A stereoselective synthesis of (3aS,6aR)-tetrahydrofuro[3,2-b]pyrrol-3-ones and (3aS,7aR)-hexahydrofuro[3,2-b]pyridine-3-ones has been developed through Fmoc protected scaffolds 12 and 13. A key design element within these novel bicyclic scaffolds, in particular the 5,5-fused system, was the inherent stability of the cis-fused geometry in comparison to that of the corresponding trans-fused. Since the bridgehead stereocentre situated beta to the ketone was of a fixed and stable configuration, the fact that cis ring fusion is both kinetically and thermodynamically stable with respect to trans ring fusion provides chiral stability to the bridgehead stereocentre that is situated alpha to the ketone. To exemplify this principle, building blocks 12 and 13 were designed, prepared and utilised in a solid phase combinatorial synthesis of peptidomimetic inhibitors 10, 45a-e, 11 and 46. Both series were chirally stable with 5,5-series 10 and 45a-e exhibiting potent in vitro activity against a range of CAC1 cysteinyl proteinases. Compound 10, a potent and selective inhibitor of cathepsin K, possessed good primary DMPK properties along with promising activity in an in vitro cell-based human osteoclast assay of bone resorption.

中文翻译：

---

双环拟肽四氢呋喃[3,2-b]吡咯-3-酮和六氢呋喃[3,2-b]吡啶-3-酮基支架：合成和半胱氨酸蛋白酶抑制。

通过Fmoc保护的支架开发了（3aS，6aR）-四氢呋喃[3,2-b]吡咯-3-酮和（3aS，7aR）-六氢呋喃[3,2-b]吡啶-3-酮的立体选择性合成。参见图12和13。在这些新颖的双环支架中，特别是5，5-融合体系中的关键设计要素是与相应的反式融合的相比，顺式融合的几何结构的固有稳定性。由于位于酮β侧的桥头立体中心具有固定且稳定的构型，因此顺式环融合相对于反式环稠合在动力学和热力学上均是稳定的这一事实为位于酮α侧的桥头立体中心提供了手性稳定性。为了体现这一原理，我们设计了第12和13个构建基块，制备并用于拟肽抑制剂10、45a-e，11和46的固相组合合成。两个系列均手性稳定，其中5,5系列10和45a-e表现出对一系列CAC1半胱氨酸蛋白酶的有效体外活性。 。化合物10是组织蛋白酶K的有效和选择性抑制剂，在体外基于细胞的人体破骨细胞骨吸收试验中，它具有良好的主要DMPK特性以及有希望的活性。