Biosynthetic podophyllotoxin

Lignans represent an extremely diverse group of compounds. This is the result of both structural diversity and stereo-selective biosynthesis. One particular plant species generally makes only one enantiomer of a particular compound. The other enantiomer may be synthesized by a different species. As a consequence, it is virtually impossible to summarize the biosynthesis of lignans in general. Instead, the focus here will be on the biosynthesis of the lignan podophyllotoxin in a number of different plant species, as an illustration of the different biosynthetic routes that can be used to synthesize the same compound. 

Xia et al (2000) proposed a biosynthetic route starting coniferyl alcohol (3.79) and subsequent formation of (+)-pinoresinol (3.82), as shown in Figure 3-12. The enzyme pinoresinol/lariciresionol reductase converts this compound to (+)-lariciresinol (3.87), and then to (-)-secoisolariciresionol (3.88). The enzyme secoisolariciresinol dehydrogenase converts (3.88) into (-)-matairesinol (3.83). The conversion from (-)-matairesinol (3.83) to podophyllotoxin (3.86) is likely to be similar to the route shown in Figure 3-11. 

Figure 4.11 Proposed biosynthetic steps involved in the biosynthesis of podophyllotoxin(-glucoside) and 6-methoxypodophyllotoxin(-glucoside). Steps catalyzed by yet unidentified enzymes are shown with dashed arrows. Enzymes involved are as follows (1) deoxypodophyllotoxin 7-hydroxylase, (2) deoxypodophyllotoxin...

Figure 4 Redox reactions in biosynthetic pathways. A one-electron oxidation of two coniferyi aicohoi monomers is the initiating step in podophyllotoxin biosynthesis, and a simiiar one-eiectron oxidation piays a key role in the biosynthesis of the aikaioid morphine. Redox reactions are also used to crosslink nascent scaffoids, as shown for vancomycin, or to add oxygen-based functionality to reduced scaffoids, as shown for taxoi.

Considerable progress has also been made in elucidating the biosynthetic pathway leading to the podophyllotoxin series (scheme 2) [38,39]. Dewick et al. have shown that demethylyatein (15a) and yatein (15b) are precursors of demethylpodophyllotoxin (18a) and podophyllotoxin (18b) respectively. Furthermore, 4 -demethyl-deoxypodophyllotoxin (16a) and deoxypodophyllotoxin (16b) undergo aromatic hydroxylation to yield a-peltatin (17a) and p-peltatin (17b) respectively. They have also shown that (-)-matairesinol (13) is efficiently incorporated into 4 -demethylpodophyllotoxin (18a), podophyllotoxin (18b), a-peltatin (17a) and p-peltatin (17b). These facts have been interpreted as indicating that matairesinol is a common precursor of both the 3,4,5-trimethoxyphenyl and 4-hydroxy-3,5-dimethoxyphenyl series. 

Figure 8.6 Podophyllotoxin biosynthetic pathway. DIR, dirigent protein PLR, pinoresinol-lariciresinol reductase SDH, sec-oisolariciresinol dehydrogenase PS, pluviatolide synthase OMT3, O-methyltransferase 3 CYPx, cytochromes P450 (CYP71CU1) OMT1, O-methyltransferase 1 and 2-ODD,...

Podophyllum peltatumJLinum flavum by Lewis and coworkers [13a] using radiolabeled substrates, whereas (-)-matairesinol (45) that serves as a biosynthetic precursor for (-)-podophyllotoxin (39) had been also determined earlier by Dewick and coworkers [13b]. These late-stage transformations include modifications of two aryl rings and subsequent Friedel-Crafts alkylation of the resultant yatein (46) just like that described from 36 to 37 (Scheme 10.5). Finally, the regio- and stereoselective hydroxylation of (-)-deoxypodophyllotoxin (47) completes the biosynthesis of (-)-podophyllotoxin (39). 

SCHEME 10.6 Biosynthetic pathway from coniferyl alcohol (40) to (-)-podophyllotoxin (39) via (-)-matairesinol (45). 

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