Esters Dieckmann cyclization

Dieckmann cyclization (Section 21 2) An intra molecular analog of the Claisen condensation Cy die p keto esters in which the ring is five to seven membered may be formed by using this reaction... 

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. 

The mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the 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 /3-keto ester product results. 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

Mechanism of the Dieckmann cyclization of a 1,7-diester to yield a cyclic /3-keto ester product. 

Dieckmann cyclization of diethyl 3-methylheptanedioate gives a mixture of two /3-keto ester products. What are their structures, and why is a mixture formed ... 

Dieckmann cyclization reaction (Section 23.9) An intramolecular Claisen condensation reaction to give a cyclic /3-keto ester. 

Preparation of the quaternary anticholinergic agent benzilonium bromide (47) is begun by conjugate addition of ethylamine to methylacrylate, giving aminoester 42. Alkylation of 42 with methyl bromo-acetate leads to diester 43, which is transformed into pyrrolidone 44 by Dieckmann cyclization, followed by decarboxylation. Reduction of 44 by lithium aluminum hydride leads to the corresponding amino-alcohol (45). Transesterification of alcohol 45 with methyl benzilate leads to 46. Benzilonium bromide (47) is obtained by alkylation of ester 46 with ethyl bromide. 2... 

In Yamada s retrosynthetic analysis (Scheme 11), elisabethin C (26) is traced back to lactone 64 which would be converted into 26 by deoxygenation and chain elongations. Key intermediate 64 could be obtained by a stereoselective Dieckmann cyclization. The required ester lactone precursor 65 would be accessible from 66 by a series of oxidation reactions. Further disconnection would lead to commercially available (+)-carvone (67). Stereoselective successive alkylation of 67 and reduction of the enone should deliver 66 [30]. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

After oxidation of the vinyl group, the C ring is constructed by a Dieckmann cyclization. The resulting jS-keto ester is subjected to nucleophilic decarboxylation by phenylthiolate [step F (4-6)]. 

In a related type of reaction, the styryl isocyanates, readily available by Curtius rearrangement of cinnamoyl azides, undergo thermal cyclization to l-isoquinolones in good yield (equation 34) the reaction can also be carrried out using Friedel-Crafts catalysts. 2,3-Dihydro-4( 1//)- isoquinolones are obtained by Dieckmann cyclization of N- (o- carbalkoxy-benzyl)glycine ester derivatives (equation 35). The same reaction has been used for the synthesis of a range of non-aromatic heterocycles (equations 36 and 37). 

It may be of interest to point out that captodative [31] substituents on a carbon atom disfavor the removal of a proton attaching to it, reactions such as alkylation would occur preferentially at an alternative site by default. Thus a synthesis of yohimbine [32] via a Dieckmann cyclization for. E-ring formation was facilitated by incorporating an extra methoxy group into one of the ester pendants. 

Hiroto Nagaoka of Tokyo University of Pharmacy and Life Science has reported (Tetrahedron Lett. 44 4649, 2003) the tandem reduction — Dieckmann cyclization of the esters 6 and 9. It is striking that the geometry of the starting alkene dictates the ring fusion of the product. Both 5/5 and 6/5 systems can be prepared this way. 

The transformation (190 — 191) exemplifies the use of transition metal reagents the reaction probably involves aminopalladation of the C = C bond (77JOC1329). 2,3-Dihydro-4(l//)isoquinolones are obtained by Dieckmann cyclization of 7V-(o-alkoxycarbonylbenzyl)glycine ester derivatives (192 - 193). 

An approach to the synthesis of angularly substituted polycyclics through the Diels-Alder cycloaddition of dihydrothiophenes has been devised (69JA7780). The easily prepared 2,5-dihydro-4-methoxycarbonyl-2-thiopheneacetic acid methyl ester (316) was heated at 180 °C with excess butadiene to yield (317). Desulfurization and double bond reduction of the cycloadduct with W-5 Raney nickel gave (318) which was characterized by conversion to the corresponding diacid and comparison with an authentic sample. Dieckmann cyclization of (318) is known to lead to the 5-methyl-1-hydrindanone (319 Scheme 68). The use of other dienes in the [4 + 2] cycloaddition process will, of course, produce more highly functionalized hydrindanones. 

An interesting variation of the Dieckmann cyclization involves vinylogous activation of a methyl group in a 2-butenyl ester. Reaction of an a-halo ester with the enethiol formed by treatment of an acetoacetic ester, which may be substituted at the a-position, with hydrogen sulfide produces (92) in satisfactory yield. Treatment of these compounds with sodium in benzene produced the 4-hydroxythiophene-2-acetic acids (94) (40JCS1385). The product undoubtedly involved the intermediate (93), in which the activated methyl goup has condensed with the ethoxycarbonyl group in typical Claisen fashion. 

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). 

Fluorinated esters have synthetic utility m Claisen condensations [24, 25] (equation 21) and Dieckmann cyclizations [26]. 

The rules of Baldwin (55) for ring closure in trigonal systems (see p. 171 for an introduction) are the following 3- to 7-Exo-Trig processes (152-156) are all favored processes. 3- to 5-Endo-Trig (157-159) are disfavored but 6- and 7-Endo-Triq (160-161) are favored. The literature is replete with examples of 3- to 7-Exo-Trig for instance, lactonization of u-hydroxy-acids and esters are of this type, the formation of lactams from w-aminoacids and also the Dieckmann cyclization of diesters. 

The desired ketone, cyclopentanone, is derived from the corresponding j8-keto ester. This key intermediate is obtained from a Dieckmann cyclization of the starting material, diethyl hexanedioate. 

Examine each carbon that is a to an ester function to see if it can lead to a five-, six-, or seven-membered cyclic /3-keto ester by a Dieckmann cyclization. 

Conversion of this intermediate to the desired /V-m c(liy 1 -4-pi pcridonc requires a Dieckmann cyclization followed by decarboxylation of the resulting /3-keto ester. 

Treatment of ethyl l- 2-[(tm-butyl, dimethylsilyl)oxy]-l-phenylethyl -6-alkylpiperidine-2-carboxylates with 10% HF in MeCN afforded diastereo-meric mixtures of 4-phenyl-6-substituted perhydropyrido[2,l-c][l,4]oxazin-1-ones (94JOC3769). Dieckmann cyclization of ethyl 4-(3-ethoxy-carbonylpropyl)morpholine-3-carboxylate with ferf-BuOK in Et20 and subsequent ester hydrolysis and decarboxylation furnished perhydropy-rido[2,l-c][l,4]-oxazin-9-one (82EUP57536 92BMC1293). Mild acidic hydrolysis of the nitrile moiety of amino nitrile 185 gave pyrido[2,l-c][l,4]ox-azin-l-one 60 (96TL4001). 

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