A kind of total synthesis method of natural product (+)-negamycin

Abstract

The invention belongs to the technical field of organic synthesis, and specifically relates to a full-synthesizing method of natural product(+)-negamycin. The method utilizes Mannich reaction to construct a C3 position chiral center, nitrine functional group introduction is achieved in a later period of a synthetic route, and use of a lot of explosive and highly-toxic product of azide is avoided; (R)-(+)-3-hydroxyl-4-chlorobutyric acid ethyl ester, an Ellman reagent of (R)-(+)-methyl propane-2-sulfinamide and Mannich reaction are utilized to construct a C4 position chiral center, full synthesis is achieved through simple 8-step reaction, and total yield reaches 30%. The full-synthesizing method disclosed by the invention has the short synthetic route and simple after treatment, and raw material sources are provided for development of antibiotic medicines based on the (+)-negamycin.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a total synthesis method of natural product (+)-negamycin. Background technique [0002] (+)-negamycin (or called negamycin, English name (+)-negamycin, see the following formula for chemical structure) is a kind of containing Nitrogen antibiotics have better resistance to more resistant Gram-positive bacteria and Gram-negative bacteria and lower toxicity (J. Antibiotics 1970, 23, 170). At the same time, negamycin is also a specific protein synthesis inhibitor, which shows the read-through effect of premature stop codons (PTCs) in prokaryotic cells, making protein coding errors (J.Antibiotics 1970,23,581; J.Antibiotics1970,23,589) . In addition, negative mycin in the Duchenne muscular dystrophy (DMD) mouse model showed the effect of inhibiting dystrophin nonsense mutations (J.Biochem.2003,134,751; Molecular Cell2014,56,541; ACS Med.Chem.Lett .2015, 6,930). [0003] ...

AI Technical Summary

Problems solved by technology

Summarizing the existing synthetic routes, there are still most of the synthetic routes that are lengthy, limited in the construction of chiral centers, and some chemical reactions have low stereoselectivity, requiring multiple column chromatography separation and purification, using expensive transition metal catalysts and At the beginning of the synthesis, the problem of using explosive and violent drugs such as sodium azide, etc., therefore, the existing synthetic routes are generally unable to synthesize a large number of required target compounds and structural derivatives, which affects the provision of a large number of samples required for subsequent structure-activity relationship research. The medicinal chemistry research of (+)-negamycin is greatly limited

In addition, the further derivatization of the obtained target structure by existing synthetic routes is also subject to the influence of the original functional groups in the molecule.

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