Synlett 2015; 26(17): 2381-2384
DOI: 10.1055/s-0034-1378817
cluster
© Georg Thieme Verlag Stuttgart · New York

Investigation of the Lithiation-Trapping of an N-Boc Bispidine-Ketal: Reactivity and Diastereoselectivity

Darren Stead
a   Department of Chemistry, University of York, Heslington, York YO10 5DD, UK   Email: peter.obrien@york.ac.uk
,
Peter O’Brien*
a   Department of Chemistry, University of York, Heslington, York YO10 5DD, UK   Email: peter.obrien@york.ac.uk
,
Adam Sanderson
b   Eli Lilly and Co. Ltd, Lilly Research Centre, Erl Wood Manor, Sunninghill Rd, Windlesham, Surrey, GU20 6PH, UK
› Author Affiliations
Further Information

Publication History

Received: 27 April 2015

Accepted after revision: 08 July 2015

Publication Date:
11 August 2015 (online)


This paper is dedicated to the memory of Manfred Schlosser for his numerous pioneering contributions to synthetic organometallic chemistry

Abstract

The lithiation-trapping of an N-Boc bispidine-ketal using s-BuLi/TMEDA has been studied. Key findings include an activating effect of the 4-ketal group on the lithiation and complete diastereoselectivity with methylation and Cu-mediated allylation. In contrast, reduced diastereoselectivity was noted for direct allylation and silylation; mechanistic explanations are proposed.

Supporting Information

 
  • References and Notes

  • 1 Breuning M, Steiner M. Synthesis 2008; 2841
  • 2 Grygorenko OO, Radchenko DS, Volochnyuk DM, Tolmachev AA, Komarov IV. Chem. Rev. 2011; 111: 5506
  • 3 Rouden J, Lasne M.-C, Blanchet J, Baudoux J. Chem. Rev. 2014; 114: 712
  • 4 Beak P, Lee WK. Tetrahedron Lett. 1989; 30: 1197
  • 5 Harrison J, O’Brien P. Tetrahedron Lett. 2000; 41: 6161
  • 6 Phuan P.-W, Ianni JC, Kozlowski MC. J. Am. Chem. Soc. 2004; 126: 15473
  • 7 Stead D, O’Brien P, Sanderson AJ. Org. Lett. 2005; 7: 4459
  • 8 Stead D, O’Brien P. Tetrahedron 2007; 63: 1885
  • 9 Stead D, O’Brien P, Sanderson A. Org. Lett. 2008; 10: 1409
    • 10a Kizirian J.-C, Caille J.-C, Alexakis A. Tetrahedron. Lett. 2003; 44: 8893
    • 10b Kizirian J.-C, Cabello N, Pinchard L, Caille J.-C, Alexakis A. Tetrahedron 2005; 61: 8939
  • 11 Coldham I, O’Brien P, Patel JJ, Raimbault S, Sanderson AJ, Stead D, Whittaker DT. E. Tetrahedron: Asymmetry 2007; 18: 2113
  • 12 Beak P, Lee WK. J. Org. Chem. 1993; 58: 1109
  • 13 For an example of the use of competition experiments to determine ligand effects, see: McGrath MJ, Bilke J, O’Brien P. Chem. Commun. 2006; 2607
  • 14 A higher yield of 13 could be obtained if the lithiation time was extended to 7 h: a 58% yield of 13 and a 24% yield of recovered 2 were isolated.
    • 15a Dieter RK, Oba G, Chandupatla KR, Topping CM, Lu K, Watson RT. J. Org. Chem. 2004; 69: 3076
    • 15b Dieter RK, Gore VK, Chen N. Org. Lett. 2004; 6: 763
  • 16 CCDC reference number: 1056851.
    • 17a Gawley RE, Hart GC, Bartolotti LJ. J. Org. Chem. 1989; 54: 175
    • 17b Gawley RE, Low E, Zhang Q, Harris R. J. Am. Chem. Soc. 2000; 122: 3344
    • 17c Gawley RE, Eddings DB, Santiago M, Vicic DA. Org. Biomol. Chem. 2006; 4: 4285

      Exo-face attack is precedented in the nucleophilic addition to bispidine iminium ions. See:
    • 18a Smissman EE, Ruenitz PC. J. Org. Chem. 1977; 42: 937
    • 18b Harrison J, O’Brien P. Tetrahedron Lett. 2000; 41: 6167
  • 19 CCDC reference number: 1056850
    • 20a Husmann R, Jörres M, Raabe G, Bolm C. Chem. Eur. J. 2010; 16: 12549
    • 20b Bauer JO, Stiller J, Marqués-López E, Strohfeldt K, Christmann M, Strohmann C. Chem. Eur. J. 2010; 16: 12553
    • 20c Stead D, Carbone G, O’Brien P, Campos KR, Coldham I, Sanderson A. J. Am. Chem. Soc. 2010; 131: 7260
  • 21 Gelardi G, Barker G, O’Brien P, Blakemore DC. Org. Lett. 2013; 15: 5424