SYNTHETIC STUDIES TOWARD THE PARTIAL ERGOT ALKALOID LY228729, A POTENT 5HT(1A) RECEPTOR AGONIST

Synthetic studies on LY228729 (3) afforded two innovative approaches f or the construction of this class of partial ergoline 5HT(1a) receptor agonists. The first synthesis is based upon a diastereoselective epox idation of racemic olefin 5, followed by ring opening and covalent res olution to furnish the key amino alcohol 8. Aziridination of amino alc ohol 8, with subsequent tandem hydrogenolysis of the benzylic aziridin e and auxiliary bonds, provided access to the optically active primary amine 13. A novel catalytic carboxamidation reaction installed the re quisite side chain, Alternatively, the chiral pool was drawn upon for the single stereogenic center by virtue of L-tryptophan, albeit by a m ore circuitous route than expected. L-Tryptophan was differentially pr otected and reduced to the indoline diastereomers 26a,b which were sep arated by fractional crystallization. The two indoline diastereoisomer s were independently cyclized by a Friedel-Crafts protocol, which unde r thermodynamic control afforded enantiomeric ketones 30a. The ketone was deoxygenated with a two-step reduction protocol to intersect the i nitial route and complete the second total synthesis. The two routes o ffer complementary access to this exciting class of partial ergot alka loids.