Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
J Am Chem Soc. 2010 Aug 18;132(32):11379-85. doi: 10.1021/ja1050023.
Photolysis of alpha-diazo-N-methoxy-N-methyl (Weinreb) beta-ketoamides derived from enantiomerically pure (EP) alpha-amino acids affords the corresponding EP beta-lactams via an intramolecular Wolff rearrangement. The photochemistry is promoted with either standard UV irradiation or through the use of a 100 W compact fluorescent light; the latter affords a safe and environmentally friendly alternative to standard photolysis conditions. A continuous-flow photochemical reactor made from inexpensive laboratory equipment reduced reaction times and was amenable to scale-up. The diastereoselectivity (cis or trans) of the product beta-lactams has been shown to vary from modest to nearly complete. An extremely facile, atom-economical method for the epimerization of the product mixture to the trans isomer, which is generally highly crystalline, has been developed. Evidence for C3 epimerization of Weinreb amide structures via a nonbasic, purely thermal route is presented. Subsequent transformations of both the Weinreb amide at C3 (beta-lactam numbering) and the amino acid side chain at C4 are well-tolerated, allowing for a versatile approach to diverse beta-lactam structures. The technology is showcased in the synthesis of a common intermediate used toward several carbapenem-derived structures starting from unfunctionalized aspartic acid.
由手性纯 (EP)α-氨基酸衍生的α-重氮-N-甲氧基-N-甲基 (Weinreb)β-酮酰胺经光解可通过分子内Wolff 重排得到相应的 EPβ-内酰胺。光化学反应可以通过标准的紫外线照射或使用 100 W 紧凑型荧光灯来促进；后者为标准光解条件提供了一种安全且环保的替代方案。由廉价实验室设备制成的连续流动光化学反应器缩短了反应时间，并且易于放大。所得到的β-内酰胺产物的非对映选择性（顺式或反式）从适度到几乎完全不等。已经开发出一种非常简便、原子经济性的方法，可将产物混合物的对映异构体转化为反式异构体，该异构体通常具有高结晶性。提出了 Weinreb 酰胺结构通过非碱性、纯热途径进行 C3 差向异构化的证据。随后，Weinreb 酰胺的 C3（β-内酰胺编号）和 C4 上的氨基酸侧链的转化都能很好地耐受，从而为各种β-内酰胺结构提供了一种通用的方法。该技术在从无功能化天冬氨酸开始合成几种碳青霉烯衍生结构的常见中间体中得到了展示。
