Phenyllactate synthesis

Smidt and Langner111"1 in their synthesis of the natural calcium blocker leualacin utilized the Mitsunobu reaction for the construction of the linear depsipeptide N-(tert-but oxycarbony I) -(3-alanyl-O-D-leucic acid benzyl ester in 69% yield. Higher yields (94-96%) were reported for two didepsipeptide units N-(/er/-butoxycarbonyl)-./V-methylleucyl-D-lactic acid diphen-ylmethyl ester and iV-(/er/-butoxycarbonyl)-yV-methylleucyl-D-phenyllactic acid diphe-nylmethyl ester in the course of the total synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on the Mitsunobu reaction.1102 ... 

Silyl ethers of hydroxy amino acids have been employed in both solid-phase and solution peptide synthesis. Since the TBDMS and TBDPS ether groups are stable to piperidine and other basic reagents, these derivatives of Ser and Thr (Tables 8 and 9) can be used in the Fmoc strategy.Homodetic peptides and depsipeptides have also been synthesized using TBDMS hydroxy protection for phenyllactic acid and hydroxyisovaleric acid, respectively. 

Early workers [103] detected benzilic acid formed during the reduction of benzophenone in dimethylformamide in the presence of carbon dioxide. The carbon dioxide radical anion system is known to have E" = —2.2V (vs. SCE) [104] and will thus not be formed in preference to the ketone radical anion. Reaction occurs through trapping of aromatic carbonyl radical anions by carbon dioxide, and this has been developed into a convenient synthesis of aryllactic acids. The modern technological process uses constant current conditions. On a small scale, a divided cell with mercury cathode has been used to obtain benzilic acids from substituted benzophenones and carbon dioxide in 70-90% yields [105] and to convert 4-isopropylacetophenone to the corresponding phenyllactic acid in 85% yield [106]. On a technical scale, these reactions are best carried out in an undivided cell using a lead cathode and a sacrificial aluminum anode with dimethylformamide as solvent... 

More recently an alternative synthesis has been proposed (91) in which the fragments C1-C5 and C6-C10 were joint together under Stille conditions (92). Starting from the suitably protected P-methyl-aspartic acid (1) its reduction to the aldehyde and conversion to the trans vinyl iodide followed by staimylation with hexamethyldistannane in the presence of freshly prepared Pd(PPh3)4 led to the trans vinylstannane 2 (Fig. 6). The commercially available (S)-phenyllactic acid (3) was converted to the Weinreb amide which was methylated at the secondary alcohol function and then converted to the propargylic ketone (4). Syn-stereoselective... 

For our approach to be useful, we need a green source for the monomers. One such source is the biosynthetic pathway for the synthesis of a-amino acids. As an example, consider the biosynthetic pathway to L-phenylalanine shown in Figure 3. The last step in the synthesis is the amination of the a-ketoacid, but interception and reduction of the ketone would provide phenyllactic acid, a substituted lactic acid that could be converted to its cyclic dimer and polymerized. Frost has shown that the biosynthetic pathway can be altered to favor production of the desired a-hydroxyacid, and proper choice of the enzyme... 

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