Claisen cyclization

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

Scheme 10.18. Solvent-free domino Wittig-Claisen cyclization-process.

Intramolecular Claisen cyclizations occur with ethyl adipate and pimelate because five- and six-membered rings are formed. 

Treatment of functionalized vinyllithium, 28, with allylmaghesium bromide in the presence of zinc bromide leads to a stereoselectively substituted, metallated cyclopropane, 29, via a tandem metalla-Claisen-cyclization reaction (equation 48 )M. The produced cyclo-... 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

An internal Claisen condensation of a diester forms a ring. Such an internal Claisen cyclization is called a Dieckmann condensation or a Dieckmann cyclization. Five- and six-membered rings are easily formed by Dieckmann condensations. Rings smaller than five carbons or larger than six carbons are rarely formed by this method. 

This finding suggests that the WAS chain extension component produces a heptaketide and catalyzes the cyclization and aromatization of the first ring. The C-terminal domain must therefore catalyze a second (Claisen) cyclization reaction to... 

Still another method for constructing the carbon skeleton of the southern half is illustrated by the synthesis of optically active synthon 74 by Hirama et al. [122]. Their synthesis begins with 69 (prepared in 5 steps from D-glucose) and uses two aldol reactions and a cylic etherification to establish the basic ring structure. Similarly, an intramolecular Claisen cyclization was the key step in the synthesis of optically active southern half 79 by Williams et al. [123, 124]. 

Starting with 1,4-anhydrosorbitol 75 (prepared from D-glucitol) their synthesis proceeded in 19 steps (4% overall) via key intermediate 77. Intramolecular Claisen cyclization of 77 afforded 78 which was converted to the more advanced intermediate 79. 

The mechanism of the intramolecular Claisen cyclization, sho-wn in Figure 17.13, is the same as that of the intermolecular Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic 8-keto ester product results. 

The cyclic 8-keto ester produced in an intramolecular Claisen cychzation can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 17.5). Alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate, for instance, yields a 2-alkylcyclohexanone. The overall sequence of (1) intramolecular Claisen cyclization, (2) 8-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

FIGURE 17.13 MECHANISM Mechanism of the intramolecular Claisen cyclization of a 1,7-diester to yield a cyclic /3-keto ester product. 

Stork and Hagedorn have reported that the highly functionalized A-ring of tetracycline can be readily constructed by Michael addition of the 3-benzyloxy-isoxazole (172) to a suitable enone substrate, followed by Claisen cyclization and hydrogenation to release the protected jS-keto-amide (Scheme 22). °... 

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