- Exploring the scope of tandem palladium and isothiourea relay catalysis for the synthesis of α-amino acid derivatives
-
The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29-70percent), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate-catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.
- Bitai, Jacqueline,Slawin, Alexandra M.Z.,Cordes, David B.,Smith, Andrew D.
-
supporting information
(2020/07/27)
-
- Regioselective hetero-Michael addition of oxygen, sulfur, and nitrogen nucleophiles to maleimides catalyzed by BF3·OEt2
-
Abstract A practical BF3·OEt2-catalyzed regioselective 1,2-addition or 1,4-hetero-Michael addition of oxygen, sulfur, and nitrogen nucleo philes to maleimides has been developed for the synthesis of alkyl fumarate derivatives or 3-su
- An, Yu-Long,Deng, Yun-Xia,Zhang, Wei,Zhao, Sheng-Yin
-
p. 1581 - 1592
(2015/03/18)
-
- Aza-peptidyl Michael acceptors. A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens
-
Aza-peptide Michael acceptors with the general structure of Cbz-Ala-Ala-AAsn-trans-CH=CHCOR are a new class of inhibitors specific for the asparaginyl endopeptidases (AE) (legumains). Structure-activity relationships (SARs) were characterized for a set of 31 aza-peptide Michael acceptors with AEs derived from three medically important parasites: the protist Trichomonas vaginalis, the hard tick Ixodes ricinus, and the flatworm Schistosoma mansoni. Despite arising from phylogenetically disparate organisms, all three AEs shared a remarkably similar SAR with lowest IC50 values extending into the picomolar range. The results suggest an evolutionary constraint on the topography of the prime side of the active site. SAR also revealed that esters in the P1′ position are more potent than disubstituted amides and that monosubstituted amides and alkyl derivatives show little or no inhibition. The preferred P1′ residues have aromatic substituents. Aza-asparaginyl Michael acceptors react with thiols, which provides insight into the mechanism of their inhibition of asparaginyl endopeptidases.
- G?tz, Marion G.,James, Karen Ellis,Hansell, Elizabeth,Dvo?ák, Jan,Seshaadri, Amritha,Sojka, Daniel,Kopá?ek, Petr,McKerrow, James H.,Caffrey, Conor R.,Powers, James C.
-
p. 2816 - 2832
(2008/12/22)
-
- Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10
-
Aza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 106 M-1 s-1. The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH2-1-Naphth)2 is the most potent compound and it inhibits caspase-3 with a k2 value of 5620000 M-1 s-1. The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1′ moiety.
- Ekici, ?zlem Do?an,Li, Zhao Zhao,Campbell, Amy J.,James, Karen Ellis,Asgian, Juliana L.,Mikolajczyk, Jowita,Salvesen, Guy S.,Ganesan, Rajkumar,Jelakovic, Stjepan,Grütter, Markus G.,Powers, James C.
-
p. 5728 - 5749
(2008/04/18)
-