Jacobsen Mikkel F, Turks Maris, Hazell Rita, Skrydstrup Troels
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark.
J Org Chem. 2002 Apr 19;67(8):2411-7. doi: 10.1021/jo0104983.
A series of C4-keto-functionalized 1-[(benzoyloxy)(ethoxycarbonyl)methyl]-2-azetidinones were prepared and studied for their tendency to undergo a Reformatsky-type cyclization to fused bicyclic or tricyclic beta-lactams with the single-electron reducing agent samarium diiodide. Whereas the azetidinone 21a underwent reductive cyclization, affording the potent antibiotic sanfetrinem's tricyclic [4.5.6] core structure as the major component, all other examples tested resulted in cyclization followed by an N to O acyl migration involving cleavage of the beta-lactam ring as the favored pathway. Highly functionalized proline derivatives were therefore accessed as single diastereomers through the reductive cyclization of benzoates 21b, 22, 23a,b, 24b, and 25-28. Pertinent for the success of these cyclizations was the addition of 1 equiv of tert-butyl alcohol, allowing for the protonation of the basic amide derivative obtained after the acyl migration step. The diastereoselectivities of these reactions deviate from those of similar cyclizations involving the corresponding lithium enolate. This divergence could be rationalized by the coordination of the metal ion of the samarium(III) enolate intermediate to the beta-lactam amide functionality in the cyclization step, which may not be possible for lithium enolates.
制备了一系列C4-酮官能化的1-[(苯甲酰氧基)(乙氧羰基)甲基]-2-氮杂环丁酮，并研究了它们与单电子还原剂二碘化钐发生Reformatsky型环化反应生成稠合双环或三环β-内酰胺的倾向。氮杂环丁酮21a发生还原环化反应，以主要成分形式得到强效抗生素三氟菌酸的三环[4.5.6]核心结构，而所有其他测试实例均导致环化反应，随后发生N到O的酰基迁移，其中β-内酰胺环的裂解是首选途径。因此，通过苯甲酸酯21b、22、23a、b、24b以及25 - 28的还原环化反应，可获得高度官能化的脯氨酸衍生物作为单一非对映异构体。这些环化反应成功的关键在于加入1当量的叔丁醇，使得酰基迁移步骤后得到的碱性酰胺衍生物发生质子化。这些反应的非对映选择性与涉及相应烯醇锂盐的类似环化反应不同。这种差异可以通过环化步骤中烯醇钐(III)中间体的金属离子与β-内酰胺酰胺官能团的配位来解释，而烯醇锂盐可能无法实现这种配位。
