Cascade Metathesis in Natural Product Synthesis

Metathesis in Natural Product Synthesis Strategies, Substrates and Catalysts. Edited by Janine Cossy, Stellios Arseniyadis, and Christophe Meyer 

Copyright 2010 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978 3-527-32440-8 

There are many combinations possible of metathesis reactions that can be used in domino metatheses, increasing process complexity with the number of transformations included. Natural product syntheses with ring-closing metathesis (RCM)-cross-metathesis (CM) sequences are described in this section. Ene-ene and ene-yne-ene cascade reactions in a two-metathesis step process will also be discussed. 

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In the previous section we have shown that tandem ene-yne-ene RCM has been broadly used for the rapid and efficient construction of complex frameworks. In principle, selective alkene metathesis can be combined with other types of transformation to achieve a cascade reaction, which will provide a tremendous increase in molecular complexity [77]. Therefore, in this section, we highlight several recent examples of cascade reaction involving selective alkene metathesis for natural product synthesis. 

When cascade reaction involving metathesis is applied in the complex natural product synthesis, proper sequence of multistage metathesis processes is crucial. The following example underscores this point. In 2006, Hoye and coworkers reported the total synthesis of (+)-gigantecin (125) [82]. In this work (Fig. 33)... 

Multiple cyclo olefinic relays are also suitable substrates to promote cascades of RCM-ROM-RCM reactions [9] (Scheme 16). Thus, W-protected polycyclic amines have been synthesized in moderate to good yields, but an increasing number of cyclopentene relays gave rise to less efficient cascade transformations. This ring rearrangement metathesis (RCM-ROM-RCM) has been extensively reported by Blechert and co-workers for its application in the synthesis of natural products [30-34]. 

A similar type of cascade reaction has been carried out with cyclic alkenes bearing only one olefinic side chain to obtain substituted heterocycles via ruthenium-catalyzed ring closing-ring opening metathesis (RCM-ROM) reactions. The preparation of enantiomerically pure cis- or trans-a,a -disubstituted piperidines has been achieved in the same yield for the two diastereoisomers [35] (Scheme 17). This reaction has also been used as a key step for the synthesis of natural products [36-39]. 

A very powerful cascade reaction had been developed by Cho and Lee in their approach to the total synthesis of (3I ,9i ,10/ )-Panaxytriol 179 (Scheme 7.37) [81], which was isolated from Panax ginseng in 1983 [82]. The cascade sequence was initiated by relay metathesis, which is then followed by metallotropic [l,3]-shift and cross-metathesis. This approach has become an efficient way for the synthesis of natural products with highly unsaturated carbon skeletons. Treatment of 174 with Grubbs second-generation catalyst in CH Clj at 40 °C in the presence of 2.0 equiv of alkene 175 generated the expected prodnet 178 in 61% yield as a mixture of Z E-isomers. Surprisingly, ruthenium alkylidene 176 was isolated in 10% yield and could be converted to 178 upon treatment with 175. This confirms that complex 176 is a catalytically viable intermediate in the catalytic cycle. 

There is only one example in the literature where an enyne RCM coupled to an intermolecular CM in a sequence process has been applied in the synthesis of a natural product. The synthesis of (-i-)-8-epi-xanthatin, isolated from the leaves extracts from Xanthium canadense, was proposed by Martin et al. through an enyne RCM-CM cascade combining ring closing of 8 with a CM with 9 [13]. The special challenge for this transformation consists in the use of an electron-poor olefin for the final metathesis reaction. The use of [Ruj-III (20mol%), the catalyst of choice for this type of transformations [14], and an excess (10 equiv.) of the methyl vinyl ketone 9 resulted in the formation of the desired product in 83% yield (Scheme 11.3). 

These types of transformations were first explored by Grubbs et al. [40] and have often been applied in the synthesis of many natural products. From a mechanistic point of view, these metathesis cascades possess an additional driving force, apart from the release of ring strain, which consists in an entropy gain with the release of a molecule of ethylene as volatile by-product. like other RRM reactions discussed, oligomerization is an important side reaction, which may be suppressed by the use of an ethylene atmosphere and by performing the reaction at higher dilution. 

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