Phenylserine synthesis

In view of this background, we developed a new chiral auxiliary to allow for the first time the efficient asymmetric a-alkylation of sulfonamides [90]. After testing some amine auxiliaries mainly based on proline, which did not show high diastereoselectivities, we synthesized the 4-biphenyl-substituted 2,2-dimethyl-l,3-dioxan-5-amine 108 as a new auxiliary. The racemate obtained according to Erlenmeyer s phenylserine synthesis was resolved with tartaric acid to give both enantiomers. 

Another method of obtaining unsaturated azlactones is through p-phenylserine [Ser(p-Ph)] derivatives. This method was initially introduced by BergmannJ56 The method involves conversion of (3-phenylserine derivatives 11 into the corresponding APhe azlactones 12 by treatment with an acetic anhydride/sodium acetate solution (Scheme 4). This has remained as one of the most popular methods of synthesis. 

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. 

Under the conditions used in peptide synthesis, unprotected aliphatic hydroxy groups can undergo two types of side reactions they can be acylated or dehydrated, the latter leading to dehydroamino acids. The hydroxy group of serine is a primary alcoholic function and therefore exhibits the highest reactivity. The secondary alcoholic functions of threonine, hydroxyproline, (3-phenylserine, hydroxynorvaline, and hydroxynorleucine, as well as of other noncoded amino acids, are less reactive and thus more suited for use in the unprotected form. The aromatic hydroxy group of tyrosine is more acidic than the ahphatic hydroxy groups nevertheless, it can be acylated to form esters. These are active esters which in turn can react with primary amines to form amide bonds. 

The synthesis of phenylserine from benzaldehyde and glycine has been observed by a number of authors 4, 4S). Bruns and Fiedler (4 ) observed that both the ij-threo- and L-erj/throamino acids are formed in the synthesis. They suggest that two different enzymes exist for the ir-threo and h-erythro... 

The names serine hydroxymethylase 89) and serine aldolase 34) have been proposed for the enzyme. The basis for the name serine aldolase is that the synthesis of serine is an aldol condensation and that a number of similar enz3une reactions are known, namely, for the decomposition of threonine to acetaldehyde and glycine and of phenylserine to benzaldehyde and glycine. It has been partially pmrified from sheep 34), beef 36), rabbit 35), and chicken 36) livers by standard procedures for protein purification. Extracts of acetone powders of liver have been used mainly as the starting materials. 

P-Hydroxy-amino acids (Figure 10.7) are multifunctional compoimds with valuable interest as intermediates for the synthesis of statine derivatives (106) [166-168], protease inhibitors [169], antivirals [170, 171], peptide mimetics [172], idulonic acid mimetics, for example, 3R,5R-dihydroxy-L-homoproline (111) [173], immimosup-pressive lipid mycestericin d (112) [174], 3,4-dihydroxyprolines (113) [175], (2S,3R)-2-amino-3-hydroxybutyrolactone, precursor of monobactam antibiotics [176], or L-ffereo-3-[4-(me ylthio)phenylserine] precursor of thiamphenicol (114), florfenicol (115) [177], sialyl Lewis x mimetics (117) [178], p-hydroxyomithine (109), a relevant building block for the p-lactamase inhibitor, clavulanic acid, and the antibiotic and anticancer acivicin [179], surveyed in previous reviews [41,57]. 

Liu, J. Q., Odani, M., Dairi, T., Itoh, N., Shimizu, S., and Yamada, H., A new route to l-fhreo-3-[4-(methylthio)phenylserine], a key intermediate for the synthesis of antibiotics Recombinant low-specificity o-threonine aldolase-catalyzed stereospecific resolution. Appl. Microbiol. Biotechnol. 1999, 51 (5), 586-591. 

Synthesis of L-threo-3,4-dihydroxy-phenylserine via asymmetric aldol reaction of 3,4-dihydroxyben-zaldehyde and glycine with a recombinant whole-cell catalyst containing a threonine aldolase. 

Furthermore, by addition of appropriate amino acid analogs, it is possible to suppress formation of the peptide antibiotics with very httle alteration of protein synthesis. For example, D-phenylalanine inhibits production of bacitracin (Snoke and Cornell, 1964) threo-j8-phenylserine, j8-2-thienylserine, a-methyl-tryptophan, 5-methyltryptophane, and -fluorophenylalanine suppress tyrocidine synthesis (Mach et aL, I963) and a combination of norvaline, norleucine, and hydroxyproline depresses formation of gramicidin S (Winnick et al., I96I). 

---