Dorota G. Piotrowska

Enantiomeric phosphonate analogs of the paclitaxel C-13 side chain

Abstract Addition of dimethyl phosphite to racemic N-Boc-phenylglycinal led to a 75:25 mixture of syn and anti dimethyl 2-[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethylphosphonates. The syn-diastereoisomer was obtained in 50% yield after a single crystallization. Resolution of the syn-isomer was achieved via the (S)-O-methylmandelate esters. Racemization-free ammonolysis gave both enantiomers in high enantiomeric excess. Benzoates of both N-Boc syn-enantiomers were transformed into dimethyl (1R,2R)- and (1S,2S)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates in good yields.

Design, Synthesis and Cytotoxicity of a New Series of Isoxazolidine Based Nucleoside Analogues

5‐Arylisoxazolidin‐3‐yl‐3‐diethoxyphosphonates have been synthesized from N‐methyl‐C‐diethoxyphosphorylnitrone and vinyl aryls in good yields and their transformation into the respective phosphonic acids has been accomplished via dealkylation procedure using trimethylsilyl bromide. Phosphonates having 1‐ and 2‐naphthyl substituents at C5 in the isoxazolidine ring as well as the respective phosphonic acids have been found cytotoxic to HeLa and K562 cells with IC50 in the 0.1–0.3 mM range. Preliminary studies on mechanism of action imply that intercalation to DNA is not responsible for their cytotoxic properties.

Enantiomerically pure N-Boc- and N-benzoyl-(S)-phenylglycinals

Abstract Enantiomerically pure N -Boc- and N -benzoyl-( S )-phenylglycinals were prepared by oxidation of the respective alcohols with Dess–Martin periodinane. The glycinals were phosphonylated with lithium O , O -dimethyl phosphonate at −70°C or (MeO) 2 POTMS at −20°C without racemisation. In the presence of 10 mol% of NEt 3 at 20°C the aldehydes racemised instantaneously, while it took a few hours for the reacemisation processes to reach completion after addition of 1 mol% of NEt 3 .

Design, synthesis and cytotoxicity of a new series of isoxazolidines derived from substituted chalcones

A new series of isomeric isoxazolidin-3-yl-3-phosphonates were synthesised from N-methyl-C-diethoxyphosphorylnitrone and substituted chalcones. The respective isoxazolidin-3-yl-3-phosphonic acids were obtained from phosphonates via dealkylation procedure using trimethylsilyl bromide. Selected phosphonates and their respective phosphonic acids were screened for their cytotoxic activity to HeLa and K562 cells with IC(50) in the 0.1-0.3mM range.

Phosphonate analogs of N-benzoyl- and N-Boc-3-phenylisoserine, the taxol C-13 side chain

Abstract Diastereoselectivity of the addition of diethyl phosphite to N-Boc-phenylglycinal reached 50% when NEt3 or KF were used as catalysts but employing lithium diethyl phosphonate lower d.e. was obtained. Separation of the required syn diethyl 2-[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethylphosphonate (8a) from the anti isomer 8b was best achieved as O-benzoate 10a or O-trimethylsilyl 9a derivatives. Diethyl 2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonate (12a) was efficiently prepared (HCl-AcOEt) from 10a in a one-step procedure. The absolute configuration at C-1 in 8a and 8b was established from 1H and 13C NMR spectral data of their N,O-isopropylidene derivatives. Acyclic phosphonates from the a series (8, 10, 12) adopt antiperiplanar conformations.

Stereochemistry of the addition of dialkyl phosphites to (S)-N,N-dibenzylphenylglycinal

Abstract The addition of various dialkyl phosphite derivatives to (S)-N,N-dibenzylphenylglycinal 6 led to the preponderance of anti over syn diastereoisomers: from 75:25 when NEt3 or Ti(OiPr)4 were used to 51:49 for Li or Mg salts. In the NEt3-catalysed reaction, partially racemised phosphonates were formed, while enantiomeric products were obtained after addition of lithium O,O-dimethylphosphonate to (S)-6 at −70°C. Because the syn-isomers were found to be resistant to O-benzoylation, mixtures of diastereoisomers were easily separated after esterification of the anti products. Hydrogenation of the syn-phosphonates in the presence of Boc2O gave enantiomeric dialkyl N-Boc-2-amino-1-hydroxy-2-phenylethylphosphonates—phosphonate analogues of the docetaxel C-13 side chain.

Racemization-Free Recovery of α-Hydroxyphosphonates from Their Carboxylic Esters

Abstract Ammonolysis (25% aqueous NH3 - alcohols or THF) of carboxylic esters obtained from diastereoisomerically pure α-hydroxyphosphonates leads to recovery of the phosphonates without racemization in good to excellent yields.

Synthesis of Novel 1-Hydroxy-2-(1,2,3-triazol-1-yl)ethylphosphonates and 2-Hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates

Abstract Several new 1-hydroxy-2-(1,2,3-triazol-1-yl)ethylphosphonates and 2-hydroxy-3-(1,2,3-triazol-1-yl)propylphosphonates as well as the respective phosphonic acids were synthesized from diethyl 1,2-epoxyethylphosphonate and 2,3-epoxypropylphosphonate in the reaction sequence including the regioselective ring opening of the epoxide with azides followed by 1,3-dipolar cycloaddition of ω-azidophosphonates and selected alkynes and finally hydrolyses of the phosphonate esters. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. GRAPHICAL ABSTRACT

Towards Convenient Precursors for α -Phosphonylated Aziridinium Ions

Mixtures of the respective 2-(N,N-dibenzylamino)-1-chloro- and 1-(N,N-dibenzylamino)-2-chlorophosphonates were obtained after mesylation of dimethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-methylbutylphosphonate and diethyl (1R,2S)-2-(N,N-dibenzylamino)-1-hydroxy-3-phenylpropylphosphonate with mesyl chloride in the presence of tetraethylammonium chloride. These mixtures are considered as useful precursors to α -phosphonylated aziridinium ions.

Stereochemistry of the Three-Component Reaction Between the Ley′S Aldehyde, Benzyl Amines, and Trialkyl Phosphites. A New Approach to the Protected Enantiomerically Pure 1-Amino-2,3-Dihydroxypropylphosphonates

Abstract Enantiomerically pure orthogonally protected dimethyl 1-aminophosphonates (2R,5R,6R,1′R)- and (2R,5R,6R,1′S)-10, phosphonate analogs of 4-hydroxythreonine, were prepared employing the three-component reaction between trimethyl phosphite, (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Ley’s aldehyde), and benzhydrylamine. Since both aminophosphonates 10 exist in a chloroform solution as single rotamers, the absolute configurations at C1′ were unequivocally established based on 1H and 13C NMR spectral data. Studies on stereochemistry of the addition of trialkyl phosphites showed that in chloroform in all cases the nucleophile preferentially attacks the si-face of the C˭N bond, while in alcohols the 1,2-stereoinduction is negligible, and sense of chirality of phenylethylamines is solely responsible for a π-facial discrimination in the 1,3-asymmetric inductions. GRAPHICAL ABSTRACT