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A novel synthesis of NMDA receptor antagonist LY235959 (1) has been achieved in 13% overall yield and 17 steps from (R)-pantolactone (7). Highlights of the synthesis include (a) use of a chiral auxiliary controlled asymmetric Diels-Alder reaction to provide the desired absolute and relative stereochemistry at C-4a, C-6, and C-8a, (b) an efficient alkylation of hindered iodide 13 using a novel amide benzophenone imine, (c) oxidative ring opening of the [2.2.2] bicyclic system to simultaneously functionalize the molecule for intramolecular cyclization and phosphonate introduction, and (d) an increased understanding of how the C-3 stereochemistry may be controlled by thermodynamic equilibration. Synthesis of epimer 20 in high overall yield makes this synthetic route attractive for future development efforts.

Synthetic studies on LY228729 (3) afforded two innovative approaches for the construction of this class of partial ergoline 5HT 1a receptor agonists. The first synthesis is based upon a diastereoselective epoxidation of racemic olefin 5, followed by ring opening and covalent resolution to furnish the key amino alcohol 8. Aziridination of amino alcohol 8, with subsequent tandem hydrogenolysis of the benzylic aziridine and auxiliary bonds, provided access to the optically active primary amine 13. A novel catalytic carboxamidation reaction installed the requisite side chain. Alternatively, the chiral pool was drawn upon for the single stereogenic center by virtue of L-tryptophan, albeit by a more circuitous route than expected. L-Tryptophan was differentially protected and reduced to the indoline diastereomers 26a,b which were separated by fractional crystallization. The two indoline diastereoisomers were independently cyclized by a Friedel-Crafts protocol, which under thermodynamic control afforded enantiomeric ketones 30a. The ketone was deoxygenated with a two-step reduction protocol to intersect the initial route and complete the second total synthesis. The two routes offer complementary access to this exciting class of partial ergot alkaloids.