5,6-Dihydroindolizines as Convenient Precursors of Indolizidine 167B and Analogues

Abstract

Starting from 5-carboxyethyl-5,6-dihydroindolizine, the title alkaloid was obtained in 25% overall yield via differently C5-substituted 5,6-dihydroindolizines and final exhaustive hydrogenation. An alternative strategy for the synthesis of optically active indolizidine 167B and analogues still based on 5,6-dihydroindolizine intermediates is given.

Keywords - (-)-indolizidine 167B - 5,6-dihydroindolizines - synthesis - 4-(pyrrol-1-yl)butanal - enantioselective hydrogenation

References

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12

Chiral gas chromatography was performed on chiral capillary column CHIRALDEX G-TA (γ-cyclodextrin trifluoroacetyl, 50 m × 0.25 mm).

13

The evaluation of ee of the olefin (-)-6′ was accomplished by transforming it into the new partially hydrogenated 5-ethyl-5,6,7,8-tetrahydroindolizine (8; Scheme [2] ) which, unlike 6′, was separated into its enantiomers by chiral gas chromatography [CHIRALDEX G-TA (γ-cyclodextrin trifluoroacetyl, 50 m × 0.25 mm) capillary column]. The chromatographic conditions were set up for analysing a racemic sample of 8 ¹⁴ prepared in the same manner. The compound 8 showed the same ee value as the starting aldehyde 5. This result gives evidence that the vinyl group hydrogenation as well as the endocyclic double bond hydrogenation do not influence the configuration of the asymmetric centre, accounting for the internal bond formation in the alkyl chain of 6, and not for its hydrogenation, as the sole step responsible for racemisation observed in the synthesis of (-)-indolizidine 167B.

14

Selected data for 8: ¹H NMR: δ = 6.67 (br s, 1 H), 6.15 (t, J = 3.1 Hz, 1 H), 5.81 (br s, 1 H), 3.94 (m, 1 H), 2.75 (m, 2 H), 2.07 (m, 2 H), 1.91 (m, 2 H), 1.68 (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H).
MS: m/z = 149 (78) [M⁺], 121 (43), 120 (100), 106 (15), 93 (14), 80 (14), 65 (7).

15

The ee evaluation was accomplished via GC chiral gas chromatography under the same analytical conditions previously adopted for the same substrate prepared in an alternative way.¹⁶