Natural product synthesis Podophyllotoxin

A combination of a Tsuji-Trost and a Heck reaction was also used by Poli and Gi-ambastiani [122] for the synthesis of the aza analogues 6/1-252 of the natural products podophyllotoxin 6/l-247a and etoposide 6/l-247b, which show pronounced... 

In many cases the isolated natural product may not be an effective drug for any of several possible reasons, but it may nevertheless have a novel pharmacophore. In such cases chemical modification of the natural product structure, either by direct modification of the natural product (semisynthesis) or by total synthesis, can often yield clinically useful drugs. Examples of this from the anticancer area are the drugs etoposide, teniposide, and topote-can, derived from the lead compounds podophyllotoxin and campothecin. 

Magedov IV, Manpadi M, Rozhkova E et al (2007) Structural simplification of bioactive natural products with multicomponent synthesis dihydropyridopyrazole analogues of podophyllotoxin. Bioorg Med Chem Lett 17 1381-1385... 

A very active area of research in S Ar chemishy is in the field of asymmehic synthesis. This chemistry involves a unique set of electrophiles—those in which a chiral environment must exist near the electrophilic reaction site. In most cases, these asymmetric synthetic reactions are accomplished with a chiral electrophile or a chiral catalyst (or counterion) in tight coordination to the electrophile. For example, Stadler and Bach used a chiral electrophile (36) in an S Ar reaction leading to the natural product (-)-podophyllotoxin 38 (Scheme 1.10) [31]. With planar sp carhocation centers, facial selectivity may be controlled by neighboring groups, in this case the adjacent vinyl group on the lactone 36. The Friedel-Crafts chemistry provides intermediate 37, which is then converted to (-)-podophyllotoxin (38) as a single enantiomer. 

Podophyllotoxin 3 is a naturally occurring antitumor antibiotic . Attempts to reduce the toxicity have resulted in the synthesis of glucosidic phenolic derivatives, VP-16 (etoposide, a semisynthetic analog) 4a and VM-26 (teniposide) 4b. Their mode of action is thought to be associated with DNA breakage . Haim et al. proposed a mechanistic pathway entailing oxidation with subsequent 0-demethylation to form the o-quinone metabolite 5a (Equation 2). In vivo conversion of methoxyl to hydroxyl has been previously observed . Electrochemical oxidation of VP-16 and other methoxyphenols also leads to quinone products. 

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