Piotr Bałczewski

Phosphonate Chemistry and Reagents in the Synthesis of Biologically Active and Natural Products

A review on the total syntheses of bioactive compounds and natural products published in the last decade using phosphonate reagents and phosphonate-based methodologies is presented.

First Approach to Nitrogen‐Containing Fused Aromatic Hydrocarbons as Targets for Organoelectronics Utilizing a New Transformation of O‐Protected Diaryl Methanols

A new concise approach for the construction of heteroatom analogues of polycyclic aromatic benzo[g]quinoline, benzo[b]carbazole, and pyrido[b]carbazole systems via diaryl methanols is described. This transformation involves formation of a central benzene ring fused to two aromatic 5- or 6-membered rings of pyrrole and/or pyridine by using a combination of two aromatic aldehydes, of which at least one contains a ring nitrogen. Analysis of the UV and fluorescent properties, Stokes shifts, quantum yields in solution, and pi-stacking interactions in the crystal structures of the new materials was performed. These polycyclic aromatic compounds show potential as small-molecule organoelectronic materials.

A new, effective approach for the CC bond formation utilizing 1-,2- and 3-phosphonyl substituted radicals derived from iodoalkylphosphonates and n-Bu3SnH/Et3B/O2 system

Abstract A new, practical synthesis of highly substituted phosphonates utilizing 1-, 2- and 3-phosphonyl substituted radicals derived from iodoalkylphosphonates and a catalytic or stoichiometric amounts of the n-Bu3SnH/Et3B/O2 reagent system is described.

Studies on the free radical carbon-carbon bond formation in the reaction of α-phosphoryl sulfides and selenides with alkenes

Abstract α-Mono- and α, α-disubstituted α-phosphoryl radicals 9 were generated from the easy accessible α-phosphoryl Sulfides 4, 5 and α-phosphoryl selenides 11, 12 and reacted with the electron rich alkenes 6 under the reductive (n-Bu 3 SnH/AIBN) conditions to give the functionalized phosphonates 7 in 32 ÷ 68% yield. Two fragmentation processes of the phosphonate α-alkoxy alkyl radicals are also described.

FREE RADICAL DESULFENYLATION AND DESELENYLATION OF α-SULFUR AND α-SELENO SUBSTITUTED PHOSPHONATES WITH THE n- Bu3SnH/AIBN REAGENTS SYSTEM1

Abstract Selective desulfenylation and deselenylation of α-sulfur- and α-seleno-substituted phosphonates under free radical conditions are described. Chemoselectivity and scope of the title reactions were studied using phosphonates additionally functionalized in the α-position by alkyl, phenyl, ethoxy, chloro, car-bonyl and sulfenyl groups. It was found that reduction of a halogen tolerates the presence of the sulfenyl group and the latter could be reduced in the presence of the sulfinyl and sulfonyl moieties. Moreover, one sulfenyl group was selectively removed from α-phosphoryl dithioacetals and the phenylsulfenyl group was reduced preferentially in the presence of the methylsulfenyl one.

A free radical approach to functionalization of phosphonates utilizing novel 2- and 3-phosphonyl radicals

Abstract A general method for the phosphonyl C2,C3C bond formation under the free radical, reductive conditions is described. The new approach is based on the synthesis of novel 2- and 3- phosphonyl radicals 6, 9 derived from the corresponding 2- and 3-halo (XCl, Br, I) substituted phosphonates 7, 10 and their reaction with alkenes 4. Functionalized phosphonates 5, 8 possessing the 2+2 and 3+2 elongated carbon chain were obtained in 24÷73% yields.

Conformation of 2-phosphoryl and 2-thiophosphoryl 1,3-dithianes and related compounds. Comments on the origin of S-C-P anomeric interactions.

A relationship was found between the γ-effect values in 13C NMR spectra and the solution conformation of the title compounds. Base-catalyzed equilibration of anancomeric 2-phosphoryl and 2-thiophosphoryl substituted 5-t-butyl-1,3-dithianes showed that axial preference increases in the order: Ph2P(S)<Ph2P(O)<(MeO)2P(O). Explanation of this phenomenon is proposed, based also on the results of molecular mechanics calculations.

High Cytotoxic Activity of Phosphonium Salts and Their Complementary Selectivity towards HeLa and K562 Cancer Cells: Identification of Tri-n-butyl-n-hexadecylphosphonium bromide as a Highly Potent Anti-HeLa Phosphonium Salt.

Quaternary ammonium and phosphonium salts have been screened for their toxic effect on HeLa and K562 cancer cell lines, as well as on normal HUVEC cells. Tri-n-butyl-n-hexadecylphosphonium bromide, the first phosphonium salt with a halogen anion tested against HeLa cells, was 12 times more potent (IC50 <5 μm after 24 and 48 h) than the clinically used reference compound cisplatin and 17 times more potent than tri-n-hexyltetradecylphosphonium bis(trifluoromethylsulfonyl)imide, which, to the best of our knowledge, is the first phosphonium salt to be evaluated in HeLa cells. However, it was inactive against K562 cells (24 and 48 h). According to a caspase-3/7 assay, its toxicity has not been connected with the induction of apoptosis. In contrast, triphenylalkylphosphonium iodides with shorter C1–5 alkyl chains were inactive against HeLa cells but very active against K562 cells (IC50=6–10 μm after 48 h). Phosphonium cations with halide counterions proved to be more potent than those with (CF3SO2)2N− as the anion, as in the anticancer agent NSC 747251, or other anions in molecules with similar alkyl chain lengths. On the other hand, a series of ammonium salts containing a short methylthiomethyl or methoxymethyl side chain revealed low cytotoxicity (IC50 >500 μm after 24 and 48 h) against both HeLa and K562 cancer cell lines as well as normal HUVEC cells, showing that the nontoxic N+CH2YMe (Y=S, O) structural motif in ammonium salts could be suitable for further optimization and development, especially in transfection experiments.

Iodine atom transfer addition reaction of 1-iodoalkyl phosphonates to alkenes in the presence of α,α′-azoisobutyronitrile (AIBN): mechanistic aspects

The objectives of this work were to elucidate the mechanistic pathway of the title reaction, which constitutes the first example of a radical iodine atom transfer addition reaction of non-fluorine-containing phosphonates, and to determine whether 2-iodo-2-methylpropionitrile, 8, can serve as a competing iodine donor with the starting diethyl 1-iodoalkyl phosphonates, 1a,b. The title reaction was found to proceed with AIBN as the sole radical initiator, not requiring poisonous tin reagents as co-initiators, and gave diethyl 3-iodoalkylphosphonates 3a–e (the final products of the propagation step, isolated in 59–95% yield), tetramethylsuccinodinitrile, 9, diethyl methylphosphonate, 4 and tetraethyl ethylenebisphosphonate 5 (all termination products, 0–10% yields). The radical character of this reaction was demonstrated using TEMPO as a radical trap. 8 (the intermediate of the initiation step), synthesized independently from AIBN and iodine, caused complete inhibition of the reaction when added to the reaction mixture, indicating that it does not behave as an iodine donor in the transfer stage, but rather as an inhibitor.

A novel synthesis of diethyl 3-iodoalkyl- and 3-iodoalkenylphosphonates via the iodine atom transfer addition reaction

Abstract Diethyl 3-iodoalkyl 7 and 3-iodoalkenylphosphonates 8 as new potent synthetic and bioactive compounds were obtained in 58–100% yields via the iodine atom transfer addition reaction of diethyl 1-iodoalkylphosphonates 1 to alkenes 3 and alkynes 4 in the presence of α,α′-azoisobutyronitrile (AIBN).