Threonine analogs

L-Threonine is produced by some auxotrophic mutants and/or threonine-analog resistant mutants and those bred by gene engineering techniques. The bacteria are Escherichia coli, Corynebacterium glutamicum, Brevibacterium lactofermentum, B.flavum, Serratia marcescens, and Proteus retgerii. 

Strain D-60 was then used to select mutants resistant to the threonine analog, S-hydroxynorvaline, following nitrosoguanidine mutagenesis (j, ). Three kinds of resistant strain were saved for subsequent use. One of these (HNr31) had an Incomplete but undefined block in methionine biosynthesis, which may have accounted for the small amount of threonine that was accumulated from homoserine being funneled into the threonine pathway. 

Akaji and Kiso" reported an efficient synthesis of 1297 (Scheme 1.331) from Boc-(l )-MeCys(Bn)-OH, Boc-Thr(Bn)-NHCH3 and 3-phenylpropionyl chloride. They improved the peptide-coupling conditions for the sterically hindered a-methylcysteine and threonine analogs normally used to prepare 1187 and 1188. 

Figure 3.13 Synthetic threonine analogs putative precursors of the enol portion of azinomycin B.

Methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, occurs even in human blood as a consequence of ethanol consumption. Serine and threonine analogously produce C-2 substituted (2J S,4S)-oxazolidine-4-carboxylic acids (2-124). Heterocyclic products, C-2 substituted (2J S,4S)-pyrimidine-4-carboxylic acids, are also produced in the reaction of aldehydes with asparagine (2-125). Phenylalanine yields C-1 substituted (lJ S,3S)-tetrahydroisoquinoline-3-carboxylic acids (2-126) and analogous products arise from tyrosine. Tryptophan reacts with aldehydes under the formation of 9H-pyrido[3,4-b]indole (also known as -carboline or norharmane) derivatives, (lJ S,3S)-l,2,3,4-tetrahydro-fi-carboline-3-carboxylic acids (2-127, R = H or alkyl or residues of other aldehydes and sugars), the reaction of tryptamine yields the corresponding (lRS)-l,2,3,4-tetrahydro-P-carbolines. 

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

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). 

The presence of two different probes, namely, Gal C-l and Thr C7, giving rise to signals situated in two different, uncrowded regions of the spectrum, with chemical-shift differences (AdC-l up to 8.35 p.p.m., and Ad Thr C7, up to 6.7 p.p.m.), allows the facile detection of any racemiza-tion occurring at either, or both, of the asymmetric carbon atoms of the threonine. It would be difficult to distinguish a-D-Gal — L-Thr (27) from its P analog (28), or / -D-Gal — D-alloThr (58) from / -D-Gal — L-alloThr (56), on the basis of the anomeric-carbon chemical-shifts only. However, they can be differentiated on the basis of Thr Cr chemical-shift data. It should be noted that neither optical rotation nor -n.m.r. spectroscopy could have elucidated this point.85... 

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

A cycloaddition analogous to that in Eq. 12 also occurs with aminocarbene 9. Thus, addition of formaldehyde to the cocondensate of C - - NH3 generates serine 18 by the mechanism in Eq. 13. This reaction is the key step in the formation of serine when water is added to the C + NH3 reaction (with C + H2O producing the CH2=0). Addition of acetaldehyde to the C - - NH3 cocondensate results in threonine and allothreonine (Eq. 14). ... 

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