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Synthetic method for chiral marine natural product with high optical activity

A technology of optical activity and synthesis method, applied in the fields of organic chemistry, bulk chemical production, organic chemistry, etc., can solve the problems of complex process, difficult mass production, cumbersome route steps, etc., and achieves broad application prospects and mild reaction conditions. , the effect of simple synthesis steps

Active Publication Date: 2015-07-22
SHANDONG UNIV
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AI Technical Summary

Problems solved by technology

The structure of this compound is relatively novel and unique, and it has a chiral center. However, the chemical extraction and separation of natural products involves complex processes, low yield and large waste, resulting in high cost of the extract and difficult to produce in large quantities. Since then, people have continued to try And successfully carried out its total synthesis research
The synthetic method of this compound that has been reported is as follows: Thomas Lindel and his colleague first reported the total synthesis of natural product midpacamide (Lindel, T.and H.Hoffmann, Liebigs Annalen, 1997,1997 (7), 1525-1528.) , however, the reagents used in these processes are rare, expensive, and cannot solve the problem of racemization
In 2001, Pilar M etc. used a new method to re-synthesize midpacamide (Fresneda, P.M., P.Molina, and M.A.Sanz, Tetrahedron letters, 2001, 42(5), 851-854.), this method is easy to get raw materials , but did not solve the problem of racemization
In 2004, Pilar M et al. tried a new method for the total synthesis of midpacamide (Fresneda, P.M., Tetrahedron letters, 2004, 45(8), 1655-1657.). This method is difficult to synthesize some reagents, and racemization has not yet been resolved. question
The steps of the above synthetic schemes are relatively cumbersome, and the most important thing is that the problem of racemization is not solved. All the routes available in the prior art have not realized that the obtained product is a single configuration product

Method used

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  • Synthetic method for chiral marine natural product with high optical activity
  • Synthetic method for chiral marine natural product with high optical activity
  • Synthetic method for chiral marine natural product with high optical activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of 2-amino-5-(((benzyloxy)carbonyl)amino)pentanoic acid

[0056] Dissolve 7.5g of L-ornithine hydrochloride in 89ml of 0.5mol / L sodium hydroxide solution, add 5.55g of anhydrous copper sulfate, react for 15min, then add 6.15g of anhydrous potassium carbonate and 8.2ml of benzyl chloroformate , reacted overnight, filtered and washed to obtain a blue solid, then added saturated disodium ethylenediaminetetraacetic acid solution, first heated to reflux for 2 hours, then overnight at room temperature, filtered, washed and dried to obtain a white solid, with a yield of 83%.

Embodiment 2

[0057] Example 2: Preparation of 2-amino-5-(((benzyloxy)carbonyl)amino)methyl pentanoate

[0058] Add 8.5ml of acetyl chloride dropwise to methanol under ice-bath condition, and rise to room temperature to react for 10min. 10.6 g of compound 1 was added to the reaction solution, refluxed for 5 hours, and the solvent was evaporated, ethyl acetate was added, after washing and drying, the solvent was evaporated to obtain a light yellow solid with a yield of 85%. 1 H-NMR (300MHz, CDCl 3 ):δ1.36-1.61(m,2H),1.74-1.82(m,2H),2.97-3.03(q,2H),3.74(s,3H),4.05(s,1H),δ5.01(s ,2H),δ7.28-7.40(m,6H),δ8.51(s,3H); 13 C-NMR (100MHz, CDCl 3 ): δ25.3, 27.4, 40.1, 52.9, 53.3, 66.5, 128.0, 128.5, 128.6, 136.7, 156.8, 170.2.

Embodiment 3

[0059] Example 3: Preparation of methyl 5-(((benzyloxy)carbonyl)amino)-2-(3-methylureido)valerate

[0060] Dissolve 11.2 g of compound 2 in a mixed solution of dichloromethane and saturated sodium bicarbonate under ice bath conditions, add 5.29 g of triphosgene, react for 15 minutes and extract quickly, and dry the organic phase to obtain a dichloromethane solution of isocyanate. Under an ice bath, the dichloromethane solution of isocyanate was dropped into the dichloromethane solution containing methylamine and triethylamine, and reacted at room temperature for 1 hour after the dropping was completed. After distilling off the solvent, ethyl acetate was added, the organic phase was washed and dried, and the solvent was distilled off. Recrystallization gave a white solid with a yield of 78% and a melting point of 114-117°C. 1 H-NMR (300MHz, DMSO-d 6 ):δ1.38-1.49(m,2H),δ1.52-1.69(m,2H),δ2.51-2.54(d,3H),2.95-3.01(q,2H),δ3.60(s, 3H),δ4.07-4.15(q,1H),δ5.00(s,2H),δ5.82(d,1H),δ6.2...

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Abstract

The invention discloses a synthetic method for a chiral marine natural product with high optical activity. According to the method, a marine natural product with the high optical activity is prepared by adopting chiral amino acid. The method specifically comprises the following steps: first, using L-ornithine monohydrochloride and D-ornithine monohydrochloride as starting raw materials, and performing copper ion complexing, amino protecting, esterifying, urea forming and cyclizing to obtain an intermediate 5; then, using N-methylpyrrole as a raw material, and performing electrophilic reaction, hydrolyzing, acidizing and acylating in sequence to obtain an intermediate 9; finally, enabling the intermediate 5 and the intermediate 9 to react to prepare corresponding chiral natural products, namely (S)-midpacamide or (R)-midpacamide. According to the synthetic method, synthetic steps are simple; the operation is simple and convenient; reaction conditions are mild; the original structure of the product prepared by the provided synthetic route is kept; the optical purity of the obtained marine natural product is greater than 99 percent; the marine natural product has a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a synthesis method of a chiral marine natural product with high optical activity. Background technique [0002] In recent years, marine natural products have become a research hotspot for scientists. Midpacamide is a marine natural product with antibacterial activity (Triana Hertiani, RuAngelie Edrada-Ebel, Sofia Ortlepp, Rob W.M.Van Soest, Nicole J.de Voogd Bioorganic & Medicinal Chemistry 2010 , 18,1297–1311) in 1977, Lionel Chevolot first reported the marine natural product midpacamide, which was isolated from an unnamed sponge in the waters near the Marshall Islands in the Western Pacific Ocean and extracted a new 3,5 Disubstituted imidazoline-2,4-dione marine alkaloids. The structure of this compound is relatively novel and unique, and it has a chiral center. However, the chemical extraction and separation of natural products involves complex processes, low yield...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12
CPCY02P20/55C07D403/12C07B2200/07
Inventor 方浩肖云丁胜勇宿莉杨新颖陈禹
Owner SHANDONG UNIV
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