Organic Process Research & Development
Article
reaction temperature below 15 °C. The mixture was warmed to
20−22 °C and stirred for 3 h. The slurry was concentrated on the
rotovap, then EtOAc (10 vol) was added, and the mixture was
filtered. The filtrate was concentrated to dryness to give 12.30 g of
crude 25. Compound 25 was taken to the next step without
purification. 1H NMR (400 MHz, CDCl3) δ 7.24 (dt, J = 6.5, 4.5 Hz,
3H), 6.41 (dd, J = 9.1, 3.1 Hz, 3H), 6.05 (dd, J = 7.2, 2.9 Hz, 3H),
4.75 (d, J = 13.4 Hz, 2H), 4.06 (dd, J = 20.8, 15.7 Hz, 3H), 3.98−
3.76 (m, 6H), 3.38−3.25 (m, 3H), 3.09−3.03 (m, 3H), 2.85−2.72
(m, 3H), 2.53−2.46 (m, 3H), 2.22 (dd, J = 7.3, 3.3 Hz, 2H), 2.06−
1.94 (m, 7H), 1.87 (d, J = 7.5 Hz, 1H), 0.96 (t, J = 7.4 Hz, 4H), 0.83
(t, J = 7.4 Hz, 5H). 13C NMR (101 MHz, CDCl3) δ 172.99, 163.14,
148.73, 148.65, 139.23, 138.57, 117.58, 117.08, 106.07, 105.07,
52.69, 51.48, 48.97, 48.63, 47.63, 34.94, 34.38, 27.53, 27.34, 26.17,
26.09, 25.85, 9.20, 9.17. IR (cm−1, neat solid): 1630.34, 1574.69,
1539.82, 1450.90, 1427.80, 1360.16, 121825, 1145.07. ESI-HRMS
(m/z) calcd for C14H19N2O2+ [M + H]+ 247.1441, found 247.1448.
(1R,5S,11aS)-3-Propionyloctahydro-1H-1,5-methanopyrido-
[1,2-a][1,5]diazocin-8(2H)-one (26). To 25 (12.30 g, 49.94 mmol)
was added EtOH (246 mL) and then PtO2 (567 mg, 2.50 mmol).
The reaction vessel was evacuated and pressurized to 50 psig
with H2 (3×). The mixture was stirred at 20−22 °C for 22 h.
(GC analysis showed 90% reaction completion). H2 gas was
recharged, and the mixture was stirred for 3 h. (GC analysis
showed 100% reaction completion.) The mixture was filtered
through a pad of Celite, which was rinsed with EtOH. The filtrate
was concentrated in vacuo to give 12.73 g of the crude 26 as a
thick oil which solidified upon standing. Compound 26 was
taken to the next step without purification. 1H NMR (400 MHz,
CDCl3) δ 4.99 (dt, J = 13.9, 2.2 Hz, 1H), 4.76 (dt, J = 13.8,
2.3 Hz, 1H), 3.92−3.83 (m, 1H), 3.44−3.31 (m, 1H), 3.21 (dt,
J = 13.2, 2.5 Hz, 1H), 2.72 (ddd, J = 13.9, 3.3, 1.9 Hz, 1H), 2.60−
2.50 (m, 1H), 2.33−2.06 (m, 4H), 2.05−1.67 (m, 6H), 1.66−
(27). To (−)-cytisine (10 g, 52.56 mmol) was added CH2Cl2
(100 mL) and triethylamine (10.64 g, 14.7 mL, 105 mmol). The
reaction mixture was cooled to 0−5 °C, then isobutyryl chloride
(6.86 g, 6.80 mL, 63.07 mmol) was added keeping the reaction
temperature below 15 °C. The mixture was warmed to 20−22 °C
and stirred for 3 h. (GC analysis showed consumption of
(−)-cytisine.) The slurry was concentrated by rotary evapo-
ration, then EtOAc (10 vol) was added, and the mixture was
filtered. The filtrate was concentrated to dryness to give crude 28.
1
Compound 28 was used directly in the next step. H NMR
(400 MHz, d6-DMSO) δ 4.83 (dq, J = 13.7, 2.2 Hz, 1H), 4.58
(dt, J = 13.6, 2.2 Hz, 1H), 3.97 (dt, J = 13.3, 2.0 Hz, 1H), 3.38−
3.23 (m, 1H), 2.82−2.63 (m, 2H), 2.58 (dd, J = 13.6, 2.7 Hz,
1H), 2.27−1.42 (m, 11H), 0.95 (dd, J = 6.7, 3.8 Hz, 1H), 0.90 (d,
J = 6.9 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz,
DMSO) δ 174.23, 167.90, 58.37, 49.69, 45.20, 41.46, 32.68,
32.51, 32.33, 28.86, 27.49, 27.31, 19.51, 19.36, 19.14. IR (cm−1,
neat solid): 1649.80, 1620.68, 1573.43, 1543.11, 1462.35,
+
1435.75. ESI-HRMS (m/z) calcd for C15H20N2NaO2
[M + Na]+ 283.1417, found 283.1420.
1.58 (m, 1H), 1.54−1.44 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H). 13
C
(1R,5S,11aS)-3-Isobutyryloctahydro-1H-1,5-methanopyrido-
[1,2-a][1,5]diazocin-8(2H)-one. To 27 (13.68 g, 52.55 mmol)
was added MeOH (274 mL), then PtO2 (597 mg, 2.63 mmol) .
The reaction vessel was evacuated and pressurized to 50 psig
with H2 (3×). The mixture was stirred at 20−22 °C for 16 h.
(GC analysis showed 90% reaction completion). H2 was
recharged and the mixture was stirred for 4 h. (GC analysis
showed 99% reaction completion). The mixture was filtered
through a pad of Celite, which was rinsed with MeOH. The
filtrate was concentrated in vacuo to give 11.00 g of the crude
product as a brown thick oil. The crude product 28 was taken to
the next step without purification. 1H NMR (d6-DMSO, 400 MHz):
δ4.82 (d, 1H); 4.59 (d, 1H); 3.99 (d, 1H); 3.46 (m, 1H); 3.27
(d, 1H); 2.70 (m, 2H); 2.59 (d, 1H); 2.18−1.41 (m, 10H); 0.90
(d, 3H); 0.85 (d, 3H). 13C NMR (d6-DMSO, 101 MHz): δ 174.27,
167.95, 58.62, 49.71, 41.48, 40.02, 32.70, 32.53, 32.34, 29.07, 27.69,
27.32, 19.53, 19.38, 19.16. IR (cm−1, neat solid): 1621.23, 1436.35,
1424.44, 1227.71, 1219.06, 1162.93, 1059.95. ESI-HRMS (m/z)
calcd for C15H25N2O2+ [M + H]+ 265.1911, found 265.1923.
(1R,5S,11aS)-3-Isobutyldecahydro-1H-1,5-methanopyrido-
[1,2-a][1,5]diazocine (16). To crude 28 (11.00 g, 41.61 mmol)
was added THF (198 mL), then LiAlH4 (9.48 g, 10.33 mL,
250 mmol) . The mixture was warmed to reflux for 21 h. (GC analysis
showed starting material consumed.) The mixture was cooled to
5−10 °C, and MTBE (100 mL) was added. The mixture was
carefully quenched with saturated Na2SO4 solution. (The reaction
temperature rose to 44−45 °C during the quench.) The slurry was
filtered through a pad of Celite, and rinsed with 9:1 CH2Cl2/MeOH
(1 L). The solution was concentrated in vacuo, and the residue
was suspended in EtOAc. The mixture was filtered through Celite
NMR (101 MHz, CDCl3) δ 172.51, 169.85, 59.28, 50.18, 45.79,
41.94, 33.52, 32.78, 32.56, 27.91, 27.65, 26.17, 19.81, 9.27. IR
(cm−1, neat solid): 1621.30, 1459.84, 1414.23, 1417.02, 1345.90,
1309.71, 1247.32, 1217.15. ESI-HRMS (m/z) calcd for
C14H23N2O2+ [M + H]+ 251.1754, found 251.1759.
(1R,5S,11aS)-3-propyldecahydro-1H-1,5-methanopyrido-
[1,2-a][1,5]diazocine (14). To 26 (12.50 g, 49.93 mmol) was
added THF (50.0 mL), then LiAlH4 (1.89 g, 49.93 mmol) . The
mixture was warmed to reflux for 16 h, after which GC analysis
showed the starting material consumed. The mixture was cooled
to 5−10 °C, and EtOAc (25 mL) was added. The mixture was
carefully quenched with saturated Na2SO4 solution. (The
reaction temperature rose to 44−45 °C during the quench.)
The slurry was filtered through a pad of Celite, and rinsed with
9:1 CH2Cl2/MeOH (1 L). The solution was concentrated in
vacuo, and the residue was suspended in EtOAc. The mixture was
filtered through Celite again, and the filtrate was concentrated in
vacuo to give a light-brown oil. The crude product was purified
by Kugelrohr distillation (130−170 °C) to give 4.29 g of 14 (37%
overall yield). 1H NMR (400 MHz, CDCl3) δ 3.03 (dt, J = 11.3,
2.3 Hz, 1H), 2.96−2.62 (m, 3H), 2.39 (ddd, J = 11.7, 10.5,
5.3 Hz, 1H), 2.21 (dddd, J = 13.8, 11.1, 3.8, 1.6 Hz, 2H), 2.07−
1.29 (m, 15H), 1.33−1.09 (m, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 66.33, 61.91, 60.68, 59.27, 57.51,
52.94, 34.92, 34.07, 30.69, 30.63, 25.73, 25.23, 19.97, 11.99. IR
(cm−1, neat): 2928.92, 2756.12, 2720.98. ESI-HRMS (m/z)
calcd for C14H27N2+ [M + H]+ 223.2169, found 223.2169.
Preparation of 16. (1R,5S)-3-Isobutyryl-3,4,5,6-tetrahy-
dro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-8(2H)-one
J
dx.doi.org/10.1021/op500040j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX