Carboxylic acid protection - [Bn ester] [Pfp ester] [Me ester] [Allyl ester]
[tButyl ester] [PMB ester] [MEM ester]
Amine protection (carbamates) - [Fmoc] [Boc] [Cbz] [Troc]
Side Chain protections - [Boc] (see carb. protections)


tBu - (tert-butyl) ester

Standard Protection Procedure

To a solution of the N-protected amino acid, DMAP (0.5 eq), and tBuOH (1.2 eq) in dry DCM at 0° under an inert atmosphere, is added EDCI (1.1. eq) and stirred for 2 h.  The mixture is then stirred at room temperature until complete by TLC (usually 14 h) and concentrated in vacuo.  The residue is redissolved in ethyl acetate and extracted twice with water, then twice with aqueous saturated sodium bicarbonate.  The organic solution is dried (magnesium sulfate) and concentrated in vacuo.  The residue is purified by flash chromatography (SiO2) if necessary.
Removal
The compound is dissolved in formic acid and stirred at room temperature until the reaction is complete by TLC (usually 12 hours).  The solution is then concentrated and coconcentrated several times with toluene.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
References
    J. Chem. Soc., Perkin Trans. 1, 1996, 985-993.
    JOC, 1982, 47, 1962-1965.
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Bn - (benzyl) ester

Standard Protection Procedure

The amino acid is stirred with dry THF and O-benzyl-N,N'-diisopropylisourea (see ref. for synthesis) at room temperature under an inert atmosphere until complete by TLC (usually 2 days).  The mixture is cooled to -20 C and filtered.  The filtrate is concentrated in vacuo and purified by flash chromatography (SiO2) if necessary.
Removal
The amino acid derivative is dissolved in 1:1 methanol:t-butanol and Pd(OH)2-C is added under a hydrogen atmosphere.  The mixture is  allowed to stir until complete by TLC (usually >3 h), then filtered and concentrated.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
References
    Macromolecules, 1978, 534-539.
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Allyl - (allyl) ester

Standard Protection Procedure

The compound is dissolved in dry DCM and allyl alcohol (1.1 eq) is added.  The solution is stirred under an inert atmosphere at 0° and dicyclohexylcarbodiimide (1 eq) is added followed by 4-N,N-dimethylaminopyridine (0.05 eq).  The reaction is allowed to warm to room temperature and is stirred until complete by TLC (usually 1-2 days).  Ethyl acetate is added and the resulting precipitate is removed by filtration.  The filtrate is concentrated in vacuo and purified by flash chromatography (SiO2) if necessary.
Removal
The amino acid and pyrrolidine (1.2 eq) are dissolved in methylene chloride and cooled to -15°.  Triphenylphosphine (0.2 eq) and Tetrakis(triphenylphosphine)palladium (0) (0.05 eq) are added and stirred under an inert atmosphere for approx. 1 h.  Water and acetonitrile are added and the resulting mixture is extracted twice with petroleum ether.  The acetonitrile layer is evaporated and purified by flash chromatography (SiO2) if necessary.
References
    Tetrahedron, 1996, 52, 12839-12852.
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PfP - (pentafluorophenyl) ester

Standard Protection Procedure

The acid is dissolved in ethyl acetate and pentafluorophenol (1.2 eq) is added.  The solution is cooled to 0° and DCC (1.2 eq) is added.  The reaction is allowed to warm to room temperature and stir until complete by TLC (usually overnight, if not complete more DCC may be added).  The solution is then filtered through celite, rinsed several times with EtOAc, and concentrated in vacuo.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
References
    J. Chem. Soc., Perkin Trans. 1, 1996, 985-993.
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Me - (methyl) ester

Standard Protection Procedure

The compound is dissolved in dry MeOH and thionyl chloride (2 eq) is added drop wise at 0° under an inert atmosphere.  The result is then refluxed until complete by TLC (usually >4 hours) and concentrated in vacuo.  The residue can then be purified by flash chromatography (SiO2) if necessary.
Removal
The ester is dissolved in methanol and 1N NaOH is added (excess).  The solution is then heated to reflux and stirred until complete by TLC (usually <1 h).  Glacial acetic acid is added until the mixture is neutral and then diluted with chloroform.  The organic solution is extracted once with water, once with brine, dried (magnesium sulfate), and concentrated in vacuo.  The residue is purified by flash chromatography (SiO2) if necessary.
References
    Eur. J. Org. Chem. 1999, 1127-1135.
    JOC, 1995, 60, 2318-2319.
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PMB - (para-methoxybenzyl) ester

Standard Protection Procedure

The acid is dissolved in dry DCM and 4-methoxybenzyl alcohol (1.1 eq) is added.  The solution is stirred under an inert atmosphere at 0° and dicyclohexylcarbodiimide (1 eq) is added followed by 4-N,N-dimethylaminopyridine (0.05 eq).  The reaction is allowed to warm to room temperature and is stirred until complete by TLC (usually 1-2 days).  Ethyl acetate is added and the resulting precipitate is removed by filtration.  The filtrate is concentrated in vacuo and purified by flash chromatography (SiO2) if necessary.
Removal
The ester is dissolved in phenol and TFA (1-2 eq) is added under an inert atmosphere at 45°.  The reaction is stirred until complete by TLC (usually <2 h) and ethyl acetate/water are added.  The aqueous layer is extracted 2 times with EtOAc and the organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 1 with 10% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo.  The residue is then purified by flash chromatography (SiO2) if necessary.
References
    Tetrahedron, 1996, 52, 12839-12852.
    Tetrahedron Lett. 1990, 31, 6661-6662.
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MEM - (methoxyethoxymethyl) ester

Standard Protection Procedure

To compound dissolved in a saturated aqueous sodium bicarbonate solution at room temperature, TBAI (1 eq) and methoxyethyloxymethyl chloride (1.2 eq) are added.  The reaction is stirred until complete by TLC (usually 16 h) and dichloromethane is added.  The organic layer is washed with water, dried (sodium sulfate), and concentrated in vacuo.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
Removal
The ester is dissolved in DCM and magnesium bromide etherate (excess) is added at room temperature under an inert atmosphere.  The mixture is stirred for 48 h and water is added.  The slurry is stirred vigorously for another 2 h and 1N aqueous hydrochloric acid is added until the pH is 1-2.  The mixture is extracted with ethyl acetate three times and the combined organic layers are dried (sodium sulfate), then concentrated in vacuo.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
References
    JOC, 1994, 59, 2314-2323.
    Synthesis, 1979, 957-961.
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Boc - (tButyloxy) carbamate

Standard Protection Procedure

The amine is dissolved in water and sodium bicarbonate (2 eq) is added with stirring.  The resulting solution is cooled to 5° and BOC anhydride (1.5 eq) is added slowly as a solution in para-dioxane (also cooled).  The resulting mixture is stirred at 0° for 1 h and allowed to warm to room temperature overnight.  Water is then added and the aqueous layer is extracted 2 times with EtOAc.  The organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 1 with 10% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
Removal
The compound is dissolved in 1:1 trifluoroacetic acid:water and stirred at room temperature until complete by TLC (usually <2 h).  The solution is concentrated in vacuo and purified by flash chromatography (SiO2) if necessary.
References
    Organic Synthesis, 1999, 76, 57-76.
    Novabiochem Catalog, 2002-2003, pg 2.64-2.65.
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Fmoc - (9-fluorenylmethyl) carbamate

Standard Protection Procedure

The amine is dissolved in water and sodium bicarbonate (2 eq) is added with stirring.  The resulting solution is cooled to 5° and Fmoc-OSu or Fmoc-Cl (1.5 eq) is added slowly as a solution in para-dioxane (also cooled).  The resulting mixture is stirred at 0° for 1 h and allowed to warm to room temperature overnight.  Water is then added and the aqueous layer is extracted 2 times with EtOAc.  The organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 1 with 10% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo. The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
Removal
The compound is dissolved in a solution of 20% piperidine in DMF.  The mixture is stirred for 30 minutes at room temperature and concentrated in vacuo. The residue can then be purified by flash chromatography (SiO2) if necessary.
References
    J. Am. Chem. Soc., 1997, 4, 656-673.
    Novabiochem Catalog, 2002-2003, pg 2.64-2.65.
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Alloc - (allyl) carbamate

Standard Protection Procedure

The amine is dissolved in water and sodium carbonate (2.7 eq) is added with stirring.  The resulting solution is cooled to 5° and allyl chloroformate (1.5 eq) is added slowly as a solution in para-dioxane (also cooled).  The resulting mixture is stirred at 0° for 1 h and allowed to warm to room temperature overnight.  Water is then added and the aqueous layer is extracted 2 times with EtOAc.  The organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 1 with 10% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo.  The resulting residue can then be purified by flash chromatography (SiO2) if necessary.
Removal
The amine is dissolved in dry THF and dimethylmalonate (7 eq) followed by tetrakistriphenylphosphine palladium (0.02 eq) are added at room temperature under an inert atmosphere.  The reaction is stirred until complete by TLC (usually 24 h) and filtered.  The solution is then concentrated in vacuo and the resulting residue is purified by flash chromatography (SiO2) if necessary.
References
    Tetrahedron, 1996, 39, 12839-12852.
    Tetrahedron Lett. 1986, 23, 2599-2602.
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Troc - (trichloroethyl) carbamate

Standard Protection Procedure

The amine is dissolved in water and sodium bicarbonate (2 eq) is added with stirring.  The resulting solution is cooled to 5° and Troc-OSu or Troc-Cl (1.5 eq) is added slowly as a solution in para-dioxane (also cooled).  The resulting mixture is stirred at 0° for 1 hour and allowed to warm to room temperature overnight.  Water is then added and the aqueous layer is extracted 2 times with EtOAc.  The organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 3 with 5% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo.  The resulting residue is purified by flash chromatography (SiO2) if necessary.
Removal
The carbamate is dissolved in glacial acetic acid:THF 1:1 and zinc dust (excess) is added.  The resulting suspension is stirred at room temperature until complete by TLC (usually <3 h).  The mixture is then filtered, concentrated in vacuo and redissolved in chloroform.  The solution is washed once with 5% aqueous sodium bicarbonate, dried (sodium sulfate), and concentrated in vacuo.  The resulting residue is purified by flash chromatography (SiO2) if necessary.
References
    Can. J. Chem. 1982, 60, 976.
    Synthesis, 1983, 671.
    JOC, 1988, 53, 3108.
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Cbz - (benzylcarboxy) carbamate

Standard Protection Procedure

The amine is dissolved in water and sodium bicarbonate (2 eq) is added with stirring.  The resulting solution is cooled to 5° and Cbz-OSu or Cbz-Cl (1.5 eq) is added slowly as a solution in para-dioxane (also cooled).  The resulting mixture is stirred at 0° for 1 h and allowed to warm to room temperature overnight.  Water is then added and the aqueous layer is extracted 2 times with EtOAc.  The organic layer is back extracted twice with saturated sodium bicarbonate solution.  The combined aqueous layers are acidified to a pH of 1 with 10% HCl, then extracted 3 times with EtOAc.  The combined organic layers are dried (sodium sulfate) and concentrated in vacuo.  The resulting residue is purified by flash chromatography (SiO2) if necessary.
Removal
The amino acid derivative is dissolved in 1:1 methanol:t-butanol and Pd(OH)2-C is added under a hydrogen atmosphere.  The mixture is  allowed to stir until complete by TLC (usually >3 h) then filtered and concentrated in vacuo.  The resulting residue is purified by flash chromatography (SiO2) if necessary.
References
    Tetrahedron Lett. 1966, 7, 4765-4768.
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tBu - (tert-butyl) ether

Standard Protection Procedure

See: JOC,1975, 6, 675-681 for general procedure.
Removal
The ether is dissolved in 1:1 trifluoroacetic acid:water and stirred at room temperature until the reaction is complete by TLC (usually <2 h).  The solution is concentrated and purified by flash chromatography (SiO2) if necessary.
References
    JOC,1975, 6, 675-681
    Novabiochem Catalog, 2002-2003, pg 2.64-2.65.
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