1998 Fiscal Year Final Research Report Summary
Synthetic Study on Biologically Active Natural Products containing alpha, alpha-Disubstituted alpha-Amino Acid Structures
| Project/Area Number |
09680574
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Keio University |
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Principal Investigator |
CHIBA Noritaka Keio University, Applied Chemistry, Associate Professor, 理工学部, 助教授 (50197612)
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| Project Period (FY) |
1997 – 1998
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| Keywords | alpha, alpha-Disubstituted alpha-Amino Acid / Lactacystin / Myriocin / Overman Rearrangement / Carbohydrates / Total Synthesis / Computational Chemistry |
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| Research Abstract |
Recently, natural products with alpha, alpha-disubstituted alpha-amino acid structures, such as lactacystin, sphingofungins, and myriocin, have been isolated. Due to their interesting and important biological activities (neurotrophic, antibiotic, immunosuppressive, and enzyme inhibitory), alpha, alpha-disubstituted a-amino acid derivatives are expected to be potent lead compounds for novel drugs.
In this project, novel synthetic approach to alpha, alpha-disubstituted alpha-amino acid derivatives starting from carbohydrates, which involved the stereoselective generation of the tetra-substituted carbon possessing amino functionality by the rearrangement of the allylic trichioroacetimidate (Overman rearrangement) was investigated.
Allylic alcohol derivatives prepared from aldohexoses (D-glucose and D-mannose) were converted into corresponding trichioroacetimidates, which underwent Overman rearrangement by heating at 140ﾟC to afford rearranged products (vinyl amides) in high yields and in moderate stereoselectivities (1 : 2 - 1 : 10). Semi-empirical molecular orbital calculations were found to be able to predict the stereoselectivities of rearrangement reactions. The sugar skeleton in rearranged products was transformed to the desired carbon frame work to furnish the total synthesis of lactacystin and the synthesis of the synthetic precursor of sphingofungin F as well as myriocin.
This study provided the novel and effective pathway to alpha, alpha-disubstituted alpha-amino acid derivatives from carbohydrates.
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