Lithium diisopropylamide lactones

The enolate generated by reaction of lactone 88 with lithium diisopropylamide (LDA) is quenched with an excess of methyl iodide to give methyl lactone 89 in excellent yield. As expected, the electrophilic attack is stereoselective for the less sterically hindered convex face of the lactone enolate, giving the product with the desired 7iJ-stereochemistry with greater than 95 5 selectivity (Equation 22) <1997TL3817>. 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

The a-cyanoenamine 21, which exists as a mixture of E- and Z-isomers, is deproto-nated by lithium diisopropylamide to give the stabilized 7V,7V-(dimethylamino)allyl anion 22. This reacts with aldehydes RCHO (R = Ph, Ar or cyclohexyl) to afford products which are readily transformed into y-lactones by the action of dilute hydrochloric acid (equation 15)34. 

A number of lactones have been selenenylated via their enolates, which are typically generated using lithium diisopropylamide (Table 1) a well-established procedure is available13. 

Nitta, Hatanaka and Ishimura11 started their synthesis of cephalosporin precursors from L-aspartic acid. The key intermediate is the lactone 1. The azidation resembles the general preparation procedure given for open-chain imide enolates in Section 7.1.1. The main differences are the generation of a dianion with lithium diisopropylamide and the application of tosyl azide. 

Aldol-iype Condensation. Dimetalation of (R)-(+)-3-(p-tolylsulfinyl)propionic acid with Lithium Diisopropylamide produces a chiral homoenolate dianion equivalent which reacts with carbonyl compounds to afford p-sulfinyl-y-hydroxy acids these spontaneously cyclize to give the corresponding p-sulfinyl 7-lactones (eq 2) ... 

KETONES Lithium diisopropylamide. Nickel carbonyl. Sodium tetiacarbonyl-ferrale(-II). Thallium(IIl) nilrale. 2,4,4,6-Tetramethyl-5,6-dihydro-l,3-(4/0-oxazine. Triphenylmcthyl hexafluorophosphate. y-KETONlTRILES Sodium cyanide. d-LACTONES Silver nitrate. 7-LACTONES a-Chloro-N-cyclohexylpro-panaldoximc. 

However, this sequence can be reversed. - Thus, the activated cyclopropane can be de-protonated by lithium diisopropylamide, reacted with an appropriate ketone and opened by various methods such as treatment with acid or desilylation with fluoride. Using this reaction sequence, y-lactones 52 with various substituents can be obtained by the intramolecular attack of the ketone oxygen on the siloxy-substituted carbon followed by oxidation with pyridinium chlorochromate. The cyclic hemiacetal intermediates 53 can be converted to the tetrahyd-rofuran derivatives 55 by deoxygenation with triethylsilane/boron trifluoride. 

The aldehyde was then used in an aldol reaction with the anion from 3-isopropylbut-2-enolide. [The lactone was prepared in the following way bromination of 3-methyl-2-butanone under kinetic conditions (-15 °C) afforded the 1-bromo derivative. The bromine was displaced by acetate on refluxing a solution in acetone with anhydrous KOAc. Reaction of the resulting keto-acetate with the anion from triethylphosphonoacetate afforded the desired butenolide in 55% yield.] The anion was generated in tetrahydrofuran from the butenolide and lithium diisopropylamide and was cooled to -78 °C before addition of the aldehyde. The temperature was maintained below -70 °C for 5h and the reaction was quenched with ammonium chloride at this temperature. Under these conditions (kinetic) the 22R23R intermediate (3) was obtained in 65% yield (26). 

A four-step synthesis for racemic acid 6 was accomplished starting with the cyclic lactone oxacyclotridecan-2-one, which was a-methylated with lithium diisopropylamide (LDA) and methyl iodide, as shown in Fig. (6). Reduction of 3-methyloxacyclotridecan-2-one with diisobutylaluminum hydride (DIBAL) in toluene at -78°C afforded... 

Lactone konnen in a-Position iiber die zuvor durch Deprotonierung mit starken Basen (Lithium-diisopropylamid, Triphenylmethyl-lithium) gebildeten Lactonenolate alkyliert werden351- 353 ... 

To conduct the first carbon-carbon bond formation at the a-carbon of the lactone 195, the lithium diisopropylamide (LDA) generated enolate was trapped with methyl iodide providing a-methylated lactone 196 as a sole product in an excellent yield. As anticipated, the electrophile attacked... 

Many examples of the formation of new six-membered rings containing a nitrogen atom in the reaction of isatoic anhydrides with ketones, diketones, various ether derivatives, lactones, and organometallic compounds are known. Thus, the anhydrides 2 and 34 condense with acetophenones and co-methoxyacetophenones in the presence of lithium diisopropylamide at low temperatures with the formation of derivatives of quinolone 35 [17, 18],... 

A method was developed for the synthesis of quinoline derivatives from isatoic anhydrides and lactones. The amino ketones formed at the first stage were then converted into the desired products by cyclocondensation after isolation or by direct heating of the reaction mass. Thus, the reaction of the anhydride 2 with the butyrolactones 94 in the presence of lithium diisopropylamide gave the amino ketones (95) (yield 99%), which when boiled in toluene gave 4-hydroxy-3-R-l-methyl-2-quinolones 96 (yield 98% with R = H or 70% with R = Me). It was established that the latter exist in two isomeric forms 96a,b [57],... 

Lithium diisopropylamide a-Alkylation of carboxylic acid esters and lactones s. 27, 843 suppl. 28... 

The synthetic technique is summarized in Scheme 3. Reaction of chaparrin (41b) with tert-butyldimethylsilyl chloride 11) afforded the crystalline disilyl derivative (93). The latter was obtained in better yield by silylation of (41b) with tert-butyldimethylsilyl enol ether of pentane-2,4-dione 105). The hydroxyl function at C-1 of (93) was effectively protected using trimethylsilyl triflate to afford the trisilyl lactone (94) which upon treatment with lithium diisopropylamide (LDA) and subsequent exposure to MoOs-pyridine-HMPA (M0O5PH) 104) gave the required 15-hydroxy lactone (95). Treatment of the latter with isovaleryl chloride afforded the crystalline ester (96) which was selectively desilylated to (97). Oxidation of the free allylic hydroxyl and complete desilylation of the resulting disilyl enone with tetrabutylammonium fluoride (BU4NF) afforded the natural cytotoxic quassinoid castelanone (34). 

Base-catalyzed alkylations of simple esters require strongly basic catalysts. Relatively weak bases such as alkoxides promote condensation reactions (Chapter 2). The techniques for successful formation of ester enolates which have been developed typically involve amide bases, most commonly lithium diisopropylamide, at low temperature. The resulting enolates can be successfully alkylated with alkyl bromides or iodides. Some examples of the alkylation of enolates of esters and lactones are presented in Scheme 1.8. 

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