Synthesis and NMR elucidation of homoisoflavanone analogues

Article abstract of DOI:10.1007/s11224-010-9703-x

A series of five homoisoflavanone analogues have been synthesized from the corresponding 3,5-methoxy phenols via chroman-4-one in three steps. The complete NMR elucidation of these homoisoflavanone analogues is reported. The use of 2D NMR techniques (COSY, NOESY, HSQC and HMBC) proved to be very useful tools in the elucidation of homoisoflavanone analogues. The homoisoflavanone analogues exhibit an AA0BB0 spin pattern in the ring B of the homoisoflavanone. These homoisoflavanone analogues are potential antifungal and anti-inflammatory agents. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s11224-010-9703-x

Struct Chem (2011) 22:161–166
DOI 10.1007/s11224-010-9703-x
ORIGINAL RESEARCH
Synthesis and NMR elucidation of homoisoflavanone analogues
•
Mahidansha Shaikh Katja Petzold
•
•
Hendrik G. Kruger Karen du Toit
Received: 20 September 2010 / Accepted: 16 November 2010 / Published online: 10 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of five homoisoflavanone analogues
have been synthesized from the corresponding 3,5-meth-
oxy phenols via chroman-4-one in three steps. The com-
plete NMR elucidation of these homoisoflavanone
analogues is reported. The use of 2D NMR techniques
(COSY, NOESY, HSQC and HMBC) proved to be very
useful tools in the elucidation of homoisoflavanone
analogues. The homoisoflavanone analogues exhibit an
AA0BB0 spin pattern in the ring B of the homoisoflavanone.
These homoisoflavanone analogues are potential antifungal
and anti-inflammatory agents.
isobonducellin, 20-methoxybonducellin and Sappanone A
have been isolated from different plants [3–8]. Few reports
on the biological activity of homoisoflavanones have been
found. However, according to previous studies, natural
homoisoflavanones exhibit anti-inflammatory, antibacte-
rial, anti-mutagenic, hypocholesterolemic [9–13], antioxi-
dant and anti-viral activities [14–16].
H3CO
O
OH
Keywords Homoisoflavanone ꢀ Synthesis ꢀ
Anti-inflammatory ꢀ Antifungal ꢀ 2D NMR
H
OCH3
O
1
Introduction
The synthesis of homoisoflavanones (3-benzylidine-4-
chromanones) is well established [17] and although a
variety of homoisoflavanones have been isolated from
many different plants, it appears that more is known about
the biosynthesis and chemistry of these compounds than
about their biological activities and its relation to their
structures. Previously, NMR study of similar type of nat-
ural homoisoflavanones was reported [18–20]. In this
study, we report the substitution of 3-benzylidene-4-chro-
manone analogues with varying substitution patterns at the
40-position of the B-ring. The lead compound (3,5-dime-
thoxy-3-benzyl-4-chromanone 1), a type of homoisoflava-
none, was isolated from southern African Hyacinthaceae
family and screened for anti-inflammatory activity [9].
Based on the lead compound we synthesized compound 3
and its analogues with different substitution patterns at the
40-position of the B-ring. The products showed good
anti-inflammatory [17] and anti-fungal activity [21].
Homoisoflavanones belong to a small homogeneous group
of naturally occurring oxygen heterocycles [1]. The basic
homoisoflavanone structure consists of a 16-carbon skele-
ton, which includes a chromane system with a benzyl or
benzylidine group at position 3 [2]. Natural homoisoflav-
anone (3-benzylidine-4-chromanones) such as bonducellin,
Electronic supplementary material The online version of this
article (doi:10.1007/s11224-010-9703-x) contains supplementary
material, which is available to authorized users.
M. Shaikh ꢀ K. Petzold ꢀ H. G. Kruger
School of Chemistry, University of KwaZulu-Natal,
Durban, South Africa
M. Shaikh ꢀ K. du Toit (&)
School of Pharmacy and Pharmacology,
University of KwaZulu-Natal, Durban, South Africa
e-mail: karent@ukzn.ac.za
123

162
Struct Chem (2011) 22:161–166
The structures of compounds 2 [22] and 4 [23, 24] have
been previously reported.
peak at 3377 cm-1. As expected, no significant differences
in the IR spectra for the remaining compounds were
observed.
Nuclear magnetic resonance (NMR) spectroscopy has
become an essential tool for studying the structure of a
broad variety of systems, and was here applied to elucidate
the structures of the substituted compounds 2–6. All 1D 1H
and 13C chemical shifts and couplings of the homoisof-
lavanone analogues are reported in Table 1. The only
methylene protons (H-2) and the well-separated H-9 alkene
proton are two convenient points of entry for the elucida-
tion of compound 2. The 1D NMR spectrum of compound
2 shows two methylene protons, which exhibit a geminal
Results and discussion
This study describes the synthesis and structural elucida-
tion of homoisoflavanones 2–6. The synthesis of homoi-
soflavanone analogues from commercially available
reagents was carried out using the general synthetic
approach shown in Scheme 1. The reaction of 3,5-dime-
thoxy phenol with 3-bromopropanoic acid using sodium
hydride as base furnished 3-(3,5-dimethoxy phenoxy) [25],
which was cyclised using polyphosphoric acid to give 7,8-
dimethoxy chroman-4-one [26]. Base catalyzed condensa-
tion of 7,8 dimethoxy chroman-4-one with different
substituted benzaldehyde results in the synthesis of
homoisoflavanones [14] (Scheme 1: 1–5).
Table 1 1H and 13C chemical shift (d) and JHH-couplings data of
compound 2
1
Atom
d Ha in ppm
J (Hz)
d
13Ca in ppm
Infrared spectroscopy (IR) is regularly used to confirm
the functional groups of organic compounds and was
therefore applied to our modified compounds 2–6. The
structure of compound 2, with no substitution at C-40 in
the ring-B, is a good starting point for the elucidation. The
basic IR peaks for compound 2 resulted in a sharp single
peak at 2940 cm-1 for the C–H stretching mode in the
aromatic rings A and B. The peak at 1602 cm-1 and
1567 cm-1 indicates the presence of a carbonyl group
(C=O, C-4) with symmetric and asymmetric conjugation
with the double bond (C=C, C-3 and C-9). The peaks at
1465 cm-1 and 1421 cm-1 represent the symmetrical
stretching of alkene (C=C) group of aromatic ring and
1339 cm-1 and 1317 cm-1 indicate asymmetrical stretch-
ing of the aromatic ring. Furthermore the peak at
1107 cm-1 indicates the C–O–C (C-8a and C-2) ether
stretching in compound 2, confirming the most prominent
functional groups in this molecule. In compound 3, the
hydroxy-group (OH) at C-40 in ring-B causes a broad single
2
5.21
1.7
–
67.4
3
–
131.9
179.5
107.2
164.7
93.6
4
–
–
4a
–
–
5
–
–
6
6.12
–
2.2
–
7
165.8
93.6
8
6.06
–
2.2
–
8a
10
20/60
30/50
40
162.8
134.8
129.9
128.6
128.9
135.8
56.1
–
–
7.27
7.27–7.34
7.27–7.34
7.82
3.91
3.82
8.0
–
–
9
–
OC(H-5)3
OC(H-7)3
–
–
55.6
9.4T Bruker Avance III (400 MHz H and 100 MHz 13C)
a
1
Referring to the solvent CDCl3
H3CO
OH
H3CO
COOH
O
Br
NaH,
PPA
COOH
°
DMF, rt, 35 %
80 C, 50 %
OCH3
OCH3
8
5'
4'
H3CO
O
R
H3CO
O
O
Substituted
8a
4a
7
2
6'
benzaldehyde
A
C
B
°
piperidine, 70-80 C
63-79 %
3'
6
3
1'
5
4
2'
9
OCH3
O
OCH3
2) R = H, 3) R = OH, 4) R = OCH3
5) R = Cl, 6) R = F
Scheme 1 General synthesis of homoisoflavanone analogues 2–6
123

Struct Chem (2011) 22:161–166
163
coupling constant (2JHH) of 1.7 Hz. The well-separated
alkene proton H-9 appears as a singlet and is deshielded in
the aromatic region due to conjugation with the carbonyl
group at C-4, as well as with the aromatic ring-B. The
1H-NMR spectrum shows only one meta-coupled proton
doublet, which is therefore assigned to H-6 and H-8 in the
aromatic ring B, respectively, indicative of a 5,7 disubsti-
quaternary alkene carbon lead to identification of C-3 and
the alkene bridge carbon C-9. These assignments were also
confirmed from the HSQC data, indicating that compound 2
is a homoisoflavanone of the 3-benzylidene-4-chromanone
type. In addition, the HMBC spectrum shows correlations
of H-6 with a quaternary carbon C-4a, a tertiary carbon C-8,
the latter confirmed by HSQC, and two quaternary carbons
bound to oxygens which were assigned to C-5 and C-7,
respectively. It was possible to distinguish between the C-5
and C-7 methoxy groups, because the HMBC spectrum
shows correlation of H-8 with carbon atom C-7, the carbon
of the methoxy group attached to C-7, and to a quaternary
carbon, assigned to C-8a. The H-6 proton shows correla-
tions to carbon atom C-5, C-7, C-4a and methoxy carbon at
C-5 but not to methoxy group at C-7. The HMBC spectrum
also allowed for the assignment of the carbon atoms in ring
B by first correlating H-9 to the quaternary carbon C-10 and
the two equivalent tertiary carbons C-20/C-60. HSQC cor-
relations of these carbons with H-20/H-60 confirm these
assignments. H-30/H-50 show HMBC correlations with the
previously assigned C-20/C-60 carbon atoms and also with
three aromatic/tertiary carbons, assigned to the chemical
equivalent C-30/C-50 and to C-40. It was possible to distin-
guish between C-30/C-50 and C-40 by utilizing the HMBC
spectrum. The details of proton and carbon chemical shifts
values for compound 2 are reported in Table 1 (Fig. 2).
1
tuted aromatic ring. Furthermore, the H-NMR spectrum
shows a doublet for two protons (by integration), which are
coupled with three adjacent protons, registering as over-
laying multiplets. These remaining protons were assigned
to H-20 and H-60 of the aromatic ring B (Fig. 1).
The COSY and NOESY spectra enabled us to confirm the
prior assignment. The COSY spectrum shows a correlation
between H-2 and the methine bridge proton H-9. COSY
correlations are most intense for vicinal H–C–C–H protons
(3JHH), the COSY correlation between H-2 and H-9 is
transferred via an additional carbon atom and is therefore
accounted as long-range couplings (4JHH). These are only
observed for specific conformations [27]. We also observed
a NOESY correlation between H-2 and H-2’/H-6’ (over-
lapping) and between H-2 and H-9, though with less
intensity, indicating that ring B is positioned as the E-isomer
(the cis-isomer). The NOESY spectrum shows correlation of
H-6 with the protons of the methoxy group OC(H-5)3 and
H-8 with the methoxy group OC(H-7)3. These observations
further indicated a disubstituted methoxy group at position
C-5 and C-7 in ring A. Confirmation of the assignments for
OC(H-5)3 and OC(H-7)3 is possible by comparing the
chemical shifts of the methyl protons. Since OC(H-5)3 is
close to the carbonyl oxygen at C-4, it should experience a
through space deshielding effect, moving the OC(H-5)3
protons at higher d value. The COSY spectrum also shows
correlation between the protons H-2’/H-6’ and H-3’/H-5’
and a complex correlation between H-30/H-50 and H-40.
After the unambiguous assignment of the existing pro-
tons, the corresponding carbon atoms were identified using
the HSQC and HMBC spectra. In the HMBC spectrum a
correlation of H-2, our preferred starting point, with a car-
bonyl carbon was observed. The latter was therefore
assigned to C-4 in ring C. Correlations of H-2 to a
1
The H and 13C NMR spectra of compounds 3–6 were
also completely assigned based on the same methodology
described for compound 2. The change in NMR data of
these compounds are reported in Tables 2 and 3.
Comparing the chemical shifts of the molecules due to
substitution at position C-40, no or only insignificantly
small changes were observed for the 1H and 13C resonances
on ring A and B, with the exception of the bridge atoms
C-9 and its surroundings, such as C-2 and C-3 (see
Tables 2, 3). The strongest changes in general, as expected
are found in the change of chemical shift for atom C-40,
followed by C-3’/C-5’, C1’ and C-2’/C-6’, with exception
of compound 5, where carbon chemical shift changes of
C-10 and C-20/C-60 are larger than for C-30/C-50.
One can hypothesize that in the ring-B of compound 3,
the electron pair of the hydroxyl group substitution at C-40
generates an electron donating effect in the aromatic ring
with the result of a larger shielding effect for C-30/C-50 than
8
5'
2'
H3CO
O
8a
4a
7
4'
2
8
6'
5'
H3CO
O
8a
4a
7
4'
2
6'
3'
6
A
C
B
3
1'
5
3'
6
9
3
1'
5
4
2'
9
OCH3
O
OCH3
O
Fig. 1 Long range interactions of homoisoflavanone found by NMR
measurements
Fig. 2 Compound 2 and labelling of atoms as used in this paper
123

164
Struct Chem (2011) 22:161–166
than for C-20/C-60. In compound 4, the protons of C-30/C-50
experience a larger de-shielding effect than H-20/H-60 due
to two opposing effects exerted by the (C-40)-Cl group: an
electron donation effect due to conjugation and an electron
withdrawal effect due to induction. However, chlorine is a
large atom and has a smaller electronegative effect there-
fore, for compound 6, the substitution of fluorine at the
C-40 position of the aromatic ring-B influences the chem-
ical shift in the opposite way than that of compound 5 most
possibly due to the smaller fluorine atom with a stronger
electron withdrawing inductive effect on ring-B. In com-
pound 6, the protons H-20/H-60 couple with protons H-30/
H-50 as well as with the fluorine atom. One therefore
expects to observe a multiplet but the splitting pattern
merged into a triplet (J = 5,8.6 Hz) [28]. The splitting
pattern for protons H-30/H-50 clearly shows a multiplet.
Interestingly, the protons on the methoxy-group at C7
Table 2 1H chemical shift differences (Dd) in ppm data between
compound 3 and 6 relative to compound 2
Atom
Compound 3 Compound 4 Compound 5 Compound 6
(Dd 1Ha) ppm (Dd 1Ha) ppm (Dd 1Ha) ppm (Dd 1Ha) ppm
2
nc
–
0.02
–
0.05
–
0.04
–
3
4
–
–
–
–
4a
5
–
–
–
–
–
–
–
–
6
nc
–
nc
–
nc
–
nc
–
7
8
nc
–
nc
–
nc
–
nc
–
8a
10
–
–
–
–
20/60
30/50
40
0.16
0.45
–
0.03
0.36
–
0.16
0.19
–
nc
0.12
–
1
[OC(H-7)3] in compound 5 shows slight shielding (Dd H
9
0.06
0.05
nc
nc
nc
nc
0.17
0.18
nc
nc
of 0.17 ppm) compared to compound 2. Furthermore, the
bridge proton H9 of compounds 3–6 shows significant
shielding in comparison to compound 2, ranging from Dd
1H = 0.05 to 0.09 ppm. The 13C chemical shift values for
compound 5 and 6 differs due to substitution with halogens
as well as in comparison to the unsubstituted compound 2.
OC(H-5)3 nc
OC(H-7)3 0.03
9.4T Bruker Avance III (400 MHz 1H and 100 MHz 13C)
a
Referring to the solvent CDCl3
nc No change was detectable
Table 3 13C chemical shift differences (Dd) in ppm data of
compounds 3 to 6
Experimental
Atom
Compound 3 Compound 4 Compound 5 Compound 6
(Dd 13Ca)
(Dd 13Ca)
(Dd 13Ca)
(Dd 13Ca)
All reagents and solvents were purchased from Aldrich,
Merck and Fluka. TLC used Kieselgel 60 F254 from Merck
(Darmstadt, Germany). All NMR spectra were recorded on
a 9.4T Bruker AVANCE III 400 MHz instrument at room
(298 K) temperature with CDCl3 as an internal standard
using a sample concentration in the range of 10 (mg/lL).
The spectrometer was equipped with a BBO probe with
400 MHz S1 and with a z gradient. The data was recorded
and analyzed with Topspin 2.1 (Bruker, Karlsruhe,
Germany). Standard Bruker pulse sequences were used: 1D
1H (32 scans) and 13C with 1H decoupling and 1024 scans,
1H and 13C hard pulse width for all experiments was 10 ls
2
nc
nc
1.2
nc
nc
3
3.1
nc
1.8
nc
nc
4
1.5
1.2
2.9
nc
nc
4a
5
1.1
nc
nc
nc
2.0
nc
1.9
nc
6
nc
7
1.1
1.3
nc
nc
1.0
nc
nc
8
nc
nc
8a
10
20/60
30/50
40
1.7
7.4
-1.7
14.5
–
nc
1.8
3.8
-1.7
13.0
–
8.6
2.0
13.9
–
2.6
2.2
-1.3
–
1
at -3 db and 8.4 ls at -2 db, respectively. H and 13C
spectral width was 20.54 and 238 ppm, respectively, and
therefore acquisition time was 1.9923 and 1.38 s. Relaxa-
tion delays were set to 1.5 and 2 s for 1H and 13C,
respectively, and carrier frequency was set to 4 ppm for 1H
or 100 ppm for 13C.
9
nc
nc
2.5
1.1
1.1
1.2
nc
OC(H-5)3 1.1
OC(H-7)3 1.1
nc
nc
nc
9.4T Bruker Avance III (400 MHz H and 100 MHz 13C)
a
1
1
2D H-13C HSQC and HMBC were acquired with the
Referring to the solvent CDCl3
same parameters, 256 and 128 complex t1 points were
recorded, respectively. The number of scans was adapted to
the sample concentration to assure a proper signal to noise
ratio. The HSQC experiment was recorded using Echo/
Antiecho-TPPI gradient selection with decoupling during
acquisition and using trim pulses for transfer of
nc No change was detectable
for C-20/C-60. Similarly the methoxy-group of compound 4
at C-40 causes an electron donating effect in the aromatic
ring which results in a larger shielding effect for C-30/C-50
123

Struct Chem (2011) 22:161–166
165
(E)-5,7-dimethoxy-3-(4-methoxybenzylidene)-4-
chromanone (4)
magnetization. The HMBC experiment was optimized for
long-range couplings and uses gradient pulses to select
1
zero and double quantum coherence. 2D H-1H NOESY
Yield 71%; mp 171–174 °C; pale yellow powder
(Rf = 0.58 in 30% ethyl acetate in hexane). IR: 2935
and COSY experiments were recorded with 256 and 128
complex t1 points, respectively. For 1H-1H NOESY
experiment the mixing time was recorded with 300 ms. For
the COSY experiment gradient pulses were used for
coherence selection. The values for chemical shift (d) is
given in ppm and coupling contants (J) in Hertz (Hz),
presented in Tables 1, 2 and 3 for compounds 2–6.
cm-1, 1664 cm-1, 1456 cm-1, 1421 cm-1, 1247 cm-1
,
1208 cm-1, 1157 cm-1, 1109 cm-1. HRMS calculated for
C19H19O5 (M ? H?) 327.1154, found 327.1225.
(E)-5,7-dimethoxy-3-(4-chlorobenzylidene)-4-
chromanone (5)
Melting points were recorded with a Mel-Temp melting
point apparatus in open capillaries and are uncorrected.
The high-resolution mass spectroscopy (HRMS) was
recorded on a Waters Micromass Q-Tof Micro mass
spectrometer with a lock spray source. The mass spec-
troscopy (MS) was recorded on a Waters Acquity Ultra
Performance LC with ZQ detector in ESI mode.
Yield 79%; mp 126–129 °C; pale yellow powder (Rf = 0.54
in 30% ethyl acetate in hexane). IR: 2947 cm-1, 1664 cm-1
,
1598 cm-1, 1464 cm-1, 1264 cm-1, 1208 cm-1, 1158
cm-1, 1105 cm-1. HRMS calculated for C18H16ClO4
(M ? H?) 331.0659, found 331.0733.
(E)-5,7-dimethoxy-3-(4-fluorobenzylidene)-4-
chromanone (6)
General procedure for the synthesis of substituted
homoisoflavanones
Yield 63%; mp 102–105 °C; pale yellow needles (Rf = 0.52
A mixture of substituted chroman-4-one (2.4 mmol,
500 mg), substituted benzaldehyde (3.6 mmol) and piper-
idine (7–10 drops) was heated at 80 °C for 2–36 h (reac-
tion was monitored by TLC—detail follow for each
compound). The reaction mixture was cooled, diluted with
water (15 mL) and acidified with 10% HCl. The ethyl
acetate layer was extracted (3 9 30 mL), the combined
ethyl acetate layers were washed with water (30 mL), brine
(30 mL) and dried over magnesium sulphate. The residue
obtained after evaporation of the solvent was chromato-
graphed using a silica gel column with a mixture of ethyl
acetate–hexane (20:80) as eluent to give homoisoflava-
nones 2–6 (63–79%) yield. The NMR data for all com-
pounds are included in Tables 1, 2 and 3.
in 30% ethyl acetate in hexane). IR: 2938 cm-1, 1664 cm-1
,
1602 cm-1, 1456 cm-1, 1249 cm-1, 1208 cm-1, 1158
cm-1, 1109 cm-1. HRMS calculated for C18H16FO4
(M ? H?) 315.0954, found 315.1047.
Conclusion
The synthesis and 2D-NMR elucidation of five homoisof-
lavanone (3-benzylidene-4-chromanone) analogues was
successfully carried out. The synthesis of these homoisof-
lavanone analogues were based on a natural lead com-
pound (3-benzyl-4-chromanone) with different substitution
patterns at the 4’-position of the B-ring. We confirmed the
influence of the R-group (R = H, OH, OMe, Cl and F) on
the chemical shift of ring B of these homoisoflavanones.
(E)-5,7-dimethoxy-3-benzylidene-4-chromanone (2)
Yield 76%; mp 100–103 °C; dark yellow powder
Acknowledgment The authors thank the University of KwaZulu-
Natal for a Competitive Research Fund, NRF (Gun RH-6030732) and
Rolexsi (Pty) Ltd for financial support. We also thank the NRF (Gun
48505) for the postdoctoral fellowship of Katja Petzold. The authors
also thank Mr. Dilip Jagjivan for valuable discussions on acquiring
the NMR data.
(Rf = 0.61 in 30% ethyl acetate in hexane). IR: 2844 cm-1
,
1602 cm-1, 1465 cm-1, 1421 cm-1, 1248 cm-1, 1209
cm-1
, . HRMS calculated for C18H17O4
1107 cm-1
(M ? H?) 297.1049, found 297.1131.
(E)-5,7-dimethoxy-3-(4-hydroxybenzylidene)-4-
chromanone (3)
References
1. Kirkiacharian BS, Gomis M, Tongo HG, Mahuteau J, Brion JD
(1984) Org Magn Reson 22:106–108
2. Adinolfi M, Lanzetta R, Laonigro G, Parrilli M, Breitmaier E
(1986) Magn Reson Chem 24:663–666
3. Purushothaman KK, Kalyani K, Subramaniam K, Shanmugha-
nathan SP (1982) Indian J Chem B 21:383
Yield 68%; mp 197–200 °C; yellow powder (Rf = 0.43 in
30% ethyl acetate in hexane). IR 3177 cm-1, 2935 cm-1
,
1602 cm-1, 1456 cm-1, 1420 cm-1, 1340 cm-1, 1205
cm-1, 1158 cm-1, 1108 cm-1. HRMS calculated for
C18H17O5 (M ? H?) 313.0998, found 313.1070.
123

166
Struct Chem (2011) 22:161–166
4. McPherson DD, Cordell GA, Soejarto DD, Pezzuto JM, Fong
HHS (1983) Phytochemistry 22:2835–2838
17. Shaikh MM, Kruger HG, Bodenstein J, Du Toit K (2010) Nat
Prod Res (Accepted)
5. Srinivas K, Rao YK, Mahender I, Das B, Krishna K, Kishore KH,
Murty USN (2003) Phytochemistry 63:789–793
18. Wang Y, Xu J, Zhang L, Qu H (2010) Helv Chem Acta
93:980–984
6. Zhao P, Iwamoto Y, Kouno I, Egami Y, Yamamoto H (2004)
Phytochemistry 65:2455–2461
19. Qian Y, Liang JY, Qu W, Che YY (2010) Chin Chem Lett
21:706–708
7. Saitoh T, Sakashita S, Nakata H, Shimokawa T, Kinjo J,
Yamahara J, Yamasaki M, Nohara T (1986) Chem Pharm Bull
34:2506–2511
8. Namikoshi M, Nakata H, Nuno M, Ozawa T, Saitoh T (1987)
Chem Pharm Bull 35:3568–3575
9. Du Toit K, Elgorashi EE, Malan SF, Drewes SE, van Staden J,
Crouch NR, Mulholland DA (2005) Bioorg Med Chem
13:2561–2568
10. Du Toit K, Elgorashi EE, Malan SF, Mulholland DA, Drewes SE,
Van Staden J (2007) S Afr J Bot 73:236–241
20. Morales-Serna JA, Jimenez C, Estrada-Reyes R, Marquez C,
Salmon M (2010) Molecule 15(5):3295–3301
21. Shaikh MM, Kruger HG, Smith P, Mumro OQ, Bodenstein J, Du
Toit K (2010) J Nat Prod (submitted)
22. Meegan MJ, Donelly DMX (1981) J Chem Res Synop 1:4
23. Krishnamurty HG, Prakash B, Seshadri TR (1974) Indian J Chem
12:554
24. Heller W, Andermatt P, Schaad WA, Tamm C (1976) Helv Chem
Acta 59:2048–2058
25. Mahapatra T, Jana N, Nanda S (2008) Tetrahedron Asymmetr
19:1224–1232
26. Parham WE, Huestis LD (1962) J Am Chem Soc 84:813
27. Katritzky AR, Akhmedov NG, Guven A, Scriven EFV,
Majumder S, Akhmedova RG, Hall CD (2006) J Mol Struct
783:191–203
28. Dolensky B, Kvicala J, Paleta O, Lang J, Dvorakova H, Cejka J
(2010) Magn Reson Chem 48:358–375
11. Heller WTC (1981) Fort Chem Org Nat 40:106
12. Della Loggia R, Del Negro P, Tubaro A, Barone G, Parrilli M
(1989) Planta Med 55:587–589
13. Amschler G, Frahm AW, Hatzelmann A, Kilian U, Muller-
Doblies D, MullerDoblies U (1996) Planta Med 62:534–539
14. Siddaiah V, Rao CV, Venkateswarlu S, Krishnaraju AV,
Subbaraju GV (2006) Bioorg Med Chem 14:2545–2551
15. Siddaiah V, Maheswara M, Venkata Rao C, Venkateswarlu S,
Subbaraju GV (2007) Bioorg Med Chem Lett 17:1288–1290
16. Foroumadi A, Samzadeh-Kermani A, Emami S, Dehghan G,
Sorkhi M, Arabsorkhi F, Heidari MR, Abdollahi M, Shafiee A
(2007) Bioorg Med Chem Lett 17:6764
123