Alkene metathesis natural product synthesis

In summary, alkyne metathesis seems about to become one of the key reactions frequently employed in the synthesis of increasingly complex natural products. Recently, Trost et al. and Fiirstner et al. reported new hydrosilylation protocols for the convenient, chemoselective transformation of alkynes to E alkenes which will extend the value of alkyne metathesis for natural product synthesis [32],... 

Ruthenium is not an effective catalyst in many catalytic reactions however, it is becoming one of the most novel and promising metals with respect to organic synthesis. The recent discovery of C-H bond activation reactions [38] and alkene metathesis reactions [54] catalyzed by ruthenium complexes has had a significant impact on organic chemistry as well as other chemically related fields, such as natural product synthesis, polymer science, and material sciences. Similarly, carbonylation reactions catalyzed by ruthenium complexes have also been extensively developed. Compared with other transition-metal-catalyzed carbonylation reactions, ruthenium complexes are known to catalyze a few carbonylation reactions, such as hydroformylation or the reductive carbonylation of nitro compounds. In the last 10 years, a number of new carbonylation reactions have been discovered, as described in this chapter. We ex-... 

Although several aspects of alkene metathesis need further improvement or remain to be solved, there is no doubt that this transformation has a profound impact on all sub-disciplines of modern organic chemistry and will continue to shape preparative carbohydrate chemistry and natural product synthesis in the future. 

Alkene metathesis has significant advantages in natural product synthesis for several reasons. First, alkene moieties broadly exist in numerous natural products, and alkene metathesis allows facile access from the readily available or easily prepared olefins to those that are difficult to access. Second, alkene metathesis reactions either do not produce any by-product or only generate the volatile ethylene. Third, alkenes are relatively stable in the multistep synthesis, and are sufficiently reactive to be used in a wide range of transformations to generate other functionalities under specific reaction conditions. Finally, and most importantly, with the help of effective catalysts, alkene metathesis can provide remarkable selectivities (regio-, chemo-, and stereoselectivity) in the challenging synthetic operations. 

In summary, alkene cross metathesis has been successfully applied to numerous total syntheses of complex natural products. In most cases, this reaction can provide high yield, and good regio-, chemo-, and F-stereoselectivities. More importantly, the outcome of selective alkene cross metathesis can be predicted based on the propensity of different olefin for dimerization, making it a reliable transformation for design and implementation of complex natural product synthesis. 

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. 

In summary, the development of catalytic enantioselective alkene metathesis has become a fascinating new direction for olefin metathesis. In this rapidly emerging field, several elegant applications in complex natural product synthesis have been reported to date. We can certainly expect that more active and robust catalysts will be developed and applied to target-oriented synthesis in the near future. 

This chapter is divided into six sections. The first three sections loosely reflect the role of alkene cross-metathesis (CM) in the general plan of the synthesis of natural products, which can be the functionaHzation of terminal olefins appending a side chain to the core of a complex compound, or couphng two fragments to build the entire skeleton of the target molecule. Afterwards, tandem processes involving CM will be presented, followed by a few examples ofene-yne and alkyne CM in natural product synthesis [1]. 

Alkene metathesis has revolutionized modern approaches to the synthesis of a wide variety of useful organic molecules with far-reaching applications in natural product synthesis. The aforementioned examples are testimony to the utihty of catalytic... 

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

The application of alkene [1] - and, more recently, enyne [2] and alkyne - metathesis to the synthesis of natural products has been triggered by the development of powerful catalysts that allow metathesis reactions to be carried out under mild conditions. Scheme 1 outlines two important cases of alkene and alkyne metathesis of particular interest to the synthesis of natural products (together with the general scheme of enyne metathesis, not discussed in this review). The metathesis products can be obtained in high yields, since ethene/2-butyne are formed as volatile products. After the alkene/alkyne metathesis, the substituents (R) of the alkenes/alkynes are located on the same multiple bond. Enyne metathesis can be considered as the more general case of alkene metathesis, because two new double bonds are again formed, albeit now connected by a single bond. 

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]. 

The specific strategy used by Nicolaou and co-workers in their synthesis of the anticancer agent epothilone was alkene metathesis (Scheme 3). This gave cyclization to 16-membered ring compounds while simultaneously cleaving the product from the resin. The alkene functionality formed in this key step was ultimately transformed into the epoxide group of the natural product. 

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