FORMATION AND ALKYLATION OF SPECIFIC ENOLATE

FORMATION AND ALKYLATION OF SPECIFIC ENOLATE ANIONS FROM AN UNSYMMETRICAL KETONE 2-BENZYL-2-METHYLCY-CL0HEXAN0NE AND 2-BENZYL— 6-METHYLCYCLOHEXANONE, 52,... 

Gall, M. House, H. O. The formation and alkylation of specific enolate anions from an unsymmetrical ketone 2-benzyl-2-methylcy-clohexanone and 2-benzyl-6-methylcyclohexa-none. Org. Synth. 1988, Coll. Vol. VI, 121-130. 

The specific formation and alkylation of enolates from enol-phosphorylated species has been described (Scheme 83)... 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

For further apphcation of this methodology to the synthesis of a specific target, an alkyl group at C-6 needs to be introduced, since the entire class of polyether antibiotics contains at least one methyl moiety on a tetrahydrofu-ran ring. Alkylation of the enolate of the o ,/ -imsaturated ester was expected to yield an Q -alkyl-/ ,y-imsaturated ester. Indeed, the dianion of methyl pro-pionyl acetate (7) reacted with benzyl 2,3-anhydro-jS-L-ribopyranoside (1) in THF at - 78 °C to afford a 1 1 mixture of the diastereoisomers 8 and 9 in 90% combined yield (Scheme 2). Due to the formation of a mixture, 50% of the desired product got lost. Treatment of the mixture of 8 and 9 with 1% TFA in CH2CI2 caused epimerization and afforded a 9 1 mixture of (6S)-8 and (6i )-10 (Scheme 2) [33]. 

The treatment of a,p-unsaturated ketones with organocopper reagents provides another method to access specific enolates of unsymmetrical ketones. Lithium dialkylcuprates (see Section 1.2.1) are used most commonly and the resulting enolate species can be trapped with different electrophiles to give a,p-dialkylated ketones (1.27). Some problems with this approach include the potential for the intermediate enolate to isomerize and the formation of mixtures of stereoisomers of the dialkylated product. The intermediate enolate can be trapped as the silyl enol ether and then regenerated under conditions suitable for the subsequent alkylation. Reaction of the enolate with phenylselenyl bromide gives the a-phenylseleno-ketone 12, from which the p-alkyl-a,p-unsaturated ketone can be obtained by oxidation and selenoxide elimination (1.28). 

Other useful specific enol equivalents of aldehydes and ketones are enamines and aza-eno-lates, which you saw in use in alkylation reactions in Chapter 25. Aza-enolates—the lithium enoiates of imines—derived from aldehydes are also useful in aldol reactions. Cyclohexylamine gives a reasonably stable imine even with acetaldehyde and this can be isolated and lithiated with LDA to give the aza-enolate. The mechanism is similar to the formation of lithium enoiates and the iithium atom binds the nitrogen atom of the aza-enolate, just as it binds the oxygen atom of an enoiate. 

The only a-alkyl substrate (R = n-Pr, X = S) reacted with poor yield (15%) and enantioselectivity (11% ee). The unique combination of the catalytic components was specifically chosen to offer a dual activation of the substrate and reagent the formation of the activated nickel-enolate complex was assisted by the presence of the noncoordinating Bronsted base, while the Lewis acidic EtsSiOTf activated NFSI to become a stronger nucleophile, without interfering with the formation of the enolate. C-F bond formation resulted from the reaction between the activated substrate and the activated electrophile, prior to product release. 

Alkylation.—Position-specific alkylation of ketones can be achieved by a number of new methods. Vinyloxyboranes, formed by reaction of trialkyl-boranes with diazoketones or by radical addition to methyl vinyl ketone, react with alkyl-lithium reagents to give the corresponding lithium enolates, which undergo facile, site-specific alkylation this allows the formation of aa-disubstituted ketones from diazoketones and a/3-disubstituted ketones from methyl vinyl ketone (Scheme 80). 

The general alkylation procedure for imidazolidinones (vide supra) is employed, however, 2 mol equivalents of base have to be used for the imidazolidine acids. (2S,4,S )-3-Benzoyl-2-rw-butyl-1 -methyl-5-oxo-4-imidazo-lidineacetic acid is not soluble in THE and is added to the solution of the base (in this case lithium diethylamide in THF/hexane) as a suspension in THF, followed by enolate formation at 0°C and recooling to — 78 "C before adding an excess of the haloalkanc (often 5- 10 mol equivalents). See Table 4 for specific examples. 

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