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Alcohol Protection (Benzyl (Bn) ether)

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Benzyl, abbreviated as Bn, is commonly used in organic synthesis as a robust protecting group for alcohols and carboxylic acids.

Most common protection methods

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[2]

  • 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

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Benzyl ethers can be removed under reductive conditions, oxidative conditions, and the use of Lewis Acids.[1]

Reductive Conditions

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  • 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:

Lewis Acid-Based

  • Trimethylsilyl iodide (Me3SiI) in dichloromethane at ambient temperature (selectivity can be achieved under specific conditions)

Alcohol Protection (2-Methoxyethoxymethyl (MEM) ether)

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2-Methoxyethoxymethyl (MEM) group is commonly used in organic synthesis as a protecting group for alcohols.

Most common protection methods

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Most common deprotection methods

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The 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)

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Methoxymethyl (MOM) is used as a protecting group for alcohols in organic synthesis.

Most common protection methods

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[8]

  • 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

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MOM group can be cleaved with acid, commonly used conditions for deprotection of MOM alcohols include:[1]

[9]

Alcohol Protection (p-Methoxybenzyl (PMB) ether)

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p-Methoxybenzyl (PMB) is used as a protecting group for alcohols in organic synthesis.

Most common protection methods

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Most common deprotection methods

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  • 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ)

[14]

  • Conditions for deprotection of benzyl group are applicable for cleavage of PMB protecting group

Alcohol Protection (Methylthiomethyl (MTM) ether)

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Methylthiomethyl (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

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Most common deprotection methods

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Alcohol Protection (Pivaloyl (Pv) ester)

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Pivaloyl (Pv) group is used as a protecting group in organic synthesis.

Most common protection methods

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  • Treatment of alcohol with pivaloyl chloride (PvCl) in presence of pyridine[16]
  • Pivaloic anhydride with Sc(OTf)3 or VO(OTf)2

Most common deprotection methods

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[20]

[1]

Alcohol Protection (Tetrahydropyranyl (THP) ether)

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In organic synthesis, 2-tetrahydropyranyl group (THP) is used as a protecting group for alcohols.

Most common protection methods

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[21]

Most common deprotection methods

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Alcohol Protection (Trimethylsilyl (TMS) ether)

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In organic synthesis, TMS group is used as a protecting group for alcohols.

Most common protection methods

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Most common deprotection methods

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  • TMS groups are susceptible to cleavage upon treatment with HF-based reagents
  • Treatment with HCl in THF/water solution

Reference

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  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ Robinson, Anna; Aggarwal, Varinder K. (2010-09-03). "Asymmetric Total Synthesis of Solandelactone E: Stereocontrolled Synthesis of the 2-ene-1,4-diol Core through a Lithiation–Borylation–Allylation Sequence". Angewandte Chemie International Edition. 49 (37): 6673–6675. doi:10.1002/anie.201003236. ISSN 1521-3773.
  22. ^ 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.
  23. ^ 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.
  24. ^ Nicolaou, K. C.; Hwang, C.-K.; Soresen, E. J.; Clairborne, C. F. (1992-01-01). "A convergent strategy towards taxol. A facile enantioselective entry into a fully functionalized ring A system". Journal of the Chemical Society, Chemical Communications (16). doi:10.1039/c39920001117. ISSN 0022-4936.
  25. ^ Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A. (1994-02-17). "Total synthesis of taxol". Nature. 367 (6464): 630–634. doi:10.1038/367630a0.
  26. ^ Nicolaou, K. C.; Claiborne, Christopher F.; Nantermet, Philippe G.; Couladouros, Elias A.; Sorensen, Erik J. (1994-02-01). "Synthesis of Novel Taxoids". Journal of the American Chemical Society. 116 (4): 1591–1592. doi:10.1021/ja00083a063. ISSN 0002-7863.