Diastereoisomerism amides

The [2 + 2] cycloaddition reaction of A -benzyl-l,4-dihydropyridine 34b with acrylonitrile, followed by catalytic reduction gave two pairs of diastereoisomeric amides 36 and 37 with a low diastereomeric excess, probably due to the large distance between the asymmetric center and the site of acrylonitrile attack. Compounds 36 and 37 were resolved into the four individual diastereoisomers (ca 5% for compound 36 and 15% for 37) [97JCR(M)321], Irradiation of 1,4-dibenzyl-1,4,5,6-tetrahydropyridine 38 in the presence of 29 gave two stereoisomers. 

The configuration of the asymmetric center in the prolyl moiety is homochiral S and the racemic amphetamine (R and S) yields diastereoisomeric amides S,R and S,S. Thus, these amides have the same configurations (5) at the center originating from the prolyl moiety, and differing configuration at the chiral center originating from heterochiral amphetamine. A similar derivatization procedure with A-trifluoroacetyl-5-prolyl chloride is used in GC to form diastereoisomeric amides. The A-TFA moiety imparts volatility and electron capture detectability to the derivatives for GC analysis.f ... 

Various methods for the preparation of enantiomerically pure P4-P3 mimetics had been published before this work. Among these were the classical co-crystallization with chiral amines [7, 8], the derivatization as diastereoisomeric amides [6, 9, 10], the synthesis of chiral intermediates following Evans methodology [10-12], or the use of lipase-catalyzed reactions [13], and the asymmetric hydrogenation of unsaturated derivatives [8, 14],... 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

Both, diastereoisomeric P-substituted a-amino acid derivatives could be formed selectively, depending on the cation provided by the base. The (R,S)-diastereoisomer was the major product with a Hthium amide, whereas the... 

The imidazopyridine 123 was synthesized by treating amino acid 122 with p-toluenesulfonyl cyanide and DCC. The yield of 123 was lower (38%) when the mtinchnone was generated with mesyl chloride (72). The minor amide product 124 is proposed to arise from the diastereoisomeric mtinchnone adduct that undergoes fragmentation rather than decarboxylation. 

The first synthesized concave bases, the concave pyridine bislactames 3 (Structures 1), possess two amide groups in each molecule. The rotational barrier for a carboxamide bond is ca. 75 kJ/mol [12b, 19]. Therefore at room temperature, E-and Z-forms are observed in the NMR spectra. Because each concave pyridine bislactame 3 contains two amide groups, diastereoisomeric conformers are observable (see Fig. 2). Structures 5 show the ZZ-, EZ- and -conformers for the concave pyridine 3c. 

The first examples of the diastereoselective aminohydroxylation of chiral acryl amides, R3CH=C(R2)CONHCH (Me)R1, have been reported. The reaction is believed to proceed within the so-called second catalytic cycle with diastereoisomeric excesses (g) reaching >99 1. The reaction relies solely on the stereochemical information provided by the enantiomerically pure starting materials. A stereochemical model for the observed asymmetric induction has been proposed.128... 

The principles outlined above were allied by Marckwald and McKenzie 18 for the partial resolution of a racemic acid with an active alcohol. Thus When df-mandelic acid was heated with less than one equivalent of 1-menthol, the resulting ester contained somewhat more J-menthyl-d-mandelate than f-menthyl-L-mandelate and the unesterified acid contained a corresponding excess of i-mandelic acid. Also, when a mixture of equal amounts of the two diastereoisomeric esters was partially hydrolyzed, the regenerated acid and that still combined in the residual ester contained unequal amounts of the two antipodes. The process has been extended to the resolution of acids and amines through the formation and hydrolysis of amides.89... 

With the use of a family of three structurally related cyclic phosphoric acids (P-mix) as resolving agent, a diastereoisomerically pure salt containing the (25,5R)-enantiomer in 99% ee precipitates. The resolved t/ rc< -(4-methylthiophenyl)serine amide (Figure 7.5) can be used as an intermediate in the synthesis of thiamphenicol.22 Note that the individual phosphoric acids give salts of lower... 

The high-yield synthesis of the racemate via a Strecker synthesis is elegantly combined with the asymmetric transformation process. Addition of the resolving agent (S)-mandelic acid results in the formation of both diastereoisomeric salts. In the presence of benzaldehyde these salts are in equilibrium with the Schiff base, which racemizes readily. The low solubility of the diastereoisomeric salts (in apolar solvents) eventually allows obtainment of a >95% yield of the (/f) (.S )-salt in more than 99% diastereoisomeric excess. After decomposition of this salt by hydrochloric acid, pure (Ah-phenylglycine amide is obtained, and the resolving agent can be recycled. 

As a second example, we recently used the readily available (W)-phenylglycine amide as a Chirality Transfer reagent (see Chapter 25).43 In this case, a Strecker reaction is performed on pivaldehyde under equilibrium conditions resulting in two covalent diastereoisomeric products (Scheme 7.9). The lower solubility of the (.S. /H-diastereoisomer results in transformation of the (R,/H-diastereoisomer into the (.S. /H-diastereoisomer in 93% yield and >99% diastereoselectivity. 

The catalyst is a cationic complex of rhodium with another diphosphine, DIPAMP. DIPAMP s chirality resides in the two stereogcnic phosphorus atoms unlike amines, phosphines are configurationally stable, rather like sulfoxides (which we will discuss in the next chapter). The catalyst imposes chirality on the hydrogenation by coordinating to both the amide group and the double bond of the substrate. Two diastereoisomeric complexes result, since the chiral catalyst can coordinate to either of the enantiotopic faces of the double bond. 

FIGURE 2. mPWlK/6-31+G(d) optimized THF-solvated diastereoisomeric TSs for deprotonation of 1 with lithium amide 4... 

The enhanced reactivity of chelated amino acid esters towards attack by other nucleophiles has been used to advantage in the sequential synthesis of small peptides equation (4l).225 Formation of the amide bond takes only seconds to minutes at room temperature in DMSO as solvent, and the peptide can be easily recovered by reducing the metal to the Co" state. Recent studies have shown that the A and A diastereoisomeric reactants are selective in their couplings to (2 ) and (S) amino acid esters and that mutarotation at the asymmetric centre of the chelated ester reactant varies from 0-6%.226 Isied and coworkers have described the use of the Co(NH3)3+ as a C-terminal protecting group for the sequential synthesis of peptides (equation 42).227 This procedure has advantages over other methods in some cases. 

The reaction of W,W-bis(methoxyethyl)amide 169 with phenyldimethylsilyllithium gave the normal product 171, small amounts of the elimination product 173, and the diastereoisomeric pyrrolidines 174. These products can be accounted for by proton transfer in 170, presumably intramolecular, followed by displacement of the phenyl group 172— 174 or/3-elimination 172—>173. 

The determination of the enantiometric purity of optically active carboxylic acids and amino acids is important not only for an evaluation of their asymmetric syntheses, but optical resolution of racemic modifications of chiral carboxylic acid derivatives and chiral amino acids is also industrially important. A separation on both an analytical and a preparative scale of the racemically modfied and commercially available carboxylic acids 21a-24a and amino acids 25a-27a was attempted by utilizing (4/ ,5S)-MPOT (5). The condensations between 5 and the carboxylic and amino acids 21a-27a were carried out as usual to afford the corresponding 3-acyl-(4/ ,5S)-MPOT derivatives 21b-27b. Their analytical separation was readily achieved by HPLC. H-NMR techniques can also be useful for the analysis of the diastereoisomeric ratio of amides 21b-27b. 

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