Synergistic nucleophilic substitution reactions (i.e., SN2 reactions) are widely used in the synthesis of C-C and C-heteroatom bonds, in which electron-deficient centers of C(sp3)-X bonds are "backattacked" by nucleophiles, resulting in products with complete stereomorphic flipping (Figure 1a). However, the SN2 nucleophilic substitution reaction (i.e., SNV σ reaction) of sp2 carbon atoms is less studied because: 1) C(sp2) is more electronegative than C(sp3), so the polarity of the C(sp2)-X bond is usually lower than that of the C(sp3)-X bond (Fig. 1b), resulting in a smaller σ* orbital lobe (orbital coefficient) of the C(sp2)-X bond, which effectively reduces the orbital overlap of the SN2 transition state; 2) Compared with alkyl halides (~109.5°→~120°), sp2 carbon is more seriously distorted in the transition state of synergistic SNV reaction (~120°→~180°), and the resulting planar square transition state is more unfavorable than that of alkyl electrophiles. 3) coplanar attack with the SP2 electrophile is unavoidable, which in turn leads to undesirable repulsion between the nucleophile and the alkene supersubstituent; 4) The LUMO of alkenyl halides is usually π* orbital, which can compete with σ* orbitals and then react with certain nucleophiles. Although only a few synergistic SNV reactions have been reported, including ipso-metallized alkenyl halide-mediated SNV reactions (Fig. 1c), the substrate range of these metallized SNV reactions is limited and the mechanism is not well understood.
Recently, the research group of Professor Guangbin Dong of the University of Chicago and the research group of Professor Peng Liu of the University of Pittsburgh (click to view the introduction) have successfully realized the stereospecific alkenyl homolog reaction of organoborate esters through the synergistic SNV reaction mediated by metallization complexes, and can iterate multiple alkene-based units, so as to obtain cross-conjugated polyenes that were previously difficult to prepare. In addition, computational studies have shown that the reduction of spatial tension in planar square transition states promotes an unusual SN2-like synergistic pathway, thus explaining the high efficiency and stereo flipping characteristics of this metallized SNV reaction. The results were published in Nature.
Figure 1. Synergistic SNV response. Image source: Nature
First, the authors selected aryl borate 1a-Tgly as the template substrate for Matteson-type reactions with trans- and cis-phenyl-substituted bromoethylene (E-2a and Z-2a), respectively (Fig. 2a), and the results showed that the Z-2a-derived lithiation reagent produced only trace amounts of the alkenyl homologue, while the more sterically hindered E-2a obtained the desired alkenyl borate Z-3a with good yield and complete stereoselectivity. To this end, the authors explored the reaction mechanism using ab initio molecular dynamics (AIMD) simulations and density functional theory (DFT) calculations, in which metakinetics-based AIMD simulations showed that the ate complex (ate-2l) generated by aryl borate 1a-neop and ethylene α-lithiated bromide underwent synergistic 1,2-migration through the transition state (TS-2l) (Fig. 2b) and that there were no intermediates in the minimum energy pathway (MEP) (Fig. 2c). In addition, the co-migration transition state (TS-2l) adopts a planar square geometry and has a relatively long C(sp2)-Br bond (3.12 Å) and a short B-Ar bond (1.70 Å). It took an average of 155.0±26.5 fs from C(sp2)-Br bond (3.12 Å) break to C(sp2)-Ar bond formation (2.14 Å). Secondly, the authors used DFT calculations to explore the origin of the differential reactivity between the E- and Z-stereoisomers of the alkene-ate complex ate-2a-Tgly (Fig. 2d), and the results showed that E-ate-2a-Tgly reacted with a relatively low energy barrier (E-TS-2a, ΔG‡=24.0 kcal/mol), while Z-ate-2a-Tgly required a higher activation energy barrier (Z-TS-2a, ΔG‡=32.3 kcal/ mol), this is because there is spatial repulsion between the phenyl substituents of the olefin and the borate oxide atom in E-ate-2a-Tgly, so the spatial repulsion between the migrating Ar and the cis-phenyl group on the olefin is reduced in the planar square aryl migration transition state E-TS-2a, and they are placed at a more optimized distance to stabilize the π/π interactions. In addition, when the alkenyl bromide E-2b-derived ate complex was reacted with 8-hydroxyquinoline, E-Ate-2b-HQ was obtained, and X-ray diffraction analysis confirmed that the reaction was stereo-retained and the geometric distortion caused by spatial repulsion was obvious, which was consistent with the DFT calculation. It is worth mentioning that E-Ate-2b-HQ can be further converted into the desired homolog Z-3b' under the action of LiOMe, which further confirms the intermediateness of the boron-ate complex in this reaction.
Figure 2. Reaction discovery and mechanistic studies. Image source: Nature
Subsequently, the authors optimized the alkenyl isologization reaction conditions of aryl borate 1a-Tgly and alkenyl bromide E-2b (Fig. 2f), and obtained the optimal conditions: E-2b was deprotonated in ether at −78°C under the action of lithium tetramethylpiperidine (LiTMP) and generated (1-bromoenyl)-lithium species in situ, and then reacted with aryl borate in the presence of LiBr(1 equiv) to obtain ate-complex intermediates, and then 1,2- After metalate rearrangement, the resulting homologated borate was converted to the more purified pinaol borate Z-3b' (yield: 89%), and the stereomorph was completely flipped. It is worth mentioning that the Z-isomer (Z-2b) of the alkenyl bromide can also be stereospecifically converted to the corresponding product E-3b' with comparable yields, which may be due to the fact that the substituents and boron groups are in the cis-configuration to increase the ground state energy. Under optimal conditions, the authors explored the substrate range of asymmetric alkenyl reagents (Fig. 3a), and the results showed that both the E- and Z-isomers of 2,2-disubstituted alkenyl bromide (2b-2d) were α-deprotonated and homologated, and the corresponding asymmetric tetrasubstituted olefins were obtained stereoselectively with excellent yields. In addition, the structurally versatile symmetric alkenyl reagent (prepared from the corresponding ketone) can also react with 1-NEOP (which is easier to purify) and convert to the desired product with a yield of 65-97% (3F-L, Figure 3B), although the simplest vinyl reagent has a lower yield (3K).
Figure 3. Substrate expansion. Image source: Nature
Next, the authors investigated the substrate range of borates (Fig. 4), and the results showed that aryl borates (4AB) and heteroaryl borates (4S, 4T) with different electrical groups in the adjac, inter, and para positions on the benzene ring were compatible with the reaction, and the corresponding products (4A-4AN) were obtained in good to excellent yields, and were able to tolerate a variety of functional groups, such as halogen atoms (4A, 4C, 4D, 4W, 4Ac-4AF, 4AM-4AN), thioether (4E), Cyano (4G, 4U), trifluoromethyl (4H, 4P), silicon-based (4J), tert-butyl (4K, 4Ah), ether (4L-4N), tertiary amine (4O), ester (4Q), alkenyl (4V) and alkyne (4AA), etc. It should be noted that the bulky o-isopropylphenyl (4AG) and trimethylphenyl (4Al) borates are also effective in achieving this conversion, indicating that the reaction can tolerate large steric hindrance. In addition, primary alkyl borates (5A-5G), secondary alkyl borates (5H), and cyclic borates of different sizes (5I-5L) were homologized smoothly, while other functional groups on the substrate remained unchanged (e.g., alkyl bromide (5E), azide (5F), and terminal olefins (5G)).
Figure 4. Borate substrate expansion. Image source: Nature
Specifically, 1a-Neop was subjected to a one-pot double homologation reaction to obtain dieneborate 6a at a yield of 85%, and the crude product was filtered by silica gel to remove inorganic salts and highly polar by-products, and then the homologation reaction was carried out again to extend the carbon chain, and finally the corresponding triene (6b), tetraene (6c) and pentene (6d) were obtained in good yields, and all olefins were tetrasubstituted with large spatial repulsion. Similarly, by iterating on different types of alkenyl-based building blocks, the authors also construct structurally diverse cross-conjugated polyenes (6e-6g) in a programmable manner. In addition, the three-dimensional controlled cross-conjugated diene (6H-6K) was synthesized at a yield of 60-85% by sequentially inserting two asymmetric alkene-based units, further demonstrating the synthesis potential of this method.
Figure 5. Synthesis of cross-conjugated polyenes. Image source: Nature
Given the widespread presence of polysubstituted olefins in bioactive and pharmaceutical molecules, the authors utilize alkenyl homologation and in-situ Suzuki coupling reactions to rapidly and modularly and stereospecifically prepare polysubstituted olefins. As shown in Figure 6, the homologation of dibromoolefin 2m with borate 7a and then Pd-catalyzed Suzuki cross-coupling with iodobenzene 8a yielded the desired olefin 93a/9a' in a total yield of 93%, followed by an SNAr reaction to obtain the target product 10 (a key synthesis intermediate for fatty acid amide hydrolase (HAAH) inhibitors) in three steps of conversion, one purification and 63% yield, whereas the previous method required seven steps of synthesis and seven purifications with a yield of only 18%. Similarly, the authors also synthesized tetrasubstituted olefins 9b and 9c, key synthesis intermediates of δ-opioid receptor agonists, by alkenyl homologation and in situ Suzuki coupling reactions, greatly simplifying the synthetic route. In addition, starting from commercially available aryl boronic acid, the chemotherapy drug bexarotene can be synthesized with a yield of 70% through two-step transformation; Or from dibromoolefin 2N, after three-step transformation, one-time purification, with a yield of 54% to synthesize the drug candidate GSK23280249 for the treatment of hot flashes in postmenopausal women. Finally, the authors also used this strategy to synthesize the anticancer drug tamoxifen and its analogues (Z- and E-droloxifene), both of which are tetrasubstituted olefins with four different substituents.
Figure 6. Synthetic applications. Image source: Nature
summary
Prof. Guangbin Dong and Prof. Peng Liu and other researchers have successfully achieved stereospecific vinyl homologation of organoborates by using metallization complex-mediated synergistic SNV reactions, and have been able to iterate multiple alkene-based units to obtain cross-conjugated polyenes that were previously difficult to prepare. In addition, the authors also used this method to stereospecifically prepare a variety of bioactive molecules and drug molecules, which greatly simplified the previous synthetic routes, and computational studies showed that the reduction of spatial tension in the planar square transition state promoted the unusual SN2-like synergistic pathway, thus providing new ideas for the development of other homologation reactions.
Stereospecific alkenylidene homologation of organoboronates by SNV reaction
Miao Chen, Christian D. Knox, Mithun C. Madhusudhanan, Thomas H. Tugwell, Coco Liu, Peng Liu & Guangbin Dong
Nature, 2024, DOI: 10.1038/s41586-024-07579-7
Instructor introduction
Dong Guangbin
https://www.x-mol.com/university/faculty/352
Liu Peng
https://www.x-mol.com/university/faculty/1732
(This article was contributed by pyridoxal)