Insight into the key factors that influence the reaction pathways in the silyl‐Prins cyclization of gem‐vinylsilyl alcohols

Insight into the Key Factors that Influence the Reaction Pathways in the Silyl-Prins Cyclization of gem-Vinylsilyl Alcohols Paula González-Andrés,aCarlos Díez-Poza,aLaura F. Peña,a Daniel Gónzalez-Pinardo,bIsrael Fernández,b,* and Asunción Barberoa,* a Department of Organic Chemistry, Faculty of Science, University of Valladolid?, 47011 Valladolid, Spain Phone: +34-983-423013 Fax: +34-983-423013 E-mail: [email protected] b Departamento de Química Orgánica y Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040-Madrid, Spain Phone: +34-3944312 E-mail: [email protected] Manuscript received: November 19, 2024; Revised manuscript received: December 10, 2024; Version of record online: January 2, 2025 Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202401437 © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Abstract: This work provides an in-depth analysis of the factors governing the different reaction pathways in the acid-catalyzed cyclization of gemvinylsilyl alcohols with aldehydes. The study evaluates the impact of both the ligands attached to silicon and the choice of the Lewis acid on the reaction outcome. Additionally, computational studies offer valuable insights into the mechanism that control these distinct pathways. The process enables the chemoand stereocontrolled formation of a variety of structural frameworks, offering significant potential for the generation of a broad range of molecular architectures. Keywords: Prins cyclization; organosilanes; computational studies; Lewis acids; Stereocontrol Introduction The fine art of Organic Synthesis has the extraordinary power of replicating some of the most fascinating molecules that nature produces. Some of these substances have changed our everyday lives by providing candidates for pharmaceutical, agriculture, cosmetic, or high-technology applications, among others. But probably medical science is the field that has concentrated more efforts in the search for biologically active molecules. Moreover, Organic Synthesis has proven invaluable for constructing analogues or derivatives of natural products, which can sometimes exhibit enhanced biological properties compared to their natural counterparts. One of the most abundant scaffolds in biologically active compounds is the tetrahydropyran motif,[1,2] and, therefore, developing methodologies for the preparation of this structural core with a range of substituents over its periphery remains a key objective in Organic Synthesis.[3,4] Additionally, the discovery of methodologies that, depending on the nature of the substrates or catalysts, may follow different reaction pathways, and therefore may afford the construction of structurally diverse scaffolds, is highly desirable. Such methods provide ample possibilities for designing structural variation in target molecules and enhance the potential for novel drug discovery. Within the various available methodologies for generating oxygenor nitrogen-containing heterocycles, the Prins cyclization has emerged as one of the most efficient approaches.[5,6] The cyclization involves the acid-catalyzed intramolecular addition of a π-donor group (typically an alkene) to an oxocarbenium ion (generated in situ by condensation of the hydroxy group of the starting alkenol with an aldehyde). Several modifications of the Prins cyclization have UPDATES doi.org/10.1002/adsc.202401437 Adv. Synth. Catal. 2025,367, e202401437 (1 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 908/915] 1 been developed by varying the nature of the π-donor or acceptor entities. In recent years, our research has focused on exploring various strategies for synthesizing oxaand azacycles through silyl-Prins cyclization,[7,8] with particular emphasis on using alkenyl silanes as activated π-donor groups. This method, known as silyl-Prins cyclization, presents multiple benefits, such as enhanced reaction selectivity and a reduction in the formation of unwanted byproducts.[9] Worth of note is the recently published discovery of a tandem silyl-Prins cyclization-aryl migration protocol which occurs with the maintenance of the silyl group in the molecule and aryl migration from silicon to the neighbouring carbon.[10] An even more intriguing finding was that the aryl migration depended on the nature of the acid catalyst (TMSOTf vs BiCl3/ TMSCl)[11] (Scheme 1). The mechanism that we have proposed for these transformations involves the initial formation of an oxocarbenium ion which will then undergo nucleophilic attack by the vinylsilyl group to give an α to silicon carbocation I(which is more stable than the corresponding β-silyl carbocation).[12] From this common intermediate, depending on the nature of the Lewis acid counterion, the reaction will evolve with either 1,2-aryl migration from silicon to carbon and final silyl cation trapping by trimethylsilanol (when TMSOTf is used), or by direct nucleophilic trapping of the tertiary carbocation (in the reaction mediated by BiCl3, TMSCl) (Scheme 2). We envisioned that a better understanding of the factors governing these alternative pathways was required to further develop this synthetically useful transformation. We herein present a deeper overview of this intriguing methodology, highlighting the effects of both the nature of the silyl ligands and the Lewis acid component on the outcome of the cyclization (Scheme 1). Moreover, computational studies have been carried out to gain more insight into the aspects influencing the occurrence of the aryl migration and the high stereocontrol observed. Results and Discussion Our initial efforts focused on exploring the influence of the ligands attached to silicon on the process. To this end, we performed further experiments involving substrates with different substituents at the silicon center. Bearing in mind that phenyldimethylsilyl derivatives 1have been previously demonstrated to undergo selective aryl migration, we thought that it would be interesting to investigate the behaviour of alkenylsilyl alcohols bearing either a diphenylalkylsilyl group or a trialkylsilyl group. Thus, we first tested the reaction with aldehydes of a model substrate 4with two phenyl groups bonded to silicon (diphenylmethylsilyl group). As expected, the reaction in the presence of TMSOTf provided the adducts of a tandem Prins cyclization-aryl migration protocol. However, there are two key differences compared to the reaction with the analogous alcohol 1 bearing the phenyldimethylsilyl group: (i) the reaction of the diphenylmethylsilyl derivative 4proceeded more slowly than the precedent one, suggesting that steric hindrance is influencing this process and (ii) the reactions now resulted in an equimolar mixture of epimers at C4 (5and 6) (Scheme 3). On the other hand, the Prins cyclization of diphenylmethylsilyl alkenol 4with p-chlorobenzaldehyde, in the presence of a mixture of BiCl3and TMSCl, provided the expected C4 halogenated tetrahydropyran 7(no phenyl migration is observed) with Scheme 1. Previous results and this work. Scheme 2. Proposed mechanism. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (2 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 909/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License stereoselectivity comparable to its phenyldimethylsilyl analog 1[11] (Scheme 4). Next, we decided to test the cyclization using the vinylsilyl alcohol 8with three alkyl groups bonded to silicon. Although the higher migratory aptitude of aryl vs alkyl groups is well known, we reasoned that the presence of a primary alkyl group attached to silicon, with higher migratory aptitude than the methyl group, could facilitate the migration. However, no migration was observed in the reaction. Instead, the intermediate tertiary cation Inow undergoes a competitive elimination reaction (9,10), rather than nucleophilic addition, probably due to the steric requirement of the nucleophile (TMSOH) (Scheme 5). In line with this hypothesis and with previous results, the cyclization of the trialkylsilyl derivative 8 with p-chlorobenzaldehyde, mediated by BiCl3/ TMSCl, furnished the expected 4-chorotetrahydropyran 11 in good yield and with excellent stereocontrol (Scheme 6). These results demonstrate that the cyclization of gem-vinylsilyl alcohols, mediated by TMSOTf, undergo a tandem Prins cyclization-aryl migration, provided that the silyl group is attached to an aryl group. However, regardless of the nature of the ligands attached to silicon, when the transformation is mediated by BiCl3/TMSCl, the reaction consistently follows a Prins cyclization pathway. To gain more insight into the pathways leading to the different outcomes of the transformation, Density Functional Theory (DFT) calculations were carried out at the dispersion corrected PCM(dichloromethane)- B3LYPD3/def2-TZVPP//PCM(dichloromethane)- B3LYP/def2-SVP level (see computational details in the Supporting Information). To this end, we investigated the process involving the initially formed oxocarbenium ion INT0 (having the SiMe2Ph moiety), typically deriving from the reaction of the alcohol fragment to the LA-complexed aldehyde,[13,14] in the presence of either TMSOTf or BiCl3/TMSCl (Figure 1). The initial intermediate INT0 is, as previously proposed (see above), transformed into the carbocation INT1 through the intramolecular nucleophilic addition of the vinylsilyl fragment to the electrophilic oxocarbenium. Depending on the conformation of the substituents at the silicon atom, two possible transition states (TS1/TS1’) and intermediates (INT1/INT1’) were located on the potential energy surface. Our calculations indicate that the process involving the phenyl group in close proximity to the tetrahydropyran ring (i.e., TS1/INT1) is favored from both kinetic and thermodynamic points of view. This is mainly due to the occurrence of a stabilizing CH-π non-covalent interaction between the axial hydrogen atoms in the ring and the π-system of the phenyl group as confirmed by the NCIPlot method (see greenish surface in the inset of Figure 1). In the presence of TMSOTf, intermediates INT1/ INT1’ then undergo a 1,2-phenyl migration via TS2/ TS2’ (with a low barrier of only ca. 4–5 kcal/mol) to produce the silyl cation intermediates INT2/INT2’, which after TMSOTf trapping (by the readily formed TMSOH) leads to the observed final products. Once again, the pathway leading to the isomer INT2’ (via TS2’) is kinetically disfavored over the analogous process leading to INT2, which is consistent with the experimentally observed preferred formation of the Scheme 3. Effect of the ligands on silicon: diphenylmethylsilyl group and TMSOTf. Scheme 4. Effect of the ligands on silicon: diphenylmethylsilyl group and BiCl3/TMSCl. Scheme 5. Effect of the ligands on silicon: trialkylsilyl group and TMSOTf. Scheme 6. Effect of the ligands on silicon: trialkylsilyl group and BiCl3/TMSCl. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (3 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 910/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License tetrahydropyran where the phenyl and R groups are placed in anti-relative position. On the other hand, in the presence of BiCl3/TMSCl, the formation of BiCl4 - as the source of chloride can be assumed. Interestingly, we found that the Prins-cyclization and chloride trapping occur in a concerted manner with a lower barrier (ΔΔG¼6 ca. 5 kcal/mol) than that computed for the formation of INT1/INT1’ (i.e., the analogous counteranion-non-assisted process). This is therefore consistent with the exclusive formation of tetrahydropyrans 3in the processes mediated by BiCl3/TMSCl. In addition, the barrier computed for this concerted cyclization/trapping reaction is lower (ΔΔG¼6 = 2.1 kcal/mol) for the process involving Cl-TS1, where the phenyl group is again placed close to the tetrahydropyran ring. This can be again ascribed to the occurrence of similar CH-π non-covalent interactions in this saddle point. This is also consistent with the preferred formation of the product where the Cl and R substituents are placed in syn-relative position (despite being thermodynamically less stable than its anticounterpart, see Figure 1) and indicates that these weak interactions are key in the selectivity of the process, regardless of the conditions (TMSOTf vs BiCl3/TMSCl) used in the experiments. The divergent outcomes observed in this process prompted us to question whether they can solely be attributed to the nature of the Lewis acid counterion or other factors might also be at play. To explore this further, we decided to study the cyclization using other halides as counterions. Initially, we examined the cyclization reaction of alcohol 1with cinnamaldehyde, in the presence of bismuth tribromide, which could play the dual role of Lewis acid and source of bromide. However, an unresolved mixture was obtained under these conditions (Table 1, entry 1) and the combination of catalytic BiBr3with stoichiometric TMSBr did not yield improved results (Table 1, entry 2). Fortunately, reaction mediated by TMSBr in dichloromethane at room temperature afforded the desired 4-bromotetrahydropyran in good yield, although with some inseparable by-products (Table 1, entry 3). By lowering the temperature to 78°C, we were able to avoid this problem (Table 1, entry 4) and the desired compound was obtained in high yield and as a single product. In contrast with the slow reaction rates observed with pure TMSCl (which made necessary the addition of BiCl3), the high reactivity of TMSBr obviates the need for additional cocatalysts, such as BiBr3. Moreover, under TMSBr activation, the use of low temperFigure 1. Computed reaction profile for the process involving the initially formed oxocarbenium intermediate INT0 in the presence of TMSOTf or BiCl3/TMSCl. Relative free energies (ΔG, at 298 K) and bond distances are given in kcal/mol and angstroms, respectively. The inset shows the contour plots of the reduced density gradient isosurfaces (density cutoff of 0.04 a.u.) for INT1 where the green surfaces indicate attractive non-covalent interactions. All data have been computed at the PCM(dichloromethane)- B3LYPD3/def2-TZVPP//PCM(dichloromethane)-B3LYP/def2-SVP level. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (4 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 911/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License ature is required to get selective reactions. Once selected the optimal conditions for this reaction (Table 1, entry 4), we next studied the scope of the process using different aldehydes. The results are shown in Table 2. The reaction is general for arylic aldehydes (either electron-rich or electron-poor) as well as for vinylic aldehydes. In addition, different substituents (including arylic groups) are tolerated on the carbinol carbon. However, the use of highly reactive aldehydes (i.e., alkylic aldehydes or p-nitrobenzaldehyde) resulted in complex mixtures from which it was difficult to isolate the corresponding 4-bromotetrahydropyrans. Interestingly, the reaction again occurs with direct trapping of the intermediate α-silyl tetrahydropyranyl cation Iby the halide (i.e., products of 1,2-phenyl migration were not observed). Furthermore, excellent diastereoselectivity towards a single diastereomer is obtained in all the examples when the reaction was performed at 78°C (12a–12j). The relative configuration of the tetrahydropyranyl products was determined by the coupling constants in 1H-NMR and NOESY experiments. Moreover, confirmation of that structure was achieved by means of single-crystal X-ray diffraction of compound 12b (Figure 2). To complete our study, and also motivated by the significance of fluorinated compounds in pharmaceutical and radiological applications, we decided to investigate whether the same reaction pathway observed with chloride and bromide metal Lewis acids is also followed when fluoride is used as the counterion. For that purpose, we choose BF3·OEt2as the activator. The results are shown in Table 3. As demonstrated, and in contrast with the behaviour of other metal halide Lewis acids, when fluoride is the counterion the reaction seems to follow a tandem silylPrins cyclization/phenyl migration pathway. This might suggest that various factors, including steric hindrance and bond strength, play a critical role in determining the reaction outcome. The reaction with BF3·OEt2is effective for both electron-rich and electron-poor aromatic aldehydes, as well as for vinylic aldehydes and even the highly reactive alkylic aldehydes. Additionally, arylic substituents attached to the carbinol are well tolerated, yielding the desired product in moderate yields. According to our DFT calculations (Figure 3), the concerted Prins-cyclization/fluoride-trapping (with BF4 -as fluoride source) also proceeds with a lower barrier than the non-assisted process. This leads to the formation of the F-3-syn/anti intermediates with no Table 1. Optimization for bromide-based Lewis acids. Entry Lewis Acid Solvent Conditions Product (yield) 1 BiBr3CH2Cl2rt, 2 h UCM[b] 2 BiBr3/TMSBr[a] CH2Cl2rt, 2 h UCM[b] 3 TMSBr CH2Cl2rt, 2 h 12j (74)[c] 4 TMSBr CH2Cl278°C, 2 h 12j (82) [a] 0.4 equiv. of BiBr3and 1.2 equiv. of TMSBr were used. [b] UCM stands for unresolved complex mixture. [c] The product could not be separated from other by-products. Table 2. Scope of the silyl-Prins cyclization of gem-vinylsilyl alcohols 1with TMSBr. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (5 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 912/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License significant selectivity. From these intermediates, a simultaneous migration of the fluoride and phenyl groups through the C-Si bond takes place to produce the observed tetrahydropyrans. This process therefore can be viewed as a type I dyotropic reaction according to the original definition by M. Reetz.[15,16] Moreover, the dyotropic reaction involving F-TS2mig is kinetically favored over the analogous process involving FTS2mig’(ΔΔG¼6 ca. 2 kcal/mol)). This fact, together with the higher thermodynamical stability of the corresponding reaction product, F-2-anti, are responsible for the high stereoselectivity observed experimentally. Since one of the added values of silicon-containing compounds is their ability to undergo a variety of functional group transformations under mild conditions, we ultimately chose to further investigate the potential of the silylated tetrahydropyrans obtained from this process. To this end, we examined two distinct silicon conversion strategies. We first tested the protodesilylation of adducts from either the cyclization-migration or the cyclization-nucleophilic trapping processes. As shown in Scheme 6, reaction of bromoderivative 12b with TBAF in THF gave the corresponding desilylated tetrahydropyran 14 in good yield and with complete retention of the configuration at C4 (Scheme 7). However, protodesilylation of tetrahydropyrans 2a or 13b, in which silicon is attached to a very crowded quaternary center,[17,18] yielded desilylated tetrahydropyrans 15 and 16 as a nearly equimolar mixture of diastereoisomers (with either retention or inversion of the configuration at C4) (Scheme 8). Despite anticipating potential steric hindrance challenges in the Fleming-Tamao oxidation of a siliconsubstituted quaternary carbon, we proceeded to evaluate the conversion of the silyl group to a hydroxyl in 4-phenyl-4-silyltetrahydropyrans 2a and 13 b. Attempts to oxidize disilane 2 a under various conditions, Figure 2. X-ray crystal structure of 12 b; displacement ellipsoids at 50% probability. H atoms are omitted for clarity. Color key: C (grey), O (red), Si (yellow), Br (orange). CCDC: 2391410. Table 3. Scope of the silyl-Prins cyclization of gem-vinylsilyl alcohols 1with BF3·OEt2. Scheme 7. Protodesilylation process of 4-bromo-4-silyl tetrahydropyran 12b. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (6 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 913/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License however, yielded only complex product mixtures. By contrast, the fluorosilane derivative 13b demonstrated greater ease of oxidation, producing the desired 4phenyl-4-hydroxytetrahydropyrans as a mixture of C4 epimers when treated with MCPBA and KF[19] (Scheme 9). Interestingly, tetrahydropyran analogs to compound 17, bearing aryl groups in C2 and C4, have been reported to exhibit significant tumor growth inhibition in various human cell lines.[20] Conclusion A deep examination of the factors controlling the different reaction pathways of the Lewis acid-catalyzed silyl-Prins cyclization of gem-vinylsilyl alcohols with aldehydes is provided. The influence on the reaction outcome of both the nature of the Lewis acid and the silicon ligands has been proven. In addition, computational analysis provides a critical insight into the mechanism accounting for the different pathways. Our methodology allows the construction of structurally Figure 3. Computed reaction profile for the process involving the initially formed oxocarbenium intermediate INT0 in the presence of BF3as the activator. Relative free energies (ΔG, at 298 K) and bond distances are given in kcal/mol and angstroms, respectively. All data have been computed at the PCM(dichloromethane)-B3LYPD3/def2-TZVPP//PCM(dichloromethane)-B3LYP/def2-SVP level. Scheme 8. Protodesilylation of 4-phenyl-4-silyl tetrahydropyrans 2a and 13b. Scheme 9. Fleming-Tamao oxidation of 4-phenyl-4-silyl tetrahydropyran 13b. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (7 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 914/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License diverse scaffolds, presenting considerable promise for the creation of an array of targets. Experimental Section Experimental details, characterization data for all new compounds, copies of 1H and 13C{1 H} NMR spectra for new compounds and X-ray crystallographic data for compound 12 b can be found in the Supporting Information. CCDC-2391410 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/structures Lewis Acid Promoted Cyclization of gem-Vinylsilyl Alcohols A solution of the homoallylic alcohol (1 equiv.) and the corresponding aldehyde (1.2 equiv.) in dry dichloromethane is cooled to the corresponding temperature (under nitrogen). Then, the Lewis acid is dropwise added. The mixture is stirred while monitored by TLC. When starting materials are consumed, it is hydrolyzed with NaOH (aq) 2 M. or sat. NaHCO3. Phases are then separated, extracting the aqueous phase three times with dichloromethane. The organic phases are combined and dried over anhydrous MgSO4. The solvent is then evaporated under reduced pressure. The crude mixture is analyzed by NMR and then purified by column chromatography in silica gel, using mixtures of hexane-ethyl acetate, yielding the corresponding tetrahydropyrans. Acknowledgements We are grateful for financial support from grants TED2021131705BC21, PID2021-125909OBI00, PID2022139318NBI00 and RED2022-134331-T, funded by MICIU/ AEI/10.13039/501100011033 and NextGenerationEU/PRTR. We also acknowledge E. Cuellar for X-ray analysis (Department of Inorganic Chemistry, University of Valladolid, Spain). L. F.-P., P. G.-A. and D. G.-P. acknowledge predoctoral fellowships funded by either the “Junta de Castilla y León”, the University of Valladolid or the Comunidad de Madrid. References [1] a) D. Kumar, P. Sharma, H. Singh, K. Nepali, G. K. Gupta, S. K. Jain, F. Ntie-Kang, RSC Adv. 2017,7, 36977–36999. [2] N. M. Nasir, K. Ermanis, P. A. Clarke, Org. Biomol. Chem. 2014,12, 3323–3335. [3] A. Shikha, S. Ayushi, S. Jay, S. Nusrat, N. Sahiba, T. Pankaj, Appl. Organomet. Chem. 2022,36, e6604. [4] L. Lempenauer, G. Lemière, E. Duñach, Adv. Synth. Catal. 2019,361, 5284–5304. [5] A. Budakoti, P. K. Mondal, P. Verma, J. Khamrai, Beilstein J. Org. Chem. 2021,17, 932–963. [6] a) C. Olier, M. Kaafarani, S. Gastaldi, M. P. Bertrand, Tetrahedron 2010,66, 413–445; b) X. Han, G. Peh, P. E. Floreancig, Eur. J. Org. Chem. 2013, 1193–1208. [7] a) A. Barbero, A. Diez-Varga, M. Herrero, F. J. Pulido, J. Org. Chem. 2016,81, 2704–2712; b) A. Diez-Varga, H. Barbero, F. J. Pulido, A. González-Ortega, A. Barbero, Chem. Eur. J. 2014,20, 14112–14119. [8] a) L. F. Peña, A. Barbero, Org. Lett. 2024,26, 5202– 5207; b) L. F. Peña, P. González-Andrés, A. Barbero, RSC Adv. 2024,14, 707–711. [9] A. P. Dobbs, S. J. J. Guesne, S. Martinovic, S. J. Coles, M. B. Hursthouse, J. Org. Chem. 2003,68, 7880–7883. [10] C. Díez-Poza, A. Barbero, Org. Lett. 2021,23, 8385– 8389. [11] C. Díez-Poza, L. Fernández-Peña, P. González-Andrés, A. Barbero, J. Org. Chem. 2023,88, 6776–6783. [12] T. A. Blumenkopf, L. E. Overman, Chem. Rev. 1986,86, 857–873. [13] S. J. Pérez, M. Purino, P. O. Miranda, V. S. Martín, I. Fernández, J. I. Padrón, Chem. Eur. J. 2015,21, 15211– 15217. [14] R. M. Carballo, J. M. Padrón, I. Fernández, D. A. Cruz, L. Grmuša, V. S. Martín, J. I. Padrón, J. Org. Chem. 2022,87, 11000–11006. [15] M. T. Reetz, Angew. Chem. Int. Ed. Engl. 1972,11, 129– 130. [16] For a review, see: I. Fernández, F. P. Cossío, M. A. Sierra, Chem. Rev. 2009,109, 6687–6711. [17] G. Maas, M. Alt, D. Mayer, U. Bergsträsser, S. Sklenak, P. Xavier, Y. Apeloig, Organometallics 2001,20, 4607– 4615. [18] A. diastereomeric mixture, now enriched in the isomer with inversion of configuration (dr 1:3), was obtained when desilylation of 2 a was done with tBuOK and 18crown-6 in DMSO. [19] K. Tamao, T. Kakui, M. Akita, T. Iwahara, R. Kanatani, J. Yoshida, F. Kumada, Tetrahedron 1983,39, 983–990. [20] P. Singh, A. Bhardwaj, J. Med. Chem. 2010,53, 3707– 3717. UPDATES asc.wiley-vch.de Adv. Synth. Catal. 2025,367, e202401437 (8 of 8) © 2025 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH Wiley VCH Mittwoch, 26.02.2025 2504 / 390276 [S. 915/915] 1 16154169, 2025, 4, Downloaded from https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.202401437 by Universidad De Valladolid, Wiley Online Library on [10/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License