Rosalyn Klein

Synthesis and evaluation of coumarin derivatives as potential dual-action HIV-1 protease and reverse transcriptase inhibitors

Baylis-Hillman-derived 3-(benzylaminomethyl)coumarins have been treated, sequentially, with chloroacetyl chloride and propargylamine to afford alkynylated coumarins as substrates for Click Chemistry reactions with azidothymidine (AZT) in the presence of a Cu(I) catalyst. The dual-action HIV-1 protease (PR) and reverse transcriptase (RT) inhibition potential of the resulting N-benzylated cycloaddition products, and a series of non-benzylated analogues, has been explored using saturation transfer difference (STD) NMR, computer modelling and enzyme inhibition techniques.

Novel furocoumarins as potential HIV-1 integrase inhibitors.

A series of seven novel, rationally designed N-substituted 3-{3,5-dimethylfuro[3,2-g]coumarin-6-yl}propanamides have been prepared as potential HIV-1 integrase (IN) inhibitors via a five-step pathway commencing with resorcinol and diethyl 2-acetylglutarate, and the HIV-1 IN inhibition potential of these compounds has been examined relative to raltegravir, a known HIV-1 IN inhibitor.

Convenient Synthesis of 3-Methylcoumarins and Coumarin-3-carbaldehydes

Abstract Rapid, microwave-assisted Baylis–Hillman reactions of substituted salicylaldehydes, followed by one-pot hydrogen iodide–mediated cyclization and reduction of the corresponding adducts, has afforded 3-methylcoumarins in up to 94% yield in the final step. Subsequent microwave-assisted selenium dioxide oxidation of selected 3-methylcoumarins has provided convenient access to the corresponding coumarin-3-carbaldehydes and permitted a significant improvement over the yield obtained using conventional heating. GRAPHICAL ABSTRACT

Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors.

DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions.

Regio-controlled Michaelis―Arbuzov reactions of 3-(halomethyl)-coumarins

3-(Iodomethyl)coumarins and 3-(chloromethyl)coumarins, obtained chemoselectively via Baylis–Hillman reactions of salicylaldehyde derivatives with t-butyl acrylate, can be reacted with triethyl phosphite to afford regioisomeric Michaelis-Arbuzov products. Under nitrogen, the 3-(iodomethyl)coumarins undergo direct displacement of iodide to afford the expected 1′-phosphonated derivatives. The reactions with 3-(chloromethyl)coumarins in air, however, proceed with overall allylic rearrangement to afford the regioisomeric 3-methyl-4-phosphonated derivatives.

Indolizine Studies, Part 5: Indolizine-2-carboxamides as Potential HIV-1 Protease Inhibitors[ 1 ]

1,1-Carbonyldiimidazole-promoted coupling of Baylis–Hillman-derived indolizine-2-carboxylic acids with a range of amine and amino acid derivatives has provided access to the corresponding carboxamides in moderate to excellent yield.

Elucidating Latent Mechanistic Complexity in Competing Acid-Catalyzed Reactions of Salicylaldehyde-Derived Baylis–Hillman Adducts

(1)H NMR-based kinetic studies have revealed the latent mechanistic complexity of deceptively simple hydrochloric acid-catalyzed reactions of salicylaldehyde-derived Baylis-Hillman adducts. Reactions conducted at 0 °C afforded 2-(chloromethyl)cinnamic acid derivatives as the major products and the corresponding 3-(chloromethyl)coumarin derivatives as the minor products. In reactions conducted in refluxing acetic acid, however, the 3-(chloromethyl)coumarin derivatives are the sole products. Variable-temperature (1)H NMR analysis permitted the determination of the rate constants and kinetic parameters involved in the pseudo-first-order formation of (Z)-2-(chloromethyl)-3-(2-hydroxyphenyl)-2-propenoic acid. The kinetic data clearly preclude the operation of classical kinetic versus thermodynamic control and indicate the operation of three independent reaction pathways. Theoretical studies of these pathways undertaken at the B3LYP/6-31G(d) level permitted rationalization of the experimental data and provided insights into the possible mechanism of the enzymic E-Z isomerization and cyclization of (E)-cinnamic acid analogues to afford coumarins.

Synthesis of Baylis–Hillman-Derived Phosphonated 3-(Benzylaminomethyl)coumarins

Treatment of Baylis–Hillman-derived 3-(chloromethyl)coumarins with benzylamine has afforded benzylamino derivatives, sequential chloroacetylation and Michaelis–Arbuzov phosphonation of which have provided access to a series of phosphonate esters as potential HIV-1 protease inhibitors.

Evaluation of Baylis–Hillman Routes to 3-(Aminomethyl)coumarin Derivatives

Abstract The relative merits of two different Baylis–Hillman approaches toward the preparation of coumarin derivatives, containing peptide-like side chains, have been explored. In one approach, use of methyl acrylate as the activated alkene requires a protecting group strategy, an approach that is not necessary when using tert-butyl acrylate. [Supplementary materials are available for this article. Go to the publishers online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT