Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals.

Although transfer of electrophilic alkoxyl ("RO+") from organic peroxides to organometallics offers a complement to traditional methods for etherification, application has been limited by constraints associated with peroxide reactivity and stability. We now demonstrate that readily prepared tetrahydropyranyl monoperoxyacetals react with sp(3) and sp(2) organolithium and organomagnesium reagents to furnish moderate to high yields of ethers. The method is successfully applied to the synthesis of alkyl, alkenyl, aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl peroxides, the displacements of monoperoxyacetals provide no evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an SN2 mechanism. Theoretical studies suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O-O bond.

Synthesis of alkyl hydroperoxides via alkylation of gem-dihydroperoxides.

2-Fold alkylation of 1,1-dihydroperoxides, followed by hydrolysis of the resulting bisperoxyacetals, provides a convenient method for synthesis of primary and secondary alkyl hydroperoxides.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

Synthesis of S,S,O-orthoesters and 1,1-difluoroalkyl ethers via reaction of peroxides with lithiated 1,3-dithianes.

Alkyl tetrahydropyranyl peroxides (ROOTHP) transfer alkoxide (OR) to lithiated 1,3-dithianes. The derived S,S,O-orthoesters undergo fluorodesulfurization with HF/pyridine and N-bromosuccinamide (NBS) to furnish difluoromethyl ethers. The overall protocol can be applied to synthesis of both terminal (ROCF2H) and internal (ROCF2R') ethers. Application of the same set of reactions to a lithiated tris(alkylthio)alkane is shown to generate a trifluoromethyl ether.