C8H10ClNO2: C, 51.21; H, 5.37; N, 7.47. Found: C, 50.80; H,
5.65; N, 6.86.
1.91 (m, 2 H), 1.95-2.08 (m, 1 H), 2.57 (dd, J ) 11.2, 7.6, 1 H),
2.78 (dd, J ) 11.2, 1.4, 1H), 2.91 (br d, J ) 11.1, 1H), 3.61 (dd,
J ) 8.7, 4.0, 1H), 4.01 (m, 1H). 13C NMR (CDCl3): δ 24.0, 24.8,
28.7, 53.5, 61.7, 70.0, 77.1, 84.8. 11b. 1H NMR (CDCl3): δ 1.25-
1.75 (m, 5 H), 1.80-1.89 (m, 1 H), 2.03-2.14 (m, 2H), 2.25 (m,
1H), 2.90-3.13 (m, 3H), 3.54 (dd, J ) 9.6, 7.3, 1H), 3.83 (d, J )
4.1, 1H), 4.21 (m, 1H). 13C NMR (CDCl3): δ 23.9, 24.5, 25.0,
53.5, 61.7, 66.7, 77.5, 80.5.
(1S,2R,8aR)-1,2-Dihydroxyoctahydro-1H-indolizinium Chlo-
ride (6). A solution of (1S,2R)-1,2-dihydroxy-2,3-dihydro-1H-
indolizinium chloride 5 (240 mg, 1.28 mmol) in ethanol (20 mL)
was stirred overnight at room temperature in the presence of PtO2·
H2O (41.8 mg, 10% mol) under an atmospheric pressure of
hydrogen. Filtration through a Celite pad and evaporation in vacuo
afforded compound 6 (231 mg, 93% yield) as a white powder. 1H
NMR (D2O): δ 1.4-2.1 (m, 6H), 2.9 (t, J ) 11.8, 1H), 3.2 (d, J
) 11.7, 1H), 3.6 (m, 1H), 3.4 (m, 2, 2H), 4.3 (t, J ) 2.1, 2H), 4.6
(m, 1H). 13C NMR (CDCl3): δ 21.6, 23, 23.1, 52.5, 57.8, 68.2,
69.3, 70.6. [R]D ) - 25 (c 1, CH3OH). IC(+)MS (MH+) m/z )
158 (100%). Anal. Calcd for C8H16ClNO2: C, 49.61; H, 8.33; N,
7.23. Found: C, 49.12; H, 8.39; N, 6.96.
(1R)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(pyridin-2-yl)]m-
ethyl 4-Methylbenzoate (12). To a solution of compound 2 (113
mg, 0.54 mmol) and p-toluoyl chloride (94 µL, 0.7 mmol) in
dichloromethane (15 mL) was added pyridine (0.13 mL, 1.62 mmol)
at 0 °C, and then the mixture was stirred for 4 h at room
temperature. The solution was evaporated, and the residue was
purified by flash chromatography. Eluting with EtOAc/cyclohexane
1
(1S,2R,8aR)-Indolizidine-1,2-diol (7).20 The hydrochloride 6
(180 mg, 0.93 mmol) was dissolved in saturated KOH (10 mL)
and extracted with THF (3 × 15 mL). Drying over K2CO3 followed
by solvent evaporation afforded compound 7 (139 mg, 95%) as a
white powder. 1H NMR (CDCl3): δ 1.20 (m, 1H), 1.51-1.89 (m,
7H), 2.26 (m, 1H), 2.91 (d, J ) 10.7, 1H), 3.01 (d, J ) 10.7, 1H),
3.60-3.90 (br s, 2H), 3.96 (s, 1H), 4.19 (s, 1H). 13C NMR
) 1/2 provided 12 (164 mg, 93%) as a colorless oil. H NMR
(CDCl3): δ 1.4 (s, 3H), 1.5 (s, 3H), 2.4 (s, 3H), 4 (m, 2H), 4.8 (q,
J ) 6.2, 1H), 6.1 (d, J ) 5.6, 1H), 7.2 (dd, J ) 5.2, 7.6, 1H), 7.24
(d, J ) 8.2, 2H), 7.4 (d, J ) 7.6, 1H), 7.7 (dt, J ) 1.5, 7.7, 1H),
8.0 (d, J ) 8.2, 2H), 8.6 (d, J ) 5.2, 1H). 13C NMR (CDCl3): δ
21.8, 25.5, 26.6, 66, 76.9, 77, 110.1, 122.1, 123.2, 127.1, 129.2,
130, 136.8, 144.1, 149.4, 156.9, 166. IC(+)MS (MH+) m/z ) 328
(100), 270. HRMS for C19H22NO4 (MH+): 328.1549, found
328.1567.
(CDCl3): δ 23.9, 24.9, 25.0, 53.5, 62.8, 68.4, 69.4, 72.3. [R]D
)
-36 (c 1, CH3OH) (lit.20a [R]D ) - 37.1, c 0.55, CH3OH).
2-[(1R,2R)-2,3-Dihydroxy-1-(4-methylbenzoyloxy)propyl]py-
ridinium Chloride (13). Applying the procedure described for
compound 4, acetonide 12 afforded pure diol 13 (139 mg, 90%) as
2-((1R,2R)-1,2,3-Trihydroxypropyl)pyridinium Chloride (8).
Applying the procedure described for compound 4, acetonide 2 (200
mg, 0.96 mmol) afforded pure triol 8 (195 mg, 99%) as a white
powder. 1H NMR (D2O): δ 3.66 (m, 1H), 3.79 (dd, J ) 11.5, 5.5,
1H), 4.0 (dt, J ) 5.6, 2.5, 1H), 5.28 (d, J ) 2.25, 1H), 7.96 (t, J
) 6.9, 1H), 8.04 (d, J ) 8.28, 1H), 8.54 (dt, J ) 7.9, 1.3, 1H),
8.68 (d, J ) 5.6, 1H). 13C NMR (D2O): δ 62.2, 69.9, 74.2, 125.2,
126.3, 140.7, 147.1, 156.2. [R]D ) -19 (c 1, CH3OH). IC(+)MS
(MH+) m/z ) 226, 212, 170 (100). Anal. Calcd for C11H15NO3:
C, 46.73; H, 5.88; N, 6.81. Found: C, 46.44; H, 5.92; N, 6.38.
(1R,2R)-1,2-Dihydroxy-2,3-dihydro-1H-indolizinium Chloride
(9). Starting from triol 8 (160 mg, 0.78 mmol), the protocol
described for compound 5 gave pure pyridinium 9 (143 mg, 98%)
as a white powder. 1H NMR (CDCl3,): δ 4.62 (dd, J ) 12.9, 5.9,
1H), 4.73 (dd, J ) 11.9, 5.6, 1H), 5.08 (dd, J ) 13, 6.3, 1H), 5.38
(d, J ) 5.5, 1H), 8.0 (t, J ) 6.7, 1H), 8.12 (d, J ) 7.9, 1H), 8.55
(t, J ) 7.8, 1H), 8.79 (d, J ) 6.2, 1H). 13C NMR (CDCl3): δ 61.4,
74.6, 77.9, 125.2, 128, 141.7, 147, 156.5.[R]D ) -19 (c 1, CH3-
OH). IE (70 eV) (M+) m/z ) 152 (100), 131, 122, 114, 99. Anal.
Calcd for C11H15NO3: C, 51.21; H, 5.37; N, 7.47. Found: C, 50.98;
H, 5.25; N, 7.06.
(1R,2R,8aR)-Octahydroindolizine-1,2-diol Hydrochloride (10a)
and (1R,2R,8aS)-Octahydroindolizine-1,2-diol Hydrochloride
(10b). Using the same procedure described for compound 6, the
pyridinium salt 9 (111 mg, 0.59 mmol) provided 10a + 10b (111
mg, 97%) as a white powder.
(1R,2R,8aR)-Octahydroindolizine-1,2-diol (11a) and (1R,2R,-
8aS)-Octahydroindolizine-1,2-diol (11b).21 The hydrochloride 10
(61 mg, 0.32 mmol) was dissolved in saturated KOH (5 mL) and
extracted with THF (3 × 10 mL). Drying over K2CO3 followed by
solvent evaporation afforded a mixture of diastereomers 11a and
11b in a 0.8:1 ratio (47 mg, 96%). 11a. 1H NMR (D2O): δ 1.16-
1.42 (m, 3H), 1.58-1.67 (m, 1 H), 1.76-1.82 (m, 1 H), 1.87-
1
a white powder. H NMR (D2O): δ 2.4 (s, 3H), 3.8 (m, 2H), 4.2
(d, J ) 3.1, 1H), 6.3 (d, J ) 3.1, 1H), 7.4 (d, J ) 8.0, 2H), 7.9 (t,
J ) 6.6, 1H), 8.0 (d, J ) 8.0, 2H), 8.1 (d, J ) 7.9, 1H), 8.5 (t, J
) 7.9, 1H), 8.7 (d, J ) 4.9, 1H). 13C NMR (D2O): δ 21.2, 61.9,
72.7, 73.6, 125.2, 125.7, 126.8, 129.8, 130.3, 142.7, 146.6, 146.7,
152.1, 167. IC(+) MS (M+ without chloride ion) m/z ) 288 (100),
282. Anal. Calcd for C16H18ClNO4: C, 59.35; H, 5.60; N, 4.33.
Found: C, 59.01; H, 5.65; N, 4.21.
(1R,2R)-2-Hydroxy-1-(4-methylbenzoyloxy)-2,3-dihydro-1H-
indolizinium Chloride (14). Starting from diol 13 (127 mg, 0.39
mmol), the protocol described for compound 5 gave pure pyridinium
1
14 (118 mg, 99%) as a white powder. H NMR (D2O): δ 2.4 (s,
3H), 3.8 (m, 2H), 4.2 (d, J ) 3.7, 2H), 5.1 (m, 1H), 5.3 (dd, J )
5.9, 13.5, 1H), 6.6 (d, J ) 3.1, 1H), 7.4 (d, J ) 8.2, 2H), 7.9 (d,
J ) 8.3, 2H), 8.1 (dd, J ) 6.6, 7.9, 1H), 8.3 (d, J ) 7.9, 1H), 8.6
(t, J ) 8.9, 1H), 9 (d, J ) 6.6, 1H).
(1R,2R,8aS)-2-Hydroxy-1-(4-methylbenzoyloxy)octahydro-
1H-indolizinium Chloride (15). Using the same procedure de-
scribed for compound 6, the pyridinium salt 14 (80 mg, 0.26 mmol)
provided compound 15 (77 mg, 95% yield) as a white powder. 1H
NMR (D2O): δ 1.4-2.1 (m, >6H, solvent impurities), 2.4 (s, 3H),
3.1 (m, 2H), 3.7 (m, 2H), 4.1 (dd, J ) 6.9, 12.9, 1H), 4.5 (t, J )
12.6, 1H), 5.3 (d, J ) 3.5, 1H), 7.3 (d, J ) 8, 2H), 7.9 (d, J ) 8,
2H). 13C NMR (D2O): δ 21.2, 21.7, 23, 23.3, 53.7, 58.8, 67.2,
72.1, 79.4, 125.5, 129.8, 130.1, 146.2, 167.1.
Acknowledgment. Dr. Christian Montalbetti (Evotec, U.K.)
is gratefully acknowledged for fruitful discussions. We thank
also Laetitia Bailly for analytical analysis.
Supporting Information Available: General experimental,
1
details, detailed procedures for the preparation of 1-15, and H
(20) (a) Paolucci, C.; Mattioli, L. J. Org. Chem. 2001, 66, 4787. (b)
Harris, T. M.; Harris, C. M.; Hill, J. E.; Ungemach, F. S. J. Org. Chem.
1987, 52, 3094.
(21) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1995, 60, 398.
and 13C NMR and MS spectra for each intermediate. This material
JO702141B
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