Diastereoselective Zwitterionic Aza-Claisen Rearrangements
3
6 (2 equiv.) in CH2Cl2 were combined in a flame-dried flask over
Na2CO3 (5 equiv.). The reaction mixture was cooled to 0 °C. Then,
AlMe3 (2 m in toluene; 1.5 equiv.) was added over 15 min by sy-
ringe. The reaction was found to be complete after stirring over-
night (the mixture had warmed to room temperature). After cool-
ing to 0 °C, the reaction was quenched by injection of some drops
of NaHCO3 (saturated aq.), and stirring was continued until the
evolution of gas had ceased. Then, the mixture was diluted with
diethyl ether, dried with MgSO4, and filtered through MgSO4 and
silica gel. The crude product was purified by column chromatog-
raphy or preparative HPLC.
5.65 (dt, 3JH,H = 10.3, JH,H = 17.0 Hz, 1 H, 9-H), 6.94–7.01 (m, 3
H, 12-H, 14-H, 16-H), 7.23–7.28 (m, 2 H, 13-H, 15-H) ppm. 13C
NMR (100 MHz, CDCl3, HSQC): δ = 25.63 (C-4), 25.94 (C-3),
41.92 (C-5), 49.20 (C-8), 59.39 (C-2), 79.44 (C-7), 115.91 (C-12, C-
16), 120.30 (C-10), 121.58 (C-14), 129.26 (C-13, C-15), 130.30 (C-
9), 157.53 (C-11), 169.69 (C-6) ppm. IR: ν = 2975 (s), 2953 (s),
˜
2881 (s), 1705 (vs), 1598 (s), 1588 (s), 1494 (m), 1434 (s), 1335 (s),
1289 (s), 1240 (s), 1173 (s), 1101 (s), 916 (s), 755 (m), 691 (s) cm–1.
HRMS (ESI): calcd. for C15H17NO2 266.1157; found 266.1155.
(1R,2R,7aS)-1-Hydroxymethyl-2-phenoxypyrrolizidin-3-one
(10):
Pyrrolizidinone 8e (65 mg, 0.27 mmol) was dissolved in methanol
(50 mL), and the mixture was cooled to –78 °C. Ozone/O2 was
bubbled through the solution until the blue colour of unreacted
ozone was observed (7 min). The excess ozone was removed by
bubbling argon through the solution for 30 min. Again at –78 °C,
NaBH4 (20.4 mg, 0.54 mmol) was added, and then the reaction
mixture was allowed to warm to 5 °C overnight. The solvent was
removed under reduced pressure. The residue was dissolved in di-
ethyl ether and water, and the solution was extracted (3ϫ) with
diethyl ether. The combined organic extracts were dried with
MgSO4 and concentrated to give pure product 10 (40 mg,
0.16 mmol, 60%) as a colourless oil. Rf (CH/EA, 1:1) = 0.1. [α]2D4
= 28.4 (c = 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3, COSY): δ
= 1.25 (s, 1 H, 10-H), 1.85–2.06 (m, 3 H, 3-H, 4a-H), 2.12–2.16 (m,
1 H, 4b-H), 2.94 (m, 1 H, 8-H), 3.13–3.18 (m, 1 H, 5a-H), 3.50–
For yields and data for 7a–d, see Supporting Information.
tert-Butyl (2S)-2{(1R)-1-[(1R)-2-Oxo-1-phenoxy-2-(1-pyrrolidinyl)-
ethyl]-2-propen-1-yl}-1-pyrrolidinecarboxylate (7e): Reaction of al-
lylamine 3 (200 mg, 0.71 mmol, 1 equiv.), acyl fluoride 6e (219 mg,
1.42 mmol, 2 equiv.), and trimethylaluminum (0.5 mL, 1.07 mmol,
1.5 equiv.) in CH2Cl2 (15 mL) with Na2CO3 (604 mg, 5.7 mmol,
8 equiv.) according to the standard procedure. Purification by col-
umn chromatography (CH/EA, 2:1) gave amide 7e (290 mg,
0.71 mmol, 100%) as a pale yellow oil, which was pure enough to
be used directly in the next reaction. Rf (CH/EA, 1:1) = 0.36.
[α]2D4 = –70.2 (c = 1.00, CH2Cl2). 1H NMR (400 MHz, CDCl3,
COSY): δ = 1.45 (s, 9 H, 22-H), 1.55–1.85 (m, 6 H, 3a-H, 4a-H,
11-H, 12-H), 1.91–2.06 (m, 2 H, 3b-H, 4b-H), 2.97–3.16 (m, 2 H,
6-H, 10a-H), 3.30–3.44 (m, 4 H, 5a-H, 10b-H, 13-H), 3.63–3.68 (m,
2
3
3.57 (m, 1 H, 5b-H), 3.77 (dd, JH,H = 12.2, JH,H = 3.3 Hz, 1 H,
2
3
1 H, 5b-H), 4.07–4.27 (m, 1 H, 2-H), 5.09 (dd, JH,H = 1.8, JH,H
= 10.1 Hz, 1 H, 15a-H), 4.66–5.30 (m, 2 H, 7-H, 15b-H), 5.71–5.84
(m, 1 H, 14-H), 6.92–6.95 (m, 3 H, 17-H, 17Ј-H, 19-H), 7.21–7.26
(m, 2 H, 18-H, 18Ј-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC):
δ = 23.22 and 23.88 (C-11, C-12), 25.67 (C-21), 26.34 (C-4), 28.49
(C-22), 29.92 (C-3), 45.76 (C-5), 46.24 (C-13), 46.95 (C-10), 50.63
(C-6), 59.28 (C-2), 79.51 (C-7), 115.04 (C-19), 188.87 (C-15), 121.37
(C-17, C-17Ј), 129.51 (C-18, C-18Ј), 133.90 (C-14), 154.76 (C-16),
2
3
9a-H), 3.84 (dd, JH,H = 12.2, JH,H = 4.5 Hz, 1 H, 9b-H), 3.90–
3
3.95 (m, 1 H, 2-H), 5.23 (d, JH,H = 7.3 Hz, 1 H, 7-H), 6.83–6.85
3
3
(m, 1 H, 12-H), 6.99 (t, JH,H = 7.3 Hz, 1 H, 14-H), 7.04 (d, JH,H
= 8.0 Hz, 1 H, 16-H), 7.15–7.18 (m, 1 H, 13-H), 7.25–7.29 (m, 1
H, 15-H) ppm. 13C NMR (100 MHz, CDCl3, HSQC): δ = 25.38
(C-3), 25.84 (C-4), 41.32 (C-5), 43.13 (C-8), 58.58 (C-9), 59.63 (C-
2), 79.21 (C-7), 115.39 and 115.54 (C-12, C-16), 122.06 (C-14),
129.32 and 129.51 (C-13, C-15), 157.77 (C-11), 170.29 (C-6) ppm.
157.56 (C-20), 168.42 (C-8) ppm. IR: ν = 2973 (w), 2879 (w), 1689
˜
IR: ν = 3369 (w, br.), 2953 (w), 1691 (vs), 1594 (m), 1494 (m), 1456
˜
(vs), 1636 (s), 1598 (w), 1587 (w), 1495 (m), 1438 (m), 1393 (s),
1364 (m), 1229 (m), 1169 (s), 1106 (m), 1038 (w), 998 (w), 922 (w),
875 (w), 817 (w), 754 (m), 691 (m) cm–1. HRMS (ESI): calcd. for
C24H34N2O4 415.2597; found 415.2609.
(m), 1353 (w), 1238 (s), 1171 (w), 1104 (w), 1049 (w), 884 (w), 755
(m), 692 (m) cm–1. HRMS (ESI): calcd. for C14H17NO3 270.1106;
found 270.1105.
(1S,2R,7aS)-1-Hydroxymethyl-2-phenoxypyrrolizidine (11; 2-O-
Phenylpetasinecine): Compound 10 (18 mg, 0.073 mmol) was dis-
solved in THF (1 mL), and the solution was cooled to 0 °C. A
solution of BH3·SMe2 (2 m in THF; 0.23 mL, 0.46 mmol) was
added dropwise, and then the reaction mixture was warmed to
room temperature and stirred for 12 h. The reaction was quenched
with ethanol (1 mL) and concentrated. The residue was dissolved in
water and extracted (3ϫ) with ethyl acetate. The combined organic
extracts were washed with brine, dried with MgSO4, and concen-
trated. Purification by semi-preparative HPLC gave product 11
(5 mg, 0.021 mmol, 31%) as a colourless oil. HPLC (Nucleosil 50-
5 i.d. 16ϫ250 mm): EA/hexane (3:7), 32 mL/min, 119 bar. k = 2,
tR = 1.8 min. Rf (CH/EA, 1:1) = 0.57. [α]2D6 = 57.9 (c = 0.50,
CH2Cl2). 1H NMR (600 MHz, CDCl3, COSY): δ = 1.66 (s, 1 H,
10-H), 1.95–1.99 (m, 1 H, 4a-H), 2.01–2.12 (m, 2 H, 3a-H, 4b-H),
General Procedure for the Acid-Induced Lactamisation: Thionyl
chloride (10 equiv.) was mixed with methanol, and amide 7
(1 equiv.) was added slowly. Then the solution was heated at reflux
overnight to remove the protecting group. After cooling to room
temperature, the pH was adjusted to approximately 9 with Na2CO3
(saturated aq.). The solution was heated at reflux overnight again.
The aqueous phase was extracted three times with CH2Cl2, the
combined organic extracts were dried with MgSO4, and the sol-
vents were evaporated. Crude products 8 were purified by HPLC.
For yields and data for 8a–d, see Supporting Information.
(1R,2R,7aS)-1-Ethenyl-2-phenoxypyrrolizidin-3-one (8e): Reaction
of amide 7e (1.2 g, 2.98 mmol, 1 equiv.) and thionyl chloride
(2.16 mL, 29.8 mmol, 10 equiv.) in methanol (50 mL) according to
the standard procedure. Purification by preparative HPLC [Gemini
NX 110-5 (i.d. 30ϫ250 mm, MeOH/H2O 75% + 0.35% NH4OH)] 2.25–2.31 (m, 1 H, 3b-H), 2.96–3.00 (m, 1 H, 8-H), 3.01–3.06 (m,
2
gave 8e (325 mg, 1.34 mmol, 45%) as colourless crystals. M.p. 99–
1 H, 5a-H), 3.32 (d, JH,H = 13.6 Hz, 1 H, 6a-H), 3.35–3.39 (m, 1
106 °C. Rf (CH/EA, 1:1) = 0.22. [α]2D3 = –30.7 (c = 0.99, CH2Cl2).
H, 5b-H), 3.55 (dd, 2JH,H = 13.6, 3JH,H = 4.1 Hz, 1 H, 6b-H), 3.83–
1H NMR (400 MHz, CDCl3, COSY, NOESY): δ = 1.71 (dq, JH,H 3.86 (m, 1 H, 2-H), 3.89 (dd, JH,H = 10.7, JH,H = 6.5 Hz, 1 H,
2
2
3
= 12.8, 3JH,H = 8.2 Hz, 1 H, 3a-H), 1.78–1.89 (m, 1 H, 3b-H), 1.91–
9a-H), 4.04 (dd, JH,H = 10.6, JH,H = 8.3 Hz, 1 H, 9b-H), 5.00 (t,
2
3
3
3
2.06 (m, 2 H, 4-H), 3.10–3.16 (m, 1 H, 5a-H), 3.53 (dt, JH,H
=
=
3JH,H = 4.3 Hz, 1 H, 7-H), 6.83 (d, JH,H = 8.2 Hz, 2 H, 12-H, 16-
3
2
3
3
3
10.3, JH,H = 6.0 Hz, 1 H, 8-H), 3.70 (dt, JH,H = 11.6, JH,H
H), 7.00 (t, JH,H = 7.4 Hz, 1 H, 14-H), 7.30 (t, JH,H = 7.8 Hz, 2
7.3 Hz, 1 H, 5b-H), 3.94 (dt, JH,H = 7.5, JH,H = 5.7 Hz, 1 H, 2- H, 13-H, 15-H) ppm. 13C NMR (150 MHz, CDCl3, HSQC): δ =
3
3
2
3
H), 5.02 (dd, JH,H = 1.6, JH,H = 17.0 Hz, 1 H, 10trans-H), 5.16
25.33 (C-4), 28.28 (C-3), 46.56 (C-8), 58.39 (C-9), 65.52 (C-5), 67.65
(C-6), 75.29 (C-2), 78.77 (C-7), 115.28 (C-12, C-16), 121.89 (C-14),
(dd, 2JH,H = 1.6, JH,H = 8.4 Hz, 1 H, 10cis-H), 5.17 (m, 1 H, 7-H),
3
Eur. J. Org. Chem. 2013, 4399–4404
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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