Total synthesis of phorbol

An enyne cycloisomerization was employed in Wender and McDonald s second-generation formal total synthesis of ( )-phorbol (128) (Scheme 6-21) [49]. In this impressive example, enyne 126 was cyclized in 58% yield to provide tricycle 127. Apparently, a tricyclic alkylpalladium intermediate is reduced in situ with (Mc2SiH)20 prior to / -hydride elimination, preventing diene formation. 

Scheme 6-21 An enyne cycloisomerization from a formal total synthesis of ( )-phorbol.

Wender incorporated this strategy into the synthetic plan for the first total synthesis of phorbol, whereby intermediate 249 was subjected to lithium-iodine exchange to yield alkenol 250, Eq. 153 [199]. 

Conceptually, a [5+2] cycloaddition involves the reaction of a five-atom species with a two-atom species. The most commonly encountered examples of such [5+2] cycloadditions are the reactions of oxidopyrylium and oxidopyridinium ions with various alkenes and alkynes. Originating more than 40 years ago with the investigations by Wood and Hurd, and continuing with contributions from Weeks, I tritzky, Sammes, Wender, and Williams, this class of [5+2] cycloadditions has serviced a number of synthetic objectives. One of the most complex examples of this process has figured in the first total synthesis of phorbol (Eq. 42), a remarkably demanding prob-... 

Finally, in a very recent disclosure, Lee et al. (165) approached the total synthesis of arteminolide using a [5 + 2] cycloaddition strategy with an oxidopyrylium ion. Despite its long history of use, Lee was the first to utilize an allene moiety both in an intra- and an intermolecular cycloaddition with oxidopyrylium ions. By utilizing a pyrone cycloaddition precursor (294) similar to those used in the Wender phorbol synthesis, Lee was able to synthesize various ring sizes and... 

The total yield of 201 was increased and the synthesis time reduced by extracting [nC]butyric acid from its lithium salt by dry 0.1% HCl/He gas mixture and carrying out its pyrolysis at 530 °C over glass beads (equation 104). The relative reactivity of 201 to primary, secondary and tertiary alcohols (equation 105a, b, c) has been found to be as 1 0.4 0.1, respectively. Several bioactive compounds have been labelled with [nC]propyl ketene, such as carbohydrate compounds193 and IV-butyl compounds, for instance /V- 11 C]butyryl THPO, 202, and some phorbol esters192, 203, 204 and 205. 

Stimulation of HA synthesis also occurs following phorbol ester (PMA) and PDGF treatment, although a direct effect on HAS has not been demonstrated. Glucocorticoids induce a nearly total inhibiton of HAS mRNA in dermal fibroblasts and osteoblasts.183 Extracts of dermal fibroblasts indicate that HAS-2 is the predominant HA synthase therein. This may be the molecular basis of the decreased HA in glucocortcoid-treated skin. However, an additional effect on rates of HA degradation has not been examined. 

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