Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• approach of modifying the internucleotide linkage is unique as it may reduce in part or in full the negative charge of ONs, including ASOs. One strategy that has been employed is the aminoalkyl phosphoramidate linkage (Table 8). Pioneering work was done by Letsinger and co-workers in 1986, who reported the

• synthesis of a 2’-deoxyadenosyl dinucleotide linked via an aminoethyl phosphoramidate linkage that was positively charged under neutral to acidic conditions [105]. A subsequent work based on these findings resulted in the synthesis of short cationic DNA ONs linked via N-alkylated phosphoramidate linkages

• - (monomer 71) and N-methyl-2-(dimethylamino)ethyl (monomer 72) phosphoramidate linkages [106]. How these N-alkylated phosphoramidate-linked ONs interacted with the complementary DNA was highly dependent on the ionic strength and the pH of the relevant medium. An inverse effect between hybridization

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• modifications N3' → P5' phosphoramidate The N3' → P5' phosphoramidate DNA (3'-NP DNA) contains a negatively charged internucleotide linkage, but one of the bridging oxygens is replaced by a nitrogen (Figure 1A). The 3'-NP linkage is generated during solid-phase synthesis where the incoming protected 5'-DMT-3

• sequence and base composition [65]. The presence of alternating phosphodiester and phosphoramidate linkages within an oligonucleotide resulted in improved binding to RNA relative to DNA. Homopyrimidine 3'-NP DNA forms a stable triplex at neutral pH with double-stranded DNA and RNA [64][65][66]. These

• (CnpGnpCnpGnpAnpAnpTnpTnpCnpGnpCnpG)-3' at 2 Å resolution [71]. It was found that the overall duplex structure adopted by 3'-NP DNA resembles that of an RNA-like A-form double helix. The deoxyribose ring of phosphoramidate DNA is locked in a northern (C3'-endo) conformation due to the decreased gauche effect between 4'-O and the 3

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• provide either a zwitterionic phosphoramidate with N+ modification or a negatively charged phosphoramidate for Ts modification in the DNA sequence. The incorporation of these N+ and Ts modifications led to the formation of thermally stable parallel DNA triplexes, regardless of the number of modifications

• ON (TG4T) with all phosphates replaced by a 4-(trimethylammonio)butylsulfonyl phosphoramidate group (N+, Scheme 1). The sequence was designed to obtain the formally charge-neutral zwitterionic N+TG4T [38]. Each negatively charged phosphoramidate is neutralised by the positively charged quaternary

• + modification in the context of DNA duplexes and triplexes and to perform cell-uptake studies. For comparison, we also evaluated the properties of ONs modified with a tosyl sulfonyl phosphoramidate (Ts) that results in a negatively charged phosphate mimic [39]. The introduction of each, N+ or Ts modification

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• ), affording a pair of optically active phosphonodepsipeptides 164 and 165 in an 86% yield and 85:15 diastereomeric ratio (Scheme 31) [51]. Following a similar strategy, the three component condensation of diethyl phosphoramidate (166), aromatic aldehydes 167, and diisopropyl (4R,5R)-2-chloro-1,3,2

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• cores for these compounds in high yields (63–83% over 3 steps) with no need for chromatography. Key to this transformation is the phosphoramidate protecting group, which is stable to metalation steps. Keywords: arginine; Horner–Wadsworth–Emmons; integrin; phosphoramidate; tetrahydronaphthyridine

• , affording phosphoramidate 9 in low yield, indicating good leaving group ability of the stabilised tetrahydronaphthyridine anion. No formation of phosphonate 10 was detected (Scheme 3). It was proposed that a deprotonation of 7-methyl-1,2,3,4-tetrahydro-1,8-naphthyridine (11) with two equivalents of sec-BuLi

• would afford phosphonate 12 upon quenching with diethyl chlorophosphate via formation of the dianion. This could then be used in a subsequent Horner–Wadsworth–Emmons reaction to construct the carbon skeleton of amine 6. Upon the addition of a single equivalent of diethyl chlorophosphate, phosphoramidate

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• motifs. Such artificial neutral linkages include, among others, sulfone [14], amide [15][16][17][18][19][20][21][22], triazole [23][24][25][26][27], phosphoramidate [28] and phosphate triester [29] moieties. Using a different approach, positive charges have been introduced into nucleic acid structures

• modifications. The synthesis and properties of the corresponding oligonucleotide analogues of types 7–10 (Figure 3) with cationic backbone linkages are described. Review Aminoalkyl phosphoramidate linkages and related systems Pioneering work in the field has been reported by Letsinger and co-workers. In 1986

• , they introduced a deoxyadenosyl dinucleotide linked by an aminoethyl phosphoramidate moiety which is positively charged under acidic and neutral conditions [40]. Based on these results, they subsequently reported the synthesis of short, cationic DNA oligonucleotides with phosphoramidate linkages of

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• it to the masked monophosphates (10 and 11, Figure 7C), which serves to facilitate transport into the infected cells, and conversion to the active triphosphate form, thereby leading to high and persistent levels [63][64][65]. The 2-ethylbutyl L-alanine phosphoramidate prodrug (Sp isomer, GS-5734, 11

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• much more nucleophilic than the hydroxy group of natural DNA, so that rapid reactions result. Figure 3 shows the structure of the phosphoramidate formed when 3'-aminoterminal DNA primers are extended, together with the phosphoramidate linkage resulting from reactions with 3'-aminoribonucleotides [21

• ], and the two regioisomeric phosphodiesters that result from the extension of RNA primers that terminate in natural ribonucleosides. We note that the phosphoramidate linkages are isoelectronic and largely isosteric to natural phosphodiesters. In our brief account, we will highlight some of the issues

• ][55][56], but not always high-yielding, unless an aminoterminal strand was reacted with the phosphate-terminated counterpart [57][58][59], to form a phosphoramidate-linked product. Efficient versions of extension of an RNA primer with in situ activation were not known to us. One difficulty in inducing

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• . Similarly, in the search for thiophosphate protecting groups with deprotection half-lives in the range of 100–200 h at 37 °C for sustained CpG ODN immunostimulation in animal models, Beaucage et al. have developed a new class of thermosensitive groups that are hydroxy-alkylated phosphoramidate

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• induced the silylation of diethyl phosphonate but also the phosphoramidate and the phosphinate functional groups. Other phosphonic acids possessing different functionalities including phosphine 56 [183], trimethylsilyl 57 [184], diazo 58 [185] or styrene 59 [186] moieties were also prepared efficiently

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• asymmetric redox bicycloisomerization of 1,6- and 1,7-enynes. This complex was used to synthesize a broad array of [3.1.0] and [4.1.0] bicycles. Sulfonamide- and phosphoramidate-containing products could be deprotected under reducing conditions. Catalysis performed with enantiomerically enriched propargyl

• benzhydryl tertiary amine 28 (Table 5, entry 5). Phosphoramidate 31 could be obtained in good yield and with an increased enantioselectivity when compared to the parent sulfonamide (Table 5, entry 6). Amide 32 also reacted, but with a lower conversion and yield, possibly due to increased coordination of the

• requirements necessary to achieve high enantioselectivity. Indeed, when tosyl- or phosphoramidate-protected 1,6-enynes were tested, excellent yields and enantioselectivities were observed (Table 7). Like the Tris substrates, branching at the propargylic and alkenyl positions were well tolerated. Carbocyclic 69

DNA display of glycoconjugates to emulate oligomeric interactions of glycans

• Alexandre Novoa and
• Nicolas Winssinger

Beilstein J. Org. Chem. 2015, 11, 707–719, doi:10.3762/bjoc.11.81

• cycloaddition (CuAAC) [25][26] has naturally inspired the use of this powerful conjugation method to prepare glycan–DNA conjugates. Chevolot and co-workers used this method to conjugate glycans at the 3’-end of DNA [27]. The DNA synthesis was initiated with H-phosphonate that was converted to a phosphoramidate

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• [8]. For the selective replacement of some phosphate linkages in otherwise native oligonucleotide structures, e.g., amide [13][14][15][16][17][18][19][20], triazole [21][22], phosphoramidate [23] and phosphate triester [24] moieties were reported alongside a considerable number of other modifications

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years. Keywords: amphiphiles; flame retardant; lipid conjugates; organophosphorus; phosphoramidate; phosphate; Review 1. Introduction The reaction of

• by chance. Indeed, these authors attempted to purify a solution of dibenzyl phosphite in carbon tetrachloride by its treatment with an aqueous ammonia solution. They observed the formation of a precipitate that was identified as O,O-dibenzyl phosphoramidate. However, no reaction occurred when

• design of phosphorus-based amphiphilic compounds. 2. Mechanism of the Atherton–Todd reaction In their initial publication, Atherton and Todd have suggested two possible mechanisms to explain the formation of phosphoramidate [1]. The first one (Scheme 2-i) was based on a two-step sequence with the

From porphyrin benzylphosphoramidate conjugates to the catalytic hydrogenation of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin

• Marcos C. de Souza,
• Leandro F. Pedrosa,
• Géssica S. Cazagrande,
• Vitor F. Ferreira,
• Maria G. P. M. S. Neves and
• José A. S. Cavaleiro

Beilstein J. Org. Chem. 2014, 10, 628–633, doi:10.3762/bjoc.10.54

• substitution was promoted by microwave irradiation in N-methyl-2-pyrrolidinone. Attempts to remove the benzyl groups of the phosphoramidate moiety by hydrogenolysis with 10% Pd/C led to the cleavage of the P–N bond and the reduction of the macrocycle to hydroporphyrin-type derivatives. The extent of the effect

• hydrogenation; chlorin; isobacteriochlorin; phosphoramidate; porphyrin; Introduction The use of porphyrin derivatives as photosensitizers is considered for the photodynamic therapy (PDT) of malignant tumors and the treatment of age-related macular degeneration in several countries [1][2]. It is already known

• convert the diisopropyl phosphoramidate ester moiety into the corresponding phosphoramidic acid in order to improve the hydrophilicity. Conventional hydrolytic methods, such as heating under reflux in 6 N HCl or the use of ClTMS/NEt3, were unsuccessful, as the P–N bond instead of the P–O bond was cleaved

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• hydrolysis of the phosphoramidate directing group the resulting pyridone 1.93 is subjected to a sequence of chlorinations rendering a suitably functionalised coupling partner for a final Stille coupling to yield etoricoxib. Although the synthesis of etoricoxib as depicted in Scheme 17 very efficiently forms