Shikimic 4,5-methylene

One of the mildest methods for preparing methylene acetals involves reaction of a diol with dimethoxymethane in the presence of a suitable activating agent such as phosphorus pentoxide,176 trimethylsilyl Inflate.177 or lithium bromide and p-toluenesulfonic acid.178 The reaction is also used to make methoxymethyl ethers (see section 4.4,1) from alcohols. Scheme 3,95 illustrates the simultaneous formation of a methoxymethyl ether and a methylene acetal from Shikimic Acid.169 The reaction was adapted to the synthesis of the methylene acetal moiety of the marine antitumour agent Mycalamide B [Scheme 3.96],179... 

Several studies of the biosynthesis of chloramphenicol have led to the conclusion that it is formed via the shikimic acid pathway, specifically from chorismic acid. An arylamine synthetase promotes formation of p-amino-L-phenyl alanine (1 ) 50>51. This product is converted to chloramphenicol (15) by oxidation of the amine function to a nitro group, by hy-droxylation of the benzylic methylene group, reduction of the carboxyl... 

Rifamycin S derived from [l- C]glycerate showed enhanced n.m.r. signals for C-3 and C-8 which is consistent with incorporation by way of intermediates on the shikimate pathway (Scheme 22). ° Greater enhancement of C-8 by [l- C]glycerate and of C-1 by [l- C]glucose was observed, compared respectively with C-3 and C-10. This indicates that C-1 derives from the methylene carbon of phosphoenol-pyruvate rather than C-4 of tetrose phosphate and that C-8 derives from the carboxy-group of phosphoenolpyruvate. It follows then that C-9 and C-10 of rifamycin S (193) would be the location of the double bond of a dehydroshikimate intermediate. Michael addition to this double bond as in (194) allows completion of the naphthoquinone moiety of rifamycin S in an analogous fashion to the formation of the menaquinones. ... 

The synthesis of phosphonate analogues of phosphates and carboxylic acids is becoming increasingly important. Intramolecular olefination of the diphosphonate (161), itself prepared by a Knoevenagel condensation of D-lyxose S-aldehyde with methylene[bis(diethyl phosphonate)], provides a novel synthesis of the phosphonate analogue (162) of shikimic acid.7 8 Olefination of the a-D-mannopyranoside (163) with methylene[bis(diethyl phosphonate)] has been used as a key step in the synthesis of the monophosphonate analogue (164) of L-myo-inositol-l,4,S-triphosphate.79 Attempts to carry out the olefination reaction directly on the diphosphate (165) failed. 

Two unexceptional steps lead through shikimic acid (5.7) to its 3-phosphate (5.8). Condensation with phosphoenolpyruvate (5.7) gives (5.9). This type of biological reaction is almost unique, only one other example being known. The mechanism suggested, and illustrated in Scheme 5.3, is based on experiments in deuterium oxide and tritiated water. [The intermediacy of (5.72) is indicated by the random incorporation of hydrogen isotope into the methylene hydrogens of (5.9) [8].]... 

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