Wednesday, June 13, 2012

R. E. Ireland's Total Synthesis of Racemic Germanicol

In celebration of the contributions of Robert Ellsworth Ireland to the field of organic synthesis, we will examine Ireland's classic total synthesis of germanicol, conducted in collaboration with the laboratory of W. S. Johnson and disclosed in JACS in 1970. This work constituted the first synthesis of a complex and unsymmetrical pentacyclic triterpene and its efficiency remained unrivaled until 2008 when Corey described a formal synthesis of germanicol that was significantly shorter than the 32 step campaign of Ireland/Johnson (0.1% yield). Ireland's preparation of germanicol constructs rings A-C in the early stages and appends the final two rings by means of a conjugate addition of a benzylic Grignard reagent to a key exocyclic enone intermediate.
The early tricyclic intermediate 4 is first prepared in seven steps from the Wieland-Miescher ketone derivative 3. Functionalization and subsequent annulation of the pro-C13 and C14 carbons was then required to introduce the terpenoidal D-ring. This was accomplished by the initial formation of an olefinic ketal (5) through standard functional group interconversions. Oxidation of the pro-C13 position to the requisite ketone is then achieved by exposure of the olefin to singlet oxygen (generated in situ from molecular oxygen in the presence of a sensitizer with irradiation) in combination with a reducing agent. Under these conditions, a Schenck ene reaction ensues and the intermediate alkyl peroxide is reduced by LAH to give a secondary alcohol. Oxidation of this alcohol with hexavalent chromium in the subsequent step secures the key enone intermediate 6 that is poised to undergo smooth conjugate addition with meta-methoxybenzylmagnesium chloride to give 2.
Intermediate 2 is advance to 7 in two straight-forward operations and cyclization of 7 occurs upon treatment with polyphosphoric acid for 30 minutes at room temperature. This efficient protocol affords the pentacyclic intermediate 8 in 90% yield. Nine additional steps are then required to install one angular methyl group, adjust the oxidation states of several carbon positions across rings C-E and, finally, to install one unit of unsaturation in the E-ring (enone C-C double bond). In the endgame of the germanicol synthesis, deconjugation of the E-ring double bond precedes a base-mediated double-methylation reaction. Finally, a Wolff-Kishner reduction of the extraneous E-ring carbonyl results in totally synthetic (+/-)-germanicol. Ireland's laboratory subsequently developed a general convergent synthesis of pentacyclic triterpenes that was used to make additional triterpenoid natural products including alnusenone and friedelin.

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