Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.

The development of efficient methods for the facile construction of important molecular architectures is a central goal in organic synthesis. An unprecedented organocatalytic asymmetric cascade Michael-alkylation reaction of alpha,beta-unsaturated aldehydes with bromomalonates has been developed. The process, efficiently catalyzed by chiral diphenylprolinol TMS ether in the presence of base 2,6-lutidine, serves as a powerful approach to the preparation of synthetically and biologically important cyclopropanes in high levels of enantio- and diastereoselectivities. Remarkably, the power of the cascade process is fueled by its high efficiency of the production of two new C-C bonds, two new stereogenic centers, and one quaternary carbon center in one single operation, which otherwise is difficult to achieve by traditional strategies. Moreover, the beauty of the cascade process is further underscored by the nature of the product formation depending on the reaction conditions. With the alternation of base from 2,6-lutidine (1.1 equiv), which is effective for the cyclopropanations, to NaOAc (4.0 equiv), the spontaneous ring-opening of cyclopropanes takes place to lead to stereoselective (E) alpha-substituted malonate alpha,beta-unsaturated aldehydes. A possible reaction mechanism, which involves a Michael-alkylation-retro-Michael pathway, is proposed and verified by experimental studies. This investigation represents the first example of an organocatalyst-promoted ring opening of the cyclopropanes, whereas such reactions have been intensively explored by Lewis acid-based catalysis.

We report the total synthesis of (±)-aspidophylline A, one of many complex furoindoline-containing alkaloids that has not been synthesized previously. Our route features a number of key transformations, including a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold as well as a late-stage interrupted Fischer indolization to install the furoindoline and construct the natural product's pentacyclic framework.

A highly enantioselective (S) diphenylpyrrolinol silyl ether promoted tandem Michael-aldol reaction of alpha,beta-unsaturated aldehydes with 2-mercaptobenzaldehydes has been developed. The method affords one-pot access to chiral and synthetically useful thiochromenes in high yields and high enantioselectivities from readily available compounds.

[reaction: see text] A novel binaphthyl-derived amine thiourea organocatalyst has been developed and demonstrated to efficiently catalyze Michael addition reactions (using as low as 1 mol % loading) of diketones to nitroalkenes with remarkably high enantioselectivities.