Serine protection

In a short synthesis of L-4,4-difluoroglutamic acid, the serinal-protected derivative 40 reacts with both lb and lc in THF at room temperature to give the adduct 41 and 42, respectively, in a fairly high -stereoselectivity (equation 28)104. 

The phenolic hydroxyl group of tyrosine, the imidazole moiety of histidine, and the amide groups of asparagine and glutamine are often not protected in peptide synthesis, since it is usually unnecessary. The protection of the hydroxyl group in serine and threonine (O-acetylation or O-benzylation) is not needed in the azide condensation procedure but may become important when other activation methods are used. 

Me2NC5H5NCPh3 Cr, CH2CI2, 25°, 16 h, 95% yield. In this case a pri-maiy alcohol is cleanly protected over a secondary alcohol. The reagent is a stable isolable salt. If the solvent is changed from CH2CI2 to DMF, the amine of serine can be selectively protected. 

The first synthesis of enterobactin, a microbial chelator and transporter of environmental iron, was accomplished by the coupling of three protected L-serine units and macrocyclization by the double activation method. 

This active ester was used for carboxyl protection of Fmoc-serine and Fmoc-threonine during glycosylation. The esters are then used as active esters in peptide synthesis. 

The cyclohexyl phosphate, used in the protection of phosphorylated serine derivatives, is introduced by the phosphoramidite method and cleaved with TFMSA/MTB/m-cresol/l,2-ethanedithiol/TFA, 4 h, 0° to rt. " ... 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

Although the tosylation reaction of fully protected serine has already been described,5 we have found that extended reaction times are required when the reaction is carried out on 100-200 mmol scale, taking from 3 to 5 days to go to completion. As a result of longer reaction times, the amount of byproducts is increased making the purification step more difficult. 

Via these optimized routes, the N-protected pyrimidine nucleoamino acids 6 and 9 were synthesized very efficiently in three high-yielding steps, starting from an inexpensive and commercially available serine derivative. The common intermediate O-MTM ether 3 can be synthesized on a multigram scale and is stable for years if stored in a refrigerator. 

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). 

FIGURE 2 Polymers that can be derived firom L-serine. (a) Poly-(serine ester) was obtained by ring opening polymerization of N-protected serine-p-lactones (19). (b) Poly(serine imine) has appar-... 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

For the elongation of the chain starting from 11 toward the N-terminal group, direct condensation of the activated p-nitrophenyl esters of such amino acids as N-protected L-cysteine, L-glutamic acid, glycine, L-leu-cine, L-proline, L-serine, L-tyrosine, andL-valine with 2-acetamido-3,4,6-... 

In a synthesis of the L-serine derivative 133, Kunz and Buchholz100 treated N-(benzyloxycarbonyl)-L-serine 2-bromoethyl ester (135) with tetra-O-benzoyl-a-D-glucopyranosyl bromide (136) protection of the... 

Elongation of the peptide chain in the direction of the N-terminal by a solid-phase procedure was introduced by Lavielle and coworkers,132 who prepared the glycopeptide [3-0-(2-acetamido-2-deoxy-/ -D-gluco-pyranosyl)-L-serine]-L-glycyl-L-alanine (189) by first coupling 168, de-protected by hydrogenolysis, to an L-alanyl resin (188), and, after re-... 

The disaccharide derivatives 196 and 197 of N-tosyl-L-serine, of interest for the study of D-galactose-binding lectins, were prepared by Kaifu and Osawa148 from 194 and 195, respectively, by protection of 0-4 and -6 with a benzylidene group, condensation of the acetal with tetra-O-acetyl-a-D-galactopyranosyl bromide (110) under Koenigs-Knorr conditions, and deprotection. 

Silyl-derived linker 36 was prepared in three steps from a silyl ether of serine and incorporated for Fmoc/tBu-based assembly of protected gly-copeptide blocks (Scheme 11) [42]. The a-carboxylic acid function of serine was protected as an allyl ester. Deprotection by a Pd(0) catalyst in the presence of dimedone liberated the carboxylic acid in order for subsequent... 

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