The synthesis of 2-benzazocines using ring-closing metathesis as a key step

Article abstract of DOI:10.1016/j.tet.2007.03.087

A number of protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benzazocines were synthesized from 2-allyl-3-isopropoxy-4-methoxybenzaldehyde using ring-closing metathesis as the key step. In addition, two 9-isopropoxy-8-methoxy-3,6-dihydro-2-benzazocin

Full text of DOI:10.1016/j.tet.2007.03.087

Tetrahedron 63 (2007) 4737–4747
The synthesis of 2-benzazocines using ring-closing metathesis
as a key step
Jenny-Lee Panayides,a Rakhi Pathak,a Helen Panagiotopoulos,b Hajierah Davids,b,y
Manuel A. Fernandes,a,z Charles B. de Koninga and Willem A. L. van Otterloa,
*
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, 1 Jan Smuts Avenue,
Johannesburg, Gauteng, South Africa
bDepartment of Pharmacy and Pharmacology, University of the Witwatersrand, 7 York Road,
Parktown, 2193, Gauteng, South Africa
Received 8 December 2006; revised 22 February 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—A number of protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benzazocines were synthesized from 2-allyl-3-isopropoxy-
4-methoxybenzaldehyde using ring-closing metathesis as the key step. In addition, two 9-isopropoxy-8-methoxy-3,6-dihydro-2-benzazocines
were synthesized from 5-isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-propenyl]benzaldehyde, which in turn was obtained from the thermal
Claisen–Cope rearrangement of 4-methoxy-3-{[(2E)-3-phenyl-2-propenyl]oxy}benzaldehyde. Finally, five of the 2-benzazocine compounds
were tested for anti-cancer activity.
Ó 2007 Elsevier Ltd. All rights reserved.
CF3
1. Introduction
O
Ph
The benzacocines are a class of benzo-fused nitrogen-
containing compounds with an eight-membered heterocyclic
ring. Members of this family of compounds include the
1-benzazocine 1 and 2-benzazocine 2 skeletons as shown
in Figure 1.
R1
R2
O
N
N
CF3
X
Y
O
3
4
X, Y = CH or N;
R1, R2 = variety of groups
Benzo-fused heterocycles have long been considered privi-
leged structures in medicinal chemistry.1 Examples include
compound 3 (Fig. 2), an unsaturated 1-benzazocine analogue
that has previously been synthesized by way of a ring-closing
metathesis (RCM) reaction. This compound was investigated
alongside a number of other pharmaceutically interesting
benzo-fused scaffolds containing 7-, 8-, 9- and 10-membered
heterocycles.2 The literature also describes the use of
1,2,3,4,5,6-hexahydro-2-benzazocine 1 (Fig. 1) as a bicyclic
Figure 2.
benzylamine-type inhibitor of phenylethanolamine N-
methyltransferase.3 This compound was made as an ana-
logue of some potent known 1,2,3,4-tetrahydroisoquinoline
inhibitors and still displayed reasonable activity in inhibiting
the N-methyltransferase enzyme. Other compounds contain-
ing an annulated eight-membered nitrogen-containing het-
erocycle can be represented by the generalized example 4
(Fig. 2). These compounds have been recently used as selec-
tive NK1 antagonists4 and this demonstrates that related
structures frequently contain other heteroatoms (in this
case oxygen) and other features (e.g., an additional carbonyl
group).
H
N
NH
1
2
Figure 1.
* Corresponding author. Tel.: +27 11 717 6707; fax: +27 11 717 6749;
e-mail: willem@chem.wits.ac.za
Author for anti-cancer activity correspondence. E-mail: hajierah.davids@
In terms of natural products, a number of interesting com-
pounds with structural similarities to 2, have been isolated.
Examples include buflavin 5 and its demethylated derivative
6 (Fig. 3), compounds isolated from an endemic South
African Amaryllidaceae species.5 In addition, compounds
y
wits.ac.za
Author for crystallographic correspondence. E-mail: manuel@hobbes.gh.
wits.ac.za
z
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.087

4738
J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
procedure (Scheme 1).11 At this point we decided to protect
NR
the secondary amine 13 with a variety of protecting groups.
This was done so that we could investigate the impact of the
various amine-protecting groups on the subsequent metath-
esis reactions, as well as to allow us to investigate the ease
of deprotection of the final benzo-fused heterocycles. Com-
pound 13 was successfully converted to the corresponding
acetyl-14a, Boc-14b, benzyl sulfonamide-14c and tosyl-
protected 14d derivatives. The key RCM step, involving
the precursors 14a–d, proceeded smoothly within 1 h, to
furnish the 2-benzazocines 15a–d in good yields ranging
from 82 to 99%.
5 R = Me
6 R = H
MeO
MeO
NHAc
O
MeO
7
OMe
CHO
(a)
N
O
MeO
MeO
H
H
N
MeO
N
MeO
MeO
MeO
OiPr 12
(c)
OiPr
(b)
11
H
N
MeO
MeO
MeO
MeO
OMe
OMe
OiPr
13
R
N
8
9
R
N
Figure 3.
(d)
MeO
MeO
OiPr
OiPr
8 and 9, with similar structures to 5 and 6, have been synthe-
sized from the well-known naturally-occurring anti-cancer
agent colchicine 7.6 These compounds were then tested for
their ability to inhibit tubulin assembly and some were tested
for their cytotoxicity.
14a-d
15a-d
Scheme 1. Reagents and conditions: (a) allyl amine, 0.1 equiv p-TsOH,
benzene, Dean–Stark, reflux, 18 h; (b) NaBH4, MeOH, 0 ꢀC, 1 h (90%
over two steps) or (a) allyl amine, solvent-free, rt, 24 h; (b) NaBH4,
MeOH, 0 ꢀC, 1.5 h (81% over two steps); (c) R¼Ac, acetic anhydride, pyr-
idine, rt, 3 h, 14a (92%), R¼Boc, Boc2O, DMAP, THF, rt, 3 h, 14b (97%),
R¼SO2Bn, benzylsulfonyl chloride, NEt3, CH2Cl2, rt, 3 h, 14c (62%),
R¼Ts, tosyl chloride, NEt3, CH2Cl2, 0 ꢀC, 3.5 h, 14d (94%); (d) 5 mol %
catalyst 10, toluene, 60 ꢀC, 1 h, 15a, R¼Ac (82%), 15b, R¼Boc (99%),
15c, R¼SO2Bn (84%), 15d, R¼Ts (98%).
Thus it should come as no surprise that strategies towards the
synthesis of these scaffolds have seen much development in
the last few years. As one of the plethora of approaches, the
synthesis of benzo-fused ring systems has been readily ac-
complished using RCM.7 A number of research groups,
including ours,8 have been successful in applying RCM,
mediated by catalysts such as the Grubbs second generation
catalyst 10 (Fig. 4), for the synthesis of annulated ring sys-
tems. However, the synthesis of the benzazocine skeletons
by RCM in particular, has seen little investigation with, to
the best of our knowledge, only one synthesis of the 1-benz-
acocine,2a 2-benzacocine8g and 2-benzazocin-1(2H)-one9
being reported. In this paper we will describe our synthetic
endeavours towards the development of general methodol-
ogy affording the 2-benzacocines using a RCM reaction as
the key step. In addition, results concerning the anti-cancer
activity of a small set of 2-benzacocines will also be dis-
closed.
A single-crystal X-ray diffraction experiment on a suit-
able crystal of 15c confirmed the formation of the eight-
membered ring by way of the RCM reaction (see the ORTEP
diagram in Fig. 5).12
At this point we were able to test the suitability of the various
protecting groups on 15a–d by applying specific conditions
known to remove some of these groups. Unfortunately,
it proved difficult to remove the sulfonamide groups of
15c and 15d under a variety of conditions. However, the
Boc-protecting group of compound 15b was readily cleaved
with trifluoroacetic acid to afford 7-isopropoxy-8-methoxy-
1,2,3,6-tetrahydro-2-benzazocine 16 in near quantitative
yield (Scheme 2). In another experiment designed to
2. Discussion
The first step in our synthetic strategy8g involved the con-
version of the readily accessible building block 1110 to the
bis-allyl product 13 using a two-step reductive amination
N
Mes
Cl
N
Mes
Ru
Cl
Ph
PCy3
10
Figure 5. ORTEP diagram of compound 15c (showing the 50% probability
thermal ellipsoids for all non-hydrogen atoms).
Figure 4.

J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
4739
evaluate the ease with which we could manipulate the het-
erocyclic ring, the alkene functionality of 15c was readily
hydrogenated with Pd/C, under 5 atm of hydrogen gas, to
afford the saturated benzo-fused heterocycle 17 in an excel-
lent yield. The structure of the hydrogenated compound 17
was also confirmed by a single-crystal X-ray diffraction
study.13
The benzaldehyde functional group of compound 21 was
then cooled into the corresponding amine 23, by way of
22, using the two-step reductive amination procedure de-
scribed previously (Scheme 4). A problem encountered in
this transformation was that the major product 23 was con-
taminated with a small amount of another compound
(<10% by NMR analysis), which we were unable to remove
by silica gel column chromatography. We postulated that
this compound had structure 26a in which the alkene had
isomerized into conjugation with the more electron-rich
aromatic ring and this was later confirmed after the RCM
reaction.
R
N
15a and 15c
MeO
OiPr
iPrO
CHO
iPrO
(a)
(a)
(b)
N
Ph
Ph
MeO
MeO
H
N
SO2Bn
N
21
22
H
N
iPrO
(b)
(c)
MeO
MeO
OiPr
OiPr
Ph
16
17
MeO
23
R
N
Scheme 2. Reagents and conditions: (a) for R¼Boc, trifluoroacetic acid,
CH2Cl2, rt, 1 h (99%); (b) for R¼SO2Bn, 10% Pd/C, 5 atm H2, EtOH, rt,
18 h (98%).
R
N
iPrO
iPrO
MeO
(d)
Ph
MeO
24a,b
25a,b
In a related project we were interested in synthesizing annu-
lated heterocycles containing an aryl substituent attached to
the heterocyclic ring portion. Under thermal conditions
(DMF at reflux), the readily available compound 18 has
been shown to give, after protection of the resultant phenol
as the isopropyloxy group, predominantly the product of
a Claisen rearrangement followed by a double bond isomer-
ization, compound 19 in acceptable yield (Scheme 3).10
However, when we attempted the Claisen rearrangement of
compound 18 in a microwave reactor, we were interested to
find that compound 18 had undergone a subsequent Cope
rearrangement to give the related regioisomer 21 as the major
product, after phenolic protection of 20 with isopropyl bro-
mide. This reaction has also been observed by Wang and
co-workers who obtained compound 20 after heating sub-
strate 18 in N,N-diethylaniline at a much higher temperature
of 217 ꢀC.14 Optimization of the microwave procedure even-
tually allowed us to isolate quantitative yields of product 21
from 18, in short reaction times. An additional benefit of this
methodology was that 21 required no further purification.
With this efficient procedure to synthesize 21 we decided
to attempt the synthesis of 2-benzazocines with a different
oxygenation pattern on the aromatic core, using the method-
ology previously established for compounds 15a–d.
Ts
R
N
iPrO
MeO
iPrO
MeO
N
Ph
27
26a R = H
26b R = Ts
Scheme 4. Reagents and conditions: (a) allyl amine, solvent-free, rt, 21.5 h
(quantitative); (b) NaBH4, MeOH, 0 ꢀC–rt, 4.5 h (75%); (c) 24a R¼Ts, tosyl
chloride, NEt3, CH2Cl2, 0 ꢀC–rt, 2.5 h (72%), 24b R¼Boc, Boc2O,
0.1 equiv DMAP, THF, rt, 3 h (79%); (d) 5 mol % catalyst 10, toluene,
60 ꢀC, 20–22.5 h, 25a R¼Ts (39%), 25b R¼Boc (73%).
Compound 23 was initially protected as the sulfonamide 24a
(R¼Ts) in an acceptable yield of 72% (Scheme 4). The
metathesis reaction was then performed on this substrate
to afford the 8,9-substituted 2-benzazocine 25a in a poor,
unoptimized yield of only 39%. Analysis of the HRMS
showed evidence of compound 27 arising from the RCM
of impurity 26b.
Compound 23 was also converted into the corresponding
Boc-protected product 24b in good yield (Scheme 4). This
time the RCM reaction gave a more favourable result as
25b was isolated in a reasonable yield of 73%. Characteriza-
tion of compound 25b by 1H NMR spectroscopy proved to
be difficult as the spectrum was complex caused by the pres-
ence of rotamers due to hindered rotation about the bulky
Boc-protecting group. However, the 13C NMR spectrum of
this compound readily allowed us to account for all the nec-
essary carbon signals.
CHO
CHO
(a),(b)
MeO
MeO
O
Ph
OiPr Ph 19
18
(c)
It would thus appear that the presence of a bulky group, such
as the isopropyloxy group, adjacent to the aromatic allyl
group is beneficial to the RCM process.15 Perhaps this
occurs as a result of a reduction in the degree of freedom
associated with this alkene fragment, as the metathesis
yields for 15a–d were high without fail and the reactions
were all deemed complete within an hour. In contrast the me-
tathesis of the substrates 24a and 24b required much longer
iPrO
CHO
HO
CHO
(d)
Ph
Ph
MeO
MeO
21
20
i
Scheme 3. Reagents and conditions: (a) DMF, 190 ꢀC; (b) PrBr, K2CO3,
60 ꢀC, 51% over two steps;10 (c) microwave, 200 ꢀC, 50 W, 150 psi max,
i
5 min run, 5 min hold (quantitative); (d) PrBr, K2CO3, 60 ꢀC, 76% over
two steps from 18.

4740
J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
reaction times (20–22 h) for the reaction to be deemed com-
plete (by TLC). These long reaction times also seemed to
contribute to the formation of side products such as dimers.
In light of the complications associated with the metathesis
of the scaffolds 24a and 24b, we did not pursue this route any
further.
convertedinto9-isopropoxy-8-methoxy-3,6-dihydro-2-benz-
azocine derivatives 25a and 25b, albeit with less success.
Lastly, cytotoxic testing proved the benzo-fused derivatives
15a–d and 17 to only have slight activity against HL-60
and K562 cancer cell lines. Our future research will endeav-
our to utilize these 2-benzazozine derivatives as scaffolds for
potentially bioactive molecules.
3. Cytotoxicity testing
5. Experimental
5.1. General
Since compounds such as 8 and 9 (Fig. 3) have been tested
for tubulin inhibition and cytotoxicity, we decided to inves-
tigate whether some of our synthesized compounds had any
anti-cancer properties. To this end, the cytotoxic effects of
the benzo-fused compounds 15a–d and 17 were evaluated
on two adherent cell lines (i.e., HT-29 and MCF-7 cells)
and two suspension cell lines (HL-60 and K562 cells) using
the tetrazolium-based MTT assay (Fig. 6).17 At an initial
dose of 100 mM, 15d and 17 were cytotoxic against the
MCF-7 cells, reducing cell viability by 12% and 30%, re-
spectively. No significant decrease in cell viability was noted
when the MCF-7 cells were treated with 15a–c. Similarly, no
significant cytotoxic effect was exerted against the HT-29
cells when treated with 15a, 15c–d and 17, where 15b de-
creased cell viability by 8%. As none of the compounds
tested reduced cell viability to less than 50% at 100 mM,
IC50 values for these compounds could not be calculated
and were thus determined to be in excess of 100 mM.
1H NMR and 13C NMR spectra were recorded either on
a Bruker AC-200, Bruker 300 or Bruker DRX 400 spectro-
meter at the frequency indicated. For most compounds
COSY and CH correlated spectra were utilized to assign
the NMR signals. Most 13C signals in the aromatic/alkene re-
gion have been assigned as quaternary (C) or non-quaternary
(CH). In the 1H NMR and 13C NMR spectra assignments with
same superscript may be interchanged. Infra-red spectra
were recorded on either a Bruker IFS 25 Fourier Transform
spectrometer or on a Bruker Vector 22 Fourier Transform
spectrometer. Mass spectra were recorded on a Kratos MS
9/50, VG 70E MS or a VG 70 SEQ mass spectrometer.
Macherey-Nagel kieselgel 60 (particle size 0.063–0.200 mm)
was used for conventional silica gel chromatography. All sol-
vents used for reactions and chromatography were distilled
prior to use according to established procedures.18
The HL-60 cells appeared to be the most sensitive cell line to
the compounds, with reductions in cell viability ranging
from approximately 34 to 48%. Finally, all compounds,
with the exception of 15a, decreased K562 cell viability
by 10–40%. As with the adherent cell lines, none of the com-
pounds tested reduced cell viability to less than 50%. IC50
values for these compounds could not be calculated and
are determined to be in excess of 100 mM.
5.1.1. N-[(2-Allyl-3-isopropoxy-4-methoxyphenyl)-
methylidene]-2-propen-1-amine 12. 2-Allyl-3-isoprop-
oxy-4-methoxybenzaldehyde 11 (7.98 mmol, 1.87 g) was
transferred directly to a round-bottomed flask and to this
was added allyl amine (0.90 cm3, 11.2 mmol). The reaction
mixture was placed under N2 atmosphere and was allowed to
stir at rt for 3 h. After this period of time the excess allyl
amine was removed in vacuo to yield a yellow oil (2.22 g,
99%). The product 12 was >95% pure by 1H NMR spectro-
scopy and no further purification was required. nmax/cmꢁ1
(NaCl plate) 1682, 1637, 1591, 1520, 1487, 1465, 1440,
1383, 1373; dH (300 MHz, CDCl3) 1.27 (6H, d, J¼6.0 Hz,
OCH(CH3)2), 3.69 (2H, dd, J¼1.5 and 4.0 Hz, ArCH2), 3.86
(3H, s, OCH3), 4.21 (2H, dd, J¼5.5 and 1.5 Hz, NCH2), 4.49
(1H, sept, J¼6.0 Hz, OCH(CH3)2), 4.86–5.24 (4H, m,
NCH2CH]CH2 and ArCH2CH]CH2), 5.90–6.09 (2H, m,
NCH2CH]CH2 and ArCH2CH]CH2), 6.83 (1H, d,
J¼8.5 Hz, 5-H), 7.73 (1H, d, J¼8.5 Hz, 6-H), 8.44 (1H,
s, N]CH); dC (100 MHz, CDCl3) 22.6 and 22.7
(OCH(CH3)2), 30.7 (ArCH2), 55.6 (OCH3), 63.7 (NCH2),
74.4 (OCH(CH3)2), 109.9 (5-C), 114.6 (NCH2CH]CH2),a
115.8 (ArCH2CH]CH2),a 124.1 (6-C), 131.7 (C), 132.5
(NCH2CH]CH2),b 136.9 (C), 137.5 (ArCH2CH]CH2),b
145.0 (C), 151.8 (C), 160.4 (N]CH); dN (40.6 MHz,
CDCl3) ꢁ62.9; m/z 272 (M+, 67%), 258 (32), 231 (68), 230
(98), 218 (100), 216 (42), 190 (30), 176 (91), 175 (75), 174
(31), 144 (20), 143 (86), 115 (39), 43 (28), 41 (61); HRMS
calculated for C17H23NO2: 272.1729, found: 272.1722.
4. Conclusion
In this paper we have successfully demonstrated that the
2-benzazocine skeleton can be readily constructed by using
RCM as the key step. In this way, benzaldehyde 11, was
transformed into the acetyl-, Boc-, benzyl sulfonyl- and
tosyl-protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-
2-benzazocines 15a–d. In addition, substrate 18 was
125
100
75
50
25
0
15a
15b
15c
15d
17
MCF-7
HT-29
Compound (100 µM)
HL-60
K 562
5.1.2. N-(2-Allyl-3-isopropoxy-4-methoxybenzyl)-2-
propen-1-amine 13. N-[(2-Allyl-3-isopropoxy-4-methoxy-
phenyl)methylidene]-2-propen-1-amine 12 (3.70 mmol,
1.01 g) was dissolved in MeOH (10 cm3) and cooled to
Figure 6. Percentage cell viability of four cell lines exposed to 100 mM
15a–d and 17 for 24 h as determined by the MTT assay.17

J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
4741
0 ꢀC (ice-water bath) before the addition of the NaBH4
(4.44 mmol, 0.167 g). The solution was allowed to stir for
90 min before the addition of H2O (10 cm3), followed by
HCl solution (1 M) until the pH was w7. The MeOH was
removed under reduced pressure to yield a yellow oil on
the aqueous layer. This was then extracted with EtOAc
(2ꢂ25 cm3) and the combined organic fractions were dried
(MgSO4). The solvent was removed in vacuo to yield the
product 13 as a yellow oil (0.828 g, 81%), which was used
without further purification. nmax/cmꢁ1 (NaCl plate) 1637,
1599, 1272; dH (300 MHz, CDCl3) 1.26 (6H, d, J¼6.0 Hz,
OCH(CH3)2), 1.42 (1H, s, NH), 3.26 (2H, dt, J¼6.0 and
1.0 Hz, ArCH2CH]CH2),a 3.54 (2H, dt, J¼6.0 and 1.5 Hz,
NHCH2CH]CH2),a 3.69 (2H, s, ArCH2NH), 3.81 (3H, s,
OCH3), 4.51 (1H, sept, J¼6.0 Hz, OCH(CH3)2), 4.94–4.98
(2H, m, ArCH2CH]CH2),b 5.11–5.21 (2H, m, NHCH2-
CH]CH2),b 5.88–5.99 (2H, m, ArCH2CH]CH2 and NH-
CH2CH]CH2), 6.75 (1H, d, J¼8.5 Hz, 5-H), 7.01 (1H, d,
J¼8.5 Hz, 6-H); dC (50 MHz, CDCl3) 22.5 (OCH(CH3)2),
29.5 (ArCH2CH]CH2), 44.6 (ArCH2NH), 55.5 (OCH3),
63.6 (NHCH2CH]CH2), 74.6 (OCH(CH3)2), 110.2 (5-C),
115.7 (ArCH2CH]CH2),a 115.8 (NHCH2CH]CH2),a
123.0 (6-C), 127.9 (C), 133.6 (C), 136.2 (NHCH2CH]
CH2),b 137.1 (ArCH2CH]CH2),b 144.4 (C), 154.6 (C);
m/z 274 (M+, 67%), 232 (18), 177 (42), 176 (100), 175
(25), 161 (34), 144 (23), 115 (21); HRMS calculated for
C17H24NO2 (M+ꢁH): 274.1807, found: 274.1809.
119.9 (6-C), 123.4 (1-C), 127.5 and 128.2 (2-C), 132.6 and
133.1 (NCH2CH]CH2),a 135.8 and 136.5 (ArCH2CH]
CH2),a 145.2 and 145.4 (3-C),b 152.1 (4-C),b 170.8 and
171.2 (C]O); m/z 317 (M+, 30%), 218 (41), 192 (53), 177
(35), 176 (100), 174 (27), 161 (28), 143 (40), 115 (20);
HRMS calculated for C19H27NO3: 317.1991, found:
317.1997.
5.1.4. tert-Butyl allyl(2-allyl-3-isopropoxy-4-methoxy-
benzyl)carbamate
14b.
N-(2-Allyl-3-isopropoxy-4-
methoxybenzyl)-2-propen-1-amine 13 (5.47 mmol, 1.51 g)
was dissolved in THF (150 cm3) and to this solution was
added Boc2O (6.56 mmol, 1.55 cm3). The solution was
stirred for 5 min before the addition of DMAP
(0.547 mmol, 0.0669 g). The reaction mixture was allowed
to stir at rt under an Ar atmosphere for 3 h after which
time the solvent was removed in vacuo. The resultant orange
oil was purified by column chromatography (5–10%
EtOAc–Hexane, Rf 0.80 in 30% EtOAc–Hexane) to yield
the desired product 14b as a pale yellow oil (1.99 g, 97%).
nmax/cmꢁ1 (NaCl plate) 1689, 1661, 1549, 1532, 1514,
1481, 1463, 1410, 1265; dH (300 MHz, CDCl3) 1.26 (6H,
d, J¼6.0 Hz, OCH(CH3)2), 1.46 (9H, br s, OC(CH3)3),
3.45 (2H, br d, J¼5.5 Hz, ArCH2CH]CH2), 3.60–3.70
(2H, very br s, NCH2CH]CH2), 3.82 (3H, s, OCH3), 4.38
(2H, br s, ArCH2N), 4.51 (1H, sept, J¼6.0 Hz, OCH(CH3)2),
4.90–4.98 (2H, m, ArCH2CH]CH2),a 5.00–5.11 (2H, m,
NCH2CH]CH2),b 5.72 (1H, br s, NCH2CH]CH2),b
5.70–5.99 (1H, m, ArCH2CH]CH2), 6.75 (1H, d, J¼
8.5 Hz, 5-H), 6.83 (1H, d, J¼8.5 Hz, 6-H); dC (50 MHz,
CDCl3) 22.6 (OCH(CH3)2), 28.3 (OC(CH3)3), 30.3 (br,
ArCH2CH]CH2), 46.6 (br, ArCH2N),a 48.2 (NCH2CH]
CH2),a 55.5 (OCH3), 74.4 (OCH(CH3)2), 80.0 (OC(CH3)3),
109.9 (5-C), 114.8 (ArCH2CH]CH2),b 116.4 (br, NCH2-
CH]CH2),b 122.8 (6-C), 124.6 (C), 128.9 (br, C), 133.7
(ArCH2CH]CH2),c 136.2 (br, NCH2CH]CH2),c 145.1
(C), 151.8 (C), 155.6 (C]O); m/z 375 (M+, 16%), 278
(32), 236 (29), 177 (38), 176 (100), 175 (32), 163 (26),
143 (36), 70 (50), 57 (54); HRMS calculated for
C22H33NO4: 375.2410, found: 375.2403.
5.1.3. N-Allyl-N-(2-allyl-3-isopropoxy-4-methoxybenzyl)-
acetamide 14a. A solution of N-(2-allyl-3-isopropoxy-4-
methoxybenzyl)-2-propen-1-amine 13 (5.47 mmol, 1.51 g)
in pyridine (5.47 mmol, 0.45 cm3) was cooled to 0 ꢀC (ice-
water bath). To this was added dropwise, a solution of
Ac2O (8.20 mmol, 0.80 cm3) in pyridine (8.20 mmol,
0.65 cm3). The ice-water bath was then removed and the re-
action mixture was stirred at rt under an Ar atmosphere for
3 h. After this time EtOAc (15 cm3) was added and the reac-
tion mixture was extracted with brine (3ꢂ10 cm3). The com-
bined aqueous layers were then extracted with CH2Cl2
(3ꢂ10 cm3). The organic layers were combined and washed
with a saturated NH4Cl solution that had been basified to pH
10 with 25% NH3 solution (15 cm3). The combined organic
portions were then dried (MgSO4) and the solvent was re-
moved in vacuo. The residue was purified by column chro-
matography (10–30% EtOAc–Hexane, Rf 0.22 in 30%
EtOAc–Hexane) to yield the desired product 14a as a yellow
oil (1.59 g, 92%). The NMR spectra proved the compound to
consist of a mixture of rotamers in 1:1 ratio. nmax/cmꢁ1
(NaCl plate) 1637, 1520, 1481, 1429, 1374, 1269, 1216;
dH (300 MHz, CDCl3, 1:1 rotameric ratio) 1.26–1.28 (6H,
m, OCH(CH3)2), 2.05 and 2.14 (3H, 2ꢂs, CH3), 3.44 (2H,
br d, J¼5.5 Hz, ArCH2CH]CH2), 3.71 and 3.72 (1H,
2ꢂs, NCH(H)CH]CH2), 3.82 and 3.83 (3H, 2ꢂs, OCH3),
3.97 and 3.99 (1H, 2ꢂs, NCH(H)CH]CH2), 4.40 (1H, s,
ArCH(H)N), 4.52 (1H, sept, J¼6.0 Hz, OCH(CH3)2), 4.57
(1H, s, ArCH(H)N), 4.82–5.21 (4H, m, ArCH2CH]CH2
and NCH2CH]CH2), 5.74–5.90 (2H, m, ArCH2CH]CH2
and NCH2CH]CH2), 6.75–6.82 (2H, m, 5-H and 6-H); dC
(50 MHz, CDCl3) 21.4 (CH3), 22.6 (OCH(CH3)2), 30.0
and 30.5 (ArCH2CH]CH2), 45.1 (ArCH2N), 48.1 and
49.2 (NCH2CH]CH2), 55.5 (OCH3), 74.5 and 74.6
(OCH(CH3)2), 110.0 and 110.1 (5-C), 114.7 and 115.1
(NCH2CH]CH2), 116.5 and 117.3 (ArCH2CH]CH2),
5.1.5.
benzyl)phenylmethanesulfonamide 14c. N-(2-Allyl-3-
isopropoxy-4-methoxybenzyl)-2-propen-1-amine 13
N-Allyl-N-(2-allyl-3-isopropoxy-4-methoxy-
(2.82 mmol, 0.780 g) was dissolved in CH2Cl2 (8 cm3) and
stirred for 5 min under an Ar atmosphere. To this was added
NEt3 (7.05 mmol, 1.00 cm3) and the reaction mixture was
stirred at rt for a further 15 min before the dropwise addition
of benzylsulfonyl chloride (3.10 mmol, 0.593 g), which had
been dissolved in CH2Cl2 (4 cm3). The reaction mixture was
stirred for 3 h at rt and then the solvent was removed in va-
cuo. The residue was purified by column chromatography
(5% EtOAc–Hexane, Rf 0.35 in 30% EtOAc–Hexane) to
yield the product 14c as a yellow oil (0.710 g, 62%). nmax
/
cmꢁ1 (NaCl plate) 1594, 1487, 1439, 1375, 1337, 1273;
dH (300 MHz, CDCl3) 1.23 (6H, d, J¼6.0 Hz, OCH(CH3)2),
3.41 (2H, br d, J¼5.5 Hz, ArCH2CH¼CH2),a 3.64 (2H, br d,
J¼6.5 Hz, NCH2CH]CH2),a 3.80 (3H, s, OCH3), 4.07 (2H,
s, ArCH2N),b 4.25 (2H, s, SO2CH2),b 4.48 (1H, sept, J¼
6.0 Hz, OCH(CH3)2), 4.80 (1H, dd, J¼1.5 and 17.0 Hz,
ArCH2CH]C(H)H),c 4.93 (1H, dd, J¼1.5 and 10.0 Hz,
ArCH2CH]C(H)H),c 5.02–5.11 (2H, m, NCH2CH]
CH2),c 5.57–5.67 (1H, m, NCH2CH]CH2),d 5.75–5.85

4742
J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
(1H, m, ArCH2CH]CH2),d 6.76 (1H, d, J¼8.5 Hz, 5-H),
7.04 (1H, d, J¼8.5 Hz, 6-H), 7.35–7.40 (5H, m, 5ꢂArH);
dC (50 MHz, CDCl3) 22.4 (OCH(CH3)2), 30.0 (ArCH2CH]
CH2), 48.1 (ArCH2NH),a 50.0 (NHCH2CH]CH2),a 55.5
(OCH3), 58.9 (SO2CH2), 74.4 (OCH(CH3)2), 110.0 (5-C),
115.0 (NHCH2CH]CH2),b 119.0 (ArCH2CH]CH2),b
123.8 (6-C), 127.1 (CH), 128.6 (C), 128.7 (2ꢂArH), 129.0
(C), 130.7 (2ꢂArH), 132.2 (C),c 132.8 (NHCH2CH]CH2),c
136.3 (ArCH2CH]CH2), 144.9 (C), 152.2 (C); m/z 429
(M+, 28%), 274 (11), 232 (32), 176 (100), 161 (12), 160
(11), 144 (10), 91 (80), 41 (10); HRMS calculated for
C24H31NO4S: 429.1974, found: 429.1971.
5.2.1. 1-[7-Isopropoxy-8-methoxy-3,6-dihydro-2-benz-
azocin-2(1H)-yl]-1-ethanone 15a. N-Allyl-N-(2-allyl-3-
isopropoxy-4-methoxybenzyl)acetamide 14a (0.288 mmol,
0.0914 g) in toluene (10 cm3), was reacted with Grubbs II
catalyst 10 (5 mol %, 0.0144 mmol, 0.0133 g). Purification
by column chromatography (5–10% EtOAc–Hexane, Rf
0.05 in 30% EtOAc–Hexane) then afforded the product
15a as a clear oil (0.0682 g, 82%), showing evidence of
rotamers due to the amide functionality. nmax/cmꢁ1 (NaCl
plate) 1631, 1522, 1481, 1427, 1378, 1333, 1216; dH
(300 MHz, CDCl3) 1.27 (6H, d, J¼6.0 Hz, OCH(CH3)2),
2.00 and 2.09 (3H, 2ꢂs, COCH3), 3.49 and 3.53 (2H, 2ꢂd,
J¼7.5 Hz, 6-H), 3.81 and 3.82 (3H, 2ꢂs, OCH3), 3.84 (un-
der OCH3) and 4.17 (2H, 2ꢂd, J¼5.0 Hz, 3-H), 4.46 and
4.48 (1H, 2ꢂsept, J¼6.0 Hz, OCH(CH3)2), 4.59 and 4.68
(2H, 2ꢂs, 1-H), 5.71–6.01 (2H, m, 4-H and 5-H), 6.82
(1H, d, J¼8.5 Hz, 9-H), 6.99 (1H, d, J¼8.5 Hz, 10-H); dC
(50 MHz, CDCl3) 22.0 and 22.4 (COCH3), 22.5 and 22.6
(OCH(CH3)2), 24.7 and 25.3 (6-C), 44.1 and 45.4 (3-C),
50.9 and 52.8 (1-C), 55.5 and 55.6 (OCH3), 74.4 and 74.8
(OCH(CH3)2), 109.5 and 109.7 (9-C), 123.7 and 125.5
(10-C), 126.9 and 127.6 (5-C),a 128.6 and 128.2 (C), 129.3
(4-C),a 132.2 and 132.6 (C), 133.1 (4-C),a 144.2 and 145.0
(C), 152.6 and 152.7 (C), 170.4 and 170.9 (C]O); m/z
289 (M+, 100%), 218 (61), 204 (30), 188 (95), 175 (43),
173 (54), 156 (37), 143 (95), 115 (34), 73 (25), 43 (55);
HRMS calculated for C17H23NO3: 289.1678, found:
289.1687.
5.1.6. N-Allyl-N-(2-allyl-3-isopropoxy-4-methoxy-
benzyl)-4-methylbenzenesulfonamide 14d. To a stirred
solution of N-(2-allyl-3-isopropoxy-4-methoxybenzyl)-2-
propen-1-amine 13 (1.45 mmol, 0.410 g) in CH2Cl2
(20 cm3) were added NEt3 (2.03 mmol, 0.300 cm3) and pre-
viously recrystallized TsCl (1.74 mmol, 0.333 g) at 0 ꢀC
under N2 atmosphere. The reaction mixture was allowed to
stir at 0 ꢀC for 3.5 h and then at rt for 40 min. Afterwards
the reaction mixture was diluted with water (20 cm3) and
then CH2Cl2 (20 cm3) was added. The combined organics
were washed with H2O (2ꢂ20 cm3) and dried (MgSO4).
The solvent was removed in vacuo and the residue was puri-
fied by column chromatography (20% EtOAc–Hexane, Rf
0.70 in 30% EtOAc–Hexane). The product 14d was obtained
as a pale yellow oil that solidified on standing (0.58 g, 94%).
Mp 46–52 ꢀC; nmax/cmꢁ1 (NaCl plate) 1599, 1487, 1439,
1341, 1273, 1216; dH (300 MHz, CDCl3) 1.25 6H, d,
J¼6.0 Hz, OCH(CH3)2), 2.44 (3H, s, CH3), 3.50 (2H, br,
J¼5.5 Hz, ArCH2CH]CH2), 3.70 (2H, d, J¼6.5 Hz,
NCH2CH]CH2), 3.82 (3H, s, OCH3), 4.25 (2H, s,
ArCH2N), 4.49 (1H, sept, J¼6.0 Hz, OCH(CH3)2), 4.82–
4.98 (4H, m, ArCH2CH]CH2 and NHCH2CH]CH2),
5.38–5.47 (1H, m, NCH2CH]CH2),a 5.82–5.91 (1H, m,
ArCH2CH]CH2),a 6.73 (1H, d, J¼8.5 Hz, 5-H), 6.98
(1H, d, J¼8.5 Hz, 6-H), 7.32 (2H, d, J¼8.0 Hz, 2ꢂArH),
7.73 (2H, d, J¼8.0 Hz, 2ꢂArH); dC (50 MHz, CDCl3)
21.5 (CH3), 22.5 (OCH(CH3)2), 30.1 (ArCH2CH]CH2),
48.3 (ArCH2N),a 49.7 (NCH2CH]CH2),a 55.5 (OCH3),
74.5 (OCH(CH3)2), 109.9 (5-C), 115.0 (NHCH2CH]
CH2),b 118.6 (ArCH2CH]CH2),b 124.3 (6-C), 126.7 (C),
127.4 (2ꢂArCH), 129.7 (2ꢂArCH), 132.6 (NCH2CH]
CH2),c 132.8 (C), 136.5 (ArCH2CH]CH2),c 137.0 (C),
143.2 (C), 145.1 (C), 152.3 (C); m/z 429 (M+, 17%), 274
(27), 232 (38), 177 (58), 176 (100), 161 (37), 144 (32);
HRMS calculated for C24H31NO4S: 429.1974, found:
429.1975.
5.2.2. tert-Butyl 7-isopropoxy-8-methoxy-3,6-dihydro-
2-benzazocine-2(1H)-carboxylate 15b. tert-Butyl allyl-
(2-allyl-3-isopropoxy-4-methoxybenzyl)carbamate
14b
(1.07 mmol, 0.402 g) was dissolved in toluene (40 cm3)
before the addition of Grubbs II catalyst 10 (5 mol %,
0.053 mmol, 0.051 g). Purification by column chromato-
graphy (5% EtOAc–Hexane, Rf 0.63 in 20% EtOAc–
Hexane) afforded the desired product 15b as a clear oil
(0.366 g, 99%). NMR spectroscopy showed the product to
be a mixture of amide rotamers (ratio 60:40). nmax/cmꢁ1
(NaCl plate) 1682, 1566, 1550, 1532, 1514, 1464, 1411,
1376, 1266; dH (300 MHz, CDCl3) 1.27 (6H, d, J¼6.0 Hz,
OCH(CH3)2), 1.34 and 1.42 (9H, 2ꢂs, OC(CH3)3), 3.51–
3.56 (2H, m consisting of 2ꢂoverlapping d, 6-H), 380 and
3.81 (3H, 2ꢂs, OCH3), 3.81–3.84 (under OCH3) and 4.00
(2H, d, J¼4.5 Hz, 3-H), 4.47 and 4.54 (2H, 2ꢂs, 1-H),
4.54 (1H, under 1-H, OCH(CH3)2), 5.66–5.90 (2H, m, 4-H
and 5-H), 6.66–6.71 (1H, 2ꢂoverlapping d, J¼7.5 Hz, 9-H),
6.83 and 6.95 (1H, 2ꢂd, J¼7.5 Hz, 10-H); dC (50 MHz,
CDCl3) 22.5 and 22.6 (OCH(CH3)2), 25.2 and 25.3 (6-C),
28.4 (OC(CH3)3), 44.5 and 44.9 (3-C), 51.7 (1-C), 55.6
(OCH3), 74.5 and 74.6 (OCH(CH3)2), 79.4 and 79.5
(OC(CH3)3), 109.2 and 109.6 (9-C), 124.5 and 125.2 (10-C),
128.1 and 128.4 (5-C),a 129.4 (C), 130.3 and 130.6 (4-C),a
132.9 and 133.2 (C), 144.4 (C), 152.2 and 152.4 (C), 155.2
and 155.5 (C]O); m/z 347 (M+, 43%), 249 (20), 204 (25),
188 (47), 175 (39), 162 (20), 143 (48), 57 (100); HRMS cal-
culated for C20H29NO4: 347.2097, found: 347.2095.
5.2. General metathetic approach to eight-
membered rings
The diene precursors 14a–d were dissolved in distilled tolu-
ene (10 cm3), after which the solution was degassed by bub-
bling N2 through it for 20 min. The solution was then heated
to 60 ꢀC before the addition of Grubbs II catalyst 10
(5 mol %). The reaction mixture was then stirred at 60 ꢀC
under an Ar atmosphere for 1 h. After this time the solvent
was removed in vacuo to yield a dark brown oil that was pu-
rified by column chromatography (5–10% EtOAc–Hexane)
to afford the desired cyclized products 15a–d. The products
synthesized in this manner are listed below.
5.2.3. 2-(Benzylsulfonyl)-7-isopropoxy-8-methoxy-
1,2,3,6-tetrahydro-2-benzazocine 15c. N-Allyl-N-(2-
allyl-3-isopropoxy-4-methoxy-benzyl)phenylmethanesulfon-
amide 14c (0.466 mmol, 0.205 g) was dissolved in toluene
(20 cm3) and Grubbs II catalyst 10 (5 mol %, 0.0233 mmol,

J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
4743
0.0194 g) was added. Column chromatography (10%
EtOAc–Hexane, Rf 0.49 in 30% EtOAc–Hexane) afforded
white crystals of compound 15c (0.157 g, 84%). Mp 119–
122 ꢀC; nmax/cmꢁ1 (NaCl plate) 1691, 1647, 1463, 1372,
1333; dH (300 MHz, CDCl3) 1.28 (6H, d, J¼6.0 Hz,
OCH(CH3)2), 3.63 (2H, d, J¼7.5 Hz, 6-H), 3.83–3.86 (7H,
m, OCH3, ArCH2N and NCH2C), 4.48–4.56 (3H, m,
OCH(CH3)2 and SO2CH2Ar), 5.58–5.64 (1H, m, 4-H),a
6.02–6.08 (1H, m, 5-H),a 6.75 (1H, d, J¼8.5 Hz, 9-H), 6.98
(1H, d, J¼8.5 Hz, 10-H), 7.23–7.26 (2H, m, 2ꢂArH),
7.30–7.32 (3H, m, 3ꢂArH); dC (50 MHz, CDCl3) 22.6
(OCH(CH3)2), 26.8 (6-C), 44.8 (3-C), 52.8 (SO2CH2Ar),
55.6 (OCH3), 59.4 (1-C), 74.6 (OCH(CH3)2), 109.8 (9-C),
125.6 (CH), 126.0 (CH), 127.7 (C), 128.3 (CH), 128.5
(2ꢂCH), 129.1 (C), 130.7 (2ꢂCH), 134.4 (C), 135.4 (CH),
144.5 (C), 152.8 (C); m/z 401 (M+, 47%), 284 (70), 265
(19), 253 (15), 252 (16), 246 (15), 204 (100), 188 (16), 175
(20), 143 (17), 91 (88); HRMS calculated for C22H27NO4S:
401.1661, found: 401.1666.
(6H, d, J¼6.0 Hz, OCH(CH3)2), 3.17 (2H, d, J¼8.0 Hz, 6-
H), 3.66 (2H, br s, 3-H), 3.76 (3H, s, OCH3), 4.21 (2H, br
s, 1-H), 4.34 (1H, sept, J¼6.0 Hz, OCH(CH3)2), 5.47–5.54
(1H, m, 4-H),a 6.11–6.16 (1H, m, 5-H),a 6.76 (1H, d,
J¼8.5 Hz, 9-H), 7.00 (1H, d, J¼8.5 Hz, 10-H), 8.84 (1H,
br s, NH); dC (50 MHz, CDCl3) 22.5 (OCH(CH3)2), 29.1
(6-C), 36.8 (3-C), 45.3 (1-C), 55.6 (OCH3), 75.2
(OCH(CH3)2), 111.2 (9-C), 117.7 (10-C), 121.6 (C), 127.0
(C), 133.4 (CH), 140.1 (CH), 144.6 (C), 154.2 (C); m/z
247 (M+, 68%), 204 (100), 190 (32), 188 (43), 176 (60),
175 (35), 162 (25), 161 (28), 143 (39), 115 (31); HRMS cal-
culated for C15H21NO2: 247.1572, found: 247.1565.
5.2.6. 2-(Benzylsulfonyl)-7-isopropoxy-8-methoxy-
1,2,3,4,5,6-hexahydro-2-benzazocine 17. 2-(Benzylsul-
fonyl)-7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benz-
azocine 15c (0.275 mmol, 0.109 g) was dissolved in
absolute ethanol (10 cm3) by sonication. To the resultant
emulsion was added 10% Pd/C (0.15 g/mmol, 0.0430 g)
and this mixture was subjected to hydrogenation in an auto-
clave at 5 atm H2 for 18 h at rt. The reaction mixture was
then filtered through Celite and rinsed with CH2Cl2
(3ꢂ50 cm3). The solvent was then removed in vacuo to yield
a cream-white solid. This was then recrystallized by dissolv-
ing the compound in the minimum amount of EtOAc and
then adding hexane dropwise to the solution until it became
cloudy. The solution was then left to stand overnight and the
recrystallized material was collected by filtration. The pure
product 17 was obtained as colourless crystals (0.108 g,
98%). Mp 141–147 ꢀC; nmax/cmꢁ1 (NaCl plate) 1521,
1490, 1425, 1332, 1212; dH (300 MHz, CDCl3) 1.25 (6H,
d, J¼6.0 Hz, OCH(CH3)2), 1.51–1.52 (2H, m, 4-H),a 1.66–
1.68 (2H, m, 5-H),a 2.87–2.91 (2H, m, 6-H),b 3.09–3.12
(2H, m, 3-H),b 3.82 (3H, s, OCH3), 4.18 (2H, s, 1-H),c
4.22 (2H, s, SO2CH2Ar),c 4.53 (1H, sept, J¼6.0 Hz,
OCH(CH3)2), 6.73 (1H, d, J¼8.5 Hz, 9-H), 6.94 (1H, d, J¼
8.5 Hz, 10-H), 7.35–7.37 (5H, m, 5ꢂArH); dC (50 MHz,
CDCl3) 22.6 (OCH(CH3)2), 24.0 (5-C),a 27.9 (4-C),a 29.3
(6-C),a 46.9 (3-C),b 49.7 (SO2CH2),b 55.5 (OCH3), 58.7
(1-C), 74.3 (OCH(CH3)2), 110.0 (9-C), 125.6 (10-C), 128.1
(C), 128.5 (CH), 128.7 (2ꢂCH), 129.5 (C), 130.7 (2ꢂCH),
135.4 (C), 144.3 (C), 152.6 (C); m/z 403 (M+, 36%), 361
(28), 253 (19), 206 (71), 205 (20), 178 (17), 177 (22), 176
(21), 120 (17), 91 (100), 30 (13), 28 (19); HRMS calculated
for C22H29NO4S: 403.1817, found: 403.1818.
5.2.4. 7-Isopropoxy-8-methoxy-2-[(4-methylphenyl)-
sulfonyl]-1,2,3,6-tetrahydro-2-benzazocine 15d. N-Allyl-
N-(2-allyl-3-isopropoxy-4-methoxybenzyl)-4-methyl-benz-
enesulfonamide 14d (0.364 mmol, 0.156 g) was dissolved in
toluene (15 cm3) and Grubbs II catalyst 10 (5 mol %,
0.0182 mmol, 0.0161 g) was added. Purification by column
chromatography (5–10% EtOAc–Hexane, Rf 0.54 in 30%
EtOAc–Hexane) afforded the desired product 15d as a pale
yellow oil (0.139 g, 95%). nmax/cmꢁ1 (NaCl plate) 1598,
1489, 1439, 1383, 1334, 1279; dH (300 MHz, CDCl3) 1.23
(6H, d, J¼6.0 Hz, OCH(CH3)2), 2.40 (3H, s, CH3), 3.54
(2H, d, J¼6.5 Hz, 6-H), 3.75 (2H, d, J¼6.5 Hz, 3-H), 3.82
(3H, s, OCH3), 4.41 (1H, sept, J¼6.0 Hz, OCH(CH3)2),
4.47 (2H, s, 1-H), 5.43-5.49 (1H, m, 4-H),a 5.75–5.81 (1H,
m, 5-H),a 6.71 (1H, d, J¼8.5 Hz, 9-H), 6.89 (1H, d,
J¼8.5 Hz, 10-H), 7.23 (2H, d, J¼8.0 Hz, 2ꢂArH), 7.62
(2H, d, J¼8.0 Hz, 2ꢂArH); dC (50 MHz, CDCl3) 21.5
(ArCH3), 22.5 (OCH(CH3)2), 26.5 (6-C), 43.3 (3-C), 50.8
(1-C), 55.6 (OCH3), 74.8 (OCH(CH3)2), 110.0 (9-C),
124.5 (10-C),a 125.4 (CH),a 127.3 (2ꢂCH), 127.7 (C),
129.4 (2ꢂCH), 133.2 (C), 133.4 (CH), 136.9 (C), 143.0
(C), 144.3 (C), 152.9 (C); m/z 401 (M+, 22%), 246 (50),
204 (100), 189 (43), 175 (52), 161 (22), 143 (35); HRMS cal-
culated for C22H27NO4S: 401.1661, found: 401.1663.
5.2.5. 7-Isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-
benzazocine 16. tert-Butyl 7-isopropoxy-8-methoxy-3,6-di-
hydro-2-benzazocine-2(1H)-carboxylate 15b (0.300 mmol,
0.104 g) was dissolved in CH2Cl2 (2 cm3) and to this solu-
tion was added triflouroacetic acid (0.45 mmol,
0.035 cm3). The reaction mixture was allowed to stir at rt
under an Ar atmosphere for 1 h, after which time the solution
had gone dark brown. To the reaction mixture was added dis-
tilled H2O (2 cm3) and the solution was diluted with EtOAc
(2 cm3). It was then neutralized using a saturated solution of
NaHCO3 and 10% aqueous AcOH. The organic layer was
kept aside and the aqueous layer was extracted with EtOAc
(3ꢂ10 cm3). The combined organics were then dried
(MgSO4) and the solvent was removed in vacuo to yield
16 as a dark orange semi-solid (0.0731 g, 99%), which
was sufficiently pure by 1H NMR spectroscopy and no fur-
ther purification was performed. nmax/cmꢁ1 (NaCl plate)
3618, 1674, 1603, 1520, 1440; dH (400 MHz, CDCl3) 1.17
5.2.7. 5-Hydroxy-4-methoxy-2-[(1E)-3-phenyl-2-prope-
nyl]benzaldehyde 20. The Claisen–Cope rearrangement
was effected by placing the 4-methoxy-3-{[(2E)-3-phenyl-
2-propenyl]oxy}benzaldehyde 18 (0.939 mmol, 0.249 g)
neat in a sealed tube for the microwave reactor. The program
was set up with the power output at 50 W, the maximum tem-
perature at 200 ꢀC, the maximum allowable pressure at
150 psi with no cooling and continuous stirring. The run
time was set to 5 min with a hold time of 5 min. This yielded
the desired compound 20 as a dark brown oil that was deemed
acceptably pure by spectroscopy and no further purification
was required (0.249 g, 100%). The NMR spectra of this com-
pound correlated well with that published in the literature.14
5.2.8. 5-Isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-pro-
penyl]benzaldehyde 21.16 The 4-methoxy-3-{[(2E)-3-
phenyl-2-propenyl]-oxy}benzaldehyde 18 (9.35 mmol,

4744
J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
2.51 g) was placed in a sealed tube for the microwave reactor
in 0.250 g batches and the Claisen–Cope rearrangement was
performed under solvent-free conditions. The program was
set up with the power output at 50 W, the maximum temper-
ature at 200 ꢀC, the maximum allowable pressure at 150 psi
with no cooling and continuous stirring. The run time was set
to 5 min, with a hold time of 5 min, for each of the 0.250 g
batches of aldehyde. All the products were combined in
a round-bottomed flask and were dissolved in DMF
(25 cm3). The solution was placed under an Ar atmosphere
and then heated to 60 ꢀC. Then K2CO3 (23.4 mmol,
3.24 g) was added and the solution was stirred until a suspen-
sion formed. Isopropyl bromide (23.4 mmol, 2.20 cm3) was
finally added and the reaction mixture was allowed to stir at
60 ꢀC under an Ar atmosphere for 19 h. After this time the
reaction mixture was cooled to rt and the inorganic solids
were filtered off through a Celite pad, which was rinsed
with CH2Cl2 (50 cm3). The solvent was then removed in va-
cuo. The crude mixture was then purified by column chro-
matography (5–10% EtOAc–Hexane, Rf 0.63 in 30%
EtOAc–Hexane) to obtain the desired product 21 as a dark
yellow oil (2.20 g, 76% over two steps). nmax/cmꢁ1 (NaCl
plate) 1679, 1594, 1510, 1423, 1266, 1216; dH (300 MHz,
CDCl3) 1.39 (6H, d, J¼6.0 Hz, OCH(CH3)2), 3.90–3.92
(5H, m, CH2 and OCH3), 4.62 (1H, sept, J¼6.0 Hz,
OCH(CH3)2), 6.38–6.39 (2H, m, CH]CHPh and CH]
CHPh), 6.77 (1H, s, 3-H), 7.16–7.32 (5H, m, 5ꢂArH),
7.42 (1H, s, 6-H), 10.20 (1H, s, CHO); dC (50 MHz,
CDCl3) 21.9 (OCH(CH3)2), 35.0 (ArCH2), 56.1 (OCH3),
71.5 (OCH(CH3)2), 113.5 (3-C), 115.6 (6-C), 126.1
(2ꢂCH), 126.8 (C), 127.3 (CH), 128.5 (2ꢂCH), 128.8
(CH), 131.4 (CH), 137.1 (C), 137.6 (C), 146.1 (C), 155.2
(C), 190.1 (CHO); m/z 310 (M+, 46%), 268 (50), 239 (18),
219 (54), 178 (15), 177 (100), 163 (82), 152 (16), 136
(33), 91 (23); HRMS calculated for C20H22O3: 310.1569,
found: 310.1583.
(CH]CHPh),a 133.1 (C), 136.3 (CH), 137.3 (C), 146.1
(C), 152.3 (C), 159.5 (N]CH); m/z 349 (M+, 18%), 348
(25), 310 (37), 268 (44), 258 (50), 219 (45), 216 (31), 177
(100), 164 (85), 136 (35), 91 (46), 41 (28); HRMS calculated
for C23H27NO2: 349.2042, found: 349.2034.
5.2.10. N-{5-Isopropoxy-4-methoxy-2-[(2E)-3-phenyl-2-
propenyl]-benzyl}-2-propen-1-amine 23.16 The N-((E)-
{5-isopropoxy-4-methoxy-2-[(2E)-3-phenyl-2-propenyl]-
phenyl}methylidene)-2-propen-1-amine 22 (6.26 mmol,
2.19 g) was dissolved in MeOH (200 cm3) and cooled to
0 ꢀC in an ice-water bath. Then sodium borohydride
(7.52 mmol, 0.294 g) was added and the reaction mixture
was allowed to warm to rt, with stirring, under an Ar atmo-
sphere for 4.5 h. After this time thin layer chromatography
showed no further change so distilled water (200 cm3) was
added to the reaction mixture. The pH was then neutralized
using 1 M HCl and saturated NaHCO3 solutions. The vola-
tiles were removed in vacuo before the aqueous layer was ex-
tracted with CH2Cl2 (4ꢂ100 cm3). The combined organics
were then extracted with distilled H2O (200 cm3) and dried
over anhydrous MgSO4. The solvent was then removed in
vacuo to give the desired product 23 as a dark yellow oil
(1.66 g, 75%). The compound contained a minor impurity
(presumed to be the isomerized compound 26) but it proved
impossible to remove this by chromatography. nmax/cmꢁ1
(NaCl plate) 1513, 1446, 1216; dH (300 MHz, CDCl3, only
major isomer listed) 1.36 (6H, d, J¼6.0 Hz, OCH(CH3)2),
1.58 (1H, br s, NH), 3.25–3.28 (2H, m, NCH2CH]CH2),
3.55 (2H, br s, ArCH2CHCH), 3.73 (2H, br s, ArCH2N),
3.82 (3H, s, OCH3), 4.53 (1H, sept, J¼6.0 Hz, OCH(CH3)2),
5.07–5.20 (2H, m, NCH2CH]CH2), 5.85–5.98 (1H, m,
NCH2CH]CH2), 6.32–6.35 (2H, m, CH]CHPh and CH]
CHPh), 6.74 (1H, s, 3-H), 6.93 (1H, s, 6-H), 7.18–7.34 (5H,
m, 5ꢂArH); dC (50 MHz, CDCl3, only major isomer listed)
22.0 (OCH(CH3)2), 35.8 (ArCH2CH), 50.2 (ArCH2N),a 51.9
(NCH2CH]CH2),a 56.1 (OCH3), 71.6 (OCH(CH3)2), 114.0
(3-C), 115.9 (CH), 117.7 (6-C), 125.9 (C), 126.0 (2ꢂCH),
127.0 (CH), 127.9 (C), 128.4 (2ꢂCH), 129.6 (CH), 130.5
(CH), 136.8 (CH), 137.4 (C), 145.6 (C), 149.5 (C); m/z
351 (M+, 18%), 294 (33), 253 (22), 252 (100), 251 (14),
237 (12), 219 (12), 204 (11), 161 (24), 91 (25); HRMS cal-
culated for C23H29NO2: 351.2198, found: 351.2193.
5.2.9. N-((E)-{5-Isopropoxy-4-methoxy-2-[(2E)-3-phenyl-
2-propenyl]phenyl}methylidene)-2-propen-1-amine
22.16 The 5-isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-pro-
penyl]-benzaldehyde 21 (6.41 mmol, 1.99 g) was trans-
ferred to the reaction flask using the minimum amount of
Et2O and the solvent was removed under high vacuum. To
the aldehyde was then added allyl amine (8.97 mmol,
0.700 cm3) and the reaction mixture was stirred at rt under
an Ar atmosphere for 21.5 h. After this time the excess allyl
amine was removed under reduced pressure and imine for-
mation was confirmed by 1H NMR spectroscopy. The prod-
uct 22 was obtained as a yellow oil (2.24 g, 100%) and no
further purification was performed. nmax/cmꢁ1 (NaCl plate)
1677, 1645, 1598, 1508, 1465, 1445, 1385, 1266, 1216; dH
(300 MHz, CDCl3, only major isomer listed) 1.37 (6H, d,
J¼6.0 Hz, OCH(CH3)2), 3.71 (2H, d, J¼2.5 Hz, ArCH2),
3.86 (3H, s, OCH3), 4.22 (2H, br d, J¼5.5 Hz, NCH2C),
4.65 (1H, sept, J¼6.0 Hz, OCH(CH3)2), 5.06–5.22 (2H, m,
ArCH2CH]CH2), 5.98–6.10 (1H, m, ArCH2CH]CH2),
6.31–6.32 (2H, m, CH]CHPh and CH]CHPh), 6.70
(1H, s, 3-H), 7.17–7.33 (5H, m, 5ꢂArH), 7.59 (1H, s, 6-
H), 8.52 (1H, s, N]CH); dC (50 MHz, CDCl3, only major
isomer listed) 22.0 (OCH(CH3)2), 35.4 (ArCH2), 55.9
(OCH3), 63.7 (NCH2CH]CH2), 71.3 (OCH(CH3)2), 113.2
(3-C), 113.6 (6-C), 115.7 (CH), 126.1 (2ꢂCH), 126.7 (C),
127.1 (CH), 128.6 (2ꢂCH), 129.3 (CH]CHPh),a 130.9
5.2.11. N-Allyl-N-{5-isopropoxy-4-methoxy-2-[(2E)-3-
phenyl-2-propenyl]benzyl}-4-methylbenzenesulfon-
amide 24a.16 N-{5-Isopropoxy-4-methoxy-2-[(2E)-3-phenyl-
2-propenyl]-benzyl}-2-propen-1-amine 23 (1.43 mmol,
0.503 g) was dissolved in CH2Cl2 (25 cm3) and the solution
was cooled to 0 ꢀC in an ice-water bath. NEt3 (2.00 mmol,
0.300 cm3) was then added and the reaction mixture was
allowed to stir for 5 min before the addition of the TsCl
(1.72 mmol, 0.331 g). The reaction mixture was then
warmed to rt with stirring for 2.5 h, before being diluted
with distilled H2O (25 cm3). The aqueous layer was then
extracted with CH2Cl2 (25 cm3); then the organic layers
were combined and washed with distilled H2O (2ꢂ25 cm3)
before being dried over anhydrous MgSO4. The solvent was
removed in vacuo to yield a dark orange oil that was then
purified by column chromatography (5–10% EtOAc–Hexane,
Rf 0.60 in 30% EtOAc–Hexane). The desired compound
24a was obtained as a yellow oil (0.521 g, 72%) that slowly
solidified into a yellow wax on standing. Mp 79–82 ꢀC;

J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
4745
nmax/cmꢁ1 (NaCl plate) 1599, 1513, 1447, 1343, 1275; dH
(300 MHz, CDCl3, only major isomer listed) 1.32 (6H, d,
J¼6.0 Hz, OCH(CH3)2), 2.43 (3H, s, ArCH3), 3.48 (2H, br
d, J¼5.0 Hz, ArCH2C), 3.70–3.74 (2H, m, NCH2CH]
CH2), 3.83 (3H, s, OCH3), 4.28–4.42 (3H, m, ArCH2N and
OCH(CH3)2), 4.84–5.00 (2H, m, NCH2CH]CH2), 5.41–
5.52 (1H, m, CH]CH2), 6.25–6.35 (2H, m, CH]CHPh
and CH]CHPh), 6.70 (1H, s, 3-H), 6.81 (1H, s, 6-H),
7.20–7.31 (7H, m, 7ꢂArH), 7.73 (2H, d, J¼8.0 Hz,
2ꢂArH); dC (50 MHz, CDCl3, only major isomer listed)
21.5 (ArCH3), 22.1 (OCH(CH3)2), 35.5 (ArCH2C), 47.8
(ArCH2N),a 49.5 (NCH2CHCH2),a 56.0 (OCH3), 71.5
(OCH(CH3)2), 113.9 (3-C), 117.3 (CH), 118.7 (6-C), 125.4
(C), 126.1 (2ꢂCH), 127.1 (CH), 127.3 (2ꢂCH), 128.3 (C),
128.5 (2ꢂCH), 129.7 (2ꢂCH), 130.8 (CH), 131.4 (CH),
132.6 (C), 137.0 (CH), 137.4 (C), 143.2 (C), 145.6 (C),
149.9 (C); m/z 505 (M+, 7%), 350 (13), 295 (15), 294 (53),
262 (39), 253 (23), 252 (100), 224 (12), 161 (22), 91 (42),
41 (15); HRMS calculated for C30H35NO4S: 505.2287, found:
505.2284.
Grubbs II catalyst 10 (5 mol %, 0.0206 mmol, 0.0176 g).
The reaction mixture was then stirred at 60 ꢀC under an
Ar atmosphere for 20 h. After this time the solvent was
removed in vacuo and the crude mixture was purified by
column chromatography (5–10% EtOAc–Hexane, Rf 0.40
in 30% EtOAc–Hexane) to give the desired compound 25a
as a milky yellow oil (0.0649 g, 39%) as well as a number
of other compounds, which were uncharacterizable in
our hands. nmax/cmꢁ1 (NaCl plate) 1600, 1517, 1425,
1334, 1216; dH (300 MHz, CDCl3) 1.32–1.39 (6H, m,
OCH(CH3)2), 2.41 (3H, br s, ArCH3), 3.41 (2H, br d,
J¼6.5 Hz, 6-H), 3.73–3.77 (2H, m, 3-H), 3.83 (3H, s,
OCH3), 4.39–4.47 (3H, m, 1-H and OCH(CH3)2), 5.41–
5.48 (1H, m, 4-H),a 5.76–5.84 (1H, m, 5-CH),a 6.61 (1H, s,
7-H),b 6.70 (1H, s, 10-H),b 7.21–7.27 (2H, m, 2ꢂArH),
7.65 (2H, d, J¼8.0 Hz, 2ꢂArH); dC (50 MHz, CDCl3) 21.5
(ArCH3), 22.1 (OCH(CH3)2), 34.3 (6-C), 43.3 (3-C), 50.5
(1-C), 56.0 (OCH3), 71.6 (OCH(CH3)2), 113.9 (CH), 118.1
(CH), 124.0 (CH), 127.2 (2ꢂCH), 128.9 (C), 129.5
(2ꢂCH), 131.1 (C), 133.3 (CH), 136.8 (C), 143.0 (C),
145.9 (C), 150.1 (C); m/z 401 (M+, 79%), 246 (47), 214
(21), 204 (100), 189 (23), 188 (21), 176 (47), 175 (63), 163
(24), 137 (26), 91 (68); HRMS calculated for
C22H27NO4S: 401.1661, found: 401.1672.
5.2.12. tert-Butyl allyl{5-isopropoxy-4-methoxy-2-[(2E)-
3-phenyl-2-propenyl]benzyl}carbamate 24b.16 The N-
{5-isopropoxy-4-methoxy-2-[(2E)-3-phenyl-2-prop-enyl]-
benzyl}-2-propen-1-amine 23 (1.47 mmol, 0.517 g) was
dissolved in freshly distilled THF (50 cm3). To this solution
was added Boc2O (1.76 mmol, 0.400 cm3) and it was stirred
for 5 min. Then DMAP (0.147 mmol, 0.0180 g) was added
and the reaction mixture was left to stir at rt under an Ar at-
mosphere for 3 h. After this time thin layer chromatography
showed consumption of the starting material so the solvent
was removed in vacuo to yield an orange oil. This was
then purified by column chromatography (5–10% EtOAc–
Hexane, Rf 0.74 in 30% EtOAc–Hexane) to obtain the
desired product 24b as a yellow oil (0.525 g, 79%). The
NMR spectra of compound 24b showed that it consisted of
a complex mixture of rotamers due to the Boc-protecting
group. nmax/cmꢁ1 (NaCl plate) 1681, 1603, 1513, 1460,
1416, 1368, 1212; dH (300 MHz, CDCl3) 1.35 (6H, d, J¼
6.0 Hz, OCH(CH3)2), 1.45 and 1.48 (9H, 2ꢂs, OC(CH3)3),
3.47 (2H, br d, J¼4.0 Hz, ArCH2C),a 3.53–3.76 (2H, very
br m, NCH2CHCH2),a 3.93 (3H, s, OCH3), 4.43–4.49 (3H,
m, ArCH2N and OCH(CH3)2), 5.02–5.10 (2H, m,
CH]CH2), 5.71–5.73 (1H, br m, CH]CH2), 6.30 (1H, br
s, CH]CHPh),b 6.73 (1H, br s, CH]CHPh),b,c 6.77 (1H,
br s, 3-H),c 7.16–7.33 (6H, m, 6-H and 5ꢂArH); dC
(50 MHz, CDCl3) 22.1 (OCH(CH3)2), 28.4 (OC(CH3)3),
35.6 (ArCH2C), 46.2 (br, ArCH2N), 48.0 (NCH2C), 56.1
(OCH3), 71.6 (OCH(CH3)2), 79.7 (OC(CH3)3), 109.9 (3-
C), 114.0 (CH), 116.4 (6-C), 126.0 (2ꢂCH), 127.0 (CH),
127.8 (C), 128.3 (C), 128.4 (2ꢂCH), 128.6 (CH), 130.6
(CH), 133.7 (CH), 137.4 (C), 145.6 (C), 149.6 (C), 155.5
(C]O); m/z 451 (M+, 22%), 295 (17), 294 (42), 281 (83),
253 (26), 252 (100), 251 (24), 239 (57), 161 (26), 91 (37),
70 (25), 57 (37); HRMS calculated for C28H37NO4:
451.2723, found: 451.2721.
5.2.14. tert-Butyl 9-isopropoxy-8-methoxy-3,6-dihydro-
2-benzazocine-2(1H)-carboxylate 25b. The tert-butyl
allyl{5-isopropoxy-4-methoxy-2-[(2E)-3-phenyl-2-propenyl]-
benzyl}carbamate 24b (0.476 mmol, 0.215 g) was dissolved
in distilled toluene (20 cm3) and the solution was heated to
60 ꢀC. Then Grubbs II catalyst 10 (5 mol %, 0.0238 mmol,
0.0237 g) was added and the reaction mixture was stirred
at 60 ꢀC under an Ar atmosphere for 22.5 h. After this
time the reaction mixture was cooled to rt and the solvent
was removed in vacuo to yield a dark brown oil. This was
then purified by column chromatography (5% EtOAc–Hex-
ane, Rf 0.58 in 30% EtOAc–Hexane) to obtain the desired
compound 25b as a viscous yellow oil (0.121 g, 73%).
1
Peak broadening was observed in the H NMR spectrum
due to the Boc-protecting group. nmax/cmꢁ1 (NaCl plate)
1683, 1603, 1513, 1464, 1411, 1369, 1268; dH (300 MHz,
CDCl3) 1.26–1.55 (15H, m, OCH(CH3)2 and OC(CH3)3),
3.36 (2H, d, J¼8.0 Hz, 6-H), 3.83–3.85 (4H, m, OCH3 and
one of NCH2CH),a 4.05 (1H, d, J¼5.0 Hz, one of
NCH2CH),a 4.44–4.53 (3H, m, ArCH2N and OCH(CH3)2),
5.65–5.91 (1H, m, 4-H),b 6.64–6.83 (1H, m, 5-H),b 7.26–
7.30 (2H, m, 7-H and 10-H); dC (50 MHz, CDCl3) 22.1
and 22.2 (OCH(CH3)2), 28.4 (OC(CH3)3), 32.6 and 33.0
(6-C), 45.0 and 45.3 (3-C), 51.6 (1-C), 56.0 (OCH3), 71.4
and 71.9 (OCH(CH3)2), 79.6 (OC(CH3)3), 113.9 and 114.3
(CH), 118.3 and 118.5 (CH), 126.0 and 126.3 (C), 127.5 and
127.9 (CH), 128.4 and 128.5 (C), 129.1 and 130.6 (CH),
131.2 and 131.5 (C), 145.0 (C), 149.5 (C]O); m/z 347 (M+,
100%), 291 (52), 290 (71), 249 (28), 204 (28), 188 (51), 179
(33), 176 (34), 175 (95), 137 (41), 57 (91), HRMS calculated
for C20H29NO4: 347.2097, found: 347.2093.
5.2.13. 9-Isopropoxy-8-methoxy-2-[(4-methylphenyl)-
sulfonyl]-1,2,3,6-tetrahydro-2-benzazocine 25a. The N-
allyl-N-{5-isopropoxy-4-methoxy-2-[(2E)-3-phenyl-2-prop-
enyl]benzyl}-4-methylbenzenesulfonamide 24a (0.411
mmol, 0.208 g) was dissolved in distilled toluene (20 cm3)
and the solution was heated to 60 ꢀC before the addition of
5.3. Cytotoxic effects—MTT assay
HT-29 (colon adenocarcinoma) cells were maintained in
DMEM containing 0.2% 60 mg/l benzyl-penicillin/100 mg/l
streptomycin and 10% foetal bovine serum (FBS). MCF-7
(breast carcinoma), K562 (chronic myelogenous leukaemia)

4746
J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
1363–1396; (b) McReynolds, M. D.; Dougherty, J. M.;
Hanson, P. R. Chem. Rev. 2004, 104, 2239–2258; (c)
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238.
and HL-60 (acute promyelocytic leukaemia) cells were rou-
tinely maintained in RPMI-1640 medium supplemented
with 10% foetal bovine serum (FBS). All cells, medium
and supplements were obtained from Highveld Biological,
South Africa.
8. For the synthesis of benzo-fused compounds by RCM from our
group, see the following recent examples and references cited
therein: (a) Pathak, R.; Panayides, J.-L.; Jeftic, T. D.; de
Koning, C. B.; van Otterlo, W. A. L. S. Afr. J. Chem. 2007,
60, 1–7 (http://blues.sabinet.co.za/sajchem/); (b) Coyanis,
E. M.; Panayides, J.-L.; Fernandes, M. A.; de Koning, C. B.;
van Otterlo, W. A. L. J. Organomet. Chem. 2006, 691, 5222–
5239; (c) van Otterlo, W. A. L.; Ngidi, E. L.; Kuzvidza, S.;
Morgans, G. L.; Moleele, S. S.; de Koning, C. B. Tetrahedron
2005, 61, 9996–10006; (d) van Otterlo, W. A. L.; Morgans,
G. L.; Madeley, L. G.; Kuzvidza, S.; Moleele, S. S.;
Thornton, N.; de Koning, C. B. Tetrahedron 2005, 61, 7746–
7755; (e) van Otterlo, W. A. L.; Coyanis, E. M.; Panayides,
J.-L.; de Koning, C. B.; Fernandes, M. A. Synlett 2005, 501–
505; (f) van Otterlo, W. A. L.; Ngidi, E. L.; de Koning, C. B.;
Fernandes, M. A. Tetrahedron Lett. 2004, 45, 659–662; (g)
van Otterlo, W. A. L.; Pathak, R.; de Koning, C. B. Synlett
2003, 1859–1861; (h) van Otterlo, W. A. L.; Ngidi, E. L.;
Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett. 2003, 44,
311–313.
The cells were seeded in 96-well plates at a density of
25,000 cells/well, in order to maintain the cells within the
exponential growth phase during testing. Cells were exposed
to a one-concentration primary screen of 100 mM compound
for 24 h at 37 ꢀC in a humidified incubator containing 5%
CO2. The effect of the compounds on cell viability was
determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyl tetrazolium bromide] assay as described by
Mosmann.17 Briefly, 50 ml 0.5% MTT solution was added
to the culture medium at the end of each experiment, and
the cells were further incubated for 2 h. The yellow MTT
dye is reduced by mitochondrial succinic dehydrogenase
of viable cells to purple formazan crystals, which were sol-
ubilized in DMSO. The optical density was read at 540 nm
against a DMSO blank. Cell numbers per well were extra-
polated from calibration curves for individual cell lines. The
percentage cell viability per well was calculated as follows:
% cell viability¼[number of viable treated cells]/[number of
viable control cells]ꢂ100%. All experiments were con-
ducted in triplicate.
9. Lane, C.; Snieckus, V. Synlett 2000, 1294–1296.
10. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J. Chem. Soc.,
Perkin Trans. 1 2000, 787–797.
11. Synthetic work done by Ms J.-L. Panayides (MSc), and Ms R.
Pathak (PhD) and biological testing by Ms H. Panagiotopoulos
(MSc).
Acknowledgements
This work was supported by the National Research Founda-
tion (NRF, GUN 2053652), Pretoria and the University of
the Witwatersrand (University and Science Faculty
Research Councils, Friedel Sellschop Award). Prof. J. P.
Michael is thanked for many helpful discussions. We also
gratefully acknowledge Mr R. Mampa and Mr T. van der
Merwe for providing the NMR and MS spectroscopy
services, respectively.
12. Crystallographic data for compound 15c: C22H27NO4S,
crystal size 0.30ꢂ0.19ꢂ0.04 mm3, crystal system monoclinic,
˚
space group P21/c, Z¼4, unit cell dimensions: a¼15.692(5) A,
˚
˚
b¼14.617(5) A,
c¼9.104(3) A,
b¼95.042(6)ꢀ,
V¼
3
2080.0(11) A , Dx¼1.282 Mg/m3, collection temperature
173(2) K; qmax¼25.00ꢀ; 10,651 reflections collected with
3670 independent reflections (Rint¼0.1309); 256 parameters;
˚
ꢁ3
˚
maximum residual electron density 0.536 and ꢁ0.550 e A
;
final R indices: R1¼0.0605, wR2¼0.1287. CCDC-626420
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.
uk/conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax (internat.): +44 1223/336-033; E-mail: deposit@
ccdc.cam.ac.uk].
References and notes
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893–930.
2. (a) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White,
A. J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org.
Chem. 2005, 70, 1545–1551; (b) Qadir, M.; Cobb, J.;
Sheldrake, P. W.; Whittall, N.; White, A. J. P.; Hii, K. K.;
Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70,
1552–1557.
13. Crystallographic data for compound 17: C22H29NO4S,
crystal size 0.35ꢂ0.24ꢂ0.07 mm3, crystal system tri-
clinic, space group
˚
P
,
Z¼4, unit cell dimensions:
ꢁ1
˚ ˚
a¼10.4070(3) A, b¼12.4260(3) A, c¼16.5460(4) A, a¼
99.2740(10)ꢀ, b¼95.2530(10)ꢀ, g¼90.3040(10)ꢀ, V¼
3. Grunewald, G. L.; Dahanukar, V. H.; Ching, P.; Criscione, K. R.
J. Med. Chem. 1996, 39, 3539–3546.
3
2102.41(9) A , Dx¼1.275 Mg/m3, collection temperature
˚
173(2) K; qmax¼28.00ꢀ; 34,736 reflections collected with
4. (a) Sato, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg. Med.
Chem. 2005, 13, 5717–5732; (b) Sato, S.; Tanioka, A.; Ikeda,
M.; Izawa, S. Bioorg. Med. Chem. Lett. 2005, 15, 1479–
1484; (c) Sato, S. Tetrahedron Lett. 2004, 45, 8475–8478.
5. Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.;
Mathee, S. Phytochemistry 1995, 40, 307–311.
10,153 independent reflections (Rint¼0.0379); 291 parameters;
ꢁ3
˚
maximum residual electron density 0.481 and ꢁ0.414 eA
;
final R indices: R1¼0.0511, wR2¼0.1332. CCDC-626421
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.
uk/conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax (internat.): +44 1223/336-033; E-mail: deposit@
ccdc.cam.ac.uk].
€
ꢀ
6. (a) Bergemann, S.; Brecht, R.; Buttner, F.; Guenard, D.; Gust,
R.; Seitz, G.; Stubbs, M. T.; Thoret, S. Bioorg. Med. Chem.
ꢀ
2003, 11, 1269–1281; (b) Brecht, R.; Seitz, G.; Guenard, D.;
Thoret, S. Bioorg. Med. Chem. 2000, 8, 557–562.
7. See the following reviews and other reviews cited therein:
(a) Schmidt, B.; Hermanns, J. Curr. Org. Chem. 2006, 10,
14. Huang, K.-S.; Wang, E.-C.; Chen, H.-M. J. Chin. Chem. Soc.
2004, 51, 585–605.

J.-L. Panayides et al. / Tetrahedron 63 (2007) 4737–4747
4747
15. For other papers commenting on the possibility of steric but-
tressing effects by ortho-groups in (i) RCM see: (a) Evans,
P.; Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 3967–
3970; (b) Evans, P.; Grigg, R.; Monteith, M. Tetrahedron
Lett. 1999, 40, 5247–5250; (ii) For Pauson–Khand reactions
see: (c) Lovely, C. J.; Seshadri, H.; Wayland, B. R.; Cordes,
A. W. Org. Lett. 2001, 3, 2607–2610.
16. The product is assumed to be mainly the E-isomer but confir-
mation of this was difficult due to the overlapping nature of
1
the alkene protons in the H NMR spectrum, so that no cou-
pling constants could be determined.
17. Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.
18. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: London, 1988.