Angewandte. Reviews A. C. Jones, B. M. Stoltz et al. DOI: 10.1002/anie.201302572 Molecules and Music Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements Amanda C. Jones,* Jeremy A. May, Richmond Sarpong, and Brian M. Stoltz* Keywords: In memory of Nelson Leonard homogeneous catalysis · sigmatropic reactions · tandem reactions Angewandte Chemie &&&& 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2014, 53,2–38 Ü Ü These are not the final page numbers! Angewandte Reaction Cascades Chemie Catalysis and synthesis are intimately linked in modern organic From the Contents chemistry. The synthesis of complex molecules is an ever evolving area of science. In many regards, the inherent beauty associated with 1. Introduction 3 a synthetic sequence can be linked to a certain combination of the 2. [3,3]-Sigmatropic creativity with which a sequence is designed and the overall efficiency Rearrangements 5 with which the ultimate process is performed. In synthesis, as in other endeavors, beauty is very much in the eyes of the beholder.[**] It is with 3. [2,3]-Sigmatropic this in mind that we will attempt to review an area of synthesis that has Rearrangements 27 fascinated us and that we find extraordinarily beautiful, namely the 4. Miscellaneous [X,Y] combination of catalysis and sigmatropic rearrangements in consec- Rearrangements 32 utive and cascade sequences. 5. Outlook 34 1. Introduction 1.1. Defining and Classifying Cascades The development of tandem processes has had a profound 1.1.1. Defining Tandem Reactions and Reaction Ensembles impact on organic synthesis and synthetic planning. Combin- ing multiple reactions in a series affords highly functionalized Chemical reactivity is difficult to define and classify. products with minimal handling. Likewise, with the growing Classifications of tandem reactions become even more body of catalytic reactions and their importance for the cumbersome because of the fact that nearly every chemical synthesis of asymmetric intermediates, it is understandable reaction comprises multiple elementary steps. Such combina- that catalysis is a broad area of focus in the 21st century. tions of elementary steps are generally not categorized as Although the coupling of highly efficient catalytic trans- tandem or cascade reactions, and are simply referred to as the formations to other processes, particularly those that are mechanism of a particular process. Alternatively, combining thermally mediated, could be expected to be a key motif for multiple reactions leads to the concept of tandem reactivity. accessing highly complicated substances with exquisite con- For our purposes, we will adhere to the definitions put forth trol and efficiency, this line of research is in its relative by Tietze, such as the overarching “sequential” or “one-pot” infancy. In this review, we cover cascade reactivity in the reaction.[1] This includes “domino” reactions (also known as context of catalytic transformations that are coupled to bond tandem or cascade) whereby “subsequent reactions result as rearrangements, specifically sigmatropic processes. We will a consequence of the functionality formed by bond formation discuss ensembles of reactions involving the combination of or fragmentation in the previous step.” “Consecutive” catalysis and sigmatropic rearrangements, including Claisen, processes would be ones where additional reagents are Cope, [2,3], [1,2], [1,3], and [1,5] rearrangements. It is our aim added without isolation of the first formed product. One that this analysis will afford future researchers the opportu- caveat that we would like to add to the literature involves nity to build on such cascades for further development of more precisely defining these processes based on the number more selective and powerful transformations. of discrete reactions involved. In fact, the need for such a classification system arose in one of our own publications involving a cascade of three reactions. We initially named this a triple tandem reaction. This descriptor unfortunately implies three sequential tandem events, or six reactions in total, which is incorrect. After a number of discussions with one of our esteemed [*] Prof. A. C. Jones colleagues, the now late Professor Nelson Leonard, we Chemistry Department, Wake Forest University developed a more precise terminology. We propose to use Box 7486, Winston Salem, NC 27109 (USA) the descriptors duet, trio, quartet, quintet, etc. for defining E-mail: [email protected] tandem events involving 2, 3, 4, 5, etc. reactions in a reaction Prof. J. A. May ensemble. Ultimately, this naming system leads one to Department of Chemistry, University of Houston envision entire symphonies of reactions occurring in con- Houston, TX 77204-5003 (USA) Prof. R. Sarpong Department of Chemistry, University of California [**] Sometimes the assessment of beauty is nearly unanimous. The first Berkeley, CA 94720 (USA) four notes of Beethoven’s 5th Symphony (Symphony No.5 in C Prof. B. M. Stoltz minor, Op.67) represent perhaps the most well-known and popular Department of Chemistry and Chemical Engineering, motif in classical music. The orchestral score is shown in the California Institute of Technology background of the cover graphic. Accessed March 20, 2013 from MC 101-20, Pasadena CA 91125 (USA) http://imslp.org/wiki/Symphony_No.5,_Op.67_%28Beethoven,_ E-mail: [email protected] Ludwig_van%29. Angew. Chem. Int. Ed. 2014, 53, 2 – 38 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org &&&& These are not the final page numbers! Ü Ü . Angewandte A. C. Jones, B. M. Stoltz et al. Reviews trolled, multi-reaction cascades. Moreover, the beauty and 1.1.3. Defining Sigmatropic Rearrangements creativity associated with music allows one to draw a more subtle analogy between music and synthesis as well as art and Woodward and Hoffmann defined a sigmatropic rear- science. The classification herein is in contrast to “concerto rangement of order [i,j] to be “the migration of a s bond, catalysis,” which seeks to improve traditional metallic cata- flanked by one or more p-electron systems, to a new position lysts by uniting them with all scales of catalytic assemblies, whose termini are iÀ1 and jÀ1 atoms removed from the from large biological macromolecules to small molecules, an original bonded loci, in an uncatalyzed, intramolecular endeavor which would require and encourage cross-discipli- process.”[3] For the purposes of this review, we will use nary thinking.[2] Both concepts appeal to the musical sense of a somewhat more loose definition based solely on the orchestration in chemical synthesis, and illustrate the goal of transformation and the bonds formed and broken. The strict chemists to attain more exquisite control over chemical uncatalyzed, unimolecular, and concerted definition of Wood- processes. ward and Hoffmann are simply too constricting for this topic. Moreover, we have deliberately limited this review to 1.1.2. Defining Catalysis sigmatropic processes and not attempted to review all pericyclic processes involved in catalyzed tandem reactions. Chemical catalysis can be defined as the utilization of There are excellent reviews written specifically on topics a reagent for the purpose of enhancing the rate of a reaction dealing broadly with tandem and/or pericyclic reactions.[4] It without altering the makeup of the reagent. This definition is was our belief that including such areas in the review would sufficiently broad to encompass catalysts used in both small be an unnecessary repetition of these topics, and the examples (substoichiometric) and large (stoichiometric and superstoi- involving sigmatropic rearrangements (of which there are chiometric) quantities as well as relatively complicated ([Ir- significantly fewer) would not stand out. By incorporating + À + (PCy3)3] BPh4 ) and simple (H ) catalysts. Because of the these two relatively simple strategies (catalysis and sigma- potentially huge numbers of reactions that could fall under tropic rearrangements) in cascade sequences, an incredible this definition, we have necessarily been somewhat selective diversity of transformations is possible. As a result, the in terms of what is included in this review. This is not material described herein does not always fall neatly into a comprehensive review; rather it is our intention to provide subcategories, and multiple transformations presented in one illustrative examples that may ultimately provide the reader section are connected to transformations presented else- with not only breadth in the area, but enough depth to push where. Figure 1 provides a visual overview to our organiza- the science beyond what is currently possible. tion; reactions are grouped according to major “themes” to Amanda C. Jones was born in Evanston, IL Richmond Sarpong was born in 1974 in in 1979. She obtained an A.B. in chemistry Bechem, Ghana. He obtained his B.A. from from Princeton University in 2001 where she Macalester College in 1995, where he worked with Maitland Jones, Jr. In 2007, she worked with Rebecca C. Hoye. In 2001, he obtained her Ph.D. from the University of obtained his Ph.D. from Princeton Univer- Wisconsin under the direction of Hans J. sity, under the direction of Martin F. Sem- Reich. She was an NIH postdoctoral scholar melhack. He was a UNCF-Pfizer postdoc- with Brian M. Stoltz from 2007–2010. In toral fellow in the group of Brian M. Stoltz 2010, she started her independent career at at Caltech from 2001–2004. In 2004, he Wake Forest University, where her research is began his independent career at the Univer- focused on mechanistic organometallic sity of California-Berkeley. His research is chemistry and NMR spectroscopy. focused on the total synthesis of biologically active and complex natural products as a platform for the development of new synthetic methods and strategies. Jeremy A. May was born in Bozeman, MT Brian M. Stoltz was born in Philadelphia, in 1975. He obtained his B.S. in chemistry Pennsylvania, USA in 1970. He obtained his from the University of Utah in 2000 where B.S. in Chemistry and B.A. in German from he worked for Peter Beal.