Cyclopropanes and Hypervalent Iodine Reagents: Exploiting

Small Rings and Weak Bonds in Catalysis and Synthesis

Davinia Fernández González, Filippo De Simone, Jonathan Brand, Stefano Nicolai, Florian de Nanteuil, Fides Benfatti and Jérôme Waser*

Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland

jerome.waser@epfl.ch http://lcso.epfl.ch/

The use of organic molecules of increasing complexity is one of the major motors of progress in multiple fields of fundamental and applied science, such as chemical biology, drug discovery or organic materials. To answer these needs, it is crucial to develop new reactions for a fast access into molecular complexity. Our group makes use of the power of catalysis to develop new reactions based on the exceptional reactivity of electrophilic acetylenes and aminocyclopropanes.

Acetylenes:1 The triple bond is one of the most versatile functional groups in organic chemistry, material sciences and chemical biology. Most alkyne-transfer reactions have been limited to the nucleophilic addition of acetylides to electrophiles. The development of efficient electrophilic alkynylation methods would give access to structurally completely different acetylenes. Our group has introduced EthynylBenziodoXolone (EBX) hypervalent iodine reagents for direct alkyne-transfer to C-H and C=C bonds. In particular, using AuCl as catalyst, the direct alkynylation of indoles, pyrroles, thiophenes, anilines and furans became possible.1a-b EBX reagents were also exceptionally active for the alkynylation of keto, cyano and nitro esters.1c Finally, the use of palladium catalysis combined with EBX reagents or bromoacetylenes led to the first intramolecular oxy- and amino- alkynylation of olefins for the synthesis of lactones, lactams, tetrahydrofurans and pyrrolidines.1d-e

Aminocyclopropanes:2 Activation of cyclopropanes with an amino and a carbonyl group led to exceptional reactivity, both in cyclization and annulation reactions. Selective cyclization on the carbon or nitrogen of indole heterocycles using either copper or Brønsted acid catalysts allowed the synthesis of the alkaloids aspidospermidine and goniomitine.2a Using Phthalimido-substituted cyclopropanes together with iron or tin catalysts, a highly diastereoselective and enantiospecific [3+2] annulation reaction with enol ethers and carbonyls gave access to multi-substituted cyclopentyl- and tetrahydrofuryl amines, key structural elements of both DNA and bioactive compounds.2b-c

1. (1)  (a) Brand, J. P.; Charpentier, J.; Waser, J., Angew. Chem., Int. Ed. 2009, 48, 9346. (b) Brand, J. P.; Waser, J., Angew. Chem., Int. Ed. 2010, 49, 7304. (c) Fernandez Gonzalez, D.; Brand, J. P.; Waser, J., Chem. Eur. J. 2010, 16, 9457. (d) Nicolai, S.; Piemontesi, C.; Waser, J., Angew. Chem., Int. Ed. 2011, 50, 4680. (e) Nicolai, S.; Waser, J., Org. Lett. 2011, 13, 6324.

2. (2)  (a) De Simone, F.; Gertsch, J.; Waser, J., Angew. Chem., Int. Ed. 2010, 49, 5767. (b) de Nanteuil, F.; Waser, J., Angew. Chem., Int. Ed. 2011, 50, 12075. (c) Benfatti, F.; de Nanteuil, F.; Waser, J., Org. Lett. 2012, 14, 386.