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1.
Chemistry ; 19(41): 13803-10, 2013 Oct 04.
Article in English | MEDLINE | ID: mdl-23983102

ABSTRACT

A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2 CCF3 )2 ], 6-methyl-2,2'-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale-up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11 mmol h(-1) by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min(-1) .


Subject(s)
2,2'-Dipyridyl/chemistry , Amidines/chemical synthesis , Carboxylic Acids/chemistry , Palladium/chemistry , Amidines/chemistry , Catalysis , Molecular Structure
2.
Chemistry ; 18(15): 4714-22, 2012 Apr 10.
Article in English | MEDLINE | ID: mdl-22374849

ABSTRACT

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion σ-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the σ-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.


Subject(s)
Benzoquinones/chemistry , Boronic Acids/chemistry , Chelating Agents/chemistry , Palladium/chemistry , Transition Elements/chemistry , Alkenes/chemistry , Catalysis , Molecular Structure , Oxidation-Reduction , Quantum Theory , Stereoisomerism
3.
J Med Chem ; 55(6): 2724-36, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-22376008

ABSTRACT

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure ß-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 µM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 µM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).


Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , Lactams/chemistry , Caco-2 Cells , Cell Membrane Permeability , Crystallography, X-Ray , HIV Protease/metabolism , HIV Protease Inhibitors/chemical synthesis , HIV Protease Inhibitors/pharmacology , HIV-1/drug effects , HIV-1/enzymology , Humans , Lactams/chemical synthesis , Lactams/pharmacology , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
4.
ChemistryOpen ; 1(1): 49-56, 2012 Feb.
Article in English | MEDLINE | ID: mdl-24551492

ABSTRACT

A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78 % isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino ß,α-diarylation-reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.

5.
J Org Chem ; 76(8): 2433-8, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21417443

ABSTRACT

A palladium(II)-catalyzed Heck-Mizoroki/Suzuki-Miyaura domino reaction involving metal coordinating dimethylaminoethyl vinyl ethers and a number of electron-rich and electron-deficient arylboronic acids has been developed. Through variation of the temperature and the concentration of the p-benzoquinone (p-Bq) ligand/reoxidant, conditions for the robust and convenient one-pot generation of diarylated-saturated ethers were identified. With the aid of coordination of the dimethylamino group to the arylpalladium intermediate, the otherwise predominant formation of the ß-arylated olefin could be reversed. A reaction route involving a chelation-controlled carbopalladation, providing a p-Bq stabilized six-membered palladacycle, followed by transmetalation and reductive elimination is suggested to explain the selective formation of saturated diarylated ether products.


Subject(s)
Boronic Acids/chemical synthesis , Ethers/chemical synthesis , Vinyl Compounds/chemistry , Benzoquinones/chemistry , Catalysis , Chelating Agents/chemistry , Chelating Agents/metabolism , Coordination Complexes/chemistry , Electrons , Green Chemistry Technology , Oxidation-Reduction , Palladium/chemistry , Stereoisomerism
6.
Chem Commun (Camb) ; (48): 7587-9, 2009 Dec 28.
Article in English | MEDLINE | ID: mdl-20024288

ABSTRACT

A mild and novel palladium(II)-catalyzed domino Heck/Suzuki alpha,beta-diarylation-reduction of a dimethylaminoethyl substituted chelating vinyl ether was developed by using electron-rich arylboronic acids in combination with p-benzoquinone. Based on the preparative results, a catalytic cycle is proposed. Further, highly regioselective palladium(II)-catalyzed alpha- or beta-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions.


Subject(s)
Boronic Acids/chemistry , Chelating Agents/chemistry , Palladium/chemistry , Vinyl Compounds/chemistry , Benzoquinones/chemistry , Catalysis , Ethers/chemical synthesis , Ethers/chemistry , Stereoisomerism
7.
J Med Chem ; 51(16): 5125-9, 2008 Aug 28.
Article in English | MEDLINE | ID: mdl-18665580

ABSTRACT

A set of 4-quinolone-3-carboxylic acids bearing different substituents on the condensed benzene ring was designed and synthesized as potential HIV-1 integrase inhibitors structurally related to elvitegravir. Some of the new compounds proved to be able to inhibit the strand transfer step of the virus integration process in the micromolar range. Docking studies and quantum mechanics calculations were used to rationalize these data.


Subject(s)
4-Quinolones/chemical synthesis , 4-Quinolones/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase/drug effects , 4-Quinolones/chemistry , Cell Line, Tumor , Cell Survival/drug effects , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Structure-Activity Relationship
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