From a-Amino Acid Esters

Aluminum chloride [7446-70-0] is a useful catalyst in the reaction of aromatic amines with ethyleneknine (76). SoHd catalysts promote the reaction of ethyleneknine with ammonia in the gas phase to give ethylenediamine (77). Not only ammonia and amines, but also hydrazine [302-01-2] (78), hydrazoic acid [7782-79-8] (79—82), alkyl azidoformates (83), and acid amides, eg, sulfonamides (84) or 2,4-dioxopyrimidines (85), have been used as ring-opening reagents for ethyleneknine with nitrogen being the nucleophilic center (1). The 2-oxopiperazine skeleton has been synthesized from a-amino acid esters and ethyleneknine (86—89). 

Diazepines represent an important class of bicyclic seven-membered heterocycles. They are the basis of several tranquilizers and are accessible from a-amino acid esters and o-azidobenzoyl chloride in the presence of triethylamine. The A/ -(o-azidobenzoyl)amino esters (333) formed in this way (Scheme 121) are cyclized by Staudinger and aza-Wittig reactions to give 2-ethoxy-l,4-benzodiazepin-5-ones (334) (92MI2). 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from a-amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the a-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The a-allyl-a-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+)-AV-dicycIohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ee[72]. 

Calcagni, A., Rossi, D., and Lucerne, G., a-Hydroxymethylation of Schiff bases derived from a-amino acid esters, Synthe.si.s. 445, 1981. 

Stereoselective olefination of carboxylic eaters or synthesis of allylamines from a-amino acid esters mediated by benzotriazole(Bt) derivatives. 

Thioxo-l,3,6-thiadiazocin-5-ones (36) are conveniently prepared from a-amino acid ester hydrochlorides in one pot by sequential treatment with carbon disulfide, followed by 2-bromoethylamine hydrobromide (Scheme 28) <90SC2675>. Starting with L-tyrosine leads to an optically active thia-diazocine indicating that racemization does not occur during the reaction. 

In the course of extending their studies of the generation of azomethine ylides from a-amino-acid esters Grigg et al. have discovered a simple one-step synthesis of N-substituted isoindolln-1-ones (Scheme 23). Treatment of -phthaldialdehyde (272) with a-amino-acids, their methyl esters, or a range of aryl or heterocyclic amines leads to isoindolin-1-ones (273) in moderate to good yields, probably via the mechanism shown. The reaction also works with aliphatic amines although less efficiently (26-40%). 

A convenient method for the synthesis and derivatization of enantiopure a-iso-cyanato carboxylic acid esters starting from a-amino acid esters has been devised [314], The isocyanates are obtained in enantiomerically pure form (> 99% ee) by a DMAP-catalyzed isocyanation with B0C2O, which proceeds in 10 min at room temperature (for typical procedures employing B0C2O, see the B0C2O Section of the present chapter). In situ derivatization of the isocyanates by reaction with amines and alcohols affords the corresponding enantiopure ureas and carbamates. Methyl esters of various amino acids 472 have been carbonylated by B0C2O at ambient temperature [314]. 

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of SchifI bases derived from a-amino-acid esters and good yields of /3-hydroxy-a-amino-acids are obtained. This type of compound is also prepared using the optically active imine (183) the t/trco-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88). The jS-hydroxy-a-amino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described. Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. L-Alanine, L-valine, and (S)-0,0-dimethyl-a-methyldopa have been used to prepare the heterocyclic intermediates (186), which give a range of amino-acids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187). ... 

Pyrrolidines and related compounds are readily available by 1,3-dipolar cycloaddition reactions of imines derived from a-amino-acid esters. The imines have now been shown to undergo a wider range of 1,3-dipolar cycloadditions with dipolarophiles such as maleic anhydride, N-phenylmaleimide, acrylonitrile, acrylate, and other activated olefins (Scheme 47). This study is an extension of earlier work which led to triazolidines. ... 

The piperonyl ester can be prepared from an amino acid ester and the benzyl alcohol (imidazole/dioxane, 25°, 12 h, 85% yield) or from an amino acid and the benzyl chloride (Et3N, DMF, 25°, 57-95% yield). It is cleaved, more readily than a p-methoxybenzyl ester, by acidic hydrolysis (CF3COOH, 25°, 5 min, 91% yield). ... 

Thus, the dianion derived from a-amino acid substitutes the /1-chloride to give the ester of 2-(phenylsulfonyl)ethenyl amino acid and subsequent desulfonylation provides N-(benzoyl)vinylalanine methyl ester (62) (equation 61). The conjugate addition of enolates to methyl styryl sulfone (63) and subsequent intramolecular addition to the carbonyl moiety provide a synthetically valuable method for the construction of bicyclic and tricyclic skeletons52. Desulfonylation of the cyclization product 64 with sodium in ethanol-THF gives the diene 65 in good yield (equation 62). 

Acyl azides (see Section 2.13) The acyl-azide method of coupling is unique for two reasons. First, it is the only case in which the immediate precursor of the activated form of the peptide is not the parent acid. The starting material is the peptide ester that is obtained from the amino acid ester by usual chain assembly (Figure 2.25, path A). Second, it is the only method that just about guarantees production of a peptide that is enantiomerically pure, provided scrupulous attention is paid to details of procedure. There is no danger for loss of chirality during conversion of the ester to the hydrazide and then the azide, but care must be taken to avoid contact of... 

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. 

Schollkopf et al.187) synthesized a-alkyl-a-amino acids (186) by the alkylation of chiral 1-substituted 2-imidazolin-5-ones (185), which can be prepared from a-amino acid (S)-phenylethylamides and orthoformic esters. The optical yields of the products (186) were in many cases higher than 95 %. 

The reaction of several a-amino acid esters with 0-lactones in chloroform solution gave hydroxyamide esters (equation 50), said to be useful fungicides (74JAP(K)74127918>. Enamines derived from cyclohexanone react smoothly with 0-propiolactone to give 3-(2-cyclo-hexanonyl)propionamides in reasonable yields (equation 51). No acylation of the enamine is observed. This reaction has been used as a key step in a new synthesis of 8-aza steroids (75JOC50). Cyclohexanone imines react in the same manner, except that the expected initial product cyclizes to give bicyclic lactams and enaminones (equation 52) (80T3047). 

The enhanced reactivity in the cupric ion-catalyzed hydrolysis cannot be due solely to the electrostatic effect of an attack of hydroxyl ion on a positively charged a -amino ester, since the introduction of a positive charge, two atoms from the carbonyl group of an ester, increases the rate constant of alkaline hydrolysis by a factor of 103 (10), whereas there is a difference of approximately 106 between the cupric ion-catalyzed and the alkaline hydrolyses of DL-phenylalanine ethyl ester. The effective charge on the cupric ion-glycine (buffer)-ester complex is +1, so that the factor of 106 cannot be explained by an increase in charge over that present in the case of betaine. Furthermore, the reaction cannot be due to attack by a water molecule on a positively charged a-amino acid ester, since the rate constant of the acidic hydrolysis of phenylalanine ethyl ester is very small. It thus seems... 

The long-chain a-amino acid esters (40), (41), and (42) form bilayers on sonication in water under acidic conditions. Liposomes prepared from (40) and (42) precipitate if the aqueous medium is neutralized by titration with NaOH. Only liposomes made from (41) are stable even in basic solutions, as shown by electron microscopy52). Polypeptide formation in oriented spherical vesicles was confirmed by FT-IR spectroscopy. The liposomal solution of (41) was freeze-dried and the spectrum obtained from the residue was comparable with one of the polycondensed monolayers. The formation of polypeptide vesicles is illustrated in Scheme 4. 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

Several examples have been reported in which anthranilamides of a-amino acid esters have been cyclized to yield benzodiazepinediones (Entries 4, 5, and 10, Table 15.37). Examples of cyclizations yielding benzodiazepines with simultaneous cleavage from the support have also been reported (Entries 9, 10 and 12 Table 15.37). Unfortunately, in most of these examples the desired products are contaminated with non-volatile by-products, and purification of the products will probably be required for most applications. 

It is well over 40 years since Pfeiffer discovered that certain reactions of a-amino acid esters, in particular, ester exchange, racemization and oxygenation, are effected very readily when their Schiff bases with salicylaldehyde are complexed to a transition metal ion (most notably Cu11). The Schiff bases result from a condensation reaction between a reactive carbonyl group and the amino group of the amino acids. Snell and his co-workers43 were also one of the first to point out that similar reactions also occurred if pyridoxal was used instead of salicylaldehyde, and that there is a close analogy with pyridoxal phosphate-promoted enzymic reactions of a-amino acid metabolism. Since then much work has been due on these and other similar systems and their reactivities. 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

Further examples of the coupling of p-lactams with a-amino acid esters are shown in Scheme 20. For instance, 57, prepared from 56, reacts with a-amino acid esters in the presence of NaN3 to give tripeptides 58 and 59. In addition, simple exposure of 57 to hydrogen over Pd/C at room temperature produces the piperazinedione 60 in 90% yield. 

Following a similar strategy, Miller [92] has documented the ring opening of a-azido (3-lactams with a-amino acid esters, Scheme 24. Treatment of a-azido (3-lactams 68/69 with glycine methyl ester thus afforded dipeptides 70/71 with differentially protected amino groups. From dipeptide 70, a synthesis of the rhodo-peptin B5 analogue 72 was further demonstrated. 

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