Sodium enolates synthesis

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

The quantitative and diastereoselective addition of the sodium enolate of te/7-buty] 5-methyl-3-oxohexanoate to the Michael acceptor 2 was used in the synthesis of 0-methyl pisiferic acid280. 

For enolates with additional functional groups, chelation may influence stereoselectivity. Chelation-controlled alkylation has been examined in the context of the synthesis of a polyol lactone (-)-discodermolide. The lithium enolate 4 reacts with the allylic iodide 5 in a hexane THF solvent mixture to give a 6 1 ratio favoring the desired stereoisomer. Use of the sodium enolate gives the opposite stereoselectivity, presumably because of the loss of chelation.61 The solvent seems to be quite important in promoting chelation control. 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Enolates can also function as masked aldehydes or ketones and a new synthesis of 2-substituted pyrimidine-5-carboxylic esters 652 used a doubly masked dialdehyde 651, where one aldehyde was protected as an acetal and the other was used in the form of its sodium enolate <2002S720>. 

Hudson, B. E., and Ch. R. Hauser Condensations. XVI. Various Acylations and Alkylations of the Sodium Enolates of Aliphatic Esters. Methods for the Synthesis of a,a-Disubstituted j -Keto Esters and of Certain Other Compounds. J. Amer. chem. Soc. 63, 3156 (1941). 

In Fig. (12) keto ester (94) was selected as starting material. It was converted to the formyl derivative (95) which yielded a,P-unsaturated aldehyde (96) by treatment with DDQ. Michael addition of the sodium enolate of tert-butyl- isovalerylacetate to aldehyde (96) afforded the adduct (97) as a mixture of C-ll diastereomers. By fractional crystallization one of the adducts could be separated but for the synthetic purpose the mixture was not separated. Treatment of the adduct (97) with p-toluenesulfonic acid in glacial acetic acid caused t-butyl ester cleavage, decarboxylation and cyclodehydration leading the formation of tricyclic enedione (98) in 80% yield. This approach was previously utilized by Meyer in the synthesis of nimbiol [29], Treatment of (98) with pyridinium bromide perbromide, followed by hydrogenolysis with palladium and carbon caused aromatization of (98) leading the formation of the phenolic ester (99). 

These substrates are as readily susceptiUe to hydroxylatitm as saturated keumes (Section 2.3.2.I.2.i). Thus enone (120) was oxygenated via the corresponding sodium enolate.Exposure to oxygen and in situ reductive work-up provided (121) in moderate yield during the synthesis of ( )-deoxyaspidodisper-mine. Similarly ( )-kjellmanianone (123) was prepared through oxygenation of the potassium enolate of the corresponding deoxy substrate (122). The enolate was deriv by the action of a less orthodox base. ... 

The acylation of the sodium enolates of esters (prepared by sodium triphenylmethide) with acyl chlorides gives the corresponding a,a-di-substituted /S-keto esters, RCOCR, CO,C,H,. The synthesis is direct, and the product is free from monoalkylation products usually encountered... 

Synthesis of Cyclopropanes. Chiral imide enolates which contain y-halide substituents undergo intramolecular displacement to form cyclopropanes. Halogenation of y,5-unsamrated acyl imides occurs at the y-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61). 

Alhylation (Acyl Species -> a-Alhylated Acyl Product) An efficient procedure for the C(a)-re alkylation of lithium and sodium enolates of Af-acylsultams with various (even nonacti-vated) primary halides in the presence of HMPA has been developed (88.7-99% de). Alkylation with ClCH2NMeC02Bn enables a two-step p-lactam synthesis. Michael-type alkylation... 

Hydroxylation of the sodium enolate of lactone (16) with (+)-( ) gives a-hydroxy lactone in 77% ee (eq 17). Kinetic resolution and asymmetric hydroxylation with (camphor-sulfonyl)oxaziridines has been applied to the synthesis of enantiomerically enriched a-hydroxy carbonyl compounds having multiple stereocenters, which may otherwise be difficult to prepare. Thus hydroxylation of the enolate of racemic 3-methylvalerolactone with substoichiometric amounts of (—)-(l) affords (25,3/J)-verrucarinolactone in 60% ee (eq 18) which on recrystallization is obtained enantiomerically pure. ... 

Oxidation of the dienolate of (17) with (+)-( ) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19) whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a - and y-hydroxylation depending on the reaction conditions (eq 20). With (+)-( ) the lithium enolate of (19) gives primarily the a -hydroxylation product (20), while the sodium enolate gives )/-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-( ) (eq 21). ... 

Nucleophilic addition of ester enolates to enantiopure nitrones, followed by cyclization of the resulting hydro-xylamine, is a general approach to isoxazolidin-5-ones and can be applied to the stereoselective synthesis of these heterocycles <2005CRC775>. In some cases, the cyclization occurs spontaneously under the reaction conditions. For example, the addition of the sodium enolate of methyl acetate to chiral nitrone 551 gave directly the isoxazolidin-5-ones 552 in quantitative yield and high ty -diastereoselectivity (Equation 91) <1998CC493>. 

During the highly stereoselective total synthesis of epothilone B by J.D. White and co-workers, the stereochemistry of the alcohol portion of the macrolactone was established by applying Davis oxaziridine oxidation of a sodium enolate. The sodium enolate was generated from the corresponding chiral oxazolidinone derivative, which upon oxidation gave 71% yield of a-hydroxylated compound. 

An efficient synthesis of the 7-deoxy zaragozic acid core was deveioped by M.A. Calter and co-workers. The assembly of this complex structure was based on the interrupted Feist-Benary reaction, which produces highiy oxygenated dihydrofuranols that can be isolated. To this end, the sodium enolate of malondialdehyde was reacted with 2-bromo-3-oxo-diethyl succinate in benzene at room temperature to afford 29% of the c/s-dihydrofuranol. This product was converted to the zaragozic acid core in four steps. 

The synthesis of barbiturate 36 (see Scheme 4.7) was performed next. The sodium enolate of diethyl malonate was reacted with 43, providing 44, which was converted to 2,2-disubstituted malonate 45 by reaction with allyl bromide. Reaction of 45 with urea in the presence of t-BuOK as base afforded the barbiturate 46, which was submitted to oxidative one-carbon demolition by the action of KMn04 to give carboxylic acid 47. Compound 47 was esterified with ethanol to give the target 36, but unfortunately in modest yields. 

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