Threonine hydroxy groups

The synthesis of the oxazole compound 45 starts with the coupling of the N-protected (/ )-methylcysteine compound 18 with threonine terf-butyl ester using bis(2-oxo-3-oxazolidi-nyl)phosphinyl chloride (BOP-Cl) [15] as a coupling reagent. Jones oxidation of the threonine hydroxy group leads to the ketoamide 44. The desired oxazole ring is closed by treatment with thionylchloride/pyridine. After deprotection, the oxazole, compound 45 is obtained. In the next step the oxazole compound 45 is coupled with the tris(thiazoline) compound 43 to yield the thioester 46. Now Fukuyama closes the fourth and last thiazoline ring (46 47). After conversion of the carboxylic acid function into a methyl-... 

An additional reason for the higher reactivity of the phenolic group compared to the sterically hindered threonine hydroxy group may be its free accessibility. In contrast, the reactivity of ring-substituted tyrosines, such as 3-iodo- or 3,5-diiodotyrosine, is relatively low, thus allowing the use of these derivatives without side-chain protection, even in solid-phase synthesis. ... 

In amino acid chemistry r-butyl ethers are also used successfully for the protection of the serine and threonine hydroxy groups. They are formed by the addition of the alcohols to isobutene and are cleaved with TFA and HBr/AcOH. t-Butyl trichloroacetimidate is also a convenient reagent for their introduction.However, the preparation of O-f-butyl serine and threonine themselves requires several steps including methyl orp-nitrobenzyl esters as intermediates. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

A comparison of direct O-mannosylation of serine or threonine on resin-bound peptides, with the incorporation of mannosylated serine or threonine building blocks, resulted in a higher overall yield for the building block approach (12.5 vs 5% for direct condensation). 134 Later it was demonstrated that resin-bound peptides are able to be glycosylated with different glycosyl trichloroacetimidates without protection of the hydroxy groups of the oligosaccharide moiety (Section 6.3.2.8). 135,136 ... 

The low-temperature fluorodehydroxylation technique is a convenient method for the preparation of fluoroamino acids from hydroxyamino acids. The displacement of hydroxy groups by fluorine proceeds with predominant inversion of configuration as exemplified by the fluorination of L-thrconine (3) and L-a//p-threonine (4).40... 

Nevertheless, rearrangements can be suppressed, in most cases, when dediazoniation is performed in hydrogen fluoride/pyridine (48 52 w/w) mixture,308,310 since this less acidic medium stabilizes carbocations (such as the phenonium cation) to a far lesser extent and provides more nucleophilic fluoride anions which, however, cannot totally match the anchimeric assistance of the aryl or hydroxy group in tyrosine (5g) and threonine (5h). 

Access to the imino group of oxazolidine-4-carboxylic acid is even more sterically hindered when substitutions are performed at the C2 position. For such cases, the typical procedure is based on the conversion of the desired serine or threonine dipeptides with unprotected hydroxy groups into the oxazolidine rings by reaction with aldehydes or ketones,1139,1691 as described in Vol. E 22a, Section 2.3.2.4. 

It should be noted that this mechanism involves a final oxidation. The need for this is avoided when amino acids with an a-hydroxy group in the sidechain (serine, threonine) are involved, as pointed out by Shibamoto and Bernhard234 (see Scheme 5.9). Baltes and Bochmann235 obtained as many as 123 pyrazines, both mono- and bicyclic, by interacting sucrose with serine and threonine under coffee-roasting conditions. 

Hydrolysis experiments with the second siderophore, parabactin, gave four products 2,3-dihydroxybenzoic acid, 2-hydroxybenzoic acid, l-threonine, and spermidine, in a ratio of 2 1 1 1. It was shown that parabactin is enzymatically built up from 34, L-threonine, and 2-hydroxy-benzoic acid. Furthermore, it was shown that the threonine amino group is... 

Figure 1.7. The same helix when the whole side chain is allowed to move freely. GRID now detects a favorable binding site where the hydroxy group (red sphere) of a threonine side chain and the terminal NHj " group (blue sphere) of the lysine can both interact simultaneously with the probe. See text.

Besides HF and TFA, the two extremes of acid treatment generally employed in the final deprotection step, alternative acids have been proposed, such as MsOH and TfOH, particularly in the context of arginine protection (Table 2). These acids, however, are known to generate serious side reactions such as aspartimide formationt and an N O shift at serine or threonine residues.Moreover, independent of the type of arylsulfonyl group employed, cations originating from the acid-mediated cleavage lead to alkylation and arylsulfonylation of reactive side chains, as present in tryptophan and tyrosine residues. Additionally, sulfation of hydroxy groups is even observed, as well as... 

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. 

Threonine contains a sterically hindered and therefore less reactive hydroxy group. The O-acylation of unprotected threonine during coupling reactions is therefore less problematic, but can nevertheless occur. Noncoded hydroxy amino acids containing a secondary hydroxy group have a reactivity similar to threonine. These hydroxy amino adds contain an additional asymmetric center at the (3-carbon atom. In the case of reactions on the secondary hydroxy group, this center is accessible to racemization, e.g. threonine can be converted into allo-threonine. 

A newer method for protection of the hydroxy groups of serine and threonine during peptide assembly consists of the formation of oxazolidine derivatives, and their use as intermediates, from which the hydroxy groups are restored after ring opening. 

Occasionally, O-acylation of hydroxy groups present in the carboxyhc acid such as in the side chains of unprotected threonine, serine, or tyrosine residues has been observed. ... 

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