Metathesis cyclization

While the Pauson-Khand reaction represents a very special cyclopentenone synthesis, our next topic - the metathesis cyclization reaction (MCR) - has the advantage of having a very broad scope in alicyclic as well as heterocyclic chemistry. 

It depends on the imagination and intuition of the chemists, the stability of the starting material, the reaction conditions, and the proper choice of the modern catalysts how high a degree of complexity can be addressed [161]. 

Important and not easy to predict aspects tend to be steric hindrance (R, Rg ), ring size (n ) and double bond configuration Z ).Very impressive progress has been made as far as ring size is concerned. Given the correct catalyst, many cyclizations that in earlier days would have been considered doubtful if not impossible have been accomplished in respectable yields [162]. 

With two comparatively simple examples, the strong influence of substitution pattern and steric hindrance on the cyclization transition states can be demonstrated. 

Although the protected ester 442a did not undergo any cyclization to form the 13-membered lactone 443, the free diol ester 442b provided the corresponding lactone 443 in 76% yield [163]. 

---

Recently, interesting high-yield olefin metathesis cyclizations have been performed in SC-CO2 under the influence of Ru and Mo catalysts A. Fiirstner, D. Koch, K. Langemann, W. Leimer, Angew. Chem. 1997, 109, 2562 Angew. Chem. Int. Ed. Engl. 1997, 36, 2466... 

Only two syntheses of the complete ring structure system present in 1 have been achieved. In 1996 Pandit s group reported the total synthesis of the ABCDE core with the correct stereochemistry at the chiral carbon-centers. Key steps in the synthetic route were the formation of both the eight- and the 13-membered rings by the aforementioned metathesis cyclization reaction [94] (see Scheme 31). 

Table 2 Metathesis cyclization strategy for the synthesis of substituted benzofurans 37...

Scheme 12 Synthesis of cyclic sulfonamides via metathesis cyclization-cleavage...

Hoye TR, Jeon J, Kopel, LC, Ryba TD, Tennakoon MA, Wang Y. Total synthesis of peloruside A through kinetic lac-toiuzation and relay ring-closing metathesis cyclization reactions. Angew. Chem. Int. Ed. 2010 49 6151-6155. 

As briefly introduced earlier (see the transformation of 42b to 42a in Scheme 9.10), in some instances the main RCM event turns out to be slower than that of bimolecular CM with other alkene-containing, methylene-donor molecules in the reaction medium. These donors are nearly always either the terminal alkene in an additional molecule of the substrate or the stoichiometric by-product of metathesis cyclization - most often ethylene. 

Alkanes, dipurin-8-yl-synthesis, 5, 574 Alkanes, poly-N-pyrazoIyl-synthesis, 5, 320 Alkanoic acids, tetrazolyl-anti-inflammatory activity, 5, 835 Alkanoic acids, 4-thienyi-cyclization, 4, 905-906 Alkene metathesis mechanism, 1, 668 Alkenes activated... 

Hexacarbonyldicobalt complexes of alkynes have served as substrates in a variety of olefin metathesis reactions. There are several reasons for complex-ing an alkyne functionality prior to the metathesis step [ 125] (a) the alkyne may chelate the ruthenium center, leading to inhibition of the catalytically active species [125d] (b) the alkyne may participate in the metathesis reaction, giving undesired enyne metathesis products [125f] (c) the linear structure of the alkyne may prevent cyclization reactions due to steric reasons [125a-d] and (d) the hexacarbonylcobalt moiety can be used for further transformations [125c,f]. 

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

---