Amino acids stereogenic center

En route to a total synthesis of an antibacterial natural product indolmycin which contains an amino-substituted oxazolone, a-hydroxy acid 254 was treated with guanidine and KOr-Bu in /-BuOH in the presence of 4 A molecular sieves to produce oxazolone 255 with minimal epimerization of the acidic stereogenic center (Scheme 75) <2001CPB1604>. 

The related 2-/-butyl derivative has also been prepared and used to advantage as a temporary protective group for the stereogenic center of amino acids during alkylations. ... 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

The use of enantiomerically pure (R)-5-menthyloxy-2(5.//)-furanone results in lactone enolates, after the initial Michael addition, which can be quenched diastereoselectively trans with respect to the /J-substituent. With aldehydes as electrophiles adducts with four new stereogenic centers arc formed with full stereocontrol and the products are enantiomerically pure. Various optically active lactones, and after hydrolysis, amino acids and hydroxy acids can be synthesized in this way317. 

Stereoselechve follow-up reactions of non-racemic cyanohydrins enable the synthesis of many other classes of important compounds with one or more stereogenic centers, such as 2-hydroxycarboxylic acids, 2-amino acids, etc. (Scheme 3). ... 

For a facial selective assembly ofthe stereogenic centers and the introduction of the amino functionality, chiral nitrogen-containing reagents, such as benzyl(2-pheny-lethyl)amine (2-19) and trimethylsilyl RAMP derivative 2-24 were applied. Treatment of diacrylates 2-18, 2-21, and 2-23 with 2-19 and 2-24, respectively, gave the protected amino acids 2-20, 2-22, and 2-25 in good yields as single isomers. 

WIN 64821 (10) and (—)-ditryptophenaline (11) syntheses [7], not only effectively differentiated the two amide moieties but also most importantly marked the first in a series of stereochemical transfer steps in which the stereochemistry of the constituent L-amino acids was relayed to ultimately define each of the relative and absolute stereochemical configurations at all eight stereogenic centers found in the target compound. Finally, /V-methylation of the base-sensitive amide in 77 % yield using methyl iodide and potassium carbonate in acetone completed the 5-step synthesis of our key tetracyclic bromide monomer starting from commercially available amino acid derivatives. 

Some generic structures of /3-amino acids are shown in Fig. 6.40. Since, in /3-amino acids, two C-atoms separate the amino and carboxylate groups, there are two possible locations for attachment of a single side chain (i.e., /32 and /33), or even two or more side chains (e.g., /32,3 and /32,2,3, respectively). In a /3-peptide, these symbols can be used as prefixes, e.g., the /33/32-dipeptide in Fig. 6.40 becomes /33-HAla- /32-HVal for R=Me and R = i-Pr. The stereodescriptors (R) and (S) should be used to specify the absolute configuration at the stereogenic centers. The same rules apply to y-amino acids and y-peptides. 

By employing A-acetamidoacrylates, rhodium-catalyzed 1,4-addition reactions can be applied to the enantioselective synthesis of a-amino acids. Unlike other typical 1,4-addition reactions, which install a stereogenic center at the p-position of the 1,4-adducts, this process deals with the formation of a stereocenter at the a-position, and thus the protonation (hydrolysis) step becomes an important step... 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

Moloney and co-workers (64) also made use of the morpholinone template in the synthesis of analogues of the kainoid group of amino acids. Treatment of the template under the conditions reported by Harwood furnished the expected adducts. In keeping with earlier observations, the reaction proceeded with complete facial selectivity generating the new C(3) stereogenic center with complete control. 

Hydroxy acids provide characteristic mono or diol synthons whereas amino acids are the natural source for 1,2-amino alcohol fragments. A stereogenic center in either configuration, with methyl brandling, may be obtained from (S)-3-hydroxy-2-methylpropanoic acid, whereas quaternary dimethyl-substituted carbons with adjacent stereogenic centers are available from the degradation of camphor or a-pincnc. 

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