2005 Fiscal Year Final Research Report Summary
Development of a method for the asymmetric construction of substituted citric acid structures and synthesis of natural products as leading compounds for drug discovery
| Project/Area Number |
15390008
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Nagasaki University |
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Principal Investigator |
HATAKEYAMA Susumi Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (20143000)
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| Project Period (FY) |
2003 – 2005
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| Keywords | alkylcitrate natural product / Baylis-Hillman reaction / Mukaiyama aldol reaction / asymmetric reaction / trachyspic acid / virifiofungin / total synthesis |
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| Research Abstract |
Alkylcitrate family of natural products such as viridiofungin and trachyspic acid have attracted so much attention due to their potent inhibitory activities against biologically important enzymes (e.g. serine-palmitoyl transferase, phospholipase A2, heparanase, squalene synthase) as well as synthetically intriguing structures. However, a general method for the construction of highly functionalized citric acid structures containing a quaternary center has not been developed yet. In this research, we focused on developing a general and efficient method for the asymmetric synthesis of such citric acid structures, and aimed to achieve total syntheses of alkylcitrate family of natural products.
In the former research, we developed a highly efficient asymmetric Baylis-Hillman reaction using dried β-isocupreidine (β-ICD). In addition, we succeeded in synthesizing two enantio-complementary catalysts to β-ICD starting from quinine. We found that β-ICD-catalyzed Baylis-Hillman reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate proceeded with high enantioselectivity in good yield. We also examined asymmetric Mukaiyama aldol reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate with the ketne silyl ether drived from S-tert-butyl pent-4-enethioate using several BOX-Cu catalysts but the encouraging results were not obtained.
In the latter research, we achieved the first total synthesis of (+)-trachyspic acid as well as (±)-trachyspic acid based on Nozaki-Hiyama-Kishi reaction, therby determining its absolute structure. Furthermore, we accomplished the first total synthesis of (-)-virifiofungin A employing olefin cross metathesis as a key step.
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