New Synthetic Method for Chiral B-Lactams

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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.