The academic year 2020 has just started with 9 graduate students and 9 undergraduate students.

"Structure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor"
Kana Shintani, Haruna Ebisu, Minagi Mukaiyama, Taisei Hatanaka, Takumi Chinen, Daisuke Takao, Yoko Nagumo, Akira Sakakura, Ichiro Hayakawa,* Takeo Usui*
ACS Med. Chem. Lett. 2020, 11 (6), 1125–1129.
DOI: 10.1021/acsmedchemlett.9b00526 LinkIcon

Gatastatin (O7-benzyl glaziovianin A) is a γ-tubulin-specific inhibitor that is used to investigate γ-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O7-benzyl group in gatastatin is important for γ-tubulin inhibition. To obtain further structural information regarding γ-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O7-benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O6-benzyl glaziovianin A is a potent α/β-tubulin inhibitor; thus, these new results suggest that the O6-position restricts affinity for α/β- and γ-tubulin. Considering that an O7-benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O6-modifications of gatastatin.

"Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction"
Yuya Araki, Natsumi Miyoshi, Kazuki Morimoto, Takayuki Kudoh, Haruki Mizoguchi, Akira Sakakura*
J. Org. Chem. 202085 (2), 798–805.
DOI: 10.1021/acs.joc.9b02811LinkIcon

A formal total synthesis of manzacidin B is described.  β,β-Disubstituted γ-hydroxy-β-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions.  By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction.

"Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers"
Ichiro Hayakawa,* Anna Nagayasu, Akira Sakakura*
J. Org. Chem. 2019, 84 (23), 15614–15623.
DOI: 10.1021/acs.joc.9b02627 LinkIcon

SB-203207 is an altemicidin-type alkaloid that potently inhibits isoleucyl tRNA synthetase activity. Its main structural feature is a hexahydro-6-azaindene framework containing a unique β-hydroxy α,α-disubstituted α-amino acid moiety on the cyclopentane portion. Herein we have established a method for constructing the four contiguous nitrogen-containing stereogenic centers of SB-203207 by using as key steps the stereoselective alkylation of bowl-shaped tricyclic lactone to construct quaternary carbon at C1, the stereoselective hydroboration–oxidation reaction to install the C2 hydroxy group, and the Curtius rearrangement to introduce a nitrogen atom onto the C1 quaternary carbon.

Poster Presentation
"Formal Total Synthesis of Manzacidin B Based on Diastereoselective Henry Reaction"
Yuya Araki, Natsumi Miyoshi, Kazuki Morimoto, Haruki Mizoguchi, Akira Sakakura
The 61st Symposium on the Chemistryof Natural Products, International Conference Center Hiroshima, Sept 11–13, 2019, P1-14

"Toward the Synthesis of Yuzurimine-type Alkaloids: Stereoselective Construction of the Heterocyclic Portions of Deoxyyuzurimine and Macrodaphnine"
Ichiro Hayakawa,* Ryosuke Nagatani, Masaki Ikeda, Dong-eun Yoo, Keita Saito, Hideo Kigoshi, and Akira Sakakura*
Org. Lett.  2019, 21 (16), 6337–6341.  
DOI: 10.1021/acs.orglett.9b02232 LinkIcon

The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration−oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular SN2 reaction to construct the F-ring portion as key steps.

"Enantioselective 1,3-Dipolar Cycloaddition Reaction of Nitrones with α-(Acyloxy)acroleins Catalyzed by Dipeptide-Derived Chiral Tri- or Diammonium Salts"
Chihiro Kidou, Haruki Mizoguchi, Tatsuo Nehira, Akira Sakakura*
Synlett  2019, 30 (15), 1835–1839.  
DOI: 10.1055/s-0039-1690133 LinkIcon

Organoammonium salts of dipeptide-derived chiral triamines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of α-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although α-(p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, α-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts.

The academic year 2019 has just started with 6 graduate students and 10 undergraduate students.