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.

Key words

ring closing metathesis - Grubbs catalyst - diastereo­selective - spirocycle

References

• 1a Bassindale MJ. Hamley P. Leitner A. Harrity JPA. Tetrahedron Lett.  1999,  40:  3247 
• 1b Bassindale MJ. Edwards AS. Hamley P. Adams H. Harrity JPA. Chem. Commun.  2000,  1035 
• 1c Wybrow RAJ. Johnson LA. Auffray B. Moran WJ. Adams H. Harrity JPA. Tetrahedron Lett.  2002,  43:  7851 
• 2 Edwards AS. Wybrow RAJ. Johnstone C. Adams H. Harrity JPA. Chem. Commun.  2002,  1542 
• 3 For lead references and a recent approach to histrionicotoxin using a single RCM reaction see: Tanner D. Hagberg L. Poulsen A. Tetrahedron  1999,  55:  1427 
• 4a Wallace DJ. Cowden CJ. Kennedy DJ. Ashwood MS. Cottrell IF. Dolling U.-H. Tetrahedron Lett.  2000,  41:  2027 
• 4b Wallace DJ. Goodman JM. Kennedy DJ. Davies AJ. Cowden CJ. Ashwood MS. Cottrell IF. Dolling U.-H. Reider PJ. Org. Lett.  2001,  3:  671 
• 4c Schmidt B. Wildemann H. J. Org. Chem.  2000,  65:  5817 
• 4d Schmidt B. Westhus M. Tetrahedron  2000,  56:  2421 
• 4e Fukuda Y. Sasaki H. Shindo M. Shishido K. Tetrahedron Lett.  2002,  43:  2047 
• 4f Fukuda Y. Shindo M. Shishido K. Org. Lett.  2003,  5:  749 
• 5 Suh Y.-G. Shin D.-Y. Jung J.-K. Kim S.-H. Chem. Commun.  2002,  1064 
• 6 For a recent example see: Wright DL. Schulte JP. Page MA. Org. Lett.  2000,  2:  1847 
• For examples of catalyst dependant diastereoselectivity see:
• 7a Huwe CM. Velder J. Blechert S. Angew. Chem., Int. Ed. Engl.  1996,  35:  2376 
• 7b Lautens M. Hughes G. Angew. Chem. Int. Ed.  1999,  38:  129 

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.