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Alcohol Protection (Benzyl (Bn) ether)
edit
Benzyl, abbreviated as Bn, is commonly used in organic synthesis as a robust protecting group for alcohols and carboxylic acids.
Most common protection methods
edit- Treatment of alcohol with a strong base such as powdered potassium hydroxide or sodium hydride and benzyl halide (BnX; X=Cl, Br)[1]
- Monobenzylation of diols can be achieved using Ag2O in dimethylformamide (DMF) at ambient to elevated temperatures[3]
- Primary alcohols can be selectively benzylated in presence of phenol functional groups using Cu(acac)2[4]
Most common deprotection methods
editBenzyl ethers can be removed under reductive conditions, oxidative conditions, and the use of Lewis Acids.[1]
Reductive Conditions
- Removed using hydrogenolysis
- Single electron process with Na/NH3 or Li/NH3
Oxidative Conditions
- Benzyl protecting group can be removed using a wide range of oxidizing agents including:
- CrO3/AcOH at ambient temperature
- Ozone
- N-Bromosuccinimide (NBS)
- N-Iodosuccinimide (NIS)
Lewis Acid-Based
- Trimethylsilyl iodide (Me3SiI) in dichloromethane at ambient temperature (selectivity can be achieved under specific conditions)
Alcohol Protection (2-Methoxyethoxymethyl (MEM) ether)
edit2-Methoxyethoxymethyl (MEM) group is commonly used in organic synthesis as a protecting group for alcohols.
Most common protection methods
edit- Treatment of alcohol with bases such as sodium hydride or potassium hydride and 2-methoxyethoxymethyl chloride in tetrahydrofuran (THF) at 0 °C[6]
- MEM group can also be installed at ambient temperature with 2-methoxyethoxymethyl chloride and a mild base such as N,N-diisopropylethylamine (DIPEA) in dichloromethane[7]
Most common deprotection methods
editThe 2-methoxyethoxymethyl protecting group can be cleaved with a range of Lewis acids, including but not limited to:
- TiCl4 or ZnBr2 in dichloromethane at 0 °C to ambient temperature
- If the solvent of choice is a protic solvent such as methanol, formic acid can be used to cleave MEM group at elevated temperatures
Alcohol Protection (Methoxymethyl (MOM) ether)
editMethoxymethyl (MOM) is used as a protecting group for alcohols in organic synthesis.
Most common protection methods
edit- Treatment of alcohol with N,N-diisopropylethylamine (DIPEA) and methoxymethyl chloride (MOM chloride) in dichloromethane at 0 °C[1]
- For reactions carried out in more polar solvents such as tetrahydrofuran (THF) or N,N-dimethylformamide (DMF), protection of alcohol can be carried out using sodium hydride at 0 °C to ambient temperatures
Most common deprotection methods
editMOM group can be cleaved with acid, commonly used conditions for deprotection of MOM alcohols include:[1]
- Concentrated hydrochloric acid in methanol or water
- Trifluoroacetic acid (TFA) in dichloromethane
- Acetyl chloride in methanol at 0 °C
Alcohol Protection (p-Methoxybenzyl (PMB) ether)
editp-Methoxybenzyl (PMB) is used as a protecting group for alcohols in organic synthesis.
Most common protection methods
edit- Strong base such as powdered potassium hydroxide or sodium hydride and p-methoxybenzyl halide (BnX; X=Cl, Br)[10][11]
- 4-methoxybenzyl-2,2,2-trichloroacetimidate can be used to install the PMB group in presence of:
- Scandium (III) triflate (Sc(OTf)3) in toluene at 0 °C[12]
- Trifluoromethanesulfonic acid (TfOH) in dichloromethane at 0 °C[13]
Most common deprotection methods
edit- 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)
- Conditions for deprotection of benzyl group are applicable for cleavage of PMB protecting group
Alcohol Protection (Methylthiomethyl (MTM) ether)
editMethylthiomethyl (MTM) group is used as a protecting group for alcohols in organic synthesis. This type of alcohol protecting group is robust under mild acidic reaction conditions.
Most common protection methods
edit- Treatment of alcohol with sodium hydride and methylthiomethyl halide
- Dimethyl sulfoxide (DMSO) and acetic acid (AcOH) in acetic anhydride (Ac2O) at ambient temperature
Most common deprotection methods
edit- Mercury (II) chloride (HgCl2); calcium carbonate (CaCO3) is used as an acid scavenger for acid sensitive substrates[15]
- Iodomethane (MeI) in presence of sodium bicarbonate (NaHCO3) at elevated temperatures (this type of reaction is generally carried out in acetone/H2O solution)[1]
- Magnesium iodide (MgI) and acetic anhydride (Ac2O) in ether at ambient temperature[1]
Alcohol Protection (Pivaloyl (Pv) ester)
editPivaloyl (Pv) group is used as a protecting group in organic synthesis.
Most common protection methods
edit
- Pivaloic anhydride with Sc(OTf)3 or VO(OTf)2
Most common deprotection methods
edit- Tetrabutylammonium hydroxide (Bu4NOH) at ambient temperatures[17]
- Treatment with aqueous methylamine (MeNH2)[18]
- Pivaloate esters can be cleaved with strong bases:
- 0.5N sodium hydroxide (NaOH) in ethanol/water solution[19]
- Potassium carbonate (K2CO3) or sodium methoxide (NaOMe) in methanol
- Methyl lithium (MeLi) in ether
- Potassium tert-butoxide in water
Alcohol Protection (Tetrahydropyranyl (THP) ether)
editIn organic synthesis, 2-tetrahydropyranyl group (THP) is used as a protecting group for alcohols.
Most common protection methods
edit- Treatment of alcohol with dihydropyran and p-toluenesulfonic acid in dichloromethane at ambient temperature[1]
- 2-hydroxytetrahydropyranyl, triphenylphosphine, diethyl azodicarboxylate (DEAD) in THF
Most common deprotection methods
edit- Acetic acid (AcOH) in THF/water solution or p-toluenesulfonic acid in water
- Pyridinium p-toluenesulfonate (PPTS) in ethanol
Alcohol Protection (Trimethylsilyl (TMS) ether)
editIn organic synthesis, TMS group is used as a protecting group for alcohols.
Most common protection methods
edit- Trimethylsilyl chloride (TMSCl) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) and base (ie. pyridine, triethylamine, or 2,6-lutidine) in dichloromethane[22][23][24][25][26]
- TMSCl and lithium sulfide (Li2S) in acetonitrile
Most common deprotection methods
edit- TMS groups are susceptible to cleavage upon treatment with HF-based reagents
- Tetrabutylammonium fluoride (Bu4NF) in THF
- Fluorosilicic acid (H2SiF6)
- Treatment with HCl in THF/water solution
Reference
edit- ^ a b c d e f g h Wuts, Peter G. M.; Greene, Theodora W. Greene's Protective Groups in Organic Synthesis, Fourth Edition - Wuts - Wiley Online Library. doi:10.1002/0470053488.
- ^ Fukuzawa, Akio; Sato, Hideaki; Masamune, Tadashi (1987-01-01). "Synthesis of (±)-prepinnaterpene, a bromoditerpene from the red alga Laurencia Pinnata Yamada". Tetrahedron Letters. 28 (37): 4303–4306. doi:10.1016/S0040-4039(00)96491-8.
- ^ Van Hijfte, Luc; Little, R. Daniel (1985-10-01). "Intramolecular 1,3-diyl trapping reactions. A formal total synthesis of (.+-.)-coriolin". The Journal of Organic Chemistry. 50 (20): 3940–3942. doi:10.1021/jo00220a058. ISSN 0022-3263.
- ^ Sirkecioglu, Okan; Karliga, Bekir; Talinli, Naciye (2003-11-10). "Benzylation of alcohols by using bis[acetylacetonato]copper as catalyst". Tetrahedron Letters. 44 (46): 8483–8485. doi:10.1016/j.tetlet.2003.09.106.
- ^ Smith, Amos B.; Zhu, Wenyu; Shirakami, Shohei; Sfouggatakis, Chris; Doughty, Victoria A.; Bennett, Clay S.; Sakamoto, Yasuharu (2003-03-01). "Total Synthesis of (+)-Spongistatin 1. An Effective Second-Generation Construction of an Advanced EF Wittig Salt, Fragment Union, and Final Elaboration". Organic Letters. 5 (5): 761–764. doi:10.1021/ol034037a. ISSN 1523-7060.
- ^ Corey, E. J.; Gras, Jean-Louis; Ulrich, Peter (1976-03-01). "A new general method for protection of the hydroxyl function". Tetrahedron Letters. 17 (11): 809–812. doi:10.1016/S0040-4039(00)92890-9.
- ^ Lee, Hong Myung; Nieto-Oberhuber, Cristina; Shair, Matthew D. (2008-12-17). "Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of Endothelial Cell Proliferation". Journal of the American Chemical Society. 130 (50): 16864–16866. doi:10.1021/ja8071918. ISSN 0002-7863.
- ^ Enders, Dieter; Geibel, Gunter; Osborne, Simon (2000-04-17). "Diastereo- and Enantioselective Total Synthesis of Stigmatellin A". Chemistry – A European Journal. 6 (8): 1302–1309. doi:10.1002/(SICI)1521-3765(20000417)6:83.0.CO;2-J. ISSN 1521-3765.
- ^ Amano, Seiji; Takemura, Noriaki; Ohtsuka, Masami; Ogawa, Seiichiro; Chida, Noritaka (1999-03-26). "Total synthesis of paniculide A from d-glucose". Tetrahedron. 55 (13): 3855–3870. doi:10.1016/S0040-4020(99)00096-4.
- ^ Marco, José L.; Hueso-Rodríguez, Juan A. (1988-01-01). "Synthesis of optically pure 1-(3-furyl)-1,2-dihydroxyethane derivatives". Tetrahedron Letters. 29 (20): 2459–2462. doi:10.1016/S0040-4039(00)87907-1.
- ^ Takaku, Hiroshi; Kamaike, Kazuo; Tsuchiya, Hiromichi (1984-01-01). "Oligonucleotide synthesis. Part 21. Synthesis of ribooligonucleotides using the 4-methoxybenzyl group as a new protecting group for the 2'-hydroxyl group". The Journal of Organic Chemistry. 49 (1): 51–56. doi:10.1021/jo00175a010. ISSN 0022-3263.
- ^ Trost, Barry M.; Waser, Jerome; Meyer, Arndt (2007-11-01). "Total Synthesis of (−)-Pseudolaric Acid B". Journal of the American Chemical Society. 129 (47): 14556–14557. doi:10.1021/ja076165q. ISSN 0002-7863. PMC 2535803. PMID 17985906.
- ^ Mukaiyama, Teruaki; Shiina, Isamu; Iwadare, Hayato; Saitoh, Masahiro; Nishimura, Toshihiro; Ohkawa, Naoto; Sakoh, Hiroki; Nishimura, Koji; Tani, Yu-ichirou (1999-01-04). "Asymmetric Total Synthesis of Taxol\R". Chemistry – A European Journal. 5 (1): 121–161. doi:10.1002/(SICI)1521-3765(19990104)5:13.0.CO;2-O. ISSN 1521-3765.
- ^ Hanessian, Stephen; Marcotte, Stéphane; Machaalani, Roger; Huang, Guobin (2003-11-01). "Total Synthesis and Structural Confirmation of Malayamycin A: A Novel Bicyclic C-Nucleoside from Streptomyces malaysiensis". Organic Letters. 5 (23): 4277–4280. doi:10.1021/ol030095k. ISSN 1523-7060.
- ^ Corey, E. J.; Bock, Mark G. (1975-01-01). "Protection of primary hydroxyl groups as methylthiomethyl ethers". Tetrahedron Letters. 16 (38): 3269–3270. doi:10.1016/S0040-4039(00)91422-9.
- ^ Robins, Morris J.; Hawrelak, S. D.; Kanai, Tadashi; Siefert, Jan Marcus; Mengel, Rudolf (1979-04-01). "Nucleic acid related compounds. 30. Transformations of adenosine to the first 2',3'-aziridine-fused nucleosides, 9-(2,3-epimino-2,3-dideoxy-.beta.-D-ribofuranosyl)adenine and 9-(2,3-epimino-2,3-dideoxy-.beta.-D-lyxofuranosyl)adenine". The Journal of Organic Chemistry. 44 (8): 1317–1322. doi:10.1021/jo01322a026. ISSN 0022-3263.
- ^ van Boeckel, C. A. A.; van Boom, J. H. (1979-01-01). "Synthesis of glucosylphosphatidylglycerol via a phosphotriester intermediate". Tetrahedron Letters. 20 (37): 3561–3564. doi:10.1016/S0040-4039(01)95462-0.
- ^ Griffin, B. E.; Jarman, M.; Reese, C. B. (1968-01-01). "The Synthesis of oligoribonucleotides—IV". Tetrahedron. 24 (2): 639–662. doi:10.1016/0040-4020(68)88015-9.
- ^ Ogilvie, Kelvin K.; Iwacha, Donald J. (1973-01-01). "Use of the tert-butyldimethylsilyl group for protecting the hydroxyl functions of nucleosides". Tetrahedron Letters. 14 (4): 317–319. doi:10.1016/S0040-4039(01)95650-3.
- ^ Paquette, Leo A.; Collado, Iván; Purdie, Mark (1998-03-01). "Total Synthesis of Spinosyn A. 2. Degradation Studies Involving the Pure Factor and Its Complete Reconstitution". Journal of the American Chemical Society. 120 (11): 2553–2562. doi:10.1021/ja974010k. ISSN 0002-7863.
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- ^ Nicolaou, K. C.; Liu, J. J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K. (1992-01-01). "Synthesis of a fully functionalized CD ring system of taxol". Journal of the Chemical Society, Chemical Communications (16). doi:10.1039/c39920001118. ISSN 0022-4936.
- ^ Nicolaou, K. C.; Yang, Zhen; Sorensen, Erik J.; Nakada, Masahisa (1993-01-01). "Synthesis of ABCtaxoid ring systems via a convergent strategy". Journal of the Chemical Society, Chemical Communications (12). doi:10.1039/c39930001024. ISSN 0022-4936.
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