6.Preparation of optically active cycloalkenes bearing all-carbon quaternary stereogenic centres via lipase–oxovanadium combo-catalysed dynamic kinetic resolution
Shinji Kawanishi, Koji Sugiyama, Yasuhiro Oki, Takashi Ikawa, shuji akai, Green Chem. , 2016, Accepted, DOI:10.1039/C6GC01995AAbstract: In this study, a novel asymmetric synthesis of all-carbon quaternary stereogenic centres is developed by the connection of three prochiral or achiral components--conjugated enones, organometallic compounds and vinyl esters--at the C-1 position of the enones. This method involves three sequential steps: 1,2-nucleophilic addition of an organometallic compound to the enone, lipase-catalysed dynamic kinetic resolution (DKR) of the tert-allylic alcohol and the Ireland-Claisen rearrangement of the optically active allyl ester thus generated. This method features the effective use of acyl moieties installed by DKR for achieving high atom economy. The application of this method to the protective-group-free asymmetric total synthesis of (-)-crinane, a core structure of a class of natural alkaloids, demonstrated that it can alter a known synthetic pathway of a racemate into an asymmetric synthesis of an optically pure molecule while reducing the total transformation steps and increasing the overall yield. With these advantages, this method is practical and attractive as a new environmentally benign protocol.
赤井周司, 化学と生物 , 54, 384–386 (2016)Abstract: The synergy of hydrolases, such as lipases, and metal catalysts can provide quantitative production of optically pure compounds from racemic compounds that cannot be available by using each single catalyst. Dynamic kinetic resolution of racemic alcohols is shown as a typical example.
好光健彦, 有機合成化学協会誌 , 74, 350-359 (2016), DOI:10.5059/yukigoseikyokaishi.74.350Abstract: The present article discusses our recent endeavors on natural product syntheses wherein radical reactions are strategically employed to access fused carbocycles. Particular emphasis is placed on the radical cyclizations that made it possible to establish the unique bond connectivity and functionalities of the target natural products. The radical chemistry-based approaches to platencin and clavilactone B are discussed here to show the utility of titanocene(III)-mediated epoxy enone cyclization, decarboxylative radical cyclization of an alkynyl carboxylic acid derivative with lead(IV) in 1,4-dioxane, and samarium(II)-mediated radical cyclization-fragmentation of an unsaturated keto ester, all of which serve as versatile means to elaborate the natural products.
3.1,3- and 1,4-Benzdiyne equivalents for regioselective synthesis of polycyclic heterocycles
Takashi Ikawa, Shigeaki Masuda, Akira Takagi, Shuji Akai, Chem. Sci. , 7, 5206–5211 (2016), DOI:10.1039/C6SC00798HAbstract: We have devised a novel 1,3-benzdiyne equivalent, capable of quadruple functionalization by sequential benzyne generation and reaction with arynophiles. The key features of this method include the chemoselective generation of two triple bonds in a single benzene ring under fluoride-mediated mild conditions, and the regiocontrol of each benzyne reaction by the substituent next to the triple bond. This method produced various benzo-fused heteroaromatic compounds via reactions with arynophiles, such as furans, azides, and diazo compounds. A validation of the method is given in the convergent synthesis of the antipsychotic drug risperidone. A similar strategy has also been applied to a 1,4-benzdiyne equivalent to construct linearly benzo-fused heteroaromatics.
2.Spatial effects of oxovanadium-immobilized mesoporous silica on racemization of alcohols and application in lipase-catalyzed dynamic kinetic resolution
Koji Sugiyama, Yasuhiro Oki, Shinji Kawanishi, Katsuya Kato, Takashi Ikawa, Masahiro Egi, Shuji Akai, Catal. Sci. Technol. , 6, 5023-5030 (2016), DOI:10.1039/c6cy00257aAbstract: We recently reported a new dynamic kinetic resolution (DKR) method based on the combination of lipase-catalyzed kinetic resolution of racemic alcohols and the V-MPS3-catalyzed in situ racemization of less reactive alcohol enantiomers. In V-MPS3, oxovanadium moieties were covalently bound to the inner surface of mesoporous silica (MPS) with a pore size of about 3 nm. The catalytic activity of V-MPS3 was much higher than that of related vanadium compounds; however, we could neither explain its unusually high activity nor confirm that the racemization predominantly occurred inside the V-MPS pores. Therefore, in this study, we prepared V-MPS2 and V-MPS4 from the corresponding MPS with pore diameters of approximately 2 nm and 4 nm, respectively and compared their racemization activities with that of V-MPS3 using some optically active alcohols with different molecular sizes and polarities. We discovered a positive correlation between the pore size of V-MPS and substrate racemization rate as well as the high polarity of the MPS pores. The results suggested that the racemization predominantly occurs in the pores of V-MPS and that a small pore size (2–4 nm) is essential to generate the polar environment of V-MPS, which probably accelerates the racemization by facilitating the C–O bond cleavage of the vanadate intermediates. Using V-MPS with a pore size suitable for each substrate, lipase/oxovanadium combo-catalyzed DKR could be applied to a wider range of alcohols including allyl alcohols, benzylic alcohols, and propargyl alcohols to give the corresponding esters in excellent isolated yields and enantioselectivities.
1.Diversity Oriented Synthesis of Allocolchicinoids with Fluoro and/or Oxygen Substituent(s) on the C-Ring from a Single Common Intermediate
Keita Takubo, Kazunori Furutsu, Takafumi Ide, Hiroyuki Nemoto, Yuko Ueda, Kazutake Tsujikawa, Takashi Ikawa, Takehiko Yoshimitsu, Shuji Akai, Eur. J. Org. Chem. , 2016, 1562–1576 (2016), DOI:10.1002/ejoc.201501624Abstract: Allocolchicinoids, with a distinct polyoxygenated dibenzocycloheptane skeleton, attract much attention as potential candidate anticancer drugs. In this study, eight C-ring fluorinated analogues of allocolchicinoids, seven C-ring oxygen-substituted analogues, and known compounds N-acetylcolchinol and NSC 51046 were synthesized as racemates from a single common intermediate by using either the deoxyfluorination/migration domino reaction or acid-promoted migration as the key step. Among the products obtained, some of the fluorinated derivatives strongly inhibited the growth of prostate DU145 and pancreas Panc 1 cancer cell lines with efficacy comparable to or better than those of N-acetylcolchinol and NSC 51046. They were also less toxic against a non-cancerous cell line than the known compounds were.