Mild and Neutral Deprotections Catalyzed by Cerium(IV) Ammonium Nitrate NUNO MAULIDE, † JEAN-CHRISTOPHE VANHERCK, † ARNAUD GAUTIER, ‡ AND ISTVÁN E. MARKÓ* ,† Laboratoire SEESIB, CNRS-UMR 6504, Département de Chimie, Université Blaise Pascal, Clermont-Ferrand II, 24 avenue des Landais, 63177 Aubière cedex, France, and Université catholique de Louvain, Département de Chimie, Bâtiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium Received December 22, 2006 ABSTRACT The development of a novel, chemoselective, and catalytic depro- tection methodology that proceeds under mild and neutral condi- tions is described, and its mechanism of action is analyzed in some detail. The scope, limitations, and advantages of this protocol are discussed. Selected applications in synthesis are also highlighted. Introduction In the art of multistep total synthesis of natural products, protection and deprotection sequences are often unavoid- able. 1 Examples abound in the chemical literature, where interesting synthetic targets could not be attained, either because the protective groups that were employed stub- bornly resisted cleavage or because the deprotection conditions that were required were too harsh for ad- vanced, sensitive synthetic intermediates. As a response to these unfortunate predicaments, a number of new methods for the cleavage of commonly employed protec- tive groups appear regularly. 2 This Account describes the genesis and development of a general and selective deprotection methodology mediated by cerium(IV) am- monium nitrate (CAN). In addition, selected applications of this procedure in diverse synthetic contexts, by us and by others, are also discussed. Initial Observations and Discovery of the Stoichiometric Procedure Within the frame of a research program aimed at the efficient preparation of functionalized, medium-sized carbocycles, 3 we became interested in the fragmentation reactions of bicycle 1. In particular, we were intrigued by Nuno Maulide was born in Lisbon, Portugal, in 1979. After receiving his B.Sc. from the Instituto Superior Técnico (Lisbon, Portugal), in 2003, he moved to the Université catholique de Louvain to pursue a Ph.D. under the supervision of Professor István E. Markó. He received a FRIA scolarship in 2003 and since 2005 became an “Aspirant FNRS” at the same university. His research focuses on novel applications of functionalized ortho esters in synthesis. Jean-Christophe Vanherck was born in Brussels, Belgium, in 1973. He studied chemistry at the Faculty of Sciences of the Université catholique de Louvain from which he graduated in 1997. He obtained his Ph.D. in 2004, for which he worked on a novel methodology for the construction of spirocyclic compounds, under the guidance of Professor István E. Markó. After that, he moved to the Institut Européen de Chimie et Biologie as a postdoctoral fellow working with Professor Léon Ghosez on the design and the syntheses of PACE4 inhibitors. In 2006, after a second postdoctoral stay for Janssen Pharmaceutica in the group of Professor István E. Markó, he joined Elbion Bioscience as a medicinal chemist. His research focuses on the design and the syntheses of bioactive molecules. * To whom correspondence should be addressed. † Université catholique de Louvain. ‡ Université Blaise Pascal. Arnaud Gautier was born in Chamalières, France. He obtained his Ph.D. from the Université d’Auvergne in 1995 and undertook postdoctoral training at Stanford University under the supervision of Professors B. M. Trost and W. S. Johnson (1995–1997). In 1997, he moved to the group of Professor István E. Markó at the Université catholique de Louvain before joining the CNRS at the Institut de Recherche en Chimie Organique Fine (Rouen, France) (1999). In 2005, he moved to his current location at the Université Blaise Pascal (UBP). He is currently one of the coordinators in the Bioactive Molecules group at UBP. His current interests include the development of click chemistry in the synthesis of ligands for transition metals and their interactions with nucleic acids and applications as anticancer agents. István E. Markó was born in Pápa, Hungary, in 1956. He received his B.Sc. (1978) and Ph.D. (1983) degrees at the Université catholique de Louvain, under the supervision of Professor Léon Ghosez. After a two-year stay as a postdoctoral associate at the same university, he pursued Postdoctoral studies at the University of Vermont (Martin Kuehne, 1985–1987) and the Massachussets Institute of Technology (K. Barry Sharpless, 1987–1988). He then joined the University of Sheffield as a Lecturer (1988–1993) before taking up his present position as Professor in Chemistry at the Université catholique de Louvain (from 1993 to the present). His main research interests are in the field of short, efficient, and stereocontrolled total synthesis of natural products, the development of new organometallic reagents, electroorganic synthesis, and ecological processes. VOLUME40 NUMBER6 ® JUNE 2007 Registered in U.S. Patent and Trademark Office; Copyright 2007 by the American Chemical Society 10.1021/ar600062b CCC: $37.00  2007 American Chemical Society VOL. 40, NO. 6, 2007 / ACCOUNTS OF CHEMICAL RESEARCH 381 Published on Web 05/01/2007