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Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis K Reviews K. C. Nicolaou et al. Synthetic Methods Palladium-Catalyzed Cross-Coupling Reactions in Total Synthesis K. C. Nicolaou,* Paul G. Bulger, and David Sarlah Keywords: Dedicated to Richard F. Heck CÀC coupling · cross-coupling · on the occasion of his 74th birthday palladium catalysis · synthetic methods · total synthesis Angewandte Chemie 4442 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200500368 Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489 Angewandte CÀC Coupling Chemie In studying the evolution of organic chemistry and grasping its From the Contents essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science 1. Introduction 4443 than carbon–carbon bond-forming reactions. The Grignard, 2. The Heck Reaction 4445 Diels–Alder, and Wittig reactions are but three prominent exam- ples of such processes, and are among those which have undeni- 3. The Stille Reaction 4452 ably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 4. The Suzuki Reaction 4458 20th century, a new family of carbon–carbon bond-forming 5. The Sonogashira Reaction 4468 reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross- 6. The Tsuji–Trost Reaction 4473 coupling reactions are the most prominent. In this Review, high- 7. The Negishi Reaction 4478 lights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these 8. Summary and Outlook 4481 processes in the art of total synthesis and underscore their future potential in chemical synthesis. 1. Introduction formally result from the substitution of a hydrogen atom in the alkene coupling partner. The first examples of this Ever since the first laboratory construction of a carbon– reaction as we would recognize it today were reported carbon bond by Kolbe in his historic synthesis of acetic acid in independently by Mizoroki (1971)[2] and, in an improved 1845, carbon–carbon bond-forming reactions have played an form, by Heck (1972).[3] However, it would prove to be more enormously decisive and important role in shaping chemical than a decade before the broader applicability of this synthesis. Aldol- and Grignard-type reactions, the Diels– transformation began to be investigated by the wider Alder and related pericyclic processes, and the Wittig and synthetic organic community. The development of catalytic related reactions are but a few examples of such processes asymmetric Heck reactions in the late 1980s led to a further that have advanced our ability to construct increasingly resurgence of interest in this field.[4] The Heck reaction now complex carbon frameworks and, thus, enabled the syntheses stands as a remarkably robust and efficient method for of a myriad of organic compounds. In the last quarter of the carbon–carbon bond formation, particularly in the generation 20th century, a new paradigm for carbon–carbon bond of tertiary and quaternary stereocenters and intramolecular formation has emerged that has enhanced considerably the ring formation, and remains a flourishing area of research. prowess of synthetic organic chemists to assemble complex Significantly, it inspired important variations that, with time, molecular frameworks and has changed the way we think have assumed their own names, identities, and place in total about synthesis. Based on transition-metal catalysis, this synthesis. newly acquired ability to forge carbon–carbon bonds between The palladium-catalyzed cross-coupling of organic elec- or within functionalized and sensitive substrates provided trophiles with vinyl organotin compounds is today known as new opportunities, particularly in total synthesis but also in the Stille reaction (Scheme 1),[5] after the late Professor J. K. medicinal and process chemistry as well as in chemical Stille who pioneered (1978)[6] and subsequently developed[7] biology and nanotechnology. this reaction, although the seeds of discovery were sown Prominent among these processes are the palladium- earlier by Kosugi and his group, who published the first catalyzed carbon–carbon bond-forming reactions. Because reports of transition-metal-catalyzed carbon-carbon bond- the historical, mechanistic, theoretical, and practical aspects forming reactions with organotin compounds a year ear- of these processes have been amply discussed,[1] in this lier.[8,9] Nearly 30 years later the Stille reaction remains one of Review we focus only on selected applications of the most commonly applied palladium-catalyzed carbon–carbon bond- [*] Prof. Dr. K. C. Nicolaou, Dr. P. G. Bulger, D. Sarlah forming reactions in total synthesis, namely, the Heck, Stille, Department of Chemistry Suzuki, Sonogashira, Tsuji–Trost, and the Negishi reactions, and The Skaggs Institute for Chemical Biology with particular emphasis on the pioneering as well as some of The Scripps Research Institute the most recent and exciting examples. In doing so, we hope to 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) illustrate the tremendous enabling ability of these modern Fax : (+1)858-784-2469 E-mail: [email protected] synthetic tools. and The Heck reaction can be broadly defined as the Department of Chemistry and Biochemistry 2 palladium-catalyzed coupling of alkenyl or aryl (sp ) halides University of California San Diego or triflates with alkenes (Scheme 1) to yield products which 9500 Gilman Drive, La Jolla, CA 92093 (USA) Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489 DOI: 10.1002/anie.200500368 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4443 Reviews K. C. Nicolaou et al. the most widely applied palladium-catalyzed carbon–carbon bond-forming reactions, in large part due to typically mild reaction conditions, the ease of preparation of a wide range of coupling partners, and the tolerance of a wide variety of sensitive functionalities in this transformation. In particular, the number of ingenious and daring applications of Stille couplings in the challenging proving ground of total synthesis bears testament to the faith placed in the robustness and versatility of this reaction by practitioners of this art. Notably, the Stille reaction can be viewed as a variation of the Heck reaction in which a hydrogen atom is replaced by a tin-bearing substituent.[10] Another extraordinarily useful palladium-catalyzed carbon–carbon bond-forming reaction involves the palla- dium-mediated coupling of organic electrophiles, such as aryl or alkenyl halides and triflates, with organoboron compounds in the presence of a base (Scheme 1),[11] a process known today as the Suzuki reaction. The first examples of this protocol were reported by the Suzuki group in 1979[12] K. C. Nicolaou was born in Cyprus and edu- cated in the UK and USA. He is Chairman of the Department of Chemistry at The Scripps Research Institute where he holds the Darlene Shiley Chair in Chemistry and the Aline W. and L. S. Skaggs Professorship in Chemical Biology. He is also Professor of Chemistry at the University of California, San Diego. His impact on chemistry, biology and medicine flows from contributions to chemical synthesis, which are described in numerous publications and patents. Paul G. Bulger was born in London (UK) in 1978. He received his M.Chem in 2000 from the University of Oxford, where he completed his Part II project under Dr. Mark G. Moloney. He obtained his D.Phil in chemistry in 2003 for research conducted under Professor Sir Jack E. Baldwin. In the fall of 2003, he joined Professor K. C. Nico- laou’s group as a postdoctoral researcher. His research interests encompass reaction mechanism and design and their application to complex natural product synthesis and Scheme 1. The most commonly utilized palladium-catalyzed chemical biology. cross-coupling reactions. David Sarlah was born in Celje, Slovenia in 1983. He is currently student in the Faculty of Chemistry and Chemical Technology, Uni- although, again, the inspiration or the seeds of this develop- versity of Ljubljana (Slovenia). Since 2001, ment can be found in earlier work by others, in this case the he has been a research assistant at the Lab- [13] [14] oratory of Organic and Medicinal Chemistry groups of Heck (1973) and Negishi (1977). The ensuing at the National Institute of Chemistry (Slov- quarter of a century saw remarkable developments in the enia) where he carried out research on field. Amongst its manifold applications, the Suzuki reaction asymmetric catalysis under the direction of is particularly useful as a method for the construction of Dr. B. Mohar. During the summer of 2004, conjugated dienes and higher polyene systems of high stereo- he was engaged in total synthesis endeavors isomeric purity, as well as of biaryl and related systems. as a member of the azaspiracid team under Furthermore, tremendous progress has been made in the Professor K. C. Nicolaou. development of Suzuki coupling reactions of unactivated 4444 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489 Angewandte CÀC Coupling Chemie alkyl halides, enabling C(sp2)–C(sp3) and even C(sp3)–C(sp3) actually predates the development of both the organostan- bond-forming processes.[15,16] The ease of preparation of nane- (Stille, 1978)[6] and organoborane-based (Suzuki, organoboron compounds (e.g. aryl, vinyl, alkyl) and their 1979)[12] procedures, with the first such examples being relative stability to air and water, combined with the relatively reported in 1977.[26] Nevertheless, the rapid and widespread mild conditions for the reaction as well as the formation of embracement of the latter two protocols by synthetic chemists nontoxic by-products, makes the Suzuki reaction a valuable during the 1980s led to the potential of organozinc reagents in addition to the armory of the synthetic organic chemist. cross-coupling processes being relatively underappreciated Indeed, it has become one of the most reliable and widely and underutilized during this time, particularly in total applied palladium-catalyzed cross-coupling reactions in total synthesis.
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