CN-122010958-A - Synthesis method of natural product Pyrroloazocine indole alkaloid skeleton

CN122010958ACN 122010958 ACN122010958 ACN 122010958ACN-122010958-A

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a method for synthesizing natural product Pyrroloazocine indole alkaloid skeleton. The method takes a commercial compound 1 and phenylhydrazine as synthesis starting points, and constructs a [2.2.2] bridged ring system through key Fischer indole synthesis, stille coupling reaction and intermolecular Diels-Alder reaction. Then realizing the construction of Pyrroloazocine indole alkaloid core skeleton through a carbene-mediated cyclopropanation reaction, a Ley-Griffith oxidation reaction, a Beckmann rearrangement and an intramolecular S N 2 cyclization tandem reaction. The method can provide a material basis for activity test of Pyrroloazocine indole alkaloids and analogues thereof, and provide a thought for design of synthetic routes of basic skeletons of more complex caged indole alkaloids.

Inventors

LI GUANG
YIN YUQI
LIU XINPENG
WANG XIN

Assignees

中国医学科学院药物研究所

Dates

Publication Date: 20260512
Application Date: 20241112

Claims (13)

1. A method for synthesizing Pyrroloazocine indole alkaloid skeletons, which is characterized by comprising the following steps: 1) Condensing the compound 1 with phenylhydrazine to form phenylhydrazone compound, and then carrying out Fischer indole synthesis reaction to obtain a compound 2; 2) Introducing benzenesulfonyl into the compound 2 under alkaline conditions to obtain a compound 3, and then hydrolyzing ketal protecting groups under acidic and heating conditions to prepare a compound 4; 3) Preparing a compound 5 by introducing a trifluoromethanesulfonyl group into the compound 4 under low temperature and alkaline conditions; 4) Preparing a compound 6 by Stille coupling reaction of the compound 5 under the condition of transition metal catalysis cross coupling, and preparing a [2.2.2] bridged ring compound 7 by intermolecular Diels-Alder reaction of the compound 6 under the action of Lewis acid; 5) Carrying out hydroboration oxidation reaction on the compound 7 to obtain a primary alcohol compound 8; 6) Protecting the alcoholic hydroxyl group in the compound 8 by using silyl ether to obtain a compound 9; 7) Preparing a compound 10 by subjecting a compound 9 to a carbene-mediated cyclopropanation reaction under alkaline conditions, and then subjecting the compound to a rearrangement reaction under acidic conditions to obtain a compound 11; 8) Hydrolyzing the ester group of the compound 11 under alkaline conditions to prepare a compound 12; 9) Compound 12 is subjected to Ley-Griffith oxidation under the action of tetrapropyl ammonium homoruthenate to prepare compound 13; 10 Compound 13 is subjected to free radical dechlorination under the action of zinc powder and calcium chloride to prepare compound 14; 11 The compound 14 is subjected to condensation reaction under alkaline and heating conditions to prepare oxime compounds 15; 12 Compound 15 undergoes Beckmann rearrangement/intramolecular S N 2 cyclization tandem reaction under acidic conditions to prepare compound 16, namely the core skeleton of natural product Pyrroloazocine indole alkaloid.
2. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 1), The compound 1 and phenylhydrazine are subjected to condensation reaction at room temperature to generate phenylhydrazone compounds (the molar ratio of the compound 1 to the phenylhydrazine is 1:1-1:1.5, preferably 1:1.05), and the generated phenylhydrazone compounds are directly heated and refluxed to perform Fischer indole synthesis reaction without separation to obtain tetrahydrocarbazole compounds 2 (the heating condition is 180-220 ℃, preferably 200 ℃).
3. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 2), The compound 2 reacts with benzenesulfonyl chloride under the alkaline condition at room temperature, benzenesulfonyl is introduced on carbazole nitrogen atom to obtain a compound 3 (alkali is sodium hydroxide, potassium hydroxide, sodium hydride, lithium hydroxide, preferably alkali is sodium hydroxide or potassium hydroxide), then the compound 3 is not separated, a crude product of the compound 3 is heated and refluxed to hydrolyze ketal protecting groups under the acidic condition to obtain a compound 4, a hydrolysis reaction solvent is a mixed solvent of acetonitrile and water (acid is p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate or 1M hydrochloric acid aqueous solution, preferably acid is p-toluenesulfonic acid or p-toluenesulfonic acid monohydrate; heating condition is 80-100 ℃, preferably 85 ℃, and the ratio of the mixed solvent is acetonitrile to water=5:1-15:1, preferably acetonitrile to water=10:1).
4. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 3), The compound 4 reacts with N-phenyl bis (trifluoromethanesulfonyl) imine under the low temperature alkaline condition to introduce trifluoromethanesulfonyl to obtain a compound 5 (the low temperature condition is minus 78 to minus 60 ℃, preferably minus 78 ℃, and the alkali is lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide, preferably the alkali is lithium bis (trimethylsilyl) amide).
5. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 4), The compound 5 and allyl tributyltin are heated and refluxed under the catalysis of transition metal palladium, stille coupling reaction is carried out to generate a compound 6 (the heating condition is 70-90 ℃, preferably 80 ℃, the metal catalyst is tetra (triphenylphosphine) palladium, the molar ratio of the compound 5 to the tetra (triphenylphosphine) palladium is 1:0.01-1:0.05, preferably 1:0.02, the molar ratio of the compound 5 to the allyl tributyltin is 1:2.5-1:5, preferably 1:3), and the compound 6 is subjected to intermolecular Diels-Alder reaction with methyl acrylate under the action of Lewis acid to prepare the [2.2.2] bridged compound 7 (the Lewis acid is diethyl aluminum chloride, dimethyl aluminum chloride and diethyl aluminum chloride, preferably the Lewis acid is diethyl aluminum chloride or dimethyl aluminum chloride, the molar ratio of the compound 6 to methyl acrylate is 1:8-1:12, preferably 1:10 ℃, and the reaction temperature is preferably 23-50 ℃).
6. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 5), The compound 7 is subjected to hydroboration reaction with 9-BBN under heating condition (preferably, the reaction temperature is 50 ℃, the mol ratio of the compound 7 to 9-BBN is 1:2.5), then the temperature is reduced to 0 ℃, and oxidation reaction is carried out with 30% hydrogen peroxide aqueous solution under alkaline condition to obtain primary alcohol compound 8 (preferably, the alkali is sodium hydroxide aqueous solution, and the concentration is 3M).
7. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 6), The compound 8 reacts with tert-butyl dimethyl chlorosilane under the alkaline condition at room temperature to protect the alcoholic hydroxyl group to obtain a silicon ether compound 9 (preferably, the alkali is imidazole).
8. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 7), The compound 9 undergoes a carbene-mediated cyclopropanation reaction under the alkaline condition at room temperature to obtain a compound 10 (preferably, the alkali is 50% sodium hydroxide aqueous solution), then, the compound is heated under the action of silver acetate to undergo a rearrangement reaction to obtain a compound 11, the reaction solvent is a mixed solvent of acetonitrile and acetic acid (preferably, the heating temperature is 50 ℃, the ratio of the mixed solvent is acetonitrile to acetic acid=5:2, and the molar ratio of the compound 9 to the silver acetate is 1:1.5-1:4, preferably, 1:2).
9. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 8), The compound 11 is heated and refluxed under alkaline condition, and the ester group is hydrolyzed to obtain a compound 12, wherein the reaction solvent is a mixed solvent of dichloromethane, methanol and water (preferably, the alkali is potassium hydroxide or sodium hydroxide, the heating temperature is 50 ℃, and the ratio of the mixed solvent is dichloromethane to methanol to water=4:4:1).
10. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 9), Compound 12 in tetrapropyl ammonium homoruthenate, N-methylmorpholine oxide And (3) carrying out Ley-Griffith oxidation reaction under the action of a molecular sieve to obtain a compound 13.
11. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 10), The compound 13 undergoes free radical dechlorination reaction under the action of zinc powder and calcium chloride to obtain a compound 14.
12. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 11), The compound 14 is subjected to condensation reaction with hydroxylamine hydrochloride under alkaline heating conditions to obtain an oxime compound 15 (preferably, the base is pyridine and is used as a solvent; the reaction temperature is 110 ℃).
13. The method for synthesizing Pyrroloazocine indole alkaloid skeleton as defined in claim 1, wherein in step 12), Compound 15 undergoes Beckmann rearrangement/intramolecular S N cyclization tandem reaction under acidic conditions at room temperature to produce compound 16, the core backbone of the natural product Pyrroloazocine indole alkaloid (preferably, the acid is thionyl chloride).

Description

Synthesis method of natural product Pyrroloazocine indole alkaloid skeleton Technical Field The invention relates to the field of organic chemical synthesis, in particular to a method for synthesizing natural product Pyrroloazocine indole alkaloid skeleton. Background Indole alkaloids are various in variety and complex in structure, most of the indole alkaloids have certain physiological activity and unique and complex biosynthesis ways, and are research hot spots in the field of natural pharmaceutical chemistry. The plant of the genus pistacia (Kopsia arborea) is an important source of indole alkaloids, most alkaloids separated from the plant have a multi-ring system, a plurality of chiral centers and a complex cage-like structure, and meanwhile, the alkaloids have rich and diverse pharmacological activities. Pyrroloazocine indole alkaloids are a class of indole alkaloids of specific structure isolated from plants of the genus pistil of the family oleaceae Kopsia grandifolia d.j. Structurally, the alkaloid has a unique 6/5/8/6/5 pentacyclic parent nucleus skeleton, a [4.2.2] aza eight-membered Zhang Liqiao ring structure and 4 chiral centers, and alkaloids LAPIDILECTINE B and Grandilodine C also have a unique endocyclic lactone structure. Thus Pyrroloazocine indole alkaloids present a great synthetic challenge. From the aspect of activity, pyrroloazocine indole alkaloids have the activities of resisting B16 melanoma cells and resisting vincristine cell strain KB cells, so that the alkaloids have potential antitumor medicinal value and have good medicament conversion prospect. Based on the complex and novel structural characteristics and good physiological activity of Pyrroloazocine indole alkaloids, the alkaloids have become hot spot molecules in the field of natural product synthesis in recent years, and a plurality of cases of total synthesis of the indole alkaloids are reported at present, wherein the total synthesis is represented by the Pearson subject group about racemization total synthesis of LAPIDILECTINE B and the ECHAVARREN team about clustered asymmetric total synthesis of Pyrroloazocine indole alkaloids. The Pearson team builds a key spiro intermediate through denitrification gas ring cyclization reaction of azidone and imine condensation tandem [3+2] cycloaddition reaction, and finally closes an eight-membered ring through intramolecular S N 2 reaction to complete the construction of a natural product skeleton, and the ECHAVARREN team builds an eight-membered ring through gold-catalyzed indolylene cyclization reaction and then builds a bridged ring skeleton through photoinduced free radical cyclization reaction. In addition to the synthetic cases described above, nishida, tamba, qin Yong, madao, hong, progenitor linkage, et al have also reported a sequential study of total synthesis of this class of alkaloids. Although there are many cases Pyrroloazocine of total synthesis reports of indole alkaloids at present, the known routes have the problems of long route, higher cost, single synthesis strategy, low efficiency and the like, meanwhile, the Pyrroloazocine indole alkaloids have low abundance in the nature and limited sources, and the traditional separation and extraction means can not meet the requirements of subsequent biological activity research, so that a novel and efficient synthesis strategy still needs to be developed at present. Disclosure of Invention In order to overcome the defects of the existing Pyrroloazocine indole alkaloid synthesis method, the invention provides a novel skeleton synthesis strategy, and the strategy can synthesize the core skeleton of Pyrroloazocine indole alkaloid through Beckmann rearrangement/intramolecular S N 2 cyclization tandem reaction, can provide a material basis for the activity test of Pyrroloazocine indole alkaloid and analogues thereof, and provides a thinking for the design of the synthesis route of the basic skeleton of more complex caged indole alkaloids. In order to achieve the above purpose, the present invention adopts the following technical scheme: a method for synthesizing Pyrroloazocine indole alkaloid skeletons, comprising the following steps: 1) Condensing the compound 1 with phenylhydrazine to obtain phenylhydrazone compound, and then carrying out Fischer indole synthesis reaction under a heating condition to prepare tetrahydrocarbazole compound 2; 2) Introducing benzenesulfonyl group into tetrahydrocarbazole compound 2 under alkaline condition to prepare compound 3, and hydrolyzing ketal protecting group under acidic and heating conditions to prepare compound 4; 3) Preparing a compound 5 by introducing a trifluoromethanesulfonyl group into the compound 4 under low-temperature and alkaline conditions; 4) Utilizing the compound 5 to generate a Stille coupling reaction under the condition of transition metal catalysis cross coupling to prepare a compound 6, and then generating an intermolecular Diels-Alder reaction under the action o