3069-52-1Relevant articles and documents
α-Aminoxy Oligopeptides: Synthesis, Secondary Structure, and Cytotoxicity of a New Class of Anticancer Foldamers
Diedrich, Daniela,Moita, Ana J. Rodrigues,Rüther, Anja,Frieg, Benedikt,Reiss, Guido J.,Hoeppner, Astrid,Kurz, Thomas,Gohlke, Holger,Lüdeke, Steffen,Kassack, Matthias U.,Hansen, Finn K.
, p. 17600 - 17611 (2016/11/28)
α-Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α-aminoxy oligopeptides we used a straightforward combination of solution- and solid-phase-supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X-ray crystal structure of an α-aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right-handed 28-helical conformation with precisely two residues per turn and a helical pitch of 5.8 ?. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 28-helix as the predominant conformation in organic solvents. In aqueous solution, the α-aminoxy peptides exist in the 28-helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α-aminoxy peptides have an increased propensity to take up a 28-helical conformation in the presence of a model membrane. This indicates a correlation between the 28-helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α-aminoxy peptides.
Total synthesis, stereochemical assignment, and antimalarial activity of gallinamide A
Conroy, Trent,Guo, Jin T.,Linington, Roger G.,Hunt, Nicholas H.,Payne, Richard J.
supporting information; experimental part, p. 13544 - 13552 (2012/01/13)
The total synthesis and stereochemical assignment of gallinamideA, an antimalarial depsipeptide of cyanobacterial origin, is described. Synthesis of the four possible N-terminal diastereoisomers of gallinamideA (including the natural product symplostatin4) was achieved using a divergent strategy from a common imide fragment. The natural product and corresponding diastereoisomers were synthesized in 30-33% overall yield in a longest linear sequence of 8 steps. Comparative NMR spectroscopic studies of the four synthetic diastereoisomers with the isolated natural product demonstrated that gallinamideA possesses a dimethylated L-isoleucyl residue at the N-terminus. As such, we have shown that gallinamideA is structurally and stereochemically identical to symplostatin4. GallinamideA and its N-terminal diastereoisomers were also shown to possess significant antimalarial activity with IC 50 values in the nanomolar range against the 3D7 strain of Plasmodium falciparum. Naturally active: The total synthesis of gallinamideA, a cyanobacterium-derived depsipeptide, is described. Four N-terminal diastereoisomers of gallinamide A were prepared by using two key fragments (see scheme). Spectroscopic comparison to the isolated natural product enabled the absolute configuration of the N,N-dimethylated isoleucyl residue to be determined as 25S, 26S. GallinamideA (and its diastereoisomers) were also shown to possess potent antimalarial activity. Copyright
Benzotriazole-mediated syntheses of depsipeptides and oligoesters
Avan, Ilker,Tala, Srinivasa R.,Steel, Peter J.,Katritzky, Alan R.
, p. 4884 - 4893 (2011/07/30)
Reactions of O-Pg(α-hydroxyacyl)benzotriazoles with (a) unprotected α-hydroxycarboxylic acids, (b) amino acids, and (c) amines afforded, respectively, chirally pure (a) oligoesters, (b) depsidipeptides, and (c) amide conjugates (yields 52-94%). N-Pg(α-Ami
Total synthesis and antimalarial activity of symplostatin 4
Conroy, Trent,Guo, Jin T.,Hunt, Nicholas H.,Payne, Richard J.
supporting information; experimental part, p. 5576 - 5579 (2011/04/15)
The first total synthesis of symplostatin 4, a marine cyanobacterium- derived natural product, is described. Notable features of the route include the efficient preparation of three key fragments and final assembly to the natural product via sequential imide and amide couplings. Symplostatin 4 was also demonstrated to possess significant antimalarial activity (ED50 of 74 nM against Plasmodium falciparum, strain 3D7).
Zinc-catalyzed enantiospecific sp3-sp3 cross-coupling of α-hydroxy ester triflates with grignard reagents
Studte, Christopher,Breit, Bernhard
supporting information; experimental part, p. 5451 - 5455 (2009/03/12)
(Chemical Equation Presented) Zinc chloride does the trick and efficiently catalyzes the enantiospecific cross-coupling of α-hydroxy ester triflates with Grignard reagents under mild conditions. Enantiopure α-hydroxy esters are directly available from the chiral pool or by diazotization of α-amino acids. Substantial variations in both reacting partners are tolerated making this methodology an attractive alternative to enolate alkylation featuring a reversal of polarity.
Synthesis and characterization of chiral N-O turns induced by α-aminoxy acids
Yang,Li,Ng,Yan,Qu,Wu
, p. 7303 - 7312 (2007/10/03)
Chiral α-aminoxy acids of various side chains were synthesized with high optical purity starting from chiral α-amino acids. The conformations of diamides 13a-e, 15, and 16 were probed by using NMR, FT-IR, and CD spectroscopic methods as well as X-ray crystallography. The right-handed turns with eight-membered-ring intramolecular hydrogen bonds between adjacent residues (called the N-O turns) were found to be preferred for D-aminoxy acid residues, and they were independent of the side chains. The rigid chiral N-O turns should have great potential in molecular design.
Selective Reductions. 37. Asymmetric Reduction of Prochiral Ketones with B-(3-Pinanyl)-9-borabicyclononane
Brown, Herbert C.,Pai, G. Ganesh
, p. 1384 - 1394 (2007/10/02)
The chiral trialkylborane B-(3-pinanyl)-9-borabicyclononane, either with the neat reagents or concentrated solutions, 2 M, reduces a wide range of prochiral carbonyl compounds with good to excellent asymmetric induction.Reduction of simple dialkyl ketones, 2-butanone, 2-octanone, 3-methyl-2-butanone, and 3,3-dimethyl-2-butanone, yields the corresponding alcohols with 43percent, 48percent, 62percent, and 0.7percent asymmetric induction.Acetophenone is reduced to 1-phenylethanol in 85percent ee.The α,β-unsaturated ketones 3-buten-2-one, 1-acetyl-1-cyclohexene, 3-methyl-2-cyclohexenone, and trans-4-phenyl-3-buten-2-one are reduced to the corresponding allylic alcohols with 57percent, 64percent, 11percent, and 97percent asymmetric induction, respecticvely.The α,β-conjugated acetylenic ketones 3-butyn-2-one, 4-methyl-1-pentyn-3-one, and 4-phenyl-3-butyn-2-one underwent a rapid reduction to afford the corresponding propargylic alcohols with 79percent, 99percent, and 91percent enantiomeric purities.The α-haloalkyl aromatic ketones α-chloroacetophenone, α-bromoacetophenone, α-iodoacetophenone, α,p-dibromoacetophenone, α-bromo-p-cyanoacetophenone,α-bromo-2'-acetonaphthone,and α,α,α-trifluoroacetophenone afforded the corresponding halohydrins with 96percent,93percent,93percent,96percent,96percent,90percent,and35percent enantiomeric purities, respectively.The corresponding aliphatic analogue 1-bromo-3-methyl-butanone gave the halohydrin in 66percent ee.The other isomer of this ketone, 3-bromo-3-methyl-2-butanone, failed to undergo reduction.Both the aliphatic and aromatic α-keto esters underwent rapid reduction to give the corresponding α-hydroxy esters with excellentenantiomeric excesses.Thus, methyl, ethyl, isopropyl, and tert-butyl pyruvates afforded the corresponding lactates with 86percent,83percent,78percent, and 92percent ee at 25 deg C,respectively.Lowering the reaction temperature to 0 deg C gave the tert-butyl lactate in 100percent ee.Other aliphatic α-keto esters such as metyl and ethyl 2-oxopentanoates, methyl 3-methyl-2-oxobutanoate, and ethyl 4-methyl-2-oxopentanoate were reduced to the corresponding α-hydroxy esters with 96percent, 96percent, 11percent, and 82percent ee.The methyl, isopropyl, and tert-butyl benzoylformates were reduced to the corresponding mendelic esters with 90percent, 96percent and 100percent ee, respectively.The reduction of the β-keto esters, however, proceeded slowly and ethyl acetoacetate gave the corresponding alcohol with 55percent ee.
