Facile preparation of α-amino ketones from oxidative ring-opening of aziridines by pyridine -oxide rg. Biomol. Chem., 2007, 5, 3428 Luo, Z.-B.; Wu, J.-Y.; ou, X.-L.; Dai, L.-X. Ts toluene Ts 80 o C John Maciejewski Current literature 01/05/08 John Maciejewski @ Wipf Group 1 2/17/2008
α-amino ketones F Et 2 (S)-2-amino-1-phenylpropan-1-one atural product found in leaves of Catha edulis Forsk upintrivir Shown to treat symptoms assoc. with common cold J. rg. Chem. 1994, 59, 8288 Tetrahedron: Asymmetry 2005, 16, 699 2 Cl Active against brucellosis (Malta fever) AAC 2007, 51, 3752 Caspase-3 Potent caspase inhibitors K i values Caspase-7 0.2 nm 4.0 nm rg. Lett. 2005, 7, 3529 John Maciejewski @ Wipf Group 2 2/17/2008
α-amino ketone preparation ften important synthetic intermediates Boc 2 Synthesis 2007, 1, 55 (-)-aphanorphin ' key synthetic intermediate (D)-tyrosine Begin from chiral pool ther methodologies include the following: 3 C C 3 C 2 Et 1) Br 2 2) (C 3 ) 2 DEAD cat.* C 2 Et J. et. Chem. 1984, 21, 1509 rg. Lett. 2007, 9, 3671 Cinchona alkaloids afford α amino ketones in high enantioselectivity John Maciejewski @ Wipf Group 3 2/17/2008
Preparation of -oxides Mild oxidants, easily prepared MMPP* ucl 3 (cat.) 2 *magnesium monoperoxyphthalate J. rg. Chem., 2007, 72, 6653 Chem. Commun., 2002, 1040 ther methods of -oxide preparation include use of peracids, 2 2, and 2 with catalysts 1 3 2 conditions 1 3 2 Synthesis 1993, 3, 263 (and references therein) ~71 kcal/mol J. Chem. Thermodynamics 1995, 27, 391 John Maciejewski @ Wipf Group 4 2/17/2008
Applications for -oxides and not to be confused with -oxide (TMA) -oxide (M) nitroxyl free radical (TEMP) s 4 /M Upjohn dihydroxylation TPAP/M Ley oxidation Br DMS/TMA Ganem oxidation -oxides used to regenerate transition metal catalysts John Maciejewski @ Wipf Group 5 2/17/2008
Applications for oxides of sulfur Br DMS B S [2,3] Br S Kornblum oxidation J. Am. Chem. Soc., 1957, 79, 6562 B Applications with aziridines 1 2 C 2 3 DMS S 2 1 C 2 3 2 C 2 3 1 SMe 2 Tetrahedron 1970, 26, 4347 Aziridine opened with DMS, followed by loss of SMe 2 to afford amino ketone Drawbacks: DMS is often difficult to remove, in addition to noxious byproduct (SMe 2 ) John Maciejewski @ Wipf Group 6 2/17/2008
xidative ring-opening of aziridines ecent advances Ts IBX!-CD Ts J. rg. Chem., 2003, 68, 9119 IBX promotes amino ketone formation, which is facilitated by β-cd Ts CA/BS Ts 2 Tetrahedron Lett., 2005, 46, 4111 The CA/BS system allows selective oxidation to the amino ketone John Maciejewski @ Wipf Group 7 2/17/2008
xidative ring-opening of aziridines rg. Biomol. Chem., 2007, 5, 3428. Initial investigations tested 1-10 equiv. of DMS in C 2 Cl 2, TF, MeC, benzene, EtAc, and Et 2 Investigations using pyridine -oxide (1.2 equiv.) DMF at 80 o C provided the desired α-amino ketone in 60% yield Toluene at 80 o C proved to give best results (70-80% yields) Increasing oxidant loading to 2-3 equiv. did not improve yields John Maciejewski @ Wipf Group 8 2/17/2008
xidative ring-opening of aziridines Electron donating pyridines accelerated reaction, but did not increase yield Electron withdrawing pyridines resulted in trace product after 40 h Sterically hindered substrates such as collidine gave low yields Aliphatic amines gave low yields of α-amino ketones, with undesired amino alcohol in moderate yields John Maciejewski @ Wipf Group 9 2/17/2008
xidative ring-opening of aziridines xidation proceeds in good yields with 5- and 6-membered rings John Maciejewski @ Wipf Group 10 2/17/2008
xidative ring-opening of aziridines John Maciejewski @ Wipf Group 11 2/17/2008
xidative ring-opening of aziridines Mechanism of oxidation Mechanism explains formation of amino ketone, but not amino alcohol. Aliphatic amine oxides provide low yields of desired amino ketone, but moderate yields of amino alcohol John Maciejewski @ Wipf Group 12 2/17/2008
xidative ring-opening of aziridines Proposed mechanism of oxidation Ts C 3 C 3 C 3 Ts C 3 C 3 Ts Aliphatic amine oxides have acidic hydrogen, where pyridine -oxides do not Authors did not address (or reference) the mechanism for the formation of amino alcohols Interesting method for preparing amino alcohols John Maciejewski @ Wipf Group 13 2/17/2008
Summary and Conclusions xidative ring-opening of aziridines Pyridine -oxides are efficient reagents for the oxidative ring-opening of aziridines The desired α-amino ketones were obtained in good yields on various substrates Aliphatic -oxides primarily afford the amino alcohol over the α-amino ketone Future work includes the development of an asymmetric version (chiral amines?) John Maciejewski @ Wipf Group 14 2/17/2008