News: New nicotine synthesis method

The reaction of nitrogen-containing aromatic heterocyclic halides has been realized, which can be used for the synthesis of (S)-nicotine and its derivatives.

Recently, the research group of Tang Wenjun of the Shanghai Institute of Organic Chemistry has realized the asymmetric Heck reaction of nitrogen-containing aromatic heterocyclic halides using bulky sterically hindered chiral phosphine ligands with P, P=O structural units. Heterocyclic substituted aryl compounds offer a new approach. The method has a wide range of substrates, excellent functional group compatibility, and can be used for the efficient asymmetric synthesis of (S)-nicotine and its derivatives.


Main Body

Chiral α-heteroaryl-substituted heterocyclic skeletons are widely found in alkaloids, natural products and drug molecules, such as nicotine, the main component of tobacco treatment of central nervous system diseases, and Harmicine has shown antispasmodic, antipyretic and anticancer properties, and Valbenazine has been approved for the treatment of tardive dyskinesia, therefore, chiral α-heteroaryl-substituted heterocycles have attracted significant attention in the synthesis. Chemists have developed several strategies for their asymmetric synthesis. In 2011, O’Brien’s team developed the enantioselective α-arylation reaction of N-Boc pyrrolidine, however, this method was cumbersome and relied on expensive soba alkaloids for chiral induction; in 2015, Academician Zhou Qilin The research group realized iridium-catalyzed asymmetric hydrogenation of 2-pyridyl cyclic imines, but its substrate scope is narrow and limited; recently, Peter Zhang’s group constructed five-membered heterocycle. From the perspective of retrosynthetic analysis, the construction of C(sp2)-C(sp3) bonds through intermolecular cross-coupling reactions (such as the Heck reaction) is the most direct and practical way to synthesize α-heteroaryl-substituted heterocycles. One of the methods, but has not been implemented before.

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Over the past two decades, asymmetric Heck reactions have been extensively used in the synthesis of natural products and drug molecules. Hayashi, Tietze et al. Synthesis of α-Aryl Substituted α-Aryl in High Yield and Enantioselectivity Using Intermolecular Heck Reaction of Aryl/Vinyl Halides with Heteroatom-Containing Intracyclic Olefins via Different Chiral Catalysts Heterocycle. However, the asymmetric Heck reaction of azaaryl halides has been an unsolved problem. The key is that the strong coordination ability of azaaryl halides (especially pyridine halides) to transition metals easily leads to catalyst deactivation. seriously affected the results of the reaction. In order to solve this problem, Tang Wenjun’s research group chose to use large sterically hindered P, P=O ligands to participate in the reaction. The ideas are as follows:

1) Large sterically hindered ligands will inhibit the formation of coordination-saturated inactive palladium species (such as inhibiting the coordination of pyridine N atoms to Pd);

2) The weak coordination effect of P=O on Pd in ​​the P, P=O ligand enables the Pd(II) obtained after oxidative addition to dissociate from the P=O ligand to get a coordination vacancy to ensure the alkene The substrate is capable of migratory insertion.

Finally, after a series of optimizations, the researchers used (S)-DTBM-SEGPHOS to realize the asymmetric Heck reaction of nitrogen-containing heterocyclic substrates for the first time.

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Conditions were optimized using 3-bromopyridine (1a) and N-Boc-protected enamine (2a) as model substrates. Among them, monophosphine ligands such as BI-DIME (L1), AntPhos (L2), etc. only obtained a trace amount of the target product 3a; bisphosphine ligands such as L3, L5-L8, etc. did not obtain the product, but P, P=O Ligand L4 afforded 3a in 34% yield. Therefore, the researchers continued to explore this type of ligand and found that the ligand L9 with the anthracenyl group had the best reaction effect. In addition, MeOH and Pd(OAc)2 were the best solvents and metal catalysts for this reaction system.

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Subsequently, when the author expanded the substrate range of this reaction, it was found that it was widely applicable to tetracyclic alkenes containing heteroatoms such as tetrahydropyridine, dihydropyran, dihydrofuran and dihydropyrrole, and for the pyridine ring Substituents (such as fluorine, cyano, trifluoromethyl, etc.) and other types of heterocycles other than pyridine (such as quinoline, pyrimidine, etc.) also have good compatibility, so this reaction has a good substrate universality sex.

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In order to elucidate the role of the P, P=O-type ligand L9 in this reaction, the authors conducted a comparative study between [Pd(L9)Cl2] and the previously reported [Pd(L11)Cl2], showing that the anthracene-containing [Pd( L9)Cl2] has a more crowded coordination pocket than [Pd(L11)Cl2] containing dimethylamine groups. Therefore, the greater steric hindrance of L9 makes it difficult to coordinate the saturation of the Pd-L9 catalyst, which increases the TON of the catalyst. In addition, the weak coordination character of P=O…Pd complexes provide a coordination vacancy for the coordination of alkene substrates for efficient reaction compared with the chelated bisphosphorus ligands combined with palladium catalysts. In general, L9 not only utilizes the large steric hindrance to cause coordination unsaturation to avoid catalyst poisoning but also selectively utilizes the weak coordination of P=O and Pd coordination to make the Heck reaction more reactive and active. Subsequently, after screening several chiral phosphine ligands, the authors found that (S)-DTBM-SEGPHOS obtained the target product 4a with an ee value of 96%, thereby realizing the asymmetric synthesis of α-heteroaryl-substituted heterocycles.

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The authors propose the following structure to explain the high enantioselectivity when (S)-DTBM-SEGPHOS is the chiral ligand. They speculate that after the oxidative addition of the Pd catalyst to the C-X bond, under the action of silver salts, a cationic Pd species with coordination vacancies will be formed in the reaction system, which provides favourable conditions for the subsequent coordination of olefins. Since (S)-DTBM-SEGPHOS restricts the coordination environment of Pd catalysts, the coordination of the Re face of cyclic olefins, such as dihydrofuran, to the Pd centre is considered to be more favourable. In addition, the other moieties linked to alkenes are located in the lower right region with less steric hindrance in the tetrahedron, thus avoiding mutual repulsion with the aryl groups carried by the ligands in the upper right region with greater steric hindrance. Based on the observed stereochemistry, migratory insertion results in a tertiary stereocenter adjacent to the oxygen atom. It is worth noting that the yields and ee values were poor when dihydropyran or tetrahydropyridine was used as the alkene substrate. The authors speculate that this is because the steric effects and half-chair conformation of these six-membered ring structures may be detrimental to the activity and enantioselectivity of the reaction under the current conditions.

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To demonstrate the practicability of this method, the authors carried out the gram-scale reaction of 1a and 2a with Pd/L9 as a catalyst, obtained the product 3a in 70% yield, and then used CF3COOH to remove the protective group in 3a, which could be 98% The yield of anabasine 5 was successfully obtained. In addition, the authors performed an asymmetric Heck reaction with 1a and 2,3-dihydrofuran (2d) at the gram scale to obtain an enantiomerically enriched product with a yield of 74% and an ee value of 96%. Next, the compound (S)-3u provided by 4a was hydrogenated with a yield of 99% and an ee value of 96%. Under the action of Pd(OAc)2 and (S)-DTBM-SEGPHOS, 1a and 2c were reacted with 64% yield and 94% ee to obtain chiral product 6. 6 was successfully converted by platinum-catalyzed hydrogenation and LiAlH4 reduction in two steps. for nicotine 7. Its absolute configuration was determined to be S by comparison with the optical rotation of naturally occurring nicotine. Here, we achieve the enantioselective synthesis of nicotine using a concise and practical asymmetric Heck reaction.

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A novel method for the synthesis of α-heteroaryl-substituted heterocycles using an asymmetric Heck reaction. This method has the advantages of a wide substrate range, good functional group compatibility and mild reaction conditions. Among them, due to the large steric hindrance of the ligand itself and the weak coordination of the P=O ligand, a P, P=O type ligand containing an anthracene-based structure is very important for this type of reaction. This reaction is the first to achieve efficient coupling between nitrogen-containing heterocyclic halides and heterocyclic alkenes (including tetrahydropyridine, dihydropyran, dihydrofuran and dihydropyrrole) and uses DTBM-SEGPHOS as a chiral ligand for the first time An asymmetric Heck reaction was achieved. Furthermore, the utility of this method was demonstrated by the efficient synthesis of (S)-nicotine, which is expected to play an important role in the synthesis of bioactive molecules with α-heteroaryl-substituted heterocyclic backbones.


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