curcuhydroquinone (140) 157
44 13C NMR spectrum of curcuhydroquinone (140) 158
45 DEPT spectrum of curcuhydroquinone (140) 159
46 MS of curcuhydroquinone (140) 160
47 MS of curcuhydroquinone diacetate (163) 161
48 IR spectrum of curcuhydroquinone diacetate (163)
162
xxi
49 13C NMR spectrum of curcuhydroquinone diacetate (163)
163
50 DEPT spectrum of curcuhydroquinone diacetate (163)
164
51 1H NMR spectrum of curcuhydroquinone diacetate (163)
165
52 IR spectrum of diacetoxydiol (164) 166
53 1H NMR spectrum of diacetoxydiol (164) 167
54 13C NMR spectrum of diacetoxydiol (164) 168
55 DEPT spectrum of diacetoxydiol (164) 169
56 DEPT spectrum of diacetoxydiol (164) 170
57 1H NMR spectrum of (S)-Mosher ester (165) 171
58 13C NMR spectrum of (S)-Mosher ester (165) 172
59 DEPT spectrum of (S)-Mosher ester (165) 173
60 MS of (S)-Mosher ester (165) 174
61 1H NMR spectrum of crude helibisabonol A (142) 175
62 1H NMR spectrum of helibisabonol A (142) after column chromatography
176
63 COSY spectrum of helibisabonol A (142) after column chromatography
177
64 1H NMR spectrum of quinone derivative of helibisabonol A (142)
178
65 IR spectrum of O-methylxanthorrhizol (167) 179
66 1H NMR spectrum of O-methylxanthorrhizol (167)
180
67 MS of O-methylxanthorrhizol (167) 181
68 IR spectrum of germacrone (6) 182
69 1H NMR spectrum of germacrone (6) 183
70 IR spectrum of methoxydiol (168) 184
71 1H NMR spectrum of methoxydiol (168) 185
72 MS of methoxydiol (168) 186
73 COSY spectrum of (S)-MTPA ester (171S) 187
74 COSY spectrum of (R)-MTPA ester (171R) 188
75 MS of (R)-MTPA ester (171R) 189
76 IR spectrum of monoacetate (169) 190
77 MS of momoacetate (169) 191
xxii
78 1H NMR spectrum of momoacetate (169) 192
79 MS of allylic acetate (170) 193
80 IR spectrum of allylic acetate (170) 194
81 1H NMR spectrum of allylic acetate (170) 195
82 IR spectrum of diacetate (175) 196
83 1H NMR spectrum of diacetate (175) 197
84 IR spectrum of hydrolysis product of diacetate (175), methoxydiol (168)
198
85 1H NMR spectrum of hydrolysis product of diacetate (175), methoxydiol (168)
199
86 MS of allylic alcohol (147) 200
87 IR spectrum of allylic alcohol (147) 201
88 1H NMR spectrum of allylic alcohol (147) 202
89(a) 1H NMR spectrum of allylic alcohol (147) (400 MHz
203
89(b) 1H NMR spectrum of allylic alcohol (147) (400 MHz)
204
90 13C NMR spectrum of allylic alcohol (147) 205
91 DEPT spectrum of allylic alcohol (147) 206
92 COSY spectrum of allylic alcohol (147) 207
93 IR spectrum of diacetate (176) 208
94 MS of diacetate (176) 209
95 1H NMR spectrum of diacetate (176) 210
96 13C NMR spectrum of diacetate (176) 211
97 DEPT spectrum of diacetate (176) 212
98 IR spectrum of monoacetate (177) 213
99 1H NMR spectrum of monoacetate (177) 214
CHAPTER 1
INTRODUCTION
1.1 General Introduction
Zingiberaceae family comprises of approximately 47 genera and about 1500
species. Plants in this family are monocotyledon and grow naturally in tropical and
sub-tropical forest in Asia, India and Australia [1].
Members of the Zingiberaceae family have been considered important as
natural spices or as medicinal plants. The well-known examples of species used as
spices are the rhizomes of Zingiber officinale (true ginger), Curcuma domestica
(turmeric) and Phaeomeria sp. (kantan). Many other species have been used in
traditional medicine including Kaempferia galanga (cekur), Z. zerumbet
(lempoyang), Alpinia galanga (lengkuas) and C. xanthorrhiza (temu lawak).
1.2 Curcuma xanthorrhiza
Curcuma xanthorrhiza, locally known as temu lawak or shu gu jiang huang (
束骨薑黄) in Chinese is a zingiberaceous plant used medicinally in Southeast Asia.
In Indonesia, its rhizome is widely used as a tonic and cholagogue. In Europe, it is
employed in choleretic drug preparations. In Thailand, the rhizome of this plant is
used by local people, especially in the eastern and northeastern parts of the country,
2
for the treatment of inflammation in postpartum uterine bleeding and also as an
emmenagogue [2].
1.3 Chemical Constituents of Curcuma xanthorrhiza
Chemical constituents of C. xanthorrhiza have been well-investigated and
previous studies on this species have yielded an assortment of monoterpenoids,
sesquiterpenoids and diarylheptanoids.
The major constituent of C. xanthorrhiza is xanthorrhizol (1), a bisabolane-
type sesquiterpenoid which was first isolated from rhizomes of C. xanthorrhiza in
1970 [3]. Xanthorrhizol (1) was also isolated from the root of Mexican medicinal
plant, Iostephane heterophylla [4,5]. John et al. assigned the absolute configuration
of (–)-xanthorrhizol (1) as R-configuration by the synthesis of (S)-(+)-xanthorrhizol
from (S)-(+)-ar-turmerone (2) [6].
Previous investigations showed that xanthorrhizol (1) possessed various
bioactivities. Aguilar et al. reported that (1) possessed antifungal activity against
Candida albicans, toxicity against Artemia salina and cytotoxicity against human
nasopharyngeal carcinoma cell line [5]. This sesquiterpenoid has been shown to
inhibit contractions in rat uterus [7], and induced endothelium-independent
relaxation of rat thoracic aorta [8]. Itokawa et al. reported that xanthorrhizol (1)
showed antitumour properties [9]. Xanthorrhizol (1) was also found to show an
antibacterial activity against Streptococcus mutans [10]. Further investigation on
antibacterial activity of xanthorrhizol showed that this compound exhibited the
highest antibacterial activity against Streptococcus sp. causing dental caries. These
OH
(1)
O
(2)
S
3
results suggest that xanthorrhizol (1) can be formulated for food and dental products
for preventing oral diseases [11].
Four bisabolane sesquiterpenes, ar-curcumene (3), ar-turmerone (4), β-
atlantone (5) and xanthorrhizol (1) were isolated as antitumour constituents from the
methanolic extract of the rhizomes of C. xanthorrhiza [9].
A low melting point colourless needles compound has been isolated from the
methanol extract of C. xanthorrhiza, which was identified as germacrone (6). This
compound showed hypothermic effect to mice [12] and anti-inflammatory action
[13].
Uehara et al. isolated three new bisabolane sesquiterpenenoids, namely
bisacurone (7), bisacumol (8), and bisacurol (9) from chloroform-soluble fractions of
the rhizomes of C. xanthorrhiza. Besides that, one known compound, curlone (10)
was also isolated in this investigation. Spectroscopy, chemical conversion and CD
exciton chirality have been employed in determining the absolute structures of these
new compounds [14].
Further investigation of the chloroform-soluble fractions of the rhizomes of
C. xanthorrhiza by the same group afforded four new bisacurone related compounds,
namely bisacurone epoxide (11), bisacurone A (12), bisacurone B (13) and
O O
(3) (4) (5)
O
(6)
O OH OH OH H
HOHO
(7) (8) (9) (10)
SS
R
S R
S
R
S
4
bisacurone C (14). Compound (11) was converted to its monoacetate to determine its
relative stereostructure by X-ray crystallography [15].
In the course of investigating terpenoids and curcuminoids in the fresh
rhizomes of C. xanthorrhiza, Uehara et al. isolated nine sesquiterpenoids,
xanthorrhizol (1), ar-curcumene (3), ar-turmerone (4), germacrone (6), β-curcumene
(15), β-sesquiphellandrene (16), curzerenone (17) and α-turmerone (18) [16].
In 1993, Pandji and co-workers investigated the insecticidal constituents from
four species of Zingiberaceae, including C. xanthorrhiza. In this study,
furanodienone (19) was isolated from the rhizomes [17]. Another closely related
sesquiterpenoids, furanodiene (20) was isolated from the rhizomes of Malaysian C.
xanthorrhiza [18].
Besides sesquiterpenoids, diarylheptanoids have also been found abundant in
the rhizomes of C. xanthorrhiza. Three major diarylheptanoids, curcumin (21),
demethoxycurcumin (22) and bisdemethoxycurcumin (23) have been isolated from
the rhizomes of this species [19].
OO
O
HOHO
O
HOHO
O
HOHO
(11) (12) (13) (14)
HOHO
RSR
S
S
S
RSR
SRR
RR
R
O
O O
(19) (20)
OH
R2R1
HO
O O(21) : R1 = OCH3, R2 = OCH3(22) : R1 = OCH3, R2 = H(23) : R1 = H, R2 = H
O
OHO
(15) (16) (17) (18)
H
5
These three curcuminoids was also isolated from turmeric (Curcuma longa
Linn.). The yellow pigment of C. xanthorrhiza and other Curcuma sp., curcumin was
isolated as early as 1815 [20] and in 1870, Daube isolated it in crystalline form [21].
The structure of curcumin was elucidated in 1910 by Lampe and co-workers [22] and
synthesised by the same group in 1918 [23]. Roughley studied the biosynthesis of
curcumin and completed the synthesis of curcumin in 1973 [24].
Curcumin shows a variety of pharmacological effects. Among others,
curcumin is an antioxidant agent, showed radical-scavenging antioxidant activity
against lipid peroxidation in various media, and suppressed free-radical-induced
oxidation of methyl linoleate in solutions and aqueous emulsion. Curcumin is
comparable to isoeugenol as an antioxidant [25].
Curcumin has also been reported to possess anti-inflammatory properties [26,
27] and inhibits platelet aggregation [28]. Curcumins (21-23) have been shown to
possess antiprotozoal activities against Plasmodium falciparum and Leishmania
major [29]. Recently, Eun-kyoung Song et al. reported that compounds (21-23)
showed free radical scavenging effects and showed significant hepatoprotective
effects on tacrine-induced cytotoxicity in human liver-derived Hep G2 Cells [30].
Uehara et al. have isolated two new diarylheptanoids, octahydrocurcumin
[(3S,5S)-1,7-bis(4-hydroxy-3-methoxyphenyl)-heptane-3,5-diol] (24) and 1-hydroxy-
1,7-bis(4-hydroxy-3-methoxyphenyl)-6-heptene-3,5-one (25) and two known
diarylheptanoids dihydrocurcumin (26) and hexahydrocurcumin (27) from methanol
extract of C. xanthorrhiza [31].
OH
OH
OMeMeO
HO
OH
OH
OMeMeO
HO
O OOH
(24)
(25)
6
OOMeMeO
HO
O
OH
OH
OMeMeO
HO
O
(26)
(27)
OH
Masuda et al. isolated another curcuminoid from the acetone extract of C.
xanthorrhiza rhizomes. Its structure has been assigned as 1-(4-hydroxy-3,5-
dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-(1E,6E)-1,6-heptadiene-3,4-
dione (28) based on its spectral data.
Compound (28) showed potent antioxidant activity against autooxidation of
linoleic acid in a water-alcohol system and it showed slightly stronger antioxidant
efficiency than curcumin (21) [19].
Bioassay-guided fractionation of hexane extract of this species has yielded
three non-phenolic diarylheptanoids, identified as trans,trans-1,7-diphenyl-1,3-
heptadien-5-one (alnustone) (29), trans-1,7-diphenyl-1-hepten-5-ol (30) and
trans,trans-1,7-diphenyl-1,3-heptadien-5-ol (31). Compound (31) was reported for
the first time as a plant constituent. Besides that, cinnamaldehyde (32) has also been
isolated and identified. All the three non-phenolic diarylheptanoids showed
significant anti-inflammatory activity in the assay of carragenin-induced hind paw
edema in rats [32].
OH
OMeMeO
HO
O O
OMe(28)
O OH
(29) (30)
7
Suksamaran et al. isolated two new phenolic diarylheptanoids from the
ethanolic extract of C. xanthorrhiza cultivated in Thailand. These two compounds
have been identified as 5-hydroxy-7-(4-hydroxyphenyl)-1-phenyl-(1E)-1-heptene
(33) and 7-(3,4-dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (34) [2].
1.4 Syntheses of Xanthorrhizol (1)
Xanthorrhizol (1) has been found to show many useful bioactivities and as a
result, intense synthetic efforts have been directed towards the synthesis of
xanthorrhizol (1) since the first isolation of this compound by Rimpler et al. from
rhizomes of C. xanthorrhiza Roxb. [3]. To the best of our knowledge, nine syntheses
have been reported for the syntheses of xanthorrhizol (1). Four syntheses of the
racemate [33-37], three syntheses of S-(+)-xanthorrhizol (35) [6, 38-39] and two
syntheses of R-(–)-xanthorrhizol (1) [40-41] have been reported. The syntheses
leading to nonracemic material is the conversion of (+)-ar-turmerone (4) into S-(+)-
xanthorrhizol (35) [6] and the conversion of (–)-parvifoline (36) into (–)-
xanthorrhizol (1). Meyers [38] and Fuganti [39] completed the asymmetric total
synthesis of S-(+)-(35). In 1999, enantiocontrolled total synthesis of R-(–)-
xanthorrhizol (1) has been completed by Sato et al. [41].
OH
(31)
O
H
(32)
OH
OH
OH
OH
OH
(33) (34)
OH
(35)
HO
Me(36)
S
8
1.4.1 Rane’s Short Synthesis of Xanthorrhizol (1) [35]
The Rane’s synthesis of xanthorrhizol (1) started with Reformatsky reaction
of 3-methoxy-4-methylacetophenone (37) with ethyl 4-bromocrotonate (38) to give
ethyl 5-hydroxy-(3-methoxy-4-methylphenyl)-2-hexenoate (39) followed by
hydrogenation over Pd-C in the presence of acetic acid to form ethyl 5-(3-methoxy-
4-methylphenyl)hexanoate (40) in high yield. Grignard reaction and iodine
dehydration furnished xanthorrhizol methyl ether (42) as shown in Scheme 1.1. A
short synthesis (four-steps) of xanthorrhizol methyl ether (42) has been achieved
compared to the ten-step earlier synthesis [33].
MeO OOEtBr
O MeO
CO2Et
OH
MeO
CO2Et
MeO
OH
RO
(37) (38) (39)
(40) (41) (42) R = Me
Zn dustcyclohexane
reflux1 h
H2, 10% Pd-CEtOH-AcOH
MeMgIEt2O
rt6 h
I2Benzene
10 h
(1) R = HMeMgI
Xylene, 140 oC Scheme 1.1: Rane’s synthesis of xanthorrhizol (1).
1.4.2 Meyers’ Asymmetric Synthesis of S-(+)-Xanthorrhizol (35) [38]
In 1997, Meyers and Stoianova reported the asymmetric synthesis of
S-(+)-xanthorrhizol (35) which is summarised in Scheme 1.2. The key chiral
oxazoline (47) was prepared in three steps from crotonic acid (43). First, crotonic
acid (43) was treated with ClCO2Et to furnish the mixed anhydride (44), then the
resulting mixed anhydride (44) was reacted with t-leucinol (45) to form amide (46).
Cyclisation of the resulting amide (46) with SOCl2 gave oxazoline (47) in 54% yield.
Stereoselective addition of (o-methoxy-p-tolyl)lithium (48) to the chiral α,β-
9
unsaturated oxazolines (47) gave compound (49). Analysis of the chromatographed
addition products (49) revealed that the diastereomeric ratio was at least 97:3.
Alcohol (50) was obtained by acid hydrolysis, acetylation and reduction of oxazoline
derivative (49). Alcohol (50) was then treated with 1,2-bis(diphenylphosphino)-
ethane tetrabromide (DIPHOSBr) (51) to yield the bromide (52). Treatment of
bromide (52) with (2,2-dimethylvinyl)lithium gave xanthorrhizol methyl ether (42)
in high yield (94%) and cleavage of the methyl ether (42) using sodium
ethanethiolate in DMF gave S-(+)-xanthorrhizol (35).
COOH
N
O MeO LiBr
MeO N
O MeO OH
THF-78 oC
1. TFA, rt, 24h2. py, Ac2O, rt, 24h3. LiAlH4, THF
DIPHOSBr (51)0 oC to rt30 min
MeO BrMeOMe2C=CHLi
THF
EtSNaDMF
HO
(43)
(47)(54%) (48)
(49)(50)(57%)
(52)(91%) (42)(94%)
(35)(92%)
S
(44)O OEt
O O
ClCO2Et, Et3N H2N
HO
(S)-t-leucinol(45)
(46)
NH
O SOCl2
Br2Ph2P PPh2Br2
DIPHOSBr (51)
dr >97:3
OH
Scheme 1.2: Meyers’ asymmetric synthesis of S-(+)-xanthorrhizol (35).
10
1.4.3 Fuganti’s Baker’s Yeast-mediated Enantioselective Synthesis of S-(+)-Xanthorrhizol (35) [39]
The most recent total synthesis of xanthorrhizol (1) came from the Fuganti’s
group as shown in Scheme 1.3 [39]. In their synthesis, the aromatic ring (56) was
constructed by benzanullation of the hexadienoic acid derivative (55). Compound
(55) was submitted to cyclisation using ethyl chlorochromate and triethylamine as
base, followed by treatment with KOH to give the acid (56), which was then
converted to benzophenone (57) in good yield by a number of straightforward
synthetic steps. The ester (58) was synthesised from the substituted acetophenone
(57) by Horner-Wadsworth-Emmons reaction with triethyl phosphonoacetate (ethyl
diethoxyphosphosphorylacetate) and sodium hydride.
The key step in this synthesis was Baker’s yeast-mediated enantioselective
conversion of the unsaturated aldehyde (59) into the saturated alcohol (60). The
result of the reduction showed a high conversion of the aldehyde (59) into the
saturated S-(+)-alcohol (60) (49% isolated yield) and gave good enantioselectivity
with enantiomeric excess >98%. To this end, the enantiopure alcohol (60) was
converted into the iodide (61) via the tosyl ester derivatives and substitution with
sodium iodide in acetone. The coupling of the iodide (61) with the Grignard reagent
(62) catalysed by copper(I) iodide furnished enantiopure (42). Demethylation of
compound (42) using sodium ethanethiolate in DMF afforded (S)-(+)-xanthorrhizol
(35)
11
O
Ph3P COOEt
COOH
COOEt
COOHBenzene
reflux74%
ClCO2Et, Et3N,THF
then aq. KOH,reflux, 86%(53) (54) (55)
COOH
OH(56)
1. Me2SO4, K2CO3, acetone2. LiAlH4, THF3. MnO2, CHCl3, reflux4. MeMgCl, THF, 0 oC5. MnO2, CHCl3, reflux 73% OMe
(EtO)2POCH2CO2Et,NaH 81%
(57)
OMe
COOEt
(58)
1. LiAlH4, THF2. MnO2, CHCl3, reflux 81%
OMe
OBaker's yeast,
4-6 days 49%
(59)
OMe
OH
(60)ee > 98%
1. TsCl, Py, CH2Cl22. NaI, acetone, reflux 84%
OMe
IMgBr
CuI cat., THF 85%(61)
(62)
O
OMe(42)
NaSEt, DMF, reflux 90%
OH(35)
Scheme 1.3: Fuganti’s Baker’s yeast-mediated enantiosynthesis of S-(+)-xanthorrhizol (35).
1.4.4 Conversion of Parvifoline (36) to R-(–)-Xanthorrhizol (1) [40]
Parvifoline (36) is a benzocyclooctene originally isolated from Cereopsis
parvifolia [42]. It was also found in Pereziae alamani var. oolepsis [43], P.
carpholepis [44] and P. longifolia [45].
Garcia and co-workers have converted parvifoline (36) to xanthorrhizol (1) in
five steps, as shown in Scheme 1.4. The first step was acid catalysed isomerisation of
12
parvifoline (36) to isoparvifoline (63). Ozonolysis of isoparvifoline (63) produced
aldehyde (64). Aldehyde (64) was decarbonylated with Wilkinson’s reagent (chloro-
tris-(triphenylphosphine)rhodium) (65) to give 5-(2’-ketoheptan-6’-yl)-2-
methylphenol (66). Reactions of this intermediate with CH3MgI followed by
dehydration yielded R-(–)-xanthorrhizol (1). This was the first synthesis of
xanthorrhizol (1) with R-configuration.
HO HOp-TsOHC6H6reflux
CHO
OH O
O3
(Ph3P)3RhCl (65), N2
50 oC, 3 hOH O
MeMgI (2.2 eq.)
OH OH
OH
I2
(36) (63)(64)
(66) (67)
(1)
Scheme 1.4: Conversion of parvifoline (36) to R-(–)-xanthorrhizol (1).
1.4.5 Shishido’s Enantiocontrolled Total Synthesis of R-(–)-Xanthorrhizol (1)
The Shishido group has published an efficient and enantiocontrolled total
synthesis of R-(–)-xanthorrhizol (1) [41]. This synthesis started with Heck reaction
between 4-iodo-2-methoxytoluene (68) and 2-tert-butyl-4,7-dihydro-1,3-dioxepine
(69) to form coupled product (70). Product (70) was submitted to ozonolysis
followed by reductive workup with sodium borohydride (NaBH4) to give the σ-
symmetrical prochiral 2-aryl-1,3-propanediol (71). Prochiral diol (71) was subjected
to asymmetric acetylation utilizing Candida antacrtica lipase (CAL) with vinyl
13
acetate as an acyl donor to afford an optically active monoacetate S-(72) with 94%
ee. On the other hand, PPL-catalysed acetylation of (71) in ether yielded the desired
monoacetate R-(72) with 83% ee in 95% yield. The R-monoacetate was then
tosylated and reductively deoxygenated with NaBH4 in hot DMSO to produce the S-
alcohol (74) in 65% yield in two steps. The monoacetate S-(72) was successfully
converted to S-(74) via a five-step sequence of reactions. Methoxymethylation of S-
(72) followed by alkaline hydrolysis gave (73). Compound (73) was submitted to
tosylation, reductive deoxygenation and acidic hydrolysis to provide S-alcohol (74).
Then, S-alcohol (74) was transformed into sulphone (75) in two steps reaction.
Prenylation of (75) was accomplished by treatment of (75) with n-butyllithium
followed by prenyl bromide to afford phenylsulphonate (76). Reductive removal of
the benzenesulphonyl group in (76) was achieved by treating with 5% sodium
amalgam in buffered methanol to give O-methylxanthorrhizol (42). L-Selectride®
(Lithium tri-sec-butylborohydride) (77) was used in this final step of the synthesis to
cleave the methyl functionality of compound (42) to produce R-(–)-xanthorrhizol (1),
the naturally occurring xanthorrhizol.
The strength of this synthesis lies in the utilisation of lipase-mediated
chemoenzymatic transformation to construct benzylic tertiary stereogenic centre. The
convergent strategy to obtain R-alcohol (74) is also noteworthy. Scheme 1.5
summarised the sequence of the synthetic methodology.
14
IMeO
Me
MeO
Me
OO
tBu
MeO
Me OH
OH
i ii
MeO
Me OH
OH
MeO
Me OAc
OH
MeO
Me OAc
OH
MeO
Me OH
OMOM
MeO
Me
iii
ix
iv, v
vi, vii
MeO
Me
MeO
Me
SO2Ph
OH
OH
RO
Me
MeO
Me
SO2Phx, xi xii
xiii
xiv (42) R=Me(1) R=H
S-72
R-72
(68) (70) (71)
(71)
(73)
(74)
(74) (75)
(76)
vi - viii
O
OtBu
(69)
BH-Li+3
L-SelectrideTM (77)L-SelectrideTM = lithium tri-sec-butylborohydride (77)
Scheme 1.5: Shishido’s enantiocontrolled total synthesis of (–)-xanthorrhizol (1).
Reagents & Conditions: (i) 2-tert-butyl-4,7-dihydro-1,3-dioxepine (69), Pd(OAc)2, Ph3P, i-Pr2NEt, DMF, 80 °C, 75%; (ii) O3, CH2Cl2, MeOH (1:1), -78 °C then NaBH4, rt, 63%; (iii) CAL, vinyl acetate, Et2O, rt, 19%; (iv) MOMCl, i-Pr2NEt, 4-DMAP, CH2Cl2, rt, 81%; (v) LiAlH4, THF, rt; (vi)TsCl, Et3N, 4-DMAP, CH2Cl2, rt; (vii) NaBH4, DMSO, 60 °C, 72% (3 steps) for the MOM ether (74), 65% (2 steps) for R-73; (viii) 10% HCl (aq.), MeOH, rt, 95%; (ix) PPL, vinyl acetate, Et2O, 39 °C, 95%; (x) nBu3P, prenyl bromide, HMPA, Ph2S, pyridine, rt, 84%; (xi) MCPBA, KHCO3, CH2Cl2, rt, 100%; (xii) n-BuLi, prenyl bromide, HMPA, THF, -78 °C, 82%; (xiii) Na-Hg, Na2HPO4, MeOH, rt, 83%; (xiv) L-Selectride® (77), THF, reflux, 78%.
15
1.5 The Sharpless Asymmetric Dihydroxylation
The cis dihydroxylation of olefins mediated by osmium tetroxide represents
an important general method for olefin functionalisation [46]. The original
dihydroxylation used stoichiometric amounts of OsO4, which is expensive, volatile,
and toxic. Over the years, the original dihydroxylation procedure has been modified
to operate the use of OsO4 in catalytic amounts, more rapid and better yield, this has
been achieved by Sharpless [47-50].
In Sharpless asymmetric dihydroxylation (AD), the source of asymmetric is a
chiral amine, which forms a complex with OsO4. In 1980, Sharpless used pyridine
(81), derived from menthol, induced ee’s of 3-18% in the dihydroxylation of trans-
stilbene (78), as shown in Scheme 1.6. Nevertheless, the reaction had to be improved
because the ee’s were too low. In the same paper, Sharpless disclosed that
dihydroxylation of olefins in the presence of dihydroquinidine acetate (82) or
dihydroquinine acetate (83) under stoichiometric conditions gave optically active
diols with 25-94% ee after hydrolysis. Cost considerations make this stoichiometric
osmylation uneconomical [51]. Breakthrough was made in 1987 when Sharpless and
co-workers discovered that the stoichiometric process become catalytic when N-
methylmorpholine-N-oxide (NMO) (84) was used as the co-oxidant in the
dihydroxylation. In this landmark paper, dihydroquinidine p-chlorobenzoate (85) and
dihydroquinine-p-chlorobenzoate (86) also were introduced as new chiral ligands
with improved enantioselective properties. The communication described the
catalytic AD of trans-stilbene (78) with 0.2 mol% of OsO4, 0.134 eq. of chiral
auxiliary, and 1.2 eq. of NMO (84) as oxidant to give (R,R)-(+)-dihydrobenzoin (79)
in 80% yield with 88% ee [52].
16
OH OHOH HO1. OsO4 (1.1 eq.), ligand
PhCH3, 25 oC, 8-24 h2. LiAlH4, Et2O
(78) (79) (80)
Nligand =
ligand =
ligand =
3-18% ee
82% ee(85% yield)
83.2% ee(90% yield)
-
-
-
(81)
(82)
(83)
N
OMe
N
HAcO
H
N
MeO
N
HOAcH
R R S S
Scheme 1.6: The first enentioselective dihydroxylation reactions developed by Sharpless.
N
OMe
N
HO
H
N
MeO
N
HOH
Cl
O
Cl
O
(85) (86)
N
O
Me ONMO (84)
Since then, four substantial improvements were made to the AD: (a) change
of the stoichiometric oxidant from NMO to K3Fe(CN)6-K2CO3, (b) method for
effecting increase in the rate of reaction, (c) new class of “dimeric” ligand combining
two alkaloid units linked by an aromatic “spacer” unit, (d) a more convenient source
of osmium(VIII).
17
The catalytic cycle for the Sharpless AD with NMO (84) as a co-oxidant is
shown in Scheme 1.7. The enantiomeric excess decreased when changing from
stoichiometric to catalytic conditions. The reason for this phenomenon is due to a
second catalytic cycle in which the chiral ligand is not involved [53]. The
osmium(VIII) trioxoglycolate (88) has access to a secondary reaction cycle, forming
a bisglycolate (89), hydrolysis of the glycolate give racemic diol [54]. However,
when the catalytic system K3Fe(CN)6-K2CO3 in t-BuOH-H2O is used [55], the
oxidant is confined to the aqueous phase, allowing the osmium(VI) glycolate (87) to
hydrolyse in the organic phase before being reoxidised.
OsO
OO
O
OsO
OO
O ORR
LOsO
O
O
L
O
R
R
HO
R
OH
R
R
R
HO
R
OH
R
R
R
OsO
OOO O
RR
R
R
L
H2O
NMO NMM
L(87) (88)
H2O L
(89)
Primary cycle (high enantioselectivity)
Secondary cycle (low enantioselectivity)
L = chiral ligandNMM = 4-methylmorpholine
Scheme 1.7: The two catalytic cycles for the Sharpless AD with NMO as a co-oxidant.
Slow reaction of trisubstituted olefins is due to the slow hydrolysis of the
osmium glycolate. However, this hydrolysis can be accelerated by addition of
methane sulphonamide. The reaction time can be as much as 50 times shorter in the
presence of this additive [56].
18
Until 1996, over 500 different ligands have been tested and a list of the most
useful ligands can be subsequently be drawn (Figure 1.1). Among these the PHAL
(phthalazine) ligands (90,91) are the most widely used in the AD due to their large
substrate applicability and are currently employed in the AD-mix formulations [56].
The analogs of PHAL ligands, bis-cinchona alkaloid ligands with a diphenyl
pyrazinopyridazine spacer (DPP) (94,95) and a diphenyl phthalazine spacer (DP-
PHAL) (96,97) are also found to give excellent enantioselectivities in the AD of
olefins. The enantioselectivies using these ligands are generally greater than or
equivalent to those of ligands (90,91) [57]. The diphenylpyrimidine (PYR) (92,93)
class is usually suitable for sterically congested olefins (especially terminal olefins)
[58]. In 1996, anthraquinone (AQN) ligands (98,99) were introduced. The
anthraquinone-based ligands lead to excellent results in the AD reactions of
allylically substituted terminal olefins. These ligands give superior enantioselectivity
in the AD of almost all olefins having only aliphatic substituents [59].
Finally, osmium tetroxide has been replaced by non-volatile osmium source,
potassium osmate(VI) dihydrate [K2OsO2(OH)4]. Until this point, all of the
ingredients in the AD are solids and an AD-mix formulation of the standard reactants
has been developed. These “AD-mixes” can be readily prepared, and there are also
commercially available as AD-mix-α [(DHQ)2PHAL] and AD-mix-β
[(DHQD)2PHAL]. The contents in 1kg of AD-mix are as follows: K3Fe(CN)6,
699.6g; K2CO3, 293.9g; (DHQD)2- or (DHQ)2-PHAL, 5.52g; and K2OsO2(OH)4,
1.04g (Figure 1.1). AD procedure needs 1.4g of this AD-mix per millimole of olefin.
The solvent used for the reaction is a 1:1 mixture of t-BuOH and water. The solvent
mixture separates into two liquid phases upon addition of the inorganic reagents. The
catalytic cycle for AD under this condition is shown in Scheme 1.8.
19
N
MeO
N
H
N
NO
NNO H
OMe
N
OMe
N
H
N
NO
N NOH
MeO
(90) (DHQ)2PHAL (91) (DHQD)2PHAL
N
MeO
N
H
N
NO O H
OMeN N
Ph
PhN
OMe
N
H
N
NOOH
MeO NN
Ph
Ph
(92) (DHQ)2PYR (93) (DHQD)2PYR
N
MeO
N
H
N
NO
NN
N N
O H
OMe
(94) (DHQ)2DPP
Ph Ph N
OMe
N
H
N
NO
N N
NN
OH
MeO
(95) (DHQD)2DPPPh Ph
N
MeO
N
H
N
NO
NNO H
OMe
Ph Ph N
OMe
N
H
N
NO
N NOH
MeO
Ph Ph
(96) (DHQ)2DP-PHAL (97) (DHQD)2DP-PHAL
N
MeO
N
H
N
NO O H
OMeOO
N
OMe
N
H
N
NOOH
MeO OO
(98) (DHQ)2AQN (99) (DHQD)2AQN reagents (DHQ)2PHAL (DHQD)2PHAL K2OsO2(OH)4 K3Fe(CN)6 K2CO3 AD-mix-α 5.52 g – 1.04 g 699.6 g 293.9 g AD-mix-β – 5.52 g 1.04 g 699.6 g 293.9 g Figure 1.1: Structure of phthalazine (90,91), pyrimidine (92,93), diphenylpyrazinopyridazine (DPP) (94,95), diphenylphthalazine (DP- PHAL) (96,97) and anthraquinone (AQN) (98,99) ligands used in the Sharpless AD and composition of AD-mix-α and AD-mix-β.
20
OsO
O
O
L
O
R
R
HO
R R
OH
OsO4 L
OsO4
2K2CO34H2O
2K2CO32H2O
2K3Fe(CN)62K2CO3
2K4Fe(CN)62KHCO3
Os
OOHOH
HOHO
OOs
OOHOH
OO
O
R
RL
2- 2-
OrganicAqueous
(87)
Scheme 1.8: Catalytic cycle for asymmetric dihydroxylation using potassium ferricyanide as co-oxidant.
First, osmylation of the olefin proceeds to form the osmium(VI) glycolate-
amine complex (87). Formation of (87) is presumed to occur in the organic phase in
which all the involved species are soluble. Next, at the organic-aqueous interface,
hydrolysis of the glycolate ester releases the diol into the organic phase and the
reduced osmium as the hydrated osmate(VI) dianion into the aqueous phase.
Oxidation of osmate(VI) by potassium ferricyanide regenerates osmium tetroxide via
an intermediate perosmate(VIII) ion gives osmium tetroxide, which then migrates
back into the organic phase to restart the cycle.
Sharpless AD is a type of ligand-accelerated catalysis because the addition of
bis-cinchona ligand increases the reaction rate of this catalytic transformation. The
principle of ligand acceleration is illustrated in Scheme 1.9 for the AD reaction [60].
21
OsO
OO
O
OsO
O
O
NR3
O
OsO
O
O
O
R3N: +
HO OH
OsO4 + NR3 catalytic
"Os" stoichiometric
Scheme 1.9: The osmylation of olefins.
Scheme 1.10 presents a mnemonic showing olefin orientation and face
selectivity. In the mnemonic, the olefin is oriented to fit the size constraints, where
RL = largest substituent, RM = medium-sized substituent, and RS = smallest
substituent other than hydrogen. The oxygens will then be delivered from the upper
face if dihydroquinidine (DHQD) derived chiral auxiliary is used and from the lower
face if a dihydroquinine (DHQ) derived auxiliary is used.
RL
RS RM
H
"HO OH"
"HO OH"NW
SW
NE
SE
dihydroquinidine derivatives (AD-mix-β)
dihydroquinine derivatives (AD-mix-α)
OHHORS RM
RL H
OHHORL H
RSRM
K2OsO4(OH)4K3Fe(CN)6, K2CO3
t-BuOH/H2O 1:1
Scheme 1.10: Mnemonic device for the AD of olefins.
Ligand without RateLigand with Rate Saturation LAE =
22
1.5.1 Recent Developments in Asymmetric Dihydroxylation
Mehltretter et al. demonstrated that the dihydroxylation in the presence of
osmium tetroxide is largely pH dependent. It was found that the reaction rates for
1,2-di-, tri-, and tetrasubstituted olefins improved at a constant pH of 12.0. In
addition, the enantioselectivity of terminal olefins at room temperature is slightly
enhanced by using a constant pH of 10 [61].
The most widely used co-oxidant for the Sharpless AD is K3Fe(CN)6 and
another widely used reoxidant is NMO (84). Besides that, reports on the utilisation of
oxygen-based reoxidants such as air, O2 and H2O2 have also been published.
Bäckvall and co-workers developed a H2O2 reoxidation process for Os(VI) by using
NMO (84) together with flavin (100) as co-catalysts in the presence of hydrogen
peroxide [62]. Krief et al. successfully designed a reaction system consisting of
oxygen, catalytic amount of OsO4, (DHQD)2PHAL (91) and selenides for the
dihydroxylation of α-methylstyrene (101) under irradiation with visible light [63].
Döbler et al. reported the osmium-catalysed dihydroxylation of aliphatic and
aromatic olefins using molecular oxygen or air as the stoichiometric oxidant, but the
enentioselectivities are occur lower than those of the classical K3Fe(CN)6 co-oxidant
system [64]. Mehltretter and co-workers developed a procedure for the
dihydroxylation of olefins using bleach (NaClO) as the terminal oxidant. Olefins
give the optically active diols in the presence of chiral ligand with good to excellent
chemo- and enantioselectivities under optimised pH conditions. This new protocol
has distinct advantages. Compared to the dihydroxylation using hydrogen peroxide
as oxidant, the procedure has the advantage that no co-catalyst (flavin, NMO) need to
be added. Compared to the dihydroxylation using dioxygen this procedure is faster
and easier to perform [65]. Sodium chlorite (NaClO2) is the most recently reported
reoxidant in Sharpless AD. Enantioselectivities of the NaClO2 AD-process are
N
N
N
NH
Et
Me
Me
O
O(100) (101)
23
comparable with the enantioselectivities of other AD-processes and the yields are
good [66].
1.5.2 Synthetic Application for 1,2-diols
If the syn-1,2-diol is not the final functionality required, manipulation of the
starting chiral compound can be performed. The first convenient approach is the
conversion of diols into acetoxy halides and conversion into epoxides. The second
method is the regioselective conversion of one of the hydroxyl group into sulphonate
ester.
1.5.2.1 Conversion of Diols into Halohydrin Esters and Epoxides
1,2-Diols (102) are converted in excellent yields to acetoxychlorides or
acetoxybromides (105,106) via acetoxonium ion intermediate (104), as shown in
Scheme 1.11.
OH
R1R2
OH
O O
R1 R2
OMeO O
R1 R2
X -
OAc
R1R2
X
X
R1R2
OAcR1R2
O
MeC(OMe)3, cat. PPTS AcX, or Me3SiX
Base, MeOH
X = Cl, Br, I
(102) (103)
(105)(106)(107)
(104)PPTS = Pyridinium 4-toluenesulphonate
Scheme 1.11: Formation of acetoxy halides and epoxides via cyclic acetoxonium ions (104).
24
The cyclic orthoacetate (103) is prepared by acid-catalysed [pyridinium 4-
toluenesulphonate (PPTS)] transesterification of diol (102) with a slight excess of
trimethyl orthoacetate. The cyclic orthoacetate (103) is then treated with Me3SiCl,
acetyl chloride or acetyl bromide to form acetoxyhalides (105,106). The formation
of acetoxyhalides (105,106) proceed through nucleophilic attack on an intermediate
1,3-dioxolan-2-ylium cation (104) with inversion of configuration. Treatment of the
acetoxy halides (105) and (106) under mildly alkaline conditions [K2CO3 or
Ambelite IRA 410 (OH-)] affords epoxide (107) in ca. 90% yield. Since both steps
can be performed in the same reaction vessel, this reaction sequence provides an
extremely efficient method for the direct conversion of 1,2-diols into epoxides with
overall retention of configuration [67].
1.5.2.2 Regioselective Sulphonylation
The primary OH group of a diol derived from a terminal olefin can be readily
converted to a sulphonate leaving group by treating with arenesulphonyl chloride in
the presence of tertiary amine. Under alkaline conditions, hydroxysulphonates are
converted to chiral epoxide. The olefin → diol → monosulphonate → epoxide
reaction sequence has been applied in a number of natural product and drug
syntheses. An example for the usefulness of this sequence is shown in Scheme 1.12.
3-(1,2-Dihydroxyethyl)-1,5-dihydro-3H-2,4-benzodioxepine (108), a protected
glyceralaldehyde can be obtained in good enantiomeric excess by the
dihydroxylation of the corresponding acrolein acetal and recrystallization from
benzene. Monotosylation, followed by treatment with sodium methoxide gives
glyceraldehydes building block (110) [68].
25
O
O OHOH
O
O OTsOH
O
O O
p-TsCl, py,0 oC to rt
NaOMe,MeOH,
reflux, 1 h
(108) (109)
(110) Scheme 1.12: Synthesis of glyceraldehyde building block (110).
1.6 Application of Sharpless AD on the Synthesis of Natural Products
1.6.1 Sharpless’s Asymmetric Synthesis of the C-13 Side Chain (115) of Taxol
Since the publication by Sharpless in 1992 [56], more researchers have been
using the AD in syntheses, including synthesis of natural products. One of the
examples was the Sharpless’s asymmetric synthesis of taxol C-13 side chain, as
shown in Scheme 1.13. Sharpless AD on the methyl cinnamate (111) furnishes the
diol (112) in 72% yield and 99% ee after recrystallisation. The original secondary
oxidant, NMO (84) was used as the co-oxidant instead of K3Fe(CN)6. This allows the
reaction to be run at a very high concentration (2M). The diol (112) was converted to
the acetoxybromoester (113) by reaction with trimethyl orthoacetate in the presence
of a catalytic amount of p-TsOH, followed by treatment with acetyl bromide. The
latter step was regioselective (6:1 mixture of the two acetoxybromo esters) favouring
the desired product.
26
Ph OMe
OPh OMe
OOH
OH
Ph OMe
OBr
OAcPh OMe
OAcHN
OH
Ph OMe
ONH
OH
Ph
O
1. (DHQ)2PHAL (0.5%), K2OsO2(OH)4 (0.2%), NMO (1.45 equiv), t-BuOH, 25 oC, 23 h (72%)2. recrystallise from toluene
1. MeC(OMe)3, p-TsOH, CH2Cl2, 25 oC, 5 h2. MeCOBr, CH2Cl2, -15 oC, 2 h (60%, 2 steps)
1. NaN3, DMF, 50 oC, 19 h
2. H2, 10% Pd-C, MeOH, 25 oC (74%, 2 steps)
1. 10% HCl (aq.), ∆, 2 h2. PhCOCl, 25 oC, 2 h (72%, 2 steps)
OHAcO
HOO
H OAcOBz
OPh
NH
OH
Ph
O
OO
(111) (112)
(113)(114)
(115)(116: taxol)
13
Scheme 1.13: Sharpless’s asymmetric synthesis of the C-13 side chain (115) of taxol
(116).
The acetoxybromo ester (113) was converted to N-acetyl-3-phenylisoserine
(114) through displacement of the bromide with azide, followed by hydrogenation of
the azide to the amine and trans-acylation to afford acetamide (114). Hydrolysis of
the acetamide, benzoylation, and hydrolysis of the ester then gives the C-13 side
chain (115) of taxol (116) in 23% overall yield from methyl cinnamate (111) [69].
1.6.2 Corey’s Total Synthesis of (–)-Ovalicin (117)
Inhibition of angiogenesis, the process of development of new blood vessel,
is a potentially valuable medical strategy to prevent the growth of solid tumours by
cutting off their blood supply. Ovalicin (117) inhibits angiogenesis has prompted
Corey and co-workers to resynthesise ovalicin (117), which has been previously
prepared as racemate [70], as shown in Scheme 1.14,
27
OH
MeO OMe
OH
MeO OMe
OHOH
O
MeO OMe
OMe
O
MeO OMe
OHOH
OMe
OMe
OO
OMeOMe
OH
H
O
O
(DHQ)2PHAL (0.01 eq.)K2OsO4 (0.01 eq.)K3Fe(CN)6 (3 eq.)
K2CO3 (3 eq.)MeSO2NH2 (1 eq.)t-BuOH:H2O (1:1)
0 oC, 4 h(118) (119) [18% ee]
PMBCl, Et3N,4-DMAP, 23 oC,
3 h (98%) same conditionsas above
(93%)
(120) (121) [>99% ee]
(122)(117)
Scheme 1.14: Corey’s total synthesis of (–)-ovalicin (117).
Direct AD of (118) with (DHQ)2PHAL as the chiral ligand gives (119) in
only 18% ee. However, AD of the p-methoxybenzyl ether (120) affords (121) in 93%
yield and the ee was dramatically increased to more than 99%. This interesting result
was attributed to attractive interactions between the PMB group and the aromatic
units on the ligand [71]. Enantiomerically pure (121) can be converted to
intermediate (122) and thence to (–)-ovalicin (117) by using a previously established
pathway [70].
1.6.3 Nicolaou’s Total Synthesis of Apoptolidin (123)
Apoptolidin (123) is a potent apoptolisis-inducing agent isolated from
Nocardiopsis sp. It has been found to induce apoptotic cell death selectively in rat
glia cells transformed with the adenovirus E1A oncogene. In addition, this 20-
28
membered macrocyclic lactone has also been shown to be an inhibitor of the
mitochondrial F0F1-ATP synthase. The interesting biological activities and novel
structure of apoptolidin (123) prompted Nicolaou and co-workers to synthesise this
compound (123) [72-73].
O
OOH
MeO
O
OH
MeO
HO
HOO OMe
O O
O
OOH OMe
OH H
HO
OH
Apoptolidin (123)
AB
C
D E
112
1927
8
21
AD of α,β-unsaturated ketone (124) is an example of AD of electron-deficient
olefins using a buffered AD-mix conditions. The use of buffered condition
circumvents problems associated with epimerisation of the α-centre and/or retroaldol
fragmentation [74-75]. AD of compound (124) with modified AD-mix-α to form the
C19–C20 syn diol system failed, leading to an inseparable mixture (ca.1:1) of the two
possible isomers (126) [72] (Scheme 1.15). However, simply removing the TBS
protecting group on the C23 oxygen dramatically increases the diastereoselectivity of
the AD to 6:1. This striking result showed that the substituent on the C23 oxygen
exerted a strong influence on the dihydroxylation reaction. This interesting result
also showed that the stereocontrolling factor (the group on the C23 oxygen) is situated
four carbon away from the olefinic site where the reaction takes place.
29
OMe
OTBS
OMe OR OPMBOTBS
O
12
19
2023 27
OMe
OTBS
OMe OR OPMBOTBS
O
12
1920
23 27
OH
OH
(124) R = TBS(125) R = H
(126) R = TBS(127) R = H
K3Fe(CN)6 (3.5 eq.), K2CO3 (3.5 eq.)NaHCO3 (4.5 eq.), MeSO2NH2 (1.3 eq.),(DHQ)2PHAL (0.05 eq.), OsO4 (0.01 eq.),t-BuOH:H2O (1:1), 0 oC, 16 h, (126) dr ca. 1:1, 85%;(127) dr ca. 6:1, 83%
Scheme 1.15: Nicolaou’s synthesis of apoptolidin (123).
1.6.4 Solid-Phase Synthesis of (3’R,4’R)-Di-O-cis-acyl 3-Carbonyl Khellactones (131)
Solid-phase synthesis of small organic molecules has emerged as an
important technology, enabling chemists to synthesise numerous interesting
pharmaceutical compounds [76-77]. Although Sharpless AD reactions have been
successfully and widely used in the solution phase, AD reactions on solid phase have
been reported only infrequently. Lee et al. used Sharpless AD as one of the key steps
in solid-phase synthesis of substituted khellactones, as shown in Scheme 1.16.
Substituted khellactone exhibits a broad range of biological activities, including
antifungal, antitumour, antiviral and anti-HIV effects. The resin used in this synthesis
was Wang resin. In the AD of the khellactone, resin (128) was subjected to Sharpless
AD using (DHQ)2-PHAL as ligand and catalytic OsO4 to yield (129) in 99% ee. The
acyl khellactones (130) were synthesised by acylation of the resin (129).
Symmetrical anhydrides were prepared from the carboxylic acid using 1 equivalent
of DIC (131) in CH2Cl2. Resin (129) was treated with excess anhydride in the
30
presence of DIEA and DMAP to furnish resin (130). The product (132) was cleaved
from the solid support (130) by 50% trifluoroacetic acid in CH2Cl2 for 2h [78].
O O O
O
O
O O O
O
O
OHOH
(DHQ)2PHAL (2.5 eq.),OsO4 (0.1 eq.),
K3Fe(CN)6 (6 eq.),K2CO3 (3 eq.),
MeSO2NH2 (1 eq.),t-BuOH:H2O (1:1), rt, 36 h
(128) (129)
O O O
O
O
OROR
(130)
1. RCOOH, DIC (131)(1 eq.)2. DIEA, DMAP
O O O
OH
O
OROR
(132)
50% TFA/CH2Cl2
DIC = [(CH3)2CH]2CH2CH2Cl.HCl (131)
Scheme 1.16: Asymmetric solid-phase synthesis of (3’R,4’R)-di-O-cis-acyl 3- carbonyl khellactones (131).
1.7 Xanthorrhizol as Chiral Starting Material for the Synthesis of Natural Products
A variety of aromatic bisabolane type natural products is widely distributed,
both in terrestrial as well as in marine organisms. In spite of their rather simple
structures, some of them have characteristic biological activities. These compounds
have attracted synthetic chemists for about 30 years. The parent hydrocarbons (+)-
ar-curcumene (3) and dehydro-ar-curcumene (133) are the basic skeleton of aromatic
bisabolanes found in many plant essential oils. Examples of the phenolic aromatic
bisabolanes are (–)-xanthorrhizol (1), allylic alcohols (134) and (135) [4, 79-80], and
the rearranged bisabolane elvirol (136) [81]. More highly oxidised aromatic
bisabolanes include triols (137) and (138) [82], (–)-curcuquinone (139), (–)-
curcuhydroquinone (140) [83], and gladulone A (141) [84].
31
OH
OH
HO
OH
HO
O
O CHO
O
O
(133) (134) (136)
(140)(139) (141)
OH
(135)
OH
OH
OH(137) C-10 = S(138) C-10 = R
OH10
Although numerous syntheses of racemic phenolic bisabolane type
sesquiterpenoids have been known, only a few stereoselective syntheses were
reported due to the difficulty of introducing a stereogenic centre in the benzylic
position. Besides total synthesis, an alternative way is using natural sesquiterpenoids
as starting material for the synthesis of aromatic bisabolane sesquiterpenoids.
However, target oriented synthesis of sesquiterpenoids starting from abundantly
available natural sesquiterpenoids is a challenging task. It is due to the target
molecule which is mostly just one specific molecule and the structural variety in the
starting material is often limited. This imposes a double problem and often new or
specific methodology has to be developed to achieve such a synthesis.
One of the potential starting materials in this method is xanthorrhizol (1),
which is the main component in the essential oil of C. xanthorrhiza. Although the
synthesis of xanthorrhizol (1) has been extensively studied (see Session 1.4), the
difficulties in isolation and supply have limit the studies on the chemistry of this
compound. To date, only one report has been published on the chemistry of
xanthorrhizol. Aguilar et al. prepared several simple derivatives of xanthorrhizol (1),
which displayed mild antifungic activities and did not show cytotoxic activities
towards certain human cell lines [85]. Xanthorrhizol (1) used in this study was
isolated from the Mexican medicinal plant, Iostephane heterophylla. Thus, it is of
great interest to study the chemistry of xanthorrhizol (1) in order to exploit the
32
readily available of this compound as a starting material to the other useful
compounds.
It is interesting to note that xanthorrhizol (1) is found to be a suitable starting
material for the synthesis of several structurally related sesquiterpenoids, viz
curcuquinone (139), curcuhydroquinone (140), allylic alcohol (134) and (135),
helibisabonol A (142) and others as shown in Scheme 1.17.
OH
OH
HO
O
O
OH
OH
OH
OH
OH
HO
OH
OH
(1)
(140)(139)
(134)(135)
(142) Scheme 1.17: Xanthorrhizol derivatives.
Besides that, xanthorrhizol (1) is a precursor for heliannane type
sesquiterpenoids, particularly heliannuol D (143). Shishido and co-workers have
prepared heliannuol D (143), an allelochemical, starting from the synthetic R-(–)-
xanthorrhizol (1) as shown in Scheme 1.18 [86].
33
MOMO OH
OHBr
PtBu2
O
MOMO
OH O
HO
OH
Pd(OAc)2, Cs2CO3,toluene, 80 oC, 17 h
steps
(144)
(145)
(146) (+)-heliannuol D (143)(32%)
3N HCl, THF,rt, 14 h, 96%
(-)-xanthorrhizol (1)
Scheme 1.18: Shishido’s synthesis of (+)-heliannuol D (143) from synthetic (–)-xanthorrhizol (1).
The starting material, (–)-xanthorrhizol (1) was previously prepared by the
same group (see Session 1.4.5). Xanthorrhizol (1) was subjected to sequential
protection, Sharpless AD and bromination to furnish MOM-protected key
intermediate (144). Treatment of (144) with palladium acetate (3 mol%) in the
presence of rac-2-(di-tert-butylphosphino)-1,1’-binaphthyl (145) (2.5 mol%) and
cesium carbonate in toluene at 80 °C produced the desired aryl ether (146) in 32%
yield. Acidic hydrolysis of compound (146) with 3N HCl in THF afforded (+)-
heliannuol D (143) in 96% yield.
Heliannuol D (143) has been isolated by Macías from the moderately polar
active fractions of the leaf aqueous extract of sunflowers (Helianthus annuus L. SH-
222). Heliannuol D (143) has been found to be a promising group of phenolic
allelochemicals that exhibit activity against dicotyledon plant species [87].
Allelopathy is a brand of science, which studies biochemical plant-plant and
plant-microorganism interactions. Allelopathy is most commonly defined as any
direct or indirect effect (stimulatory or inhibitory) by one plant, including
microorganisms, on another plant or microorganism through the production of
chemical compounds released into the environment [88]. Allelochemicals have been
implicated as biocommunicators and are an important potential source for new
herbicides and agrochemicals [89].
34
1.8 Objectives
The first objective is to isolate xanthorrhizol (1) from the essential oil of C.
xanthorrhiza by VLC purification. The second goal is to convert xanthorrhizol (1) to
several bisabolane-type sesquiterpenoids, viz. both diastereomers of 10,11-dihydro-
10,11-dihydroxyxanthorrhizols (137,138), curcuquinone (139), curcuhydroquinone
(140), helibisabonol A (142) and allylic alcohol derivative of O-methylxanthorrhizol
(147), as shown in the flow chart (Figure 1.2).
Figure 1.2: Isolation of xanthorrhizol (1) and transformation of xanthorrhizol (1) to several bisabolane type sesquiterpenoids.
Fresh Rhizomes of C. xanthorrhiza
Essential Oil
Xanthorrhizol
Hydrodistillation
VLC
Chemical Reactions
OH
HO
O
O
OH
HO
OH
OH
(140)(139)
(142)
OMe
(147)OH
OH
OH(137) C-10 = S(138) C-10 = R
OH10
CHAPTER 4
CONCLUSION
The essential oil of C. xanthorrhiza was obtained by hydrodistillation
technique in 0.93% average yield. Fractionation of the essential oil of C.
xanthorrhiza gave xanthorrhizol (1) in 20.2% yield. Xanthorrhizol (1) has been
successfully converted to several bisabolane-type sesquiterpenoids in optically active
form. This include the first enantioselective synthesis of both diastereomers of
xanthorrhizoldiols (137) and (138), enantioselective synthesis of helibisabonol A
diacetate (164) and the allylic alcohol derivative of O-methylxanthorrrhizol (145), in
which all of the derivatives involved Sharpless AD as the key step to introduce the
stereogenic centre at C-10 selectively. The unexpected difficulty in deprotection of
helibisabonol A diacetate (164) is due to acidic, basic and air-sensitive natures of
helibisabonol A (142). Besides terrestrial natural products, marine sesquiterpenoids,
curcuquinone (139) and curcuhydroquinone (140) have also been synthesised from
xanthorrhizol (1) in a short and facile way. The results showed that it is able to
prepare several analogues of bisabolane-type sesquiterpenoids using several methods
from xanthorrhizol (1). These findings demonstrated that xanthorrhizol (1) is a
versatile precursor for the preparation of naturally occurring bisabolane
sesquiterpenoids and derivatives thereof. Moreover, xanthorrhizol (1) can be
converted to bioactive heliannane-type sesquiterpenoids, which hitherto is the
desirable targets for synthetic chemists. It was found that selecting a better protecting
group for curcuhydroquinone (140) was necessary so that it can be removed without
using either acidic or basic conditions. In this aspect benzyl protecting group was
recommended because it can be cleaved via hydrogenation to give the free phenolic
form hopefully without complication.
References
1. Holttum, R. E. The Zingiberaceae of the Malay Peninsular. Gard. Bull. Sing.
1950. 13: 1-249.
2. Suksamran, A., Eiamong, S., Piyachaturawat, P. and Charoenpiboonsin, J.
Phenolic Diarylheptanoids from Curcuma xanthorrhiza. Phytochemistry
1994. 36: 1505-1508.
3. Rimpler, H., Hänsel, R. and Kochendoerfer, L. Xanthorrhizol, a New
Sesquiterpene from Curcuma xanthorrhiza. Z. Naturforsch. B: Anorg.
Chem., Org. Chem., Biochem., Biophy., Biol. 1970. 25: 995-998.
4. Aguilar, M. I., Delgado, G., Bye, R. and Linaress, E. Bisabolenes, Polycyclic
Diterpenoids and Other Constituents from the Roots of Iostephane
heterophylla. Phytochemistry 1993. 33: 1161-1163.
5. Mata, R., Martínez, E., Bye, R., Morales, G., Singh, M. P., Janso, J. E.,
Maiese, W. M. and Timmermann, B. Biological and Mechanistic Activities
of Xanthorrhizol and 4-(1’,5’-Dimethylhex-4’-enyl)-2-methylphenol Isolated
from Iostephane heterophylla. J. Nat. Prod. 2001. 64: 911-914.
6. John, T. K. and Rao, G. S. K. Absolute Configuration of Naturally Occuring
(–)-Xanthorrhizol. Indian J. Chem. 1985. 24B: 35-37.
7. Ponce-Monter, H., Campos, M. G., Aguilar, M. I. And Delgado, G. Effect of
Xanthorrhizol, Xanthorrhizol Glycoside and Trachylobanoic Acid Isolated
from Cachani Complex Plants upon the Contractile Activity of Uterine
Smooth Muscle. Phytother. Res. 1999. 13: 202-205.
8. Campos, M. G., Oropeza, M. V., Villanueva, T., Aguilar, M. I., Delgado, G.
and Ponce, H. A. Xanthorrhizol Induces Endothelium-independent
Relaxation of Rat Thoracic Aorta. Life Sci. 2000. 67: 327-333.
9. Itokawa, H., Hirayama, F., Funakoshi, K. and Takeya, K. Studies on the
Antitumor Bisabolane Sesquiterpenoids Isolated from Curcuma
xanthorrhiza. Chem. Pharm. Bull. 1985. 33: 3488-3492.
98
10. Hwang, J.-K., Shim, J.-S., Baek N.-I. and Pyun Y.-R.. Xanthorrhizol: A
Potential Antibacterial Agent from Curcuma xanthorrhiza Against
Streptococcus mutans. Planta Med. 2000. 66: 196-197.
11. Hwang J.-K., Shim, J.-S. and Pyun, Y.-R. Antibacterial Activity of
Xanthorrhizol from Curcuma xanthorrhiza Against Oral Pathogens.
Fitoterapia 2001. 71: 321-323.
12. Yamazaki, M., Maebayashi, Y., Iwase, N. and Kaneko, T. Studies on
Pharmacologically Active Principles from Indonesia Crude Drugs. II.
Hypothermic Principle from Curcuma xanthorrhiza Roxb. Chem. Pharm.
Bull. 1988. 36: 2075-2078
13. Ozaki, Y. Anti-inflammatory Effect of Curcuma xanthorrhiza Roxb, and its
Active Principles. Chem. Pharm. Bull. 1990. 38: 1045-1048.
14. Uehara, S-I., Yasuda, I., Takeya, K. and Itokawa, H. New Bisabolane
Sesquiterpenoids from the Rhizomes of Curcuma xanthorrhiza
(Zingiberaceae). Chem. Pharm. Bull. 1989. 37: 237-240.
15. Uehara, S-I., Yasuda, I., Takeya, K., Itokawa, H. and Iitaka, Y. New
Bisabolane Sesquiterpenoids from the Rhizomes of Curcuma xanthorrhiza
(Zingiberaceae) II. Chem. Pharm. Bull. 1990. 38: 261-263.
16. Uehara, S-I., Yasuda, I., Takeya, K. and Itokawa, H. Terpenoids and
Curcuminoids of the Rhizomes of Curcuma xanthorhiza Roxb. Yakugaku
Zasshi 1992. 112: 817-823.
17. Pandji, C., Grimm, C., Wray, V., Witte, L. and Proksch, P. Insecticidal
Constituents from Four Species of the Zingiberaceae. Phytochemistry 1993.
34: 415-419.
18. Pua, S. S. Kandungan Kimia dan Kajian Bioaktiviti Sebatian Semula Jadi
daripada Rizom Curcuma xanthorrhiza. B.Sc. Thesis. Universiti Teknologi
Malaysia; 1999.
19. Masuda, T., Isobe, J., Jitoe, A. and Nakatani, N. Antioxidative Curcuminoids
from Rhizomes of Curcuma xanthorrhiza. Phytochemistry 1992. 3: 3645-
3647.
20. Vogel and Pelletier. J. Pharm. 1815. 2: 50.
21. Daube, F. W. Ueber Curcumin, den Farbstoff der Curcumawurzel. Ber.
Dtsch. Chem. Ges. 1870. 3: 609-613.
99
22. Lampe, V., Milobedzka, J. and Konstanecki, St. V. Curcumin. Ber. Dtsch.
Chem. Ges. 1910. 43: 2163-2170; Chem. Abstr. 4: 15671.
23. Lampe, V. Synthesis of Curcurmin. Ber. Dtsch. Chem. Ges. 1918. 51: 1347-
1355; Chem. Abstr. 7: 23218.
24. Roughley, P. J. and Whiting, D. A. Experiments in the Biosynthesis of
Curcumin. J. Chem. Soc., Perkin Trans. 1. 1973. 2379-2388.
25. Noguchi, N., Komuo, E., Niki, E. and Willson, R. L. Action of Curcumin as
an Antioxidant Against Lipid Peroxidation. J. Jpn. Oil Chem. Soc. 1994. 43:
1045-1051.
26. Ammon, H. P. T., Safayhi, H., Safayhi, H., Mack, T. and Sabieraj, J.
Mechanism of Antiinflammatory Actions of Curcumine and Boswellic
Acids. J. Ethnopharmacol. 1993. 38: 113-119.
27. Satoskar, R. R., Shah, S. J. and Shenoy, S. G. Evaluation of Anti-
inflammatory Property of Curcumin (Diferuloyl Methane) in Patients with
Postoperative Inflammation. Int. J. Pharmacol. Ther. Toxicol. 1986. 24: 651-
654.
28. Srivastava, K. C., Bordia, A. and Verma, S K. Curcumin, a Major
Component of Food Spice Turmeric (Curcuma longa) Inhibits Aggregation
and Alters Eicosanoid Metabolism in Human Blood Platelets.
Prostaglandins, Leukotrienes and Essential Fatty Acids. 1995. 52: 223-227.
29. Rasmussen, H. B., Christensen, S. B., Kvist, L. P. and Karazmi, A. A Simple
and Efficient Separation of the Curcumins, the Antiprotozoal Constituents of
Curcuma longa. Planta Med. 2000. 66: 396-398.
30. Song, E.-K., Cho, H., Kim J.-S., Kim N.-Y., An, N.-H., Kim, J.-A., Lee, S.-
H. and Kim, Y.-C. Diarylheptanoids with Free Radical Scavenging and
Hepatoprotective Activity in vitro from Curcuma longa. Planta Med. 2001.
67: 876-877.
31. Uehara, S-I., Yasuda, I., Akiyama, K., Morita, H., Takiya, K. and Itokawa,
H. Diarylheptanoids from the Rhizomes of Curcuma xanthorrhiza and
Alpinia officinarum. Chem. Pharm. Bull. 1987. 35: 3298-3304.
32. Claeson, P., Panthong, A., Tuchinda, P., Reutrakul, V., Kanjanapothi, D.,
Taylor, W. C. and Santisuk, T. Three Non-phenolic Diarylheptanoids with
Anti-Inflammatory Activity from Curcuma xanthorrhiza. Planta Med. 1993.
59: 451-454.
100
33. Mane, R. B. and Rao G. S. K. Terpenoids. XXIX. Synthesis of
Xanthorrhizol. Indian J. Chem. 1974. 12B: 938-939.
34. ApSimon, J. The Total Synthesis of Natural Products. Vol. 5. USA: John
Wiley & Sons. 1983. 42-43.
35. Rane, R. K., Desai, U. V. and Mane, R. B. A Short Synthesis of
Xanthorrhizol. Indian J. Chem. 1987. 26B: 572-573.
36. Krause, W. and Bohlmann, F. Synthesis of Hydroxycadalene and
Hydroxycalamenene via 13-Hydroxyxanthorrhizol, A Possible Precursor of
Parvifoline. Tetrahedron Lett. 1987. 28: 2575-2578.
37. Nagumo, S., Irie, S., Hayashi, K. and Akita, H. A Formal Total Synthesis of
Xanthorrhizol Based on Nucleophilic Opening of Vinyloxirane by
Arylcopper Reagent. Heterocycles 1996. 43: 1175-1178.
38. Meyers, A.I. and Stoianova, D. Short Asymmetric Synthesis of (+)-α-
Curcumene and (+)-Xanthorrhizol. J. Org. Chem. 1997. 62: 5219-5221.
39. Fuganti, C. and Serra, S. Baker’s Yeast-mediated Enantioselective Synthesis
of the Bisabolene Sesquiterpenes (+)-Curcuphenol, (+)-Xanthorrhizol, (–)-
Curcuquinone and (+)-Curcuhydroquinone. J. Chem. Soc., Perkin Trans. 1.
2000. 3758-3764.
40. Garcia G, E., Mendoza, V. and Guzman B, A. Perezone and Related
Sesquiterpenes from Parvifoline. J. Nat. Prod. 1987. 50: 1055-1058.
41. Sato, K., Bando, T., Shindo, M. and Shishido, K. An Enantiocontrolled Total
Synthesis of (–)-Xanthorrhizol. Heterocycles 1999. 50: 11-15.
42. Bohmmann, F. and Zdero, C. Über Die Inhaltsstoffe von Cereopsis
parvifolia Blake. Chem. Ber. 1977. 110: 468-473; Chem Abstr. 86: 190242.
43. Joseph-Nathan, P., Hernández, J. D., Román, L. U., García, E., Mendoza, V.
and Mendoza, S. Coumarin and Terpenoids from Perezia alamani var.
oolepis. Phytochemistry 1982. 21: 1129-1132.
44. Joseph-Nathan, P., Hernández, J. D., Pomán, L.U., García, E. and Mendoza,
V. Sesquiterpenes from Pereziae carpholepsis. Phytochemistry 1982. 21:
669-672.
45. García, E., Mendoza, V. and Guzmán B. J. A. Sesquiterpenes from Perezia
longifolia. J. Nat. Prod. 1988. 51: 150-151.
46. Schröder, M. Osmium Tetroxide: Cis Hydroxylation of Unsaturated
Substrates. Chem. Rev. 1980. 80: 187-213.
101
47. Johnson, R. A. and Sharpless, K. B. Catalytic Asymmetric Dihydroxylation.
In: Ojima, I. (ed.). Catalytic Asymmetric Synthesis. New York: VCH
Publishers. 227-272; 1993.
48. Lohray, B. B. Recent Advances in the Asymmetric Dihydroxylation of
Alkenes. Tetrahedron: Asymmetry 1992. 3: 1317-1349.
49. Kolb, H. C., VanNieuwenhze, M. S. and Sharpless, K. B. Catalytic
Asymmetric Dihydroxylation. Chem. Rev. 1994. 94: 2483-2547.
50. Bonini, C. and Righi, G. A Critical Outlook and Comparison of
Enantioselective Oxidation Methodologies of Olefins. Tetrahedron 2002. 58:
4981-5021.
51. Hentges, S. G. and Sharpless, K. B. Asymmetric Induction in the Reaction of
Osmium Tetroxide with Olefins. J. Am. Chem. Soc. 1980. 102: 4263-4265.
52. Jacobsen, E. N., Markó, I., Mungall, W. S., Schröder, G. Sharpless, K. B.
Asymmetric Dihydroxylation via Ligand-Accelerated Catalysis. J. Am.
Chem. Soc. 1988. 110: 1968-1970.
53. Kwong, H.-L., Sorato, C., Ogino, Y., Chen, H. and Sharpless, K. B.
Preclusion of the “Second Cycle” in the Osmium-Catalysed Asymmetric
Dihydroxylation of Olefins Leads to a Superior Process. Tetrahedron Lett.
1990. 31: 2999-3002.
54. Wai, J. S. M., Marko, I., Svendsen, J. S., Finn, M. G., Jacobsen, E. N. and
Sharpless, K. B. A Mechanistic Insight Leads to a Greatly Improved
Osmium-catalyzed Asymmetric Dihydoxylation Process. J. Am. Chem. Soc.
1989. 111: 1123-1125.
55. Minato, M., Yamamoto, K. and Tsuji, J. Osmium Tetroxide Catalyzed
Vicinal Hydroxylation of Higher Olefins by Using Hexacyanoferrate(III) Ion
as a Cooxidant. J. Org. Chem. 1990. 55: 766-768.
56. Sharpless, K. B., Amberg, W., Bennani, Y. L., Crispino, G. A., Hartung, J.,
Jeong, K.-S., Kwong, H.-L., Morikawa, K., Wang, Z.-M., Xu, D. and Zhang,
X.-L. The Osmium-Catalysed Asymmetric Dihydroxylation: A New Ligand
Class and a Process Improvement. J. Org. Chem. 1992. 57: 2768-2771.
57. Becker, H., King, S. B., Taniguchi, M., Vanhessche, K. P. M. and Sharpless,
K. B. New Ligands and Improved Enantioselectivities for the Asymmetric
Dihydroxylation of Olefins. J. Org. Chem. 1995. 60: 3940-3941.
102
58. Amberg, W., Bennani, Y. L., Chadha, R. K., Crispino, G. A., Davis, W. D.,
Hartung, J., Jeong, K.-S., Ogino, Y., Shibata, T. and Sharpless, K. B.
Syntheses and Crystal Structures of the Alkaloid Derivatives Used as
Ligands in the Osmium-catalysed Asymmetric Dihydroxylation of Olefins.
J. Org. Chem. 1993. 58: 844-849.
59. Becker, H. and Sharpless, K. B. A New Ligand Class for the Asymmetric
Dihydroxylation of Olefins. Angew. Chem., Int. Ed. Engl. 1996. 35: 448-451.
60. Berrisford, D. J., Bolm, C. and Sharpless, K. B. Ligand-Accelerated
Catalysis. Angew. Chem., Int. Ed. Engl. 1995. 34: 1059-1070.
61. Mehltretter, G. M., Döbler, C., Sundermeier, U. and Beller, M. (2000). An
Improved Version of the Sharpless Asymmetric Dihydroxylation.
Tetrahedron Lett. 41: 8083-8087.
62. Jonsson, S. Y., Färnegårdh, K. and Bäckvall, J.-E. Osmium-Catalyzed
Asymmetric Dihydroxylation of Olefins by H2O2 Using a Biomimetic
Flavin-Based Coupled Catalytic System. J. Am. Chem. Soc. 2001. 123: 1365-
1371.
63. Krief, A. and Colaux-castillo, C. Catalytic Asymmetric Dihydroxylation of
α-Methylstryene by Air. Tetrahedron Lett. 1999. 40: 4189-4192.
64. Döbler, C., Mehltretter, G. M., Sundermeier, U. and Beller, M. Osmium-
Catalyzed Dihydroxylation of Olefins Using Dioxygen or Air as the
Terminal Oxidant. J. Am. Chem. Soc. 2000. 122: 10289-10297.
65. Mehltretter, G. M., Bhor, S., Klawonn, M., Döbler, C., Sundermeier, U.,
Eckert, M., Militzer, H.-C. and Beller, M. A New Practical Method for the
Osmium-Catalyzed Dihydroxylation of Olefins using Bleach as the Terminal
Oxidant. Synthesis 2003. 2: 295-301.
66. Junttila, M. H. and Hormi, O. E. O. Sodium Chlorite as an Efficient Oxidant
and Hydroxy Ion Pump in Osmium-Catalyzed Asymmetric Dihydroxylation.
J. Org. Chem. 2004. 69: 4816-4820.
67. Kolb, H. C. and Sharpless, K. B. A Simplified Procedure for the
Stereospecific Transformation of 1,2-Diols into Epoxides.” Tetrahedron
1992. 48: 10515-10530.
68. Oi, R. and Sharpless, K. B. Asymmetric Dihydroxylation of Acrolein
Acetals: Synthesis of Stable Equivalents of Enantiopure Glyceraldehyde and
Glycidaldehyde. Tetrahedron Lett. 1992. 33: 2095-2098.
103
69. Wang, Z.-M., Kolb, H. C. and Sharpless, K. B. Large-Scale and Highly
Enantioselective Synthesis of the Taxol C-13 Side Chain through
Asymmetric Dihydroxylation. J. Org. Chem. 1994. 59: 5104-5105.
70. Corey, E. J. and Dittami, J. P. Total Synthesis of (±)-Ovalicin. J. Am. Chem.
Soc. 1985. 107: 256-257.
71. Corey. E. J., Guzman-Perez, A. and Noe, M. C. Short Enantioselective
Synthesis of (–)-Ovalicin, a Potent Inhibitor of Angiogenesis, Using
Substrate-Enhanced Catalytic Asymmetric Dihydroxylation. J. Am. Chem.
Soc. 1994. 116: 12109-12110.
72. Nicolaou, K. C., Fylaktakidou, K. C., Monenschein, H., Yiwei Li,
Weyershausen, B., Mitchell, H. J., Wei, H.-X., Guntupalli, P., Hepworth, D.
and Sugita K. Total Synthesis of Apoptolidin: Construction of
Enantiomerically Pure Fragments. J. Am. Chem. Soc. 2003. 125: 15433-
15442.
73. Nicolaou, K. C., Yiwei Li, Sugita, K., Monenschein, H., Guntupalli, P.,
Mitchell, H. J., Fylaktakidou, K. C., Vourloumis, D., Giannakakou, P. and
O’Brate, A. Total Synthesis of Apoptolidin: Completion of the Synthesis and
Analogue Synthesis and Evaluation. J. Am. Chem. Soc. 2003. 125: 15443-
15454.
74. Walsh, P. J. and Sharpless, K. B. Asymmetric Dihydroxylation (AD) of α,β-
Unsaturated Ketones. Synlett. 1993: 605-606.
75. Bennani, Y. L. and Sharpless, K. B. Asymmetric Dihydroxylation (AD) of
N,N-Dialkyl and N-methoxy-N-methyl α,β– and β,γ–Unsaturated Amides.
Tetrahedron Lett. 1993. 34: 2079-2082.
76. Balkenhohl, F., Bussche-Hunnefeld, C, Lansky, A. and Zechel, C.
Combinatorial Synthesis of Small Organic Molecules. Angew. Chem., Int.
Ed. Engl. 1996. 35: 2289-2337.
77. Ellman, J. A. and Thiompson, L. A. Synthesis and Applications of Small
Molecule Libraries. Chem. Rev. 1996. 96: 555-600.
78. Xia, Y., Yang, Z-Y., Brossi, A. and Lee, K.-H. Asymmetric Solid-phase
Synthesis of (3’R,4’R)-Di-O-cis-acyl 3-Carbonyl Khellactones. Org. Lett.
1999. 1: 2113-2115.
104
79. Manguro, L. O. A., Mukonyi, K. M. and Githiomi, J. K. Bisabolenes and
Furanosesquiterpernoids of Kenyan Commiphora kua Resin. Planta Med.
1996. 62: 84-85.
80. Manguro, L. O. A., Ugi, I. And Lemmen, P. Further Bisabolenes and
Dammarane Triterpenes of Commiphora kua Resin. Chem. Pharm. Bull.
2003. 51: 479-482.
81. Dennison, N. R., Mirrington, R. N. and Stuart, A. D. The Synthesis of a
Phenolic Sesquiterpene Isolated from Elvira biflora (Compositae). Aust. J.
Chem. 1975. 28: 1339-1343.
82. Aguilar, M. I., Delgado, G., Hernández, L. and Villarreal, M. L. Bioactive
Compounds from Iostephane heterophylla. Nat. Prod. Lett. 2001. 15: 93-
101.
83. McEnroe, F. J. and Fenical, W. Structures and Synthesis of Some New
Antibacterial Sesquiterpenoids from the Gorgonian Coral Pseudopterogorgia
rigida. Tetrahedron 1978. 34: 1661-1664.
84. Spring, O., Rodon, U. and Macías, F. A. Sesquiterpenes from Noncapitate
Glandular Trichomes of Helianthus annuus. Phytochemistry 1992. 31: 1541-
1544.
85. Aguilar, M. I., Delgado, G. and Villarreal, M. L. New Bioactive Derivatives
of Xanthorrhizol. Rev. Soc. Quim. Mex. 2001. 45: 56-59.
86. Kishuku, H. Yoshimura, T., Kakehashi, T., Shindo, M. and Shishido, K.
Enantiocontrolled Total Synthesis of (+)-Heliannuol D via Palladium-
Mediated Heterocyclization. Heterocycles 2003. 61: 125-131.
87. Macías, F. A., Molinillo, J. M. G., Varela, R. M., Torres, A. and Fronczek,
F. R. Structural Elucidation and Chemistry of a Novel Family of Bioactive
Sesquiterpenes: Heliannuols. J. Org. Chem. 1994. 59: 8261-8266.
88. Vyvyan, J. R. Allelochemicals as Leads for New Herbicides and
Agrochemicals. Tetrahedron 2002. 58: 1631-1646.
89. Macías, F.A., Varela, R.M., Torres, A. and Molinillo, J. M. G. Heliannuol E.
A Novel Bioactive Sesquiterpene of the Heliannane Family. Tetrahedron
Lett. 1999. 40: 4725-4728.
90. Ohtani, I, Kusumi, T., Kashman, Y. and Kakisawa, H. High-Field FT NMR
Application of Mosher’s Method. The Absolute Configuration of Marine
Terpenoids. J. Am. Chem. Soc. 1991. 113: 4092-4096.
105
91. Büchi, G., Weinreb, S. M. Total Syntheses of Aflatoxins M1 and G1 and an
Improved Synthesis of Aflatoxin B1. J. Am. Chem. Soc. 1971. 93: 746-752.
92. Vidari, G., Rosa, A. D., Zanoni, G. and Bicchi, C. Enantioselective Synthesis
of Each Stereoisomer of the Pyronoid Linalool Oxides: the Linalool Route.
Tetrahedron: Asymmetry 1999. 10: 3547-3557.
93. Macías, F. A., Torres, A., Galindo, J. L. G., Varela, R. M., Álvarez, J. A.,
Molinillo, J. M. G. Bioactive Terpenoids from Sunflower Leaves cv.
Peredovick®. Phytochemistry 2002. 61: 687-692.
94. Sánchez, I. H., Lemini, C. and Joseph-Nathan, P. Short, High-yield
Syntheses of (±)-Curcuhydroquinone and (±)-Curcuquinone. J. Org. Chem.
1981. 46: 4666-4667.
95. Ono, M., Yamamoto, Y., Todoroki, R. and Akita, H. A Facile Synthesis of
4-Aryl-5-hydroxy-(2E)-pentenoate Derivative and its Applications to the
First Synthesis of (±)-Curcudiol, (±)-Curcuquinone and (±)-
Curcuhydroquinone. Heterocycles 1994. 37: 181-185.
96. Ono, M., Yamamoto, Y. and Akita, H. Reaction of Methyl 4,5-epoxy-(2E)-
pentenoate with Arenes. II. Application to the synthesis of (±)-Curcudiol,
(±)-Curcuphenol, (±)-Curcuhydroquinone and (±)-Curcuquinone. Chem.
Pharm. Bull. 1995. 43: 553-558.
97. Kad, G. L., Khurana, A., Singh, V and Singh, J. Microwave-assisted
Efficient Synthesis of Alliodorin and (±)-Curcuhydroquinone. J. Chem. Res.
(S). 1999. 164-165.
98. Vyvyan, J. R., Loitz, C., Looper, R. E., Mattingly, C. S., Peterson, E. A. and
Staben, S. T. Synthesis of Aromatic Bisabolene Natural Products via
Palladium-Catalyzed Cross-Couplings of Organozinc Reagents. J. Org.
Chem. 2004. 69: 2461-2468.
99. Takabatake, K., Nishi, I., Shindo, M. and Shishido, K. Enantioselective Total
Synthesis of Heliannuols D and A. J. Chem. Soc., Perkin Trans. 1. 2000.
1807-1808.
100. Yoshimura, T., Kisyuku, H., Kamei, T., Takabatake, K., Shindo, M.,
Shishido, K. Enantiocontrolled Synthesis of (+)-curcuquinone and (–)-
Curcuhydroquinone. Arkivoc. 2003. 8: 247-255.
101. Macías, F. A., Marín, D., Chinchilla, D. and Molinillo, J. M. G. First Total
Synthesis of (±)-Helibisabonol A. Tetrahedron Lett. 2002. 43: 6417-6420.
106
102. Thompson, M. J. and Zeegers, P. J. A Theoretical Study on the Two-phase
Nitration of Phenols. Tetrahedron 1989. 45: 191-202.
103. Thompson, M. J. and Zeegers, P. J. Studies on the Two-phase Nitration of
Phenols 9 (part 2). Tetrahedron 1990. 46: 2661-2674.
104. Zeegers, P. J. Nitration of Phenols: A Two-phase System. J. Chem. Edu.
1993. 70: 1036-1037.
105. El Sayed, K. A., Yousaf, M., Hamann, M. T., Avery, M. A., Kelly, M. and
Wipf, P. Microbial and Chemical Transformation Studies of the Bioactive
Marine Sesquiterpenes (S)-(+)-Curcuphenol and -Curcudiol Isolated from a
Deep Reef Collection of the Jamaican Sponge Didiscus oxeata. J. Nat. Prod.
2002. 65: 1547-1553.
106. Behrman, E. J. The Persulfate Oxidation of Phenols and Arylamines (The
Elbs and the Boyland-Sims Oxidations). Org. React. 1986. 35: 421-511.
107. Watson, K. G. and Serban, A. Evaluation of the Elbs Persulfate Oxidation
Reaction for the Preparation of Aryloxyphenoxypropionate Herbicides. Aust.
J. Chem. 1995. 48: 1503-1509.
108. Hadfield, J. A., McGown, A. T. and Butler, J. A High-yielding Synthesis of
the Naturally Occurring Antitumour Agent Irisquinone. Molecules 2000. 5:
82-88.
109. Bohlmann, F., Zdero, C., Robinson, H. and King, R. M. A Diterpene, a
Sesquiterpene Quinone and Flavanones from Wyenthia helenioides.
Phytochemistry 1981. 20: 2245-2248.
110. Miller, S. L., Tinto, W. F., Mclean, S., Reynolds, W. F. and Yu, M.
Bisabolane Sesquiterpenes from Barbadian Pseudopterogorgia spp. J. Nat.
Prod. 1995. 58: 1116-1119.
111. Huber, D., Leclerc, G. and Andermann, G. The Use of Lithium Borohydride
for Deprotecting Acetylated Alcohols and Phenols in the Presence of N-
Acetylated Guanidines. Tetrahedron Lett. 1986. 27: 5731-5734.
112. Mori, K., Tominaga, M., Takagawa, T. and Matsui, M. A Mild
Transesterification Method. Synthesis 1973. 790-791.
113. Herzig, J., Nudelman, A., Gottlieb, H. E. and Fischer, B. Studies in Sugar
Chemistry. 2. A Simple Method for O-Deacylation of Polyacylated Sugars.
J. Org. Chem. 1986. 51: 727-730.
107
114. Dale, J. A. and Mosher, H. S. Nuclear Magnetic Resonance Enantiomer
Reagents. Configurational Correlation via Nuclear Magnetic Resonance
Chemical Shifts of Diastereomeric Mandelate, O-Methylmandelate, and α-
Methoxy-α-trifluoromethylphenylacetate (MTPA) esters. J. Am. Chem. Soc.
1973. 95: 512-519.
115. Kusumi, T., Fukushima, T., Ohtani, I. and kakisawa, H. Elucidation of the
Absolute Configuration of Amino Acids and Amines by the Modified
Mosher’s Method. Tetrahedron Lett. 1991. 32: 2939-2942.
116. Yamaguchi, S. Nuclear Magnetic Reonance Analysis Using Chiral
Derivatives. In: Morrison, J. D. Asymmetric Synthesis. Vol. 1: Analytical
Methods. Orlando: Academic Press. 125-152; 1983.
117. Gawley, R. E. and Aubé, J. Analytical Methods. In: Tetrahedron Organic
Chemistry Series 14: Principles of Asymmetric Synthesis. UK: Elsevier. 51-
55; 1996.
118. Tamelen, E. E. V. and Leiden, T. M. Biogenetic-Type Total Synthesis of
(±)-Triptonide and (±)-Triptolide. J. Am. Chem. Soc. 1982. 104: 1785-1786.
119. Yadav, J. S., Mysorekar, S. V. and Rao, A.V. R. Synthesis of (1R)-(+)-Cis-
Chrysanthemic Acid. Tetrahedron 1989. 45: 7353-7360.