Concise and stereoselective syntheses of the eight natural ant defense alkaloids (+)-tetraponerine-1 to (+)-tetraponerine-8 according to the CN(R,S) strategy

Article abstract of DOI:10.1021/jo960398a

The asymmetric syntheses of all the known defense alkaloids of the ant Tetraponera sp. tetraponerines T-1 to T-8 have been accomplished in five or six steps with 20-45% overall yields. The synthesis involved in the cross-condensation of (R)-piperidin-2-ylacetaldehyde with 4-aminobutyraldehyde which upon quenching by cyanide ion gave a stable tricyclic amino nitrile 3 with both a high yield and complete diastereoselectivity. This amino nitrile is the common precursor of four tetraponerines. A similar synthesis using (R)-pyrrolidine-2-ylacetaldehyde provided the tricyclic amino nitrile 2 precursor of the four other tetraponerines.

Full text of DOI:10.1021/jo960398a

J . Org. Chem. 1996, 61, 4949-4954
4949
Con cise a n d Ster eoselective Syn th eses of th e Eigh t Na tu r a l An t
Defen se Alk a loid s (+)-Tetr a p on er in e-1 to (+)-Tetr a p on er in e-8
Accor d in g to th e CN(R,S) Str a tegy
Chongwei Yue, Isabelle Gauthier, J acques Royer,* and Henri-Philippe Husson
Institut de Chimie des Substances Naturelles du CNRS, 91198 Gif-sur-Yvette, France
Received February 27, 1996X
The asymmetric syntheses of all the known defense alkaloids of the ant Tetraponera sp.
tetraponerines T-1 to T-8 have been accomplished in five or six steps with 20-45% overall yields.
The synthesis involved in the cross-condensation of (R)-piperidin-2-ylacetaldehyde with 4-ami-
nobutyraldehyde which upon quenching by cyanide ion gave a stable tricyclic amino nitrile 3 with
both a high yield and complete diastereoselectivity. This amino nitrile is the common precursor of
four tetraponerines. A similar synthesis using (R)-pyrrolidine-2-ylacetaldehyde provided the tricyclic
amino nitrile 2 precursor of the four other tetraponerines.
Ants often use powerful defensive stings; although
most of the venoms are of proteinic nature, some of them
consist of alkaloids. This is the case for some Myrmicinae
species as solenopsis or monomorium genus whose ven-
oms contain dialkylated-piperidine, -pyrrolidine, or -in-
dolizidine derivatives.1 All these substances exhibit
interesting insecticide properties. It was reported in
1988 by Braeckman, Daloze, and co-workers that the
venom of pseudomyrmecine ants Tetraponera sp. consists
of eight toxic alkaloids with an original tricyclic structure
and which have been named tetraponerine-1 to tetrapon-
erine-8 (T-1 to T-8).2
Among these toxic substances, the structure and the
relative configuration of the major component, tetrapon-
erine-8, has been established by X-ray diffraction
analysis.2b Although erroneous structures were first
published for T-3, T-5, T-6, and T-7,2a very recently
reported studies3 fully established that the structures of
F igu r e 1.
tetraponerines, as deduced from their spectroscopic
characteristics together with syntheses (T-5 and T-6)3a
and X-ray analysis (T-8),2b are those represented in
Figure 1. A doubt remains for the structures of T-1 and
T-2 which were isolated in very small amounts, and
indeed no NMR data have been reported for these
compounds.
T-8 and (+)-T-7 was recently described.3a Nevertheless,
no synthesis of T-1 and T-2, nor asymmetric synthesis
of T-4, T-5, and T-6 has yet been accomplished.
The asymmetric synthesis of (+)-T-8, described in a
preliminary report,5 enabled us to determine the absolute
configuration of the natural enantiomer as that depicted
in Figure 1. The absolute configuration of T-3, T-4 and
T-7 have been determined by circular dichroism.3a
From the recently revised structures,3 it appears that
the strategy we used for the asymmetric synthesis of T-85
would allow us to synthesize the eight tetraponerines T-1
to T-8 in a convergent and concise approach. We describe
herein these diastereoselective asymmetric syntheses.
The unprecedented tricyclic skeleton along with the
interesting insecticidal activities of the tetraponerines
(LD50 ) 2 × 10-9 mol/ant mg2b) have made them attrac-
tive targets for total synthesis. Indeed, very soon after
their isolation, a total synthesis of the racemic form of
the major alkaloid (+)-tetraponerine-8 was published by
Merlin et al.,4 and its first asymmetric total synthesis
was accomplished by our group.5 Other total syntheses
of (()-T-8 have also appeared6 as well as those of (()-
T-4,6b (()-T-5, (()-T-6.3b An asymmetric synthesis of (+)-
Resu lts a n d Discu ssion
The structure of the tetraponerines is characterized by
a 1,3-diaza tricyclic system. The construction of this kind
of system has been already reported in the literature
using the Hofmann-Lo¨fler photocyclization,7 the in-
tramolecular condensation of secondary amines with
aldehydes,8 the reductive intramolecular cyclization of
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
(1) Braekman, J .-C.; Daloze, D. In Studies in Natural Products
Chemistry; Atta-ur-Rhaman Ed., Elsevier: New York, 1990; Vol. 6, p
421.
(2) (a) Merlin, P.; Braekman, J .-C.; Daloze, D.; Pasteels, J .-M. J .
Chem. Ecol. 1988, 14, 517. (b) Braekman, J .-C.; Daloze, D.; Pasteels,
J .-M.; Vanhecke, P.; Declercq, J .-P.; Sinnwell, V.; Franke, W. Z.
Naturforsch. 1987, 42c, 627.
(3) (a) Marcours, P.; Braekman, J . C.; Daloze, D. Tetrahedron, 1995,
51, 1415. (b) Devijver, C.; Marcours, P.; Braekman, J . C.; Daloze, D.;
Pasteels, J . Tetrahedron 1995, 51, 10913.
(4) (a) Merlin, P.; Braekman, J .-C.; Daloze, D. Tetrahedron Lett.
1988, 29, 1691. (b) Merlin, P.; Braekman, J .-C.; Daloze, D. Tetrahedron
1991, 47, 3805.
(6) (a) J ones, T. H. Tetrahedron Lett. 1990, 31, 1535. (b) J ones, T.
H. Tetrahedron Lett. 1990, 31, 4543. (c) Barluenga, J .; Toma`s, M.;
Kouznetsov, V.; Rubio, E. J . Org. Chem. 1994, 59, 3699.
(7) (a) Ban, Y.; Kimura, M.; Oishi, T. Chem. Pharm. Bull. 1976, 24,
1490. (b) Kimura, M.; Ban, Y. Synthesis 1976, 201.
(8) (a) Winterfeld, K.; Go¨bel, W. Chem. Ber. 1959, 92, 637. (b) Ayer,
W.; Piers, K. Can. J . Chem. 1967, 45, 451.
(5) Yue, C.; Royer, J ; Husson, H.-P. J . Org. Chem. 1990, 55, 1140.
S0022-3263(96)00398-2 CCC: $12.00 © 1996 American Chemical Society

4950 J . Org. Chem., Vol. 61, No. 15, 1996
Yue et al.
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
secondary amines with lactams or imides,9 and the
condensation of diamines with dialdehydes.10 Our strat-
egy is based on a cross-condensation of two different
amino aldehydes to give cyano aminals 2 or 3 (Scheme
1).
Tetraponerines T-1 to T-8 may be represented by the
general formula 1 with (i) n ) 1 or 2, (ii) a R- or
S-configuration at C-5, and (iii) R ) n-propyl or n-pentyl.
A general access to all the tetraponerines will thus be
possible starting from amino nitriles 2 or 3 if we are able
to introduce the alkyl groups in the proper configuration.
Previous studies from this laboratory have shown that
alkylation of amino nitriles can be stereoselectively
controlled which constitutes the basis of the so-called CN-
(R,S) method.11,12 The synthesis of amino nitriles 2 or 3
might appear as a rather difficult task; nevertheless,
structural similarities with chiral 2-cyano-6-oxazolopip-
eridine 4 suggested a preparation according to a similar
route. We have already shown11 that 4 can be obtained
as a single isomer through a second-order asymmetric
induction (namely a series of equilibria leading to the
more stable isomer 4) by the condensation of a dialdehyde
with a chiral amino alcohol in the presence of cyanide
(Scheme 2). It was thus assumed that the cross-
condensation of two amino aldehydes would also lead
through equilibrated reactions to the more stable stere-
omer of amino nitriles 2 or 3 in which the rings have
stable trans-junctions and the CN group is axial as
imposed by the anomeric effect. The asymmetric syn-
thesis of all the tetraponerines was therefore undertaken
with this strategy.
Syn th esis of (+)-T-3, (+)-T-4, (+)-T-7, a n d (+)-T-8.
The asymmetric synthesis of these four alkaloids started
with cyanooxazolidine 4 which was converted to amino
acetal 7 in three steps and 76% overall yield as previously
described5 and shown in Scheme 3. The hydride reduc-
tion step permitted the total diastereoselective prepara-
tion of acetal 6: only one diastereomer was found in the
reaction mixture as indicated by NMR and chromato-
graphic analyses. A 2R configuration was assigned to 7
on the basis of our previous work.11b
Amino acetal 7, after hydrolysis with aqueous 10% HCl
at room temperature to liberate the aldehyde, was
treated in the same pot with the commercially available
4-aminobutyraldehyde diethyl acetal and potassium cya-
nide to afford cyano aminal 3. The formation of the
compound can be explained as follows: a cross-condensa-
tion between these amino aldehydes occurred instantly
to give probably the unstable tricyclic N,O-acetal inter-
mediate which is in equilibrium with the corresponding
iminium 8 (Scheme 4). The latter was trapped by
cyanide to form the cyano aminal 3 in 84% yield. The
presence of the aminal function and amino nitrile group
was clearly proved by the 13C NMR analysis, showing two
signals at 79.0 and 116.2 ppm.
(9) (a) Yamada, S.; Hino, T.; Ogawa, K. Chem. Pharm. Bull. 1963,
11, 674. (b) Gribble, G. W. J . Org. Chem. 1970, 35, 1944. (c) Takahata,
H.; Okjima, H.; Yamazaki, T. Chem. Pharm. Bull. 1980, 28, 3632. (d)
Scovill, J .-P.; Burckhatter, J . H. J . Heterocycl. Chem. 1980, 17, 23.
(10) (a) Kukla, M.-J .; Breslin, H.-J . J . Org.Chem. 1987, 52, 5046.
(b) Zhu, J .; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1989, 30,
5137.
(11) (a) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org.
Syntheses 1991, 70, 54. (b) Guerrier, L.; Royer, J .; Grierson, D. S.;
Husson, H.-P. J . Am. Chem. Soc. 1983, 105, 7754. (c) Royer, J .; Husson,
H.-P. J anssen Chim. Acta 1993, 11, 3.
It should be noted that this reaction is thermodynami-
cally controlled and is pH-dependent. After several
experiments using a variety of pH conditions, it was
eventually found that the trapping is favored at pH 2-3.
Furthermore, in the basification step, the pH should not
(12) CN(R,S) method refers to the desire to obtain
a R or S
configuration R to the nitrogen by substitution of the CN group.

Syntheses of Natural Ant Defense Alkaloids
J . Org. Chem., Vol. 61, No. 15, 1996 4951
Sch em e 5
Sch em e 6
exceed pH 9. At higher pH values elimination of HCN
and formation of the corresponding enamine becomes the
main reaction. In this cross-condensation step, two new
chiral centers and three bonds were created, neverthe-
less, only one single diastereomer could be isolated. It
was assumed that the thermodynamically more stable
product 3 was obtained (second-order asymmetric induc-
tion), and the relative configuration was confirmed by
careful NMR analysis. This analysis revealed that the
Syn th esis of (+)-T-1, (+)-T-2, (+)-T-5, a n d (+)-T-6.
For the asymmetric synthesis of these alkaloids, the same
strategy as above was applied starting from the 2-cyano-
5-oxazapyrrolidine 11. This compound has received less
attention than the piperidine analogue; nevertheless, it
can be easily prepared13 and has already been shown to
undergo highly diastereoselective alkylations.14
3
protons at C-6a and C-11a are both axial (exhibiting J
Cyanooxazolidine 11 was diastereoselectively trans-
formed into the pyrrolidine acetal derivative 14 in three
steps and 83% overall yield (Scheme 6). It should be
noted that the alkylation of the anion of 11 gave amino
nitrile 12 as a mixture of two diastereomers in a 7:3
ratio.15 These diastereomers could be easily separated
by flash chromatography, but were reduced as a mixture
using NaBH4 to give a single14 amino alcohol 13 in a
quantitative yield. Removal of the chiral appendage of
13 by hydrogenolysis gave 14 in high yield. The cross-
condensation of 14 with aminobutyraldehyde was then
attempted, and we were pleased to obtain the amino
nitrile 2 upon quenching with cyanide ion as a single
diastereomer (albeit with a lower yield, 57%, compared
to the piperidine series). The relative configuration of 2
was assigned as that depicted in Scheme 6 on the basis
of 1H NMR analysis and thermodynamic hypotheses. As
already reported for the pyridopyrrolopyrimidine series
(vide supra), the thermodynamically more stable com-
pound was formed, in which the rings are fused with a
trans-junction and the CN group occupies an axial
position.
coupling constants of 8 and 10 Hz, respectively) and that
the cyano group occupies an axial position at C-5 (ano-
meric effect).
After ensuring the correct configuration of 3, it was
necessary to introduce the alkyl side chain at C-5 in the
proper position to obtain the desired isomer.
It has been previously shown, according to the CN(R,
S) method,11 that replacement of CN group of the synthon
4 by an alkyl chain could be directed to produce either
equatorial or axial R-alkyl piperidine derivatives as
required.
Introduction of the alkyl side chain in the equatorial
position necessitates two steps. The alkylation of cyano
aminal 3 was achieved via its anion (LDA-HMPA, and
then n-C5H11Br) to give 10 in 62% yield (Scheme 5). This
compound was obtained as a single isomer, and its
configuration was tentatively assigned to that one de-
picted on Scheme 5 (with CN axial by comparison with
the starting material). The stereoselective decyanation
of 10 using Na in liquid ammonia yielded (97%) exclu-
sively all-cis tetraponerine-8 (+)-T-8 ([R]20 +99°, lit.:
D
[R]20 +102°) (Scheme 5). Using a similar procedure
Amino nitrile 2 was the precursor of the four remaining
tetraponerines, using our methodology to introduce the
alkyl (propyl or pentyl) group in the correct configuration
(Scheme 7).
D
tetraponerine-4 (+)-T-4 was prepared from 3 via 9 in 65%
yield for the two steps. Synthetic (+)-T-4 had identical
spectral data of those of natural material and has a [R]D
+105° (CHCl3, c 0.3), lit.3a +94° (CHCl3, c 0.2).
Treatment of 2 in ether at -20 °C by n-propyl Grignard
reagent gave (+)-T-1 ([R]20 +11° (CHCl3, c 0.14)), as an
As expected, the direct nucleophilic alkylation of cyano
aminal 3 with propylmagnesium bromide in ether at -20
°C led, via iminium ion 8, to the introduction of the side
chain in an axial position to give tetraponerine (+)-T-3
in 77% yield. Careful examination of the crude reaction
mixture allowed us to assess a 97% de for this alkylation
step; the minute amount of C-5 epimeric material ((+)-
T-4) was easily removed and pure (+)-T3 [R]D +31°,
CHCl3, c 3.1) was obtained in 70% yield. Alkylation of 3
with pentylmagnesium bromide in the same conditions
gave (+)-T-7 ([R]D +30°, CHCl3, c 2.8) in 69% yield (75%
yield of crude mixture with 97% de).
D
unique isomer in 51% yield after purification. In a
similar fashion, n-pentylmagnesium bromide added ste-
reoselectively to 2 to give (+)-T-5 ([R]20 +10° (CHCl3, c
D
0.24); lit. 3a[R]20 +10° (CHCl3, c 0.2)) identical in all
D
aspects to the natural compound.3b In this case no trace
of the epimeric compound could be found.
(13) Royer, J .; Husson, H.-P. Tetrahedron Lett. 1987, 28, 6175.
(14) Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Husson, H.-P.
Tetrahedron 1988, 44, 2457.
(15) The cheaper bromoacetaldehyde diethyl acetal was used in this
case.

4952 J . Org. Chem., Vol. 61, No. 15, 1996
Yue et al.
244 (82), 227 (39), 214 (100), 148 (74); 1H NMR (200 MHz,
CDCl3) δ 7.2-7.5 (m, 5 H), 4.85 (dd, J ) 5, 6 Hz, 1 H), 4.21
(m, 2 H), 4.05 (dd, J ) 5, 9 Hz, 1 H), 3.7-3.9 (m, 5 H), 2.2
(brd, J ) 9 Hz, 2 H), 1.95 (dd, J ) 5, 14 Hz, 1 H), 1.6, 1.75 (m,
4 H), 1.5 (dd, J ) 6, 14 Hz, 1 H); 13C NMR (50 MHz, CDCl3) δ
20.1, 29 4, 35.1, 43.4, 59.7, 62.2, 64.4, 64.8, 74.8, 92.0, 100.8,
118.4, 127.0, 127.7, 128.9, 144.0. Anal. Calcd for
Sch em e 7
C
18H22N2O3: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.55; H,
7.23; N, 8.69.
2-[2-([1,3]Dioxola n -2-ylm et h yl)p ip er id in -1-yl]-2-p h e-
n yleth a n ol (6). To a suspension of NaBH4 (5.5 g, 140 mmol)
in ethanol (180 mL) was added a solution of 5 (3.66 g, 11.6
mmol) in ethanol (20 mL); the mixture was refluxed for 2 h
and then cooled to room temperature. Water (ca. 100 mL) was
added, and the mixture was extracted with CH2Cl2. The
combined organic phases were dried and evaporated to give 6
(3.39 g, 100%) as a colorless oil which can be used in the next
step without purification. Flash chromatography on silica gel
(CH2Cl2/CH3OH 20:1) furnished analytical sample: [R]20D -74°
(CHCl3, c 0.44); MS (EI) m/z 291 (M+, 1), 260 (52), 204 (11),
174 (100); 1H NMR (200 MHz, CDCl3) δ 7.3 (m, 5 H), 4.85 (dd,
J ) 5, 6 Hz, 1 H), 3.6-4.0 (m, 7 H), 3.25 (m, 1 H), 2.33-2.67
(m, 2 H), 1.28-2.0 (m, 9 H); 13C NMR (50 MHz, CDCl3) δ 19.5,
25.7, 29.3, 30.4, 43.6, 52.7, 62.6, 64.8, 67.9, 103.8, 127.6, 128.4,
128.8, 155.9. Anal. Calcd for C17H25NO3: C, 70.07; H, 8.65;
N, 4.81. Found: C, 70.11; H, 8.51; N, 4.75.
Alkylation of the anion of 2 (LDA-HMPA, THF, -78
°C) with propyl bromide or pentyl bromide gave the
corresponding amino nitriles 16 and 17 which were
decyanated, respectively, to (+)-T-2([R]20 +36° (CHCl3,
D
c 1,8)) and (+)-T-6 ([R]20D +35° (CHCl3, c 0.31); lit.3a [R]20
+35° (CHCl3, c 0.15)).
D
As only minute amounts of tetraponerines (+)-T-1 and
(+)-T-2 had been isolated from the natural source,3a
physical data were scarce and indeed no optical rotations
or NMR data was reported. The authenticity of these
two compounds has been obtained by comparison of
synthetic and natural material by GC.16 Identical reten-
tion times in separate as well as in coinjections experi-
ments were further evidences for their structures.
We have thus prepared all eight natural tetraponerines
through a concise, convergent, and efficient synthesis in
five or six steps and 20-45% overall yields. The CN-
(R,S) strategy was used twice in these syntheses: firstly
in the diastereoselective preparation of the chiral pip-
eridine or pyrrolidine acetaldehyde, which allowed the
incorporation of the first asymetric center, and secondly
in the diastereoselective alkylation of the tricyclic amino
nitriles 2 or 3 leading to the final alkaloids.
(2R)-2-([1,3]Dioxola n -2-ylm eth yl)p ip er id in e (7). Com-
pound 6 (3.2 g, 11.0 mmol) in methanol (150 mL) was
hydrogenated in the presence of 10% Pd/C at atmospheric
pressure and room temperature for 40 min. The mixture was
filtered through Celite, and the filtrate was concentrated in
vacuo. Purification by flash chromatography on silica gel (CH2-
Cl2/CH3OH/NH4OH 20:1:0.1) gave 7 (1.71 g, 91%) as a colorless
oil: [R]20D +9° (CHCl3, c 0.1); IR (neat) 3330, 2931, 1140 cm-1
;
MS (CI) m/z 172 (MH)+; H NMR (200 MHz, CDCl3) δ 5.0 (t,
J ) 5 Hz, 1 H), 3.92 (m, 4 H), 3.05 (brd, J ) 11.5 Hz, 1 H),
2.50-2.77 (m, 3 H), 1.10-1.78 (m, 8 H); 13C NMR (50 Mz,
CDCl3) δ 24.7, 26.0, 33.2, 40.9, 46.8, 53.2, 64.5, 64.7, 103.3.
Anal. Calcd for C9H17NO2: C, 63.13; H, 10.01; N, 8.18.
Found: C, 63.15; H, 9.76; N, 7.94.
1
Deca h yd r o-5H-p yr id o[1,2-c]p yr r olo[1,2-a ]p yr im id in e-
5-ca r bon itr ile (3). Piperidine 7 (1.62 g, 9.47 mmol) in 5%
aqueous HCl (30 mL) was stirred at room temperature
overnight. Then, to the above solution were added successively
aminobutyraldehyde diethyl acetal (3 mL, 15 mmol) and KCN
(1.8 g, 17.4 mmol) while the pH was controlled between 2 and
3 by the addition of diluted aqueous HCl. After 2 h at room
temperature the mixture was basified by slow addition of a
saturated NaHCO3 to pH 8 and then extracted with CH2Cl2.
The organic phase was dried and concentrated to dryness to a
orange colored oil which was purified by flash chromatography
(CH2Cl2/CH3OH 20:1) to give 3 (1.63 g, 84%) as a colorless oil
Exp er im en ta l Section
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium/benzophenone ketyl immediately prior to use. Diiso-
propylamine was distilled from and stored over KOH. Final
solutions before rotary evaporation were dried over Na2SO4,
and flash chromatography was carried out using 230-400
mesh silica gel. Melting points are uncorrected. Optical
rotations werte recorded at 20 °C in a 1 dm cell. Microanalyses
were carried out at the Service de Microanalyse at the Institut
de Chimie des Substances Naturelles.
that crystallized upon standing: mp 75 °C (CH2Cl2); [R]20
D
+9.5° (CHCl3, c 0.4); IR (neat) 3040, 221 0, 1210 cm-1; MS
1
(CI) m/z 206 (MH)+, 179 (MH - HCN)+; H NMR (400 MHz,
CDCl3) δ 4.1 (dd, J ) 2.1, 4.9 Hz, 1 H), 3.0 (dt, J ) 2.5, 8.5 Hz,
1 H), 2.9 (brd, J ) 11.5 Hz, 2 H), 2.78 (dd, J ) 6.1, 8.5 Hz, 1
H), 2.6 (q, J ) 8.5 Hz, 1 H), 2.2 (tt, J ) 2.5, 10 Hz, 1 H), 1.20,
2.10 (m, 13 H); 13C NMR (50 MHz, CDCl3) δ 19.3, 23.8, 25.1,
28.7, 31.5, 34.8, 49.3, 49.8, 50.4, 57.5, 79.0, 116.2. Anal. Calcd
for C12H19N3: C, 70.20; H, 9.33; N, 20.47. Found: C, 70.28;
H, 9.21; N, 20.52.
5-([1,3]Dioxola n -2-ylm et h yl)-3-p h en yl-h exa h yd r o-ox-
a zolo[3,2-a ]p yr id in e-5-ca r bon itr ile (5). To a stirred solu-
tion of LDA [prepared from 6.1 mL (43.3 mmol) of diisopro-
pylamine and 27.1 mL (43.4 mmol) of 1.6M n-BuLi in hexane]
in THF (15 mL) and HMPA (15 mL, 86.6 mmol) was added
dropwise a solution of 4 (3.94 g, 17.3 mmol) in THF (30 mL)
at -78 °C. After 20 min, a solution of 2-(bromomethyl)-1,3-
dioxolane (2.6 mL, 25 mmol) in THF (2.5 mL) was added. After
stirring for 2 h at -78 °C, the mixture was quenched by
saturated aqueous NH4Cl and extracted with CH2Cl2. The
combined organic phases were dried and evaporated in vacuo
to give a residue which was purified by flash chromatography
(hexane/Et2O 2:1) to afford 5 (4.6 g, 85%) as a colorless oil:
(+)-T-3. To a cooled (-20 °C) solution of cyano aminal 3
(410 mg, 2 mmol) in Et2O (15 mL) was added 2 M n-
propylmagnesium bromide in Et2O (2.5 mL, 5 mmol). The
resulted suspension was stirred at -20 °C for 90 min, and then
saturated aqueous NH4Cl was added and the mixture was
extracted with CH2Cl2. The combined organic phases were
dried and evaporated to give crude product that was purified
(CH2Cl2-MeOH-NH4OH 96:4:0.05) to afford (310 mg, 70%)
[R]20 -156° (CHCl3, c 1.2); IR (neat) 2953, 2880, 2100, 1134
of pure (+)-T-3 as a colorless oil. [R]20 +31° (CHCl3, c 3.1);
D
D
cm-1; MS (EI) m/z 314 (M+, 30), 313 (31), 288 (19), 287 (73),
lit.3a [R]20 +27° (CHCl3, c 0.07) Anal. Calcd for C14H26N2: C,
D
75.61; H, 11.78; N, 12.59, Found: C, 75.17; H, 11.85; N, 12.97.
The first column chromatography fractions (40 mg) showed
the presence of ca. 15% of epimeric tetraponerine (T-4) as
(16) This experiment has kindly been carried out by Prof. Daloze
and Braekman at the University of Brussels.

Syntheses of Natural Ant Defense Alkaloids
J . Org. Chem., Vol. 61, No. 15, 1996 4953
determined by 13C NMR, corresponding to a 97% de for the
crude reaction mixture.
NH4Cl and extracted with CH2Cl2. The organic layers were
combined, dried, and concentrated in vacuo. The crude oil was
then purified by flash chromatography (heptane/EtOAc 7:3)
to afford 12 (2.7 g, 86%) as a colorless oil and a 7:3 mixture of
diastereoisomers. They can be separated to furnish analytical
sample of each epimer.
(+)-T-7. According to the same procedure, 3 (410 mg, 2
mmol) was treated with 2 M n-pentylmagnesium bromide to
give (+)-T-7 (305 mg, 69%) as a colorless oil: [R]20 +30°
D
(CHCl3, c 2.8); lit.3a [R]20 +30° (CHCl3, c 0.22) Anal. Calcd
D
for C16H30N2: C, 76.74; H, 12.07; N, 11.18, Found: C, 76.95;
H, 11.91; N, 11.46. The first chromatography fractions (32 mg)
showed the presence of ca. 15% of epimeric tetraponerine (T-
8) as determined by 13C NMR, corresponding to a 97% de for
the crude reaction mixture.
Major compound (less polar): [R]20 -147° (CHCl3, c 2.38);
D
IR (neat) 2988, 2880, 2224, 1131 cm-1; MS (CI) m/z 331 (MH)+;
1H NMR (250 MHz, CDCl3) δ 7.0-7.5 (m, 5 H), 5.06 (dd, J )
2.5, 6 Hz, 1 H), 4.69 (t, J ) 8 Hz, 1 H), 4.65 (dd, J ) 4, 7 Hz,
1 H), 4.54 (t, J ) 7 Hz, 1 H), 3.3-3.6 (m, 4 H), 3.62 (dd, J )
7, 8 Hz, 1 H), 1.8-2.6 (m, 6 H), 1.14 (t, J ) 7 Hz, 3 H), 1.11 (t,
J ) 7 Hz, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 15.2, 15.3, 29.2,
38.4, 42.8, 61.3, 62.1, 62.7, 63.9, 75.8, 97.9, 99.8, 120.6, 126.3,
127.5; 128.8, 141.7. Anal. Calcd for C19H26N2O3: C, 69.06;
H, 7.93; N, 8.47. Found: C, 68.75; H, 7.67; N, 8.19.
5-P en tyl-d eca h yd r o-5H-p yr id o[1,2-c]p yr r olo[1,2-a ]p y-
r im id in e-5-ca r bon itr ile (10). To a solution of LDA (pre-
pared with 0.9 mL (6.43 mol) of diisopropylamine and 4 mL
(6.4 mmol) of 1.6 M n-BuLi in hexane) in THF (6 mL) and
HMPA (1.5 mL, 8.6 mmol) was added a solution of 3 (440 mg,
2.15 mmol) in THF (20 mL) at -78 °C. The resulted yellow-
brown solution was stirred at -78 °C for 30 min, and then
pentyl bromide (0.55 mL, 4.3 mmol) in THF (5 mL) was added.
After 30 min, the reaction was quenched by saturated aqueous
NH4Cl and extracted by CH2Cl2. The combined extracts were
dried and concentrated in vacuo. The crude product was
purified by flash chromatography (Et2O-hexane 5:1) to afford
10 (364 mg, 62%) as a colorless oil. [R]20D +61° (CHCl3, c 1.0);
IR (neat) 2954, 2305 cm-1; MS (CI) m/z 276 (MH+), 249, 206;
1H NMR (200 MHz, CDCl3) δ 3.1 (ddd, J ) 2, 8, 8.5 Hz, 1 H),
2.90 (brd, J ) 12 Hz, 1 H), 2.81 (dd, J ) 6, 8 Hz, 1 H), 2.45 (q,
J ) 8.5 Hz, 1 H), 2.18 (tt, J ) 2.5, 10 Hz, 1 H), 1.20-2.10 (m,
21 H), 0.90 (t, J ) 7 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ
13.8, 19.1, 22.3, 22.9, 24.0, 25.2, 29.0, 31.6, 31.7, 38.3, 40.4,
46.1, 50.6, 58.9, 61.2, 80.4, 118.7. Anal. Calcd for C17H29N3:
C, 74.13; H, 10.61; N, 15.26. Found: C, 74.08; H, 10.40; N,
15.34.
Minor compound (more polar): 1H NMR (250 MHz, CDCl3)
δ 7.0-7.5 (m, 5 H), 5.05 (d, J ) 4.6 Hz, 1 H), 4.71 (dd, J ) 3.5,
7.4 Hz, 1 H), 4.50 (t, J ) 7.5 Hz, 1 H), 4.29 (t, J ) 7.5, 8.2 Hz,
1 H), 3.4-3.8 (m with t, J ) 8.2 Hz at 3.54, 5 H), 2-2.5 (m, 6
H), 1.24 (t, J ) 7 Hz, 3 H), 1.16 (t, J ) 7 Hz, 3 H); 13C NMR
(62.8 MHz, CDCl3) δ 15.0 (2 carbons), 29.4, 36.2, 38.2, 61.3,
61.9, 62.5, 63.6, 74.3, 97.6, 101.0, 121.6, 126.3, 127.5; 128.8,
141.2; HRMS (CI) calcd for C19H25N2O3 + H+: 331.2022; found
331.2028.
2-[2-(2,2-Dieth oxyeth yl)p yr r olid in -1-yl]-2-p h en yleth a -
n ol (13). Following the procedure described above for prepa-
ration of 6, amino nitrile 12 (2.65 g, 8 mmol, as a mixture of
diastereomers) afforded 13 (2.4 g, 100%) as a colorless oil which
can be purified by flash chromatography (CH2Cl2/CH3OH/NH4-
OH 20:1:0.1), but was pure enough for the next step: [R]20
D
+7° (CHCl3, c 1.67); IR (neat) 3394, 2988, 2880, 1131 cm-1
;
MS (CI) m/z 308 (MH)+; 1H NMR (250 MHz, CDCl3) δ 7.0-7.5
(m, 5 H), 4.37 (dd, J ) 4.2, 6.8 Hz, 1 H), 3.96 (dd, J ) 9.0,
12.4Hz, 1 H), 3.8 (m, 2 H), 3.3-3.6 (m, 4 H), 3.08 (m, 3 H), 2.8
(m, 1 H), 1.4-1.8 (m, 6 H), 1.11 (t, J ) 7 Hz, 3 H), 1.08 (t, J
) 7 Hz, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 15.3, 23.1, 30.6,
38.4, 52.3, 56.8, 60.7, 61.3, 63.4, 68.2, 101.4, 127.7, 128.3, 128.8,
138.9. Anal. Calcd for C18H29NO3: C, 70.32; H, 9.50; N, 4.55.
Found: C, 70.14; H, 9.31; N, 4.52.
5-P r op yl-d eca h yd r o-5H-p yr id o[1,2-c]p yr r olo[1,2-a ]p y-
r im id in e-5-ca r bon itr ile (9). Following the procedure de-
scribed above for the preparation of 10, amino nitrile 3 (220
mg, 1.07 mmol) was reacted with C3H7Br to give 9 as a
colorless oil (183mg, 69%): [R]20 +38° (CHCl3, c 0.66); MS
D
(EI) m/z 248, 247 (M+), 246, 219, 218, 179, 177; 1H NMR (200
MHz, CDCl3) δ 3.13 (dt, J ) 2, 8.5 Hz, 1 H), 2.90 (brd, J ) 12
Hz, 1 H), 2.83 (dd, J ) 6, 8 Hz, 1 H), 2.45 (t, J ) 8.5 Hz, 1 H),
2.20 (tt, J ) 2.5, 10 Hz, 1 H), 1.20-2.10 (m, 17 H), 0.77 (t, J )
7 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 14.1, 16.7, 19.2, 24.1,
25.3, 29.0, 31.7, 40.6 (2 carbons), 46.8, 50.7, 50.9, 61.3, 80.5,
118.8. Anal. Calcd for C15H25N3: C, 72.83; H, 10.19; N, 16.99.
Found: C, 72.59; H, 10.24; N, 17.15.
(2R)-2-(2,2-Dieth oxyeth yl)p yr r olid in e (14). Following
the procedure described for 7, compound 13 (2.4 g, 7.81 mmol)
was hydrogenated to give 14 (1.41 g, 97%) as a colorless oil:
[R]20 +2° (CHCl3, c 4.07); IR (neat) 3387, 2975, 1131 cm-1
;
D
MS (CI) m/z 188 (MH)+; 1H NMR (250 MHz, CDCl3) δ 4.65 (t,
J ) 4.6 Hz, 1 H), 3.67 (dq, J ) 7.0, 9.3 Hz, 2 H), 3.52 (dq, J )
7.0, 9.1 Hz, 2 H), 3.35 (m, 1 H), 3.1 (m, 1 H), 3.02 (ddd, J )
6.1, 8.4, 10.8 Hz, 1 H), 1.8-2 (m, 6 H), 1.45 (m, 1 H), 1.21 (t,
J ) 7 Hz, 6 H); 13C NMR (62.8 MHz, CDCl3) δ 15.3 (2 carbons),
24.2, 31.4, 38.2, 45.4, 55.9, 61.6, 61.7, 101.3; HRMS (CI) calcd
for C10H21NO2 + H+ 188.1650; found: 188.1652.
Tetr a p on er in e-8 (T-8). To 30 mL of liquid ammonia was
added sodium metal (140 mg, 6.1 mmol) at -78 °C. After 30
min, a deep blue colored solution was obtained to which was
added a solution of 10 (194 mg, 0.71 mmol) in THF at -78 °C.
After stirring for 20 min, the reaction was quenched by the
addition of methanol (1 mL), the mixture was then warmed
to room temperature to evaporate excess of ammonia. After
addition of saturated aqueous NH4Cl and extraction with CH2-
Cl2, the combined extracts were dried and concentrated to give
crude product. After flash chromatography (hexane-acetone
4:1 saturated by NH4OH), (+)-tetraponerine-8 (171 mg, 97%)
was obtained as a white solid: mp 40 °C (hexane-acetone);
[R]20 +99° (CHCl3, c 0.6), lit.1b [R]20 +102° (CHCl3, c 0.15).
Deca h ydr o-5H-d ip yr r olo[1,2-a :1′,2′-c]pyr im id in e-5-ca r -
bon itr ile (2). Following the procedure outlined for compound
3, pyrrolidine 14 (1.18 g, 6.32 mmol) was reacted with
aminobutyraldehyde diethyl acetal (2 mL, 10.1 mmol) and
KCN (784 mg, 11.56 mmol) to provide 2 (688 mg, 57%) as a
colorless oil: [R]20D +41° (CHCl3, c 0.75); IR (neat) 3409, 2966,
2804, 2221, 1390 cm-1; MS (CI) m/z 192 (MH)+; 1H NMR (250
MHz, CDCl3) δ 4.14 (dd, J ) 2.0, 4.9 Hz, 1 H), 3.04 (dt, J )
3.0, 8.5 Hz, 1 H), 3.02 (dt, J ) 3.0, 8.5 Hz, 1 H), 2.92 (dd, J )
6.0, 8.3 Hz, 1 H), 2.64 (q, J ) 8.5 Hz, 1 H), 2.3 (m,1 H), 2.2 (q,
J ) 8.7 Hz, 1 H), 2.1-2.2 (m, 10 H); 13C NMR (62.8 MHz,
CDCl3) δ 19.8, 20.9, 28.5, 29.2, 32.2, 48.5, 48.8, 49.2, 59.8, 78.7,
116.4. Anal. Calcd for C11H17N3: C, 69.07; H, 8.95; N, 21.96.
Found: C, 68.77; H, 8.71; N, 21.68.
5-P r op yl-d eca h yd r o-5H-d ip yr r olo[1,2-a :1′,2′-c]p yr im i-
d in e-5-ca r bon itr ile (16). To a solution of LDA [prepared
with 0.3 mL (2.19 mmol) of diisopropylamine and 1.36 mL
(2.18 mmol) of 1.6 M n-BuLi in hexane] in THF (2 mL) and
HMPA (0.51 mL, 2.92 mmol) was added a solution of 2 (140
mg, 0,73 mmol) in THF (3.5 mL) at -78 °C. The resulted
brown solution was stirred at -78 °C for 30 min, and then
n-propyl bromide (0.33 mL, 1.46 mmol) in THF (1.7 mL) was
added. After 30 min, the reaction was quenched by the
addition of saturated aqueous NH4Cl and extracted by CH2-
Cl2. The combined extracts were dried and concentrated in
D
D
Anal. Calcd for C16H30N2: C, 76.74; H, 12.07; 11.19. Found:
C, 76.40; H, 12.12; N, 11.08.
Tetr a p on er in e-4 (T-4). According to the same procedure
described above for (+)-tetraponerine-8, amino nitrile 9 (140
mg) produced (+)-T-4 (120 mg, 95% yield) as a colorless oil:
[R]20 +105° (CHCl3, c 0 3), lit.3a [R]20 +94° (CHCl3, c 0 2).
D
D
Anal. Calcd for C14H26N2: C, 75.62; H, 11.78; N, 12.60.
Found: C, 75.60; H, 11.58; N, 12.52.
5-(2,2-Dieth oxyeth yl)-3-p h en yl-h exa h yd r o-p yr r olo[2,1-
b]oxa zole-5-ca r bon itr ile (12). To a stirred solution of LDA
[prepared from 4 mL (28.5 mmol) of diisopropylamine and 17.8
mL (28.4 mmol) of 1.6 M n-BuLi in hexane] in THF (30 mL)
and HMPA (7.9 mL, 45.1 mmol) was added dropwise a solution
of 11 (2 g, 9.3 mmol) in THF (10 mL) at -78 °C. After 30
min, a solution of bromoacetaldehyde diethyl acetal (2.8 mL,
18.7 mmol) in THF (2.5 mL) was added. After stirring for 4 h
at -78 °C, the mixture was quenched by saturated aqueous

4954 J . Org. Chem., Vol. 61, No. 15, 1996
Yue et al.
vacuo. The crude product was purified by flash chromatog-
raphy (EtOAc/heptane 8:2) to give 16 (78 mg, 46%) as a
colorless oil: IR (neat) 3409, 2964, 2818, 2214, 1390 cm-1; MS
1 H), 2.58 (t, J ) 6.5 Hz, 1 H), 2.19 (m, 2 H), 2.06 (q, J ) 8.5
Hz, 1 H), 1.95 (m, 1 H), 1.2-1.9 (m, 18 H), 0.88 (t, J ) 6.9 Hz,
3 H); 13C NMR (62.8 MHz, CDCl3) δ 14.2, 20.2, 21.2, 22.8, 25.3,
28.9, 29.9, 32.4, 33.9, 34.0, 47.7, 49.1, 60.7, 64.2, 83.8. Anal.
Calcd for C15H28N2: C, 76.21; H, 11.94; N, 11.85; found: C,
75.91; H, 11.51; N, 11.11.
1
(CI) m/z 234 (MH)+; H NMR (250 MHz, CDCl3) δ 3.12 (dt, J
) 2.7, 8.5 Hz, 1 H), 3.04 (dt, J ) 2.5, 8.5 Hz, 1 H), 2.88 (dd, J
) 5.8, 6.8 Hz, 1 H), 2.48 (q, J ) 8.5 Hz, 1 H), 2.3 (m, 1 H),
2.22 (q, J ) 8.5 Hz, 1 H), 1.2-2.1 (m, 14 H), 0.96 (t, J ) 7.2
Hz, 3 H); 13C NMR (62.8 MHz, CDCl3) δ 14.1, 16.6, 19.4, 21.1,
28.7, 29.4, 37.7, 40.5, 45.4, 48.8, 60.7, 79.5, 118.5; HRMS (CI)
calcd for C14H23N3 + H+ 234.1970; found: 234.1979.
(+)-Tet r a p on er in e-1 (T-1). According to the procedure
described for T-3, cyanoaminal 2 (300 mg, 1.57 mmol) was
reacted with n-propylmagnesium bromide to afford (+)-T-1
(167 mg, 51%) as a colorless oil: [R]20 +11° (CHCl3, c 0.14);
D
IR (neat) 3400, 2950, 2881, 1375 cm-1; MS (CI) m/z 209 (MH)+;
1H NMR (250 MHz, CDCl3) δ 3.39 (brd J ) 4.5 Hz, 1 H), 3.09
(q, J ) 7.4 Hz, 1 H), 2.96 (m, 2 H), 2.81 (dd, J ) 4.9, 6.7 Hz,
1 H), 2.06 (m, 1 H), 1.25-1.95 (m, 15 H), 0.91 (t, J ) 7.2 Hz,
3 H); 13C NMR (62.8 MHz, CDCl3) δ 14.2, 20.1, 20.5, 21.2, 29.4,
29.6, 30.9, 33.9, 49.9, 50.2, 53.5, 58.3, 76.8; HRMS (CI) calcd
for C13H24N2 + H+ 209.2018; found: 209.2028.
5-P en tyl-d eca h yd r o-5H-d ip yr r olo[1,2-a :1′,2′-c]p yr im i-
d in e-5-ca r bon itr ile (17). According to the same procedure,
amino nitrile 2 (140 mg, 0.73 mmol) reacted with n-pentyl
bromide to give 17 as a colorless oil (109 mg, 57%): IR (neat)
3409, 2964, 2818, 2214, 1390 cm-1; MS (CI) m/z 262 (MH)+;
1H NMR (250 MHz, CDCl3) δ 3.10 (dt, J ) 2.3, 8.5 Hz, 1 H),
3.04 (dt, J ) 2.6, 8.5 Hz, 1 H), 2.88 (dd, J ) 5.8, 9.2 Hz, 1 H),
2.47 (q, J ) 8.5 Hz, 1 H), 2.31 (m, 1 H), 2.20 (q, J ) 8.5 Hz, 1
H), 1.3-2.1 (m, 18 H), 0.89 (t, J ) 7.2 Hz, 3 H); 13C NMR (62.8
MHz, CDCl3) δ 13.8, 19.5, 21.1, 22.4, 22.9, 28.8, 29.3, 31.7,
37.8, 38.3, 45.4, 48.9, 60.8, 79.6, 118.7; HRMS (CI) calcd for
C16H27N3 + H+ 262.2283; found: 262.2281.
(+)-Tet r a p on er in e-5 (T-5). According to the procedure
described for T-3, cyano aminal 2 (140 mg,0.73 mmol) was
treated with n-pentylmagnesium bromide to give (+)-T-5 (107
mg, 62%) as a colorless oil: [R]20 +10° (CHCl3, c 0.24); lit.
D
[R]20 +10° (CHCl3, c 0.2); IR (neat) 3400, 2950, 2881, 1375
D
(+)-Tet r a p on er in e-2 (T-2). According to the procedure
cm-1; MS (EI) m/z 236 (M•+,87), 179 (100); 1H NMR (250 MHz,
CDCl3) δ 3.39 (brd, J ) 3.3 Hz, 1 H), 3.08 (q, J ) 8.0 Hz, 1 H),
2.97 (dt, J ) 2.4, 8.7 Hz, 1 H), 2.90 (q, J ) 7.2 Hz, 1 H), 2.82
(m, 1 H), 2.18 (m, 1 H), 2.05 (m, 1 H), 1.2-2 (m, 18 H), 0.95 (t,
3 H); 13C NMR (62.8 MHz, CDCl3) δ 14.2, 20.2, 21.3, 22.8, 27.2,
29.4, 29.7, 30.9, 31.6, 32.1, 50.0, 50.3, 53.9, 58.3, 76.8. Anal.
Calcd for C15H28N2: C, 76.21; H, 11.94; N, 11.85. Found: C,
75.84; H, 11.43; N, 11.09.
described for the preparation of T-8, tetraponerine (+)-T-2(65
mg) was obtained as a colorless oil in 92% yield: [R]20 +36°
D
(CHCl3, c 1.79); IR (neat) 3368, 2956, 2868, 1375 cm-1; MS
(EI) m/z 208 (M•+, 50), 207 (100), 179 (47); 1H NMR (250 MHz,
CDCl3) δ 3.14 (dt, J ) 3.2, 8.5 Hz, 1 H), 3.03 (dt, J ) 2.8, 8.5
Hz, 1 H), 2.76 (t, J ) 6.0 Hz, 1 H), 2.29 (m, 2 H), 2.11 (q, J )
8.5 Hz, 1 H), 2 (m, 1 H), 1.2-1.9 (m, 14 H), 0.91 (t, J ) 5.9 Hz,
3 H); 13C NMR (62.8 MHz, CDCl3) δ 14.5, 18.8, 20.2, 21.1, 28.7,
29.9, 33.7, 36.3, 47.2, 48.8, 60.3, 63.9, 83.6; HRMS (EI) calcd
for C13H24N2 208.1940; found: 208.1930.
Ack n ow led gm en t. We are grateful to Prof. J .-C.
Braekman and Prof. D. Daloze for the comparison of our
synthetic materials with natural T-1 and T-2 and for
valuable discussions.
(+)-Tetr a p on er in e-6 (T-6). (+)-T-6 was obtained in an
identical fashion with a yield of 75%: [R]20 +35° (CHCl3, c
D
0.31); lit. [R]20 +35° (CHCl3, c 0.15); IR (neat) 3368, 2956,
D
2868, 1375 cm-1; MS (CI) m/z 236 (MH)+; 1H NMR (250 MHz,
CDCl3) δ 3.13 (dt, J ) 3.1, 8.5 Hz, 1 H), 3 (dt, J ) 2.5, 8.5 Hz,
J O960398A