SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2018, 50, 3749–3786 review 3749 en Syn thesis I. Cheng-Sánchez, F. Sarabia Review Recent Advances in Total Synthesis via Metathesis Reactions Iván Cheng-Sánchez Francisco Sarabia* Department of Organic Chemistry, Faculty of Sciences, University of Málaga, Campus de Teatinos s/n. 29071- Málaga, Spain [email protected] Received: 16.04.2018 ly explained by the emergence, design, and development of Accepted after revision: 30.05.2018 powerful catalysts that are capable of promoting striking Published online: 18.07.2018 DOI: 10.1055/s-0037-1610206; Art ID: ss-2018-z0262-r transformations in highly efficient and selective fashions. In fact, the ability of many of them to forge C–C bonds be- Abstract The metathesis reactions, in their various versions, have be- tween or within highly functionalized and sensitive com- come a powerful and extremely valuable tool for the formation of car- pounds has allowed for the preparation of complex frame- bon–carbon bonds in organic synthesis. The plethora of available cata- lysts to perform these reactions, combined with the various works, whose access were previously hampered by the lim- transformations that can be accomplished, have positioned the me- itations of conventional synthetic methods. Among the tathesis processes as one of the most important reactions of this centu- myriad of recent catalysts, those developed and designed to ry. In this review, we highlight the most relevant synthetic contributions promote metathesis reactions have had a profound impact published between 2012 and early 2018 in the field of total synthesis, reflecting the state of the art of this chemistry and demonstrating the and created a real revolution in the field of total synthesis, significant synthetic potential of these methodologies. by virtue of their ability to promote a stunning number of 1 Introduction synthetic transformations, depending on the nature of the 2 Alkene Metathesis in Total Synthesis starting materials and reaction conditions. Metathesis reac- 2.1 Total Synthesis Based on a Ring-Closing-Metathesis Reaction tions1 include the alkene-, enyne-, and alkyne-metathesis 2.2 Total Synthesis Based on a Cross-Metathesis Reaction 2.3 Strategies for Selective and Efficient Metathesis Reactions of reactions, together with multiple variants of polyalkenic or Alkenes polyalkenynic systems as starting precursors involved in 2.3.1 Temporary Tethered Ring-Closing Metathesis cascade processes.2 Among these, the alkene metathesis re- 2.3.2 Relay Ring-Closing Metathesis action (Scheme 1, A), in which cyclic olefins or linear 2.3.3 Stereoselective Alkene Metathesis alkenes are formed through ring-closing metathesis (RCM), 2.3.4 Alkene Metathesis in Tandem Reactions 3 Enyne Metathesis in Total Synthesis cross-metathesis (CM) process, or their different guises 3.1 Total Syntheses Based on a Ring-Closing Enyne-Metathesis Reac- (stereoselective, rearrangement, tethered or relay ring-clos- tion ing metatheses), is the most extensively employed. Indeed, 3.2 Total Syntheses Based on an Enyne Cross-Metathesis Reaction these transformations occupy a privileged position in mod- 3.3 Enyne Metathesis in Tandem Reactions This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ern organic synthesis. Less frequently used, but no less im- 4 Alkyne Metathesis in Total Synthesis 4.1 Total Synthesis Based on a Ring-Closing Alkyne-Metathesis Reac- portant, are the enyne and alkyne metatheses (Scheme 1, B tion and C), which have also become valuable synthetic reac- 4.2 Other Types of Alkyne-Metathesis Reactions tions with additional advantages over alkene metatheses. 5 Conclusions Such is the case of enyne metathesis involved in cascade Key words alkene metathesis, alkyne metathesis, enyne metathesis, processes, or the case of alkyne metathesis owing to the natural products, total synthesis versatility of the alkyne group by allowing for further transformations, thus considerably expanding the structur- al diversity of the products that can be formed. 1 Introduction Certainly, behind the success of all these processes are the unique catalysts themselves that enable these transfor- The outstanding and impressive level that organic syn- mations. Since the discovery of the first well-defined tung- thesis has reached in the last few decades, especially in the sten carbene catalyst by Katz3 and the elucidation of the field of the total synthesis of natural products, can be large- mechanism of alkene metathesis by Chauvin4 in the 1970s, © Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 3749–3786 3750 Syn thesis I. Cheng-Sánchez, F. Sarabia Review key innovations were the Schrock catalyst 1 in 19905 and more detail later in the alkyne metathesis section. Together the discovery of the ruthenium-based catalyst 2 by Grubbs with the prominent activity and stability of the aforemen- in 1993.6 These discoveries marked the beginning of an ex- tioned catalysts, another feature that has been improved in traordinary and burgeoning race towards more efficient the evolution of catalyst design27 is the exceptional func- catalysts in terms of activity, stability, and functional group tional group tolerance that all these catalysts display, which tolerance, represented by the ruthenium species 3–147–18 in turn has positioned them as one of the most powerful (Figure 1). synthetic tools in modern organic synthesis. Consequently, These highly efficient catalysts are representative mem- total synthesis has enormously benefitted from the metath- bers of three generations of ruthenium complexes, in which esis reactions, as demonstrated by the extensive use of the introduction of an N-heterocyclic carbene (NHC) ligand these reactions in their intramolecular and intermolecular (see 4, 6–14) resulted in an increase in the catalytic activity versions. In fact, the flurry of contributions, in which the and thermal stability of the catalysts. The catalysts, devel- metathesis reaction represents either the key step for the oped between 1996–2007, gave rise to the rational design successful completion of a synthesis or a useful and effi- of new catalysts to enable both stereoselective and stereo- cient synthetic tool employed along the synthetic course, is retentive metathesis processes, leading to the molybde- a growing component of the organic chemistry literature. num, tungsten, and ruthenium carbene complexes 15–27, Given the relevance and impact of this reaction in the among others.19–22 Additions to this armory of valuable cat- field of organic chemistry, a large number of reviews, alysts, are the water-soluble catalysts in form of PEGylated books, and book chapters have been devoted to all aspects complexes23 or ruthenium-based catalysts supported on ac- of these reactions. Among all the excellent reviews focused tivated surfaces,24 which expand even further the scope and on the applications of metathesis reactions in natural prod- applications of the chemistry, particularly in regards to ad- ucts synthesis,28 some key contributions by Nicolaou dressing environmental concerns.25 All these catalysts are (2005),29 Pérez-Castells (2006),30 and Prunet (2011)31 are appropriate for alkene and enyne metatheses.26 Interesting- notable. A review published in 2017 by Vanderwal32 is ly, for the latter case, the process can be also effected by noteworthy, wherein the most relevant contributions in the other transition-metal-based catalysts such as those based field of the last years were highlighted, but in a very generic on Pt, Pd, or Ir via a completely different mechanism. A sep- form. On the other hand, an excellent book was published arate case is the alkyne-metathesis reaction, which despite dealing with metathesis reactions in the synthesis of natu- the mechanistic similarity with alkene metathesis, requires ral products, covering all the aspects of these reactions in a different type of catalyst. Indeed, in this case, the variety the field of total synthesis up to 2010.33 In addition, numer- of catalysts available is not as great as those developed for ous reviews have been published on very specific items, the alkene metathesis reactions, as will be discussed in dealing with a particular type of metathesis reaction or a Biographical Sketches Iván Cheng Sánchez was 2015 he started his Ph.D. stud- modomain inhibitors for cancer born in Málaga (Spain) in 1992. ies under the guidance of Prof. treatment. His current research He received his B.Sc. in chemis- F. Sarabia. In 2017 he joined the focuses on total synthesis of try in 2014 and his M.Sc. in laboratories of Prof. C. Nevado natural products and design chemistry in 2015 from Málaga at University of Zurich for a and synthesis of new bioactive University, after conducting re- short research stay of 3 months agents inspired by natural prod- search in the laboratories of where he was involved in the ucts through novel asymmetric This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Prof. F. Sarabia. In November synthesis of novel ATAD2 bro- methodologies. Francisco Sarabia received his to Full Professor in 2011. Prof. new synthetic methodologies Ph.D. degree from University of Sarabia has been visiting profes- and medicinal chemistry, and Málaga (Spain) in 1994 under sor in the Technological Insti- the discovery of new bioactive the supervision of Prof. López- tute of Zürich (ETH) in 1998 compounds. He is the chairman Herrera. After postdoctoral re- with Prof. A. Vasella, The Scripps of the Department of Organic search with Prof. K. C. Nicolaou Research Institute in 2001 with Chemistry since 2014 and sci- at the Scripps Research Institute Prof. Nicolaou, and Scripps Flor- entific responsible of the NMR in La Jolla (1995–1997), he re- ida in 2013 with Prof. W. R. facilities of the University of turned to the University of Roush. His research interests in- Málaga. Málaga in 1998 as Assistant Pro- clude the total synthesis of nat- fessor, where he was promoted ural products, development of © Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 3749–3786 3751 Syn thesis I.