40 β-ラクタム環合成における立体制御手法(口頭発表の部)

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Recent achievements in our laboratory on the stereodivergent approaches to either diastereomer of the addition products of organometallics to chiral carbonyl and imino compounds have prompted us to explore a new synthetic method for β-lactam skeletons in a highly stereodivergent manner. Optically active β-lactams are an important class of compounds for the synthesis of a series of β-lactam antibiotics and β-lactamase inhibitors. In this presentation diastereoselective addition reaction of ester enolates to a chiral imine 1 possessing (4S,5S)-4,5-dimethoxymethyl-2-methyl-1,3-dioxane ring as a chiral auxiliary is reported, in which varying enolate metals resulted in the selective formation of either (4S)- or (4R)-β-lactam from a single chiral imine 1. Addition reaction of the enolates of ethyl α,α-disubstituted acetate to the imine 1 gave (4S)- or (4R)-β-lactam 6 selectively depending on the metal enolate species used. The reaction with the lithium enolate gave (4S)-β-lactams, whereas (4R)-isomers were obtained from the triisopropoxytitanium enolate. For the preparation of β-lactam without a substituent at the 3-position, by using the triisopropoxytitanium or lithium enolate derived from t-butyl acetate, (3S)-β-amino ester 7 was initially obtained predominantly, whereas the chlorozinc enolate gave (3R)-β-amino ester 7 predominantly. Those β-amino esters were readily converted without racemization into (4S)- and (4R)-β-lactams 9, respectively in good overall yields. The reaction of the metal enolates of α-mono-alkylacetic acid t-butyl esters realized the stereodivergent synthesis of four possible diastereomers of 3,4-disubstituted β-lactams. The metal enolates of t-butyl propionate or butyrate underwent diastereoselective addition reaction to the imine 1 followed by the facile transformation into β-lactams as in the case with t-butyl acetate to give (3R,4S)-isomers 12 (R = Me or Et) from the triisopropoxytitanium enolates, (3S,4S)-isomers 12 (R = Me or Et) from the lithium enolates, and (3R,4R)-isomers 12 (R = Me or Et) from the chlorozinc enolates, respectively, with excellent selectivity. Upon treatment with potassium t-butoxide cis-3R,4R)-β-lactams 12 (R = Me or Et) were readily converted into trans-(3S,4R)-isomers 12 (R = Me or Et). In particular, (3R,4S)-isomer 12 (R = Et) was shown to be a good intermediate for the synthesis of an antibiotic PS-5. Thus, a new method for the stereodivergent construction of β-lactam skeleton possessing substituents at 3- and/or 4-positions from a single chiral imine has been developed by taking advantage of different coordination states of the lithium, titanium, and zinc enolates. Almost complete reversal of the diastereoface-discrimination with respect to the C-4 of the β-lactam skeleton attained in the present system coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary offers a useful and practical addition to the existing methodologies
天然有機化合物討論会の論文
1992-09-10

40 β-ラクタム環合成における立体制御手法(口頭発表の部)

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