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An efficient synthetic pathway to a series of novel “reverse” fosmidomycin analogues has been developed, commencing from substituted benzylamines. In these analogues, the fosmidomycin hydroxamate moiety is reversed and the tetrahedral methylene carbon adjacent to the phosphonate moiety is replaced by a nitrogen atom bearing different benzyl groups. The resulting phosphonate esters were designed as potential antimalarial “pro-drugs”.

In an attempt to identify potential new agents that are active against HIV-1 IN, a series of novel coumarin-3-carbohydrazide derivatives were designed and synthesised. The toxicity profiles of these compounds showed that they were non-toxic to human cells and they exhibited promising anti-HIV-1 IN activities with IC50 values in nM range. Also, an accompanying molecular modeling study showed that the compounds bind to the active pocket of the enzyme.

A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg

Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.

A series of N-benzylated phosphoramidate esters, containing a 3,4-dihydroxyphenyl Mg2+-chelating group, has been synthesised in five steps as analogues of fosmidomycin, a Plasmodium falciparum 1-deoxy-1- d -xylulose-5-phosphate reductoisomerase (PfDXR) inhibitor. The 3,4-dihydroxyphenyl group effectively replaces the Mg2+-chelating hydroxamic acid group in fosmidomycin. The compounds showed very encouraging anti-parasitic activity with IC50 values of 5.6–16.4 µM against Plasmodium falciparum parasites and IC50 values of 5.2 – 10.2 µM against Trypanosoma brucei brucei (T.b.brucei). Data obtained from in silico docking of the ligands in the PfDXR receptor cavity (3AU9)5 support their potential as PfDXR inhibitors.

Pyridinium chlorochromate oxidation of Baylis-Hillman-derived tert -butyl 2 H -chromene-3-carboxylates affords chromone-3-carboxylate esters, providing the first application of Baylis-Hillman methodology in a direct and convenient three-step synthesis of chromone derivatives.

Synthetic pathways have been developed to access a series of N-benzylated phosphoramidic acid derivatives as novel, achiral analogues of the established Plasmodium falciparum 1-deoxy- d -xylulose-5-phosphate reductase (PfDXR) enzyme inhibitor, FR900098. Bioassays of the targeted compounds and their synthetic precursors have revealed minimal antimalarial activity but encouraging anti-trypanosomal activity – in one case with an IC50 value of 5.4 µM against Trypanosoma brucei, the parasite responsible for Nagana (African cattle sleeping sickness). The results of relevant in silico modelling and docking studies undertaken in the design and evaluation of these compounds are discussed.

Reaction of tert-butyl 3-(2-hydroxyphenyl)-2-methylenepropanoate esters with aqueous KOH provides convenient and chemoselective one-pot access to 2H-chromene-3-carboxylic acids, the overall transformation involving tandem conjugate addition, hydrolysis and elimination steps. The methodology complements the chemoselective, acid-catalysed route to 3-substituted coumarins from the same substrates by switching the regioselectivity of cyclisation.

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 publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]

(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.

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.

3-(Chloromethyl)coumarins, obtained via acid-catalysed cyclisation of salicylaldehyde-derived Baylis–Hillman adducts, have been treated with propargylamine; reaction of the resulting 3-alkynylmethylcoumarins with azidothymidine (AZT) in the presence of a Cu(I) catalyst has afforded a series of cycloaddition products for evaluation, in their own right, as potential dual-action HIV-1 protease and non-nucleoside reverse transcriptase inhibitors, and as scaffolds for further structural elaboration.

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.

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.

A majority of chemistry graduates seek employment in a rapidly changing chemical industry. Our attempts to provide the graduates with skills in entrepreneurship and the ability to understand and communicate with their chemical engineering colleagues, in addition to their fundamental knowledge of chemistry, are described. This is done at second-year level with practical projects in which student teams formulate and prepare relatively simple chemical products for marketing, followed a year later by a more advanced study of the feasibility of producing and marketing a fine chemical on a commercial scale.

An apparently routine metal–halogen exchange (MHE) reaction gave variable low yields under typical conditions. 13C and 7Li NMR studies suggested a diversity of organolithiums were formed in the MHE reaction leading to a plethora of products on subsequent electrophilic aromatic substitution with geranyl bromide. A reversal of reagent addition simplified the 7Li NMR spectrum and the product distribution, in addition to increasing the isolated yield of the desired product from a variable 5-40% to a consistent 65%.

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.

Photodegradation of 4-nitrophenol (4-Np) in the presence of zinc tetrasulfophthalocyanine (ZnPcS 4 ), zinc octacarboxyphthalocyanine (ZnPc(COOH) 8 ) and a sulfonated ZnPc containing a mixture of differently sulfonated derivatives (ZnPcS mix ), as photocatalysts is reported. ZnPcS mix is the most effective catalyst in terms of a high quantum yield for 4-Np degradation and the stability of the catalyst. However ZnPc(COOH) 8 degrades readily during the catalysis, but it has a higher quantum yield ( Φ 4-Np ) for 4-Np degradation than the rest of the complexes. The Φ 4-Np values were closely related to the singlet oxygen quantum yields Φ Δ and hence aggregation. The rate constants for the reaction with 4-Np were k r = 0.67 × 10 6 mol −1 dm 3 s −1 for ZnPcS mix and 2.8 × 10 8 mol −1 dm 3 s −1 for ZnPc(COOH) 8 .

Two triprenylated toluquinone and toluhydroquinone marine fungal metabolites, 5-methyl-2-[(2′ E ,6′ E )-3′,7′,11′-trimethyl-2′,6′,10′-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione and 5-methyl-2-[(2′ E ,6′ E )-3,7,11-trimethyl-2′,6′,10′-dodecatrienyl]-1,4-benzenediol, were synthesized in four and five steps, respectively, from 2-methyl-1,4-benzoquinone. The synthesis extends the applicability of the oxidative ether cleavage of hydroquinone dimethyl ethers with argentic oxide under acidic conditions to include the oxidative demethylation of polyprenylated-1,4-dimethoxy-toluhydroquinones with a quantitative survival of the oxidation- and acid-sensitive polyprenyl side chain.

A selection of N -substituted 2-lithiopyrrolidines were prepared and their structures were investigated by 6 Li and 13 C NMR spectroscopy. Evidence is presented for aggregation and dynamic solvation effects, depending on the nature of the N -substituent and substituents on the pyrrolidine ring. Studies were performed with N -Boc (coordinating carbonyl group), N -methoxyethyl (coordinating methoxy group) and N -alkyl (no coordinating group) heterocycles to represent three different classes of organolithiums: dipole-stabilized, unstabilized and chelated, and unstabilized.

The influence of substituents and structure on the 13C NMR spectra of four series of benzoxathiepine derivatives has been investigated. Signal assignments in the 13C NMR spectra have been facilitated by the use of several predictive methods, permitting comparison of their relative efficacy.

Kinetics experiments have been used to establish the free energy, enthalpy, and entropy of activation for the enantiomerization of three structural classes of 2-lithiopyrrolidines. We find that alpha-aminoorganolithiums chelated by a N-methoxyethyl or N-Boc group have a barrier to enantiomerization (DeltaG++) 2-3 kcal/mol lower than that of unstabilized alpha-aminoorganolithiums at 273 K. Density functional calculations were performed to clarify possible ground state and transition structures and to identify possible pathways for inversion of these chiral organolithium species.

Two different Baylis—Hillman approaches for the synthesis of coumarin derivatives containing peptide-like side chains are investigated.

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.

In contrast to time-consuming, conventional thermal approaches, microwave irradiation provides rapid and convenient access to unsymmetrical N′-substituted N -mesitylimidazolium salts, which are important precursors for NHC ligands used in the construction of metal–NHC complexes.

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.

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.

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.

Phosphonate esters (V) are prepared via Arbuzov reaction as potential HIV-1 protease inhibitors.

Coupling of Baylis—Hillman-derived indolizine-2-carboxylic acids (I) with various amine and amino acid derivatives provides access to corresponding carboxamides as truncated ritonavir analogues.

3-Ilodomethyl)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.

The kinetics of tin−lithium exchange in heterocyclic α-aminoorganostannanes have been studied using 119Sn rapid-injection NMR. By comparison of the observed relative rate constants, the effects of ring size, configuration, and conformation can be discerned. Stannylpyrrolidines transmetalate extremely rapidly, whereas the rate of transmetalation of stannylpiperidines varies from negligible transmetalation to rapid transmetalation. The evidence suggests that only one conformation of N-methyl-2-(tributylstannyl)piperidine transmetalates. N-Boc stannyl piperidines transmetalate at rates that vary somewhat, due in part to conformational effects.