Cross-metathesis outcomes

Table 2.10 Expected cross-metathesis outcomes as a function of the classifications of the alkenes employed ...

Consider a telomer being formed from a cyclopentenyl polymer growing under the pairwise mechanism (Scheme 12.14) with growth being curtailed by cross-metathesis under two extreme conditions (i) with only pent-2-ene present (C4 C5 C6 = 0 100 0) and (ii) with a fully equilibrated mixture of acyclic monoalkenes (C4 C5 C6 = 1 2 1). Under condition (i), one would expect the formation of only hierarchical telomers (n = 1,2,3,4,5, etc.) of the type (C2)-[(cyc-C5) ]-(C3) as the pent-2-ene is split into a C2 and a C3 unit across the growing cyclo polyene. In contrast, under condition (ii), one would expect each hierarchical telomer to be formed in a 1 2 1 ratio of (C2)-[(cyc-C5)n]-(C2) (C2)-[(cyc-C5) ]-(C3) (C3)-[(cyc-Q)n]-(C3)> depending on whether there is cross-metathesis with C4, C5 or C6 (ratio = 1 2 1). The outcome will thus depend on how quickly the pent-2-ene is equilibrated by homo-metathesis to yield the C4, C5 and C6 mixture. Analysis of the rate of pent-2-ene homo-metathesis showed that it was not fast. Indeed, it proceeded at approximately the same rate as the telomerisation reaction. One would thus expect the telomer product early in the reaction to be essentially pure (C2)-[(cyc-C5) ]-(C3) species. Then, as C4 and C6 increase in concentration relative to C5, formation of the (C2)-[(cyc-C5) ]-(C2) and (C3)-[(cyc-C5) ]-(C3) telomers should increase proportionally. This was not found to be the case. 

The overall mechanistic picture that these experiments paint is summarized in Scheme 10.25. For clarity, the processes involved in catalyst activation (i.e., reactions of neophylidene 11) have been omitted. Ethylene opens two pathways that result in isomerization of the metal center direct epimerization of the metal-methylidene species via an unsubstituted metallacycle and interception of the substrate-bound intermediate via cross metathesis to generate a metal methylidene. At low conversions, when the concentration of ethylene in the system is low, these degenerate processes are not kinetically significant, and the initial enantioselectivity is low. As RCM proceeds and ethylene is generated, the rate of epimerization is increased, which, in turn, increases the enantiomeric excess of the cyclized product. These processes also provide an explanation for why the ultimate stereochemical outcome is not dependent on the diastereomer of the catalyst used. 

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. 

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