Total Synthesis Highlights
Total Synthesis Highlights
Total Synthesis Highlights
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85. <strong>Total</strong> <strong>Synthesis</strong> of Ingenol<br />
The total synthesis of the tetracyclic Euphorbia tetraol ingenol 3 reported by Keiji Tanino of<br />
Hokkaido University (J. Am. Chem. Soc. 2003, 125, 1498.) illustrates the power of<br />
diastereoselective carbocationic rearrangements, as exemplified by the conversion of 1 to 2.<br />
The construction of the tricyclic epoxide depended on several highly diastereoselective<br />
transformations. The addition of lithio t-butyl acetate to ketone 4 proceeded to give 5 as a single<br />
diastereomer, even though the ketone is flanked by a quaternary center. The authors speculate that<br />
lithium chelation with the methyl ether directed addition. Even more spectacular was the<br />
cyclization of the propargylic acetate 7 to 10. The Co complex activated the acetate for ionization,<br />
while at the same time establishing the proper geometric relationship for bond formation.<br />
Dissolving metal reduction of the Co complex then gave the alkene.<br />
The elegant pinacol rearrangement of 1 to 2, mediated by (ArO) 2 AlCH 3 , exposed a ketone that<br />
might usually need to be protected. In this case, however, the ketone is so buried in the<br />
inside-outside ingenol skeleton that it is unreactive. After several further manipulations, a<br />
spectacular osmylation of the diene 12 led to ingenol 3, in an overall 45-step sequence.<br />
The ingenol 3 prepared by this route was racemic. It is interesting to speculate how one might<br />
efficiently prepare 4 or its precursors in enantiomerically-pure form.