Synthesis of Oxepane Ring Containing Monocyclic, Conformationally Restricted Bicyclic and Spirocyclic Nucleosides from d-Glucose: A Cycloaddition Approach

Carbohydrate-derived substrates having (i) C-5 nitrone and
C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and
(iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic
isoxazolidinooxepane/-pyran ring systems upon intramolecular nitrone cycloaddition reactions. Deprotection of the 1,2-acetonides of these derivatives followed by introduction of
uracil base via Vorbrüggen reaction condition and cleavage
of the isooxazolidine rings as well as of benzyl groups by
transfer hydrogenolysis yielded an oxepane ring containing
bicyclic and spirocyclic nucleosides. The corresponding
oxepane based nucleoside analogues were prepared by
cleavage of isoxazolidine and furanose rings, coupling of
the generated amino functionalities with 5-amino-4,6-dichloropyrimidine, cyclization to purine rings, and finally aminolysis.

具有(i) C-5位硝酮与C-3-O-烯丙基、(ii) C-4位乙烯基与C-3-O-锚定硝酮、(iii) C-5位硝酮与C-4-烯丙氧基甲基结构的碳水化合物衍生底物，经分子内硝酮环加成反应可生成四环异恶唑烷并氧杂环庚烷/吡喃环系。对该类衍生物的1,2-丙酮叉保护基进行脱保护后，通过Vorbrüggen反应条件引入尿嘧啶碱基，再经转移氢解反应裂解异恶唑烷环与苄基，最终得到含氧杂环庚烷环的双环及螺环核苷。针对对应的氧杂环庚烷类核苷类似物，可通过以下步骤制备：先裂解异恶唑烷环与呋喃糖环，将生成的氨基官能团与5-氨基-4,6-二氯嘧啶偶联，随后环化生成嘌呤环，最终经氨解反应得到目标产物。