Lithium enolate, benzylation

The effect of chelating polyamines on the rate and yield of benzylation of the lithium enolate of 1-tetralone was compared with HMPA and DMPU. The triamine... 

We next contemplated whether the unsaturation site could be encompassed in the context of a properly positioned benzo linkage. We were intrigued to discover that excellent diastereoface selectivity was obtained in the aldol condensation of the Z-lithium enolate with the benzyl-substituted formyl moiety, entry g. 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

The proportions of the desired 2,6-isomer and the unwanted 2,2-isomer in the alkylated product will vary depending on the rate and efficiency of mixing of the benzyl bromide with the lithium enolate. If the alkylation of the initially formed enolate could be effected without any eiiolatci equilibration, less than 2% of the unwanted 2,2-isom( r would be e. )oct( d. ... 

An unexpected result was obtained when DTBB-catalyzed lithiation was applied to the vinyl-oxetane 313 . After work-up, lactone 314 was isolated, the process being explained by an elimination reaction via a radical pathway more than by reduction of the benzyl radical into the anion. Thus, this hypothetical intennediate reacted with the lithium enolate of acetaldehyde, generated in situ by reductive decomposition of THF (Scheme 92). 

Reductive O-debenzylation yielded lV-hydroxyazetidin-2-one 373 (Scheme 55) <2000T5719>. The latter compound afforded iV-tosyloxyazetidin-2-one 374 on treatment with TsCl in triethylamine. A substituent with an active methine proton on the ring nitrogen underwent benzylation via a lithium enolate (Equation 148) <1995ACR383>. 

The second synthesis of lasubine II (6) by Narasaka et al. utilizes stereoselective reduction of a /3-hydroxy ketone O-benzyl oxime with lithium aluminum hydride, yielding the corresponding syn-/3-amino alcohol (Scheme 5) 17, 18). The 1,3-dithiane derivative 45 of 3,4-dimethoxybenzaldehyde was converted to 46 in 64% yield via alkylation with 2-bromo-l,l-dimethoxyethane followed by acid hydrolysis. Treatment of the aldol, obtained from condensation of 46 with the kinetic lithium enolate of 5-hexen-2-one, with O-benzylhydroxylamine hy-... 

Finally, the alkylation of the hexameric di-solvated lithium enolate of methyl 3-amino-butyrate with benzyl bromide in THF shows a conversion-dependent deceleration attributed to the formation of LiBr (this is relevant for NMR results). Interestingly, the side dibenzylated product results from the alkylation of the enolate formed by deprotonation of the syn isomer (km/kan,i = 7)288. Kinetic studies performed under pseudo-first-order conditions reveal approximate first-order dependencies in THF (n = 1.3) and enolate. The idealized rate law implicates a direct alkylation of the hexamer without deaggregation. Moreover, the hypothesis of an anti alkylation taking place at either end of the open form of the hexamer (Scheme 81), although unusual, was not excluded by MNDO calculations. 

The solvent effect has long been recognized as an important factor in that it affects the lithium-oxygen bond polarization but also the electrophilic reagent380,398. The effect on aggregation was evaluated by measurement and comparison of the reactivities of monomeric, dimeric and tetrameric forms of LiPhIBP and LiPhAT or LiPhIBP in various ethers252. In the less polar solvent methyl-tert-butyl ether, lithium enolates are tetrameric and do not react with benzyl bromide. On the contrary, with added HMPA the dissociation of the tetrameric LiPhIBP is accompanied by solvation of each monomer by 1 -2... 

TABLE 3. External vs internal benzylation and butylation of lithium enolate derived from heptan-2-one a... 

SCHEME 89. Benzylation of l,5-dimethylpyrrolidin-2-one lithium enolate and the computed transition state for the methylation430... 

SCHEME 99. Enantioselective benzylation of 1 -tetralone lithium enolate in the presence of a stoi-chiometric amount of chiral cyclic urea485... 

SCHEME 100. Enantioselective benzylation of lithium enolates of lactams and lactones in the presence of a stoichiometric amount of chiral tetramine489... 

SCHEME 101. Enantioselective benzylation of tetralones lithium enolates in the presence of catalytic amounts of chiral tetramines494... 

The enantioselective a-benzylation of the lithium enolate of acyclic carboxamides, such as propionamides and butyramides, generated with CLA derived from original pen-tamines bearing several asymmetric centers has been reported495. Complementary, cyclic carboxamides such as perhydropyrimidinones lithium enolates, obtained from more classic Simpkins-type CLAs, were methylated or benzylated in toluene at —78 °C in the... 

A remarkable example of tandem conjugate addition-aldol reaction has been recently reported by Tomioka and coworkers. The transient lithium enolate, generated by 1,4-addition of benzyl lithium thiolate onto the corresponding a,-unsaturated ester182,595, is followed by an intramolecular aldol tandem cyclization, resulting in a five-membered... 

Evans and co-workers have reported successful diazo transfer from p-nitrobenzenesulfonyl azide (PNBSA) to the enolate derivatives of an N-acyloxazolidinone and a benzyl ester (a) Evans, D. A. Britton, T. C. Ellman, J. A. Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. However, we have not been able to achieve efficient diazo transfer to ketone enolates employing these conditions. For example, exposure of the lithium enolate of acetophenone to 1.2 equiv of PNBSA in THF at -TS C for 15 min gave a-diazoacetophenone in only 21% yield. 

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