Natural amino acid esters

Applying only a few simple operations, the dibenzylaminocyclopropanes 133-R, prepared as described above from N,N-dibenzyl-a-benzyloxyacetamide in 33—48% yield (see Scheme 11.16 and Table 11.9), have been transformed into N-Boc-protected methyl esters of amino acids 138-R containing a cyclopropane moiety (Scheme 11.35) [109,110], Several such analogues of natural amino acids, also referred to as methanoamino acids, exhibit important biological activities [128],... 

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 iminium salt 132, generated from benzylamine hydrochloride and aqueous formaldehyde, reacts with cyclopentadiene during 3 h at room temperature to give, after basification, the cycloadduct 133 in nearly quantitative yield (equation 70). Other examples of this reaction are shown in equations 71-75. The separable diastereomers 134 and 135 are formed in the ratio 4 1 from cyclopentadiene, (—)-a-methylbenzylamine hydrochloride and aqueous formaldehyde in a combined yield of 86% (equation 75)62. Hydrochlorides 136 of methyl esters of natural amino acids [(S )-valine, (S )-isoleucine] react with cyclopentadiene and formaldehyde in aqueous THF to produce mixtures of the diastereomers 137 and 138, in which the former predominate (equation 76)63. 

Isolation of individual amino acids started about 1820 by 1904 all of the naturally occurring amino acids in proteins had been isolated except methionine (Mueller, 1922) and threonine (Rose, 1937). One of the earliest methods for the separation of amino acids was through the differential volatility of their methyl or ethyl esters (Emil Fischer, 1901). This approach led to the discovery of valine, proline, and hydroxyproline. [In the 1970s Fischer s method was modified for microanalysis of proteins, separating the amino acid esters by gas phase chromatography. Separation is now usually performed by hplc (high pressure liquid chromatography).]... 

Parmar et al have developed a method for resolving racemic mixtures of a variety of natural and nonnatural amino acids using the ethyl ester of the amino acid protected at the amino position hy the formation of a Schiff base with an aromatic aldehyde such as /)-chlorobenzaldehyde. Both chymotrypsin and Lip such as porcine Lip gave good yields of the L-amino acid which precipitates out of solution as the amino acid ester released from the imine is cleaved by the hydrolase. 

Treatment of the bislactim ethers with two equivalents of 0.25 N hydrochloric acid at room temperature leads to their hydrolysis to their constituent amino acid esters under these conditions (Scheme 56). The hydrolysis does not proceed via the piperazine-2,5-dione since the products are the esters and not the free amino acids. The rate of hydrolysis depends on the number and nature of the substituents at the 3 and 6 positions (83CJC1397). 

Apart from C02 and metal carbonates, the most abundant carbonyl compounds of natural origin are carboxylic esters and amides. These occur as fats and lipids, which are esters of long-chain alkanoic acids (pp. 789-791), and as proteins, which are polyamides of natural amino acids. The same struc-... 

The ability of metal ions to catalyze the hydrolysis of peptide bonds has been known for 50 years, while the catalytic effect on the hydrolysis of amino acid esters was highlighted in the 1950s. As Hay and Morris point out in their review,76 the major problem with the kinetically labile systems is determining the nature of the reactive complex in solution. Such problems generally do not arise in the more inert systems and consequently reactions involving Co111 have been the more popular for study. 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

A number of workers have observed amino acids in lipide extracts, including those of microbial origin (11, 12, 17, 29). Recently, Macfar-lane (34) has reported that most of the phospholipide in Clostridium welchii is bound to amino acids and that some of this material occurs as the O-amino acid ester of phosphatidylglycerol. The relatively prominent occurrence of lipides in cell membranes has led to the recurrent suggestion that transport of hydrophilic substances through such membranes would be greatly facilitated by combination with hydrophobic substances. Consequently, most workers who have observed the incorporation of amino acids into lipide fractions quite naturally... 

The assessment of the chemistry and the rehearsal of the monomer set were run in parallel, with some important findings. Many natural a-amino acid esters (Mi) gave good results, as did the aromatic aldehydes (M2) in general, while aliphatic and deactivated aromatic aldehydes were less satisfactory and thus rejected. Commercially... 

A method based on the DKR of 4-substituted-2-phenyloxazolin-5-one has been apphed to the large-scale synthesis of N-benzoyl-t-t-leucine-butyl ester 19, an important non-natural amino acid intermediate of several biomimetic peptides. The procedure is based on the alcoholysis of 4-t-butyl-2-phenyloxazoUn-5-one 18 with -butanol catalyzed by the lipase from Mucor miehei (Scheme 13.15) [42]. The unreactive enantiomer is racemized in situ by a base-catalyzed reaction. The... 

Eow-spin Fe porphyrins continue to be of major interest to many investigators, both because of the large number of different low-spin complexes that can be prepared, and because of the relevance of this spin state to a variety of heme proteins. Ligands that give rise to low-spin complexes of Fe porphyrins include two imidazoles, two imidazolates, two pyridines (for TPPs but not OEP and natural porphyrins for lower-basicity pyridines), " two thioethers, two thiolates, two isocyanides, two phosphines, two anunonia molecules, two primary amines (as amino acid esters), two cyanides, two nitrite ions, two methoxide ions, two alkyl... 

Now see what happens if we replace the achiral benzyl ester group with an amide derived from the natural amino acid valine (Chapter 49). The diastereoselectivity remains the same but the chiral environment created by the single enantiomer covalently bonded to the dienophile has a remarkable effect only one enantiomer of the product is formed. 

Boc-L-Leucinal 1s a useful chiral synthon in the preparation of the natural amino acid statine [S-(R, R )]-4-am1no-3-hydroxy-6-methylheptanoic acid (3S.4S). The procedure reported here Is based on the method of Fehrentz and Castro for the preparation of optically active Boc amino aldehydes from a-amino acids. It Is satisfactory on a kilogram scale. Boc-L-Leucinal has also been prepared by the reduction of Boc-L-leucine methyl ester with d1Isobutyl aluminum hydride or by oxidation of Boc-L-leucinolThe reaction conditions described here differ from those In the literature. The N-... 

Kazmaier, U. Reactions of chelated amino acid ester enolates and their application to natural product synthesis. Bioorg. Chem. 1999, 201-206. 

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