New Synthetic Method for Chiral B-Lactams

酰胺铜酸盐试剂(R_2N)_2CuLi和高阶氰基铜酸盐(R_2N)_2Cu(CN)Li_2是一类新的氮亲核试剂。这些试剂与α、β、伽马、三角洲-二烯酸酯发生区域选择性的1，4-加成反应，而R_2NH生成1，6-加成产物，锂试剂R_2NLi生成1，4-和1，2-加成产物的混合物。将酰胺铜酸盐加到具有8-苯基薄荷基或冰片磺胺手性助剂的手性α、β、伽马、三角洲-二烯酸酯中，以良好到高的非对映选择性生成1，4-加合物。将[BNN(TMS)]_2CuLi和[BNN(TMS)]_2Cu(CN)Li_2加到8-苯基-5-苯基-2，4-戊二烯酸酯或5-苯基-2，4-戊二烯酰基硼磺酰胺上，在β-位产生(R)-手性。将[BNN(TMS)]_2Cu(CN)Li_2与冰片磺胺1，4-加成，然后用乙醛捕获，即可得到单异构体的α-(1-羟乙基)-β-氨基衍生物。N-苄基-N-((R)-1-苯乙基)胺与(R)-(E)-叔丁基5-((tert-butyldimethylsilyl)oxy)-4-methyl-2-pentenoate共轭生成(3S，4R)-合成产物，产率为84%；而(S)-胺与戊烯酸酯反应生成(3R，4R)-反加合物，产率为95%。合成产物经二异丙胺锂-甲基二氯化铝-乙醛连续处理后转化为关键中间体；关键中间体的非对映异构体比：关键中间体与其他非对映异构体的非对映异构体之比为80：20。根据已知的步骤，转化为1β-甲基碳青霉烯类关键中间体很容易。

Amide cuprate reagents, (R_2N)_2CuLi and higher order cyano cuprates (R_2N)_2Cu(CN)Li_2, have been developed as a new class of nitrogen nucleophiles. These reagents underwent regioselective 1,4-addition to alpha, beta, gamma, delta-dienoates whereas R_2NH gave a 1,6-addition product and the lithium reagent R_2NLi afforded a mixture of 1,4-and 1,2-addition products. The amide cuprates were added to chiral alpha, beta, gamma, delta-dienoates having a 8-phenylmenthyl or bornanesultam chiral auxiliary to produce 1,4-adducts in good to high diastereoselectivity. The addition of [BnN(TMS)]_2CuLi and [BnN(TMS)]_2Cu(CN)Li_2 to 8-phenylmenthyl 5-phenyl-2,4-pentadienoate or 5-phenyl-2,4-pentadienoylbornanesultam produced (R) -chirality at the beta-position. The 1,4-addition of [BnN(TMS)]_2Cu(CN)Li_2 to the bornanesultam followed by trapping withacetaldehyde gave the alpha-(1-hydroxyethyl)-beta-amino derivative as a single isomer in good yield. This three component coupling was used in an asymmetric synthesis of a beta-lactam.Conjugate addition of N-benzyl-N-((R)-1-Phenylethyl)amine to (R)-(E)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)-4-methyl-2-pentenoate produced the (3S,4R)-syn-adduct with essentially 100% de in 84% yield, whereas the addition of (S)-amine to the pentenoate afforded the (3R,4R) -anti-adduct with essentially 100% de in 95% yield. The syn adduct was converted upon sequential treatment with lithium diisopropylamide-methylaluminum dichloride-acetaldehyde to the key intermediate ; the diastereoisomer ratio of the key intermediate : the diastereoisomer ratio of the key intermediate to other diasteroisomers was 80 : 20. Conversion to a 1beta-methylcarbapenem key intermediate was carried out readily according to the known procedures.