A General Approach to the Core of the Anti-tumor 6, 7 seco-ent-Kauranes

描述（由申请人提供）：本提案中概述的研究目标是研究串联分子内不对称Heck环化/羰基化/亲核试剂捕获反应作为2-氧杂螺[5.5]十一烷核心的一般入口的范围和效用。进一步的化学，如transmethalo，杂原子和氢化物添加到酰基钯中间体将进行研究，以确定亲核试剂捕获的范围。2-氧杂螺[5.5]十一烷核心是存在于属于6，7-开环-对映-贝壳杉烷二萜类的超过100种化合物中的潜在分子结构，已知其具有抗菌、抗肿瘤、抗炎和拒食活性。最初的努力将集中在赫克环化/羰基化反应序列的成功开发，这可能涉及钯预催化剂以及手性双齿膦配体的精心筛选。在实现这一目标之后，有效的化学合成将允许将适当官能化的2-氧杂螺[5.5]十一烷核心加工成天然产物maoecrystal Z，该化合物对人肿瘤细胞系K562白血病、MCF 7乳腺癌和A2780卵巢癌表现出微摩尔亲和力。这将建立必要的合成基础，需要获得这种生物活性的二萜类家族。具有挑战性的结构以及令人兴奋的生物学特性使这种二萜成为不对称全合成的有趣化合物。 公共卫生相关性：对抗癌症的斗争正在进行中，小分子仍然作为治疗和治疗选择发挥着非常重要的作用。许多对映贝壳杉烷二萜，包括maoecrystal Z，因其抗肿瘤活性和低毒性而被公认，使其成为有吸引力的抗癌药物候选者。这些化合物的一般方法，允许获得类似物是一个值得的奋进。

DESCRIPTION (provided by applicant): The goal of the research outlined in this proposal is to investigate the scope and utility of a tandem intramolecular asymmetric Heck cyclization / carbonylation / nucleophile trapping reaction as a general entry to the 2-oxaspiro[5.5]undecane core. Further chemistry, such as transmetallation, heteroatom and hydride addition to the acyl-palladium intermediate will be investigated to determine the scope of the nucleophile trapping. The 2-oxaspiro[5.5]undecane core is an underlying molecular architecture present in greater than 100 compounds belonging to the 6,7-seco-ent-kaurane diterpenoids, which are known to possess antibacterial, anti-tumor, anti-inflammatory, and anti-feeding activity. Initial efforts will focus on the successful development of the Heck cyclization / carbonylation reaction sequence, which could involve an elaborate screening of palladium precatalysts as well as chiral bidentate phosphine ligands. Following the realization of this goal, an efficient chemical synthesis will allow elaboration of the properly functionalized 2- oxaspiro[5.5]undecane core into the natural product maoecrystal Z, a compound exhibiting micromolar affinity against the human tumor cell lines K562 leukemia, MCF7 breast, and A2780 ovarian. This will establish the necessary synthetic groundwork needed for access to this biologically active family of diterpenoids. The challenging structure as well as the exciting biological profile makes this diterpene an intriguing compound for asymmetric total synthesis. PUBLIC HEALTH RELEVANCE: The battle against cancer is ongoing, and small molecules still play a very important role as therapeutics and treatment options. Many of the ent-kaurane diterpenes, including maoecrystal Z, are recognized for their anti-tumor activity and low toxicity, making them attractive anticancer drug candidates. A general approach to these compounds that allows access to analogues is a worthwhile endeavor.