Lactone enol phosphonates

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

The construction of the C2-C3 bond of the 1-hydroxyethylene moiety by the addition of a two-carbon fragment to aminoalkyl epoxides, amino ketones, p-amino-a-hydroxy aldehydes, or 4-amino-3-oxo phosphonates was also studied. As summarized in Scheme 14, Evans et al.[28] added a malonate to an aminoalkyl epoxide and the product spontaneously cyclized, leading to a lactone.— Then, the second side chain was incorporated into the a-carbon of the lactone, providing a mixture of C2 epimers. The final compound was obtained by hydrolysis and decarboxylation. The lack of diastereoselectivity of this method is offset by the small number of steps and the accessibility to all eight possible stereoisomers. Biihlmayer et al.[30] also used a similar method, but they transformed the epoxide into the apparently more reactive iodide. Then, the iodide compound was treated with an enolate. 

The preparation of a-selenoketones, esters, nitriles and related compounds can easily be performed via alkylation of the corresponding enolates or stabilized carbanions [21]. These compounds have found many synthetic applications in radical chemistry. In Eq. (9), a typical example involving a ketone is depicted [22]. The stability of a-selenoketones such as 41 is remarkable. Similar reactions with lactones have been performed. For instance, this approach has been applied to the stereoselective synthesis of oxygen-containing rings to either faces of a bicyclic structure [23]. The approach based on a-selenenylation/radical allyla-tion compares favorably with classical enolate allylation procedures, which usually leads to mixture of mono- and diallylated compounds. Furthermore, this strategy is excellent for the preparation of quaternary carbon centers [24] as shown by the conversion of 43 to 45, a key intermediate for the synthesis of fredericamycin A, [Eq. (10)] [25]. Similar reactions with sulfoxides [26] and phosphonates [27] have also been reported. 

The reaction of ketene with diethyl hydrogen phosphonate leads to diethyl ace-toxyvinylphosphonate (equation 46) This reaction was assumed to involve the initial formation of acetylphosphonate, which underwent enolization and reaction with a second molecule of ketene to the final product. Infrared spectral examination of the product mixture revealed the formation of an additonal product, presumably a jS-lactone (v = 1830 cm ) which could be formed through 2 + 2 cycloaddition of a ketene molecule to the C=0 group of the acetylphosphonate. 

The phosphonate a-anion reacts with the lactone carbonyl. This produces the opening of the lactone and the formation of a p-keto phosphonate and an enol, which tautomerizes to a ketone. 

The mannose-derived lactone 40, produced by ozonolysis of the corresponding alkene, undergoes a modified Fujimoto-Belleau reaction yielding the vinyl phosphonate cyclohexenone 41.1 The epimeric lactone 43 however, yields the anticipated cyclcohexenone 42 (Scheme 12). Formation of 41 is rationalized by invoking hydroxide elimination from an enolate intermediate rather than the anticipated elimination of (MeO)2P(0)OH. 

An approach to the synthesis of 16-ketosteroids utilizes monoalkylation of a 1-tetralone with 2,3-dlchloropropene in the presence of methylmagneslurn carbonate in DMF. Alkylidenetrlphenylphosphoranes and dialkyl phosphonate anions attack a variety of cyclic enol lactones to give intermediate ketophosphoranes which yield, in one step, the desired cyclic a, g-unsaturated ketones.21 Thus, the reaction of I7p-acetoxy-4-oxaandrost-5-en-3-one with methylene triphenylphos-phorane for 18 hours at 20 affords testosterone acetate. 

Provide a mechanistic interpretation of this transformation. See Henrick, C. A. Boehme, E. Edwards, J. A. Fried, J. H. Reaction of phospho-ranes and phosphonate anions with enol lactones. A new method for the preparation of cyclic a,)8-unsaturated ketones J. Am. Chem. Soc. 1968, 90, 5926-5927 for more information. (Steroids-4)... 

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