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Method for synthesizing amino acids with large steric hindrance and oligopeptides through palladium catalytic carboxylic acid guided arylation

A technology for catalyzing carboxylic acids and amino acids, applied in peptide preparation methods, chemical instruments and methods, peptides, etc., can solve problems such as limited modification range, and achieve high activity, high efficiency, and mild reaction conditions

Active Publication Date: 2020-02-11
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this kind of ligands achieves asymmetric transformation pioneeringly, there are still some problems, such as limited modification range

Method used

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  • Method for synthesizing amino acids with large steric hindrance and oligopeptides through palladium catalytic carboxylic acid guided arylation
  • Method for synthesizing amino acids with large steric hindrance and oligopeptides through palladium catalytic carboxylic acid guided arylation
  • Method for synthesizing amino acids with large steric hindrance and oligopeptides through palladium catalytic carboxylic acid guided arylation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] In the reactor, add 0.3 mmol of phthaloyl-protected L-type tertiary amino acid, 0.9 mmol of 4-methoxyiodobenzene, 0.03 mmol of palladium acetate catalyst, 0.3 mmol of silver phosphate, 0.3 mmol of acetyl Tert-leucine, 0.3 mmol potassium carbonate and 3 milliliters of hexafluoroisopropanol were reacted in an air atmosphere at 70° C. for 24 hours, and then the reaction was finished for post-treatment, and product 1 and product 1′ were obtained by thin-layer silica gel plate chromatography. The rates were 58% and 10%, respectively, and the ee values ​​were 99% and 96%. The HPLC spectrum of compound 1, 1' and its racemate is shown in figure 1 , figure 2 .

[0034] The structure of product 1 is as follows (wherein, Phth is phthaloyl):

[0035]

[0036] The structural characterization data are as follows:

[0037] 1 H NMR (400MHz, CDCl 3 )δ7.92–7.82(m,2H),7.79–7.70(m,2H), 7.09(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),4.86(s,1H ),3.79(s,3H), 3.01(d,J=13.3Hz,1H),2.83(d,J=13....

Embodiment 2～15

[0044] The operation steps are the same as in Example 1, the difference is that by changing the substituent on the raw material iodobenzene, different arylated products can be obtained (see Table 1).

[0045] Table 1 Embodiment 2~15 synthetic big sterically hindered amino acid experimental result

[0046]

Embodiment 16

[0048] Add 0.3 mmol L-type 3-bromophthaloyl tertiary amino acid, 0.9 mmol 4-methoxyiodobenzene, 0.03 mmol palladium acetate catalyst, 0.3 mmol silver phosphate, 0.3 mmol acetyl tertiary leucine , 0.3 millimoles of potassium carbonate and 3 milliliters of hexafluoroisopropanol, reacted in an air atmosphere at 70 ° C for 24 hours and then finished the reaction for post-treatment, and obtained product 16 and product 16 'yields were 61% by thin-layer silica gel plate chromatography. %, 15%.

[0049] The structure of product 16 is as follows:

[0050]

[0051] Product characterization data are as follows:

[0052] 1H NMR (400MHz, CDCl3) δ7.99(s, 1H), 7.87(d, J=7.7, 1H), 7.72(d, J=7.9Hz, 1H), 7.08(d, J=8.2Hz, 2H) ,6.82(d,J=8.1Hz,2H),4.83(s,1H), 3.79(s,3H),3.00(d,J=13.3Hz,1H),2.81(d,J=13.3Hz,1H) ,1.16(s,3H), 0.99(s,3H).13C NMR(101MHz,CDCl3)δ173.09,167.22,166.68, 158.17,137.32,134.29,133.23,131.82,130.11,129.69,129.31,712.504, 6 113.36,55.20,44.56,39.34,28.01,24.78,24.64.HRMS(E...

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Abstract

The invention discloses a method for synthesizing amino acids with large steric hindrance and oligopeptides through palladium catalytic carboxylic acid guided arylation. According to the method, a substrate is not racemized in a reaction process, so that the product can be directly used as a ligand to participate in an asymmetric catalytic reaction; the palladium catalytic arylation reaction is characterized in that double-protection L-tert-leucine and an oligopeptide compound containing L-tert-leucine are used as substrates, aryl iodide is used as an arylation reagent, and aryl is introducedto the gamma position of an amino acid to synthesize an amino acid with large steric hindrance and a polypeptide, wherein the reaction is carried out in a hexafluoroisopropanol solvent, palladium acetate is used as a metal catalyst, acetyl tert-leucine is used as an auxiliary agent, and silver phosphate and potassium carbonate are used as additives; and with the method, a variety of branched chainlarge steric hindrance amino acids and oligopeptide compounds can be efficiently synthesized, the compounds are chiral ligands with characteristics of high activity and high selectivity, and the ligands show high chiral induction in applications.

Description

technical field [0001] The invention relates to a palladium-catalyzed C-H bond arylation method for synthesizing large sterically hindered amino acids and polypeptides, and belongs to the field of carbon-hydrogen bond activation catalyzed by oriented transition metals. Background technique [0002] Amino acids are the basic structural units of proteins and play an important role in life activities. It is worth mentioning that amino acids and peptides with large steric hindrance are ubiquitous in organic catalysis, natural products, and drug molecules. In particular, the synthesis and application of large hindrance amino acids have attracted much attention in recent years. Double-protected amino acids as chiral ligands participating in asymmetric catalytic reactions have rapidly developed into a hot field of asymmetric carbon-hydrogen bond activation. At the same time, the most commonly used ligands for chiral dirhodium catalysts are also chiral pure tertiary leucine or ada...

Claims

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Application Information

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IPC IPC(8): C07D209/48C07D221/14C07D207/452C07D209/60C07D209/76C07K5/107C07K7/06C07K1/02
CPCC07D207/452C07D209/48C07D209/60C07D209/76C07D221/14C07K1/02C07K5/1016C07K7/06
Inventor 史炳锋刘蕾
Owner ZHEJIANG UNIV
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