Enantioselective synthesis of axial chiral alkenyl boron compounds

On January 5, 2023, Professor Song Qiuling’s research group published an article entitled “Synthesis of axially chiral alkenylboronates through combined copper- and palladium-catalysed atroposelective arylboration of alkynes” in the journal Nature Synthesis” Research results.

The group used Cu/Pd bicatalysis to promote the synthesis of axial alkenyl boron compounds by using the simple alkyne enoselective aryl boronation strategy promoted by Cu/Pd bicatalysis. This protocol describes readily available reagents and simple conditions, and provides a flexible platform for the construction of axial chiral alkenyl boron compounds with high yields, significant Z/E selectivity, and good enantioselectivity. It also exhibits excellent regional selectivity for asymmetric alkynes.

The corresponding author of the paper is Professor Song Qiuling of Fuzhou University, and the first author is Li Wangyang, a doctoral student of Fuzhou University.

Axial chiral compounds have attracted widespread attention in the fields of synthetic chemistry, medicinal chemistry, catalysis and materials science. However, the development of asymmetric synthesis of axial chiral styrene compounds remains challenging compared to the development of mature biaryl axial chiral compounds (Figure 1a). Functional grouping of alkynes is one of the simplest and most direct methods for synthesizing potential shaftal chiral olefins (Figure 1b), and the synthesis of axial chiral styrene compounds by functional grouping of alkynes containing steric hindrance substituents has developed rapidly, although the synthesis of axial chiral styrene compounds by functional grouping of simple alkynes has not been reported (Figure 1c). Alkenyl boron compounds are a class of boron-containing intermediates widely used in organic synthesis, and are widely used in the construction of stereospecificity of olefins through Suzuki-Miyaura cross-coupling, Zweifel alkenylation, Petasis reaction and other transformations. Therefore, the integration of chiral axes and different functional groups into alkenylboron compounds will further increase their structural diversity and synthetic application value (Figure 1d).

Professor Song Qiuling’s team has been committed to the research of organic boron chemistry, and has made a series of research progress in the field of organic boron chemistry (such as Acc. Chem. Res.2021, 54, 2298–2312;Angew. Chem. Int. Ed.2022, 61, e202212740; ACS Cent. Sci. 2022, 1134-1144;Nat. Commun.2022, 13, 2624-2637;Nat. Commun.2022, 13, 1748-1760;J. Am. Chem. Soc.2021, 143, 10048-10053;J. Am. Chem. Soc.2021, 143, 13124-13134;Nat. Commun. 2022, 13, 3524-3536;Nat. Commun.2021, 12, 441; Chem, 2020, 6, 2347-2363;Angew. Chem. Int. Ed., 2020, 59, 3294-3299;Angew. Chem. Int. Ed., 2019, 58, 13421-13426;Nature Commun., 2019, 10, 5709.)。 Recently, Professor Song Qiuling’s research group in Nat. The aryl boronation reaction of simple alkynes in Cu/Pd biurged was reported on Synth., enabling enantioselective synthesis of tetrasubstituted axial chiral alkenyl borate (Figure 1e). This method has good functional group tolerance, significant Z/E selectivity and excellent enantioselectivity, and also has good regional selectivity for asymmetric alkynes, which has great application value.

Figure 1: Research background

Through a series of condition optimizations, the authors determined that the optimal conditions were IPr•CuCl and Pd(OAc)2 as metal catalysts, (R)-AntPhos as chiral ligands, tAmONa as base, and nBu4NBr as additives, at 20°C.1With B2pin2 and2The novel shaftal alkenyl boron compound was obtained by reacting in homotrimylene with a separation yield of 93% and a 95:5 e.r3 (Figure 2).3The absolute configuration of was determined by X-ray diffraction analysis as the R configuration (CCDC: 2171042). Moreover, the reaction has complete Z/E selectivity, and only cis-addition aryl boruleation products are obtained.

Figure 2: Reaction optimal conditions

After determining the optimal conditions, the compatibility of a range of substrates was examined (Figures 3, 4). This novel enantioselective alkyne aryl borylation reaction has a wide range of substrates (103 examples) and is well compatible not only with symmetric alkynes, but also with asymmetric alkynes, but also with different aryl bromides. It is worth mentioning that the reaction system can also be compatible with a series of heteroatoms and heterocycles.

Figure 3: Substrate range for symmetric alkynes and aryl bromides

Figure 4: Substrate ranges for asymmetric alkynes and aryl bromides

To illustrate the excellent functional group compatibility and potential application value of this reaction, the authors selected a range of bioactive and drug molecule-derived alkynes or aryl bromides to obtain axonal alkenyl boron compounds with excellent enantioselectivity or enantioselectivity under standard reaction conditions, illustrating that this method can be a simplified pathway for the discovery of other bioactive molecules (Figure 5).

Figure 5: Bioactive and pharmaceutical molecular modifications

Finally, in order to further reflect the application value and transformation value of the axial chiral alkenyl boron compound in the synthesis, the authors did a gram-level preparation reaction and a large number of application transformation reactions (Figure 6), and the formation of new C(sp2)-C(sp3) and C(sp2)-C(sp) bonds could be realized by coupling reactions for borates. For ester groups, they can be converted into new functional groups by hydrolysis reaction, reduction reaction, etc.; For ketones, Pd-catalyzed intramolecular cyclization can be realized, and the conversion of axial chirality to central chirality can be realized, and excellent enantioselectivity and rich late conversion will reflect the application potential and value of axial alkenyl boron compounds.

Figure 6: Gram-level preparation and application transformation

The authors studied the reaction mechanism, first by controlling experiments (Figure 7a) to determine the reaction mechanism of Cu/Pd double catalysis. Subsequently, by changing the configuration of the chiral ligand, it was found that the configuration of the product also changed, indicating that the absolute configuration of the chiral ligand determines the absolute configuration of the product (Figure 7b). Then, the possibility of catalytic reactions in higher-order Pd species was determined by nonlinear relationship experiments (Figure 7c, Figure 7d), and a possible catalytic cycle was proposed (Figure 7e): for the copper catalytic cycle, Cu catalyzed the boronization reaction of alkynes to generate β-boronylenyl copperI。 Among them, the electron effect of aryl group is used to induce the copper part to add the α position of aryl, so as to realize the regional selective control of asymmetric alkynes. At the same time, for palladium-catalyzed cycling, aryl bromide chiral L*Pd(0) oxidative addition forms aryl Pd(II) intermediatesII, followed by β-boronylalkyl copperITransmetallization occurs and enantioselective generation of intermediatesIIIAt lastIIIReduction elimination occurs to obtain the target productIV。 Finally, the authors determined the rotational barrier and half-life of axial chiral alkenyl boron compounds through thermal racemic experiments, indicating that the novel axial chiral alkenyl boron compounds have high stability, which provides necessary conditions for subsequent application transformation.

Figure 7: Mechanism experiments and possible catalytic cycles


This method provides a method for enantioselective synthesis of axial chiral alkenyl boron compounds. The enantioselective aryl boronation reaction promoted by Cu/Pd dual catalysis has good compatibility with multifunctional groups, which is confirmed by a wide range of substrates and later modifications of bioactive compounds or drug molecules, thus opening up a new avenue for the functionalization of alkynes with excellent Z/E selectivity, enantioselectivity and regional selectivity for the synthesis of tetrasubstituted olefins. At the same time, the diversified transformation of axial alkenyl boron compounds shows that axial chiral alkenyl boron compounds have great potential in the synthesis of multifunctional axial chiral compounds with novel structures. (Source: Science Network)

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