Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo- and regio- selective study

Derek R. Boyd, Narain D. Sharma, Tayeb Belhocine, John F. Malone, Stuart T. McGregor, Jordan Atchison, Peter A. B. McIntyre, Paul J. Stevenson*

*Corresponding author for this work

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5 Citations (Scopus)

Abstract

The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S(N)2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S(N)2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S(N)2 and S(N)2 reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S(N)2 mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S(N)2 mechanism. 

Original languageEnglish
Pages (from-to)997-1008
Number of pages12
JournalJournal of Physical Organic Chemistry
Volume26
Issue number12
Early online date14 Aug 2013
DOIs
Publication statusPublished - Dec 2013

Keywords

  • dihydrodiols
  • vinyl epoxides
  • bromoacetates
  • S(N)2
  • sigmatropic rearrangement mechanisms
  • CHEMOENZYMATIC TOTAL-SYNTHESIS
  • ARENE OXIDATION-PRODUCT
  • BIASED 3,3-SIGMATROPIC REARRANGEMENT
  • ASYMMETRIC ALLYLIC ALKYLATION
  • BENZENE CIS-1,2-DIHYDRODIOLS
  • SUBSTITUTION-REACTIONS
  • INHIBITORY-ACTIVITIES
  • AZIDE REARRANGEMENT
  • EFFICIENT SYNTHESIS
  • BUILDING-BLOCKS

Cite this

Boyd, D. R., Sharma, N. D., Belhocine, T., Malone, J. F., McGregor, S. T., Atchison, J., McIntyre, P. A. B., & Stevenson, P. J. (2013). Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo- and regio- selective study. Journal of Physical Organic Chemistry, 26(12), 997-1008. https://doi.org/10.1002/poc.3183