Total synthesis and biological evaluation of neodysiherbaine A and analogues
Total synthesis and biological evaluation of neodysiherbaine A and analogues
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DOI：
10.1021/jo0605593
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发表时间：
2006-07-07
影响因子：
3.6
通讯作者：
Sasaki, Makoto
中科院分区：
文献类型：
--
作者：
Shoji, Muneo;Akiyama, Nobuyuki;Sasaki, Makoto
[图表]Dysiherbaine（1）及其同系物neodysiherbaine A（2）是天然存在的兴奋性氨基酸，对离子型谷氨酸受体具有选择性和强效激动活性。本文描述了2及其结构类似物3-8的全合成。高级关键中间体16被用作分支点，以组装一系列这些类似物3-8的C-8和C-9官能团，其通过天然产物本身的操作是不可接近的。关键中间体16的合成特征在于（i）立体控制的C-糖基化以设置C-6立体中心，（ii）通过外烯烃的化学和立体选择性二羟基化和内烯烃的立体选择性环氧化，随后环氧开环/5-外环闭合，简明合成双环醚骨架，和（iii）烯酰胺酯的催化不对称氢化以构建氨基酸附件。一个初步的生物学评价类似物对小鼠的体内毒性和谷氨酸受体的结合亲和力表明，C8和C9官能团的类型和立体化学影响红藻氨酸受体家族成员的dysiherbaine类似物的亚型选择性。
[GRAPHICS]Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C-8 and C-9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C-6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.