Asymmetric desymmetrization of copper-catalyzed meso-dibromocyclic olefins

- Jul 13, 2018-

The asymmetric desymmetrization reaction of meso compounds is one of the commonly used methods for synthesizing chiral compounds in organic chemistry. This method can construct molecules containing multiple chiral centers by one-step reaction starting from sigma-symmetric precursors. The desymmetrization process of mesocyclic 2-ene-1,4-diol derivatives by asymmetric allyl substitution (AAS) reaction is a very effective method for constructing polyfunctional chiral cyclic compounds, and It has been used in the total synthesis of a variety of natural products. Such compounds are usually desymmetrized by a palladium-catalyzed or rhodium-catalyzed process. The palladium-catalyzed reaction generally participates in the reaction of the SN2 product through a soft nucleophile, while the rhodium-catalyzed reaction generally obtains SN2 and SN2' through the reaction of the arylboronic acid. product. Although palladium-catalyzed or rhodium-catalyzed methods show strong advantages in achieving this conversion, these metals are all precious metals, and it is necessary to find a catalytic process in which cheap and readily available metals are involved.

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Recently, a team of Professor Ben L. Feringa from the University of Groningen in the Netherlands reported on the copper-catalyzed AAS desymmetrization process using meso-1,4-dibromo-2-cycloalene as a starting material in copper catalysts and chiral sub- A series of chiral brominated cyclic olefin products were synthesized with high efficiency and high selectivity by reacting with organolithium reagent under the action of phosphoramide ligand. The method can also be used to further construct important structural units of chiral cyclic amino alcohols. Related work was published on J. Am. Chem. Soc.


The meso- 3,6-dibromocyclohex-1-ene (1) was selected as an electrophile and commercialized as a nucleophile design template reaction, and the reaction conditions were screened. In the reaction, CuBr•SMe2 was used as a copper salt to examine different chiral ligands. In addition to the formation of the target product 2d in the reaction, there were also two addition products 3 and cis- 4-bromo-3-butylcyclohex-1-ene (4) by-product. Eventually they weighed the conversion and enantioselectivity, the ligand L3 stood out, the target product 2d was obtained with a selectivity of 90:0:10:0 and an er value of 98:2, and its absolute configuration passed the X-ray of the diol 5. Single crystal diffraction analysis was confirmed.

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      Under the optimal conditions, the authors explored the scope of application of the substrate, mainly to investigate the size of the cyclic olefin ring and the effect of different types of alkyl lithium reagent on the reaction. Good results can be obtained whether it is a six-membered ring olefin or a five-membered ring olefin. 

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Next, the substrate 8 of the seven-membered ring type was investigated. When attempting to purify the product 9a-9e by silica gel column chromatography, the rearranged products 10a-10e were obtained, and the yield and enantioselectivity remained. good. (The structural analysis and mechanism of this rearrangement process can be found in J. Am. Chem. Soc., 2018, 140, 4986)


Figure 4. Investigation of the applicable range of the seven-membered mesocyclic dibromocyclic olefin substrate. Image source: J. Am. Chem. Soc.

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To demonstrate the practicality of the reaction, the authors performed a series of derivatization experiments on products 2d and 9f. First, epoxidation occurred in 2d, benzylamine was used as a nucleophile to attack and ring opening, and two-step reaction gave compound 12,12 to react with nucleophilic sodium azide, and hydrogenation reduction to efficiently construct polysubstituted cyclic diammonols. Compound. Compound 9f is first subjected to a dihydroxylation reaction, followed by a sodium azide nucleophilic substitution and a hydrogenation reduction two-step reaction to efficiently obtain a polyfunctional macrocyclic compound 14.

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      Figure 6. Derivatization experiments of the product. Image source: J. Am. Chem. Soc.

Macrocycle 14 is a precursor of the synthetic 2-phenyl tropinol reported by Pollini et al., which is the core backbone of many alkaloids.

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 Figure 7. Cycloalkane base molecules. Image source: J. Am. Chem. Soc.


to sum up


Prof. Ben L. Feringa reported the asymmetric allyl substitution (AAS) desymmetrization reaction of copper-catalyzed meso-dibromocyclic olefins with organolithium reagents. A series of chiral brominations were synthesized with high efficiency and selectivity. A cyclic olefin product. The product obtained by the reaction can be further converted into a chiral polyfunctional cyclic amino alcohol, which is convenient for efficient synthesis of complex natural products and drug molecules comprising the structural unit.

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