Chiral Methyl 7,8,9-Trichloro-6,7,8,9-tetrahydro-5-oxopyrido-[2,3-a]indolizine-10-carboxylates (OPIC)

The 3,3'-dihydoxycarbonyl-2,2'-bipyridine acid 1 used for the preparation of diastereoisomeric compounds 2a-b has been obtained by described method of Blau [1].

Procedure A: To 10 mL of clean thionyl chloride (new bottle without further distillation), were added 600 mg (2.5 mmol) of 3,3'-dihydroxycarbonyl-2,2'-bipyridine 1 and the mixture was refluxed for 5 h. Then the excess of SOCl₂ was removed under vacuum to leave an unstable yellow residue [1]. 20 mL of toluene and then 1 mL of MeOH were added and the solution was heated at reflux for 3 h. 40 mL of chloroform were added and the organic phase was washed with a cooled solution of sodium hydrogen carbonate (2.5%), and then dried on sodium sulfate. The crude product was chromatographed on silica column. Only compound 3 was obtained as product of reaction (55-60%); the rest is the unreacted stating material 1.

Procedure B: When we used an old bottle of SOCl₂, in the same conditions (procedure A), three white solids were successively obtained: a mixture of petroleum ether/dichloromethane 10/90 eluted first compound 2a (310 mg, 31 %), and then in the ratio 5/95 derivative 2b (70 mg, 7%) was recovered; and finally with ether/acetone 40/60, the diester 3 (450 mg, 52%) was eluted, which has been described elsewhere [2].

Compound 2a: methyl (7S,8R,9S)-7,8,9-trichloro-5-oxo-5,7,8,9-tetrahydropyrido-[2,3-a] indolizine-10-carboxylate (Labelling used for NMR assignments)

m.p. = 121-122 °C; Analysis Calc. (Found) for C₁₃H₉N₂O₃Cl₃: C 44.94 (44.98), H 2.59 (2.63), N 8.06 (7.99); Mass spectrum : m/z = 347.0 (Calc. for C₁₃H₉N₂O₃Cl₃: 346.60); IR (KBr) n cm^-1: 1744 (C=O, s), 1717 (C=O, s), 1601,1581 (C=C, w), 1434 (C=N, m), 1297 (C-O, w); ¹H NMR (250.14 MHz; CDCl₃) d ppm: 8.9 (dd, H₂, ³J_H2-H3 = 4.9 Hz, ⁴J_H2-H4 = 1.6 Hz), 8.2 (dd, 1 H, H₄,³J_H4-H3 = 7.8 Hz,⁴J_H4-H2 = 1.6 Hz), 7.53 (dd, 1 H, H₃, ³J_H3-H4 = 7.8 Hz, ³J_H3-H2 = 4.9 Hz), 6.49 (dd, 1 H, H₇, ³J_H7-H8 = 1.33 Hz, ⁴J_H7-H9 = 2.1 Hz), 5.35 (t, 1 H, H₈, ³J_H8-H7 = 1.33 Hz, ³J_H8-H9 = 1.33 Hz), 5.03 (dd, 1 H, H₉, ³J_H9-H8 = 1.33 Hz,⁴J_H7-H9 = 2.1 Hz), 4.0 (s, 3 H, CH₃).

Compound 2b: methyl (7R,8R,9S)-7,8,9-trichloro-5-oxo-5,7,8,9-tetrahydropyrido-[2,3-a]-indolizine-10-carboxylate

Mass spectrum : m/z = 347.0 (Calc. for C₁₃H₉N₂O₃Cl₃: 346.60); ¹H NMR (200.131 MHz; CDCl₃) d ppm: 8.86 (dd, 1 H, H₂, ³J_H2-H3 = 4.9 Hz, ⁴J_H2-H4 = 1.6 Hz), 8.14 (dd, 1 H, H₄, ³J_H4-H3 = 7.8 Hz, ⁴J_H4-H2 = 1.6 Hz), 7.48 (dd, 1 H, H₃, ³J_H3-H4 = 7.8 Hz, ³J_H3-H2 = 4.9 Hz), 6.47 (d,1 H, H₈, ³J_H8-H9 = 3 Hz), 5.26 (d, 1 H, H₁₀, ³J_H10-H9 = 9.8 Hz), 4.52 (dd, 1 H, H₉, ³J_H9-H8 = 3.05 Hz, ³J_H9-H10 = 9.75 Hz), 3.96 (s, 3H, CH₃).