Pyrrolidone enolates

The enolate of dimethyl trifluoromethylmalonate, formed by the action of cesium fluonde [II9] or of an electrolytically generated pyrrolidone anion [120], can be alkylated with methyl iodide (equation 103)... 

Carbanions of active methylene compounds also react with aziridine-2-car-boxylic esters to give ring-opened products [129]. The ring-opened intermediates usually cyclize spontaneously to pyrrolidones. Treatment of 190 (Scheme 3.70) with the sodium enolate of dimethyl malonate 191, for example, afforded pyrroli-done 192 in 15% isolated yield, together with 30% of the debenzoylated product 193. 

Enantioselective synthesis of the antidepressant rolipram can be done by the asymmetric Michael addition of the enolate of IV-acetyloxazolidone to nitrostyrene. Chirally branched pyrrolidones like rolipram are highly active antidepressants with novel postsynaptic modes of action. The synthesis is shown in Scheme 4.13.78... 

Formation of the enolate from 1-methyl-2-pyrrolidone (a y-lactam) is accomplished by treatment with lithium diethylamide in hexamethylphosphoric triamide/benzene at — 20 °C. Addition of bromomethane or (chloromethyl)benzene then results in good yield of the a-alkylation product15. 

Thus, treatment of l-benzyl-5-ethoxy-2-pyrrolidone (1, R1 = Bn) with 1.2 equivalents of lithium diisopropylamide at — 78 °C in tetrahydrofuran gave the enolate which, when treated with iodoalkanes, furnished approximately 60 40 ratios of diastereomers in good yields (75-85%). Relative configurations were not determined16-18. 

Treatment of the pyrrolidone mixture 5 with 2.1 equivalents of lithium diisopropylamide at — 78 °C for 1 hour, and then — 25 °C for 1 hour, yields the dianionic enolate. Alkylation at -117 °C or - 78 °C then provides a 50-80% yield of the (3S)-alkylated 3,4-tran.v-product as a 85 15 mixture of the 5-epimers19,20. No trace of the 3,4-a.s-product could be detected by NMR. The electrophile attacks from the side opposite to the alkoxide group. Evidently, in this case, the stereogenic center in the 5-position has no influence on the stereoselectivity. 

For some related examples of alkylations of enolates from achiral 2-pyrrolidone see reference 32. 

It has been demonstrated that the oxygen anion of initially formed product (36) effectively catalysed the [2,3]-Wittig rearrangement as a Lewis base. Other Lewis-base catalysts such as lithio or sodio 2-pyrrolidone promote the same [2,3]-Wittig rearrangement of silyl enolates generated from a-allyloxy ketones, whereas rearrangements of enolates from a-allyloxy esters were efficiently catalysed by ammonium 4-methoxybenzoate.24... 

Silyl enolates generated from a-allyloxy ketones undergo the [2,3]-Wittig rearrangement in the presence of a catalytic Lewis base such as lithium 2-pyrrolidone, lithium acetamide, or lithium hexamethyldisilazide (Scheme ll).15... 

Pyrrolizidines compounds have been produced in connection with syntheses of other types of natural products. For example, Gensler and Hu prepared the dioxopyrrolizidine ester (46) as an intermediate in the synthesis of ( + )-slaframine, an indolizidine alkaloid obtained from cultures of Rhizoctonia leguminicola. The pyrrolidone ester (47), prepared from l-glutamic acid [Eq. (14)], was optically active, but the cyclized product, formed in quantitative yield from 47, was completely racemized. The synthesis of 2-acetyl-1,3-dioxopyrrolizidine (48) was carried out by Kruger and Arndt to assist with their investigations on model compounds aimed toward the total synthesis of a-cyclopiazonic acid, the main toxic principle of Penicillium cyclopium The spectra of the product (48) obtained in 30% overall yield was typical of an intramolecularly H-bonded enolized )S-... 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

Fuchigami and coworkers have formed enolates with electrogenerated bases (equations 10 and 11).42-43 The basic anions of 2,6-di-f-butyl-p-cresol and a-pyrrolidone were obtained by cathodic reduction. Countercations with a weak affinity for the fluorine atom (e.g. quaternary ammonium, phosphonium or tertiary sulfonium cations) had to be used in the example shown in equation (11) in order to impede defluorination. 

Lithium acetate (LiOAc)-catalyzed aldol reactions between trimethylsilyl enolates and aldehydes proceed smoothly in anhydrous DMF or pyridine to afford corresponding aldols in good to excellent yields under weakly basic conditions (Scheme 20) (120,121). Obviously, it was further evidence that water could accelerate the aldol reaction of ketene silyl acetals with carbonyl compounds (120). Other lithium salts, for example, lithium pyrrolidone, was also an effective catalyst in the aldol reaction between trimethylsilyl enolates and aldehydes (123). 

Pyrrolidone anion as EGB generates (trifluoromethyl) malonic ester enolate from malonic ester bearing a CF3 moiety at the a-position (Eq. 26). Generally, it is difficult to generate the enolate anion with a-CFg group, because the enolate anion undergoes... 

Stamm and his co-workers have shown that pyrrolidones can be obtained from aziridines by reaction with sodium enolates of simple esters, and if or R = H in (99), then further amidoethylation can result. 

For the synthesis of 2-pyrrolidone III-16, we followed the procedure described by Germanas and coworkers for the enantioselective alkylation of proline [118]. This procedure was based on a method reported by Seebach [119], in which proline is condensed with pivaldehyde to give a single stereoisomer of 2-f-butyl-l-aza-3-oxabicylo[3.3.0]octan-4-one III-42 [120], which is deprotonated with LDA to give a chiral enolate that can be alkylated with an electrophile (Scheme 4.21). 

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