1990 Fiscal Year Final Research Report Summary
A Short Asymmetric Synthesis of Podophyllotoxin Related Antitumor Agent
| Project/Area Number |
01571143
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TOMIOKA Kiyoshi Univ. of Tokyo Fac. of Pharm. Sci. Assoc. prof., 薬学部, 助教授 (50114575)
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| Project Period (FY) |
1989 – 1990
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| Keywords | podophyllotoxin / anticancer agent / synthesis / asymmetric synthesis / ligand / diether / bond formation / selectivity |
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| Research Abstract |
Design and synthesis of podophyllotoxin related compound with antitumor activity and development of a novel strategy for the enantioselective asymmetric reaction have been successfully achieved.
(1) Design and synthesis of azapodophyllotoxin
Substitution of a carbon atom by nitrogen atom alpha to the lactone carbonyl group of podophyllotoxin would be expected to solve the two problems, isomerization at the site and increase of electron density at the oxygen atom of the carbonyl group.
Synthesis of the designed target has been successfully carried out in the short steps starting from the corresponding amino acid.
(2) Development of the novel asymmetric reaction
An efficient asymmetric reaction relies on a rational design of three components complex constituted from organometallic reagent, substrate, and chiral ligand. We designed a model which has two stereocontrolling groups at the both sites of chelating heteroatoms up and down faces of the five membered chelate.
Realization of the model complex would come from coordination of organolithium to a chiral diether which would form an expected complex. Reaction of organolithium with alpha, beta-unsaturated imines or esters in the presence of the chiral diether provided the corresponding conjugate addition products in high enantiomeric excess and in absolute configuration predicted from three component complex model.
By employing a substoichiometric amount of the diether catalytic asymmetric carbon-carbon bond formation has also been realized in the reaction of aryllithiums with BHA esters of 1- and 2- naphthalenecarboxylic acid to provide the corresponding conjugate addition products in high ee.
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