Yusuke Ogura

Involvement of 14-3-3 proteins in the second epidermal growth factor-induced wave of Rac1 activation in the process of cell migration.

Background: The spatiotemporal regulation of Rac1 controls cell migration. Results: EGF induced two waves of Rac1 activation in the process of cell migration. Conclusion: 14-3-3 proteins regulate the second EGF-induced wave of Rac1 activation by interacting with RacGEF. Significance: The second wave of Rac1 activation might be required for EGF-induced cell migration. Immense previous efforts have elucidated the core machinery in cell migration, actin remodeling regulated by Rho family small GTPases including RhoA, Cdc42, and Rac1; however, the spatiotemporal regulation of these molecules remains largely unknown. Here, we report that EGF induces biphasic Rac1 activation in the process of cell migration, and UTKO1, a cell migration inhibitor, inhibits the second EGF-induced wave of Rac1 activation but not the first wave. To address the regulation mechanism and role of the second wave of Rac1 activation, we identified 14-3-3ζ as a target protein of UTKO1 and also showed that UTKO1 abrogated the binding of 14-3-3ζ to Tiam1 that was responsible for the second wave of Rac1 activation, suggesting that the interaction of 14-3-3ζ with Tiam1 is involved in this event. To our knowledge, this is the first report to use a chemical genetic approach to demonstrate the mechanism of temporal activation of Rac1.

Total Synthesis of Amphirionin-4

An expeditious enantioselective total synthesis of amphirionin-4, a remarkably potent promoter of the proliferation of ST-2 cells, has been achieved from (±)-(E)-1,4-hexadien-3-ol by an 8-pot sequence that features the Sharpless kinetic resolution, iodoetherification, and the CBS reduction to install the stereocenters, utilization of four one-pot transformations to streamline the synthetic process, and the Stille coupling reaction at nearly the center of the target molecule to complete the total synthesis.

Synthesis of the Epimeric Secosteroids Strophasterols A and B

Two epimeric rearranged ergostanes, strophasterols A and B, with an unprecedented carbon skeleton were synthesized from ergosterol, both in 17 steps via a common secosteroidal intermediate. The conversion of ergosterol into the pivotal intermediate involved an efficient acid-catalyzed double-bond migration from ring B to ring D, oxidative cleavage of the double bond, and a completely diastereoselective acyl radical cyclization to form an isolated cyclopentanone ring unique to this recently discovered family of steroidal compounds produced by mushrooms. The intermediate was transformed stereodivergently into two epimeric cyclopentane derivatives through hydrogenation using two types of catalysts. One epimer was elaborated into strophasterol B by utilizing peracid oxidation of an iodide to provide an epoxide directly, and the other epimer was elaborated into strophasterol A, which is known to be a suppressor of endoplasmic reticulum stress.

Synthesis of the (9R,13R)-isomer of LDS1, a flower-inducing oxylipin isolated from Lemna paucicostata

The first synthesis of the (9R,13R)-stereoisomer of LDS1, a flower-inducing oxylipin isolated from Lemna paucicostata, has been achieved from a known allylic alcohol by a seven-step sequence that involves the Horner–Wadsworth–Emmons olefination to construct its full carbon framework and an enzymatic hydrolysis of a penultimate methyl ester intermediate to provide the target molecule. Graphical abstract flower-inducing substance in Lemna paucicostata.

Enantioselective Total Synthesis of (+)-Anthecularin

An enantioselective total synthesis of (+)-anthecularin, an antiplasmodial and antitrypanosomal sesquiterpene lactone, has been achieved in 3.9% overall yield through 18 steps from a known dibromo alcohol. The key features of the synthesis include an intramolecular Claisen-type cyclization of a formyl-protected hydroxyl lactone to construct a bicyclic intermediate with a quaternary stereogenic center and a stereocontrolled 1,2-addition of vinyllithium to a methoxyethyl-protected spirocyclic hydroxyl enone to install a tetrasubstituted asymmetric center with excellent diastereoselection. This first enantioselective synthesis of anthecularin enabled the determination of its absolute configuration as 2 R, 3 R, 4 S, 8 R.

Two approaches to 14,15-secoergostane intermediates for the synthesis of strophasterols

Abstract Two protected 14,15-secoergostane derivatives suitable as pivotal intermediates for the synthesis of strophasterols A and B, anti-MRSA and neuronal cell-protecting natural products bearing a recently discovered strophastane skeleton, have been synthesized by two different routes. The first approach employed an oxidative cleavage of an α-hydroxy ketone intermediate with the Jones reagent as the key step to reach the targeted secoergostane from ergosterol in ten steps. In the second approach, an unprecedented reaction cascade composed of four reactions enabled us to obtain the secoergostane more efficiently in six steps. Two approaches to 14,15-secoergostane intermediates for the synthesis of strophasterols