Synthesis of - -Podophyllotoxin

2003) complementary total syntheses of 1 and of its enantiomer,. The key step in each of these syntheses is a spectacular intramolecular alkene arylation, exemplified by the conversion of 4 to 5. 

The absolute configuration of 1 was set by conjugate addition to the oxazoline 3 followed by trapping of the product anion, following the precedent of Meyers. Reduction of the oxazoline to the alcohol followed by thionocarbonate formation then set the stage for the key aryl transfer reaction. 

The aryl transfer is thought to be initiated by addition of the silyl radical to the thiocarbonyl. The radical so formed adds to the alkene to generate the benzylic radical 7. This radical adds to the arene to give 8, which fragments to 5. 

Oxidation of the silyl group of 5 to the ketone followed by Pd-mediated decarboxylation led to the ketone 9. The conversion of 9 to podophyllotoxin 1 followed the literature precedent. 

We last reviewed organic synthesis applications of the Grubbs reaction on April 19, 2004. The (relatively) robust nature of the commercially-available catalyst and its commercial availability have spurred the expanding exploration of the scope of this reaction. Through this month, we will feature some recent highlights. 

FRIEDEL-CRAFTS ALKYLATION OF ARENES IN TOTAL SYNTHESIS 

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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).

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

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]. 

The 2,4,6-triisopropylbenzophenone chromophore has been incorporated into a polymer in order to examine whether the photocyclisation to a benzocyclobutenol could be used as the basis for a photoresponsive polymer material. Benzocyclobutenol formation has also been used to prepare a potential synthon for the synthesis of podophyllotoxin thus benzophenones (384) have been converted to benzocyclobutenols (385). The reaction is highly regioselective and yields the stereochemistry expected from thermal electrocyclic ring closure of an E,E enol (386), which is in agreement with the conclusions of Wagner described above. 

Scheme (35). Asymmetric synthesis of (-)-podophyllotoxin by Jones and co-workers...

Lithiated a-amino nitriles derived from an enantiomerically pure secondary amine have been used to achieve the asymmetric synthesis of trfl 5-dibenzylbutyrolactones (scheme 10) [58]. Enantiomeric excesses of greater than 96% were obtained after removing the chiral auxiliary. When aromatic aldehydes were used as electrophiles the benzylic alcohols were obtained as a mixture of the two epimers with a diastereomeric excess of 60-75%. Addition of a chiral sulfoxide, prepared using a modified Sharpless oxidation, to butenolide has also been utilised as part of an expeditious synthesis of podophyllotoxin (scheme 11) [59]. 

In contrast, Rodrigo et al. have used the isobenzofuran adduct (117) as the key intermediate in their synthesis of podophyllotoxin derivatives (scheme 40) [99]. Stereoselective reduction of the carbon-carbon double bond followed by hydrogenolysis affords access to the isopodophyllotoxin series,. whereas C-3 epimerisation prior to... 

Diels Alder reactions have been used in several asymmetric syntheses of podophyllotoxin and its stereoisomers. Thus, Choy used the benzocyclobutene (120) as the diene precursor and a non-racemic butenolide as the dienophile in his synthesis of (-)-epiisopodophyllotoxin (106) (scheme 42) [101]. However, the unfortunate regioselectivity of the Diels Alder reaction makes the overall synthesis unnecessarily lengthy. In contrast, Charlton et al. used the aldehyde (105) as the diene precursor and a non-racemic fumarate as the dienophile in their synthesis of podophyllotoxin (113) (scheme 43) [102,103]. 

Intramolecular Diels Alder reactions have also been employed. Macdonald and Durst used a urethane linkage to attach the dienophile to a benzocyclobutene in (125), leading ultimately to podophyllotoxin (113) (scheme 46) [110], Another synthesis of podophyllotoxin by Kraus and Wu involves a Diels Alder reaction of a photo-enol to which the dienophile is attached by an acetal linkage (scheme 47) [111]. Unfortunately, the later steps proceed in low yield and involve epimerisation at C-2 to give picropodophyllone (126). 

Finally, Meyers et al. have carried out an asymmetric synthesis of (-)-podophyllotoxin involving conjugate addition to an aryl oxazoline (scheme 59) [129]. The penultimate step involves C-2 epimerisation favouring the cw-1,2-geometry. 

Synthesis of Podophyllotoxin glucoside derivatives(VI) from compound (I )... 

This strategy was recently used in a key step in the asymmetric total synthesis of (-)-podophyllotoxin. In this case, high e/uto-selectivity and high facial selectivity were observed, and only one Diels-Alder product is formed. 

Scheme 5 Total synthesis of podophyllotoxin via Pd-catalyzed directed C-H arylation...

SCHEME 15.5 (a) Synthesis of podophyllotoxin (13) via anionic oxidative dearomatization, (b) Anionic dearomatization-alkylation of a simple oxazolinyl arene en route to carbocychc sugar analogues. 

Scheme 4.51 Oxidative approach in the total synthesis of podophyllotoxin (20S).

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