Alkenes metathesis cyclization

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... 

Dienes are cyclized by intramolecular metathesis. In particular, cyclic alkenes 43 and ethylene are formed by the ring-closing metathesis of the a,co-diene 46. This is the reverse reaction of ethenolysis. Alkene metathesis is reversible, and usually an equilibrium mixture of alkenes is formed. However, the metathesis of a,co-dienes 46 generates ethylene as one product, which can be removed easily from reaction mixtures to afford cyclic compounds 43 nearly quantitatively. This is a most useful reaction, because from not only five to eight membered rings, but also macrocycles can be prepared by RCM under high-dilution conditions. However, it should be noted that RCM is an intramolecular reaction and competitive with acyclic diene metathesis polymerization (ADMET), which is intermolecular to form the polymer 47. In addition, the polymer 47 may be formed by ROMP of the cyclic compounds 43. 

Cleavage via alkene metathesis is particularly useful because clean and selective scissoring of molecules is possible. Cleavage by metathesis can be performed either by cyclization during cleavage [95-101] (ring closing metathesis, RCM), inter-molecular metathesis [101] (cross metathesis), or intramolecular metathesis [95] (Scheme 6.1.23). 

Scheme 10.13 Dialkylammonium and crown ether cyclizations via alkene metathesis.

Besides enyne metathesis [66] (see also the chapter Recent Advances in Alkenes Metathesis in this volume), which generally produces 1-vinylcyclo-alkenes, ruthenium-catalyzed enyne cycloisomerization can proceed by two major pathways via hydrometallation or a ruthenacycle intermediate. The RuClH(CO)(PPh3)3 complex catalyzed the cyclization of 1,5- and 1,6-enynes with an electron-withdrawing group on the alkene to give cyclized 1,3-dienes, dialkylidenecyclopentanes (for n=2), or alkylidenecyclopentenes (for n= 1) [69,70] (Eq. 51). Hydroruthenation of the alkyne can give two vinylruthenium complexes which can undergo intramolecular alkene insertion into the Ru-C bond. 

All the above cascade alkene metathesis reactions are based on the ROM of a cycloalkene moiety. Harrity and co-workers have described the synthesis of functionalized spiro cyclic systems by cascade selective olefin ringclosing metathesis reactions from an acyclic tetraalkene. The selectivity for five-membered ring closure over seven-membered ring closure would be the result of a kinetically favored cyclization process [42] (Scheme 20). The syn-... 

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. 

Successful completion of step ii in Scheme 16.5 was crucial for the whole synthetic project. The interaction of the two terminal double bonds to form the macrocyclic ring, a process clearly against entropic requirements, is fascinating. Known as the Grubbs reaction [31, 32], according to one of its inventors (although many outstanding synthetic chemists substantially contributed to its development and broad application [33, 34]), this cyclization deserves detailed analysis. It is the cyclic variant of an acyclic alkene metathesis, both are presented in Scheme 16.6. 

Dotz reaction, methylenation of ketones and alkene metathesis (dimerization, cyclization). 

As alkene metathesis is extended to more and more chaUenging substrates, improved catalysts and solvents are required. Robert H. Cirubbs ofCaltech developed (Organic Zeft. 2008, iO, 441) the diisopropyl complex 1, that efficiently formed the trisubstituted alkene 6 by cross metathesis of 4 with 5. Herve Clavier and Stephen P. Nolan of ICIQ, Tarragona, and Marc Mauduit of ENSC Rennes found J. Org. Chem. 2008, 73, 4225) that after cyclization of 7 with the complex 2b, simple filtration of the reaction mixture through sihca gel dehv-ered the product 8 containing only 5.5 ppm Ru. 

The merit of CH Cl as a solvent for alkene metathesis is that the catalysts (e.g. 1-3) are very stable. Claire S. Adjiman of Imperial College and Paul C. Taylor of the University of Warwick established Chem. Commun. 2008, 2806) that although the second generation Grubbs catalyst 3 is not as stable in acetic acid, for the cyclization of 9 to 10 it is a much more active catalyst in acetic acid than in CH Clj. Bruce H. Lipshutz of the University of California, Santa Barbara observed Adv. Synth. Cat. 2008, 350, 953) that even water could serve as the reaction solvent for the challenging cyclization of 11 to 12, so long as the solu-bihty-enhancing amphiphile PTS was included. 

Although alkene metathesis is often run in CH Cl, benzene or toluene, these are not necessarily the optimal solvents. Siegfiied Blechert of the TU Berlin established Tetrahedron Lett. 2008, 49, 5968) that for the difficult cyclization of 16 to 17, hexafluo-robenzene worked particularly well. 

In the previous section we have demonstrated that alkene RCM is a powerful and broadly applicable method for the synthesis of complex natural products. However, not every diene or polyene substrate can be successfully cyclized even with the significant advantages available by variation of reaction conditimis including catalyst selection, additive use, solvent choice, and concentration, etc. In this regard, selective relay alkene metathesis provides synthetic chemists with an alternative for reviving these otherwise dead systems when such a limitation is encountered. 

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. 

Similar reactivity is observed in the cyclization of enynes in the presence of the yttrium-based catalyst 70 and a silane reductant [53,54]. The 1,6- and 1,7-enynes 90 and 91 provide -E-alkylidene-cyclopentancs 92 and -cyclohexanes 93 in very good yield (Eq. 15, Scheme 20) [55]. These transformations likely proceed by syn hydrometallation of the 7r-basic alkyne, followed by insertion of the alkene and a-bond metathesis. The reaction of 1,6-enynes tolerated... 

Enyne metathesis is unique and interesting in synthetic organic chemistry. Since it is difficult to control intermolecular enyne metathesis, this reaction is used as intramolecular enyne metathesis. There are two types of enyne metathesis one is caused by [2+2] cycloaddition of a multiple bond and transition metal carbene complex, and the other is an oxidative cyclization reaction caused by low-valent transition metals. In these cases, the alkyli-dene part migrates from alkene to alkyne carbon. Thus, this reaction is called an alkylidene migration reaction or a skeletal reorganization reaction. Many cyclized products having a diene moiety were obtained using intramolecular enyne metathesis. Very recently, intermolecular enyne metathesis has been developed between alkyne and ethylene as novel diene synthesis. 

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