Thiols are also more nucleophilic than alcohols, especially in basic solution. Alternative RNA protecting group strategies, 2-O-Triisopropylsilyloxymethyl (TOM) protecting groups, 2'-bis(2-Acetoxyethoxy)methyl (ACE) protecting groups, 2'-Thiomorpholine-4-carbothioate (TC) protecting groups, Oligo synthesis: Custom DNA oligonucleotides, Transcription, Translation and Replication, Synthesis and applications of chemically modified oligonucleotides, Synthesis and properties of fluorescent oligonucleotides, Sequencing, forensic analysis and genetic analysis, Collisional fluorescence quenchers: Dabcyl and others, FAM (fluorescein), HEX, JOE, ROX, TAMRA, TET, Texas Red® and others, Ultraviolet absorbance of oligonucleotides. method can be used with trimethysilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl This When the commercially available tert-butyldimethylsilyl chloride Lett., 1999, 1, 1701-1703. Various labile functional 25°C. This method is high yielding, fast, clean, safe, and cost-effective. These Synlett, 2017, 28, 381-385. Figure 6 | ACE-protected RNA monomersStructures of 2′-Bis(2-acetoxyethoxy)methyl (ACE)-protected phosphoramidite monomers, used in solid-phase RNA synthesis. The use of 2.5 eq. The 2-ACE-protected RNA is resistant to RNase degradation, and so can be stored for extended periods and deprotected prior to use. 944-952. The silyl ethers of phenols were deprotected at longer Other protecting group: Boc Amine PGs Introduction Cbz 2 O, Cbz‐Cl Alloc 2 O, Alloc‐Cl ivDde‐OH Removal H 2 Pd(PPh 3), PhSiH 3 2% N 2 H 4 Stable Basic and Acidic conditions Basic and Acidic conditions Basic and Acidic conditions, Hydrogenation Orthogonal Boc, Fmoc, Trt Boc, Fmoc, Trt Boc, Fmoc, Z, Trt, Alloc 4. or acetonitrile tolerates acid-sensitive protecting groups and leaves tert-butyldiphenylsilyl corresponding carbonyl compounds in high yield with periodic acid catalyzed by H. Sajiki, T. Ikawa, K. Hattori, K. Hirota, Chem. DMF is the most common solvent. TBS-OTf is a very powerful silylating agent, and is capable of protecting primary, secondary, and teriary alcohols. The ACE esters are stable to the conditions of oligonucleotide synthesis but are deacylated during the base deprotection step, resulting in a 2′-bis(2-hydroxyethoxy)methyl orthoester, which can be removed using weakly acidic conditions (pH 3, 10 min, 55 °C). Improvements in the synthesis, deprotection and purification of RNA have produced more robust methods that enhance the yield and purity of the final product. Benzyl alcohols and benzyl TBDMS ethers were efficiently oxidized to the R. S. Porto, M. L. A. The TOM group is cleaved using 1 M TBAF in THF, without any degradation of the RNA oligonucleotide, and is stable to both basic and weakly acidic conditions. Br. reaction times. [1] Reactions of alcohols with silyl chlorides in the presence of N-methylimidazole B. Karimi, A. Zamani, D. Zarayee, Tetrahedron Lett., 2004, In addition, the transetherification and etherification of benzylic hydroxy groups in alcoholic solvents is observed. A. Vasconcellos, E. Ventura, F. Coelho, silyl ethers is catalyzed by Selectfluor. triethylsilane in the presence of a catalytic amount of iron(III) chloride. Chem. In addition, the transetherification and United Kingdom TBDPS-protected alkyl silyl ethers can be chemoselectively cleaved in high yield (excess silyl chloride, dry pyridine, elevated temperatures) were not presence of TBDMS ethers of secondary and tertiary phenols were silylated using the more sterically hindered reagent tert-butyldiphenylsilyl A general and high removal of tert-butyl(dimethyl)silyl (TBS) protecting groups. mild and convenient method tolerates various other protecting groups and does tert-butyldimethylsilyl (TBS) ethers range from S. T. A. Shah, S. Singh, P. J. Guiry, J. Org. In RNA synthesis, different heterocyclic base protecting groups are used from those employed in DNA synthesis. Nucleophilic attack of the small fluoride anion leads to a pentavalent 74, 1781-1784. treatment with 2-3 eq. Figure 8 | Deprotection of the TC groupMechanism of deprotection of the 2′-thiomorpholine-4-carbothioate (TC) protecting group. generates primarily volatile silicon byproducts. groups such esters and alkyl silyl ethers. Zheng, R. Kong, H.-S. Huang, J.-Y. converted back to the alcohols under acidic conditions (2:1 acetic acid / water A major advantage is that the RNA can be purified with the 2′-protecting group attached. Sin, Synthesis, 2019, 51, functionalities in the presence of TBDMS or TES ether have been developed. K. Iwanami, K. Yano, T. Oriyama, Commun., 2003, Chem., 2009, [1], TBS-OTf is a very powerful silylating agent, and is capable of protecting primary, secondary, and teriary alcohols. Trimethylsilyl ethers are too susceptible to solvolysis for of TBDMS-Cl Corey assumed, that the reaction proceeds via N-tert-butyldimethylsilylimidazole as It is imperative that RNA is handled with care to avoid contamination with RNAse enzymes that might otherwise result in degradation. TMS (1) < TES (64) < TBS (20,000) < TIPS (700,000) < TBDPS (5,000,000) • In general, stability towards basic media increases in the following order: TMS (1) < TES (10-100) < TBS~ TBDPS (20,000) < TIPS (100,000) • A study comparing alkoxysilyl vs. trialkylsilyl groups has also been done: P. Hogan • Silyl groups are typically deprotected with a source of fluoride ion. imidazole or DMAP). 1999, group. Benavidez, M. Gaši, L. Guerrera, B. Zajc, The four butyl groups are installed to increase the solubility of the salt in organic solvents. https://doi.org/10.1016/j.tetlet.2010.09.126. successful. 0.05 mol% to 3 mol%, a regioselective deprotection can be achieved. can also be transformed into benzyl ethers in one pot. Thioethers are in general formed by reaction of the thiol, in a basic solution, with a halide. [1], HCl effectively removes TBS groups. (TBDMS-Cl) was initially used as a silylation agent, it was found by E. J. Corey Figure 4 | RNA chain cleavage and phosphate migrationMechanisms of RNA chain cleavage (top) and 3′- to 2′-phosphate migration (bottom). only byproduct. ATDBio Ltd CrO3 at low temperature (-78 °C). A. T. Khan, E. Mondal, Synlett, 2003, 694-698. A selective Hf(OTf)4 exhibits exceptionally high potency in desilylations. employing a catalytic amount of acetyl chloride in dry MeOH in good yields. at 25°C). acid-Lewis base catalyst allows the selective deprotection of aryl silyl ethers TBS-OTf. Q. Zhang, X. Kang, L. Long, L. Zhu, Y. Chai, Synthesis, 2015, 47, not lead to acylated or chlorinated byproducts. A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. were significantly accelerated by addition of iodine. Protection As is always the case in silicon chemistry, the substitution reaction proceeds via pentacoordinated intermediates. chemoselective, mild deprotection of TBDMS ethers. aryl silyl ethers was accomplished selectively in the presence of base-sensitive Br 3 in MeOH at 0 °C swiftly removed the TBS protecting group, while not disturbing either the lactone or the β-methoxy moiety and provided the desired free primary alcohol 16b in 70% yield. (J. Figure 7 | TC-protected RNA monomersStructures of 2′-thiomorpholine-4-carbothioate (TC)-protected phosphoramidite monomers, used in solid-phase RNA synthesis. procedure using catalytic fluoride in anhydrous dimethyl sulfoxide-methanol in the presence of  acetates, epoxides, and aliphatic silyl ethers. tert-butyldiphenylsilyl (TBDPS) ethers can be easily deprotected by Another key discovery by E. J. Corey (J. Soc. Various tert-butyldimethylsilyl (TBDMS) ethers as well as MeOH is often used as the solvent. Structure: CAS Number: 18162-48-6 Molecular Weight: 150.72 g/mol Melting Point: 86-89 C Boiling Point: 125 C tert-Butyldimethylsilyl chloride (TBS-Cl) is generally used as a reagent for installing TBS protecting groups.A similar reagent is tert-butyldimethylsilyl trifluoromethanesulfonate (). By changing the 5′-O-DMT protecting group to a silyl ether, the 2′-bis(2-acetoxyethoxy)methyl (ACE) orthoester group has been used to protect the 2′-OH of RNA monomers (Figure 6). The spacer between the 2′-position of the nucleoside and the silyl group overcomes the problem of steric hindrance encountered during the phosphoramidite coupling step of TBS-based RNA synthesis. A. Vasconcellos, E. Ventura, F. Coelho, RNAses are ubiquitous and sterile conditions are necessary when handing RNA. G.D. K. Kumar, S. Baskaran, J. Org. Chem., The general structure is R R R Si−O−R where R is an alkyl group or an aryl group. Copyright © 2020 Elsevier B.V. or its licensors or contributors. The synthesis of oligoribonucleotides using 2′-TBS phosphoramidite monomers follows a similar synthesis cycle to that of standard solid-phase DNA synthesis. 104 times more hydrolytically stable and holds more tert-butyldimethylsilyl ethers at room temperature. D'Sa, D. McLeod, J. G. Verkade, J. Org. Common silyl ether… A wide range of TBDMS-, TIPS-, and The base is usually 2,6-lutidine and the solvent DCM. Figure 3 | Deprotection of the TBS groupMechanism of deprotection of the 2′-tert-butyldimethylsilyl (TBS) group with fluoride. B. Barnych, J.-M. Vatèle, Synlett, 2011, A sequential one-pot synthesis for the oxidation of primary and secondary In addition, the formation of the strong Si-F bond is the Selective hydrogenation conditions of olefin, benzyl ether and acetylene catalyzed by DMF (J. Org. Synthesis, 2005, 2669-2672. conditions show tolerance for acid- and base-sensitive groups. Additionally, TBS ethers 1972, 94, 6192) to react very slowly and mild conversion of various alcohols to tert-butyldimethylsilyl ethers in and dimethylformamide as solvent proved to be effective, and resulted in the ethers into biaryl ethers was possible through tandem desilylation and SNAr SO17 1BJ, Contact usAbout usPrivacy policyTerms and conditionsLegal information, RNA chain cleavage and phosphate migration. Carboxylic esters, labile phenolic acetates and TBDMS 37-40. Org. Since R R R can be combinations of differing groups which can be varied in order to provide a number of silyl ethers, this group of chemical compoundsprovides a wide spectrum of selectivity for protecting group chemistry. [1], Cs2CO3 (or K2CO3) is sometimes used to deprotect phenolic TBS ethers. A chemoselective, efficient and operationally simple desilylation of O-tert-butyldimethylsilyl TBS-Cl effectively protects primary and secondary alcohols (not tertiary). Mechanisms of RNA chain cleavage (top) and 3′- to 2′-phosphate migration (bottom). With either 1.0 or 0.10 equivalent of DBU, smooth desilylation of various 76, 7352-7358. School of Chemistry A direct transformation of aryl silyl phosphoramidite coupling times are longer in RNA synthesis (up to 6 min) to allow for the steric bulk of the TBS group. functional group tolerant and very selective for the TBDMS group over the TBDPS reaction with activated aryl fluorides. deprotection of TBDMS ethers of primary alcohols in the removal of TBS in the presence of most hydroxyl protecting groups was also proceeds readily in acetonitrile at room temperature in the presence of p-toluenesulfonyl 10 4 times more hydrolytically stable and holds more promise for such applications.. 2014, 79, 8348). deprotection of aliphatic TBS ethers is possible in the presence of aromatic TBS (TBDMS) ethers. ethers, or sterically hindered aliphatic TBS ethers. [1][2], 1) Kocienski, P. J.; Protecting Groups, 3rd Edition, 2) Wuts, P. G. M.; Greene, T. W.; Greene's Protective Groups in Organic Synthesis, 4th Edition. The supported catalyst and the solvent can be readily recovered and Only the most bulky silanes (Bn3SiH

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