A convergent approach to huperzine A and analogues

Article abstract of DOI:10.1039/b305869g

We describe a concise and convergent synthesis of (rac)-5-methoxy-6-azatricyclco[7.3.1.0^2,7]trideca-2(7),3,5,11-tetraen -13-ol, which has the basic ring system of huperzine A, a potent inhibitor of acetylcholinesterase. We also describe the syn

Full text of DOI:10.1039/b305869g

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A convergent approach to huperzine A and analogues†
Seán A. Kelly,a Yann Foricher,a John Mann*a and Jonathan M. Bentleyb
a School of Chemistry, Queen’s University Belfast, Stranmillis Road, Belfast BT9 5AG,
Northern Ireland
b Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh,
Wokingham RG41 5UA, England
Received 29th May 2003, Accepted 7th July 2003
First published as an Advance Article on the web 18th July 2003
We describe a concise and convergent synthesis of (rac)-5-methoxy-6-azatricyclco[7.3.1.02,7]trideca-2(7),3,5,11-
tetraen-13-ol, which has the basic ring system of huperzine A, a potent inhibitor of acetylcholinesterase. We also
describe the synthesis of the novel system 5-methoxy-6-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-trien-10-one and a series
of related systems.
Table 1 Syntheses of the Heck precursors from cyclohexenone
Introduction
Product
Y
X
R
Yield (%)
Ratio syn : anti
9a
9b
10
CH
CH
N
Br
I
Br
H
H
OMe
62
36
45
3 : 2
4 : 1
3 : 2
4-substituted-cyclohexa-2,5-dienone, though the subsequent
chemistry was not productive.5 However, this work did provide
multi-gram quantities of 3-bromo-6-methoxy-2-methylpyridine
2, which was also the starting material for route B. This second
strategy involves attachment of a trisubstituted pyridine to a
4-susbtituted cyclohexenone with a subsequent intramolecular
Heck reaction to complete the construction of the basic
skeleton.
Our starting material 2 was oxidised to the aldehyde 3 via
formation of the N-oxide 4 (mCPBA), rearranged to provide
the acetate 5 (acetic anhydride), and thence the aldehyde by
hydrolysis and oxidation with manganese dioxide. The overall
yield for the process was 61% (Scheme 2).
In order to establish the optimum conditions for the intra-
molecular Heck-type reaction,6 we carried out model studies on
the aldol product 6 (X = halogen, Y = CH, R = H) produced by
reaction of the enolate of cyclohexenone 7 and either 2-bromo-
benzaldehyde or 2-iodobenzaldehyde. As shown in the Table 1,
there was only modest stereoselectivity in this reaction. The
syn-aldol product could be distinguished from the anti-product
since the coupling constant between H-6 and H-7 observed by
1H NMR was less than 4 Hz for the former products and
greater than 6 Hz for the latter products. Initial attempts to
achieve an intramolecular Heck reaction with aldol adduct 6 or
its acetate derivative proved unsuccessful. It became apparent
that the hydroxy group of 6 must be protected and that only the
Huperzine A 1 from the club moss Huperzia serrata1 has
proven activity as an inhibitor of the enzyme acetylcholin-
esterase, and extracts of the moss have been used as the basis of
Chinese folk remedies for memory loss in elderly patients. In the
USA huperzine A is undergoing clinical trials as a potential
treatment for Alzheimer’s disease (AD), while in China the
natural product has already been approved for the treatment of
AD. Huperzine A has been the target of several total syntheses
and a number of analogues have also been prepared.2
A
comprehensive review of much of the structure activity data
presently available has been provided recently by Bai3 and
Kozikowski.4 All of the synthetic approaches to date have been
essentially linear, and are thus not ideal for analogue prepar-
ation. We have been trying to devise a more convergent
approach to this interesting molecule and structural analogues
and our overall approach is summarised in Scheme 1.
Results and discussion
We have already recorded our attempts to proceed via route A,
in which a 3-pyridylcuprate was successfully reacted with a
† Electronic supplementary information (ESI) available: further
experimental details. See http://www.rsc.org/suppdata/ob/b3/b305869g/
Scheme 1 Retrosynthetic analysis.
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 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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dimethylacetamide. Around 10% of an alternative reduced tri-
cycle 12 (Y = CH, R = H) was also produced. The results of the
key experiments are summarised in Table 2. These model
studies suggested that the overall strategy was viable and we
thus turned our attentions to the huperzine precursor 10
(Y = N, X = Br, R = OMe).
Reaction of the pyridine aldehyde 3 with the enolate of
cyclohexenone 7 (LDA, THF, Ϫ78 ЊC) provided the aldol prod-
ucts 8 (Y = N, X = Br, R = OMe) as a separable mixture of
isomers in the ratio of 2 : 3 (syn : anti). The disappointing yield
of the desired syn-isomer was unexpected from previous results
in the benzene series. Each isomer was converted into its TBS
ethers 10 in good yield.
Huperzine precursor 10 was reacted under the optimised
conditions as described for 9b, but failed to provide any cyclis-
ation products. With triphenylphosphine and triethylamine in
dimethylformamide, reaction did occur to produce two major
tricyclic products : the novel system 5-methoxy-8-tert-butyl-
dimethylsilyloxy-6-azatricyclo[7.2.2.02.7]trideca-2(7),3,5-trien-
10-one 12b (Y = N, R = OMe), and the desired tricycle 11b
(Y = N and R = OMe), which has the skeleton of huperzine A
(Scheme 4 and Table 2).7 However, the yield of tricycle 11b was
less than 10% in all experiments, and it was clear that major
modifications would be required if the natural product and
analogues were to be obtained in useful quantities.
Scheme 2 Reagents and conditions: (i) m-CPBA, CHCl3, rt, 15 h, 91%;
(ii) Ac2O, 120 ЊC, 2 h, 80%; (iii) a) K2CO3, MeOH, rt, 40 min, quant.,
b) MnO2, CHCl3, rt, 12 h, 84%.
syn-aldol product as its TBS ether 9 (Scheme 3) would provide
the desired tricycle 11 (Y = CH, R = H) (Scheme 4). Molecular
modelling studies suggest that there is steric impedance to the
anti-isomer cyclising.
The acetate 5 was hydrolysed to the alcohol 13 and then
converted into the iodide 14. Alternatively, bromide 15 was
synthesised by NBS bromination8 of 3-bromo-6-methoxy-2-
methylpyridine 2 (Scheme 5).
Scheme 3 Reagents and conditions: (i) LDA, THF, Ϫ78 ЊC, 1 h, then
aldehyde, Ϫ78 ЊC, 2 h; (ii) TBSOTfl, Et3N, THF, 0 ЊC, 2 h.
Scheme
5
Reagents and conditions: (i) K2CO3, MeOH, 95%;
(ii) imidazole, Ph3P, iodine, DCM, 66%; (iii) NBS, AIBN, CCl4, AcOH,
hν 71%.
Attempted alkylations with the kinetic enolate from cyclo-
hexenone provided a number of products in low yield, but
alkylation with cyclohexanone was very effective to provide the
ketone 16 (Scheme 6). Reaction of ketone 16 with LDA and
PhSeCl in THF–DMPU produced the syn- and anti-phenyl-
seleno-derivatives 17 as a separable mixture of isomers (syn :
Scheme 4 Intramolecular Heck ring closure with TBS silyl ethers
precursors.
1
anti 2 : 3).9 The H NMR spectra of these two isomers were
quite different, and most significantly, for compound syn-17
2-H appeared at 4.11 ppm (dd) with 6-H at 3.20 ppm (m), while
for compound anti-17 both 2-H and 6-H appeared as a complex
multiplet at 3.95 ppm. The syn–anti mixture readily yielded the
alkylated cyclohexenone 18 (77% isolated yield) upon treatment
with sodium periodate.9
The highest yield (46%) of 11 (Y = CH, R = H) from the
precursor 9a was produced when palladium acetate (0.1 equiv.)
was used in conjunction with tri-(o-tolyl)phosphine (0.2 equiv.)
as ligand and triethylamine (12 equiv.) as base in dimethyl-
formamide. However, this poor yield could be raised to around
60% when the same palladium complex and iodide 9b were
employed in the presence of pentamethylpiperidine (2 equiv.) in
The carbocyclic model compound 21 was produced in a simi-
lar way from 2-bromobenzyl bromide via the alkylated product
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Table 2 Study of intramolecular Heck ring closure with TBS silyl ethers precursors
Precursor
Y
X
R
Liganda
Baseb
Solvent
Yield 11 : 12 (%)
syn-9a
syn-9b
syn-10
CH
CH
N
Br
I
H
PPh3
POT
PPh3
POT
PPh3
Et3N
Et3N
Et3N
PMP
Et3N
CH3CN
DMF
CH3CN
DMA
21 : 23
47 : 27
30 : 11
60 : 11
8 : 40
H
Br
OMe
DMF
a 0.4 equivalent of PPh3 or 0.2 equivalent of tri(o-tolyl)phosphine (POT) was used. b 12 equivalents of Et3N or 2 equivalents of 1,2,2,6,6-
pentamethylpiperidine (PMP) were used.
Table 3
Table 4 Study of intramolecular Heck ring closure with alkylated
precursor 21
Product
Y
R
Yield (%)
Ratio syn : anti
Yield (%)
16
17
18
19
20
21
N
N
N
CH
CH
CH
OMe
OMe
OMe
H
H
H
81
86
77
83
85
78
Base (equiv.)
Ligand (equiv.)a
Solvent
22
23
24
2 : 3
2 : 3
Et3N (12)
Et3N (12)
Et3N (12)
PMP (2)
PMP (2)
Et3N (12)
PPh3 (0.2)
PPh3 (0.4)
POT (0.2)
PPh3 (0.4)
POT (0.2)
PPh3 (0.4)
DMF
DMF
DMF
DMF
DMF
DMA
14
48
22
44
21
63
8
19
4
5
16
25
—
—
3
—
16
6
a POT = tri(oϪtolyl)phosphine. PMP = 1,2,2,6,6-pentamethylpiper-
idine.
NMR spectrum of molecule 23 showed two olefinic signals at
5.71 and 5.87 ppm. Analysis of the 13C NMR spectrum con-
firmed the presence of 2 olefinic carbons 11-C and 12-C, as well
as two C-H groups and two CH2 groups. Together with HetCor
and COSY data, the structure 23 was assigned to the molecule.
The mechanisms suggested for formation of cycloadducts 22,
23 and 24 are outlined in Scheme 8.
A 6-exo-trig cyclisation affords compound 23, due to
syn-elimination of proton Hb and the palladium() species
from intermediate 25 (Scheme 8). syn β-Elimination with Ha
was impossible.
Formation of intermediate 26 involves
a 7-endo-trig
cyclisation. However, this intermediate does not possess a syn
β-hydrogen and furthermore it is difficult to form a double
bond at such a bridgehead position. It is then proposed that
nucleophilic displacement of the palladium() species by a
hydride ion yields the tricycle 22, although the source of the
hydride ion has not been resolved.
Tricycle 24 is most likely to be formed via double bond
migration from 23. The mechanism probably involves a Pd
metal hydride addition–elimination (Scheme 8), since pal-
ladium hydride species are often intermediates in catalytic
reactions. The hydride adds to the double bond of 23, providing
an unstable alkylpalladium species with a β-hydrogen. As a
result an equilibrium is set up between the alkene and the alkyl-
palladium species. The hydride elimination (olefin insertion) is
believed to proceed by way of an olefin π-complex to yield
alkene 24.
Using the same reaction conditions with the substituted
pyridine 18 provided a poor yield of the desired tricycle 27 and
the reduced tricycle 28 as the major product (Table 5 and
Scheme 9).
We reasoned that the preference for the ‘Michael-type’
adducts could be overturned if we removed the conjugated
carbonyl, and so the ketones 18 and 21 were reduced with
Scheme 6 Reagents and conditions: (i) LDA, Ϫ78 ЊC, DMPU–HMPA,
then 14/15 or benzyl bromide; (ii) LDA, Ϫ78 ЊC, PhSeCl; (iii) NaIO4,
MeOH, H2O
19 and the selenides 20 (syn : anti 2 : 3). Oxidation of 20 pro-
vided enone 21 in 78% yield. All these results are collected in
Table 3.
The model compound 21 was then used to explore the intra-
molecular Heck reaction in a series of parallel reactions. Using
a large variety of conditions including those used in the first
series of Heck reactions, the major product was always the
reduced tricycle 22 with smaller amounts of the desired tricycle
23. In some cases, and in particular with the ligand tri(o-tolyl)-
phosphine, the double bond isomer 24 was also isolated (Table
4 and Scheme 7).
The structure of compound 22 was determined by analysis of
its NMR data. It was clearly not the desired tricycle as it con-
tained no signals in the olefin region of the 1H NMR spectrum.
The spectrum contained four aromatic protons and ten others.
13C NMR spectroscopy confirmed the presence of four CH2
groups and two CH groups. From analysis of COSY and
HetCor couplings the structure 22 was proposed and this was
confirmed by mass spectrometry and microanalysis. The 1H
Scheme 7 Intramolecular Heck ring closure with alkylated benzene precursor 21.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Scheme 8 Mechanisms for formation of cycloadducts 22, 23 and 24.
Scheme 9 Intramolecular Heck ring closure with alkylated pyridine precursor 18.
Table 5 Study of intramolecular Heck ring closure with alkylated
precursor 18
which are deshielded due to the electron withdrawing effect of
their respective alcohol groups.
Determination of the stereochemistry of H-13 proved more
difficult. NOE studies were undertaken on both 31 and 32
(Fig. 1). A molecular model demonstrated that H-13 in both
isomers was a similar distance in space away from H-1 and H-9,
and that the tricyclic framework was quite rigid and inflexible.
From the model, it seemed that irradiation of the H-13 signals
of the endo isomer 31 and the exo isomer 32 would give identi-
cal enhancements for H-1 and H-9. The experiment was run in
CDCl3, and as expected, enhancements were almost identical
and so proved of no use for ascertaining the stereochemistry
H-13.
Base (equiv.)
Liganda
Solventb
Yield 27 : 28 (%)
Et3N (12)
Et3N (12)
PMP (2)
PPh3
PPh3
POT
DMF
DMA
DMA
0 : 33
6 : 60
0 : 41
a 0.2 equivalent of ligand was used for all experiments. b DMF at
120 ЊC, DMA at 140 ЊC.
sodium borohydride under Luche conditions to provide a
mixture of alcohols 29 and 30 respectively (Scheme 10).
To our delight, the intramolecular Heck reaction using
syn–anti-29 produced a mixture of alcohols 31 and 32 with the
desired skeleton. Small amounts of the alternative tricycle 33
and the previously synthesised tricycle 22 were also isolated
(Scheme 11 and Table 6).
1
Signals for H-8, H-9 and H-10 overlapped in the H NMR
spectrum run in CDCl3 and the NOE experiment was repeated
in C6D6. Now, irradiation of H-13 of the endo isomer led to a
small but significant enhancement of H-10Љ, confirming tricycle
31 as the endo stereoisomer. Enhancement of H-8Љ was
observed when H-13 of the exo isomer was irradiated. The
corresponding effect on H-13 from H-8Љ was also seen, confirm-
ing the exo-stereochemistry of compound 32. Irradiation of
H-8Ј of 32 led to enhancement of H-10Ј and vice versa,
confirming the position of the bridge double bond.
1
The H NMR and 13C signals for tricycles 31 and 32 exhib-
ited all of the expected signals for both the desired tricyclic
compounds. The stereoisomers were separated by column
chromatography and both showed two olefinic 1H NMR signals
in the region δH 5.5–δH 5.8. Both 13C spectra also showed two
olefinic signals. Apparent singlets are observed at δH 3.94 and δH
4.22, corresponding to H-13 for the respective stereoisomers,
Tricycles 31 and 32 are formed via a 6-exo-trig cyclisation to
give the palladium() intermediate, which undergoes syn
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Table 6 Study of intramolecular Heck closure with allylic alcohol precursor syn–anti29
Yield (%)
Precursor
Solvent
Base (equiv.)
Ligand (equiv.)
31
32
33
22
syn–anti 29
syn–anti 29
DMA
DMA
Et3N (12)
Et3N (12)
PPh3 (0.4)
PPh3 (0.2)
50
49
26
21
15
14
5
13
β-hydride elimination to yield the products (Scheme 12). The
cycloadduct 22 is likely to have been formed via a 7-endo-trig
cyclisation. The Pd() intermediate does possess a syn β-hydro-
gen which undergoes the elimination step to give the enol,
which converts to the more stable ketone 22. Tricycle 33 is
probably formed via an intramolecular π-allyl substitution
reaction (Scheme 12).
Carrying out the reaction on syn-30 in refluxing DMA had a
considerable effect on the reaction. Compound 36 was syn-
thesised in excellent yield with the use of 0.2 equiv. tri(o-tolyl)-
phosphine and triethylamine as base (entry 2). The double
bond isomer 35 was isolated along with an equal amount of the
desired tricycle 34. The isolation of the isomer 35 was a new
development in our intramolecular Heck cyclisation investi-
gations. Importantly, the compound has the double bond in the
correct position for the natural product huperzine A. The
reduced tricycle 28 was also identified as a minor side product
of the reaction.
Using 0.2 equivalents of PPh3 (entry 3), the major
product was again the two-carbon bridged tricycle 36. The
two compounds 34 and 35 with the huperzine A core,
were isolated in low yield along with some of the reduced tri-
cycle 28. A considerable amount of starting material was
recovered.
Scheme 10 Reagents and conditions: (i) NaBH4, CeCl3, MeOH–DCM.
It is known that increasing ligand concentration can
inhibit double bond isomerisation. We were gratified to
find that by increasing the ligand concentration to 0.4 equiv-
alents, isomerisation to 35 was completely suppressed and
the expected tricycle 34 was isolated in excellent yield
(entry 4).
Reaction of anti-30 with 0.2 equivalents of both tri(o-tolyl)-
phosphine and PPh3 led to equal amounts of the tricycles 38
and 39 (Scheme 14, entries 5 and 6 in Table 8). The stereo-
chemistry of the alcohol group was determined by a series of
NOE experiments.
A striking difference was observed between the reactions of
syn and anti-30 with tri(o-tolyl)phosphine (entries 3 and 5). The
novel tricycle 36, isolated in 50% yield with the syn-30 isomer,
was only a trace product when anti-30 was subject to identical
conditions. For the anti-30 isomer in general, compound 36 is
only isolated in trace amounts.
Increasing the ligand concentration to 0.4 equivalents led to
an excellent yield of compound 38 (entry 7, Table 8). In all
reactions with the anti-isomer, the reduced tricycle 28 was iso-
lated in modest yield (entries 5, 6 and 7).
When comparing the reaction of anti and syn isomers
under the best Heck conditions (entry 4 and 7), it was clear that
the 6-exo-trig cyclisation performed better with anti-30. To
reinforce these results, the Heck reaction was carried out
on a syn–anti mixture of alcohols. Indeed, the tricycle 38 was
shown to be the major product when a syn–anti mixture
was subjected to cyclisation under our best Heck conditions
(Table 9).
It is likely that this can be explained if one considers the
steric requirement for cyclisation. It is probable than the steric
crowding caused by the OH group pointing inward towards the
pyridyl-bromide accounts for the lower yield obtained for the
reaction of the syn alcohol compared to that of the anti alcohol
where the OH group points away and does not interfere
(Scheme 15).
Fig. 1
Encouraged by these results, a series of reactions were carried
out on the pyridine system using precursors syn- and anti-30
(Tables 7, 8 and 9).
Reaction of syn-30 with triethylamine in acetonitrile (entry
1, Table 7) provided the correct skeleton 34, with a small
amount of the novel tricycle 36. The major product of the
reaction, however, was compound 37, the result of reductive
dehalogenation (hydrodehalogenation) of the starting material
(Scheme 13).
Scheme 11 Intramolecular Heck closure with syn–anti-29.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Table 7 Study of intramolecular Heck ring closure with allylic alcohol syn-30
Yield (%)
Entry
Precursor
Solvent
Base (equiv.)
Ligand (equiv.)
34
35
36
28
37
1
2
3
4
syn-30
syn-30
syn-30
syn-30
CH3CN
DMA
DMA
DMA
Et3N (12)
Et3N (12)
Et3N (12)
Et3N (12)
PPh3 (0.4)
POT (0.2)
PPh3 (0.2)
PPh3 (0.4)
18
19
7
4
50
27
20
25
19
7
9
11
15
61
Table 8 Study of intramolecular Heck ring closure with allylic alcohol anti-30
Yield (%)
Entry
Precursor
Solvent
Base (equiv.)
Ligand (equiv.)
38
39
36
28
5
6
7
anti-30
anti-30
anti-30
DMA
DMA
DMA
Et3N (12)
Et3N (12)
Et3N (12)
POT (0.2)
PPh3 (0.2)
PPh3 (0.4)
29
30
66
29
30
—
2
3
2
20
19
25
Table 9 Study of intramolecular Heck ring closure with syn–anti-30
Yield (%)
Entry
1
Precursor
Solvent
DMA
Base (equiv.)
Et3N (12)
Ligand (equiv.)
PPh3 (0.4)
38
34
36
28
syn/anti-30
39
33
15
10
Scheme 12 Mechanisms for formation of compounds 31, 32, 33 and 22.
ethylidene group at C-13, and most importantly an amino
group at C-1.
Conclusion
Since compounds 34 and 38 can be oxidised with PCC to pro-
duce the same ketone 27, and compounds 35 and 39 can be
oxidised to ketone 4010 (Scheme 16), we have achieved a highly
convergent synthesis of the basic tricyclic skeleton of huperzine
A, with most reactions carried out on at least the half gram
scale. Comparison of the structure of compound 40 with
huperzine A reveals that it lacks a methyl group at C-11, an
In consequence, our present investigations are directed
towards the synthesis of the key intermediate 41, which we
hope to convert into both the natural product and a variety of
analogues. In addition, our investigations have shown that by
subtle manipulation of the conditions employed in the intra-
molecular Heck reaction, it is possible to produce a number of
novel ring systems. We propose converting these into a range of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Scheme 13 Intramolecular Heck ring closure with syn-30.
Scheme 14 Intramolecular Heck ring closure with anti-30.
42.02 mmol) in CHCl3 (130 mL) over a period of 3 h. The
reaction mixture was stirred overnight and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (20–100% diethyl ether–
petroleum ether solvent gradient) to afford the N-oxide as a
yellow oil (5.61 g, 91% based on recovered starting material).
νmax(film)/cmϪ1 3503, 1605, 1493; δH(400 MHz; CD3OD) 2.69
(3H, s, 7-H), 4.09 (3H, s, OCH3), 7.10 (1H, d, J 9.2 Hz, 5-H),
7.76 (1H, d, J 9.2 Hz, 4-H); m/z (CI) 218 (MHϩ, 100%), 202
(31), 171 (24), 93 (11), 65 (10); C7H9BrNO2 [MHϩ and 79Br]
required 217.9817, found 217.9806.
Scheme 15
new compounds that incorporate at least two nitrogen atoms,
for assessment of their structure–biological activity profiles.
2-(Acetoxymethyl)-3-bromo-6-methoxypyridine (5)
Experimental
All solvents were pre-dried. Acetonitrile, dichloromethane, di-
ethyl ether and methanol were distilled from calcium hydride
under nitrogen or argon. Tetrahydrofuran was dried by distil-
lation in the presence of sodium and benzophenone. DMF was
dried over 4 Å molecular sieves. For flash column chromato-
graphy, ether and petroleum ether 40–60 ЊC (Pet.Ether) was
used. Thin layer chromatography was used to monitor reactions
using Polygram® SIL G/UV254 precoated plastic sheets with a
0.2 mm layer of silica gel containing fluorescent indicator
UV254. Plates were visualised using a 254 nm UV lamp, potas-
sium permanganate and phosphomolybdic acid stain. Flash
column chromatography was carried out using Sorbsil C60
silica gel (40–60 mesh) with the eluent or the gradient of eluents
reported. NMR spectra were recorded using JEOL EX400,
Bruker DPX250, Bruker WM250, Brucker Avance300 and
Brucker DRX500 spectrometers. Samples were dissolved in
CDCl3 with tetramethylsilane as a reference or in D4-methanol.
IR spectra were recorded using a Perkin-Elmer 881 series
double beam spectrophotometer, Perkin-Elmer 1720-X FT-IR
spectrophotometer. CI-MS experiments as well as and EI-MS
experiments were carried out on a VG Autospec spectrometer.
Elemental analyses were carried out by Medac Ltd (Brunel
University) and ASEP (Queen’s University of Belfast). Analy-
ses with ASEP were carried out with a precision of 0.3%. Melt-
ing points were recorded on a Kofler hot plate or Stuart melting
point apparatus and are uncorrected.
A solution of N-oxide 4 (5.61 g, 25.72 mmol) in acetic
anhydride (32 mL) was heated to 120 ЊC for 3 h under nitrogen.
Methanol was added to the reaction mixture and the solvent
was then removed under reduced pressure. The crude product
was taken up in Et2O and the resulting solution was washed
successively with a saturated aqueous solution of sodium
bicarbonate (3 × 60 mL), water (80 mL) and brine (50 mL).
Finally the organic extract was dried over MgSO4 and concen-
trated under reduced pressure to produce the pure acetate as an
yellow oil (5.33 g, 80%).
νmax/cmϪ1 2915, 1745, 1652, 1580; δH(400 MHz; CDCl3) 2.18
(3H, s, OCOCH3), 3.89 (3H, s, OCH3), 5.22 (2H, s, 7-H), 6.59
(1H, d, J 8.8 Hz, 5-H), 7.66 (1H, d, J 8.8 Hz, 4-H); δC(125 MHz;
CDCl3) 20.7 (CH3, OCOCH3), 53.6 (CH3, OCH3), 65.7 (CH2,
7-C), 110.7 (C, 3-C), 111.8 (CH, 5-C), 142.6 (CH, 4-C), 150.2
(C, 2-C), 162.7 (C, 6-C), 170.6 (C, OCOCH3).
3-Bromo-2-formyl-6-methoxypyridine (3)
A 1 M aqueous solution of potassium carbonate (58 mL,
58 mmol) was added to a solution of acetate 5 (8.76 g, 33.68
mmol) in MeOH at room temperature and the resulting solu-
tion was stirred for 1 h. The solvent was removed under reduced
pressure and the residue was dissolved in CHCl3. The resulting
solution was washed with brine (70 mL), dried over MgSO4
and concentrated under reduced pressure to produce the pure
alcohol as an orange oil (7.26 g, quant.).
νmax/cmϪ1 3460, 1575, 1468; δH(400 MHz; CDCl3) 3.97 (3H, s,
OCH3), 4.68 (2H, s, 7-H), 6.61 (1H, d, J 8.6 Hz, 5-H), 7.68 (1H,
d, J 8.6 Hz, 4-H); δC(100 MHz; CDCl3) 53.8 (CH3, OCH3), 62.9
(CH2, 7-C), 110.9 (C, 3-C), 111.0 (CH, 5-C), 142.6 (CH, 4-C),
3-Bromo-6-methoxy-2-methylpyridine N-oxide (4)
m-CPBA (18.13 g, 63.03 mmol) was added portionwise to a
solution of 3-bromo-6-methoxy-2-methylpyridine (8.49 g,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Scheme 16
2-(Iodomethyl)-3-bromo-6-methoxypyridine (14)
To a solution of iodine (1.71 g, 6.74 mmol) and imidazole
(0.46 g, 6.74 mmol) in dry dichloromethane (15 mL) at 0 ЊC was
added portionwise triphenylphosphine (1.77 g, 6.74 mol) and
the resultant solution was stirred at this temperature for 20 min
prior to the addition of the alcohol (1.23 g, 5.63 mmol). The
reaction mixture was quenched with water (15 mL), taken up
with ether, washed with water, dried over MgSO4, and concen-
trated under reduced pressure to yield a crude brown oil. Purifi-
cation through a plug silica column yielded the iodomethyl
pyridine as a yellow oil (1.22 g, 66%).
153.5 (C, 2-C), 162.4 (C, 6-C); m/z (CI) 218 (MHϩ, 100%),
202 (13), 188 (39), 170 (21), 119 (12), 80 (12), 58 (15), 43
(32). C7H9BrNO2 [MHϩ and 79Br] required 217.9817, found
217.9821.
Manganese dioxide (20.1 g, 0.23 mol) was added to a solu-
tion of the alcohol (4.2 g, 0.19 mol) in CHCl3 (1.5 L). The
reaction mixture was stirred for 3 days and was filtered through
a pad of Celite. The filtrate was concentrated under reduced
pressure to afford the pure aldehyde as a white solid (3.52 g,
84%).
νmax/cmϪ1 2982, 2948, 1579, 1465, 1416, 1321, 1262, 1037,
1010, 823, 643, 574, 508; δH(500 MHz; CDCl3) 3.91 (3H, s,
OCH3), 4.56 (2H, s, 7-H), 6.54 (1H, d, J 8.7 Hz, 5-H), 7.61 (1H,
d, J 8.7 Hz, 4-H); δC(125 MHz; CDCl3) 6.3 (CH2, 7-C), 53.9
(CH3, OCH3), 110.3 (C, 2-C), 112.2 (CH, 5-C), 143.1 (CH,
4-C), 153.1 (C, 3-C), 162.7 (6-C); m/z (EI) 329 (32%), 202 (70),
127 (68), 78 (100), 63 (61), 51 (56), 38 (53); C7H7BrINO [Mϩ,
79Br] required 326.8758, found 326.8756; CHN analysis found C
26.24, H 2.20, N 4.50 required C 25.64, H 2.15, N 4.27%.
νmax/cmϪ1 2924, 1715, 1582, 1466; δH(400 MHz; CDCl3) 4.02
(3H, s, OCH3), 6.85 (1H, d, J 8.8 Hz, 5-H), 7.82 (1H, d, J 8.8
Hz, 4-H), 10.15 (1H, s, CHO); δC(100 MHz; CDCl3) 54.1 (CH3,
OCH3), 114.0 (C, 3-C), 117.4 (CH, 5-C), 144.5 (CH, 4-C), 145.2
(C, 2-C), 163.0 (C, 6-C), 190.5 (CH, CHO); C7H7BrNO2 [MHϩ
and 79Br] required 215.9660, found 215.9666.
2-(Bromomethyl)-3-bromo-6-methoxypyridine (15)
5-Bromo-6-methyl-2-methylpyridine (1.22 g, 6.05 mmol),
n-bromosuccinimide (1.08 g, 6.05 mmol), 2,2Ј-azobisisobutyro-
nitrile (0.15 g, 0.91 mmol), acetic acid (1.75 mL) in CCl4
(60 mL) under argon was irradiated (150 W Hg lamp) for 4
hours. Flash chromatography (5%, EtOAc–hexane) and con-
centration under reduced pressure gave pure 2-bromomethyl-3-
bromo-6-methoxypyridine as a brown oil (1.21 g, 71%).
νmax/cmϪ1 2983, 2950, 2857, 1581, 1464, 1417, 1324, 1263,
1219, 1105, 1037, 1013, 835; δH(500 MHz; CDCl3) 3.92 (3H, s,
OCH3), 4.60 (2H, s, 7-H), 6.58 (1H, d, J 8.7 Hz, 5-H), 7.66 (1H,
d, J 8.7 Hz, 4-H); δC(125 MHz; CDCl3) 33.4 (CH2, 7-C), 53.9
(CH3, OCH3), 109.5 (C, 3-C), 112.8 (CH, 5-C), 143.0 (CH,
4-C), 151.8 (C, 2-C), 162.8 (C, 6-C); m/z (EI) 280 (100%), 200
(72), 78 (36); C7H7Br2NO [Mϩ and 79Br] required 278.8894,
found 278.8907.
2-(Hydroxymethyl)-3-bromo-6-methoxypyridine (13)
Stirring 2-(acetoxymethyl)-3-bromo-6-methoxypyridine 5 (1.10
g, 4.23 mmol) with K2CO3 (1 M solution, 7.28 mL, 7.28 mmol)
in methanol (110 mL) for 50 min provided the alcohol (0.88 g,
96% yield) as a white solid.
Mp 45–47 ЊC; νmax/cmϪ1 3447, 2949, 2860, 1575, 1467, 1405,
1321, 1196, 1121, 1070, 1022, 954, 823, 668; δH(500 MHz;
CDCl3) 3.97 (3H, s, OCH3), 4.01 (1H, br s, OH ), 4.68 (2H, s,
7-H), 6.60 (1H, d, J 8.7 Hz, 5-H), 7.68 (1H, d, J 8.7 Hz, 4-H);
δC(125 MHz; CDCl3) 53.9 (CH3, OCH3), 63.0 (CH2, 7-C),
108.8 (C, 3-C), 110.9 (CH, 5-C), 142.7 (CH, 4-C), 153.7 (C,
2-C), 162.5 (6-C); m/z (EI) 217 (86%), 190 (100), 173 (45), 63
(38), 40 (48); C7H8BrNO2 [Mϩ, 79Br] required 216.9738, found
216.9742.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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Synthesis of alkylated adducts
7.18 (3H, m, Harom), 7.50 (2H, m, Harom), 7.54 (1H, d, J 8.6 Hz,
4Ј-H); δC(75 MHz, CDCl3) 22.1 (CH2, 4-C), 33.3 (CH2, 5-C),
34.0 (CH2, 7-C), 36.2 (CH, 3-C), 44.5 (CH, 2-C), 51.1 (CH,
6-C), 53.6 (CH3, OCH3), 109.7 (CH, 5Ј-C), 112.2 (C, 3Ј-C),
127.0–134.0 (5 × CH, Carom), 142.2 (CH, 4Ј-C), 155.3 (C, 2Ј-C),
162.2 (C, 6Ј-C), 208.7 (C, 1-C).
anti-Isomer: δH(500 MHz; CDCl3) 1.52 (1H, m, 5-H), 1.80
(1H, m, 4-H), 1.95 (1H, m, 4-H), 2.09 (1H, m, 5-H), 2.24 (1H,
m, 3-H), 2.32 (1H, m, 3-H), 2.70 (1H, dd, J 7.5 and 15.5 Hz,
7-H), 3.38 (1H, dd, J 5.7 and 15.5 Hz, 7-H), 3.87 (1H, s, OCH3),
3.94 (2H, m, 6-H and 2-H), 6.45 (1H, d, J 8.6 Hz, 5Ј-H), 7.25
(3H, m, Harom), 7.49 (2H, m, Harom), 7.61 (1H, d, J = 8.6 Hz,
4Ј-H); δC(75 MHz, CDCl3) 22.5 (CH2, 4-C), 33.7 (CH2, 3-C),
34.0 (CH2, 5-C), 36.7 (CH2, 7-C), 45.0 (CH, 2-C), 52.0 (CH,
6-C), 54.1 (CH3, OCH3), 110.1 (CH, 5Ј-C), 112.6 (C, Carom),
128.4–134.4 (5 × CH, Carom), 142.7 (CH, 4Ј-C), 155.8 (C, 2Ј-C),
162.6 (C, 6Ј-C), 209.1 (C, 1-C).
n-BuLi was added to a solution of diisopropylamine in dry
THF at 0 ЊC, and stirred under nitrogen at this temperature for
15 min. The reaction mixture was cooled to Ϫ78 ЊC and HMPA
or DMPU was then added. After stirring for a further 15 min
cyclohexanone was added. After stirring for 45 min at Ϫ78 ЊC
the halide reagent was slowly added. The reaction mixture was
stirred for 2 h at Ϫ78 ЊC, allowed to warm to room temperature
overnight, and then quenched with aqueous ammonium chlor-
ide. The organic layer was taken up with diethyl ether, washed
with water and brine, dried over MgSO4 and concentrated
under reduced pressure to yield the crude ketone. Purification
by flash chromatography (10% EtOAc–hexane) yielded the pure
ketone.
2-[(3-Bromo-6-methoxypyridin-2-yl)methyl]cyclohexanone (16)
6-(Iodomethyl)-5-bromo-2-methoxypyridine (18.0 g, 0.055
mol), with a solution of LDA [diisopropylamine (8.30 mL,
0.059 mol), n-BuLi (23.2 mL, 2.5 M in hexane, 0.058 mol)] and
cyclohexanone (5.40 mL, 0.055 mol) in THF (230 mL) and
HMPA (19.5 mL, 0.112 mol) yielded after flash chromato-
graphy the pure ketone 16 as a white solid (13.3 g, 81%).
Mp 53–55 ЊC. νmax/cmϪ1 2939, 2859, 1712, 1575, 1459, 1417,
1297, 1268, 1191, 1125, 1036, 1011, 820, 664, 642; δH(500 MHz;
CDCl3) 1.51 (1H, m, 3-H), 1.65–1.71 (2H, m, 4-H and 5-H),
1.86 (1H, m, 4-H), 2.09 (2H, m, 5-H and 3-H), 2.42 (2H, m,
6-H), 2.74 (1H, dd, J 7.7 and 15.6 Hz, 7-H), 3.12 (1H, m, 2-H),
3.35 (1H, dd, J 5.8 and 15.6, Hz, 7-H), 3.97 (3H, s, OCH3), 6.45
(1H, d, J 8.6 Hz, 5Ј-H), 7.61 (1H, d, J 8.6 Hz, 4Ј-H); δC(75
MHz, CDCl3) 25.1 (CH2, 4-C), 28.0 (CH2, 5-C), 33.5 (CH2,
3-C), 35.9 (CH2, 7-C), 41.9 (CH, 6-C), 49.1 (CH, 2-C), 53.2
(CH3, OCH3), 109.4 (CH, 5Ј-C), 112.1 (C, 3Ј-C), 142.0 (CH,
4Ј-C), 155.2 (C, 2Ј-C) 162.0 (C, 6Ј-C); m/z (EI) 299 (70%), 297
(68), 271 (56), 269 (61), 242 (64), 240 (61), 218 (40), 203 (100),
201 (86), 190 (51), 162 (35); C13H16BrNO2 [Mϩ, 79Br] required
297.0364, found 297.0365.
Oxidation of phenylseleno derivatives
The phenylseleno derivative was dissolved in methanol and
cooled to 0 ЊC. Sodium periodate dissolved in a minimum of
water was added dropwise. The reaction mixture was warmed
to room temperature and allowed stir for 5 hours. The mixture
was filtered, washed with methanol, diluted with ether and
dried over MgSO4. Purification by wet flash chromatography
(Et2O–Pet. Ether) yielded the pure α,β unsaturated ketone.
6-[(3-Bromo-6-methoxypyridin-2-yl)methyl]cyclohex-2-enone
(18)
6-[(3-Bromo-6-methoxypyridin-2-yl)methyl]-2-phenylseleno-
cyclohexanone (8.61 g, 0.020 mol) dissolved in methanol
(250 mL) with sodium periodate (4.89 g, 0.023 mol) in a mini-
mum water yielded after work up and chromatography the pure
α,β unsaturated ketone as an orange oil (4.34 g, 77%).
νmax/cmϪ1 2944, 1682, 1575, 1457, 1417, 1387 1297, 1118,
1037, 897, 820, 740; δH(500 MHz; CDCl3) 1.85 (1H, m, 5-H),
2.01 (1H, m, 5-H), 2.40 (2H, m, 4-H), 2.89 (1H, dd, J 9.1 and
15.3 Hz, 7-H), 3.05 (1H, m, 6-H), 3.48 (1H, dd, J 4.1 and
15.3 Hz, 7-H), 3.85 (3H, s, OCH3), 6.06 (1H, ddd, J 1.4, 2.6 and
10.0 Hz, 2-H), 6.47 (1H, d, J 8.6 Hz, 5Ј-H), 6.96 (1H, m, 3-H),
7.62 (1H, d, J 8.6 Hz, 4Ј-H); δC(75 MHz, CDCl3) 25.7 (CH2,
4-C), 27.7 (CH2, 5-C), 36.0 (CH2, 7-C), 45.7 (CH, 6-C), 53.6
(CH3, OCH3), 109.8 (CH, 5Ј-C), 112.4 (C, 3Ј-C), 129.6 (CH,
2-C), 142.3 (C, 4Ј-C), 149.6 (CH, 3-C), 155.1 (C, 2Ј-C), 162.3
(C, 6Ј-C), 200.7 (C, 1-C); m/z (EI) 297 (58%), 227 (40), 217 (94),
210 (85), 188 (57), 123 (80), 68 (67), 39 (100); C13H13BrO
[Mϩ, 79Br] required 295.2079, found 295.0204.
Synthesis of phenylseleno derivatives
n-BuLi was added to a solution of diisopropylamine in dry
THF at 0 ЊC and stirred under nitrogen at this temperature
for 30 min. HMPA was then added at Ϫ78 ЊC and stirred for
30 min. The ketone was slowly added at Ϫ78 ЊC and stirred for
1 h at this temperature. Phenylselenyl chloride in THF was
slowly added to the reaction mixture, stirred for 30 min at
Ϫ78 ЊC, and then quenched with aqueous ammonium chloride.
The organic layer was taken up with diethyl ether, washed with
water and brine, dried over MgSO4 then concentrated under
reduced pressure to yield the crude diastereomeric mixture.
Purification by flash chromatography yielded the syn-selenide
and the anti-selenide.
Synthesis of allylic alcohols
Sodium borohydride was added to a solution of ketone
and cerium() chloride heptahydrate in a mixture of dichloro-
methane–methanol. The resulting suspension was stirred for
20 min. The reaction was concentrated by rotary evaporation
and diluted with water and 2.5 M HCL. The layers were separ-
ated, and the aqueous phase was extracted with diethyl ether.
The combined organic portions were washed with brine, dried
over MgSO4, filtered and concentrated under reduced pressure.
6-[(3-Bromo-6-methoxypyridin-2-yl)methyl]-2-phenyl-
selenocyclohexanone (17)
Phenylselenyl chloride (9.29 g, 0.049 mol), with a solution of
LDA [diisopropylamine (7.29 mL, 0.051 mol), n-BuLi (2.5 M in
hexane, 20.4 mL, 0.051 mol)] and 2-[(3-bromo-6-methoxy-
pyridin-2-yl)methyl]cyclohexanone (13.2 g, 0.044 mol) in THF
(7.0 mL) and HMPA (17.1 mL, 0.098 mol) yielded after
chromatography the syn-isomer as a white solid (10.8 g, 54%
yield) and anti-isomer as a white solid (6.54 g, 32% yield).
νmax/cmϪ1 (syn–anti mixture) 2931, 2856, 1709, 1575, 1460,
1417, 1298, 1269, 1123, 1022, 910, 821, 736, 692.
syn-Isomer: δH(500 MHz; CDCl3) 1.50 (1H, m, 5-H), 1.81
(2H, m, 3-H and 4-H), 2.08 (2H, m, 4-H and 5-H), 2.27 (1H, m,
3-H), 2.72 (1H, dd, J 7.1 and 15.8 Hz, 7-H), 3.20 (1H, m, 6-H),
3.31 (1H, dd, J 6.2 and 15.8 Hz, 7-H), 3.76 (3H, s, OCH3), 4.11
(1H, dd, J 5.9 and 12.9 Hz, 2-H), 6.39 (1H, d, J 8.6 Hz, 5Ј-H),
6-[(3-Bromo-6-methoxypyridin-2-yl)methyl]cyclohex-2-en-1-ol
(30)
2-[6-(Cyclohex-2-enone)]methyl-3-bromo-6-methoxypyridine
(4.30 g, 0.014 mol) in dichloromethane–methanol (100 mL–
100 mL) with sodium borohydride (0.57 g, 0.015 mol) and
cerium() chloride heptahydrate (5.56 g, 0.015 mol) yielded
after work up and chromatography the syn-alcohol as a white
solid (1.96 g, 46%) and the anti-alcohol as a white solid (1.96 g,
46%).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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syn-Isomer: νmax/cmϪ1 3419, 2924, 2874, 1575, 1464, 1417,
1320, 1260, 1118, 1037, 1013, 820; δH(400 MHz; CDCl3) 1.56
(1H, m, 5-H), 1.66 (1H, m, 5-H), 2.04 (1H, m, 4-H and 6-H),
2.15 (1H, m, 4-H), 2.87 (1H, dd, J 10.8 and 13.2 Hz, 7-H), 3.08
(1H, dd, J 5.2 and 13.2 Hz, 7-H), 3.78 (1H, m, 1-H), 3.90 (3H, s,
OCH3), 5.81 (1H, m, 2-H), 5.92 (1H, m, 3-H), 6.52 (1H, d, J 8.7
Hz, 5Ј-H), 7.64 (1H, d, J 8.7 Hz, 4Ј-H); δC(100 MHz, CDCl3)
23.8 (CH2, 5-C), 25.8 (CH2, 4-C), 39.0 (CH2, 7-C), 39.3
(CH, 6-C), 53.7 (CH3, OCH3), 64.1 (CH, 1-C), 110.4
(CH, 5Ј-C), 111.9 (C, 3Ј-C), 127.7 (CH, 3-C), 131.4 (CH, 2-C),
143.1 (CH, 4Ј-C), 155.9 (C, 2Ј-C), 162.3 (C, 6Ј-C); m/z (EI) 299
(30%), 297 (31), 280 (15), 228 (57), 203 (97), 201 (100);
C13H15BrO [Mϩ, 79Br] required 297.0364, found 297.0363; CHN
analysis found C 52.45, H 5.44, N 4.80 required C 52.36, H
5.41, N 4.70%.
1727, 1601, 1479; δH (250 MHz; CDCl3) Ϫ0.01 (3H, s, SiCH3),
0.16 (3H, s, SiCH3), 0.76 (9H, s, SiC(CH3)3), 1.66 (3H, m, 12-H
and 13-H), 2.00 (1H, m, 13-H), 2.50 (2H, m, 11-H), 2.92 (1H,
m, 9-H), 3.07 (1H, m, 1-H), 3.85 (3H, s, OCH3), 4.78 (1H, d,
J 7.4 Hz, 8-H), 6.53 (1H, d, J 8.3 Hz, 4-H), 7.26 (1H, d, J 8.3
Hz, 3-H); δC (62.5 MHz; CDCl3; Me4Si) Ϫ5.2 (CH3, SiCH3),
Ϫ4.2 (CH3, SiCH3), 18.2 (C, SiC(CH3)3), 20.3 (CH2, 12-C),
25.7 (CH3, SiC(CH3)3), 25.8 (CH2, 13-C), 37.5 (CH, 1-C), 46.4
(CH2, 11-C), 52.7 (CH, 9-C), 53.4 (CH3, OCH3), 77.6 (CH,
8-C), 110.2 (CH, 4-C), 130.0 (C, 2-C), 140.1 (CH, 3-C), 153.9
(C, 7-C), 162.7 (C, 5-C), 213.2 (C, 10-C); m/z (CI) 348 (MHϩ,
32%), 290 (100), 216 (14), 174 (28); C19H30NO3Si [MHϩ]
required 348.1995, found 348.1984.
5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,11-tetraen-
13-one (27)
anti-Isomer: mp 77–78 ЊC; νmax/cmϪ1 3423, 3024, 2924, 1574,
1464, 1416, 1320, 1260, 1118, 1037, 1013, 820; δH(400 MHz;
CDCl3) 1.51 (1H, m, 5-H), 1.83 (1H, m, 5-H), 2.06 (3H, m, 4-H
and 6-H), 2.94 (1H, dd, J 6.3 and 14.5 Hz, 7-H), 3.10 (1H, dd,
J 5.9 and 14.5 Hz, 7-H), 3.27 (1H, br s, 7-H), 3.90 (3H, s,
OCH3), 4.08 (1H, m, 1-H), 5.70 (1H, m, 2-H), 5.77 (1H, m,
3-H), 6.49 (1H, m, J 8.7 Hz, 5-H), 7.64 (1H, d, J 8.7 Hz, 4-H);
δC(100 MHz, CDCl3) 24.9 (CH2, 4-C), 26.7 (CH2, 5-C), 40.7
(CH2, 7-C), 41.4 (CH, 6-C), 53.7 (CH3, OCH3), 72.1 (CH, 1-C),
110.1 (CH, 5Ј-C), 112.2 (C, 3Ј-C), 128.8 (CH, 3-C), 130.3 (CH,
2-C), 142.7 (CH, 4Ј-C), 156.2 (C, 2Ј-C), 162.4 (C, 6Ј-C); m/z
(EI) 297 (12%), 280 (8), 228 (42), 201 (100), 188 (10); C13H15BrO
[Mϩ, 79Br] required 297.0364, found 297.0357; CHN analysis C
52.24, H 5.49, N 4.69 required C 52.36, H 5.41, N 4.70%.
Colourless oil; νmax/cmϪ1 2938, 1732, 1597, 1474, 1421, 1312,
1268, 1030; δH(500 MHz; CDCl3) 2.64 (1H, dd, J 4.6 and
16.9 Hz, 10-H), 2.95 (2H, m, 9-H and 10-H), 3.23 (1H, d,
J 18.5 Hz, 8-H), 3.52 (1H, dd, J 8.7, 18.5 Hz, 8-H), 3.73 (1H, d,
J 5.7 Hz, 1-H), 3.88 (3H, s, OCH3), 5.75 (1H, m, 11-H), 5.89
(1H, m, 12-H), 6.54 (1H, d, J 8.4 Hz, 4-H), 7.22 (1H, d, J 8.4
Hz, 3-H); δC(125 MHz, CDCl3) 39.7 (CH2, 10-C), 42.3 (CH2,
8-C), 42.6 (CH, 9-C), 49.9 (CH, 1-C), 53.5 (CH3, OCH3), 108.7
(CH, 4-C), 125.8 (CH, 10-C), 126.9 (C, Carom), 131.3 (CH,
11-C), 138.0 (CH, 3-C), 152.5 (C, Carom), 162.8 (C, Carom), 211.0
(C, 13-C); m/z (EI) 185 (90%), 157 (85), 141 (70), 127 (73), 116
(100), 39 (84); C13H12O required 184.0888, found 184.0882;
CHN analysis found C 72.54, H 6.21, N 6.50 required C 72.54,
H 6.09, N 6.51%.
General method for synthesis of cycloadducts using the Heck
reaction.
5-Methoxy-6-azatricyclo[7.2.2.02,7]trideca-2(7),3,5-trien-10-one
(28)
Palladium acetate was added to a solution of the starting
material in the presence of ligand [PPh3 or P(o-tolyl)3] and
base (Et3N, PMP) in a solvent such as acetonitrile, dimethyl-
formamide, dimethylacetamide (for more details see Table 2).
The mixture was heated to reflux and the solution was either
concentrated under reduced pressure and extracted with diethyl
ether or directly extracted with diethyl ether. The combined
organic extracts were washed with a saturated aqueous solution
of sodium bicarbonate, with brine and dried over MgSO4. The
solvent was removed under reduced pressure. The crude prod-
ucts were purified by flash chromatography (eluent, Et2O :
Pet. ether 5 : 95) to yield separately the tricycles in a ratio and
yield dependent upon the starting material and experimental
conditions (see Tables 2, 4, 5, 6, 7, 8 and 9). The reactions were
routinely carried out on 1–3 mmol scale.
νmax/cmϪ1 2938, 1710, 1596, 1577, 1477, 1420, 1313, 1270, 1031;
δH(400 MHz; CDCl3) 2.01 (4H, m, 12-H and 13-H), 2.64 (2H,
m, 11-H), 2.81 (1H, m, 9-H), 3.08 (1H, m, 1-H), 3.16 (1H, dd,
J 3.9 and 18.5 Hz, 8-H), 3.34 (1H, ddd, J 1.6, 4.2 and 18.5 Hz,
8-H), 3.86 (3H, s, OCH3), 6.47 (1H, d, J 8.3 Hz, 4-H), 7.26 (1H,
d, J 8.3 Hz, 3-H); δC(125 MHz, CDCl3) 24.2 (CH2, 13-C), 27.7
(CH2, 12-C), 36.1 (CH, 1-C), 42.0 (CH2, 8-C), 45.8 (CH, 9-C),
46.5 (CH2, 11-C), 53.2 (CH3, OCH3), 107.9 (CH, 4-C), 132.0
(C, 2-C), 139.9 (CH, 3-C), 153.4 (C, 5-C), 162.4 (C, 7-C), 214.9
(C, 10-C); m/z (EI) 217 (100%), 188 (32), 174 (85), 160 (53);
C13H15NO2 required 217.1103, found 217.1110.
(13R)-5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,11-
tetraen-13-ol (34)
8-(tert-Butyldimethylsilyloxy)-5-methoxy-6-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5,11-tetraen-13-one (11b)
White solid; mp 87–89 ЊC; νmax/cmϪ1 3292, 2905, 1599, 1582,
1476, 1428, 1308, 1258, 1070, 1034; δH(500 MHz; C6D6) 1.87
(1H, m, 10-H), 2.31 (2H, m, 9-H and 10-H), 2.73 (1H, d, J 19.0
Hz, 8-H), 3.05 (1H, m, 1-H), 3.50 (1H, dd, J 8.3 and 19.0 Hz,
8-H), 3.94 (3H, s, CH3), 4.06 (1H, ap t, J 3.3 Hz, 13-H), 5.41
(1H, m, 11-H), 5.73 (1H, m, 12-H), 6.60 (1H, d, J 8.2 Hz, 4-H),
6.92 (1H, d, J 8.2 Hz, 3-H); δC(75 MHz, C6D6) 33.9 (CH, 9-C),
37.0 (CH2, 10-C), 37.7 (CH2, 8-C), 43.0 (CH, 1-C), 54.2 (CH3,
OCH3), 69.9 (CH, 13-C), 109.2 (CH, 4-C), 126.0 (C, 11-C),
126.8 (C, 2-C), 132.5 (CH, 10-C), 140.2 (C, 3-C), 155.6 (C, 7-C),
163.6 (C, 5-C); m/z (EI) 217 (100%), 199 (69), 198 (72), 188 (42),
160 (27), 147 (22); C13H15NO2 required 217.1103, found
217.1100.
Colourless oil; νmax/cmϪ1 2935, 1736, 1601, 1474; δH(250 MHz;
CDCl3) Ϫ0.19 (3H, s, SiCH3), 0.00 (3H, s, SiCH3), 0.64 (9H, s,
SiC(CH3)3), 2.37 (1H, d, J 6.9 Hz, 10-H), 2.68 (2H, m, 10-H and
9-H), 3.43 (1H, d, J 6.9 Hz, 1-H), 3.70 (3H, s, OCH3), 4.75 (1H,
d, J 1.9 Hz, 8-H), 5.32 (1H, m, 11-H), 5.74 (1H, m, 12-H), 6.41
(1H, d, J 8.6 Hz, 4-H), 7.02 (1H, d, J 8.6 Hz, 3-H); δC(62.5
MHz; CDCl3) Ϫ5.0 (CH3, SiCH3), Ϫ4.4 (CH3, SiCH3), 18.2 (C,
SiC(CH3)3), 25.7 (CH3, SiC(CH3)3), 33.3 (CH2, 10-C), 49.0
(CH, 1-C), 52.3 (CH, 9-C), 53.6 (CH3, OCH3), 80.6 (CH, 8-C),
111.2 (CH, 4-C), 126.5 (CH, 11-C), 127.7 (C, 2-C), 131.5 (CH,
12-C), 138.3 (CH, 3-C), 151.4 (C, 5-C), 162.7 (C, 7-C), 208.6 (C,
1-C); m/z (CI) 346 (MHϩ, 28%), 288 (100), 186 (28), 75 (12).
C19H28NO3Si [MHϩ] required 346.1838, found 346.1824.
(13R)-5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,10-
8-(tert-Butyldimethylsilyloxy)-5-methoxy-6-azatricyclo-
[7.2.2.02,7]trideca-2(7),3,5-trien-10-one (12b)
tetraen-13-ol (35)
Yellow solid; mp 88–90 ЊC; νmax/cmϪ1 3273, 2913, 1600, 1579,
1477, 1447, 1425, 1311, 1262, 1079, 1034, 824, 711; δH(300
MHz; CDCl3) 1.60 (1H, br s, 14-H), 2.09 (1H, dd, J 4.7 and 17.8
White solid; mp 95–98 ЊC (CHCl3) (Found C 65.2, H 8.2, N 3.4;
C19H29NO3Si requires C 65.6, H 8.4, N 4.0%); νmax/cmϪ1 2935,
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Hz, 12-H), 2.64 (1H, m, 12-H), 2.67 (1H, d, J 17.6 Hz, 8-H),
2.74 (1H, m, 9-H), 3.04 (1H, m, 1-H), 3.17 (1H, dd, J 5.6 and
17.6 Hz, 8-H), 3.90 (3H, s, OCH3), 4.19 (1H, m, 13-H), 5.50
(1H, m, 11-H), 5.77 (1H, m, 10-H), 6.56 (1H, d, J 8.3 Hz, 4-H),
7.44 (1H, d, J 8.3 Hz, 3-H); δC(125 MHz, CDCl3) 32.7 (CH2,
8-C), 35.1 (CH, 9-C), 35.5 (CH2, 12-C), 39.3 (CH, 1-C), 53.3
(CH3, OCH3), 68.5 (CH, 13-C), 108.8 (CH, 4-C), 124.3 (CH,
11-C), 125.0 (C, 2-C), 130.4 (CH, 10-C), 140.5 (CH, 3-C), 152.4
(C, 7-C), 162.6 (C, 5-C); m/z (EI) 217 (100%), 199 (69), 198 (72),
188 (42), 160 (27), 147 (22); C13H15NO2 required 217.1103,
found 217.1100.
8-C), 36.4 (CH, 9-C), 37.7 (CH2, 12-C), 38.8 (CH, 1-C), 53.7
(CH3, OCH3), 68.5 (CH, 13-C), 108.8 (CH, 4-C), 124.3 (CH,
11-C), 126.8 (C, 2-C), 128.0 (CH, 10-C), 140.2 (CH, 3-C), 152.4
(C, 5-C), 162.7 (C, 7-C); C13H15NO2 required 217.1103, found
217.1099.
Synthesis of 5-methoxy-6-azatricyclo[7.3.1.02,7]trideca-
2(7),3,5,10-tetraen-13-one (40)
A
mixture of alcohols (13R)-5-methoxy-6-azatricyclo-
[7.3.1.02,7]trideca-2(7),3,5,10-tetraen-13-ol 35 and (13S)-5-
methoxy-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,10-tetraen-
13-ol 39 (0.08 g, 0.37 mmol) and pyridiniun chlorochromate
(0.12 g, 0.55 mmol) in dry dichloromethane (3 ml) was stirred at
room temperature for 3 h. The reaction mixture was diluted
with ether and filtered through a silica pad with ether–
dichloromethane. The product was further purified by wet flash
chromatography (Et2O–Pet. Ether) to yield the pure ketone as a
yellow oil (0.055 g, 70%).
5-Methoxy-6-azatricyclo[7.2.2.02,7]trideca-2(7),3,5,10-tetraene
(36)
Orange oil; νmax/cmϪ1 2935, 1594, 1576, 1474, 1418, 1307, 1256,
1038, 700; δH(400 MHz; CDCl3) 1.76 (2H, m, 12-H), 1.79 (1H,
m, 13-H), 1.96 (1H, m, 13-H), 2.62 (1H, m, 9-H), 2.94 (2H, m,
8-H), 3.07 (1H, m, 1-H), 3.76 (3H, s, OCH3), 6.06 (1H, ap t,
J 7.9 Hz, 10-H), 6.32 (1H, d, J 8.2 Hz, 4-H), 6.34 (1H, ap t, J 8.2
Hz, 11-H), 7.10 (1H, d, J 8.2 Hz, 3-H); δC(125 MHz, CDCl3)
26.0 (CH2, 12-C), 30.9 (CH2, 13-C), 31.4 (CH, 9-C), 38.9 (CH,
1-C), 42.6 (CH2, 8-C), 53.6 (CH3, OCH3), 107.1 (CH, C-10),
131.8 (CH, 11-C), 132.0 (C, 2-C), 136.3 (CH2, 4-C), 139.3 (CH2,
3-C), 155.6 (C, 7-C), 162.3 (C, 5-C); m/z (EI) 201 (100%), 173
(92), 158 (73), 143 (66), 115 (45), 77 (53), 39 (53); C13H15NO
required 201.1154, found 201.1153.
Yellow oil; νmax/cmϪ1 2929, 1734, 1599, 1476, 1421, 1312,
1263, 822, 708; δH(500 MHz; CDCl3) 2.56 (1H, ddd, J 1.5,
4.6 and 17.6 Hz, 12-H), 2.97 (1H, m, 12-H), 3.12 (1H, m,
9-H), 3.23 (1H, d, J 17.5 Hz, 8-H), 3.34 (1H, dd, J 5.4 and 17.5
Hz), 3.90 (3H, s, OCH3), 5.64 (1H, m, 11-H), 5.80 (1H, m,
10-H), 6.62 (1H, d, J 8.6 Hz, 4-H), 7.27 (1H, d, J 8.6 Hz,
3-H); δC(125 MHz, CDCl3) 40.0 (CH2, 12-C), 41.0 (CH2, 8-C),
46.2 (CH, 9-C), 48.0 (CH, 1-C), 53.4 (CH3, OCH3), 68.5 (CH,
13-C), 109.4 (CH, 4-C), 125.0 (C, 2-C), 125.1 (CH, 11-C),
130.5 (CH, 10-C), 139.0 (CH, 3-C), 155.4 (C, 7-C), 163.2 (C,
5-C), 211.7 (C, 13-C); m/z (EI) 215 (100%), 186 (80), 172 (75),
158 (60), 51 (53), 39 (55); C13H12O required 215.0946, found
215.0955.
6-[(6Ј-Methoxypyridin-2-yl)methyl]cyclohexen-2-en-1-ol (37)
Yellow oil; νmax/cmϪ1 3401, 2923, 1601, 1579, 1467, 1415, 1313,
1264, 1034; δH(500 MHz; CDCl3) 1.54 (1H, m, 5-H), 1.63 (1H,
m, 5-H), 1.89 (1H, m, 6-H), 2.02 (1H, m, 4-H), 2.12 (1H, m,
4-H), 2.71 (1H, dd, J 4.9 and 13.2 Hz, 7-H), 2.88 (1H, dd, J 11.1
and 13.2 Hz, 7-H), 3.86 (1H, ap s, 1-H), 3.92 (3H, s, OCH3),
4.48 (1H, s, OH), 5.83 (1H, m, 2-H), 5.90 (1H, m, 3-H), 6.60
(1H, d, J 8.3 Hz and 11-H), 6.77 (1H, d, J 7.2 Hz, 13-H), 7.51
(1H, dd, J 7.2 and 8.3 Hz, 12-H); δC(125 MHz, CDCl3) 24.2
(CH2, 5-C), 25.8 (CH2, 4-C), 40.2 (CH2, 7-C), 41.2 (CH, 6-C),
53.4 (CH3, OCH3), 64.0 (CH, 1-C), 108.5 (CH, 11-C), 116.1
(CH, 13-C), 128.2 (CH, 2-C), 131.0 (CH, 3-C), 139.5 (CH,
12-C), 158.3 (C, 10-C), 162.4 (C, 8-C); m/z (EI) 219 (34%), 200
(21), 150 (67), 123 (100); C13H17NO2 required 219.1259, found
219.1256.
Acknowledgements
Seán Kelly and Yann Foricher thank the McClay Trust for
studentships and John Mann thanks Vernalis Ltd. for generous
funding.
References
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tetraen-13-ol (38)
Orange oil; ν max/cmϪ1 3400, 2607, 1597, 1475, 1425, 1308, 1254,
1197, 1038, 821, 729, 694; δH(500 MHz; C6D6) 1.88 (1H, m,
10-H), 2.31 (2H, m, 9-H and 10-H), 2.72 (1H, d, J 7.2 Hz, 8-H),
3.05 (1H, m, 1-H), 3.49 (1H, dd, J 8.3 Hz and 18.9 Hz, 8-H),
3.94 (3H, s, OCH3), 4.06 (1H, m, 13-H), 5.41 (1H, m, 11-H),
5.72 (1H, m, 12-H), 6.60 (1H, d, J 8.2 Hz, 4-H), 6.92 (1H, d,
J 8.2 Hz, 3-H); δC(75 MHz, C6D6) 33.9 (CH, 9-C), 37.0 (CH2,
10-C), 37.7 (CH2, 8-C), 43.0 (CH, 1-C), 54.2 (CH3, OCH3), 69.9
(CH, 13-C), 109.2 (CH, 4-C), 126.0 (CH, 11-C), 132.5 (CH,
12-C), 140.2 (CH, 3-C), 155.6 (C, 7-C), 163.6 (C, 5-C); C13H15-
NO2 required 217.1103, found 217.1101.
(13S )-5-Methoxy-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,5,10-
tetraen-13-ol (39)
Yellow oil; νmax/cmϪ1 3273, 2913, 1600, 1579, 1477, 1447, 1425,
1311, 1262, 1079, 1034, 824, 711; δH(300 MHz; CDCl3) 1.91
(1H, dd, J 4.5, 17.8 Hz, 12-H), 2.20 (1H, br s, 14-H), 2.64 (2H,
m, 9-H, 12-H), 2.85 (1H, d, J 18.4 Hz, 8-H), 3.01 (1H, m, 1-H),
3.13 (1H, dd, J 5.8, 17.8 Hz, 8-H), 3.87 (3H, s, OCH3), 4.12 (1H,
m, 13-H), 5.66 (2H, m, 10-H, 11-H), 6.55 (1H, d, J 8.4 Hz, 4-H),
7.30 (1H, d, J 8.4 Hz, 3-H); δC(125 MHz, CDCl3) 29.6 (CH2,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 8 6 5 – 2 8 7 6
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24, 1367.
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97, 5434.
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