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Method for preparing natural product (3S,9S)-Ciliatamides C

A technology for natural products and compounds, applied in organic chemistry and other directions, can solve problems such as high price, poor amino selectivity, and product racemization

Inactive Publication Date: 2008-09-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In addition, the above two strategies also have the following common disadvantages: 1. Carrying out the cyclization reaction under strong alkali conditions is easy to make the product racemization, reducing the yield
2. The selectivity of further protection of the amino group in the product molecule is very poor
3. If the product of the R configuration is synthesized (3R)-amino-piperidin-2-one (10'), the above two strategies must use very expensive non-natural D-ornithine

Method used

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  • Method for preparing natural product (3S,9S)-Ciliatamides C
  • Method for preparing natural product (3S,9S)-Ciliatamides C
  • Method for preparing natural product (3S,9S)-Ciliatamides C

Examples

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Effect test

Embodiment 1

[0039] Step 1 Synthesis of (S)-2-amino-5-(benzyloxy)carboxy-pentanoic acid 2

[0040] The compound was purchased directly from the market or prepared according to the literature: that is, under nitrogen protection, benzyl alcohol (34.0 mmol) and 60% concentrated sulfuric acid (27.2 mmol) were added to L-glutamic acid (1, 27.2 mmol) at 70°C. Vacuum dehydration for 6 hours. The reaction system was quenched by adding saturated sodium bicarbonate (27.2 mmol) overnight, and filtered to obtain compound 2 (40-50.0%).

[0041] Step 2 Synthesis of (S)-5-(benzyloxy)carboxy-2-tert-butoxycarbonylamino--pentanoic acid 3

[0042] Compound 2 (50 mmol) was dissolved in a mixed solvent of 150 mL of dioxane and 150 mL of water, di-tert-butyl carbonate and triethylamine were added at 0 °C, reacted at 0 °C to rt. for 12 hours, concentrated and diluted with water, Extracted twice with ether, acidified the aqueous phase with 5 mol / L hydrochloric acid to pH=1 and extracted three times with ethyl a...

Embodiment 2

[0067] Step 1 Synthesis of (R)-2-amino-5-(benzyloxy)carboxy-pentanoic acid 2'

[0068] The compound was purchased directly from the market or prepared according to the literature: that is, under nitrogen protection, benzyl alcohol (34.0 mmol) and 60% concentrated sulfuric acid (27.2 mmol) were added to D-glutamic acid (1', 27.2 mmol) at 70°C. Dehydrated under vacuum for 6 hours. The reaction system was quenched by adding saturated sodium bicarbonate (27.2 mmol) overnight, and filtered to obtain compound 2' (40-50.0%).

[0069] Step 2 Synthesis of (R)-5-(benzyloxy)carboxy-2-tert-butoxycarbonylamino--pentanoic acid 3'

[0070] The synthesis of compound 3' was the same as in step 2 described in Example 1.

[0071] Step 3 Synthesis of (R)-5-(benzyloxy)-1-methyl-2-tert-butoxycarbonylamino-glutaric acid diester 4' Synthesis of Compound 4' and Step 3 described in Example 1 same.

[0072] Step 4 Synthesis of (R)-4-tert-butoxycarbonylamino-5-(methoxy)carboxy-pentanoic acid 5'

[0...

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Abstract

The present invention belongs to the field of chemical synthesis and relates to the asymmetric synthetic technology of chiral piperidine compounds, in particular to a preparation method of marine natural products, (3S, 9S)-Ciliatamides C and a synthetic fragment thereof, (3R) or (3S)-amido-piperidine-2-one. In the method, natural compound L or D-glutamic acid, which is cheap and can be easily prepared, is used as starting raw material to asymmetrically synthesize the compound (3R) or (3S)-amido-piperidine-2-one; simultaneously, the (3S)-amido-piperidine-2-one is used as the molecule of a key synthetic fragment to asymmetrically synthesize the marine natural products, (3S, 9S)-Ciliatamides C, which has inhibitory activity for the toxicity of HeLa cells. The method has the advantages of simple operation, easy separation, high yield and excellent stereoselectivity. And the agents that are used in the method are ordinary agents that are cheap and can be easily prepared.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to asymmetric synthesis technology of chiral piperidine compounds, in particular to a natural product (3S,9S)-Ciliatamides C and its synthetic fragment (3R) or (3S)-amino-piperidine-2 - Method for the preparation of ketones. Background technique [0002] (3R) or (3S)-amino-piperidin-2-one is an important organic synthesis fragment or intermediate for the preparation of Sulpostin (DPP-IV) and (3S, 9S)-Ciliatamides C which have inhibitory effects on HeLa cytotoxicity The structural formula of the above compound is as described in formula 1. DPP-IV is a compound with strong activity isolated from Streptomyces sp. MK251-43F3 in 2001 (Abe, Masatoshi et al. J. Antibiot. 2001, 54, 744-746); Ciliatamides C is the first time that Japanese scholars isolated from deep sea in 2008 A novel lipopeptide isolated from the sponge Aaptosciliata (Nakao, Yoichi et al. J. Nat. Prod. 2008, 71, 469-472) ...

Claims

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Application Information

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IPC IPC(8): C07D211/74
Inventor 魏邦国黄伟孙逊林国强
Owner FUDAN UNIV
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