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Ring Closing Enyne Metathesis: a Powerful Tool for the Synthesis of Heterocycles

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Ring Closing Enyne Metathesis: a Powerful Tool for the Synthesis of Heterocycles TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews Ring closing enyne metathesis: A powerful tool for the synthesis of heterocycles He´le`ne Villar,ab Marcus Fringsa and Carsten Bolm*a Received 2nd August 2006 First published as an Advance Article on the web 4th October 2006 DOI: 10.1039/b508899m The ring closing metathesis (RCM) is a powerful method in organic synthesis for the preparation of cyclic compounds by formation of new carbon–carbon bonds. In the past years a particular subclass of the RCM, the ring closing enyne metathesis (RCEYM), has attracted attention due to its synthetic potential in the generation of ring structures with 1,3-diene moieties, which can subsequently be further functionalised. In this tutorial review mechanistic considerations will be described and the synthetic power of this useful and attractive carbon–carbon bond forming reaction will be illustrated by recent examples of RCEYM applications in the preparation of heterocyclic compounds. 1. Introduction and both academia and industry largely benefited from their findings. The Nobel Prize in Chemistry 2005 was equally shared by Yves Metathesis, with its multiple facets, has become one of the Chauvin (Institut Franc¸ais du Pe´trole, Rueil-Malmaison, most important chemical transformations.2–7 Depending on France), Robert H. Grubbs (California Institute of the type of unsaturated bond involved in the metathesis Technology, Pasadena, USA) and Richard R. Schrock process, three major categories of olefin metathesis can be (Massachusetts Institute of Technology, Cambridge, USA) distinguished: diene, enyne and diyne metathesis. The struc- for their outstanding contributions in the area of olefin tural change, which occurs during the process, can be further 1 metathesis reactions. Chauvin had investigated the mechan- subdivided into ring closing, ring opening, and cross meta- ism of this unusual carbon–carbon-bond forming reaction, and thesis. Here, we will focus on one of these classes, which has studies by Grubbs and Schrock have led to synthetically highly recently been shown to be a highly powerful method for the efficient ruthenium, molybdenum, and tungsten metathesis generation of ring structures from functionalised molecules catalysts. As apparent from today’s textbooks, their discov- with tethered alkenes and alkynes: the ring closing enyne eries had a tremendous impact on modern organic chemistry metathesis. The first reaction of this type was reported by Katz and aInstitut fu¨r Organische Chemie der RWTH Aachen, Landoltweg 1, Sivavec in 1985, who used a Fischer tungsten carbene complex 52074 Aachen, Germany. E-mail: [email protected] b in an intramolecular enyne metathesis giving an all-carbon New address: Equipe Mate´riaux Tensioactifs, BP 239, Polyme`res et 8 Colloı¨daux, 54506 Vandœuvre-le`s-Nancy, UMR 7565 CNRS-UHP, product in moderate (31%) yield. Later, analogous transfor- Universite´ Henri Poincare´ Nancy I, France mations have been performed with molybdenum and He´le`ne Villar studied chemistry Marcus Frings was born in at the University PARIS XI in Eschweiler (Germany) and Orsay (France). In 2003 she studied chemistry at the finished her doctoral work with RWTH Aachen University Dr Guibe´inOrsayonthe (Germany). In 2005 he com- mechanistic study of 3-exo-trig pleted his diploma thesis under radical cyclisation induced by the supervision of Professor samarium diiodide. She Bolm in which he investigated obtained an Alexander von the application of sulfoximines Humboldt postdoctoral fellow- in ring closing metathesis. ship to join the group of Currently, he is a doctoral Professor Bolm at RWTH student in the group of Aachen University Professor Bolm. His project (Germany), where she worked is focused on methodology He´le`ne Villar on synthesis of heterocyclic Marcus Frings development and the synthesis sulfoximines by ring closing of sulfoximine-containing bio- metathesis. Since 2005 she has been a lecturer in Professor logically active compounds. Ge´rardin’s group at the Henri Poincare´ University in Nancy (France), studying conception, synthesis and properties of polyfunctionalised perfluorinated amphiphilic compounds. This journal is ß The Royal Society of Chemistry 2007 Chem. Soc. Rev., 2007, 36, 55–66 | 55 chromium carbene complexes. Subsequently, the development of well-defined ruthenium carbene catalysts with a wide functional group tolerance has considerably improved the selectivity and scope of RCEYM reactions. The most common catalysts are presented in Fig. 1. Grubbs’ tremendous accomplishments resulted in three different generations of ruthenium metathesis complexes, Ru1, Ru2 and Ru3.9 Hoveyda’s and Blechert’s ruthenium complexes Ru410 and Ru511 can be considered as derivatives of the Grubbs catalyst family bearing loosely chelating groups.12 2 Mechanism outlines Despite the fact that enyne metathesis is closely related to alkene metathesis, the mechanism of the former is by far less understood than the latter metathesis reaction. Formally, in a RCEYM reaction a carbon–carbon bond formation between an olefinic and an alkynylic carbon occurs affording a cyclic 1,3-diene. The process is complex and involves a number of steps. Fig. 1 Common ruthenium carbene complexes used in metathesis Two mechanisms for enyne metathesis reactions have been reactions. discussed in the literature: first, a metal salt-catalysed enyne bond reorganization, and, second, a metal carbene-mediated the metal salt generating 2, followed by oxidative cyclisation to enyne metathesis reaction. After a short presentation of both give metalacyclopentene 3. Next, reductive elimination occurs mechanisms, we will focus on transformations following the to produce cyclobutene 4. The process is completed by bond second mechanistic pathway. isomerisation and ring opening of 4 to afford diene 5. Scheme 1 illustrates a generic pathway of such ‘metal-templated enyne 2.1 Metal salt-catalyzed enyne bond reorganisation bond reorganisation’. Depending on the nature of catalyst, a second pathway can 15 Trost pioneered the employment of late transition metal salts be considered. For Pt(II)Fu¨rstner proposed a mechanism 13,14 such as Pd(II) for triggering enyne bond reorganisation. involving a p-alkyne activation by the metal (Scheme 2).16 The reaction starts by a bidentate coordination of enyne 1 to On one hand, an intermolecular attack of the metal- coordinated alkyne 6 by an external nucleophile in an anti- manner can lead to open-chain products 7a and 7b. If this Carsten Bolm studied chemis- attack occurs in an intramolecular (exo-orendo-) fashion, try at the TU Braunschweig in metallated intermediates 8–12 and 13–15 result, which Germany and at the University represent canonical forms of a non-classical homoallyl- of Wisconsin in Madison (USA). In 1987 he finished cyclopropylmethyl-cyclobutyl cation. his doctoral work with This concept was further elaborated by Echavarren, who Professor Reetz in Marburg concluded on basis of DFT calculation results that ‘the (Germany). After postdoc- similarities between the intramolecular reactions of alkynes toral studies at MIT, with alkene catalyzed by late transition metal complexes and Cambridge (USA), with the carbocationic rearrangements of the cyclopropyl-methyl- Professor Sharpless, Carsten cyclobutyl manifold, pointed out by Fu¨rstner, is remarkable. Bolm began to work on his habilitation in Basel (Switzerland) in the group of Carsten Bolm Professor Giese. In 1993 he became Professor of Organic Chemistry at the University of Marburg (Germany), and since 1996 he has been a full professor for Organic Chemistry at the RWTH Aachen University (Germany). He has had visiting professorships at the universities in Madison, Wisconsin (USA), Paris (France), Florence (Italy), Milan (Italy), Namur (Belgium) and Tokyo (Japan). His list of awards includes the Heinz–Maier–Leibnitz prize, the ADUC-Jahrespreis for habili- tands, the annual prize for Chemistry of the Akademie der Wissenschaften zu Go¨ttingen, the Otto-Klung prize, the Otto- Bayer award, a fellowship of the Japan Society for the Promotion of Science and the Prix Franco-Allemand by the Socie´te´ Francaise de Chimie. Scheme 1 Metal-templated enyne bond reorganisation. 56 | Chem. Soc. Rev., 2007, 36, 55–66 This journal is ß The Royal Society of Chemistry 2007 Scheme 2 General representation of metal-assisted alkyne activation. However, differences undoubtedly exist due to the metal Possible reaction courses are shown in Schemes 3 and 4. If stabilization of reactive species.17 the RCEYM proceeds by initial reaction of the alkynylic part of enyne 1 with the ruthenium carbene complex (Ru), the 2.2 Metal carbene-mediated enyne metathesis sequence of events is called ‘yne-then-ene pathway’ (Scheme 3). Two alternative reaction pathways (entitled a-exo and a-endo) The ruthenium carbenes developed by Grubbs reveal an can then be envisaged. On one hand, the metal side of the excellent catalytic efficiency in enyne metathesis ruthenium carbene complex (Ru) can combine with the reactions, and their application in synthesis is attractive internal carbon of the alkyne of 1 forming ruthenacyclobutene because they possess a remarkable functional group tolerance. 16 (Scheme 3, left; a-exo pathway). Ring-opening of 16 leads to Several aspects of the RCEYM mechanisms have been vinylic ruthenium carbene complex 17, and subsequent questioned, and either they lack or have incomplete intramolecular [2 + 2] cycloaddition affords ruthenacyclobu- 18,19 answers. For example: (1) Which
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