Asymmetric synthesis of -podophyllotoxin

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

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. 

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. 

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]. 

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]. 

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. 

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. 

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