Cyclic peptide compound simulating structure of natural product and preparation method of cyclic peptide compound
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A technology of natural products and compounds, which is applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problem of amino acids not being able to be used, and achieve the effect of broadening the application range of hydrocarbon activation
Active Publication Date: 2019-08-30
NANKAI UNIV
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This reaction can be carried out very efficiently, but the introduction of the alkyl chain containing AQ into the polypeptide backbone can only be limited to the carbonyl β-position of the straight-chain carboxylic acid for intramolecular arylation, and many amino acids cannot be utilized
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Embodiment 1-9
[0069] Screening of reaction solvents:
[0070]
[0071]The linear polypeptide (No. S4) (43.4mg, 0.05mmol, 1.0equiv), AgOAc (12.6mg, 0.075mmol, 1.5equiv) and Pd (OAc) 2 (2.2mg, 10mol%) was weighed into an 8mL reaction vial (sealed with a PTFE lid), then 2mL of solvent was added at room temperature and stirred for 5 minutes, then heated to 110°C for 6 hours. The reaction was cooled to room temperature, 5 mL of acetone was added to the reaction system to dilute, and then filtered with celite, and the obtained filtrate was evaporated to dryness to obtain an oil, which was purified by column chromatography to obtain the final white ring-closing product. The difference between Examples 1-9 is only in the reaction solvent, as shown in Table 1.
[0072] The screening of table 1 reaction solvent
[0073]
[0074] As can be seen from the results of Examples 1-9, when the solvent is selected as HFIP, the yield is higher.
Embodiment 10-16
[0076] Screening of different divalent palladium metal catalysts:
[0077]
[0078] The preparation method of Examples 10-16 is basically the same as that of Example 6, except that the divalent palladium metal catalyst used in Examples 10-16 is different, as shown in Table 2.
[0079]
[0080] As can be seen from the results of Examples 10-16, when the palladium metal catalyst is selected as Pd(CH 3 EN) 4 (BF 4 ) 2 , the yield is higher.
Embodiment 17-24
[0082] Screening of different silver salts:
[0083]
[0084] The preparation method of Examples 17-24 is basically the same as that of Example 14, the only difference is that the silver salt used in Examples 17-24 is different, as shown in Table 3.
[0085] Table 3 Screening of different silver salts
[0086]
[0087] As can be seen from the results of Examples 17-24, when the silver salt is selected as the AgOAc of Example 14, the yield is higher.
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Abstract
The invention relates to a cyclic peptide compound simulating the structure of a natural product and a preparation method of the cyclic peptide compound. The preparation method comprises the followingsteps of enabling a compound as shown in a formula I, a bivalent Pd catalyst and silver salt to have an intramolecular arylation reaction in a solvent under the effects of heating and stirring to construct cyclic peptide, and generating a compound as shown in a formula II. According to the cyclic peptide compound prepared by the preparation method disclosed by the invention, an arylation site hasdiversity, side chain gamma-site methyl or methylene of most of hydrophobic amino acids (amino acids of which N-ends are connected with PA) can be expanded to be subjected to the intramolecular arylation reaction to construct the cyclic peptide, the shortcoming that the originally selected amino acid kinds are limited is overcome, and a novel aromatic ring support type cyclic peptide compound iseffectively constructed. The aromatic ring support structure of the cyclic peptide can be completely integrated into a framework of a cyclic peptide molecule, a novel 3D structure similar to that of the natural product is formed, and extremely favorable support is provided for construction of a cyclic peptide molecule library and screening of high-flux medicines subsequently.
Description
technical field [0001] The invention belongs to the field of chemical synthesis of polypeptides, and in particular relates to a cyclic peptide compound simulating the structure of natural products and a preparation method thereof. Background technique [0002] At this stage, synthetic chemistry has been significantly improved for the development of small molecule drugs (MW<500D). But chemists are lagging behind in exploring the larger "middle molecules" (500-2000D) for pharmaceutical research. This type of molecule occupies a very large space between small molecule drugs and biopharmaceuticals, and has great potential to intervene and regulate some very difficult biological pathways, such as protein-protein interactions. To be able to freely explore this field for drug discovery, new strategies for the design and construction of relatively large molecules with diverse structures and biophysical properties are necessary. Cyclic peptide compounds have a combination of var...
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