SYNTHESIS OF SEVERAL BISABOLANE SESQUITERPENOIDS FROM
XANTHORRHIZOL ISOLATED FROM C. XANTHORRHIZA
NGAI MUN HONG
UNIVERSITI TEKNOLOGI MALAYSIA
PSZ 19:16 (Pind. 1/97)
UNIVERSITI TEKNOLOGI MALAYSIA
BORANG PENGESAHAN STATUS TESIS♦
JUDUL :
SYNTHESIS OF SEVERAL BISABOLANE SESQUITERPENOIDS
FROM XANTHORRHIZOL ISOLATED FROM
C. XANTHORRHIZA
SESI PENGAJIAN: 2004/2005
Saya :
NGAI MUN HONG
(HURUF BESAR)
mengaku membenarkan tesis ( PSM / Sarjana / Doktor Falsafah )* ini disimpan di
Perpustakaan Universiti Teknologi Malaysia dengan syarat-syarat kegunaan seperti
berikut:
1. Tesis adalah hakmilik Universiti Teknologi Malaysia.
2. Perpustakaan Universiti Teknologi Malaysia dibenarkan membuat salinan untuk
tujuan pengajian sahaja.
3. Perpustakaan dibenarkan membuat salinan tesis ini sebagai bahan pertukaran antara
institusi pengajian tinggi.
4. **Sila tandakan ( √ )
√
SULIT
(Mengandungi maklumat yang berdarjah keselamatan atau
kepentingan Malaysia seperti yang termaktub dalam AKTA
RAHSIA RASMI 1972)
TERHAD
(Mengandungi maklumat TERHAD yang telah ditentukan
oleh organisasi/badan di mana penyelidikan dijalankan)
TIDAK TERHAD
Disahkan oleh
______________________________
(TANDATANGAN PENULIS)
Alamat Tetap:
102, Blok 14, Seksyen 24,
40300, Shah Alam,
Selangor Darul Ehsan.
Tarikh: 9 MARCH 2005
________________________________
(TANDATANGAN PENYELIA)
PROF. DR HASNAH M. SIRAT
Nama Penyelia
Tarikh: 9 MARCH 2005
CATATAN: * Potong yang tidak berkenaan.
** Jika tesis ini SULIT atau TERHAD, sila lampirkan surat daripada pihak
berkuasa/organisasi berkenaan dengan menyatakan sekali sebab dan tempoh
tesis ini perlu dikelaskan sebagai SULIT atau TERHAD.
♦ Tesis dimaksudkan sebagai tesis bagi Ijazah Doktor Falsafah dan Sarjana secara
penyelidikan, atau disertasi bagi pengajian secara kerja kursus dan penyelidikan,
atau Laporan Projek Sarjana Muda (PSM).
“I hereby declare that I have read this thesis and in my opinion this thesis
is sufficient in terms of scope and quality for the award of the degree
of Master of Science (Chemistry)”.
Signature
:
………………………….
Name of Supervisor :
Prof. Dr Hasnah M. Sirat
Date
9.3.2005
:
BAHAGIAN A ⎯ Pengesahan Kerjasama*
Adalah disahkan bahawa projek penyelidikan tesis ini telah dilaksanalan melalui
kerjasama antara _______________________ dengan ________________________
Disahkan oleh:
Tandatangan : _________________________________ Tarikh: ______________
Nama
: _________________________________
Jawatan
: _________________________________
(Cop rasmi)
* Jika penyediaan tesis/projek melibatkan kerjasama.
BAHAGIAN B ⎯ Untuk Kegunaan Pejabat Sekolah Pengajian Siswazah
Tesis ini telah diperiksa dan diakui oleh:
Nama dan Alamat Pemeriksa Luar
: Prof. Dr Zuriati Zakaria
School of Chemical & Food Technology,
Faculty of Science & Technology,
Universiti Kebangsaan Malaysia
43600 UKM, Bangi, Selangor.
Nama dan Alamat Pemeriksa Dalam : Assoc. Prof. Dr Farediah Ahmad
Dept. of Chemistry, Faculty of Science,
Universiti Teknologi Malaysia,
81310 Skudai, Johor.
Nama Penyelia Lain (jika ada)
: _____________________________________
_____________________________________
_____________________________________
_____________________________________
Disahkan oleh Penolong Pendaftar di SPS:
Tandatangan : _________________________________ Tarikh: ______________
Nama
: Ganesan A/L Andimuthu
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
ii
I declare that this thesis entitled “SYNTHESIS OF SEVERAL BISABOLANE
SESQUITERPENOIDS FROM XANTHORRHIZOL ISOLATED FROM C.
XANTHORRHIZA” is the results of my own research except as cited in the
references. The thesis has not been accepted for any degree and is not concurrently
submitted in candidature of any other degree.
Signature
: ____________________
Name
: NGAI MUN HONG
Date
: 9.3.2005
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)-(3methoxy-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 Ometilxantorizol,
(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
1
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
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
2
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
RESULTS AND DISCUSSION
2.1 Extraction and Isolation of Xanthorrhizol
35
2.2 Synthesis of (10R/10S)-10,11-dihydro-10,11dihyroxyxanthorrhizols (137 and 138) from
Xanthorrhizol (1)
38
x
3
4
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
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
CONCLUSION
96
REFERENCES
97
APPENDICES
108
xi
LIST OF TABLES
TABLE NO.
TITLE
H and 13C NMR data of xanthorrhizol (1)
PAGE
2.1
1
2.2
1
H NMR and C NMR data of xanthorrhizyl
acetate (148)
39
2.3
1
H NMR and COSY data of acetoxydiols
(149) and (150)
40
2.4
13
C NMR data of acetoxydiols (149-150) and
triols (137-138)
41
2.5
1
H NMR, COSY and HMBC data of triols
(137) and (138)
42
2.6
1
H and 13C NMR data of curcuquinone (139)
and curcuhydroquinone (140)
57
2.7
1
H and 13C NMR data of curcuhydroquinone
diacetate (163) and diol (164)
58
2.8
1
H NMR data of helibisabonol A (142) and
quinone (166)
61
2.9
1
H NMR data of methoxyxanthorrhizol (167)
and methoxydiol (168)
66
2.10
1
H NMR data of MTPA esters (171S) and
(171R)
67
2.11
1
H NMR data of monoacetate (169), allylic
acetate (170) and diacetate (175)
72
2.12
1
74
2.13
1
H and 13C NMR data of diacetate (176) and
monoacetate phenol (177)
76
2.14
Summary of results
77
13
H NMR data of allylic alcohol (147)
37
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)-10,11dihydro-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
1
H NMR spectra of (7R,10S)-triol (137) and
(7R,10R)-(138)
46
2.4
1
H-1H COSY spectrum of (7R,10S)-triol (137)
47
2.5
1
H-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
1
68
H NMR spectra of the (S)-and (R)-MTPA
esters of compound (168)
xv
2.9
Difference in 1H chemical shift (∆δ 1H 171S174R) 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
amu
asymmetric dihydroxylation
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
1
116
4
13
5
1
6
13
7
IR spectrum of xanthorrhizyl acetate (148)
120
8
MS of xanthorrhizyl acetate (148)
121
9
1
122
10
13
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
1
129
16
COSY spectrum of (S)-Mosher ester (151)
130
17
CIMS of (S)-Mosher ester (151)
131
18
1
132
19
13
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
1
137
H NMR spectrum of xanthorrhizol (1)
C NMR spectrum of xanthorrhizol (1)
H NMR spectrum of xanthorrhizyl acetate (148)
C NMR spectrum of xanthorrhizyl acetate (148)
H NMR spectrum of (7R,10S)-acetoxydiol (149)
C NMR spectrum of (7R,10S)-acetoxydiol (149)
H NMR spectrum of (S)-MTPA ester (151)
H NMR spectrum of (7R,10R)-acetoxydiol (150)
C NMR spectrum of (7R,10R)-acetoxydiol (150)
H NMR spectrum of (S)-MTPA ester (152)
117
118
119
123
133
xx
24
COSY spectrum of (S)-Mosher ester (152)
138
25
IR spectrum of (10S)-10,11-dihydro-10,11dihydroxyxanthorrhizol (137)
139
26
13
C NMR spectrum of (10S)-10,11-dihydro10,11-dihydroxyxanthorrhizol (137)
140
27
DEPT spectrum of (10S)-10,11-dihydro-10,11dihydroxyxanthorrhizol (137)
141
28
MS of (10S)-10,11-dihydro-10,11dihydroxyxanthorrhizol (137)
142
29
IR spectrum of (10R)-10,11-dihydro-10,11dihydroxyxanthorrhizol (138)
143
30
13
C NMR spectrum of (10R)-10,11-dihydro10,11-dihydroxyxanthorrhizol (138)
144
31
DEPT spectrum of (10R)-10,11-dihydro10,11dihydroxyxanthorrhizol (138)
145
32
MS of (10R)-10,11-dihydro-10,11dihydroxyxanthorrhizol (138)
146
33
IR spectrum of 4-nitroxanthorrhizol (157)
147
34
1
148
35
IR spectrum of 2,4-dinitroxanthorrhizol (158)
149
36
1
H NMR spectrum of 2,4-dinitroxanthorrhizol
(158)
150
37
IR spectrum of curcuhydroquinone (140) prepared
by Elbs persulphate hydroxylation
151
38
1
H NMR spectrum of curcuhydroquinone (140)
prepared by Elbs persulphate hydroxylation
152
39
IR spectrum of curcuquinone (139)
153
40
1
154
41
MS of curcuquinone (139)
155
42
IR spectrum of curcuhydroquinone (140)
156
43
1
157
44
13
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
H NMR spectrum of 4-nitroxanthorrhizol (157)
H NMR spectrum of curcuquinone (139)
H NMR spectrum of curcuhydroquinone (140)
C NMR spectrum of curcuhydroquinone (140)
158
xxi
49
13
C NMR spectrum of curcuhydroquinone
diacetate (163)
163
50
DEPT spectrum of curcuhydroquinone diacetate
(163)
164
51
1
H NMR spectrum of curcuhydroquinone
diacetate (163)
165
52
IR spectrum of diacetoxydiol (164)
166
53
1
167
54
13
55
DEPT spectrum of diacetoxydiol (164)
169
56
DEPT spectrum of diacetoxydiol (164)
170
57
1
171
58
13
59
DEPT spectrum of (S)-Mosher ester (165)
173
60
MS of (S)-Mosher ester (165)
174
61
1
175
62
1
H NMR spectrum of helibisabonol A (142) after
column chromatography
176
63
COSY spectrum of helibisabonol A (142) after
column chromatography
177
64
1
H NMR spectrum of quinone derivative of
helibisabonol A (142)
178
65
IR spectrum of O-methylxanthorrhizol (167)
179
66
1
H NMR spectrum of O-methylxanthorrhizol
(167)
180
67
MS of O-methylxanthorrhizol (167)
181
68
IR spectrum of germacrone (6)
182
69
1
183
70
IR spectrum of methoxydiol (168)
184
71
1
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
H NMR spectrum of diacetoxydiol (164)
C NMR spectrum of diacetoxydiol (164)
H NMR spectrum of (S)-Mosher ester (165)
C NMR spectrum of (S)-Mosher ester (165)
H NMR spectrum of crude helibisabonol A (142)
H NMR spectrum of germacrone (6)
H NMR spectrum of methoxydiol (168)
168
172
xxii
78
1
79
MS of allylic acetate (170)
193
80
IR spectrum of allylic acetate (170)
194
81
1
195
H NMR spectrum of momoacetate (169)
H NMR spectrum of allylic acetate (170)
192
82
IR spectrum of diacetate (175)
196
83
1
197
84
IR spectrum of hydrolysis product of diacetate
(175), methoxydiol (168)
198
85
1
H 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
1
202
89(a)
1
H NMR spectrum of allylic alcohol (147) (400
MHz
203
89(b)
1
H NMR spectrum of allylic alcohol (147) (400
MHz)
204
90
13
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
1
210
96
13
97
DEPT spectrum of diacetate (176)
212
98
IR spectrum of monoacetate (177)
213
99
1
214
H NMR spectrum of diacetate (175)
H NMR spectrum of allylic alcohol (147)
C NMR spectrum of allylic alcohol (147)
H NMR spectrum of diacetate (176)
C NMR spectrum of diacetate (176)
H NMR spectrum of monoacetate (177)
211
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 bisabolanetype 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].
OH
O
S
(1)
(2)
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
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), βatlantone (5) and xanthorrhizol (1) were isolated as antitumour constituents from the
methanolic extract of the rhizomes of C. xanthorrhiza [9].
(3)
O
O
(4)
(5)
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].
O
(6)
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].
HO
HO
S
S
R
O
S
(7)
OH
S
H
OH
R
R
(8)
(9)
S
H
O
(10)
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
4
bisacurone C (14). Compound (11) was converted to its monoacetate to determine its
relative stereostructure by X-ray crystallography [15].
HO
HO
R S
HO
HO
S
O
R S
O
S
R
HO
HO
S
R
R
R
O
HO
HO
R
R
R
O
O
S
(12)
(11)
(13)
(14)
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].
O
H
H
(18)
(17)
(16)
(15)
O
O
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].
O
O
O
(20)
(19)
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].
O
O
R1
R2
HO
OH
(21) : R1 = OCH3, R2 = OCH3
(22) : R1 = OCH3, R2 = H
(23) : R1 = H, R2 = 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-hydroxy1,7-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
MeO
HO
OMe
(24)
OH O
O
MeO
HO
OH
OMe
(25)
OH
6
O
O
MeO
OMe
HO
OH
(26)
O
OH
MeO
OMe
HO
OH
(27)
Masuda et al. isolated another curcuminoid from the acetone extract of C.
xanthorrhiza rhizomes. Its structure has been assigned as 1-(4-hydroxy-3,5dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-(1E,6E)-1,6-heptadiene-3,4dione (28) based on its spectral data.
O
O
MeO
OMe
HO
OH
OMe
(28)
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-1,3heptadien-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].
O
(29)
OH
(30)
7
O
OH
H
(32)
(31)
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].
OH
OH
OH
OH
(33)
1.4
(34)
OH
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
HO
Me
S
(35)
(36)
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-methoxy4-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].
O
MeO
O
OEt
H2, 10% Pd-C
EtOH-AcOH
(39)
(38)
(37)
MeO
CO2Et
(40)
Br
OH
Zn dust MeO
cyclohexane
reflux
1h
MeMgI
Et2O
rt
6h
MeO
OH
(41)
I2
Benzene
10 h
CO2Et
RO
MeMgI
o
Xylene, 140 C
(42) R = Me
(1) R = H
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).
O
COOH
ClCO2Et, Et3N
O
(44)
(43)
OH
O
N
H
(46)
MeO
LiBr THF
-78 oC
(48)
(47)(54%)
MeO
1. TFA, rt, 24h
2. py, Ac2O, rt, 24h
3. LiAlH4, THF
N
dr >97:3
(49)
0 C to rt
H2N
(S)-t-leucinol
(45)
N
O
o
OEt
O
SOCl2
DIPHOSBr (51)
HO
O
MeO
Br
MeO
OH
(50)(57%)
Me2C=CHLi MeO
THF
30 min
(42)(94%)
(52)(91%)
EtSNa
DMF
HO
S
Br2Ph2P
PPh2Br2
DIPHOSBr (51)
(35)(92%)
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
Ph3P
O
COOH
(53)
(54)
COOH
OH
(56)
OMe
COOH
(55)
O
(EtO)2POCH2CO2Et,
NaH
81%
OMe
(57)
1. LiAlH4, THF
2. MnO2, CHCl3, reflux
81%
O
Baker's yeast,
4-6 days
49%
OMe
(59)
(58)
OH
OMe
Benzene
reflux
74%
1. Me2SO4, K2CO3, acetone
2. LiAlH4, THF
3. MnO2, CHCl3, reflux
4. MeMgCl, THF, 0 oC
5. MnO2, CHCl3, reflux
73%
COOEt
ClCO2Et, Et3N,
THF
then aq. KOH,
reflux, 86%
COOEt
COOEt
(60)
MgBr
1. TsCl, Py, CH2Cl2
2. NaI, acetone, reflux
84%
I
OMe
ee > 98%
(61)
(62)
CuI cat., THF
85%
NaSEt, DMF, reflux
90%
OMe
(42)
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(65)
tris-(triphenylphosphine)rhodium)
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.
p-TsOH
C6H6
reflux
HO
CHO
HO
O3
OH
(63)
(36)
(64)
(Ph3P)3RhCl (65), N2
MeMgI (2.2 eq.)
50 oC, 3 h
OH
(66)
O
O
I2
OH
OH
(67)
OH
(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 σsymmetrical 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 Salcohol (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
t
O
MeO
I
i
OH
O
MeO
Me
Bu
MeO
ii
OH
Me
Me
(71)
(70)
(68)
OMOM
OH
iii
MeO
OH
iv, v
MeO
Me
OH
Me
OAc
(73)
S-72
MeO
OH
Me
ix
(71)
vi - viii
OH
MeO
vi, vii MeO
Me
OAc
Me
OH
(74)
R-72
OH x, xi
MeO
MeO
SO2Ph
Me
Me
(74)
(75)
MeO
xiii
Me
O
t
Bu
O
(69)
RO
SO2Ph
xii
Me
BH-Li+
3
(76)
xiv
(42) R=Me
(1) R=H
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 R73; (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 transstilbene (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 Nmethylmorpholine-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
OH
1. OsO4 (1.1 eq.), ligand
PhCH3, 25 oC, 8-24 h
2. LiAlH4, Et2O
(78)
R
HO
OH
S
R
(80)
(79)
ligand =
N
S
3-18% ee
-
82% ee
(85% yield)
-
(81)
N
AcO
ligand =
H
H
OMe
N
(82)
N
OAc
H
ligand =
MeO
83.2% ee
(90% yield)
-
H
N
(83)
Scheme 1.6: The first enentioselective dihydroxylation reactions developed by
Sharpless.
O
O
O
H
N
Me O
NMO (84)
N
N
H
H
OMe
MeO
O
O
H
Cl
N
(85)
N
(86)
Cl
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.
O
O Os
O
O
R
R
R
HO
Primary cycle
(high enantioselectivity)
L
R
OH
H2O
R
HO
O Os O
O
L
(87)
R
OH
H2O
O
O Os O
O
O
L
R
O
R
NMM
NMO
L
L
(88)
Secondary cycle
(low enantioselectivity)
R
R
O
O
O
Os
O
O
R
R
R
R
R
R
L = chiral ligand
NMM = 4-methyl
morpholine
(89)
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 (DPPHAL) (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
H
N
N N
O
O
N
H
N
N N
O
H
O
H
OMe MeO
MeO
OMe
N
N
N
(90) (DHQ)2PHAL
(91) (DHQD)2PHAL
N
Ph
N
O
O
H
N
MeO
N
H
N
N
N
H
MeO
N
N
H
Ph
Ph
N
N
O
H
H
OMe
N
N
Ph
Ph
N
N
N N
N
O
N
(95) (DHQD)2DPP
(94) (DHQ)2DPP
N
N
N N
O
H
OMe MeO
N
OMe
(93) (DHQD)2PYR
O
N
H
N
Ph
N
N
N N
O
N
O
MeO
(92) (DHQ)2PYR
N
Ph
O
H
OMe
Ph
N
N
O
O
H
H
N
N N
O
H
OMe MeO
MeO
N
Ph
Ph
O
H
MeO
O
O
N
N
O
H
OMe MeO
N
(98) (DHQ)2AQN
(DHQ)2PHAL
5.52 g
–
N
N
H
O
Ph
(97) (DHQD)2DP-PHAL
N
N
Ph
N
N
(96) (DHQ)2DP-PHAL
reagents
AD-mix-α
AD-mix-β
OMe
O
N
O
H
OMe
O
N
(99) (DHQD)2AQN
(DHQD)2PHAL
–
5.52 g
K2OsO2(OH)4 K3Fe(CN)6 K2CO3
1.04 g
699.6 g
293.9 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 (DPPHAL) (96,97) and anthraquinone (AQN) (98,99) ligands used in the
Sharpless AD and composition of AD-mix-α and AD-mix-β.
20
R
R
OsO4 L
L
R
R
O
O Os O
(87)
O
L
OsO4
R
R
HO
OH
Organic
Aqueous
2K2CO3
4H2O
HO
HO
O
Os
O
2OH
OH
2- 2K CO
2
3
2H2O
O
OH
Os
O
OH
O
2K3Fe(CN)6
2K2CO3
O
2K4Fe(CN)6
2KHCO3
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) glycolateamine 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
R3N: +
O
O Os O
O
NR3
O
O Os
O
O
OsO4 + NR3 catalytic
HO
O
Os
O
LAE =
OH
O
O
"Os" stoichiometric
Saturation Rate with Ligand
Rate without Ligand
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.
dihydroquinidine derivatives (AD-mix-β)
NW
"HO
RS
RL
OH"
RM
OH"
HO
K2OsO4(OH)4
K3Fe(CN)6, K2CO3
t-BuOH/H2O 1:1
H
SW
"HO
NE
SE
RS
RL
OH
RM
H
RS
RM
H
HO
OH
RL
dihydroquinine derivatives (AD-mix-α)
Scheme 1.10: Mnemonic device for the AD of olefins.
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].
H
N
Me
N
N
Et O
(100)
N
O
Me
(101)
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
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
R1
R2
MeC(OMe)3,
O
cat. PPTS
R1
OH
(102)
OMe
O
AcX, or Me3SiX
X(104)
X
R1
R2
Base, MeOH
OAc
R2
R1
OAc
(107)
R2
R1
R2
(103)
PPTS = Pyridinium 4-toluenesulphonate
O
O
O
(106)
R2
R1
X
(105)
X = Cl, Br, I
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 4toluenesulphonate (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
(108)
O
OH
OH
p-TsCl, py,
0 oC to rt
O
O
OH
OTs
O
O
(109)
NaOMe,
MeOH,
reflux, 1 h
O
(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
O
Ph
OMe
(111)
AcHN
Ph
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
Ph
OMe
OH
(112)
1. MeC(OMe)3, p-TsOH,
CH2Cl2, 25 oC, 5 h
2. MeCOBr, CH2Cl2, -15 oC,
2 h (60%, 2 steps)
Br
1. NaN3, DMF, 50 oC, 19 h
Ph
O
OMe
NH O
Ph
O
Ph
OMe
O
OMe
OAc
(113)
2. H2, 10% Pd-C, MeOH,
25 oC (74%, 2 steps)
OH
(114)
1. 10% HCl (aq.), ∆, 2 h
2. PhCOCl, 25 oC, 2 h (72%, 2 steps)
O
Ph
OH O
AcO
NH O
Ph
OH
(115)
O
OH
O OH
13
H
HO
OAc
OBz
(116: taxol)
O
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
(118)
PMBCl, Et3N,
4-DMAP, 23 oC,
3 h (98%)
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
OMe
OH
OH
OH
MeO OMe
(119) [18% ee]
OMe
same
conditions
as above
O
OH
OH
(93%)
MeO
OMe
(120)
O
MeO OMe
(121) [>99% ee]
OH
O
O
O
H
OMe
OMe
(117)
OMe
(122)
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].
OH
HO
8
A
MeO
O
12
B
1
OH
O
O
OH H
MeO
O
HO 21
C
19
27
O
OH
HO
OMe
O
D
O
OH
E
O
OMe
Apoptolidin (123)
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
12
OTBS
20
OMe
19
27
23
O
OR O
TBS
(124) R = TBS
(125) R = H
OMe
OPMB
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%
12
OH
OTBS
19
20
27
23
OMe OH O
OR O
TBS
(126) R = TBS
(127) R = H
OMe
OPMB
Scheme 1.15: Nicolaou’s synthesis of apoptolidin (123).
1.6.4
Solid-Phase
Synthesis
Khellactones (131)
of
(3’R,4’R)-Di-O-cis-acyl
3-Carbonyl
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].
(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
O
O
O
O
O
O
O
O
O
OH
(128)
O
OH
(129)
DIC = [(CH3)2CH]2CH2CH2Cl.HCl (131) 1. RCOOH, DIC (131)(1 eq.)
2. DIEA, DMAP
O
O
OH
O
O
O
O
50% TFA/CH2Cl2
O
O
OR
OR
(132)
O
OR
OR
(130)
Scheme 1.16: Asymmetric solid-phase synthesis of (3’R,4’R)-di-O-cis-acyl 3carbonyl 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
OH
OH
(134)
(133)
OH
(137) C-10 = S
(138) C-10 = R
(136)
O
OH
O
HO
O
10
(135)
O
OH
HO
CHO
OH
(139)
(140)
(141)
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.
O
OH
O
HO
(139)
OH
(140)
OH
OH
OH
OH
(134)
(135)
(1)
OH
HO
OH
(142)
OH
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
(-)-xanthorrhizol (1)
steps
OH
MOMO
Br
(144)
MOMO
3N HCl, THF,
rt, 14 h, 96%
O
(32%)
(146)
OH
PtBu2
(145)
OH
Pd(OAc)2, Cs2CO3,
toluene, 80 oC, 17 h
HO
O
OH
(+)-heliannuol D (143)
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. SH222). 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-dihydro10,11-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).
Fresh Rhizomes of
C. xanthorrhiza
Hydrodistillation
Essential Oil
VLC
Xanthorrhizol
Chemical Reactions
O
OH
O
10
OH
HO
OH
(139)
OH
(140)
(137) C-10 = S
(138) C-10 = R
OMe
OH
HO
OH
OH
(142)
OH
(147)
Figure 1.2: Isolation of xanthorrhizol (1) and transformation of xanthorrhizol (1)
to several bisabolane type sesquiterpenoids.
CHAPTER 2
RESULTS AND DISCUSSION
2.1
Extraction and Isolation of Xanthorrhizol
The fresh rhizomes of C. xanthorrhiza were divided into two batches (CX-1
and CX-2) and subjected to hydrodistillation to yield the essential oils in 0.72% and
1.14% yields, respectively. Fractionation of the essential oil from CX-1 using PEEt2O with increasing proportion of Et2O yielded two major combined fractions
labelled as cxe(1) 4-9 and cxe(1) 11. Fraction cxe(1) 11 was used without further
purification. Essential oil from CX-2 was also subjected to vacuum liquid
chromatography (VLC) to give two major combined fractions, cxe(2) 10-12 and
cxe(2) 13. Fractions cxe(2) 13 was used without further purification whereas fraction
cxe(2) 10-12 was subjected to VLC again to give three combined fractions, cxe(2) 78a, cxe(2) 10a and cxe(2) 13. Fraction cxe(2) 7-8a was combined with fraction
cxe(1) 4-9 from CX-1 and the combined fraction was separated on VLC to furnish
fractions cxe 4-5b and cxe 6-11b. The extraction and fractionation procedure for
xanthorrhizol (1) is summarised in Figure 2.1. In summary, hydrodistillation of C.
xanthorrhiza gave essential oil in 0.93% average yield, while fractionation of the
essential oil yielded xanthorrhizol (1) in 20.2%.
Xanthorrhizol (1), [α]D –49.4° (c 1.0, MeOH), was isolated as a pale yellow
oil. The molecular ion [M+] at m/z 218 was in agreement with the molecular formula
C15H22O (Appendix 1). The IR spectrum (Appendix 2) displayed bands characteristic
for a hydroxyl group at 3387 cm-1, an olefinic bond at 1621 cm-1 and an aromatic
ring at 1587, 1422 and 813 cm-1.
36
Fresh Rhizomes of C. xanthorrhiza
1.85 kg (CX-1)
1.50 kg (CX-2)
Hydrodistillation
Hydrodistillation
17.17 g (1.14%)
13.39 g (0.72%)
13.39 g
15.40 g
VLC
VLC
Fr. 4–9
1.24 g
(9.27%)
Fr. 11
1.55 g
(11.61%)
Fr. 10–12
5.64 g
(36.60%)
Fr. 13
1.70 g
(11.01%)
cxe(1) 4-9
cxe(1) 11*
cxe(2) 10-12
cxe(2) 13*
5.26 g
VLC
Fr. 7–8
2.65 g
(50.45%)
Fr. 10
0.79 g
(15.11%)
Fr. 11
0.15 g
(2.76%)
cxe(2) 7-8a cxe(2) 10a* cxe(2) 11a§
3.89 g
VLC
*
§
Fr. 4-5
0.85 g
(21.86%)
Fr. 6-11
0.78 g
(20.05%)
cxe 4-5b*
cxe 6-11b§
Xanthorrhizol, quite pure (two spots on TLC)
Xanthorrhizol, pure (one spot on TLC)
Figure 2.1: Extraction and fractionation of xanthorrhizol from C. xanthorrhiza.
37
The 1H NMR spectrum of (1) (Appendix 3, Table 2.1) showed the presence
of 1,2,4-trisubstituted benzene ring moiety (δ 6.62, 1H, d, J 1.5 Hz, H-2; 7.03, 1H, d,
J 7.5 Hz, H-5; 6.70, 1H, dd, J 7.5, 1.5 Hz, H-6). The 1H NMR spectrum also revealed
the presence of four methyl groups; one secondary (δ 1.20, d, J 6.9 Hz, H-15), two
tertiary (δ 1.54, s, H-12; δ 1.68, s, H-13) one aromatic (δ 2.22, s, H-14); an olefinic
proton (δ 5.09, tt, J 8.4, 1.5 Hz, H-10) and a benzylic methine (δ 2.61, sext, J 6.9 Hz,
H-7). Multiplets at δ 1.56-1.64 and δ 1.88 were assigned to methylene protons at H-8
and H-9, respectively. The
13
C NMR spectrum of xanthorrhizol (1) (Appendix 4)
revealed 15 carbon signals as shown in Table 2.1. Compound (1) was assigned as
xanthorrhizol (1) based on its physical properties and comparison of its spectral data
with the xanthorrhizol isolated from C. xanthorrhiza [9].
Table 2.1: 1H and 13C NMR data of xanthorrhizol (1).
Position
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-OH
13
1
C NMR
δ (ppm)
147.2
113.5
153.6
120.8
130.3
119.4
39.0
38.4
26.1
124.5
131.4
17.7
25.7
15.3
22.4
-
H NMR
δ (ppm)
6.62
7.03
6.68
2.61
1.56-1.64
1.88
5.09
1.54
1.68
2.22
1.20
4.66
14
4
1
15
OH
13
2
11
7
10
(1)
12
Multiplicity
(J in Hz)
d(1.5)
d(7.5)
dd(7.5,1.5)
sext(6.9)
m
m
tt(8.4,1.5)
s
s
s
d(6.9)
br s
38
2.2
Synthesis of (10R/10S)-10,11-dihydro-10,11-dihyroxyxanthorrhizols (137
and 138) from Xanthorrhizol (1)
10,11-Dihydro-10,11-dihydroxyxanthorrhizol (137) (or 12,13-dihydro-12,13-
dihydroxyxanthorrhizol), is a bisabolane-type sesquiterpenoid isolated from the roots
of the Mexican medicinal plant, Iostephane heterophylla. Compound (137) was
isolated as a 1:1 mixture, which could not be separated and elicited weak
antidermatophytic effects against T. mentagrophytes and M. gypseum [82].
Compound (137) has been prepared in racemic form by trans-hydroxylation
of xanthorrhizol (1) [82], but no stereoselective synthesis has been accomplished.
Here a short synthesis of compound (137) employing Sharpless AD as the key step
was envisaged in which the stereocentre at C-10 could be introduced by Sharpless
AD, as shown in Scheme 2.1.
14
OR
AD-mix-α
MeSO2NH2
t-BuOH:H2O (1:1)
o
(1) R = H
Ac2O
py, 72.1% (148) R = Ac
OAc
0 C, 50%
OR
5
6
15
2
1
7
R
OH
S
10 11 12
OH
sat. NaHCO3
MeOH:H2O (2:1)
rt, 79.2%
(149) R = Ac
(137) R = H
OAc
AD-mix-β
MeSO2NH2
t-BuOH:H2O (1:1)
0 oC, 35.2%
13
R
R
OH
OH
(148)
sat. NaHCO3
MeOH:H2O (2:1)
rt, 72.9%
(150) R = Ac
(138) R = H
Scheme 2.1: Stereoselective synthesis of (10R/10S)-10,11-dihydro-10,11dihydroxyxanthorrhizols (137 and 138).
Xanthorrhizol (1) was first protected as its acetate derivative by treatment
with acetic anhydride-pyridine. The 13C and 1H assignments for compound (148) are
listed in Table 2.2. The 1H NMR spectrum of (148) (Appendix 5) showed an
acetoxyl signal at δ 2.33 (3H, s). The presence of a carbonyl group was attributed to
39
the 13C NMR (Appendix 6) resonances at δ 169.3. The presence of an acetoxyl group
was suggested by strong IR absorption (Appendix 7) at 1766 cm-1 and disappearance
of hydroxyl band of xanthorrhizol (1) at 3387 cm-1. The acetate ester of xanthorrhizol
(148) was subjected to AD employing AD-mix-α to give the acetoxydiol (149) in
50% isolated yield. The diastereomeric excess was more than 98% as determined by
1
H NMR analysis of its (S)-MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid]
ester derivative (151) (Appendix 15). The absolute configuration of the newly
formed stereogenic centre was deduced to be S from literature precedents [56] and by
means of the modified Mosher method [90] of its analogue, O-methylxanthorrhizol
(167) (see session 2.4.1). The C-10 epimer of acetoxydiol (149) was prepared by
using AD-mix-β following the same reaction conditions to give acetoxydiol (150) in
35.2% yield as a colourless liquid with the ee of more than 98% as determined by 1H
NMR analysis of its (S)-MTPA ester (152) (Appendix 23).
Table 2.2: 1H NMR and 13C NMR data of xanthorrhizyl acetate (148).
Position
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-OAc
C=O
13
C NMR
δ (ppm)
146.9
120.3
149.3
124.7
130.8
124.4
38.9
38.3
26.1
127.2
131.5
17.7
25.7
15.8
22.2
20.9
169.3
1
H NMR
δ (ppm)
6.84
7.16
6.99
2.69
1.55-1.66
1.88-1.95
5.10
1.53
1.69
2.16
1.24
2.33
-
Multiplicity
(J in Hz)
d(1.8)
d(7.8)
dd(7.8,1.8)
sext(6.9)
m
m
tt(7.2,1.2)
s
s
s
d(6.9)
s
-
40
O
OAc
OMe
S
CF3
10
(S)-MTP
OH
(S)-MTP O
(151) C-10 = S
(152) C-10 = R
The 1H NMR spectrum of (7R,10S)-acetoxydiol (149) (Appendix 9) showed
very close similarity to (7R,10R)-acetoxydiol (150) (Appendix 18). The 1H NMR
spectrum of acetoxydiol (149) showed a ddd peak integrating for one proton
indicating the presence of an oxymethine proton, H-10 at δ 3.32 with coupling
constants of J 10.5, 5.1, 2.1 Hz. In the COSY spectrum (Appendix 13), the C-10
methine proton showed coupling with the C-9 methylene and hydroxyl protons.
However, compound (150), the stereoisomer of acetoxydiol (149), showed a broad
doublet peak at δ 3.21 (J 9.6 Hz) which was assigned to H-10. The 1H NMR
spectrum of acetoxydiol (149) showed resonances for the presence of methylene
groups at δ 1.40 (1H, m, H-9) and δ 1.15 (1H, m, H-9’), while the signals for H-9 and
H-9’ of acetoxydiol (150) was overlapping at δ 1.31. The 1H and COSY data for
diols (149) and (150) are tabulated in Table 2.3.
Table 2.3: 1H NMR and COSY data of acetoxydiols (149) and (150).
Position
Acetoxydiol (149)
Acetoxydiol (150)
1
1
H NMR
COSY
H NMR
δ (ppm)
δ (ppm)
2
6.83 (d, 1.8)
H-6
6.83 (d, 1.8)
5
7.14 (d, 7.8)
H-6
7.14 (d, 7.8)
6
6.97 (dd, 7.8, 1.8)
H-2,H-5
6.97 (dd, 7.8, 1.8)
7
2.70 (m)
H-8,H-8’,H-15
2.67 (sext, 6.9)
8
1.83 (m)
H-7,H-8’,H-9,H-9’
1.84 (m)
8’
1.62 (m)
H-7,H-8’,H-9,H-9’
1.63 (m)
1.31 (m)
9
1.40 (m)
H-8,H-8’,H-9’
9’
1.15 (m)
H-8,H-8’,H-9’,
H-10
10
3.32 (ddd, 10.5, 5.1,
H-9, OH
3.21 (br d, 9.6)
2.1)
12
1.07 (s)
1.09 (s)
13
1.13 (s)
1.11 (s)
14
2.14 (s)
2.14 (s)
15
1.24 (d, 6.9)
H-7
1.23 (d, 6.9)
OAc
2.31 (s)
2.31 (s)
OH
2.02 (d, 5.1)
H-10
-
41
The 13C NMR data of acetoxydiols (149-150) and triols (137-138) are shown
in Table 2.4. The 13C NMR data of acetoxydiols (149) and (150) (Appendices 10 and
19) were very similar. It confirmed the presence of five methyls, one oxymethine
moiety, two methylenes, one methine, three aromatic methine carbons, four
quaternary carbons and one carbonyl at δ 169.3 for acetoxydiol (149) and δ 169.4 for
acetoxydiol (150).
The IR spectra of both acetoxydiols (149) and (150) (Appendices 12 and 21)
showed absorptions at 3416 cm-1 for hydroxyl groups and 1746 cm-1 for carbonyl
groups. The optical rotation for acetoxydiol (149) was –38.2° (c 1.02, CHCl3), while
acetoxydiol (150) has an opposite sign of rotation, +5.37° (c 1.08, CHCl3). These
results showed that acetoxydiols (149) and (150) are diastereomer with their absolute
configurations (7R,10S) and (7R,10R), respectively.
Table 2.4: 13C NMR data of acetoxydiols (149-150) and triols (137-138).
Carbon
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-OAc
C=O
Acetoxydiol
(149)
(150)
146.2
146.7
124.7
124.7
149.3
149.3
127.3
127.3
131.0
130.9
120.4
120.3
39.1
39.6
34.9
35.2
29.5
29.8
78.4
78.5
73.1
73.1
23.2
23.1
26.4
26.4
15.8
15.8
22.6
22.2
20.7
20.8
169.3
169.4
Triol
(146)
146.4
113.3
153.9
121.3
130.9
119.4
39.3
35.0
29.6
78.6
73.3
23.0
26.5
15.4
23.2
-
(147)
146.9
113.4
153.8
121.1
130.9
119.1
39.7
35.5
29.9
78.8
73.1
23.4
26.5
15.3
23.1
-
The acetoxydiols (149) and (150) were further transformed to the (7R,10S)triol (137) in 79.2 % yield, [α]D –64.7° (c 0.51, MeOH) and (7R,10R)-triol (138) in
72.8 % yield, [α]D +3.33° (c 0.30, MeOH) {lit. [82] [α]D –57° (c 0.30, MeOH)} by
saponification with aqueous sodium bicarbonate [91]. The MS of triol (137)
(Appendix 28) showed a molecular ion at m/z 252 which was in agreement with the
42
molecular formula C15H24O3. An additional peak at m/z 234 [M–H2O]+ and the
absorption band in the IR spectrum (Appendix 25) at 3361 cm-1, suggested the
presence of a hydroxyl group. The MS of (137) (Appendix 28) showed a base peak at
m/z 135, which corresponded to [M–C6H13O2]+. The prominent peak at m/z 59
indicating the presence of –C(OH)Me2 moiety.
The IR spectra of (137) and (138) (Appendices 25 and 29) showed no
carbonyl band hence confirmed that the acetyl group has been hydrolysed. This was
further supported by the disappearance of acetoxyl signal in the 1H NMR spectra.
The 1H NMR of triol (137) (Table 2.5, Figure 2.2) showed signals at δ 6.61
(1H, d, J 1.8 Hz, H-2), δ 7.02 (1H, d, J 7.8 Hz, H-5) and δ 6.66 (1H, dd, J 7.8, 1.8
Hz, H-6), corresponding to a 1,2,4-trisubstituted benzene ring, an aromatic methyl
Table 2.5: 1H NMR, COSY and HMBC data of triols (137) and (138).
(7R,10S)-Triol (137)
H NMR
COSY
δ (ppm)
6.61 (d, 1.8)
1
2
5
6
8
7.02 (d, 7.8)
6.66 (dd,
7.8, 1.8)
2.64 (sext,
6.9)
1.86 (m)
8’
1.60 (m)
9
1.40 (m)
9’
1.18 (m)
10
12
3.37 (br d,
10.2)
1.08 (s)
13
14
15
OH
7
H-6
H-5
H-8,H-8’,
H-15
H-7,H-8’,
H-9,H-9’
H-7,H-8,
H-9,H-9’
H-8,H-8’,
H-9,H-10
H-8,H-8’,
H-9,H-10
H-9,H-9’
1
H NMR
δ (ppm)
6.62 (d, 1.8)
(7R,10R)-Triol (138)
COSY
HMBC
-
C-3,C-4,
C-6,C-7
C-1,C-3,C-14
C-2,C-4,C-7
7.02 (d, 7.8)
H-6
6.67 (dd, 7.8,
H-5
1.8)
2.61 (sext,
H-8,H-8’,HC-1,C-2,C-6,
6.9)
15
C-8,C-15
1.85 (m)
H-7,H-8’,H-9,
C-1
H-9’
1.58 (m)
H-7,H-8,H-9,
C-9
H-9’
1.34 (m)
H-8,H-8’,H- C-8,C-12,C-13
10
H-9,H-9’
-
-
3.30 (dd, 9.9,
2.1)
1.11 (s)
-
1.15 (s)
-
1.14 (s)
-
2.21 (s)
1.23 (d, 6.9)
5.06 (s)
H-7
-
2.21 (s)
1.22 (d, 6.9)
5.03 (s)
H-7
-
C-10,C-11,
C-13
C-10,C-11,
C-12
C-3,C-4,C-5
C-1,C-7,C-8
-
43
group at δ 2.21 (3H, s, H-14) and two methyl groups located at an oxygenated
quaternary carbon (δ 1.08, s and δ 1.15, s; H-12 and H-13). The presence of an
oxymethine group was attributed to the 1H NMR resonance at δ 3.37 (br d, J 10.2 Hz,
H-10). The H-10 oxymethine signal of triol (138) appeared upfield compared with
(137) and resonated at δ 3.30 (1H, dd, J 9.9, 2.1 Hz, H-10).
Structure of triol (137) was further supported by 1H-1H correlations found in
the 2D COSY spectrum (Table 2.5, Figure 2.4), which showed the following series
of connectivities in the alkane side chain: the signal of H-10 (δ 3.37, br d, J 10.2 Hz)
was coupled with H-9 (δ 1.40, m) and with H-9’ (δ 1.18, m); H-9 and H-9’ were
coupled with H-8 (δ 1.86, m) and H-8’ (δ 1.60, m); both H-8 and H-8’ were coupled
with benzylic proton H-7 (δ 2.64, sext, J 6.9 Hz), and the latter with the methyl
group H-15 (δ 1.23, d, J 6.9 Hz).
Triol (138) showed the same connectivities as (137) except the signals of H-9
and H-9’ were not resolved and appeared as multiplet at δ 1.34, as shown in Figure
2.5 and Table 2.5. The structure was further supported by the HMBC experiment.
The HMBC of (7R,10R)-triol (138) (Figure 2.7(b)) showed the benzylic methine
proton (δH 2.61/δC 39.7, H-7) correlated to C-1 (2J) as well as to C-2 and C-6 (3J)
provided confirmation for the attachment of the side chain at C-1 in triol (138)
(Figure 2.2). The benzylic methine proton was also correlated with C-15 and C-8
(Figure 2.7(a)). The direct attachment of C-12 and C-13 methyls to C-11 are
supported by the correlation from H-12 and H-13 to C-11 in the HMBC spectrum
(Figure 2.7(a)). The substitution pattern of the trisubstituted aromatic ring was
revealed by HMBC experiment. Long range 1H–13C correlations were observed from
the aromatic methyl group (δH 2.21/δC 15.3, H-14) to C-3, C-4 and C-5 indicating
that H-14 was attached to C-4 (Figure 2.7(b)). The position of the aromatic hydroxyl
group at C-3 (δ 153.8) was evident from the HMBC cross peaks observed between
H-2 to C-3, C-4, C-6 and C-7 as well as H-5 to C-3 (Figure 2.7 (c) and (d)). The
long range 1H-13C correlation of triol (138) are shown in Figure 2.2. The 13C NMR
spectra of triols (137) and (138) (Appendices 26 and 30) were almost identical. The
signals of C-10 (δ 78.6 and δ 78.8) and H-10 (δ 3.37 and δ 3.30) indicated the
epimeric nature of triols (137) and (138).
44
15
15
HO
3
1
7
OH
HO
3
1
7
10
OH
10
H
14
H'
OH
H
H'
14
(138)
OH
(138)
Figure 2.2: HMBC correlations of (7R,10R)-triol (138).
The spectroscopic properties of synthetic (137) and (138) were identical with
those of the natural products except the optical rotation of triol (138). The optical
rotation of synthetic (7R,10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (138) is
[α]D +3.33° (c 0.30, MeOH), while the naturally occurring (138) (obtained from βcellulase hydrolysis of xanthorrhizol glycoside) has an opposite sign of rotation, [α]D
–57°, (c 0.30, MeOH) [82]. The spectral data of naturally occurring (138) matched
with those of the synthetic (138) but slightly different with spectral data of synthetic
(137) [(7R,10S-isomer), [α]D –64.7° (c 0.51, MeOH)]. Based on the spectral data, the
natural (138) may be considered as (7R,10R)-enantiomer as reported by Aguilar et al.
despite different in its optical rotation with the synthetic (138). This may be due to
incorrect optical rotation value reported in the literature [82].
Another different is the coupling constants of H-10. The coupling constants
reported in the literature [δ 3.37 (dd, J 12.6, 2.7 Hz) and δ 3.30 (dd, J 13.9, 4.8 Hz)]
are larger than those of synthetic products [δ 3.37 (br d, J 10.2 Hz) and δ 3.30 (dd, J
9.9, 2.1 Hz)]. However, it is interesting to note that the coupling constants of
oxymethine proton of closely related compounds (153) and (154) are J 10.0, 2.0 Hz
and J 9.6, 2.8 Hz, respectively [86], which are very close to our values and thus
supported the stereochemistry of the triols (137) and (138). The signal of oxymethine
group in (3S,6R)-linalyl acetate diol (155) [92] (obtained by Sharpless AD of (R)linalyl acetate with AD-mix-α) was resonated at δ 3.30 as a broad doublet with a
coupling constant of 10.0 Hz was also very close to our values. Therefore, based on
these comparisons, the J values for oxymethine group of synthetic triols (137) and
(138) are in agreement with the reported values.
45
MOMO
10
OH
MOMO
OH
(153)
10
Br
HO 3
6
OH
OH
(154)
OAc
OH
(155)
(7R,10S)-Triol (137) and (7R,10R)-triol (138) were prepared in 28.55% and
18.48% overall yield from xanthorrhizol (1), respectively.
H-13
14
H-5
3
H-2
H-6
H-14
OH
1
R
15 7
H-15
S 11
H-12
OH
OH
(137)
H-7
H-10
H-8’
H-8 H-9
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
Figure 2.3: 1H NMR spectra of (7R,10S)-triol (137) and (7R,10R)-triol (138).
46
14
3
1
R
15 7
OH
S 11
OH
OH
(137)
Figure 2.4: 1H-1H COSY spectrum of (7R,10S)-triol (137).
47
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
Figure 2.5: 1H-1H COSY spectrum of (7R,10R)-triol (138).
48
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
49
Figure 2.6: HMBC spectrum of (7R,10R)-triol (138).
14
3
OH
1
R
15 7
R 11
OH
OH
(138)
50
Figure 2.7(a): HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 10-90 ppm, δH 0-2.8 ppm).
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
51
Figure 2.7(b): HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 100-160 ppm, δH 1.0-2.8 ppm).
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
52
Figure 2.7(c): HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 5-90 ppm, δH 6.3-7.2 ppm).
14
3
1
R
15 7
OH
R 11
OH
OH
(138)
53
Figure 2.7(d): HMBC spectrum of (7R,10R)-triol (138) (Expansion: δC 100-160 ppm, δH 6.0-7.5 ppm).
54
2.3
Synthesis of Curcuquinone, Curcuhydroquinone and Helibisabonol A
Diacetate from Xanthorrhizol
Helibisabonol A (142) is a highly oxygenated aromatic bisabolane
sesquiterpenoid isolated from the leaves of sunflower, Helianthus annuus L. cv.
Peredovick® by Macías et al. The relative steoreochemistry at the chiral centres C-7
and C-10 were proposed to be 7R*,10S*. This sesquiterpenoid was found to inhibit
the growth of etiolated wheat coleoptiles [93].
Curcuquinone (139) and curcuhydroquinone (140) are two phenolic
bisabolane
sesquiterpenoids
isolated
from
the
Caribbean
gorgonian
Pseudopterogorgia rigida by Fenical et al. and show modest antibacterial activity
against Staphylococcus aureas and the marine pathogen Vibrio anguillarium [83].
Several literatures on the synthesis of (139) and (140) as the racemic forms [94-98]
have been published. However, very few synthesis reports on the optically active
forms [39, 99-100].
O
O
OH
HO
OH
HO
OH
(139)
(140)
OH
(142)
To date, only one total synthesis of helibisabonol A (142) as the racemic form
has been published [101], and there is still no published report on the optically active
form has been published. Thus, it is interesting to synthesise the helibisabonol A
(142) in a stereoselective manner.
The strategy of this synthesis is illustrated in Scheme 2.2. We envisaged
preparing the target molecules from the protected hydroquinone (156) via Sharpless
AD. Compound (156) would be derived from xanthorrhizol (1) via a sequential
oxidation, reduction and protection.
55
OH
HO
OH
OR
Sharpless AD
RO
OH
OH
(156)
(142)
(1)
Scheme 2.2: Retrosynthetic analysis of helibisabonol A (142).
Embarking on the synthesis of helibisabonol A (142), the first task was to
prepare the key intermediate curcuhydroquinone (140). The first attempt was
conversion of xanthorrhizol (1) to curcuhydroquinone (140) by nitration-reductionhydroxylation strategy. The nitration of xanthorrhizol (1) is shown in Scheme 2.3.
Xanthorrhizol (1) was nitrated according to the nitrous acid-catalysed two-phase
nitration method described by Zeegers et al. [102-104]. Nitration of (1) gave the
desired p-nitroxanthorrhizol (157) in only 12.0% yield and the isolation was difficult
due to formation of several by-products. Since phenols are active molecules and tend
to be oxidised, the nitration of phenols is difficult and gives low yield. There has
corroboration available in the literature for the low yield of nitration of phenolic
bisabolane sesquiterpenoid, nitration of (S)-(+)-curcuphenol (159), an isomer of
xanthorrhizol (1), gave 4-nitrocurcuphenol (160) and 2-nitrocurcuphenol (161) in
only 4.53% and 1.58% yield, respectively, as illustrated in Scheme 2.4 [105].
OH
3M H2SO4, NaNO3,
NaNO2, Et2O, rt
O2N
(1)
OH
OH
O2N
(157) (12.0%)
NO2
(158) (7.45%)
Scheme 2.3: Nitration of xanthorrhizol (1).
conc. HCl, NaNO2,
OH
(159)
0 oC, 30 min
O2N
NO2
OH
(160) (4.53%)
Scheme 2.4: Nitration of curcuphenol (159).
OH
(161) (1.58%)
56
Due to the low yields of nitration, an alternative route was explored. Elbs
persulphate oxidation was used to prepare curcurhydroquinone (140) as shown in
Scheme 2.5. Treatment of xanthorrhizol (1) with potassium persulphate,
neutralisation with CO2 and then hydrolysis with boiling acetic acid gave
curcuhydroquinone (140) in only 5.7% overall yield [106-107].
OH
K2S2O8,
NaOH, H2O, rt,
OH
1) CO2
2) CH3COOH, reflux
(140)
5.7% over two steps
KO3SO
(1)
(162)
Scheme 2.5: Elbs persulphate oxidation of xanthorrhizol (1).
At
this
point
an
alternative
approach
was
sought,
in
which
curcuhydroquinone (140) was prepared via curcuquinone (139) as shown in Scheme
2.6.
O
Xanthorrhizol (1)
(KO3S)2NO (Fremy's salt)
O
MeOH, NaH2PO4 - Na2HPO4
pH 6.75, rt, 60%
(139)
Na2S2O4
THF-H2O (3:2)
rt, 100%
OAc
AcO
DMAP, Et3N, Ac2O,
rt, 78.6%
OH
HO
(163)
AD-mix-α,
14
MeSO2NH2
OAc
t-BuOH-H2O (1:1), 0 oC 3
61.8%
6
AcO
1
15
7
10
(140)
OH
OH
(164)
Scheme 2.6: Synthesis of helibisabonol A (142) from xanthorrhizol (1).
57
Xanthorrhizol (1) was first converted to curcuquinone (139) by using
Fremy’s salt (potassium nitrosodisulphonate, a stable free radical salt) under buffered
condition (pH 6.75) [108]. Curcuquinone (139) was isolated as a yellow oil which
showed quinoid absorption at 1656 cm-1 in its IR spectrum (Appendix 39). The 1H
NMR spectrum of curcurquinone (139) (Appendix 40) showed two quinoid protons
at δ 6.56 (q, J 1.8 Hz, H-3) and at δ 6.48 (d, J 0.9 Hz, H-6) as well as an quinoid
methyl was observed at δ 2.01 (d, J 1.8 Hz), suggesting the presence of para-quinone
moiety in compound (139). The spectroscopic data of curcuquinone (139) listed in
Table 2.6 was in good agreement with those of synthetic [39, 100] and natural
products [44, 109].
Table 2.6: 1H and 13C NMR data of curcuquinone (139) and curcuhydroquinone
(140).
Position
1
2
3
4
5
6
7
8
9
10
Curcuquinone (139)
1
H NMR
δ (ppm)
6.56 (q, 1.8)
6.48 (d, 0.9)
2.82 (sext, 6.9)
1.35-1.50 (m)
1.93 (m)
5.02 (tt, 5.2, 1.5)
11
12
13
14
15
1.52 (s)
1.63 (s)
2.01 (d, 1.8)
1.08 (d, 6.9)
Curcuhydroquinone (140)
1
C NMR
H NMR
δ
(ppm)
δ (ppm)
131.8
146.7
117.9
6.53 (s)
121.7
147.8
113.4
6.56 (s)
31.4
2.92 (sext, 6.9)
37.3
1.54-1.64 (m)
26.0
1.91 (m)
123.8
5.10 (t with further
unresolved couplings)
132.1
17.7
1.52 (s)
25.7
1.66 (s)
15.4
2.15 (s)
21.1
1.18 (d, 6.9)
13
Curcuquinone (139) was reduced to curcuhydroquinone (140) in quantitative
yield by sodium dithionite. Curcuhydroquinone (140) has an IR absorption
(Appendix 42) characteristic of hydroxyl functionality at 3354 cm-1. The
spectroscopic properties of curcuhydroquinone (140) were identical to literature
values [39,82,100,109]. Curcuhydroquinone (140) was isolated as white crystals, mp
92-96 °C (lit. [110] mp 86-87 °C), it was isolated and prepared previously as a
colourless oil and on one occasion it was isolated from Pseudopterogorgia acerosa
58
as white crystals [110]. Prior to Sharpless AD, curcuhydroquinone (140) was
protected as its diacetate derivative (163). The MS of curcuhydroquinone diacetate
(163) (Appendix 47) showed a molecular ion peak at m/z 318 which was in
agreement with the molecular formula C19H26O4. The IR spectrum of
curcuhydroquinone diacetate (163) (Appendix 48) showed absorption band due to
carbonyl group at 1761 cm-1, and the absence of hydroxyl band indicating the
presence of ester functionality. The presence of the carbonyl function in
curcuhydroquinone diacetate (163) is confirmed by the carbons resonance at δ 168.9
and δ 169.3 in the
13
C NMR spectrum (Appendix 49). The 1H NMR spectrum of
(163) (Appendix 51) showed many common features with that of curcuhydroquinone
(140), except for the acetoxyl signals resonated at δ 2.29 and δ 2.30 as listed in Table
2.7. Based on these data, compound (163) was characterised as the diacetate
derivative of curcuhydroquinone (140).
Table 2.7: 1H and 13C NMR data of curcuhydroquinone diacetate (163) and diol
(164).
Position
Diacetate (163)
1
C NMR
H NMR
δ (ppm)
δ (ppm)
137.9
145.8
124.5
6.87 (s)
128.4
147.3
120.5
6.84 (s)
32.0
2.79 (sext,
7.2)
38.9
1.46-1.62 (m)
25.9
1.90 (m)
124.2
5.06 (t, 5.4)
131.0
17.6
1.53 (s)
25.7
1.66 (s)
15.9
2.12 (s)
20.9
1.16 (d, 7.2)
20.8
2.29 (s)
20.9
2.30 (s)
168.9
169.3
-
13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3CO
CH3CO
C=O
C=O
Diol (164)
1
C NMR
H NMR
δ (ppm)
δ (ppm)
137.1
145.8
124.6
6.88 (s)
128.6
147.2
124.6
6.93 (s)
32.8
2.86 (m)
13
33.8
29.4
78.4
73.0
26.2
23.3
15.8
21.7
20.8
20.9
169.8
170.3
1.36–1.93 (m)
3.29 (br d, 10.5)
1.08 (s)
1.14 (s)
2.15 (s)
1.21 (d, 6.9)
2.32 (s)
2.32 (s)
-
59
Treatment of curcuhydroquinone diacetate (163) with AD-mix-α in the
presence of methanesulphonamide in aqueous tert-butanol at 0 °C afforded diol
(164) in 61.8% isolated yield. The enantiomeric excess was >98% as determined by
1
H NMR analysis of its (S)-MTPA ester derivative (165) (Appendix 57). The
absolute configuration of newly generated stereogenic centre was deduced to be S
from literature precedents [56]. Diol (164) was obtained as white crystals, mp 78-81
°C, with [α]D –37.5° (c 0.24, CHCl3). The IR spectrum (Appendix 52) was similar to
that of curcuhydroquinone diacetate (163), except the presence of an additional broad
hydroxyl band at 3344 cm-1 due to the diol function. The olefinic signal was not
observed in the 1H NMR spectrum of diol (164) (Appendix 53, Table 2.7), but it
exhibited a broad doublet at δ 3.29 (J 10.5 Hz, H-10) attributable to an oxymethine
proton. As compared to curcuhydroquinone diacetate (163), the signals of H-12 and
H-13 is now shifted upfield to δ 1.08 and δ 1.14, while the resonances of the
corresponding methyl carbons, C-12 and C-13, are shifted downfield from δ 17.6 and
δ 25.7 to δ 23.3 and 26.2, respectively. The presence of a low field, quaternary
carbon signal at δ 73.0, indicated that one of the hydroxyl groups attached to a
quaternary carbon, i.e. C-11. These observations showed that C-12 and C-13 are also
attached to C-11. Another low field carbon signal at δ 78.4 was attributed to C-10.
These observations, coupled with the polar nature of diol (164), and the absence of
the C-10 olefinic signal in the 13C NMR spectrum, suggested that compound (164) is
the diol derivative of diacetate (163).
Having prepared the desired protected diol (164), next attempt was to cleave
the diacetate protecting group to form the targeted molecule, helibisabonol A (142),
as shown in Scheme 2.7. In the first attempt to remove the diacetoxyl group, aqueous
sodium bicarbonate in methanol was used, however this has led to a complex
decomposition. A variety of methods was used to cleave the diacetate group
including treatment with activated zinc in methanol, 3N HCl in acetone and 1% Et3N
in MeOH. Unfortunately, none of these conditions provided any desired product;
some reactions gave complex mixtures. In addition, the reaction products are
unstable under the acidic or basic work-up conditions and led to complex
decomposition.
60
OAc
OH
(i)
AcO
HO
OH
OH
(164)
(i) Variety of methods including:
aq. NaHCO3/MeOH,
activated Zn/MeOH,
3N HCl/Acetone, 1% Et3N/MeOH
OH
(142)
OH
Scheme 2.7: Attempted deprotection of diol (164).
At this point a new deprotecting strategy was sought. It was postulated that a
hydride transfer reaction would work to reduce the acetyl group to the desired
phenol. Thus, lithium borohydride (LiBH4) in ether was used in an attempt to
deprotect the acetyl group. LiBH4 was selected because it has greater reducing
properties than NaBH4 but less than lithium aluminium hydride [111]. Treatment of
diol (164) in dry ether with 1.35 M LiBH4 solution in THF furnished helibisabonol A
(142) as shown in Scheme 2.8.
OAc
1.35M LiBH4 in THF,
Et2O, rt, 80%
HO
OH
AcO
(164)
OH
OH
OH
(142)
OH
Scheme 2.8: Deprotection of diol (164) with LiBH4.
The 1H NMR spectrum of (142) (Appendix 61, Table 2.8) recorded in
deuterated acetone without purification showed that the acetoxyl signal has
disappeared, and the signals of aromatic protons, H-3 and H-6 were shifted upfield.
These observations indicated that both the acyl groups have been reduced. Next, the
crude product was subjected to column chromatography and afforded two
compounds. The less polar compound (Rf 0.32, 100% Et2O) was isolated as a yellow
liquid. The 1H NMR spectrum (Appendix 62, Table 2.8) showed two signals at δ
6.59 (q, J 1.5 Hz, H-3) and at δ 6.54 (d, J 1.2 Hz, H-6) attributable to a para-quinone
moiety, a quinoid methyl group appeared as a doublet at δ 2.04 and characteristic
signals due to the diol side chain fragment. These observations showed the presence
61
of a curcuquinone residue. Based on the spectral data, this compound (166) was
identified as quinone derivative of helibisabonol A (142), which probably formed by
air-oxidation of helibisabonol A (142).
Table 2.8: 1H NMR data of helibisabonol A (142) and quinone (166).
(142)a
Position
(166)b
3
6.55 (s)
6.59 (q, 1.5)
6
6.60 (s)
6.54 (d, 1.2)
7
3.14 (m)
2.96 (sext, 6.9)
8
1.86 (m)
1.82 (m)
8’
1.52 (m)
9
1.38 (m)
1.45 (m)
9’
10
3.91 (dd, 7.5, 6.0)
3.33 (br d, 10.2)
12
1.06 (s)
1.12 (s)
13
1.04 (s)
1.19 (s)
14
2.08 (s)
2.04 (d, 1.5)
15
1.14 (d, 6.9)
1.14 (d, 7.2)
a
Spectrum recorded in deuterated acetone.
b
Spectrum recorded in CDCl3.
14
O
3
O
15
1
6
13
10
7
OH
12
OH
(166)
The more polar compound (Rf 0.21, 100% Et2O) was obtained in amorphous
form. Examination of the 1H NMR spectrum (Appendix 63) showed that it is a
mixture of two compounds, and it was further supported by the presence of two spots
[Rf 0.21 (major); Rf 0.32 (minor)] on TLC with 100% ether as an eluent. The 1H
NMR spectrum of the major compound shared many common features to that of
spectral data of helibisabonol A (142) reported in the literature [93], but our data
showed some differences as compared to the reported data. The chemical shift of H10 differs from literature value by shifted downfield to δ 3.91, H-10 also showed
different coupling constants (dd, J 7.5, 6.0 Hz) to that reported in the literature (dd, J
4.9, 1.4 Hz). The presence of a benzylic methyl group was indicated by a doublet at δ
1.14 (d, J 6.9 Hz) in our data, however, the reported value showed δ 1.09 and the
62
coupling constants of only 5.1 Hz, which is very unusual. The minor compound was
determined to be quinone derivative of the major compound by comparison with the
spectrum of quinone (166). It was probably formed by air-oxidation of the major
compound. Standing in deuterated acetone for a few days, proved the increasing
amounts of quinone derivative. Thus, this result showed that the major compound
(142) was air-sensitive and tends to be air-oxidised to its quinone derivative.
Besides 1H NMR, other experiments could not be carried out on deprotected
product (142) because it is acidic, basic and air-sensitives, as well as only available
in a small amounts. Therefore, based on the 1H NMR data, this compound was
tentatively identified as helibisabonol A (142).
Since the quinone derivative (166) has been identified, further reactions were
carried out to reduce the quinone to the corresponding helibisabonol A (142). So,
quinone (166) was treated with NaBH4 in MeOH. TLC of the reaction mixture
indicated that the starting material has been reduced to its hydroquinone derivative
within 15 min, unfortunately when the reaction was quenched with 10% aqueous
NH4Cl, some of the products reverted to the starting material and this was supported
by TLC that showed the presence of two compounds after workup. This confirmed
that helibisabonol A (142) is acidic and air-sensitives.
Disappointed by this result, another approach was searched to remove the
protecting group in diol (164). The method chosen was cyanide-catalysed
deprotection of acetyl groups [112-113]. In an attempt to remove the acetyl groups in
(164), diol (164) in methanol was treated with catalytic amounts of potassium
cyanide (KCN) at room temperature, as shown in Scheme 2.9. Although the reaction
was only performed on a 100 µg scale, it was clear from the TLC analysis that
deprotection of (164) with KCN did not give the desired helibisabonol A (142),
instead it gave the corresponding quinone (166).
63
OAc
KCN (cat.), MeOH,
rt
AcO
OH
HO
OH
OH
(164)
OH
(142)
OH
Scheme 2.9: Attempted deacetylation of diol (164) with KCN.
At this point deprotection of the diol (164) was discontinued due to paucity of
material, and discouraged by acidic, basic and air-sensitive natures of helibisabonol
A (142); it could not survive under the reaction/quench/workup conditions as
indicated by the experiments. It tends to oxidise or decompose, makes this compound
so difficult to be prepared and handled. The results show that acetyl is not a suitable
protecting group for the synthesis of helibisabonol A (142). Thus a better protecting
group should be studied, probably benzyl ether is an ideal choice because it can be
cleaved under mild and neutral conditions by catalytic hydrogenation.
2.4
Synthesis of Allylic Alcohol Derivative of O-methylxanthorrhizol
Allylic alcohol derivative of xanthorrhizol, 2-methyl-5-(4(S)-hydroxy-1(R),5-
dimethylhex-5-enyl)phenol (134) is a bisabolane-type sesquiterpenoid found in
Mexican medicinal plant, Iostephane heterophylla [4] and recently has been isolated
from the resins of African plant, Commiphora kua [80]. In 1993, Aguilar et al.
assigned 7R configuration for allylic alcohol (134) isolated from I. heterophylla, but
the absolute configuration at C-10 was not determined due to insufficient quantity of
(134). While in 2003, the absolute stereochemistry of compound (134) isolated from
C. kua resin was established to be (7R,10S). Manguro et al. reported that allylic
alcohol (134) inhibited the growth of the plant pathogenic fungus Cladosporium
cucumerinum on TLC assay. To date, there is no report on the synthesis of allylic
alcohol (134). We now report a synthesis of the methyl ether derivative of this
compound,
(3S,6R)-(3-methoxy-4-methylphenyl)-2-methylhept-1-en-3-ol
starting from (–)-xanthorrhizol (1).
(147),
64
14
3
12
1
R
7
15
OR
S
10
OH
(134) R = H
(147) R = Me
The synthetic strategy is illustrated in Scheme 2.10, which employs Sharpless
AD as the key step to introduce stereocentre at C-10. Xanthorrhizol (1) was
converted to O-methylxanthorrhizol (167) by treatment with MeI and K2CO3 in
refluxing acetone. Column chromatography of the crude product yielded O-methylxanthorrhizol (167) as a colourless oil and germacrone (6) as a minor compound.
Lack of hydroxyl band in the IR spectrum (Appendix 65) and additional methoxyl
signal at δ 3.85 in the 1H NMR spectrum (Appendix 66) of O-methylxanthorrhizol
(167) indicated that phenol has been converted to methoxyl group. This was
corroborated by the MS spectrum (Appendix 67) that showed a molecular ion peak at
m/z 232, which was in agreement with the molecular formula C16H24O. Germacrone
(6) was isolated as colourless needles, mp 51-54 °C, lit. [13] 52-54 °C. Its IR and 1H
NMR spectra (Appendix 68 and 69, respectively) are virtually identical with those
reported for germacrone (6) isolated from C. xanthorrhiza [13]. Gemacrone (6) is a
constituent of the essential oil of C. xanthorrhiza incorporated as the impurities of
xanthorrhizol (1).
OR
AD-mix-α,
MeSO2NH2
t-BuOH-H2O (1:1), 0 oC
90.6%
K2CO3, MeI,
(1) R=H
acetone, reflux, 8 h, (167) R=Me
65.3%
MsCl, Et3N,
R
S
OH
OR
py, Ac2O,
CH2Cl2, rt, 24 h, (168) R=H
(169) R=Ac
95.1%
OMe
DMAP, CH2Cl2
0 oC
OMe
K2CO3, MeOH
rt, 90.5%
OMe
rt, 3.75 h,
47.3%
OAc
(170)
OH
(147)
Scheme 2.10: Synthesis of allylic alcohol of O-methylxanthorrhizol.
65
The protected compound methoxyxanthorrhizol (167) was subjected to
asymmetric dihydroxylation employing dihydroquinine-base AD-mix-α in the
presence of methanesulphonamide in aqueous tert-butanol at 0 °C under vigorous
stirring to give methoxydiol (168) in 90.6% isolated yield. In order to determine the
enantiomeric composition of methoxydiol (168), it was converted to its (S)-MTPA
ester (171S) by treatment with (R)-(–)-MTPA-Cl (172R). The signal due to the
carbomethoxyl group was used for determination of enantiomeric purity. Since the
MTPA ester (171S) showed exclusively a quartet at δ 3.55 (q, J 1.6 Hz) (Figure 2.8),
it enantiomeric excess was determined to be more than 98%.
O
OMe
Cl
R
OMe
CF3
OH
OMTP
(172R)
(171S)
The IR spectrum (Appendix 70) of methoxydiol (168) displayed a strong
stretching band for the hydroxyl group at 3414 cm-1. The HRMS of this compound
(Appendix 71) gave a molecular ion at 266.1882, which was assigned for C16H26O3.
The signal due to the olefinic proton was not observed in the 1H NMR spectrum
(Appendix 72), instead a broad doublet with a coupling constant of 10.2 Hz at δ 3.37
was attributed to an oxymethine proton at C-10. The signals for two methyl groups at
C-11 were shifted upfield to δ 1.15 and δ 1.08, compared to that of Omethylxanthorrhizol (167) suggesting that the two methyl groups were attached to an
oxygenated quaternary carbon. This was supported by the base peak at m/z 59, which
was attributed to –C(OH)Me2 fragment. The 1H NMR data of methoxydiol (168) is
summarised in Table 2.9.
66
Table 2.9: 1H NMR data of methoxyxanthorrhizol (167) methoxydiol (168).
Position
2.4.1
Methoxyxanthorrhizol (167) Methoxydiol (168)
2
5
6
7
8
6.68 (d, 1.5)
7.07 (d, 7.5)
6.72 (dd, 7.5, 1.5)
2.69 (sext, 6.9)
1.56-1.67 (m)
9
1.89-2.00 (m)
10
12
13
14
15
OMe
5.13 (tt, 7.5, 1.5)
1.56 (s)
1.70 (s)
2.21 (s)
1.26 (d, 6.9)
3.85 (s)
6.65 (d, 1.5)
7.04 (d, 7.5)
6.69 (dd, 7.5, 1.5)
2.69 (sext, 6.9)
1.82-1.93 (m)
1.57-1.69 (m)
1.36-1.46 (m)
1.16-1.18 (m)
3.36 (br d, 10.2)
1.15 (s)
1.08 (s)
2.18 (s)
1.26 (d, 6.9)
3.82 (s)
Determination of the Absolute Configuration of Methoxydiol (168) by
Mosher’s Method
Mosher’s method was used in determining the absolute configuration of 10-
position in methoxydiol (168). The Mosher ester procedure [114] and modified
Mosher’s method [90, 115-117] are based on the diamagnetic effect of an introduced
phenyl ring to assign the absolute stereochemistry of organic compounds by
measuring
and
comparing
the
resultant
diastereomeric
α-
(trifluoromethyl)phenylacetic acid (MTPA) esters. The MTPA ester derivatives
obtained are suitable for this purpose because they are thermally stable, do not
undergo racemisation and can be readily analysed by 1H NMR spectroscopy.
In order to determine the absolute configuration of methoxydiol (168), two
portions of methoxydiol (168) were treated with (S)-(+)- and (R)-(–)-MTPCl (172S
and 172R) to afford (R)- and (S)-MTPA esters derivative (171R and 171S
respectively) of methoxydiol (168). 1H NMR spectra of these two compounds are
shown in Figure 2.8, the chemical shifts of CH3-12, CH3-13 and CH3-15 of (171S)
and (171R) are clearly different, and these data have been tabulated in Table 2.10.
The differences in 1H chemical shifts between 171R and 171S [∆δ 1H 171S
67
(S-MTPA ester) – 171R (R-MTPA ester)] are illustrated directly on the planar
structure of the Mosher ester in Figure 2.9.
Table 2.10: 1H NMR data of MTPA esters (171S) and (171R).
Position
S-MTPA ester
R-MTPA ester
COSY*
(171S)
(171R)
2
6.51 (s)
6.59 (1.5)
H-6
5
6.90 (d, 7.5)
7.02 (d, 7.5)
H-2, H-6
6
6.52 (dd, 7.5, 1.5) 6.61 (dd, 7.5, 1.5)
H-5
7
2.61 (m)
2.66 (m)
H-8, H-15
8
1.47 (m)
1.59 (m)
H-7, H-9
9
1.37 (m)
1.44 (m)
H-8, H-10
10
5.03 (br d, 9.9)
5.02 (br d, 9.9)
H-9
12
1.07 (s)
1.04 (s)
13
1.13 (s)
1.08 (s)
14
2.17 (s)
2.18 (s)
15
1.12 (d, 6.9)
1.21 (d, 6.9)
H-7
4’, 8’
7.60 (m)
7.56 (m)
H-5’, H-6’ , H-7’
5’, 6’, 7’
7.40 (m)
7.39 (m)
H-4’, H-8’
OMe
3.77 (s)
3.79 (s)
OMe’
3.55 (q, 1.6)
3.50 (q, 1.6)
* See appendices 73 & 74
δs - δR
-0.08
-0.12
-0.09
-0.05
-0.12
-0.07
+0.01
+0.03
+0.05
-0.01
-0.09
+0.04
+0.01
-0.02
+0.05
Ar-OMe
(S)-MTPA ester (171S)
H-5’
H-6’
H-7’
H-4’
H-8’
H-13
H-14
C-OMe
H-12
H-2
H-5
H-6
H-10
H-7
(R)-MTPA ester (171R)
H-13
H-12
68
Figure 2.8: 1H NMR spectra of the (S)-and (R)-MTPA esters of compound (168). The chemical shifts of CH3-12, CH3-13 and CH3-15 of (171S)
and (171R) are clearly different, H-12 and H-13 of (171R) showed evident upfield shifts when compared to those of (171S).
69
+0.04
+0.01
3' OMe
2' CF3
+0.04
5'
4'
O
-0.12
O
+0.01 +0.05
-0.09 8
-0.05
-0.07H
OH
1
+0.03
-0.08
-0.09
3
-0.12
4
OMe
-0.02
-0.01
(171)
Figure 2.9: Difference in 1H chemical shift (∆δ 1H 171S-171R) between the two
Mosher esters (171S) and (171R). Positive values indicate that
resonance for isomer (171R) is upfield (shielded) relative to (171S);
negative values indicate that (171S) is upfield (shielded) relative to
(171R).
Analysis of ∆δ values summarised in Figure 2.8 reveals a positive values for
1
∆δ H (171S-171R) at the H-12 and H-13 methyl groups lying to the right of the
secondary alcohol chiral centre and negative values for the H-8 and H-9 protons lying
to the left of the chiral centre. According to Mosher’s theory, this result implies an S
absolute configuration for the secondary alcohol (168) [90].
The rationale for this prediction is that the atoms comprising the ester linkage
(i.e. O–C(1’)=O) and the two “flaking” carbon atom (i.e. C-10/C-2’) adopt a planar
conformation as shown in Scheme 2.11. The phenyl group of the Mosher ester
located directly in juxtaposition either with H-12/13 in the case of (171R) or with H7/8/9 in the case of (171S) (clearly shown in the models in Figure 2.10). In
consequence, 1H chemical shifts for H-12/13 in 171R are shifted upfield due to the
shielding effect of the phenyl group, whilst in compound (171S) it is the H-7/8/9
protons which are shifted upfield. The S absolute configuration determined by
Mosher’s method is in agreement with absolute configuration assigned by Sharpless
mnemonic device [56]. Thus, the absolute configuration at C-10 is unequivocally
deduced as S. Based on these results, the structure of compound (168) was assigned
as (7R,10S)-O-methylxanthorrhizol-10,11-diol.
70
NMR signals of this region should
appear upfield relative to those of the
(S)-MTPA ester due to the diamagnetic
effect of the benzene ring
12
HO
13
MeO
Cl
7
R
8
S
9
CF3
O
OH (S)-(+)-MTPCl (172S) MeO
HO
S
(168)
Cl
R
10
H
HO
OMe
CF3
O
O
H
(R)-(-)-MTPCl (172R)
CF3
O
(171R)
H
MeO
MeO R
O 1' 2'
S
OMe
CF3
O
MeO
(171S)
Scheme 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.
(171R)
(171S)
Figure 2.10: Models of R- and S-MTPA esters (171R and 171S) of methoxydiol
(168) (models generated by CS Chem3D Ultra 6.0).
71
Reaction of methoxydiol (168) with acetic anhydride and pyridine provided
monoacetate (169) in 95.1% yield. Monoacetate (169) was obtained as a pale yellow
oil, [α]D –7.38° (c 1.68, CHCl3). The IR spectrum (Appendix 76) showed bands due
to the hydroxyl at 3450 cm-1 and carbonyl at 1733 cm-1. The MS of Monoacetate
(169) (Appendix 77) showed a molecular ion peak at m/z 308, which was in
agreement with the molecular formula C18H28O4. The 1H NMR spectrum (Appendix
78) showed a signal at δ 1.23 as doublet (J 6.9 Hz) for H-15 and two singlets at δ 1.12
and δ 1.14 were attributed to H-12 and H-13. A singlet at δ 2.10 integrated for three
protons was assigned to acetoxyl protons. Signal for H-10 was shifted downfield to δ
4.84 (dd, J 9.9, 2.1 Hz) compared to that of methoxydiol (168), suggesting that the
acetoxyl group was attached to C-10 (Table 2.11). The monoacetate (169) was used
in next reaction without purification.
Next, treatment of monoacetate (169) with methanesulphonyl chloride (5.0
eq.) in the presence of triethylamine (3.0 eq.) and N,N-dimethylaminopyridine
(DMAP) (0.05 eq.) afforded allylic acetate (170) in 47.3% yield after
chromatographic separation [118-119]. In this one-pot tandem reaction, the following
chemical transformations were accomplished: 1) tertiary mesylate formation, 2)
removal of a proton at β-position by triethylamine, followed by elimination of the
mesylate group to form the olefin via the E2 mechanism. These sequences of reaction
to the allylic acetate (170) formation are summarised in Scheme 2.12.
OMe
OMe
1) mesylation
2) β-elimination
OAc
H
OMs
OH
(169)
OMe Et3N:
OMs
OAc
(173)
OAc
(174)
OMe
OAc
(170)
Scheme 2.12: Reaction sequences led to the allylic acetate (170).
72
Allylic acetate (170) was isolated as a pale yellow oil, [α]D –13.3° (c 1.40,
CHCl3). The MS of allylic acetate (170) (Appendix 79) showed a molecular ion peak
at m/z 290, differing from monoacetate (169) by 18 amu, indicating the loss of one
mole of water. In the IR spectrum of allylic acetate (170) (Appendix 80), a strong
band at 1739 cm-1 showed that the ester group was not cleaved. The 1H NMR
spectrum of allylic acetate (170) (Appendix 81) showed a broad singlet at δ 1.66
assigned to methyl protons at H-13. The two olefinic geminal protons =CH2 appeared
as multiplets at δ 4.86 and at δ 4.91. The oxymethine signal was appeared as multiplet
at δ 5.15, the value is shifted to lower field than monoacetate (169). The other proton
signals also fit the 1H NMR spectrum that corresponds to the assigned structure for
allylic acetate (170) as summarised in Table 2.11.
Table 2.11: 1H NMR data of monoacetate (169), allylic acetate (170) and diacetate
(175).
Position
2
5
6
7
8
9
10
12a
12b
13
14
15
OMe
OAc
OAc
Monoacetate (169)
6.63 (d, 1.5)
7.04 (d, 7.5)
6.67 (dd, 7.5, 1.5)
2.67 (sext, 6.9)
1.41-1.62 (m)
Allylic acetate (170)
6.63 (d, 1.5)
7.04 (d, 7.5)
6.68 (dd, 7.5, 1.5)
2.65 (m)
1.47-1.62 (m)
Diacetate (175)
6.64 (s)
7.04 (d, 7.5)
6.67 (d, 7.5)
2.67 (sext, 6.9)
1.43-1.65
4.84 (dd, 9.9, 2.1)
1.12 (s)
5.15 (m)
4.91 (m)
4.86 (m)
1.66 (s)
2.18 (s)
1.24 (d, 6.9)
3.83 (s)
2.04 (s)
-
5.23 (dd, 9.9, 2.1)
1.37 (s)
1.14 (s)
2.18 (s)
1.23 (d, 6.9)
3.82 (s)
2.10 (s)
-
1.40 (s)
2.18 (s)
1.22 (d, 6.9)
3.83 (s)
2.08 (s)
1.91 (s)
Another more polar compound (175) was also isolated from the reaction
mixture in a small amount. The IR spectrum of this compound (175) (Appendix 82)
showed bands due to ester at 1741 cm-1, aromatic at 1612 and 1583 cm-1 as well as CO functions at 1232 cm-1. The 1H NMR of (175) (Appendix 83) was generally similar
with those of O-methylxanthorrhizoldiol monoacetate (169), except for the presence
of a singlet at δ 1.91 attributed to an acetoxyl group. The signals of H-12 and H-13
methyl groups of compound (175) were shifted downfield to δ 1.37 and δ 1.40,
respectively, compared to monoacetate (169). The signal of H-10 was also shifted
73
downfield to δ 5.23 (dd, J 9.9 and 2.1 Hz) compared to that of monoacetate (169).
Based on these spectroscopic data, coupled with lack of hydroxyl band in the IR
spectrum, compound (175) was identified as diacetate derivative of O-methylxanthorrhizoldiol. This was further supported by hydrolysis of diacetate (175) with
K2CO3/MeOH to afford the methoxydiol (168) as shown in Scheme 2.13. The IR and
NMR spectra (Appendix 84 and 85 respectively) were identical to those of
methoxydiol (168) prepared previously, and no racemisation of H-10 alcohol was
detected based on the NMR spectrum. Diacetate derivative (175) was probably came
from the impurities found in reaction mixture which was not purified further prior to
the next reaction. This means that the acetylation of methoxydiol (168) afforded
diacetate derivative (175) as a minor product.
14
3
OMe
6
13
1
15
7
K2CO3, MeOH,
rt, 100%
10
OAc
(175)
OMe
OAc
OH
12
OH
(168)
Scheme 2.13: Hydrolysis of diacetate (175).
Completion of the reaction sequence was carried out by hydrolysis of the
allylic acetate (170) with K2CO3 in methanol to furnish the allylic alcohol (147) in
90.5% yield. Allylic alcohol (147) was obtained as a pale yellow oil, [α]D –16.6° (c
1.34, CHCl3), showed a molecular ion peak at m/z 248 corresponding to C16H24O2.
In its MS (Appendix 86), a characteristic McLafferty process involving the
elimination of the side chain produced an ion at m/z 162 [M–C5H10O]+ and another
one at m/z 149 [M–C6H10O]+, both fragments were consistent with the presence of a
secondary hydroxyl function. Its IR spectrum (Appendix 87) displayed a broad
hydroxyl band at 3382 cm-1 and the disappearance of the carbonyl band. The 1H
NMR spectrum (Appendix 88) indicated that the acetoxyl group has been cleaved by
the disappearance of a singlet around δ 2.10. The 1H NMR spectrum of allylic
alcohol (147) (Table 2.12) instead showed a signal for oxymethine group at carbon
bearing the OH group shifted to upfield of δ 4.03 (m, H-10) compared to that of
74
allylic acetate (170). In addition, the 1H NMR spectrum of allylic alcohol (147)
showed signals for vinylic protons at δ 4.82 (m, H-12b) and δ 4.91 (m, H-12a) and a
vinylic methyl at δ 1.66 (t, J 1.2 Hz, H-13). Aromatic protons were observed at δ
6.64 (d, J 1.5 Hz, H-2), δ 6.68 (dd, J 7.5 and 1.5 Hz, H-6) and δ 7.04 (dd, J 7.5, 0.6
Hz, H-5), indicating the presence of a 1,2,4-trisubstituted aromatic ring. From these
spectral data, the structure of allylic alcohol (147) was deduced to be (6R)-(3methoxy-4-methylphenyl)-2-methylhept-1-en-(3S)-ol. At this point, enantioselective
synthesis of allylic alcohol (147) was completed in 24.08% yield over five steps from
natural R-(–)-xanthorrhizol (1) isolated from the essential oil of C. xanthorrhiza.
Table 2.12: 1H NMR data of allylic alcohol (147).
Position
1
2
3
4
5
6
7
8
9
10
11
12a
12b
13
14
15
OMe
2.5
13
C NMR
δ (ppm)
146.4
108.8
157.7
124.0
130.5
118.6
39.9
34.0
32.9
75.9
147.5
111.0
15.9
17.6
22.6
55.2
1
H NMR
δ (ppm)
6.64(d, 1.5)
7.04(dd, 7.5, 0.6)
6.68(dd, 7.5, 1.5)
2.66(sext, 6.9)
1.39-1.64(m)
4.03(m)
4.91(m)
4.82(m)
1.66(t, 1.2)
2.18(s)
1.25(d, 6.9)
3.83(s)
COSY
H-6
H-6
H-2,H-5
H-8,H-15
H-7,H-9
H-8,H-10
H-9
H-12b,H-13
H-12a,H-13
H-12a,H-12b
H-7
-
Attempted Synthesis of 2-methyl-5-(4(S)-hydroxy-1(R),5-dimethylhex-5enyl)phenol (134) from Acetoxydiol (149)
Having converted the side chain of O-methylxanthorrhizol (167) into the
optically active allylic alcohol (147), together with the readily available acetoxydiol
(149), it was then decided to apply the same sequence on acetoxydiol (149). We
envisaged that in the final deprotection step, both the phenolic and alcoholic acetates
75
will be cleaved to furnish naturally occurring allylic alcohol (134), as shown in
Scheme 2.14.
OAc
MsCl, Et3N,
10
OH
?
DMAP, CH2Cl2
OH
0 oC rt
OR
Ac2O, py (149) R=H
54.4% (176) R=Ac
OAc
OH
OAc
(177)
K2CO3, MeOH,
rt
OAc
(178)
OH
OH
(134)
Scheme 2.14: Route to synthesis of the allylic alcohol (134) from diacetate (176).
Treatment of acetoxydiol (149) with acetic anhydride in catalytic amounts of
pyridine provided diacetate (176) as a pale yellow oil, [α]D –20.5° (c 1.12, CHCl3).
The IR spectrum (Appendix 93) of diacetate (176) displayed strong and broad bands
for hydroxyl at 3469 cm-1, carbonyl at 1733 cm-1 and C-O function at 1221 cm-1. The
MS (Appendix 94) of this compound (176) gave a molecular ion peak at m/z 336,
which was in agreement with the molecular formula C19H28O5. A peak due to the loss
of H2O was observed at m/z 318, indicating the presence of a hydroxyl group.
The 1H NMR spectrum (Appendix 95) (Table 2.13) of diacylated derivative
(176) exhibited a signal for aromatic acetoxyl group at δ 2.33, and a new three-proton
singlet for acetoxyl group was observed at δ 2.11, compared to that of starting
acetoxydiol (149) (see Table 2.3). The presence of two acetoxyl groups were further
confirmed by the characteristic low field signals for acetoxyl carbonyls at δ 169.2 and
δ 171.3, and also signals for acetoxyl methyls at δ 20.8 and δ 21.0. Another
significant difference was the downfield shift of H-10 from δ 3.32 (ddd, J 10.5, 5.1,
2.1) in acetoxydiol (149) to δ 4.83 (br d, J 10.2 Hz) in diacetate (176), which proved
the presence of acetoxyl group at C-10 position.
76
Reaction of diacetate (176) with MsCl (8.0 eq.)/Et3N (10.0 eq.)/DMAP (0.05
eq.) following the previous procedure unfortunately led to a mixture of products.
Column chromatographic purification of the reaction mixture failed to isolate the
desired allylic acetate (178), instead the more polar monoacetate (177) was isolated.
Monoacetate (177) was isolated as white needles, mp 131-134 °C. Comparison of the
1
H NMR spectral data of the starting diacetate (176) (Appendix 95) with monoacetate
(177) (Appendix 99), revealed some notable changes as summarised in Table 2.13.
The signal of the carboacetoxyl group was still intact, but the signal due to the
phenolic acetyl function was absent in monoacetate (177). In addition, the aromatic
signals were shifted upfield to δ 6.60 (1H, d, J 1.5 Hz, H-2), δ 6.64 (1H, dd, J 7.5, 1.5
Hz, H-6) and δ 7.02 (1H, d, J 7.5 Hz, H-5), while the resonances for the benzylic
methyl and benzylic methine, H-15 and H-7, were also shifted upfield from δ 1.23
and δ 2.68 to δ 1.19 and δ 2.61, respectively. It was found that the signals at aromatic
region of monoacetate (177) were similar to that of triol (137) (Table 2.5), suggesting
that the phenolic acetoxyl group was cleaved and was confirmed by the presence of
Table 2.13: 1H and 13C NMR data of diacetate (176) and monoacetate phenol (177).
Position
(176)
13
C NMR
δ (ppm)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3CO
CH3CO
C=O
C=O
Ph-OH
146.0
124.5
149.3
127.4
131.0
120.5
38.9
34.1
27.2
79.5
72.3
25.0
26.4
15.8
22.6
20.8
21.0
169.2
171.3
-
1
H NMR
δ (ppm)
6.83 (d, 1.5)
7.16 (d, 7.5)
6.97 (dd, 7.5, 1.5)
2.68 (sext, 6.9)
1.45-1.59 (m)
1.68 (m)
4.83 (br d, 10.2)
1.13 (s)
1.14 (s)
2.15 (s)
1.23 (d, 6.9)
2.11 (s)
2.33 (s)
-
(177)
H NMR
δ (ppm)
6.60 (d, 1.5)
7.02 (d, 7.5)
6.64 (dd, 7.5, 1.5)
2.61 (m)
1.48–1.56 (m)
1
4.83 (dd, 9.9, 2.4)
1.12 (s)
1.14 (s)
2.21 (s)
1.19 (d, 6.9)
2.10 (s)
5.11 (s)
77
phenolic OH signal at δ 5.11 (1H, s). Based on these observations, monoacetate (177)
was
identified
as
2-methyl-5-(4(S)-acetoxy-1(R),5-dimethylhex-5-enyl)-2-
methylphenol (177).
The formation of the monoacetate (177) indicated that the more labile
phenolic acetoxyl group did not survive the reaction conditions, being hydrolysed to
phenol group under the basic reaction condition.
The elimination reaction may have given the desired allylic acetate (178), but
failed to isolate it due to the small amounts of product (small scale reaction). In
addition, the elimination reaction needs to be optimised to reduce the formation of
side products.
However, the optimisation and effort to get the targeted compound was not
further attempted due to lack of time.
2.6
Summary of Results
In summary, several bisabolane sesquiterpenoids have been prepared from
naturally occurring (–)-xanthorrhizol (1), which including the first enantioselective
synthesis of triols (137) and (138), a short and facile synthesis of (–)-curcuquinone
(139) and (–)-curcuhydroquinone (140) as well as the enantioselective synthesis of
unnatural analogues, helibisabonol A diacetate (164) and allylic alcohol (147). The
results are listed in Table 2.14.
Table 2.14: Summary of results.
Product
(7R,10S)-Triol (137)
(7R,10R)-Triol (138)
(–)-Curcuquinone (139)
(–)-Curcuhydroquinone (140)
Helibisabonol A diacetate (164)
Allylic alcohol (147)
*from xanthorrhizol
Step*
3
3
1
2
4
5
Yield*
28.6%
18.5%
60.0%
100%
29.1%
24.1%
CHAPTER 3
EXPERIMENTAL
3.1
General Procedures
Dry diethyl ether (ether) and tetrahydrofuran (THF) were obtained by drying
over Na/benzophenone and methylene chloride (CH2Cl2) was obtained by drying
over CaH2. Petroleum ether refers to boiling range 60-80 °C and was redistilled
before use. Yields refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise stated. Reagents were used without further
purification, unless otherwise stated. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60 F254), and
compounds were visualised with UV light and acidic p-anisaldehyde. Merck silica
gel 60 (0.040-0.063 mm) was used for vacuum liquid chromatography and column
chromatography was carried out using Merck silica gel 60 (0.063-0.200 mm). Mass
spectral data were obtained from Kent Mass Spectrometry Service, UK. 1H and 13C
NMR spectra (300 and 75 MHz respectively) were recorded on a Bruker Avance 300
Spectrometer using CDCl3 or acetone-d6 as solvents. 400 MHz NMR spectra were
recorded on a Varian Inova 400 spectrometer. Chemicals shifts are reported in ppm
with reference to residual solvent [1H NMR, CHCl3 (7.26), CHD2COCD3 (2.05); 13C
NMR, CDCl3 (77.0), CD3COCD3 (29.8)]. IR spectra were recorded on a Shimadzu
8000 or a Perkin-Elmer series 1600 spectrometers as thin film (NaCl windows) for
liquid samples or KBr pellet for solid samples. Optical rotations were determined on
a JASCO DIP-370 digital polarimeter. Melting points (uncorrected) were measured
on a Leica Galen III Kofler micro melting points apparatus.
79
3.2
Extraction and Isolation
The fresh rhizomes of C. xanthorrhiza were divided into two batches (CX-1
and CX-2). The chopped fresh rhizomes (CX-1, 1.85 kg) were subjected to
hydrodistillation in a Dean-Stark apparatus for 10 h. The oil-water was extracted
with ether (3 x 10 mL), the combined organic phase containing essential oil was
dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded a pale
yellow oil (13.39 g, 0.72%). The second batch of fresh rhizomes (CX-2, 1.5 kg) was
treated in the similar way as CX-1 to give a pale yellow oil (17.17 g, 1.14%).
The essential oil from CX-1 (13.39 g) was fractionated by VLC (120 g, 10 x
10 cm, PE, PE-Et2O, Et2O) to give 18 fractions. These fractions were combined
according to TLC profile and yielded two combined fractions that containing
xanthorrhizol labelled as cxe(1) 4-9 (1.24 g, 9.27%) and cxe(1) 11 (1.55 g, 11.61%).
The essential oil from CX-2 (15.40 g) was fractionated to yield two combined
fractions, cxe(2) 10-12 (5.64 g, 36.60%) and cxe(2) 13 (1.70 g, 11.01%). Fraction
cxe(2) 13 was used without further purification but fraction cxe(2) 10-12 was
repurified by VLC to give three combined fractions, cxe(2) 7-8a (2.65 g, 50.45%),
cxe(2) 10a (0.79 g, 15.11%) and cxe(2) 11a (0.15 g, 2.76%), in which the last two
fractions were used without further purification. Fraction cxe(2) 7-8a was combined
with fraction cxe(1) 4-9 and subjected to VLC to afford two combined fractions that
contained xanthorrhizol, cxe 4-5b (0.85 g, 21.86%) and cxe 6-11b (0.78 g, 20.05%).
Xanthorrhizol (1) was isolated as a colourless oil.
Xanthorrhizol (1): Rf = 0.26 (PE/Et2O, 9/1); [α]D –49.4° (c 1.00, MeOH)
{lit. [3] [α]D –52.5° (CHCl3)}; IR (neat) 3387, 2962, 2922, 2856, 1621, 1587, 1504,
1422, 1377, 1356, 1255, 1179, 1121, 993,813 cm-1; 1H NMR (CDCl3) δ 1.20 (3H, d,
J 6.9 Hz, H-15), 1.54 (3H, s, H-12), 1.56-1.64 (2H, m, H-8), 1.68 (3H, s, H-13), 1.88
(2H, m, H-9), 2.22 (3H, s, H-14), 2.61 (1H, sext, J 6.9 Hz, H-7), 4.66 (1H, br s, OH),
5.09 (1H, tt, J 8.4, 1.5 Hz, H-10), 6.62 (1H, d, J 1.5 Hz, H-2), 6.70 (1H, dd, J 7.5, 1.5
Hz, H-6), 7.05 (1H, d, J 7.5 Hz, H-5); 13C NMR δ 15.3 (C-14), 17.7 (C-12), 22.4 (C15), 25.7 (C-13), 26.1 (C-9), 38.4 (C-8), 39.0 (C-7), 113.5 (C-2), 119.4 (C-6), 120.8
(C-4), 124.5 (C-10), 130.3 (C-5), 131.4 (C-11), 147.2 (C-1), 153.6 (C-3); EIMS m/z
80
218 (35) [M+, C15H22O], 148 (27), 136 (100), 121 (71), 81 (35), 77 (20), 55 (24), 47
(67).
3.3
Synthesis of Triols (137) and (138)
Xanthorrhizyl acetate [5-(1,5-dimethylhex-4-en-1-yl)-2-methylphenyl acetate]
(148). To a stirred solution of xanthorrhizol (1) (1.00 g, 4.580 mmol) in diethyl ether
(1 mL) was added acetic anhydride (0.935 g, 9.159 mmol) and pyridine (85 mg,
0.933 mmol). The reaction mixture was left to stir at rt for 73 h. The organic layer
was washed with 5% HCl solution (3 x 5 mL) followed by saturated NaHCO3
solution (2 x 5 mL) and dried over anhydrous MgSO4. The solvent was evaporated to
leave an oil which was chromatographed on silica gel (PE/Et2O = 9/1) to give
xanthorrhizyl acetate (148) (0.8453 g, 72.1%) as a colourless oil: Rf=0.45
(PE/Et2O, 9/1); IR (neat) 2962, 2924, 1766, 1677, 1577, 1507, 1452, 1370, 1214,
1119, 1031, 821 cm-1; 1H NMR (CDCl3) δ 1.24 (3H, d, J 6.9 Hz, H-15), 1.53 (3H, s,
H-12), 1.55-1.66 (2H, m, H-8), 1.69 (3H, s, H-13), 1.88-1.95 (2H, m, H-9), 2.16 (3H,
s, H-14), 2.33 (3H, s, OAc), 2.69 (1H, sext, J 6.9 Hz, H-7), 5.10 (1H, tt, J 7.2, 1.2
Hz, H-10), 6.84 (1H, d, J 1.8 Hz, H-2), 6.99 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.16 (1H, d,
J 7.8 Hz, H-5); 13C NMR δ 15.8 (C-14), 17.7 (C-12), 20.9 (C-17), 22.2 (C-15), 25.7
(C-13), 26.1 (C-9), 38.3 (C-8), 38.9 (C-7), 120.3 (C-2), 124.4 (C-6), 124.7 (C-4),
127.2 (C-10), 130.8 (C-5), 131.5 (C-11), 146.9 (C-1), 149.3 (C-3), 169.3 (C=O);
EIMS m/z 260 (17) [M+, C17H24O2], 218 (10), 203 (1), 190 (8), 177 (11), 161 (7), 148
(38), 136 (100), 121 (32), 115 (7), 105 (9), 91 (25), 77 (11), 69 (7), 55 (16).
(7R,10S)-Acetoxydiol [(3S,6R)-6-(3-Acetoxy-4-methyl)phenyl-2-methylheptane2,3-diol] (149). A 25 mL round-bottomed flask, equipped with a magnetic stirrer,
was charged with tert-butanol (5 mL), H2O (5 mL), AD-mix-α (1.620 g), and
MeSO2NH2 (110 mg, 1.156 mmol, 1.0 eq.). The mixture was stirred at rt until both
phases were clear, and then cooled to 0 °C, whereupon the inorganic salts partially
precipitated. Xanthorrhizyl acetate (148) (300 mg, 1.152 mmol) was added at once,
and the heterogeneous slurry was stirred vigorously at 0 °C for 117 h. The reaction
was quenched at 0 °C by addition of Na2SO3 (1.73 g) and then warmed to rt and
81
stirred for 35 minutes. The reaction mixture was extracted with ethyl acetate (3 x 10
mL) and the combined organic extract was washed with 2N KOH solution (2 x 20
mL) and dried over anhydrous MgSO4. The ethyl acetate extracts were evaporated to
leave crude diol which was chromatographed on silica gel (Hex/EtOAc = 4/6) to
provide acetoxydiol (149) (169.5 mg, 50%) as a colourless oil: Rf = 0.34 (PE/Et2O,
1/9); [α]D –38.2° (c 1.02, CHCl3); IR (neat) 3418, 2928, 1747, 1506, 1371, 1219,
1119, 1015, 822 cm-1; 1H NMR (CDCl3) δ 1.07 (3H, s, H-12), 1.13 (3H, s, H-13),
1.15 (1H, m, H-9’), 1.24 (3H, d, J 6.9 Hz, H-15), 1.40 (1H, m, H-9), 1.62 (1H, m, H8’), 1.83 (1H, m, H-8), 2.02 (1H, d, J 5.1 Hz, OH), 2.14 (3H, s, H-14), 2.31 (3H, s,
OAc), 2.70 (1H, m, H-7), 3.32 (1H, ddd, J 10.5, 5.1, 2.1 Hz), 6.83 (1H, d, J 1.8 Hz,
H-2), 6.97 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.14 (1H, d, J 7.8 Hz, H-5); 13C NMR δ 15.8
(C-14), 20.7 (C-17), 22.6 (C-15), 23.2 (C-12), 26.4 (C-13), 29.5 (C-9), 34.9 (C-8),
39.1 (C-7), 73.1 (C-11), 78.4 (C-10), 120.4 (C-6), 124.7 (C-2), 127.3 (C-4), 131.0
(C-5), 146.2 (C-1), 149.3 (C-3), 169.3 (C-16); EIMS m/z 276 [M–H2O]+ (14), 258
(5), 235 (29), 217 (33), 194 (79), 175 (100), 161 (21), 148 (74), 135 (88), 121 (17),
109 (13), 91 (16), 77 (6), 59 (32); HRCIMS (methane) Calcd for C17H26O4 295.1909
(M+H), found 295.1914 (M+H).
(10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizol [(3S,6R)-6-(3-hydroxy-4methylphenyl)-2-methylheptane-2,3-diol] (137). A solution of acetoxydiol (149)
(65.6 mg, 0.223 mmol) in 2 mL of methanol and 1 mL of water was treated with
saturated solution of sodium bicarbonate (1 mL) and stirred at rt for 17 h. The
solution was acidified with 10% HCl solution and extracted with ethyl acetate (3 x
10 mL). The combined organic extract was washed with saturated solution of
NaHCO3 (2 x 10 mL) and dried over anhydrous MgSO4. The solvent was evaporated
and the crude product was chromatographed on silica gel (Hex/EtOAc = 3/7 to
EtOAc 100%) to give triol (137) (44.6 mg, 79.2%) as a colourless oil: Rf = 0.29
(PE/Et2O, 1/9); [α]D –64.7 (c 0.51, MeOH); IR (neat) 3361, 2960, 2927, 1619, 1589,
1456, 1421, 1377, 1260, 1124, 814 cm-1; 1H NMR (CDCl3) δ 1.08 (3H, s, H-12),
1.15 (3H, s, H-13), 1.18 (1H, m, H-9’), 1.23 (3H, d, J 6.9 Hz, H-15), 1.40 (1H, m, H9), 1.60 (1H, m, H-8’), 1.86 (1H, m, H-8), 2.21 (3H, s, H-14), 2.64 (1H, sext, J 6.9
Hz, H-7), 3.37 (1H, br d, J 10.2 Hz, H-10), 5.06 (1H, s, OH), 6.61 (1H, d, J 1.8 Hz,
H-2), 6.66 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.02 (1H, d, J 7.8 Hz, H-5); 13C NMR δ 15.4
(C-14), 23.0 (C-12), 23.2 (C-15), 26.5 (C-13), 29.6 (C-9), 35.0 (C-8), 39.3 (C-7),
82
73.3 (C-11), 78.6 (C-10), 113.3 (C-2), 119.4 (C-6), 121.3 (C-4), 130.9 (C-5), 146.4
(C-1), 153.9 (C-3); EIMS m/z 252 (29) [M+, C15H24O3], 234 (2), 216 (7), 194 (53),
175 (64), 161 (24), 148 (89), 135 (100), 121 (21), 109 (27), 91 (21), 77 (11), 67 (6),
59 (95).
(7R,10R)-Acetoxydiol [(3R,6R)-6-(3-Acetoxy-4-methyl)phenyl-2-methylheptane2,3-diol] (150). Xanthorrhizyl acetate (148) (300 mg, 1.152 mmol) was
dihydroxylated in the presence of AD-mix-β (1.62 g) and MeSO2NH2 (110 mg,
1.156 mmol, 1.0 eq.) under the same conditions as described for (3S,6R)-(149) to
afford acetoxydiol (150) (119.5 mg, 35.2%) as a colourless oil: Rf = 0.34 (PE/Et2O,
1/9); [α]D +5.37° (c 1.08, CHCl3); IR (neat) 3416, 2928, 1746, 1508, 1369, 1215,
1119, 820 cm-1; 1H NMR (CDCl3) δ 1.09 (3H, s, H-12), 1.11 (3H, s, H-13), 1.23 (3H,
d, J 6.9 Hz, H-15), 1.31 (2H, m, H-9 and H-9’), 1.63 (1H, m, H-8’), 1.84 (1H, m, H8), 2.14 (3H, s, H-14), 2.31 (3H, s, OAc), 2.67 (1H, sext, J 6.9 Hz, H-7), 3.21 (1H, br
d, J 9.6 Hz, H-10), 6.83 (1H, d, J 1.8 Hz, H-2), 6.97 (1H, dd, J 7.8, 1.8 Hz, H-6),
7.14 (1H, d, J 7.8 Hz, H-5); 13C NMR δ 15.8 (C-14), 20.8 (C-17), 22.2 (C-15), 23.1
(C-12), 26.4 (C-13), 29.8 (C-9), 35.2 (C-8), 39.6 (C-7), 73.1 (C-11), 78.5 (C-10),
120.3 (C-6), 124.7 (C-2), 127.3 (C-4), 130.9 (C-5), 146.7 (C-1), 149.3 (C-3), 169.4
(C-16); EIMS m/z 276 [M–H2O]+ (4), 258 (2), 235 (25), 217 (29),194 (72), 175
(100), 161 (20), 148 (66), 135 (88), 121 (17), 109 (15), 91 (17), 77 (6), 59 (39);
HRCIMS (methane) Calcd for C17H26O4 295.1909 (M+H), found 295.1917 (M+H).
(10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol [(3R,6R)-6-(3-hydroxy-4methylphenyl)-2-methylheptane-2,3-diol] (138). Acetoxydiol (150) (30 mg, 0.102
mmol) was treated the same way as (10S)-(146) to give triol (138) (18.7 mg, 72.8%)
as a colourless oil: Rf = 0.29 (PE/Et2O, 1/9); [α]D +3.33° (c 0.30, MeOH); IR (neat)
3382, 2962, 2927, 1619, 1589, 1503, 1456, 1421, 1256, 1124, 993 cm-1; 1H NMR
(CDCl3) δ 1.11 (3H, s, H-12), 1.14 (3H, s, H-13), 1.22 (3H, d, J 6.9 Hz, H-15), 1.34
(2H, m, H-9 and H-9’), 1.58 (1H, m, H-8’), 1.85 (1H, m, H-8), 2.21 (3H, s, H-14),
2.61 (1H, sext, J 6.9 Hz, H-7), 3.30 (1H, dd, J 9.9, 2.1 Hz, H-10), 6.62 (1H, d, J 1.8
Hz, H-2), 6.67 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.02 (1H, d, J 7.8 Hz, H-5); 13C NMR δ
15.3 (C-14), 23.1 (C-15), 23.4 (C-12), 26.5 (C-13), 29.9 (C-9), 35.5 (C-8), 39.7 (C7), 73.1 (C-11), 78.8 (C-10), 113.4 (C-2), 119.1 (C-6), 121.1 (C-4), 130.9 (C-5),
146.9 (C-1), 153.8 (C-3); EIMS m/z 252 (11) [M+, C15H24O3], 234 (2) [M–H2O]+,
83
216 (3), 194 (17), 175 (36), 161 (15), 148 (47), 135 (100), 121 (31), 109 (17), 91
(52), 77 (28).
3.4
Attempted Synthesis of Helibisabonol A (142)
4-Nitroxanthorrhizol (157) (two-phase nitration of xanthorrhizol). Xanthorrhizol
(207 mg, 0.948 mmol) in Et2O (1 mL) was added to NaNO3 (90 mg, 1.058 mmol) in
3M H2SO4 (1 mL) containing a trace amount of NaNO2 (1.7 mg, 0.025 mmol) and
the resulting two-phase mixture was stirred mechanically at rt for 26 h. TLC analysis
showed that the reaction did not proceed at all. NaNO3 (50 mg, 0.588 mmol) and
NaNO2 (2 mg, 0.029 mmol) were then added and the reaction mixture was further
stirred for another 8 h. The organic layer was separated and the aqueous layer was
extracted with Et2O (3 x 5 mL). The ether layer was dried over MgSO4 and
concentrated under reduced pressure to afford a dark brown sticky oil. The crude
product was chromatographed on silica gel (14.0 g) using PE:Et2O gradient system to
yield 4-nitroxanthorrhizol (157) (29.9 mg, 12.0%) and 2,4-dinitroxanthorrhizol
(158) (18.6 mg, 7.45%).
4-Nitroxanthorrhizol (157): Brown oil; Rf = 0.40 (PE/Et2O, 7/3); IR (neat) 3416,
2966, 2926, 1624, 1583, 1524, 1334, 1266, 1169, 1022, 894 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.26 (3H, d, J 6.84 Hz, H-15), 1.43 (3H, s, H-12), 1.48-1.61 (2H, m,
H-9), 1.65 (3H, s, H-13), 1.87-1.94 (2H, m, H-8), 2.25 (3H, s, H-14), 3.41 (1H, m, H7), 5.03 (1H, t, H-10), 5.53 (1H, br s, OH), 6.76 (1H, s, H-6), 7.68 (1H, s, H-3);
2,4-Dinitroxanthorrhizol (158): Brown oil; Rf = 0.44 (PE/Et2O, 1/4); IR (neat)
3416, 2969, 2929, 1538, 1454, 1376, 1235, 1027, 759 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.27 (3H, d, J 6.84Hz, H-15), 1.45 (3H, s, H-12), 1.63 (3H, s, H-13), 1.671.72 (2H, m, H-9), 1.86-1.90 (2H, m, H-8), 2.34 (3H, s, H-14), 3.03 (1H, m, H-7),
7.58 (1H, s, H-3).
84
Curcuhydroquinone [2-(1,5-dimethylhex-4-en-1-yl)-5-methylbenzene-1,4-diol]
(140) (Elbs persulphate hydroxylation of xanthorrhizol). A solution of potassium
persulphate, K2S2O8 (619 mg, 2.29 mmol, 1.0 eq.) in water (15 mL) was added
dropwise over a period of 5 min to a stirred solution of xanthorrhizol (1) (500 mg,
2.29 mmol) and sodium hydroxide (495 mg, 12.38 mmol, 5.4 eq.). The reaction
mixture was stirred for 24h at rt, and carbon dioxide was then passed through the
solution until the pH became neutral. The mixture was extracted with Et2O (3 x 10
mL), and unreacted xanthorrhizol (1) (328.9 mg) was recovered from the ether
extracts. The aqueous solution was evaporated to dryness under vacuum and the solid
residue was stirred and extracted with a hot ethanol/water solution (20:1, 3 x 20 mL).
The combined aqueous ethanolic extracts were evaporated to dryness to give a pale
brown solid (438.3 mg, 54.3%). Acetic acid (3 mL) was added to the solid (398.3
mg) and the mixture was heated under reflux for 2 h. The acetic acid was removed
under vacuum and the residue was partitioned between water (10 mL) and CH2Cl2 (4
x 10 mL). The combined organic extract was washed with saturated NaHCO3
solution (20 mL) and dried (MgSO4). Evaporation of the solvent yielded a brown oil
(110.2 mg, 20.54%). The crude product was chromatographed on silica gel (PE:Et2O
= 9/1 to 100% Et2O) to give curcuhydroquinone (140) (27.8 mg, 5.7% overall
yield) as a pale yellow oil. Rf = 0.34 (PE/Et2O, 7/3); IR (neat) 3358, 2963, 2920,
1516, 1418, 1187, 875, 832 cm-1; 1H NMR (CDCl3) δ 1.22 (3H, d, J 6.9Hz, H-15),
1.56 (3H, s, H-12), 1.63 (2H, m, H-8), 1.70 (3H, s, H-13), 1.88 – 2.04 (2H, m, H-9),
2.19 (3H, s, H-14), 2.96 (1H, sext, J 6.9 Hz, H-7), 5.14 (1H, tt, J 7.1, 1.5 Hz, H-10),
6.56 (1H, s, H-3), 6.60 (1H, s, H-6).
Curcuquinone [2-(1,5-dimethylhex-4-en-1-yl)-5-methylbenzo-1,4-quinone] (139).
To buffered aqueous solution (250 mL, pH 6.75, 200 mL 0.2M NaH2PO4 and 120
mL 0.2M Na2HPO4) of Fremy’s salt (4.5046 g, 16.79 mmol, 3.0 eq.), a methanolic
solution (70 mL) of xanthorrhizol (1) (1.2041 g, 5.515 mmol) was added in one
portion. The reaction mixture was left to stir under a nitrogen atmosphere at rt for 27
h. The aqueous phase was extracted with EtOAc (5 x 100 mL). The combined
organic extract was washed with brine (2 x 100 mL) and dried over anhydrous
MgSO4. Evaporation of the solvent yielded the crude quinone as a yellow oil. The
crude quinone was chromatographed on silica gel (PE:Et2O = 99/1 to 80/20) to give
curcuquinone (139) (0.7566 g, 60%) as a yellow oil: Rf = 0.47 (PE/Et2O, 9/1); [α]D
85
–4.58° (c 2.62, CHCl3) {lit. [82] [α]D –1.3° (c 9.1, CHCl3)}. IR (neat) 2965, 2925,
2857, 1656, 1611, 1451, 1378, 1353, 1243, 1138, 1123, 1005, 913 cm-1; 1H NMR
(CDCl3) δ 1.08 (3H, d, J 6.9 Hz, H-15), 1.34-1.50 (2H, m, H-8), 1.52 (3H, s, H-12),
1.63 (3H, s, H-13), 1.93 (2H, m, H-9), 2.01 (3H, d, J 1.8, H-14), 2.83 (1H, sext, J 6.9
Hz, H-7), 5.02 (1H, tt, J 5.2, 1.5Hz, H-10), 6.48 (1H, d, J 0.9 Hz, H-6), 6.56 (1H, q, J
1.8 Hz, H-3); EIMS m/z 232 (4) [M+, C15H20O2], 217 (1), 189 (2), 175 (2), 164 (3),
151 (100), 133 (2), 122 (42), 107 (7), 91 (9), 79 (8), 69 (8), 55 (8).
Curcuhydroquinone [2-(1,5-dimethylhex-4-en-1-yl)-5-methylbenzene-1,4-diol]
(140). A solution of curcuquinone (139) (500 mg, 2.152 mmol) in THF (12 mL) had
added a solution of Na2S2O4 (3.75 g, 21.54 mmol, 10 eq.) in H2O (8 mL) and was
stirred at rt for 2 h. The mixture was extracted with Et2O (3 x 15 mL). The combined
organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, filtered
and concentrated to give curcuhydroquinone (140) as white solids (503 mg, 100%):
mp 93-96 °C (lit. [110] mp 86-87 °C); Rf = 0.34 (PE/Et2O, 7/3); [α]D –48.3° (c 0.89,
CHCl3) {lit. [100] [α]D –48.0° (c 2.78, CHCl3)}; IR (KBr pellet) 3354, 2963, 2924,
1630, 1512, 1454, 1420, 1188, 874, 833 cm-1; 1H NMR (CDCl3) δ 1.18 (3H, d, J 6.9
Hz, H-15), 1.52 (3H, s, H-12), 1.54-1.64 (2H, m, H-8), 1.66 (3H, s, H-13), 1.91 (2H,
m, H-9), 2.15 (3H, s, H-14), 2.92 (1H, sext, J 6.9 Hz, H-7), 5.10 (1H, t with further
unresolved couplings, H-10), 6.54 (1H, s, H-3), 6.56 (1H, s, H-6); 13C NMR δ 15.4
(C-14), 17.7 (H-12), 21.1 (C-15), 25.7 (C-13), 26.0 (C-9), 31.4 (C-7), 37.3 (H-8),
113.4 (C-6), 117.9 (C-3), 121.7 (C-4), 123.8 (C-10), 131.8 (C-1), 132.1 (C-11), 146.7
(C-2), 147.8 (C-5); EIMS m/z 234 (54) [M+, C15H22O2], 191 (2), 177 (5), 164 (15),
112 (100), 137 (17), 124 (7), 110 (3), 95 (8), 77 (6), 69 (9).
Curcuhydroquinone
diacetate
[2-(1,5-dimethylhex-4-en-1-yl)-5-methyl-1,4-
phenylene diacetate] (163). A mixture of curcuhydroquinone (140) (325 mg, 1.387
mmol) in CH2Cl2 (5 mL), triethylamine (246 mg, 4.163 mmol, 3.0 eq.), acetic
anhydride (425 mg, 4.163 mmol, 3.0 eq.), and DMAP (35 mg, 0.286 mmol, 0.2 eq.)
were stirred for 22 h at rt. The reaction mixture was washed with 2N HCl solution (3
x 5 mL) followed by saturated solution of NaHCO3 (2 x 10 mL). The organic layer
was dried over anhydrous MgSO4. The solvent was evaporated and the crude was
chromatographed on silica gel with Hex/Et2O = 9/1 to give curcuhydroquinone
diacetate (163) (0.3362 g, 78.6%) as a pale yellow oil: Rf = 0.44 (PE/Et2O, 7/3); [α]D
86
–28.2° (c 1.00, CHCl3); IR (neat) 2928, 2856, 1761, 1504, 1369, 1205, 1155, 924 cm1 1
; H NMR (400 MHz, CDCl3) δ 1.16 (3H, s, d, J 7.2 Hz, H-15), 1.46-1.62 (2H, m,
H-8), 1.53 (3H, s, H-12), 1.66 (3H, s, H-13), 1.90 (2H, m, H-9), 2.12 (3H, s, H-14),
2.29 (3H, s, OAc), 2.30 (3H, s, OAc), 2.79 (1H, sext, J 7.2 Hz, H-7), 5.06 (1H, t, J
5.4 Hz), 6.84 (1H, s, H-6), 6.87 (1H, s, H-3); 13C NMR (75 MHz, CDCl3) δ 15.9 (C14), 17.6 (C-12), 20.8 (COMe), 20.9 (COMe), 20.9 (C-15), 25.7 (C-13), 25.9 (C-9),
32.0 (C-7), 38.9 (C-8), 120.5 (C-6), 124.2 (C-10), 124.5 (C-3) 128.4 (C-4), 131.0 (C11), 137.9 (C-1), 145.8 (C-2), 147.3 (C-5), 168.9 (C=O), 169.3 (C=O); EIMS m/z
318 (17) [M+, C19H26O4], 276 (15), 258 (1), 248 (1), 234 (100), 193 (14), 177 (6),
164 (21), 151 (82), 137 (11), 124 (6), 95 (10), 79 (8), 69 (10), 55 (11).
(7R,10S)-Diacetoxydiol (164). Curcuhydroquinone acetate (163) (170 mg, 0.551
mmol) was dihydroxylated in the presence of AD-mix-α (0.772 g) and MeSO2NH2
(53 mg, 0.357 mmol) under the same conditions as described for (3S,6R)-(149) to
afford crude (164) as a sticky yellow oil. The residue was purified by column
chromatography (silica gel, Hex/EtOAc = 4/6) to afford diacetoxydiol (164) (120
mg, 61.8 %) as white solids: mp 78-81 °C; Rf = 0.40 (Et2O/EtOAc, 4/1); [α]D –37.5°
(c 0.24, CHCl3); IR (KBr pellet) 3343, 2975, 2923, 2880, 1762, 1497, 1376, 1212,
1149, 1017, 924 cm-1; 1H NMR (CDCl3) δ 1.08 (3H, s, H-12), 1.14 (3H, s, H-13),
1.21 (3H, d, J 6.9 Hz, H-15), 1.36-1.93 (4H, m, H-8 and H-9), 2.15 (3H, s, H-14),
2.32 (2 x 3H, s, H-17 and H-19), 2.86 (1H, m, H-7), 3.29 (1H, br d, J 10.5 Hz, H-10),
6.88 (1H, s, H-3), 6.93 (1H, s, H-6); 13C NMR δ 15.8 (C-14), 20.8 (C-17), 20.9 (C15), 21.7 (C-19), 23.3 (C-13), 26.2 (C-12), 29.4 (C-9), 32.8 (C-7), 33.8 (C-8), 73.0
(C-11), 78.4 (C-10), 124.6 (C-3 and C-6), 128.6 (C-4), 137.1 (C-1), 145.8 (C-2),
147.2 (C-5), 169.8 (C-16), 170.3 (C-18); EIMS m/z 310 (1) [M–CH2CO]+, 294 (18),
250 (46), 233 (34), 210 (36), 192 (33), 177 (8), 164 (38), 151 (100), 137 (13), 125
(8), 99 (4), 85 (10), 67 (4), 59 (34); HRCIMS (methane) Calcd for C19H28O6
353.1964 (M+H), found 353.1965 (M+H).
Helibisabonol
A
[2-(4,5-dihydroxy-1,5-dimethylhexyl)-5-methylbenzene-1,4-
diol] (142) [LiBH4 reduction of (7R,10S)-diacetoxydiol (164)]. To a solution of
(7R,10S)-diacetoxydiol (164) (12 mg, 0.034 mmol) in ether (2 ml) was added
dropwise a ~1.35 M LiBH4 solution in THF (200 µL, ~6 mg, 0.28 mmol). The
resulting mixture was stirred for 42 h at rt; 10% NH4Cl solution (2 mL) was added to
87
the reaction mixture and left to stir for another 5 min. The organic phase was
separated and the aqueous phase was extracted with EtOAc (2 x 3 mL). The organic
layer was dried over anhydrous MgSO4. Removal of the solvent yielded a colourless
oil (7.2 mg, 80%): Rf = 0.46 (Et2O/EtOAc, 3/7); 1H NMR (Acetone-d6) δ 1.06 (3H, s,
H-12), 1.11 (1H, m, H-9’), 1.16 (3H, d, J 6.9 Hz, H-15), 1.23 (3H, s, H-13), 1.38
(1H, m, H-9), 1.57 (1H, m, H-8’), 1.78 (1H, m, H-8), 2.08 (3H, s, H-14), 3.15 (1H,
sext, J 6.9 Hz, H-7), 3.91 (1H, dd, J 7.2, 6.0 Hz, H-10), 6.57 (1H, s, H-3), 6.61 (1H,
s, H-6). The crude product (6 mg) was subjected to column chromatography (silica
gel, PE/Et2O = 7/3 to 100% Et2O) to give quinone derivative (166) (0.7 mg) as a
yellow oil and helibisabonol A (142) (2.9 mg) as a colourless oil.
Quinone derivative (166): Rf = 0.32 (100% Et2O); 1H NMR (CDCl3) δ 1.12 (3H, s,
H-13), 1.14 (3H, d, J 7.2 Hz, H-15), 1.19 (3H, s, H-12), 1.27 (1H, m, H-9’), 1.45
(2H, m, H-8’ and H-9), 1.82 (1H, m, H-8), 2.04 (3H, d, J 1.2 Hz, H-14), 2.86 (1H,
sext, J 6.9 Hz, H-7), 3.33 (1H, br d, J 10.2 Hz, H-10), 6.54 (1H, d, J 1.2 Hz, H-6),
6.59 (1H, q, J 1.5Hz, H-3).
Helibisabonol A (142): Rf = 0.21 (100% Et2O); 1H NMR (Acetone-d6) δ 1.04 (3H, s,
H-12), 1.06 (3H, s, H-13), 1.14 (3H, d, J 6.9 Hz, H-15), 1.38 (2H, m, H-9), 1.52 (1H,
m, H-8’), 1.86 (1H, m, H-8), 2.08 (3H, s, H-14), 3.14 (1H, m, H-7), 3.91 (1H, dd, J
7.5, 6.0 Hz, H-10), 6.55 (1H, s, H-3), 6.60 (1H, s, H-6).
Reduction of quinone (166). NaBH4 (~1.0 mg, 0.026 mmol) was added to quinone
derivative (166) (0.7 mg, 0.0026 mmol) in MeOH (500 µL). The reaction mixture
was stirred at rt for 15 min. The reaction was followed by TLC in which after
completion, 10% aq. NH4Cl (0.3 mL) was added to the reaction mixture and the
mixture was then extracted with ethyl acetate (3 x 3 mL). The organic phase was
dried over anhydrous MgSO4 and concentrated under reduced pressure to afford a
pale yellow oil (0.6 mg, 85.7%). TLC showed a mixture of quinone (166) and
helibisabonol A (142): Rf = 0.20 (129) and 0.34 (148) (100% Et2O).
Deacetylation of diacetoxydiol (164) by KCN-catalysed transesterification. KCN
(9 µg, 0.14 µmol, 0.015M solution in MeOH) was added to a stirred solution of
(7R,10S)-diacetoxydiol (164) (0.1 mg, 0.29 µmol) in MeOH (200 µL). The reaction
mixture was stirred at rt for 2.5 h. The reaction mixture was then filtered through
88
silica gel and the eluent was evaporated to dryness to give quinone (166) (~0.1 mg)
as a yellow oil: Rf = 0.32 (100% Et2O).
3.5
Synthesis of Allylic Alcohol (147)
O-Methylxanthorrhizol [4-(1,5-dimethylhex-4-en-1-yl)-2-methoxy-1-methylbenzene] (167). MeI (25.0 g, 176.1 mmol, 6.4 eq.) and K2CO3 (12.5 g, 90.44 mmol,
3.29 eq.) were added to xanthorrhizol (1) (6.00 g, 27.50 mmol) in acetone (30 mL)
and the reaction mixture was refluxed for 8 h. The reaction mixture was filtered and
dried over anhydrous MgSO4. The solvent was removed and the product was purified
by column chromatography (silica gel, PE/Et2O = 97/3 to 80/20) to give Omethylxanthorrhizol (167) (4.1767 g, 65.3%) as a colourless oil and germacrone
(6) (18.4 mg, 0.31%) as colourless needles (impurities present in xanthorrhizol).
O-Methylxanthorrhizol (167): Rf = 0.70 (PE/Et2O, 9/1); IR (neat) 2959, 2923,
1612, 1583, 1512, 1454, 1414, 1256, 1134, 1043, 852, 815 cm-1; 1H NMR (CDCl3) δ
1.26 (3H, d, J 6.9 Hz, H-15), 1.56 (3H, s, H-12), 1.56-1.67 (2H, m, H-8), 1.70 (3H, s,
H-13), 1.89-2.00 (2H, m, H-9), 2.21 (3H, s, H-14), 2.69 (1H, sext, J 6.9 Hz, H-7),
3.85 (3H, s, -OMe), 5.13 (1H, tt, J 7.2, 1.5 Hz, H-10), 6.68 (1H, d, J 1.5 Hz, H-2),
6.72 (1H, dd, J 7.5, 1.5 Hz, H-6), 7.07 (1H, d, J 7.5 Hz, H-5); EIMS m/z 232 (30)
[M+, C16H24O], 175 (5), 162 (15), 150 (100), 135 (55), 119 (8), 115 (6), 105 (4), 91
(7).
Germacrone (6): mp 51-54 °C (lit. [13] mp 52-54 °C); Rf = 0.51 (PE/Et2O, 9/1); IR
(KBr pellet) 2981, 2918, 2854, 1672, 1442 1383, 1254, 1132, 1000, 856, 751, 537,
458 cm-1; 1H NMR (CDCl3) δ 1.44 (3H, s, H-14), 1.63 (3H, s, H-15), 1.73 (3H, s, H12), 1.77 (3H, s, H-13), 2.05-2.41 (4H, m, H-2 and H-3), 2.92 (3H, m, H-6 and H9b), 3.41 (1H, d, J 10.5 Hz, H-9a), 4.71 (1H, dd, J 11.1, 3.3 Hz, H-5), 4.99 (1H, d, J
10.8 Hz, H-1).
89
(7R,10S)-Methoxydiol [(3S,6R)-6-(3-methoxy-4-methylphenyl)-2-methylheptane2,3-diol] (168). AD-mix-α (30.13 g) was added to a mechanically stirred 1:1 mixture
of tert-butanol:H2O (200 mL), and was further stirred at rt until two bright yellow
phases were obtained. MeSO2NH2 (2.05 g, 21.55 mmol) was added, followed by Omethylxanthorrhizol (167) (5.0 g, 21.52 mmol) at 0 °C. The heterogeneous mixture
was stirred vigorously at 0 °C for approximately 52 h. The reaction mixture was
quenched at 0 °C by addition of sodium sulphite (32.28 g) and then warmed to rt and
stirred for 30 min. The organic phase was separated and water (120 mL) was added
to the organic phase. The aqueous tert-butanol phase was extracted with ethyl acetate
(3 x 50 mL). The combined organic extract was washed with 2N KOH solution (5 x
50 mL) and dried over anhydrous MgSO4. Removal of the solvent yielded crude oil
as a sticky yellow oil. The crude diol was purified by column chromatography (silica
gel, hex/EtOAc = 6/4 to 20/80) to give methoxydiol (168) (5.12 g, 90.6%) as an
amber oil: Rf = 0.17 (PE/Et2O, 4/6); [α]D –65.4° (c 1.12, CHCl3); IR (neat) 3414,
2928, 1612, 1582, 1508, 1462, 1379, 1256, 1161, 1136, 1042, 853, 816, 648 cm-1; 1H
NMR (CDCl3) δ 1.08 (3H, s, H-13), 1.15 (3H, s, H-12), 1.16-1.18 (1H, m, H-9’),
1.26 (3H, d, J 6.9 Hz, H-15), 1.36-1.46 (1H, m, H-9), 1.57-1.69 (1H, m, H-8’), 1.821.93 (1H, m, H-8), 2.18 (3H, s, H-14), 2.69 (1H, sext, J 6.9 Hz, H-7), 3.37 (1H, br d,
J 10.2 Hz, H-10), 3.82 (3H, s, -OMe), 6.65 (1H, d, J 1.5 Hz, H-2), 6.69 (1H, dd, J
7.5,1.5 Hz, H-6), 7.04 (1H, d, J 7.5 Hz, H-6); EIMS: m/z 266 (62) [M+, C16H26O3],
249 (6), 233 (1), 208 (47), 189 (55), 162 (58), 135 (22), 123 (40), 105 (14), 91 (37),
71 (18), 59 (100); HRCIMS (isobutane) Calcd for C16H26O3 266.1882, found
266.1882.
(7R,10S)-Monoacetate [(1S,4R)-(1-(1-hydroxy-1-methylethyl)-4-(3-methoxy-4methylphenyl)pentyl acetate] (169). A solution of methoxydiol (168) (2.50 g, 9.385
mmol) in CH2Cl2 (5 mL), pyridine (1 mL) and acetic anhydride (2.88 g, 28.17 mmol)
was stirred for 24 h at rt. Water (15 mL) was added to the reaction mixture and the
aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic
extract was washed with water (20 mL), 5% HCl solution (2 x 20 mL), saturated
NaHCO3 solution (2 x 20 mL), brine (2 x 20 mL) and dried (MgSO4). Removal of
the solvent yielded a pale yellow oil (2.75 g, 95.1%): Rf = 0.29 (PE/Et2O, 4/6); [α]D –
7.38° (c 1.68, CHCl3); IR (neat) 3450, 2960, 2929, 1733, 1612, 1511, 1462, 1374,
90
1254, 1135, 1027 cm-1; 1H NMR (CDCl3) δ 1.12 (3H, s, H-12), 1.14 (3H, s, H-13),
1.23 (3H, d, J 6.9 Hz, H-15), 1.41-1.62 (4H, m, H-8 and H-9), 2.10 (3H, s, -OAc),
2.18 (3H, s, H-14), 2.67 (1H, sext, J 6.9 Hz, H-7), 3.82 (3H, s, -OMe), 4.84 (1H, dd,
J 9.9, 2.1 Hz, H-10), 6.63 (1H, d, J 1.5 Hz, H-2), 6.67 (1H, dd, J 7.5, 1.5 Hz, H-6),
7.04 (1H, d, J 7.5 Hz, H-5); EIMS m/z 308 (20) [M+, C18H28O4], 250 (4), 215 (5),
113 (28), 91 (16), 71 (47), 57 (100); HRCIMS (isobutane) Calcd for C18H28O4
308.1987, found 308.1983.
(7R,10S)-Allylic acetate [(1S,4R)-1-isopropenyl-4-(3-methoxy-4methylphenyl)pentyl acetate] (170). A mixture of monoacetate (169) (2.3040 g,
7.47 mmol), triethylamine (3.77 g, 37.26 mmol) and DMAP (46 mg, 0.377 mmol) in
dry CH2Cl2 (15 mL) was cooled to 0 °C and mesyl chloride (2.56 g, 22.35 mmol) in
dry CH2Cl2 (5 mL) was added dropwise to the mixture. The reaction mixture was
stirred at rt for about 4 h. Crushed ice was added to the reaction mixture and left to
stir for another 30 min. The reaction mixture was extracted with CH2Cl2 (3 x 20 mL),
washed with brine (2 x 40 mL), dried (MgSO4) and concentrated to yield a dark
brown oil. The residue was purified by column chromatography (silica gel, PE/Et2O
= 95/5 to 25/75) to give allylic acetate (170) (1.0132 g, 47.3%) and diacetate (175)
(51.1 mg, 2.4%) as a pale yellow oil.
Allylic acetate (170): Rf = 0.41 (PE/Et2O, 8/2); [α]D –13.3° (c 1.40, CHCl3); IR
(neat) 2927, 1739, 1653, 1612, 1583, 1511, 1415, 1372, 1242, 1043, 1021, 903, 816
cm-1; 1H NMR (CDCl3) δ 1.24 (3H, d, J 6.9 Hz, H-15), 1.47-1.62 (4H, m, H-8 and H9), 1.65 (3H, s, H-13), 2.04 (3H, s, -OAc), 2.18 (3H, s, H-14), 2.65 (1H, m, H-7),
3.83 (3H, s, -OMe), 4.86 (1H, m, H-12b), 4.91 (1H, m, H-12a), 5.15 (1H, m, H-10),
6.63 (1H, d, J 1.5 Hz, H-2), 6.68 (1H, dd, J 7.5, 1.5 Hz, H-6), 7.05 (1H, d, J 7.5 Hz,
H-5); EIMS m/z 290 (3) [M+, C18H26O3], 248 (2), 230 (7), 215 (7), 202 (3), 187 (19),
175 (13), 162 (100), 149 (100), 135 (55), 117 (28), 105 (22), 91 (75), 77 (24);
HREIMS Calcd for C18H26O3 291.1960 (M+H), found 291.1963 (M+H).
Diacetate (175): Rf = 0.31 (PE/Et2O, 8/2); IR (neat) 2929, 2870, 1741, 1612, 1583,
1416, 1369, 1232, 1135, 1023, 853, 817 cm-1; 1H NMR (CDCl3) δ 1.22 (3H, d, J 6.9
Hz, H-15), 1.37 (3H, s, H-12), 1.40 (3H, s, H-13), 1.43-1.65 (4H, m, H-8 and H-9),
1.91 (3H, s, C-OAc), 2.08 (3H, s, Ar-OAc), 2.18 (3H, s, H-14), 2.67 (1H, sext, J 6.9
91
Hz, H-7), 3.83 (3H, s, -OMe), 5.23 (1H, dd, J 9.9, 2.1 Hz), 6.64 (1H, s, H-2), 6.67
(1H, d, J 7.5 Hz, H-6), 7.04 (1H, d, J 7.5 Hz, H-5); HRCIMS (Isobutane) Calcd for
C20H30O5 350.2093, found 350.2099.
Hydrolysis of diacetate (175). Diacetate (175) (24.8 mg, 0.0641 mmol) was stirred
with K2CO3 (36.4 mg, 0.263 mmol) in methanol (2 mL) for 6 h. Water (5 mL) was
added to the reaction mixture and was extracted with EtOAc (3 x 5 mL), dried
(MgSO4) and concentrated to give methoxydiol (168) (19 mg, 100%) as a pale
yellow oil: Rf = 0.17 (PE/Et2O, 4/6); IR (neat) 3412, 2926, 1611, 1583, 1501, 1465,
1414, 1256, 1134, 1042, 815 cm-1; 1H NMR (CDCl3) δ 1.08 (3H, s, H-13), 1.15 (3H,
s, H-12), 1.11-1.26 (1H, m, H-9’), 1.26 (3H, d, J 6.9 Hz, H-15), 1.36-1.47 (1H, m, H9), 1.57-1.69 (1H, m, H-8’), 1.82-1.96 (1H, m, H-8), 2.18 (3H, s, H-14), 2.69 (1H,
sext, J 6.9 Hz, H-7), 3.37 (1H, dd, J 10.2, 1.8 Hz, H-10), 3.82 (3H, s, -OMe), 6.65
(1H, br s, H-2), 6.69 (1H, dd, J 7.5,1.5 Hz, H-6), 7.04 (1H, d, J 7.5 Hz, H-6).
Allylic alcohol [6-(3-methoxy-4-methylphenyl)-2-methylhept-1-en-3-ol] (147).
Allylic acetate (170) (850 mg, 2.927 mmol) was stirred with K2CO3 (415 mg. 3.00
mmol, 1.02 eq.) in methanol (10 mL) for 7 h 10 min. The reaction mixture was
filtered and methanol was removed by rotary evaporator. Water (20 mL) was added
and the mixture was extracted with EtOAc (5 x 10 mL). The combined organic
extract was washed with saturated solution of NaHCO3 (20 mL), brine (20 mL) and
dried (MgSO4). evaporation of the solvent yielded allylic alcohol (147) (0.6582g,
90.5%) as a pale yellow oil: Rf = 0.24 (PE/Et2O, 8/2); [α]D –16.6° (c 1.34, CHCl3);
IR (neat) 3382, 3069, 2868, 1651, 1612, 1583, 1512, 1454, 1414, 1255, 1135, 1043,
900, 853, 815, 647 cm-1; 1H NMR (CDCl3) δ 1.25 (3H, d, J 6.9 Hz, H-15), 1.39-1.64
(4H, m, H-8, H-9), 1.66 (3H, t, J 1.2 Hz, H-13), 2.18 (3H, s, H-14), 2.66 (1H, sext, J
6.9 Hz, H-7), 3.83 (3H, s, -OMe), 4.03 (1H, m, H-10), 4.82 (1H, m, H-12b), 4.91
(1H, m, H-12a), 6.64 (1H, d, J 1.5 Hz, H-2), 6.68 (1H, dd, J 7.5, 1.5 Hz, H-6), 7.04
(1H, dd, J 7.5, 0.6 Hz, H-5); 13C NMR δ 15.9 (C-13), 17.6 (C-14), 22.6 (C-15), 32.9
(C-9), 34.0 (C-8), 39.9 (C-7), 55.2 (OMe), 75.9 (C-10), 108.8 (C-2), 111.0 (C-12),
118.6 (C-6), 124.0 (C-4), 130.5 (C-5), 146.4 (C-1), 147.5 (C-11), 157.7 (C-3); EIMS
m/z 248 (37) [M+, C16H24O2], 230 (2) [M–H2O]+, 205 (4), 189 (5), 175 (4), 162
(100), 149 (100), 135 (47), 123 (41), 117 (19), 105 (16), 91 (51), 84 (6), 77 (20), 71
(26); HREIMS Calcd for C16H24O2 248.1776, found 248.1773.
92
3.6
Attempted Synthesis of Allylic Alcohol Derivative of Xanthorrhizol
Diacetate (176). A mixture of acetoxydiol (149) (0.7219 g, 2.45 mmol), acetic
anhydride (0.125 g, 4.16 mmol, 1.7 eq.) and pyridine (0.051g, 0.55 mmol, 0.22 eq.)
in Et2O (5 mL) was stirred at rt overnight. The organic layer was extracted with
water (3 x 10 mL). The organic layer was dried over anhydrous MgSO4. Removal of
the solvent yielded crude product as a yellow oil. The crude product was purified by
column chromatography (silica gel, PE/Et2O = 80/20) to give diacetate (176)
(0.4419 g, 54.4%) as a pale yellow oil: Rf = 0.37 (PE/Et2O, 3/7); [α]D –20.5° (c 1.12,
CHCl3); IR (neat) 3469, 2963, 2930, 1733, 1507, 1455, 1372, 1221, 1120, 1023, 948,
823 cm-1; 1H NMR (CDCl3) δ 1.13 (3H, s, H-12), 1.14 (3H, s, H-13), 1.23 (3H, d, J
6.9 Hz, H-15), 1.45-1.59 (2H, sext, J 6.9 Hz, H-8), 1.68 (2H, m, H-9), 2.11 (3H, s,
H-17), 2.15 (3H, s, H-14), 2.33 (3H, s, H-19), 2.68 (1H, m, H-7), 4.83 (1H, d, J 10.2
Hz, H-10), 6.83 (1H, d, J 1.5 Hz, H-2), 6.97 (1H, dd, J 7.5, 1.5 Hz, H-6), 7.16 (1H, d,
J 7.5 Hz, H-5); 13C NMR δ 15.8 (C-14), 20.8 (C-19), 21.0 (C-17), 22.6 (C-15), 25.0
(C-12), 26.4 (C-13), 27.2 (C-9), 34.1 (C-8), 38.9 (C-7), 72.3 (C-11), 79.5 (C-10),
120.5 (C-6), 124.5 (C-2), 127.4 (C-4), 131.0 (C-5), 146.0 (C-1), 149.3 (C-3), 169.2
(C=O), 171.3 (C=O); EIMS m/z 336 (1) [M+, C19H28O5], 318 (8) [M–H2O]+, 294 (4),
276 (6), 236 (14), 216 (10), 202 (7), 190 (28), 176 (56), 161 (23), 148 (100), 135
(53), 121 (10), 109 (4), 91 (10), 77 (4), 59 (23); HRCIMS (methane) Calcd for
C19H28O5 (M+H) 337.2015, found 337.2006 (M+H).
Attempted synthesis of allylic acetate (178). A mixture of diacetate (176) (50.3 mg,
0.1495 mmol), trieythylamine (151 mg, 1.495 mmol, 10 eq.), and DMAP (1 mg,
0.008 mmol, 0.05 eq.) in CH2Cl2 (5 mL) was cooled to 0 °C and mesyl chloride (137
mg, 1.196 mmol, 8 eq.) was added dropwise to the reaction mixture. The reaction
mixture was left to stir for 48 h at rt. Then, crushed ice was added and stirred for 1 h.
The reaction mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic
extract was washed with water (2 x 20 mL) and dried over anhydrous MgSO4.
Evaporation of the solvent yielded a brown oil (71 mg, 151%). The residue was
purified by column chromatography (silica gel, PE/Et2O = 70/30) to give
monoacetate (177) (7.9 mg, 16.5%) as white needles but no desired allylic acetate
(160) was isolated: mp 131-134 °C; Rf = 0.21 (PE/Et2O, 4/6); IR (KBr pellet) 3442,
3314, 2962, 1707, 1425, 1380, 1270, 1246, 1032, 882, 861 cm-1; 1H NMR (CDCl3) δ
93
1.12 (3H, s, H-12), 1.14 (3H, s, H-13), 1.19 (3H, d, J 6.9 Hz, H-15), 1.48-1.56 (4H,
m, H-8 and H-9), 2.10 (3H, s, -OAc), 2.21 (3H, s, H-14), 2.61 (1H, m, H-7), 4.83
(1H, dd, J 9.9, 2.4 Hz, H-10), 5.11 (1H, s, OH), 6.60 (1H, d, J 1.5 Hz, H-2), 6.64
(1H, dd, J 7.5, 1.5 Hz, H-6), 7.02 (1H, d, J 7.5, H-5).
(S)-MTPA ester (151) [(S)-MTPA ester of (7R,10S)-acetoxydiol-(149)]. To a
solution of (7R,10S)-acetoxydiol (149) (8.1 mg, 0.0275 mmol) in pyridine (20 µL)
was added R-MTPCl (172R) (16 mg, 12 µL, 0.0633 mmol). The solution was
allowed to stand for 25 h at rt. 3-Dimethylamino-1-propylamine (9 µL, 7.29 mg,
0.0713 mmol, 2.0 eq) was added and the mixture was allowed to stand for 10 min. It
was then diluted with ether, washed with cold 1% HCl solution (2 x 2 mL), cold
saturated Na2CO3 (2 x 2 mL) and dried over anhydrous MgSO4. Removal of the
solvent and column chromatography (silica gel, PE/Et2O = 3/7) provided (S)-MTPA
ester (151) (1.4 mg, 8%) as a colourless oil: Rf = 0.47 (PE/Et2O, 3/7); [α]D –36.8° (c
0.19, CHCl3); 1H NMR (CDCl3) δ 1.07 (3H, s, H-12), 1.11 (3H, s, H-13), 1.14 (3H,
d, J 6.9 Hz, H-15), 1.18-1.45 (4H, m, H-8 and H-9), 2.13 (3H, s, H-14), 2.30 (3H, s,
OAc), 2.63 (1H, sext, J 6.9 Hz, H-7), 3.56 (3H, q, J 1.2 Hz, OMe), 5.01 (1H, br d, J
9.6 Hz, H-10), 6.70 (1H, d, J 1.8 Hz, H-2), 6.80 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.10
(1H, d, J 7.8 Hz, H-5), 7.39 (3H, m, H-5’, H-6’ and H-7’), 7.61 (2H, m, H-4’ and H8’); CIMS (methane) m/z 511 (29) [(M+H)+, C27H32O6F3], 493 (100), 468 (25), 443
(7), 391 (4), 277 (100), 217 (66), 189 (100), 127 (41), 105 (11), 71 (6).
(S)-MTPA ester (152) [(S)-MTPA ester of (7R,10R)-acetoxydiol (150)]. The same
procedure for the preparation of (S)-MTPA ester (151) was followed with the use of
(7R,10R)-acetoxydiol (150) (10.0 mg, 0.034 mmol) and R-MTPCl (172R) (17 mg, 13
µL, 0.0673 mmol) at rt for 25 h to give (S)-MTPA ester (152), after
chromatographic purification (silica gel, Hex/EtOAc = 1/1), as a colourless oil (1.9
mg, 11.1%): Rf = 0.47 (PE/Et2O, 3/7); [α]D +0.34° (c 0.21, CHCl3); 1H NMR
(CDCl3) δ 1.07 (3H, s, H-12), 1.09 (3H, s, H-13), 1.17 (3H, d, J 6.9 Hz, H-15), 1.501.58 (4H, m, H-8 and H-9), 2.14 (3H, s, H-14), 2.31 (3H, s, OAc), 2.61 (1H, sext, J
6.9 Hz, H-7), 3.55 (3H, br s, OMe), 4.92 (1H, m, H-10), 6.78 (1H, d, J 1.8 Hz, H-2),
6.92 (1H, dd, J 7.8, 1.8 Hz, H-6), 7.14 (1H, d, J 7.8 Hz, H-5), 7.40 (3H, m, H-5’, H6’ and H-7’), 7.59 (2H, m, H-4’ and H-8’).
94
(S)-MTPA ester (165) [(S)-MTPA ester of (7R,10S)-diacetoxydiol (164)]. The
same procedure for the preparation of (S)-MTPA ester (151) was followed with the
use of (7R,10S)-diacetoxydiol (164) (8.0 mg, 0.023 mmol) and R-MTPCl (172R) (22
mg, 16 µL, 0.087 mmol) at rt for 25 h to give (S)-MTPA ester (165) as a colourless
oil (12 mg, 92%): Rf = 0.35 (PE/Et2O, 3/7); [α]D –32.7° (c 1.15, CHCl3); 1H NMR
(CDCl3) δ 1.05 (6H, s, H-12 and H-13), 1.08 (3H, d, J 6.9 Hz, H-15), 1.33-1.49 (2H,
m, H-9), 1.60-1.67 (1H, m, H-8’), 1.79-1.89 (1H, m, H-8), 2.12 (3H, s, H-14), 2.30
(3H, s, OAc), 2.35 (3H, s, OAc), 2.86 (1H, m, H-7), 3.57 (3H, q, J 1.2 Hz, OMe),
4.98 (1H, t, H-10), 6.71 (1H, s, H-3), 6.86 (1H, s, H-6), 7.40 (3H, m, H-5’, H-6’ and
H-7’), 7.63 (2H, m, H-4’ and H-8’); 13C NMR δ 15.9 (C-14), 20.7 (CH3CO), 21.0 (C15), 22.3 (CH3CO), 23.9 (C-12), 26.3 (C-13), 26.9 (C-9) 31.2 (C-7), 31.9 (C-8), 55.5
(OCH3), 72.5 (C-10), 81.4 (C-11), 84.7 (q, J 27.5 Hz, C-2’), 120.4 (C-6), 123.5 (q, J
287 Hz, CF3), 124.6 (C-3), 127.6 (C-4’, C-8’), 128.4 (C-5’, C-7’), 128.9 (C-4), 129.6
(C-6’), 132.2 (C-3’), 136.0 (C-1), 145.9 (C-2), 147.3 (C-5), 167.0 (C-1’), 169.0
(C=O), 170.0 (C=O); EIMS m/z 568 (1) [M+, C29H35O8F3], 526 (26), 484 (42), 426
(5), 335 (2), 293 (7), 250 (57), 189 (92), 151 (100), 105 (15), 77 (8).
(S)-MTPA ester (172S) [(S)-MTPA ester of (7R,10S)-methoxydiol (168)]. The
same procedure for the preparation of (S)-MTPA ester (151) was followed with the
use of (7R,10S)-methoxydiol (168) (1.2 mg, 0.0045 mmol) and R-MTPCl (171R)
(4.1 mg, 3 µL, 0.016 mmol) at rt for 22 h to give (S)-MTPA ester (172S) as a
colourless oil (2.1 mg, 95.5%): Rf = 0.53 (PE/Et2O, 3/7); [α]D –15.2° (c 0.21,
CHCl3); 1H NMR (CDCl3) δ 1.07 (3H, s, H-12), 1.12 (3H, d, J 6.9 Hz, H-15), 1.13
(3H, s, H-13), 1.37 (2H, m, H-9), 1.47 (2H, m, H-8), 2.17 (3H, s, H-14), 2.61 (1H, m,
H-7), 3.55 (3H, q, J 1.6 Hz, C-OMe), 3.77 (3H, s, Ar-OMe), 5.03 (1H, br d, J 9.9 Hz,
H-10), 6.51 (1H, s, H-2), 6.52 (1H, dd, J 7.5, 1.5 Hz, H-6), 6.90 (1H, d, J 7.5 Hz, H5), 7.40 (3H, m, H-5’, H-6’ and H-7’), 7.60 (2H, m, H-4’ and H-8’).
(R)-MTPA ester (172R) [(R)-MTPA ester of (7R,10S)-methoxydiol (168)]. The
same procedure for the preparation of (S)-MTPA ester (151) was followed with the
use of (7R,10S)-methoxydiol (168) (5.0 mg, 0.017 mmol) and S-MTPCl (171S) (9.0
mg, 7 µL, 0.036 mmol) at rt for 23 h to give (S)-MTPA ester (172R) as a colourless
oil (6.6 mg, 75.9%): Rf = 0.53 (PE/Et2O, 3/7); [α]D +0.30 (c 0.66, CHCl3); 1H NMR
95
(CDCl3) δ 1.04 (3H, s, H-12), 1.08 (3H, s, H-13), 1.21 (3H, d, J 6.9 Hz, H-15), 1.44
(2H, m, H-9), 1.59 (2H, m, H-8), 2.18 (3H, s, H-14), 2.66 (1H, m, H-7), 3.50 (3H, q,
J 1.6 Hz, C-OMe), 3.79 (3H, s, Ar-OMe), 5.02 (1H, br d, J 9.9 Hz, H-10), 6.58 (1H,
br s, H-2), 6.60 (1H, dd, J 7.5, 1.5 Hz, H-6), 7.02 (1H, d, J 7.5 Hz, H-5), 7.39 (3H,
m, H-5’, H-6’ and H-7’), 7.56 (2H, m, H-4’ and H-8’); EIMS m/z 483 (1) [M+,
C26H33O5F3], 482 (14), 231 (4), 189 (100), 149 (100), 135 (31), 119 (21), 105 (47),
91 (43), 77 (29).
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.
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Appendices
108
Appendix A: Reprint
109
110
111
112
113
14
5
3
6
OH
12
1
15
7
(1)
10
13
Appendix 1: MS of xanthorrhizol (1).
114
14
5
3
6
OH
12
1
15
7
(1)
10
13
115
Appendix 2: IR spectrum of xanthorrhizol (1).
H-14
14
5
3
6
H-12
12
1
15
H-15
OH
7
(1)
10
H-6
13
H-13
OH
H-5
H-8
H-2
H-10
H-7
116
Appendix 3: 1H NMR spectrum of xanthorrhizol (1).
H-9
14
5
3
6
OH
12
1
15
7
(1)
10
13
C-6
C-5
C-2
C-10
C-1
C-3
C-11
C-4
C-13
C-7
C-12
C-15
C-8
C-9
C-14
Appendix 4: 13C NMR spectrum of xanthorrhizol (1).
117
OAc
14
5
3
6
OAc
12
1
15
7
10
(148)
13
118
Appendix 5: 1H NMR spectrum of xanthorrhizyl acetate (148).
14
5
3
6
OAc
12
1
7
15
10
13
(148)
C-4
C-6
C-12
C-13
C-5
C-2
C-1
C=O
C-3
C-10
C-11
C-9
C-14
119
Appendix 6: 13C NMR spectrum of xanthorrhizyl acetate (148).
C-7 C-8
14
5
3
6
OAc
12
1
15
7
10
(148)
13
120
Appendix 7: IR spectrum of xanthorrhizyl acetate (148).
14
5
3
6
OAc
12
1
15
7
10
(148)
13
121
Appendix 8: MS of xanthorrhizyl acetate (148).
OAc
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
OH
13
H-10
122
Appendix 9: 1H NMR spectrum of (7R,10S)-acetoxydiol (149).
14
5
3
6
15
R
OAc
12
1
S
10
7
OH
(149)
OH
13
C-10
C-1
C-3
C=O
C-5
C-15
C-11
C-2
C-4
C-8
C-13
C-9
C-12
C-6
C-14
123
Appendix 10: 13C NMR spectrum of (7R,10S)-acetoxydiol (149).
C-7
COCH3
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
OH
13
124
Appendix 11: DEPT spectrum of (7R,10S)-acetoxydiol (149).
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
OH
13
125
Appendix 12: IR spectrum of (7R,10S)-acetoxydiol (149).
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
126
Appendix 13: COSY spectrum of (7R,10S)-acetoxydiol (149).
OH
13
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
127
Appendix 13(a): COSY spectrum of (7R,10S)-acetoxydiol (149).
OH
13
14
5
3
6
15
R
OAc
12
1
7
S
10
OH
(149)
128
Appendix 14: MS of (7R,10S)-acetoxydiol (149).
OH
13
14
H-5’
H-6’
H-7’
H-4’
H-8’
3
OAc
1
15
R
7
O
1'
O
F3C S
MeO
(151)
C-OMe
OH
S
10
4'
5'
H-10
129
Appendix 15: 1H NMR spectrum of (S)-MTPA ester (151).
14
3
OAc
1
15
R
7
OH
S
10
O
1'
F3C S
MeO
O
4'
5'
(151)
130
Appendix 16: COSY spectrum of (S)-Mosher ester (151).
100%
05070904: Scan 10 (2.13 min)
Base: 189.00 Int: 6.5535e+006 Sample: VG 70-SE Positive CI-Methane
189
277
493
14
90%
3
80%
OAc
1
70%
15
217
R
7
OH
S
10
O
60%
1'
O
F3C S
MeO
50%
4'
5'
(151)
127
40%
30%
511
468
20%
105
10%
443
71
391
528
0%
50
100
150
200
250
300
m/z
350
400
500
550
600
131
Appendix 17: CIMS of (S)-Mosher ester (151).
450
14
5
6
15
3
OAc
13
1
R
7
10
R
OH
(150)
OH
12
132
Appendix 18: 1H NMR spectrum of (7R,10R)-acetoxydiol (150).
14
5
6
15
3
OAc
13
1
R
7
10
R
OH
(150)
OH
12
133
Appendix 19: 13C NMR spectrum of (7R,10R)-acetoxydiol (150).
14
5
6
15
3
OAc
13
1
R
7
10
R
OH
(150)
OH
12
134
Appendix 20: DEPT spectrum of (7R,10R)-acetoxydiol (150).
14
5
6
15
3
OAc
13
1
R
7
10
R
OH
(150)
OH
12
135
Appendix 21: IR spectrum of (7R,10R)-acetoxydiol (150).
14
5
6
15
3
OAc
13
1
R
7
10
R
OH
(150)
OH
12
136
Appendix 22: MS of (7R,10R)-acetoxydiol (150).
14
3
OAc
1
15
R
7
OH
R
10
O
1'
O
F3C S
MeO
(152)
4'
5'
137
Appendix 23: 1H NMR spectrum of (S)-MTPA ester (152).
14
3
OAc
1
15
R
7
OH
R
10
O
1'
F3C S
MeO
(152)
4'
5'
138
Appendix 24: COSY spectrum of (S)-Mosher ester (152).
O
14
5
3
6
15
R
OH
12
1
7
S
10
OH
(137)
OH
13
139
Appendix 25: IR spectrum of (10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (137).
14
5
3
6
15
R
OH
12
1
7
S
10
OH
(137)
OH
13
C-6
C-13
C-10
C-3
C-2
C-1
C-7
C-11
C-9
C-15
C-12
C-8
C-5
C-4
140
Appendix 26: 13C NMR spectrum of (10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (137).
C-14
14
5
3
6
15
R
OH
12
1
7
S
10
OH
(137)
OH
13
141
Appendix 27: DEPT spectrum of (10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (137).
14
5
3
6
15
R
OH
12
1
7
S
10
OH
(137)
OH
13
142
Appendix 28: MS of (10S)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (137).
14
5
6
15
3
OH
13
1
R
7
10
R
OH
(138)
OH
12
143
Appendix 29: IR spectrum of (10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (138).
14
5
6
15
3
OH
13
1
R
7
10
R
OH
(138)
OH
12
144
Appendix 30: 13C NMR spectrum of (10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (138).
14
5
6
15
3
OH
13
1
R
7
10
R
OH
(138)
OH
12
145
Appendix 31: DEPT spectrum of (10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (138).
105%
04070904: Scan 9 (1.90 min)
Base: 135.00 Int: 1.81113e+006 Sample: VG 70-SE Electron Impact
135
90%
14
80%
5
6
70%
Sample: xtb
3
R
7
10
R
OH
(138)
91
50%
13
1
15
60%
OH
OH
12
148
40%
175
121
30%
77
20%
109
194
161
252
10%
85
216
0%
65
100
150
200
234
250
300
m/z
146
Appendix 32: MS of (10R)-10,11-dihydro-10,11-dihydroxyxanthorrhizol (138).
14
O2N
1
4
15
OH
13
R
7
10
(157)
12
NO2 stretch
(asym)
147
Appendix 33: IR spectrum of 4-nitroxanthorrhizol (157).
NO2 stretch
(sym)
14
O2N
1
4
15
OH
13
R
7
10
(157)
12
(400 MHz)
148
Appendix 34: 1H NMR spectrum of 4-nitroxanthorrhizol (157).
14
O2N
1
4
15
2
R
7
OH
NO2 13
10
(158)
12
149
Appendix 35: IR spectrum of 2,4-dinitroxanthorrhizol (158).
14
O2N
1
4
15
2
R
7
OH
NO2 13
10
(158)
12
(400 MHz)
150
Appendix 36: 1H NMR spectrum of 2,4-dinitroxanthorrhizol (158).
14
OH
HO
2
15
13
1
R
7
10
(140)
12
151
Appendix 37: IR spectrum of curcuhydroquinone (140) prepared by Elbs persulphate hydroxylation.
14
OH
HO
2
15
13
1
R
7
10
(140)
12
152
Appendix 38: 1H NMR spectrum of curcuhydroquinone (140) prepared by Elbs persulphate hydroxylation.
14
O
O
13
2 1
15
R
7
10
(139)
12
153
Appendix 39: IR spectrum of curcuquinone (139).
H-3
14
H-6
O
O
H-14
13
2 1
15
R
7
10
(139)
12
154
Appendix 40: 1H NMR spectrum of curcuquinone (139).
14
O
O
13
2 1
15
R
7
10
(139)
12
155
Appendix 41: MS of curcuquinone (139).
14
OH
HO
2
15
13
1
R
7
10
(140)
12
156
Appendix 42: IR spectrum of curcuhydroquinone (140).
14
OH
HO
2
15
13
1
R
7
10
(140)
12
H-6
H-3
157
Appendix 43: 1H NMR spectrum of curcuhydroquinone (140).
14
OH
HO
2
13
1
15
R
7
10
12
(140)
C-10
C-13
C-3
C-8
C-9
C-6
C-15
C-12
C-7
C-2
C-5
C-1
C-11
C-4
158
Appendix 44: 13C NMR spectrum of curcuhydroquinone (140).
C-14
14
OH
HO
2
15
13
1
R
7
10
(140)
12
159
Appendix 45: DEPT spectrum of curcuhydroquinone (140).
14
OH
HO
2
15
13
1
R
7
10
(140)
12
160
Appendix 46: MS of curcuhydroquinone (140).
14
OAc
AcO
2
15
13
1
R
7
10
(163)
12
161
Appendix 47: MS of curcuhydroquinone diacetate (163).
14
OAc
AcO
2
15
13
1
R
7
10
(163)
12
162
Appendix 48: IR spectrum of curcuhydroquinone diacetate (163).
14
OAc
AcO
2
13
1
R
7
15
10
(163)
12
C-9
C-13
C-3
C-5
C=O
C-15
C-8
C-7
C-11
C-12
C-6
C-2
C=O
C-10
COCH3
C-1
C-4
163
Appendix 49: 13C NMR spectrum of curcuhydroquinone diacetate (163).
C-14
14
OAc
AcO
2
15
13
1
R
7
10
(163)
12
164
Appendix 50: DEPT spectrum of curcuhydroquinone diacetate (163).
14
OAc
AcO
2
13
1
15
R
7
10
(163)
12
(400 MHz)
165
Appendix 51: 1H NMR spectrum of curcuhydroquinone diacetate (163).
14
OAc
AcO
2
15
1
R
7
13
S
10
OH
(164)
OH
12
166
Appendix 52: IR spectrum of diacetoxydiol (164).
14
OAc
AcO
2
15
1
R
7
13
S
10
OH
(164)
OH
12
167
Appendix 53: 1H NMR spectrum of diacetoxydiol (164).
COCH3
C-15
14
C-8 C-7
C-8
OAc
AcO
2
15
1
R
7
C=O
C-2 C-1
C-12
C-13
C-14
13
S
10
OH
(164)
C=O
C-9
C-3
C-4
COCH3
OH
12
C-6
C-10
C-11
C-5
168
Appendix 54: 13C NMR spectrum of diacetoxydiol (164).
14
OAc
AcO
2
15
1
R
7
13
S
10
OH
(164)
169
Appendix 55: DEPT spectrum of diacetoxydiol (164).
OH
12
14
OAc
AcO
2
15
1
R
7
13
S
10
OH
(164)
170
Appendix 56: MS of diacetoxydiol (164).
OH
12
14
OAc
AcO
2
15
1
R
7
OH
S
10
O
1'
F3C S
MeO
O
4'
5'
(165)
171
Appendix 57: 1H NMR spectrum of (S)-Mosher ester (165).
14
OAc
2
AcO
1
15
R
7
OH
S
10
O
1'
O
F3C S
MeO
4'
C-7
5'
C-8
(165)
C-4
C-5’
C-7’
C-12
C-13
C-9
C-14
C-4’
C-8’
C-6’
C=O
C=O
C-1’
C-5
C-2
C-1
C-3’
C-3
C-10
C-6
C-11
OMe
C-2’
172
Appendix 58: 13C NMR spectrum of (S)-Mosher ester (165).
173
Appendix 59: DEPT spectrum of (S)-Mosher ester (165).
100%
04070904: Scan 187 (43.43 min)
Base: 151.00 Int: 3.90985e+006 Sample: VG 70-SE Electron Impact
151
189
90%
14
80%
OAc
Sample: rmdchqa
70%
AcO
60%
2
1
15
250
R
7
O
50%
OH
S
10
1'
F3C S
MeO
484
40%
O
4'
5'
(165)
30%
526
20%
105
10%
77
293
426
335
0%
50
200
568
300
400
500
600
750
m/z
174
Appendix 60: MS of (S)-Mosher ester (165).
14
OH
HO
2
15
1
R
7
13
S
10
OH
(142)
OH
12
(Acetone-d6)
175
Appendix 61: 1H NMR spectrum of crude helibisabonol A (142).
H-6
14
H-3
H-10
O
H-7
O
2
15
1
R
7
13
S
10
OH
(166)
OH
12
H-14
176
Appendix 62: 1H NMR spectrum of quinone derivative of helibisabonol A (166).
14
OH
HO
2
15
1
R
7
13
S
10
OH
(142)
OH
12
(Acetone-d6)
177
Appendix 63: 1H NMR spectrum of helibisabonol A (142) after column chromatography.
14
OH
HO
2
15
1
R
7
13
S
10
OH
(142)
OH
12
(Acetone-d6)
178
Appendix 64: COSY spectrum of helibisabonol A (142) after column chromatography.
14
5
6
15
3
OMe
13
1
R
7
10
(167)
12
179
Appendix 65: IR spectrum of O-methylxanthorrhizol (167).
H-5
H-6
H-2
14
5
6
15
3
OMe
OMe
13
1
R
7
H-12
10
(167)
H-14
H-15
H-13
12
H-9
H-10
H-7
H-8
180
Appendix 66: 1H NMR spectrum of O-methylxanthorrhizol (167).
14
5
6
15
3
OMe
13
1
R
7
10
(167)
12
181
Appendix 67: MS of O-methylxanthorrhizol (167).
1
9
O
15
4
14
13
6
(6)
12
182
Appendix 68: IR spectrum of germacrone (6).
H-13
H-12
1
9
O
15
4
14
H-15
13
6
(6)
12
H-6
H-9b
H-9a
H-2
H-3
H-14
H-1 H-5
183
Appendix 69: 1H NMR spectrum of germacrone (6).
14
5
6
15
3
OMe
13
1
R
7
S
10
OH
OH
(168)
12
184
Appendix 70: IR spectrum of methoxydiol (168).
14
5
6
15
3
OMe
13
1
R
7
S
10
OH
(168)
185
Appendix 71: MS of methoxydiol (168).
OH
12
H-5
H-6
H-2
H-12
H-13
OMe
14
5
6
15
3
H-15
OMe
OH
13
1
R
7
H-14
S
10
OH
(168)
OH
12
H-10
H-7
H-9’
186
Appendix 72: 1H NMR spectrum of methoxydiol (168).
H-8’
H-8
H-9
14
5
6
15
3
OMe
13
1
R
7
S
10
O
OH
12
O
F3C S 3' 4'
MeO
5'
(171S)
187
Appendix 73: COSY spectrum of (S)-MTPA ester (171S).
14
5
6
15
3
OMe
13
1
R
7
S
10
O
OH
12
O
MeO R 3' 4'
F3C
5'
(171R)
188
Appendix 74: COSY spectrum of (R)-MTPA ester (171R).
100%
04070904: Scan 163 (37.83 min)
Base: 149.00 Int: 801450 Sample: VG 70-SE Electron Impact
149
189
14
90%
5
Sample: smadxm
80%
6
15
70%
3
OMe
13
1
R
7
S
10
O
OH
12
O
MeO R 3' 4'
F3C
60%
50%
5'
(171R)
105
91
40%
135
77
30%
119
20%
482
10%
231
0%
60
100
150
200
250
300
350
400
450
500
m/z
189
Appendix 75: MS of (R)-MTPA ester (171R).
14
5
6
15
3
OMe
13
1
R
7
S
10
OAc
(169)
OH
12
190
Appendix 76: IR spectrum of monoacetate (169).
100%
02271103: Scan 280 (65.13 min) - Back
Base: 149.00 Int: 4.67969e+006 Sample: VG 70-SE Electron Impact
149
90%
80%
14
70%
5
6
60%
OMe
13
1
R
7
15
50%
40%
3
S
10
OAc
(169)
OH
12
57
167
30%
20%
71
279
113
10%
308
91
215
0%
40
100
150
200
250
250
m/z
300
350
450
500
191
Appendix 77: MS of momoacetate (169).
400
OAc
14
5
6
15
3
OMe
13
1
R
7
H-14
S
10
OH
OAc
(169)
12
H-10
192
Appendix 78: 1H NMR spectrum of momoacetate (169).
100%
04070904: Scan Avg 29-33 (6.57 - 7.50 min)
Base: 149.00 Int: 1.3794e+006 Sample: VG 70-SE Electron Impact
162
149
Sample: edxma
90%
80%
91
70%
60%
14
135
50%
5
6
40%
15
30%
OMe
12
1
R
7
S
10
13
OAc
(170)
117
77
105
20%
3
187
175
10%
215
202
0%
65
100
150
200
230
248
250
290
300
m/z
193
Appendix 79: MS of allylic acetate (170).
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OAc
(170)
194
Appendix 80: IR spectrum of allylic acetate (170).
H-12a H-12b
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OAc
(170)
195
Appendix 81: 1H NMR spectrum of allylic acetate (170).
14
5
6
15
3
OMe
13
1
R
7
S
10
OAc
(175)
OAc
12
196
Appendix 82: IR spectrum of diacetate (175).
OAc
OAc
14
5
H-14
6
15
3
OMe
13
1
R
7
S
10
OAc
(175)
OAc
12
H-10
197
Appendix 83: 1H NMR spectrum of diacetate (175).
14
5
6
15
3
OMe
13
1
R
7
S
10
OH
(168)
OH
12
198
Appendix 84: IR spectrum of hydrolysis product of diacetate (175), methoxydiol (168).
14
5
6
15
3
OMe
13
1
R
7
S
10
OH
(168)
OH
12
199
Appendix 85: 1H NMR spectrum of hydrolysis product of diacetate (175), methoxydiol (168).
100%
04070904: Scan 53 (12.17 min)
Base: 149.00 Int: 6.5535e+006 Sample: VG 70-SE Electron Impact
149
162
90%
80%
Sample: sae
70%
14
60%
5
50%
6
91
135
40%
15
123
3
OMe
12
1
R
7
S
10
13
OH
(147)
30%
248
71
20%
77
117
105
10%
84
175
189
205
230
0%
65
100
150
m/z
250
200
Appendix 86: MS of allylic alcohol (147).
200
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OH
(147)
201
Appendix 87: IR spectrum of allylic alcohol (147).
14
5
6
15
H-12a
H-12b
3
OMe
12
1
R
7
S
10
13
OH
(147)
H-13
H-10
202
Appendix 88: 1H NMR spectrum of allylic alcohol (147).
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OH
(147)
203
Appendix 89(a): 1H NMR spectrum of allylic alcohol (147) (400 MHz).
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OH
(147)
204
Appendix 89(b): 1H NMR spectrum of allylic alcohol (147) (400 MHz).
14
5
6
15
C-3
C-5
1
R
7
C-7
12
S
10
C-14
13
C-8
C-10
C-4
C-11
OMe
OH
(147)
C-6
C-1
3
OMe
C-9
C-2
C-15
C-13
C-12
205
Appendix 90: 13C NMR spectrum of allylic alcohol (147).
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OH
(147)
206
Appendix 91: DEPT spectrum of allylic alcohol (147).
14
5
6
15
3
OMe
12
1
R
7
S
10
13
OH
(147)
207
Appendix 92: COSY spectrum of allylic alcohol (147).
14
5
6
15
3
OAc
12
1
R
7
S
10
OAc
(176)
OH
13
208
Appendix 93: IR spectrum of diacetate (176).
14
5
6
15
3
OAc
12
1
R
7
S
10
OAc
(176)
209
Appendix 94: MS of diacetate (176).
OH
13
Ar-OAc
C-OAc
14
5
6
15
3
12
1
R
7
H-14
OAc
S
10
OAc
(176)
OH
13
210
Appendix 95: 1H NMR spectrum of diacetate (176).
14
5
6
15
3
OAc
12
1
R
7
S
10
OH
OAc
(176)
13
C-10
C-3 C-1
C=O
C=O
C-11
C-5 C-6
C-2
C-4
C-14
C-7
211
Appendix 96: 13C NMR spectrum of diacetate (176).
C-8
14
5
6
15
3
OAc
12
1
R
7
S
10
OAc
(176)
OH
13
Appendix 97: DEPT spectrum of diacetate (176).
212
14
5
3
OH
12
1
15
R
7
S
10
OH
OAc
(177)
13
213
Appendix 98: IR spectrum of monoacetate (177).
C-OAc
H-12
14
5
3
OH
15
R
7
H-14
C-15
12
1
S
10
H-13
OAc
(177)
OH
13
OH
H-10
214
Appendix 99: 1H NMR spectrum of monoacetate (177).