Enolate anions, lactones, reaction with

An abnormal unidirectional Claisen reaction has been reported for the addition of deprotonated cyclohexyl [l- C]acetate (58) to the carbonyl group of the a-N-Boc-substituted lactone 59, providing hemiketal 60 (Figure 6.24). The competitive condensation of the enolate anion of 59 with 58 is probably hindered for steric reasons by the deprotonated A-Boc group or because of its negative charge. Subsequent catalytic reduction furnished a mixture of the A-Boc-amino diol 61 and its epimer. Deprotection of the desired epimer followed by base-catalyzed cyclization provided lactam 62, the key intermediate in the synthesis of [3- C]castanospermine 63. ... 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Besides ordinary esters (containing an a hydrogen), the reaction can also be carried out with lactones and, as in 16-38, with the y position of a,p-unsaturated esters (vinylogy). There are also cases, where the enolate anion of an amide was condensed with an aldehyde. ... 

The utility of the creation of a y-lactone enolate through 1,4-addition of a carbanion and its interception by an electrophile has also been demonstrated in other classes of natural products, e.g., in the enantioselective synthesis of 10-oxa-l 1-methyl PGE2 analogues22. This synthesis starts with 1,4-addition of the sulfone-stabilized anion from 27 to ( + )-(S )-4-methyl-2-buteno-lide which has been prepared in three steps from (—)-(S)-l,2-epoxypropane. The intermediate enolate 28 is reacted with the acetylenic iodide to give the trisubstituted diastereomeric mixture of lactones 29, which is eventually converted into the pure compound 30, both reactions occurring with high diastereoselectivity. 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

Just occasionally it is possible to carry out cross-condensations between two different enolizable molecules under equilibrating conditions, A notable example is the base-catalysed reaction between methyl ketones and lactones. With sodium hydride—a strong base that can convert either starting material entirely into its enolate anion—good yields of products from the attack of the enolate of the ketone on the electrophilic lactone can be obtained. 

A study of the reaction of benzoquinone with alkenes has sought to identify the nature of the transients involved. In the case of reaction with tetraphenylallene irradiation in carbon tetrachloride at 355 or 532 nm yields the indene (376) as the sole product. When methanol is added to the reaction mixture the same indene (376) is accompanied by the methoxy derivative (377), The suggested mechanism for the formation of the indene (376) involves electron transfer to yield the radical cation / radical anion pair (378). Protonation followed by combination yields the cation (379) which is the key intermediate to the final product.Benzoquinone adds photochemically to the enol lactones (380) and (381) to give the oxetans (382) and (383)... 

In the conversion of 66 to 67, we saw that HMPA was used as an additive. Another useful ingredient in many alkylation reactions is hexamethylphosphorus triamide [HMPT, (Me2N)3P], which coordinates with the enolate anion, diminishing the aggregate state and increasing reactivity. This additive also enhances the polarity of the solvent and thereby enhances the facility of the Sn2 alkylation step (sec. 2.7.A.i). The use of an additive such as HMPA or HMPT is very common when the enolate anion reacts slowly and/or the halide is relatively unreactive. Other acid derivatives such as lactones can react with LDA to give an enolate anion, which then reacts with alkyl halides in the usual manner. 

Dianions of this type react with ketones, epoxides,and esters " as well as a wide variety of other electrophiles. As an example, the dilithio anion of 2-methylpropionic acid was condensed with the epoxide moiety in 229 to form an hydroxy acid, which cyclized to form the lactone ring in 230. Since most of the enolates of acid derivatives contain a leaving group, the alkoxide resulting from reaction with an epoxide often displaces that leaving group to give the lactone. 

The preference for the lowest energy conformation of the enolate anion is seen in larger ring systems as well (sec. 1.5.B,C), leading to good selectivity in alkylation and condensation reactions. The methyl group provides only small steric encumbrance to approach of the electrophile in enolate 505 (derived from lactone 504 and LDA). The preferred mode of attack for this relatively stable conformation was from the top face (path a, pseudoequatorial attack) and gave the syn diastereomer (506) with >99 1 selectivity.- ... 

An unexpected result was obtained when DTBB-catalyzed lithiation was applied to the vinyl-oxetane 313 . After work-up, lactone 314 was isolated, the process being explained by an elimination reaction via a radical pathway more than by reduction of the benzyl radical into the anion. Thus, this hypothetical intennediate reacted with the lithium enolate of acetaldehyde, generated in situ by reductive decomposition of THF (Scheme 92). 

Scheme 10.14 rationalizes the divergent behavior of the two catalytic systems in these selective transformations of pent-l-yn-ols. The presence of phosphine ligands promotes the formation of ruthenium vinylidene species which are key intermediates in both reactions. The more electron-rich (p-MeOC6Fl4)3P phosphine favors the formation of a cyclic oxacarbene complex which leads to the lactone after attack of the N-hydroxysuccinimide anion on the carbenic carbon. In contrast, the more labile electron-poor (p-FC6H4)3P) phosphine is exchanged with the N-hydroxysuccinimide anion and makes possible the formation of an anionic ruthenium intermediate which liberates the cyclic enol ether after protonation. 

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. 

Ynolate anions react with acylsilanes at low temperature to give P-lactones 48 in good yields. When the reaction is conducted at room temperature the isolated product is a (1-silyl-a,p-unsaturated ester via a P-lactone enolate intermediate <02JACS6840>. 

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