Solid-phase Synthesis of Phosphorus Derivatives

Author(s): Vasile Simulescu* , Gheorghe Ilia* .

Journal Name: Current Organic Chemistry

Volume 23 , Issue 6 , 2019

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Abstract:

The solid-phase synthesis (SPS) of phosphorus-containing compounds is based mainly on the fact that the chemical process is conducted in a two-phase system. One of the components is connected via covalent bonds to a solid support, which is in general an insoluble polymer, representing the solid phase of the process. The other components involved into the process are solubilized in a solution. The method is suitable to be applied to almost any organic compounds. A common example of using solid-phase synthesis is for obtaining products nucleotide containing, similar to nucleic acids. During the whole process, the nucleotide is always on the solid phase, after the condensation reaction, except for the last step, when the synthesis is already finished. Then, the product is released and separated very easily by filtration. The obtained polymer-oligonucleotide product can participate further in condensation reactions as well. Other important biomolecules synthesized by solid-phase approach during the last decades are nucleoside di- and triphosphates, nucleoside diphosphate sugars and dinucleoside polyphosphates. Those products are precursors of deoxysugars, aminodeoxysugars, uronic acids or glycoconjugates, and are also necessary for DNA and RNA synthesis. The use of the solid-phase method in the context of immobilized oligomers is of great interest nowadays. The solid-phase synthesis offers many advantages in comparison with the conventional solution-phase method, because it takes much less time, it is highly stereoselective, the products are separated and purified usually by a simple filtration or decantation, solvents with high boiling points could be used, the whole process is based on solid polymer support and the obtained compounds should not be isolated.

Keywords: Solid phase synthesis, phosphorus, oligonucleotides, nucleobases, nucleoside, polymers, phosphates, phosphonates.

[1]
Bumcrot, D.; Manoharan, M.; Koteliansky, V.; Sah, D.W.Y. RNAi therapeutics: A potential new class of pharmaceutical drugs. Nat. Chem. Biol., 2006, 2(12), 711-719.
[2]
Shukla, S.; Sumaria, C.S.; Pradeepkumar, P.I. Exploring chemical modifications for siRNA therapeutics: A structural and functional outlook. ChemMedChem, 2010, 5(3), 328-349.
[3]
Seto, A.G. The road toward microRNA therapeutics. Int. J. Biochem. Cell Biol., 2010, 42(8), 1298-1305.
[4]
Echeverri, C.J.; Perrimon, N. High-throughput RNAi screening in cultured cells: a user’s guide. Nat. Rev. Genet., 2006, 7(5), 373-384.
[5]
Verma, S.; Eckstein, F. Modified oligonucleotides: Synthesis and strategy for users. Annu. Rev. Biochem., 1998, 67, 99-134.
[6]
Guga, P.; Koziołkiewicz, M. Phosphorothioate nucleotides and oligonucleotides - recent progress in synthesis and application. Chem. Biodivers., 2011, 8(9), 1642-1681.
[7]
Oka, N.; Wada, T. Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms. Chem. Soc. Rev., 2011, 40(12), 5829-5843.
[8]
Leznoff, C.C. The use of insoluble polymer supports in organic chemical synthesis. Chem. Soc. Rev. Chem. Soc. Rev, 1974, 3, 65-85.
[9]
Frechet, J.M.J. Synthesis and applications of organic polymers as supports and protecting groups. Tetrahedron, 1981, 37, 663-683.
[10]
Crowley, J.I.; Rapoport, H. Solid-phase organic synthesis: Novelty or fundamental concept? Acc. Chem. Res., 1976, 9, 135-144.
[11]
Krchnak, V.; Holladay, M.W. Solid phase heterocyclic Chemistry. Chem. Rev., 2002, 102(1), 61-92.
[12]
Simulescu, V.; Crasmareanu, E.; Ilia, G. Synthesis, properties and structures of phosphorus-nitrogen heterocycles. Heterocycles, 2011, 83(2), 275-291.
[13]
Kondo, Y.; Shinkai, H.; Tanji, K. Solid phase synthesis of heterocyclic compounds. J. Synth. Org. Chem., 1998, 56(1), 2-10.
[14]
Hughes, I. Application of polymer-bound phosphonium salts as traceless supports for solid phase synthesis. Tetrahedron Lett., 1996, 37(42), 7595-7598.
[15]
Slade, R.M.; Phillips, M.A.; Berger, J.G. Application of an almost traceless linker in the synthesis of 2-alkylthiobenzimidazole combinatorial libraries. Mol. Divers., 1998, 4(4), 215-219.
[16]
Lopez-Cremades, P.; Molina, P.; Aller, E.; Lorenzo, A. Solid-phase synthesis of bis(guanidines) based on an aza Wittig/carbodiimide-mediated annulation process. Synlett, 2000, 10, 1411-1414.
[17]
Brase, S.; Dahmen, S.; Heuts, J. Solid-phase synthesis of substituted cinnolines by a richter type cleavage protocol. Tetrahedron Lett., 1999, 40(34), 6201-6203.
[18]
Nukaga, Y.; Yamada, K.; Ogata, T.; Oka, N.; Wada, T. Stereocontrolled solid-phase synthesis of phosphorothioate oligoribonucleotides using 2′-O-(2-cyanoethoxymethyl)-nucleoside 3′-o-oxazaphospholidine monomers. J. Org. Chem., 2012, 77(18), 7913-7922.
[19]
Nukaga, Y.; Oka, N.; Wada, T. Stereocontrolled solid-phase synthesis of phosphate/phosphorothioate (PO/PS) chimeric oligodeoxyribonucleotides on an automated synthesizer using an oxazaphospholidine–phosphoramidite method. J. Org. Chem., 2016, 81(7), 2753-2762.
[20]
Nukaga, Y.; Takemura, T.; Iwamoto, N.; Oka, N.; Wada, T. Enhancement of the affinity of 2′-O-Me-oligonucleotides for complementary RNA by incorporating a stereoregulated boranophosphate backbone. RSC Advances, 2015, 5(4), 2392-2395.
[21]
Shiba, Y.; Masuda, H.; Watanabe, N.; Ego, T.; Takagaki, K.; Ishiyama, K.; Ohgi, T.; Yano, J. Chemical synthesis of a very long oligoribonucleotide with 2-cyanoethoxymethyl (CEM) as the 2′- O -protecting group: Structural identification and biological activity of a synthetic 110mer precursor-microRNA candidate. Nucleic Acids Res., 2007, 35(10), 3287-3296.
[22]
Nagata, S.; Hamasaki, T.; Uetake, K.; Masuda, H.; Takagaki, K.; Oka, N.; Wada, T.; Ohgi, T.; Yano, J. Synthesis and biological activity of artificial mRNA prepared with novel phosphorylating reagents. Nucleic Acids Res., 2010, 38(21), 7845-7857.
[23]
Oka, N.; Yamamoto, M.; Sato, T.; Wada, T. Solid-phase synthesis of stereoregular oligodeoxyribonucleoside phosphorothioates using bicyclic oxazaphospholidine derivatives as monomer units. J. Am. Chem. Soc., 2008, 130(47), 16031-16037.
[24]
Wolf, S.; Zismann, T.; Lunau, N.; Meier, C. Reliable synthesis of various nucleoside diphosphate glycopyranoses. Chem. Eur. J., 2009, 15(31), 7656-7663.
[25]
Mondek, J.; Kalina, M.; Simulescu, V.; Pekar, M. Thermal degradation of high molar mass hyaluronan in solution and in powder; comparison with BSA. Polym. Degrad. Stabil., 2015, 120, 107-113.
[26]
Simulescu, V.; Kalina, M.; Mondek, J.; Pekar, M. Long-term degradation study of hyaluronic acid in aqueous solutions without protection against microorganisms. Carb. Pol, 2016, 137, 664-668.
[27]
Ohgi, T.; Masutomi, Y.; Ishiyama, K.; Kitagawa, H.; Shiba, Y.; Yano, J. A new RNA synthetic method with a 2‘-o-(2-cyanoethoxymethyl) protecting group. Org. Lett., 2005, 7(16), 3477-3480.
[28]
Eckstein, F. Phosphorothioate oligodeoxynucleotides: What is their origin and what is unique about them? Antisense Nucleic Acid Drug Dev., 2000, 10(2), 117-121.
[29]
Dirin, M.; Winkler, J. Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides. Expert Opin. Biol. Ther., 2013, 13(6), 875-888.
[30]
Sharma, V.K.; Sharma, R.K.; Singh, S.K. Antisense oligonucleotides: Modifications and clinical trials. MedChemComm, 2014, 5(10), 1454-1471.
[31]
Stein, C.A.; Subasinghe, C.; Shinozuka, K.; Cohen, J.S. Physicochemical properties of phospborothioate oligodeoxynucleotides. Nucleic Acids Res., 1988, 16(8), 3209-3221.
[32]
Lebedev, A.V.; Koukhareva, I.I.; Beck, T.; Vaghefi, M.M. Preparation of oligodeoxynucleotide 5′-triphosphates using solid support approach. Nucleosides Nucleotides Nucleic Acids, 2001, 20(4-7), 1403-1409.
[33]
Gaur, R.K.; Sporat, B.S.; Krupp, G. Novel solid phase synthesis of 2′-o-methylribonucleoside 5′-triphosphates and their α-thio analogues. Tetrahedron Lett., 1992, 33(23), 3301-3304.
[34]
Brownlee, G.G.; Fodor, E.; Pritlove, D.C.; Gould, K.G.; Dalluge, J.J. Solid phase synthesis of 5′-diphosphorylated oligoribonucleotides and their conversion to capped m7 Gppp-oligoribonucleotides for uase as primers for influenza A virus RNA polymerase in vitro. Nucleic Acids Res., 1995, 23(14), 2641-2647.
[35]
Galderisi, U.; Di Bernardo, G.; Melone, M.A.B.; Galano, G.; Cascino, A.; Giordano, A.; Cipollaro, M. Antisense inhibitory effect: A comparison between 3′-partial and full phosphorothioate antisense oligonucleotides. J. Cell. Biochem., 1999, 74(1), 31-37.
[36]
Guga, P. P-chiral oligonucleotides in biological recognition processes. Curr. Top. Med. Chem., 2007, 7(7), 695-713.
[37]
Wilk, A.; Grajkowski, A.; Phillips, L.R.; Beaucage, S.L. Deoxyribonucleoside cyclic N-acylphosphoramidites as a new class of monomers for the stereocontrolled synthesis of oligothymidylyl- and oligodeoxycytidylyl- phosphorothioates. J. Am. Chem. Soc., 2000, 122(10), 2149-2156.
[38]
Pruzan, R.; Zielinska, D.; Rebowska-Kocon, B.; Nawrot, B.; Gryaznov, S.M. Stereopure oligonucleotide phosphorothioates as human telomerase substrates. New J. Chem., 2010, 34, 870-874.
[39]
LaPlanche, L.A.; James, T.L.; Powell, C.; Wilson, W.D.; Uznanski, B.; Stec, W.J.; Summers, M.F.; Zon, G. Phosphorothioate-modified oligodeoxyribonucleotides. III. NMR and UV spectroscoptc studies of the Rp-Rp,Sp-Sp, and Rp-Sp duplexes, [d(GGsAATTCC)]2, derived from diastereomeric O-ethyl phosphorothioates. Nucleic Acids Res., 1986, 14(22), 9081-9083.
[40]
Kanaori, K.; Tamura, Y.; Wada, T.; Nishi, M.; Kanehara, H.; Morii, T.; Tajima, K.; Makino, K. Structure and stability of the consecutive stereoregulated chiral phosphorothioate DNA duplex. Biochem, 1999, 38(49), 16058-16066.
[41]
Wozniak, L.A.; Gora, M.; Bukowiecka-Matusiak, M.; Mourgues, S.; Pratviel, G.; Meunier, B.; Stec, W.J. The P-stereocontrolled synthesis of PO/PS-chimeric oligonucleotides by incorporation of dinucleoside phosphorothioates bearing an O-4-nitrophenyl phosphorothioate protecting group. Eur. J. Org. Chem., 2005, 2005(14), 2924-2930.
[42]
Zlatev, I.; Lavergne, T.; Debart, F.; Vasseur, J-J.; Manoharan, M.; Morvan, F. Efficient solid-phase chemical synthesis of 5′-triphosphates of DNA, RNA, and their analogues. Org. Lett., 2010, 12(10), 2190-2193.
[43]
Ponomarov, O.; Laws, A.P.; Hanusek, J. 1,2,4-Dithiazole-5-ones and 5-thiones as efficient sulfurizing agents of phosphorus(III) compounds - a kinetic comparative study. Org. Biomol. Chem., 2012, 10, 8868-8876.
[44]
Nawrot, B.; Rebowska, B.; Cieslinska, K.; Stec, W.J. New approach to the synthesis of oligodeoxyribonucleotides modified with phosphorothioates of predetermined sense of P-chirality. Tetrahedron Lett., 2005, 46(39), 6641-6644.
[45]
Hayakawa, Y.; Hirabayashi, Y.; Hyodo, M.; Yamashita, S.; Matsunami, T.; Cui, D-M.; Kawai, R.; Kodama, H. A strategy for the stereoselective preparation of thymidine phosphorothioates with the (R) or the (S) configuration at the stereogenic phosphorus atom and their application to the synthesis of oligodeoxyribonucleotides with stereochemically pure phosphate/phosphoro-thioate chimeric backbones. Eur. J. Org. Chem., 2006, 2006(17), 3834-3844.
[46]
Nawrot, B.; Widera, K.; Wojcik, M.; Rebowska, B.; Nowak, G.; Stec, W.J. Mapping of the functional phosphate groups in the catalytic core of deoxyribozyme 10-23. FEBS J., 2007, 274(4), 1062-1072.
[47]
Krieg, A.M.; Guga, P.; Stec, W.J. P-chirality-dependent immune activation by phosphorothioate CpG oligodeoxynucleotides. Oligonucleotides, 2003, 13(6), 491-499.
[48]
Wojcik, M.; Cieslak, M.; Stec, W.J.; Goding, J.W.; Koziolkiewicz, M. Nucleotide pyrophosphatase/phosphodiesterase 1 is responsible for degradation of antisense phosphorothioate oligonucleotides. Oligonucleotides, 2007, 17(1), 134-145.
[49]
Beaucage, S.L.; Iyer, R.P. Advances in the synthesis of oligonucleotides by the phosphoramidite approach. Tetrahedron, 1992, 48(12), 2223-2311.
[50]
Stec, W.J.; Karwowski, B.; Boczkowska, M.; Guga, P.; Koziolkiewicz, M.; Sochacki, M.; Wieczorek, M.W.; Blaszczyk, J. Deoxyribonucleoside 3‘-O-(2-Thio- and 2-Oxo-“spiro”-4,4-pentamethylene-1,3,2-oxathiaphospholane)s: Monomers for stereocontrolled synthesis of oligo(deoxyribonucleoside phosphorothioate)s and chimeric PS/PO oligonucleotides. J. Am. Chem. Soc., 1998, 120(29), 7156-7167.
[51]
Guga, P.; Okruszek, A.; Stec, W.J. Recent Advances in Stereocontrolled Synthesis of P-Chiral Analogues of Biophosphates. In:New Aspects in Phosphorus Chemistry I; Majoral, J.P., Ed.; Springer: Berlin, Heidelberg, 2002, pp. 169-200.
[52]
McBride, L.J.; Caruthers, M.H. An investigation of several deoxynucleoside phosphoramidites useful for synthesizing deoxyoligonucleotides. Tetrahedron Lett., 1983, 24(3), 245-248.
[53]
Iwamoto, N.; Oka, N.; Sato, T.; Wada, T. Stereocontrolled solid-phase synthesis of oligonucleoside H-phosphonates by an oxazaphospholidine approach. Angew. Chem. Int. Ed., 2009, 48(3), 496-499.
[54]
Oka, N.; Kondo, T.; Fujiwara, S.; Maizuru, Y.; Wada, T. Stereocontrolled synthesis of oligoribonucleoside phosphorothioates by an oxazaphospholidine approach. Org. Lett., 2009, 11(4), 967-970.
[55]
Warnecke, S.; Meier, C. Synthesis of nucleoside di- and triphosphates and dinucleoside polyphosphates with cyclosal-nucleotides. J. Org. Chem., 2009, 74(6), 3024-3030.
[56]
Radzikowska, E.; Baraniak, J. Synthesis of PS/PO-chimeric oligonucleotides using mixed oxathiaphospholane and phosphoramidite chemistry. Org. Biomol. Chem., 2015, 13, 269-276.
[57]
Song, Q.; Wang, Z.; Sanghvi, Y.S. A short, novel, and cheaper procedure for oligonucleotide synthesis using automated solid phase synthesizer. Nucleosides Nucleotides Nucleic Acids, 2003, 22(5-8), 629-633.
[58]
Wincott, F.; DiRenzo, A.; Shaffer, C.; Grimm, S.; Tracz, D.; Workman, C.; Sweedler, D.; Gonzalez, C.; Scaringe, S.; Usman, N. Synthesis, deprotection, analysis and purification of RNA and ribosomes. Nucleic Acids Res., 1995, 23(14), 2677-2684.
[59]
Meier, C. cycloSal phosphates as chemical trojan horses for intracellular nucleotide and glycosylmonophosphate delivery - Chemistry meets biology. Eur. J. Org. Chem., 2006, 2006(5), 1081-1102.
[60]
Epple, R.; Kudirka, R.; Greenberg, W.A. Solid-phase synthesis of nucleoside analogues. J. Comb. Chem., 2003, 5(3), 292-310.
[61]
Butler, K.V.; He, R.; McLaughlin, K.; Vistoli, G.; Langley, B.; Kozikowski, A.P. Stereoselective HDAC inhibition from cysteine-derived zinc-binding groups. ChemMedChem, 2009, 4(4), 1292-1301.
[62]
Zamyatina, A.; Gronow, S.; Puchberger, M.; Graziani, A.; Hofinger, A.; Kosma, P. Efficient chemical synthesis of both anomers of ADP l-glycero- and d-glycero-d-manno-heptopyranose. Carbohydr. Res., 2003, 338(23), 2571-2589.
[63]
Wolf, S.; Zismann, T.; Lunau, N.; Warnecke, S.; Wendicke, S.; Meier, C. A convenient synthesis of nucleoside diphosphate glycopyranoses and other polyphosphorylated bioconjugates. Eur. J. Cell Biol., 2010, 89(1), 63-75.
[64]
Barucki, H.; Black, R.M.; Kinnear, K.I.; Holden, I.; Read, R.W.; Timperley, C.M. Solid-phase synthesis of some alkyl hydrogen methylphosphonates. Phosphorus Sulfur Silicon Relat. Elem., 2003, 178(10), 2279-2286.
[65]
Timmons, S.C.; Jakeman, D.L. Stereoselective chemical synthesis of sugar nucleotides via direct displacement of acylated glycosyl bromides. Org. Lett., 2007, 9(7), 1227-1230.
[66]
Wagner, G.K.; Pesnot, T.; Field, R.A. A survey of chemical methods for sugar-nucleotide synthesis. Nat. Prod. Rep., 2009, 26(9), 1172-1194.
[67]
Timperley, C.M.; Bird, M.; Holden, I.; Black, R.M. Organophosphorus chemistry. Part 1. The synthesis of alkyl methylphosphonic acids. J. Chem. Soc., Perkin Trans. 1, 2001, 1, 26-30.
[68]
Tonn, V.C.; Meier, C. Solid-phase synthesis of (poly)phosphorylated nucleosides and conjugates. Chem. Eur. J., 2011, 17(35), 9832-9842.
[69]
Ahmadibeni, Y.; Parang, K. Selective diphosphorylation, dithiodiphosphorylation, triphosphorylation, and trithiotriphosphorylation of unprotected carbohydrates and nucleosides. Org. Lett., 2005, 7(25), 5589-5592.
[70]
Ahmadibeni, Y.; Parang, K. Application of a solid-phase β-triphosphitylating reagent in the synthesis of nucleoside β-triphosphates. J. Org. Chem., 2006, 71(15), 5837-5839.
[71]
Ahmadibeni, Y.; Dash, C.; Hanley, M.J.; Le Grice, S.F.J.; Agarwal, H.K.; Parang, K. Synthesis of nucleoside 5′-O-α,β-methylene-β-triphosphates and evaluation of their potency towards inhibition of HIV-1 reverse transcriptase. Org. Biomol. Chem., 2010, 8, 1271-1274.
[72]
Crauste, C.; Prigaud, C.; Peyrottes, S. Insights into the soluble peg-supported synthesis of cytosine-containing nucleoside 5′-mono-, di-, and triphosphates. J. Org. Chem., 2009, 74(23), 9165-9172.
[73]
Heutz, F.J.L.; Samuels, M.C.; Kamer, P.C.J. Solid-Phase synthesis of Recyclable Diphosphine Ligands. Catal. Sci. Technol., 2015, 5, 3296-3301.
[74]
Heutz, F.J.L.; Kamer, P.C.J. Modular solid-phase synthesis, catalytic application and efficient recycling of supported phosphine–phosphite ligand libraries. Dalton Trans., 2016, 45, 2116-2123.
[75]
Samuels, M.C.; Swennenhuis, B.H.G.; Kamer, P.C.J. Phosphorus(III) Ligands in Homogeneous Catalysis. In:Design and Synthesis; Kamer, P.C.J.; van Leeuwen, P.W.N.M., Eds.; John Wiley & Sons, Ltd, 2012, pp. 463-479.
[76]
Goudriaan, P.E.; Van Leeuwen, P.W.N.M.; Birkholz, M.N.; Reek, J.N.H. Libraries of Bidentate Phosphorus Ligands; Synthesis strategies and application in catalysis. Eur. J. Inorg. Chem., 2008, 2008(19), 2939-2958.
[77]
Farkas, G.; Balogh, S.; Szöllősy, Á.; Ürge, L.; Darvas, F.; Bakos, J. Novel phosphine–phosphites and their use in asymmetric hydrogenation. Tetrahedron Asymmetry, 2011, 22, 2104-2109.
[78]
Lühr, S.; Holz, J. Börner. A. The Synthesis of chiral phosphorus ligands for use in homogeneous metal catalysis. ChemCatChem, 2011, 3(11), 1708-1730.
[79]
Chikkali, S.H.; Van der Vlugt, J.I.; Reek, J.N.H. Hybrid diphosphorus ligands in rhodium catalysed asymmetric hydroformylation. Coord. Chem. Rev., 2014, 262, 1-15.
[80]
Fernandez-Perez, H.; Etayo, P.; Panossian, A. Vidal-Ferran. A. Chem. Rev, 2011, 111(3), 2119-2176.
[81]
Li, G.Y.; Fagan, P.J. Watson. P.L. Versatile Approaches to the Polymer-Supported Synthesis of Bidentate Phosphorus-Containing Ligands. Angew. Chem. Int. Ed., 2001, 40(6), 1106-1109.
[82]
Mansour, A.; Portnoy, M. Synthesis and characterisation of β-aminophosphine ligands on a solid support. J. Chem. Soc., Perkin Trans. 1, 2001, 9, 952-954.
[83]
Bar-Nir Ben-Aroya, B.; Portnoy, M. Preparation of α-aminophosphines on solid support: Model studies and parallel synthesis. Tetrahedron, 2002, 58(25), 5147-5158.
[84]
Mansour, A.; Portnoy, M. Synthesis of a diverse set of phosphorus ligands on solid support and their screening in the Heck reaction. Tetrahedron Lett., 2003, 44(10), 2195-2198.
[85]
van Leeuwen, P.W.N.M.; Kamer, P.C.J.; Claver, C.; Pamies, O.; Dieguez, M. Phosphite-containing ligands for asymmetric catalysis. Chem. Rev., 2011, 111(3), 2077-2118.
[86]
Czauderna, C.F.; Cordes, D.B.; Slawin, A.M.Z.; Müller, C.; van der Vlugt, J.I.; Vogt, D.; Kamer, P.C.J. Synthesis and reactivity of chiral, wide-bite-angle, hybrid diphosphorus ligands. Eur. J. Inorg. Chem., 2014, 2014(10), 1797-1810.


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VOLUME: 23
ISSUE: 6
Year: 2019
Page: [679 - 688]
Pages: 10
DOI: 10.2174/1385272823666190213112019
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