Reviews K. C. Nicolaou et al. Synthethic Methods Metathesis Reactions in Total Synthesis K. C. Nicolaou,* Paul G. Bulger, and David Sarlah Keywords: Dedicated to Professor Thomas J. Katz alkene metathesis · alkyne metathesis · on the occasion of his 70th birthday enyne metathesis · natural products · total synthesis Angewandte Chemie 4490 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200500369 Angew. Chem. Int. Ed. 2005, 44, 4490 – 4527 Angewandte Metathesis Reactions Chemie With the exception of palladium-catalyzed cross-couplings, no From the Contents other group of reactions has had such a profound impact on the formation of carbon–carbon bonds and the art of total synthesis in 1. Introduction 4491 the last quarter of a century than the metathesis reactions of olefins, 2. The Alkene-Metathesis Reaction 4493 enynes, and alkynes. Herein, we highlight a number of selected examples of total syntheses in which such processes played a crucial 3. The Enyne-Metathesis Reaction 4512 role and which imparted to these endeavors certain elements of novelty, elegance, and efficiency. Judging from their short but 4. The Alkyne-Metathesis Reaction 4517 impressive history, the influence of these reactions in chemical 5. Summary and Outlook 4520 synthesis is destined to increase. 1. Introduction Ever since the birth of the art of organic synthesis, as marked by Wöhlers synthesis of urea in 1828, progress in this field has, to a large degree, been dependent on our ability to construct carbon frameworks through carbon–carbon bond- forming reactions. The Grignard,[1] Diels–Alder,[2] and Wittig reactions[3] are three of the most prominent such processes that played decisive roles in shaping the science of chemical synthesis as we know it today. During the last quarter of the previous century, two more such reactions emerged as rivals to the aforementioned carbon–carbon bond-forming proc- esses: the palladium-catalyzed cross-coupling reactions and those collectively known as metathesis reactions. As a most Scheme 1. The most commonly employed alkene-metathesis reactions stringent test, total synthesis often serves as a measure of the in organic synthesis. power of a given reaction. Surveys of relevant applications of enabling reactions are, therefore, of importance in that they not only help to underscore the scope and generality of such HØrisson and Chauvin in 1971,[8] with key experimental processes in chemical synthesis, but they also serve to place evidence for its validity subsequently being provided by the into perspective that particular reaction within the field, and Casey,[9] Katz,[10] and Grubbs groups,[11] and invokes metal to inspire future improvements and new applications. In the carbene intermediates as key propagating species in the preceding Review in this issue (“Palladium-Catalyzed Cross- catalytic cycle. From a practical viewpoint, a key milestone in Coupling Reactions in Total Synthesis”),[4] such a critical the evolution of alkene metathesis was the demonstration by analysis was provided. The purpose of this Review is to do the Katz and co-workers in 1976 that single-component, well- [5] same for the alkene, enyne, and alkyne metathesis reactions. defined tungsten carbenes, for example Ph2C=W(CO)5, could Alkene metathesis, in all its various guises (Scheme 1), has initiate alkene metathesis without added coactivators.[12,13] arguably influenced and shaped the landscape of synthetic This discovery ushered in the modern era of rational catalyst organic chemistry more than any other single process over the design, and after further development, the alkene-metathesis last 15 years.[6] The wealth of synthetic transformations that reaction has developed into one of the most powerful carbon– can be accomplished when this reaction is applied to carbon bond-forming reactions currently available to the appropriate substrates is astonishing, since the same catalyst synthetic chemist. (initiator) systems can promote several different types of reactions, depending on the substrates and reaction condi- [*] Prof. Dr. K. C. Nicolaou, Dr. P. G. Bulger, D. Sarlah tions employed. The history of alkene metathesis is a Department of Chemistry fascinating one, beginning with its serendipitous discovery and The Skaggs Institute for Chemical Biology nearly 50 years ago through to the design and application of The Scripps Research Institute the latest initiators available today.[7] The elucidation of the 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) mechanistic pathway was, itself, the culmination of nearly two Fax : (+1)858-784-2469 E-mail: [email protected] decades of extensive, if not collaborative or competitive, and research by numerous groups, and the subject of lively debate Department of Chemistry and Biochemistry in the literature during that period. The generally accepted University of California San Diego mechanism of alkene metathesis was originally proposed by 9500 Gilman Drive, La Jolla, CA 92093 (USA) Angew. Chem. Int. Ed. 2005, 44, 4490 – 4527 DOI: 10.1002/anie.200500369 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4491 Reviews K. C. Nicolaou et al. Although alkene metathesis constitutes, by far, the most metals, including ruthenium,[21] iridium,[22] and platinum.[23] widely utilized type of metathesis reaction, recent years have Nevertheless, in terms of both scope and frequency of use, the witnessed the discovery and development of a number of metal carbene mediated reactions are the most widely related processes employing a broader range of substrates. employed among the enyne-metathesis processes. Prominent amongst these is the enyne-metathesis reaction, Most recently, it has proven to be the turn of alkyne which involves the union of an alkene with an alkyne to form metathesis to emerge from the shadow of alkene metathesis a 1,3-diene system (Scheme 2).[14] Unlike the corresponding and become a valuable addition to the armory of the synthetic chemist in its own right.[24] Unlike enyne metathesis, alkyne metathesis is a direct analogue of the alkene-metathesis reaction and involves the mutual exchange of alkylidyne units between two acetylene moieties (Scheme 3). Alkyne meta- Scheme 2. Enyne-metathesis reactions in organic synthesis. alkene-metathesis reactions, enyne metatheses are wholly Scheme 3. Alkyne-metathesis reactions in organic synthesis. atom economical (that is, no olefin-containing by-product is released during the process)[15] and are therefore driven by enthalpic rather than entropic factors, principally the stability thesis can be applied in both inter-and intramolecular of the conjugated diene system thus produced. Another contexts, although the application and development of these distinction is that enyne metathesis can occur by any one of processes in the field of total synthesis is still very much in its several independent mechanistic pathways, with the course of infancy. The first examples of homogeneously catalyzed the reaction being dictated by whether metal carbene species alkyne-metathesis reactions were reported by Mortreux and or low-valent transition-metal complexes mediate the process, Blanchard in 1974,[25, 26] with a mechanistic rationale (involv- although the net outcome is (usually) the same. The enyne- ing a Chauvin-type series of metal carbyne and metallacyclo- metathesis reaction was discovered by Katz and his group, butadiene intermediates as the propagating species) being put who reported the first examples of this process in 1985 in the forward by Katz and McGinnis less than a year later.[10] As presence of catalytic amounts of tungsten Fischer carbene was the case with alkene metathesis, however, the acknowl- complexes.[16] At the same time, these workers proposed the edgment that alkyne metathesis could serve as a synthetically currently accepted mechanism for this type of process, useful tool in the construction of complex molecules would be invoking a sequence of [2+2] cycloaddition and cyclorever- postponed until the development of newer generations of sion steps involving metal carbene species, which closely more practical catalyst systems that could operate efficiently parallels the mechanism of alkene metathesis. Subsequently, under mild conditions and in the presence of sensitive the Trost group documented the cycloisomerization of 1,n- functionality. Breakthroughs in alkyne-metathesis chemistry enyne systems in the presence of palladium(ii) complexes to within the last decade, largely spearheaded by the pioneering generate 1,3-diene systems, which formally arise as the result work of the Bunz and Fürstner groups, include the develop- of enyne ring-closing metathesis, yet proceed through non- ment of practical, selective ring-closing and intermolecular carbenoid mechanistic pathways.[17] This type of transforma- (cross) alkyne-metathesis versions. These processes are often tion forms an important subset of a larger class of transition- complementary to the corresponding alkene-metathesis reac- metal-mediated reactions.[18–20] This transformation can also tions and have propelled this field to the forefront of the be effected by complexes of a number of other late transition emerging metathesis technology. The impact of K. C. Nicolaou’s career on Paul G. Bulger was born in London (UK) in chemistry, biology, and medicine flows from 1978. He received his M.Chem in 2000 his contributions to chemical synthesis, from the University of Oxford, where he which have been described in numerous completed his Part II project under Dr. publications and