8) Protein engineering of lipase A from Candida antarctica to improve esterification of tertiary alcohols
Karla Wagner, Anke Hummel, Jianing Yang, Satoshi Horino, Kyohei Kanomata, Shuji Akai and Harald Gröger
ChemBioChem, 2024, 25, e202400082
DOI: doi.org/10.1002/cbic.202400082
Abstract: Chiral tertiary alcohols are important organic compounds in science as well as in industry. However, their preparation in enantiomerically pure form is still a challenge due to their complex structure and steric hindrances compared with primary and secondary alcohols, so kinetic resolution could be an attractive approach. Lipase A from Candida antarctica (CAL-A) has been shown to catalyze the enantioselective esterification of various tertiary alcohols with excellent enantioselectivity but low activity. Here we report a mutagenesis study by rational design to improve CAL-A activity against tertiary alcohols. Single mutants of CAL-A were selected, expressed, immobilized and screened for esterification of the tertiary alcohol 1,2,3,4-tetrahydronaphthalene-1-ol. A double mutant V278S+S429G showed a 1.5-fold higher reaction rate than that of the wild type CAL-A, while maintaining excellent enantioselectivity.
7) Strategies to Design Chemocatalytic Racemization of Tertiary Alcohols: State of the Art & Utilization for Dynamic Kinetic Resolution
Harald Gröger, Satoshi Horino, Kyohei Kanomata, Shuji Akai
Chem. Eur. J. 2024, e202304028
DOI: doi.org/10.1002/chem.202304028
Abstract: In this “Concepts”-article, the difficulties in racemizing tertiary alcohols are described as well as a summary of the different chemocatalytic concepts to overcome these hurdles and to pave a way for efficiently racemizing of tertiary alcohols. When combined with the enantioselective enzymatic esterification of tertiary alcohols, the racemization protocols enable a DKR to convert the racemates into enantiomerically pure esters of tertiary alcohols, which are of high interest in the field of pharmaceutically active products. Very recently, various research groups have succeeded in solving the challenging task of identifying suitable chemocatalysts for an efficient racemization of tertiary alcohols and simultaneously suppressing unwanted dehydration side-reactions. It is noteworthy that such methods are based on different, complementary catalysis concepts. Besides Brønsted acids, oxovanadium catalysts as well as piperidine as a representative of an organocatalyst have been found to be useful for the racemization of each type of alcohols. The latter two types of catalysts also turned out to be compatible with lipase-catalyzed kinetic resolution, thus leading to the first two examples of a proof-of-concept for chemoenzymatic DKR of tertiary alcohols.
6) Kinetic Resolution of Cyclic Tertiary Alcohols with Lipase A from Candida Antarctica
Satoshi Horino, Karla Wagner, Anke Hummel, Kyohei Kanomata, Harald Gröger, Shuji Akai
Eur. J. Org. Chem. 2024, e202400242
DOI: doi.org/10.1002/ejoc.202400242
Abstract: Enzyme-catalyzed acylative kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic primary and secondary alcohols have been widely reported to produce esters with high enantiomeric purity. In contrast, similar KRs of tertiary alcohols have been reported for only a limited range of substrates and require prolonged reaction times of several days. To gain deeper insight into the substrate scope and increase the process efficiency, we examined the reaction conditions using commercially available immobilized lipase A from Candida antarctica and found that the addition of the heterogeneous, inorganic base sodium carbonate significantly increased the reaction rate while maintaining high enantioselectivity. The use of vinyl hexanoate as the acyl donor provided esters that were stable during chromatography purification. The optimized reaction conditions were then successfully applied to a range of cyclic tertiary alcohols containing tetralin, dihydroindene, chromane, and thiochromane skeletons having, in part, a substituent on the aromatic ring. In this study on the structure–reactivity relationship of enzymatic KR-type reactions, we achieved >30% conversion for various tertiary alcohols in 24 h at 25 °C, producing optically active esters with 88–99% ee.
5) 「位置選択的重水素化ならびに多重重水素化の開発と創薬への利用」
澤間善成、赤井周司
未来社会共創を目指す研究シーズ集2024 p.33
4) Versatile Biaryls and Fused Aromatics through Oxidative Coupling of Hydroquinones with (Hetero)Arenes
Takaaki Aijima, Rina Ueda, Takanori Nakane, Fumiaki Makino, Yusuke Ohnishi, Jin Tokunaga, Keiichiro Nakajima, Shinichiro Kamino, Genji Kurisu, Keiichi Namba, Hiroki Nakata, Kaiki Mogi, Hironao Sajiki, Shuji Akai, and Yoshinari Sawama
ChemistrySelect accepted
Abstract: Hydroquinones bearing an electron-withdrawing group at the C2-position can effectively underwent oxidative coupling with (hetero)arenes (e.g., indoles, electron-rich benzene derivatives) in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and FeCl3 to produce the corresponding biaryl products. In the present reactions, the DDQ-mediated oxidation of hydroquinone derivatives produce benzoquinone intermediate, which subsequently underwent FeCl3-catalyzed nucleophilic addition of (hetero)arenes to the a,b-unsaturated carbonyl moiety to give the biaryl product in a one-pot manner. Especially, the indole-based biaryl products were further converted into tetracyclic aromatics through DDQ-mediated oxidation followed by FeCl3-catalyzed intramolecular cyclization. Thiophene derivatives were also applicable to give the tetracyclic aromatics. Moreover, the photophysical properties of the indole- and thiophene-based tetracyclic aromatics in the solution and the solid states were investigated.
3) Nucleophilic Deprotection of p-Methoxybenzyl Ethers Using Heterogeneous Oxovanadium Catalyst
Rei Ikeda, Tomoya Nishio, Kyohei Kanomata , Shuji Akai
Chem. Pharm. Bull. 2024, 72, 2, 213-219
DOI:10.1248/cpb.c23-00897
Featured Article
大阪大学リポジトリOUKA（オープンアクセス）https://hdl.handle.net/11094/94660
Abstract: Nucleophilic deprotection of p-methoxybenzyl (PMB) [p-methoxyphenylmethyl (MPM)] ethers was developed using a heterogeneous oxovanadium catalyst V-MPS4 and a thiol nucleophile. The deprotection method had a wide reaction scope, including PMB ethers of primary, secondary, and tertiary alcohols bearing various functional groups. In addition, the PMB ether of an oxidation-labile natural product was successfully removed by V-MPS4 catalysis, while a common oxidative method of PMB deprotection afforded a complex mixture. The V-MPS4 catalyst was reusable up to six times without a significant loss in the product yield. The advantages of using the heterogeneous catalyst were further demonstrated by conducting the deprotection reaction in a continuous flow process, which resulted in a 2.7-fold higher catalyst turnover number and 60-fold higher turnover frequency compared to those of the corresponding batch reaction.
2) Furanyl Bis(indolyl)methane as a Palladium Ion-Selective Chromogenic Agent
Kazuho Ban, Shiho Nozaki, Takaaki Aijima, Shuki Oyama, Hirofumi Tsujino, Yusuke Kanematsu, Shuji Akai and Yoshinari Sawama
Org. Biomol. Chem. 2024, accepted
Abstract: The colorless solution of furan-2-yl bis(indolyl)methanes (BIMs) were newly reveled to work as palladium (Pd2+) ion-selective chromogenic agent to turn orange. 5-(N-methyl-N-phenyl-aminomethyl)-furan-2-yl BIM could be synthesized from 5-chloromethylfurfural as a biorenewable feedstock via one pot and double functionalizations, and a mixture of its solution and Pd2+ ion indicated the highest absorbance at 465 nm in UV-Vis analysis. On the other hand, other metal ions (Cu2+, Cr2+, Cr3+, Fe2+, Fe3+, Ni2+, Zn2+, In2+, Pt2+, or Ce3+) possessed no response.
1) First atroposelective Chan–Lam coupling for the synthesis of C–N linked biaryls
Moeka Ishida, Rina Adachi, Kazuki Kobayashi, Yukiko Yamamoto, Chinatsu Kawahara, Tsuyoshi Yamada, Hiroshi Aoyama, Kyohei Kanomata, Shuji Akai, Patrick Y. S. Lam, Hironao Sajiki and Takashi Ikawa
Chem. Commun., 2024, 60, 678–681
DOI: 10.1039/D3CC05447K
Abstract: The first atroposelective Chan–Lam coupling for the synthesis of C–N axial enantiomers is reported with good yields and ee. MnO2 additive is crucial for the success of the coupling. The longstanding problem of the lack of enantioselective synthesis to make chiral C–N linked atropisomers is solved.