Keto lactones, synthesis

A stereoselective total synthesis of the antifungal mould metabolite ( )-LL-Z1271a (165) from the readily available Wieland-Miescher diketone, via the keto-lactone (164), has been described. A synthesis of grindelic acid (167) from the unsaturated 7-toluene-p-sulphonate (166) utilized an intramolecular solvolysis of the toluene-p-sulphonate to construct the 9—13 ether bridge. 

After purification, the dimethyl 1,3-dioxinone unit of 2 was hydrolysed with mild base to furnish the P-keto acid. Acidification then brought about lactonisation to the enolised p-keto lactone 1. To facilitate work-up and isolation, the latter was converted to the vinylogous ester 24 with potassium carbonate and dimethylsulfate in acetone. Mild acid hydrolysis of 24 with 0.1 N H2S04 in EtOAc eventually furnished (-)-ACRL toxin 1 in good yield after six days, completing this very elegant and beautifully crafted synthesis. 

We next investigated the total synthesis of kuehneromycin A (7). Partial hydrolysis of 111 in trifluoroacetic acid (TFA) gave alcohol, which was oxidized to keto-lactone 112 (Scheme 18). Treatment of 112 with TFA followed by triethylamine caused unexpected decarboxylation, providing a mixture of kuehneromycin B (113) and panudial (114), which are known as natural products related to 7 [3]. The synthesis of... 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

Danishefsky and coworkers have demonstrated the conversion of lactones to carbocycles by the 3,3-sigmatropic shift of silylketene acetals. Jq the total synthesis of the Fusarium toxin equisetin, for example, keto lactone (138) was converted to its bissilyl derivative (139) by reaction with 2 equiv. of LDA and an excess of TMS-Cl. In situ thermolysis of ketene acetal (1 ) led to a very smooth transformation into ester (140), which was carried on to equisetin (Scheme 26). This methodology was also applied by Schreiber and Smith in the preparation of the cyclohexyl moiety of the immunosuppressive agent FK-506. Ireland-Claisen rearrangement of silylketene acetal (142), prepared by treatment with TBDMS-OTf and triethylamine at low temperature, provided, after hydrolysis of the silyl ester, the carboxylic acid (143) in 71% overall yield (Scheme 27). The strict translation of configuration via a boatlike transition state is typical for this permutation. 

A different approach (Scheme 39) to the synthesis of the 14,18-oxyethano-iV-methylimino-bridge of batrachotoxinin used the epoxy-pregnane (473) as starting material. This was converted by conventional techniques into the keto-lactone (474). Bromination and dehydrobromination of (474) gave the A -16-ketone, which was reduced to the allylic alcohol and epoxidized to (475). Hydride... 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

The foregoing conditions were applied successfully in the synthesis of diplodialide A (175 Scheme 37). Since earlier studies had demonstrated that the sulfide-contraction conditions were not compatible with a,3-unsaturated thioamides, the 3-acetoxy precursor (173) was used instead. The intramolecular sulfide-contraction reaction successfully accomplished the cyclization to generate the P-keto lactone (174) in modest yields. Elimination of the acetoxy group yielded diplodialide A (175). 

Of particular interest is the regio- and enantiospecific reduction of diketo acid with Margarlnomyces bubaki affording the keto lactone 8. The latter serves as the chiral starting point in an asymmetric total synthesis (+)-estr-4-ene-3,17-dione via key intermediate 9 (9). 

We obtained 7-oxoisodrimenin by oxidation of the keto diol (131) with an excess of PCC [92], On oxidation of (131) with Mn02 or PCC (2 mol. equivalents), a mixture of the semiacetals (132) and (133) and keto lactone (136) was obtained. One of these semiacetals, (133) was isolated by crystallization, and its structure and stereochemistry were confirmed by X-ray data [93]. The mixture of semiacetals (132) and (133) was further oxidised to the keto lactone (136). This lactone has no biological activity itself, but it has been used as an intermediate in the total synthesis of bioactive ( )-warburganal (16) [84]. The ethylene ketal (140) of the keto lactone (136) was converted into the keto diol (131), whose transformation to warburganal (16) was discussed above (Scheme 23). 

The total synthesis of casimiroedine (17), isolated from Casimiroa edulis, has been achieved. The synthesis also establishes the trans-cinnamamide stereochemistry, a point which had remained unresolved in the original structural elucidation study. The reaction of the keto-lactone (18) with the imidazolyl-lithium (19) generated in situ yields a number of products,the major ones being the pilocarpine-related (20) and the ditetrahydrofuran (21). Treatment... 

As already demonstrated tra 5-dibenzylbutyrolactones are valuable as precursors for the synthesis of a wide range of lignans. For example, the keto-lactones (90) and (91), which have both been prepared by tandem conjugate addition reactions, provide key intermediates for the synthesis and asymmetric synthesis respectively of lignans of the furofuran type (scheme 30) [85,86]. 

The synthesis of y,8-unsaturated-P-keto lactones was achieved by tandem CM or lactonization reactions [63]. A 16-membered macrolide antibiotic (-)-A26771B 79 was prepared by such a way (Scheme 31). The key reaction step involved the CM of 75 and 76 to give 77 in the presence of Hoveyda catalyst 5. The lactonization led to the macrocycle 78 which was transformed into the macrolid 79 [63]. 

The absolute configuration of eldanolide, the pheromone from the wing glands of the male African sugar-cane borer, has been determined by a chiral synthesis of both of its enantiomers. (-t-)-Pantolactone (141) has been synthesized (in 40% yield) by a short sequence from (—)-(5 )-dimethyl malate. 1,2-0-Isopropyl-idene-D-glyceraldehyde is a useful chiral starting material for the synthesis of butyrolactones such as (142). The keto-lactone (143) is a useful intermediate in the synthesis of (+)-D-pantothenic acid it is prepared from readily available starting materials. ... 

The synthesis of the vinyl-substituted lactone 19 started with the reaction of ethylacetoacetate 20 with 2 equiv. of LDA. The interesting bis-enolate 21 was then trapped with freshly distilled acrolein 22 to produce the intermediate 23. The regioselectivity of this reaction can be explained by product development control, because this intermediate retains the more stable conjugated enolate. Upon hydrolyses, intermediate 23 spontaneously cyclizes to the p-keto lactone 24, whose enol tautomer underwent direct 0-alkylation with dimethyl sulfate. This sequence could be carried out in multigram scale with isolated overall yields of 52% (Scheme 8). 

A. Kishida, H. Nagaoka, Samarium(ll) iodide-induced cascade reaction for tricyclic y-lactone synthesis from acycUc keto diesters. Tetrahedron Lett. 49 (2008) 6393-6397. 

The synthesis of alpinine illustrates a different approach to rhoeadine alkaloids, and is based on the photosensitized oxidation of the enaminoketone (A) and rearrangement of the resuiting dioxetan to a spiro keto lactone (B). The rest of the synthesis closely follows the pathway laid down earlier at Hoffman-La Roche for the synthesis of rhoeadine. ... 

He, W., Pinard, E., and Paquette, L.A. (1995) Total synthesis of crenulatane diterpenes strategy and stereocontrolled construction of a bicyclic keto-lactone building block. Hdv. Chim. Acta, 78, 391 02. 

The 1,6-difunctional hydroxyketone given below contains an octyl chain at the keto group and two chiral centers at C-2 and C-3 (G. Magnusson, 1977). In the first step of the antithesis of this molecule it is best to disconnect the octyl chain and to transform the chiral residue into a cyclic synthon simultaneously. Since we know that ketones can be produced from add derivatives by alkylation (see p. 45ff,), an obvious precursor would be a seven-membered lactone ring, which is opened in synthesis by octyl anion at low temperature. The lactone in turn can be transformed into cis-2,3-dimethyicyclohexanone, which is available by FGI from (2,3-cis)-2,3-dimethylcyclohexanol. The latter can be separated from the commercial ds-trans mixture, e.g. by distillation or chromatography. 

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