447454-26-4Relevant academic research and scientific papers
Stereoselective total synthesis of etnangien and etnangien methyl ester
Li, Pengfei,Li, Jun,Arikan, Fatih,Ahlbrecht, Wiebke,Dieckmann, Michael,Menche, Dirk
supporting information; experimental part, p. 2429 - 2444 (2010/07/06)
A highly stereoselective joint total synthesis of the potent polyketide macrolide antibiotics etnangien and etnangien methyl ester was accomplished by a convergent strategy and proceeds in 23 steps (longest linear sequence). Notable synthetic features include a sequence of highly stereoselective substrate-controlled aldol reactions to set the characteristic assembly of methyl- and hydroxyl-bearing stereogenic centers of the propionate portions, an efficient diastereoselective Heck macrocyclization of a deliberately conformationally biased precursor, and a late-stage introduction of the labile side chain by means of a high-yielding Stille coupling of protective-group-free precursors. Along the way, an improved, reliable protocol for a Z-selective Stork?Zhao?Wittig olefination of aldehydes was developed, and an effective protocol for a 1,3-syn reduction of sterically particularly hindered β-hydroxy ketones was devised. Within the synthetic campaign, a more detailed understanding of the intrinsic isomerization pathways of these labile natural products was elaborated. The expedient and flexible strategy of the etnangiens should be amenable to designed analogues of these RNA-polymerase inhibitors, thus enabling further exploration of the promising biological potential of these macrolide antibiotics.
Total synthesis of etnangien
Li, Pengfei,Li, Jun,Arikan, Fatih,Ahlbrecht, Wiebke,Dieckmann, Michael,Menche, Dirk
supporting information; experimental part, p. 11678 - 11679 (2009/12/08)
(Chemical Equation Presented) The first total synthesis of the potent RNA-polymerase inhibitor etnangien is described, which establishes unequivocally the relative and absolute configuration of this sensitive macrolide antibiotic. Key features of the expe
Photoaffinity analogues of farnesyl pyrophosphate transferable by protein farnesyl transferase
Chehade, Kareem A. H.,Kiegiel, Katarzyna,Isaacs, Richard J.,Pickett, Jennifer S.,Bowers, Katherine E.,Fierke, Carol A.,Andres, Douglas A.,Spielmann, H. Peter
, p. 8206 - 8219 (2007/10/03)
Farnesylation is a posttranslational lipid modification in which a 15-carbon farnesyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins in a reaction catalyzed by protein farnesyltransferase (FTase). We synthesized analogues (3-6) of farnesyl pyrophosphate (FPP) to probe the range of modifications possible to the FPP skeleton which allow for efficient transfer by FTase. Photoaffinity analogues of FPP (5, 6) were prepared by substituting perfluorophenyl azide functional groups for the ω-terminal isoprene of FPP. Substituted anilines replace the ω-terminal isoprene in analogues 3 and 4. Compounds 3-5 were prepared by reductive amination of the appropriate anilines with 8-oxogeranyl acetate, followed by ester hydrolysis, chlorination, and pyrophosphorylation. Additional substitution of three methylenes for the β-isoprene of FPP gave photoprobe 6 in nine steps. Preparation of the analogues required TiCl4-mediated imine formation prior to NaBH(OAc)3 reduction for anilines with a pKa 3PCl2 conversion of allylic alcohols 13-16 into corresponding chlorides 17-20. Analogues 3-6 are efficiently transferred to target N- dansyl-GCVLS peptide substrate by mammalian FTase. Comparison of analogue structures and kinetics of transfer to those of FPP reveals that ring fluorination and para substituents have little effect on the affinity of the analogue pyrophosphate for FTase and its transfer efficiency. These results are also supported with models of the analogue binding modes in the active site of FTase. The transferable azide photoprobe 5 photoinactivates FTase. Transferable analogues 5 and 6 allow the formation of appropriately posttranslationally modified photoreactive peptide probes of isoprene function.
