Reduction dienolates, alkylation

The Birch reduction has been used by several generations of synthetic organic chemists for the conversion of readily available aromatic compounds to alicyclic synthetic intermediates. Birch reductions are carried out with an alkali metal in liquid NH3 solution usually with a co-solvent such as THF and always with an alcohol or related acid to protonate intermediate radical anions or related species. One of the most important applications of the Birch reduction is the conversion of aryl alkyl ethers to l-alkoxycyclohexa-l,4-dienes. These extremely valuable dienol ethers provide cyclohex-3-en-l-ones by mild acid hydrolysis or cyclohex-2-en-l-ones when stronger acids are used (Scheme 1). 

The reduction of benzoic acids affords the dienolate (77) which may be alkylated in situ by a variety of electrophiles to afford 1-substituted derivatives. Clearly, the addition of alcohol must be avoided or limited to small quantities. It may also be necessary to remove the ammonia before adding the electrophile. The vast majority of applications have been based on reactions with alkyl halides to form (78), but additions of (77) to formaldehyde, epoxides and a,p-unsaturated esters to form the range of adducts (79) to (81) have also been reported (Scheme 14). 

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). 

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

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. ... 

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. 

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. ... 

LDA, LiCl) afforded the dienolate intermediate, which was alkylated with iodoethane. Four additional steps including a reductive cleavage of the chiral auxiliary, the protection of the resulting primary alcohol, the oxidative cleavage of the double bond under Johnson-Lemieux conditions, and the formation of the silyl enol ether led to the desired fragment 187. 

Total syntheses of steroids by the allgrlation of cyclic 1,3-diketones with bicyclic bromides are illustrated in Scheme 34. The product of the Birch reduction of resorcinol dimethyl ether (350), which is in the dienol ether of the diketone (338) gives, on alkylation with the bromide (3) and hydrolysis, the tricyclic ABD diketone (351), the cyclization of which with polyphosphoric acid leads to the 18-nor-D-homo derivative (352) [447]. 

In Scheme 3, two general mechanistic pathways that may be operative for the Ni-catalyzed coupling of 1,3-enynes with carboxaldehydes are depicted. The first pathway involves a prior oxidative addition of Ni(0) to the reductant M R leading to a metal hydride or a metal alkyl species A. The reactive catalyst A may proceed by sequential insertion into the alkyne bond and the carbonyl bond of the electrophile to the formation of the polysubstituted 2,4-dienol 5 via vinyl nickel 4. 

A useful expansion of reductive alkylation strategies to include extended dienolates has been developed by Stork in the context of a Wichterle annula-tion [46, 47]. Dienone 30 was found to undergo regio- and diastereoselective alkylation to give the product resulting from a-alkylation of the less hindered enolate diastereoface (Scheme 3.4) [47]. The resulting dione 32 obtained after hydrolysis was utilized as a key intermediate in the total synthesis of adre-nosterone (33). 

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