Andrzej E. Wróblewski

Strongly Basic Proazaphosphatranes: P (EtNCH2CH2)3N and P (iso-PrNCH2CH2)3N

The two new azaphosphatranes HP(RNCH2CH2)3N+Cl− (R = Et, 2c and R = i-Pr, 2d) were prepared from the corresponding (RNHCH2CH2)3N and CIP(NEt2)2. They were transformed into the title proazaphosphatranes 3c and 3d, respectively, with tert-BuOK. Alternatively, 3d was prepared by the transamination reaction of PCl(NMe2)2 with (iso-PrNCH2CH2)3N followed by deprotonation with tert-BuOK. Azaphosphatrane cation salts of 3d, [Z-P (iso-PrNCH2CH2)3N]+ (Z = H, 2d; X = D, 2d-D) were obtained from the reaction of 3d with ZCl. Competitive deprotonations of azaphosphatrane cation pairs with a stoichiometric deficit of tert-BuOK in DMSO showed the order of basicity: 3c > 3d > P (MeNCH2CH2)3N (3b). Compound 3d is also a more efficient catalyst for the trimerization of phenyl isocyanate to phenylisocyanurate than is 3b. A strong correlation (r = 0.996) of the transannular distance with the distance of the P from the plane of its amido nitrogens in nine compounds of the type [ZP(RNCH2CH2)N]+ is observed. The molecular struct...

Analogues of branched-chain tetrafuranosides having phosphorus in the anomeric position

Abstract Treatment of [(2 R )-2,4-dibenzyloxy-3-oxo-butyl] dimethyl phosphite ( 2 ) with water afforded a 2:1 mixture of (2 R , 3 R , 4 R )-(3 3a ) and (2 s , 3 R , 4 R )-4-O-benzyl-3-(benzyloxymethyl)-2-methoxy-2-oxo-1, 2-oxaphospholane-3,4-diol ( 3b ) and 1,3-di- O -benzyl-2- C -(dimethoxyphosphoryl)-D-erythritol( 4 ) together with a trace of 1,3-di- O -benzyl-2- C -(dimethoxyphosphoryl)-D-threitol ( 6 ). Addition of dimethyl (trimethylsilyl) phosphite to 1,3-di- O -benzyl-4- O -( tert -butyldimethylsilyl)-D- glycero -tetrulose ( 7 ) gave a 1:1 mixture of the phosphonates 5 and 6 . Triethylamine-catalysed cyclisations of 5 as well as of 6 produced 2:1 mixtures of 3a and 3b and their C-3 epimers 4a and 4b , respectively. Isopropylidenation studies on the debenzylated, 3 , and 4 , allowed us to assign the configurations at C-3 to be R in 3a and 3b , and S in 4a and 4b . Stereochemistry of the 1,2-oxaphospholane ring closure is discussed.

Synthesis of 2-amino-1,3-dihydroxypropylphosphonates from Garner aldehyde

Abstract In the presence of triethylamine or ionic fluoride catalysts, the addition of dimethyl or diethylphosphite to Garner aldehyde proceeded with good (1:9) diastereoselectivity leading to a separable mixture of (1 S ,2 S )- and (1 R ,2 S )-hydroxyphosphonates. Almost equal amounts (43:57) of the respective phosphonates were formed when titanium(IV) isopropoxide was applied as a catalyst. The e.e.s of the hydroxyphosphonates reached 93–97% in the reactions catalysed by Ti(O i Pr) 4 and dropped to 80–91% when triethylamine was used to catalyse the reaction.

Towards enantiomeric 2,3-epoxypropylphosphonates†

Abstract Hydrolysis of diethyl 2,3-epoxypropylphosphonate in the presence of ( R , R )-salen–Co(III)-OAc after 19 h afforded a mixture of ( S )-epoxide (82% ee) and diethyl ( R )-2,3-dihydroxypropylphosphonate (98% ee). Improved enantiomeric excess (93%) of the ( S )-epoxide was obtained in the 72 h hydrolytic kinetic resolution experiment. Acid-catalyzed hydrolysis of ( S )-epoxide (91% ee) gave ( S )-diol (72% ee) due to low C-3 regioselectivity of the reaction.

An Efficient Synthesis of Enantiomeric (S)-Phosphocarnitine

Diethyl (S)-2,3-epoxypropylphosphonate [(S)-3] was transformed into (S)-phosphocarnitine [(S)-2] in the following sequence of reactions: a C-3 regioselective opening of the oxirane ring with magnesium bromide, quantitative bromide displacement with trimethylamine, and ester hydrolysis. The epoxide ring opening of 3 with HCl/EtOAc gave a 92:8 mixture of 3- and 2-chloro-substituted phosphonates. Reaction of (S)-3 with aqueous NMe3 gave diethyl 3-hydroxy-1-propenylphosphonate as a major product. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of enantiomeric diethyl (1R,2R)- and (1S,2R)-1,2,3-trihydroxypropylphosphonates

Abstract Addition of diethyl phosphite to 2,3- O -cyclohexylidene-D-glyceraldehyde catalyzed by triethylamine or fluorides led to ca . 35:65 mixtures of diethyl (1 R ,2 R )- and (1 S ,2 R )-2,3- O -cyclohexylidene-1,2,3-trihydroxypropylphosphonates ( 4a ) and ( 4b ). Application of lithium diethylphosphonate only slightly improved diastereoselectivity. Through chromatographic separation of 4a and 4b the protected trihydroxypropylphosphonates became available for the first time as pure enantiomers. The 1 S configuration in the major diastereoisomer 4b was assigned on the basis of conformational and configurational analysis of 1,2- O -isopropylidene derivatives obtained from the title compounds.

Synthesis and Biological Evaluation of Novel 1,2,3-Triazolonucleotides

A general procedure for the preparation of 1,2,3‐triazole analogs of nucleosides from diethyl 2‐azidoethoxymethyl‐ and 2‐azidoethoxyethylphosphonates was elaborated. The application of microwave irradiation shortened the reaction time to 10 min in comparison to ca. 48 h when 1,3‐dipolar cycloadditions were performed under standard conditions. All compounds were evaluated in vitro for inhibitory activity against a broad variety of DNA and RNA viruses. None of the compounds were antivirally active at subtoxic concentrations. Compound 17k exhibited moderate inhibitory effects on the proliferation of human T‐lymphocyte cells (IC50 = 64 µM for CEM).

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, antiviral, and cytotoxic evaluation of novel phosphonylated 1,2,3-triazoles as acyclic nucleotide analogues.

The 1,3-dipolar cycloaddition of diethyl 2-azidoethyl-, 3-azidopropyl-, 2-azido-1-hydroxyethyl-, 3-azido-2-hydroxypropylphosphonates with selected N-propargyl nucleobases gave a series of the phosphonylated 1,2,3-triazole acyclonucleosides in which the phosphonate residue and nucleobases were linked by three- and four-carbon chains. Under standard conditions (TMSBr, ethanol), all synthesized O,O-diethylphosphonates were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses. Unfortunately, no antiviral activity was observed at 100 μM.

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.