A//o-Threonine

The detection limits for threonine and a//o-threonine are less than 100 ng substance per chromatogram zone. 

A. Gotfbiowski and J. Jurczak, High-pressure [4+2]cycloaddition of 1 -methoxy-1,3-butadiero to N.O-protected D-threoninals and D-a//o-threoninals, Tetrahedron 47 1037 (1991). 

Diastereoisomers. Whereas compounds with one chiral center exist as an enantiomorphic pair, molecules with two or more chiral centers also exist as diastereoisomers (diastereomers). These are pairs of isomers with an opposite configuration at one or more of the chiral centers, but which are not complete mirror images of each other. An example is L-threonine which has the 2S, 3R configuration. The diastereoisomer with the 2S, 3S configuration is known as i-a//o-threonine. L-isoleucine, whose side chain is -CH(CH3) CH2CH3, has the 2S, 3R configuration. It can be called 2(S)-amino-3(R)-methyl-valeric acid but the simpler name L-isoleucine implies the correct configuration at both chiral centers. 

In various mammalian tissues an enzymatic activity has been reported [451-453] which causes the liberation of glycine 149 and acetaldehyde from L-threonine 150 and has therefore been named threonine aldolase (ThrA EC 4.1.2.5). It is curious that a//o-threonine 151 seems to be a more active substrate for this enzyme than is 150. Cleavage of L-3-phenylserine is also catalyzed by mammalian ThrA enzymes [454-456], which in direction of synthesis nonselec-tively produce both threo (152) and erythro (153) configurated adducts from benzaldehyde and 149 [454], The same enzyme preparations were also able to act on 150. Thus, considerable disagreement still exists in the literature about the true nature of these enzymatic activities. 

The L-amino add with the opposite configuration in the side chain is L-a//o-threonine. 

Retrosynthetic analysis of lincosamine (Scheme 22), offers the possibility of application of the [4 4- 2]-cycloaddition reaction between dienes 80 and 89 with N,0-protected D-a//o-threoninal 73 as the key step in the synthetic sequence. Moreover, the use of anyone of the four threonine diastereoisomers, combined with stereocontrol of cycloaddition, permits an easy access to each diastereo-isomer of lincosamine modified in the C5, C, or C7 positions. 

The application of appropriately protected D-a//o-threoninal 73a in the reaction with diene 80 afforded the desired adduct 100a with very high diastereoselectivity. The stereochemical interpretation of these results calls for an analysis of the transition-state models A, B, and C, shown in Scheme 25 [53-55]. 

Intramolecular nucleophilic substitution by an active methylene linked to the nitrogen atom of a-substituted carboxamides was first utilized in azetidinone synthesis by Sheehan and Bose in 1950 [27]. When 3-hydroxyethylazetidinones became an important research target, it was realized that L-threonine or D-allo-treonine, easily converted to bromohydrins 57,61 or to epoxyacid 64, are by this method one of the most convenient natural chiral source for penem and carbapenem synthesis. Shiozaki et al. [28] at Sankyo s laid down the fundaments of the threonine route . Early works from D-a//o-threonine-derived 2R-bromo-3R-hydroxybutyric acid 57 were run using malonate anions as the nucleophilic moiety, as shown in amide 58, which in presence of DBN cyclized to azetidinone 59a with complete inversion of configuration [28a, c]. 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

While enantiomers normally bear the same name and are differentiated by the prefixes (+)- and (-)-, diastereomers may have different chemical names, as in the case of threonine and a//o-threonine above, although within each enantiomeric pair the enantiomers are still denoted (+)- and (-)- and have the same name. To take a well... 

Perhaps the most common case in which an asymmetric reaction leads to a pair of diastereomers is when one of the reactants is chiral. If we consider reduction of the carbonyl group in (55) for example, the two possible products are (-)-threonine (56) and (+)-a//o-threonine (57) which, as we have already seen, are diastereomeric with each other. 

Alternative routes to labeled anri-/3-hydroxy-a-amino acids of the a//o-threonine type are described in Section 11.3.9. They involve aldol reactions of haloacetyl-Evans and -Oppolzer auxiliaries to give iyn-/3-hydroxy-a-halo derivatives, whose a-halo groups are then inverted by nucleophilic displacement with azide ion. ... 

Figure 9 D-a-Amino acids and unnatural L-a-amino acids produced by hydantoinase process, (a) D-p-Hydroxyphenylglycine (b) D-phenylglycine (c) (2i ,4/ ,5S)-2-amino-4,5-(l,2-cyclohexyl)-7-phosphonoheptanoic acid (d) D-terr-leucine (e) D-leucine (f) D-a/to-isoleucine (g) D-serine (h) d-a//o-threonine (i) D-histidine (j) D-phenylalanine (k) D-p-chlorophenylalanine (1) D-3 -pyridyl-alanine (m) D-p-naphthylalanine (n) D-citralline (o) a)-ureido-D-5 -aminoethylcysteme (p) D-lysine (q) D-glutamate (r) L-p-chlorophenylalanine (s) p-trimethylsilylphenylalanine (t) l- -naphthylalanine (u) L-a-naphthylalanine.

Metabolism of P-hydroxy-a-amino acids involves pyridoxal phosphate-dependent enzymes that catalyze a reversible cleavage to aldehydes (Fig, 31) and glycine (89). The distinction between L-threonine aldolase (ThrA EC 4.1.2.5), L-a//o-threonine aldolase (EC 4.1.2.6), or serine hydroxymethyltransferase (SHMT EC 2.1,2.1) has often been rather vague since many catalysts display only poor capacity for erythro/threo (i.e., 91/90) discrimination [22]. Many enzymes display a broad substrate tolerance for the aldehyde acceptor, notably including variously substituted aliphatic as well as aromatic aldehydes (Fig. 31) however, a,P-unsaturated aldehydes are not accepted. 

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