Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
J Org Chem. 2011 Aug 19;76(16):6475-87. doi: 10.1021/jo200398v. Epub 2011 Jul 18.
Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust, flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined, the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization. In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies.
提出了两种方法，旨在解决苯并呋喃形成的长期问题，并生成红霉烷家族类型的螺缩酮。首先，使用替代的断键方法，研究了半缩醛共轭加成到萘醌亲电试剂。所需亲电试剂的合成深入了解了萘部分的选择性氧化和官能化。其次，调整了异香豆素环系统的电子特性，相应的反应性进一步支持了电子富的异香豆素能够螺缩酮化的假设。从简单的前体制备了坚固、灵活的合成方法，允许生成多种还原异香豆素。综合来看，本文所呈现的数据深入了解了该家族的敏感性，并阐明了其他潜在的螺缩酮化方法。此外，含有不同萘醌和异香豆素亚基的底物的会聚组装突出了我们的 1,3-偶极环加成方法的实用性，可用于生成这些结构的类似物以进行 SAR 以及化学反应性研究。
