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Coupling Activators for the Oligonucleotide Synthesis Via Phosphoramidite Approach

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Coupling Activators for the Oligonucleotide Synthesis Via Phosphoramidite Approach Tetrahedron 69 (2013) 3615e3637 Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron report number 1002 Coupling activators for the oligonucleotide synthesis via phosphoramidite approach Xia Wei a,b,* a AM Biotechnologies, LLC., 12521 Gulf Freeway, Houston, TX 77034, USA b University of Houston-Clear Lake, 2700 Bay Area Boulevard, Houston, TX 77058, USA article info Article history: Received 4 August 2012 Available online 7 March 2013 Contents 1. Introduction . ................................................3616 1.1. Nucleoside phosphoramidites . ......................3616 1.2. Typical oligonucleotide synthesis via nucleoside phosphoramidite approach . ......................3617 2. Azole coupling activators . ................................................3619 2.1. 1H-Tetrazole and its activation mechanism . ......................3619 2.2. Modified tetrazole coupling activators . ......................3620 2.2.1. 5-Nitrophenyl-1H-tetrazole (NPT) . ......................3620 2.2.2. 5-(Bis-3,5-trifluoromethylphenyl)-1H-tetrazole (Activator 42) . .................................3622 2.2.3. 5-Ethylthio-1H-tetrazole (ETT) . ......................3622 2.2.4. 5-Benzylthio-1H-tetrazole (BTT) . ......................3623 2.2.5. 5-Methylthio-1H-tetrazole (MTT) . ......................3624 2.2.6. 5-Mercapto-tetrazole (MCT) . ......................3624 2.2.7. Chiral tetrazoles for stereocontrolled synthesis . ......................3624 2.3. Other azole coupling activators . ......................3625 2.3.1. Imidazole activators . ......................3625 2.3.2. 1-Hydroxy-benzotriazole activators . ......................3626 2.3.3. 3-Nitrotriazole activators . .. ......................3626 3. Salt complex coupling activators . .......................................... 3626 3.1. Pyridinium salt complexes . ......................3627 3.2. Azolium salt complexes . ......................3628 3.3. Saccharin salt complexes . ......................3630 3.4. Ammonium salt complexes . ......................3630 4. Other coupling activators for phosphoramidite approach . ...................................3631 4.1. Carboxylic acid coupling activators . ......................3631 4.2. Lewis acid coupling activators . ......................3632 4.3. Trimethylchlorosilane (TMCS) . ......................3632 4.4. 2,4-Dinitrophenol (DNP) . ......................3632 5. Summary ........................................................................ ............................................... 3633 Acknowledgements . ......................3634 6. Abbreviations . ............................................... 3634 References and notes . ......................3635 Biographical sketch . ......................3637 * Tel.: þ1 806 252 8398; e-mail address: [email protected]. 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.03.001 3616 X. Wei / Tetrahedron 69 (2013) 3615e3637 1. Introduction A: DMTrO Chemical synthesis of oligonucleotides has paved the way for N B e DMTrO O fi 1 4 B the advancement of many elds in life sciences. The comple- O Cl OR1 mentary base paring property of oligonucleotides enables them to + P NR2 O be a fundamental tool for biological research. They are used as 2 1 OH R O P primers for polymerase chain reaction to amplify a particular DNA 2 NR 2 sequence and serve as probes for detecting RNA or DNA by hy- bridizing to their counterparts in a sequence specific manner. 1 2 3 Oligonucleotides are also of great interest in biomedical research B: and drug development. For antisense therapy, a single strand DNA, RNA, or a chemical analog can be designed to bind to a gene and RN N DMTrO OR3 B inhibit the expression of the corresponding protein that is known N O OR3 P to be causative of a particular disease.5 Small interfering RNA, N N P N N + a class of double strand RNA molecules, interferes with the Cl Cl R = H, TMS N N OH expression of a specific gene via the RNA interference pathway.6 4 5 1 Aptamers, also referred as chemical antibodies, are nucleic acid binding species for biomarker discovery and as diagnostic and DMTrO R4 therapeutic isolated by in vitro selection. They are able to bind to B O DMTrO TMS N B a wide range of targets with high affinity and have shown great O R4 potential reagents.7,8 O The increased interests require the preparation of oligonucleo- R3O P O tide in ever larger amounts. Previously, the oligonucleotide could be N R3O P N 4 synthesized through H-phosphonate, phosphodiester, phosphor- NR 2 e N triester, or phosphite triester method.9 12 After being discovered e 67 and modified in early 1980s,13 21 phosphoramidite method has become dominant in the oligonucleotide synthesis due to its high C: fi H Cl coupling ef ciency and rapid turnaround time. N DMTrO B DMTrO O B N 1.1. Nucleoside phosphoramidites O OMe Cl + P N N O fi MeO P Nucleoside phosphoramidites, the key building blocks, rst in- OH troduced by Beaucage and Caruthers in 1981,13 act as phosphity- N lating agents in this synthetic strategy. They are relatively stable under mild basic and neutral conditions, while are very sensitive in 18 9 the presence of even mild acids. Several pathways can be used to Scheme 1. Preparation pathways to phosphoramidites. prepare phosphoramidites (Scheme 1). In the method A, the pro- tected nucleoside 1 reacts with phosphorochloridite 2 in the presence of base, most commonly diisopropylethylamine, pro- e ducing phosphoramidite 3.14 17,21 But the phosphorochloridite is suggested that both N-morpholino and N,N-diisopropylmethoxy hard to handle due to the poor stability, and the side formation of phosphoramidites can be reagents of choice for the oligonucleo- amine hydrochloride in the process causes isolation and purifica- tide synthesis (Fig. 1). tion problems, which precludes the pathway A as a reliable method The key feature of nucleotide phosphoramidites lies in the for automatic synthesis.19 To improve the synthesis, Fourrey and ability to rapidly react with nucleophilic groups in the mediation Varenne developed another approach outlined in method B. The in of mild acids, resulting in products with the replacement of an situ prepared bistriazolophosphine 5 reacts with protected nucle- amino moiety by an incoming nucleophile.10 In order to avoid side oside 1, yielding intermediate 6, which then transfers to phos- reactions, all other active functionalities in nucleosides, such as phoramidite 7 by treating with N,N-dialkyltrimethylsilylamine.17,19 the phosphite moiety, exocyclic amino groups on nucleobases, Almost at the same time, Beaucage discovered method C by means and hydroxyl groups at the 50-and20-positions, have to be of a phosphitylation between bispyrrolidinomethoxyphosphine 8 selectively protected by proper groups that can also be easily re- and nucleoside 1 under the activation of weak acid, such as 4,5- moved after the completion of the oligonucleotide synthesis. The dichloroimidazole.20 Compared with other two routes, method C most commonly used protecting groups are briefly introduced represents as a simpler and more economical approach to prepare herein. phosphoramidites. Methyl group and 2-cyanoethyl group are often employed to In an attempt to select proper phosphoramidite building blocks, protect the phosphite site of phosphoramidites. The deprotection various deoxynucleoside N,N-dialkylaminomethoxy phosphor- of methyl group by a treatment of either a mixture of thiophenol/ amidites were examined for their stabilities and reactivities in the triethylamine/dioxane or a mixture of tert-butylamine/methanol oligonucleotide synthesis.14 The 31P NMR analysis indicated that takes a long time to react. But 2-cyanoethyl group can be essentially pure N-morpholino and N,N-diisopropylmethoxy removed very easily using concentrated aqueous ammonia, phosphoramidites could be isolated, but N,N-dimethyl, N-pyroli- which is compatible with other deprotection conditions for dino, and 2,2,6,6-tetra-methyl-N-piperidino phosphoramidites oligomers and therefore can be performed in a single depro- were quite heterogeneous and subject to 5e20% hydrolysis tection step (Fig. 1).15,21,22 during the work-up procedure. Furthermore, both N-morpholino The most popular way to protect the 50-hydroxyl site of and N,N-diisopropylmethoxy phosphoramidites were very stable a phosphoramidite is tritylation, by which acid labile trityl ether 23 even after 40 days storage in a sealed tube of CD3CN. The derivatives can be formed. The stronger the electron-donating following reactivity examination by the activation of 1H-tetrazole property of a specific trityl ether linkage, the more sensitive the X. Wei / Tetrahedron 69 (2013) 3615e3637 3617 3 O O R O B O NH NH T: U: N O N O O OR2 P R1 NHR NHR' O Me i-Pr N N N CR: AR': N GR'': NH R1 = N , N N O N N Me i-Pr N N NHR'' N O , N , N Exocyclic amino protecting groups: O O O 2 Me , CH CH CN R = 2 2 Me Bz Ac IBu R' O O Tr: R' = R'' = R''' = H H MMTr: O R3 = C R'' R' = R'' = H; R''' = OMe O DMTr: Me R' = H; R'' = R''' = OMe N Me TMTr: R' = R'' = R''' = OMe Me PAC MAC dmf R''' Fig. 2. Typical protecting groups for nucleobases. Fig. 1. Representative phosphoramidites. tert-butyldithiomethyl (DTM),32 2-cyanoethoxymethyl (CEM),33 pivaloyloxymethyl (PivOM),34 and bis(2-acetoxyethyloxy)methyl 35 trityl group is to the acidic cleavage conditions.10,24 The in- (ACE), have also been developed. The recent effort reported by corporation of electron-donating p-methoxy substituents
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