Revízia štruktúry prvého vnútrobunkového inhibítora prenosu ceramidov Z ER do Golgiho aparátu.
Multigramová syntéza HPA-12, prvého inhibítora nevezikulárneho transportu ceramidov a revízia konfigurácie účinného stereoizoméru z pôvodného anti-(R,R)- na syn-(R,S)-diasteromér.
Andrej Ďuriš, Tomáš Wiesenganger, Daniela Moravčíková, Peter Baran, Jozef Kožíšek, Adam Daich, and Dušan Berkeš Expedient and Practical Synthesis of CERT-Dependent Ceramide Trafficking Inhibitor HPA-12 and Its Analogues Org. Lett., 2011, 13 (7), 1642–1645.
The practical stereodivergent route to both syn- and anti-diastereomers of 1-substituted-3-aminobutane-1,4-diols based on the CIAT approach was completed. This lead to the revision of the reported stereochemistry of the first inhibitor of CERT-dependent ceramide trafficking HPA-12 from (R,R)-anti- to the (R,S)-syn-enantiomer. Due to the expeditiousness of production and inexpensive conditions developed, a series of alkyl and aryl substituted analogues of HPA-12 is also efficiently reported.
Naše výsledky boli potvrdené originátormi v roku 2013:
Masaharu Ueno, Yi-Yong Huang, Akihito Yamano, and Shu̅ Kobayashi Revised Stereochemistry of Ceramide-Trafficking Inhibitor HPA-12 by X-ray Crystallography Analysis Org. Lett. 2013 15 (11), 2869-2871.
In response to Berkešʼs report revising the stereochemistry of HPA-12, an important ceramide-trafficking inhibitor that was discovered, synthesized, and its stereochemistry determined in 2001, we reinvestigated the synthesis and the stereochemistry. It was found that the benzylic positions of intermediates and derivatives of HPA-12 were relatively easy to epimerize. We developed a gram-scale synthetic method for HPA-12 based on a Zn-catalyzed asymmetric Mannich-type reaction in water for the preparation of the material. Finally, single crystals of HPA-12 for X-ray crystallographic analysis were obtained from ethyl propionate/n-hexane at room temperature, and the stereochemistry was definitely determined to be 1R,3S, consistent with Berkešʼs revised structure.