Development of a unified electrophilic activation of amides and applications to novel stereoselective Claisen rearrangements and cationic shifts, double bond functionalisations and innovative concepts for macrolactonisation

• Applicant: Professor Dr. Nuno Maulide
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 158729287

• Final Report Year: 2016

Final Report Abstract

The amide functional group is traditionally regarded as the most stable among carboxylic acid derivatives. This should not come as a surprise, given that known robustness of polyamides and the presence of the amide bond in the skeletal constituents of our bodies (proteins and polypeptides). Through this project, we have challenged this notion. Indeed, our results show that amides can be activated under mild conditions, and this even in the presence of other functional groups conventionally seen as more reactive. Most importantly, this activation generates highly reactive intermediates that we exploited in several different contexts. For instance, a direct lactonization of alcohols and protected ethers was developed. This enables the direct preparation of lactones and may allow the saving of up to two unproductive steps in synthetic sequence. Furthermore, we have shown that elusive benzyl-Claisen rearrangements become possible, as well as novel cationic shifts. An asymmetric variant of this chemistry was also sought, with a method that complements the well-known Myers asymmetric alkylation being developed in our laboratory. Finally, a novel approach to a-arylation, not originally foreseen, was logically deduced from prior results of our group and forms a very promising avenue for further developments.

Publications

• "Keteniminium Salts: More Than the Nitrogen Analogues of Ketenes”, Chemistry - An Asian Journal 2011, 6, 2224-2239
  Claire Madelaine, Viviana Valerio and Nuno Maulide
  
• "Steering Reaction Pathways: From Benzyl Claisen Rearrangements to Powerful Ionic Shifts”, Chemistry - A European Journal 2011, 17, 4742-4745
  Viviana Valerio, Claire Madelaine and Nuno Maulide
  
• "Cascade Electrophilic Activation of Amides: Stereoselective Synthesis of Substituted Lactones”, Ph.D. Thesis, Ruhr-Universität Bochum, 2013
  Viviana Valerio
  
• "Direct Room-Temperature Lactonisation of Alcohols and Ethers onto Amides: an "Amide Strategy” for Synthesis”, Chemistry - A European Journal 2013, 19, 2606-2610
  Valerio, Viviana; Petkova, Desislava; Madelaine, Claire & Maulide, Nuno
  
• "Electrophilic Rearrangements of Chiral Amides: a Traceless Asymmetric g-Allvlation". Journal of the American Chemical Society 2013, 135, 14968-14971
  Peng, Bo; Geerdink, Danny & Maulide, Nuno
  
• "Chemoselective Intermolecular a-Arylation of Amides”, Angewandte Chemie International Edition 2014, 53, 54625466. Angewandte Chemie 2014, 126, 5566-5570
  Peng, Bo; Geerdink, Danny; Farès, Christophe & Maulide, Nuno
  
• "Development of a New Lactonisation Method Based on Amide Activation”, Ph.D. Thesis, University of Vienna, 2014
  Desislava Petkova
  
• "Investigation of cationic Claisen-type electrophilic rearrangements of amides”, Tetrahedron 2015, 71, 5994-6005
  Padmanaban, Mohan; Carvalho, Luísa C.R.; Petkova, Desislava; Lee, Ji-Woong; Santos, A. Sofia; Marques, M. Manuel B. & Maulide, Nuno