Intramolecular Dieckmann

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Dihydrofuranones can be generated by Michael addition of anions derived from a-hydroxyesters to a,/3-unsaturated substrates. The resulting intramolecular Dieckmann condensation yields substituted furanone rings (Scheme 82) (57HCA1157). 

Intramolecular Dieckmann cyclization of polystyrene-bound pimelates has been used to prepare (l-keto esters (Entry 4, Table 3.41). Oxidative cleavage reactions leading to the formation of aldehydes include the ozonolysis of resin-bound alkenes, the periodate-mediated cleavage of 1,2-diols, and the oxidation of Wang resin derived ethers (Entries 5-7, Table 3.41). 

Quinuclidine ring formation starting from piperidine derivatives is carried out usually by (a) intramolecular alkylation or acylation or (b) intramolecular Dieckmann condensation. 

A library of di- and trisubstituted 5-amino-l 77-1-benzazepine derivatives was assembled through attachment of a preformed 1-benzazepine unit to an aminomethylated polystyrene resin. The initial solution phase synthesis of the 1-benzazepine moiety was based on an intramolecular Dieckmann cyclization (type d) followed by a ketone to primary amino group transformation via reduction ( NaBH3CN) of an imine intermediate <2007JC0487>. 

The first cyclative cleavage of a small molecule was Crowley and Rapo-port s study41 of intramolecular Dieckmann condensations on solid phase (Fig. 13), which was complicated by the reversible nature of the cyclization. Despite the unique opportunities afforded by C-C rather than C-X bond formation during cleavage, there are few examples from the combinatorial age. A modern version of the Claisen-type condensation by Kulkarni and Ganesan42 uses a strongly acidic active methylene group to ensure unidirectional cyclization, and furnishes tetramic acids with three points of diversity. 

Original Synthesis. The first attempted synthesis of 5 -biotin in 1945 afforded racemic biotin (Fig. 1). In this synthetic pathway, L-cysteine [52-90-4] (2) was converted to the methyl ester [5472-74-2] (3). An intramolecular Dieckmann condensation, during which stereochemical integrity was lost, was foUowed by decarboxylation to afford the thiophanone [57752-72-4] (4). Aldol condensation of the thiophanone with the aldehyde ester [6026-86-4]... 

Application of intramolecular Dieckmann-condensation for the solid-phase synthesis of lactones by Rapoport et al. (7. Macromol. Sci. Chem. 1973,1117)... 

In the first and asymmetric total synthesis of rubriflordilactone A shown below, the advanced intermediate furofuranone was constructed through an intramolecular Dieckmann condensation followed by a cationic deoxygenation reaction (14JA16477). 

Tenuazonic acid (741), a phytotoxin produced by Alternaria spp., is structurally related to the tetramic acid family of compounds, and has been found to exhibit antibiotic activity (511). Since 1964, there have been several publications on the total synthesis of 741 (512-515), including the report by Poncet and his group in 1990 (516) (Scheme 11.10). A general method to synthesize the tetramic acids is an intramolecular Dieckmann cyclization of (V-acyl amino esters. Beginning with methyl L-isoleucinate 780, the A/-acyl compound 782 was obtained through a nucleophilic reaction (512), which then cyclized to tenuazonic acid 741 under basic conditions and neutralization by acidic work-up. The synthetic product showed a diastereomeric excess of 89%, with the major epimer presenting the same configuration as its precursor (517). 

In Summary Claisen condensations are endothermic and therefore would not take place without a stoichiometric amount of base strong enough to deprotonate the resulting 3-ketoester. Mixed Claisen condensations between two esters are nonselective, unless they are intramolecular (Dieckmann condensation) or one of the components is devoid of a-hydrogens. Ketones also participate in selective mixed Claisen reactions because they are more acidic than esters. 

Claisen condensation 2 Esters — j8-ketoester 1,7-diester cyclic /3-ketoester (intramolecular Dieckmann condensation) (23-1)... 

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