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