Elsevier

Tetrahedron

Volume 71, Issue 7, 18 February 2015, Pages 989-1009
Tetrahedron

Tetrahedron report number 1066
Palladium-catalysed macrocyclisations in the total synthesis of natural products

https://doi.org/10.1016/j.tet.2014.11.009Get rights and content

Introduction

Macrocyclic compounds occupy a singular position in the fields of chemistry and biology.1, 2 Their unique chemical, physical and medicinal properties make them distinct from acyclic compounds or those containing smaller rings. Much of the recent interest in large-ring compounds has derived from their favourable biological characteristics: the conformational constraint inherent in any cyclic system coupled with the flexibility of a large ring makes it possible to bind selectively to biological targets with high potency. This, along with their other drug-like properties such as good lipophilicity, membrane penetration and solubility, means that macrocycles are often excellent candidates for pharmaceutical compounds.3, 4, 5, 6 Indeed, macrocyclic compounds are finding increasing clinical use, especially as antitumour compounds, immunosuppressants, antibiotics and antifungals.

The majority of macrocyclic drug molecules are currently derived from naturally occurring compounds, either natural products employed directly in the clinic (e.g., vancomycin), or closely related analogues (e.g., ixabepilone,7 a synthetic analogue of epothilone B). The total synthesis of such natural products has historically played an important part in the discovery of new macrocyclic drugs. A number of recent reviews have been published describing families of related biologically active macrocyclic natural products and their chemical synthesis.8, 9, 10, 11 They remain intriguing and challenging targets for chemists, and it is perhaps this synthetic challenge which has hindered the exploration of macrocyclic drugs much beyond those found in nature. Efficient synthetic routes to macrocycles are therefore of utmost importance in the quest for new therapeutic molecules.

There are a number of common methods used for the synthesis of macrocyclic natural products. Since a large number of macrocycles contain an ester or amide linkage, macrolactonisation and macrolactamisation have traditionally played a major role.12 Since its popularisation by Grubbs, ring-closing olefin (alkene) metathesis has likewise become a major route for the synthesis of large-ring compounds.13 Many other methods have also been used including substitution reactions and radical cyclisation approaches.14 Whilst many of these methods have been employed with great success, they are not always efficient and frequently place specific functional-group constraints on the resulting macrocycle. Pd-catalysed reactions represent a major class of macrocyclisation reaction in the context of natural product total synthesis, which have been well developed and utilised over the past several decades. This review is intended to provide an overview of the different Pd-catalysed macrocyclisation reactions used in the synthesis of naturally occurring compounds. The review highlights the potential of Pd-catalysed macrocyclisations as a complementary but alternative approach to other commonly employed macrocyclisation strategies.

Section snippets

Palladium-catalysed macrocyclisation

Pd catalysis has become an invaluable tool in the total synthesis of natural products, allowing the efficient and selective formation of carbon–carbon bonds.15 The main reactions employed (Scheme 1) are the cross-coupling of a halide, or pseudohalide, with organostannanes (Stille),16, 17 organoboron compounds (Suzuki–Miyaura),18, 19 alkenes (Heck)20, 21 or terminal alkynes (Sonogashira).22 The coupling of a nucleophile with an allylic electrophile such as an acetate or carbonate (Tsuji–Trost)23

The Stille reaction

To date, the Stille cross-coupling reaction has unquestionably been the most widely utilised method of palladium-catalysed macrocyclisations in the field of natural product total synthesis. This can be partly explained by the fact that naturally occurring macrocycles frequently contain conjugated alkenes, a group which is arguably best accessed by the Stille reaction, but also due to its reliability, mildness, and the stability and ease of handling of the reagents required. All of these aspects

The Suzuki–Miyaura reaction

The Suzuki–Miyaura reaction has found extensive use in the total synthesis of macrocyclic natural products. Unlike the Stille coupling, mainly used for vinyl–vinyl couplings, the Suzuki reaction has also frequently been used for aryl–aryl or aryl–vinyl macrocyclisations.

The first reported macrocyclisation using this methodology was by Miyaura and co-workers in their 1984 total synthesis of the sesquiterpene natural product humulene (71, Scheme 18), an 11-membered macrocyclic hydrocarbon.72

The Heck reaction

The Heck reaction was one of the first Pd-catalysed carbon–carbon bond forming reactions to be discovered, and has since found extremely wide use in organic synthesis. In an intramolecular sense, the Heck reaction can proceed to give one of two different products as a result of endo- or exo-cyclisation (Scheme 28).100 Whilst the endo-cyclisation is more thermodynamically favoured, affording the more stable substituted alkene, it is also more sterically demanding. In general therefore, normal

The Sonogashira reaction

Whilst it has found some use in the synthesis of macrocyclic peptides119, 120 and rigid synthetic ring systems,121, 122, 123, 124, 125, 126 the Sonogashira reaction has found comparatively little use in the synthesis of macrocyclic natural products, presumably due to the paucity of natural ring systems containing conjugated alkynes.

An early and elegant example was reported by Schreiber and co-workers in their studies towards structural variants of the antitumour natural product dynemicin A (137

The Tsuji–Trost reaction

As in the Heck cyclisation, the intramolecular reaction between a nucleophile and an allylic electrophile presents the possibility of forming two isomeric rings with a difference in ring size of two atoms.132 Whilst the ratio of these two products depends on a variety of factors, and in smaller ring systems (4–9 membered) mixtures are possible, in larger systems (>10 membered) terminal substitution appears to dominate, corresponding to the larger ring size.

Having been one of the first

Miscellaneous reactions

There are a number of original and inventive palladium-catalysed macrocyclisation methods which have been employed in natural product total synthesis but which fall outside the classifications of traditional cross-coupling reactions.

Denmark and co-workers have reported an innovative silicon-assisted palladium-catalysed cross-coupling reaction. Originally developed for medium-ring compounds,148 its synthetic utility was showcased in the total synthesis of nine-membered cyclic ether

Conclusion

This review has collated a diverse array of Pd-catalysed reactions, which have been exemplified in the total syntheses of some challenging macrocyclic natural products. Macrocycles can be formed in a mild and efficient manner in both complex and multifunctional systems showcasing Pd-based chemistry as a key reaction class for total synthesis. Moreover, we believe there is much potential in the utilisation of Pd-catalysed reactions in the synthesis of other types of macrocyclic compounds, which

Thomas O. Ronson was born in Bristol (U.K.) in 1989. He obtained his M.Chem. from the University of Oxford in 2011, having completed his Part II project under Dr Jeremy Robertson. He is currently pursuing a Ph.D. at the University of York under the joint supervision of Professors Ian J. S. Fairlamb and Richard J.K. Taylor. His research involves the development of new methodology utilising palladium catalysis and its application to the total synthesis of naturally occurring and structurally

First page preview

First page preview
Click to open first page preview

References and notes (176)

  • C.J. Roxburgh

    Tetrahedron

    (1995)
  • N. Miyaura et al.

    Tetrahedron Lett.

    (1979)
  • K. Sonogashira et al.

    Tetrahedron Lett.

    (1975)
  • J. Tsuji et al.

    Tetrahedron Lett.

    (1965)
  • J.E. Baldwin et al.

    Tetrahedron

    (1992)
  • R.J. Boyce et al.

    Tetrahedron Lett.

    (1996)
  • G. Pattenden et al.

    J. Organomet. Chem.

    (2002)
  • I.S. Mitchell et al.

    Tetrahedron Lett.

    (2002)
  • I. Paterson et al.

    Tetrahedron Lett.

    (1999)
  • Y. Fukuyama et al.

    Tetrahedron Lett.

    (1999)
  • N. Miyaura et al.

    Tetrahedron Lett.

    (1984)
  • T. Esumi et al.

    Tetrahedron Lett.

    (2004)
  • H. Hioki et al.

    Bioorg. Med. Chem. Lett.

    (2009)
  • C. Thebtaranonth et al.

    Tetrahedron

    (1990)
  • E. Marsault et al.

    J. Med. Chem.

    (2011)
  • C.M. Madsen et al.

    Eur. J. Org. Chem.

    (2011)
  • X. Yu et al.

    Molecules

    (2013)
  • J. Mallinson et al.

    Future Med. Chem.

    (2012)
  • E.M. Driggers et al.

    Nat. Rev. Drug Discovery

    (2008)
  • F. Giordanetto et al.

    J. Med. Chem.

    (2013)
  • A. Conlin et al.

    Nat. Rev. Drug Discovery

    (2007)
  • D.C. Harrowven et al.

    Nat. Prod. Rep.

    (2012)
  • T. Gulder et al.

    Nat. Prod. Rep.

    (2012)
  • F. Kopp et al.

    Nat. Prod. Rep.

    (2007)
  • J. Xie et al.

    Chem. Rev.

    (2014)
  • A. Parenty et al.

    Chem. Rev.

    (2006)
  • A. Gradillas et al.

    Angew. Chem., Int. Ed.

    (2006)
  • K.C. Nicolaou et al.

    Angew. Chem., Int. Ed.

    (2005)
  • D. Milstein et al.

    J. Am. Chem. Soc.

    (1978)
  • D. Milstein et al.

    J. Am. Chem. Soc.

    (1979)
  • N. Miyaura et al.

    J. Chem. Soc., Chem. Commun.

    (1979)
  • T. Mizoroki et al.

    Bull. Chem. Soc. Jpn.

    (1971)
  • R.F. Heck et al.

    J. Org. Chem.

    (1972)
  • B.M. Trost et al.

    J. Am. Chem. Soc.

    (1973)
  • G. Illuminati et al.

    Acc. Chem. Res.

    (1981)
  • M.A. Winnik

    Chem. Rev.

    (1981)
  • E. Brehm et al.

    Org. Biomol. Chem.

    (2013)
  • J.K. Stille et al.

    J. Am. Chem. Soc.

    (1987)
  • J.K. Stille et al.

    Organometallics

    (1991)
  • J.E. Baldwin et al.

    J. Chem. Soc., Chem. Commun.

    (1991)
  • A. Kalivretenos et al.

    J. Org. Chem.

    (1991)
  • K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1993)
  • A.B. Smith et al.

    J. Am. Chem. Soc.

    (1995)
  • V. Farina et al.

    J. Am. Chem. Soc.

    (1991)
  • G. Pattenden et al.

    Synlett

    (1993)
  • A.B. Smith et al.

    J. Am. Chem. Soc.

    (1998)
  • Y. Kim et al.

    Angew. Chem., Int. Ed.

    (1998)
  • D.A. Entwistle et al.

    J. Chem. Soc., Perkin Trans. 1

    (1996)
  • D.A. Entwistle et al.

    Synthesis

    (1998)
  • K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (2000)
  • Cited by (46)

    View all citing articles on Scopus

    Thomas O. Ronson was born in Bristol (U.K.) in 1989. He obtained his M.Chem. from the University of Oxford in 2011, having completed his Part II project under Dr Jeremy Robertson. He is currently pursuing a Ph.D. at the University of York under the joint supervision of Professors Ian J. S. Fairlamb and Richard J.K. Taylor. His research involves the development of new methodology utilising palladium catalysis and its application to the total synthesis of naturally occurring and structurally interesting macrocycles.

    Richard J. K. Taylor obtained B.Sc. and Ph.D. (Dr D. Neville Jones) from the University of Sheffield. Postdoctoral periods at Syntex (USA) and University College London (Prof. Franz Sondheimer) were followed by lectureships at the Open University and then UEA, Norwich. In 1993 he moved to the Chair of Organic Chemistry at the University of York. Taylor's research interests centre on the synthesis of bioactive natural products and the development of new synthetic methodology. His awards include the RSC's Pedler (2007), Synthetic Organic Chemistry (2008) and Natural Product Chemistry (2012) prizes. Taylor is a past President of the International Society of Heterocyclic Chemistry and of the RSC Organic Division and is the current UK Editor of Tetrahedron.

    Ian J.S. Fairlamb was born in Crewe (U.K.) in 1975. He was appointed to a lectureship in Organic Chemistry at the University of York in 2001, following Ph.D. study with Dr Julia M. Dickinson in Manchester (1996–1999), and a post-doctoral research project with Prof. Guy C. Lloyd-Jones in Bristol (2000–2001). He was a Royal Society University Research Fellow (2004–2012) and promoted to full Professor in Chemistry in York in January 2010. He was awarded the 2003 RSC Meldola Medal and Prize and was a recipient of an AstraZeneca younger research award (2007–2010). Fairlamb's research interests interface with catalysis, green chemical synthesis, spectroscopy, biophysics and antibiotics. He is known for work involving Pd catalyst and ligand design, the involvement of higher order Pd species (e.g., nanoparticles) and exploiting mechanistic understanding in end-user applications. The Fairlamb group collaborates with several academic and industrial groups from around the world.

    View full text