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===Alcohol protecting groups=== The classical protecting groups for alcohols are [[ester]]s, deprotected by [[nucleophile]]s; [[Organosilanols|triorganosilyl]] [[Silyl ether|ethers]], deprotected by acids and fluoride ions; and [[Acetal|(hemi)acetals]], deprotected by weak acids. In rarer cases, a carbon [[ether]] might be used. The most important esters with common protecting-group use are the [[Acetate ester|acetate]], [[Benzoate ester|benzoate]], and [[pivalate ester]]s, for these exhibit differential removal. Sterically hindered esters are less susceptible to nucleophilic attack: : Chloroacetyl > acetyl > benzoyl > pivaloyl [[File:Tms_protecting.svg|thumb|Trimethylsilyl chloride, activated with imidazole, protects a secondary alcohol]] Triorganosilyl sources have quite variable prices, and the most economical is [[chlorotrimethylsilane]] (TMS-Cl), a [[Müller-Rochow synthesis|Direct Process]] byproduct. The trimethylsilyl ethers are also extremely sensitive to acid hydrolysis (for example [[silica gel]] suffices as a proton donator) and are consequently rarely used nowadays as protecting groups. Aliphatic methyl ethers cleave with difficulty and only under drastic conditions, so that these are in general only used with quinonic phenols. However, hemiacetals and acetals are much easier to cleave. [[File:THPmeth.png|440x440px|alt=Protection of alcohol as tetrahydropyranyl ether followed by deprotection. Both steps require acid catalysts.|center|frameless]] ==== List ==== Esters: * [[Acetyl]] (Ac) – Removed by acid or base (see [[Acetoxy group]]). * [[Benzoyl]] (Bz) – Removed by acid or base, more stable than Ac group. * [[Pivaloyl]] (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other acyl protecting groups. Silyl ethers: * {{Anchor|TBDMS}}[[Trimethylsilyl]] (TMS) — [[Potassium fluoride]], [[acetic acid]] or [[potassium carbonate]] in [[methanol]]<ref>P.J. Kocieński: ''Protecting Groups'', p. 29.</ref> * [[Triethylsilyl group|Triethylsilyl]] — 10–100× stabler than a TMS group.<ref>P.J. Kocieński: ''Protecting Groups'', p. 31.</ref> Cleaved with trifluoroacetic acid in water/[[tetrahydrofuran]],<ref>Tod K Jones, Robert A. Reamer, Richard Desmond, Sander G. Mills: "Chemistry of tricarbonyl hemiketals and application of Evans technology to the total synthesis of the immunosuppressant (−)-FK-506", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp. 2998–3017; [[doi:10.1021/ja00164a023]].</ref> acetic acid in water/tetrahydrofuran,<ref>Dieter Seebach, Hak-Fun Chow, Richard F.W. Jackson, Marius A. Sutter, Suvit Thaisrivongs, Jürg Zimmermann: "(+)-11,11{{prime}}-Di-O-methylelaiophylidene – preparation from elaiophylin and total synthesis from (R)-3-hydroxybutyrate and (S)-malate", in: ''[[Liebigs Ann. Chem.]]'', '''1986''', pp. 1281–1308; [[doi:10.1002/jlac.198619860714]].</ref> or [[hydrogen fluoride]] in water or pyridine<ref>David A. Evans, Stephen W. Kaldor, Todd K. Jones, Jon Clardy, Thomas J. Stout: "Total synthesis of the macrolide antibiotic cytovaricin", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp. 7001–7031; [[doi:10.1021/ja00175a038]].</ref> * {{Anchor|TOM}}''tert''-Butyldimethylsilyl (TBDMS or TBS) — Cleaved with acetic acid in tetrahydrofuran/water,<ref>James A. Marshall, Richard Sedrani: "A convergent, highly stereoselective synthesis of a C-11-C-21 subunit of the macbecins", in: ''[[J. Org. Chem.]]'', '''1991''', ''56'', pp. 5496–5498; [[doi:10.1021/jo00019a004]].</ref> Pyridinium tosylate in methanol,<ref name="JACS_1990_49913">James D. White, Motoji Kawasaki: "Total synthesis of (+)-[[latrunculin]] A", in: ''[[J. Am. Chem. Soc.]]'', '''1990''', ''112'', pp. 4991–4993; [[doi:10.1021/ja00168a071]].</ref> trifluoroacetic acid in water,<ref>Morris J. Robins, Vicente Samano, Mark D. Johnson: "Nucleic acid-related compounds. 58. Periodinane oxidation, selective primary deprotection, and remarkably stereoselective reduction of tert-butyldimethylsilyl-protected ribonucleosides. Synthesis of 9-(β-D-xylofuranosyl)adenine or 3'-deuterioadenosine from adenosine", in: ''[[J. Org. Chem.]]'', '''1990''', ''55'', pp. 410–412; [[doi:10.1021/jo00289a004]].</ref> hydrofluoric acid in [[acetonitrile]],<ref>R. Roger F. Newton, Derek P. Reynolds, Colin F. Webb, Stanley M. Roberts: "A short and efficient total synthesis of (±) prostaglandin D<sub>2</sub> methyl ester involving a new method for the cleavage of a dimethyl-t-butylsilyl ether", in: ''[[J. Chem. Soc., Perkin Trans. 1]]'', '''1981''', pp. 2055–2058; [[doi:10.1039/P19810002055]].</ref> pyridinium fluoride in tetrahydrofuran,<ref>Kyriacos C. Nicolaou, R. A. Daines, T. K. Chakraborty: "Total synthesis of amphoteronolide B", in: ''[[J. Am. Chem. Soc.]]'', '''1987''', ''109'', pp. 2208–2210; [[doi:10.1021/ja00241a063]].</ref> [[tetrabutylammonium fluoride]] in THF.<ref>Leo A. Paquette, Annette M. Doherty, Christopher M. Rayner: "Total synthesis of furanocembranolides. 1. Stereocontrolled preparation of key heterocyclic building blocks and assembly of a complete seco-pseudopterane framework", in: ''[[J. Am. Chem. Soc.]]'', '''1991''', ''109'', pp. 3910–3926; [[doi:10.1021/ja00036a045]].</ref> Commonly protects 2'-hydroxy function in [[oligonucleotide synthesis]]. * Triisopropylsilyl (TIPS) ethers) — Similar conditions to TBS but longer reaction times.<ref>P.J. Kocieński: ''Protecting Groups'', p. 40.</ref> * ''tert''{{Nbh}}Butyldiphenylsilyl (TBDPS) — Similar conditions to TBS but even longer reaction times (100–250× slower than TBS and 5–10× slower than TIPS) Benzyl ethers: *[[Benzyl]] (Bn) — Removed by [[hydrogenolysis]].<ref>P.J. Kocieński: ''Protecting Groups'', pp. 46–49.</ref> Bn group is widely used in sugar and nucleoside chemistry. * [[Trityl]] (triphenylmethyl, Tr) — Removed by acid<ref>Michel Bessodes, Dimitri Komiotis, Kostas Antonakis: "Rapid and selective detritylation of primary alcohols using formic acid", in: ''[[Tetrahedron Lett.]]'', '''1986''', ''27'', pp. 579–580; [[doi:10.1016/S0040-4039(00)84045-9]].</ref><ref>B. Helferich: ''[[Carbonhydr. Chem. Biochem.]]'', '''1948''', ''3'', pp. 79.</ref><ref>M.L. García, J. Pascual, L. Borràs, J.A. Andreu, E. Fos, D. Mauleón, G. Carganico, F. Arcamone: "Synthesis of new ether glycerophospholipids structurally related to modulator", in: ''[[Tetrahedron]]'', '''1991''', ''47'', pp. 10023–10034; [[doi:10.1016/S0040-4020(01)96051-X]].</ref> and hydrogenolysis * [[PMB ether|''p''-Methoxybenzyl ether]] (PMB) — Removed by acid, hydrogenolysis, or oxidation – commonly with [[2,3-Dichloro-5,6-dicyano-1,4-benzoquinone|DDQ]].<ref>Yuji Oikawa, Tadao Yoshioka, Osamu Yonemitsu: "Specific removal of o-methoxybenzyl protection by DDQ oxidation", in: ''[[Tetrahedron Lett.]]'', '''1982''', ''23'', pp. 885–888; [[doi:10.1016/S0040-4039(00)86974-9]].</ref> * ''p'',''m''{{Nbh}}Dimethoxybenzyl ether — Removed via oxidation with DDQ or ceric ammonium chloride<ref>See literature for ''p''{{nbh}}methoxybenzyl.</ref> Acetals: * [[Dimethoxytrityl]]{{Anchor|DMT}}, [bis-(4-methoxyphenyl)phenylmethyl] (DMT) — Removed by weak acid. DMT group is widely used for protection of 5'-hydroxy group in nucleosides, particularly in [[Oligonucleotide synthesis#Phosphoramidite building blocks|oligonucleotide synthesis]]. * Methoxytrityl [(4-methoxyphenyl)diphenylmethyl] (MMT) – Removed by acid and hydrogenolysis. * [[Benzyloxymethyl group|Benzyloxymethyl]] — Comparable stability to MOM, MEM und SEM,<ref>P.J. Kocieński: ''Protecting Groups'', p. 77.</ref> but also admits reductive removal: sodium in liquid ammonia,<ref>H. Nagaoka, W. Rutsch, G. Schmidt, H. Ito, M.R. Johnson, Y. Kishi: "Total synthesis of rifamycins. 1. Stereocontrolled synthesis of the aliphatic building block", in: ''[[J. Am. Chem. Soc.]]'', '''1980''', ''102'', pp. 7962–7965; [[doi:10.1021/ja00547a037]].</ref><ref>W. Clark Still, Dominick Mobilio: "Synthesis of asperdiol", in: ''[[J. Org. Chem.]]'', '''1983''', ''48'', pp. 4785–4786; [[doi:10.1021/jo00172a070]].</ref> catalytic hydrogenation (palladium hydroxide on activated carbon), or Raney nickel in ethanol<ref>Masahiro Hirama, Mitsuko Uei: "A chiral total synthesis of compactin", in: ''[[J. Am. Chem. Soc.]]'', '''1982''', ''104'', pp. 4251–4253; [[doi:10.1021/ja00379a037]].</ref><ref>W. Clark Still, Shizuaki Murata, Gilbert Revial, Kazuo Yoshihara: "Synthesis of the cytotoxic germacranolide eucannabinolide", in: ''[[J. Am. Chem. Soc.]]'', '''1983''', ''105'', pp. 625–627; [[doi:10.1021/ja00341a055]].</ref> * Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N [[hydrochloric acid]]<ref>{{cite journal |last=Kamaya |first=Yasushi |author2=T Higuchi |year=2006 |title=Metabolism of 3,4-dimethoxycinnamyl alcohol and derivatives by Coriolus versicolor |journal=FEMS Microbiology Letters |volume=24 |issue=2–3 |pages=225–229 |doi=10.1111/j.1574-6968.1984.tb01309.x |doi-access=free}}</ref> * [[2-Methoxyethoxymethyl chloride|Methoxyethoxymethyl ether]] (MEM) — Removed by hydrobromic acid in tetrahydrofuran<ref>Serge David, Annie Thieffry, Alain Veyrières: "A mild procedure for the regiospecific benzylation and allylation of polyhydroxy-compounds via their stannylene derivatives in non-polar solvents", in: ''[[J. Chem. Soc., Perkin Trans. 1]]'', '''1981''', pp. 1796–1801; [[doi:10.1039/P19810001796]].</ref> or [[zinc bromide]] in dichloromethane<ref>Kaoru Fuji, Shigetoshi Nakano, Eiichi Fujita: "An Improved Method for Methoxymethylation of Alcohols under Mild Acidic Conditions", in: ''[[Synthesis (journal)|Synthesis]]'', '''1975''', pp. 276–277.</ref> * [[Methoxymethyl ether]] (MOM) — Removed by 6 M hydrochloric acid in tetrahydrofuran/water<ref>Paul A. Wender, Carlos R. D. Correia: "Intramolecular photoinduced diene-diene cyaloadditions: a selective method for the synthesis of complex eight-membered rings and polyquinanes", in: ''[[J. Am. Chem. Soc.]]'', '''1987''', ''109'', pp. 2523–2525; [[doi:10.1021/ja00242a053]].</ref> * [[Tetrahydropyranyl]] (THP) — Removed by acetic acid in tetrahydrofuran/water,<ref>Karel F. Bernady, M. Brawner Floyd, John F. Poletto, Martin J. Weiss: "Prostaglandins and congeners. 20. Synthesis of prostaglandins via conjugate addition of lithium trans-1-alkenyltrialkylalanate reagents. A novel reagent for conjugate 1,4-additions", in: ''[[J. Org. Chem.]]'', '''1979''', ''44'', pp. 1438–1447; [[doi:10.1021/jo01323a017]].</ref> ''p''{{nbh}}toluenesulfonic acid in methanol<ref>Elias J. Corey, Haruki Niwa, Jochen Knolle: "Total synthesis of (S)-12-hydroxy-5,8,14-cis,-10-trans-eicosatetraenoic acid (Samuelsson's HETE)", in: ''[[J. Am. Chem. Soc.]]'', '''1978''', ''100'', pp. 1942–1943; [[doi:10.1021/ja00474a058]].</ref> * [[Methylthiomethyl ether]] — Removed by acid{{Citation needed|date=February 2024}} or [[HSAB theory|soft]] metal oxidants: base-buffered [[Mercury(II) chloride|mercuric chloride]] in wet acetonitrile<ref>Elias J. Corey, Mark G. Bock: "Protection of primary hydroxyl groups as methylthiomethyl ethers", in: ''[[Tetrahedron Lett.]]'', '''1975''', ''16'', pp. 3269–3270; [[doi:10.1016/S0040-4039(00)91422-9]].</ref> or [[silver nitrate]] in wet tetrahydrofuran<ref>Elias J. Corey, Duy H. Hua, Bai Chuan Pan, Steven P. Seitz: "Total synthesis of aplasmomycin", in: ''[[J. Am. Chem. Soc.]]'', '''1982''', ''104'', pp. 6818–6820; [[doi:10.1021/ja00388a074]].</ref> * Tris(isopropyl)silyloxymethyl (TOM) — Commonly protects 2'-hydroxy function in [[oligonucleotide synthesis]]. * [[(Trimethylsilyl)ethoxymethyl group|β{{nbh}}(Trimethylsilyl)ethoxymethyl]] — More labile than MEM and MOM to acid hydrolysis: 0.1 M hydrochloric acid in methanol,<ref>Robert C. Gadwood, Renee M. Lett, Jane E. Wissinger: "Total synthesis of (±)-poitediol and (±)4-epipoitediol", in: ''[[J. Am. Chem. Soc.]]'', '''1984''', ''106'', pp. 3869–3870; [[doi:10.1021/ja00325a032]].</ref> concentrated hydrofluoric acid in acetonitrile,<ref name="JACS_1990_49913"/> boron trifluoride etherate in dichloromethane,<ref>Steven D. Burke, Gregory J. Pacofsky: "The ester enolate claisen rearrangement. Total synthesis of (±)-ethisolide", in: ''[[Tetrahedron Lett.]]'', '''1986''', ''27'', pp. 445–448; [[doi:10.1016/S0040-4039(00)85501-X]].</ref> or [[tetrabutylammonium fluoride]] in HMPT ([[Hexamethyl phosphoric acid triamide]]) or in tetrahydrofuran<ref>Toshiyuki Kan, Masaru Hashimoto, Mitsutoshi Yanagiya, Haruhisa Shirahama: "Effective deprotection of 2-(trimethylsilylethoxy)methylated alcohols (SEM ethers). Synthesis of thyrsiferyl-23 acetate", in: ''[[Tetrahedron Lett.]]'', '''1988''', ''29'', pp. 5417–5418; [[doi:10.1016/S0040-4039(00)82883-X]].</ref><ref>Joseph P. Marino, Scott L. Dax: "An efficient desilylation method for the generation of o-quinone methides: application to the synthesis of (+)- and (−)-hexahydrocannabinol", in: ''[[J. Org. Chem.]]'', '''1984''', ''49'', pp. 3671–3672; [[doi:10.1021/jo00193a051]].</ref> Other ethers: * ''p''-Methoxyphenyl ether (PMP) – Removed by oxidation.{{Citation needed|date=February 2024}} * [[Butyl group#Tert-butyl as Protecting group|Tert-butyl ethers]] (tBu) – Removed with anhydrous trifluoroacetic acid, [[hydrogen bromide]] in acetic acid, or 4 N hydrochloric acid<ref>P.J. Kocieński: ''Protecting Groups'', pp. 59–60.</ref> * [[Allyl group|Allyl]] — Removed with potassium ''tert''{{nbh}}butoxide<ref>P.J. Kocieński: ''Protecting Groups'', p. 62.</ref> [[DABCO]] in methanol, palladium on activated carbon, or diverse platinum complexes – conjoined with acid workup.<ref>R.E. Ireland, D.W. Norbeck: "Convergent synthesis of polyether ionophore antibiotics: the synthesis of the monensin bis(tetrahydrofuran) via the Claisen rearrangement of an ester enolate with a β-leaving group", in: ''[[J. Am. Chem. Soc.]]'', '''1985''', ''107'', pp. 3279–3285; [[doi:10.1021/ja00297a038]].</ref> * Methyl ethers – Cleavage is by TMSI in dichloromethane or acetonitrile or chloroform. An alternative method to cleave methyl ethers is BBr<sub>3</sub> in DCM * [[Tetrahydrofuran]] (THF){{Clarification needed|reason=Where does the ether attach?|date=February 2024}} – Removed by acid.
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