Macrocycli zations

We later determined that with lower catalyst loadings (15 mol% 2), reaction efficiency suffers (<50% conversion). When Ru complex lb was used (20 mol%, benzene, 80°C), 5-10% dimer derived from reaction of the terminal olefins was formed as the only product. Continued investigation of the catalytic macrocycli-zation indicated that, with freshly prepared and recrystallized Mo catalyst, the metathesis process occurs smoothly at 22 °C to afford 2 in 90% isolated yield after only 4 h. With 40 mol% 2, the yield improved to 97%, and less than 20 mol% catalyst gave notably lower conversions and yields. 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

Boger and coworkers reported the first total synthesis of chloropeptin II and later its transformation into chloropeptin I (2009JA16036). The key step to this total synthesis was macrocycHzation of peptide 31 by an intramolecular Larock indole heteroannulation. This intramolecular reaction between a substituted 2-bromoaniline with a removable terminal alkyne substituent afforded simultaneous regioselective indole ring formation and macrocycli-zation. The TES substituent of the alkyne dictates indole cyclization regio-selectivity (Scheme 20). 

We had thus successfully synthesized the macrolactone skeleton of 1 via acyl ketene macrocyclization of 67. However, the synthesis of the macrocycli-zation precursor 67 was far from satisfactory with respect to the overall synthetic efficiency. At this point, we preferred to reconsider our synthesis plan, rather than resorting to hrute-force synthesis. 

SCH EME 17.4 Hydrogen templated synthesis of trefoil knot obtained by [3 + 3] macrocycli-zation.2 Right Crystal structure (adapted from CCDC 139484) of trefoil knot with intrastrand H-bonding interactions. H atoms, cyclohexyl, and methyl groups are omitted for clarity. 

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