Keisuke Nishikawa (Assistant Professor)

1. My Most Current Research and Principal Research Interests

My research interests include the total synthesis of bioactive natural products, its biological activities, the structure-activity relationship study and new synthesis method for the total synthesis.

(1) Total Synthesis of 10-Isocyano-4-cadinene and Its Stereoisomers and Evaluations of Antifouling Activities

@@10-Isocyano-4-cadinene (1), a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae by Okino et al., exhibits potent antifouling activity against the larvae of the barnacle Balanus amphitrite (EC50 0.14 ƒĘg/mL). 1 is expected to be new nontoxic antifouling agents. Furthermore, the absolute stereochemistry of 1 has not been determined. To access these issues, we started the enantioselective total synthesis toward 1.
@@@The synthesis toward 1 was commenced with the known imide 2, which was converted into the dieneacetate 3. The Diels-Alder reaction between 3 and methyl acrylate with MeAlCl2 afforded cyclohexene 4 as a mixture of four diasereomers. This mixture was epimerized to two isomers, the desired carboxylic acid 5 as a major product and the ester 6, by the treatment of NaOMe followed by selective hydrolysis with 1 M HCl in one-pot. The carboxylic acid 5 was transformed into the aldehyde 7, which was cyclized by SmI2-initiated Barbier-type reaction to provide the alcohol 8. At last, the total synthesis of 1 was achieved via the introduction of the functional groups at C10. The absolute configuration of 1 was determined as (1S, 6S, 7R, 10S) by comparison of the optical rotations between natural and synthetic samples. In addition, I successfully synthesized 10-epi-10-isocyano-4-cadinene (9), di-1,6-epi-10-isocyano-4-cadinene (10) and its enantiomers (ent-1,  ent-9 and ent-10) through the same synthetic pathway. Antifouling activities against Balanus amphitrite with the cadinenes were also evaluated.

(2) Confirmation of the Configuration of 10-Isothiocyanato-4-cadinene Diastereomers Through Synthesis

@@The marine sponge metabolite 10-isothiocyanato-4-cadinene (11) was first isolated by Garson et al. from Acanthella cavernosa in 2000. The same structure 11 was later reported by Wright from the nudibranch Phyllidiella pustulosa and its sponge diet, but with different NMR data. The syntheses of both enantiomers of 11 were accomplished through the isothiocyanation of (+)-10-isocyano-4-cadinene (1) and (-)-1. The correct spectroscopic data and specific rotation value of the structure 11 were determined on the basis of the syntheses. The NMR data of synthetic 11 matched those of the isothiocyanate isolated by Garson and differed from those reported by Wright.

(3) Total Synthesis of Stemonamine Using Ynolate

@@@Stemonamine (12) was isolated from the roots of Stemona japonica Miq. as a member of the Stemona alkaloid family. Although the racemic total synthesis of 12 has been reported by three groups, its enantioselective synthesis has not been achieved so far. In this work, the total synthesis of 12 using two key reactions, the ynolate-initiated tandem reaction and the intramolecular acylation, is described.
Our total synthesis commenced with condensation of the known optically active carboxylic acid 13 and the lactone 14 to give the iodide 15. The intramolecular acylation of 15 using tBuLi afforded the 7-membered ring 16 in high yield. The NaBH4 reduction of 16 followed by acetylation provided the diacetate 17. After the removal of the acetoxy group on the C-ring via the SmI2-mediated reduction, the obtained monoacetate was transformed to the g-ketoester 18. As the second key step, the tandem [2+2] cycloaddition-Dieckmann condensation using the ynolate 19 and 18 was performed to successfully provide the tricyclic compound 20, the ABC-ring system of 12, in high yield. The total synthesis of 12 was achieved via the known construction method of the D-ring. The spectroscopic data of our synthetic 12 were in good agreement with those recorded in the literature.

(4) The Present Research
@@@In the present work, the asymmetric total syntheses of (-)-lepadiformine A (21) and (-)-histrionicotoxin (22) are now ongoing.

2. Selected Publications

1. g Confirmation of the configuration of 10-isothiocyano-4-cadinene diastereomers through synthesis h K. Nishikawa, T. Umezawa, M. J. Garson, F. Matsuda J. Nat. Prod. 75, 2232?2235 (2012).

2. g Key structural features of cis-cinnamic acid as an allelochemical h M. Abe, K. Nishikawa, H. Fukuda, K. Nakanishi, Y. Tazawa, T. Taniguchi, S.-Y. Park, S. Hiradate, Y. Fujii, K. Okuda, M. Shindo Phytochemistry 84, 56?67 (2012).

3. g Stereoselective synthesis of b-glycosyl esters of cis-cinnamic acid and its derivatives using unprotected glycosyl donors h K. Matsuo, K. Nishikawa, M. Shindo Tetrahedron Lett. 52, 5688?5692 (2011).

4. g Total synthesis of 10-isocyano-4-cadinene and its stereoisomers and evaluations of antifouling activities h K. Nishikawa, H. Nakahara, Y. Shirokura, Y. Nogata, E. Yoshimura, T. Umezawa, T. Okino, F. Matsuda J. Org. Chem. 76, 6558?6573 (2011).

5. g Total synthesis of 10-isocyano-4-cadinene and determination of its absolute configuration h K. Nishikawa, H. Nakahara, Y. Shirokura, Y. Nogata, E. Yoshimura, T. Umezawa, T. Okino, F. Matsuda Org. Lett. 12, 904?907 (2010).