1999 Fiscal Year Final Research Report Summary
Synthetic Approach to the Total Synthesis of Natural Marine Isoquinoline Alkaloid
| Project/Area Number |
10672005
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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 |
Chemical pharmacy
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| Research Institution | MEIJI PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
KUBO Akinori FACULTY OF PHARMACY, MEIJI PHARMACEUTICAL UNIVERSITY, PROFESSOR, 薬学部, 教授 (60097201)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Naoki FACULTY OF PHARMACY, MEIJI PHARMACEUTICAL UNIVERSITY, ASSISTANT PROFESSOR, 薬学部, 講師 (80142545)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Natural Marine Product / Isoquinoline / Ecteinascidin / Baeyer-Villiger Reaction / Protecting Group / Total Synthesis / Regioselective / Anti-cancer Agent |
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| Research Abstract |
Ecteinascidins are natural marine products discovered from Ecteinascidia turbinate and which exhibit potent antitumor activity. Among of them, Et743 is currently being evaluated in phase II clinical trials. It is a tetrahydroisoquinoline derivative that is structurally related to microbial safracins. Because of their novel and diverse structure, a general approach to their construction has been sought.
A summary of our results on a synthetic strategy for the preparation of ecteinascidins, which have challenging structural features, follows :
1) We completed an improved synthesis of the ABC ring model of compound, which has a structure common to ecteinascidins and safracins From 3- (4-methoxy-3-methylphenylmethyl) -1-methyl-2, 5-piperazinedione, this introduces a phenolic hydroxy group at an early stage by formylation followed by proton-catalyzed Baeyer-Villigeroxidation.
2) We are finishing the practical synthesis of 3-hydroxy-4-methoxy-5-methylbenzaldehyde derivative prepared in seven steps from 2, 3-dihydroxytoluene and used to protect the phenolic hydroxy functionality as an isopropyl group.
3) We succeeded in a practical synthesis of the ABC ring model of ecteinascidins from benzaldehyde derivative in 15 steps. The overall yield was 27%.
4) We have efficiently synthesized a key tricyclic lactam intermediate having a protected phenol in the E-ring.
Application of this strategy to the total synthesis of ecteinascidin natural products is now being intensive investigation in our laboratories.
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