Intramolecular Heck reactions of seven (Z)-α,β-unsaturated 2-iodoanilides catalyzed by Pd−BINAP were surveyed using two reaction conditions: (1) silver-promoted cyclizations in the presence of 2 ...equiv of Ag3PO4 and (2) base-promoted cyclizations in the presence of 4 equiv of 1,2,2,6,6-pentamethylpiperidine (PMP). A comparison of these results with the outcome of the corresponding intramolecular Heck reactions of the E stereoisomers leads to the following conclusions: (1) (E)- and (Z)-α,β-unsaturated 2-iodoanilides give opposite enantiomers of the Heck product when Ag3PO4 is the HI acceptor (cationic pathway); the absolute configuration of the product is independent of alkene geometry when the HI acceptor is PMP (neutral pathway). (2) When the 2-substituent is Me or prim-alkyl, stereoinduction is optimal in PMP-promoted insertions of Z substrates which occur with ee's as high as 97%. (3) When the 2-substituent is large, stereoinduction is optimal in insertions of E substrates carried out in the presence of Ag3PO4. (4) Contributions from the β-alkene substituent are minor. The neutral Heck reaction manifold can be entered from triflate substrates by carrying out the cyclization in the presence of added halide salts. The ability to vary both the alkene geometry and the Heck reaction pathway allows chiral 3,3-disubstituted-2-oxindoles having a wide range of substituents at the quaternary carbon (Me, prim-alkyl, tert-alkyl, and aryl) to be prepared with useful levels of enantioselection (72−97% ee). A number of studies were carried out aimed at clarifying the mechanism of the neutral Heck reaction pathway. Key results are the following: (1) Chiral amplification studies show that the catalyst is monomeric Pd−BINAP. (2) Investigations of monophosphine analogues of BINAP, which were designed to mimic a partially dissociated BINAP chelate, support the conclusion that BINAP is chelated during the enantioselective step. (3) Enantioselectivity is insensitive to solvent polarity. From these data, we propose that the stereochemistry determining step of the neutral pathway occurs during the process in which iodide is displaced by the tethered alkene (Figure , 41 → 47 → 45). In light of the variety of pentacoordinate intermediates that could be involved, it is premature to advance a model to rationalize stereoinduction in asymmetric Heck reactions proceeding by the neutral pathway. Nonetheless, the finding that the enantioselective step of asymmetric Heck reactions taking place by the neutral pathway involves five-coordinate intermediates significantly broadens the vista for design of asymmetric ligands for this and related reactions.
We have previously reported the discovery of our P2–P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy ...designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
Novel Gram-positive (Gram+) antibacterial compounds consisting of a DNA polymerase IIIC (pol IIIC) inhibitor covalently connected to a topoisomerase/gyrase inhibitor are described. Specifically, ...3-substituted 6-(3-ethyl-4-methylanilino)uracils (EMAUs) in which the 3-substituent is a fluoroquinolone moiety (FQ) connected by various linkers were synthesized. The resulting “AU−FQ” hybrid compounds were significantly more potent than the parent EMAU compounds as inhibitors of pol IIIC and were up to 64-fold more potent as antibacterials in vitro against Gram+ bacteria. The hybrids inhibited the FQ targets, topoisomerase IV and gyrase, with potencies similar to norfloxacin but 10-fold lower than newer agents, for example, ciprofloxacin and sparfloxacin. Representative hybrids protected mice from lethal Staphylococcus aureus infection after intravenous dosing, and one compound showed protective effect against several antibiotic-sensitive and -resistant Gram+ infections in mice. The AU−FQ hybrids are a promising new family of antibacterials for treatment of antibiotic-resistant Gram+ infections.
A practical synthetic route to various 2-alkylpropane-1,3-sultones, the key intermediates for the preparation of 2-substituted homotaurines as analogs of tramiprosate, was developed.
The potency and selectivity of a previous series of low molecular weight thrombin inhibitors were improved through modifications of the P1 and P3 residues. Introduction of diphenyl substituted ...sulfonamides in the P3 moiety led to highly efficacious compounds. By correctly selecting the combination of P1 and P3 residues, high levels of potency, selectivity and in vivo efficacy were obtained.
Bicyclic piperazinone based thrombin inhibitors of general structure 2 were prepared and evaluated in vitro and in vivo. These inhibitors, having in common an electrophilic basic ...trans-cyclohexylamine P1 residue, displayed high thrombin affinity, high selectivity against trypsin and good in vivo efficacy in the rat arterial thrombosis model.
A simple and versatile method for preparation of (D)-Phe-Pro peptidomimetic bicyclic thiazolidine lactams is presented. These bicyclic lactams have chemical diversity α to the lactam carbonyl and, ...when linked to electrophilic arginines, provide potent thrombin inhibitors.
A simple and versatile method for preparation of (D)-Phe-Pro peptidomimetic bicyclic thiazolidine lactams is presented. These bicyclic lactams have chemical diversity α to the lactam carbonyl and, when linked to electrophilic arginines, provide pofent thrombin inhibitors.
Peptidomimetic inhibitors of thrombin lacking the important Ser195–carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through ...a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.
Peptidomimetic inhibitors of thrombin lacking the important Ser195–carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.
Article Saied, Okba; Bachand, Benoit; Wuest, James D
Canadian journal of chemistry,
04/1998, Letnik:
76, Številka:
4
Journal Article
Recenzirano
Carbonyl oxygen atoms have two formal lone pairs of electrons. In principle, both can be used simultaneously to form complexes with two or more Lewis acids. This multiple coordination promises to ...have a variety of interesting consequences; unfortunately, however, complexes of carbonyl compounds with multiple Lewis acids are extremely rare. To promote multiple coordination, we have made a series of symmetric ketodiesters and related compounds in which the carbonyl group of a ketone is flanked by two additional sites of Lewis basicity. In such compounds, the flanking bases and both lone pairs of the central ketone are available for binding two equivalents of suitable Lewis acids, thereby producing symmetric double chelates in which the central ketone interacts with two Lewis acids at the same time. As expected, treatment of 3-oxoglutarates and 4-oxopimelates with TiCl 4 in a 1:1 ratio yielded unsymmetric single chelates in which the carbonyl groups of the ketone and one ester bind TiCl 4 , while the other ester remains free. Unfortunately, treatment of the same ketodiesters with TiCl 4 in a 1:2 ratio did not produce the desired symmetric double chelates. Instead, 2:4 complexes were formed in which the free esters of the unsymmetric single chelates bind TiCl 4 in the normal way, without assistance from the keto group. We attribute this observation to the inherent reluctance of ketones to bind multiple Lewis acids, as well as to unfavorable Cl · · ·Cl interactions created in the hypothetical double chelates by the simultaneous attachment of two octahedrally coordinated atoms of titanium to a single carbonyl oxygen atom.Key words: Lewis acids, chelation, ketodiesters, TiCl 4 .
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