Andrew D. Gibb

Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP-4 Inhibitor

A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.

Synthesis of an Estrogen Receptor Beta Agonist

Significance: The target tetrahydrofluorene is an estrogen receptor β agonist that is of interest for the treatment of symptoms associated with reduced estrogen levels in post-menopausal women. The large-scale synthesis depicted features a chiral auxiliary mediated dialkylation to construct the quaternary center in G with excellent stereocontrol. Note the intramolecular enolate alkylation F → G in which phenoxide ion is the leaving group. Comment: This route delivered more than 30 kg of drug candidate in 21% overall yield through a longest linear sequence of 13 steps and with >99% ee. For syntheses of related tetrahydrofluorenes, see: M. A. Huffman et al. Tetrahedron 2007, 63, 4459; J. P. Scott et al. Org. Process Res. Dev. 2008, 12, 723; D. J. Wallace, R. A. Reamer Tetrahedron Lett. 2013, 54, 4425. N O