Ingenol esters

The major stmctural types known are the phorbol esters [e.g., a tigliane from Sapium japonicum (17)] Croton, Sap-ium, Aleurites, Mancinella, Baliospermum, and Euphorbia), ingenol esters [e.g., ingenane (18)] Euphorbia), and daph-nanes [e.g., daphnetoxin (19)] Euphorbia, Hura, Hip-pomane, Excoecaria, Baliospermum, Thymelaeaceae) (Fig. 22.7) most of the plants that contain these diterpenes are in subfamilies Crotonoideae and Euphorbioideae (Kinghom, 1979 Webster, 1975). 

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

A number of plant toxins are cyclic members of this series. Huratoxin is the piscicidal constituent of Hura crepitans (Euphorbiaceae). X-Ray analysis showed 34 jjg structure [117 R - H, R = CH CH-CH CH(CH2)8Me] was related to daphnetoxin (117 R = H, R = Ph). Mezerein (117) which is the toxic principle of Daphne mezereum, containsthe cinnamylidene acetic ester (R ) and orthobenzoate (R ) units. Ingenol (118), as its 3-hexadecanoic acid ester, is an irritant isolated from Euphorbia ingens Its structure was determined by X-ray analysis of the triacetate. 

A, 1,6 rearrangement of macrocyclic lactone 14, prepared from ( + )-carene via enantiomeri-cally pure hydroxy ester 13, is used in the construction of the tricyclic ingenol precursor 16. which allows the rare in-out bridged bicyclic stereochemistry to be controlled. The stereochemistry of 16 arises from a boatlike transition state559. 

Ingenol-3-hexadecanoate is one member of a structurally diverse group of compounds, including the phorbol esters, the teleocidins, and the aplysiatoxins, which are believed to promote tumor formation by activating protein kinase C. 

Photocycloaddition of the allylic chloride 246 proceeds in 60% yield to give the desired photoadduct 247. Fragmentation of 247 with methanolic potassium carbonate generates ester 248. Reduction of the ester with lithium aluminium hydride, elimination of the chloride with DBU, and silylation of the primiary alcohol with tert-butyldimethylsilyl chloride (TBSCl), give 249 as a 7 1 mixture of the C-6 a [3 epimers in 35% yield from 247. Ingenol is derived from 247 in a 24-step sequence. 

---