Job/Unit: O42563
/KAP1
Date: 13-08-14 18:25:35
Pages: 5
Total Synthesis of a Pyrrole Lactone Alkaloid, Longanlactone
nologies LC-MSD trap SL spectrometer. All reagents and solvents
were of reagent grade and used without further purification unless
otherwise stated. Technical-grade EtOAc and hexanes for column
chromatography were distilled before use. THF, when used as a
reaction solvent, was freshly distilled from sodium benzophenone
ketyl. Column chromatography was performed with silica gel (60–
120 mesh) packed in glass columns. All reactions were performed
under N2 in flame- or oven-dried glassware with magnetic stirring.
ide (0.32 mL, 4.2 mmol) in N,N-dimethylformamide (DMF, 10 mL)
was added zinc (273 mg, 4.2 mmol), and the reaction mixture was
stirred for 5 h. Saturated NH4Cl (10 mL) solution was added, and
the compound was extracted with ethyl acetate (2 X 15 mL). The
organic layer was dried with Na2SO4 and concentrated in vacuo to
afford the crude oil, which was purified by column chromatog-
raphy, eluted with hexanes/EtOAc (80:20) to give 7 (1 g, 90%) in a
1:1 ratio of inseparable diastereomers; the identity of the obtained
product was confirmed by NMR spectroscopy. IR (KBr): ν = 3031,
˜
Dimethyl (2S)-2-[bis(tert-butyloxy)amino]butane-1,4-dioate (5): To a
suspension of l-aspartic acid (4) (4.0 g, 30.07 mmol) in methanol
(25 mL) at 0 °C under nitrogen, thionyl chloride (3.2 mL,
45.11 mmol) was added dropwise over 15 min. The reaction mix-
ture was warmed to room temperature and heated to reflux for 4 h.
The solution was concentrated in vacuo to give a colorless oil. To
this crude oil, hexane was added, and the mixture was stirred for
10 min. Then, the hexane was decanted, and this procedure was
repeated two more times to afford a solid compound. To this solid
in dichloromethane (60 mL) at 0 °C under nitrogen, triethylamine
(8.4 mL, 60.15 mmol) and (Boc)2O (9.80 g, 45.11 mmol) were
added dropwise. The reaction mixture was warmed to room tem-
perature and stirred for 4 h. The reaction mixture was washed with
water (100 mL) and brine (100 mL), dried with Na2SO4, and con-
centrated under reduced pressure. The crude residue was used for
the next step without further purification. To a stirred solution of
the N-Boc amino ester (7.3 g, 27.96 mmol) and DMAP (665 mg,
5.59 mmol, 0.2 equiv.) in dry CH3CN (50 mL) was added (Boc)2O
(6.59 g, 30.76 mmol, 1.1 equiv.) at room temp. The reaction became
slightly red with gas evolution. The mixture was stirred for 2 h,
after which time TLC showed that some starting material still re-
mained. More (Boc)2O (3.2 g, 13.98 mmol, 0.5 equiv.) was added,
and the mixture was additionally stirred overnight. The solvent was
evaporated, and the crude product was then diluted by the addition
of ice cold water (50 mL) and ether (50 mL); the organic layer was
separated, and the aqueous phase was extracted with diethyl ether
(2ϫ 40 mL). The combined organic layers were washed with brine
(50 mL) and dried with Na2SO4, and the organic solvent was evap-
orated under reduced pressure. The crude residue was purified by
flash column chromatography (silica gel, hexanes/EtOAc 95:05) to
give 5 (9.17 g, 95%) as a solid, m.p. 57–58 °C. [α]2D0 = –61.5 (c =
1
2979, 1781, 1756, 1611, 1370, 1249, 1122 cm–1. H NMR (CDCl3,
500 MHz): δ = 5.09 (t, J = 5.9 Hz, 1 H), 5.04 (dd, J = 5.0, 9.7 Hz,
1 H), 4.07–3.99 (m, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.33–3.28 (m,
1 H), 2.59–2.45 (m, 3 H), 2.43–2.36 (m, 2 H), 2.29–2.36 (m, 2 H),
2.07 (t, J = 2.5 Hz, 1 H), 2.04 (t, J = 2.5 Hz, 1 H), 1.50 (s, 36 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 171.3, 171.2, 152.3, 151.9,
83.7, 83.3, 80.6, 80.3, 71.0, 70.5, 67.7, 66.6, 55.6, 55.3, 52.3, 52.2,
37.3, 36.5, 27.9, 27.8, 27.2, 26.9 ppm. MS(ESI): m/z = 394 [M +
Na]+. HRMS (ESI): calcd. for C18H29NO7Na [M + Na]+ 394.1841;
found 394.1854.
(3S,5R)-5-(Prop-2-yn-1-yl)-3-(1H-pyrrol-1-yl)dihydrofuran-2(3H)-
one (8a): Di-Boc compound 7 (0.8 g, 2.3 mmol) was dissolved in
dichloromethane/TFA (1:1, 10 mL) in a 50 mL flask, and the mix-
ture was then cooled to 0 °C. The reaction mixture was stirred for
2 h at same temperature. The mixture of solvents was evaporated
under reduced pressure to afford a thick red oil. Dichloroethane
(10 mL) and water (10 mL) were added to the above crude mixture,
followed by 2,5-dimethoxytetrahydrofuran (0.45 mL, 3.5 mmol).
The resulting solution was stirred for 45 min at 80 °C. The solution
was diluted with water (20 mL) and extracted with dichlorometh-
ane (3ϫ 15 mL). The combined organic layers were washed with
saturated NaHCO3 solution (1ϫ 25 mL) and saturated NaCl solu-
tion (1ϫ 25 mL) and dried with Na2SO4. The solvent was evapo-
rated under reduced pressure, and the obtained crude product was
purified by silica gel column chromatography to afford a separable
mixture of the two diastereomers 8a (179 mg, 44 %) and 8b
(163 mg, 40%) as brown solids, m.p. 147–149 °C. [α]2D0 = –8.3 (c =
1.00, CHCl ). IR (KBr): ν = 3127, 2922, 2854, 1777, 1490, 1322,
˜
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1175, 1020, 731 cm–1. H NMR (CDCl3, 300 MHz): δ = 6.76 (t, J
1
= 2.1 Hz, 2 H), 6.25 (t, J = 2.1 Hz, 2 H), 4.99 (dd, J = 12.3, 9.0 Hz,
1 H), 4.65 (ddd, J = 16.0, 10.6, 5.1 Hz, 1 H), 2.97 (ddd, J = 13.0,
8.9, 3.4 Hz, 1 H), 2.79–2.74 (m, 2 H), 2.53 (ddd, J = 12.5, 10.2,
2.6 Hz, 1 H), 2.14 (t, J = 2.6 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 172.3, 119.8, 109.5, 77.2, 73.8, 72.2, 58.0, 35.1, 24.5
ppm. MS(ESI): m/z = 190 [M + H]+. HRMS (ESI): calcd. for
C11H11NO2Na [M + Na]+ 212.0687; found 212.0692.
2.00, CHCl ). IR (KBr): ν = 3032, 2989, 1791, 1750, 1698, 1370,
˜
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1249, 1142 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 5.44 (d, J =
6.8 Hz, 1 H), 3.69 (s, 3 H), 3.72 (s, 3 H), 3.24 (dd, J = 16.5, 6.8 Hz,
1 H), 2.72 (dd, J = 16.4, 6.8 Hz, 1 H), 1.49 (s, 18 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 170.9, 170.1, 151.4, 83.4, 54.7, 52.4,
51.8, 35.5, 27.8 ppm. MS (ESI): m/z = 362 [M + H]+.
(S)-Methyl 2-[Di(tert-butoxycarbonyl)amino]-4-oxobutanoate (6):
To a stirred solution of the dimethyl ester 5 (6 g, 16.6 mmol) in dry
Et2O (50 mL, 0.1 m) was added dropwise DIBAL-H (12.36 mL,
25% in toluene, 19.28 mmol, 1.1 equiv.) at –78 °C. The reaction
mixture was stirred for 15 min at the same temperature and
quenched with H2O (2 mL, 7 equiv.). The mixture was stirred for
30 min and then warmed to 0 °C; Na2SO4 was added, and the mix-
ture was filtered through a pad of Celite. The solvent was evapo-
rated, and the crude product was purified by silica gel column
chromatography to afford 6 (4.84 g, 88%) as an oil. [α]2D0 = –54.5
(3S,5S)-5-(Prop-2-yn-1-yl)-3-(1H-pyrrol-1-yl)dihydrofuran-2(3H)-
one (8b): M.p. 167–169 °C. [α]2D0 = –103 (c = 1.00, CHCl3). IR
(KBr): ν = 3032, 2989, 1791, 1750, 1698, 1370, 1249, 1142 cm–1.
˜
1H NMR (CDCl3, 500 MHz): δ = 6.73 (t, J = 2.0 Hz, 2 H), 6.24
(t, J = 2.0 Hz, 2 H), 5.17 (t, J = 9.2 Hz, 1 H), 4.86 (ddd, J = 12.1,
7.9, 4.0 Hz, 1 H), 2.86–2.69 (m, 4 H), 2.14 (t, J = 2.5 Hz, 1 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 172.7, 119.6, 109.6, 77.7,
74.9, 72.3, 56.5, 34.1, 25.2 ppm. MS (ESI): m/z = 212 [M + Na]+.
Longanlactone (1a): To a stirred solution of 8a (175 mg, 0.75 mmol)
in CH2Cl2 (5 mL) were added Ac2O (92 mg, 0.91 mmol) and
BF3·Et2O (10 mol-%) at 0 °C, and the mixture was stirred for 1 h.
Water was added to the reaction mixture, which was then extracted
with chloroform (2ϫ 10 mL), dried with sodium sulfate, concen-
trated under reduced pressure, and purified by column chromatog-
raphy, eluted with 20% EtOAc in hexane to give product 1a
(c = 1.00, CHCl ). IR (KBr): ν = 3022, 2988, 1791, 1749, 1698,
˜
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1370, 1267, 1142 cm–1. H NMR (CDCl3, 300 MHz): δ = 9.76 (s,
1
1 H), 5.50 (dd, J = 6.8, 6.6 Hz, 1 H), 3.71 (s, 3 H), 3.38 (dd, J =
17.0, 6.9 Hz, 1 H), 2.82 (dd, J = 17.0, 6.8 Hz, 1 H), 1.48 (s, 18 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 198.3, 170.2, 151.6, 83.6,
52.8, 52.5, 44.9, 27.9 ppm. MS (ESI): m/z = 332 [M + H]+.
Methyl
(2S)-2-[Di(tert-butoxycarbonyl)amino]-4-hydroxyhept-6- (200 mg) in 95% yield as white acicular crystals, m.p. 197–199 °C.
ynoate (7): To a solution of 6 (1 g, 3.0 mmol) and propargyl brom-
[α]2D0 = –9.2 (c = 1.00, acetone). IR (KBr): ν = 3304, 3141, 2929,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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