Synthesis ingenol

Indoline synthesis 38,143 Indolizidine synthesis 8, 30, 182 Ingenol synthesis 14, 134 Ionic Liquid... 

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). 

The total synthesis of the tetracyclic Euphorbia tetraol ingenol 3 reported by Keiji Tanino of Hokkaido University (J. Am. Chem. Soc. I25 1498,2003) illustrates the power of diastereoselective carbocationic rearrangements, as exemplified by the conversion of 1 to 2. 

Natural Product Synthesis Using Grubb Metathesis Lasubine II, Ingenol, and Ophirin ... 

A number of different furan-based approaches to the synthesis of 7-membered ring systems were reported in 2003. In the novel example shown below, the furan participated in an intramolecular [4+3] cycloaddition with nitrogen-stabilized chiral oxyallyl cation to form polycyclic structures <03JA12694>. Attempts to construct the [4.4.1] bicychc BC ring system of ingenol via a type-II intramolecular [4+3] cycloaddition between furan and an oxyallyl cation produced the desired product but only in 14% yield <03JOC7899>. 

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

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... 

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 and Kuwajima used a guanidine base promoted elimination reaction in the synthesis of ingenol (110) [33]. Reaction of ketone 108 with MTBD resulted in an elimination reaction and subsequent isomerization to give conjugated diene 109, which was efficiently led to ingenol (110) (Scheme 7.23). 

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

In studies directed toward the synthesis of ingenol, Kuwajima investigated Lewis acid catalysis for seven-membered ring formation. Initial cyclization and subsequent rearrangement provides a bridged bicyclo[4.4.1] system (Eq. 6), incorporating the rather exotic in-out... 

Winkler employed a photochemical approach to the in-out tricyclic core of ingenol, beautifiilly illustrating the utility of a fragmentation strategy in complex molecule synthesis (Eq. 33). ... 

The ingenol diterpenes are very important synthetic targets, due to their impressive structures and biological activities, reinforced by the recent drug approval of Picato (ingenolmebutate) gel for treatment of actinic keratoses. The synthesis shown in Scheme 23 requires the RCM to close the central seven-membered ring, on the way to an oxyingenol derivative [58]. 

The Winkler laboratory has made significant contributions to the synthesis of the important diterpene ingenol. The two seven-membered rings intercoimected by a one-carbon bridge, with the in-out stereochemistry, represent a formidable challenge. The Winkler approach utilizes exactly the de Mayo sequence, before the final elaboraticHis (Scheme 56) [93]. 

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