Isoleucine stereochemistry

In this section, tetramic acids with an acyl group substituent at C-3 are discussed. The simplest of the naturally occurring 3-acyl tetramic acids, tenuazonic acid (6), was first isolated from the culture filtrate of Alter-naria tenuis [18] and, subsequently, from other fungal species (A. alternate, A. longipes, Pyricularia oryzae) [19,20]. Species of Altemaria are known to produce more than 70 secondary metabolites, many of which, particularly those from the Altemaria altemata complex, are mycotoxins [19]. The absolute stereochemistry of 6 (55,65) was deduced from the formation of L-isoleucine on ozonolysis followed by acid hydrolysis [21]. 

A novel technique for dating archaeological samples called amino acid racemiza-tion (AAR) is based on the stereochemistry of amino acids. Over time, the configuration at the a-carbon atom of a protein s amino acids is lost in a reaction that follows first-order kinetics. When the a carbon is the only chirality center, this process corresponds to racemization. For an amino acid with two chirality centers, changing the configuration of the a carbon from L to D gives a diastereomer. In the case of isoleucine, for example, the diastereomer is an amino acid not normally present in proteins, called alloisoleucine. 

These differences in the control of the product stereochemistry have recently been investigated by molecular modeling techniques [60,154], From these studies, the relevance of the side-chain of isoleucine 476 (PDCS.c.) (Table 2) for the stereo-control during the formation of aromatic a-hydroxy ketones became obvious, since this side-chain may protect one site of the ot-carbanion/enamine 6 (Scheme 3) against the bulky aromatic cosubstrate. Nevertheless, the smaller methyl group of acetaldehyde can bind to both sites of the a-carbanion/en-amine. The preference for one of the two acetoin enantiomers has been interpre-tated in terms of different Boltzmann distributions between the two binding modes of the bound acetaldehyde [155],... 

Several V- IJ<>c-A-MOM-a-am ino acid derivatives undergo a-methylation in 78% to nearly 93% ee with retention of the configuration upon treatment with KHMDS followed by methyl iodide at —78°C. The substituents of the nitrogen are essential for control of the stereochemistry. How much is the stereochemical course of the reaction affected by an additional chiral center at C(3) of substrates a-Alkylation of A -lioc-A-MOM-L-isoleucine derivative 61 and its C(2)-epimer, D-a/fo-isoleucine derivative 62, were investigated (Scheme 3.16). If the chirality at C(2) is completely lost with formation of the enolate, a-methylation of either 61 or 62 should give a mixture of 63 and 64 with an identical diastereomeric composition via common enolate intermediate K. On the other hand, if the chirality of C(2) is memorized in enolate intermediates, 61 and 62 should give products with independent diastereomeric compositions via diastereomeric enolate intermediates. 

Highlighting the synthetic utility of this methodology, the group of Du Bois reported a three step synthesis of the amino acid (K) ( > isoleucine starting from the chiral sulfamate ester 11. Oxidative cyclization with retention of stereochemistry and a simple Cbz protection hydrolysis oxidation sequence provided the amino acid (Scheme 12.11) [17]. 

The branched-chain amino acids valine, leucine, and isoleucine have very similar biosyntheses and catabolism. Valine 179 and leucine 205 have diastereotopic methyl groups and leucine 205 and isoleucine 212 have diastereotopic hydrogen atoms. These may be differentiated by labeling so that the stereochemistry of the biological processes involving these amino acids may be studied. 

Valinoctins A and B inhibited bovine brain FPTase with IC50 values of 3.2 and 3.5 pM, respectively [150]. The FPTase activity of stereoisomers derived from stereospecific synthesis was also evaluated. The 25, 3R- or 25, 35-stereochemistry of the 2-hydroxy-3-amino acid were optimal for FPTase inhibitory activity. Substitution of valine with isoleucine or phenylalanine (IC50 values of 1.7-4 pM) had a trivial impact on inhibitory activity while substitution with alanine completely eliminated activity (IC50= > 75 pM) [151]. Mechanism of inhibition or selectivity data for these compounds has not been reported. 

Optically pure opine-tjrpe secondary amine carboxylic acids were also synthesized from amino acids and their analogs, such as L-methionine, L-isoleucine, L-leucine, L-valine, L-phenylalanine, L-alanine, L-threonine, L-serine, and L-phenylalaninol, and a-keto acids, such as glyoxylic, pyruvic, and 2-oxobutyric acids, using the enzyme with regeneration of NADH with FDH from Moraxella sp. C-1 [13]. The absolute configuration of the nascent asymmetric center of the opines was of the D stereochemistry with > 99.9% e.e. One-pot synthesis of N-[l-D-(carboxyl)ethyl]-L-phenylalanine from phenylpyruvic and pyruvic acid by using ODH, FDH, and phenylalanine dehydrogenase (PheDH) from Bacillus sphaericus... 

Pyrrolizidine Alkaloids.— Two molecules of L-isoleucine are used for the biosynthesis of the senecic acid component of senecionine (15). In order to understand how the two isoleucine fragments are linked together (C-6 of one joins to C-4 of the other), further work has been undertaken. First, 2-methyl-3-oxobutanoic acid and the five-carbon intermediates in isoleucine metabolism, i.e. 2-methylbutanoic acid and angelic acid (17), were examined as precursors for the senecic acid fragment of senecionine (15), with negative results [angelic acid rather than the isomeric tiglic acid, see (13), was examined since its stereochemistry is the same as that around C-15-C-20 in (15)]. 

The origin of the )8-methylproline moiety present in paraherquamide A and several congeners has recently been investigated. Examination of the absolute stereochemistry of paraherquamide A, which possesses the (S)-absolute stereochemistry at C-14, led Williams et al. to speculate that the methylated proline may be derived from L-isoleucine as opposed to proline and S-adenosylmethio-nine (SAM) and this possibility was experimentally tested in Penicillium felluta-num (ATCC 20841) as shown in Fig. 5 [39]. The position of incorporation in paraherquamide A was determined using NMR and the percentage of the labeled amino acid incorporated was also determined using NMR. 

Cahill R, Crout DHG, Gregorio MVM, Mitchell MB, Miiller US (1983) Pyrrolizidine alkaloid biosynthesis stereochemistry of the formation of isoleucine in senecio species and of its conversion into necic acid. J Chem Soc, Perkin Trans 1173-180... 

Cahill, R., D. H. G. Crout, M. B. Mitchell, and U. S. Muller Isoleucine Biosynthesis and Metabolism Stereochemistry of the Formation of L-isoleucine and of its conversion into Senecic and Isatinecic Acids in Senecio Species. J. Chem. Soc., Chem. Commun. 1980, 419. 

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