Chiral compounds, Amino acids Esters

Alkylation of a-amino esters with 9-bromo-9-phenylf uorene serves as the principal step in the preparation of N-(9-phenylfluoren-9-yl)-a-amino carbonyl compounds which are useful chiral educts for asymmetric synthesis. A discussion of the synthetic utility of N-9-phenylfluoren-9-yl derivatives of amino adds and amino acid esters appears in the procedure following. 

Chiral discrimination between enantiomeric amino-acid />-nitrophenyl ester hydrobromides in addition to enhanced rate of transacylation were reported by Chao and Cram (1976) for chiral 3,3 -Ws(mercaptomethyl)dinaphthyl-20-crown-6 [323]. Compared with a non-cyclic reference compound (5)-[324] the rates for a series of amino-acid esters are enhanced by factors of 102 to 103, except for L-proline. This once more demonstrates that reaction takes place in... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

The lithium derivatives described above react with electrophiles such as alkyl halides, carbonyl compounds, and thiocarbonyl compounds, resulting in the corresponding 3-substituted derivatives (190). Hydrolysis of these products by dilute acid as described in Section B,1 gives the new nonproteinogenic amino acid ester (191) along with the original amino acid ester used as the chiral auxiliary. The chemical yields are above 80% (83MI1). 

The requisite hydroxylamine function for such cyclizations can also be generated from a precursor having a nitro group. This novel route has provided access to hitherto unknown l-hydroxy-6-allyl-, and -6,6-bisallyl-piperazine-2,5-diones (91UP1). The starting material is an W-nitroacetyl amino acid ester that can be either mono-or bis-allylated at the methylene adjacent to the nitro group. Reduction of the N02 to NHOH using zinc/ ammonium chloride, followed by cyclization, leads to the desired products (Scheme 76). Compound (215) is unique in that it possesses a chiral center at C-3 and a quaternary carbon at C-6 on a l-hydroxypiperazine-2,5-dione system. 

The resolution of optically active compounds by gas chromatography with chiral phases is a well-established procedure, and the separation of IV-perfluoro-acetylated amino acid ester enantiomers in 1967 was the first successful application of enantioselective gas-liquid chromatography [39] Amino acids have been resolved as their A-trifluoroacetyl esters on chiral diamide phases such as N-lauroyl-L-valine rerr-butylamide or iV-docosanoyl-L-valine fert-butylamide [40,41,... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Many of the chiral molecules containing amide groups were bonded to a solid support for the preparation of CSPs [16-19]. The racemic compounds resolved on these CSPs include a-hydroxycarbonyls, /i-hydroxycarbonyls, amino acids, amino alcohols, amine, and derivatized and underivatized diols. The preliminary chiral diamide phase [(/V-foriuyl-L-valyl)aminopropyl)silica gel] has sufficient separability for racemic /Y-acylatcd a-amino acid esters but not in other types of enantiomer [16]. Most of the eluents used with these CSPs are of normal phase mode, including w-hcxanc, 2-propanol, chlorinated organic solvents, and acetonitrile. 

Chiral homoallylamines are valuable intermediates for the preparation of compounds such as amines, P-amino acids, 1-amino-3,4-epoxides, and 1,3-amino alcohols.24 High 1,3-asymmetric induction has been achieved during the allylation of imines derived from chiral auxiliaries such as P-amino alcohols and a-amino acid esters.25 Drawbacks of these methods are the limited availability... 

The first successful chiral phases used under GC conditions were N-trifluoro-acetyl (TFA)-L-a-amino acid esters. These phases separated race-mates of the more volatile members of the same compounds [33]. Replacing the A-TFA moiety of the selector with trichloroacetyl reduced the enantiose-lectivity by half, while substituting with isobutyryl caused a total loss of the chiral separation. 

Another approach to this enantioselective cyclization involves the formation of imines from N-)S-(3-indolyl)ethyl amino acid esters and a variety of aryl aldehydes. These imines give tetrahydro-)S-carbolines with diastereomer ratios of up to 98.5 1.5 (Scheme 27) <94T11865>. The chiral auxilliary group can be removed after cyclisation. The iminophosphorane (103), derived from a dehydrotryptophan, reacts thermally with aldehydes to give the /J-carbolines (104) (Equation (28)) <92TL289i>. In contrast, the dehydrotryptophan (105) itself interacts with aldehydes to form compounds (106) with the clavicipitic acid skeleton (Scheme 28) <86TL4757>. 

The well known chiral carbon skeleton designated as binaphthyl hinge has been introduced into asymmetric synthesis and resolution of racemates in the form of the derivatives of 2,2 -dihydroxy-l,r-binaphthyl (84, binaphthol). The application of chiral crown compounds containing this binaphthyl tmit for the separation of amino acids and amino acid esters by use of liquid/liquid chromatography has been described particularly by Cram et al. in detail... 

Cellulose and amylose derivatives are the best chiral selectors for the enantioseparation of various compounds. However, tris(3,5-dimethylcarbamate)s of cellulose and amylose only showed high resolving power for N-benzyloxycarbamoyl a-amino acid esters. 

One such nonnatural function of natural ionophores is the complexation of organic ammonium cations for example, protonated amino acid esters. Since natural ionophores are chiral compounds, the process can be enantioselec-tive. Binding of ammonium cations by such receptors as monensin or lasalocid (Fignre 1) is efficient bnt lack the expected enantioselectivity. However, cyclic or podand-type derivatives of monensin like 1 or 2 (Figure 1) show significant enantioselectivity the ratios of binding constants of the R and S enantiomers of protonated methyl esters of phenylglycine, phenylalanine, and leucine to 2 are A r/ZCs = 5.1, 6.2, and 7.6, respectively. Crown-ether type derivatives like 1 show lower enantioselectivities. 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

The tetrahydrophthalic ester of prednisolone, an anti-inflammatory drug, consists of two diastereoisomers. Olszewska et al. [66] describes the effect of addition of an optically active compound (amino acids, cyclodextrins, camphosulfonic acid) on the capacity ratios, k, and separation factors of these diastereoisomers by TLC. They used both mobile phases containing a chiral additive and stationary phases impregnated with an optically active compound, for example, silica gel plates impregnated with amino acids. The best resolution was obtained by impregnation of the stationary phase with o-camphosulfonic acid and copper acetate, and use of dichloromethane-isopropanol (90+10, v/v) as mobile phase. The addition of chiral compound to the mobile phase had less effect on the resolution of diastereoisomers. 

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