Podophyllotoxin synthesis

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

Scheme 3.16. Domino radical cyclization in the total synthesis of (+)-podophyllotoxin (3-59).

Nicolaou and coworkers used this approach also for the synthesis of hamigerans A and B [30], as well as of several of their epimers [29, 31]. The group of Kraus succeeded in a formal total synthesis of the anticancer agent podophyllotoxin 5-103 from 5-100 [32] (Scheme 5.19) [33]. The method allows a rapid access to the central core 5-102 via 5-101. 

Scheme 5.19. Photoenolization/Diels-Alder reaction sequence is the synthesis of podophyllotoxin (5-103).

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 addition to the simple substitutions shown in Scheme 1, this reaction has been used in a variety of complex systems as a route to optically active substances. For example, use of chiral oxazolines in this coupling process has led to an asymmetric synthesis of (-)-steganone,3 podophyllotoxin,4 (-)-schizandrin,5 and (+)-phylictralin.6 The synthesis of (-)-schizandrin is sketched in Scheme 2. 

When the TMS group is absent and if the reaction is carried out in methanol, a platinum(ll)-catalyzed alkoxycy-clization takes place (Scheme 87).308 This cyclization catalyzed by Pt(ll) was found to be mechanistically similar to the carbohydroxypalladation reported by Genet.309 310 This process has intrinsic importance in organic synthesis since it allows the simultaneous and generally stereoselective formation of a C-O and a C-C bond to occur from an enyne system. This reaction has been applied for the synthesis of a key intermediate of podophyllotoxin.311... 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

Tu SJ, Zhang Y, Zhang JY, Jiang B, Jia RH, Zhang JP, Ji SJ (2006) A simple procedure for the synthesis of 4-aza-podophyllotoxin derivatives in water under microwave irradiation conditions. Synlett 2785-2790... 

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. 

Synthesis of podophyllotoxin (3.86) in cell culture of Linum album results in yields comparable to those of the most efficient tissue cultures of Podophyllum hexandrum. In order to further improve L. album cultures, Seidel et al. (2002) investigated the biosynthesis of podophyllotoxin (3.86). They fed a number of labeled compounds that to L. album cell cultures to identify which of these compounds could be used as precursors to podophyllotoxin. They determined that the substitution pattern on the benzene ring is critical. The substitution has to be either 3-methoxy, 4-hydroxy, as in ferulic acid (3.33), or, alternatively, 3,4-methylenedioxycinnamic acid (3.90) can serve as precursor. The precursor of podophyllotoxin in L. album appears to be deoxypodophyllotoxin (3.83), based on the higher level of isotope incorporation in the latter compound. This means that 7-hydroxymatairesinol, the precursors of 5-methoxypodophyllotoxin in L. flavum (Xia et al., 2000), is not a precursor of podophyllotoxin in L. album. 

There have been many succesful syntheses of tricyclic structures by Diels-Alder reactions of the o-xylylenols formed from o-alkylphenyl ketones. Below is an intramolecular example aimed at the synthesis of podophyllotoxin [75]. 

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