Alkylation lithium dienolates

For the reaction of 1,3-dioxin -ones with electrophiles, activation by deprotonation of the side-chain alkyl group is required. Typically lithium diisopropylamide (LDA) is used as a base. The resulting lithium dienolates react with aldehydes <2002EJ0718> or with allyl bromides in the presence of Ar,Ar -dimethylpropyleneurea (DMPU) <2005AGE820, 2006CEJ2488> exclusively at the side-chain double bond, albeit in modest yields (Equation 25). 

The addition of lithium alkoxydienolates to a,P-enones occurs exclusively in the l,4(a)-mode. For example, alkoxydienolate (202), obtained from ethyl senecioate, adds efficiently, in a tandem conjugate addition-allylation protocol, to cyclopentenone to afford the a,(3-functionalized cyclopentanone (203),153 In contrast, the lithium dienolate (204), from 5-methylbutenolide, affords exclusive y-alkylation,154 b while the analogous phthalide enolates (206) can be exploited to accomplish regiospecific polynuclear aromatic syntheses (Scheme 76).l54c ... 

A variety of lithium dialkylamide bases can be used to produce cross-conjugated lithium dienolates, which may then be alkylated with even less reactive alkylating agents, e.g. propyl iodide, in good to excellent yields without equilibration to the corresponding extended dienolates. a -Alkylations of cyclo-hex-2-enones, certain cyclopent-2-enones, l(9)-octalin-2-ones and steroidal 4-en-3-ones have been accomplished by this procedure. ... 

Stork and Danheiser have developed a highly useful procedure for the synthesis of 4-alkylcyclohex-2-enones, which involves a -alkylations of cross-conjugated lithium dienolates of 3-alkoxycyclohex-2-enones, followed by metal hydride reduction of the carbonyl group and hydrolysis (Scheme 30). Numerous applications of this procedure have been reported.Two different alkyl groups may be introduced at the 6-position of a cyclohex-2-enone derivative without difficulty. While dialkylation is generally not a problem in alkylations of cross-conjugated dienolates of cyclohex-2-enones, it was observed when relatively acidic 3-chlorocyclohex-2-enones were employed. ... 

Although the reaction failed with cyclopent-2-enone itself, methylations of kinetic lithium dienolates of 3-alkylcyclopent-2-enones have been carried out in acceptable yields.Intramolecular a -alkylations... 

The spiro-dihydrofuran (61) is converted into the cyclobutane derivative (62) under the influence of trifluoroacetic acid. The lithium dienolate (64), derived from the furanone (63), yields solely y-alkylated products on treatment with alkyl halides. Thermolysis of the t-butylperoxybutenolide (65) produces about equal amounts of the hydroxy-furanone (67) and the indenone (68), presumably via the oxide radical (66). Attack of iodide ion on the salt (69) results in the formation of methyl iodide, butanolide, and (surprisingly) methyl 4-iodobutanoate. A description of a study of the photochemical rearrangement of the tetrahydrofurans (70) to the bicyclic oxetans (71) has been presented. ... 

Copper dienolates of unsaturated acids (and esters) are alkylated mainly at the o- rather than the y-carbon. In contrast, copper dienolates are alkylated mainly at the y-carbon. These compounds are prepared by prior formation of the dilithium dianion (LDA) followed by addition of Cul ( - 78 °). The example formulates the preferential y-alkylation of crotonic acid. 

This was followed shortly by a stereo- and enantiocontrolled synthesis of (—)-chimonanthine (154) and calycanthine (150) as well as a second route to meso-chimonanthine (152). The central step in this synthesis features the use of a double Heck cyclization to create vicinal quaternary carbon centers in high yields and with complete stereocontrol 124). The synthesis commenced with a double alkylation of the lithium dienolate of dimethyl succinate 194 and tartrate-derived diiodide 195 to give a diastereomeric mixture of the saturated diesters. Subsequent oxidation of the diesters, followed in succession by aminolysis, A-benzylation, removal of the benzyl ethers, and silylation, provided the cyclization substrate 197, which on Heck cyclization yielded a single product, 198, a pentacyclic bisoxindole, subsequently shown to have the meso relationship of the two oxindole groups. Further manipulations of 198 led eventually to the diazide derivative 199, which can be processed to we.so-chimonanthine (152), following the procedure established in the preceding synthesis (Scheme 14). 

The idiospermuline synthesis (127,128) (Scheme 18) required preparation of the differentially functionalized dihydroisoindigo derivative 214, followed by the crucial alkylation of the lithium dienolate with enantiopure ditriflate 215, to selectively produce the desired pentacycle 216 (four distinct Ci-symmetric dialkylation products are possible). It was found that the stereoselection in this step is crucially dependent on the choice of solvent, temperature, and concentration, to deliver the dielectrophile from the... 

Rearrangement and Chemospecific Epoxidations. PhS02 CHD-epoxide reacts with alkyl lithium reagents to produce various addition adducts and 3-benzenesulfonyl-cyclohexa-2,4-dienol in modest yield. The conversion was considerably improved by exposing the epoxide to LiHMDS to furnish the dienol in quantitative yield (eq 2). The emergent alkoxide can be protected in situ with ferf-butyldimethylsilyl chloride in the same yield. Nucleophilic epoxidation of both dienes, protected and... 

Routes to cyclonona-2,3- and -3,4-dienols from related 9,9-dibromobicyclo-[6,1,0]nonanes and alkyl-lithium are reported/ and cyclodeca-2,3-dienol is obtained similarly from 10,10-dibromobicyclo[7,l,0]decan-2-ol. Oxymercuration of cyclonona-l,2,6-triene with mercuric chloride in ethanol followed by reduction gives the expected cis,cis-cyclonona-2,6-dienyl ethyl ether, but cyclodeca-l,2,5,8-tetraene gives largely (164) and (165) on reaction with mercuric sulphate in acetic acid the carbenoid (166) is implicated. ... 

The regioselectivity of alkylations of silyl dienol ethers has been studied87,88. These reactions favor y-alkylation products. In contrast, alkylations of the corresponding lithium enolates mainly occur in the a-position. Substituents on the silyl diene unit, as well as the substituents at the silicon, strongly influence the regioselectivity of the reaction87 91,... 

Copper dienolate of a p,y-unsaturated acid (cf., 7, 82-83). The site of alkylation of the dienolate of the acid 1 is markedly dependent on the counterion. The lithium... 

Syntheses of (2) and flOf were conveniently effected tScheme 4) starting from diethyl succinate (12) (28). The resultant dienolate (13). obtained by the action of two equivalent of lithium di-isopropylamide (29) gave on alkylation with methylenedioxybenzyl bromide in excellent yield a mixture of the ( )-ester (14) and meso-cster (15) which by alkaline hydrolysis yielded the dicarboxylic acid mixture (16) and (17). Without separation, this mixture on heating wih acetic anhydride gave the known /ron.r-dipiperonylsuccinic anhydride (18) (30). Reduction of (18) with lithium aluminium hydride gave ( )-dihydrocubebin Q), acetylation of which yielded ( )-ariensin (10). 

In general, the thermodynamically stable extended dienolates (M) have been prepared by deprotonation of enones (62) with sodium or potassium alkoxides in protic solvents or with sodium or potassium hydride in aprotic solvents.Kinetically formed cross-conjugated lithium enolates may be converted into the corresponding extended systems in the presence of excess ketone but in certain cases equilibration is quite slow. Presumably, because the Tr-electron density is higher at the a-carbon than the y-carbon, extended dienolates normally react with alkylating agents to produce a-alkyl-f3,y-unsaturated ketones. 

Stoik et al. have shown that heteroannular extended dienolates such as (73), which contain substituents at both the a- and y-positions, undergo predominantly equatorial alkylation (Scheme 35). The dienolate (73) was product by lithium-ammonia reduction of the tricyclic dienone (72) and the product of its alkylation wiA I-bromo-3-chloro-2-butene and hydrolysis of the resulting enol ether, i.e. (74), was a key intermediate in a short, highly stereoselective synthesis of ( )-adrenosterone. It was pointed out that equatorial alkylation is obtained with dienolates such as (73) and related compounds brcause a peri interaction (Me OMe) of the a- and y-substituents forces the ring a to adopt a half-boat conformation in which the a-face of the ir-system is accessible to attack. 

The synthetic use of acylsilanes depends to a large extent on the ease of migration of Si to an alternative site in the molecule after addition of a suitable nucleophile. For instance, enolate anions add to the carbonyl carbon atom of a-chloroacyltrimethylsilanes, the McsSi unit migrating to the a-C atom with displacement of Cl. In this case, the product can be desilylated to give a /8-diketone. Alternatively, the Si can migrate to the carbonyl O atom, as in Scheme 14, where either a homoenolate ion is set up for further alkylation or, in the case of 2-furyl-lithium addition, the furyl ring opens to give a cumulated dienolate system. 

A further example of the remarkable effect on the regiospecificity of alkylation caused by changing a carbanion counterion from lithium to copper has been reported in the elaboration of isoprenoid 2,6-dienoic acids from dienolates of a/3-unsaturated acids, and allyl halides. 

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