Tetrahedron Letters 55 (2014) 6156–6162 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Digest Paper Divergent strategy in natural product total synthesis ⇑ Jun Shimokawa Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan article info abstract Article history: Divergent strategy in natural product synthesis allows the comprehensive synthesis of family natural Received 24 July 2014 products. Efficient formulation of this idea requires the biosynthetic/biosynthesis-inspired insight toward Revised 13 September 2014 the well-orchestrated design of a pluripotent late-stage intermediate, in concomitant with the applicabil- Accepted 15 September 2014 ity of the intermediates for versatile transformations. This digest focuses on the actual applications of Available online 22 September 2014 those strategies in natural product synthesis with an emphasis on the recipes for the choice of the com- mon intermediates. Keywords: Ó 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY license Diversity-oriented synthesis (http://creativecommons.org/licenses/by/3.0/). Diverted total synthesis Collective total synthesis Divergent total synthesis Contents Introduction. ........................................................................................................ 6156 Divergent approach allows the streamlined syntheses of biosynthetically similar natural products . ............................... 6157 Baran’s syntheses of eudesmane terpenes8 ............................................................................. 6157 Fukuyama’s syntheses of all the amathaspiramides9 ..................................................................... 6158 Movassaghi’s syntheses of all agelastatins10 ............................................................................ 6159 Li’s syntheses of Taiwaniaquinols and Taiwaniaquinones11 ................................................................ 6159 Baran’s syntheses of meroterpenoids12 ................................................................................ 6160 Boger’s divergent syntheses of Kopsia alkaloids13 ....................................................................... 6160 MacMillan’s syntheses of several families of indole alkaloids6 ............................................................. 6160 Oguri’s syntheses of biogenetically related indole alkaloids14 .............................................................. 6161 Conclusion . ........................................................................................................ 6162 References and notes . ........................................................................................ 6162 Introduction has to deal with structurally complex molecules, serendipitous discoveries emerge. It is also important to note that reaching to Chemists have often made an analogy of natural product total the single summit of the highest peak is not always the purpose synthesis with climbing the mountain. During the climbing, one of climbing the mountain. Walking along the ridge line of the has to find out a mountain path that you believe would go to the adjoining peaks of the mountain range has its own allure. Likewise, summit of the heap. By trying for those shorter and more efficient the synthesis of an array of compounds with small structural routes, there would be more chances for gaining unfamiliar and differences has its rich potential information. When combined, unexpected precious experiences. This shows similarity to the pro- information on those compounds is able to provide a detailed cess toward the evolution of the artificial synthetic route of the tar- structure–activity relationship, which would not be available from get natural product. By keeping this endeavor, one may notice a a single-shot scrutiny of a certain molecule.1 The aim of those novel synthetic method that would be hard to get across without divergent syntheses is the streamlined construction of a set of trying to manage such synthetic challenges. Therefore, when one invaluable compounds, which contrasts to the traditional target- oriented linear or convergent synthesis (Fig. 1). One of the most popular ideas of those kinds is called ‘Diversity-oriented synthe- ⇑ Tel.: +81 (0) 52 788 6105; fax: +81 (0) 52 789 2959. sis’.2 This idea was originally proposed by Schreiber and has E-mail address: [email protected] http://dx.doi.org/10.1016/j.tetlet.2014.09.078 0040-4039/Ó 2014 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 6157 naturally occurring molecules as a synthetic intermediate. This is because of the high polarity or instability that would not be com- patible with most of the laboratory organic synthesis techniques. Thus the selection of the one or several target molecules and designing of the artificial common synthetic intermediate would be the most significant and difficult points of the divergent way of total synthesis. This digest thus deals with the recent inspiring examples of nat- ural product synthesis that deals with an appreciable collection of biosynthetic relatives. With an emphasis on the strategy for choos- ing the common intermediate, the potential of this productive strategy will be discussed. Divergent approach allows the streamlined syntheses of biosynthetically similar natural products Baran’s syntheses of eudesmane terpenes8 Figure 1. Schematic explanation of linear, convergent, and divergent synthesis. The construction of the core structure of certain family of influenced much to the drug discovery. Another important concep- natural products, especially terpenes, could be made possible by tual approach proposed by Danishefsky is named ‘Diverted total two-phase synthesis. The common carbon skeleton of the family synthesis’.3 This is an approach toward the preparation of a natural is synthesized first by reducing the use of protective groups and product-like compound library by the derivatization of a versatile functionality-manipulating steps. This is followed by the introduc- synthetic intermediate. These concepts led to the successful find- tion of hetero- or carbon-functionalities. Their approach was most ing of various bioactive compounds, which showcased its poten- impressively presented in their syntheses of various eudesmane tials to reach the real drug candidate.4 terpenes by the diverse way of introducing oxygen functionality It is natural to infer that these ramifying approaches have an to the common precursor dihydrojunenol (1)(Scheme 1). Diphe- effect on the natural product synthesis. The original definition of nylprolinol methyl ether-mediated enantioselective Michael–aldol this ‘Divergent total synthesis’ approach was given by Boger to combination between 2 and 3 gives enone 4, followed by a side be ‘the synthesis of at least two members of the class of com- chain introduction and Heck reaction to give 5. This was pounds’ from the common, advanced synthetic intermediate.5 transformed to dihydrojunenol (1) in a very efficient manner via Application of divergent synthesis could be encompassed even to 1,4-addition and reduction on a gram scale. These eudesmane ter- the groups of molecules with different family names. The method pene members with various oxidation states were biosynthesized with this widened applicability to several skeletons is what Mac- following these transformations via P450 oxidation. The regiose- Millan defines as ‘Collective total synthesis’.6 The syntheses that lectivity observed in Nature is usually difficult to reproduce in lab- could fall into this type seem to be gathering more and more atten- oratory synthesis. The evolution of C–H oxidation procedure with tion.7 Upon planning the synthetic route to these projects, it is nec- predictable regio- and chemoselectivity is thus necessary for exe- essary to set the pluripotent late-stage synthetic intermediate that cuting the diversified syntheses of this natural products family. could transform into the array of the desired target families. In The oxidation of unactivated terpene C–H bond is made possible most cases, those targets are in one or several biosynthetic families by the functional group-tethered method. One is the TFDO that share the same biosynthetic intermediate. The mutual rela- (methyl(trifluoromethyl)dioxirane)-mediated C–H oxidation that tionship among those target compounds, about appendage, stereo- regioselectively oxidizes the C–H bond within the bicyclic core chemical or skeletal diversity, has a great influence on the strategy structure. Interestingly, C–H bromination by Hofmann–Löffler– chosen. The biosynthetic intermediates could be a candidate for Freytag (HLF) reaction, the other C–H functionalization process the common intermediate, but it is often difficult to use those they employed, mediated the functionalization of the other C–H Scheme 1. Baran’s syntheses of eudesmane alkaloids. 6158 J. Shimokawa / Tetrahedron Letters 55 (2014) 6156–6162 Scheme 2. Fukuyama’s syntheses of all the amathaspiramides. position of side chain isopropyl group. With this orthogonal oxida- to find out the pluripotent late-stage intermediate for the compre- tion procedures and 1,2-directed oxidation methodology, various hensive syntheses of all the members of this family. To this end, an eudesmane terpenoids were synthesized