Ergot alkaloids, exhibiting what is arguably the greatest diversity of pharmacological activity of any class of natural products, are an ideal chemical starting point from which to produce a range of libraries as probes of new biological targets. The high density of bioactivities among the naturally occurring members of this class, ranging from neuroreceptor agonism and antagonism to tyrosine kinases inhibition, suggests that constructing a synthetic library of analogous structures would yield a large number of active compounds. The fact that seemingly small changes in the structure of ergolines can produce striking differences in pharmacology also lends credence to the idea that such a library would exhibit a wide spectrum of activities.
The aims of the current project are to construct such a library by varying constituents on the A (phenyl) ring of the two primary classes of ergot alkaloids: lysergamides and clavinets. In order to achieve this goal, a recently published total synthesis of the lysergic acid nucleus is used as a starting point to design a new route to lysergamides and clavinets which is optimized for library production, allowing rapid synthesis of variants of the lysergic acid nucleus from phenylhydrazines in only four steps or from ortho-iodoanilines in five. As an added bonus, the method allows, through incorporation of conjugated A-ring constituents, for tuning of the natural fluorescence wavelength of lysergamides to yield a set of biological probes with inherent self-reporting fluorescence properties. ? ? ?
| Burley, Scott D; Lam, Vicky V; Lakner, Frederick J et al. (2013) New route to the ergoline skeleton via cyclization of 4-unsubstituted indoles. Org Lett 15:2598-600 |
