Total Synthesis of Ingenol

The total synthesis of the tetracyclic Euphorbia tetraol ingenol 3 reported by Keiji Tanino of Hokkaido University (J. Am. Chem. Soc. I25 I498, 2003) illustrates the power of diastereoselective carbocationic rearrangements, as exemplified by the conversion of 1 to 2. 

The elegant pinacol rearrangement of 1 to 2, mediated by (ArO)2AlCH3, exposed a ketone that might usually need to be protected. In this case, however, the ketone is so buried in the inside-outside ingenol skeleton that it is unreactive. After several further manipulations, a spectacular osmylation of the diene 12 led to ingenol 3, in an overall 45-step sequence. 

The ingenol 3 prepared by this route was racemic. It is interesting to speculate how one might efficiently prepare 4 or its precursors in enantiomerically-pure form. 

Benzyl ethers are among the most commonly used protecting groups for alcohols. Usually, these are prepared using an excess of NaH and benzyl bromide. Okan Sirkecioglu of Istanbul Technical University has found (Tetrahedron Lett. 44 8483, 2003) that heating a primary or secondary alcohol neat with benzyl chloride and a catalytic amount of Cu(acac)2 smoothly yields the benzyl ether, with evolution of HCI. The reaction can also be run in solvent THF, but it proceeds more slowly. Note that primary alcohols react more quickly than secondary alcohols. 

Several years ago, Jim-Min Fang of National Taiwan University reported that an aldehyde 9 was smoothly converted into the corresponding nitrile 10 by iodine in aqueous ammonia. He has now observed (J. Org. Chem. 68 1158, 2003) that the intermediate nitrile can be carried on in situ to the amide 11, the tetrazole 12, or the triazine 13. 

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A synthetic application is demonstrated by Tanino and his co-workers who reported a total synthesis of ingenol 14 using this methodology.Use of methylaluminum bis(2,6-dimethyl-4-nitrophenoxide) promoted both cyclization and following rearrangement reactions smoothly to construct an ingenane skeleton 15 (Scheme 2). 

During the total synthesis of (+)-ingenol by I. Kuwajima and co-workers, an advanced tricyclic diol intermediate was... 

The Corey-Kim protocol was successfully applied late in the multi-step total synthesis of ingenol (51) to convert diol 49 to a-ketol 50 where it was the less hindered hydroxyl group that was selectively oxidized.14 The newly formed ketone was then used to construct the allylic alcohol moiety of ingenol after several steps. 

Tanino, K.,Ontiki,K., Asano, K.era/. (2003) Total synthesis of ingenol.7oMrna/o/t/ eAmencan Chemical Society, 125, 1498-1500. 

Scheme 1.19 Use of a semipinacol rearrangement to access unique core in the total synthesis of ingenol...

Scheme 1.8 Use of a vinylogous pinacol rearrangement as part of the total synthesis of ingenol (54). ...

Kigoshi s formal synthesis (Scheme 1.54) relies on the efficient spirocyclization reaction of ketone 296 also prepared from 3-carene. The AC ring system was then further elaborated into 1,8-diene 298 that could be cyclized to 299 in 87% yield using [Ru]-II (25 mol%). A dramatic temperature and solvent effect was observed as no reaction took place in dichloromethane. AUylic oxidation then delivered aldehyde 300, an intermediate in Winkler s total synthesis of ingenol [74]. 

Additions to Cyclohexenones and Related Systems. Irradiation of the diox-enone derivative (29) in acetonitrile-acetone at 0°C affords the adduct (30) in 60% yield. This compound was a key intermediate in the first total synthesis of racemic ingenol. A further study has shown that the enone (31) also undergoes cycloaddition on irradiation under the same conditions. This yields the adduct... 

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