2122▌2122 SHORT REVIEW Accessshort review to High Value Natural and Unnatural Products through Hyphenating Chemical Synthesis and Biosynthesis KevinApproaches to AccessingP. P. Natural Mahoney, Products and Their Analogues Duncan R. M. Smith, Emma J. A. Bogosyan, Rebecca J. M. Goss* School of Chemistry and BSRC, University of St Andrews, St Andrews, KY16 9ST, UK Fax +44(1334)463808; E-mail: [email protected] Received: 08.04.2014; Accepted after revision: 04.06.2014 Abstract: Access to natural products and their analogues is crucial. Such compounds have, for many years, played a central role in the area of drug discovery as well as in providing tools for chemical biology. The ability to quickly and inexpensively acquire genome sequences has accelerated the field of natural product research. Ac- cess to genomic data coupled with new technologies for the engi- neering of organisms is resulting in the identification of large numbers of previously undiscovered natural products as well as an increased understanding of how the biosynthetic pathways respon- sible for the biogenesis of these compounds may be manipulated. This short review summarizes and reflects upon approaches to ac- cessing natural products and has a particular focus on approaches combining molecular biology and synthetic chemistry. 1 Introduction 2 CHEM: Total Synthesis 3 BIO-CHEM: Semi-Synthesis 4 CHEM-BIO: Precursor Directed Biosynthesis 5 BIO-CHEM-BIO: Mutasynthesis 6 BIO-BIO: Combinatorial Biosynthesis Kevin Mahoney (top left) completed his BSc in Medicinal Chemistry 7 BIO-BIO-CHEM: Genochemetics: Gene Expression En- at Queen’s University Belfast in 2009. He then worked in the pharma- abling Synthetic Diversification ceutical industry as a process and development chemist for two years 8 Conclusions and Future Directions in Natural Product Ana- before joining the Goss group in 2011 to study towards a PhD in elu- logue Generation cidating and manipulating natural product biosynthesis, with a partic- Key words: alkyl halides, antibiotics, antifungal agents, antitumor ular focus upon glycosylation. agents, biosynthesis, chemoselectivity, cross-coupling Duncan Smith (top right) completed his MChem degree at the Uni- versity of East Anglia in 2012, where he undertook a Masters research project within the Goss group. He then joined the Goss group as a PhD student and moved with the group to the University of St 1 Introduction Andrews, where he is currently working on designing genochemetic systems that use epoxides as functionalizable handles. Emma Bogosyan (bottom left) completed her BSc degree in chemis- Natural products provide an unparalleled starting point for try at the University of East Anglia where she received the Katritzky drug discovery – over 60% of anticancer agents and over Prize and Medal for outstanding performance in the Final Assess- 70% of antibiotics entering clinical trials in the last three ment. She is currently studying towards a PhD with Dr Rebecca Goss decades were based on such compounds.1 In order to gain developing genochemetic systems. a full understanding of how a drug works and to generate Rebecca Goss (bottom right) is a Reader (Associate Professor) in Organic Chemistry and Biomolecular Chemistry in the School of compounds with improved biological activity and physi- Chemistry and BSRC at the University of St Andrews Scotland. Her cochemical properties, ready synthetic access to series of research focuses on natural products of medicinal value, elucidating analogues is essential. In recent years, pharmaceutical in- biosynthetic pathways, and in combining organic synthesis and bio- dustries have shied away from natural products due to the synthesis to enable rapid access to series of natural product analogues. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. perceived synthetic intractability of such analogues and She is the recent recipient of an ERC Consolidator grant. the misconception that it is not possible to carry out thor- ough structure activity relationship (SAR) assessment on these compounds. Libraries of natural products are often moieties. Whilst these combinatorial libraries may be eas- not readily accessible using conventional synthetic organ- ily made, they have so far delivered little of pharmaceuti- ic chemistry alone; this has caused the pharmaceutical in- cal interest. Christopher Lipinski, a key figure and dustry to pursue combinatorial libraries of non-natural authority in medicinal chemistry, urged in a C&EN cover story for scientists to return to and focus on natural prod- ucts for drug discovery. As a result of largely abandoning SYNTHESIS 2014, 46, 2122–2132 natural products, industry’s drug discovery pipelines are Advanced online publication: 09.07.20140039-78811437-210X beginning to run dry.2 DOI: 10.1055/s-0034-1378359; Art ID: ss-2014-m0231-sr © Georg Thieme Verlag Stuttgart · New York SHORT REVIEW Approaches to Accessing Natural Products and Their Analogues 2123 Natural products are privileged molecules; being generat- synthesis.7,8 Halaven represents a step-change for the ed by proteins, they are predisposed to interact with pro- pharmaceutical industry, being considerably more com- teins. Rather than dismiss such a treasure trove of useful plex than other marketed pharmaceuticals that have been drug leads, new approaches to address access to syntheti- accessed through total synthesis and demonstrating the cally challenging series of natural product analogues are enhanced skill and determination of this industry. required. This short review highlights the approaches Me available for accessing new to nature compounds, exam- +H N 3 OH O ines their pros and cons and provides case studies exem- O – plifying these routes to these designer molecules. If Me S O H O O O analogue access is the true goal, the philosophy must be to O O H H utilize the most expeditious combinations of synthetic or- O O ganic chemistry and harnessed biosynthesis, as dictated O O by the natural product target and the desired analogues, to yield sufficient of each analogue for downstream studies. O To best summarize the different approaches that are avail- able to access natural product analogues we defer to the A: eribulin mesylate simple classification as defined by Kirschning and Hahn,3 4 H which we have previously utilized. In this system, two HO H H H HO O O abbreviations are used: CHEM, referring to total or partial O O HO O H O O O O chemical synthesis, and BIO, describing a series of bio- H H H O O synthetic steps. For example, precursor-directed biosyn- H H H O thesis, where a biosynthetic pathway is coerced to accept O O O and incorporate a synthetic substrate into a natural prod- uct, is termed CHEM-BIO; the biosynthetic substrate an- O alogue is first synthesized (CHEM), then administered to an organism and incorporated by the organism’s biosyn- B: halichondrin B thetic machinery (BIO) to generate an analogue of the nat- ural product. Figure 1 Eribulin mesylate (A) with 19 stereogenic atoms is a phar- maceutically optimized analogue of halichondrin (B) and provides a challenging case for total synthesis, which is the only option for non- innate production due to a lack of natural intermediates necessary for 2 CHEM: Total Synthesis – The Traditional 8 Approach semi-synthetic processes. The two traditional methods of accessing natural product Total synthesis, as well as being essential to enable access analogues are total synthesis (CHEM) of which a series of to certain bioactive natural products, can also be invalu- 5 highlights are reviewed in ‘Classics in Total Synthesis’, able for full structural and stereochemical characterization and semi-synthesis (BIO-CHEM, section 3). For certain of newly isolated compounds or providing insight into a natural products, total synthesis may currently provide the natural product’s biogenesis. The exquisite structures of only means of access as isolation from a rare natural many of these molecules has provided inspiration for syn- source may only have been achieved once. In other cases, thetic chemists to develop novel methods, of particular the organism may be difficult to cultivate, intractable to note is Aggarwal’s elegant assembly of polyketides and genetic or chemical manipulation, or produce only low polyketide like molecules using lithiation-borylation levels of the natural product or the analogues. For simple chemistry (Scheme 1).9 natural products, total synthesis may represent the most economical and expedient approach to accessing series of It is not always possible for isolation chemists to fully analogues or even the parent natural product itself. structurally characterize the natural products that they dis- cover by spectroscopic methods alone and in certain chal- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. A multitude of pharmaceutically attractive compounds lenging cases total synthesis is essential to confirm 6 are found in the marine environment. Bioactive com- structural characterization.10–13 Examples include the syn- pounds which are isolated from tunicates and sponges thesis of chamuvarinin (Scheme 2), an acetogenin from may often prove difficult to culture in laboratories and ac- the roots of the West African plant Uvaria chamae, en- cess to more than a few milligrams of such compounds is abling the relative and absolute stereochemistry to be as- uncommon leaving total synthesis providing the sole op- signed across the rare motif at the center of the structure tion. Eribulin mesylate (Figure 1), a polyketide macrocy- in which a tetrahydropyran is linked to a bis-tetrahydrofu- cle (marketed by Eisai Ltd. as Halaven) has potent ran;14 synthesis of the C1–C12 fragment of tedanolide C anticancer activity and is used in the treatment of breast (Scheme 3);15 and synthesis of the stereochemically con- cancer. This analogue of halichondrin B (Figure 1), pro- troversial C′D′E′F′ domain of vast marine polyketide mai- duced by the Halichondria genus of sponge, is structural- totoxin (Scheme 4).16 ly complex and is accessed through an impressive total © Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 2122–2132 2124 K.