Dieckmann condensation, lithium

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. 

The indole-2-carboxylate (70.2) undergoes a Dieckmann condensation usine sodium in benzene. An excess of lithium bis(trimethyl ily )atni()Q (LB At thf at -78 C for 5 min cyclizes the thio ester (70.3) to the stereoisomer shown as the only product. The same base has been used (30671 to svnthe ir biologically promising carbapenems. 

The cis relationship between the phenyl and methoxyl groups in CLIX has been confirmed by recent synthetic studies of Uyeo and his co-workers (86). Dihydroisotazettinol (in which the 3-hydroxyl and the phenyl are trans) was oxidized by manganese dioxide to CLIXa. Treatment of CLIXa with lithium aluminum hydride and cyclization of the resultant triol with dilute sulfuric acid gave an ether (CLIXb), the methi-odide of which afforded the neutral compound CLIXc upon Emde reduction. The synthesis of CLIXc started with CLIXd, the condensation product of piperonyl cyanide and methyl acrylate. Dieckmann... 

The additional carbon atom required for building the five-membered ring D is then added by means of methyl-magnesium bromide (16-4). The ester at future C15 is reduced to a carbinol by reaction with lithium aluminum hydride. Swern oxidation (dimethyl sulfoxide and oxalyl chloride) next serves to oxidize each of the two resulting hydroxyl groups to carbonyl functions (16-5). Dieckmann-like base-catalyzed condensation then closes the five-membered ring... 

In this connection it should be remembered that Karl Ziegler had already used metallated secondary amines for condensation purposes. For the synthesis of larger ring compounds he applied the lithium ethylanilide in a type of Dieckmann reaction to ring close dinitriles, such as XIII. Since the metallated amine is soluble in ether, he succeeded in forcing the cyclization by the principle of dilution. 

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