Synthesis and biological evaluation of some enantiomerically pure C8cC15 monoseco analogues of the phenanthroquinolizidine-type alkaloids cryptopleurine and julandine

Article abstract of DOI:10.1071/CH08190

A series of enantiomerically pure C8cC15 monoseco analogues, 2330, of the alkaloids cryptopleurine (1) and julandine (2) have been prepared using cinnamyl chloride 37 and (S)- or (R)-2-methylpiperidine as key building blocks. Two related compounds, 31 and

Full text of DOI:10.1071/CH08190

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 506–520
www.publish.csiro.au/journals/ajc
Synthesis and Biological Evaluation of Some
Enantiomerically Pure C8c–C15 Monoseco Analogues
of the Phenanthroquinolizidine-Type Alkaloids
Cryptopleurine and Julandine∗
Magne O. Sydnes,A Anna Bezos,B Christopher Burns,C Irma Kruszelnicki,C
Christopher R. Parish,B Stephen Su,C A. David Rae,A Anthony C. Willis,A
and Martin G. BanwellA,D
AResearch School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra, ACT 0200, Australia.
BJohn Curtin School of Medical Research, Institute of Advanced Studies, Australian National
University, Canberra, ACT 0200, Australia.
CCytopia Pty Ltd, 576 Swan Street, Richmond, VIC 3121, Australia.
DCorresponding author. Email: mgb@rsc.anu.edu.au
A series of enantiomerically pure C8c–C15 monoseco analogues, 23–30, of the alkaloids cryptopleurine (1) and julandine
(2) have been prepared using cinnamyl chloride 37 and (S)- or (R)-2-methylpiperidine as key building blocks. Two related
compounds, 31 and 32, have also been synthesized. Each of these analogues has been subjected to various biological
evaluations and most of them show dramatically reduced cytotoxicity compared with parent system 1. Nevertheless,
they are potent anti-angiogenic agents. The formation and single-crystal X-ray analysis of the spirocyclic dienone 54,
a by-product arising from attempts to prepare analogue 32, is also described.
Manuscript received: 5 May 2008.
Final version: 26 May 2008.
OMe
2
OMe
Introduction
3
MeO
MeO
MeO
MeO
The plant-derived natural product cryptopleurine (1,[1] Fig. 1)
possesses significant anti-cancer, anti-fungal, anti-microbial,
and anti-viral activity as well as being a powerful vesicant.[2,3]
As a result numerous efforts have been directed towards the syn-
thesis of this natural product[3] and the related alkaloid julandine
(2),[4] which displays a similar biological profile.[5]
1
H
N
15
H
N
15
8c
8c
4
5
8
6
7
Some work has also been carried out on the preparation
of simpler analogues of these compounds on the basis that
they might display equivalent or even improved biological
properties.[6,7] Thus, a Spanish group described the synthe-
sis of a piperidine analogue, 3 (Fig. 2), of julandine although
they also reported that it showed no activity against protein
synthesis in yeast ribosomes.[6a] Further work from the same
group resulted in the synthesis of the cryptopleurine analogues
4–10[6b,6c] and the first of these was shown to possess the
desired activity.[6b] Foldeak has detailed the preparation of ana-
logues 11–14 together with several variations thereof.[7] Such
pentacyclic systems were screened for anti-fungal activity and
1
2
Fig. 1. Structures of the alkaloids cryptopleurine (1) and juladine (2).
Anand et al. reported the synthesis of the naphthoquino-
lizidine salts 15–22 (Fig. 3) as analogues of cryptopleurine
and stated that none of these showed any significant anti-
cancer activity.[6g] In a separate study, Bargar and coworkers[6f]
found compound 22 to be a rather potent in vitro inhibitor
of HeLa cell colonies (IC50 0.6 µg mL−1). Interestingly, this
tetracyclic system did not exhibit significant in vivo activity
in a P-388 pre-screen, thus implying that the compound has
some cytoselective properties. Recently, Lee et al. reported that
7-methoxycryptopleurine possesses potent anti-inflammatory
activity, both in vitro and in vivo, as well as cytotoxic activity
compound 11 was found to display an IC50 of 0.05 µg mL−1
,
a value that compares favourably with that reported[7] for 1
itself (0.04 µg mL−1). Three other analogues were also found
to possess some anti-fungal activity.
∗Aspects of this work have been reported in preliminary form: M. G. Banwell, A. Bezos, C. Burns, I. Kruszelnicki, C. R. Parish, S. Su, M. O. Sydnes, Bioorg.
Med. Chem. Lett. 2006, 16, 181.
© CSIRO 2008
10.1071/CH08190
0004-9425/08/070506

Analogues of Cryptopleurine and Julandine
507
OMe
MeO
X
X
N
N
N
NH
MeO
4
5
3
6
X
X
OH
X
NH
N
NH
N
7
8
9
10
OMe
OMe
OMe
MeO
MeO
MeO
MeO
HO
H
N
H
N
H
N
H
N
MeO
Cl
11
12
13
14
X ϭ H or OH
Fig. 2. Structures of compounds 3–14.
against certain cancer cell lines, particularly gastric carcinoma
(NUGC-3) and nasopharyngeal carcinoma (HONE-1).[6j]
As a consequence of the situation described above and our
recent development of a relevant synthetic strategy,[8] we pre-
pared, and now report on the C8c–C15 monoseco analogues
23–26 (Fig. 4) of julandine (2) as well as the corresponding
phenanthrene-type systems 27–30, which represent the
equivalent analogues of cryptopleurine (1). The simpler ana-
logues 31 and 32 were also considered to be relevant in estab-
lishing the structure–activity relationship (SAR) profile of such
compounds. The fact that these seco-analogues bear significant
structural resemblances to combretastatin A4 (33), a potent cell
growth, tubulin polymerization, and angiogenesis inhibitor,[9]
provided a further motivation for the work reported here.
acquired by treatment of amine 34 with (R)-(−)-mandelic acid.
The optical rotations of the salts obtained by such means were in
full agreement with the values reported in the literature.[10] The
free amines, (S)-33 and (R)-33, could be generated by treating
the respective precursor salts with aqueous sodium hydroxide.
After extensive extraction with diethyl ether the free amines were
isolated in 80–90% yield.
Independent treatment of each of the amines (S)-34
and (R)-34 with chloride 37[8] and triethylamine in N,N-
dimethylformamide (DMF) at 60◦C for 4 h (Scheme 2) gave the
expected styrenes 38 and 39, respectively, in excellent yields
(∼98%). The spectroscopic data obtained for compound 39
matched those obtained for enantiomer 38. In keeping with
expectations, the optical rotation of each compound was of the
same magnitude but opposite sign. Using the optimized condi-
tions established during our previous work,[8] both substrates
38 and 39 could be readily engaged in Suzuki–Miyaura cross-
coupling with the known boronate 40.[8] By such means products
23 and 24 were obtained in 73 and 74% yield, respectively. The
1H and 13C NMR spectra of the former compound indicated
that the second aryl group had been installed, thus producing
the required stilbene unit. The Z-configuration about the double
bond within compound 23 was confirmed using nuclear over-
hauser effect correlation spectroscopy (NOESY) techniques. In
particular, a strong interaction between the alkenyl proton and
its methylenic counterparts was observed. The analogous NMR
spectra of its enantiomer 24 were also in full agreement with the
assigned structure.
Results and Discussion
Synthetic Studies
As suggested above, the first eight and previously unre-
ported target compounds 23–30 were considered likely to be
accessible using protocols we had described earlier.[8] The
required and enantiomerically pure samples of (S)- and (R)-2-
methylpiperidine were obtained following a procedure described
by Aggarwal and coworkers[10] (Scheme 1). Thus, treatment of
the commercially available racemate 34 with (S)-(+)-mandelic
acid afforded, after fractional crystallization, the optically pure
(+)-2-methylpiperidine mandelate salt 35 in 28% yield.The cor-
responding (−)-(2)-methylpiperidine mandelate salt 36 could be

508
M. O. Sydnes et al.
H
respectively. Treatment of these product stilbenes with tetra-
n-butylammonium fluoride (TBAF) in tetrahydrofuran (THF)
at room temperature for 0.5 h gave, after flash chromatogra-
phy, compounds 25 and 26 in 87 and 85% yield, respectively.
The appearance of an OH-stretching band in the infrared spec-
trum of each of these products confirmed the presence of the
free phenolic residue within them. Incorporation of the second
ϩ
N
N
ϩ
H
Ϫ
Br
Ϫ
Br
15
17
19
16
18
20
1
aryl group was also confirmed by H and 13C NMR spectro-
scopies. Thus, the 1H NMR spectra revealed the expected cou-
pling patterns associated with the second aryl-group, while the
Z-configuration about the double bond incorporated within
the latter product was confirmed using NOESY techniques.
The optical rotation for each of the two enantiomers was of the
same order of magnitude but opposite sign. Upon treatment with
Liepa’s reagent (VOF3),[11] compounds 43 and 44 could each be
converted into phenanthrenes 45 and 46 which were obtained
in 58 and 68% yield, respectively. Treatment of ethers 45 and
46 with TBAF efficiently converted each into the corresponding
phenols 29 (82%) and 30 (93%). The optical rotation of each
was as expected, that is, it was of the same order of magnitude
but opposite sign.
cis-Stilbene 49 (Scheme 4) was considered to be a suit-
able intermediate for the synthesis of the last two analogues
required in the present study, namely compounds 31 and 32.
Compound 49 itself was prepared in 45% yield by condensing
aldehyde 47 with acid 48 under conditions defined by Oishi
and Kurosawa.[12] Treatment of product 49 with oxalyl chlo-
ride followed by in situ reaction of the ensuing acid chloride
with dimethylamine afforded amide 50 in 68% yield. The car-
bonyl moiety within the latter compound was then reduced, with
LiAlH4 in THF, to the corresponding tertiary amine 51 (74%).
Treatment of product 51 with Liepa’s reagent following the same
procedure as used previously (see below) gave the corresponding
phenanthrene 31 in 56% yield. The physical and spectroscopic
data obtained for this compound were in full agreement with
those reported in the literature.[13]
OMe
MeO
N
N
ϩ
ϩ
Ϫ
Br
Ϫ
Br
OMe
MeO
MeO
H
ϩ
N
ϩ
N
H
Ϫ
Br
Ϫ
Br
OMe
OMe
MeO
H
H
ϩ
N
ϩ
N
H
H
Ϫ
Ϫ
Br
Br
21
22
The last remaining target compound, phenanthrene 32, was
thought likely to be available in two steps from cis-stilbene 49
through an initial VOF3-promoted oxidation reaction followed
by decarboxylation of the anticipated product 52 (Scheme 5).
However, despite numerous attempts, phenanthrene 52 failed to
form when cis-stilbene 49 was subjected to the usual oxidative
cyclization conditions. Such attempts only resulted in the recov-
ery of starting material. Accordingly, efforts were made to effect
a photochemically induced cyclization of compound 49 using
conditions defined by Castedo and coworkers.[14] Unfortunately,
these efforts were also in vain, with only starting material being
recovered.
The lack of reactivity of the cis-stilbene 49 under the speci-
fied conditions was puzzling. However, a consideration of some
earlier work by two different groups[12,15] prompted the conver-
sion of acid 49 into methyl ester 53 (Scheme 5) on the basis
that the latter compound should undergo the desired oxidative
cyclization reaction. In the event, treatment of compound 53
with Liepa’s reagent under the usual conditions failed to give the
corresponding phenanthrene. Once again, only starting material
was recovered. In contrast, when substrate 53 was subjected to
the related conditions described by Halton et al.[15] a reaction
did take place although still none of the hoped-for phenanthrene
was obtained. The only isolable product of this reaction was
subjected to detailed spectroscopic analysis, including a single-
crystal X-ray study (see Fig. 5 and Experimental section), and
by such means it was shown to possess the spirocyclic structure
Fig. 3. Structures of compounds 15–22.
Compounds 23 and 24 were each converted into the corre-
sponding phenanthrenes, 27 and 28 respectively, by a Liepa-type
oxidation[11] that involved their treatment with vanadium(v)
oxytrifluoride (VOF3) in dichloromethane at 0◦C for 0.25 h.
Subsequent addition of trifluoroacetic acid (TFA), stirring the
reaction mixture at 0◦C for a further 0.25 h, and then quench-
ing it with 10% aqueous sodium hydroxide solution allowed
for a straightforward workup. By such means, and after flash
chromatography, enantiomers 27 and 28 were isolated in 48 and
63% yield, respectively.The spectroscopic data obtained for each
compound were in full agreement with the assigned structures.
With the four trimethoxylated target compounds 23, 24,
27, and 28 to hand, efforts were then directed toward the
synthesis of those congeners, 25, 26, 29, and 30, which incor-
porated a free phenolic moiety in the lower aryl ring. Initial
attempts (Scheme 3) to synthesize compound 25 directly by
a Suzuki–Miyaura cross-coupling of alkenyl bromide 38 and
boronate 41 gave only traces of the desired product. As a
consequence the OH group within coupling partner 41 was
protected as the corresponding tert-butyldiphenylsilyl (TBDPS)
ether 42 (67%). Cross-coupling of the latter compound under
Suzuki–Miyaura conditions with either alkenyl bromide 38 or
enantiomer 39, afforded compounds 43 (69%) and 44 (73%),

Analogues of Cryptopleurine and Julandine
509
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
15
8c
N
N
N
N
MeO
MeO
MeO
MeO
HO
HO
23
24
25
26
OMe
OMe
OMe
OMe
MeO
MeO
15
8c
N
N
N
N
MeO
MeO
HO
HO
27
28
29
30
OMe
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO
HO
N
MeO
31
32
33
Fig. 4. Structures of analogues 23–32 and the structure of combretastain A-4 (33).
OMe
OMe
MeO
MeO
HN
(a)
Cl
34
N
(a)
(c)
Ph
Br
Br
38 (S-enantiomer)
39 (R-enantiomer)
37
OH
OH
Ϫ
CO2
Ϫ
CO2
H2N
ϩ
H2N
ϩ
Ph
O
B
35
(b)
36
O
(b)
(b)
MeO
40
HN
HN
(c)
23 or 24
27 or 28
(S)-34
(R)-34
Scheme 2. Reagents and conditions: (a) (S)-(+)-34 (1.05 mol equiv.) or
(R)-(−)-34 (1.05 mol equiv.), Et3N, DMF, 60◦C, 4 h; (b) compound 40 (2.1
mol equiv.), PdCl2(dppf) (∼7 mol %), 1:7 v/v ethanol/benzene, Na2CO3
(2 m aqueous solution), reflux, 6–7 h; (c) VOF3 (4.4 mol equiv.), CH2Cl2,
0◦C, 0.25 h then TFA (12 mol equiv.), 0◦C, 0.25 h.
Scheme 1. Reagents and conditions: (a) (S)-(+)-mandelic acid (0.95 mol
equiv.), methanol/ether, 0◦C; (b) aqueous NaOH, 18◦C, and then extraction
with ether; (c) (R)-(−)-mandelic acid (0.97 mol equiv.), methanol/ether, 0◦C.
54 (16%). When cis-stilbene 53 was stirred in a solution of
TFA and dichloromethane at 0◦C for 1 h and then treated with
VOF3 a 27% yield of product 54 was obtained. However, the
dominant product (66%) was now a bis-phenanthrene tenta-
tively assigned structure 55. The unsymmetrical nature of this
dimeric species follows from, among other things, an analy-
sis of the coupling patterns observed in the aromatic region of
the H NMR spectrum which revealed two mutually coupled
1
(J 9.5 Hz) one-proton doublets at δ 7.42 and 9.00. The chemical

510
M. O. Sydnes et al.
OMe
O
B
MeO
OMe
O
MeO
MeO
(a)
CHO
HO
47
ϩ
(a)
41
O
B
CO2H
O
CO2H
MeO
TBDPSO
49
42
48
38 or 39
(b)
(b)
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
(c)
(c)
(d)
N
N
31
N
N
TBDPSO
TBDPSO
O
MeO
MeO
45 (S-enantiomer)
46 (R-enantiomer)
43 (S-enantiomer)
44 (R-enantiomer)
51
50
Scheme 4. Reagents and conditions: (a) compound 47 (1 mol equiv.),
compound 48 (1 mol equiv.), 2:1 v/v acetic anhydride/Et3N, reflux, 2.5 h;
(b) oxalyl chloride (3 mol equiv.), THF, 18◦C, reflux, 0.66 h and then
dimethylamine (21 mol equiv.),THF, 18◦C, 16 h; (c) LiAlH4 (5.9 mol equiv.),
THF, 18◦C, 2 h; (d) VOF3 (4.4 mol equiv.), CH2Cl2, 0◦C, 0.25 h and then
TFA (13 mol equiv.), 0◦C, 0.25 h.
(d)
(d)
25 or 26
29 or 30
Scheme 3. Reagents and conditions: (a) tert-butyldiphenylsilyl chloride
(TBDPS-Cl) (1.2 mol equiv.), imidazole (1.4 mol equiv.), DMF, −30 to
18◦C, 16 h; (b) compound 42 (2 mol equiv.), PdCl2(dppf) (17 mol %), 1:9
v/v ethanol/benzene, Na2CO3 (2 m aqueous solution), reflux, 6 h; (c) VOF3
(5.2 mol equiv.), CH2Cl2, 0◦C, 0.25 h and then TFA (13 mol equiv.), 0◦C,
0.25 h; (d) tetra-n-butylammonium fluoride (TBAF) (1.4 mol equiv.), THF,
18◦C, 0.5 h.
The physical and spectroscopic data derived from this product
were in full accord with those reported in the literature.[17]
A reaction pathway that accounts for the observed conversion
53 → 54 (Scheme 5) is shown in Fig. 6 and is based on arguments
advanced by others to explain the outcomes of related processes
that lead to similar products.[18] Thus, a one-electron oxidation
of substrate 53 by VOF3 would be expected to deliver the radi-
cal cation 58 that then engages in the relevant spirocyclization
process. After a second one-electron oxidation and proton loss
the oxonium ion 59 would be formed. Hydrolysis of the last
species would then be expected to produce the observed spiro-
cyclic dienone 54.The formation of the unsymmetrical dimer 55
from precursor 53 under the conditions indicated in Scheme 5 is
a rare example of aVOF3-promoted version of such a process.[19]
The significant selectivity associated with this oxidative dimer-
ization process is notable but, at the present time, we cannot offer
any satisfactory explanation for this particular outcome.
shift of the latter resonance is attributed to the deshielding effects
of an adjacent carbomethoxy group. Eight one-proton singlets
also appeared in the aromatic region of the same spectrum. The
appearance of a methoxymethyl singlet at δ 2.74 presumably
arises from the shielding effects of the adjacent phenanthrene
residue.The EI mass spectrum of compound 55 showed a molec-
ular ion at m/z 650 and an accurate mass measurement on
this species established that it possessed the molecular formula
C38H34O10. Resonances attributable to all 38 carbons embodied
within substrate 55 could be detected in the 13C NMR spectrum.
A synthesis of the required phenanthrene 32 was finally estab-
lished by treating, in the first step of the reaction sequence, acid
49 with dry CuSO4 in refluxing quinoline[16] (Scheme 5). In this
manner the required decarboxylation reaction took place and so
generated cis-stilbene 56 (70%) together with small amounts
(5%) of the chromatographically separable trans-isomer 57. Ini-
tial attempts to convert substrate 56 into phenathrene 32 by
treating it, under the conditions detailed above, that is withVOF3
in CH2Cl2 followed by treatment with TFA, only resulted in the
isolation of trans-stilbene 57 (35%). As demonstrated by con-
ducting the relevant control experiment, the conversion of 56
into 57 is a simple TFA-catalyzed process. In contrast, when
a solution of cis-stilbene 56 in 35:1 v/v ether/dichloromethane
that contained catalytic amounts of iodine was irradiated with
light from a medium pressure Hg vapour lamp the by now long-
sought-after phenanthrene 32 could be generated in 51% yield.
Biological Assays
Cytotoxicity Testing
Each of compounds 23–32 was screened, at eight different
concentrations, against a panel of 19 human and other cancer cell
lines as listed in Table 1. An authentic sample of natural product
1 was also tested against the same panel. As a consequence it
became clear that the monoseco analogues, 27–30, of crypto-
pleurine (1) are approx. three orders of magnitude less cytotoxic
than the parent compound whereas the related cis-stilbenes show
essentially no toxicity whatsoever. Furthermore, the configura-
tion (R versus S) at the single stereogenic centre within these
analogues has essentially no impact on activity. Clearly, then,

Analogues of Cryptopleurine and Julandine
511
OMe
OMe
OMe
MeO
OMe
MeO
MeO
MeO
MeO
(a) or (b)
(c)
(d)
X
CO2H
CO2H
CO2Me
CO2Me
MeO
O
MeO
(f)
52
49
53
54
(e)
OMe
OMe
OMe
MeO
MeO
MeO
ϩ
ϩ
54
CO2Me
OMe
MeO
MeO
MeO
OMe
OMe
57
56
(a)
35%
(b)
32
CO2Me
55
Scheme 5. Reagents and conditions: (a) see text; (b) air, I2 (cat.), 1:35 v/v CH2Cl2/diethyl ether, hν, 2 h; (c) oxalyl chloride (3 mol equiv.), THF,
18◦C to reflux, 0.66 h and then methanol, 18◦C, 16 h; (d) 3:2 v/v TFA/CH2Cl2 then VOF3 (3.4 mol equiv.) in 3:1 v/v TFA/EtOAc, 0◦C, 1 h; (e) 2:1 v/v
TFA/CH2Cl2, 0◦C, 1 h and then VOF3 (3.4 mol equiv.) in 3:1 v/v TFA/EtOAc, 0◦C, 0.33 h; (f) CuSO4 (2.2 mol equiv.), quinoline, reflux, 1 h.
OMe
OMe
C21
C6
MeO
MeO
MeO
MeO
O20
VOF
3
O22
Ϫe
CO2Me
CO2Me
C5
C4
C23
C7
C8
53
58
C9
C1
Cyclization
VOF
C3
C2
3
Ϫe, ϪHϩ
C14
O17
C16
C13
OMe
OMe
C10
MeO
MeO
MeO
C11
C12
O18
H O
2
O15
C19
ϪMeOH,
ϪHϩ
CO2Me
CO2Me
O
Fig. 5. Molecular structure of compound 54 (C18H16O5) with labelling of
selected atoms. Anisotropic displacement ellipsoids show 30% probability
levels. Hydrogen atoms are drawn as circles with small radii.
ϩ
54
59
Fig. 6. Possible pathway for the conversion of stilbene 53 into spiro-
cycle 54.
Anti-angiogenic Testing
the scission of the C8c–C15 bond within the title natural prod-
ucts leads to derivatives with dramatically reduced cytotoxicity
profiles. The phenanthrenes 31 and 32 also proved to be only
weakly cytotoxic.
The anti-angiogenic properties of compounds 23–32 were
determined in an in vitro assay using rat aorta blood ves-
sel fragments.[20] Unfortunately, solubility problems prevented

512
M. O. Sydnes et al.
Table 1. IC50 values (× 10−6 m) determined for compounds 1 and 23–32 in cytotoxicity testing against a range of cancer cell
linesA
TFI, human erythroleukaemia; CTLL2, murine cytotoxic T-cells; BT20, human breast carcinoma; MatLyLu, rat prostate carcinoma;
KHOS-NP, human osteosarcoma;A431, human epidermoid carcinoma;A375, human melanoma;A549, human lung carcinoma; HCT-
15, human colon carcinoma; HT1376, human bladder carcinoma; PA-1, human ovarian teratocarcinoma; HEPG2, human hepatoma;
HEK293, human embryonic kidney cells; BUD-8, human fibroblast; RAMOS, Burkitt lymphoma; DAUDI, Burkitt lymphoma;
MES-SA, human uterine sarcoma; MES-SA-Dx5, human uterine sarcoma derived from MES-SA; MCF-7, human breast carcinoma
Cell line
Compound
27 28
(−)-1B
23
24
25
26
29
9.80
30
8.40
31
6.75
32
C
TFI
CTLL2
BT20
MatLyLu
KHOS-NP
A431
A375
A549
HCT-15
HT1376
PA-1
HEPG2
HEK293
BUD-8
RAMOS
DAUDI
MES-SA
MES-SA-Dx5
MCF-7
—
—
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
>20
7.20
7.61
7.65
8.10
>20
C
9.09
13.73
>20
15.43
13.77
11.25
16.55
8.41
8.10
11.57
>20
13.42
20.00
9.38
15.18
7.97
3.39
7.38
17.34
17.14
5.37
7.10
17.03
8.27
17.50
0.003
0.003
0.010
0.003
0.003
0.003
0.003
0.004
0.002
10.24
10.89
>20
>20
>20
>20
>20
>20
>20
>20
>20
∼15
∼15
12.28
8.12
8.96
11.25
7.82
9.68
7.38
8.12
15.50
13.99
8.09
10.05
12.02
8.33
9.51
7.27
8.31
6.04
7.88
4.16
C
∼8
—
—
—
—
—
—
—
—
C
C
C
C
—
—
7.27
17.08
8.33
—
—
—
—
C
C
C
C
14.83
18.24
18.16
13.50
14.12
11.79
C
0.006
0.003
0.002
0.003
0.003
0.003
>20
>20
9.08
>20
>20
>20
>20
>20
>20
>20
>20
C
15.50
12.04
9.04
16.65
15.71
9.10
16.78
18.59
C
C
10.07
11.73
C
8.46
C
C
C
C
C
C
C
C
—
—
—
—
—
—
—
—
ADMSO was used as solvent in these assays unless otherwise stated.
BMethanol used as solvent in the assaying of this compound because of difficulties dissolving it in DMSO.
CNot tested.
at the 1 µg mL−1 level. It is worth noting that every single one of
these analogues of alkaloids 1 and 2 is more active, at least at the
100 µg mL−1 level, than PI-88, a polysulfated oligosaccharide
that exhibits anti-angiogenic properties in vivo and which is now
in clinical development as an agent for the treatment of certain
cancers.[21] A further important facet of these results is that the
phenanthrenes seem to be more active than the corresponding
cis-stilbenes while chirality has little or no impact on the anti-
angiogenic properties of the title analogues. Furthermore, those
phenanthrenes that incorporate a free hydroxy group are slightly
less active than their methoxy counterparts, perhaps because
of a reduction in their lipophilic properties. Interestingly, the
phenanthrene and aminomethyl subunits associated with com-
pounds 23–30 both seem to be making important contributions
to their anti-angiogenic properties as judged by the test results
observed for the simpler analogues 31 and 32.
Table2. Anti-angiogenicpropertiesofcompounds23–32asdetermined
in a rat aorta assayA
Compound
% Inhibition of blood vessel growth
at 100 µg mL−1 at 10 µg mL−1 at 1 µg mL−1 at 0.1 µg mL−1
23
24
25
26
27
28
29
30
100
100
100
100
100
43
62
42
68
59
53
43
42
48
58
47
22
22
36
31
C
65
—
100
100
74
17
29
35
18
7
B
—
100
100
85
C
31
32
PI-88
—
100
42
C
C
83
74
—
—
—
—
C
C
C
—
The origins of the significant anti-angiogenic properties
of compounds 23–32 have not been established thus far.
However, the capacity of certain combretastatin A4 deriva-
tives/analogues to act as vascular targeting agents by binding
to tubulin in newly formed endothelial cells that line the tumour
vasculature[9b,22] suggests this mode of action may be involved
in the present case. This situation, coupled with the consid-
erable interest in the possibility of separating any cytotoxic
activity of combretastatin-type compounds from their ability
to effect vascular shutdown,[9a,22] serves to highlight the ther-
apeutic potential of C8c–C15 monoseco analogues, such as
compounds 23–30, of the title alkaloids.
AAssays conducted according to the method of Brown et al.[20] using
DMSO as solvent.
BNot tested at this concentration due to lack of solubility.
CNot tested.
analogous testing of cryptopleurine itself. Nevertheless, the
results shown in Table 2 indicate that most of the analogues
completely inhibited blood vessel growth at 100 µg mL−1. Even
more significantly, compounds 27 and 28 also completely
inhibited blood vessel growth at the 10 µg mL−1 level, whereas
several others were still able to inhibit growth by more than 50%

Analogues of Cryptopleurine and Julandine
513
Conclusions
(34) (6.16 mL, 52.4 mmol, ex. Aldrich Chemical Co.) in
methanol (20 mL) maintained at 0◦C and the resulting mixture
swirled until the solid had dissolved. The temperature was main-
tained at 0◦C without stirring and diethyl ether (10 × 10 mL)
was added in 10 portions, once every 0.5 h, so as to initiate
precipitation. A further aliquot of diethyl ether (15 mL) was
then added and the mixture was maintained at 0◦C for an addi-
tional 3 h and then filtered. The crystalline solid thus obtained
was washed (cold diethyl ether) and then dried under reduced
pressure to give salt 35[10] (3.44 g, 28%) as a white, crys-
talline solid, mp 108–110◦C (lit.[10] 118–119◦C), [α]2D0 −60◦
(c 2.5, MeOH) {lit.[10] [α]2D0 −60◦ (c 2.5, MeOH)} (Found:
C 66.8, H 8.7, N 5.3. C14H21NO3 requires C 66.9, H 8.4,
N 5.6%). δH (300 MHz, CDCl3) 9.30 (2H, br s), 7.42 (2H,
m), 7.29–7.14 (3H, complex m), 4.83 (1H, s), 2.94 (1H, br
d, J 12.9), 2.71–2.58 (1H, complex m), 2.24–2.13 (1H, com-
plex m), 1.70–1.58 (1H, complex m), 1.58–1.45 (3H, complex
m), 1.30–0.98 (2H, complex m), 1.06 (3H, d, J 6.4) (one sig-
nal not observed). δC (75 MHz, CDCl3) 178.2 (COO), 142.5
(C), 128.0 (2 × CH), 127.0 (CH), 126.6 (2 × CH), 74.4 (CH),
52.2 (CH), 43.8 (CH2), 30.2 (CH2), 22.5 (CH2), 21.7 (CH2),
19.1 (CH3). νmax (KBr)/cm−1 3165 (br), 2947, 2858, 2704,
2593, 2545, 2507, 1609, 1478, 1446, 1393, 1330, 1280, 1268,
1186, 1089, 1060, 1028, 730, 695, 561, 487. m/z (EI, 70 eV)
152 [19%, (M − C6H13N•)+], 107 (100), 84 (82), 79 (77),
77 (66).
The mother liquors arising from recrystallization of the man-
delate salt of (R)-(−)-2-methylpiperidine were concentrated
under reduced pressure to give a syrup that was dissolved
in water (15 mL) and the resulting solution was then basified
(using 20 mL of a 10% w/v aqueous NaOH). The aqueous phase
was extracted with diethyl ether (3 × 15 mL) and the combined
organic phases was dried (MgSO4), filtered, and concentrated
under reduced pressure to give amine 34 (1.48 g, 14.95 mmol)
now partially enriched in the (R)-(−)-enantiomer. This material
was dissolved in methanol (15 mL) and the resulting solution
cooled to 0◦C. (S)-(+)-Mandelic acid (2.20 g, 14.46 mmol, ex.
Aldrich Chemical Co.) was added and the resulting mixture
swirled until all the solids had dissolved. The temperature was
maintained at 0◦C and diethyl ether was added in 11 portions,
(11 × 10 mL), once every 0.5 h, to allow precipitation to begin.
A final aliquot of diethyl ether (25 mL) was then added and the
mixture was left to stand, without stirring, for an additional 3 h
at 0◦C. The mixture was then filtered and the crystalline solid
thus obtained was washed (cold diethyl ether) then dried under
reduced pressure to give compound 36[10] (777 mg, 21%) as a
white solid, mp 106–108◦C (lit.[10] 145–146◦C), [α]1D7 +60.8◦
(c 2.6, MeOH) {lit.[10] [α]2D0 +60◦ (c 2.5, MeOH)} (Found:
C 66.9, H 8.7, N 5.5. C14H21NO3 requires C 66.9, H 8.4,
N 5.6%). δH (300 MHz, CDCl3) 9.30 (2H, br s), 7.42 (2H,
m), 7.29–7.14 (3H, complex m), 4.83 (1H, s), 2.94 (1H, br
d, J 13.0), 2.70–2.57 (1H, complex m), 2.24–2.11 (1H, com-
plex m), 1.71–1.59 (1H, complex m), 1.57–1.41 (3H, complex
m), 1.29–0.98 (2H, complex m), 1.06 (3H, d, J 6.6) (one sig-
nal not observed). δC (75 MHz, CDCl3) 178.2 (COO), 142.5
(C), 128.0 (2 × CH), 127.0 (CH), 126.5 (2 × CH), 74.4 (CH),
52.2 (CH), 43.8 (CH2), 30.2 (CH2), 22.5 (CH2), 21.7 (CH2),
19.1 (CH3). νmax (KBr)/cm−1 3164 (br), 3027, 2970, 2947,
2857, 2704, 2593, 2545, 2507, 1608, 1478, 1446, 1393, 1330,
1280, 1268, 1186, 1089, 1068, 730, 695, 561, 488. m/z (EI,
70 eV) 152 [18%, (M − C6H13N•)+], 107 (100), 84 (68), 79 (77),
77 (65).
Four cis-stilbene analogues, 23–26, of julandine (2) and six
phenanthrene analogues, 27–32, of cryptopleurine (1) have
been synthesized in good overall yields. While these analogues
display only modest cytotoxicities, their anti-angiogenic proper-
ties, especially those displayed by phenanthrenes 27 and 28, are
particularly striking. As such these compounds should serve as
significant leads for further work in this area.
Experimental
General Procedures
Melting points were measured on a Reichert hot-stage micro-
scope apparatus and are uncorrected. Unless otherwise specified,
proton (1H) and carbon (13C) NMR spectra were acquired at
20◦C. Proton and carbon NMR spectra were recorded on either
aGemini300NMRspectrometer, operatingat300 MHz(forpro-
ton) and 75 MHz (for carbon) or aVarian Inova 500 spectrometer
operating at 500 MHz (for proton) and 126 MHz (for carbon).
NMR spectra are referenced to residual chloroform (δ 7.24, 1H;
δ 77.0, 13C), methanol (δ 3.30, 1H; δ 49.0, 13C) or benzene
(δ 7.15, 1H; δ 128.0, 13C). Deuterated chloroform (CDCl3) was
filtered through basic alumina immediately before use. Chemi-
cal shifts were recorded as δ values in parts per million (ppm).
Infrared spectra (νmax) were recorded on a Perkin–Elmer 1800
Series FTIR spectrometer and samples were analyzed as thin
films on NaCl plates unless otherwise specified. A VG Fisions
AutoSpec three-sector (E/B/E) double-focusing mass spectro-
meter (located at theAustralian National University) or a Kratos
Analytical Concept ISQ instrument (located at the University
of Tasmania) operating in a positive-ion electron-impact mode
were used to obtain low and high resolution electron impact (EI)
spectra. Optical rotations were measured with a Perkin–Elmer
241 polarimeter at the sodium-D line (589 nm) and the con-
centrations (c) (g/100 mL) indicated using spectroscopic grade
CHCl3 unless otherwise specified. The measurements were car-
ried out between 15 and 21◦C in a cell with a path length (l)
of 1 dm. Specific rotations [α]D were calculated using the equa-
tion [α]D = 100α/(cl), where α represents the measured rotation,
and are given in 10−1 deg cm2 g−1. Elemental analyses were
performed by the Australian National University’s Microanalyt-
ical Services Unit based at the Research School of Chemistry,
Canberra,Australia. Dichloromethane was distilled, under nitro-
gen, from calcium hydride. THF and diethyl ether (ether) was
distilled, under nitrogen, from sodium benzophenone ketyl.
Methanol was distilled from magnesium methoxide. DMF and
triethylamine were both distilled from and stored over potassium
hydroxide pellets.A 28% aqueous ammonia solution was used as
additive in some of the eluting systems for flash chromatography
as well as for the workup of reaction mixtures. Where necessary,
reactions were performed under a nitrogen atmosphere. Unless
otherwise specified the organic phases arising from the workup
of reaction mixtures were dried over anhydrous magnesium sul-
fate. The reaction mixture was then filtered and concentrated
underreducedpressureonarotaryevaporatorwiththewaterbath
temperature generally not exceeding 40◦C. Room temperature
is assumed to be ∼18◦C.
Synthetic Studies
Mandelate Salts of (S)-(+)- and
(R)-(−)-2-Methylpiperidine (35 and 36, Respectively)
(R)-(−)-Mandelic acid (7.58 g, 49.8 mmol, ex. Aldrich
ChemicalCo.)wasaddedtoasolutionof( )-2-methylpiperidine

514
M. O. Sydnes et al.
(S)-(+)- and (R)-(−)-2-Methylpiperidine [(S)-(+)-34
spectroscopic data obtained on this material matched those
presented above for the corresponding S-enantiomer.
and (R)-(−)-34, Respectively]
NaOH (50% w/v aqueous solution) was added, dropwise,
to a magnetically stirred solution of salt 35 or 36 (500 mg,
1.99 mmol) in water (10 mL) maintained at 18◦C until a pH
of 14 was achieved. The aqueous phase was extracted with
diethyl ether (5 × 15 mL) and the combined organic fractions
were then dried (MgSO4), filtered, and concentrated under
reduced pressure to give a concentrated solution of (S)-(+)- or
(R)-(−)-2-methylpiperidine in diethyl ether.
(S)- and (R)-2-Methyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-
dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-methoxyphenyl)prop-
2ꢀ-enyl]piperidines (23 and 24, Respectively)
A magnetically stirred mixture of alkenyl bromide 38 or 39
(100.0 mg, 0.28 mmol), 4-methoxyphenyl pinacolboronate 40[8]
(139 mg, 0.59 mmol), ethanol (1.8 mL), and Na2CO3 (4.0 mL of
a 2 m aqueous solution) in benzene (14.4 mL) was treated with
PdCl2(dppf) (17.2 mg, 0.02 mmol) and the resulting mixture was
heated at reflux under an atmosphere of nitrogen for 6–7 h while
being protected from light. The cooled reaction mixture was
then diluted with diethyl ether (20 mL) and the separated organic
phase washed with NaHCO3 (2 × 10 mL of a saturated aqueous
solution) and brine (1 × 10 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-
yellow oil. This material was subjected to flash chromatography
(silica, 95:4.25:0.75 v/v/v dichloromethane/methanol/aqueous
ammonia elution) and concentration of the relevant fractions
(RF 0.2) gave the cis-stilbene 23 or 24.
(S)-(+)-2-Methylpiperidine [( S)-(+)-34][23] was obtained
as a clear, colourless ethereal solution in 80–90% yield. δH
(300 MHz, CD3OD) 3.01–2.94 (1H, complex m), 2.63–2.51
(2H, complex m), 1.82–1.70 (1H, complex m), 1.68–1.51 (2H,
complex m), 1.48–1.30 (2H, complex m), 1.16–1.02 (1H, com-
plex m), 1.04 (3H, d, J 6.3) (signal due to N–H not observed).
δC (75 MHz, CD3OD) 53.3 (CH), 47.6 (CH2), 35.1 (CH2), 26.5
(CH2), 25.7 (CH2), 22.7 (CH3).
(R)-(−)-2-Methylpiperidine [( R)-(−)-34][23] was obtained
as a clear, colourless ethereal solution in 80–90% yield. δH
(300 MHz, CD3OD) 3.02–2.97 (1H, complex m), 2.65–2.54
(2H, complex m), 1.81–1.71 (1H, complex m), 1.68–1.51 (2H,
complex m), 1.48–1.31 (2H, complex m), 1.17–1.02 (1H, com-
plex m), 1.05 (3H, d, J 6.4) (signal due to N–H not observed).
δC (75 MHz, CD3OD) 53.4 (CH), 47.5 (CH2), 34.9 (CH2), 26.3
(CH2), 25.6 (CH2), 22.5 (CH3).
(S)-2-Methyl -1-[(E)-3ꢀ -(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-
methoxyphenyl)prop-2ꢀ-enyl]piperidine ( 23) (77.8 mg, 73%)
was obtained as a light-yellow oil, [α]2D0 +26.8◦ (c 1.7, MeOH)
(Found: M+• 381.2305. C24H31NO3 requires M+• 381.2304).
δH (300 MHz, CD3OD) 7.14 (2H, d, J 8.8), 6.89 (2H, d, J 8.8),
6.71 (1H, d, J 8.4), 6.61 (1H, dd, J 1.9 and 8.4), 6.53 (1H, s), 6.40
(1H, d, J 1.9), 3.84 (1H, d, J 13.7), 3.77 (3H, s), 3.73 (3H, s), 3.39
(3H, s), 3.15 (1H, d, J 13.7), 3.08–2.99 (1H, complex m), 2.34
(1H, br s), 2.13 (1H, broad t, J 11.0), 1.68–1.22 (6H, complex
m), 1.05 (3H, d, J 6.1). δC (75 MHz, CD3OD) 160.4 (C), 149.4
(C), 149.2(CH), 138.3(C), 134.3(C), 131.5(C), 131.4(2 × CH),
130.7 (C), 123.7 (CH), 115.2 (2 × CH), 113.3 (CH), 112.2 (CH),
63.5 (CH2), 58.1 (CH), 56.3 (CH3), 55.7 (CH3), 55.6(6) (CH3),
53.4 (CH2), 35.1 (CH2), 26.6 (CH2), 25.0 (CH2), 19.5 (CH3).
νmax (KBr)/cm−1 2932, 1606, 1512, 1464, 1268, 1243, 1142,
1028. m/z (EI, 70 eV) 381 (43%, M+•), 366 (8), 284 (46), 283
(41), 252 (26), 237 (22), 112 (100).
(S)- and (R)-2-Methyl-1-[2ꢀ-bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-
dimethoxyphenyl)prop-2ꢀ-enyl]piperidines
(38 and 39, Respectively)
Triethylamine (47 µL, 0.337 mmol) was added to a magnet-
ically stirred solution of chloride 37[8] (90.0 mg, 0.31 mmol)
and the relevant enantiomeric form of 2-methylpiperidine
(0.325 mmol), i.e., (S)-(+)-34 or (R)-(−)-34, in DMF (1.0 mL)
maintained at 18◦C. The ensuing mixture was heated at 60◦C
for 4 h under an atmosphere of nitrogen and then cooled to 18◦C
and diluted with ethyl acetate (30 mL). The resulting solution
was washed with brine/water (5 × 20 mL of a 1:1 v/v mixture)
and brine (1 × 20 mL) before being dried (MgSO4), filtered, and
concentrated under reduced pressure to give either compound
38 or 39.
(R)-2-Methyl -1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-2ꢀ -(4ꢀꢀ-
methoxyphenyl)prop-2ꢀ-enyl]piperidine ( 24) (78.9 mg, 74%)
was obtained as a yellow oil, [α]1D9 −26.7◦ (c 0.1, MeOH). The
remaining spectroscopic data obtained on this material matched
those presented above for the corresponding S-enantiomer.
(S)-2-Methyl-1-[(Z)-2ꢀ-bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)
prop-2ꢀ-enyl]piperidine ( 38) (107.5 mg, 98%) was obtained as a
yellow oil, [α]1D5 +59.4◦ (c 1.7, MeOH) (Found: M+• 355.0965.
C17H2481BrNO2 requires M+• 355.0970). δH (300 MHz,
CD3OD) 7.36 (1H, d, J 1.9), 7.18 (1H, dd, J 1.9 and 8.4), 6.99
(1H, s), 6.89 (1H, d, J 8.4), 3.80(9) (3H, s), 3.80(5) (3H, s), 3.76
(1H, dd, J 0.8 and 14.9), 3.15 (1H, d, J 14.9), 2.96–2.88 (1H,
complex m), 2.48–2.35 (1H, complex m), 2.12 (1H, dt, J 3.8
and 10.8), 1.71–1.44 (3H, complex m), 1.44–1.23 (3H, complex
m), 1.11 (3H, d, J 6.3). δC (75 MHz, CD3OD) 150.3 (C), 149.7
(C), 131.0 (C), 129.7 (CH), 123.7 (CH), 122.5 (C), 113.5 (CH),
112.2 (CH), 65.5 (CH2), 57.8 (CH), 56.4 (CH3), 56.3 (CH3),
53.2 (CH2), 35.2 (CH2), 26.7 (CH2), 24.9 (CH2), 19.6 (CH3).
νmax (KBr)/cm−1 2931, 2853, 2790, 1602, 1582, 1515, 1463,
1271, 1143, 1028, 804. m/z (EI, 70 eV) 355 (2.9%), 353 (3.1,
(S)- and (R)-2-Methyl-1-[(2,3,6-trimethoxphenanthren-
9-yl)methyl]piperidines (27 and 28, Respectively)
VOF3 (27.5 mg, 0.22 mmol) was added to a magnetically
stirred solution of cis-stilbene 23 or 24 (17.5 mg, 0.05 mmol)
in dichloromethane (2.0 mL) maintained at 0◦C under an atmo-
sphere of nitrogen. The ensuing mixture was stirred at this
temperature for 0.25 h and then trifluoroacetic acid (50 µL,
0.61 mmol) was added dropwise. After being stirred for a
further 0.25 h at 0◦C the reaction mixture was poured into
NaOH (10 mL of a 10% w/v aqueous solution). After 5 min
of additional stirring the aqueous phase was extracted with
dichloromethane (3 × 15 mL) and the combined organic phases
were dried (MgSO4), filtered, and concentrated under reduced
pressure to give a yellow oil.This material was subjected to flash
chromatography (silica, 90:8:2 → 80:18:2 v/v/v hexane/ethyl
acetate/triethylamine gradient elution) and concentration of the
appropriate fractions (RF 0.2 in 4:1 v/v hexane/ethyl acetate)
gave the relevant phenanthrene.
M
+•), 340 (3.9), 338 (4.1), 274 (100), 257 (30), 255 (31), 176
(59), 175 (89).
(R)-2-Methyl-1-[(Z)-2ꢀ-bromo-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)
prop-2ꢀ-enyl]piperidine ( 39) (108.6 mg, 99%) was obtained
as a yellow oil, [α]2D0 −54.9◦ (c 0.5, MeOH). The remaining

Analogues of Cryptopleurine and Julandine
515
(S)-2-Methyl-1-[(2,3,6-trimethoxphenanthren-9-yl)methyl]
piperidine ( 27) (9.1 mg, 48%) was obtained as an oily white
solid, mp 46–48◦C, [α]D19 +33.1◦ (c 0.2, benzene) (Found: M+•
379.2155. C24H29NO3 requires M+• 379.2147). δH (300 MHz,
C6D6) 8.70 (1H, d, J 9.0), 8.08 (1H, d, J 2.4), 7.91 (1H, s), 7.64
(1H, s), 7.31 (1H, dd, J 2.4 and 9.0), 7.07 (1H, s), 4.61 (1H, d, J
12.9), 3.54 (6H, s), 3.51 (3H, s), 3.38 (1H, d, J 12.9), 2.85 (1H,
dt, J 3.8 and 11.5), 2.39–2.27 (1H, complex m), 2.00 (1H, m),
1.64–1.20 (6H, complex m), 1.23 (3H, d, J 6.1). δC (126 MHz,
C6D6) 158.6 (C), 150.7 (C), 150.0 (C), 132.5 (C), 132.2 (C),
127.7 (C), 127.5 (CH), 126.3 (C), 125.4 (CH), 124.8 (C), 115.0
(CH), 109.0 (CH), 104.9 (CH), 104.6 (CH), 58.7 (CH2), 57.9
(CH), 55.6 (CH3), 55.3 (CH3), 54.9 (CH3), 52.2 (CH2), 35.1
(CH2), 26.6 (CH2), 24.2 (CH2), 18.9 (CH3). νmax (KBr)/cm−1
2929, 1611, 1511, 1467, 1259, 1232, 1159. m/z (EI, 70 eV) 379
(7%, M+•), 364 (1), 281 (58), 57 (100).
phase was washed with NaHCO3 (2 × 10 mL of a saturated aque-
ous solution) brine (1 × 10 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-
yellow oil. This material was subjected to flash chromatography
(silica, 80:18:2 v/v/v hexane/ethyl acetate/triethylamine elution)
and concentration of the appropriate fractions (RF 0.2) gave
either stilbene 43 or 44.
(S)-2-Methyl -1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)- 2ꢀ-(4ꢀꢀ-
tert-butyldipenylsilanoxyphenyl)prop-2ꢀ -enyl]piperidine ( 43)
(96.0 mg, 69%) was obtained as a clear oil, [α]1D8 +10.8◦ (c
0.5, MeOH)(Found: M+• 605.3338. C39H47NO3SirequiresM+•
605.3325). δH (300 MHz, CD3OD) 7.70 (4H, m), 7.46–7.33 (6H,
complex m), 6.94 (2H, d, J 8.7), 6.70 (2H, d, J 8.7), 6.65 (1H, d,
J 8.4), 6.53 (1H, dd, J 1.9 and 8.4), 6.45 (1H, s), 6.38 (1H, d, J
1.9), 3.72 (3H, s), 3.70 (1H, d, J 13.9), 3.35 (3H, s), 3.07 (1H,
d, J 13.9), 2.95–2.87 (1H, complex m), 2.26–2.15 (1H, complex
m), 2.04 (1H, dt, J 11.2 and 3.0), 1.66–1.12 (6H, complex m),
1.07 (9H, s), 0.96 (3H, d, J 6.2). δC (75 MHz, CD3OD) 156.1
(C), 149.4 (C), 149.2 (C), 138.6 (C), 136.6 (CH), 135.2 (C),
134.0 (C), 131.4 (C), 131.2 (CH), 131.1(6) (CH), 130.4 (CH),
128.9 (CH), 123.6 (CH), 120.9 (CH), 113.4 (CH), 112.2 (CH),
63.4 (CH2), 57.7 (CH2), 56.3 (CH3), 55.8 (CH3), 53.4 (CH),
47.0 (CH2), 35.3 (CH2), 27.0 (CH3), 26.7 (CH2), 25.1 (CH3),
20.2 (C). νmax (KBr)/cm−1 2932, 2858, 1603, 1506, 1464, 1428,
1257, 1114, 1029, 919, 701. m/z (EI, 70 eV) 605 (24%, M+•),
508 (29), 451 (25), 112 (100).
(R)-2-Methyl-1-[(2,3,6-trimethoxphenanthren-9-yl)methyl]
piperidine ( 28) (11.9 mg, 63%) was obtained as a light-yellow
and oily solid, mp 53–55◦C, [α]1D9 −36.7◦ (c 0.3, benzene). The
remaining spectroscopic data obtained on this material matched
those presented above for the corresponding S-enantiomer.
2-[4-(tert-Butyldiphenylsilanoxyphenyl)]-4,4,5,5-
tetramethyl[1,3,2]dioxaborolan (42)
tert-Butyldiphenylsilyl chloride (0.28 mL, 1.077 mmol) was
added, dropwise, to a magnetically stirred solution of boronate
41 (199 mg, 0.904 mmol, ex. Boron Molecular) and imidazole
(86 mg, 1.263 mmol) in DMF (1.0 mL) maintained at −30◦C
under an atmosphere of nitrogen. The ensuing mixture was then
allowed to warm to 18◦C and stirred at this temperature for 16 h
before being diluted with ethyl acetate (20 mL) washed with
brine/water (5 × 15 mL of a 1:1 v/v mixture) and then brine
(1 × 15 mL). The separated organic phase was dried (MgSO4)
then filtered and concentrated under reduced pressure to give a
light-brown and oily solid. This material was subjected to flash
chromatography (silica, 95:5 v/v hexane/ethyl acetate eluent)
and concentration of the relevant fractions (RF 0.3) gave the title
boronate 42 (279 mg, 67%) as a white, crystalline solid, mp 119–
120◦C (Found: M+• 458.2447. C 73.1, H 8.0. C28H3511BO3Si
requires M+• 458.2449. C 73.4, H 7.7%). δH (300 MHz, CDCl3)
7.79 (4H, m), 7.65 (2H, d, J 8.5), 7.49–7.37 (6H, complex m),
6.84 (2H, d, J 8.5), 1.34 (12H, s), 1.17 (9H, s). δC (75 MHz,
CDCl3) 158.3 (C), 136.2 (CH), 135.4 (CH), 132.6 (C), 129.9
(CH), 127.8 (CH), 119.2 (CH), 83.4 (C), 26.4 (CH3), 24.8 (CH3),
19.4 (C) (one signal obscured or overlapping). νmax (KBr)/cm−1
2980, 2933, 2895, 2860, 1603, 1516, 1472, 1428, 1397, 1360,
1319, 1143, 1113, 1090, 915, 859, 822, 733, 701, 654, 613. m/z
(EI, 70 eV) 458 (11%, M+•), 402 (52), 401 (100), 400 (44), 301
(24), 197 (41), 83 (31).
(R)-2-Methyl -1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ- dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-
tert-butyldipenylsilanoxyphenyl)prop-2ꢀ-enyl ]piperidine ( 44)
(104.3 mg, 73%) was obtained a clear, colourless oil, [α]1D8 −8.8◦
(c 0.9, MeOH). The remaining spectroscopic data obtained on
this material matched those presented above for the correspond-
ing S-enantiomer.
(S)- and (R)-2-Methyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-
dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-hydroxyphenyl)prop-2ꢀ-enyl]
piperidines (25 and 26, Respectively)
TBAF (70 µL of a 1 m solution in THF, 0.07 mmol) was
added, dropwise, to a magnetically stirred solution of cis-stilbene
43 or 44 (30.0 mg, 0.05 mmol) in THF (2.0 mL) maintained at
18◦C. The reaction mixture was then stirred under an atmo-
sphere of nitrogen for 0.5 h before being diluted with ethyl
acetate (15 mL). The organic phase was washed with water
(2 × 10 mL) and brine (1 × 10 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to give a
yellow oil. This material was then subjected to flash chromato-
graphy (silica, 90:9.5:0.5 v/v/v chloroform/methanol/ammonia
solution elution) and concentration of the appropriate frac-
tions (RF 0.3) gave the title alcohols in the yields specified
below.
(S)-2-Methyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-
hydroxyphenyl)prop-2ꢀ-enyl]piperidine ( 25) (15.9 mg, 87%)
was obtained as a yellow oil, [α]1D9 +26.1◦ (c 0.38, MeOH)
(Found: M+• 367.2151. C23H29NO3 requires M+• 367.2147).
δH (500 MHz, CD3OD) 7.07 (2H, d, J 8.5), 6.78 (2H, d, J 8.5),
6.73 (1H, d, J 8.3), 6.65 (1H, dd, J 1.9 and 8.3), 6.56 (1H, s), 6.43
(1H, d, J 1.9), 3.95 (1H, d, J 13.6), 3.74 (3H, s), 3.41 (3H, s), 3.34
(1H, d, J 13.6), 3.12 (1H, d, J 11.7), 2.51 (1H, br s), 2.30 (1H, t, J
10.7), 1.71–1.61 (3H, complex m), 1.57–1.47 (1H, complex m),
1.42–1.29 (2H, complex m), 1.12 (3H, d, J 6.3) (signal due to OH
proton not observed). δC (126 MHz, CD3OD) 158.3 (C), 149.4
(C), 136.8 (C), 132.2 (C), 131.8 (C), 131.4 (CH), 131.2 (C),
123.9 (CH), 116.8 (CH), 113.6 (CH), 112.2 (CH), 63.0 (CH2),
58.7 (CH), 56.3 (CH3), 55.7 (CH3), 53.3 (CH2), 34.4 (CH2), 25.9
(S)- and (R)-2-Methyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-
dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-tert-
butyldipenylsilanoxyphenyl)prop-2ꢀ-enyl]
piperidines (43 and 44, Respectively)
A magnetically stirred solution of the alkenyl bromide
38 or 39 (80.0 mg, 0.23 mmol), boronate ester 42 (207 mg,
0.45 mmol), ethanol (1.5 mL), and Na2CO3 (3.2 mL of a 2 m
aqueous solution) in benzene (11.5 mL) was treated with
PdCl2(dppf) (32.8 mg, 0.04 mmol) and the ensuing mixture
heated at reflux under an atmosphere of nitrogen for 6 h while
being protected from light. The cooled reaction mixture was
diluted with diethyl ether (20 mL) and the separated organic

516
M. O. Sydnes et al.
(CH2), 24.5 (CH2), 19.2 (CH3). νmax (KBr)/cm−1 3215 (broad),
2933, 2855, 2789, 1609, 1582, 1513, 1464, 1454, 1421, 1327,
1268, 1239, 1160, 1142, 1026, 841, 735. m/z (EI, 70 eV) 367
(32%, M+•), 270 (21), 269 (26), 112 (100).
was subjected to flash chromatography (silica, 90:9.5:0.5 v/v/v
chloroform/methanol/ammonia solution elution), and concen-
tration of the appropriate fractions (RF 0.3) gave the title phenols
in the yields specified below.
(R)-2-Methyl-1-[(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-
hydroxyphenyl)prop-2ꢀ-enyl]piperidine ( 26) (15.5 mg, 85%)
was obtained as a yellow oil, [α]1D9 −29.2◦ (c 0.39, MeOH). The
remaining spectroscopic data obtained on this material matched
those presented above for the corresponding S-enantiomer.
(S)-2-Methyl-1-[(2,3-dimethoxy-6-hydroxyphenanthren-9-yl)
methyl]piperidine ( 29) (8.9 mg, 82%) was obtained as a yel-
low oil, [α]1D8 +44.5◦ (c 0.1, MeOH). (Found: M+• 365.2001.
C23H27NO3 requires M+• 365.1991). δH (300 MHz, CD3OD)
8.19 (1H, d, J 9.0), 7.86 (1H, d, J 2.5), 7.85(8) (1H, s), 7.40
(1H, s), 7.23 (1H, s), 7.09 (1H, dd, J 2.5 and 9.0), 4.57 (1H, d, J
13.0), 4.00 (3H, s), 3.95 (3H, s), 3.40 (1H, d, J 13.0), 2.82–2.70
(1H, complex m), 2.49 (1H, m), 2.07 (1H, m), 1.76–1.61 (2H,
complex m), 1.59–1.30 (4H, complex m), 1.35 (3H, d, J 6.2) (sig-
nal of OH proton not observed). δC (500 MHz, CD3OD) 157.0,
150.8, 150.3, 133.5, 132.1, 128.5, 128.1, 126.2, 126.0, 125.4,
116.8, 109.5, 107.1, 104.8, 59.4, 58.4, 56.4, 56.3, 53.3, 35.5,
29.2, 26.7, 21.8. νmax (KBr)/cm−1 3434 (br), 2933, 1610, 1511,
1467, 1260, 1241, 1202, 1158. m/z (EI, 70 eV) 365 (17%, M+•),
350 (8), 268 (50), 267 (100).
(S)- and (R)-2-Methyl-1-[(2,3-dimethoxy-6-tert-
butyldiphenylsilanoxyphenanthren-9-
yl)methyl]piperidines (45 and 46, Respectively)
VOF3 (32.1 mg, 0.26 mmol) was added to a magnetically
stirred solution of cis-stilbene 43 or 44 (30.0 mg, 0.05 mmol)
in dichloromethane (2.3 mL) maintained at 0◦C under an atmo-
sphere of nitrogen. The reaction mixture was stirred for 0.25 h
before trifluoroacetic acid (0.05 mL, 0.66 mmol) was added
dropwise. The reaction mixture was stirred for an additional
0.25 h at 0◦C before the reaction mixture was poured into
NaOH (10 mL of a 10% aqueous solution) and the ensuing mix-
ture stirred vigorously for 5 min. The aqueous phase was then
extracted with dichloromethane (3 × 15 mL) and the combined
organic phases were dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil. This material was
subjected to flash chromatography (silica, 95:4.25:0.75 v/v/v
dichloromethane/methanol/ammonia solution elution), and con-
centration of the relevant fractions (RF 0.3) under reduced
pressure gave the title phenanthrenes in the yields specified
below.
(S)-2-Methyl-1-[(2,3-dimethoxy-6-tert-butyldiphenylsilan-
oxyphenanthrene-9-yl)methyl]piperidine ( 45) (17.5 mg, 58%)
was obtained as a yellow oil, [α]1D7 +16.1◦ (c 0.3, benzene)
(Found: M+• 603.3170. C39H45NO3Si requires M+• 603.3169).
δH (500 MHz, C6D6) 8.51 (1H, d, J 9.3), 8.16 (1H, d, J 2.4), 7.90
(4H, m), 7.60 (1H, s), 7.46 (1H, s), 7.40 (1H, dd, J 2.4 and 9.3),
7.10 (6H, m), 7.00 (1H, s), 4.46 (1H, d, J 13.2), 3.47 (3H, s), 3.43
(3H, s), 3.30 (1H, d, J 13.2), 2.78 (1H, m), 2.28 (1H, br s), 1.94
(1H, t, J 9.3), 1.59–1.48 (2H, complex m), 1.43–1.12 (4H, com-
plex m), 1.25 (9H, s), 1.14 (3H, d, J 6.8). δC (126 MHz, C6D6)
154.5, 150.5, 149.9, 136.0, 135.9, 135.8, 133.6(2), 133.6(0),
132.4, 132.1, 130.2, 126.5, 125.4, 124.7, 119.7, 111.7, 108.8,
103.9, 58.4, 57.8, 55.4, 55.2, 52.3, 35.1, 26.9, 26.5, 24.2, 19.8,
18.8. νmax (KBr)/cm−1 2932, 1608, 1509, 1465, 1428, 1250,
1235, 1202, 1159, 1114, 935, 855, 822, 701. m/z (EI, 70 eV) 603
(14%, M+•), 507 (36), 506 (100), 505 (82), 449 (34), 224 (33).
(R)-2-Methyl-1-[(2,3-dimethoxy-6-tert-butyldiphenylsilan-
oxyphenanthren-9-yl)methyl]piperidine ( 46) (20.5 mg, 68%)
was obtained as a yellow oil, [α]1D9 −15.7◦ (c 0.4, benzene). The
remaining spectroscopic data obtained on this material matched
those presented above for the corresponding S-enantiomer.
(R)-2-Methyl-1-[(2,3-dimethoxy-6-hydroxyphenanthren-9-yl)
methyl]piperidine ( 30) (10.2 mg, 93%) was obtained as a yellow
oil, [α]1D9 −44.7◦ (c 0.4, MeOH). The remaining spectroscopic
data obtained on this material matched those presented above
for the corresponding S-enantiomer.
(E)-3,4-Dimethoxy-(4-methoxyphenyl)cinnamic
Acid (49)
A solution of 3,4-dimethoxybenzaldehyde (47) (11.20 g,
67.4 mmol), 4-methoxyphenylacetic acid (48) (11.20 g,
67.4 mmol), acetic anhydride (25 mL), and triethylamine
(12 mL) was heated at reflux for 2.5 h under an atmosphere of
nitrogen. The reaction mixture was then cooled to 18◦C and
NaOH (100 mL of a 5% w/w aqueous solution) was added.
The water phase was extracted with diethyl ether (1 × 50 mL)
and then neutralized with acetic acid, and the aqueous layer
was extracted with ethyl acetate (2 × 50 mL). The combined
organic fractions were washed with water (1 × 50 mL) and brine
(1 × 50 mL) before being dried over MgSO4. Filtration and con-
centration under reduced pressure followed by recrystallization
of the ensuing solid (methanol) gave the title acid 49[6a,12]
(9.42 g, 45%) as a light-yellow solid, mp 212–213◦C (lit.[6a]
213–214◦C) (Found: M+• 314.1149. C18H18O5 requires M+•
314.1154). δH (300 MHz, CDCl3) 7.84 (1H, s), 7.18 (2H, d, J
8.8), 6.94 (2H, d, J 8.8), 6.84 (1H, dd, J 2.1 and 8.5), 6.72 (1H,
d, J 8.5), 6.50 (1H, d, J 2.1), 3.83 (3H, s), 3.80 (3H, s), 3.44 (3H,
s) (signal of carboxylic acid proton not observed). δC (75 MHz,
CDCl3) 173.3 (COO), 159.2 (C), 150.2 (C), 148.1 (C), 142.2
(CH), 131.2 (CH), 128.7 (C), 127.9 (C), 127.2 (C), 125.8 (CH),
114.3 (CH), 112.4 (CH), 110.4 (CH), 55.8 (CH3), 55.3 (CH3),
55.1 (CH3). νmax (KBr)/cm−1 2953, 2936, 2908, 2837, 2611,
1666, 1597, 1574, 1509, 1465, 1424, 1291, 1267, 1244, 1202,
1174, 1145, 1022, 805. m/z (EI, 70 eV) 314 (100%, M+•), 252
(19), 237 (20), 210 (23), 209 (39).
(S)- and (R)-2-Methyl-1-[(2,3-dimethoxy-6-
hydroxyphenanthren-9-yl)methyl]piperidine
(29 and 30, Respectively)
(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-Dimethoxyphenyl)-2ꢀ-
TBAF (40 µL of a 1 m solution inTHF, 0.04 mmol) was added
dropwise to a magnetically stirred solution of phenanthrene 45
or 46 (17.0 mg, 0.03 mmol) inTHF (1.0 mL) maintained at 18◦C.
The reaction mixture was then stirred under an atmosphere of
nitrogenfor0.5 hbeforebeingdilutedwithethylacetate(15 mL).
The organic phase was washed with water (2 × 10 mL) and brine
(1 × 10 mL) before being dried (MgSO4), filtered, and concen-
trated under reduced pressure to give a yellow oil. This material
(4ꢀꢀ-methoxyphenyl)prop-2ꢀ-enyl)dimethyl Amide (50)
Oxalyl chloride (0.083 mL, 0.95 mmol) was added drop-
wise to a magnetically stirred solution of acid 49 (100 mg,
0.318 mmol) in THF (3 mL) maintained at 18◦C. After the
initial vigorous reaction had subsided the reaction mixture
was heated at reflux for 0.66 h and then cooled and concen-
trated under reduced pressure. Dimethylamine (3.4 mL of a

Analogues of Cryptopleurine and Julandine
517
2 m solution in THF, 6.8 mmol) was then added to the ensu-
ing concentrate and the resulting mixture was stirred for 16 h at
18◦C before water (10 mL) was added. The aqueous phase was
extracted with dichloromethane (3 × 10 mL) and the combined
organic fractions were then dried (MgSO4), filtered, and concen-
trated under reduced pressure gave a dark-yellow oil that was
subjected to flash chromatography (silica, 95:4.25:0.75 v/v/v
dichloromethane/methanol/ammonia solution eluent). Concen-
tration of the relevant fractions (RF 0.3) gave the title amide 50
(74.1 mg, 68%) as a viscous yellow oil (Found: M+• 341.1629.
C20H23NO4 requires M+• 341.1627). δH (300 MHz, CDCl3)
7.23 (2H, d, J 8.5), 6.78 (2H, d, J 8.5), 6.70 (1H, dd, J 1.8 and
8.4), 6.65 (1H, d, J 8.4), 6.57 (1H, d, J 1.8), 6.52 (1H, s), 3.77
(3H, s), 3.72 (3H, s), 3.47 (3H, s), 2.94 (6H, s). δC (75 MHz,
CDCl3) 171.8 (CO), 159.0 (C), 148.4 (C), 147.9 (C), 135.5 (C),
130.1 (CH), 128.9 (CH), 128.1 (C), 127.9 (C), 122.5 (CH), 113.9
(CH), 111.7 (CH), 110.4 (CH), 55.6 (CH3), 55.2 (CH3), 55.1
(CH3), 38.5 (CH3), 34.9 (CH3). νmax (KBr)/cm−1 3476, 3002,
2935, 2837, 1633, 1512, 1463, 1393, 1289, 1248, 1165, 1137,
1027, 840, 799, 730. m/z (EI, 70 eV) 341 (99%, M+•), 269 (100),
194 (55).
dichloromethane/methanol/ammonia solution elution) and con-
centration of the relevant fractions (RF 0.2) under reduced
pressure gave the title phenanthrene 31[13] (25.7 mg, 56%) as
a white solid, mp 139–140◦C (lit.[13] 139◦C) (Found: M+•
325.1678. C20H23NO3 requires M+• 325.1678). δH (300 MHz,
C6D6) 8.59 (1H, d, J 9.1), 8.06 (1H, d, J 2.5), 7.90 (1H, s), 7.50
(1H, s), 7.31 (1H, dd, J 2.5 and 9.1), 7.03 (1H, s), 3.76 (2H, s),
3.54 (3H, s), 3.53 (3H, s), 3.52 (3H, s), 2.21 (6H, s). δC (75 MHz,
C6D6) 158.6 (C), 150.6 (C), 150.1 (C), 132.5 (C), 131.9 (C),
128.2 (CH), 127.8 (C), 126.2 (C), 125.3 (CH), 124.9 (C), 115.1
(CH), 108.9 (CH), 104.7 (CH), 104.5 (CH), 63.9 (CH2), 55.5
(CH3), 55.2 (CH3), 54.9 (CH3), 45.5 (CH3). νmax (KBr)/cm−1
3476, 3293, 2938, 2855, 2815, 2768, 1697, 1611, 1513, 1467,
1430, 1253, 1232, 1208, 1159, 1070, 1038. m/z (EI, 70 eV) 325
(31%, M+•), 282 (38), 281 (100), 149 (36), 58 (57).
(E)-3,4-Dimethoxy-(4-methoxyphenyl)cinnamic
Acid Methyl Ester (53)
Oxalyl chloride (0.43 mL, 4.93 mmol) was added dropwise to
a magnetically stirred solution of acid 49 (524 mg, 1.67 mmol)
in THF (15 mL) at 18◦C. After the initial vigorous reaction sub-
sided the reaction mixture was heated at reflux for 0.66 h and
then cooled and concentrated under reduced pressure. The con-
centrate was diluted with methanol (20 mL) and the resulting
mixture stirred at 18◦C for 16 h and then diluted with ethyl
acetate (50 mL) and washed with water (2 × 30 mL) and brine
(1 × 30 mL) before being dried (MgSO4). Filtration and concen-
tration of the filtrate under reduced pressure gave a red oil that
was subjected to flash chromatography (silica, 7:3 v/v hexane/
ethyl acetate). Concentration of the relevant fractions (RF 0.4)
gave a pink wax that was triturated (methanol) to give the title
est◦er 53[24] (496 mg, 91%) as a white crystalline solid, mp 91–
92 C (Found: M+• 328.1301. C 69.7, H 6.1. C19H20O5 requires
M+• 328.1311. C 69.5, H 6.1%). δH (300 MHz, CDCl3) 7.71
(1H, s), 7.11 (2H, d, J 8.8), 6.88 (2H, d, J 8.8), 6.76 (1H, dd, J
1.9 and 8.4), 6.64 (1H, d, J 8.4), 6.41 (1H, d, J 1.9), 3.74 (3H,
s), 3.73 (3H, s), 3.70 (3H, s), 3.38 (3H, s). δC (75 MHz, CDCl3)
168.2 (CO), 158.8 (C), 149.5 (C), 147.7 (C), 140.0 (C), 130.8
(C), 129.3 (CH), 128.1 (CH), 127.2 (CH), 125.0 (C), 113.9 (CH),
112.0 (CH), 110.1 (CH), 55.4 (CH3), 54.9 (CH3), 54.7 (CH3),
51.9 (CH3). νmax (KBr)/cm−1 3002, 2951, 2838, 1701, 1599,
1577, 1513, 1464, 1436, 1422, 1333, 1253, 1174, 1144, 1025.
m/z (EI, 70 eV) 328 (100%, M+•), 269 (12), 181 (45).
(E)-3ꢀ-(3ꢀꢀ,4ꢀꢀ-Dimethoxyphenyl)-2ꢀ-(4ꢀꢀ-
methoxyphenyl)prop-2ꢀ-enyl)dimethyl Amine (51)
A solution of the amide 50 (70.0 mg, 0.205 mmol) in THF
(6 mL) was added dropwise to a magnetically stirred suspen-
sion of LiAlH4 (46.0 mg, 1.21 mmol) maintained at 0◦C. The
ensuing mixture was stirred at 18◦C for 2 h and then quenched
with KOH (30%, w/w aqueous solution, 14 mL). The aque-
ous phase was extracted with diethyl ether (2 × 20 mL) before
the organic fractions were combined, and then dried (MgSO4),
filtered, and concentrated under reduced pressure to give a light-
yellow oil. Subjection of this material to flash chromatography
(silica, 95:4.25:0.75 v/v/v dichloromethane/methanol/ammonia
solution elution) and concentration of the relevant fractions (RF
0.2)underreducedpressuregavethetitlecompound 51(49.7 mg,
74%) as a clear oil (Found: M+• 327.1834. C20H25NO3 requires
M
+• 327.1834). δH (300 MHz, CD3OD) 7.14 (2H, d, J 8.8), 6.89
(2H, d, J 8.8), 6.72 (1H, d, J 8.3), 6.63 (1H, dd, J 1.9 and 8.3), 6.50
(1H, s), 6.43 (1H, d, J 1.9), 3.76 (3H, s), 3.73 (3H, s), 3.40 (3H,
s), 3.31 (2H, d, J 1.1), 2.22 (6H, s). δC (75 MHz, CD3OD) 160.5
(C), 149.4 (C), 149.3 (C), 138.3 (C), 133.6 (C), 131.2 (CH),
130.7 (CH), 123.8 (CH), 115.3 (CH), 113.4 (CH), 112.2 (CH),
69.5 (CH2), 56.2 (CH3), 55.7 (CH3), 55.6 (CH3), 45.4 (CH3)
(one signal obscured or overlapping). νmax (KBr)/cm−1 3476,
3294, 2938, 2852, 2836, 2815, 2771, 1696, 1606, 1580, 1512,
1464, 1267, 1243, 1174, 1161, 1142, 1028. m/z (EI, 70 eV) 328
(55%), 327 (93, M+•), 312 (50), 284 (43), 283 (66), 58 (100).
Methyl 5ꢀ,6ꢀ-Dimethoxy-4-oxospiro[cyclohexa
(2,5)diene-1,1ꢀ-indene]-2ꢀ-carboxylate (54) and
Methyl 2,3,6-Trimethoxy-[7,5ꢀ]-(methyl
2ꢀ,3ꢀ,6ꢀ-trimethoxyphenanthrene-9-
carboxylate)phenanthrene-9-carboxylate (55)
[(2,3,6-Trimethoxyphenanthren-9-
yl)methyl]dimethylamine (31)
Method A: A solution of VOF3 (130 mg, 1.05 mmol) in TFA
(3.3 mL) and ethyl acetate (1.7 mL) was added dropwise to a
magnetically stirred solution of ester 53 (100 mg, 0.305 mmol)
in TFA (4.5 mL) and dichloromethane (3.0 mL) maintained at
0◦C under an atmosphere of nitrogen. The reaction mixture was
stirred at 0◦C for 0.33 h before being poured into citric acid
(50 mL of a 5% aqueous solution) and the pH was then adjusted
to 8 by adding ammonia (28% v/v aqueous solution). The water
phase was extracted with dichloromethane (3 × 40 mL) and the
combined organic fractions were washed with water (1 × 50 mL)
and brine (1 × 50 mL) before being dried (MgSO4), filtered, and
concentrated under reduced pressure to give a yellow oil that was
subjected to flash chromatography (silica, 6:4 v/v hexane/ethyl
acetate elution). Concentration of the relevant fractions (RF 0.2)
VOF3 (78.0 mg, 0.63 mmol) was added to a magnetically
stirred solution of cis-stilbene 51 (46.5 mg, 0.142 mmol) in
dichloromethane (6 mL) maintained at 0◦C under an atmosphere
of nitrogen. The reaction mixture was stirred for 0.25 h before
being treated, dropwise, with trifluoroacetic acid (0.14 mL,
1.82 mmol), stirred for an additional 0.25 h at 0◦C, and then
poured into NaOH (20 mL of a 10% aqueous solution) and
stirred vigorously for 5 min. The separated aqueous phase was
extracted with dichloromethane (3 × 20 mL) and the combined
organic phases were dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil. Subjection of this
material to flash chromatography (silica, 95:4.25:0.75 v/v/v

518
M. O. Sydnes et al.
gave the title spirodienone 54 (15 mg, 16%) as a light-yellow
solid, mp211–212◦C(Found:M+• 312.0996. C18H16O5 requires
M+• 312.0998). δH (500 MHz, CDCl3) 7.87 (1H, s), 7.04 (1H,
s), 6.62 (1H, s), 6.51 (2H, d, J 9.8), 6.33 (2H, d, J 9.8), 3.91 (3H,
s), 3.84 (3H, s), 3.72 (3H, s). δC (126 MHz, CDCl3) 186.4 (CO),
163.2 (C), 151.3 (C), 150.1 (C), 147.4 (CH), 144.8 (CH), 137.4
(C), 135.5 (C), 134.4 (C), 130.6 (CH), 106.6 (CH), 106.5 (CH),
56.3(CH3), 56.2(CH3), 51.7(CH3)(onesignalobscuredorover-
lapping). νmax (KBr)/cm−1 1703, 1672, 1605, 1552, 1497, 1465,
1324, 1283, 1238, 1219, 1183, 1107, 1039, 1030, 852. m/z (EI,
70 eV) 312 (48%, M+•), 284 (49), 225 (100), 181 (32), 57 (40).
Method B: A solution of ester 53 (29 mg, 0.09 mmol) in TFA
(1.3 mL) and dichloromethane (0.75 mL) was stirred at 0◦C for
1 h and then a solution of VOF3 (38.2 mg, 0.308 mmol) in TFA
(0.8 mL) and ethyl acetate (0.4 mL) was added dropwise. The
ensuing mixture was then stirred an additional 0.33 h at 0◦C
before being poured into citric acid (10 mL of a 5% aqueous
solution) and the pH was then adjusted to 8 by addition of
ammonia (28% v/v aqueous solution).The separated water phase
was extracted with dichloromethane (3 × 15 mL) and the com-
bined organic fractions were then dried (MgSO4), filtered, and
concentration under reduced pressure to give a yellow oil. This
material was subjected to flash chromatography (silica, 6:4 v/v
hexane/ethyl acetate elution) and thus affording two fractions,
A and B.
give a brown oil. Subjection of this material to flash chro-
matography (silica, 4:1 hexane/ethyl acetate) afforded fractions
A and B.
Concentration of fraction A [RF 0.3(2)] afforded compound
56[25] (316 mg, 70%) as a yellow oil (Found: M+• 270.1253.
C17H18O3 requires M+• 270.1256). δH (300 MHz, CDCl3) 7.20
(2H, d, J 8.8), 6.82–6.68 (5H, complex m), 6.42 (2H, d, J 1.5),
3.80 (3H, s), 3.71 (3H, s), 3.61 (3H, s). δH (300 MHz, C6D6)
7.30 (2H, d, J 8.9), 6.94 (1H, partially obscured dd, J 2.1 and
7.8), 6.92 (1H, s), 6.64 (2H, d, J 8.9), 6.51 (2H, d, J 1.0), 6.49
(1H, partially obscured dd, J 7.8), 3.34 (3H, s), 3.27 (3H, s),
3.23 (3H, s). δC (75 MHz, CDCl3) 158.3 (C), 148.0 (C), 147.7
(C), 129.8(5) (CH), 129.8(1) (C), 129.6 (C), 128.3 (CH), 128.2
(CH), 121.4 (CH), 113.2 (CH), 111.3 (CH), 110.5 (CH), 55.4
(CH3), 55.1 (CH3), 54.8 (CH3). νmax (KBr)/cm−1 3003, 2953,
2835, 1606, 1580, 1505, 1463, 1418, 1254, 1172, 1134, 1027,
871, 816, 787, 766. m/z (EI, 70 eV) 270 (100%, M+•), 255 (27).
Concentration of fraction B [RF 0.2(8)] afforded compound
57[25] (23.6 mg, 5%) as a white crystalline solid, mp 136–137◦C
(lit.[25] 135–137◦C) (Found: M+• 270.1252. C17H18O3 requires
M
+• 270.1256). δH (300 MHz, CDCl3) 7.42 (2H, d, J 8.8), 7.04–
6.99 (2H, complex m), 6.91–6.82 (5H, complex m), 3.93 (3H,
s), 3.88 (3H, s), 3.81 (3H, s). δH (300 MHz, C6D6) 7.37 (2H, d, J
8.8), 7.04–7.00 (4H, complex m), 6.82 (2H, d, J 8.8), 6.62 (1H,
d, J 8.8), 3.46 (3H, s), 3.41 (3H, s), 3.32 (3H, s). δC (75 MHz,
CDCl3) 159.0 (C), 149.0 (C), 148.5 (C), 130.7 (C), 130.2 (C),
127.4 (CH), 126.3(1) (CH), 126.2(8) (CH), 119.4 (CH), 114.0
(CH), 111.1 (CH), 108.4 (CH), 55.9 (CH3), 55.8 (CH3), 55.3
(CH3). νmax(KBr)/cm−1 1607, 1514, 1264, 1226, 1173, 1153,
1140, 1024, 956, 839, 815. m/z (EI, 70 eV) 270 (100%, M+•),
255 (27).
Concentration of fraction A (RF 0.2) afforded compound 54
(7.4 mg, 27%) that was identical, in all respects, with the material
obtained by Method A.
Concentration of fraction B (RF 0.1) gave the title dimer
55 (19.1 mg, 66%) as a light-yellow solid, mp 230–231◦C
(Found: M+• 650.2150. C38H34O10 requires M+• 650.2152). δH
(500 MHz, CDCl3) 9.00 (1H, d, J 9.5), 8.83 (1H, s), 8.33 (1H,
s), 8.23 (1H, s), 8.00 (1H, s), 7.89 (1H, s), 7.42 (1H, d, J 9.5),
7.33 (1H, s), 7.31 (1H, s), 7.15 (1H, s), 4.16 (3H, s), 4.06 (3H, s),
4.03 (3H, s), 3.90 (3H, s), 3.85 (3H, s), 3.84 (3H s), 3.80 (s, 3H),
2.74 (3H, s). δC (126 MHz, CDCl3) 168.6 (CO), 167.9 (CO),
156.9 (C), 156.3 (C), 151.1 (C), 149.7 (C), 148.9 (C), 148.4
(C), 131.2 (C), 130.9 (C), 130.8 (C), 130.0 (CH), 129.9 (CH),
129.7 (CH), 127.8 (CH), 127.5 (C), 126.9 (C), 126.6 (C), 125.6
(C), 124.6 (C), 124.3 (C), 124.0 (C), 123.9 (C), 122.5 (C), 112.3
(CH), 109.4 (CH), 109.0 (CH), 108.9 (CH), 102.9 (CH), 102.4
(CH), 56.8 (CH3), 56.1 (CH3), 56.0 (CH3), 55.9 (CH3), 55.7
(CH3), 54.4 (CH3), 52.2 (CH3), 52.0 (CH3). νmax (KBr)/cm−1
1711, 1616, 1516, 1466, 1432, 1242, 1192, 1144, 1115. m/z (EI,
70 eV) 650 (11%, M+•), 530 (4), 304 (31), 245 (100), 227 (36),
199 (65), 185 (46), 135 (49).
2,3,6-Trimethoxyphenanthrene (32)
Air was bubbled through a magnetically stirred solution of
cis-stilbene 56 (20.6 mg, 0.0763 mmol) in diethyl ether (35 mL)
and dichloromethane (1 mL) for 10 min. A catalytic amount of
iodine (2 mg) was then added and the reaction mixture was irra-
diated for 2 h with a medium pressure Hg vapour lamp. The
crude product was then concentrated on silica and submitted to
flash chromatography (silica, 4:1 v/v hexane/ethyl acetate elu-
tion). Concentration of the relevant fractions (RF 0.2) gave the
title phenanthrene 32[17] (10.5 mg, 51%) as a light-yellow solid,
mp 128–129◦C (lit.[17] 132–133◦C) (Found: M+• 268.1100.
C17H16O3 requires M+• 268.1099). δH (300 MHz, CDCl3) 7.87
(1H, s), 7.85 (1H, d, J 2.5), 7.78 (1H, d, J 8.8), 7.58 (1H, d, J 8.7),
7.50 (1H, d, J 8.7), 7.21 (1H, s), 7.18 (1H, dd, J 2.5 and 8.8),
4.10 (3H, s), 4.03 (3H, s), 4.01 (3H, s). δC (75 MHz, CDCl3)
158.1 (C), 149.3 (C), 149.0 (C), 130.9 (C), 130.1 (CH), 127.5
(C), 126.1 (C), 124.9 (CH), 124.1 (C), 123.6 (CH), 115.3 (CH),
108.2 (CH), 103.8 (CH), 103.2 (CH), 56.0 (CH3), 55.9 (CH3),
55.5 (CH3). νmax (KBr)/cm−1 1622, 1608, 1513, 1463, 1267,
1218, 1201, 1160, 1102, 1032, 862, 835. m/z (EI, 70 eV) 268
(100%, M+•), 253 (8), 225 (14), 182 (16), 139 (15).
(Z)-1-(4-Methoxyhenyl)-2-(3,4-dimethoxyphenyl)
ethene (56) and
(E)-1-(4-Methoxyphenyl)-2-(3,4-
dimethoxyphenyl)ethene (57)
Anhydrous CuSO4 (590 mg, 3.70 mmol) was added to a solu-
tion of acid 49 (523 mg, 1.67 mmol) in freshly distilled quinoline
(16 mL). While being maintained under an atmosphere of nitro-
gen, the reaction mixture was heated at reflux for 1 h and
then cooled to 18◦C and poured into HCl (150 mL of a 2 m
aqueous solution). The aqueous phase was extracted with ben-
zene (3 × 100 mL) and the combined organic fractions were
then washed with NaOH (1 × 100 mL of a 0.2 m aqueous solu-
tion), water (1 × 100 mL), brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure to
X-Ray Crystallographic Study on Compound 54
Crystal Data
C18H16O5, M 312.32, T 200(1) K, monoclinic, space group
P21/a, Z 4, a 7.1178(2), b 13.6458(4), c 15.9051(5) Å, β
95.471(2)◦,V 1537.79(8) Å3, Dx 1.349 g cm−3, 3506 unique data
(2θmax 55.0◦), 2835 with I > 3.0σ(I), R 0.051; Rw 0.066, S 1.68.

Analogues of Cryptopleurine and Julandine
519
Structure Determination
(maximum final concentration of test compound 100 µg mL−1
)
and each treatment was performed in six wells. Control cultures
received medium that contained 1% DMSO but without any test
compound. Vessels were cultured at 37◦C in 5% CO2 in air for
5 days and the medium, with or without test compound, was
changed on day 4. Vessel growth was quantified manually under
40× magnification on day 5, with growth being estimated as the
percentage of the field (×40) around the vessel fragment that
was occupied by vessel outgrowths.
Images were measured on a Nonius Kappa CCD diffracto-
meter (MoKα, graphite monochromator, λ 0.71073 Å) and data
extracted using the DENZO package.[26] The structure was
solved by direct methods (SIR92).[27] The crystal studied was
a 0.688(4) : 0.312 twin. The constrained least-squares refine-
ment program RAELS2000[28] was used because it could account
for the partial overlap of reflections arising from the twinning
perpendicular to c∗. Details are given in the deposited material.
Atomic coordinates, bond lengths and angles, and displace-
ment parameters have been deposited at the Cambridge Crys-
tallographic Data Centre (CCDC number 681077). These data
can be obtained free of charge from www.ccdc.cam.ac.uk/data_
request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Acknowledgements
We thank the Institute of Advanced Studies for financial support including
the provision of a PhD Scholarship to MOS. Dr Paul Savage of CSIRO
Molecular Science (Melbourne) is thanked for providing an authentic sample
of the alkaloid cryptopleurine (1). CRP andAB are supported by an NHMRC
Program grant.
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