Selective Monophosphorylation of Aliphatic Diamines

The Journal of Organic Chemistry, 1993

The phosphonate analogs of naturally occurring phosphoric acid esters have recently found an increasing number of applications in biological research. For example, replacing the POC fragment of phosphodiesters with a PCHzC fragment affords a class of compounds that effectively inhibits the enzymes catalyzing the reactions of phosphoric acid derivatives.lJ Very recently, the effect of a 3'-methylene phosphonate moiety on the conformation of an A-DNA octamer double helix has been ~t u d i e d .~ Accordingly, the knowledge of the chemical behavior of these phosphonic acid esters compared to their phosphoric acid counterparts is of considerable interest. For this purpose we now report on intermolecular transesterification of the phosphonate analogs (3',5'-GpcU, 4, and 2',5'-GpcU, 5) of guanylyl(3'-5')uridine and guanylyl(2'd')uridine, containing a PCHzC linkage in place of the PO5'C linkage.

Metal-Based Drugs, 1994

The metal-binding abilities of a wide variety of bioactive aminophosphonates, from the simple aminoethanephosphonic acids to the rather large macrocyclic polyaza derivatives, are discussed with special emphasis on a comparison of the analogous carboxylic acid and phosphonic acid systems. Examples are given of the biological importance of metal ion-aminophosphonate interactions in living systems, and also of their actual and potential applicability in medicine.

Russian Chemical Bulletin, 1997

The reaction of aryl and aralkyl aldoximes with hypophosphorous acid resulted in aminophosphinic acids, which were oxidized into the corresponding aminophosphonic acids.

European Journal of Medicinal Chemistry, 2011

A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis-amidates in excellent yields (83e98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity. Prepared from acid 5. 1 H NMR (DMSO-d 6 , 500 MHz) d 8.10 (s, 1H, H-8), 7.73 (bs, 2H, 6-NH 2 ), 4.49 (dd, 1 H, J HeNeP ¼ 12.1, J NHeCH ¼ 10.3, NH), 4.34 (dd, 1H, J HeNeP ¼ 11.3, J NHeCH ¼ 10.3, NH), 4.20 (dd, 1H, J gem ¼ 14.4, J 1 0 ae2 0 ¼ 3.7, H-1 0 a), 4.12e3.98 (m, 5H, COOeCH 2 and H-1 0 b), 3.98 (m, 1 H, H-2 0 ), 3.86e3.76 (m, 2H, NHeCH), 3.63 (dd, 1H, J gem ¼ 13.0, J HeCeP ¼ 8.0, OeCH 2 eP), 3.55 (dd, 1H, J gem ¼ 13.0, J HeCeP ¼ 9.1, OeCH 2 eP), 1.24e1.21 (m, 6H, NHeCHeCH 3 ), 1.18 (t, 3H, J CH3eCH2 ¼ 7.1, COOeCH 2 eCH 3 ), 1.16 (t, 3H, J CH3eCH2 ¼ 7.1, COOeCH 2 eCH 3 ), 1.02 (d, 3H, J 3 0 e2 0 ¼ 6.3, H-3 0 ). 13 C NMR (DMSO-d 6 , 126 MHz) d 174.20e174.16 (m, COO), 158.86 (d, J 2-F ¼ 203.2, C-2), 5.2.8. (2S,2 0 S)-Diethyl 2,2 0 -{[({2 -[(2,6-diaminopyrimidin-4-yl)oxy] ethoxy}methyl)phosphoryl]bis(azanediyl)}dipropanoate (20) Prepared from diester 12 [33]. 1 H NMR (DMSO-d 6 , 500 MHz) d 6.02 (bs, 2 H, NH 2 ), 5.87 (bs, 2H, NH 2 ), 5.03 (s, 1H, H-5), 4.57 (dd, 1H, J HeNeP ¼ 11.2, J NHeCH ¼ 10.9, NHP), 4.50 (t, 1H, J HeNeP ¼ J NHeCH ¼ 10.3, NHP), 4.20 (t, 2H, H-1 0 ), 4.10e4.00 (m, 4H, COOeCH 2 ), 3.88e3.82 (m, 2H, CHCOO), 3.71 (t, 2H, H-2 0 ), 3.62 (d,

Tetrahedron, 2001

ÐThe synthesis of two new series of functional phosphines oxides is described: analogs of glyphosate [a-aminomethylbis-(hydroxymethyl)phosphine oxide] and bisphosphonic acids [bis(hydroxymethyl)phosphoryl methylphosphonic acid] substituting the phosphonic group [±P(O)(OH) 2 ] by the bis(hydroxymethyl)phosphoryl group [±P(O)(CH 2 OH) 2 ], have been synthesized in good yields, using the bis(benzyloxymethyl)chloromethyl phosphine oxide as a common precursor. The further purpose of this work is to evaluate the biological interest of the bis(hydroxymethyl)phosphoryl group in comparison to the phosphonic group present in a wide range of biological molecules.

Phosphorus, Sulfur, and Silicon and the Related Elements, 2009

Bioorganic & Medicinal Chemistry, 2000

AbstractÐThe vinyl phosphonate derivatives of uridine, cytidine, and cytosine arabinoside (ara-C) have been prepared through oxidation of appropriately protected nucleosides to the 5 H aldehydes and Wittig condensation with [(diethoxyphosphinyl)methylidine]triphenylphosphorane. Dihydroxylation of these vinyl phosphonates with an AD-mix reagent generated the new 5 H ,6 H -dihydroxy-6 H -phosphonates. After hydrolysis of the phosphonate esters and the various protecting groups, the six phosphonic acids were tested for their ability to serve as substrates for the enzyme nucleotide monophosphate kinase and for their toxicity to K562 cells.

Organic Letters, 2007

2. Preparation of bis(diisopropylamino)chlorophosphine (1). S3 6. Preparation of polymer-bound mono-, di-, tri-, and tetraphosphitylating reagents (14-17). S7 7. Solid-phase synthesis of symmetrical 5′,5′-dinucleoside mono-, di-, tri-, and tetraphosphodiesters (31-34a-e) using polymer-bound mono-, di-, tri-, and tetraphosphitylating reagents 14-17. S8 8. 1 H NMR, 13 C NMR, and 31 P NMR spectra of hydroxyphosphoramidite form of mono-, di-, tri-, and tetraphosphitylating reagents (1′, 5′, 9′, 12′) and symmetrical 5′,5′-dinucleoside mono-, di, tri-, and tetraphosphodiesters (31-34a-e). S19 9. Analytical HPLC Profiles of Final Compounds S55 S3 1. General Information. All solid-phase reactions were carried out in Bio-Rad polypropylene columns by shaking and mixing using Glass-Col small tube rotator in dry conditions at room temperature unless otherwise stated. Real-time monitoring of loading of compounds on resin beads was carried out with a Thermo-Nicolet 380 FT-IR spectrophotometer using OMNIC software. The chemical structures of final desalted products were characterized by nuclear magnetic resonance spectrometry ( 1 H NMR, 13 C NMR, 31 P NMR) determined on a Bruker NMR spectrometer (400 MHz). 13 C NMR spectra are fully decoupled. Chemical shifts are reported in parts per millions (ppm). The chemical structures of final products were confirmed by a high-resolution PE Biosystems Mariner API time-of-flight electrospray mass spectrometer and quantitative phosphorus analysis. The substitution of the resins for each step was estimated from the weight gain of the resin. Total isolated yields for final products were calculated based on the loading of aminomethyl polystyrene resin-bound mono-, di-, tri-, and tetraphosphitylating reagents 14-17 and the amount of symmetrical 5′-5′-dinucleoside mono-, di-, tri-, and tetraphosphodiesters products. The synthesis of phosphitylating reagents 1, 5, 9, and 12 was carried out under extremely dry conditions and nitrogen. The polymer-bound p-acetoxybenzyl alcohol (13) was synthesized according to the previously reported procedure. 25 Phosphorus trichloride (875 µL, 10 mmol) and N,N-diisopropylethylamine (DIEA, 3.5 mL, 20 mmol) were added to anhydrous THF (35 mL). Diisopropylamine (2.8 mL, 20 mmol) was added dropwise in 10 min to the solution and the mixture was stirred for 65 min at 0 °C to yield 1. The reaction mixture containing 1 was immediately used in the coupling reaction with swelled solution of polymer-bound p-acetoxybenzyl alcohol 13 (2.50 mmol) in THF in the presence of DIEA (10 mmol) as described later. A small amount of 1 was converted to the hydroxyphosphoramidite form (1′) using water (1 equiv) in the presence of DIEA (1 equiv). The precipitate was filtered off under nitrogen and the solvent was evaporated in vacuum to afford 1′ (76%). The chemical structure of the hydroxyphosphoramidite form (1′) was confirmed by 1 H NMR, 13 C NMR, 31 P NMR, and high-resolution ESI mass spectrometry. Further stability studies on 1′ using high-resolution

Mono-amidated P(V) pro-drugs predominately contribute to the vastly improved delivery of phosphate and phosphonate-containing anti-viral/cancer nucleotide analogues. However, synthetic approaches towards their formation are often harsh and unreliable, which may hamper the identification of novel, more effective amine pro-drugs. Here, we show that direct mono-amidation of structurally complex phosphonic and phosphoric acids may be accomplished in as quickly as seconds by re-purposing the PPh3/DIAD redox pair. Where the triphenylphosphine oxide byproduct is often cited as a vulnerability, we use its formation as an asset. Juxtaposing the anionic nature of the generated mono-amidated product, the desired product may be isolated with a single water extraction. Compared to state-of-the-art strategies towards phosphoramidates, our approach is mild, reliable, and enables access to a variety of aliphatic and benzylic amines for pro-drug attachment.

European Journal of Organic Chemistry, 2009

The Tavs reaction of 2-amino-and 2-acylamido-3-bromopyridines 1 and 2 with triethyl phosphite in the presence of palladium acetate or chloride allows the synthesis of 2-aminoand 2-acylamidopyridine-3-phosphonates 3 and 4. A second ring nitrogen atom causes strong activation and leads to excellent yields in the phosphonylation of 2-amino-3-chloroquinoxalines. 2,3-Dichloroquinoxaline does not need a catalyst and undergoes double phosphonylation with sodium diethyl phosphite under Michaelis-Becker conditions. The results show an activating influence of pyridine nitrogen (-M) and deactivating influence of the amino group (+M). The reactivity of 1 and 2 in the Tavs coupling is compared with that of the 3-NH-2-bromopyridine position isomers and 2-bromo- [a] Due to its strong electron deficiency, 2,3-dichloroquinoxaline is more reactive towards nucleophiles than bromoand in particular chloropyridines. This allows for phosphonylation without a transition metal catalyst. Heating with sodium diethyl phosphite leads to a double Michaelis-Becker reaction with formation of quinoxaline-2,3-diphosphonate 6. Selective mono-phosphonylation could not be Eur.

Nucleosides & …, 1998

Tetrahedron Letters, 1989

thymidine (1) is converted into the triethylarmnonium salt of its 3'-phosphonodithioate (2a) in good yield; the latter compound is converted into a dinucleoside phosphonothioate (4a) and thence into a dinucleoside phosphorodithioate (&) in good overall yield. Phosphorothioate analogues of oligonucleotides have shown potential as antiviral agentsl, and are of value in other studies involving interactions with nucleic acids and proteinsa. The latter analogues contain chiral internucleotide linkages and therefore suffer from the potential disadvantage that they may consist of complex mixtures of diastereoisomers; they are also to some extent susceptible to phosphodiesterase-promoted digestion. For these reasons, an interest has developed recently3r4 in the preparation and properties of phosphorodithioate analogues of oligonucleotides. The synthetic methodology used in the work published so far has been based mainly on the phosphoramidite approach' to oligonucleotide synthesis. However, a report has just appeared6 (see below) on the synthesis of dinucleoside phosphonothioates and hence of dinucleoside phosphorodithioates based on the use of protected nucleoside 3'-phosphonothioates [corresponding to (2; X = 0)] as starting materials. We now present an alternative and convenient approach to the synthesis of phosphorodithioate analogues which involves the use of protected nucleoside 3'-phosphonodithioates [e.g. (a)] as starting materials. The triethylammonium salt of 5'-O-(9-phenylxanthen-9-yl)thymidine 3'-phosphonodithioate (2a) was prepared from the corresponding nucleoside derivative (1)7 by the procedure indicated in the Scheme and, following chromatography on silica gel, was isolated as a stable, colourless precipitated solid in 75% yield; it was found to be t.1.c. homogeneous [RF 0.65 in PriOH-ag. NH3 (d 0.88)-H20 (7:1:2 v/v)], and was identified by n.m.r. spectroscopy [6P (CDC13) 85.0 (JPH 546.3 Hz)]. When the latter compound [(2a), 3.0 mol. eguiv.] was allowed to react with 3'-O-acetylthymidine8 [(i), 1.0 mol. eguiv.] and pivaloyl chloride9 [2 x 3.0 mol. eguiv.] for 20 min at room temperature, the fullyprotected dinucleoside phosphonothioate (g)l" [RF 0.44 in CBC13-MeOH (9:l v/v); bP (CDC13) 70.8 (JPH 669.8 Hz), 72.2 (JPH 664.0 Hz)] was obtained and isolated in 60% yield [based on (z)]. However, when the crude reaction products were first allowed to react with sulphur [lO.O mol. eguiv.] for 15 min at room temperature and then worked-up and

Phosphorus, Sulfur, and Silicon and the Related Elements, 1997

Tetrahedron Letters, 2008

Helvetica Chimica Acta, 1996