19 3-ヘテロ置換β-ラクタム環合成における立体制御手法(口頭発表の部)

抄録

Addition reaction of ester enolates possessing an α-heteroatom to a chiral imine 1 possessing (4S,5S)-4,5-dimethoxymethyl-2-methyl-1,3-dioxane ring as a chiral auxiliary is studied, in which varying the metal enolate species and the ester parts resulted in the stereodivergent synthesis of each of the possible stereoisomers. As to the preparation of α-amino derivatives, the triisopropoxytitanium enolate derived from t-butyl N,N-dibenzylglycinate reacted with the imine 1 to give directly cyclized (3R,4S)-β-lactam 2 as a sole product. Complete reversal of the diastereoselectivity was observed in the case of the corresponding chlorozinc enolete, giving (3S,4R)-β-lactam 2 exclusively. Solvent effects were also studied, and the addition of HMPA increased the product yields, but the diastereofacial selectivity was decreased in the case of the chlorozic enolate. α-Sulfenylacetates added to the imine 1 in a stereoselective fashion to give β-lactams, where the effects of the substitutents at sulfur reflected the diasteroselectivity, and a relatively small substituent, methylthio group, met with a reversal of the diastereoselectivity: the triisopropoxytitanium enolate of t-butyl methylthioacetate reacted with the imine 1 to give the directly cyclized (3R,4R)-β-lactam 3 exclusively, whereas the corresponding chlorozinc enolate afforded, after cyclization of the initially formed β-amino ester, (3R,4S)-β-lactam 3 predominantly. α-Alkoxyacetic acids also participated in the stereodivergent addition to the chiral imine 1. Although the α-methoxy derivative did not show reversal of the diastereoselectivity, α-pheoxy and t-butoxy derivatives effected the stereodivergent synthesis of the 3-alkoxy-β-lactams, in which the triisopropoxytitanium enolate gave (3R,4R)-β-lactam 4 exclusively, and the chorozinc enolate predominantly afforded (3R,4S)-β-lactam 4 after cyclization of the initially formed β-amino ester. Furthermore, the triisopropoxytitanium enolates prepared from t-butyl chloro- or fluoroacetate underwent addition reaction with the imine 1 to give (3R,4R)-β-lactam 5 (X=Cl or F) exclusively, whereas the formation of aziridine 6 was observed with the lithium or chlorozinc enolate. Factors for the reversal of the diastereoselectivity were also discussed using MM2 calculations and possible transition state models.