An efficient synthesis of bridged heterocycles from an Ir(I) bis-amination/ring-closing metathesis sequence.

The amination of bis-allylic imidates using an Iridium(I) catalyst leads to the efficient formation of 2,6-divinyl heterocycles. Careful screening of amines, solvents, and conditions has led to the discovery of a system that favors formation of the desired cis products with synthetically useful levels of diastereoselectivity, and these results are further explained by computer based transition state energy calculations. Exposure of the heterocycles to ring-closing metathesis catalysts leads to the desired bridged heterocyclic systems.

[1]  Hyun-Ju Park,et al.  Synthesis of N-protected allylic amines from allyl ethers , 2001 .

[2]  Alexander Deiters,et al.  Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis. , 2004, Chemical reviews.

[3]  S. Martin,et al.  Synthesis of bridged azabicyclic structures via ring-closing olefin metathesis. , 2003, The Journal of organic chemistry.

[4]  E. Dequeker,et al.  Synthesis of a chiral 2,6-bridged morpholine system: trans-6,7-diol derivatives of 8-oxa-3-azabicyclo[3.2.1]octane , 1995 .

[5]  J. Hartwig,et al.  Iridium-catalyzed kinetic asymmetric transformations of racemic allylic benzoates. , 2010, Journal of the American Chemical Society.

[6]  M. H. Lee,et al.  Novel synthetic method for N-allylcarbamates from allyl ethers using chlorosulfonyl isocyanate , 2000 .

[7]  P. Evans,et al.  Unlocking ylide reactivity in the metal-catalyzed allylic substitution reaction: stereospecific construction of primary allylic amines with aza-ylides. , 2009, Journal of the American Chemical Society.

[8]  Keiji. Yamamoto,et al.  Palladium(0)-Catalyzed Amination of Allylic Acetate with Methyl Carbamate , 1989 .

[9]  Brian Samas,et al.  A highly enantioselective allylic amination reaction using a commercially available chiral rhodium catalyst: resolution of racemic allylic carbonates. , 2009, Organic letters.

[10]  L. Toral-Barza,et al.  Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent. , 2010, Bioorganic & medicinal chemistry letters.

[11]  T. Nagano,et al.  Palladium-catalyzed allylic amination using aqueous ammonia for the synthesis of primary amines. , 2009, Journal of the American Chemical Society.

[12]  Robert H. Grubbs,et al.  Ring-Closing Metathesis and Related Processes in Organic Synthesis , 1995 .

[13]  R. Matunas,et al.  Iridium-catalyzed selective N-allylation of hydrazines , 2005 .

[14]  A. Hoveyda,et al.  The remarkable metal-catalysed olefin metathesis reaction , 2007, Nature.

[15]  O. Singh,et al.  Iridium(I)-catalyzed stereospecific decarboxylative allylic amidation of chiral branched benzyl allyl imidodicarboxylates. , 2007, Organic letters.

[16]  T. Mansour,et al.  Stereoselective synthesis of an active metabolite of the potent PI3 kinase inhibitor PKI-179. , 2010, The Journal of organic chemistry.

[17]  L. Toral-Barza,et al.  Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[18]  E. Carreira,et al.  Iridium-catalyzed synthesis of primary allylic amines from allylic alcohols: sulfamic acid as ammonia equivalent. , 2007, Angewandte Chemie.

[19]  I. Godovikov,et al.  Synthesis of Bridged Azabicycles from Pyridines and Pyrrole by a Diallylboration – Ring Closing Metathesis Sequence , 2006 .

[20]  W. Greenlee,et al.  Design, synthesis, and structure-activity relationship studies of N-arylsulfonyl morpholines as γ-secretase inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[21]  E. Carreira,et al.  Stereospecific substitution of allylic alcohols to give optically active primary allylic amines: unique reactivity of a (P,alkene)Ir complex modulated by iodide. , 2010, Journal of the American Chemical Society.

[22]  S. Streiff,et al.  Highly enantioselective syntheses of heterocycles via intramolecular Ir-catalyzed allylic amination and etherification. , 2005, Organic letters.

[23]  K. Nicolaou,et al.  An expedient procedure for the oxidative cleavage of olefinic bonds with PhI(OAc)2, NMO, and catalytic OsO4. , 2010, Organic letters.

[24]  Mark J. Pouy,et al.  Enantioselective iridium-catalyzed allylic amination of ammonia and convenient ammonia surrogates. , 2007, Organic letters.

[25]  S. Shekhar,et al.  Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products. , 2006, Journal of the American Chemical Society.

[26]  N. Brooijmans,et al.  Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors. , 2009, Journal of medicinal chemistry.

[27]  M. Rogers-Evans,et al.  A concise asymmetric route to the bridged bicyclic tropane alkaloid ferruginine using enyne ring-closing metathesis. , 2004, Organic letters.

[28]  R. Takeuchi,et al.  Iridium complex-catalyzed allylic amination of allylic esters. , 2001, Journal of the American Chemical Society.

[29]  Y. Luo,et al.  Highly regio- and enantioselective Pd-catalyzed allylic alkylation and amination of monosubstituted allylic acetates with novel ferrocene P,N-ligands. , 2001, Journal of the American Chemical Society.

[30]  E. Carreira,et al.  Direct, enantioselective iridium-catalyzed allylic amination of racemic allylic alcohols. , 2012, Angewandte Chemie.

[31]  C. Shao,et al.  Total synthesis of (-)-cocaine and (-)-ferruginine. , 2011, The Journal of organic chemistry.