Model studies toward the synthesis of kirkine

Article abstract of DOI:10.1039/b416763e

In model studies towards the synthesis of kirkine, the carbon skeleton was constructed using a radical cascade reaction. Two different approaches towards the synthesis have been examined as well as the regioselectivity of the radical cyclisation. The Roya

Full text of DOI:10.1039/b416763e

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A R T I C L E
Model studies toward the synthesis of kirkine
Gillian L. Barclay, Be´atrice Quiclet-Sire, Graciela Sanchez-Jimenez and Samir Z. Zard*
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, 91128, Palaiseau,
France. E-mail: zard@poly.polytechnique.fr; Fax: +33 (0)169 333851; Tel: +33 (0)169 334863
Received 8th November 2004, Accepted 15th December 2004
First published as an Advance Article on the web 28th January 2005
In model studies towards the synthesis of kirkine, the carbon skeleton was constructed using a radical cascade
reaction. Two different approaches towards the synthesis have been examined as well as the regioselectivity of the
radical cyclisation.
Introduction
Results and discussion
Kirkine (3), a lycorine type alkaloid isolated from the bulbs
of the East African grassland plant Crinum kirkii, exhibits
interesting antiviral activity. It is characterised by its galanthane
type tetracyclic skeleton, substituted on the aromatic ring by a
methoxy group at the C-9 position and a hydroxyl group at the
C-8 position. The C-1 position also bears a hydroxyl group in
the axial position and the fusion of cycles B and C is in the cis
mode.1
Two important issues needed to be addressed when planning
the synthesis of kirkine: the construction of the carbon skeleton
and the regioselectivity. Our approach hinged on a radical
cyclisation sequence to put the ring system in place, starting with
an amidyl radical produced from a thiosemicarbazide precursor
1 (Scheme 1).
The synthesis of a simplified thiosemicarbazide precursor
9 was first implemented to test our cyclisation strategy
(Scheme 2). Alkylation of commercially available ethyl 2-
oxocyclohexanecarboxylate (4) with a masked aldehyde in the
form of a dioxolane, followed by reduction of the ketone using
sodium borohydride gave alcohol 5.4 This was subsequently
transformed into the corresponding mesylate,5 which underwent
elimination upon heating in the presence of DBU to produce
olefin 6.6 The formation of hydrazide 8 was achieved by
deprotection under acidic conditions, followed by condensation
of the resulting aldehyde with thiosemicarbazide 7.7 Reduction
of the hydrazone with sodium cyanoborohydride gave the cor-
responding hydrazide 8, which was subsequently acylated with
4-methoxybenzoyl chloride to produce the requisite thiosemi-
carbazide 9.
Scheme 1 Proposed route to kirkine.
This would result in the formation of rings B and D in one step,
giving a structure in which the junction of rings B and C would be
cis, as required for the synthesis of kirkine. The feasibility of such
a radical cascade has already been demonstrated by our recent
synthesis of c-lycorane,2,3 whereby the galanthane structure was
obtained by treatment of a thiosemicarbazide precursor with
tributylstannane under reflux conditions to give c-lycorane as
a 6 : 4 mixture of regioisomers in 60% yield. Although, the
regiochemical issues for this synthesis still needed to be resolved,
this was an encouraging route for application to the synthesis of
kirkine.
Scheme 2 Reagents and conditions: i, 2-bromomethyl-1,3-dioxolane,
K2CO3–KI, DMSO, 100 ◦C, 61%; ii, NaBH4, MeOH–H2O, rt, 75%; iii,
MeSO2Cl, pyridine, rt, 76%; iv, DBU, NaI, 80 ◦C, 88%; v, 7, HCl (10%),
EtOH, rt, 93%; vi, NaBH3CN, MeOH–AcOH, 89%; vii, 4-methoxyben-
zoyl chloride, pyridine, 80 ◦C, 93%; viii, DLP, chlorobenzene, reflux,
81% (79% 10; 2% 11).
It was envisaged that the hydroxyl group on ring C of the
kirkine skeleton could be introduced early in the synthesis with
the olefin being introduced later following cyclisation, then
reduction of the lactam would produce kirkine (3).
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 2 3
©

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To avoid the use of tin as in the synthesis of c-lycorane, lauroyl
peroxide (DLP) was employed as initiator for the cyclisation
as well as an oxidant for the cyclohexadienyl radical arising
from the cyclisation to the aromatic ring (hence the need
for stoichiometric amounts). Gratifyingly, addition of lauroyl
peroxide to a refluxing solution of 9 in chlorobenzene yielded
81% of the cyclised product 10 and its isomer 11 in a ratio of 40 : 1
in favour of the cis configuration.
We next examined the regioselectivity issue. To implement
these studies, the C-9 position of the aromatic ring was
substituted with various groups exhibiting different electronic
properties in the meta position (Scheme 3).
Scheme 4 Reagents and conditions: i, SeO2–HCO2H, dioxane, reflux,
63%; ii, PhCOCl, pyridine, rt, 74%; iii, 7, HCl (10%), MeOH, rt, 80%;
iv, NaBH3CN, MeOH–AcOH, rt, 91%; v, 4-methoxybenzoyl chloride,
pyridine, 80 ◦C, 64%; vi, DLP, chlorobenzene, reflux, 71% (45% 25; 26%
26).
to that of analogue 9 (Scheme 2). The mixture of allylic alcohol
isomers 21 could be oxidised to the corresponding ketone and
then selectively reduced to give the precursor with the desired
relative stereochemistry.
Scheme 3 Reagents and conditions: i, m-RC6H4COCl, pyridine, rt; ii,
DLP, chlorobenzene, reflux.
As expected, the methyl group on the C-9 position of
hydrazide 12 did not have much effect on the regioselectivity
of the cyclisation, resulting in almost equal formation of the
para and ortho (with respect to the newly formed bond) isomers
15 and 18 respectively (1.1 : 1). The electron donating methoxy
group on 13 did, however, slightly favour the formation of the
ortho isomer 19 over the para isomer 16 (1.7 : 1). In addition,
the electron withdrawing trifluoro group on 14 favoured the
formation of the para isomer 17 over the ortho isomer 20 (2.7 : 1).
The influence of the R group on the C-9 position of the aromatic
ring was thus observed to have an interesting, but rather small
effect on the resulting regioselectivity of the radical cyclisation
and was therefore considered to be a minor concern, which we
hoped to later resolve for the overall synthesis of kirkine.
For our synthesis, the alcohol on the C-1 position of ring C
was to be introduced prior to cyclisation, followed by the olefin
later in the synthesis. Allylic oxidation of olefin 6 was therefore
accomplished with selenium dioxide in the presence of formic
acid to furnish the corresponding allylic alcohol 21 in 63% yield
(improved to 77% overall yield after regeneration of alcohol 21
from the corresponding ketone and formate ester side products)
as a mixture of isomers (2 : 1) (Scheme 4).8
The alcohol was subsequently protected as a benzoate, using
benzoyl chloride in pyridine.9 The synthesis of the thiosemicar-
bazide 23 was achieved by condensation of hydrazide 7 with
the aldehyde formed from hydrolysis of acetal 22, followed
by subsequent reduction. Acylation with 4-methoxybenzoyl
chloride gave precursor 24 in good yield. Hydrazide derivative
24 was then subjected to radical conditions, resulting in the
formation of two isomers 25 and 26 in 71% yield, in a ratio
of 1.7 : 1. It can be noticed that the presence of the benzoate
group has little influence on the cyclisation as the yield is close
The next step required the introduction of a hydroxyl group
at the C-8 position of the aromatic ring. Compound 23 had thus
to be acylated with a benzoyl chloride containing a methoxy
group in the 4-position and a protected hydroxyl group in the
3-position. The protecting group could also serve to control
the regiochemistry of the ring closure on the aromatic nucleus.
Therefore, it was thought that a bulky group such as a pivaloyl
would be sufficient to direct the cyclisation in the correct
position. Compound 23 was thus acylated with 4-methoxy-
3-pivaloylbenzoyl chloride in the presence of triethylamine to
furnish cyclisation precursor 27 (Scheme 5).10 The thiosemicar-
bazide 27 was then subjected to the action of lauroyl peroxide
to give two pairs of regioisomers in an overall yield of 66%.
The sequential cyclisation gave a 1 : 1.2 ratio of the mixture
of regioisomers, in favour of the desired para regiochemistry
(36%), of which, 15% had the same stereochemistry of kirkine,
with respect to the benzoyl group at C-1. Unfortunately, the
bulky pivalate group had not directed the cyclisation efficiently.
Surprisingly, however, when the radical cascade was per-
formed on precursor 28, containing a 3,4-dimethoxy group on
the aromatic ring, the two pairs of regioisomers were formed in
an overall improved yield of 86%. The pair of epimers with the
desired regiochemistry were produced in a total of 78% yield,
a great improvement on the previous case. The reason for this
increased and welcome regioselectivity is not clear at the moment
but may be due to a repulsion from the 4-methoxy group pushing
the neighbouring 3-methoxy into the path of the radical and
hindering its approach.
With an efficient method permitting access to the kirkine
skeleton in hand, the necessary functionalisation steps were
investigated. The remaining reactions required saponification
of the benzoate 35, followed by decarboxylation providing the
8 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

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in ethanol, followed by formation of the corresponding acid
chloride (Scheme 7). This was subsequently dissolved in a
cyclohexane–toluene mixture and added slowly to N-hydroxy-
2-thiopyridone and DMAP to give the Barton ester,11 which
furnished, upon heating, compound 40 in an overall yield
of 55%. This was then oxidised to the sulfoxide, using m-
CPBA in dichloroethane and subsequent elimination by heating
in toluene rather disappointingly gave a mixture of three
unsaturated compounds. These were not isolated, but NMR
analysis indicated the structures to be compounds 41, 42 and
43. At this point in our studies, it became evident that this route
for the synthesis of Kirkine was proving to be laborious, due to
the formation of various mixtures of different regioisomers and
stereoisomers at different stages along the synthesis.
Scheme 5 Reagents and conditions: i, 4-methoxy 3-pivaloylbenzoyl
chloride or 3,4-dimethoxybenzoyl chloride, Et3N, Et2O–heptane; ii,
DLP, chlorobenzene, reflux.
double bond on cycle C to give 38, reduction of the amide
on cycle B and finally selective deprotection of the methoxy
group on ring A (Scheme 6). It was also important to us to
recycle benzoate 32 to give the desired stereochemistry on C-1 to
increase the yield. Therefore an oxidation of the alcohols derived
from 32 was also considered followed by selective reduction to
give the correct isomer 37.
Scheme 7 Reagents and conditions: i, NaOH, EtOH, rt, 100%, ii,
(COCl)2, CH2Cl2; iii, N-hydroxy-2-thiopyridone, DMAP, toluene–
cyclohexane, reflux; iv, m-CPBA, CH2Cl2; v, reflux.
Subsequent problems were also encountered in the oxidation
of the alcohol derived from benzoate 32, in an attempt to
correct the stereochemistry.12 Under various standard oxidation
conditions decomposition was observed. It was apparent that
this route whereby the hydroxyl group was introduced early in
the synthesis was providing further stereochemical problems.
Alternative synthetic routes to try to avoid such problems were
therefore sought.
We envisaged that reductive alkylation of benzoic acid to 44,
followed by iodolactonisation,13 would provide a derivative 46
that would allow many possibilities for the functionalisation of
ring C later in the synthesis (Scheme 8). The lactone would
protect the free acid and also provide a more direct route to the
kirkine skeleton than our previous synthesis.
The synthesis of reduced product 44 under Birch conditions
was achieved in 76% yield. The acid 44 was then transformed into
the corresponding amide 45,14 followed by iodolactonisation to
furnish lactone 46 in good yield. The thiosemicarbazide radical
precursor 52 was subsequently prepared using the same methods
as in the previous synthesis. Unfortunately, when compound 52
was subjected to radical conditions, the desired cyclised product
was not formed and decomposition was observed. This is likely
to be due to the presence of the iodine resulting in subsequent
side reactions under the cyclisation conditions. The iodine was
thus removed from the lactone 46 using tributylstannane to yield
reduction product 47.15 The corresponding radical precursor
53 was synthesised using the same conditions as for analogue
52. Gratifyingly, when subjected to radical conditions, cyclised
product 54 was produced in 60% yield.
Scheme 6 Final steps required for the synthesis of kirkine.
The proposed decarboxylation was firstly tested on the simpler
cyclised analogue 10 to allow us to develop our method.
The ethyl ester of 10, was saponified using sodium hydroxide
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 2 5

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Due to the problems posed by having a halogen on the C
ring, we decided that it would be simpler and more direct
to keep both double bonds of the reduction product 44 in
place and simply protect the acid as an ester. This would
allow further functionalisation of the resulting olefin following
cyclisation. Protection of the acid using methyl iodide and DBU
gave the corresponding methyl ester, which was subsequently
transformed to the thiosemicarbazide radical precursor 58 using
standard conditions (Scheme 10). We were concerned that the
easily abstractable allylic hydrogens (corresponding to C-1)
would cause difficulties with the more reactive radicals derived
from DLP. Tributylstannane was therefore initially used to give
the desired cyclised product 59 in 55% yield.17 However, our
worries were unfounded, since with DLP the same compound
was obtained in 59% yield.
Scheme 10 Reagents and conditions: i, DBU, MeI, THF; ii, HCO2H–
H2O; iii, 7, AcOH–MeOH; iv, NaBH3CN, MeOH (80% over 4 steps);
v, 4-methoxybenzoyl chloride, DMAP, pyridine, 80 ◦C, 82%; vi, DLP,
chlorobenzene, reflux, 59%.
Scheme 8 Reagents and conditions: i, Li, NH3; ii, 2-bromomethyl-
1,3-dioxolane, THF, −78 ◦C, 76%; iii, (PhO)2P(O)N3, pyrrolidine, Et3N,
DMF, 0 ◦C, 88%; iv, I2, THF, rt, 78%; v, Bu3SnH, AIBN, benzene,
reflux; vi, HCO2H–H2O, 0 ◦C; vii, 7, AcOH–MeOH, rt; viii, NaBH3CN,
MeOH, rt; ix, 4-methoxybenzoyl chloride, DMAP, pyridine, 80 ◦C; x,
DLP, chlorobenzene, reflux.
These preliminary model studies have allowed us to establish
the feasibility of obtaining the tetracyclic structure of kirkine
with various substituents in place and without the need to use
tributylstannane. A number of difficulties were brought to light
and many were overcome. We hope to be able to use the olefin in
ring C in a compound such as 60 to both introduce the hydroxy
group at C-1 and direct the decarboxylative elimination in the
correct direction (Scheme 11).
Although we were pleased to find that the cyclisation had
been successful after the removal of the iodine, the C ring would
now be more difficult to functionalise. We therefore envisaged
replacing the iodine with the less reactive bromine. Bromo-
lactonisation of reduction product 44 was thus carried out using
NBS in DMF, but this unfortunately gave the b-lactone 55 in 91%
yield (Scheme 9).16 Bromolactonisation of the corresponding
amide 45 was also attempted, however, this gave an inseparable
mixture of the b- and c-lactones 55 and 56 respectively (1 : 1.5).
Scheme 11 Final steps envisaged for the synthesis of kirkine.
Experimental
General experimental
All reactions were carried out under an inert atmosphere.
Commercial reagents were used as received without further
purification. All products were purified using silica gel SDS 60
C. C. 40–63 or by crystallisation. NMR spectra were recorded in
Scheme 9 Reagents and conditions: i, NBS, DMF, rt, 91%; ii, NBS,
THF–H2O, rt
8 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

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CDCl3 with TMS as an internal standard at room temperature
on a Bruker AMX400 or Bruker AMX300. Infrared absorption
spectra were recorded using KBr disks with a Perkin-Elmer
1600 Fourier Transform Spectrophotometer. Mass spectra were
determined at 70 eV with an AutoSpec Micromass or an
HP 5989B mass spectrometer using ammonia as the reagent
gas. Melting points were determined by Reichert microscope
apparatus and are uncorrected.
(CH2), 25.2 (CH2), 19.5 (CH2), 18.5 (CH2), 13.5 (CH3); MS
m/z 353 (M + NH3). Minor product (yellow oil); mmax/cm−1
=
2940 (OCHO), 1727 (C O), 1353 (O2SCH3); dH (300 MHz,
CDCl3) 5.27 (1H, d, J = 4.0 Hz, CHOSO2CH3), 4.95 (1H, t, J =
5.0 Hz, OCHO), 4.14–4.24 (2H, dq, J = 6.5, 3.0 Hz, OCH2CH3),
3.80–3.98 (4H, m, OCH2CH2O), 3.07 (3H, s, SCH3), 1.37–2.16
(10H, m, 5CH2), 1.29 (3H, t, J = 7.3 Hz, CH3); dC (75 MHz,
=
CDCl3) 173.2 (C O), 101.5 (OCHO), 81.3 (CHOSO2), 65.0
(OCH2CH2O), 64.7 (OCH2CH2O), 60.6 (CH3CH2O), 48.3 (Cq),
39.2 (CH2CHO), 38.8 (SCH3), 36.7 (CH2), 36.0 (CH2), 21.7
(CH2), 19.9 (CH2), 14.0 (CH3); MS m/z 353 (M + NH3). A
solution of the sulfonyl derivative (2.9 g, 8.62 mmol) and NaI
(0.49 g, 3.5 mmol) in DBU (18.0 mL) was heated at 80 ◦C
for 7 h. Saturated aq. NH4Cl was added and the mixture was
extracted with Et2O, dried (Na2SO4) and concentrated in vacuo.
Purification by flash column chromatography (heptane–EtOAc
19 : 1) gave olefin 6 (1.8 g, 88%) as a colourless oil. mmax/cm−1 2867
1-[1,3]Dioxolan-2-ylmethyl-2-hydroxycyclohexanecarboxylic
acid ethyl ester (5)
A solution containing ethyl 2-oxocyclohexanecarboxylate (4)
(5.0 g, 29.4 mmol), 2-bromomethyl-1,3-dioxolane (9.8 g,
58.7 mmol), potassium carbonate (12.2 g, 88.1 mmol) and
potassium iodide (4.8 g, 29.4 mmol) in DMSO (30 mL) was
stirred at 100 ◦C for 20 h. When the starting material was
completely consumed, cold H2O was added and the mixture
was extracted with CHCl3, dried (Na2SO4) and the solvent
removed in vacuo. Purification by flash column chromatography
(heptane–EtOAc 19 : 1 to 9 : 1) afforded the desired alcohol
(4.6 g, 61%) as a colourless oil. mmax/cm−1 2893 (O–CH–O),
=
=
(OCHO) 1728 (C O), 733 (CH CH, cis); dH (300 MHz, CDCl3)
=
5.75–5.85 (2H, m, CH CH), 4.93 (1H, t, J = 5 Hz, OCHO),
4.12 (2H, dq, J = 7.5, 3.6 Hz, OCH2CH3), 3.78–3.96 (4H, m,
OCH2CH2O), 1.94–2.22 (2H, m, CH2) 1.54–1.74 (6H, m, CH2),
1.26 (3H, t, J = 7.0 Hz, CH3); dC (75 MHz, CDCl3) 175.7
=
1715 (C O), 945 (O–CH2–CH2–O); dH (300 MHz, CDCl3) 5.03
=
=
=
(C O), 129.3 (CH CH), 128.9 (CH CH), 102.3 (OCHO),
64.8 (OCH2CH2O), 64.7 (OCH2CH2O), 60.7 (OCH2CH3), 44.7
(Cq), 43.6 (CH2CHO), 31.4 (CH2), 24.8 (CH2), 19.5 (CH2), 14.3
(CH3); MS m/z 241 (M + H+).
(1H, t, J = 4.5 Hz, OCHO), 4.19–4.26 (2H, dq, J = 7.5, 1.2,
OCH2CH3), 3.78–3.95 (4H, m, OCH2), 2.48–2.65 (2H, m, CH2),
2.31 (1H, dd, J = 14.4, 4.2 Hz, CH2CHO), 2.00–2.04 (1H, m,
CH2), 1.90 (1H, dd, J = 14.3, 7.5 Hz, CH2CHO), 1.50–1.77 (5H,
m, CH2); 1.27 (3H, t, J = 7.2 Hz, 3H, CH3); dC (75 MHz, CDCl3)
General procedure for the preparation of thiosemicarbazones 8
and 23
=
=
207.4 (C O), 171.5 (OC O), 101.9 (OCHO), 64.8 (OCH2),
64.6 (OCH2), 61.5 (OCH2CH3), 58.7 (Cq), 40.9 (CH2CH), 39.1
(CH2), 36.7 (CH2), 27.6 (CH2), 22,4 (CH2), 14.1 (CH3); MS m/z
257 (M + H+), 274 (NH4+). The above alcohol (3.7 g, 14.5 mmol)
was dissolved in MeOH (94 mL) and sodium borohydride (1.9 g,
50.2 mmol) in H2O (20 mL) was added. The reaction mixture
was stirred at ambient temperature for 2 h. When the starting
material was consumed, aq. AcOH (10%) was added and the
solvent was removed in vacuo. The mixture was extracted with
CH2Cl2, dried (Na2SO4) and concentrated in vacuo. Purification
by flash column chromatography (heptane–EtOAc 4 : 1 to 7 :
3) gave alcohol 5 (2.8 g, 75%) as a colourless oil. mmax/cm−1
A solution of HCl (10%) in EtOH (2.4 mL) was added to a
solution of the dioxolane (1.0 mmol) dissolved in EtOH (9 mL).
Thiosemicarbazide 7 (240 mg, 1.2 mmol) was added, and the
mixture was left stirring at ambient temperature until the starting
material had been consumed. The solvent was then removed
in vacuo, H2O was added and the mixture was extracted with
Et2O. A drop of H2O was added, followed by copper sulfate,
and the mixture was left stirring, until the hydrazine had been
removed. The mixture was then filtered, washed with Et2O, dried
(Na2SO4) and the solvent removed in vacuo to give the desired
hydrazide product. The hydrazide (1.0 mmol) was then dissolved
in MeOH (8.5 mL mmol−1) and sodium cyanoborohydride
(182 mg, 2.9 mmol) was added. The solution was cooled to
0 ◦C and AcOH was added dropwise until the solution reached
a pH between 4–5. The reaction mixture was then allowed to
warm to ambient temperature and was left stirring for 20 h.
During this time a further 2.5 eq. of sodium cyanoborohydride
was added. EtOAc was added and the mixture was washed with
H2O, followed by brine, dried (Na2SO4), and the solvent removed
in vacuo to give the desired thiosemicarbazone.
=
3497 (OH), 1719 (C O), 1034 (CHOH), 943 (OCH2CH2O); dH
(300 MHz, CDCl3) 5.11 (1H, t, J = 5.0 Hz, OCHO), 4.23 (2H,
dddd, J = 11.0, 9.0, 4.5 Hz, OCH2CH3), 3.79–3.97 (2H, m,
OCH2CH2O), 3.53 (1H, s, HOCH), 2.22 (1H, dd, J = 15.0 Hz,
6.0 Hz, CH2CHO), 1.97 (1H, dd, J = 14.4, 5.0 Hz, CH2CHO),
1.47–1.92 (8H, m, CH2), 1.30 (3H, t, J = 7.1 Hz, CH3); dC
=
(75 MHz, CDCl3) 176.3 (C O), 102.3 (OCHO), 74.7 (CHOH),
65.2 (OCH2CH3), 64.0 (OCH2), 60.7 (OCH2), 49.5 (Cq), 41.3
(CH2), 32.5 (CH2), 31.3 (CH2), 23.6 (CH2), 22.3 (CH2), 14.3
(CH3); MS m/z 259 (M + H+), 276 (M + NH4+).
1-[2-(Methylsulfanylthiocarbonylphenylhydrazino)ethyl]-
cyclohex-2-enecarboxylic acid ethyl ester (8). Crystallisation
(CH2Cl2–heptane) gave the reduced product 8 (89%) as white
crystals; mp 79–80 ◦C (CH2Cl2–heptane); mmax/cm−1 3202
1-[1,3]Dioxolan-2-ylmethylcyclohex-2-enecarboxylic acid ethyl
ester (6)
Alcohol 5 (3.0 g, 11.6 mmol) was dissolved in pyridine (23.2 mL)
and MeSO2Cl (2.7 mL, 35 mmol) was added at 0 ◦C. The
reaction mixture was stirred for 30 min, allowed to warm up
to ambient temperature and left stirring for 15 h. Cold H2O and
CH2Cl2 were then added, and the mixture was extracted with
CH2Cl2, dried (Na2SO4) and concentrated in vacuo. Purification
by flash column chromatography (heptane–EtOAc 9 : 1 to
4 : 1) gave the desired mesylate product (2.9 g, 76%) as a
mixtur◦e of isomers (2 : 1). Major product (white crystals); mp
83–85 C (CH2Cl2–heptane); mmax/cm−1 2872 (O–CH–O), 1731
=
(N–H), 3028 (Ph), 1720 (C O), 1354 (SCH3), 1058 (NCSS), 731
=
(CH CH); dH (300 MHz, CDCl3) 7.31–7.45 (5H, m, CHAr),
=
5.73–5.79 (1H, dt, J = 10.6, 3.4 Hz, CH CH), 5.63 (1H, d, J =
=
10.2 Hz, CH CH), 4.08 (2H, dq, J = 7.2, 2.3 Hz, OCH2CH3),
2.86–2.92 (2H, m, NHCH2), 2.54 (3H, s, SCH3), 1.36–1.94 (7H,
m, CH2, NH), 1,19 (3H, t, J = 7.0 Hz, CH3), 0.75–0.82 (2H, m,
=
CH2); dC (75 MHz, CDCl3) 175.3 (C O), 129.2, 129.0, 128.9,
=
127.5, (5CHAr, CH CH), 60.5 (OCH2CH3), 45.3(Cq), 44.2
(CH2NH), 36.9 (CH2), 30.7 (CH2), 24.7 (CH2), 19.4 (CH2), 20.0
(SCH3), 14.1 (CH3); MS m/z 287 (M − SCSMe), 379 (M +
H+).
=
(C O), 1350 (O2S–CH3); dH (300 MHz, CDCl3) 5.01 (1H, s,
CHOSO2CH3), 4.92 (1H, t, J = 5.0 Hz, OCHO), 4.17 (2H,
m, OCH2CH3), 3.80–3.95 (4H, m, OCH2CH2O), 2.98 (3H, s,
SCH3), 2.04–1.53 (10H, m, 5CH2), 1.29 (3H, t, J = 7.5 Hz,
Benzoic acid 4-ethoxycarbonyl-4-[2-(Nꢀ-methylsulfanylthio-
carbonyl-Nꢀ-phenylhydrazino)ethyl]cyclohex-2-enyl ester (23).
Purification by flash column chromatography (heptane–EtOAc
95 : 5) gave the reduced product 23 (91%) as a colourless
=
CH3); dC (75 MHz, CDCl3) 173.2 (C O), 101.0 (OCHO),
82.6 (CHOSO2), 64.3 (OCH2CH2O), 64.1 (OCH2CH2O), 60.4
(CH3CH2O), 47.1 (Cq), 38.1 (SCH3), 36.1 (CH2CHO), 26.5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 2 7

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oil. mmax/cm−1 3290 (N–H), 1714 (C O, CO2CH2CH3, BzO),
1353 (SCH3), 1024 (N–N), 1058 (N–CS–S), 1024 (N–N),
(1H, s, CH CH), 3.98 (2H, s, OCH2CH3), 3.80 (3H, s, OCH3),
3.64 (1H, s, NCH2), 3.47 (1H, s, NCH2), 2.59 (3H, s, SCH3),
2.35–1.34 (8H, m, CH2), 1.27 (3H, s, OCH2CH3); dC (75 MHz,
=
=
=
735 (CH CH); dH (300 MHz, CDCl3) 78.03 (2H, d, J =
=
=
=
7.5 Hz, CHAr), 7.34–7.55 (8H, m, CHAr), 5.85–5.95 (2H, m,
CDCl3) 188.2 (C S), 174.8 (C O), 159.4 (N–C O), 135.9
=
=
CH CH), 5.45 (1H, s, BzOCH), 4.12–4.14 (2H, m, OCH2CH3),
(CAr), 129.5, 129.3, 128.3, 127.1 (CHAr), 118.6 (CH CH),
=
2.95 (2H, s, CH2NH), 2.54 (3H, s, SCH3), 1.53–2.29 (5H, m,
CH2, NH), 1.20–1.27 (3H, dt, J = 7.5, 2.0 Hz, CH3), 0.82–0.91
116.8 (CH CH), 60.7 (OCH2CH3), 55.2 (OCH3), 47.2 (Cq),
36.8 (CH2), 30.3 (CH2), 29.9 (CH2), 24.6 (CH2), 20.5 (SCH3),
(2H, m, CH2); dC (75 MHz, CDCl3) 174.1 (CH3CH2OC O),
19.2 (CH2), 14.0 (OCH2CH3); MS m/z 514 (M + H+).
=
=
165.8 (PhC O), 134.3, 133.2, 129.4, 129.2, 129.0, 127.8, 127.4,
126.4 (10CHAr, CH CH), 130.2 (CAr), 68.6 (BzOCH), 60.9
1-{2-[Nꢀ-Methylsulfanylthiocarbonyl-Nꢀ-phenyl-N-(3-trifluoro-
methylbenzoyl)hydrazino]ethyl}cyclohex-2-enecarboxylic acid
ethyl ester (14). Purification by flash column chromatography
(heptane–EtOAc 19 : 1) gave desired acylated product 14 (83%)
=
(OCH2CH3), 45.4 (CH2N), 44.0 (Cq), 36.3 (CH2), 27.7 (CH2),
25.6 (CH2), 20.4 (SCH3), 15.2 (CH3); MS m/z 499 (M + H+).
as a yellow oil. mmax/cm−1 1722 (C O, CO2CH2CH3), 1678
=
General procedure for the preparation of acylated
thiosemicarbazide products 9, 12–14, and 24
=
(NC O), 1266–1208 (Ar–CF3), 1072 (N–CS–S); dH (300 MHz,
CDCl3) 6.66–7.78 (9H, m, CHAr), 5.66 (1H, s, CH CH),
5.33–5.42 (1H, m, CH CH), 3.88–4.08 (2H, m, OCH2CH3),
3.31–3.55 (2H, m, NCH2), 2.48 (3H, s, SCH3), 0.76–2.27 (11H,
m, 4CH2, OCH2CH3); dC (75 MHz, CDCl3) 203.0 (C S),
175.1 (C O), 142.0 (CAr), 141.2 (CAr), 135.7 (CAr), 131.1,
130.2, 129.4, 128.4, 127.9, 127.2, 126.7, 125.2, 123.8, 121.6
(9CHAr, CH CH), 60.6 (OCH2CH3), 45.3 (Cq), 36.7 (CH2),
=
The hydrazide derivative (1.0 mmol) was dissolved in pyridine
(2.0 mL), and the acid chloride (2.0 mmol) was added. The
mixture was heated at 80 ◦C until the starting material had
been consumed. The mixture was extracted with CH2Cl2, dried
(Na2SO4) and the solvent was removed in vacuo. The oil obtained
was dissolved in a mixture of H2O–CH2Cl2, and NaHCO3 was
added, followed by a few drops of Et3N and the reaction mixture
was stirred for 12 h at ambient temperature to eliminate the
anhydride formed during the acylation. The mixture was re-
extracted with CH2Cl2, dried (Na2SO4), concentrated in vacuo
and the product purified by flash column chromatography.
=
=
=
=
31.6 (CH2), 29.1 (CH2), 24.5 (CH2), 20.4 (SCH3), 19.1 (CH2),
14.9 (OCH2CH3); 552 (M + H+).
Benzoic acid 4-ethoxycarbonyl-4-{2-[N-(4-methoxybenzoyl)-Nꢀ-
methylsulfanylthiocarbonyl-Nꢀ -phenylhydrazino]ethyl}cyclohex-
2-enyl ester (24). Purification by flash column chromatography
(heptane–EtOAc 19 : 1 to 9 : 1) gave desired acylated product 24
1-{2-[N-(4-Methoxybenzoyl)-Nꢀ-methylsulfanylthiocarbonyl-
Nꢀ-phenylhydrazino]ethyl}cyclohex-2-enecarboxylic acid ethyl
ester (9). Purification by flash column chromatography
(heptane–EtOAc 19 : 1 to 4 : 1) gave desired acylated product
(64%) as a pale yellow oil. mmax/cm−1 1720 (C O, CO2CH2CH3),
=
=
1670 (NC O), 1268, 1024 (N–CS–S); dH (300 MHz, CDCl3)
=
8.06–6.90 (14H, m, CHAr), 5.89–5.96 (2H, m, CH CH),
9 (93%) as a yellow oil. mmax/cm−1 3055 (Ph), 1727 (C O,
=
5.45 (1H, m, BzOCH), 4.10 (2H, s, OCH2CH3), 3.85 (3H, s,
CH3O), 3.79 (2H, s, NCH2), 2.61 (3H, s, SCH3), 1.55–2.26 (6H,
m, CH2), 1.23–1.26 (3H, s, OCH2CH3); dC (75 MHz, CDCl3)
203.8 (C S), 173.8 (C O, CO2CH2CH3), 166.0 (PhCO2), 161.9
(NC O), 142.6 (CAr), 133.0, 132.3, 130.3, 129.6, 129.5, 128.4,
=
CO2CH2CH3), 1674 (NC O), 1606 (Ar–OCH3), 1331 (SCH3),
1062 (NC–S-S); dH (300 MHz, CDCl3), 8.08 (1H, dd, J =
10.5, 8.7 Hz, CHAr), 7.64 (2H, d, J = 8.0 Hz, CHAr), 7.39
(2H, s, CHAr), 6.91–6.99 (4H, m, CHAr), 5.77–5.83 (1H,
m, CH CH), 5.60 (1H, s, CH CH), 4.05–4.13 (2H, m,
OCH2CH3), 3.87 (3H, s, OCH3), 3.62–3.77 (2H, m, NCH2),
2.60 (3H, s, SCH3), 2.08–2.11 (8H, m, CH2), 0.87 (3H, t,
=
=
=
=
=
=
126.9, 126.6 (14CHAr), 125.3 (CAr), 114.1, 113.8, (CH CH),
109.7 (–C–), 67.0 (CHOBz), 61.2 (OCH2CH3), 55.3 (OCH3),
47.8 (NCH2), 45.5 (Cq), 36.3 (CH2), 27.6 (CH2), 25.8 (CH2),
21.4 (SCH3), 14.0 (OCH2CH3); 552 (M + H+). Anal. calcd for
C34H36O6N2S2: C, 64.54, H 5.73; found: C, 64.89, H, 5.93%.
=
J = 7.0 Hz, OCH2CH3); dC (75 MHz, CDCl3) 171.0 (C O),
=
137.0, 133.0, 129.7, 129.6, 128.8 (CAr), 114.3 (CH CH), 113.9
=
(CH CH), 60.9 (OCH2CH3), 58.6 (Cq), 55.8 (OCH3), 45.5
(CH2), 36.9 (CH2), 30.6 (CH2), 24.9 (CH2), 20.4 (SCH3), 19.6
(CH2), 14.3 (OCH2CH3); MS m/z 287 (M − SCSMe), 514 (M +
H+). Anal. calcd for C27H32O4N2S2: C, 63.25, H 6.29; found: C,
63.32, H, 6.46%.
Benzoic acid 4-(2-{N-[3-(2,2-dimethylpropionyloxy)-4-methoxy-
benzoyl]-Nꢀ-methylsulfanylthiocarbonyl-Nꢀ-phenylhydrazino}-
ethyl)-4-ethoxycarbonylcyclohex-2-enyl ester (27)
To a solution of 4-hydroxy-4-methoxybenzoic acid (1.00 g,
6.0 mmol) in pyridine (18.0 mL), pivaloyl chloride (1.45 mL,
12.0 mmol) was added at 0 ◦C. The solution was allowed to
warm to ambient temperature and stirred for 48 h. During this
time a further 2 eq. of pivaloyl chloride were added. H2O was
then added until the mixture turned transparent and the reaction
mixture was stirred for a further 12 h. Saturated aq. NaHCO3
was added slowly and the mixture was extracted with Et2O,
dried (Na2SO4) and the solvent removed in vacuo. Crystalli-
sation (CH2Cl2–heptane) gave 1,3-(2,2-dimethylpropionyloxy)-
4-methoxybenzoic acid (1.24 g, 82%). To a solution of the
acid (0.76 g, 3.0 mmol) dissolved in freshly distilled CH2Cl2
(6.0 mL), DMF (0.25 mL), followed by oxalyl chloride (1.30 mL,
15.0 mmol) were added at 0 ◦C. The reaction mixture was
stirred for 2 h and the solvent was removed in vacuo. The acid
chloride obtained was added slowly to hydrazide 23 (0.50 g,
1.0 mmol) in Et2O (2.0 mL) and Et3N (0.8 mL) at 0 ◦C, the
reaction mixture was allowed to warm to ambient temperature
and was stirred for 3 h. The mixture was then filtered, extracted
with Et2O and work-up was carried out as described for
the general acylation procedure. Purification by flash column
chromatography (heptane–EtOAc 9 : 1 to 4 : 1) gave desired
acylated product 27 (50%) as a yellow mousse. mmax/cm−1 2930
1-{2-[N-(3-Methylbenzoyl)-Nꢀ-methylsulfanylthiocarbonyl-Nꢀ-
phenylhydrazino]ethyl}cyclohex-2-enecarboxylic acid ethyl ester
(12). Purification by flash column chromatography (heptane–
EtOAc 19 : 1 to 9 : 1) gave desired acylated product 12 (97%)
as a yellow oil. mmax/cm−1 1723 (C O, CO2CH2CH3), 1683
=
=
(NC O), 1063 (N–CS–S); dH (300 MHz, CDCl3), 7.18–7.68
=
=
(9H, m, CHAr), 5.77 (1H, m, CH CH), 5.31 (1H, s, CH CH),
3.99 (2H, m, OCH2CH3), 3.62 (2H, s, NCH2), 2.63 (3H, s,
SCH3), 2.39 (3H, s, CH3), 1.16–2.15 (8H, m, CH2), 0.88–0.90
=
(3H, s, OCH2CH3); dC (75 MHz, CDCl3) 174.7 (C O), 141.8
=
(NC O), 138.2 (CAr), 134.6 (CAr), 131.4, 130.2, 129.2,
=
128.2, 127.4, 126.7, 125.1, 123.8 (CHAr), 109.5 (CH CH),
66.2 (OCH2CH3), 44.9 (Cq), 36.7 (CH2), 30.2 (CH2), 29.5
(CH2), 24.5 (CH2), 22.5 (CH3), 21.2 (SCH3), 19.2 (CH2),
13.9 (OCH2CH3); MS m/z 498 (M + H+). Anal. calcd for
C27H32N2O3S2: C, 65.29, H 6.49; found: C, 65.61, H, 6.86%.
1-{2-[N-(3-Methoxybenzoyl)-Nꢀ -methylsulfanylthiocarbonyl-
Nꢀ-phenylhydrazino]ethyl}cyclohex-2-enecarboxylic acid ethyl
ester (13). Purification by flash column chromatography
(heptane–EtOAc 19 : 1) gave desired acylated product 13 (95%)
as a yellow oil. mmax/cm−1 1723 2872 (OCH3), 1718 (C O,
=
=
CO2CH2CH3), 1675 (NC O), 1063 (N–CS–S); dH (300 MHz,
=
=
CDCl3), 6.76–7.68 (9H, m, CHAr), 5.76 (1H, s, CH CH), 5.50
(OCH3), 1758 (O–C O, Pv), 1727 (CO2CH2CH3, BzO), 1655
8 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

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=
(N–C O), 1069 (N–CS–S); dH (300 MHz, CDCl3) 6.93–8.03
330 (M + H+). Anal. calcd for C19H23NO4: C, 69.27, H 7.04;
found: C, 68.75, H, 7.14%. Minor isomer 11 (2%); dH (300 MHz,
CDCl3) 8.41 (1H, d, J = 8.8 Hz, CHAr), 7.04–7.08 (1H, dd, J =
8.0, 2.5 Hz, CHAr), 6.93 (1H, d, J = 2.3 Hz, CHAr), 4.35 (2H,
q, J = 7.5 Hz, OCH2CH3), 4.32 (1H, d, J = 7.0 Hz, NCH),
4.12–4.21 (1H, m, NCH2), 3.93 (4H, s + m, OCH3; NCH2),
2.96–3.03 (1H, m, CH), 2.56–2.78 (2H, m, CH2), 2.01–2.14
(2H, m, CH2), 1.55–1.75 (2H, m, CH2), 1.26 (3H, t, J = 7.5 Hz,
OCH2CH3), 1.04–1.08 (2H, m, CH2); dC (75 MHz, CDCl3)
179.5 (C O), 162.4 (NC O), 143.4 (CAr), 128.6 (CHAr),
125.9 (CAr), 113.6 (CHAr), 62.5 (OCH2CH3), 52.8 (NCH),
55.2 (OCH3), 52.0 (Cq), 44.5 (NCH2), 39.0 (CH), 36.0 (CH2),
34.8 (CH2), 25.4 (CH2), 21.8 (CH2), 14.7 (OCH2CH3); MS m/z
330 (M + H+).
9-Methyl-7-oxo-2,3,4,5,11b,11c-hexahydro-1H,7H-pyrrolo-
[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester (15) and
11-methyl-7-oxo-2,3,4,5,11b,11c-hexahydro-1H,7H -pyrrolo-
[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester (18).
Purification by flash column chromatography (heptane–EtOAc
19 : 1 to 4 : 1) gave isomer 15 (35%) as white crystals; mp 103–
=
(13H, m, CHAr), 5.90–5.97 (2H, m, CH CH), 5.46 (1H, s,
BzOCH), 4.11 (2H, q, J = 7.0 Hz, OCH2CH3), 3.89 (3H, s,
CH3O), 3.80 (2H, s, NCH2), 2.59 (3H, s, SCH3), 1.58–2.30 (6H,
m, CH2), 1.36 (9H, s, CH3), 1.24 (3H, t, J = 6.8 Hz, OCH2CH3);
=
=
dC (75 MHz, CDCl3) 203.7 (C S), 176.3 (C O, CO2CH2CH3),
=
=
=
170.2 (C O, CO2Pv), 166.0, (C O, CO2Ph), 156.6, (NC O),
140.3 (CAr), 132.9, 130.3, 129.6, 129.5, 128.3, 126.4, 125.1, 124.7
=
(13CHAr), 121.9 (CAr), 121.2 (CAr), 111.8 (CH CH), 111.5
=
=
=
(CH CH), 68,6 (CHOCOPh), 61.2 (OCH2CH3), 56.2 (OCH3),
45.5 (Cq), 39.0 (CH2), 36.1 (CH2), 27.6 (3CH3), 27.0 (CH2), 25.7
(CH2), 21.0 (SCH3), 14.2 (OCH2CH3); MS m/z 734 (M + H+),
751 (M + NH4+).
Benzoic acid 4-{2-[N-(3,4-dimethoxybenzoyl)-Nꢀ-methyl-
sulfanylthiocarbonyl-Nꢀ-phenylhydrazino]ethyl}-4-
ethoxycarbonylcyclohex-2-enyl ester (28)
To a solution of 3,4-dimethoxybenzoic acid (2.19 g, 12.0 mmol)
dissolved in freshly distilled CH2Cl2 (24 mL), DMF (1.0 mL),
followed by oxalyl chloride (5.2 mL, 60.0 mmol) were added
at 0 ◦C. The reaction mixture was stirred for 2 h and the
solvent was removed in vacuo. The acid chloride obtained
was added slowly to hydrazide 23 in heptane (2.5 mL) and
Et3N (3.4 mL) at 0 ◦C, the reaction mixture was allowed to
warm to ambient temperature and was stirred for 3 h. The
mixture was then filtered, extracted with Et2O and work-up was
carried out as described for the general acylation procedure.
Purification by flash column chromatography (heptane–EtOAc
4 : 1 to 1 : 1) gave desired acylated product 28 (71%) as a white
105 ◦C; mmax/cm−1 1725 (C O, CO2CH2CH3), 1651 (NC O);
dH (300 MHz, CDCl3) 7.82 (s, 1H, CH), 7.18 (1H, d, J = 7.5 Hz,
CHAr), 7.05 (1H, d, J = 8.4 Hz, CHAr), 4.17 (2H, q, J =
6.8 Hz, OCH2CH3), 4.13 (1H, d, J = 4.8Hz, NCH), 3.80 (1H, t,
J = 10.5 Hz, NCH2), 3.58–3.68 (1H, m, NCH2), 2.99–3.06 (1H,
ddd, J = 13.0, 9.0, 4.5 Hz, CH), 2.31 (3H, s, CH3), 1.33–2.11
(6H, m, CH2), 1.25 (3H, t, J = 7.0 Hz, OCH2CH3), 1.19 (2H, s,
=
=
=
=
CH2); dC (75 MHz, CDCl3) 173.9 (C O), 163.7 (NC O),
139.9 (CAr), 136.8 (CAr), 132.7 (CHAr), 128.1 (CHAr), 127.5
(CAr), 127.3 (CHAr), 61.1 (OCH2CH3), 59.3 (NCH), 51.4
(Cq), 42.7 (NCH2), 37.1 (CH), 33.2 (CH2), 29.9 (CH2), 28.8
(CH2), 21.9 (CH2), 18.5 (CH3), 14.3 (OCH2CH3); MS m/z
314 (M + H+). Anal. calcd for C19H23NO3: C, 72.82, H, 7.40;
found: C, 72.65, H, 7.51%. Isomer 18 (31%) as white crystals;
mousse. mmax/cm−1 1715 (C O, CO2CH2CH3, Ph–CO–O), 1673
=
=
(N–C O), 1606 (Ph–OCH3), 1331 (SCH3), 1067 (N–CS–S); dH
(300 MHz, CDCl3) 6.86–8.04 (13H, m, CHAr), 5.97 (1H, s,
=
=
CH CH), 5.43 (1H, s, CH CH) 5.48–5.43 (1H, m, BzOCH),
4.13 (2H, s, OCH2CH3), 3.86–3.94 (8H, m, 2CH3O, NCH2), 2.61
(3H, s, SCH3), 1.42–2.29 (6H, m, CH2), 1.26 (3H, s, OCH2CH3);
mp 110–112 ◦C; mmax/cm−1 1725 (CO2CH2CH3), 1651 (NC O),
=
=
1592 (CH CH); dH (300 MHz, CDCl3) 7.99 (1H, d, J = 7.2 Hz,
=
=
dC (75 MHz, CDCl3) 203.3 (C S), 174.0 (C O), 166.2 (166.0)
(C O, OBz), 151.6 (NC O), 148.8 (CAr), 134.1 (CHAr),
132.9 (CHAr), 130.4 (CAr), 129.6–126.9 (11CHAr), 126.7
CHAr), 7.22–7.32 (2H, dd, J = 15.0, 7.5 Hz, CHAr), 4.25 (2H,
q, J = 7.0 Hz, OCH2CH3), 4.18 (1H, d, J = 4.0 Hz, NCH),
3.85–3.92 (2H, m, NCH2), 3.26–3.34 (1H, ddd, J = 12.5, 8.5,
4.3 Hz, CH), 2.38 (3H, s, CH3), 1.43–2.19 (6H, m, CH2), 1.33
(3H, t, J = 7.2 Hz, OCH2CH3), 1.19–1.24 (2H, s, CH2); dC
=
=
=
(CAr), 110.8 (CH CH), 68.7 (CHOBz), 61.2 (OCH2CH3), 56.0
(OCH3), 55.8 (OCH3), 48.1 (NCH2), 45.7 (Cq), 36.3 (CH2), 39.7
(CH2), 25.7 (CH2), 21.1 (SCH3), 14.2 (OCH2CH3); MS m/z 542
(M − OBz), 664 (M + H+).
=
=
(75 MHz, CDCl3) 173.0 (C O), 163.7 (NC O), 130.7 (CAr),
134.5 (CAr), 133.8 (CHAr), 128.7 (CHAr), 126.6 (CHAr),
125.9 (CHAr), 61.1 (OCH2CH3), 58.9 (CHN), 51.5 (C4), 42.6
(NCH2), 34.1 (CH), 33.3 (CH2), 28.9 (CH2), 26.7 (CH2), 21.9
(CH2), 18.5 (CH3), 14.3 (OCH2CH3); MS m/z 314 (M + H+).
Anal. calcd for C19H23NO3: C, 72.82, H 7.40; found: C, 72.43,
H, 7.21%.
General procedure for the preparation of cyclised products 10,
11, 15–20, 25, 26, and 29–36
The hydrazide (2.0 mmol) was dissolved in chlorobenzene
(10 mL) and the resulting solution was degassed under argon
for 15 min. DLP (3.0 mmol) was dissolved in chlorobenzene
(22 mL), and the solution was degassed under argon for 15 min.
The solution containing the DLP (0.5 mmol) was added every
20 min until the starting material had been consumed.
9-Methoxy-7-oxo-2,3,4,5,11b,11c-hexahydro-1H,7H-pyrrolo-
[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester (16)
and 11-methoxy-7-oxo-2,3,4,5,11b,11c-hexahydro-1H,7H-pyr-
rolo[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester (19).
Purification by flash column chromatography (heptane–EtOAc
19 : 1 to 7 : 3) gave the major isomer 16 (48%) as a pale yellow
10-Methoxy-7-oxo-2,3,4,5,11b,11c-hexahydro-1H,7H-pyrrolo-
[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester (10)
and (11). Purification by flash column chromatography
(heptane–EtOAc 19 : 1 to 3 : 2) gave the major isomer 10 (79%)
as white crystals; mp 146 ◦C; mmax/cm−1 2931 (OCH3), 1726
(C O, CO2CH2CH3), 1636 (NC O); dH (300 MHz, CDCl3)
8.04 (1H, d, J = 8.1 Hz, CHAr), 6.84–6.88 (1H, dd, J = 8.4 Hz,
2.0 Hz, CHAr), 6.72 (1H, d, J = 2.1 Hz, CHAr), 4.25 (2H, q,
J = 7.1 Hz, OCH2CH3), 4.21 (1H, d, J = 4.8 Hz, NCH), 3.91
(1H, s, NCH2), 3.81 (3H, s, CH3O), 3.63–3.73 (1H, m, NCH2),
3.06–3.13 (1H, ddd, J = 12.0, 7.5, 4.4 Hz, CH), 2.00–2.13 (2H,
m, CH2), 1.37–1.73 (4H, m, CH2), 1.32 (3H, t, J = 7.1 Hz,
OCH2CH3), 1.25–1.28 (m, 2H, CH2); dC (75 MHz, CDCl3)
oil; mmax/cm−1 1726 (C O, CO2CH2CH3), 1646 (NC O), 1605
(Ar–OCH3); dH (300 MHz, CDCl3) 7.78 (1H, d, J = 7.8 Hz,
CHAr), 7.28 (1H, t, J = 8.3 Hz, CHAr), 6.98 (1H, d, J = 7.8 Hz,
CHAr), 4.23 (2H, q, J = 6.4 Hz, OCH2CH3), 4.14 (1H, d, J =
4.5Hz, NCH), 3.84–3.87 (4H, s + m, OCH3 NCH), 3.67–3.74
(1H, m, NCH2), 3.45–3.53 (1H, ddd, J = 12.0, 8.6 4.3 Hz, CH),
1.26–2.17 (6H, m, CH2), 1.30 (3H, t, J = 6.3 Hz, OCH2CH3),
=
=
=
=
=
1.16 (2H, s, CH2); dC (75 MHz, CDCl3) 173.9 (C O), 163.4
(NC O), 155.7 (CAr), 131.2 (CAr), 129.4 (CAr), 127.4
=
(CHAr), 120.9 (CHAr), 113.4 (CHAr), 61.0 (OCH2CH3), 59.0
(NCH), 55.5 (OCH3), 51.5 (Cq), 42.6 (NCH2), 33.4 (CH2), 30.9
(CH), 28.8 (CH2), 26.7 (CH2), 21.8 (CH2), 14.2 (OCH2CH3);
MS m/z 330 (M + H+). Anal. calcd for C19H23NO4: C, 69.28,
H 7.04; found: C, 68.82, H, 7.24%. Isomer 19 (27%) as a pale
=
=
173.9 (C O), 163.5 (NC O), 145.0 (CAr), 129.8 (CHAr),
121.3 (CAr), 122.4 (CHAr), 61.1 (OCH2CH3), 59.1 (NCH),
55.4 (OCH3), 51.4 (Cq), 45.5 (NCH2), 37.9 (CH), 33.3 (CH2),
29.7 (CH2), 28.8 (CH2), 21.9 (CH2), 14.3 (OCH2CH3); MS m/z
yellow oil; mmax/cm−1 1723 (CO2CH2CH3), 1653 (N–C O),
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 2 9

View Article Online
1606 (ArOCH3); dH (300 MHz, CDCl3) 7.59 (1H, s, CHAr),
7. 13 (2H, d, J = 8.4 Hz, CHAr), 4.23 (2H, q, J = 7.2 Hz,
OCH2CH3), 4.20 (1H, d, J = 3.9 Hz, NCH), 3.86–3.91 (4H, s +
m, OCH3, NCH2), 3.63–3.74 (1H, m, NCH2), 3.03–3.10 (1H,
ddd, J = 13.0, 8.5, 4.2 Hz, CH), 1.40–2.17 (6H, m, CH2),
1.30 (3H, t, J = 7.0 Hz, OCH2CH3), 1.14 (2H, s, CH2); dC
(1H, t, J = 4.8 Hz, CH), 1.64–2.27 (6H, m, CH2), 1.33 (3H, t,
=
J = 7.0 Hz, OCH2CH3); dC (75 MHz, CDCl3) 173.7 (C O),
=
165.7 (PhCO2), 163.6 (NC O), 139.5 (CAr), 133.0 (CHAr),
130.1 (CHAr), 129.9 (CHAr), 129.3 (CHAr), 123.9 (CAr),
113.2 (CHAr), 112.5 (CHAr), 70.9 (CH), 61.4 (OCH2CH3),
57.6 (NCH), 55.3 (OCH3), 51.2 (Cq), 42.4 (NCH2), 39.9 (CH),
33.1 (CH2), 26.1 (CH2), 22.6 (CH2), 14.2 (OCH2CH3); MS m/z
450 (M + H+).
=
=
(75 MHz, CDCl3) 174.1 (C O), 163.3 (NC O), 158.7 (CAr),
135.0 (CAr), 129.6 (CAr), 128.4 (CHAr), 119.2 (CHAr), 111.1,
(CHAr), 61.0 (OCH2CH3), 59.3 (CHN), 55.5 (OCH3), 51.3
(Cq), 42.6 (NCH2), 36.9 (CH) 33.2 (CH2), 29.9 (CH2), 28.7
(CH2), 21.8 (CH2), 14.2 (OCH2CH3); MS m/z 330 (M + H+).
Anal. calcd for C19H23NO4: C, 69.28, H 7.04; found: C, 68.82,
H, 7.24%.
1-Benzoyloxy-9-(2,2-dimethylpropionyloxy)-10-methoxy-7-
oxo-2,3,4,5,11b,11c-hexahydro-1H,7H -pyrrolo[3,2,1-de]phenan-
thridine-3a-carboxylic acid ethyl ester (29) and (31), 1-
benzoyloxy-11-(2,2-dimethylpropionyloxy)-10-methoxy-7-oxo-
2,3,4,5,11b,11c-hexahydro-1H,7H-pyrrolo[3,2,1-de]phenanthri-
dine-3a-carboxylic acid ethyl ester (33) and (35). Purification
by flash column chromatography (heptane–EtOAc 19 : 1 to 3 :
2) gave two pairs of diastereoisomers in an overall yield of
65%. Isomer 29 (15%) as a pale yellow mousse; mmax/cm−1 2855
7-Oxo-9-trifluoromethyl-2,3,4,5,11b,11c-hexahydro-1H,7H-
pyrrolo[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl ester
(17) and 7-oxo-11-trifluoromethyl-2,3,4,5,11b,11c-hexahydro-
1H,7H-pyrrolo[3,2,1-de]phenanthridine-3a-carboxylic acid ethyl
ester (20). Purification by flash column chromatography
(heptane–EtOAc 19 : 1 to 7 : 3) gave the major isomer 17
=
=
(CH3), 1754 (C O, Pv), 1723 (C O, CO2CH2CH3, Bz), 1654
(NC O), 1397, 1368, 1267 (CH3); dH (300 MHz, CDCl3) 7.78
=
(40%) as white crystals; mp 109–110 ◦C; mmax/cm−1 1727 (C O,
=
(2H, d, J = 7.6 Hz, CHAr), 7.66 (1H, s, CHAr), 7.49 (1H, t, J =
7.4 Hz, CHAr), 7.39 (2H, t, J = 7.6 Hz, CHAr), 6.82 (1H, s,
CHAr), 5.38 (1H, s, CH), 4.37 (1H, d, J = 5.2 Hz, NCH), 4.26
(2H, q, J = 7.3 Hz, OCH2CH3), 3.95–4.00 (1H, m, NCH2),
3.84 (3H, s, OCH3), 3.74–3.82 (1H, m, NCH2), 3.45 (1H, t, J =
4.8 Hz, CH), 1.59–2.38 (6H, m, CH2), 1.26–1.37 (12H, s + m,
=
CO2CH2CH3), 1662 (NC O), 1165, 1124 (CF3); dH (300 MHz,
CDCl3) 8.37 (1H, s, CHAr), 7.71 (1H, d, J = 6.9 Hz, CHAr),
7.38 (1H, d, J = 6.9 Hz, CHAr), 4.26 (2H, q, J = 7.0 Hz,
OCH2CH3), 4.23 (1H, d, J = 4.3 Hz, NCH), 3.88–3.95 (1H,
m, NCH2), 3.69–3.79 (1H, m, NCH2), 3.27 (1H, ddd, J =
12.6, 8.1, 4.5Hz, CH), 1.45–2.17 (6H, m, CH2), 1.32 (3H,
t, J = 7.1 Hz, OCH2CH3), 1.27 (s, 2H, CH2); dC (75 MHz,
=
CH3); dC (75 MHz, CDCl3) 173.5 (C O), 164.5 (PhCO2), 162.7
=
(NC O), 136.5 (CAr), 133.2 (CAr), 129.7 (CAr), 128.6 (CAr),
=
=
CDCl3) 173.7 (C O), 162.2 (NC O), 146.4 (CAr), 129.2
(CAr), 128.4 (CHAr), 128.1 (CHAr), 125.0 (CHAr), 119.4
(CAr), 61.3 (OCH2CH3), 58.9 (NCH), 51.3 (Cq), 42.8 (NCH2),
37.4 (CH), 33.1 (CH2), 29.6 (CH2), 28.7 (CH2), 21.7 (CH2),
14.2 (OCH2CH3); MS m/z 368 (M + H+). Anal. calcd for
C19H20F3NO3: C, 62.12, H 5.49; found: C, 62.12, H, 5.52%.
122.2 (CAr), 110.6 (CHAr), 70.8 (CH), 61.5 (OCH2CH3), 57.8
(NCH), 56.2 (OCH3), 51.3 (Cq), 42.5 (NCH2), 39.9 (CH), 33.2
(CH2), 29.8 (CH2), 29.4 (Cq), 27.2 (3CH3), 22.8 (CH2), 14.2
(OCH2CH3); 550 (M + H+). Anal. calcd for C31H35NO8: C,
67.74, H 6.42; found: C, 68.12, H, 6.84%. Isomer 31 (21%) as
white crystals; mp 213–216 ◦C; mmax/cm−1 2854 (OCH3), 1759
Isomer 20 (15%) as a colourless oil; mmax/cm−1 1728 (C O,
=
=
=
=
(C O, Pv), 1729 (C O, CO2CH2CH3, Bz), 1660 (NC O),
1395, 1366, 1266 (CH3); dH (300 MHz, CDCl3) 8.20 (2H, d,
J = 7.2 Hz, CHAr), 7.72 (1H, s, CHAr), 7.56 (H, t, J =
7.4 Hz, CHAr), 7.43 (2H, t, J = 7.8 Hz, CHAr), 6.79 (1H, s,
CHAr), 4.98–5.04 (1H, ddd, J = 10.8, 10.8, 4.0 Hz, CH),
4.46 (1H, d, J = 4.0 Hz, NCH), 4.24–4.30 (2H, dq, J = 7.2,
3.6 Hz, OCH2CH3), 3.83–3.92 (1H, m, NCH2), 3.65–3.74
(1H, m, NCH2), 3.44 (3H, s, OCH3), 3.34–3.38 (1H, dd, J =
10.6, 4.4 Hz, CH), 2.27–2.31 (1H, m, CH2), 2.11–2.17 (3H,
m, CH2), 1.81–1.88 (1H, m, CH2), 1.60–1.69 (1H, m, CH2),
1.25–1.39 (12H, s + m, OCH2CH3, 3CH3); dC (75 MHz, CDCl3)
=
CO2CH2CH3), 1651 (NC O); dH (300 MHz, CDCl3) 8.33
(1H, d, J = 8.0 Hz, CHAr), 7.80 (1H, d, J = 7.5 Hz, CHAr),
7.47 (1H, d, J = 7.8 Hz, CHAr), 4.25 (2H, q, J = 7.2 Hz,
OCH2CH3), 4.20 (1H, d, J = 4.0 Hz, NCH), 3.73–3.91 (4H,
m, NCH2), 3.57–3.65 (1H, ddd, J = 12.3, 8.3, 4.3 Hz, CH),
1.45–2.19 (6H, m, CH2), 1.32 (3H, t, J = 7.0 Hz, OCH2CH3),
=
1.26 (2H, br s, CH2); dC (75 MHz, CDCl3) 174.6 (C O), 161.7
=
(N–C O), 141.3 (CAr), 131.8 (CHAr), 130.9 (CAr), 129.4
(CHAr), 128.2 (CAr), 127.1 (CHAr), 61.4 (OCH2CH3), 58.9
(NCH), 51.5 (Cq), 42.8 (NCH2), 34.7 (CH), 33.3 (CH2), 28.8
(CH2), 28.5 (CH2), 22.1 (CH2), 14.2 (OCH2CH3); MS m/z 368
(M + H+).
=
=
173.8 (C O), 165.5 (PhCO2), 163.2 (NC O), 153.9 (CAr),
140.2 (CAr), 137.8 (CAr), 133.8 (CHAr), 130.0 (CHAr), 128.9
(CHAr), 122.2 (–C–), 123.1 (CH), 113.0 (CH), 73.9 (CH),
61.9 (OCH2CH3), 61.5 (NCH), 56.1 (OCH3), 51.8 (Cq), 42.9
(NCH2), 42.5 (CH), 33.2 (CH2), 30.2 (Cq), 29.2 (CH2), 28.1
(CH2), 27.6 (3CH3), 14.8 (OCH2CH3); MS m/z 550 (M +
H+). Isomer 33 (17%) as an amorphous solid; mp 213–216 ◦C;
1-Benzoyloxy-10-methoxy-7-oxo-2,3,4,5,7a,11a,11b,11c-octa-
hydro-1H,7H -pyrrolo[3,2,1-de]phenanthridine-3a-carboxylic
acid ethyl ester (25) and (26). Purification by flash column
chromatography (heptane–EtOAc 9 : 1) gave the cyclised
products (71%) in a 2 : 1 ratio. Major isomer 25 (45%) as
a yellow mousse; mmax/cm−1 3583 (C O, OBz), 1720 (C O,
mmax/cm−1 1758 (O–C O, Pv), 1725 (C O, CO2CH2CH3, OBz),
4(NC O), 1366, 1319, 1267(CH3); 1395, 1366, 1266 (CH3); dH
(300 MHz, CDCl3) 6.78–8.04 (7H, m, CHAr), 5.33 (1H, s, CH),
4.36 (1H, d, J = 4.8 Hz, NCH), 4.21–4.28 (2H, m, OCH2CH3),
3.98 (1H, t, J = 10.2 Hz, NCH2), 3.78–3.82 (4H, m, OCH3,
NCH2), 3.42 (1H, t, J = 4.9 Hz, CH), 1.90–2.23 (4H, m, CH2),
1.23–1.45 (12H, m, CH3), 0.82–0.94 (2H, m, CH2); dC (75 MHz,
=
=
=
=
=
=
CO2CH2CH3), 1650 (NC O); dH (300 MHz, CDCl3) 6.76–
8.02 (8H, m, CHAr), 4.95–5.05 (1H, m, CH), 4.38 (1H, d,
J = 4.5 Hz, NCH), 4.28 (2H, q, J = 7.5 Hz, OCH2CH3),
3.85–3.95 (1H, m, NCH2), 3.66–3.78 (1H, m, NCH2), 3.55
(3H, s, OCH3), 3.32–3.38 (1H, dd, J = 10.5, 4.5 Hz, CH),
1.55–2.32 (6H, m, CH2), 1.32 (3H, t, J = 7.0 Hz, OCH2CH3);
=
=
=
=
dC (75 MHz, CDCl3) 173.4 (C O), 165.3 (C O, PhCO2),
CDCl3) 189.7 (C O), 173.2 (C O), 166.3 (PhCO2), 133.1
(CAr), 132.9, 129.8, 128.5, 128.3, 127.0 (CHAr), 126.2 (CAr),
111.1 (CHAr), 74.2 (CH), 69.4 (OCH2CH3), 61.4 (NCH), 56.2
(OCH3), 51.0 (Cq), 43.0 (NCH2), 42.5 (CH), 36.7 (CH2), 34.8
(Cq), 32.7 (CH2), 28.2 (CH2), 27.2 (3CH3), 14.4 (OCH2CH3);
MS m/z 550 (M + H+). Isomer 35 (13%) as white crystals;
=
163.3 (NC O), 140.2 (CAr), 133.1 (CHAr), 129.5 (CHAr),
128.4 (CHAr), 121.6 (CAr), 114.2 (CHAr), 113.7 (CHAr),
73.5 (CH), 61.4 (OCH2CH3), 61.1 (NCH), 55.0 (OCH3), 51.3
(Cq), 42.4 (NCH2), 39.9 (CH), 32.8 (CH2) 27.7 (CH2), 27.6
(CH2), 14.3 (OCH2CH3); 450 (M + H+). Isomer 26 (26%) as
a yellow mousse; mmax/cm−1 3576 (C O, CO2Ar), 1720 (C O,
mp 217–220 ◦C; mmax/cm−1 1756 (O–C O, Pv), 1727 ( (C O,
=
=
=
=
=
=
CO2CH2CH3), 1650 (N–C O); dH (300 MHz, CDCl3) 6.78–7.99
CO2CH2CH3, OBz), 1657, 1613 (NC O), 1366, 1281, 1325; dH
(8H, m, CHAr), 5.36 (1H, s, CH), 4.36 (1H, d, J = 5.0 Hz,
NCH), 4.30 (2H, q, J = 7.2 Hz, OCH2CH3), 3.93–3.97 (1H, m,
NCH2), 3.81 (3H, s, OCH3), 3.73–3.78 (1H, m, NCH2), 3.35
(300 MHz, CDCl3) 8.06 (1H, d, J = 7.6 Hz, CHAr), 7.96 (1H, d,
J = 8.6 Hz, CHAr), 7.77 (1H, d, J = 8.4 Hz, CHAr), 7.45–7.54
(1H, m, CHAr), 7.34–7.41 (2H, m, CHAr), 6.89 (1H, d,
8 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

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J = 8.6 Hz, CHAr), 4.92 (1H, t, J = 10.0 Hz, CH), 4.31 (1H, d,
J = 4.0 Hz, NCH), 4.17–4.26 (2H, m, OCH2CH3), 3.93–3.88
(1H, m, NCH2), 3.68–3.86 (4H, m, OCH2, NCH2), 3.45 (1H, dd,
J = 10.6, 3.6 Hz, CH), 1.60–2.26 (4H, m, CH2), 1.27–1.42
(12H, m, CH3), 0.85–0.88 (2H, m, CH2); dC (75 MHz, CDCl3)
188.2 (C O), 173.5 (CO2CH2CH3), 162.8 (NC O), 154.1
(CAr), 133.1 (CAr), 129.8 (CAr), 129.7 (CAr), 128.6 (CHAr),
126.3 (CAr), 111.1 (CHAr), 69.4 (CH), 61.4 (OCH2CH3),
57.5 (NCH), 56.1 (OCH3), 51.2 (Cq), 42.4 (NCH2), 39.6 (Cq),
36.8 (CH), 33.1 (CH2), 28.2 (CH2), 27.3 (3CH3), 22.9 (CH2),
14.4 (OCH2CH3); MS m/z 550 (M + H+). Anal. calcd for
C31H35NO8: C, 67.74, H 6.42; found: C, 67.51, H, 6.51%.
1-(1,3-Dioxolan-2-ylmethyl)-4-hydroxycyclohex-2-enecarboxylic
acid ethyl ester (21)
Formic acid (0.87 mL, 23.05 mmol) was added to a solution
of selenium dioxide (1.48 g, 23.05 mmol) in dioxane (23 mL).
Olefin 6 (2.77 g, 11.53 mmol) in dioxane (11.6 mL) was added
dropwise and the reaction mixture was heated under reflux for
7 h. The reaction mixture was allowed to cool to ambient
temperature and then filtered through Celite. H2O was then
added to the filtrate and the mixture was extracted with Et2O,
dried (Na2SO4) and the solvent removed in vacuo. Purification
by flash column chromatography (heptane–EtOAc 19 : 1 to 7 :
3) gave alcohol 21 (63%) as a colourless oil. mmax/cm−1 3434
=
=
=
(OH), 1726 (C O), 944 (O–CH–O); dH (300 MHz, CDCl3) 6.05
=
=
(1H, s, CH CH), 5.85 (2H, m, CHOH, CHCH CH), 4.91
(1H, t, J = 4.8 Hz, OCHO), 4.15 (2H, dq, J = 7.2, 3.6 Hz,
OCH2CH3), 3.77–3.95 (4H, m, OCH2CH2O), 1.55–2.33 (6H, m,
3CH2), 1.26 (3H, t, J = 7.2 Hz, CH3CH2O); dC (75 MHz, CDCl3)
1-Benzoyloxy-9,10-dimethoxy-7-oxo-2,3,4,5,11b,11c-hexa-
hydro-1H,7H-pyrrolo[3,2,1-de]phenanthridine-3a-carboxylic acid
ethyl ester (30) and (32), 1-benzoyloxy-10,11-dimethoxy-7-oxo-
2,3,4,5,11b,11c-hexahydro-1H,7H -pyrrolo[3,2,1-de]phenanthri-
dine-3a-carboxylic acid ethyl ester (34) and (36). Purification
by flash column chromatography (heptane–EtOAc 9 : 1 to
3 : 7) gave two pairs of diastereoisomers in an overall yield
of 86%. Isomer 30 (31%) as a white mousse; mmax/cm−1 2926,
=
=
=
174.8 (C O), 132.1, 129.3 (CH CH), 131.3, 129.6 (CH CH),
101.9, 101.8 (OCHO), 65.9 (CHOH), 64.7 (OCH2CH2O), 64.6
(OCH2–CH2O), 60.9 (OCH2CH3), 44.8 (Cq), 42.9 (CH2CHO),
29.5 (CH2), 28.8 (CH2), 14.1 (OCH2CH3); MS m/z 239 (M −
H2O), 257 (M + H+ − H2O), 274 (M + NH4 − H2O).
+
=
=
1726 (C O, CO2CH2CH3), 1651 (NC O); dH (300 MHz,
CDCl3) 77.79 (2H, d, J = 7.2 Hz, CHAr), 7.55 (1H, s, CHAr),
7.37–7.50 (3H, m, CHAr), 6.75 (1H, s, CHAr), 5.38 (1H, s,
CH), 4.36 (1H, d, J = 5.0 Hz, NCH), 4.29 (2H, q, J = 7.2 Hz,
OCH2CH3), 3.99–3.95 (1H, m, NCH2), 3.92 (3H, s, OCH3),
3.86 (3H, s, OCH3), 3.66–3.82 (1H, m, NCH2), 3.41 (1H, t,
J = 4.5 Hz, CH), 2.29–1.65 (4H, m, CH2), 1.35 (3H, t, J =
7.2 Hz, OCH2CH3), 1.27 (2H, s, CH2); dC (75 MHz, CDCl3)
Benzoic acid 4-(1,3-dioxolan-2-ylmethyl)-4-
ethoxycarbonylcyclohex-2-enyl ester (22)
A solution of alcohol 21 (0.50 g, 1.95 mmol) in pyridine
(10.0 mL) was cooled to 0 ◦C and benzoyl chloride (1.1 mL,
9.70 mmol) was added slowly. The reaction mixture was then
allowed to warm to ambient temperature and left stirring for
1 h. After this time the solvent was removed in vacuo, CH2Cl2
was then added, followed by NaHCO3 and the mixture was
stirred at ambient temperature for 1 h to remove the mixed
anhydride and acid formed. The mixture was then extracted
with CH2Cl2, dried (Na2SO4) and the solvent removed in vacuo.
Purification by flash column chromatography (heptane–EtOAc
19 : 1 to 4 : 1) gave the benzoyl protected isomers 22 (74%) as
white crystals in a 2 : 1 ratio. Major isomer (63%); mmax/cm−1 2886
=
=
173.9 (C O), 165.8 (PhCO2), 163.7 (NC O), 152.0 (CAr),
145.5 (CAr), 133.1 (CHAr), 130.9 (CAr), 129.7 (CHAr), 128.5
(CHAr), 124.1 (CAr), 109.8 (CHAr), 109.7 (CHAr), 70.8 (CH),
61.4 (OCH2CH3), 57.9 (NCH), 56.2 (OCH3), 56.1 (OCH3),
51.3 (Cq), 42.6 (NCH2), 39.6 (CH), 33.2 (CH2), 27.8 (CH2),
26.2 (CH2), 14.4 (OCH2CH3); 480 (M + H+). Anal. calcd
for C27H29NO7: C, 67.63, H 6.10; found: C, 68.07, H, 6.22%.
Isomer 32 (47%) as a white mousse; mmax/cm−1 1726 (C O,
CO2CH2CH3), 1651 (NC O), 1266 (CH3); dH (300 MHz,
=
=
=
=
(O–CH–O), 1716 (C OCO2CH2CH3, OBz), 716 (CH CH;
CDCl3) 8.04 (2H, d, J = 7.2 Hz, CHAr), 7.61 (1H, s, CHAr),
7.40–7.57 (3H, m, CHAr), 6.71 (1H, s, CHAr), 5.03 (1H, ddd,
J = 10.8, 10.8, 4.3 Hz, CH), 4.45 (1H, d, J = 4.5 Hz, NCH),
4.28 (2H, q, J = 7.2 Hz, OCH2CH3), 3.95–4.11 (2H, m, NCH2),
3.91 (3H, s, OCH3), 3.50 (3H, s, OCH3), 3.30 (1H, dd, J =
10.8, 4.7 Hz, CH), 1.69–2.25 (4H, m, CH2), 1.36 (3H, t, J =
7.2 Hz, OCH2CH3), 1.36 (2H, s, CH2); dC (75 MHz, CDCl3)
=
cis); dH (300 MHz, CDCl3) 8174.4 (O COCH2CH3), 166.2
=
(PhC O), 133.7, 132.9, 127.7 (5CHAr), 130.4 (CAr), 129.7
=
=
(CH CH), 128.3 (CH CH), 101.9 (OCHO), 68.7 (CHOBz),
64.8 (OCH2CH2O), 64.7 (OCH2CH2O), 61.0 (OCH2CH3), 44.7
(Cq), 42.7 (CH2CHO), 28.4 (CH2), 25.7 (CH2), 14.2 (CH3); dC
=
=
(75 MHz, CDCl3) 174.8 (C O), 132.1, 129.3 (CH CH), 131.3,
129.6 (CH CH), 101.9, 101.8 (OCHO), 65.9 (CHOH), 64.7
=
=
=
173.6 (C O), 165.2 (PhCO2), 163.4 (NC O), 151.3 (CAr),
148.6 (CAr), 133.2 (CHAr), 131.9 (CAr), 129.7 (CHAr), 128.5
(CHAr), 121.6 (CAr), 115.5 (CHAr), 110.2 (CHAr), 73.9 (CH),
61.5 (OCH2CH3), 58.0 (NCH), 56.1 (OCH3), 55.5 (OCH3),
51.5 (Cq), 42.5 (NCH2), 41.8 (CH), 32.9 (CH2), 29.8 (CH2),
22.8 (CH2), 14.2 (OCH2CH3); MS m/z 480 (M + H+). Isomer
34 (6%) as an amorphous solid; mp 213–216 ◦C; mmax/cm−1
(OCH2CH2O), 64.6 (OCH2CH2O), 60.9 (OCH2CH3), 44.8 (Cq),
42.9 (CH2CHO), 29.5 (CH2), 28.8 (CH2), 14.1 (OCH2–CH3);
MS m/z 239 (M − BzO), 256 (M − OBz + NH3). Minor isomer
(37%); mmax/cm−1 2888 (O–CH–O), 1716 (C O, CO2CH2CH3,
=
=
OBz), 716 (CH CH; cis); dH (300 MHz, CDCl3) 8.03 (2H, d, J =
7.2 Hz, CHAr), 7.56 (1H, t, J = 7.7 Hz, CHAr), 7.43 (2H, t, J =
=
7.2 Hz, CHAr), 6.10 (1H, d, J = 10.0 Hz, CH CH), 5.91 (1H,
=
=
2928, 1727 (C O, CO2CH2CH3), 1652 (NC O), 1602, 1267;
dH (300 MHz, CDCl3) 8.03 (2H, d, J = 7.2 Hz, CHAr), 7.77
(1H, d, J = 8.0 Hz, CHAr), 7.35–7.59 (3H, m, CHAr), 6.69
(1H, d, J = 9.5 Hz, CHAr), 5.37 (1H, s, CH), 4.34 (1H, d,
J = 5.5 Hz, NCH), 4.26 (2H, q, J = 6.7 Hz, OCH2CH3),
3.65–3.99 (9H, m, NCH2, 2OCH3, CH), 2.15–1.32 (m, 6H,
CH2), 0.86 (3H, t, J = 6.8 Hz, OCH2CH3); MS m/z 480 (M +
=
dd, J = 10.3, 4.0 Hz, CH CHCHOBz), 5.44 (1H, q, J = 4.2 Hz,
CHOBz), 4.98 (1H, t, J = 4.5Hz, OCHO), 4.12–4.22 (2H, dq,
J = 7.2, 2.5 Hz, OCH2CH3), 3.78–3.98 (4H, m, OCH2CH2O),
1.88–2.27 (6H, m, 3CH2), 1.27 (3H, t, J = 7.0 Hz, OCH2CH3);
=
=
dC (75 MHz, CDCl3) 174.3 (C O), 166.2 (C O, Bz), 134.7,
=
132.9, 126.2 (5CHAr), 130.6 (CAr), 129.7 (CH CH), 128.4
(CH CH), 102.1 (OCHO), 67.3 (CHOCOPh), 64.9 (OCH2),
64.7 (OCH2), 61.0 (OCH2CH3), 44.9 (Cq), 42.9 (CH2CHO),
27.5 (CH2), 25.6 (CH2), 14.2 (CH3); MS m/z 239 (M − Bz), 256
(M + NH3 − Bz).
=
H+). Isomer 36 (2%) as a white mousse; mmax/cm−1 3405 (C O,
=
=
=
Bz), 1720 (C O, CO2CH2CH3), 1653 (NC O); dH (300 MHz,
=
=
CDCl3) 173.5 (C O), 166.3 (PhCO2), 163.2 (NC O), 155.5
(CAr), 146.6 (CAr), 132.8 (CHAr), 132.1 (CAr), 130.5 (CAr),
129.9 (CHAr), 128.3 (CHAr), 124.5 (CHAr), 122.5 (CAr),
111.7 (CHAr), 74.4 (CH), 61.9 (OCH3), 61.4 (OCH2CH3), 61.1
(NCH), 55.9 (OCH3), 51.3 (Cq), 42.5 (NCH2), 35.9 (CH), 33.1
(CH2), 28.2 (CH2), 27.9 (CH2), 14.3 (OCH2CH3); MS m/z 480
(M + H+). Anal. calcd for C27H29NO7: C, 67.63, H 6.10; found:
C, 67.37, H, 6.11%.
10-Methoxy-3a-(pyridin-2-ylsulfanyl)-2,3,4,5,11b,11c-
hexhahydro-1H,7H-pyrrolo[3,2,1-de]phenanthridine-7-
(2H)-one (40)
Ester 10 (100 mg, 0.30 mmol) was added to a solution of
NaOH in EtOH (0.03 M, 1.3 mL) and the reaction mixture
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 3 1

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was stirred at ambient temperature for 30 h. The solvent was
then removed in vacuo and the residue was dissolved in H2O
and then acidified with 6 M HCl, until the saponified product
precipitated. The crystals obtained were filtered and dried in
vacuo. To a solution of the acid formed (40 mg, 0.12 mmol) in
freshly distilled CH2Cl2 (0.24 mL), a drop of DMF followed by
added dropwise over 15 min at 0 ◦C. The reaction mixture was
stirred at 0 ◦C for 3 h, diluted with Et2O, washed with brine,
dried (Na2SO4) and the solvent removed in vacuo. Purification
by flash column chromatography (EtOAc–petroleum ether 1 : 9
to 1 : 1) gave the desired amide 45 (9.1 g, 88%) as white crystals;
◦
mp 56–58 C; mmax/cm−1 1622 (C O), 1411, 1389 (NC O); dH
=
=
◦
=
oxalyl chloride (0.05 mL, 0.60 mmol) were added at 0 C. The
(400 MHz, CDCl3) 5.89 (2H, d, J = 10.0 Hz, CH CH), 5.60
=
reaction mixture was stirred for 2 h and the solvent was removed
in vacuo. N-hydroxypyridine (21 mg, 0.14 mmol) and DMAP
(3 mg, 0.02 mmol) were dissolved in a mixture of cyclohexane–
toluene (1 : 1, 0.6 mL) and the mixture was heated under reflux
for 10 min. To this mixture a solution of the acid chloride in
a mixture of cyclohexane–toluene (1 : 1, 0.6 mL) was added
via cannula and the reaction mixture was heated under reflux
for 2 h. The reaction mixture was then allowed to warm to
room temperature, filtered over Celite and the solvent removed in
vacuo. Purification by flash column chromatography (petroleum
ether–EtOAc 1 : 19) gave the Barton derivative 40 (24 mg, 55%)
as a yellow mousse. dH (300 MHz, DMSO-d6) 8.46–8.47 (1H, d,
J = 4.8 Hz, NCH), 8.01–8.04 (1H, d, J = 8.8 Hz, CHAr), 7.52–
7.56 (1H, dt, J = 7.9, 2.4 Hz, CH), 7.33–7.35 (1H, d, J = 8.4 Hz,
CH), 7.08–7.11 (1H, dt, J = 7.6, 2.4 Hz, CH), 6.84–6.86 (1H, dd,
J = 8.4, 2.4 Hz, CHAr), 6.73 (1H, d, J = 2.4 Hz, CHAr), 4.18–
4.19 (1H, d, J = 4.0 Hz, NCH), 3.82–3.88 (4H, s + m, OCH3,
NCH), 3.62–3.70 (1H, m, NCH), 3.09–3.14 (1H, m, CH), 2.44–
2.60 (2H, m, CH2), 2.09–2.13 (1H, m, CH2), 1.82–1.89 (1H, m,
CH2), 1.55–1.73 (2H, m, CH2), 1.25–1.41 (ddd, J = 16.0, 13.2,
(2H, d, J = 9.6 Hz, CH CH), 4.92 (1H, t, J = 4.4 Hz, OCHO),
3.91–3.94 (2H, m, OCH2), 3.71–3.78 (2H, m, OCH2), 3.46–3.49
(4H, m, CH2CH2), 2.70 (2H, m, CH2), 2.19 (2H, d, J = 4.0 Hz,
CH2OCHO), 1.71–1.83 (4H, m, NCH2CH2); dC (100 MHz,
=
=
=
CDCl3) 170.6 (NC O), 127.2 (2CH CH), 125.3 (2CH CH),
103.1 (CH), 64.5 (2OCH2), 48.2 (NCH2), 46.2 (NCH2), 43.6
=
(CH2CO2CH2), 27.0 (CH2CH CH), 26.1 (NCH2CH2), 23.3
(Cq); MS (CI, NH3) m/z 263 (M+), 264 (M + H+); HRMS
calcd for C15H22NO3 264.1600 found 264.1594. Anal. calcd for
C15H21NO3: C, 68.42, H 8.04; found: C, 68.37, H, 8.00%.
1-(1,3-Dioxolan-2-ylmethyl)-8-iodo-6-oxabicyclo[3.2.1]oct-2-en-
7-one (46)
Iodine (15.0 g, 58.9 mmol) was added in one portion to a
mixture of amide 45 (6.0 g, 20.3 mmol) in THF–H2O (1 :
1, 150 mL). The reaction mixture was stirred for 14 h at
ambient temperature, diluted with EtOAc, washed with sodium
thiosulfite, followed by brine, dried (Na2SO4) and the solvent
removed in vacuo. Purification by flash column chromatography
(EtOAc–petroleum ether 1 : 9) gave iodolactone 46 (5.3 g, 73%)
=
3.2 Hz, 2H, CH2); dC (75 MHz, DMSO-d6) 163.5 (NC O), 156.8
as a white solid; mp 113–115 ◦C; mmax/cm−1 1777 (C O); dH
=
(CNAr), 149.9 (CNAr), 144.9 (MeOCAr), 136.5 (CHAr), 130.2
(CHAr), 126.8 (CHAr), 121.6 (CHAr), 112.6 (CHAr), 112.4
(CHAr), 70.6 (Cq), 60.8 (NCH), 55.5 (OCH3), 42.6 (NCH2),
(CH), 36.7 (CH2), 30.5 (CH2), 29.8 (CH2), 21.2 (CH2); MS m/z
367 (M + H+).
=
(400 MHz, CDCl3) 5.85 (1H, d, J = 9.2 Hz, CH CH), 5.43
=
(1H, d, J = 9.2 Hz, CH CH), 5.09 (1H, t, J = 5.0 Hz, OCHO),
4.83 (1H, d, J = 5.6 Hz, OCH), 4.75 (1H, m, CHI), 3.93–4.04
(2H, m, OCH2), 3.79–3.89 (2H, m, OCH2), 2.83 (1H, dd, J =
19.4, 2.2 Hz, CH2), 2.55 (1H, dd, J = 19.4, 2.2 Hz, CH2), 2.29
(1H, dd, J = 14.6, 5.0 Hz, CH2OCHO), 1.95 (1H, dd, J =
1-(1,3-Dioxolan-2-ylmethyl)-2,5-cyclohexadiene-1-carboxylic
acid (44)
=
14.6, 5.0 Hz, CH2OCHO); dC (100 MHz, CDCl3) 171.4 (C O),
=
=
129.8 (2CH CH), 126.9 (2CH CH), 101.0 (CHCO2CH2),
76.5 (CHOCI), 65.1 (OCH2), 64.4 (OCH2), 46.7 (Cq), 33.7
A solution of benzoic acid (12.2 g, 100.0 mmo◦l) in THF (100 mL)
was added to ammonia (∼500 mL) at −78 C. Lithium metal
(∼2.0 g) was then added in small portions until the solution
turned blue, and maintained this colour. The solution was left
stirring at −78 ◦C for 30 min, after which a few drops of isoprene
were added until the solution turned from blue to yellow. 2-
Bromomethyl-1,3-dioxolane (21 mL, 186.0 mmol) was added
and the solution was left for 1 h at −78 ◦C, then allowed to
reflux in a water bath for 1 h, followed by the addition of
ammonium chloride (∼15 g). The ammonia was allowed to
evaporate, after which, the mixture was partitioned between
EtOAc and H2O and the layers were separated. The water layer
was acidified with HCl (2 M) and extracted with EtOAc. The
combined organic layers were washed with brine, dried (Na2SO4)
and the solvent removed in vacuo. Purification by flash column
chromatography (petroleum ether–EtOAc 9 : 1 to 7 : 3) gave
acid 44 (16.5 g, 76%) as white crystals; mp 72–73 ◦C; mmax/cm−1
=
(CH2CO2CH2), 30.1 (CH2CH CH), 24.5 (CHOCI); MS (CI,
NH3) m/z 336 (M+), 337 (M + H+), 354 (M + NH4+); HRMS
calcd for C11H14O4I 336.9937 found 336.9921. Anal. calcd for
C11H13IO4: C, 39.31, H 3.90; found: C, 39.40, H, 3.84%.
General procedure for the preparation of thiosemicarbazones 48
and 49
A solution of the acetal (1.0 mmol) in formic acid–water (9 :
1; 10 mL) was stirred at 0 ◦C for 8–10 h. After this time, the
mixture was diluted with CH2Cl2, washed with H2O, followed
by saturated aq. NaHCO3 and brine, dried (Na2SO4), and the
solvent removed in vacuo to give the corresponding aldehyde.
The aldehyde was dissolved in MeOH–AcOH (1 : 1, 0.1 mmol
mL−1) and hydrazide 7 (0.22 g, 1.1 mmol) was added. The
resulting solution was left stirring at ambient temperature for
2–12 h and the solvent was removed in vacuo. The crude mixture
was dissolved in EtOAc and washed with H2O followed by
saturated aq. NaHCO3 and brine, dried (Na2SO4), and the
solvent removed in vacuo.
=
2817–3035 (CO2H), 1702 (C O); dH (400 MHz, CDCl3) 9.75
=
(1H, br, CO2H), 5.90–5.94 (2H, m, CH CH), 5.80–5.83 (2H,
=
m, CH CH), 4.93 (1H, t, J = 4.8 Hz, OCHO), 3.89–3.95 (2H,
m, OCH2), 3.78–3.84 (2H, m, OCH2), 2.67 (2H, s, CH2), 2.11
(2H, d, J = 4.8 Hz, CH2OCHO); dC (100 MHz, CDCl3) 179.6
8-Iodo-6-oxabicyclo[3.2.1]-1-[2-(methylsulfanylthiocarbonyl-
phenylhydrazono)ethyl]oct-2-en-7-one (48). Purification by
flash column chromatography (EtOAc–petroleum ether 1 : 9)
gave the desired thiosemicarbazone derivative 48 (86%) as a
=
=
=
(C O), 126.3 (2CH CH), 125.8 (2CH CH), 101.8 (CH), 64.4
=
(2OCH2), 45.2 (Cq), 43.2 (CH2CO2CH2), 25.6 (CH2CH CH);
MS (CI, NH3) m/z 211 (M + H+), 228 (M + NH4+); HRMS
calcd for C11H15NO4 211.0970 found 211.0977. Anal. calcd for
C11H14O4: C, 62.85, H 6.71; found: C, 62.89, H, 6.67%.
white solid; mp 65–67 ◦C; mmax/cm−1 1779 (C O), 1590 (C N),
1323 (SCH3), 1220, 1075 (N–CS–S); dH (400 MHz, CDCl3)
7.45–7.53 (3H, m, CHAr), 7.16 (2H, d, J = 7.5 Hz, CHAr),
=
=
1-(1,3-Dioxolan-2-ylmethyl)-2,5-cyclohexadienyltetrahydro-1H-
1-pyrrolylmethanone (45)
=
6.80 (1H, t, J = 4.4 Hz, N CH), 5.91 (1H, dt, J = 9.6, 4.4 Hz,
=
=
CH CH), 5.43 (1H, d, J = 9.2 Hz, CH CH), 5.25 (1H, d,
J = 5.6 Hz, OCH), 4.85 (1H, d, J = 1.2 Hz, CHI), 2.65 (3H, s,
SCH3), 2.57–2.85 (4H, m, 2CH2); dC (100 MHz, CDCl3) 202.2
To a solution of acid 44 (8.3 g, 39.3 mmol), pyrrolidine
(4.1 mL, 51.1 mmol), and diphenyl phosphonylaziate (10.1 mL,
47.2 mmol) in DMF (80 mL), Et3N (12.8 mL, 88.7 mmol) was
=
=
(C S), 170.8 (C O), 142.5 (CAr), 138.4, 130.2, 129.4, 128.7,
8 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

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=
128.5, 127.4 (5 CHAr, CH CH), 76.5 (CHOCI), 47.6 (Cq),
General procedure for acylation of hydrazides 52, 53 and 58
=
=
32.1 (CH2CH N), 30.0 (CH2CH CH), 23.6 (CHOCI), 18.9
(SCH3); MS (CI, NH3) m/z 473 (M + H+); HRMS calcd
for C17H18N2O2S2I 472.9854 found 472.9838. Anal. calcd for
C17H17N2O2S2I: C, 43.23, H 3.63; found: C, 43.02, H, 3.68%.
The hydrazide derivative (0.01 g, 1.0 mmol) was dissolved
in pyridine (1.7 mL mmol−1), and 4-methoxybenzoyl chloride
(0.85 g, 5.0 mmol) followed by DMAP (0.01 g, 0.1 mmol) were
added. The mixture was heated at 80 ◦C for 12 h and the solvent
was then removed in vacuo.
1-[2-(Methylsulfanylthiocarbonylphenylhydrazono)ethyl]-6-
oxabicyclo[3.2.1]oct-2-en-7-one (49). Purification by flash
column chromatography (Et2O–petroleum ether 1 : 1) gave
the desired thiosemicarbazone derivative 49 (77%) as an oil.
8-Iodo-6-oxabicyclo[3.2.1]-1-{2-[N-(4-methoxybenzoyl)-Nꢀ-
methylsulfanylthiocarbonyl-Nꢀ -phenylhydrazino]ethyl}oct-2-en-
7-one (52). Purification by flash column chromatography
(EtOAc–petroleum ether 1 : 9 to 100% EtOAc) gave the desired
acylated hydrazide 52 (63%) as a yellow oil. mmax/cm−1 1778
mmax/cm−1 1778 (C O), 1590 (C N), 1323 (SCH3), 1219, 1075
(N–CS–S); dH (400 MHz, CDCl3) 7.46–7.56 (3H, m, CHAr),
7.14 (2H, d, J = 7.4 Hz, CHAr), 6.79 (1H, t, J = 5.0 Hz,
=
=
=
=
(C O), 1668 (N–C O), 1606 (Ar–OCH3), 1306, 1063; dH
(400 MHz, CDCl3) 7.90 (1H, br, CHAr), 7.72 (2H, d, J =
8.0 Hz, CHAr), 7.45 (4H, br, CHAr), 6.98 (2H, d, J = 6.4 Hz,
=
=
N CH), 5.76 (2H, m, CH CH), 4.87 (1H, dd, J = 6.0,
1.2 Hz, OCH), 2.67 (1H, m, CHCH2CHO), 2.59 (3H, s, SCH3),
2.43–2.47 (2H, m, CH2), 2.43–2.45 (1H, m, CH2), 2.10 (1H, m,
=
=
CHAr), 5.90 (1H, br, CH CH), 5.49 (1H, br, CH CH),
4.60 (1H, br, CH2), 3.88 (3H, s, OCH3), 2.52–2.85 (2H, m,
CH2), 2.65 (3H, s, SCH3), 2.64 (2H, m, CH2), 2.20 (2H, s,
=
=
CH2); dC (100 MHz, CDCl3) 202.2 (C S), 177.0 (C O), 143.9
=
(CH N), 138.6 (CAr), 130.2, 129.4, 128.6, 126.7 (5 CHAr,
=
CH2); dC (100 MHz, CDCl3) 162.0 (C O), 132.2, 129.5, 129.1,
128.2, 127.2, 126.5, 114.0, 113.7 (12 CAr, CH CH), 76.3
(CHOCI), 55.4 (ArOCH3), 47.4 (Cq), 30.9 (CH2CH2NH),
=
=
CH CH), 74.6 (CHOCH2), 43.7 (Cq), 37.1 (CH2CH N), 34.4
=
=
(CH2CH CH), 31.3 (CHOCH2), 18.8 (SCH3); MS (CI, NH3)
m/z 346 (M+), 347 (M + H+); HRMS calcd for C17H19N2O2S2
=
30.0 (CH2CH2NH), 27.8 (CH2CH CH), 22.8 (CHOCI), 20.6
347.0888 found 347.0896.
(SCH3); MS (CI, NH3) m/z 608 (M+); 609 (M + H+); HRMS
calcd for C25H26N2O4S2I 609.0379 found 609.0380.
1-{2-[N-(4-Methoxybenzoyl)-Nꢀ-methylsulfanylthiocarbonyl-
Nꢀ -phenylhydrazino]ethyl}-6-oxabicyclo[3.2.1]oct-2-en-7-one
(53). Purification by flash column chromatography (EtOAc–
petroleum ether 1 : 9 to 100% EtOAc) gave the desired acylated
General procedure for the preparation of hydrazides 50 and 51
The thiosemicarbazone derivative (1.0 mmol) was dissolved
in MeOH (10 mL mmol−1) and sodium cyanoborohydride
(2.5 mmol) was added. The solution was cooled to 0 ◦C and
AcOH was added dropwise until the solution reached a pH
between 4–5. The reaction mixture was then allowed to warm
up to ambient temperature and was left stirring for 12–20 h.
During this time a further 2.5 eq. of sodium cyanoborohydride
was added. EtOAc was added and the mixture was washed with
H2O, followed by brine, dried (Na2SO4), and the solvent removed
in vacuo to give the corresponding reduced hydrazide product.
hydrazide 53 (82%) as a white solid. mmax/cm−1 1771 (C O),
=
=
1670 (N–C O), 1606 (Ar–OCH3), 1304, 1063; dH (400 MHz,
CDCl3) 7.66 (2H, d, J = 6.8 Hz, CHAr), 7.32 (5H, br, CHAr),
=
6.68 (2H, d, J = 6.8 Hz, CHAr), 5.74 (1H, br, CH CH),
=
4.79 (1H, br, CH CH), 3.87–3.91 (1H, m, CH2), 3.86 (3H, s,
OCH3), 3.70–3.73 (1H, m, CH2), 2.61 (3H, s, SCH3), 2.17 (2H,
m, CH2), 2.04–2.10 (2H, br, CH2); dC (100 MHz, CDCl3) 161.6
(C O), 130.2, 129.2, 127.1, 113.5 (12 CAr, CH CH), 74.1
(CHOCH2), 55.1 (ArOCH3), 47.0 (Cq), 36.5 (CH2CH2NH),
=
=
8-Iodo-6-oxabicyclo[3.2.1]-1-[2-(Nꢀ-methylsulfanylthiocarbonyl-
Nꢀ-phenylhydrazino)ethyl]oct-2-en-7-one (50). Purification by
flash column chromatography (EtOAc–petroleum ether 1 : 9
to 3 : 7) gave the desired reduced hydrazide product 50 (91%)
=
36.3 (CH2CH2N), 31.2 (CH2CH CH), 29.6 (CHOCH2), 20.0
(SCH3); MS (CI, NH3) m/z 483 (M + H+), 500 (M + NH4+);
HRMS calcd for C25H27N2O4S2 483.1412 found 483.1400.
Methyl-1-{2-[N-(4-methoxybenzoyl)-Nꢀ-methylsulfanylthio-
carbonyl-Nꢀ -phenylhydrazono]ethyl}-2,5-cyclohexadiene carb-
oxylate (58). Purification by flash column chromatography
(EtOAc–petroleum ether 1 : 9 to 100% EtOAc) gave the desired
as a yellow oil. mmax/cm−1 3202 (N–H), 1779 (C O), 1354
=
(SCH3), 1060 (N–CS–S); dH (400 MHz, CDCl3) 7.42–7.46 (3H,
m, CHAr), 7.35 (2H, d, J = 6.8 Hz, CHAr), 5.82 (1H, d, J =
=
=
8.8 Hz, CH CH), 5.36 (1H, d, J = 9.2 Hz, CH CH), 4.63
(1H, br, OCH), 4.40 (1H, br, CHI), 3.10 (1H, br, NH), 2.99
(2H, br, CH2), 2.63 (2H, m, CH2), 2.61 (3H, s, SCH3), 2.15–2.23
(1H, m, CH2), 1.77–1.83 (1H, m, CH2); dC (100 MHz, CDCl3)
acylated hydrazide 55 (82%) as an oil. mmax/cm−1 1729 (C O),
1672 (N–C O), 1605 (Ar–OCH3); dH (400 MHz, CDCl3) 7.65
=
=
(2H, d, J = 8.0 Hz, CHAr), 7.42 (5H, br, CHAr), 6.95 (2H,
=
d, J = 8.4 Hz, CHAr), 5.89 (2H, br, CH CH), 5.66 (2H, br,
=
129.3, 129.2, 129.0, 128.7, 127.4, 126.5 (6 CAr, CH CH), 76.0
(CHOCI), 47.2 (Cq), 43.0 (CH2CH2NH), 29.7 (CH2CH2NH),
=
CH CH), 3.65 (2H, br, CH2), 3.89 (3H, s, OCH3), 3.70 (3H, s,
OCH3), 2.64 (3H, s, SCH3), 2.59 (2H, br, CH2), 2.24 (2H, br,
=
26.8 (CH2CH CH), 22.8 (CHOCI), 20.5 (SCH3); MS (CI,
NH3) m/z 475 (M + H+); HRMS calcd for C17H20N2O2S2I
=
=
CH2); dC (100 MHz, CDCl3) 174.2 (C O), 161.9 (NC O),
132.3 (CqAr), 129.6, 129.4, 128.4, 126.9, 126.8, 125.8, 113.8
475.0011 found 475.0003.
=
(11 CAr, 2CH CH), 55.4 (ArOCH3), 52.4 (CO2CH3), 46.4
=
(Cq), 35.8 (CH2CH2N), 26.0 (CH2CH CH), 20.3 (SCH3); MS
1-[2-(Nꢀ -Methylsulfanylthiocarbonyl-Nꢀ -phenylhydrazino)-
ethyl]-6-oxabicyclo[3.2.1]oct-2-en-7-one (51). Purification by
flash column chromatography (EtOAc–petroleum ether 3 :
7) gave the desired reduced hydrazide product 51 (84%) as a
(CI, NH3) m/z 497 (M + H+); HRMS calcd for C26H29N2O4S2
497.1569 found 497.1549.
1-(1,3-Dioxolan-2-ylmethyl)-6-oxabicyclo[3.2.1]oct-2-en-7-one
(47)
yellow oil. mmax/cm−1 3209 (N–H), 1775 (C O), 1350 (SCH3);
=
dH (400 MHz, CDCl3) 7.43–7.50 (3H, m, CHAr), 7.34 (2H,
=
d, J = 6.8 Hz, CHAr), 5.67–5.71 (2H, m, CH CH), 4.78
Iodolactone 46 (334 mg, 0.99 mmol) was dissolved in benzene
(15 mL) and the mixture was degassed under argon for 15 min.
Tri-n-butyltin hydride (0.34 mL, 1.10 mmol) and AIBN (12 mg,
0.08 mmol) were then added and the mixture was heated
under reflux for 1.5 h. The solvent was removed in vacuo and
purification by flash column chromatography (100% petroleum
ether to petroleum ether–Et2O 1 : 1) gave the desired lactone
(1H, d, J = 7.2 Hz, OCH), 3.07 (1H, br, CH2), 2.96 (1H, br,
CH2), 2.55 (3H, s, SCH3), 2.41 (1H, s, CH2), 2.04 (1H, br,
NH), 1.87–1.9 (4H, m, 2CH2); dC (100 MHz, CDCl3) 177.7
=
=
(C O), 131.0, 129.2, 127.3, 126.6 (6 CAr, CH CH), 74.1
(CHOCH2), 44.0 (CH2CH2NH), 43.6 (Cq), 36.5 (CH2CH2NH),
=
31.2 (CH2CH CH), 29.3 (CHOCH2), 20.0 (SCH3); MS (CI,
NH3) m/z 349 (M + H+); HRMS calcd for C17H21N2O2S2
47 (192 mg, 92%) as a colourless oil. mmax/cm−1 1770 (C O);
dH (400 MHz, CDCl3) 5.83 (1H, d, J = 8.0 Hz, CH CH),
=
=
349.1044 found 349.1046.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 3 3

View Article Online
=
5.73 (1H, d, J = 8.0 Hz, CH CH), 4.99 (1H, t, J = 5.0 Hz,
General procedure for the preparation of cyclised products 54, 59
OCHO), 4.81–4.83 (1H, m, CHO), 3.95–3.97 (2H, m, OCH2),
3.83–3.86 (2H, m, OCH2), 2.43 (2H, s, CH2), 2.39 (1H, t, J =
5.6 Hz, CH2), 2.23 (1H, dd, J = 14.5, 4.9 Hz, CH2), 2.05
(1H, d, J = 11.6 Hz, CH2), 1.99 (1H, dd, J = 14.5, 4.9 Hz,
The thiosemicarbazide derivative (1.0 mmol) was dissolved in
chlorobenzene (10 mL) and the solution was heated under
reflux and degassed under argon for 15 min. DLP (0.1 g,
0.25 mmol) was then added every 20 min, whilst heating under
reflux, until consumption of starting material was observed by
TLC (generally, this required the addition 1.5–2.0 mmol of
DLP). The solvent was removed in vacuo and purification by
column flash column chromatography gave the desired cyclised
product.
=
=
CH2); dC (100 MHz, CDCl3) 177.1 (C O), 131.1 (CH CH),
126.1 (CH CH), 101.8 (CHCO2CH2), 74.4 (CHOCH2), 64.5
(CHOCH2), 64.4 (CHOCH2), 42.5 (Cq), 37.5 (CH2CHCO2),
35.9 (CH2CH CH), 31.1 (CHOCH2); MS m/z 211 (M + H ),
=
+
=
228 (M + NH4+).
4-Methoxy-14-oxa-9-azapentacyclo[7.7.1.1.0.0]octadeca-2,4,6-
triene-8,13-dione (54). Purification by flash column chromato-
graphy (EtOAc–petroleum ether 1 : 9 to 100% EtOAc)
6-Bromo-2a-(1,3-dioxolan-2ylmethyl)-2a,5,6,6a-tetrahydro-2H-
1-benzoxet-2-one (55)
gave the desired cyclised product 54 (60%) as colourless
NBS (196 mg, 1.1 mmol) was added to acid 44 (210 mg,
1.0 mmol) in DMF (10 mL) at ambient temperature. The mixture
was left stirring for 3 h, after which EtOAc was added and
the mixture was washed with water, followed by brine, dried
(Na2SO4) and the solvent removed in vacuo. Purification by
flash column chromatography (EtOAc–petroleum ether 1 : 9)
gave lactone 55 (263 mg, 91%) as a colourless oil. mmax/cm−1
◦
crystals; mp 245–247 C; mmax/cm−1 2930 (OCH3), 1779 (C O,
=
=
CO2CH2CH3), 1646, 1604 (NC O); dH (400 MHz, CDCl3) 8.10
(1H, d, J = 8.8 Hz, CHAr), 6.88 (1H, dd, J = 8.8, 2.4 Hz,
CHAr), 6.63 (1H, s, CHAr), 4.89 (1H, t, J = 5.0 Hz, CHO),
3.97 (1H, d, J = 8.0 Hz, NCH), 3.85 (3H, s, OCH3), 3.79
(2H, dd, J = 10.2, 4.6 Hz, NCH2), 3.53 (1H, dt, J = 14.0,
8.8 Hz, CH), 2.45–2.51 (1H, m, CH2), 2.24–2.37 (2H, m, CH2),
1.91–1.98 (2H, m, CH2), 1.45–1.51 (1H, m, CH2); dC (100 MHz,
=
1826 (C O); dH (400 MHz, CDCl3) 6.00 (1H, dt, J = 9.2,
=
=
4.0 Hz, CH CH), 5.74 (1H, d, J = 10.4 Hz, CH CH),
5.12 (1H, d, J = 2.8 Hz, OCH), 5.10 (1H, t, J = 4.8 Hz,
OCHO), 4.55 (1H, dt, J = 6.4, 3.2 Hz, CHBr), 3.98–4.60
(2H, m, OCH2), 3.88–3.91 (2H, m, OCH2), 2.70–2.72 (2H,
m, CH2), 2.30 (1H, dd, J = 14.8, 4.6 Hz, CH2OCHO),
2.24 (1H, dd, J = 14.8, 4.8 Hz, CH2OCHO); dC (100 MHz,
=
=
CDCl3) 173.7 (CH3OC O), 161.7 (CAr), 160.9 (NC O),
139.8 (CAr), 129.4 (CHAr), 119.1 (CAr), 111.9 (CHAr), 111.5
(CHAr), 74.8 (CHOCH2), 57.7 (NCH), 54.4 (ArOCH3), 49.8
(Cq), 42.3 (NCH2), 34.4 (CHOCH2), 33.3 (NCH2CH2), 28.7
(CHCH2CHO), 27.0 (NCHCH); MS (CI, NH3) m/z 300 (M +
H+); HRMS calcd for C17H18NO4 300.1236 found 300.1230.
=
=
=
CDCl3) 168.2 (C O), 126.7 (CH CH), 123.3 (CH CH), 101.1
(CHCO2CH2), 74.8 (CHOCBr), 64.7 (OCH2), 64.4 (OCH2),
Methyl 10-methoxy-7-oxo-3a,4,5,7,11b,11c-hexahydro-1H-
pyrrolo[3,2,1-de]phenanthridine-3a-carboxylate (59). Purifi-
cation by flash column chromatography (EtOAc–petroleum
ether 1 : 9 to 100% EtOAc) gave the desired cyclised product
59 (59%) as a white solid; mp 113–114 ◦C; mmax/cm−1 2950
=
55.6 (Cq), 41.0 (CH2CO2CH2), 36.1 (CH2CH CH), 27.4
(CHOCI); MS 289, 291 (M + H+).
Methyl-1-[2-(Nꢀ-methylsulfanylthiocarbonyl-Nꢀ-
phenylhydrazino)ethyl]-2,5-cyclohexadiene carboxylate (57)
=
=
(OCH3), 1731 (C O, CO2CH2CH3), 1645, 1606 (NC O); dH
(400 MHz, CDCl3) 8.01 (1H, d, J = 8.6 Hz, CHAr), 6.88 (1H,
dd, J = 8.6, 2.4 Hz, CHAr), 6.75 (1H, s, CHAr), 5.97 (1H,
DBU (12.8 mL, 85.0 mmol), followed by methyl iodide (6.5 mL,
105.0 mmol) were added to a solution of acid 46 (14.9 g,
70.6 mmol) in THF (150 mL). The mixture was left stirring
for 3 h at ambient temperature, after which it was diluted with
EtOAc and washed with saturated aqueous NH4Cl, followed
by brine, dried (Na2SO4) and the solvent removed in vacuo.
This gave the desired ester (15.7 g, 100%) as a colourless oil,
=
=
m, CH CH), 5.70 (1H, d, J = 10.0 Hz, CH CH), 4.37 (1H,
d, J = 8.0 Hz, NCH), 3.90–3.95 (1H, m, CH), 3.87 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 3.41–3.49 (1H, m, CH2), 3.16–3.21
(1H, m, CH2), 2.25–2.38 (2H, m, CH2), 2.15–2.20 (1H, m,
CH2), 1.97–2.00 (1H, m, CH2); dC (100 MHz, CDCl3) 173.0
(CH3OC O), 163.3 (CAr), 162.2 (NC O), 145.4 (CAr), 130.1
(CH CH), 129.6 (CHAr), 124.9 (CH CH), 121.8 (CAr),
112.3 (CHAr), 112.1 (CHAr), 59.0 (Cq), 58.7 (NCH), 55.4
=
=
without need for further purification. mmax/cm−1 1732 (C O),
=
=
=
=
1434; dH (400 MHz, CDCl3) 5.89–5.91 (2H, m, CH CH), 5.82–
=
=
(ArOCH3), 52.5 (CO2CH3), 42.5 (CH2CH CH), 34.5 (NCH2),
5.85 (2H, m, CH CH), 4.90 (1H, t, J = 4.8 Hz, OCHO),
33.3 (NCH2CH2), 28.2 (NCHCH); MS (CI, NH3) m/z 314
(M + H+); HRMS calcd for C18H20NO4 314.1392 found
314.1397.
3.92–3.95 (2H, m, OCH2), 3.78–3.82 (2H, m, OCH2), 2.70
(2H, s, CO2CH3), 2.66–2.67 (2H, m, CH2), 2.10 (2H, d, J =
=
4.0 Hz, CH2OCHO); dC (100 MHz, CDCl3) 174.5 (C O),
=
=
127.1 (CH CH), 125.5 (CH CH), 102.0 (CHCO2CH2), 64.7
(2OCH2), 52.3 (CO2CH3), 45.6 (Cq), 43.9 (CH2CH), 25.9
Acknowledgements
+
=
(CH2CH CH); MS (CI, NH3) m/z 225 (M + H ), 242 (M +
NH4+); HRMS calcd for C10H15N3O3 225.1113 found 225.1119.
Hydrolysis of the acetal and condensation with hydrazide 7,
was carried out as described for thiosemicarbazones 48 and
49, and the following reduction as for hydrazides 50 and 51.
Purification by flash column chromatography (petroleum ether–
EtOAc 9 : 1) gave the hydrazone 58 (80%, over 3 steps) as an oil.
We thank CONACyT for a PhD grant (to G. S.-J.) and Ecole
Polytechnique for a post-doctoral fellowship (to G. L. B.).
References
1 J. Bastida, C. Codina, P. Peeters, M. Rubiralta, M. Orozco, F. J.
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2 X. Hoang-Cong, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett.,
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3 For reviews of cyclisations of nitrogen-centered radicals, see: (a) A. G.
Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543; (b) S. Z. Zard,
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4 S. Torii, T. Inokuchi, K. Mizuguchi and M. Yamazaki, J. Org. Chem.,
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5 (a) T. Imanishi, Y. Hirokawa, M. Yamashita, T. Tanaka, K. Miyashita
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mmax/cm−1 3286, 3199 (N–H), 1729 (C O), 1593, 1351 (SCH3);
=
dH (400 MHz, CDCl3) 7.47–7.53 (3H, m, CHAr), 7.36 (2H, d,
=
J = 7.2 Hz, CHAr), 5.89–5.93 (2H, m, CH CH), 5.73 (2H,
=
d, J = 10.4 Hz, CH CH), 3.72 (3H, s, CO2CH3), 2.41 (2H,
t, J = 7.6 Hz, CH2), 2.65 (2H, br, CH2), 2.56 (3H, s, SCH3),
1.98 (2H, t, J = 7.6 Hz, CH2); dC (100 MHz, CDCl3) 174.6
=
=
(C O), 129.4, 129.2, 127.6, 126.5, 126.4 (6 CAr, 2CH CH),
52.3 (CO2CH3), 46.7 (CH2CH2NH), 44.4 (CH2CH2NH), 36.7
=
(Cq), 26.1 (CH2CH CH), 20.2 (SCH3); MS (CI, NH3) m/z
363 (M + H+); HRMS calcd for C18H23N2O2S2 363.1201 found
363.1205.
8 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5

View Article Online
6 Y. Naruta, N. Nagai, Y. Arita and K. Maruyama, J. Org. Chem.,
1987, 52, 3956.
7 K. A. Jensen, U. Anthoni and A. Holm, Acta Chem. Scand., 1969,
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Kametani, M. Nishimura, K. Higurashi, Y. Suzuki, M. Tsubuki and
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10 It was observed that when pyridine was employed for the acylation,
cyclisation of the hydrazide onto the olefin took place, resulting
in formation of a 5-membered ring and expulsion of the benzoate
group.
11 D. H. R. Barton, D. Crich and W. B. Motherwell, Tetrahedron, 1985,
41, 3901.
12 The oxidation was carried out on the unseparated mixture of
stereoisomers 30 and 32.
13 C.-P. Chuang, J. C. Gallucci and D. J. Hart, J. Org. Chem., 1988, 53,
3210.
14 When iodolactonisation was carried out directly from acid 46, using
I2 and KOH in THF, the b-lactone was formed.
15 C.-P. Chuang, J. C. Gallucci, D. J. Hart and C. Hoffman, J. Org.
Chem., 1988, 53, 3218.
16 H. Yu and H. Simon, Tetrahedron, 1991, 47, 9035.
17 D. P. Curran, H. Qi, N. C. Demello and C.-H. Lin, J. Am. Chem.
Soc., 1994, 116, 8430.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 8 2 3 – 8 3 5
8 3 5