Macrocyclization Dieckmann condensation

Another general method for the introduction of a nitrogen atom into a macrocyclic skeleton is via the Beckmann reaction. Rearrangement of cyclotridecanone oxime led to cyclic lactam, which was reduced to amine by lithium aluminium hydride (LAH). Further substitution yielded 14-membered mutuporamine <1999TL5401>. Dieckmann condensation was used for the preparation of 14-membered aza ketone 15 <1999JA2919>, but no experimental details were given. 

Hurd and Shah [147] found that the Dieckmann condensation is suitable for macrocyclization and superior to the parallel Thorpe-Ziegler condensation. For example, zearalanone 246) was prepared from diester 243 by using this method... 

Due to the availability of long-chained aliphatic dicarboxylic acids by biotechnological processes [124b], a Dieckmann condensation reaction may also possibly be a useful route to produce this macrocyclic ketone [124c]. 

Hurd and Tsuji promoted the formation of the macrocycle at the ketone using an internal Dieckmann condensation or an intramolecular alkylation of a protected cyanohydrin (368, 369). 

Dieckmann condensation followed by hydrolysis-decarboxylation to give the unsaturated macrocyclic ketone 9-cycloheptadecen- 1-one, whose cis form, civetone, is an attractive perfume component [4,5] equation (2). Moreover, unsaturated dicarboxylic esters and acids are interesting starting materials for the manufacture of polyesters and polyamides [6]. On the other hand, the co-product 9-octadecene can be dimerized and hydrogenated to give 10,11-dioctyleicosane, a lube-oil-range hydrocarbon intermediate [7]. 

Seven-membered and larger rings can be prepared by this method and the yields can often be satisfactory. Carefully controlled nonequilibrium conditions and high dilution techniques are often required. Medium rings (9-12) are either not formed, or formed in low yield, a combination of a Claisen condensation followed by a Dieckmann reaction giving macrocyclic diketones. The conformational energies of the linear precursor influences ring closure. Examples are illustrated in Scheme 19. 

Combination of 1 with 2 led to 15, which was condensed with catechol to give the macrocycle 16. Exposure of 16 to base effected Dieckmann cyclization, to deliver the ring-contracted macrolactone 17, which was carried on to (-)-rapamycin 3. 

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