Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China.
Beilstein J Org Chem. 2007 Nov 8;3:41. doi: 10.1186/1860-5397-3-41.
Spiroketals and the corresponding aza-spiroketals are the structural features found in a number of bioactive natural products, and in compounds possessing photochromic properties for use in the area of photochemical erasable memory, self-development photography, actinometry, displays, filters, lenses of variable optical density, and photomechanical biomaterials etc. And (1R,8aS)-1-hydroxyindolizidine (3) has been postulated to be a biosynthetic precursor of hydroxylated indolizidines such as (+)-lentiginosine 1, (-)-2-epilentiginosine 2 and (-)-swainsonine, which are potentially useful antimetastasis drugs for the treatment of cancer. In continuation of a project aimed at the development of enantiomeric malimide-based synthetic methodology, we now report a divergent, concise and highly diastereoselective approach for the asymmetric syntheses of an aza-spiropyran derivative 7 and (1S,8aR)-1-hydroxyindolizidine (ent-3).
The synthesis of aza-spiropyran 7 started from the Grignard addition of malimide 4. Treatment of the THP-protected 4-hydroxybutyl magnesium bromide with malimide 4 at -20 degrees C afforded N,O-acetal 5a as an epimeric mixture in a combined yield of 89%. Subjection of the diastereomeric mixture of N,O-acetal 5a to acidic conditions for 0.5 h resulted in the formation of the desired functionalized aza-spiropyran 7 as a single diastereomer in quantitative yield. The stereochemistry of the aza-spiropyran 7 was determined by NOESY experiment. For the synthesis of ent-3, aza-spiropyran 7, or more conveniently, N,O-acetal 5a, was converted to lactam 6a under standard reductive dehydroxylation conditions in 78% or 77% yield. Reduction of lactam 6a with borane-dimethylsulfide provided pyrrolidine 8 in 95% yield. Compound 8 was then converted to 1-hydroxyindolizidine ent-3 via a four-step procedure, namely, N-debenzylation/O-mesylation/Boc-cleavage/cyclization, and O-debenzylation. Alternatively, amino alcohol 8 was mesylated and the resultant mesylate 12 was subjected to hydrogenolytic conditions, which gave (1S,8aR)-1-hydroxyindolizidine (ent-3) in 60% overall yield from 8.
By the reaction of functionalized Grignard reagent with protected (S)-malimide, either aza-spiropyran or (1S,8aR)-1-hydroxyindolizidine skeleton could be constructed in a concise and selective manner. The results presented herein constitute an important extension of our malimide-based synthetic methodology.
螺环缩酮和相应的氮杂螺环缩酮是许多生物活性天然产物以及具有光致变色性质的化合物的结构特征，可用于光化学可擦除存储器、自显影摄影、光化学计量学、显示器、滤光片、可变光密度透镜和光机械生物材料等领域。并且，（1R，8aS）-1-羟基吲哚里西啶（3）被假定为羟化吲哚里西啶的生物合成前体，如（+）-扁豆灵 1、（-）-2-表扁豆灵 2 和（-）-苦马豆素，它们可能是用于治疗癌症的有效的抗转移药物。在继续进行旨在开发对映体马来酰亚胺基合成方法的项目中，我们现在报告了一种用于不对称合成氮杂螺吡喃衍生物 7 和（1S，8aR）-1-羟基吲哚里西啶（ent-3）的发散、简洁和高度非对映选择性方法。
氮杂螺吡喃 7 的合成始于马来酰亚胺 4 的格氏加成。在-20°C下，将 THP-保护的 4-羟基丁基溴化镁与马来酰亚胺 4 一起处理，以 89%的总收率得到非对映异构体混合物的 N，O-缩醛 5a。将非对映异构体混合物 N，O-缩醛 5a 置于酸性条件下 0.5 小时，可定量得到所需的功能化氮杂螺吡喃 7，为单一非对映异构体。氮杂螺吡喃 7 的立体化学通过 NOESY 实验确定。对于 ent-3 的合成，氮杂螺吡喃 7 或更方便地 N，O-缩醛 5a 在标准的还原去羟化条件下转化为内酰胺 6a，收率为 78%或 77%。内酰胺 6a 用硼烷-二甲硫醚还原得到吡咯烷 8，收率为 95%。然后通过四步程序将化合物 8 转化为 1-羟基吲哚里西啶 ent-3，即去苄基/O-甲磺酸酯/Boc 裂解/环化和去苄基。或者，将氨基醇 8 甲磺酸酯化，所得甲磺酸酯 12 进行氢解条件处理，从 8 得到（1S，8aR）-1-羟基吲哚里西啶（ent-3），总收率为 60%。
通过功能化格氏试剂与保护的（S）-马来酰亚胺的反应，可以简洁、选择性地构建氮杂螺吡喃或（1S，8aR）-1-羟基吲哚里西啶骨架。本文所述的结果是对我们基于马来酰亚胺的合成方法的重要扩展。
