Freund Robert R A, Gobrecht Philipp, Rao Zhigang, Gerstmeier Jana, Schlosser Robin, Görls Helmar, Werz Oliver, Fischer Dietmar, Arndt Hans-Dieter
Institut für Organische Chemie und Makromolekulare Chemie , Friedrich-Schiller-Universität , Humboldtstr. 10 , 07743 Jena , Germany . Email:
Lehrstuhl für Zellphysiologie , Ruhr-Universität Bochum , Universitätsstr. 150, ND/4 , 44780 Bochum , Germany.
Chem Sci. 2019 Jun 26;10(31):7358-7364. doi: 10.1039/c9sc01473j. eCollection 2019 Aug 21.
The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-()-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for β,β'-disubstituted α,β-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (-)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all the isomers tested in cell culture, only (-)-parthenolide showed potent inhibition of microtubule detyrosination in living cells, confirming its exquisite selectivity on tubulin carboxypeptidase activity. On the other hand, the anti-inflammatory activity of the parthenolides was weaker and less selective with regard to compound stereochemistry.
醛的2-(硅氧基甲基)烯丙基硼酸化反应已被确立，能够在温和条件下立体选择性地合成α-()-亚甲基γ-丁内酯。该反应耐受对酸不稳定的官能团和手性羰基化合物。对于β,β'-二取代的α,β-环氧醛，观察到了优异的不对称诱导效果。这些发现促成了倍半萜天然产物(-)-小白菊内酯、其非天然的(+)-对映体以及非对映异构体的对映选择性全合成。在细胞培养中测试的所有异构体中，只有(-)-小白菊内酯对活细胞中的微管去酪氨酸化表现出强烈抑制作用，证实了其对微管蛋白羧肽酶活性具有极高的选择性。另一方面，小白菊内酯类化合物的抗炎活性较弱，且在化合物立体化学方面选择性较低。
