Threonine esterification

While in the uncatalyzed reaction of l-ethyleneimino-2-hydroxy-3-butene in THF, refluxing for four hours was necessary to produce 70% of the ester, in the presence of NaNH2 a 90% yield was achieved at room temperature after only five minutes.[13 14] An especially interesting example of the use of the imidazolide method for ester synthesis is illustrated by the total synthesis of actinomycin C3.[15],[16] Working with N-protected L-TV-methylvaline and CDI, esterification of the hydroxyl group on the threonine residue proved successful whereas this could not be accomplished by any of the conventional methods. 

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

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. 

After removing the MOM group, esterification with threonine derivative 677, and deprotection of the the TBS group, dye-sensitized photooxygenation of 684 cleanly affords triamide 685. Without isolation, 685 is lactonized to the antimycin A3 dilactone 686 in xylene in the presence of a catalytic amount of PPTS. 

The D-enantiomer of 393 was obtained in an identical sequence of reactions starting frc m 2,3-0-isopropylidene-4-deoxy-D-threitol (395). This compound was prepared from L-threonine (394) in the following way the amino acid was deaminated to 25 3/ -dihydroxy-butyric acid. Esterification of the carboxyl group and protection of both hydroxyl groups with an isopropylidene grouping gave methyl 4-deoxy-2,3-0-isopropylidene-D-threonate. Reduction of the ester group afforded 395 smoothly. 

Substitution of polar groups yields a less polar and therefore more volatile material. Acetylation with acetic anhydride modifies the terminal amino group, the side chain amino group in lysine residues and also the hydroxyl groups in serine and threonine side chains in the desired sense. Volatility can be further increased by esterification of free carboxyls by treatment of the solution of the acetyl derivative in methanol with diazomethane ... 

In the mixture of amino acids obtained by hydrolysis three different forms of threonine were found, L-threonine, D-a//othreonine and N-methyl-L-a//othreonine. Their stereochemistry was elucidated by gas chromatography of the derivatives obtained by esterification with (+ )-3-methyl-2-butanol and trimethylsilylation. Synthetic compounds were used for comparison. 

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