Synthesis of Enantiomerically Pure Amino Acids

The reductive radical alkylation of oxazines using triethylborane as reagent or catalyst (Scheme 8) is also applicable to dihydrooxazines, and can be performed stereoselectively <2003CC426, 2005jOC3324>. This gives the reaction importance in the synthesis of enantiomerically pure amino acids, and it is discussed further in Section 8.06.11.3. 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

Among the principal methods for the enzymatic synthesis of enantiomerically pure amino acids depicted in Scheme 2.10, the most widely applied strategy is the resolution of racemic starting material (synthetically prepared from inexpensive bulk chemicals) employing easy-to-use hydrolytic enzymes such as proteases, esterases, and lipases. In contrast, more complex procedures requiring special expertise are the (1) reductive amination of a-keto acids using a-amino acid... 

Synthesis of Enantiomerically Pure Amino Acids CHAPTER 26... 

Babad H, Zeiler AG (1973) Chemistry of phosgene. Chem Rev 73(1) 75-91 Norwich JS, Powell NA, Nguyen TM, Noronha G (1992) An improved method for the synthesis of enantiomerically pure amino acid estta- isocyanates. J Org Chem 57(26) 7364— 7366... 

Birchall, A.C. and North, M. (1998) Synthesis of highly branched block copolymers of enantiomerically pure amino acids, Chem. Commun. 1335-1336. 

A general approach to the synthesis of enantiomerically pure y, as weU as y " -amino acids has been developped by Brenner and Seebach [206, 207, 230]. It involves the Michael addition of Ti-enolates generated from acyl-oxazohdin-2-ones to nitroolefms in the presence of a Lewis acid (TiCU, Et2AlCl) as the key step... 

Synthesis of Enantiomerically Pure p-Amino Acid from 2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1 H)-pyrimidinone (S)-p-Tyrosine-O-methyl Ether. 

Since the migrating group retains its configuration, the use of enantiomerically enriched oximes provides a direct entry to enantiomerically pure lactams. These lactams may be used as a key building block for the synthesis of diverse compounds. Westermann and Gedrath applied this strategy to the stereoselective synthesis of enantiomerically pure o-.a-disubstituted a-amino acids (equation 135), bicyclic lactams and the spirocyclic framework of Histrionicotoxins (equation 136). 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Discussion Amino acids are often utilized as sources of chiral information in the synthesis of enantiomerically pure products. In the present synthesis, however, it is the abnormal enantiomer tf-prolinc that is required, a compound 14 times as expensive as the natural 5 enantiomer. 

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached > 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

The asymmetric alkylation of cyclic ketones, imines of glycine esters, and achiral, enolizable carbonyl compounds in the presence of chiral phase-transfer organoca-talysts is an efficient method for the preparation of a broad variety of interesting compounds in the optically active form. The reactions are not only highly efficient, as has been shown impressively by, e.g., the synthesis of enantiomerically pure a-amino acids, but also employ readily available and inexpensive catalysts. This makes enantioselective alkylation via chiral phase-transfer catalysts attractive for large-scale applications also. A broad range of highly efficient chiral phase-transfer catalysts is also available. 

Glycosylamines were shown efficient stereodifferentiating templates in the synthesis of enantiomerically pure P-amino acids. They react with silylketene acetals and zinc(II) chloride as the promoting Lewis acid via a Mannich-type pathway to give P-amino acid esters 12 in high yields and high diastereoselectivity [26], (Scheme 9). 

The enantioselective hydrogenation of a-(acylamino)acrylic acids (Figure 14.67) is mainly used for the preparation of R- (unnatural) and -configured (natural) amino acids. Such enantiomerically pure amino acids are needed, among others, for the synthesis of peptide-based antibiotics and peptide mimetics. 

The diversity-oriented synthesis of enantiomerically pure seven- and eight-membered ring systems was reported from easily accessible naturally occurring. Y-amino acids and their readily prepared derivatives as chiral synthons <2007JC0321>. Intramolecular Mitsunobu reaction was used as a key transformation to construct the 1,4-diazocines 224 (Scheme 27) and 1,4-oxazocines 225 (Scheme 28) <2007JC0321>. 

SYNTHESIS OF ENANTIOMERICALLY PURE 0-AMINO ACIDS FROM 2-tert-BUTYL-1 -CAR BOM ETHOXY-2,3-DIHYDRO-4(1H)-PYRIMIDI NONE ... 

Recently, we have demonstrated that 3 functions as an attractive chiral auxiliary for the synthesis of scalemic a-substituted carboxylic acids.22 In addition, we have extended the scope of the (3-amino add synthesis to include alkyl groups through a protected derivative of heterocycle 3.23 Thus, a unified approach to the synthesis of enantiomerically pure p-amino acids has been developed from 3. Recent efforts by Seebach, Juaristi, and co-workers24 on a saturated analog of 3 have developed routes to products substituted at Cs (a to the carbonyl). 

The product imine diastereomers can usually be separated by chromatography, which enables synthesis of enantiomerically pure a-amino acids even if the reaction is not completely diastere-oselective, and provides an alternative to the resolution of racemic a-amino acids. The imine is cleaved by mild hydrolysis with aqueous citric acid or by reaction with hydroxylammonium acetate. 

A new synthesis of enantiomerically pure 2-amino-3-phenyl-l-cyclopropane-phosphonic acid, a constrained analogue of phaclofen (267), has been described. The sulfoxide (268) of (S) configuration was found to undergo cyclopropanation... 

The transition metai cataiyzed Overman rearrangement allows the reaction to take place at or around room temperature, so thermally sensitive substrates can be used. In the laboratory of M. Mehmandoust, this approach was applied for the synthesis of enantiomerically pure ( )- 3,y-unsaturated a-amino acids, which are potent enzyme inhibitors. ° The trichloroimidate substrates were derived from optically pure monoprotected diallylalcohols and were exposed to 10 mol% of Pd " -salt. The rearrangements took place rapidly at room temperature with complete transfer of chirality. 

In order to use fluorinated amino acids to study biological systems, they need to be synthesized and incorporated. Despite the challenges in both steps, there are several methods available. For instance, enantiomerically pure fluorinated amino acids may be prepared by asymmetric synthesis or by stereochemical resolution using enzymatic methods [48], Fluorinated amino acids can be introduced into proteins biosynthetically, or chemically by SPPS. Several reviews that detail the synthesis of enantiomerically pure fluorinated amino acids and incorporation methods into proteins are available [48-51],... 

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