Investigation of Diastereoselective Tandem Ring Closing Metathesis Reactions Toward the Synthesis of Functionalised Spirocyclic Piperidines

Abstract

The stereoselective synthesis of a spiropiperidine through a diastereoselective tandem ring closing metathesis (RCM) reaction is reported. The efficient relay of stereochemistry from a pentyl chain to the newly formed spirocentre three carbon atoms away was found to be particularly dependant on the nature of the Ru-catalyst employed - 1st generation Grubbs catalyst was found to be significantly more selective than the more active 2nd generation carbene complexes.

ring closing metathesis - Grubbs catalyst - diastereo­selective - spirocycle

References

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8

Experimental Procedure for the Synthesis of 2,2,2-Trifluoro-1-(2-pentyl-1-aza-spiro[5.5]-undeca-4,7-dien-1-yl)-ethanone ( 13): To a solution of tetraene 12 (50 mg, 0.14 mmol) in CH₂Cl₂ (0.5 ml) was added Ru-catalyst I (11.5 mg, 0.014 mmol). The reaction was heated at reflux for 16 h, allowed to cool and the solvent removed in vacuo. Purification of the resulting residue by silica gel chromatography (100:1 hexanes:EtOAc) afforded spirocycle 13 as a colourless oil (42 mg, 99%). ¹H NMR (250 MHz, C₆D₆): δ = 0.66 (3 H, t, J = 7.0 Hz), 0.73-2.08 (15 H, m), 2.26-2.50 (1 H, m), 3.67-3.85 (1 H, br m), 4.87-4.96 (1 H, m), 5.05 (1 H, ddd, J = 10.0, 7.0, 2.5 Hz), 5.34 (1 H, dd, J = 10.5, 2.5 Hz), 5.51 (1 H, ddd, J = 10.0, 5.5, 2.5 Hz). ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.9, 19.9, 22.5, 23.3, 26.5, 27.2, 30.6, 31.6, 34.5, 52.3, 59.2, 116.5 (q, J = 289 Hz), 118.4, 127.1, 130.1, 130.4, 155.4 (q, J = 35 Hz). FT-IR (film): 2933 (s), 2871 (m), 1694 (s), 1201 (s), 1136 (s)cm^-1. HRMS: calcd for C₁₇H₂₅NOCF₃ (MH⁺): 316.1888. Found: 316.1889.