7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.

Cyclization reactions of donor-acceptor (D-A) cyclopropanes are recognized as versatile methods for construction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular reactivity of donor-acceptor cyclopropanes is widely reported, reviews that center on their intramolecular chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor-acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D-A acceptor cyclopropanes as reactive subunits in natural product synthesis is underscored.

Scheme 1. In(OTf) 3 -catalyzed cycloisomerizations of 3,3-dicarbonyl cyclopropene substrates. Tf = trifluoromethanesulfonyl.Scheme 2. Rhodium(II)-catalyzed cyclopropenation.

A general protocol for the catalytic homo-Nazarov cyclization of cyclopropyl heteroaryl ketones has been developed, which employs indium triflate as the promoter. A range of heteroaromatic ring-fused cyclohexanones was synthesized in 56-91% yield using this protocol. An example of a tandem cyclopropanation/homo-Nazarov cyclization is also reported in which the one-pot yield is greater than the overall yield of the two individual steps.

Herein, an efficient Lewis acid catalyzed protocol for the homo-Nazarov cyclizations of alkenyl cyclopropyl ketones is reported. Alkenes bearing β-hydrogens (or silyl groups) provide 1.5:1 mixtures of methylene cyclohexenols and cyclohexenones. When no β-hydrogens (or silyl groups) are present, only cyclohexenones are observed. Products are rapidly formed in good to high yields (up to 93%) under mild conditions and could be readily derivatized.