Chiral sp³-rich bicyclo[3.3.1]nonane scaffolds 10–12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI₂-mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp³-rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC₅₀ values in the range of 17.2–31.7 µM, whereas their effects on cell viability were varied (IC₅₀ = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton.

富含手性 sp ³的双环[3.3.1]壬烷支架10 – 12由醛 9合成为单一的非对映异构体，醛9由 4,4-二甲氧基环六-2,5-二烯酮通过铜催化的对映选择性还原制备。研究了三种不同类型的分子内加成反应：SmI ₂介导的还原环化、碱基促进的羟醛反应和一锅曼尼希反应。我们成功地将三个侧链引入支架11并构建了一个 sp ³通过简单地改变配体的手性，两种对映体变体中的丰富化合物库。生物学评估表明，所有合成的化合物都表现出对缺氧诱导因子 1 (HIF-1) 转录活性的浓度依赖性抑制，IC ₅₀值在 17.2–31.7 µM 范围内，而它们对细胞活力的影响各不相同（IC ₅₀  = 3.5 至 > 100 µM）。最活跃的化合物16f抑制 HIF-1α 蛋白和 mRNA 在缺氧中的积累，表明它的作用机制明显不同于其他已知的具有常见双环[3.3.1]壬烷骨架的化合物。