Highly diastereoselective approach toward (±)-tetraponerine T6 and analogues via the double cycloisomerization-reduction of bis-alkynylpyrimidines

Article abstract of DOI:10.1021/jo049259g

A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomerization-reduction of bis-alkynylpyrimidines 3a-m, has been developed. The requisite bis-alkynylpyrimidines 3a-m were readily prepared via regioselective seque

Full text of DOI:10.1021/jo049259g

High ly Dia ster eoselective Ap p r oa ch tow a r d (()-Tetr a p on er in e T6
a n d An a logu es via th e Dou ble Cycloisom er iza tion -Red u ction of
Bis-a lk yn ylp yr im id in es
J oseph T. Kim, J ason Butt, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 875 West Taylor Street,
Chicago, Illinois 60607-7061
vlad@uic.edu
Received April 30, 2004
A new, short, and efficient approach toward tricyclic alkaloids, involving the double cycloisomer-
ization-reduction of bis-alkynylpyrimidines 3a -m , has been developed. The requisite bis-
alkynylpyrimidines 3a -m were readily prepared via regioselective sequential Sonogashira coupling
reactions of dibromopyrimidines 1. Bis-alkynylpyrimidines 3a -m were converted into the 5-6-5
tricyclic heteroaromatic cores 4a -m via the Cu(I)-assisted double cycloisomerization reaction. The
reaction proceeded stepwise, which was confirmed by the isolation of the mono-pyrrolization
intermediate 5. The structure of 5 was assigned by 2D NMR and by independent synthesis.
Cycloisomerization of 5 under standard conditions afforded tricyclic 4g in 89% yield. The PtO2-
catalyzed hydrogenation of bis-pyrrolopyrimidines 4d , 4g, and 4i in acidic media afforded stable
amidinium derivatives, 11a , 11b, and 11c. Further reduction of the latter with LiAlH4 allowed for
the highly diastereoselective total synthesis of (()-tetraponerine T6 and its analogues.
In tr od u ction
erine T6, employing a totally different approach3 involv-
ing exhaustive hydrogenation/reduction of the bis-
pyrrolopyrimidine skeleton obtained via the double
cycloisomerization of bis-alkynylpyrimidine (Scheme 1).
This strategy represents a conceptually novel and highly
expeditious route toward certain polycyclic alkaloid
skeletons. Herein, we provide a full account of this work
as well as additional mechanistic studies and syntheses
of tetraponerine analogues.
The tetraponerines are a group of eight toxic alkaloids
that are found in the venom of the New Guinean
pseudomyrmecine ant Tetraonera sp.1 and are composed
of 1,3-diaza tricyclic systems (5-6-5 and 6-5-6), highly
unusual cores for alkaloids isolated from animals. More-
over, these alkaloids represent the major constituents of
the contact poison, showing profound insecticidal activi-
ties (LD50 of 5 × 10-9 mol/ant mg). The unprecedented
tricyclic skeleton, along with the interesting insecticidal
activities of the tetraponerines, has made them attractive
targets for total synthesis. Tetraponerine T6 is made of
a 5-6-5 skeleton and is one of the major venom
alkaloids. Prior to our studies, four diastereo- and enan-
tioselective syntheses of tetraponerine T6 had been
reported.2 These syntheses, representing two synthetic
approaches toward assembling a tricyclic core of tet-
raponerine T6, are summarized in Scheme 1. Blechert
assembled the tricyclic 5-6-5 core via a cascade Pd-
catalyzed cyclization.2a Another approach, utilized by
Plehiers,2b Royer,2c and Devijver,2d employed different
modes of double condensation of proline homologues with
cyclic imines. We have recently communicated a short
and highly diastereoselective synthesis of (()-tetrapon-
Resu lts a n d Discu ssion
Recently, we developed a novel, general, and efficient
method for the construction of pyrrole rings and fused
aromatic pyrroloheterocycles via the Cu-assisted cyclo-
isomerization of alkynyl imines.4 The synthetic useful-
ness of this novel methodology was further demonstrated
by achieving the shortest synthesis of (()-monomorine
in three steps and 47% overall yield (Scheme 2). This
successful result encouraged us to investigate the pros-
pect of multiple pyrrolization protocols en route to
tricyclic alkaloid structures. To test this idea, we inves-
tigated the possibility of constructing a 5-6-5 tricyclic
heteroaromatic skeleton via the double Cu(I)-assisted
cycloisomerization of bis-alkynylpyrimidines.
To this end, we synthesized various bis-alkynylpyri-
midine derivatives 3a -m employing Sonogashira coup-
ling reactions5 of 1,3-dibromo-pyrimidines 1 (Table 1).
Double-fold Sonogashira coupling of dibromopyrimidines6
with propyne proceeded smoothly to give bis-propynylpy-
(1) (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., C: Biosci. 1987, 42c, 627.
(2) (a) Stragies, R.; Blechert, S. J . Am. Chem. Soc. 2000, 122, 9584.
(b) Plehiers, M.; Heilporn, S.; Ekelmans, D.; Leclercq, S.; Sangermano,
M.; Braekman, J . C.; Daloze, D. Can. J . Chem. 2000, 78, 1030. (c) Yue,
C.; Gauthier, I.; Royer, J .; Husson, H. P. J . Org. Chem. 1996, 61, 4949.
(d) Devijver, C.; Macours, P.; Braekman, J . C.; Daloze, D.; Pasteels, J .
M. Tetrahedron 1995, 51, 10913.
(3) Kim, J . T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697.
(4) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J . Am. Chem. Soc.
2001, 123, 2074.
10.1021/jo049259g CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/17/2004
5638
J . Org. Chem. 2004, 69, 5638-5645

Tetraponerine T6 and Analogues
SCHEME 1. Ap p r oa ch es tow a r d Tetr a p on er in e T6
TABLE 1. Syn th esis of Bis-a lk yn ylp yr im id in es
yielda (%)
entry
R1
R2
R3
R4
2
3
1
2
3
4
5
6
H
H
CH3
H
CH3
H
H
CH3
H
C5H11
CH3
H
H
H
H
H
H
H
H
H
H
H
100 (a )
100 (b)
100 (c)
100 (d )
100 (e)
77 (f)
C2H5
C2H5
7
8
9
10
11
12
13
H
C5H11
H
C3H7
C2H5
C2H5
(CH2)2Ph
OCH3
(CH2)2Ph
C3H7
C3H7
C2H5
C2H5
OCH3
(CH2)2Ph
C3H7
79 (g)
CH3
CH3
CH3
CH3
CH3
CH3
100 (h )
100 (i)
82 (j)
100 (k )
100 (l)
75 (m )d
CH3
CH3
CH3
CH3
CH3
80
46b
c
(CH2)2Ph
a
Isolated yields. All reactions were performed with 0.4 mol % of CuI and 0.2 mol % of Pd(PPh3)2Cl2 in Et3N. See the Experimental
Section for details. 18% of the starting material was recovered. c Monoalkynyl pyrimidine 2j, which was obtained in 80% yield (entry
10), was subjected to the reaction with 1-pentyne in stepwise fashion. The reaction was performed under one-pot procedure conditions.
b
d
SCHEME 2. Sh or t Syn th esis of (()-Mon om or in e
alkynylpyrimidines 3j-m , possessing different alkynyl
substituents (Table 1, entries 10-13). Here, we took
advantage of the known, different reactivity of bromides
in dibromopyrimidines 1.7 First, we accessed bis-alky-
nylpyrimidines 3j-l in stepwise fashion. Accordingly,
employment of 1 equiv of alkyne allowed for selective
coupling at the C-4 position to give the corresponding
bromopyrimidine 2 in reasonable to good yields. Subse-
quent coupling of the C-2 bromide with another alkyne
provided the unsymmetrical bis-alkynylpyrimidines in
excellent overall yield (Table 1, entries 10-12). It was
rimide derivatives in quantitative yields (Table 1, entries
1-5). Analogously, employment of higher alkyne ana-
logues, such as pentyne and hexyne, allowed for the
efficient syntheses of symmetric bis-alkynylpyrimidines
3f-i (Table 1, entries 6-9). Next, we synthesized bis-
(6) For the syntheses of dibromopyrimidines, see Experimental
Section. J anin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.; Decaudin,
D.; Monneret, C.; Poupon, M. F. J . Chem. Soc., Perkin Trans. 1 2002,
529.
(7) For selective mono cross-coupling reactions of pyrimidine diha-
lides, see: (a) Tullis, J . S.; VanRens, J . C.; Natchus, M. G.; Clark, M.
P.; De, B.; Hsieh, L. C.; J anusz, M. J . Bioorg. Med. Chem. Lett. 2003,
13, 1665. (b) Simkovsky, N. M.; Ermann, M.; Roberts, S. M.; Parry, D.
M.; Baxter, A. D. J . Chem. Soc., Perkin Trans. 1 2002, 1847. (c) Gong,
Y.; Pauls, H. W. Synlett 2000, 829. (d) Mangalagiu, I.; Benneche, T.;
Undheim, K. Acta Chem. Scand. 1996, 50, 914.
(5) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467. (b) Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol.
3, p 521.
J . Org. Chem, Vol. 69, No. 17, 2004 5639

Kim et al.
TABLE 2. Op tim iza tion of th e Cu (I)-Assisted Dou ble
Cycloisom er iza tion of 3d
TABLE 3. Cycloisom er iza tion of Differ en tly Su bstitu ted
Bis-a lk yn ylp yr im id in es
entry Cu(I) (equiv) concn (M) temp (°C) time (h) yielda (%)
1
2
3
4
5
6
7
8
CuI (2)
CuI (2)
CuI (2)
CuI (1)
CuI (0.5)
CuI (0.3)
CuI (0.3)
CuCl (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
CuBr (1)
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
130
110
80
12
9
2
6
6
12
5
6
6
6
<5
<5
NR
27
30
24
<5
28
34
50
52
34
47
entry
R1
R2
R3
R4
yielda (%)
1
2
3
4
5
6
7
8
H
H
CH3
H
CH3
H
H
H
H
H
H
H
H (a )
H (b)
H (c)
H (d )
H (e)
37
51
48
52
51
41
68
40
70
40
43
75
64
150
150
150
110
150
150
150
150
150
150
CH3
H
C5H11
CH3
H
C2H5
C3H7
C2H5
C2H5
(CH2)2Ph
OCH3
(CH2)2Ph
C3H7
C2H5 (f)
C3H7 (g)
C2H5 (h )
C2H5 (i)
OCH3 (j)
(CH2)2Ph (k )
C3H7 (l)
9
0.1
H
C5H11
H
10
11
12c
13
0.02
0.02b
0.02d
0.02e
CH3
CH3
CH3
CH3
CH3
CH3
10
22
12
9
CH3
CH3
CH3
CH3
CH3
10
11
12
13
a
b
Isolated yields. Slow addition of 3d via syringe pump over 5
(CH2)2Ph (m )
h at 150 °C. c Bu3N was used instead of Et3N. Slow addition of
d
3d via syringe pump over 20 h at 150 °C. e Slow addition of 3d
a
Isolated yields.
via syringe pump over 12 h at 150 °C.
entries 2-8) to good yields for tetra-alkyl-substituted
heterocycles (Table 3, entries 9, 12, 13). For reasons
which are not completely understood, the introduction
of a methoxy substituent (R3 or R4) led to substantial
decrease in the reaction yields (Table 3, entries 10, 11).
also found that the cross-coupling of 1 with two different
alkynes can efficiently be performed under a one-pot
procedure condition without isolation of monobromopy-
rimidine intermediate 2 (Table 1, entry 13).
Next, bis-alkynylpyrimidine 3d , a potential precursor
of tetraponerine T6, was chosen for optimization of the
double cycloisomerization process (Table 2). The attempts
at double cycloisomerization of 3d in the presence of 2
equiv of CuI at various temperatures were unsuccessful;
at higher temperatures (Table 2, entries 1, 2), the
substrate polymerized, whereas at lower temperatures
(Table 2, entry 3), no reaction occurred. Reduction of the
CuI amount had a somewhat positive effect on the
reaction course (Table 2, entries 4-6). Further improve-
ment was achieved by switching to CuBr (Table 2, entry
9). Dilution of the reaction mixture allowed for additional
improvement of the reaction yields (Table 2, entries 10,
11). Taking into account that the yield for each pyrroliza-
tion in the transformation of 3d to 4d is about 70% and
that the cycloisomerization yields for propyne derivatives
are normally 10-20% lower than that of their higher
homologues,8 we considered 50-52% yield for the double
pyrrolization to be a rather satisfactory result.
The optimized conditions were applied to the double
cycloisomerization of the differently substituted bis-alkyn-
ylpyrimidines (Table 3). It was found that the double
cycloisomerization of bis-alkynylpyrimidines generally
allowed for the assembly of tricyclic aromatic compounds
in moderate to good yields. Double cycloisomerization of
3a provided low yield of nonsubstituted bis-pyrrolopyri-
midine 4a (Table 3, entry 1). Notably, introduction of
additional alkyl substituents into bis-alkynylpyrimidines
had a positive effect on the yields of the resulting bis-
pyrrolopyrimidines, ranging from moderate yields for
mono-, di-, and trisubstituted heterocycles (Table 3,
Apparently, the double cycloisomerization of bis-alkyn-
ylpyrimidines proceeds via an alternative sequence of
single cycloisomerization steps. As depicted in Scheme
3, the first pyrrolization of bis-alkynylpyrimidine 3g can
proceed in three possible ways (Scheme 3, paths A-C).
Among them, paths A and B, after the first cycloisomer-
ization, will produce pyrrolopyrimidines 5 and 6, which,
after the second pyrrolization, will give rise to the desired
product 4g. In contrast to these cases, path C leads to
the dead-end intermediate 7. Under standard reaction
conditions (1 equiv of CuBr in dilute Et3N-DMA at
150°C), no other low-molecular-weight compounds, be-
sides 4g, were detected by GC-MS analyses of the crude
reaction mixture. In contrast, when the reaction was
performed at both reduced temperature (130 °C) and
copper loading (30 mol %), GC-MS analysis revealed the
presence of one isomeric compound along with starting
material 3g and product 4g. This intermediate had quite
a different Rf value from those of starting material 3g or
product 4g, and thus it was easily separated by column
chromatography and its structure assigned as 5 on the
basis of extensive 2D NMR studies, including COSY,
heteronuclear multiple-quantum coherence (HMQC), and
heteronuclear multiple-bond correlation (HMBC). The
structure of intermediate 5 was additionally proven by
an independent synthesis, depicted in Scheme 4. Thus,
known dichloropyrimidine 8 (Scheme 4) was first coupled
with 1 equiv of hexyne under mild Sonogashira reaction
conditions to give mono-alkynylated pyrimidine 9, which
was cycloisomerized into mono-pyrrolopyrimidine 10. The
subsequent high-temperature Sonogashira coupling of 10
with another molecule of hexyne produced 5, which was
identical to the isolated intermediate in all respects.
(8) For lower thermal stability of the terminal allenic intermediates,
see ref 1 and: Kel’in, A. V.; Gevorgyan, V. J . Org. Chem. 2002, 67, 95.
5640 J . Org. Chem., Vol. 69, No. 17, 2004

Tetraponerine T6 and Analogues
SCHEME 3. P ossible P a th w a ys tow a r d Bis-p yr r olop yr im id in e 4g
SCHEME 4. Syn th esis of Mon o-p yr r olop yr im id in e In ter m ed ia te 5
TABLE 4. Exh a u stive Red u ction of
Bis-p yr r olop yr im id in es
tetraponerine T6 was completed by a highly diastereo-
selective reduction of crude 11a with LiAlH4 to give 12a
(T6) as the sole stereoisomer in 64% yield over two
steps.
Exhaustive hydrogenation/reduction of trisubstituted
bis-pyrrolopyrimidine 4g and the tetrasubstituted ana-
logue 4i proceeded with high diastereoselectivity, produc-
ing all-cis-multisubstituted tetraponerine analogues 12b-c
in 88:12 diastereomeric ratios with a minor unidentified
diastereomer. Notably, tetraponerine 12a and its tetra-
substituted analogue 12c are very stable compounds. In
contrast, 12b, possessing slightly longer side chains,
appeared to be extremely unstable and was characterized
as crude. Diastereomeric purity of each compound was
determined by 1H NMR and GC-MS analyses of the
crude reaction mixtures.
entry R1
R2
R3
R4
yield of 12a (%) drb (%)
1
2
3
H
H
C5H11
H
H (4d )
64 (a )
87 (b)c
41 (c)
100:0
88:12
88:12
C5H11 C3H7 C3H7 (4g)
CH3 CH3
C2H5 C2H5 (4i)
a
b
Isolated yield over two steps. Diastereomeric ratios were
determined by 1H NMR and GC-MS analyses of the crude reaction
mixture. c NMR yield using CH2Br2 as an internal standard.
When 5 was subjected to the cycloisomerization condi-
tions, it was smoothly converted into 4g in 89% yield
(Scheme 4).
The highly diastereoselective installation of the last
stereogenic center at C-2 via the reduction of 11a , which
we believe is both sterically and stereoelectronically
controlled, deserves a special note.11 Our molecular
mechanics force field (MMFF) calculations predicted that
Next, we drew our attention to the exhaustive reduc-
tion of bis-pyrrolopyrimidines (Table 4). Direct, complete
hydrogenation of heteroaromatic compound 4d to 12a
proved not to be straightforward. It is well-known that
catalytic hydrogenation of pyrimidine derivatives in
acidic media is cis-diastereoselective and stops at the
stage of formation of stable amidinium derivatives.9
Accordingly, catalytic hydrogenation of 4d over PtO2
under acidic conditions gave stable amidinium salt 11a
as a single cis-isomer.10 The total synthesis of (()-
(9) For hydrogenation of pyrimidines, see: (a) Brown, D. J . The
Pyrimidines; The Chemistry of Heterocyclic Compounds; J ohn Wiley
& Sons: New York, 1994; Vol. 52, pp 790-793. (b) Brown, D. J . The
Pyrimidines Supplement I; The Chemistry of Heterocyclic Compounds;
J ohn Wiley & Sons: New York, 1970; pp 337-341.
(10) 13C NMR analysis of the crude material revealed that 11d was
formed as a single diastereomer. The relative configuration of its
stereogenic centers was assigned by NOE experiment after the
subsequent reduction step.
J . Org. Chem, Vol. 69, No. 17, 2004 5641

Kim et al.
manner, this method can serve as a new, short, and
efficient approach toward selected polycylic alkaloid
structures.
Exp er im en ta l Section
All manipulations were conducted under argon atmosphere
using a combination of glovebox and standard Schlenk tech-
niques. Anhydrous Et3N and DMA were purchased from
Aldrich and stored over calcium hydride. Anhydrous THF and
benzene were distilled over sodium/benzophenone. 6-Pentyl-
1H-pyrimidine-2,4-dione was prepared according to the known
procedures.12
F IGURE 1. Two major conformations of amidinium ion 11a .
Rep r esen ta tive P r oced u r e for Syn th eses of Dibr o-
m op yr im id in es (1, R1 ) CH3, R2 ) CH3). 5,6-Dimethyl-2,4-
(1H,3H)-pyrimidinedione (2.08 g, 14.84 mmol), potassium
carbonate (6.15 g, 44.50 mmol), and phosphorus oxybromide
(12.76 g, 44.50 mmol) were heated to reflux in dry acetonitrile
(100 mL) for 72 h. The mixture was cooled to room tempera-
ture, poured into ice, and neutralized (solid potassium carbon-
ate). The aqueous phase was thoroughly extracted with
CH2Cl2. The combined organic extracts were washed (brine),
dried (anhydrous Na2SO4), and concentrated under reduced
pressure. The residue was purified by silica gel chromatogra-
phy with 10% EtOAc/hexanes to give 2,4-dibromo-5,6-dimeth-
yl-pyrimidine as a solid with mp 125 °C (3.28 g, 83%).
Rep r esen ta tive P r oced u r e for Mon o-Son oga sh ir a Re-
a ction 2j. The mixture of 2,4-dibromo-5,6-dimethyl-pyrimidine
(580 mg, 2.18 mmol), CuI (17 mg, 0.09 mmol), and Pd(PPh3)2-
Cl2 (31 mg, 0.04 mmol) was stirred at room temperature, and
then pent-4-ynyl-bezene (280 µL, 2.43 mmol) was added to the
mixture and stirred for 12 h. The mixture was quenched
(aqueous NH4Cl). The phases were separated, and the aqueous
phase was thoroughly extracted with hexanes. The combined
organic extracts were washed (brine), dried (anhydrous Na2-
SO4), and concentrated under reduced pressure. The residue
was purified by silica gel chromatography with 5-10% EtOAc/
hexanes to give 2j as an oil (574 mg, 80%).
F IGURE 2. Proposed transition states for the nucleophilic
attack of hydride at amidinium ion 11a .
delivery of the hydride can be sterically controlled,
favoring â-face attack at the most stable amidinium ion
conformer with alkyl substituents occupying the equato-
rial position (11a -eq), as well as at another conformer
11a -ax (Figure 1). Stereoelectronic reasons can also
account for the delivery of hydride to the C-2 of the
amidinium ion. The nucleophilic attack by the hydride
proceeds from the â-face to give (()-T6 through the most
favorable chairlike transition state i, instead of an R-face
delivery of a hydride through the disfavored boatlike
transition state ii to form an epi-(()-T6 (Figure 2). The
relative configurations of (()-tetraponerine T6 and its
analogues were confirmed by NOESY and 1H NOE
experiments.
1
2j. H NMR (500 MHz, CDCl3, δ): 7.30-7.18 (5H, m), 2.77
(2H, t, J ) 7.6 Hz), 2.50 (2H, t, J ) 7.1 Hz), 2.48 (3H, s), 2.32
(3H, s), 1.97 (2H, quint, J ) 7.5 Hz). 13C NMR (125 MHz,
CDCl3, δ): 168.9, 152.0, 148.9, 141.0, 129.4, 128.5 (×4), 126.1,
100.7, 77.7, 34.9, 29.6, 22.5, 19.0, 15.0. MS m/z (relative
intensity): 329 (M+, 14), 300 (27), 224 (100), 91 (89).
1
2k . H NMR (500 MHz, CDCl3, δ): 4.32 (2H, s), 3.39 (3H,
s), 2.44 (3H, s), 2.29 (3H, s). 13C NMR (125 MHz, CDCl3, δ):
169.4, 150.8, 148.9, 129.7, 94.5, 82.0, 60.1, 58.1, 22.5, 14.9. MS
m/z (relative intensity): 255 (M+, 1), 224 (100), 143 (48), 77
(62).
Rep r esen ta tive P r oced u r e for Syn th eses of Di-p r op -
1-yn yl-p yr im id in e (3c). Using a high-pressure tube, propyne
(10 mL) was condensed in a mixture of 2,4-dibromo-5-methyl-
pyrimidine (2.50 g, 9.92 mmol), CuI (76 mg, 0.4 mmol), Pd-
(PPh3)2Cl2 (140 mg, 0.2 mmol), and Et3N (50 mL) at -78 °C.
The mixture was slowly warmed and stirred at 50 °C for 3 h.
Then, the mixture was cooled to room temperature and
quenched (aqueous NH4Cl). The phases were separated, and
the aqueous phase was thoroughly extracted with hexanes.
The combined organic extracts were washed (brine), dried
(anhydrous Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography
with 20% EtOAc/hexanes to give 3c as a solid (1.69 g, >99%).
Rep r esen ta tive P r oced u r e for Sequ en tia l Son oga sh -
ir a Rea ction (3m ). The mixture of 2,4-dibromo-5,6-dimethyl-
pyrimidine (380 mg, 1.43 mmol), CuI (11 mg, 0.06 mmol), and
Pd(PPh3)2Cl2 (20 mg, 0.03 mmol) was stirred at room temper-
Con clu sion s
In summary, the Cu(I)-assisted double pyrrolization of
bis-alkynylpyrimidine to the 5-6-5 heteroaromatic core
was demonstrated. A highly selective hydrogenation/
reduction of the resulting bis-pyrrolopyrimidine allowed
for the short, efficient, and highly diastereoselective total
synthesis of (()-tetraponerine T6 and its analogues.
Considering that the assembly of a 5-6-5 tricyclic
skeleton by this double pyrrolization-reduction func-
tionalization protocol allows for the quick installation of
up to 6 stereo centers in a highly diastereoselective
(11) For stereoelectronic control in addition of nucleophiles to an
amidinium ion, see: (a) Perrin, C. L.; Young, D. B. J . Am. Chem. Soc.
2001, 123, 4451. (b) Fu¨lo¨p, F.; Simon, K.; To´th, G.; Hermecz, I.;
Me´sza´ros, Z.; Berna´th, G. J . Chem. Soc., Perkin Trans. 1 1982, 12,
2801. (c) Kirby, A. J . Stereoelectronic effects; Oxford Chemistry Primer
36; Oxford University Press: Oxford, 1996, pp 54-55. (d) Barluenga,
J .; Toma´s, M.; Kouznetsov, V.; Rubio, E. J . Org. Chem. 1994, 59, 3699.
(12) (a) Yanai, M.; Naito, T. J . Pharm. Soc. J pn. 1941, 61, 99. (b)
Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082. (c) Botta,
M.; Cavalieri, M.; Ceci, D.; Angelis, F. D.; Finizia, G.; Nicoletti, R.
Tetrahedron 1984, 40, 3313. (d) Danel, K.; Larsen, E.; Pedersen, E. B.
Synthesis 1995, 934.
5642 J . Org. Chem., Vol. 69, No. 17, 2004

Tetraponerine T6 and Analogues
ature, and then n-hexyne (173 µL, 1.5 mmol) was added to
the mixture and stirred for 12 h. The reaction progress was
monitored by TLC and GC-MS analyses. Pent-4-ynyl-benzene
(430 µL, 2.83 mmol) was added to the mixture and stirred for
12 h at 45 °C. The mixture was cooled to room temperature
and quenched (aqueous NH4Cl). The phases were separated,
and the aqueous phase was thoroughly extracted with hexanes.
The combined organic extracts were washed (brine), dried
(anhydrous Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by silica gel chromatography
with 2-10% EtOAc/hexanes to give 3m as an oil (355 mg,
75%).
29.7, 22.6, 19.0, 15.4. MS m/z (relative intensity): 318 (M+,
23), 290 (14), 214 (100), 91 (93).
3k . 1H NMR (500 MHz, CDCl3, δ): 7.21-7.08 (5H, m), 4.30
(2H, s), 3.38 (3H, s), 2.70 (2H, t, J ) 7.5 Hz), 2.41 (3H, s), 2.38
(2H, t, J ) 7.1 Hz), 2.30 (3H, s), 1.89 (2H, quint, J ) 7.6 Hz).
13C NMR (125 MHz, CDCl3, δ): 166.6, 150.0, 149.1, 141.2,
129.2, 128.4 (×2), 128.3 (×2), 125.9, 92.7, 88.9, 82.7, 80.0, 60.1,
58.0, 34.8, 29.5, 22.6, 18.7, 15.3. MS m/z (relative intensity):
318 (M+ - 1, 19), 214 (100), 91 (73).
1
3l. H NMR (500 MHz, CDCl3, δ): 7.24-7.12 (5H, m), 2.72
(2H, t, J ) 7.5 Hz), 2.44 (2H, t, J ) 7.1 Hz), 2.42 (3H, s), 2.37
(2H, t, J ) 7.2 Hz), 2.30 (3H, s), 1.90 (2H, quint, J ) 7.6 Hz),
1.55 (2H, quint, J ) 7.3 Hz), 1.40 (2H, sext, J ) 7.3 Hz), 0.86
(3H, t, J ) 7.3 Hz). 13C NMR (125 MHz, CDCl3, δ): 166.1,
150.1, 149.9, 141.1, 128.8, 128.4 (×4), 126.0, 98.8, 89.4, 79.7,
78.2, 34.8, 30.0, 29.7, 22.5, 22.1, 18.9 (×2), 15.3, 13.6. MS m/z
(relative intensity): 330 (M+, 35), 301 (29), 226 (90), 91 (100).
3m . 1H NMR (500 MHz, CDCl3, δ): 7.26-7.11 (5H, m), 2.72
(2H, t, J ) 7.6 Hz), 2.44 (2H, t, J ) 7.1 Hz), 2.42 (3H, s), 2.40
(2H, t, J ) 7.1 Hz), 2.29 (3H, s), 1.91 (2H, quint, J ) 7.5 Hz),
1.57 (2H, quint, J ) 7.5 Hz), 1.44 (2H, sext, J ) 7.6 Hz), 0.88
(3H, t, J ) 7.3 Hz). 13C NMR (125 MHz, CDCl3, δ): 166.0,
150.3, 149.9, 141.3, 128.6, 128.4 (×4), 125.9, 99.4, 88.5, 80.2,
77.7, 34.9, 30.1, 29.7, 29.5, 22.6, 19.2, 18.7, 15.2, 13.5. MS m/z
(relative intensity): 229 (M+ - 1, 19), 239 (11), 226 (100), 91
(49).
3a . Mp 58 °C. 1H NMR (500 MHz, CDCl3, δ): 8.49 (1H, d, J
) 5.1 Hz), 7.08 (1H, d, J ) 5.1 Hz), 2.00 (3H, s), 1.99 (3H, s).
13C NMR (125 MHz, CDCl3, δ): 157.5, 153.5, 151.8, 121.6, 93.2,
86.9, 79.4, 78.2, 4.8, 4.6. MS m/z (relative intensity): 156 (M+,
100), 128 (5), 91 (14), 64 (52).
1
3b. Mp 68 °C. H NMR (500 MHz, CDCl3, δ): 6.88 (1H, s),
2.29 (3H, s), 1.90 (3H, s), 1.89 (3H, s). 13C NMR (125 MHz,
CDCl3, δ): 167.8, 152.9, 151.3, 121.1, 92.2, 86.3, 79.3, 78.2,
24.2, 4.7, 4.5. MS m/z (relative intensity): 170 (M+, 100), 78
(14), 64 (38).
1
3c. Mp 143 °C. H NMR (500 MHz, CDCl3, δ): 8.44 (1H, s),
2.31 (3H, s), 2.12 (3H, s), 2.04 (3H, s). 13C NMR (125 MHz,
CDCl3, δ): 157.8, 151.4, 151.1, 130.8, 96.6, 85.9, 79.3, 77.0,
16.6, 5.0, 4.7. MS m/z (relative intensity): 170 (M+, 100), 78
(33), 66 (33).
Rep r esen ta tive P r oced u r e for Dou ble Cycloisom er -
iza tion Rea ction (4l). Using a high-pressure tube, the
mixture of compound 3l (370 mg, 1.12 mmol) and CuBr (161
mg, 1.12 mmol) in Et3N (6 mL) and DMA (40 mL) was stirred
at 150 °C for 18 h. The reaction was protected from the light
by covering the flask with aluminum foil. Then, the mixture
was cooled to room temperature and quenched (aqueous NH4-
Cl). The phases were separated, and the aqueous phase was
thoroughly extracted with hexanes. The combined organic
extracts were washed (brine), dried (anhydrous Na2SO4), and
concentrated under reduced pressure. The residue was purified
by silica gel chromatography with 5% EtOAc/hexanes (1% Et3N
was used for deactivation of the silica gel) to give 4l as a solid
(278 mg, 75%).
3d . 1H NMR (500 MHz, CDCl3, δ): 6.99 (1H, s), 2.63 (2H, t,
J ) 7.8 Hz), 2.03 (3H, s), 2.02 (3H, s), 1.64 (2H, quint, J ) 7.7
Hz), 1.28-1.25 (4H, m), 0.83 (3H, t, 3.2 Hz). 13C NMR (125
MHz, CDCl3, δ): 171.8, 153.1, 151.4, 120.5, 92.0, 86.1, 79.5,
78.3, 38.0, 31.7, 28.9, 22.7, 14.2, 4.7, 4.6. MS m/z (relative
intensity): 226 (M+, 2), 197 (8), 183 (17), 170 (100). Anal. Calcd
for C15H18N2: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.57; H,
7.98; N, 12.29.
3e. Mp 122 °C. 1H NMR (500 MHz, CDCl3, δ): 2.36 (3H, s),
2.23 (3H, s), 2.02 (3H, s), 1.95 (3H, s). 13C NMR (125 MHz,
CDCl3, δ): 166.1, 151.2, 150.6, 129.0, 93.8, 83.8, 81.0, 78.2,
22.5, 15.1, 4.1, 3.8. MS m/z (relative intensity): 184 (M+, 100),
142 (14), 78 (52).
1
4a . Mp 145 °C. 1H NMR (500 MHz, CDCl3, δ): 7.34-7.33
(1H, m), 7.23 (1H, d, J ) 7.6 Hz), 6.86 (1H, dd, J ) 3.1, 1.7
Hz), 2.42 (3H, s), 6.64 (1H, dd, J ) 3.7, 2.8 Hz), 6.58 (1H, d, J
) 7.6 Hz), 6.48 (1H, t, J ) 3.3 Hz), 6.40 (1H, dd, J ) 3.7, 1.3
Hz), 6.17-6.16 (1H, m). 13C NMR (125 MHz, CDCl3, δ): 129.0,
126.1, 118.9, 113.2, 112.4, 112.1, 110.1, 103.6, 103.3, 88.1. MS
m/z (relative intensity): 156 (M+, 100), 129 (14), 102 (10). Anal.
Calcd for C10H8N2: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.94; H, 5.21; N, 17.91.
3f. H NMR (500 MHz, CDCl3, δ): 8.15 (1H, d, J ) 5.1 Hz),
7.11 (1H, d, J ) 5.1 Hz), 2.37-2.33 (4H, m), 1.61-1.55 (4H,
m), 0.99-0.94 (6H, m). 13C NMR (125 MHz, CDCl3, δ): 157.0,
153.2, 151.5, 121.3, 97.0, 90.6, 79.9, 78.7, 21.4 (×2), 21.3, 21.2,
13.6, 13.5. MS m/z (relative intensity): 212 (M+, 5), 184 (100),
164 (11).
3g. 1H NMR (500 MHz, CDCl3, δ): 7.01 (1H, s), 2.65 (2H, t,
J ) 7.8 Hz), 2.40 (4H, t, J ) 7.3 Hz), 1.66-1.64 (2H, m), 1.60-
1.55 (4H, m), 1.42 (4H, sext, J ) 7.5 Hz), 1.30-1.27 (4H, m),
0.90 (3H, t, J ) 7.4 Hz), 0.88 (3H, t, J ) 7.1 Hz), 0.85 (3H, t,
J ) 7.1 Hz). 13C NMR (125 MHz, CDCl3, δ): 171.8, 153.2,
151.6, 120.7, 96.5, 90.5, 80.4, 79.2, 38.1, 31.9, 30.4 (×2), 29.0,
22.8, 22.5, 22.4, 19.5, 19.4, 14.3, 14.0, 13.9. MS m/z (relative
intensity): 310 (M+, 2), 281 (10), 267 (16), 254 (100).
3h . 1H NMR (500 MHz, CDCl3, δ): 8.44 (1H, s), 2.45 (2H, t,
J ) 7.0 Hz), 2.38 (2H, t, J ) 7.0 Hz), 2.31 (3H, s), 1.66-1.61
(4H, m), 1.03 (3H, t, J ) 7.3 Hz), 1.01 (3H, t, J ) 7.3 Hz). 13C
NMR (125 MHz, CDCl3, δ): 157.7, 151.6, 151.2, 130.8, 101.1,
90.0, 80.2, 77.9, 44.3, 22.0, 21.9, 21.6, 16.7, 14.1, 14.0. MS m/z
(relative intensity): 226 (M+, 8), 198 (100), 181 (9), 169 (9).
1
4b. Mp 45 °C. H NMR (500 MHz, CDCl3, δ): 7.34 (1H, d,
J ) 1.0 Hz), 6.91 (1H, dd, J ) 3.1, 1.6 Hz), 6.65 (1H, dd, J )
3.5, 2.8 Hz), 6.55 (1H, t, J ) 3.4 Hz), 6.43 (1H, s), 6.32 (1H,
dd, J ) 3.6, 1.1 Hz), 6.25 (1H, dd, J ) 3.8, 1.6 Hz), 2.47 (3H,
s). 13C NMR (125 MHz, CDCl3, δ): 129.4, 126.9, 126.8, 112.3,
112.2, 110.0, 109.4, 101.9, 101.5, 88.5, 18.3. MS m/z (relative
intensity): 170 (M+, 100), 155 (24), 142 (10), 115 (7), 85 (10).
Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found:
C, 77.69; H, 5.95; N, 16.45.
1
4c. Mp 68 °C. H NMR (500 MHz, CDCl3, δ): 7.37 (1H, dd,
J ) 2.7, 1.4 Hz), 7.07 (1H, d, J ) 1.2 Hz), 6.83 (1H, d, J ) 1.4
Hz), 6.67 (1H, dd, J ) 3.7, 2.8 Hz), 6.47 (1H, t, J ) 3.1 Hz),
6.41 (1H, dd, J ) 3.7, 1.4 Hz), 6.16 (1H, d, J ) 3.6 Hz), 2.28
(3H. s). 13C NMR (125 MHz, CDCl3, δ): 128.5, 128.4, 116.6,
113.5, 112.2, 111.9, 111.5, 109.6, 102.2, 87.5, 15.4. MS m/z
(relative intensity): 170 (M+, 100), 155 (43), 142 (14), 115 (10),
85 (11). Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46.
Found: C, 77.38; H, 5.92; N, 16.46.
1
3i. H NMR (500 MHz, CDCl3, δ): 2.41 (3H, s), 2.40 (2H, t,
J ) 7.1 Hz), 2.34 (2H, t, J ) 7.1 Hz), 2.29 (3H, s), 1.62-1.57
(4H, m), 0.99 (3H, t, J ) 7.4 Hz), 0.97 (3H, t, J ) 7.4 Hz). 13C
NMR (125 MHz, CDCl3, δ): 166.4, 150.7, 150.4, 129.1, 99.6,
89.3, 80.3, 78.3, 22.9, 22.0, 21.9 (×2), 21.6, 15.6, 14.1, 14.0.
MS m/z (relative intensity): 240 (M+, 8), 225 (9), 212 (100),
195 (8).
1
1
3j. H NMR (500 MHz, CDCl3, δ): 7.29-7.17 (5H, m), 4.31
4d . Mp 53 °C. H NMR (500 MHz, CDCl3, δ): 7.29 (1H, dd,
(2H, s), 3.43 (3H, s), 2.77 (2H, t, J ) 7.5 Hz), 2.48 (2H, t, J )
7.1 Hz), 2.47 (3H, s), 2.37 (3H, s), 1.95 (2H, quint, J ) 7.5
Hz). 13C NMR (125 MHz, CDCl3, δ): 166.3, 150.3, 149.2, 141.1,
129.6, 128.5 (×4), 126.1, 99.2, 84.9, 82.9, 78.1, 60.0, 57.9, 34.9,
J ) 2.4, 1.2 Hz), 6.93 (1H, dd, J ) 3.1, 1.6 Hz), 6.59 (1H, dd,
J ) 3.6, 2.9 Hz), 6.50 (1H, t, J ) 3.5 Hz), 6.41 (1H, s), 6.28
(1H, dd, J ) 3.6, 1.3 Hz), 6.19 (1H, dd, J ) 3.8, 1.6 Hz), 2.75
(2H, t, J ) 7.6 Hz), 1.77 (2H, quint, J ) 7.6 Hz), 1.47-1.38
J . Org. Chem, Vol. 69, No. 17, 2004 5643

Kim et al.
(4H, m), 0.94 (3H, t, J ) 7.1 Hz). 13C NMR (125 MHz, CDCl3,
δ): 131.0, 129.4, 126.8, 112.2 (×2), 109.9, 109.3, 101.6, 100.7,
88.2, 32.0, 31.6, 26.9, 22.9, 14.4. MS m/z (relative intensity):
226 (M+, 50), 197 (7), 183 (14), 170 (100). Anal. Calcd for
(1H, d, J ) 3.5 Hz), 3.50 (2H, d, J ) 7.9 Hz), 3.21 (2H, d, J )
7.9 Hz), 3.10 (2H, d, J ) 7.7 Hz), 2.67 (3H, s), 2.30 (3H, s),
1.82 (2H, sext, J ) 7.6 Hz), 1.14 (3H, t, J ) 7.3 Hz). 13C NMR
(125 MHz, CDCl3, δ): 141.5 (×2), 129.5, 128.4 (×4), 125.9,
125.7, 123.7 (×2), 109.5, 108.8, 108.4, 99.3, 88.6, 35.1, 32.7,
30.7, 23.4, 15.8, 14.0, 13.6. MS m/z (relative intensity): 330
(M+, 30), 239 (100), 209 (19), 91 (9). HRMS (EI) calcd for
C23H26N2 (M+) 330.2096, found 330.2092.
C
15H18N2: C, 79.61; H, 8.02; N, 12.38. Found: C, 79.67; H,
8.03; N, 12.40.
4e. Mp 116 °C. 1H NMR (500 MHz, CDCl3, δ): 7.34 (1H,
dd, J ) 2.7, 1.4 Hz), 6.90 (1H, dd, J ) 2.8, 1.5 Hz), 6.64 (1H,
dd, J ) 3.6, 3.0 Hz), 6.50 (1H, t, J ) 3.4 Hz), 6.33 (1H, dd, J
) 3.7, 1.3 Hz), 6.20 (1H, dd, J ) 3.7, 1.2 Hz), 2.44 (3H, s), 2.30
(3H, s). 13C NMR (125 MHz, CDCl3, δ): 129.0, 128.9, 123.0,
112.6, 112.0, 109.4, 109.3, 107.9, 100.9, 87.8, 14.1, 13.6. MS
m/z (relative intensity): 184 (M+, 100), 142 (14), 115 (7), 104
(10), 78 (52). Anal. Calcd for C12H12N2: C, 78.23; H, 6.57; N,
15.21. Found: C, 78.41; H, 6.57; N, 15.20.
4m . Mp 76 °C. 1H NMR (500 MHz, CDCl3, δ): 7.41-7.30
(5H, m), 6.37 (1H, d, J ) 3.5 Hz), 6.33 (2H, s), 6.25 (1H, d, J
) 3.4 Hz), 3.41 (2H, d, J ) 7.8 Hz), 3.12-3.06 (4H, m), 2.65
(3H, s), 2.26 (3H, s), 1.89 (2H, sext, J ) 7.5 Hz), 1.17 (3H, t, J
) 7.3 Hz). 13C NMR (125 MHz, CDCl3, δ): 141.5 (×2), 129.3
(×2), 128.4 (×4), 126.0, 124.9, 123.4, 109.6, 108.9, 108.7, 99.4,
88.7, 36.5, 32.8, 31.0, 22.1, 16.1, 14.0, 13.7. MS m/z (relative
intensity): 330 (M+, 23), 239 (100), 209 (21), 91 (11). HRMS
(EI) calcd for C23H26N2 (M+) 330.2096, found 330.2080.
Rep r esen ta tive P r oced u r e for Exh a u stive Red u ction
of Bis-p yr r olop yr im id in es (12a , T6). PtO2 (23 mg) and HBr
(235 µL, 2.1 mmol, 48% in H2O) were added to the solution of
4d (230 mg, 1.02 mmol) in MeOH (10 mL). The mixture was
stirred under hydrogen pressure (50 psi) for 40 h. After this
period, the mixture was filtered through Celite and concen-
trated under reduced pressure to give the amidinium salt 11a .
Without further purification, crude 11a was dissolved in
anhydrous THF (10 mL). Molecular sieves (4Å)(300 mg) were
added to the mixture, stirred for 30 min and cooled to 0 °C.
LiAlH4 (5.0 mL, 1.0 M in THF) was added to the mixture
dropwise at 0 °C. The mixture was warmed to room temper-
ature and stirred for 2 h. After this period, saturated aqueous
Na2SO4 was added to the mixture dropwise, and the white
precipitate was filtered off through Celite. The filtrate was
concentrated under reduce pressure and purified by silica gel
chromatography with 5% EtOH/CH2Cl2 to give (()-tetrapon-
erine T6 (12a ) as an oil (154 mg, 64%).
1
4f. H NMR (500 MHz, C6D6, δ): 6.58 (1H, d, J ) 7.6 Hz),
6.46 (1H, d, J ) 3.7 Hz), 6.44 (1H, d, J ) 3.7 Hz), 6.27 (1H, d,
J ) 5.0 Hz), 6.26 (1H, s), 6.23 (1H, d, J ) 3.7 Hz), 3.00 (2H, q,
J ) 7.4 Hz), 2.37 (2H, q, J ) 7.4 Hz), 1.29 (3H, t, J ) 7.4 Hz),
1.18 (3H, t, J ) 7.4 Hz). 13C NMR (125 MHz, C6D6, δ): 131.2,
128.5, 125.9, 124.6, 114.6, 109.1, 105.8, 102.9, 102.5, 89.7, 22.0,
19.2, 13.3, 12.5. MS m/z (relative intensity): 212 (M+, 43), 197
(100), 181 (16), 91 (21), 78 (52). HRMS (EI) calcd for C14H16N2
(M+) 212.1314, found 212.1314.
4g. Mp 60 °C. 1H NMR (500 MHz, CDCl3, δ): 6.28 (1H, d, J
) 3.9 Hz), 6.25 (1H, s), 6.24 (1H, d, J ) 3.7 Hz), 6.21 (1H, d,
J ) 3.9 Hz), 6.12 (1H, d, J ) 3.7 Hz), 3.30 (2H, t, J ) 7.5 Hz),
2.90 (2H, t, J ) 7.4 Hz), 2.87 (2H, t, J ) 7.7 Hz), 1.80 (2H,
sext, J ) 7.5 Hz), 1.72-1.63 (4H, m), 1.44-1.35 (4H, m), 1.08
(3H, t, J ) 7.3 Hz), 1.03 (3H, t, J ) 7.3 Hz), 0.93 (3H, t, J )
7.1 Hz). 13C NMR (125 MHz, CDCl3, δ): 131.5, 130.3, 128.8,
126.1, 125.6, 109.7, 109.1, 102.7, 99.6, 89.4, 32.8, 32.0, 31.3,
30.9, 28.8, 23.5, 22.5, 22.2, 14.0 (×2). MS m/z (relative
intensity): 310 (M+, 33), 281 (100), 209 (26), 195 (23). HRMS
(EI) calcd for C21H30N2 (M+) 310.2409, found 310.2398.
1
1
4h . Mp 55 °C. H NMR (500 MHz, CDCl3, δ): 6.95 (1H, s),
12a (T6). H NMR (500 MHz, C6D6, δ): 3.14 (1H, m), 3.02
6.35 (1H, d, J ) 3.6 Hz), 6.32 (1H, d, J ) 3.6 Hz), 6.25 (1H, d,
J ) 2.3 Hz), 6.18 (1H, s), 3.19 (2H, q, J ) 3.4 Hz), 2.77 (2H, q,
J ) 7.4 Hz), 2.27 (3H, s), 1.44 (3H, t, J ) 7.4 Hz), 1.38 (3H, t,
J ) 7.4 Hz). 13C NMR (125 MHz, CDCl3, δ): 131.5, 127.8,
127.7, 124.2, 112.4, 111.1, 108.1, 104.7, 100.2, 86.3, 21.7, 19.1,
15.1, 13.1, 12.3. MS m/z (relative intensity): 226 (M+, 45), 211
(100), 195 (19), 98 (17). HRMS (EI) calcd for C15H18N2 (M+)
226.1470, found 226.1484.
(1H, dt, J ) 8.6, 2.4 Hz), 2.98 (1H, t, J ) 5.2 Hz), 2.52 (1H,
m), 2.44 (1H, m), 2.05-1.98 (2H, m), 1.90-1.34 (18H, m), 0.99
(3H, t, J ) 7.2 Hz). 13C NMR (125 MHz, C6D6, δ): 83.3, 64.1,
59.6, 49.1, 45.7, 34.7, 33.3, 32.6, 30.6, 29.2, 25.9, 23.1, 21.3,
21.0, 14.4. MS m/z (relative intensity): 235 (M+ - 1, 100), 179
(87), 138 (81), 96 (81), 70 (52). HRMS (EI) calcd for C15H27N2
(M+ - 1) 235.2174, found 235.2163.
1
12b (Cr u d e). H NMR (500 MHz, C6D6, δ): 2.71 (2H, m),
4i. Mp 123 °C. 1H NMR (500 MHz, CDCl3, δ): 6.31 (1H, m),
6.24 (1H, s), 6.20 (1H, d, J ) 3.5 Hz), 3.16-3.10 (4H, m), 2.61
(3H, s), 1.44 (3H, t, J ) 7.3 Hz), 1.36 (3H, t, J ) 7.3 Hz). 13C
NMR (125 MHz, CDCl3, δ): 130.9, 129.8, 128.3, 127.3, 123.7,
108.4, 108.9, 107.7, 99.2, 88.7, 23.8, 22.1, 16.0, 14.2, 13.6, 13.1.
MS m/z (relative intensity): 240 (M+, 54), 225 (100), 210 (21),
105 (24). HRMS (EI) calcd for C16H20N2 (M+) 240.1627, found
240.1614.
2.44 (1H, m), 2.36-2.32 (1H, m), 2.0 (1H, m), 1.90-1.65 (9H,
m), 1.54-1.25 (17H, m), 1.03-0.89 (9H, m). 13C NMR (125
MHz, C6D6, δ): 87.7, 66.7, 62.5, 61.2, 58.6, 42.2, 39.3, 36.7,
35.5, 32.5, 30.3, 30.2, 29.8, 29.5, 28.7, 25.7, 22.9, 19.6, 14.5,
14.4, 14.1. MS m/z (relative intensity): 319 (M+ - 1, 11), 263
(16), 152 (100), 82 (32). HRMS (EI) calcd for C21H39N2 (M+
-
1) 319.3113, found 319.3089.
1
12c. H NMR (500 MHz, C6D6, δ): 2.63 (1H, dd, J ) 10.0,
3.9 Hz), 2.58-2.54 (1H, m), 2.51 (1H, dq, J ) 6.8, 2.6 Hz),
2.40-2.34 (1H, m), 2.21 (1H, ddd, J ) 11.3, 5.0, 2.8 Hz), 1.83-
1.45 (13H, m), 1.19 (3H, d, J ) 4.2 Hz), 1.17 (3H, d, J ) 4.3),
0.98 (3H, t, J ) 7.5 Hz), 0.96 (3H, t, J ) 7.5 Hz). 13C NMR
(125 MHz, C6D6, δ): 89.0, 71.3, 62.6, 62.0, 59.9, 38.1, 32.1, 30.6,
29.8, 29.1, 28.1, 26.3, 19.8, 10.2, 10.0, 8.0. MS m/z (relative
intensity): 249 (M+ - 1, 36), 125 (20), 96 (100), 82 (24). HRMS
(EI) calcd for C16H29N2 (M+ - 1) 249.2331, found 249.2327.
1
4j. H NMR (500 MHz, CDCl3, δ): 7.38-7.26 (5H, m), 6.28
(1H, d, J ) 3.3 Hz), 6.16 (1H, d, J ) 3.6 Hz), 6.10 (1H, s), 5.56
(1H, s), 3.86 (3H, s), 3.37 (2H, t, J ) 7.9 Hz), 3.11 (2H, t, J )
7.9 Hz), 2.60 (3H, s), 2.19 (3H, s). 13C NMR (125 MHz, CDCl3,
δ): 142.7, 141.6, 128.5, 128.4 (×4), 126.0, 123.1, 122.7, 109.0,
107.5, 99.5, 85.6, 85.1, 58.6, 35.1, 30.6, 14.8, 13.1. MS m/z
(relative intensity): 318 (M+, 26), 227 (100), 212 (74), 183 (64),
91 (40). HRMS (EI) calcd for C21H22N2O (M+) 318.1732, found
318.1738.
1
5. H NMR (500 MHz, CDCl3, δ): 6.93 (1H, s), 6.56 (1H, d,
1
4k . Mp 122 °C. H NMR (500 MHz, CDCl3, δ): 7.36-7.25
J ) 3.8 Hz), 6.27 (1H, d, J ) 3.8 Hz), 3.31 (2H, t, J ) 7.6 Hz),
2.58 (2H, t, J ) 7.6 Hz), 2.52 (2H, t, J ) 7.3 Hz), 1.76 (2H,
sext, J ) 7.6 Hz), 1.68-1.66 (4H, m), 1.49 (2H, sext, J ) 7.6
Hz), 1.34-1.32 (4H, m), 1.00 (3H, t, J ) 7.3 Hz), 0.95 (3H, t,
J ) 7.4 Hz), 0.88 (3H, t, J ) 7.0 Hz). 13C NMR (125 MHz,
CDCl3, δ): 142.9, 134.0, 131.1, 126.3, 115.5, 110.1, 97.7, 95.3,
76.6, 36.5, 31.5, 30.5, 29.7, 28.9, 23.4, 22.6, 22.3, 19.6, 13.9,
13.6. MS m/z (relative intensity): 310 (M+, 33), 281 (100), 254
(10), 182 (19).
(5H, m), 6.48 (1H, s), 6.24 (1H, s), 6.06 (1H, d, J ) 2.4 Hz),
5.73 (1H, s), 3.98 (3H, s), 3.35 (2H, t, J ) 8.1 Hz), 3.03 (2H, t,
J ) 8.1 Hz), 2.59 (3H, s), 2.17 (3H, s). 13C NMR (125 MHz,
CDCl3, δ): 144.2, 141.6, 128.3 (×4), 127.4, 126.0, 125.0, 122.7,
120.7, 108.6, 108.2, 97.0, 89.2, 87.4, 58.4, 36.5, 32.6, 16.0, 13.1.
MS m/z (relative intensity): 318 (M+, 23), 227 (90), 212 (100),
183 (96), 91 (40). HRMS (EI) calcd for
318.1732, found 318.1729.
C
21H22N2O (M+)
4l. Mp 79 °C. 1H NMR (500 MHz, CDCl3, δ): 7.46-7.34 (5H,
m), 6.42 (1H, d, J ) 3.0 Hz), 6.41 (1H, s), 6.31 (1H, s), 6.29
9. H NMR (400 MHz, CDCl3, δ): 7.06 (1H, s), 2.67 (2H, t,
1
J ) 9.6 Hz), 2.43 (2H, t, J ) 8.8 Hz), 1.68 (2H, quint, J ) 9.4
5644 J . Org. Chem., Vol. 69, No. 17, 2004

Tetraponerine T6 and Analogues
Hz), 2.59 (2H, quint, J ) 9.0 Hz), 1.43 (2H, sext, J ) 9.6 Hz),
1.33-1.28 (4H, m), 0.90 (3H, t, J ) 9.2 Hz), 0.86 (3H, t, J )
8.5 Hz). 13C NMR (100 MHz, CDCl3, δ): 174.5, 160.9, 153.2,
120.5, 98.1, 78.2, 37.5, 31.4, 29.9, 28.4, 22.4, 22.0, 19.1, 13.9,
13.5. MS m/z (relative intensity): 263 (M+ - 1, 1), 235 (11),
221 (23), 208 (100).
24.4, 23.0, 14.5, 14.2. MS m/z (relative intensity): 264 (M+,
14), 235 (100), 178 (14).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(GM-64444).
10. 1H NMR (500 MHz, CDCl3, δ): 6.90 (1H, s), 6.58 (1H, d,
J ) 3.8 Hz), 6.31 (1H, d, J ) 3.8 Hz), 3.22 (2H, t, J ) 7.6 Hz),
2.56 (2H, t, J ) 7.5 Hz), 1.76 (2H, sext, J ) 7.5 Hz), 1.70-
1.64 (2H, m), 1.37-1.30 (4H, m), 1.01 (3H, t, J ) 7.3 Hz), 0.90
(3H, t, J ) 7.0 Hz). 13C NMR (125 MHz, CDCl3, δ): 143.3,
136.4, 135.8, 127.4, 117.1, 109.7, 99.5, 36.4, 32.1, 31.8, 29.0,
Su p p or tin g In for m a tion Ava ila ble: General information
1
and copies of H and 13C NMR spectra for 4f-m , 5, 12a , and
12c. Copies of NOESY spectra for 12a and 12c. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O049259G
J . Org. Chem, Vol. 69, No. 17, 2004 5645