Wieland-Miescher diketones

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. 

The Welch group tackles stereoselective synthesis of LL-Z1271a using Wieland-Miescher diketone 144 [82] (3% overall yield) (Scheme 4). This synthesis includes, as key steps, the stereoselective introduction of the methyl on carbon 4 in an equatorial position, the formation of the y-lactone via bromolactonization and the construction of the 5-lactone C ring through a Meyer-Schuster rearrangement. 

In this context, it is well worth citing the classic example of the L-proline-catalyzed intramolecular asymmetric aldol reaction, involving cyclodehydration of achiral triketone 1 to yield the unsaturated Wieland-Miescher diketone 2 (Scheme 8.1) [7, 8]. In early papers, it was reported that in the presence of 20 mol% of L-proline, the diketone 2, an important intermediate in steroid synthesis, is obtained in high yield and in approximately 70-90% enantiomeric excess (e.e.). 

The key intermediate in the synthesis of the derivatives of 19-F3-androstane is the trifluoro analogue of the Wieland-Miescher ketone. Its preparation involves a Diels-Alder reaction between a trifluoromethyi ketone and a siloxy diene. Another original step is the regioselective reduction of a diketone only the ketone function in P of CF3 (probably activated by this substituent) is reduced (Figure 4.6). " Then, a succession of classical reactions leads to derivatives of androstane from the trifluoro analogue of the Wieland-Miescher ketone (Figure 4.7). ... 

The bicyclic ketones 9 a and b were unreactive under Weitz Scheffer conditions, while diketone 9c yielded 10c as a single product with excellent yield. Similarly, Wieland-Miescher 11 ketone gave single epoxide 12 and its monoacetal 13 yielded isomeric epoxide 1480. 

Therefore several reactions were subjected to various antibody catalyses, e. g., ester and enol ether cleavage, transesteiification, ketone reduction. Cope rearrangement, ring closure via epoxide opening, or Diels-Alder cycloaddition [74, 75]. An exceptional reaction is the antibody-catalyzed Robinson annulation of triketone 28 to the Wieland-Miescher ketone 29 on a preparative scale. Surprisingly, even the alkylation of diketone 27 with methyl vinyl ketone was catalyzed by the same antibody, but at moderate rates (Scheme 15) [76]. 

Sometimes even the aldol reaction fails to perform with its usual reliability and we must give it some help. The bicyclic enone 33 continues the contrast with Robinson annelation as it resembles the Wieland-Miescher ketone, used as a starting material for steroid syntheses,12 but with two five-membered instead of two six-membered rings. Aldol disconnection reveals the 1,4-diketone 34 but it turns out that closing the second five-membered ring this way works rather badly. 

Fig.(9) The transformation of the Wieland-Miescher ketone (1) to the conjugated diene (93) is described. It was converted to the diketone (95) whicch proved a potencial intermediate for the epoxy dilactone (98). The cleavage of the lactone ring of (98) yielded alcohol which was converted a-methylene-Y-butyrolactone (101) by a series of organic reactions. The opening of the epoxide ring of (101) gave the product (102) whose methacrylate derivative on deformylaton provided eriolanin (104).

Fig. (11) The Wieland-Miescher Ketone (1) is converted to keto glycol (125) and then to acetonide conjugated ketone (128) this on sujection to diels-alder reaction with dimethoxybenzocyclobutene affords the adduct (129) which is converted to the triol (132) by the standard organic reactions. The oxidation and cyclization of (132) yield the fiiran-diketone system (133). Its conversion to (+)-halenaquinone (134) is accomplished by the oxidative cleavage, halenaquinol (135) is obtained by reduction of hal enaquinone (134).

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [ 10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) andEder, Sauer, and Wiechert... 

Probably the most important organocatalytic addition to a,P-unsaturated ketones is the synthesis of the Wieland-Miescher ketone. This bicyclic diketone is obtained by a Robinson aimulation consisting of a first Michael addition to vinyl methyl ketone followed by an intramolecular aldol reaction. 

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