Alkylation of amino acid

Modica, E. Zanaletti, R. Freccero, M. Alkylation of amino acids and glutathione in water by o-quinone methide. Reactivity and selectivity. J. Org. Chem. 2001, 66, 41-52. 

Belokon et al. (261) subsequently found that salen-Cu(II) complexes are effective catalysts for the asymmetric alkylation of amino acid derivatives. Excellent se-lectivities are observed with 1 mol% of 88b-Cu in toluene at ambient temperature, Eq. 225. Although no stereochemical model is advanced to account for the selec-tivities, these workers suggest the catalyst may be acting as a chiral phase-transfer agent. 

Lipo-amino acid derivatives are readily obtained in good yields by direct alkylation of amino acids esters with the related alkyl halides, e.g. farnesyl bromide, under careful control of the reaction conditions to avoid exhaustive alkylation of the amino group. 128 Alternatively, peptoid chemistry is applied for N-alkylation of glycine ester via reaction of alkyl amines, e.g. hexadecylamine, with ethyl bromoacetate. 36,98 ... 

Reductive Alkylation of Amino Acids and Their Derivatives... 

A variety of monomers for PNA have been prepared. 126 These monomers are based on A -(2-BocNH-ethyl) amino acid esters, which were prepared by reductive alkylation of amino acid benzyl esters with BocNHCH2CHO. 

Pivaldehyde, (CH3)3CCHO (1), Mol. wt. 86.13, m.p. 6°. Supplier Aldrich, Fluka. a-Alkylation of amino acids.12 The N-methyl amide (2) of an a-amino acid... 

These products (4) can be used to effect a-alkylation of amino acids with retention or inversion of configuration. Thus either (S)- or (R)-a-methyldopa (6) can be prepared from (S)-alanine, as shown in equations (I) and (II). 

Alkylation of amino acids.1 This base is preferable to LDA for dideprotonation of di-f-butyl N-formylaspartate (1) to give 2. The dianion is alkylated by CH3I, CH2 CHCH2Br, and C6H5CH2Br to give a mixture of / - and a-alkylated aspartate derivatives (3 and 4) in a ratio of ca. 7 2. As expected, the /3-alkylated a-amino acid esters 3 are optically pure surprisingly, the products 4 are also optically active and, after crystallization, can be obtained in optical yields of 60%. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

In an attempt to develop a PEG-supported version of a chiral phase-transfer catalyst the Cinchona alkaloid-derived ammonium salt 15 used by Corey and Lygo in the stereoselective alkylation of amino acid precursors was immobilized on a modified PEG similar to that used in the case of 13. The behaviour of the catalyst obtained 16, however, fell short of the expectations (Danelli et al. 2003). Indeed, while this catalyst (10 mol%) showed good catalytic activity promoting the benzy-lation of the benzophenone imine derived from tert-butyl glycinate in 92% yield (solid CsOH, DCM, -78 to 23 °C, 22 h), the observed ee was only 30%. Even if this was increased to 64% by maintaining the reac-... 

Alkylation of amino acids has also been achieved by first foiming heterocyclic derivatives. For example, the oxazolidinone fitrni CBZ-phoiylalanine and foimalddtyde reacts with potassium hexar methyldisilazide followed 1 allyl bnxnide to give the expected product in 76% yield.Chiral tetrahy-dro-l,4-oxazin-2-oiies have be used in a similar manna to give amino acids with a degree of diastereoselectivity. ... 

Methylation of diamines with formaldehyde and formic acid yields the tetramethyl derivatives, e.g., tetramethyldiaminobutane (92%). In most instances, alkylation of amino acids by this same combination gives complex products, although a-dimethylaminobutyric acid can be made from the corresponding a-amino acid in 80% yield. Reaction of the readily available amino alcohols like N-raethylethanolamine and 2-isopropylamino-ethanol gives the N,N-dialkyl derivatives. ... 

Recently silicon-based protection has matured into a new Ix oad area of protecting group chemistry (see Section 3.1.3.2) and amines can also be conveniently blocked with appropriate silicon reagents. In organometallic syntheses, e.g. in the alkylation of amino acid enolates, the so-called stabase adducts (30) serve to temporarily protect the a-amino group (Scheme 21). In the absence of hard nucleophiles, in particular of 0-nucleophiles, the Si—N bonds are stable, but deprotection is readily effected in the presence of water and acids. 

Ramanjulu, J. M., Joullie, M. M. N-alkylation of amino acid esters using sodium triacetoxyborohydride. Synth. Commun. 1996, 26,1379-1384. 

The advent during the early 1990s of the O DonneU-Corey-Lygo protocol for the highly enantioselective alkylation of amino acids imines under PTC conditions, catalyzed by quaternized cinchona alkaloids, led to a series of investigations on the use of supported catalysts in these reactions [15]. 

An efficient one-pot protocol has been developed for the solution-phase synthesis of thiohydantoins (Scheme 4) [10]. After reductive alkylation of amino acid esters 16, the isothiocyanate was added together with triethylamine, leading to thiohydantoin products 18. The work-up procedure was performed by adding gly-... 

Scheme 10.17 Insoluble supports for chiral PTC and their use in the alkylation of amino acids imines.

Very strong uncharged polyaminophosphazene bases with good chemical and thermal stability, their pKa ranging from 24 to 47 in the absolute MeCN scale and relatively non-nucleophilic. Useful in alkylation of enolates, in enantioselective a-alkylation of amino acids, in Ullmann synthesis. 

The ferrocenylmethy1 group, which can be introduced by catalytic reductive alkylation of amino acids or amino acid esters... 

Alkylation of amino acids. A general method for indirect alkylation of glycine involves preparation of the Schiflf base 1, which is an active methylene compound. This imine can be alkylated under the usual phase-transfer conditions to give... 

Because of the good nucleophilicity of amines, alkylation of amino acids is an important widespread reaction in both organic and biological systems. A simple methylation may proceed as follows ... 

Seebach D, Wasmuth D. Alkylation of amino acids without loss of optical activity a- and p-alkylation of an aspartic acid derivative. A/jgcw. Chem. Int. Ed. 1981 93 1007-1008. 

Seehach D, Boes M, Naef R, Saweizer WB. Alkylation of amino acids without loss of the optical activity preparation of a-substituted proUne derivatives. A case of selfreproduction of chirahty. 7. Am. Chem. Soc. 1983 105 5390 5398. 

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