Job/Unit: O50063
/KAP1
Date: 02-04-15 14:22:25
Pages: 6
G. Smits, R. Zemribo
a MW tube and dried over P2O5 in a vacuum drying chamber over-
FULL PAPER
19.9 Hz, 1 H), 3.83 (d, J = 7.0 Hz, 1 H), 3.24 (AB m, 1 H), 3.00–
2.95 (m, 1 H), 2.94–2.87 (m, 1 H), 2.69 (AB m, 1 H), 2.35 (q, J = night. The tube was tightly sealed and purged with argon (3ϫ). Dry
8.2 Hz, 1 H), 2.17 (AB m, 1 H), 2.08–1.99 (m, 1 H), 1.85–1.78 (m, DCM (6 mL) and freshly distilled (from sodium) Me2NEt (1.3 mL,
1 H), 1.73–1.69 (m, 2 H), 1.55–1.52 (m, 1 H), 1.43 (s, 9 H), 0.99
884 mg, 12.091 mmol) were added. The mixture was cooled to 0 °C
and then treated with Et2BOTf (878 mg, 4.030 mmol). After 1 h,
(d, J = 7.0 Hz, 3 H), 0.85 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.47, 146.06, 114.17, 81.04, 80.40, 61.39, the reaction mixture was warmed to ambient temperature, stirred
59.43, 54.07, 40.25, 32.33, 30.77, 28.06, 22.21, 19.58, 17.88 ppm.
for 1 h, and then heated in the MW at 50 °C for 1 h. The mixture
was diluted with water (approximately 6 mL), and 10% aqueous
HCl (20 drops) was added. The biphasic mixture was stirred vigor-
ously for 1 h and then evaporated. Benzyl alcohol (435 mg,
4.030 mmol), EDC (772 mg, 4.030 mmol), HOBt·H2O (411 mg,
2.686 mmol), Et3N (1359 mg, 13.434 mmol), and dry DMF (6 mL)
were added, and the obtained slurry was stirred for 16 h. The reac-
tion was diluted with brine, and the resulting mixture was extracted
DCM (2ϫ). The combined organic layers were dried with anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by preperative LC–MS. Fractions that contained (Z)-12
and (E)-12 were concentrated in vacuo, and the residue was dis-
solved in MeOH. The solution was treated with Dowex® 1X8100
basic resin and then concentrated in vacuo again. The residue was
purified by flash column chromatography (petroleum ether/EtOAc,
9:1 to 3:2) to give the desired isomer (Z)-12 (160 mg, 38%) as a
HRMS (ESI): calcd. for C17H32NO3 [M + H]+ 298.2384; found
298.2372. IR (film): ν = 3440, 2967, 1729, 1652, 1151 cm–1. [α]20
=
˜
D
–66.8 (c = 1, CHCl3).
(4S,10aS)-4-Isopropyl-5-methylenehexahydro-1H-pyrrolo[2,1-d]-
[1,5]oxazocin-2(4H)-one (7): To a stirred solution of allylic alcohol
10 (2.83 g, 9.53 mmol) in DCM (25 mL) was added dropwise TFA
(25 mL). The mixture was stirred for 4 h, as the color changed to
black. The volatiles were removed in vacuo, and the residue was
dissolved in dry DCM (10 mL). The resulting solution was added
dropwise to a stirred solution of HBTU (14.45 g, 38.12 mmol) and
DMAP (11.64 g, 95.28 mmol) in dry DCM (800 mL) over a period
of 1 h. The obtained slurry was stirred for 16 h. The reaction was
diluted with brine, and the mixture was extracted with DCM (2ϫ).
The combined organic layers were dried with anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography [petroleum ether/EtOAc, 9:1 (+2%
Et3N) to 4:1 (+2% Et3N)] to give compound 7 (1.77 g, 83% in two
1
pale yellow oil. H NMR (400 MHz, CDCl3): δ = 7.39–7.32 (m, 5
H), 5.12 (s, 2 H), 5.09 (d, J = 9.0 Hz, 1 H), 3.84 (d, J = 12.1 Hz, 1
H), 3.05 (td, J = 6.6, 2.3 Hz, 1 H), 2.61–2.52 (m, 1 H), 2.47 (s, 1
H), 2.44 (s, 1 H), 2.39–2.26 (m, 2 H), 2.22–2.18 (m, 2 H), 1.95–1.77
(m, 2 H), 1.74–1.65 (m, 1 H), 1.53–1.43 (m, 1 H), 0.97 (d, J =
6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3, rotamers): δ = 173.60, 135.93, 133.53, 129.45, 128.48,
128.12, 128.02, 127.43, 126.82, 66.08, 65.10, 53.63, 52.25, 48.11,
37.48, 28.74, 26.52, 23.44, 23.16, 21.01 ppm. HRMS (ESI): calcd.
1
steps) as a pale yellow oil. H NMR (400 MHz, CDCl3): δ = 5.24
(s, 1 H), 5.03 (s, 1 H), 4.49 (d, J = 8.6 Hz, 1 H), 3.79 (d, J =
12.5 Hz, 1 H), 3.17 (s, 1 H), 2.93 (d, J = 12.5 Hz, 1 H), 2.81–2.77
(m, 2 H), 2.39–2.33 (m, 1 H), 2.29–2.23 (m, 1 H), 2.11–1.95 (m, 2
H), 1.87–1.76 (m, 2 H), 1.70–1.62 (m, 1 H), 1.10 (d, J = 6.6 Hz, 3
H), 0.86 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 174.19, 145.14, 119.24, 88.99, 59.33, 58.92, 56.76, 41.34, 32.11,
31.09, 22.62, 19.30, 19.06 ppm. HRMS (ESI): calcd. for
for C20H28NO2 [M + H]+ 314.2115; found 314.2114. IR (film): ν =
˜
2962, 1734, 1641, 1457, 1238, 1166 cm–1. [α]2D0 = +3.04 (c = 1,
C13H22NO2 [M + H]+ 224.1658; found 224.1644. IR (film): ν =
˜
CHCl3).
2962, 1743, 1642, 1457, 1146 cm–1. [α]2D0 = –73.6 (c = 1, CHCl3).
[(8R,8aS,Z)-6-(2-Methylpropylidene)octahydroindolizin-8-yl]methyl
4-Methylbenzenesulfonate (13): To a stirred solution of ester (Z)-12
(230 mg, 0.734 mmol) in dry DCM (3 mL) at –78 °C was added
DIBAL-H (1.2 m in toluene, 3.057 mL, 529 mg, 3.669 mmol), and
the obtained solution was stirred for 5 h. The reaction mixture was
quenched at the same temperature by the addition of MeOH and
then warmed to ambient temperature. The mixture was treated with
a saturated aqueous solution of sodium potassium tartrate, and the
resulting mixture was extracted with DCM (2ϫ). The combined
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was dissolved in DCM (3 mL),
and pyridine (0.178 mL, 174 mg, 2.202 mmol) and 4-toluenesulf-
onyl chloride (TsCl, 210 mg, 1.101 mmol) were added. The ob-
tained mixture was stirred for 16 h. The reaction was diluted with
brine, and the mixture was extracted DCM (2ϫ). The combined
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography (petroleum ether/EtOAc, 1:1 to 0:1) to give com-
pound 13 (80 mg, 35% in two steps) as a yellow oil. 1H NMR
(300 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H), 7.35 (d, J =
8.0 Hz, 2 H), 5.03 (d, J = 9.0 Hz, 1 H), 3.97 (dd, J = 9.7, 4.6 Hz,
1 H), 3.88 (dd, J = 9.7, 6.0 Hz, 1 H), 3.83 (d, J = 12.3 Hz, 1 H),
3.05 (t, J = 8.6 Hz, 1 H), 2.60–2.48 (m, 1 H), 2.45 (s, 3 H), 2.35 (d,
J = 12.1 Hz, 1 H), 2.22–2.09 (m, 2 H), 1.91–1.75 (m, 4 H), 1.71–
1.55 (m, 4 H), 1.41–1.32 (m, 1 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.88
(d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.78, 133.95, 133.43, 132.83, 129.83, 127.87, 72.01, 65.45, 53.78,
52.37, 41.67, 36.79, 28.32, 26.52, 23.47, 23.17, 21.62, 21.03 ppm.
General Procedure for Ireland–Claisen Rearrangement of 7: Lactone
7 (50 mg, 0.224 mmol) was placed in a MW tube and then dried
over P2O5 in a vacuum drying chamber overnight. The tube was
tightly sealed and purged with argon (3ϫ). Dry DCM (1 mL) and
the freshly distilled (from sodium) tertiary amine[18] (2.015 mmol)
were added, and the mixture was cooled to 0 °C and treated with
the appropriate triflate (0.672 mmol).[19] After 1 h, the reaction
mixture was warmed to ambient temperature, stirred for 1 h, and
then heated in the MW at 50 °C for 1 h. The mixture was then
diluted with water (approximately 1 mL), and 10% aqueous HCl
(3 drops) was added. The biphasic mixture was stirred vigorously
for 1 h and then evaporated. Benzyl alcohol (73 mg, 0.672 mmol),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 215 mg,
1.119 mmol), 1-hydroxybenzotriazole hydrate (HOBt·H2O, 68 mg,
0.448 mmol), Et3N (226 mg, 2.239 mmol), and dry N,N-dimethyl-
formamide (DMF, 1 mL) were added, and the obtained slurry was
stirred for 16 h. The reaction was diluted with brine, and the re-
sulting mixture was extracted with DCM (2ϫ). The combined or-
ganic layers were dried with anhydrous Na2SO4, filtered, and con-
centrated in vacuo.[20] The residue was purified by preperative LC–
MS. Fractions that contained (Z)-12 and (E)-12 were concentrated
in vacuo, and the residue dissolved in MeOH. The solution was
treated with Dowex® 1X8100 basic resin and then concentrated in
vacuo again.[21] The residue was purified by flash column
chromatography (petroleum ether/EtOAc, 9:1 to 3:2) to give the
desired isomer (Z)-12 as a pale yellow oil.
(8R,8aS,Z)-Benzyl 6-(2-Methylpropylidene)octahydroindolizine-8-
carboxylate (Z-12): Lactone 7 (300 mg, 1.343 mmol) was placed in [α]2D0 = +3.0 (c = 1, CHCl3).
4
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