Chemo- and Diastereoselective Oxidation

The treatment of unsaturated amines with electrophiles presents issues with chemoselectivity as the nitrogen lone pair and the olefinic bond are both potential sites for reaction. We have developed a range of methodologies to combat this problem and developed several stereoselective processes, such as the chemo- and diastereoselective oxidation protocol described below, that have proven useful in total synthesis.

There is sometimes a chemoselectivity issue associated with functionalisation of allylic amines as electrophiles often react preferentially with the (more nucleophilic) N-lone pair. We have demonstrated that treatment of allylic amines with trichloroacetic acid [Cl3CCO2H] followed by mCPBA gives the corresponding α-hydroxy trichloroacetate ester as the major product with no evidence of competing N-oxide formation. This outcome is consistent with initial protonation of the amine by the acid, which has the dual effect of rendering the nitrogen non-nucleophilic since it is protected as the ammonium ion, whilst simultaneously generating a species capable of acting as a hydrogen-bond donor. Attack of the peracid is then hydrogen-bond directed to give the corresponding epoxide. Ring-opening of the epoxide by the trichloroacetic acid gives the α-hydroxy trichloroacetate ester. This metal free sequence of reactions leads to very highly diastereoselective transformations in cyclic systems.
 

Ammonium directed oxidation
 

The propensity of allylic amines to undergo initial N-oxidation is not necessarily detritic. We have demonstrated that the oxidation of allylic N-oxides constitutes a useful process that is complementary to the ammonium-directed process. Oxidation of 3-N,N-dibenzylaminocyclohex-1-ene N-oxide in the presence of Cl3CCO2H proceeds with high levels of anti-diastereoselectivity (98:2 dr), with no competing side reactions.
 

Diastereoselective oxidation of an allylic N-oxide
 

Key Publications:

  1. Syntheses of dihydroconduramines (±)-B-1, (±)-E-1 and (±)-F-1 via diastereoselective epoxidation of
    N-protected 4-aminocyclohex-2-en-1-ols
    Brennan, M.; Csatayová, K.; Davies, S. G.; Fletcher, A. M.; Green, W. D.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. J. Org. Chem. 201580, 6609 [View Journal Page]
  2. Epoxidation of trans-4-aminocyclohex-2-en-1-ol derivatives: competition of hydroxyl-directed and ammonium-directed pathways
    Brennan, M. B.; Davies, S. G.; Fletcher, A. M.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.
    Aust. J. Chem. 201568, 610 [View Journal Page]
  3. Hydrogen bond directed epoxidation: diastereoselective olefinic oxidation of allylic alcohols and amines
    Davies, S. G.; Fletcher, A. M.; Thomson, J. E. Org. Biomol. Chem. 201412, 4544 [View Journal Page]
  4. Ammonium-directed olefinic oxidation: kinetic and mechanistic insights
    Brennan, M. B.; Claridge, T. D. W.; Compton, R. G.; Davies, S. G.; Fletcher, A. M.; Henstridge, M. C.; Hewings, D. S.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Schoonen, A. K.; Thomson, J. E. J. Org. Chem. 2012, 77, 7241 [View Journal Page]
  5. Ammonium-directed oxidation of cyclic allylic and homoallylic amines
    Bond, C. W.; Cresswell, A. J.; Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735 [View Journal Page]
  6. Highly diastereoselective anti-dihydroxylation of 3-N,N-dibenzylamino-cyclohex-1-ene N-oxide
    Aciro, C.; Davies, S. G.; Kurosawa, W.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Lett. 2009, 11, 1333 [View Journal Page]
  7. Ammonium directed dihydroxylation: metal-free synthesis of the diastereoisomers of 3-amino-cyclohexane-1,2-diol
    Aciro, C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762 [View Journal Page]
  8. Ammonium directed dihydroxylation of 3-amino-cyclohex-1-enes: development of a metal-free dihydroxylation protocol
    Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751 [View Journal Page]



     

 

 

 


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