Allylic Azide Rearrangement in Tandem with Intramolecular Huisgen Cycloaddition for Iminosugar and Glycomimetic Synthesis: Functionalized Piperidine, Pyrrolidine, and Pyrrolotriazoles from d-Mannose

Intramolecular Huisgen azide-alkene cycloaddition reaction of 7-azido-hepta-1,5-diene-3,4-diols, prepared from methyl α-d-man­no­pyranoside, were carried out. Allylic azide rearrangement to secondary azides occurred in tandem with triazoline formation and this intermediate was then decomposed in the presence of nucleophilic reagents to give pyrrolidines, piperidines, or azepanes depending on whether cyclic constraint was incorporated or not, on diol stereochemistry and on the nucleophile. The tandem reaction worked best when aziridine formation from the triazoline was efficient, and this efficiency improved on removal of cyclic constraint. Proposals to account for the observed diastereoselectivities are provided. The allylic azide rearrangement in tandem with the intramolecular Huisgen azide-alkyne cycloaddition was also investigated from azidoheptaenyne diols and gave dihydropyrrolotriazoles. All reactions were diastereoselective, and this was high in some cases. Two X-ray crystal structural determinations, 13C NMR data, and 1D and 2D NOESY experiments were used for stereochemical assignments.

本研究开展了以α-D-吡喃甘露糖苷甲酯为原料制备的7-叠氮基-1,5-庚二烯-3,4-二醇的惠斯根氮杂-烯烃分子内环加成反应（Huisgen azide-alkene cycloaddition）。反应过程中，烯丙基叠氮重排生成仲叠氮化合物的过程与三唑啉（triazoline）中间体的生成同步进行；该中间体随后在亲核试剂作用下发生分解，可得到吡咯烷、哌啶或氮杂环庚烷，产物类型取决于环约束的引入情况、二醇的立体化学结构以及所选用的亲核试剂。当三唑啉中间体高效转化为氮丙啶（aziridine）时，该串联反应的效果最佳，且移除环约束可进一步提升反应效率。针对实验观测到的非对映选择性（diastereoselectivities），本文提出了相应的解释机制。此外，本研究还以叠氮基庚炔二醇为底物，考察了伴随烯丙基叠氮重排的分子内惠斯根氮杂-炔烃环加成反应，得到了二氢吡咯并三唑类产物。所有反应均具有非对映选择性，部分案例中该选择性尤为突出。本研究通过两次X射线晶体结构解析、碳-13核磁共振（13C NMR）数据以及一维、二维核Overhauser效应谱（NOESY）实验完成了产物的立体化学归属。