Protecting group

Source: Wikipedia, the free encyclopedia.
(Redirected from
Deprotection
)

Ethylene glycol protects a ketone (as an acetal) during an ester reduction, vs. unprotected reduction to a diol

A protecting group or protective group is introduced into a molecule by chemical modification of a

multistep organic synthesis.[1]

In many preparations of delicate

carbonyl groups, and cannot be discouraged by any means. When an ester must be reduced in the presence of a carbonyl, hydride attack on the carbonyl must be prevented. One way to do so converts the carbonyl into an acetal
, which does not react with hydrides. The acetal is then called a protecting group for the carbonyl. After the hydride step is complete, aqueous acid removes the acetal, restoring the carbonyl. This step is called deprotection.

Protecting groups are more common in small-scale laboratory work and initial development than in industrial production because they add additional steps and material costs. However, compounds with repetitive functional groups – generally, biomolecules like peptides, oligosaccharides or nucleotides – may require protecting groups to order their assembly. Also, cheap chiral protecting groups may often shorten an enantioselective synthesis (e.g. shikimic acid for oseltamivir).

As a rule, the introduction of a protecting group is straightforward. The difficulties honestly lie in their stability and in selective removal. Apparent problems in synthesis strategies with protecting groups are rarely documented in the academic literature.[2]

Orthogonal protection

hydroxyl group
of Tyrosine.

Orthogonal protection is a strategy allowing the specific deprotection of one protective group in a multiply-protected structure. For example, the amino acid tyrosine could be protected as a benzyl ester on the carboxyl group, a fluorenylmethylenoxy carbamate on the amine group, and a tert-butyl ether on the phenol group. The benzyl ester can be removed by hydrogenolysis, the fluorenylmethylenoxy group (Fmoc) by bases (such as piperidine), and the phenolic tert-butyl ether cleaved with acids (e.g. with trifluoroacetic acid).

A common example for this application, the Fmoc peptide synthesis, in which peptides are grown in solution and on solid phase, is very important.[3] The protecting groups in solid-phase synthesis regarding the reaction conditions such as reaction time, temperature and reagents can be standardized so that they are carried out by a machine, while yields of well over 99% can be achieved. Otherwise, the separation of the resulting mixture of reaction products is virtually impossible (see also § Industrial applications).[4]

  • Schematic diagram of a solid-state peptide synthesis with orthogonal protecting groups X and Y
    Schematic diagram of a solid-state peptide synthesis with orthogonal protecting groups X and Y
  • Fmoc solid state peptide synthesis with orthogonal protecting groups
    Fmoc solid state peptide synthesis with orthogonal protecting groups

A further important example of orthogonal protecting groups occurs in

hydroxyl groups
exhibit very similar reactivities, a transformation that protects or deprotects a single hydroxy group must be possible for a successful synthesis.

Cleavage categorization

Many reaction conditions have been established that will cleave protecting groups. One can roughly distinguish between the following environments:[5]

  • Acid-labile protecting groups
  • Base
    -labile protecting groups
  • Fluoride-labile protecting groups
  • Enzyme-labile protecting groups
  • Reduction
    -labile protecting groups
  • Oxidation
    -labile protecting groups
  • Protecting groups cleaved by heavy metal salts or their complexes.
  • Photolabile protecting groups
  • Double-layered protecting groups

Various groups are cleaved in acid or base conditions, but the others are more unusual.

Fluoride ions form very strong bonds to

steric hindrance
. The advantage of fluoride-labile protecting groups is that no other protecting group is attacked by the cleavage conditions.

temperatures
(30–40 °C). Because enzymes have very high substrate specificity, the method is quite rare, but extremely attractive.

Catalytic hydrogenation removes a wide variety of benzyl groups: ethers, esters, urethanes, carbonates, etc.

Only a few protecting groups can be detached oxidatively: the methoxybenzyl ethers, which oxidize to a

dichlorodicyanobenzoquinone
(DDQ).

Allyl compounds will isomerize to a vinyl group in the presence of noble metals. The residual enol ether (from a protected alcohol) or enamine (resp. amine) hydrolyzes in light acid.

Photolabile protecting groups bear a chromophore, which is activated through radiation with an appropriate wavelength and so can be removed.[6] For examples the o-nitrobenzylgroup ought be listed here.

Mechanism of photodeprotection of an o-nitrobenzyl ether and formation of an alcohol

The rare double-layer protecting group is a protected protecting group, which exemplify high stability.

Common protecting groups

Alcohol protecting groups

The classical protecting groups for alcohols are esters, deprotected by nucleophiles; triorganosilyl ethers, deprotected by acids and fluoride ions; and (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, benzoate, and pivalate esters
, for these exhibit differential removal. Sterically hindered esters are less susceptible to nucleophilic attack:

Chloroacetyl > acetyl > benzoyl > pivaloyl
Trimethylsilyl chloride, activated with imidazole, protects a secondary alcohol

Triorganosilyl sources have quite variable prices, and the most economical is

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.

Protection of alcohol as tetrahydropyranyl ether followed by deprotection. Both steps require acid catalysts.

List

Esters:

Silyl ethers:

Benzyl ethers:

Acetals:

Other ethers:

1,2-Diols

The 1,2‑diols (

isopropylidene and cyclohexylidene or cyclopentylidene
acetals.

Applied acetal

An exceptional case appears with the benzylideneprotecting group,which also admits reductive cleavage. This proceeds either through catalytic hydrogenation or with the hydride donor diisobutyl aluminum hydride (DIBAL). The cleavage with DIBAL deprotects one alcohol group, for the benzyl moiety stays as a benzyl ether on the second, sterically hindered hydroxy group.[45][46]

Cleaving a benzylidene acetal with DIBAL

Amine protecting groups

bases. These characteristics imply that new protecting groups for amines are always under development.[47]

Amine groups are primarily protected through acylation, typically as a carbamate. When a carbamate deprotects, it evolves carbon dioxide
. The commonest-used carbamates are the tert-butoxycarbonyl, benzoxycarbonyl, fluorenylmethylenoxycarbonyl, and allyloxycarbonyl compounds.

Other, more exotic amine protectors are the

catalytic hydrogenation
or Birch reduction, but have a decided drawback relative to the carbamates or amides: they retain a basic nitrogen.

Selection

Carbamates:

Other amides:

Benzylamines:

Carbonyl protecting groups

The most common protecting groups for carbonyls are acetals and typically cyclic acetals with diols. The runners-up used are also cyclic acetals with 1,2‑hydroxythiols or dithioglycols – the so-called O,S– or S,S-acetals.

Ethylene glycol
1,3‑Propadiol

Overall, trans-acetalation plays a lesser role in forming protective acetals; they are formed as a rule from glycols through dehydration. Normally a simple glycol like ethylene glycol or 1,3-propadiol is used for acetalation.Modern variants also use glycols, but with the hydroxyl hydrogens replaced with a trimethylsilyl group.[60][61]

Acetals can be removed in acidic aqueous conditions. For those ends, the mineral acids are appropriate acids. Acetone is a common cosolvent, used to promote dissolution. For a non-acidic cleavage technique, a palladium(II) chloride acetonitrile complex in acetone[62] or iron(III) chloride on silica gel can be performed with workup in chloroform.[63]

Cyclic acetals are very much more stable against acid hydrolysis than acyclic acetals. Consequently acyclic acetals are used practically only when a very mild cleavage is required or when two different protected carbonyl groups must be differentiated in their liberation.[64]

Besides the O,O-acetals, the S,O- and S,S-acetals also have an application, albeit scant, as carbonyl protecting groups too. Thiols, which one begins with to form these acetals, have a very unpleasant stench and are poisonous, which severely limit their applications. Thioacetals and the mixed S,O-acetals are, unlike the pure O,O-acetals, very much stabler against acid hydrolysis. This enables the selective cleavage of the latter in the presence of sulfur-protected carbonyl groups.

The formation of S,S-acetals normally follows analogously to the O,O-acetals with acid catalysis from a dithiol and the carbonyl compound. Because of the greater stability of thioacetals, the equilibirum lies on the side of the acetal. In contradistinction to the O,O‑acetal case, it is not needed to remove water from the reaction mixture in order to shift the equilibrium.[65]

S,O-Acetals are hydrolyzed a factor of 10,000 times faster than the corresponding S,S-acetals. Their formation follows analogously from the thioalcohol. Also their cleavage proceeds under similar conditions and predominantly through mercury(II) compounds in wet acetonitrile.[66]

For aldehydes, a temporary protection of the carbonyl group the presence of ketones as hemiaminal ions is shown below. Here it is applied, that aldehydes are very much more activated carbonyls than ketones and that many addition reactions are reversible.[67][68]

Temporary protection of an aldehyde

Types of protectants

  • Ketals
    – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.
  • Lewis acids
    .
  • Dithianes – Removed by metal salts or oxidizing agents.

Carboxylic acid protecting groups

The most important protecting groups for carboxylic acids are the esters of various alcohols. Occasionally, esters are protected as ortho-esters or oxazolines.[69]

Many groups can suffice for the alcoholic component, and the specific cleaving conditions are contrariwise generally quite similar: each ester can be hydrolyzed in a basic water-alcohol solution. Instead, most ester protecting groups vary in how mildly they can be formed from the original acid.

Protecting groups

Alkene

Alkenes rarely need protection or are protected. They are as a rule only involved in undesired side reactions with electrophilic attack, isomerization or catalytic hydration. For alkenes two protecting groups are basically known:

  • Temporary halogenation with bromine to a trans‑1,2‑dibromoalkane: the regeneration of the alkene then follows with preservation of conformation via elemental zinc[86][87][88][89][90] or with titanocene dichloride.[91]
  • Protection through a
    Diels-Alder reaction: the transformation of an alkene with a diene leads to a cyclic alkene, which is nevertheless similarly endangered by electrophilic attack as the original alkene. The cleavage of a protecting diene proceeds thermically, for the Diels-Alder reaction is a reversible (equilibrium) reaction.[92][93][94]
Schemata of alkene protecting groups

Phosphate protecting groups

  • 2-cyanoethyl – removed by mild base. The group is widely used in oligonucleotide synthesis.
  • Methyl
    (Me) – removed by strong nucleophiles e.c. thiophenole/TEA.

Terminal alkyne protecting groups

For alkynes there are in any case two types of protecting groups. For terminal alkynes it is sometimes important to mask the acidic hydrogen atom. This normally proceeds from deprotonation (via a strong base like

tetrabutylammonium fluoride.[96]

Alkyne TMS protection
Alkyne TMS protection

In order to protect the triple bond itself, sometimes a transition metal-alkyne complex with dicobalt octacarbonyl is used. The release of the cobalt then follows from oxidation.[97][98][99][100][101]

Alkyne protection with Co

Other

Criticism

The use of protective groups is pervasive but not without criticism.

chemical yield. Crucially, added complexity impedes the use of synthetic total synthesis in drug discovery. In contrast biomimetic synthesis does not employ protective groups. As an alternative, Baran presented a novel protective-group free synthesis of the compound hapalindole U. The previously published synthesis[104][105][106]
according to Baran, contained 20 steps with multiple protective group manipulations (two confirmed):

Protected and unprotected syntheses of the marine alkaloid, hapalindole U.
Tosyl
protecting groups (shown in blue).
Phil Baran
's protecting-group free synthesis, reported in 2007.

Industrial applications

Although the use of protecting groups is not preferred in industrial syntheses, they are still used in industrial contexts, e.g.

Roche synthesis of oseltamivir
(Tamiflu, an antiviral drug)

An important example of industrial applications of protecting group theory is the synthesis of

ascorbic acid (Vitamin C) à la Reichstein
.

The Reichstein synthesis (of ascorbic acid)

In order to prevent oxidation of the secondary alcohols with potassium permanganate, they are protected via acetalation with acetone and then deprotected after the oxidation of the primary alcohols to carboxylic acids.[107]

A very spectacular example application of protecting groups from

natural product synthesis is the 1994 total synthesis of palytoxin acid by Yoshito Kishi's research group.[108] Here 42 functional groups (39 hydroxyls, one diol, an amine group, and a carboxylic acid) required protection. These proceeded through 8 different protecting groups (a methyl ester, five acetals, 20 TBDMS esters, nine p‑methoxybenzyl ethers, four benzoates, a methyl hemiacetal, an acetone acetal and an SEM ester).[109]

Palytoxin

The introduction or modification of a protecting group occasionally influences the reactivity of the whole molecule. For example, diagrammed below is an excerpt of the synthesis of an analogue of

Danishefsky.[110]

Part of the synthesis of an analogue of Mitomycin C with modified reactivity through protecting-group exchange

The exchange of a protecting group from a methyl ether to a MOM-ether inhibits here the opening of an epoxide to an aldehyde.

Protecting group chemistry finds itself an important application in the automated synthesis of peptides and nucleosides. The technique was introduced in the field of peptide synthesis by Robert Bruce Merrifield in 1977.[111] For peptide synthesis via automated machine, the orthogonality of the Fmoc group (basic cleavage), the tert‑butyl group (acidic cleavage) and diverse protecting groups for functional groups on the amino acid side-chains are used.[112] Up to four different protecting groups per nucleobase are used for the automated synthesis of DNA and RNA sequences in the oligonucleotide synthesis. The procedure begins actually with redox chemistry at the protected phosphorus atom. A tricoordinate phosphorus, used on account of the high reactivity, is tagged with a cyanoethyl protecting group on a free oxygen. After the coupling step follows an oxidation to phosphate, whereby the protecting group stays attached. Free OH-groups, which did not react in the coupling step, are acetylated in an intermediate step. These additionally-introduced protecting groups then inhibit, that these OH-groups might couple in the next cycle.[113]

Automatic oligonucleotide synthesis

References

  1. ISBN 978-0-471-16019-9
    .
  2. ^ Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2194; doi:10.1002/ange.19961081805 (in German).
  3. ISBN 978-0-19-963724-9
    .
  4. ^ Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, S. 10–12.
  5. ^ Michael Schelhaas, Herbert Waldmann: "Schutzgruppenstrategien in der organischen Synthese", in: Angewandte Chemie, 1996, 103, pp. 2195–2200; doi:10.1002/ange.19961081805 (in German).
  6. ^ V.N. Rajasekharan Pillai: "Photoremovable Protecting Groups in Organic Synthesis", in: Synthesis, 1980, pp. 1–26.
  7. ^ P.J. Kocieński: Protecting Groups, p. 29.
  8. ^ P.J. Kocieński: Protecting Groups, p. 31.
  9. J. Am. Chem. Soc., 1990, 112, pp. 2998–3017; doi:10.1021/ja00164a023
    .
  10. Liebigs Ann. Chem., 1986, pp. 1281–1308; doi:10.1002/jlac.198619860714
    .
  11. J. Am. Chem. Soc., 1990, 112, pp. 7001–7031; doi:10.1021/ja00175a038
    .
  12. J. Org. Chem., 1991, 56, pp. 5496–5498; doi:10.1021/jo00019a004
    .
  13. ^
    J. Am. Chem. Soc., 1990, 112, pp. 4991–4993; doi:10.1021/ja00168a071
    .
  14. J. Org. Chem., 1990, 55, pp. 410–412; doi:10.1021/jo00289a004
    .
  15. J. Chem. Soc., Perkin Trans. 1, 1981, pp. 2055–2058; doi:10.1039/P19810002055
    .
  16. J. Am. Chem. Soc., 1987, 109, pp. 2208–2210; doi:10.1021/ja00241a063
    .
  17. J. Am. Chem. Soc., 1991, 109, pp. 3910–3926; doi:10.1021/ja00036a045
    .
  18. ^ P.J. Kocieński: Protecting Groups, p. 40.
  19. ^ P.J. Kocieński: Protecting Groups, pp. 46–49.
  20. Tetrahedron Lett., 1986, 27, pp. 579–580; doi:10.1016/S0040-4039(00)84045-9
    .
  21. ^ B. Helferich: Carbonhydr. Chem. Biochem., 1948, 3, pp. 79.
  22. ^ 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.
  23. Tetrahedron Lett., 1982, 23, pp. 885–888; doi:10.1016/S0040-4039(00)86974-9
    .
  24. ^ See literature for p‑methoxybenzyl.
  25. ^ P.J. Kocieński: Protecting Groups, p. 77.
  26. J. Am. Chem. Soc., 1980, 102, pp. 7962–7965; doi:10.1021/ja00547a037
    .
  27. J. Org. Chem., 1983, 48, pp. 4785–4786; doi:10.1021/jo00172a070
    .
  28. J. Am. Chem. Soc., 1982, 104, pp. 4251–4253; doi:10.1021/ja00379a037
    .
  29. J. Am. Chem. Soc., 1983, 105, pp. 625–627; doi:10.1021/ja00341a055
    .
  30. doi:10.1111/j.1574-6968.1984.tb01309.x
    .
  31. J. Chem. Soc., Perkin Trans. 1, 1981, pp. 1796–1801; doi:10.1039/P19810001796
    .
  32. ^ Kaoru Fuji, Shigetoshi Nakano, Eiichi Fujita: "An Improved Method for Methoxymethylation of Alcohols under Mild Acidic Conditions", in: Synthesis, 1975, pp. 276–277.
  33. J. Am. Chem. Soc., 1987, 109, pp. 2523–2525; doi:10.1021/ja00242a053
    .
  34. J. Org. Chem., 1979, 44, pp. 1438–1447; doi:10.1021/jo01323a017
    .
  35. J. Am. Chem. Soc., 1978, 100, pp. 1942–1943; doi:10.1021/ja00474a058
    .
  36. Tetrahedron Lett., 1975, 16, pp. 3269–3270; doi:10.1016/S0040-4039(00)91422-9
    .
  37. J. Am. Chem. Soc., 1982, 104, pp. 6818–6820; doi:10.1021/ja00388a074
    .
  38. J. Am. Chem. Soc., 1984, 106, pp. 3869–3870; doi:10.1021/ja00325a032
    .
  39. Tetrahedron Lett., 1986, 27, pp. 445–448; doi:10.1016/S0040-4039(00)85501-X
    .
  40. Tetrahedron Lett., 1988, 29, pp. 5417–5418; doi:10.1016/S0040-4039(00)82883-X
    .
  41. J. Org. Chem., 1984, 49, pp. 3671–3672; doi:10.1021/jo00193a051
    .
  42. ^ P.J. Kocieński: Protecting Groups, pp. 59–60.
  43. ^ P.J. Kocieński: Protecting Groups, p. 62.
  44. J. Am. Chem. Soc., 1985, 107, pp. 3279–3285; doi:10.1021/ja00297a038
    .
  45. ^ András Lipták, János Imre, János Harangi, Pál Nánási, András Neszmélyi: "Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-D-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH4-AlCl3 reagent", in: Tetrahedron, 1982, 38, pp. 3721–3727; doi:10.1016/0040-4020(82)80083-5.
  46. ^ James A. Marshall, Joseph D. Trometer, Bruce E. Blough, Thomas D. Crute: "Stereochemistry of SN2' additions to acyclic vinyloxiranes", in J. Org. Chem., 1988, 53, pp. 4274–4282 doi:10.1021/jo00253a020.
  47. ^ P.J. Kocieński: Protecting Groups, p. 186.
  48. Tetrahedron Lett., 1984, 25, pp. 2093–2096; doi:10.1016/S0040-4039(01)81169-2
    .
  49. ^ P.J. Kocieński: Protecting Groups, pp. 220–227.
  50. ^ P.J. Kocieński: Protecting Groups, p. 195.
  51. J. Am. Chem. Soc., 1988, 110, p. 1547–1557; doi:10.1021/ja00213a031
    .
  52. J. Org. Chem., 1978, 43, pp. 2285–2286; doi:10.1021/jo00405a045
    .
  53. J. Am. Chem. Soc., 1992, 114, pp. 998–1010; doi:10.1021/ja00029a031
    .
  54. ^ Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis, pp. 27–30.
  55. ^ Gregg B. Fields: Methods for Removing the Fmoc Group. (PDF; 663 kB) In: Michael W. Pennington, Ben M. Dunn (eds.): Peptide Synthesis Protocols volume 35, 1995, ISBN 978-0-89603-273-6, pp. 17–27.
  56. ^ B. Liebe, H. Kunz: Festphasensynthese eines tumorassoziierten Sialyl-Tn-Antigen-Glycopeptids mit einer Partialsequenz aus dem "Tandem Repeat" des MUC-1-Mucins In: Angew. Chem. volume 109, 1997, pp. 629–631 (in German).
  57. ^ ChemPep Inc.: Fmoc Solid Phase Peptide Synthesis. retrieved 16 November 2013.
  58. ^ P.J. Kocieński: Protecting Groups, pp. 199–201.
  59. doi:10.1055/s-2006-951530
    .
  60. Tetrahedron Lett., 1980, 21, pp. 1357–1358; doi:10.1016/S0040-4039(00)74575-8
    .
  61. Chem. Lett., 1981, 10, pp. 375–376; doi:10.1246/cl.1981.375
    .
  62. Tetrahedron Lett., 1985, 26, pp. 705–708; doi:10.1016/S0040-4039(00)89114-5
    .
  63. J. Org. Chem., 1986, 51, pp. 404–407; doi:10.1021/jo00353a027
    .
  64. ^ P.J. Kocieński: Protecting Groups, S. 167–170.
  65. ^ P.J. Kocieński: Protecting Groups, pp. 176.
  66. ^ P.J. Kocieński: Protecting Groups, pp. 178–180.
  67. J. Am. Chem. Soc., 1988, 110, pp. 6890–6891; doi:10.1021/ja00228a051
    .
  68. J. Am. Chem. Soc., 1991, 113, pp. 3850–3866; doi:10.1021/ja00010a030
    .
  69. ^ P.J. Kocieński: Protecting Groups, pp. 119.
  70. Helv. Chim. Acta, 1983, 66, pp. 2501–2511; doi:10.1002/hlca.19830660815
    .
  71. Helv. Chim. Acta, 1986, 69, pp. 621–625; doi:10.1002/hlca.19860690311
    .
  72. J. Am. Chem. Soc., 1990, 112, pp. 1607–1617; doi:10.1021/ja00160a047
    .
  73. Tetrahedron Lett., 1992, 33, pp. 2565–2566; doi:10.1016/S0040-4039(00)92243-3
    .
  74. ^ G. Bauduin, D. Bondon, Y. Pietrasanta, B. Pucci: "Reactions de transcetalisation – II: Influence des facteurs steriques et electroniques sur les energies de cetalisation", in: Tetrahedron, 1978, 34, pp. 3269–3274; doi:10.1016/0040-4020(78)80243-9.
  75. J. Am. Chem. Soc., 1972, 94, pp. 7132–7137; doi:10.1021/ja00775a044
    .
  76. J. Org. Chem., 1986, 51, pp. 773–784; doi:10.1021/jo00356a002
    .
  77. ^ F. Zymalkokowski: Katalytische Hydrierung, Ferdinand Enke Verlag, Stuttgart 1965, pp. 127–133.
  78. ^ P.J. Kocieński: Protecting Groups, pp. 136.
  79. Tetrahedron Lett., 1983, 24, pp. 3573–3576; doi:10.1016/S0040-4039(00)88171-X
    (in German).
  80. J. Am. Chem. Soc., 1987, 109, pp. 287–289; doi:10.1021/ja00235a052
    .
  81. J. Am. Chem. Soc., 1975, 97, pp. 2287–2288; doi:10.1021/ja00841a058
    .
  82. Tetrahedron Lett., 1978, 19, pp. 3051–3054; doi:10.1016/S0040-4039(01)94936-6
    .
  83. ^ F. Huet, A. Lechevallier, M. Pellet, J.M. Conia: "Wet Silica Gel; A Convenient Reagent for Deacetalization", in: Synthesis, 1978, pp. 63–64.
  84. doi:10.1016/j.tetlet.2012.07.094
    .
  85. ^ P.J. Kocieński: Protecting Groups, pp. 139–142.
  86. Chem. Rev., 1996, 96, pp. 2035–2052; doi:10.1021/cr950083f
    .
  87. J. Org. Chem., 1974, 39, pp. 1426–1427; doi:10.1021/jo00926a024
    .
  88. J. Org. Chem., 1998, 63, pp. 169–176; doi:10.1021/jo9713363
    .
  89. Tetrahedron Lett., 1990, 31, pp. 6291–6293; doi:10.1016/S0040-4039(00)97045-X
    .
  90. ^ Corrado Malanga, Serena Mannucci, Luciano Lardicci: "Carbon-halogen bond activation by nickel catalyst: Synthesis of alkenes, from 1,2-dihalides", in: Tetrahedron, 1998, 54, pp. 1021–1028; doi:10.1016/S0040-4020(97)10203-4.
  91. ^ Byung Woo Yoo, Seo Hee Kim, Jun Ho Kim: "A Mild, Efficient, and Selective Debromination of vic-Dibromides to Alkenes with Cp2TiCl2/Ga System", in: Bull. Korean Chem. Soc., 2010, 31, pp. 2757–2758; doi:10.5012/bkcs.2010.31.10.2757.
  92. Chem. Rev., 1999, 99, pp. 1163–1190; doi:10.1021/cr9803840
    .
  93. Org. Lett., 2001, 3, pp. 679–681; doi:10.1021/ol0070029
    .
  94. J. Chem. Soc., Perkin Trans. 1, 2000, pp. 3555–3558; doi:10.1039/b006759h
    .
  95. ISBN 978-0-19-850346-0
    .
  96. Chem. Rev., 1967, 67, pp. 73–106; doi:10.1021/cr60245a003
    .
  97. ^ Barry J. Teobald: "The Nicholas reaction: the use of dicobalt hexacarbonyl-stabilised propargylic cations in synthesis", in: Tetrahedron, 2002, 58, pp. 4133–4170; doi:10.1016/S0040-4020(02)00315-0.
  98. Tetrahedron Lett., 1971, 37, pp. 3475–3478; doi:10.1016/S0040-4039(01)97209-0
    .
  99. J. Organomet. Chem., 1977, 125, C45–C48; doi:10.1016/S0022-328X(00)89454-1
    .
  100. Tetrahedron Lett., 1977, pp. 4163–4166; doi:10.1016/S0040-4039(01)83455-9
    .
  101. J. Organomet. Chem., 1972, 44, C21–C24; doi:10.1016/0022-328X(72)80037-8
    .
  102. PMID 17555322
    .
  103. S2CID 4357378
    .
  104. doi:10.1016/S0040-4020(01)96005-3
  105. doi:10.1016/S0040-4020(01)96006-5
  106. doi:10.1016/S0040-4020(01)96007-7
  107. Helv. Chim. Acta, 1934, 17, pp. 311–328; doi:10.1002/hlca.19340170136
    .
  108. ^ K.C. Nicolaou, E.J. Sorensen: Classics in Total Synthesis: Targets, Strategies, Methods, VCH Verlagsgesellschaft mbH, Weinheim 1996, pp. 711–729, ISBN 3-527-29284-5.
  109. ^ Peter G.M. Wuts, Theodora W. Greene: Green's Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons Inc., Hoboken, New Jersey, pp. 10–13; ISBN 0-471-69754-0.
  110. J. Am. Chem. Soc., 1993, 115, pp. 6094–6100; doi:10.1021/ja00067a026
    .
  111. doi:10.1016/0307-4412(79)90078-5
    .
  112. ^ Weng C. Chan, Peter D. White: Fmoc Solid Phase Peptide Synthesis. Reprint 2004, Oxford University Press, ISBN 0-19-963724-5.
  113. ^ Serge L. Beaucage, Radhakrishman P. Iyer: "Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach", in: Tetrahedron, 1992, 48, pp. 2223–2311; doi:10.1016/S0040-4020(01)88752-4.

Further reading

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