Asymmetric Total Synthesis of (+)-6-epi-Castanospermine
(400 MHz, CDCl3): δ = 7.25 (d, J = 8.6 Hz, 2 H, PMP), 6.87 (d,
J = 8.6 Hz, 2 H, PMP), 6.04 (ddd, J = 17.3, 10.7, 6.6 Hz, 1 H,
Dowex 50WX-8 column (eluted with water followed by 1 NH3).
The collected product was then passed through a Dowex 1X2–400
NCH2CH=CH2), 5.94–5.84 (m, 1 H, CHCH=CH2), 5.29 (m, 1 H, column (OH– form, eluted with MeOH and then water) to afford
CHCH=CH2), 5.22 (m, 1 H, NCH2CH=CH2), 5.15 (dd, J = 17.1, 1 (10 mg, 30% over three steps) as a colorless viscous oil. 1H NMR
1.1 Hz, 1 H, CHCH=CH2 ), 5. 07 (d, J = 10. 1 Hz, 1 H, (400 MHz, D2O): δ = 4.43–4.40 (m, 1 H, 1-H), 4.02 (dd, J = 5.0,
NCH2CH=CH2), 4.67 (AB system, J = 6.7 Hz, 1 H, OCH2OCH3), 3.1 Hz, 1 H, 6-H), 3.90 (t, J = 9.6 Hz, 1 H, 8-H), 3.56 (dd, J = 9.6,
4.61 (AB system, J = 6.7 Hz, 1 H, OCH2OCH3), 4.51 (d, J = 3.5 Hz, 1 H, 7-H), 3.16–3.08 (m, 2 H, 3-H, 5-H), 2.39–2.33 (m, 1
11.6 Hz, 1 H, CH2PMP), 4.40–4.35 (m, 2 H, OCH2OCH3, H, 2-H), 2.30 (dd, J = 12.5, 1.8 Hz, 1 H, 5-H), 2.17 (q, J = 9.1 Hz,
CH2PMP), 4.10 (q, J = 6.0 Hz, 1 H, 3-H), 3.81 (s, 3 H, ArOMe),
3.61 (dd, J = 13.6, 5.0 Hz, 1 H, NCH2CH=CH2), 3.36 (s, 3 H,
OCH2OCH3), 3.15 (ddd, J = 9.6, 7.2, 4.0 Hz, 1 H, 5-H), 2.85 (dd,
1 H, 3-H), 1.94 (dd, J = 9.6, 4.4 Hz, 1 H, 8a-H) 1.75 (dtd, J = 14.3,
9.0, 2.0 Hz, 1 H, 2-H) ppm. 13C NMR (100 MHz, D2O): δ = 77.3,
73.6, 72.1, 70.8, 69.2, 57.2, 53.6, 34.6 ppm. [α]2D0 = +6 (c = 0.84,
J = 13.8, 7.9 Hz, 1 H, NCH2CH=CH2), 2.78 (dd, J = 6.6, 3.9 Hz, MeOH) {ref.[4d,4g] [α]2D0 = +2.2 (c = 0.7, MeOH)}. HRMS (ESI):
1 H, 5-H), 2.24 (q, J = 7.4 Hz, 1 H, 2-H), 1.97–1.82 (m, 2 H, 4-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 137.3, 136.0,
130.7, 129.3, 116.5, 116.3, 113.6, 94.7, 79.4, 77.5, 70.9, 70.0, 58.6,
calcd. for C8H16O4N [M + H]+ 190.1074; found 190.1075.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for compounds 1, 3, 4a, 5, 6, 8, 9,
55.5, 55.2, 50.8, 30.1 ppm. IR: ν = 2881, 1613, 1513, 1441, 1354,
˜
10, 11 and 12.
1301, 1246, 1149, 1112, 1034, 915, 820 cm–1. [α]2D0 = +61.5 (c =
0.97, CHCl3). HRMS (ESI): calcd. for C20H30O4N [M + H]+
348.2169; found 348.2163.
Acknowledgments
(+)-(1S,8S,8aR)-1-(4-Methoxybenzyloxy)-8-(methoxymethoxy)-
1,2,3,5,8,8a-hexahydroindolizine (12): Grubbs II catalyst (212 mg,
0.25 mmol) was added to a solution of N-allylamine 11 (823 mg,
2.40 mmol) in toluene (140 mL) and the mixture was heated at
100 °C. After 2 h, a second portion of the catalyst (212 mg,
0.25 mmol) was added and the mixture was heated at reflux for
an additional 2 h. The mixture was then allowed to cool to room
temperature and the solvents were evaporated. Purification of the
residue by flash chromatography on silica gel (50–70% EtOAc/cy-
clohexane) afforded 12 (601 mg, 80%) as a brown oil. 1H NMR
(400 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H, PMP), 6.84 (d, J
= 8.8 Hz, 2 H, PMP), 5.82–5.75 (m, 2 H, 6-H, 7-H), 4.73 (d, J =
6.6 Hz, 1 H, OCH2OCH3), 4.66–4.62 (m, 2 H, OCH2OCH3, 8-H),
4.54 (AB system, J = 11.4 Hz, 1 H, CH2PMP), 4.33 (AB system, J
= 11.4 Hz, 1 H, CH2PMP), 4.17–4.13 (m, 1 H, 1-H), 3.78 (s, 3 H,
ArOMe), 3.44 (d, J = 16.9 Hz, 1 H, 5-H), 3.35 (s, 3 H, OCH2-
OCH3), 3.28–3.23 (m, 1 H, 3-H), 2.70 (d, J = 16.4 Hz, 1 H, 5-H),
2.24–2.15 (m, 2 H, 3-H, 8a-H), 2.10–2.03 (m, 1 H, 2-H), 1.98–1.90
(m, 1 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 130.5,
129.4, 128.1, 126.6, 113.6, 96.7, 76.9, 72.3, 70.3, 68.5, 55.4, 55.3,
We are grateful to the Centre National de la Recherche Scientifique
(CNRS) and GlaxoSmithKline for a Ph. D. grant (to J. L.).
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53.0, 52.3, 29.4 ppm. IR: ν = 2935, 1613, 1514, 1442, 1301, 1248,
˜
1147, 1123, 1036, 990, 915, 821, 692 cm–1. [α]2D0 = +75.0 (c = 0.11,
CHCl3). HRMS (ESI): calcd. for C18H26O4N [M + H]+ 320.1856;
found 320.1846.
(+)-(1S,6R,7R,8R,8aR)-Octahydroindolizine-1,6,7,8-tetraol [(+)-6-
epi-Castanospermine] (1): OsO4 (2.5 wt.% in tert-butyl alcohol,
225 µL, 0.02 mmol) followed by NMO (28 mg, 0.24 mmol) was
added to a solution of 12 (70 mg, 0.22 mmol) in a mixture of ace-
tone (2.1 mL) and water (0.1 mL) at 0 °C. The mixture was stirred
at 0 °C for 3 h and quenched with Na2SO3 (1 g). After stirring for
1 h of at room temp., the solvents were evaporated in vacuo and
the resulting mixture was filtered through a short pad of silica gel
(eluting with 10% MeOH/EtOAc). The solvents were evaporated
and the crude product was used in the next step without further
purification.
HCl (4 in 1,4-dioxane, 210 µL, 0.85 mmol) was added to a solu-
tion of crude product (30 mg, 0.09 mmol) in MeOH (5 mL) and
the mixture was heated at reflux for 2 h. The solvents were then
evaporated and the residue was taken up in MeOH (5 mL) and Pd/
C (10wt.-% on calcium carbonate, 30 mg) was added. The flask
was purged with H2 (ϫ3) and the mixture was stirred overnight at
room temp. under H2 (1 atm). It was then filtered through Celite
and the filtrate was evaporated. The residue was passed through a
Eur. J. Org. Chem. 2010, 2921–2926
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