Macrocyclization olefin metathesis

Transition metals have been used to complex Lewis-basic centers in metathesis substrates and to arrange the reacting olefins in such a way that cycliza-tion is facilitated. Olefin metathesis of 122, for example, proceeds with good yield to the bispyridine macrocycle 123 (Eq. 17) [115]. 

Samuel Danishefsky s group at the Sloan Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of their syntheses also used the olefin metathesis reaction (not shown). The synthesis in Scheme 13.62 used an alternative approach to create the macrocycle, as indicated in the retrosynthetic scheme. The stereochemistry at C(6), C(7), and C(8) was established by a TiCl4-mediated cyclocondensation (Step A). The thiazole-containing side chain was created by reaction sequences F and G. The... 

Hodge, R Kamau, S. D. Entropically driven ring-opening-metathesis polymerization of macrocyclic olefins with 21-84 ring atoms. Angew. Chem. Int. Ed. 2003,42, 2412-2414. 

Metathesis is the most useful reaction in recent synthetic organic chemistry.In this reaction, bond fission of two double bonds occurs and two new double bonds are simultaneously formed after exchange (Equation (1)). Ring-closing olefin metathesis is now used for the synthesis of five-membered to macrocyclic ring compounds. 

Analogs of cyclic peptides have been prepared using a variety of spacers and reaction conditions to achieve the macrocyclization. These include olefin metathesis (Section 5.2.3), nucleophilic substitution (Sections 8.2 and 7.2.3), and the Heck reaction [82]. 

Along with diene and diyne metathesis, ene-yne metathesis has also been employed to form macrocycles. This type of metathesis is performed with the catalysts used for olefin metathesis, and the yields are improved in the presence of ethylene, which forms the highly reactive [Ru]=CH2 species. Shair and coworkers took advantage of this reaction twice in the course of their total synthesis of longithorone A [40]. When ene-ynes 51 and 52 are treated with ruthenium complex G1 under an atmosphere of... 

Fig. 27 Examples of thermodynamically controlled reactions employed in the near-quantitative synthesis of MIMs. (a) Disulfide-exchange reaction permits equilibration between a bis(ammo-nium) disulfide dumbbell and a crown ether macrocycle to yield a mixture of [2]- and [3]rotaxanes quantitatively [194], (b) Olefin metathesis at high concentration on a benzylic amide macrocycle greatly favors the catenated species [196]. (c) Self-correcting imine bonds allow for nearly quantitative selection of a [2]rotaxane from an appropriate dynamic combinatorial library [76], (d) A weak nucleophile (E) equilibrates the components of a donor-acceptor [2]catenane in a dynamic Sn2 reaction [205]...

The formation of the macrocycle (O Scheme 26), which had been a serious problem, was achieved hy ring-closing olefin metathesis (RCM). RCM of orthoester 136 was performed... 

Two routes for synthesizing macrolides via olefin metathesis (WCl6/Me4Sn catalyst) have been described by Villemin one route involves the preparation of co-hydroxyacid by metathesis followed by cyclization, the second involves macrocyclic ring closure by metathesis of co,co -diunsaturated ester. 

Nishioka, T., Iwabuchi, Y, Irie, H., and Hatakeyama, S., Concise enantioselective synthesis of (-t)-aspicilin based on a ruthenium catalyzed olefin metathesis reaction. Tetrahedron Lett.. 39, 5597, 1998. Williams, D.R., and Clark, M.P., The macrocyclic domain of phorboxazole A. A stereoselective synthesis of the Cj-Cjj macrolactone. Tetrahedron Lett., 40, 2291. 1999. 

Olefin metathesis has been used by a number of workers to produce macrocyclic musks. One of the earliest examples is Mol s synthesis of civetone from methyl oleate. This takes advantage of the ideally placed double bond in the starting oleic acid. Unfortunately, the ds-geometry of the olefin is lost on metathesis and a mixture of isomers results. Furthermore, almost half of the weight of the starting material is lost as the unwanted 9-octadecene. Dieckmann cyclisation of the metathetical diester, followed by hydrolysis and decarboxylation, gives a mixture of E- and Z-civetone. The synthesis is shown in Figure 4.59. 

Olefin metathesis in synthesis of heterocycles including macrocycles 00AG(E)3012. 

Efficient construction of the macrocyclic ring is essential for achievement of the total synthesis of macrolide antibiotics. Macrolactonization and intramolecular Wittig-type reaction have been frequently used so far. In recent years, olefin metathesis and Stille-type reaction for formation of C-C bonds have been efficiently applied to the construction of macrocyclic rings. 

The problems hindering the total synthesis of epothilones involve (1) stereoselective construction of C3, C6, C7, and C8 chiral centers, (2) synthesis of the thi-azole unit having a 15S-hydroxyl group, (3) construction of (12Z)-olefin, (4) macrocyclization, and (5) stereoselective epoxidation of (12Z)-olefin. The total syntheses of epothilones have been achieved via three strategies for the macrocyclization (Fig. 9) (1) macroaldolization, (2) ring-closing olefin metathesis, and... 

---