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C-alpha-mannosylated tryptophan intermediate as well as preparation method and application thereof

A technology of mannosyl and tryptophan, applied in organic chemistry, bulk chemical production, peptides, etc., can solve the problems of limited reagent application, lengthy synthesis steps, low reaction efficiency, etc., achieve simple and efficient synthesis, and simplify synthesis difficulty , the effect of simple synthesis steps

Active Publication Date: 2020-06-02
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis steps of these three fragments in Isobe's route are tedious and the reaction efficiency is not high, which limits the reagent application of this method
[0006] In summary, although C-α-mannosylated tryptophan (compound 2) has been reported on synthetic methods, all of them have the problems of lengthy synthetic steps and low reaction efficiency, which have great limitations. Therefore, , the development of a highly efficient and highly stereoselective C-α-mannosylated tryptophan (compound 2) synthetic method is an important problem to be solved at present

Method used

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  • C-alpha-mannosylated tryptophan intermediate as well as preparation method and application thereof
  • C-alpha-mannosylated tryptophan intermediate as well as preparation method and application thereof
  • C-alpha-mannosylated tryptophan intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-5

[0043] Add amide material (compound 23) (29.2mg, 0.1mmol, 1.0mol / L), chlorosugar (112mg, 0.2mmol, 2.0mol / L), palladium acetate (2.2mg, 0.01mmol, 0.1mol / L), acetyl isoleucine (Ac-Ile-OH) (5.2mg, 0.03mmol, 0.3mol / L), potassium acetate (14.7mg, 0.15mmol, 1.5mol / L), add 1mL solvent , cover the reaction vial cap (without particularly strict anhydrous and oxygen-free conditions), and stir at 110° C. for 12 hours. After the reaction was complete, the reaction bottle was cooled to room temperature, filtered, concentrated, and separated by column chromatography to obtain compounds 24-C and 24-N. The preparation steps of Examples 1-9 are basically the same, the difference lies in the use of different reaction solvents.

[0044]

[0045] The investigation of table 1 reaction solvent

[0046]

[0047] a:NMR Yield

[0048] It can be found from Examples 1-5 that when the reaction solvent is PhMe, the yield of Example 3 is the best.

[0049] Wherein the test data of compound 24-C a...

Embodiment 6-12

[0059] The preparation method of embodiment 6-12 is basically the same as the preparation method of embodiment 3, and the only difference is that the divalent palladium metal catalyst selected in embodiment 6-12 is different, specifically as shown in table 2:

[0060] The screening of table 2 divalent palladium metal catalyst

[0061]

[0062] a:NMR Yield

[0063] Can find by embodiment 6-12, when divalent palladium metal catalyst is Pd(OAc) 2 When, the productive rate of embodiment 3 is the best.

Embodiment 13-17

[0065] The preparation method of Examples 13-17 is basically the same as the preparation method of Example 3, the only difference being that the alkali selected in Examples 13-17 is different, specifically as shown in Table 3

[0066] The investigation of table 3 alkali

[0067]

[0068] a: NMR Yield

[0069] Can find by embodiment 13-17, when alkali is potassium acetate, the productive rate of embodiment 3 is the best.

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Abstract

According to the invention, a self-designed amide raw material is utilized, wherein the amide raw material has bidentate guide groups; a Pd catalyzed bidentate guide group assisted far-end aromatic hydrocarbon C(sp<2>)-H activation method is used for the first time to realize simple, efficient and high-stereoselectivity synthesis of the C-alpha-mannosylated tryptophan intermediate; and the synthesized C-alpha-mannosylated tryptophan intermediate is further applied, and decrystallized glycopeptide hormone can be simply and quickly synthesized, so that the problems of long synthesis steps and low reaction efficiency in the prior art are effectively avoided. The synthesis method disclosed by the invention has very good practicability; the synthesis steps of the sugar donor (compound 10) and the amino acid fragment used in the method are simple; the C-alpha-mannosylated tryptophan intermediate is suitable for large-scale production and application; and the used guide groups are various invariety and easy to remove, and thus the synthesis difficulty of the compounds is greatly simplified.

Description

technical field [0001] The invention belongs to the technical field of metal catalysis and natural product synthesis application, and specifically relates to a C-α-mannosylated tryptophan intermediate and a preparation method and application thereof. Background technique [0002] In 1992, Gade reported the isolation of Cam-HrTH-I (that is, the compound with sequence number 1, such as figure 1 shown), which is a decrystallized glycopeptide hormone (Proefke, M.L. Biochem. Biophys. Res. Commun. 1992, 189, 1303-1309). Notably, Cam-HrTH-I has a very unusual hexose modification on the tryptophan (Trp,W) residue, although the identities of its hexose and sugar chain structures are unclear. Soon, Hofsteenge reported related glycosylation-modified Trp ribonucleases and determined that the sugar fragment was linked at the C2 position of tryptophan indole. Based on these pioneering studies, C-α-Mannosyl Tryptophan (C-α-Mannosyl Tryptophan) has gradually been recognized as a common PT...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/14C07D405/04C07K7/06
CPCC07D401/12C07D405/14C07D405/04C07K7/06Y02P20/55
Inventor 陈弓何刚王权权安爽祝婉君
Owner NANKAI UNIV
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