Synthesis of a Racemic Nicotine-Lobeline Hybrid

Abstract

The first synthesis of a racemic nicotine-lobeline hybrid is described based on a diastereoselective allylation and an RCM ­reaction as key steps. This synthetic route paves the way to the preparation of original potential ligands of nAChRs.

alkaloids - ring-closing metathesis - total synthesis - neuronal nicotinic acetylcholine receptors

References and Notes

1

Present address: Université de Bordeaux, Institut des Sciences Moléculaires, UMR-CNRS-5255, 351 Cours de la Libération, 33405 Talence, France.

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20

Selected Physico-Chemical Data for Compound 6
^¹H NMR (300 MHz, CDCl₃): δ = 8.39-8.46 (m, 2 H), 7.57-7.64 (m, 1 H), 7.15-7.22 (m, 1 H), 7.13-7.34 (m, 5 H), 5.18 (dd, 1 H, J = 3.0, 11.5 Hz), 2.99 (dd, 1 H, J = 3.0, 11.2 Hz), 2.46-2.57 (m, 1 H), 2.26 (ddd, 1 H, J = 3.6, 11.2, 15.1 Hz), 2.16 (s, 3 H), 2.04 (dq, 1 H, J = 3.2, 12.5 Hz), 1.65-1.87 (m, 3 H), 1.46-1.58 (m, 2 H), 1.35-1.49 (m, 1 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 149.0, 148.8, 145.1, 140.1, 134.4, 128.3 (2×), 127.0, 125.5 (2×), 124.0, 71.9, 68.4, 63.7, 41.4, 39.9, 36.2, 29.9, 24.2 ppm. HRMS (CI): m/z calcd for C₁₉H₂₅N₂O [M + H⁺]: 297.1961; found: 297. 1967.

21

Selected Physico-Chemical Data for Compound 7
^¹H NMR (300 MHz, CDCl₃): δ = 8.58 (br s, 1 H), 8.52 (br d, 1 H, J = 4.6 Hz), 8.02 (dm, 2 H, J = 7.4 Hz), 7.66-7.82 (m, 1 H), 7.56-7.65 (m, 1 H), 7.46-7.56 (m, 2 H), 7.22-7.31 (m, 1 H), 3.42-3.57 (m, 1 H), 3.10-3.22 (m, 1 H), 2.84-3.07 (m, 2 H), 2.01 (s, 3 H), 1.70-1.88 (m, 3 H), 1.47-1.66 (m, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 199.2, 149.3, 148.5, 148.4, 137.2, 134.8, 133.2, 128.7 (2 C), 128.2 (2 C), 123.6, 68.2, 60.5, 44.6, 40.9, 36.1, 32.9, 24.4 ppm. HRMS (CI): m/z calcd for C₁₉H₂₃N₂O [M + H⁺]: 295.1805; found: 295.1810.