Asymmetric synthesis method of chiral tryptanthrin beta hydroxy ester compounds
Inactive Publication Date: 2019-04-26
WENZHOU UNIVERSITY
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Recently, this series of compounds has been prepared by a synthetic strategy, which is to prepare Cephalanthrin A of the corresponding structure by Tryptanthrin (tryptanthrin), and then convert it into an acid chloride and further react with methanol to prepare and synthesize Phaitanthrin B. The synthesis process requires After three steps of addition, acylation and esterification, the steps are cumbersome and the reaction system is complicated
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Embodiment 1
[0033] R 1 for hydrogen, R 2 Ordinary Tryptanthrin (tryptanthrin) for hydrogen, R 3 The molar ratio of methyl monomethyl malonate and catalyst is 1.0:2.0:0.1, that is, substrate tryptanthrin 496mg (2mmol), monomethyl malonate 472mg (4mmol), acetic acid tetrahydrate 49.6mg (0.2mmol) of nickel, 172.6mg (0.22mmol) of chiral ligand L; 10.0g of tetrahydrofuran as the organic solvent, the total amount of which is 20 times that of the substrate tryptanthrin.
[0034] At room temperature, add the metal catalyst and chiral ligand L1 into the reaction kettle, fully dissolve it with tetrahydrofuran, stir thoroughly for 30-60 minutes, then add tryptanthrin and monomethyl malonate into the reaction kettle, at 50 Under the condition of ℃, stir to make it react for 12 hours and end.
[0035] After the reaction was completed, separation and purification were performed, and a white solid was obtained after drying, which was the chiral target compound Phaitanthrin B 1a 579.6 mg, with a yield...
Embodiment 2
[0040] Substrate tryptanthrin 496mg (2mmol), monomethyl malonate 472mg (4mmol), nickel acetate tetrahydrate 49.6mg (0.2mmol), chiral ligand L373.5mg (0.22mmol); organic solvent is tetrahydrofuran 10.0g , and its total amount is 20 times that of the substrate tryptanthrin.
[0041] The rest was the same as in Example 1, and 560.3 mg of the target product 1a was obtained with a yield of 87%, an enantioselective excess of 45% ee, and a purity of 99.4%.
Embodiment 3
[0043]Substrate tryptanthrin 496mg (2mmol), monomethyl malonate 472mg (4mmol), nickel acetate tetrahydrate 49.6mg (0.2mmol), chiral ligand L586.5mg (0.22mmol); organic solvent is tetrahydrofuran 10.0g , and its total amount is 20 times that of the substrate tryptanthrin.
[0044] The rest was the same as in Example 1, and 495.9 mg of the target product 1a was obtained with a yield of 77%, an enantioselective excess of 1% ee, and a purity of 98.9%.
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Abstract
The invention discloses an asymmetric synthesis method of chiral tryptanthrin beta hydroxy ester compounds. The method comprises following steps: tryptanthrin compounds and mono-alkyl malonate are taken as raw materials, metal and a chiral ligand which are taken as catalysts are subjected to a direct sufficient reaction in an organic solvent, a reaction solution is separated and purified after thereaction is ended, and the chiral tryptanthrin beta hydroxy ester compounds with high stereoselectivity, namely, Phaitanthrin B-series pharmaceutical molecules as natural products, are obtained. Themethod has main beneficial effects as follows: 1, operation is simple; 2, cost is low; 3, reaction yield is high; 4, stereoselectivity is high, thereby having higher fundamental research value and social and economic benefits.
Description
technical field [0001] The present application discloses that the present invention relates to the field of organic chemistry, and in particular refers to an asymmetric synthesis method of chiral tryptanthrin β-hydroxy acid ester compounds (Phaitanthrin B series drug molecules). Background technique [0002] Phaitanthrin B is a chiral tertiary alcohol-containing structure alkaloid, which is a natural product of the Tryptanthrin series extracted from Hedinglan violet, and has good physiological activity. It has good cytotoxicity to breast cancer (MCF-7), lung cancer (NCI-H460), central nervous system cancer (SF-268) and other tumor cells. Therefore, the development of Phaitanthrin B series compounds with simple operation, low cost, high yield and high stereoselectivity is of great significance for drug development and basic research. [0003] In the existing reports, the early acquisition of Phaitanthrin B was mainly extracted from orchids. The process was cumbersome and the...
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