Lactones substitution

An analogous dehydration in the synthesis of lactone substituted derivatives of digitoxigenin is reported in reference [21a]. 

The enolates of l,3-dioxolan-4-ones 1 and l,3-oxathiolan-4-ones2, which are y-lactones substituted with a heteroatom, can be prepared using normal conditions (LDA, THF) and subsequently alkylated. If one takes, e.g.. a nonracemic a-hydroxy acid such as lactic acid 3, then on formation of the heterocycles 1 (R1 = CH3 R2 = alkyl) chirality is transferred from the a-po-sition (C-5) in the starting acid to C-2 in 1, forming (2R,5R)-4 and (2S,5R)-5. If 4 and 5 are easily separable or, even better, if one of them is formed diastereoselectively from 3 then 4 and/or 5 can be transformed to the respective enolates 6 and 7 and alkylated with R X. 

Reaction of the spiroepoxy lactone 125 with phenylenediamine in EtOH at reflux provided the 1,5-benzodiazepin-2-one after amide formation, mediated by /-BuMgBr (Scheme 75) <2003S1209>. The scope of this approach may be limited since the single spiroepoxy lactone substituted on the epoxide ring that was studied was an ineffective partner. 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

Tylosin is a polyketide lactone substituted with three deoxyhexose sugars. It is used as an antimicrobial growth promoter in animals. Acquired resistance has been observed in potentially human pathogenic strains isolated from animals (1). Of further concern is the fact that tylosin confers cross-resistance on erythromycin (2). 

As pointed out earlier, cycloalkylation reactions can also result from the reaction of arenes with bifunctional alkylating agents or in cases where bifunctional intermediates are involved. An example of the former is shown in equation (114), where a chiral, lactone-substituted alkene cyclizes with the arene to produce a chiral tetrahydronaphthalene derivative. 

Tylosin is the prototype of the second large division of 16-merabered macrolides, which differ from the leucomycins in aglycone structure [201]. Tylosin is composed of the usual 16-membered macrocyclic lactone substituted with a disaccharide chain in position 3, composed of an aminosugar, o-mycaminose, and a neutral sugar, L-mycarose. In addition, it is substituted with another neutral sugar, L-mycinose, in position 23. 

In the cited Figure 5 [see page 93 in (1870)], only the following five lactones (substituted coumarins) of the nearly two dozen identified in tobacco and/or tobacco smoke were depicted, namely, scopoletin (7-hydroxy-6-methoxy-2//-l-ben-zopyran-2-one), scopolin [7-(p-D-glucopyranosyloxy)-6-met-hoxy-2//-l-benzopyran-2-one], esculetin (6,7-dihydroxy-2//-l-benzopyran-2-one), cichoriin [7-(p-D-glucopyranosy-loxy)-... 

Synthesis of Hyptolide Hyptolide 4 is a naturally occurring, a,(3-unsaturated, six-membered ring 8-lactone substituted with a poly-oxygenated chain isolated from the species of Hyptis, Syncolostemon, and related genera of the family Lamiaceae, and it shows interesting pharmacological properties. In particular, such a plant is used in traditional Mexican medicine for the treatment of... 

For the preparation of 4-substituted coumarins, a phenol may be condensed with ethyl acetoacetate under the influence of sulphuric acid. Thus resorcinol (II) readily undergoes this condensation (which is represented diagrammatically above) to give 7-hydroxy-4-methyl-coumarin (III). Note that the coumarins, like all 2 pyrones, are systematically lactones. 

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

The wM-diacetate 363 can be transformed into either enantiomer of the 4-substituted 2-cyclohexen-l-ol 364 via the enzymatic hydrolysis. By changing the relative reactivity of the allylic leaving groups (acetate and the more reactive carbonate), either enantiomer of 4-substituted cyclohexenyl acetate is accessible by choice. Then the enantioselective synthesis of (7 )- and (S)-5-substituted 1,3-cyclohexadienes 365 and 367 can be achieved. The Pd(II)-cat-alyzed acetoxylactonization of the diene acids affords the lactones 366 and 368 of different stereochemistry[310]. The tropane alkaloid skeletons 370 and 371 have been constructed based on this chemoselective Pd-catalyzed reactions of 6-benzyloxy-l,3-cycloheptadiene (369)[311]. 

No 0-allylation is observed in formation of the six-membered ring compound 79 by intramolecular allylation of the /3-keto ester 78(15,57]. Intramolecular allylation is useful for lactone fonnation. On the other hand, exclusive formation of the eight-membered ring lactone 81 from 80 may be in part derived from the preference for the nucleophile to attack the less substituted terminus of the allyl system[58]. 

Substituted allylic alcohols are carbonylated using the o.vidizing system of PdCl2 and CuCU in the presence of HCl and oxygen at room temperature and 1 atm of CO to give the 7-lactone 16 in moderate ylelds[20]. Carbonylation of secondary and tertiary allylic alcohols catalyzed by Pd2(dba)j and dppb affords the 7-lactone 17 by selective attack of CO at the terminal carbon under fairly severe conditionsf21]. 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

Lactones, l xictides, iMciams, and Lactims. When the hydroxy acid from which water may be considered to have been eliminated has a trivial name, the lactone is designated by substituting -olactone for -ic acid. Locants for a carbonyl group are numbered as low as possible, even before that of a hydroxyl group. 

Double Fiiedel-Ciafts alkylation of configuiationally pure pyiocene (a substituted lactone) with aiomatics results in the formation of cycloalkylation product with retention of configuration at the chiral center (63). 

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

The reaction involves nucleophilic substitution of for OR and addition of R MgX to the carbonyl group. With 1,4-dimagnesium compounds, esters are converted to cyclopentanols (40). Lactones react with Grignard reagents and give diols as products. 

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