RCM-based macrocyclizations

Scheme 28 (Z)-selective RCM-based macrocyclization in the penultimate step in the total synthesis of halicholactone (151) [82]...

In order to properly assess the scope of such RCM-based macrocyclizations, however, it is important to comment further on the effect of conformational con-... 

RCM-based macrocyclization reactions as they potentially sequester the catalyst in an unproductive form. A recent total synthesis of gloeosporone 86 addresses this aspect and describes a simple, yet efficient way to overcome this limitation [31]. 

One drawback of RCM-based macrocyclizations is the formation of /Z-isomeric mixtures. Because high yields are often obtained, however, and the experimental set-up is simple, RCM is an attractive route to macrocyclic compounds. 

When large rings are constructed by RCM, 2JE- somer c mixtures can result. Hence RCM-based macrocyclizations are best suited for the preparation of intermediates in which the C-C double bond formed by metathesis can be removed (by, e.g., hydrogenation or oxidation) at a later stage of the synthesis. 

Although the experimental data summarized above provide convincing evidence that a subtle and transient template effect resulting from a finely tuned Lewis-acid/Lewis-base interaction is operative in productive RCM-based macrocyclizations, it should be emphasized that a detailed spectroscopic characterization of the key intermediates involved has not yet been achieved. Therefore structure A represents just a mnemotic device indicating that polarity, distance, and affinity are key issues in such transformations but does not imply any structural information [32]. 

The results obtained with the various metathesis substrates depicted in Scheme 44 demonstrate the lack of a stereopredictive model for the RCM-based formation of macrocycles, not only by the strong influence that may be exhibited by remote substituents, but also by the fact that the use of more reactive second-generation catalysts may be unfavorable for the stereochemical outcome of the reaction. Dienes 212a-f illustrate the influence of the substitution pattern. All reactions were performed with Grubbs first-generation catalyst A... 

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. 

Furstner s group reported syntheses of tricolorin A and G [200,201] based on macrocyclization by ring-closing metathesis (RCM), affording macrocycles in high yields. In this section, total synthesis of woodrosin I [202], which may possess the most intricate stmcture in this series, reported by Furstner s group is described [203,204,205]. 

This assumption, however, has been totally revised in recent years surprisingly enough, RCM turned out to be among the best entries into macrocycles even with con-formationally flexible diene substrates, provided that a few basic parameters are properly assessed [32]. These key features indicate that a subtle template effect is responsible for the effectiveness and scope of RCM-based ring closure reactions. 

The importance of conformational effects on RCM-based macrocychzations was also highlighted by Bajwa and Jennings, who discoimected aigialomycin D at the Cl -C2 linkage (Scheme 7.22c) [83]. It was shown that the stereochemistry at C6 dramatically influences the outcome of the macrocyclization. RCM on triene 196 led to the exclusive formation of six-membered ring, whereas the reaction on the 6 -epimer of 196 was efficient in generating the 14-membered macrocycle [83]. 

Metaferia et al. reported on the synthesis and cytotoxicity of C3 -C4 linked macrocyclic taxoids in 2001. The synthetic strategy was also based on RCM. Similar to Ojima et al. s finding, these compounds (100) are less active than paclitaxel in both cytotoxicity and tubulin assays.However, after careful inspection of the bioactive conformations of taxoids with computer simulation and nuclear magnetic resonance (NMR) experiments, they designed several C-4 and C3 -Ph orf/io-position linked taxoids (101) that were highly active, several times better than paclitaxel. ... 

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