Synthesis of new analogues of the tetraponerines

Article abstract of DOI:10.1002/ejoc.200900064

To evaluate the influences of the tetraponerine alkyl chains and tricyclic ring systems on their cytotoxic activities, we have prepared a series of alkyl derivatives (3a, 3b and 4a-f) of the non-natural tricyclic skeletons d.ecahyd.ro-2H,6fi-dipyrido[1.,2-a:1.2'-c]pyrimidine (3, 6-6-6 skeleton) and. dodecahydro-2W-l,8a-diazaphenanthrene (4, iso-6-6-6 skeleton). In this study, two ways to synthesise the 6-6-6 analogues have been developed and compared. One is based, on the condensation of a-tripiperideme with diethyl malonate (DBM) in. water at pH11. This yielded, oxo ester 11, precursor of the amino nitrile 8, but only in moderate yield. In the second pathway, the key intermediate 8 was more efficiently synthesised by starting from. 2-(2-piperidyl)ethanol. Treatment of 8 with alkyl Grignard reagents led to the 6-6-6 analogues 3a and 3b. When the one-pot reaction between a-tripiperideine and DEM was performed in water at pH 8, the lactam 12, precursor of the iso-6-6-6 skeleton, was obtained, in a yield of 76 %. The same lactam was also obtained in a yield of 86 % by treatment of tetrahydroanabasine 14 with DEM in water at pH 8. Lactam 12 was transformed into the iso-6-6-6 analogues 4a-4f. The cytotoxic activities of the 6-6-6 and. i.so-66-6 analogues against H.T29 cancer cells were compared with those of the 5-6-5 and 6-6-5 tetraponerines and. with those of solenopsin analogues. 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900064

FULL PAPER
DOI: 10.1002/ejoc.200900064
Synthesis of New Analogues of the Tetraponerines
Anne Rouchaud[a] and Jean-Claude Braekman*[a]
Keywords: Tetraponera / Tetraponerine analogues / Alkaloids / Structure–activity relationships / Nitrogen heterocycles
To evaluate the influences of the tetraponerine alkyl chains
and tricyclic ring systems on their cytotoxic activities, we
have prepared a series of alkyl derivatives (3a, 3b and 4a–f)
of the non-natural tricyclic skeletons decahydro-2H,6H-dipy-
rido[1,2-a:1Ј,2Ј-c]pyrimidine (3, 6–6–6 skeleton) and dodeca-
hydro-2H-1,8a-diazaphenanthrene (4, iso-6–6–6 skeleton). In
this study, two ways to synthesise the 6–6–6 analogues have
been developed and compared. One is based on the conden-
sation of α-tripiperideine with diethyl malonate (DEM) in
water at pH 11. This yielded oxo ester 11, precursor of the
amino nitrile 8, but only in moderate yield. In the second
pathway, the key intermediate 8 was more efficiently synthe-
sised by starting from 2-(2-piperidyl)ethanol. Treatment of 8
with alkyl Grignard reagents led to the 6–6–6 analogues 3a
and 3b. When the one-pot reaction between α-tripiperideine
and DEM was performed in water at pH 8, the lactam 12,
precursor of the iso-6–6–6 skeleton, was obtained in a yield
of 76%. The same lactam was also obtained in a yield of 86%
by treatment of tetrahydroanabasine 14 with DEM in water
at pH 8. Lactam 12 was transformed into the iso-6–6–6 ana-
logues 4a–4f. The cytotoxic activities of the 6–6–6 and iso-6–
6–6 analogues against HT29 cancer cells were compared
with those of the 5–6–5 and 6–6–5 tetraponerines and with
those of solenopsin analogues.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Pseudomyrmecine ants of the genus Tetraponera utilise
their modified stings to smear enemies with a contact poi-
son that contains a mixture of eight tricyclic alkaloids.[1–3]
These alkaloids, named tetraponerines T-1 to T-8, can be
divided into two structural families, based either on the de-
cahydrodipyrrolo[1,2-a:1Ј,2Ј-c]pyrimidine skeleton (1, 5–6–
5 skeleton, Figure 1) or on the decahydro-5H-pyrido[1,2-c]-
pyrrolo[1Ј,2Ј-a]pyrimidine skeleton (2, 6–6–5 skeleton). In
each family, the compounds differ from each other in the
lengths (n-Pr or n-pentyl) and the stereochemistries of the
alkyl chains attached at C-5.[1–3]
In the context of a program involving the search for bio-
active compounds in insects, preliminary tests indicated that
the tetraponerines and some of their derivatives presented
interesting cytotoxic activities. It has also been shown that
these molecules possess neurotoxic[4] and insecticidal activi-
ties.[1] To evaluate the influences of the alkyl chains and of
the tricyclic ring systems on the cytotoxic activity, we de-
cided to prepare a series of 6-alkyl derivatives of the non-
natural tricyclic skeleton decahydro-2H,6H-dipyrido[1,2-
a:1Ј,2Ј-c]pyrimidine (3, 6–6–6 skeleton). In this study we
have compared two pathways starting from ∆1-piperideine
Figure 1. Structures of the tricyclic skeletons of the tetraponerines
and their analogues.
found a simple and effective way to synthesise 9-alkyl deriv-
atives of the isomeric dodecahydro-2H-1,8a-diazaphen-
anthrene skeleton (4, iso-6–6–6 skeleton).
that permit access to these derivatives. In addition, we also Results and Discussion
Several syntheses of derivatives based on the 5–6–5 (1)
and 6–6–5 (2) skeletons and substituted at C-5 have been
reported.[2,3,5,6] In particular, a short and practical synthesis
of compound 5 (Scheme 1), a pivotal intermediate in the
synthesis of derivatives related to the 5–6–5 skeleton and
[a] Department of Organic Chemistry, CP 160/06, Faculty of
Sciences, Université Libre de Bruxelles,
50 Avenue F. D. Roosevelt, 1050 Brussels, Belgium
Fax: +32-2-650-2798
E-mail: braekman@ulb.ac.be
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Synthesis of New Analogues of the Tetraponerines
alkylated at C-5, has been achieved.[6] The key step of this formed. Moreover, they observed that ∆1-piperideine di-
synthesis was a one-pot stereoselective process in which two merises to form tetrahydroanabasine (14), which may fur-
molecules of ∆1-pyrroline (6) react with one molecule of ther react with a third molecule of 9 to generate trimer 13.
diethyl malonate (DEM) to afford the tricyclic lactam ester The rate of formation of tetrahydroanabasine (14) is at its
7. Hydrolysis of the ethoxycarbonyl group and subsequent maximum at pH 8 and that of isotripiperideine (13) at pH
decarboxylation yielded a lactam that was then converted values between 9 and 10. In view of these results, we have
into the α-amino nitrile 5 (Scheme 1).
to admit that pH 11 is probably the best compromise be-
tween the rate of formation of ∆1-piperideine (9) and its
undesired transformation into dimer 14, and thus that it is
at this pH that the conditions are the most appropriate for
the condensation of two molecules of 9 with one of DEM
to form the amide 11. It should be noted that, in addition
to compound 11, several derivatives originating from com-
peting reactions were identified. Malonic acid monoester
and malonic acid, resulting from the hydrolysis of DEM,
isotripiperideine (13) from isomerisation of α-tripiperideine
(10) and high-molecular-weight material from polymerisa-
tion of ∆1-piperideine (9), for instance, were also isolated
from the reaction mixture. This could explain the low yield
of compound 11.
Scheme 1. Synthesis of the key intermediates 8 and 11.
To synthesise the 6–6–6 derivative 8 corresponding to 5,
we decided to follow the same pathway but with the replace-
ment of ∆1-pyrroline by ∆1-piperideine (9, Scheme 1). Be-
cause this compound is unstable, it must be prepared in
situ. Three different methods for generating ∆1-piperideine
were attempted: treatment of lysine with NBS,[7] dehydroha-
Scheme 2. Synthesis of the key intermediate 12.
Moreover, during this reaction we isolated also small
logenation of N-chloropiperidine[8] and detrimerisation of amounts (4% yield) of an isomer of the amide 11, the spec-
α-tripiperideine (10).[9]
tral properties of which indicated that it was the iso-6–6–6
Numerous assays were carried out to study the influence derivative 12. Again, only one diastereoisomer was ob-
of different parameters – such as temperature, proportion tained, corresponding to the most stable configuration
of reactants, method of formation of 9 and pH – on the (trans ring junctions and equatorial ethoxycarbonyl group).
outcomes of the reactions. The best yield (34%) of the lac- It is reasonable to assume that amide 12 results from the
tam ester 11 (Scheme 1) was obtained by generation of 9 by reaction between traces of tetrahydroanabasine (14) and
slow detrimerisation of α-tripiperideine in water at pH 11 1 equiv. of DEM through a Robinson–Schöpf condensa-
and simultaneous addition of DEM (2 equiv.). As observed tion. To support this hypothesis, α-tripiperideine (10) was
by Plehiers et al.[6] for the formation of 7, only one dia- detrimerised in HCl (1 ). The pH was then raised to 8 and
stereoisomer of 11 was obtained, possessing trans stereo- maintained at this value for 5 h to generate dimer 14, avoid-
chemistry at both ring junctions and an equatorial ethoxy- ing the formation of trimer 13. DEM was then added, and
carbonyl group at C-7. These configurations were assigned the mixture was further left at pH 8 for 17 h. This afforded
on the basis of the coupling constant data for 7-H, 7a-H amide 12 in 76% yield. Compound 11 was not formed un-
and 12a-H (see Exp. Sect.), which were consistent with the der these conditions. Moreover, when the bis(hydrobrom-
presence of axial protons.
ide) of 2-hydroxy-3-[2-piperidyl]piperidine (15), prepared
To understand why the yield is at its optimum at pH 11, according to Schöpf et al.[12] from α-tripiperideine (10), was
we have to take into account the pH-sensitive isomerisation condensed at pH 8 with DEM, we obtained compound 12
of α-tripiperideine (10) into isotripiperideine (13), which in 86% yield.
implies the occurrence of the transient dimer 14, tetra-
By application to 12 of a procedure similar to that uti-
hydroanabasine (Scheme 2). Indeed, Schöpf et al.[10,11] have lised the transformation of 7 into 5, the amino nitrile 16
shown that the trimer 10 is stable at pH values above 12, was obtained in an overall yield of 52% (Scheme 3). Treat-
whereas at pH values below 2 the monomer 9 is quickly ment of this compound with appropriate Grignard reagents,
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A. Rouchaud, J.-C. Braekman
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followed by removal of the protecting group, led stereose- aldehyde 17, which can be easily prepared from the com-
lectively to the alkylated compounds 4a–c. Methylation of mercially available amino alcohol 18 as shown in Scheme 4
the secondary amine through a modified Eschweiler–Clarke by successive protection of the secondary amine, oxidation
reaction provided compounds 4d–f. This represents a par- of the primary hydroxy group, transformation of the re-
ticularly attractive route for the synthesis of such derivatives sulting aldehyde into an acetal and subsequent deprotection
(26% yield from 12).
of the amino group by catalytic hydrogenolysis. By this
pathway, the key compound 8 was obtained in an overall
yield of 38% from 18. No other diastereoisomers were de-
tected. This high stereoselectivity is probably the result of
thermodynamic control that leads to the more stable dia-
stereoisomer in which the ring junctions are trans and the
cyano group occupies an axial position, forced by the an-
omeric effect. These configurations are deduced from the
coupling constants of 6-H, 7a-H and 12a-H (see the Experi-
mental Section). Subsequent alkylation of the amino nitrile
8 with appropriate alkylmagnesium bromides led via imin-
ium ions to the 6-alkylated 6–6–6 derivatives 3a and 3b.
This last scheme thus appears to be the most convenient
and effective method to prepare 6–6–6 derivatives alkylated
at C-6.
Scheme 3. Synthesis of the iso-6–6–6 analogues 4a–4f. Reagents
and conditions: (i) 5% KOH/MeOH, 20 °C, 2 h; (ii) (a) 10% HCl
Ǟ pH 4–5, 0 °C, (b) 70 °C, 2 h, 85%; (iii) Na2CO3, BnBr, CH2Cl2/
H2O, reflux, 3 h, 98%; (iv) (a) Dibal-H (1 equiv.)/hexane, –78 °C,
Et2O, 3 h, (b) 10% HClO4/EtOH Ǟ pH 3, (c) KCN (5.5 equiv.)/
H2O, room temp. overnight, 60%; (v) RMgBr (5 equiv.), Et2O/
THF, –10 °C to room temp., 40 h, average yield: 90%; (vi) H2, 10%
Pd/C, MeOH/12.5  HCl (98:2), atmospheric pressure, 20 °C, 16 h,
average yield: 97%; (vii) (a) 37% aq. HCHO (11.6 equiv.), MeOH,
reflux, 20 h, (b) room temp., NaBH4 (3.9 equiv.), 2 h, average yield:
65%.
It is notable that, despite our efforts, the two other means
to obtain ∆1-piperideine – namely treatment of lysine with
NBS and the use of a solution of 9 freshly prepared by
dehydrohalogenation of N-chloropiperidine under condi-
tions avoiding its trimerisation – led to very low yields not
only of 11 but also of 12. Nevertheless, in one set of experi-
ments by using N-chloropiperidine as starting material with
maintenance of the pH between 6 to 12, a yield of about
20% of compound 12 could be isolated, suggesting the for-
mation of relatively small amounts of tetrahydroanabasine
(14) under these conditions. In addition, to improve the
yields of 11, we carried out the condensation between 10
Scheme 4. Synthesis of the 6–6–6 analogues 3a and 3b. Reagents
and conditions: (i) ClCO2Bn, K2CO3, EtOH/H2O, 0 °C to room
temp., 2.5 h, 99%; (ii) PCC/Al2O3, room temp., 6 h, 71%; (iii)
EtOH abs., pTosOH, molecular sieves (3 Å), 35 °C, 40 h, 63%; (iv)
H2, 10% Pd/C, EtOH, atmospheric pressure, 20 °C, 16 h, 98%; (v)
and DEM in organic solvents instead of water; similar con- (a) 5% aq. HCl, room temp., 16 h, (b) α-tripiperideine, pHǞ2.5,
densations of activated methylene compounds with ∆1-pip-
1 h, (c) KCN, 2ՅpHՅ3, room temp., 21 h, 88%; (vi) RMgBr
(5 equiv.), Et2O/THF, –10 °C to room temp., 40 h, average yield:
78%.
erideine generated by detrimerisation of α-tripiperideine
(10) in organic solvents have been reported to proceed with
good yields.[13–15] Unfortunately, though, none of our
Now having several analogues, differing in their alkyl
attempts led to the desired compound 11. In CH2Cl2 or substituents, at our disposal for each of the tricyclic skel-
EtOH/EtONa, for example, in addition to unchanged α- etons [5–6–5, 6–6–5, 6–6–6, and iso-6–6–6], we compared
tripiperideine (10), the α-tripiperideine isomer 13 was ob- their cytotoxicities against HT29 cancer cells. The measured
tained in 47 and 70% yields, respectively, and in EtOH IC50 values are collected in Table 1. Compounds 1a and 1b
compound 12 was formed (20% yield). These results sug- were prepared as reported by Plehiers et al.[6] and com-
gested that in these organic solvents the formation of dimer pounds 2a–2g by the procedure described by Devijver et
14 is favoured.
al.[2] The syntheses of 3a, 3b and 4a–4f are described in this
At this point, because the yields in preparing the 6–6–6 paper. The results clearly indicated that the cytotoxicities
derivatives were not very satisfactory, another approach was are highly sensitive to the size of the alkyl substituents,
used to prepare the key derivative 8. This approach con- whereas the natures of the tricycle ring systems have no
sisted of condensation of ∆1-piperideine (9) with the amino significant effect. Indeed, the long-chain derivatives system-
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Synthesis of New Analogues of the Tetraponerines
1
sities are expressed as % values relative to the base peak. The H
atically display the lowest IC50 values over all four types of
skeletons. It is also interesting to point out that the toxic
activities are not sensitive to the stereochemistries of the
alkyl substituents. This is also true for alkylation of the sec-
ondary amine in the iso-6–6–6 series.
NMR spectra were recorded in CDCl3 at 300 MHz with a Bruker
Avance TM 300 or at 600 MHz with a Varian Unity 600 instrument
and are reported in ppm from internal TMS on the δ scale. Data
are reported as follows: chemical shift [multiplicity (s: singlet, d:
doublet, dd: double doublet, ddd: double double doublet, t: triplet,
dt: double triplet, tt: triple triplet, q: quartet, m: multiplet), coup-
ling constants in Hz, integration, assignment]. The 13C NMR spec-
tra were recorded in CDCl3 at 75.4 MHz with a Bruker Avance
TM 300 instrument. The IR spectra were recorded with a Bruker
IFS 25 instrument as films on an NaCl disk. Thin layer chromatog-
raphy (TLC) was performed with 0.25 mm Polygram silica gel
SILG/UV254 precoated plates (Macherey–Nagel). Chromatog-
raphy was performed on silica gel columns (MN Kieselgel 60 0.04–
0.063 mm) by the flash technique or on basic alumina (MN Alu-
miniumoxid, basisch, Activity 1).
Table 1. IC50 values of compounds 1–4, 20 and 21 [µ] against
HT29 cancer cells.
Compound
R
X
IC50 [µM]
1a, T-5
1b
2a, T-4
2b
β-C5H11
α-C18H37
α-C3H7
–
–
–
–
–
–
–
–
–
Ͼ10
5
Ͼ100
100
50
2
20
100
2
Ͼ10
5
Ͼ10
Ͼ10
2
Ͼ10
Ͼ10
6
α-C4H9
2c, T-8
2d
α-C5H11
α-C12H25
α-C18H37
β-C4H9
β-C12H25
β-C3H7
β-C12H25
β-C3H7
β-C5H11
β-C12H25
β-C3H7
2e
2f
∆1-Piperideine (9): Fresh solutions of ∆1-piperideine were prepared
according to the procedure of Bender et al.[8] Piperidine (1.29 g,
15.18 mmol) was added to a solution of N-chlorosuccinimide
(3.752 g, 28.21 mmol) in diethyl ether (100 mL). The solution was
stirred at room temp. for 1 h. After filtration and rinsing of the
precipitate with diethyl ether (10 mL), the diethyl ether solution
was washed with water (2ϫ100 mL) and brine (50 mL) and then
dried with MgSO4. Just before dehydrohalogenation, the N-chloro-
piperidine solution was filtered and concentrated at reduced pres-
sure to about 20 mL. The resulting solution was added dropwise
to a solution of KOH (85%, 1 g, 15.16 mmol) in absolute ethanol
(16 mL), while the temp. was maintained between 5 and 10 °C. Af-
ter addition, the mixture was stirred at room temp. for 24 h and
filtered, and the precipitate was rinsed with absolute ethanol
(15 mL).
2g
3a
–
–
3b
4a
H
H
H
CH3
CH3
CH3
–
4b
4c
4d
4e
β-C5H11
β-C12H25
β-C5H11
β-C15H31
4f
20
Ͼ10
10
21
–
In addition, we have observed that the influence of the
size of the alkyl chain on the cytotoxicity is comparable
to that observed for the solenopsins, a group of 6-alkyl-2-
methylpiperidines that are the main constituents of the
venom of fire ants.[16] Indeed, the natural derivative 21 (so-
lenopsin C, Figure 2) is cytotoxic against HT29 cells,
whereas the short-chain derivative 22 is inactive (Table 1).
These two derivatives were prepared starting from 2,6-di-
methylpyridine by the route described by MacConnell et
al.[17] In the case of the solenopsins, it has been demon-
strated that their cytotoxicities are linked to their amphi-
philic characters, which lead to breaking of the plasma
membranes of cells. It follows from our results that a similar
mechanism of action could also be proposed for the long-
chain derivatives of the tetraponerines and their analogues.
Such a mechanism would also be in good agreement with
the fact that the structures of the tricyclic moieties of these
compounds have almost no influence on their toxicity po-
tency.
α-Tripiperideine (10): α-Tripiperideine was prepared according to
the procedure of Claxton et al.,[9] starting from a solution of N-
chloropiperidine prepared as described above. This solution was
added dropwise to
a boiling solution of KOH (85%, 2 g,
30.32 mmol) in absolute ethanol (32 mL). The mixture was heated
at reflux for 2.5 h and was then allowed to stand at room temp. for
36 h. The precipitate was removed by filtration and washed with
absolute ethanol. The washes and the filtrate were combined, and
the solvent was removed by distillation. The residue and the pre-
cipitate were then combined and dissolved in water (50 mL). The
resulting solution was extracted with diethyl ether. The diethyl
ether extract was dried with MgSO4, filtered and concentrated in
vacuo. The resulting oily residue was dissolved in acetone (3 mL),
and the solution was cooled to –20 °C and left overnight. The crys-
tals were filtered off and washed with cold acetone. This afforded
10 with a mean yield of 37% (minimum yield 32%, maximum yield
42%). The spectral properties of the crystals were identical to those
reported by Kessler et al. for α-tripiperideine.[18]
Condensation between ∆1-Piperideine (9) and Diethyl Malonate
(DEM): A fresh solution of ∆1-piperideine in ethanol/diethyl ether
was concentrated to dryness, and the residue was dissolved in water
(10 mL). Aqueous HCl (1 ) was added dropwise at 0 °C until the
desired pH was reached, and diethyl malonate (1.266 g, 7.91 mmol,
or 2.532 g, 15.83 mmol) was then poured into the solution in one
portion. The mixture was stirred under nitrogen at room temp.
overnight. The pH was then brought to 8 with ammonia, and the
solution was extracted with CH2Cl2. The combined organic phases
were dried, and the solvents were removed to dryness to give a
crude product that was flash-chromatographed on silica gel
[CH2Cl2/CH3OH (99:1) + 1% NH4OH]. The following yields of 11
and 12 were obtained: at pH 14 and with 1 equiv. of DEM 4 and
Figure 2. Structures of the solenopsin analogues.
Experimental Section
General: EIMS and EIHRMS were performed with a Fisons VG
Micromass Autospec instrument (70 eV). In all cases, peak inten-
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2669

A. Rouchaud, J.-C. Braekman
FULL PAPER
0%, respectively, at pH 13 and with 2 equiv. of DEM 1 and 0%,
respectively, at pH 12 and with 2 equiv. of DEM 0 and 22%, respec-
tively, and at pH 6 and with 2 equiv. of DEM 0 and 17%, respec-
tively.
for C15H24N2O3 280.1786), 207.1488 (calcd. for C12H19N2O
207.1497).
Oxo Ester 12 from 15: A solution of 15[12] (200 mg, 0.58 mmol) and
diethyl malonate (186 mg, 1.16 mmol, 2 equiv.) dissolved in a buffer
solution (pH 7.8, 20 mL) was stirred under nitrogen at room temp.
for 16 h. The pH was brought to 10 by addition of NH4OH,and
the resulting aqueous solution was extracted with CH2Cl2. The
combined organic layers were filtered through a WA filter paper,
and the solvent was evaporated in vacuo to give a residue that was
flash-chromatographed on silica gel [CH2Cl2/CH3OH (98:2) + 1%
concd. NH4OH]. This afforded 12 (140 mg, 0.50 mmol, 86%) as a
colourless oil.
Oxo Ester 11: Diethyl malonate (2.841 g, 17.76 mmol) was added
to a solution of α-tripiperideine (10, 1.46 g, 5.86 mmol) dispersed
in a buffer solution [Na2HPO4 (0.15 , 340 mL), NaOH (0.1 ,
160 mL), pH 11.3, 100 mL]. The pH of the mixture was maintained
at 11.3 by regular addition of aqueous NaOH. The mixture was
stirred at room temp. for 18 h and was then extracted with CH2Cl2
(3ϫ100 mL). The combined organic phases were dried and con-
centrated to give a crude product that was flash-chromatographed
on silica gel [CH2Cl2/CH3OH (99:1) + 1% concd. NH4OH] to af-
ford 11 (841.3 mg, 3.01 mmol, 34%) as white crystals. 1H NMR
(600 MHz, CDCl3): δ = 1.26 (m, 2 H, 1-H, 8-H), 1.30 (t, J = 7.2 Hz,
3 H, 3Ј-H3, m, 1 H, 9-H), 1.36 (qt, J = 13.2, 3.6 Hz, 1 H, 3-H),
1.45 (qt, J = 13.2, 3.6 Hz, 1 H, 2-H), 1.58 (m, 1 H, 10-H), 1.65 (m,
1 H, 3-H), 1.70 (m, 3 H, 8-H, 9-H, 10-H), 1.88 (br. dd, J = 13.0,
2.0 Hz, 1 H, 2-H), 2.14 (m, 2 H, 1-H, 11-H), 2.45 (td, J = 13.0,
2.0 Hz, 1 H, 4-H), 2.84 (br. t, J = 11.0 Hz, 1 H, 7a-H), 3.10 (br. d,
J = 11.0 Hz, 1 H, 11-H), 3.27 (d, J = 10.2 Hz, 1 H, 7-H), 3.62 (dd,
J = 10.0, 2.0 Hz, 1 H, 12a-H), 4.19, 4.28 (m, 2 H, 2Ј-H2), 4.76 (dt,
J = 13.0, 2.0 Hz, 1 H, 4-H) ppm. 13C NMR (75.3 MHz, CDCl3):
δ = 14.3 (C-3Ј), 22.6 (C-9), 23.5 (C-2), 24.8 (C-3), 25.3 (C-10), 30.8
(C-8), 32.4 (C-1), 42.2 (C-4), 49.8 (C-11), 55.0 (C-7), 56.7 (C-7a),
61.2 (C-2Ј), 78.0 (C-12a), 164.1 (C-6), 169.4 (C-1Ј) ppm. IR (KBr):
Dodecahydro-2H-1,8a-diazaphenanthren-9-one: Compound 12
(204.7 g, 0.73 mmol) was dissolved in aqueous KOH (5%, 7 mL),
and the mixture was stirred at 20 °C for 4 h. HCl (10%) was then
added dropwise at 0 °C until pH 2.5 was reached. The resulting
mixture was heated at 70 °C for 2 h, basified with NH4OH and
extracted with CH2Cl2 (3ϫ30 mL). The combined organic layers
were filtered through a WA filter paper, and the solvents were evap-
orated in vacuo to yield an oily residue that was flash-chromato-
graphed on silica gel [CH2Cl2/MeOH/10% NH4OH (95:5:0.1 to
9:1:0.1)]. This afforded dodecahydro-2H-1,8a-diazaphenanthren-9-
one (129 g, 0.62 mmol, 85%). 1H NMR (600 MHz, CDCl3): δ =
1.1 (m, 2 H, 4-H, 5-H), 1.22 (m, 1 H, 4a-H), 1.38 (m, 2 H, 6-H, 7-
H), 1.53 (q, J = 13.2 Hz, 1 H, 3-H), 1.69 (br. d, J = 11.0 Hz, 1 H,
7-H), 1.74 (br. d, J = 13.0 Hz, 1 H, 3-H), 1.86 (br. d, J = 11.0 Hz,
1 H, 6-H), 2.01 (m, 1 H, 4-H), 2.05 (m, 1 H, 5-H), 2.21 (t, J =
16.2 Hz, 1 H, 10-H), 2.36 (t, J = 12.1 Hz, 1 H, 8-H), 2.50 (dd, J =
16.8, 3.6 Hz, 1 H, 10-H), 2.58 (td, J = 10.2, 4.2 Hz, 1 H, 10a-H),
2.63 (t, J = 12.0 Hz, 1 H, 2-H), 2.82 (t, J = 10.5 Hz, 1 H, 4b-H),
3.06 (br. d, J = 11.0 Hz, 1 H, 2-H), 4.78 (d, J = 13.2 Hz, 1 H, 8-
H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 24.0 (C-6), 24.8 (C-
7), 25.5 (C-3), 27.9 (C-4), 31.5 (C-5), 39.4 (C-10), 41.8 (C-8), 44.4
(C-4a), 45.6 (C-2), 53.0 (C-10a), 60.8 (C-4b), 167.4 (C-9) ppm. IR
ν = 2944, 2857, 2805, 1733, 1652, 1454, 1393, 1372, 1347, 1177,
˜
1125, 1006, 729 cm–1. EIMS: m/z (%) = 280 (46) [M]+·, 251 (30),
238 (13), 223 (8), 207 (59), 197 (12), 179 (8), 169 (25), 123 (100),
84 (51). EIHRMS: m/z (%) = 280.1781 (calcd. for C15H24N2O3
280.1787), 279.1704 (calcd. for C15H23N2O3 279.1709), 251.1394
(calcd. for C13H19N2O3 251.1396), 238.1313 (calcd. for
C12H18N2O3 238.1317), 207.1492 (calcd. for C12H19N2O 207.1497),
197.1047 (calcd. for C10H15NO3 197.1052), 123.0920 (calcd. for
C7H11N2 123.0922), 84.0814 (calcd. for C5H10N 84.0813).
(NaCl): ν = 2936, 2855, 2791, 1642, 1444, 1263 cm–1. EIMS: m/z
˜
(%) = 208 (13) [M]+·, 207 (22) [M+· – H·], 165 (7), 150 (12), 122
Oxo Ester 12 from α-Tripiperideine (10):
A buffer solution
(8), 110 (5), 97 (60) [C6H11N]+, 84 (100) [C5H10N]+, 68 (8), 55 (10).
[Na2HPO4 (0.2 , 486 mL), citric acid (0.1 , 14 mL), pH 7.8,
200 mL] was added to a solution of α-tripiperideine (1.53 g,
6.15 mmol) in HCl 1  (20 mL). The mixture was stirred at room
temp. under nitrogen. After 5 h, diethyl malonate (2.949 g,
18.43 mmol) was added, and the mixture was stirred for additional
16 h. The mixture was then basified by addition of NH4OH
(pH 10) and extracted with CH2Cl2. The combined organic phases
were dried and the solvents were removed to dryness to give a yel-
low oil that was flash-chromatographed [CH2Cl2/CH3OH (98:2) +
1% concd. NH4OH]. This afforded 12 (1.95 g, 6.96 mmol, 76%) as
1-Benzyl-dodecahydro-2H-1,8a-diazaphenanthren-9-one: A solution
of Na2CO3 (113 mg, 1.07 mmol) in water (0.5 mL) and benzyl bro-
mide (64 µL, 0.54 mmol) was added to a solution of dodecahydro-
2H-1,8a-diazaphenanthren-9-one (113 mg, 0.54 mmol) in CH2Cl2
(1 mL). The mixture was heated at reflux for 3 h and was then
extracted with CH2Cl2 (3ϫ1 mL). The combined organic layers
were filtered through a WA filter paper, and the solvent was evapo-
rated in vacuo to give a solid residue that was flash-chromato-
graphed on silica gel [CH2Cl2/MeOH/10% NH4OH (99:1:0.1)].
This afforded 1-benzyl-dodecahydro-2H-1,8a-diazaphenanthren-9-
1
a colourless oil. H NMR (600 MHz, CDCl3): δ = 1.04–1.16 (qd,
J = 12.6, 3.6 Hz, 2 H, 4-H, 5-H), 1.31 (t, J = 6.6 Hz, 3 H, 3Ј-H), one (0.157 g, 0.53 mmol, 98%) as a colourless oil. 1H NMR
1.32 (m, 1 H, 4a-H), 1.34 (m, 1 H, 7-H), 1.38 (br. d, J = 13.0 Hz,
(300 MHz, CDCl3): δ = 0.85 (qd, J = 12.1, 4.4 Hz, 1 H, 4-H), 1.14
1 H, 6-H), 1.51 (qt, J = 13.2, 3.6 Hz, 1 H, 3-H), 1.70 (m, 1 H, 7- (qd, J = 11.6, 3.7 Hz, 1 H, 5-H), 1.35–1.78 (m, 6 H, 3-H2, 4a-H,
H), 1.72 (m, 1 H, 3-H), 1.87 (br. d, J = 11.0 Hz, 1 H, 6-H), 2.02
(br. d, J = 13.0 Hz, 2 H, 4-H, 5-H), 2.40 (br. t, J = 13.0 Hz, 1 H,
6-H, 7-H2), 1.80–2.0 (m, 3 H, 2-H, 5-H, 6-H), 2.03 (br. d, J =
13.0 Hz, 1 H, 4-H), 2.20 (td, J = 9.8, 3.6 Hz, 1 H, 10-H), 2.33 (m,
8-H), 2.63 (td, J = 12.0, 2.4 Hz, 1 H, 2-H), 2.87 (td, J = 11.4, 1 H, 10a-H), 2.39 (td, J = 12.5, 2.7 Hz, 1 H, 8-H), 2.80 (m, 2 H,
2.4 Hz, 1 H, 4b-H), 2.96 (t, J = 11.1 Hz, 1 H, 10a-H), 3.05 (br. d,
J = 12.0 Hz, 1 H, 2-H), 3.22 (d, J = 11.4 Hz, 1 H, 10-H), 4.20, 4.33
2-H, 4b-H), 3.07 (dd, J = 15.9, 3.7 Hz, 1 H, 10-H), 3.18 (d, J =
13.5 Hz, 1 H, CH2Ph), 4.04 (d, J = 13.5 Hz, 1 H, CH2Ph), 4.83 (d,
(m, 2 H, 2Ј-H), 4.74 (br. d, J = 14.0 Hz, 1 H, 8-H) ppm. 13C NMR J = 12.0 Hz, 1 H, 8-H), 7.29 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 14.2 (C-3Ј), 24.3 (C-6), 25.1 (C-7), 25.6 (75.3 MHz, CDCl3): δ = 24.3 (C-6), 24.7, 25.0 (C-3, C-7), 28.1 (C-
(C-3), 28.4 (C-4), 31.9 (C-5), 42.6 (C-8), 43.3 (C-4a), 45.9 (C-2), 4), 32.1 (C-5), 38.1 (C-10), 42.0 (C-8), 44.3 (C-4a), 52.2 (C-2), 57.3
55.4 (C-10a), 56.6 (C-10), 61.0 (C-4b), 61.3 (C-2Ј), 164.5 (C-9),
(CH2Ph), 58.0 (C-4b), 60.8 (C-10a), 126.8, 128.1, 129.1, 138.2 (Ar-
170.0 (C-1Ј) ppm. IR (NaCl): ν = 2934, 2854, 1735, 1643, 1443,
C), 167.6 (C-9) ppm. IR (film): ν = 3084, 3060, 3026, 2934, 2855,
˜
˜
1369, 1314, 1264, 1173, 1132 cm–1. EIMS: m/z (%) = 281 (20) [M+·
+ H·], 280 (8) [M]+·, 279 (10) [M+· – H·], 235 (6), 207 (100), 165
(11), 152 (6), 123 (4), 84 (5). EIHRMS: m/z (%) = 280.1771 (calcd.
2793, 1645, 1444 cm–1. EIMS: m/z (%) = 298 (56) [M]+·, 255 (18),
·
239 (14), 221 (11) [M+· – C6H5 ], 212 (13), 207 (54), 186 (51), 172
(35), 91 (100) [C7H7]+, 84 (36) [C5H10N]+.
2670
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2666–2674

Synthesis of New Analogues of the Tetraponerines
1-Benzyl-9-cyano-dodecahydro-2H-1,8a-diazaphenanthrene (16): A
solution of DIBALH (1 ) in hexane (0.36 mL, 0.36 mmol) was
added to the protected lactam (107 mg, 0.36 mmol) dissolved in
anhydrous diethyl ether (5 mL). The mixture was stirred under ni-
trogen at –78 °C for 3 h. The mixture was then acidified with an
ethanolic perchloric acid solution (10%) until pH 3 was reached.
KCN (128 mg, 1.97 mmol) dissolved in H2O (1 mL) was added,
and the mixture was left at 20 °C overnight. After addition of a
satd. NaHCO3 solution (pH 8), the mixture was extracted three
times with CH2Cl2. The combined organic layers were filtered
through a WA filter paper, and the solvents were evaporated in
vacuo. Chromatography on a silica gel column [hexane/acetone/
10% NH4OH (9:1:0.1)] yielded nitrile 16 (66.9 mg, 0.22 mmol,
60%). 1H NMR (600 MHz, CDCl3): δ = 0.90 (qd, J = 12.6, 4.2 Hz,
3Ј-H2, 4Ј-H2), 1.47 (m, 2 H, 1Ј-H, 4a-H), 1.53 (m, 2 H, 3-H2), 1.67
(m, 2 H, 7-H, 1Ј-H), 1.75 (m, 2 H, 6-H, 7-H), 1.85 (td, J = 2.4,
12.6 Hz, 2 H, 4-H, 10-H), 1.95–1.99 (m, 2 H, 2-H, 5-H), 2.10 (td,
J = 9.0, 3.0 Hz, 1 H, 10a-H), 2.19 (br. d, J = 13.1 Hz, 1 H, 10-H),
2.27 (m, 1 H, 4b-H), 2.58 (td, J = 2.4, 10.8 Hz, 1 H, 8-H), 2.64 (d,
J = 13.2 Hz, CH2Ph), 2.78 (br. d, J = 11.0 Hz, 1 H, 8-H), 2.82 (br.
d, J = 11.0 Hz, 1 H, 2-H), 3.00 (m, 1 H, 9-H), 4.50 (d, J = 13.2 Hz,
1 H, CH2Ph), 7.23, 7.30 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 14.1 (C-5Ј), 22.7 (C-3Ј), 23.8 (C-6), 24.3
(C-1Ј), 24.9 (C-3), 25.3 (C-7), 27.2 (C-4), 27.4 (C-4Ј), 29.9 (C-5),
31.6 (C-10), 32.1 (C-2Ј), 45.6 (C-4a), 52.2 (C-8), 53.4 (C-2), 56.8
(CH2Ph), 58.3 (C-4b), 59.7 (C-10a), 60.9 (C-9), 126.7, 128.2, 129.0,
139.7 (Ar-C) ppm. IR (NaCl): ν = 3081, 3061, 3025, 2929, 2854,
˜
2791, 1494, 1452, 1371, 1122, 1028, 968, 736, 698 cm–1. EIMS: m/z
1 H, 4-H), 1.07 (qd, J = 13.2, 3.6 Hz, 1 H, 5-H), 1.20–1.29 (m, 2 (%) = 354 (5) [M]+·, 283 (33) [M+· – C5H11·], 263 (83) [M+· – C7H7 ],
·
H, 4a-H, 6-H), 1.53 (qt, J = 12.6, 3.6 Hz, 2 H, 3-H, 7-H), 1.61 (br.
d, J = 13.0 Hz, 1 H, 3-H), 1.67 (br. d, J = 13.0 Hz, 1 H, 7-H), 1.78
(m, 1 H, 6-H), 1.80 (m, 1 H, 10-H), 1.85 (dd, J = 10.8, 1.8 Hz, 1
H, 4-H), 1.95 (br. d, J = 13.0 Hz, 1 H, 5-H), 2.00 (td, J = 12.0,
3.0 Hz, 1 H, 2-H), 2.03 (td, J = 10.2, 2.4 Hz, 1 H, 4b-H), 2.27 (td,
J = 9.0, 3.0 Hz, 1 H, 10a-H), 2.38 (dt, J = 13.2, 3.0 Hz, 1 H, 10-
H), 2.44 (td, J = 12.0, 2.4 Hz, 1 H, 8-H), 2.70 (br. d, J = 11.0 Hz,
1 H, 8-H), 2.81 (br. d, J = 11.0 Hz, 1 H, 2-H), 3.25 (d, J = 13.8 Hz,
1 H, CH2Ph), 3.88 (br. t, J = 4.0 Hz, 1 H, 9-H), 3.99 (d, J =
13.8 Hz, 1 H, CH2Ph), 7.23, 7.30 (m, 5 H, Ar-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 23.9 (C-6), 25.1 (C-3), 25.4 (C-7), 26.6 (C-
4), 29.8 (C-5), 32.8 (C-10), 46.1 (C-4a), 53.4 (C-2), 54.2 (C-8), 55.1
(C-9), 57.4 (CH2Ph), 60.3 (C-4b), 61.6 (C-10a), 117.2 (CN), 126.9,
166 (11), 110 (100) [C7H12N]+, 91 (37) [C7H7]+, 84 (12) [C5H10N]+,
55 (10).
1-Benzyl-9-dodecyl-dodecahydro-2H-1,8a-diazaphenanthrene: This
compound was prepared according to the same procedure as uti-
lised for preparing the corresponding propyl derivative but by start-
ing from dodecylmagnesium bromide (yield 90%). 1H NMR
(300 MHz, CDCl3): δ = 0.80 (m, 1 H), 0.88 (t, J = 6.2 Hz, 3 H, 3Ј-
H3), 1.27 (br. s, 23 H), 1.41 (m, 1 H), 1.48–2.02 (m, 10 H), 2.08
(td, J = 4.0, 11.9 Hz, 1 H, 10a-H), 2.20 (m, 2 H, 4b-H, 10-H), 2.55
(m, 1 H, 8-H), 2.68 (d, J = 13.4 Hz, 1 H, CH2Ph), 2.73 (br. d, J =
11.0 Hz, 1 H, 8-H), 2.82 (br. d, J = 12.0 Hz, 1 H, 2-H), 2.94 (m, 1
H, 9-H), 4.51 (d, J = 13.4 Hz, 1 H, CH2Ph), 7.22–7.29 (m, 5 H,
Ar-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.2 (C-12Ј), 22.8,
23.9, 24.2, 24.9, 25.5, 27.2, 27.8, 29.4, 29.7, 29.7, 29.8, 29.8, 29.9,
30.0, 31.7, 32.0, 45.7 (C-4a), 52.1 (C-8), 53.4 (C-2), 56.9 (CH2Ph),
58.0 (C-4b), 59.8 (C-10a), 60.7 (C-9), 126.8, 128.2, 129.1, 139.5 (Ar-
127.9, 128.8, 139.4 (Ar-C) ppm. IR (NaCl): ν = 3084, 3060, 3026,
˜
2932, 2855, 2793, 2219, 1645, 1442 cm–1. EIMS: m/z (%) = 309 (15)
·
[M]+·, 281 (41), 226 (20), 218 (97) [M+· – CH2C6H5 ], 191 (39), 173
(15), 134 (45), 110 (37), 91 (69) [C7H7]+, 84 (100) [C5H10N]+.
C) ppm. IR (NaCl): ν = 3085, 3065, 3025, 2926, 2854, 2791, 1494,
˜
1453, 1118, 735, 695 cm–1. EIMS: m/z (%) = 452 (33) [M]+·, 361
1-Benzyl-9-propyl-dodecahydro-2H-1,8a-diazaphenanthrene: A solu-
tion of propylmagnesium bromide, prepared from magnesium
(18 mg, 0.74 mmol) and propyl bromide (67 µL, 0.74 mmol) in di-
ethyl ether (1 mL), was added at –10 °C to a solution of α-amino
nitrile 16 (46.1 mg, 0.15 mmol) in THF (1 mL). The mixture was
stirred at room temp. for 40 h, treated with a satd. aqueous solution
of NH4Cl and extracted three times with CH2Cl2. The combined
organic phases were dried, and the solvents were removed to dry-
ness, leading to a yellow oil that was flash-chromatographed on
silica gel [CH2Cl2/MeOH/10% NH4OH (95:5:0.1)] to give 1-benzyl-
(64) [M+· – CH2C6H5 ], 283 (36) [M+· – C12H25·], 191 (6) [M+·
–
·
CH2C6H5 – C12H25·], 110 (100) [C7H12N]+, 91 (23) [C7H7]+, 84 (8)
·
[C5H10N]+.
9-Propyl-dodecahydro-2H-1,8a-diazaphenanthrene (4a): 1-Benzyl-9-
propyl-dodecahydro-2H-1,8a-diazaphenanthrene
(51.9 mg,
0.12 mmol) dissolved in MeOH/12.5  HCl (98:2, 6 mL) was
stirred under hydrogen in the presence of Pd/C (10%, 30 mg) at
atmospheric pressure and room temp. for 16 h. The mixture was
filtered through Celite and concentrated in vacuo, and the solid
residue was flash-chromatographed on silica gel [CH2Cl2/MeOH/
10% NH4OH (9:1:0.1)]. This yielded 4a (36.1 mg, 0.15 mmol, 96%)
9-propyl-dodecahydro-2H-1,8a-diazaphenanthrene
(41.8 mg,
0.128 mmol, 86%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 0.89 (m, 1 H, 4-H), 0.95 (t, J = 6.6 Hz, 3 H, 3Ј-H),
1.07–1.78 (m, 13 H), 1.80–2.02 (m, 3 H), 2.03–2.23 (m, 3 H), 2.53
(m, 1 H, 8-H), 2.66 (d, J = 13.5 Hz, 1 H, CH2Ph), 2.71 (br. d, J =
10.0 Hz, 1 H, 8-H), 2.81 (br. d, J = 12.0 Hz, 1 H, 2-H), 2.93 (m, 1
H, 9-H), 4.52 (d, J = 13.5 Hz, 1 H, CH2Ph), 7.21–7.29 (m, 5 H,
Ar-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.5 (C-3Ј), 21.1,
24.1 (C-6, C-1Ј), 25.0 (C-3), 25.8 (C-7), 26.6 (C-4), 27.3 (C-5), 30.4
(C-10), 32.0 (C-2Ј), 46.0 (C-4a), 52.2 (C-8), 53.5 (C-2), 56.9
(CH2Ph), 58.0 (C-4b), 60.0 (C-10a), 60.5 (C-9), 126.7, 128.2, 129.0,
1
as a colourless solid. H NMR (600 MHz, CDCl3): δ = 0.93 (t, J
= 7.2 Hz, 3 H, 3Ј-H3), 0.98 (qd, J = 12.0, 3.6 Hz, 1 H, 4-H), 1.13–
1.17 (m, 2 H, 5-H, 6-H), 1.22 (m, 2 H, 4a-H, 2Ј-H), 1.38 (m, 2 H,
1Ј-H, 2Ј-H), 1.60 (m, 4 H, 3-H, 7-H2, 1Ј-H), 1.70 (m, 2 H, 3-H, 6-
H), 1.78 (td, J = 4.8, 12.0 Hz, 1 H, 10-H), 1.84 (m, 3 H, 4-H, 5-H,
10-H), 2.12 (br. t, J = 7.0 Hz, 1 H, 4b-H), 2.51 (br. t, J = 2.0,
11.4 Hz, 2 H, 8-H, 10a-H), 2.66 (m, 2 H, 2-H, 8-H), 2.89 (m, 1 H,
9-H), 3.16 (br. d, J = 11.0 Hz, 1 H, 2-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 14.4 (C-3Ј), 20.9 (C-2Ј), 24.0 (C-6), 25.9
(C-3), 26.0 (C-7), 26.4 (C-1Ј), 26.6 (C-4), 30.0 (C-5), 34.1 (C-10),
46.2 (C-2), 46.7 (C-4a), 52.1 (C-8), 54.8 (C-10a), 57.5 (C-4b), 60.3
139.9 (Ar-C) ppm. IR (NaCl): ν = 3084, 3060, 3026, 2931, 2871,
˜
2793, 1494, 1452, 1372, 1122, 974, 736, 698 cm–1. EIMS: m/z (%)
= 326 (8) [M]+·, 283 (33) [M+· – C3H5 ], 235 (99) [M+· – CH2C6H5 ],
·
·
(C-9) ppm. IR (NaCl): ν = 3391, 2932, 2855, 2802, 1447, 1373,
˜
152 (6), 138 (10), 207 (54), 110 (100).
1146, 1122 cm–1. EIMS: m/z (%) = 236 (7) [M]+·, 221 (2) [M+·
–
1-Benzyl-9-pentyl-dodecahydro-2H-1,8a-diazaphenanthrene:
This
CH3 ], 207 (2) [M+· – C2H5 ], 193 (76) [M+· – C3H7 ], 138 (8), 124
·
·
·
compound was prepared according to the same procedure as uti-
lised for preparing the corresponding propyl derivative but by start-
ing from pentylmagnesium bromide (yield 90%). 1H NMR
(6), 110 (100) [C7H12N]+, 96 (10), 84 (14).
9-Pentyl-dodecahydro-2H-1,8a-diazaphenanthrene (4b): This com-
(600 MHz, CDCl3): δ = 0.85 (m, 1 H, 4-H), 0.91 (t, J = 6.6 Hz, 3 pound was prepared according to the same procedure as utilised
H, 5Ј-H3), 1.18–1.27 (m, 2 H, 5-H, 6-H), 1.29–1.35 (m, 6 H, 2Ј-H2, for preparing the corresponding propyl derivative 4a (yield 95%).
Eur. J. Org. Chem. 2009, 2666–2674
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2671

A. Rouchaud, J.-C. Braekman
FULL PAPER
1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.5 Hz, 3 H, 5Ј-H3),
0.96–2.22 (m, 21 H), 2.26 (br. t, J = 9.0 Hz, 1 H, 4b-H), 2.55 (m,
1 H, 8-H or 10a-H), 2.77 (m, 3 H, 2-H, 8-H, 10a-H or 8-H), 2.95
(m, 1 H, 9-H), 3.36 (br. d, J = 12.0 Hz, 1 H, 2-H), 7.2 (br. s, 1 H,
NH) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.2 (C-5Ј), 22.6,
N-Methyl Derivative 4f: This compound was prepared according to
the same procedure as utilised for preparing the corresponding pro-
pyl derivative 4d (yield 60%). 1H NMR (300 MHz, CDCl3): δ =
0.88 (br. t, J = 6.0 Hz, 4 H, 12Ј-H3), 0.9–1.18 (m, 3 H), 1.27 (s, 20
H), 1.36–1.79 (m, 9 H), 1.86 (br. t, J = 11.0 Hz, 2 H), 2.04 (m, 3
23.4, 24.0, 25.5, 25.5, 27.2, 29.4, 31.7, 32.0, 43.6 (C-4a), 44.9 (C-2), H), 2.23 (s, 3 H, NCH3), 2.48 (td, J = 3.6, 7.4 Hz, 1 H, 8-H), 2.65
52.0 (C-8), 55.0 (C-10a), 57.4 (C-4b), 60.5 (C-9) ppm. IR (NaCl): ν
(br. d, J = 11.3 Hz, 1 H, 8-H), 2.87 (m, 2 H, 2-H, 9-H) ppm. 13C
NMR (75.3 MHz, CDCl3): δ = 14.3 (C-12Ј), 22.8, 24.0, 24.3, 25.5,
26.1, 27.2, 27.8, 29.5, 29.8, 29.8, 30.1, 30.7, 31.9, 32.1, 42.5 (NCH3),
46.2 (C-4a), 52.2 (C-8), 57.6 (C-2), 57.8 (C-4b), 60.4 (C-9), 62.1 (C-
˜
= 3402, 2933, 2856, 2805, 2529, 1593, 1456, 1374, 1243, 1123,
·
1061 cm–1. EIMS: m/z (%) = 264 (46) [M]+·, 249 (5) [M+· – CH3 ],
235 (5) [M+· – C2H5 ], 220 (10) [M+· – H· – C3H7 ], 206 (16) [M+·
–
·
·
H· – C4H9 ], 193 (68) [M+· – C5H11·], 110 (100), 96 (6), 84 (8).
10a) ppm. IR (NaCl): ν = 2924, 2852, 2775, 1461, 1371, 1126 cm–1.
·
˜
EIMS: m/z (%) = 376 (7) [M]+·, 264 (6) [M+· – C8H17·], 207 (80)
[M+· – C12H25·], 149 (8), 136 (7), 124 (12), 110 (100), 96 (7), 84
(20).
9-Dodecyl-dodecahydro-2H-1,8a-diazaphenanthrene (4c): This com-
pound was prepared according to the same procedure as utilised
for preparing the corresponding propyl derivative 4a (yield 99%).
1H NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H, 12Ј- 2-[2-(1-Benzyloxycarbonyl)piperidyl]ethanol: A solution of K2CO3
H3), 0.93–1.43 (m, 25 H), 1.51–1.97 (m, 10 H), 2.13 (m, 1 H, 4b-
H), 2.53 (br. t, J = 2.0, 10.0 Hz, 2 H, 8-H, 10a-H), 2.68 (m, 2 H,
2-H, 8-H), 2.86 (m, 1 H, 9-H), 3.18 (br. d, J = 12.0 Hz, 1 H, 2-H),
4.57 (br. s, 1 H, NH) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.2
(C-12Ј), 22.8, 23.9, 24.2, 25.8, 25.9, 26.5, 27.8, 29.5, 29.8, 29.9, 30.0,
(1.074 g, 7.8 mmol) in water (5 mL) was added to a solution of 2-
(2-piperidyl)ethanol (18, 496.4 mg, 3.85 mmol) in ethanol (5 mL).
The reaction mixture was cooled in an ice bath, and benzyl chloro-
formate (650 µL, 4.6 mmol) was added with vigorous stirring. The
ice bath was maintained for 15 min. The mixture was then allowed
32.0, 34.0 (C-10), 46.1 (C-2), 46.5 (C-4a), 52.1 (C-8), 54.8 (C-10a), to warm progressively to room temp. After 3 h, the mixture was
57.5 (C-4b), 60.7 (C-9) ppm. IR (NaCl): ν = 3397, 2926, 2853,
extracted with CH2Cl2, the combined organic layers were filtered
through a WA filter paper, and the solvent was evaporated in vacuo
to give a residue that was flash-chromatographed on silica gel [hex-
ane/AcOEt (8:2)]. This afforded 2-[2-(1-benzyloxycarbonyl)piperi-
dyl]ethanol (1002 mg, 3.81 mmol, 99%) as a colourless oil. 1H
NMR (300 MHz, CDCl3): δ = 1.3–1.85 (m, 7 H, 3-H2, 4-H2, 5-H2,
7-H), 1.95 (br. t, J = 12.0 Hz, 1 H, 7-H), 2.77 (t, J = 13.4 Hz, 1 H,
6-H), 3.39 (m, 1 H, 8-H), 3.57 (m, 1 H, 8-H), 4.05 (br. d, J =
13.0 Hz, 1 H, 6-H), 4.47 (m, 1 H, 2-H), 5.13 (br. s, 2 H, 10-H2),
7.35 (m, 5 H, Ar-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 19.0,
25.4, 29.1, 32.3, 39.3, 53.5 (C-2), 60.4 (C-8), 67.3 (C-10), 127.8,
˜
2804, 1463, 1372, 1306, 1123, 1062 cm–1. EIMS: m/z (%) = 362 (57)
[M]+·, 361 (48) [M+· – H·], 347 (6) [M+· – CH3 ], 333 (4) [M+·
–
·
·
·
·
C2H5 ], 318 (12) [M+· – H· – C3H7 ], 304 (22) [M+· – H· – C4H9 ],
290 (6) [M+· – H· – C5H11·], 278 (34) [M + H+ – C6H13·], 264 (59)
[M + H+ – C7H15·], 250 (4) [M + H+ – C8H17·], 236 (4) [M + H+
–
C9H19·], 221 (15) [M+· – C10H21·], 207 (15) [M+· – C11H23·], 193
(100) [M+· – C12H25·], 110 (84), 97 (14), 84 (14).
N-Methyl Derivative 4d: Aqueous formaldehyde (37%, 55 µL,
0.74 mmol) was added to a solution of 4a (13 mg, 0.054 mmol) in
MeOH (0.5 mL). The mixture was heated at reflux for 3 h and was
then allowed to cool to room temp. NaBH4 (8 mg, 0.21 mmol) was
then added. After stirring at room temp., for 2 h the mixture was
extracted with CH2Cl2. The combined organic layers were filtered
through a WA filter paper, and the solvent was evaporated in vacuo
to give a residue that was flash-chromatographed on silica gel
[CH2Cl2/MeOH/10% NH4OH (97:3:0.1)]. This afforded 4d (10 mg,
0.039 mmol, 72%) as a colourless oil. 1H NMR (300 MHz,
128.1, 128.5, 136.6 (C-11), 171.1 (C-9) ppm. IR (NaCl): ν = 3446,
˜
3093, 3068, 3034, 2948, 2900, 1699, 1435, 1270, 1058, 763 cm–1.
EIMS: m/z (%) = 263 (7) [M]+·, 218 (68), 174 (99), 156 (20), 126
(18), 108 (32), 91 (100), 79 (46), 65 (34), 55 (24).
2-[2-(1-Benzyloxycarbonyl)piperidyl]ethanal: PCC (547 mg, 2.54
mmol) and neutral alumina (360 mg, previously dried under re-
duced pressure at room temp. for 1 d) were ground together and
CDCl3): δ = 0.85 (m, 1 H), 0.94 (t, J = 7.1 Hz, 3 H, 3Ј-H3), 1.00– placed under nitrogen in freshly distilled dichloromethane (3 mL).
1.76 (m, 14 H), 1.86 (br. t, J = 12.0 Hz, 2 H), 1.95–2.13 (m, 3 H),
2.2 (s, 3 H, NCH3), 2.50 (td, J = 3.8, 10.9 Hz, 1 H, 8-H), 2.65 (m,
1 H, 8-H), 2.87 (m, 2 H, 2-H, 9-H) ppm. 13C NMR (75.3 MHz,
CDCl3): δ = 14.6 (C-3Ј), 21.0, 24.3, 25.5, 26.1, 26.4, 27.2, 30.7,
31.9, 42.4 (NCH3), 46.1 (C-4a), 52.2 (C-8), 57.6 (C-2), 57.7 (C-4b),
2-[2-(1-Benzyloxycarbonyl)piperidyl]ethanol (221.6 mg, 0.84 mmol)
dissolved in CH2Cl2 (3 mL) was quickly added with vigorous stir-
ring. The progress of the reaction was monitored by TLC on silica
gel [hexane/EtOAc (7:3)]. After 6 h at room temp., the mixture was
filtered through a Florisil column and eluted with diethyl ether.
This yielded 2-[2-(1-benzyloxycarbonyl)piperidyl]ethanal (156 mg,
60.1 (C-9), 62.1 (C-10a) ppm. IR (NaCl): ν = 2931, 2871, 2856,
˜
2776, 1456, 1373, 1126 cm–1. EIMS: m/z (%) = 250 (11) [M]+·, 235 0.60 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ = 1.45–1.74 (m,
(3) [M+· – CH3 ], 221 (2) [M+· – C2H5 ], 207 (51) [M+· – C3H7 ], 178
6 H, 3-H2, 4-H2, 5-H2), 2.54–2.79 (m, 2 H, 7-H2), 2.85 (t, J =
13.4 Hz, 1 H, 6-H), 4.05 (br. d, J = 14.0 Hz, 1 H, 6-H), 4.91 (m, 1
H, 2-H), 5.12 (s, 2 H, 10-H2), 7.34 (m, 5 H, Ar-H), 9.68 (s, 1 H, 8-
H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 18.7, 25.1, 28.6 (C-3,
C-4, C-5), 39.5, 44.4 (C-6, C-7), 46.1 (C-2), 67.1 (C-10), 127.8,
127.9, 128.4, 136.6 (C-11), 155.1 (C-9), 200.4 (C-8) ppm. IR
·
·
·
(6), 138 (10), 124 (10), 110 (100), 96 (6), 84 (11).
N-Methyl Derivative 4e: This compound was prepared according
to the same procedure as utilised for preparing the corresponding
1
propyl derivative 4d (yield 62%). H NMR (300 MHz, CDCl3): δ
= 0.81 (m, 1 H), 0.90 (t, J = 7.1 Hz, 3 H, 5Ј-H3), 1.00–1.45 (m, 10
H), 1.47–1.78 (m, 8 H), 1.86 (td, J = 2.8, 12.6 Hz, 2 H), 2.06 (m,
3 H), 2.23 (s, 3 H, NCH3), 2.49 (td, J = 3.8, 10.9 Hz, 1 H, 8-H),
2.66 (br. d, J = 11.0 Hz, 1 H, 8-H), 2.87 (m, 2 H, 2-H, 9-H) ppm.
13C NMR (75.3 MHz, CDCl3): δ = 14.2 (C-5Ј), 22.8, 24.0, 24.3,
25.5, 26.1, 27.2, 27.5, 30.6, 31.8, 32.3, 42.4 (NCH3), 46.1 (C-4a),
(NaCl): ν = 3092, 3063, 3035, 2942, 2865, 2731, 1729, 1692, 1421,
˜
1258, 1056 cm–1. EIMS: m/z (%) = 261 (6) [M]+·, 233 (32), 219 (25),
218 (174), 170 (16), 126 (43), 108 (26), 91 (100), 84 (15), 77 (13),
65 (51).
1-Benzyloxycarbonyl-2-(2,2-diethoxyethyl)piperidine: 2-[2-(1-Ben-
52.2 (C-8), 57.6 (C-2), 57.8 (C-4b), 60.4 (C-9), 62.1 (C-10a) ppm. zyloxycarbonyl)piperidyl]ethanal (1.523 g, 5.84 mmol) dissolved in
IR (NaCl): ν = 2930, 2853, 2775, 1464, 1373, 1126 cm–1. EIMS:
dry ethanol (17 mL) was stirred under nitrogen at 35 °C in the pres-
m/z (%) = 278 (5) [M]+·, 207 (24) [M+· – C5H11·], 193 (9), 166 (8), ence of p-toluenesulfonic acid monohydrate (56 mg, 0.3 mmol) and
110 (100), 96 (7), 84 (9). molecular sieves (3 Å) for 17 h. Dry ethanol (10 mL) was added,
˜
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Synthesis of New Analogues of the Tetraponerines
and the mixture was further stirred at 35 °C for 22 h. The disap-
pearance of the aldehyde was complete after 40 h. The mixture was
filtered through Celite, and the filtrate was concentrated in vacuo.
The solid residue was washed with a satd. aqueous NaHCO3 solu-
tion and extracted with CH2Cl2. The combined organic phases
were dried, and the solvents were removed to dryness. The crude
product was then flash-chromatographed on silica gel [hexane/Ac-
OEt (9:1 to 7:3)] to afford 1-benzyloxycarbonyl-2-(2,2-diethoxye-
thyl)piperidine (1.217 g, 3.63 mmol, 63%) as a colourless oil. 1H
NMR (300 MHz, CDCl3): δ = 1.15 (t, J = 7.0 Hz, 6 H, 18-H3, 20-
H3), 1.53–1.62 (m, 6 H, 3-H2, 4-H2, 5-H2), 1.68–1.79 (m, 1 H, 7-
H), 2.04 (m, 1 H, 7-H), 2.88 (t, J = 13.1 Hz, 1 H, 6-H), 3.38–3.64
(m, 4 H, 17-H2, 19-H2), 4.06 (br. d, J = 13.0 Hz, 1 H, 6-H), 4.46
(m, 2 H, 2-H, 8-H), 5.12 (s, 2 H, 10-H2), 7.31–7.36 (m, 5 H, Ar-H)
ppm. 13C NMR (75.3 MHz, CDCl3): δ = 15.3 (C-18, C-20), 19.0,
25.6, 29.1 (C-3, C-4, C-5), 34.2, 39.3 (C-6, C-7), 47.9 (C-2), 60.6,
62.0 (C-17, C-19), 67.0 (C-10), 101.3 (C-8), 127.8, 127.9, 128.4 (C-
2933, 2858, 2796, 2730, 2221, 1455, 1287, 1246, 1113 cm–1.
EIHRMS: m/z (%) = 219.1722 (calcd. for C13H21N3 219.1735),
192.1618 (calcd. for C12H20N2 192.1626), 163.1176 (calcd. for
C10H15N2 163.1235), 152.1320 (calcd. for C9H16N2 152.1313).
Propyl Derivative 3a: A solution of propylmagnesium bromide, pre-
pared from magnesium (31 mg, 1.28 mmol) and propyl bromide
(116 µL, 1.28 mmol) in diethyl ether (2 mL), was added to a solu-
tion of α-amino nitrile 8 (53 mg, 0.24 mmol) in THF (1 mL) and
cooled to –10 °C. The mixture was stirred at room temp. for 40 h
and was then hydrolysed by addition of a satd. aqueous NH4Cl
solution and extracted three times with CH2Cl2. The organic
phases were combined and dried, and the solvents were removed
to dryness. This afforded a yellow oil that was flash-chromato-
graphed on silica gel [CH2Cl2/MeOH/10% NH4OH (95:5:0.1)] to
give 3a (45 mg, 0.19 mmol, 79%) as a colourless oil. 1H NMR
(300 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H, 3Ј-H3), 1.17–1.38
(m, 8 H), 1.40–1.76 (m, 12 H), 1.89 (td, J = 2.4, 12.0 Hz, 1 H, 11-
H), 2.15 (br. t, J = 10.0 Hz, 1 H, 7a-H), 2.47 (m, 1 H, 4-H), 2.64
(m, 1 H, 4-H), 3.01 (br. d, J = 11.0 Hz, 1 H, 12a-H), 3.10 (m, 2 H,
6-H, 11-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 14.3 (C-3Ј),
20.7, 20.8, 24.5, 26.2, 26.3, 28.9, 30.4, 32.6, 33.9, 49.3 (C-4), 50.2
12–16), 137.0 (C-11), 155.4 (C-9) ppm. IR (NaCl): ν = 3089, 3065,
˜
3033, 2977, 2937, 2870, 1694, 1419, 1256, 1057 cm–1. EIMS: m/z
(%) = 335 (10) [M]+·, 306 (29), 290 (9), 262 (14), 218 (35), 198(73),
174 (59), 154 (100), 126 (13), 91 (88), 65 (11).
(C-11), 57.1 (C-6), 59.2 (C-7a), 73.2 (C-12a) ppm. IR (NaCl): ν =
˜
2-(2,2-Diethoxyethyl)piperidine (19): 1-Benzyloxycarbonyl-2-(2,2-
diethoxyethyl)piperidine (545.2 mg, 1.63 mmol) dissolved in etha-
nol (50 mL) was stirred under hydrogen in the presence of Pd/C
(10%, 57 mg) at atmospheric pressure and room temp. for 21 h.
The mixture was filtered through Celite, and the filtrate was con-
centrated in vacuo. Flash chromatography on neutral alumina
[CH2Cl2/MeOH (9:1)] gave 19 (319.1 mg, 1.59 mmol, 98%) as a
colourless oil. 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz,
6 H, 10-H3, 12-H3), 1.32–1.79 (m, 8 H, 3-H2, 4-H2, 5-H2, 7-H2),
2.29 (br. s, 1 H, NH), 2.61–2.67 (m, 2 H, 2-H, 6-H), 3.03 (br. d, J
= 11.0 Hz, 1 H, 6-H), 3.42–3.70 (m, 4 H, 9-H2, 11-H2), 4.62 (t, J
= 5.5 Hz, 1 H, 8-H) ppm. 13C NMR (75.3 MHz, CDCl3): δ = 15.1,
15.2 (C-10, C-12), 24.7, 25.9, 33.0, 40.4, 46.6, 53.5 (C-2), 61.0, 61.5
2930, 2858, 2796, 2730, 1442, 1373, 1316, 1226, 1134 cm–1. EIMS:
m/z (%) = 236 (36) [M]+·, 207 (100) [M+· – C2H5 ], 193 (11) [M+·
–
·
·
C3H7 ], 179 (20), 166 (23), 152 (28), 138 (22), 124 (9), 110 (25), 84
(32).
Dodecyl Derivative 3b: This compound was prepared according to
the same procedure as utilised for preparing the corresponding pro-
pyl derivative 3a (yield 76%) but by using dodecylmagnesium bro-
1
mide. H NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 6.1 Hz, 3 H,
12Ј-H3), 1.23 (br. s, 24 H), 1.32–1.72 (m, 12 H), 1.86 (td, J = 2.4,
12.0 Hz, 1 H, 11-H), 2.14 (br. t, J = 10.0 Hz, 1 H, 7a-H), 2.45 (m,
1 H, 4-H), 2.60 (m, 1 H, 4-H), 2.98 (br. d, J = 11.0 Hz, 1 H, 12a-
H), 3.09 (m, 2 H, 6-H, 11-H) ppm. 13C NMR (75.3 MHz, CDCl3):
δ = 14.2 (C-12Ј), 20.7, 22.8, 24.5, 26.1, 26.2, 27.6, 28.1, 28.9, 29.4,
29.7, 29.8, 29.9, 32.0, 32.5, 33.8, 49.2 (C-4), 50.2 (C-11), 57.1 (C-
(C-9, C-11), 101.5 (C-8) ppm. IR (NaCl): ν = 3353, 2976, 2931,
˜
2857, 1456, 1373, 1124, 1061 cm–1. EIMS: m/z (%) = 201 (2) [M]+·,
172 (5), 156 (29), 136 (31), 126 (14), 110 (5), 103 (12), 84 (100), 75
(13), 56 (16).
6), 59.5 (C-7a), 73.3 (C-12a) ppm. IR (NaCl): ν = 2928, 2853, 1455,
˜
1377, 1317, 1229, 1137 cm–1. EIMS: m/z (%) = 362 (20) [M]+·, 333
·
·
(5) [M+· – C2H5 ], 305 (6) [M+· – C4H9 ], 277 (7) [M+· – C6H13·],
6-Cyano-decahydro-2H,6H-dipyrido[1,2-a:1Ј,2Ј-c]pyrimidine (8): A
solution of 19 (57.5 mg, 0.29 mmol) in aqueous HCl (5%, 995 µL)
was stirred at room temp. overnight. Ground α-tripiperideine (10,
42 mg, 0.17 mmol) was then added to this solution. The pH was
then raised to 2.5 by slow addition of satd. aqueous NaHCO3,
and this pH was maintained for 1 h. Potassium cyanide (33 mg,
0.51 mmol) was then slowly added, while the pH was maintained
between 2 and 3 by regular addition of diluted aqueous HCl. After
21 h at room temp., the mixture was basified (pH 8) by addition of
a satd. aqueous NaHCO3 solution and was then extracted with
CH2Cl2/EtOH (3:2). The organic phases were combined and dried,
and the solvents were removed to dryness. The resulting yellow oil
was flash-chromatographed on silica gel [CH2Cl2/CH3OH (99:1) +
1% concd. NH4OH]. This yielded 8 (54.9 mg, 0.25 mmol, 88%) as
264 (7) [M+· – C7H15·], 249 (8) [M+· – C8H17·], 235 (5) [M+·
–
C9H19·], 221 (13) [M+· – C10H21·], 207 (100) [M+· – C11H23·], 194
(34), 179 (11), 166 (23), 152 (34), 138 (11), 124 (11), 110 (31), 84
(38).
Acknowledgments
A. R. would like to thank the Fonds pour la Formation à la Re-
cherche dans l’Industrie et l’Agriculture (FRIA) for financial sup-
port. The authors would also like to thank Dr. M. Luhmer and
Mrs. R. d’Orazio for the NMR spectra and Mr. M. Pamart for the
mass spectra. Entomed S. A. is gratefully acknowledged for finan-
cial support and Unibioscreen S. A. for performing the cytotoxicity
tests.
1
a colourless oil. H NMR (600 MHz, CDCl3): δ = 1.27–1.37 (ms,
4 H, 1-H, 2-H, 8-H, 9-H), 1.52–1.65 (ms, 4 H, 3-H2, 8-H, 10-H),
1.65–1.73 (ms, 2 H, 9-H, 10-H), 1.76 (m, 1 H, 7-H), 1.81 (m, 1 H,
2-H), 1.87 (td, J = 2.4, 12 Hz, 1 H, 11-H), 1.98 (td, J = 4.8, 13.2 Hz,
1 H, 7-H), 2.17 (m, 1 H, 1-H), 2.3 (t, J = 10.8 Hz, 1 H, 7a-H), 2.53
(td, J = 3.0, 11.4 Hz, 1 H, 4-H), 2.72 (td, J = 3.0, 9.6 Hz, 1 H, 4-
H), 2.74 (dd, J = 3.0, 9.6 Hz, 1 H, 12a-H), 3.17 (br. d, J = 11.0 Hz,
1 H, 11-H), 3.84 (dd, J = 1.8, 4.8 Hz, 1 H, 6-H) ppm. 13C NMR
(75.3 MHz, CDCl3): δ = 23.1 (C-2), 23.6 (C-9), 24.8 (C-3), 25.7 (C-
10), 29.3 (C-1), 32.8 (C-8), 34.4 (C-7), 48.3 (C-11), 53.5 (C-4), 54.5
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˜
Eur. J. Org. Chem. 2009, 2666–2674
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Received: January 21, 2009
Published Online: April 15, 2009
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Eur. J. Org. Chem. 2009, 2666–2674