Of ingenol

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). 

In contrast to the extensively developed type-I intramolecular [4+3] cycloadditions as illustrated above, type-II intramolecular [4+3] cycloadditions with cation moieties tethered to the 3-position of furans have not been shown to be versatile transformations. As shown in Equation (51), an attempt on the cycloaddition of furan 69 only resulted in a low yield of the fused tricycle product that resembled the BC ring of ingenol <2003JOC7899>. 

As shown in Equation (52), the intramolecular [6+4] cycloaddition between a furan and a tropone was successfully achieved for the first time during the construction of the highly functionalized ABC ring of ingenol <2005SL2501>. 

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>. 

Matsumoto T, Cyong JC, Yamada H. Stimulatory effects of ingenols from Euphorbia kansui on the expression of macrophage Ec receptor. Planta Med. 1992 58 255-258. 

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

Cyclization-reairangement. Intramolecular capture of a propargyl cation, which is stabilized by hexacarbonyldicobalt complexation at the triple bond by the double bond of an ally lie alcohol, is followed by rearrangement to give a cyclic ketone. The tricyclic portion of ingenol is thereby created. The present organoaluminum catalyst appears to be the most efficient among those screened. 

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. 

A synthetic route that provides rapid access to the tetracyclic core of ingenol was recently described by Cha in which a Shapiro reaction is used for the construction of a key C-C bond.23 As shown below, treatment of trisylhydrazone 41 with two equivalents of r-BuLi followed by addition of hindered ketone 42 provided allylic alcohol 43 in 75-88% yield. The carbonyl addition occurred with high diastereoselectivity for approach of the nucleophile from the less hindered face. Alcohol 43 was converted to the tetracyclic core of the natural product (44) via a 7-step sequence. 

Hydride shift. An alkoxide-accelerated hydride shift establishes the [in,out] bridgehead configurations that are characteristic of ingenol. Thus, heating a dicarbocyclic dienol with KH/18-crown-6 in dioxane gives the desired enone in 64% yield. ... 

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. 

Obviously, metal-assisted higher-order cycloadditions offer unique and efficient entries into the intricate molecular structures of a number of natural product targets. For example, the BC ring system of ingenol 51 can be readily assembled by employing [6-1-4] reaction (Scheme 15) [29]. 

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... 

Contractions of larger rings to seven-membered rings have also been investigated. Funk reported the Ireland-Claisen rearrangement of a macrocyclic lactone to provide the in-out bicyebe core of ingenol (Eq. 32). ... 

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). ... 

Some cycloadditions can be used to simultaneously generate two rings and one is a seven-membered ring. An example of this approach is found in the work of Rigby directed at the preparation of ingenol through an impressive [6+4] cycloaddition (. 46). The reaction... 

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

The second exanple is more recent and was a critical part of a 14-step, gram-scale synthesis of ingenol (54, Scheme 1.81 by the Bar an research group. This case illustrates that the... 

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

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