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
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
Viviana Valerio, Desislava Petkova, Claire Madelaine and Nuno Maulide
(See online at https://doi.org/10.1002/chem.201203906) - "Electrophilic Rearrangements of Chiral Amides: a Traceless Asymmetric g-Allvlation". Journal of the American Chemical Society 2013, 135, 14968-14971
Bo Peng, Danny Geerdink and Nuno Maulide
(See online at https://doi.org/10.1021/ja408856p) - "Chemoselective Intermolecular a-Arylation of Amides”, Angewandte Chemie International Edition 2014, 53, 54625466. Angewandte Chemie 2014, 126, 5566-5570
Bo Peng, Danny Geerdink, Christophe Fares and Nuno Maulide
(See online at https://doi.org/10.1002/anie.201402229) - "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
Mohan Padmanaban, Luisa C. R. Carvalho, Desislava Petkova, Ji-Woong Lee, A. Sofia Santos, M. Manuel B. Marques and Nuno Maulide
(See online at https://doi.org/10.1016/j.tet.2015.06.027)
