Approaches to Bioactive Aminoimidazole Natural Products

描述(由申请人提供)：本意见书中描述的研究的长期目标是提供一系列合成转化，将简单的咪唑类化合物精制成具有生物相关性的天然产品和同系物。提出了两个不同的项目，它们依赖于机械上不同的反应，但都以这样或那样的方式涉及到咪唑环的芳香性的破坏。第一个项目旨在开发4-乙烯基咪唑的分子间和分子内的Dieis-Alder反应，作为一种手段来构建多环分子，这些分子可能在合成天然产物的过程中有用，特别是从海绵中分离出来的oroidin派生的吡咯咪唑类化合物。这一反应有望成为一系列靶标组装的关键步骤，包括具有抗菌特性的Agelas生物碱(例如，ageliferin)，以及更复杂的Palau‘amine及其相关靶标，Konbu’acidin A，Stloguanine和Aaxinellamine A。Palau‘Amine是一种六环、含双胍的生物碱，是一种有效的免疫抑制剂，在混合淋巴细胞反应中显示出纳米分子的IC50。此外，帕劳胺对P-388和A-549癌细胞有明显的抑制作用，其IC50‘S分别为0.2fM和0.5fM。相关的酰化同系物Konbu‘acidin A抑制细胞周期蛋白依赖性激酶4，因此可能被证明是一种有用的抗癌先导化合物，而硫代巴比妥类化合物是几丁质酶抑制剂。第二个项目将集中在最近发现的二甲基二氧六环诱导双环咪唑(四氢苯并咪唑)氧化重排为螺环咪唑酮。建议调查这一潜在重要反应的范围和局限性。特别是，将研究咪唑取代基对氮和C2的影响，以及C4和C5上的外围取代基对重排的立体化学结果的作用。预计这一反应将在合成帕劳胺、康布酸苷A、苯乙基胍和紫杉胺A的方法中发挥关键作用。此外，还计划建立重排对咪唑并[4，5-b]吡啶的适用性，如果成功，重排产物可能作为关键中间体用于合成几种单体奥罗里丁衍生的生物碱，如菲凯林、岩藻毒素和斑点麻黄碱。最后的项目将把在该计划的探索阶段开发的方法应用于一些二聚体oroidin衍生的海洋生物碱(I)ageliferin，(Ii)axinellamine A，(Iii)Palau‘amine，(Iv)konbu’acidin A和(V)Stloguanine。

DESCRIPTION (provided by applicant): The long-term goals of the research described in this submission are to provide a set of synthetic transformations for elaborating simple imidazoles into biologically relevant natural products and congeners. Two distinct projects are proposed that rely on mechanistically diverse reactions, but all involve, in one way or another, the disruption of the aromaticity of the imidazole ring. The first project seeks to develop the inter- and intramolecular Dieis-Alder reaction of 4-vinylimidazoles as a means to construct polycyclic molecules that may be useful en route to natural products, in particular the oroidin derived pyrroloimidazole class of compounds isolated from marine sponges. This reaction is expected to feature as the key step in the assembly of a number of targets including the Agelas alkaloids (e.g., ageliferin), which possess antibacterial properties, and the more complex palau'amine and related targets, konbu'acidin A, styloguanidine and axinellamine A. Palau'amine, a hexacyclic, bisguanidine-containing alkaloid, is a potent immunosuppressant, exhibiting a nanomolar IC50 in the mixed lymphocyte reaction. Furthermore, palau'amine showed significant activity against P-388 and A-549 cancer cell lines, with IC50's of 0.2 and 0.5 fM respectively. The related acylated congener, konbu'acidin A, inhibits cyclin dependent kinase 4 and thus may prove useful as an anti-cancer lead, whereas styloguanidine is a chitinase inhibitor. The second project will focus on the recently discovered dimethyldioxirane induced oxidative rearrangement of bicyclic imidazoles (tetrahydrobenzimidazoles) to spiro imidazolones. It is proposed to investigate the scope and limitations of this potentially important reaction. In particular, the influence of both imidazole substituents on nitrogen and at C2 will be investigated along with the role of peripheral substituents at C4 and C5 on the stereochemical outcome of the rearrangement. It is anticipated that this reaction will play a pivotal role in approaches to palau'amine, konbu'acidin A, styloguanidine and axinellamine A. Also, it is planned to establish the applicability of the rearrangement to imidazo[4,5-b]pyridines, if successful, the rearranged products might function as key intermediates in approaches to several monomeric oroidin-derived alkaloids, such as phakellin, saxitoxin and cantharelline. The final projects will apply the methodology developed during the exploratory phases of this program to a number of the dimeric oroidin-derived marine alkaloids (i) ageliferin, (ii) axinellamine A, (iii) palau'amine, (iv) konbu'acidin A and (v) styloguanidine.