Phorbol skeleton

Shibasaki and co-workers (47) modified bis(oxazoline) (55c) by slightly increasing the steric demand and found that the resulting ligand-copper complex exhibited good facial selectivity in the intramolecular cyclopropanation of enolsilanes. Enantioselectivity was improved from 78% for 55c to 92% for 55e. The product cyclopropane (73) is a component of the phorbol skeleton. 

Shibasaki and co-workers used an intramolecular nitrile oxide cycloaddition to prepare the skeleton of phorbol (272) (Scheme 6.99), a tumor promoter that activates protein kinase C (PKC) (333). Nitroalkene 268 was elaborated in several steps from (+)-3-carene (267) and was subjected to cycloaddition by means of -chlorophenyl isocyanate-triethylamine to give cycloadduct 269 in 88% yield. Reductive hydrolysis employing Raney Ni and boric acid afforded hydroxyketone 270, that was subsequently used for the construction of the optically active derivative 271, which contains the phorbol skeleton (333). 

The phorbol skeleton to yield 61 was also assembled in one step via rhodium catalyzed carbenoid formation, Eq. 42 [71]. 

Scheme 102.6 The biosynthesis of tetracyclic diterpenoids based on (a) ent-kaurene and (b) phorbol skeletons...

The Cu semicorrin complex (68a) has been successfully used as the catalyst for cyclization of alkenyl diazoketones, though the reactions of some substrates showed modest enantioselectivity (Scheme 74).276 Shibasaki et al. have successfully used the cyclization of diazoketone with Cu bis(oxazoline) (101) for the construction of the CD ring skeleton of phorbol.277... 

Plants of the Euphorbiaceae family and particularly members of the Euphorbia genus have long been known to yield latexes with irritant and carcinogenic properties and these properties have been associated with diter-penes of the phorbol class. Members of the Euphorbia genus also contain diterpenes with other skeletons, among them the ingenane derivative PEP005 (38). " ... 

Aza Analogues of the Tricyclic Skeleton of Daphnane and the ABC Ring System of Phorbol... 

The 5-7-6-tricyclic framework exists in many natural products, which often shows biological activities. For example, phorbol 40 (Figure 5.1) is extensively used in studies of tumor promotion because of its ability to activate protein kinase The related 5-7-6 daphnane skeleton is exemplified by the antileukemic agent gnidilatin (41) and by the irritant resiniferatoxin, which also possesses analgesic properties. However, the stereocontrolled construction of such 5-7-6-tricyclic systems is still a challenge. ... 

Diterpenes.— Diterpenes may also display structures which are based on an azulene skeleton, compounds typical of this class being phorbol (80), ... 

In Scheme 102.6b reports the key biosynthetic steps for the formation of atisane-type diterpenoids based on a tigliane tetracyclic skeleton whose consecutive oxidation affords phorbol that is esterified in nature giving rise to phorbol ester such as that shown in the Scheme, 12-O-myristoylphorbol 13-acetate. 

Lee et al. reported an intermolecular [4+3] cycloaddition route to the skeleton of tigliane diterpene phorbol 59... 

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