Synthesis method of Beta-silicon group-substituted amino acid derivative

A synthesis method and amino acid technology, applied in chemical instruments and methods, compounds of group 4/14 elements of the periodic table, organic chemistry, etc., can solve problems such as limited scope of application of substrates, and achieve mild reaction conditions and stereoselectivity The effect of high compatibility and strong versatility of response

Inactive Publication Date: 2016-08-03
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods all involve directed transition metal catalysis, and this type of directed transition metal catalyzes sp in the carbon-hydrogen bond 3 Most of the carbon-hydrogen bonds are limited to the highly active carbon-hydrogen bonds, and the scope of substrate application is particularly limited

Method used

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  • Synthesis method of Beta-silicon group-substituted amino acid derivative
  • Synthesis method of Beta-silicon group-substituted amino acid derivative
  • Synthesis method of Beta-silicon group-substituted amino acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In the reactor, add 0.1 mmol of alanine whose nitrogen end is protected with phthaloyl group and whose carboxyl end is introduced into 8-aminoquinoline, 0.5 mmol of hexamethyldisilane 2, 0.01 mmol of palladium acetate catalyst, 0.02 Millimoles of L-N-Boc-Val-OH, 2.0 millimoles of silver carbonate and 1 milliliter of tert-butanol were reacted at 140 ° C for 12 hours and then the reaction was completed for post-treatment, and the β-silylation as in structural formula 1 was obtained by silica gel column chromatography Product 3a in 84% yield. 1 HNMR (400MHz, CDCl 3 )δ10.47(br,1H),8.74-8.70(m,2H),8.14(dd,J=8.4,1.2Hz,1H),7.90(dd,J=5.2,3.2Hz,2H),7.75(dd ,J=5.2,3.2Hz,2H),7.50(d,J=4.8Hz,2H),7.42(dd,J=8.0,4.0Hz,1H),5.23(dd,J=12.0,4.8Hz,1H) ,2.08(dd,J=14.4,12.0Hz,1H),1.66(dd,J=14.4,4.8Hz,1H),0.05(s,9H); 13 CNMR (101MHz, CDCl 3 )δ168.41, 168.19, 148.50, 138.77, 136.40, 134.34, 134.21, 132.11, 128.03, 127.45, 123.73, 121.98, 121.73, 116.77, 52.41, 17.31, -1.31.

[0036] The pr...

Embodiment 2

[0039] In the reactor, add 0.1 mmol of L-phenylalanine whose nitrogen end is protected with phthaloyl group and carboxyl end with 8-aminoquinoline, 0.5 mmol of hexamethyldisilane 2, 0.015 mmol of palladium acetate Catalyst, 1.5 mmol 2,6-dimethoxy-1,4-benzoquinone, 0.5 mmol silver carbonate and 0.5 mmol lithium acetate and 1 ml 1,4-dioxane, react at 125°C for 12 hours After finishing the reaction, the post-treatment was carried out, and the β-silylation product 3b according to the structural formula 2 was obtained by silica gel column chromatography, and the yield was 71%. 1 HNMR (400MHz, CDCl 3 )δ10.93(br,1H),8.93(dd,J=4.0,1.6Hz,1H),8.82-8.77(m,1H),8.14(dd,J=8.4,1.6Hz,1H),7.69(m ,2H),7.57(td,J=5.2,2.0Hz,2H),7.53(d,J=1.6Hz,1H),7.52(s,1H),7.46(dd,J=8.4,4.0Hz,1H) ,7.25-7.17(m,4H),6.95(ddd,J=8.8,5.2,3.6Hz,1H),5.60(d,J=13.6Hz,1H),3.89(d,J=13.6Hz,1H), 0.02(s,9H); 13 CNMR (100MHz, CDCl 3 )δ168.26, 167.32, 148.81, 139.66, 138.98, 136.27, 134.61, 134.04, 131.37, 128.37, 128.07, 12...

Embodiment 3～12

[0043] The operation steps are the same as in Example 2, the difference is that: according to Table 1, the substituent R of the amino acid substrate is changed to obtain different β-silylated phenylalanine derivatives, and the reaction formula is as follows:

[0044]

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Abstract

The invention discloses a synthesis method of a Beta-silicon group-substituted amino acid derivative. The synthesis method comprises the following steps: using amino acid of N-terminus amino group-protected and carboxy-terminus-introduced 8-aminoquinoline and hexamethyl disilane as raw materials; using hexamethyl disilane as a silicon group forming agent; using palladium acetate as a catalyst; using substituted quinone as an oxidant; using silver salt and acetate as additives; performing silicon group reaction in an organic solvent; performing column chromatography separation and purification to obtain the Beta-silicon group-substituted amino acid derivative. The synthesis method provided by the invention is mild in reaction condition, simple in process, convenient to operate and high in stereoselectivity.

Description

technical field [0001] The invention relates to a high-efficiency synthesis method for palladium-catalyzed β-silicon-based substitution of non-natural amino acids, which belongs to the field of carbon-hydrogen bond-activated carbon-silicon bond coupling catalyzed by oriented transition metals. Background technique [0002] β-Silicon-substituted amino acid derivatives are structural fragments of some biologically active natural products; more importantly, with the development of biochemistry and medicinal chemistry, this type of structure appears in many drug molecules or molecules with amino acid or lactic acid fragments in drug intermediates. Recently, it has been reported in the literature that the introduction of silicon groups into amino acids can promote the lipophilicity of amino acids and inhibit protein degradation. The structures of some highly active silylated amino acids are shown in the following formula: [0003] [0004] The construction of aryl substituen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/10
CPCC07F7/0812
Inventor 史炳锋刘悦进
Owner ZHEJIANG UNIV
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