Airiau et al.
JOCNote
(4 steps, 34%); if the piperidine rings are decorated with an
allylic side chain, the sequence was applicable to the synthesis
of quinolizidines such as (()-9-epi-195C (24) (5 steps, 27%).
Following a related approach the CHC ring closing provided
a synthesis of (þ)-tetraponerine T-3 (8 steps, 14%). Previous
asymmetric synthesis of Tetraponerine T-3 were accomplished
in more than 8 steps including chromatographic separations of
diastereomers.19g,j Our group is currently exploring further
applications of the hydroformylation in the synthesis of bio-
logically active heterocycles.
was filled with 5 bar of H2/CO (1:1) and heated to 60 °C with
stirring for 12 h. Then, the autoclave was cooled to room tem-
perature and gases were slowly and carefully released. The solvent
was evaporated under reduced pressure. The residue was purified
by flash chromatography (95:5 pentane/Et2O) to give 11 as a
colorless oil (990 mg, 84%). Rf 0.50 (90:10 pentane/Et2O); IR
1
(film) 2954, 2871, 1694, 1411, 1306, 1069, 696 cm-1; H NMR
(CDCl3 filtered on basic Al2O3, 400 MHz)
δ 7.37-
7.32 (m, 5H), 5.51 (br s, 0.5H), 5.38 (br s, 0.5H), 5.18-5.15 (m,
2H), 4.25 (br s, 0.5 H), 4.17 (br s, 0.5H), 3.31 (br s, 1.5H), 3.23 (br s,
1.5H), 1.93-1.81 (m, 2H), 1.75-1.68 (m, 3H), 1.62-1.52 (m, 2H),
1.43-1.24 (m, 3H), 0.95-0.89 (m, 3H); 13C NMR (CDCl3, 100
MHz) δ 156.9/156.1 (C), 136.8 (C), 128.6 (CH), 128.2 (2ꢀCH),
128.1 (2ꢀCH), 82.4 (CH), 67.4/67.3 (CH2), 55.7/55.2 (CH), 51.0
(CH3), 36.0/35.5 (CH2), 30.8 (CH2), 27.7/27.3 (CH2), 20.6 (CH2),
14.1 (CH3), 13.8 (CH2); HRMS-ESI (m/z) calcd
for C17H25NO3Na [M þ Na]þ 314.1727, found 314.1729 (Δ =
1.8 ppm).
Experimental Section
General Procedure for Aza-Sakurai-Hosomi. In a dry flask
under argon was introduced aldehyde (1, 2, or 3) in CH2Cl2
(to reach a concentration of 0.4 M) and the solution was cooled
at 0 °C by means of an ice bath. Benzylcarbamate 5 (1 equiv) and
allyltrimethylsilane 4 (1 equiv) were added. BF3 Et2O (1 equiv; 2
3
General Procedure for Hydrogenolysis. In a high-pressure
reactor under inert atmosphere, to a solution of substrate in
MeOH (10 mL) was added Pearlman’s catalyst (Pd(OH)2/C
20%, 10% w/w). The mixture was set under 5 bar of hydrogen
and was shacked overnight. The residue was filtrated over a
Celite pad and concentrated HCl was added (1-2 mL). The
solvent was removed under reduced pressure. Et2O and NaOH
15% were added and the aqueous layer was extracted with Et2O
(3 times). The organic layer was dried over Na2SO4, filtered, and
carefully concentrated under reduced pressure to give the de-
sired alkaloid.
(()-Coniine (13): yield 85%; colorless oil; IR (film) 3270,
2955, 2925, 2855, 1461, 1262, 1120, 743 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.07 (dddd, J=11.7, 4.0, 2.2, 1.8 Hz, 1H), 2.62 (ddd,
J=11.7, 11.6, 2.6 Hz, 1H), 2.48-2.43 (m, 1H), 1.80-1.74 (m,
1H), 1.68-1.56 (m, 2H), 1.42-1.28 (m, 7H), 1.11-1.01 (m, 1H),
0.91 (dd, J=7.0, 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
56.8 (CH), 47.3 (CH2), 39.7 (CH2), 33.0 (CH2), 26.7 (CH2), 25.0
(CH2), 19.1 (CH2), 14.4 (CH3); LRMS-ESI (m/z) 128.2 (M þ 1);
HRMS-ESI (m/z) calcd for C8H18N [M þ H]þ 128.1434, found
128.1436 (Δ=2.1 ppm).
equiv for 2) was added dropwise and the solution was stirred for
2 h at 0 °C and allowed to warm to room temperature for 30 min.
Na2CO3 solution was added and the aqueous layer was ex-
tracted with CH2Cl2 (3 times). The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography to yield the
desired homoallylamine.
Benzyl hept-1-en-4-ylcarbamate (6): yield 90%; white solid; Rf
0.33 (90:10 pentane/Et2O); mp 38-40 °C; IR (film) 3300, 2952,
1686, 1541, 1264, 1234, 1020, 745, 696 cm-1; 1H NMR (CDCl3,
400 MHz) δ 7.37-7.30 (m, 5H), 5.78 (ddt, J = 17.8, 9.3, 6.9 Hz,
1H), 5.10-5.05 (m, 4H), 4.55 (br d, J = 6.9 Hz, 1H), 3.75 (m,
1H), 2.32-2.16 (m, 2H), 1.51-1.45 (m, 1H), 1.43-1.34 (m, 3H),
0.92 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.1
(C), 136.8 (C), 134.4 (CH), 128.6 (2ꢀCH), 128.1 (3ꢀCH), 117.9
(CH2), 66.6 (CH2), 50.6 (CH), 39.6 (CH2), 36.9 (CH2), 19.2
(CH2),14.0(CH3);LRMS-ESI(m/z) 248.1(Mþ 1), 204.1 (M - 44);
HRMS-ESI (m/z) calcd for C15H21NO2K [M þ K]þ 286.1204,
found 286.1217 (Δ=3.5 ppm).
Benzyl 1-(pyridin-3-yl)but-3-enylcarbamate (7): yield 50%;
pale yellow oil; Rf 0.45 (95:5 CH2Cl2/MeOH); IR (film) 3305,
(4R*,6S*,9aR*)-4-Methyl-6-propyloctahydro-1H-quinolizine,
(()-9-epi-195C (24): yield 80%; slightly yellow oil; IR (film)
3033, 1695, 1530, 1328, 1254, 1040, 1025, 713, 696 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 8.57 (br s, 1H), 8.53 (dd, J =
4.7, 1.3 Hz, 1H), 7.6 (br d, J=8.0 Hz, 1H), 7.38-7.33 (m, 6H),
5.67 (ddt, J=17.5, 9.8, 6.7 Hz, 1H), 5.17-5.07 (m, 5H), 4.83 (br
d, 2H), 2.56 (br t, J=6.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ 155.7 (C), 148.7 (CH), 148.2 (CH), 136.4 (C), 134.2 (C), 133.0
(CH), 128.8 (2ꢀCH), 128.7 (CH), 128.4 (CH), 128.2 (2ꢀCH),
123.6 (CH), 119.4 (CH2), 67.2 (CH2), 52.7 (CH), 40.8 (CH2);
LRMS-ESI (m/z) 283.1 (M þ 1); HRMS-ESI (m/z) calcd for
C17H18N2O2K [M þ K]þ 321.0999, found 321.1014 (Δ=3.5 ppm).
Typical Procedure for Hydroformylation. Benzyl 2-Methoxy-
6-methylpiperidine-1-carboxylate (11). A solution of Rh(CO)2-
acac (0.25 mol %, 2.6 mg, 0.010 mmol) and biphephos (0.5 mol %,
15.9 mg, 0.020 mmol) in anhydrous degassed THF (0.5 mL),
prepared in a Schlenk glassware under inert atmosphere, was
introduced under inert atmosphere into a stainless steel auto-
clave containing 6 (1000 mg, 4.04 mmol) in anhydrous degassed
MeOH to reach a final concentration of 0.2 M. The autoclave
was flushed with H2/CO (1:1) three times. Then, the autoclave
1
2962, 1455, 1375 cm-1; H NMR (CDCl3, 400 MHz) δ 2.64-
2.59 (m, 1H), 2.56-2.51 (m, 1H), 2.46 (t app, J=10.5 Hz, 1H),
1.83-1.75 (m, 1H), 1.67-1.61 (m, 3H), 1.52-1.44 (m, 5H),
1.40-1.20 (m, 7H), 1.12 (, J=6.4 Hz, 3H), 0.91 (t, J=7.3 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 58.1 (CH), 57.1 (CH), 55.9
(CH), 39.7 (CH2), 34.3 (CH2), 33.4 (CH2), 30.6 (CH2), 23.7
(CH2), 22.7 (CH2), 22.4 (CH3), 20.2 (CH2), 17.7 (CH2), 14.4
(CH3); HRMS-ESI (m/z) calcd for C13H26N [M þ H]þ 196.2060,
found 196.2070 (Δ=0.1 ppm).
ꢁ
Acknowledgment. This work was supported by the Ministere
ꢀ ꢀ ꢀ ꢁ
delegue a l’Enseignement Superieur et a la Recherche (E.A.).
ꢀ
ꢁ
Supporting Information Available: Full experimental pro-
cedures, characterization data, and copies of 1H and 13C spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8673