Threonine scheme

Nunes proposed also a second mode of biogenesis, based on L-threonine (Scheme 6). This scheme makes first use of an aldol condensation, analogous to the early proposal of Leete, followed by esterification to the lactone. In both schemes the last step is a selective methylation of N by S-adenosyl-methionine. 

The traditional method for preparing (m-butyl ethers involves reacting a large excess of isobutene with a solution of the alcohol in dichloromethane in the presence of concentrated sulfuric acid, p-toluenesulfonic acid or phosphoric acid and the method is effective for protecting the side chain hydroxyl functions of serine, threonine [Scheme 4.123], and tyrosine.223 224 A more convenient method involving use of Amberlyst H-15 resin in hexane as the acid catalyst deserves wider attention.217... 

In the 2010s, Aitken et al. demonstrated that a solvent-free organocata-lysed aldol reaction could be achieved by addition of 2-hydroigr-cyclobutanone 11 n = 1) to 4-nitrobenzaldehyde in the presence of L-threonine (Scheme 12.4). The temperature played an important role in the stereochemical outcome, as the -adduct 12 was obtained at low temperature, whereas the same reaction performed at 25 °C and/or in wet DMF led mainly to the a t/-adduct regardless of the amino acid structure. 

Chemical synthesis provides an array of powerful methods to access the conjugates 1-5 of the five major tumour-associated carbohydrates linked to serine and threonine (Scheme 1). 

On the other hand, a-transaminases have been used extensively in the production of amino acids through kinetic resolution and asymmetric synthesis. While many studies rely on the use of an excess of cosubstrate to drive the reaction to completion, some multienzymatic approaches have been developed as well. As an example, aspartate has been used as an amino donor in a multienzymatic synthesis of L-2-aminobutyrate from L-threonine (Scheme 4.8). ° The rather complex multistep sequence started with the in situ formation of 2-ketobutyrate from L-threonine catalysed by threonine deaminase (ThrDA) from E. coli. A tyrosine transaminase (lyrAT) from E. coli converted 2-ketobutyrate and L-aspartie acid to L-2-aminobutyrate and oxaloacetate, which spontaneously decarboiq lated to give pyruvate. Since the... 

Of special importance to the synthesis was the choice of condensing agents and cbnditions. HATU-HOAF was of particular value in these final stages. Condensation of the threonine carboxyl of 24 (from Scheme 5) with the pyrrolidine N s of the bisindolyl compound 15 (from Scheme 3) afforded 25. Removal... 

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]. 

Similar experiments suggested that 4-hydroxy-L-threonine (43) was an intermediate in synthesis of the three-carbon unit, C-6, C-5, C-5 (after decarboxylation). This was rigorously proved by a chemical synthesis of 4-hydroxy-L-(2,3-13C2)threonine. Incubation of E. coli mutant WG2 with this substrate produced a sample of pyridoxol that was examined by l3C NMR. The presence of doublets in the signals originating from C-5 and C-6 of pyridoxol exclusively, showed that the C-2-C-3 bond of the substrate had been incorporated intact into the predicted site (Scheme 18).42... 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

Scheme 1 summarizes our synthetic approach. By protecting the carboxyl groups using a suitable protecting group, the three hydroxy amino acids, serine, threonine and tyrosine were conveniently coupled with Boc-Phe-OH to obtain the corresponding peptides (1-4) in good yields. 

Scheme 1 Phosphinite derivatives of serine, threonine and tyrosine containing dipeptides 1 R = H, Boc-Phe-Ser(OPPh2)OMe 2 R = Me, Boc-Phe-Thr(OPPh2)OMe 3 R = Ph, Boc-Phe-Tyr(OPPh2)OMe 4R = cyhex, Boc-Phe-Tyr(OPcyhex2)OMe.

Extension of this strategy enables syntheses of both protected D-threonine and L-allo-threonine, in which reagent-controlled stereoselective epoxidation of a common intermediate is the key step (Scheme 4.8).53... 

Chiral enolates of l,3-dioxalan-4-ones, methyl l,3-oxazolidine-4-carboxylates, and 1,3-imi-dazolidine-4-ones derived from chiral natural sources such as (S )-proline, (Sj-serine, and (S )-threonine are added to nitroalkenes in high diastereoselectivity (Scheme 4.12).77... 

Moser et al. (1968) (one of the co-authors was Clifford Matthews) reported a peptide synthesis using the HCN trimer aminomalonitrile, after pre-treatment in the form of a mild hydrolysis. IR spectra showed the typical nitrile bands (2,200 cm ) and imino-keto bands (1,650 cm ). Acid hydrolysis gave only glycine, while alkaline cleavage of the polymer afforded other amino acids, such as arginine, aspartic acid, threonine etc. The formation of the polymer could have occurred according to the scheme shown in Fig. 4.9. 

More recent developments are the SerPHOX catalyst 22 [20] and the Thre-PHOX catalyst 23 [21] (Fig. 29.9), derived from serine or threonine, respectively (Scheme 29.4). 

Since the discovery of the CBS catalyst system, many chiral //-amino alcohols have been prepared for the synthesis of new oxazoborolidine catalysts. Compounds 95 and 96 have been prepared93 from L-cysteine. Aziridine carbi-nols 97a and 97b have been prepared94 from L-serine and L-threonine, respectively. When applied in the catalytic borane reduction of prochiral ketones, good to excellent enantioselectivity can be attained (Schemes 6-42 and 6-43). 

Scheme 39 Diastereoselective anodic decarboxylative substitution of a threonine derivative.

---