Ketone displacement and migration enabled by trifunctionalization of vinyl triflates

Domain: chemistry
Published: 2026-02-27
Editorial outcome: minor_revision

Abstract
Functional group displacement and migration represent powerful, yet underexplored strategies in synthetic chemistry, offering unique opportunities for molecular diversification and drug discovery. Here, we report a nickel-catalyzed deoxygenative trifunctionalization of vinyl triflates, which enables the efficient synthesis of structurally diverse, boron-containing polysubstituted cyclohexanes featuring quaternary carbon centers. This reaction is a key step enabling aryl displacement of a ketone group and its migration to an adjacent carbon center. Notably, the transformation exhibits broad substrate scope and exceptional, programmable diastereoselectivity in arylative ketone migration. Moreover, this transformation enables efficient α-arylation of unsymmetrical ketones with excellent regio- and diastereoselective control—an outcome that remains challenging to achieve using existing methods. Furthermore, this strategy is particularly well-suited for the late-stage functionalization of structurally complex bioactive molecules, facilitating the rapid generation of analogs.

Introduction
The displacement and migration of key functional groups within complex bioactive molecules have emerged as powerful strategies in contemporary drug design and discovery, offering the potential to significantly enhance or even transform biological activity (Fig. 1a)1-9. For instance, substitution of a C1–NH group with a methyl group followed by migration to the C2 position resulted in a 365-fold increase in CCR6 antagonist potency10. Likewise, replacing a C1–O group with a benzene ring and relocating it to C2 produced a twofold improvement in androgen receptor modulation11. Notably, exchanging a ketone with an alkene moiety, followed by positional migration, converted monoamine oxidase inhibitory activity into selective cyclooxygenase-2 inhibition (Fig. 1b)12,13. Consequently, developing a simple and versatile procedure that facilitate the selective displacement and migration of key functional group within complex molecular architectures is highly valuable.

Ketone groups are among the most prevalent and synthetically valuable functionalities found in pharmaceuticals and bioactive molecules14-16. The ability to precisely manipulate these moieties, particularly through 1,2-ketone migration, has emerged as a powerful strategy for late-stage functionalization17,18. For example, the Dong group reported a Catellani-type process that enables 1,2-carbonyl transposition with enhanced modularity and efficiency19. Later, the Bhawal and Morandi group developed a complementary approach grounded in Willgerodt–Kindler reaction, providing an alternative route for ketone migration20. Although these pioneering strategies laid important groundwork, achieving general displacement and migration of ketone groups remains underdeveloped21,22. On the other hand, vinyl triflates have been readily prepared from ketone precursors and, as pseudohalides, have participated in metal-catalyzed cross-coupling reactions via C–O bond activation, enabling the efficient construction of various C–C and C–X bonds23-25. However, to date, the trifunctionalization of vinyl triflates has remained rarely explored and continues to represent a significant challenge. In line with our ongoing interest in nickel-catalyzed alkene difunctionalization26-29, we have developed a nickel-catalyzed deoxygenative trifunctionalization of vinyl triflates that allows the synthesis of boron-containing polysubstituted cyclohexanes featuring quaternary carbon centers30,31 under mild conditions (Fig. 1c). Importantly, this transformation provides a strategic platform for programmable arylative ketone migration, proceeding with excellent regio- and stereoselectivity.

Results
Reaction development
Given the ease of accessing vinyl triflates from ketone precursors23,24,32,33, our investigation began with the use of commercially available vinyl triflate (1a), bis(pinacolato)diboron (B₂pin₂, 2), and bromobenzene (3a) as model substrates. After extensive optimization, we identified the combination of NiCl₂·DME as the catalyst, LiOMe as the base, and sBuOH as the solvent at 60 °C as the optimal reaction conditions. Under these conditions, the desired trifunctionalized arylboration product (4a) was obtained in 82% yield with excellent diastereoselectivity. As illustrated in Fig. 2, replacing NiCl₂·DME with other nickel sources led to diminished yields. When a palladium catalyst was employed, only the boron–Heck-type byproduct was observed. Solvent screening revealed that alcohols are crucial for the reaction’s efficiency, with sBuOH proving to be optimal. Notably, the reaction also proceeded well under ambient air or in the presence of stoichiometric water, with only a slight decrease in yield, highlighting the operational robustness and practicality of the protocol.

Mechanistic investigations
To gain mechanistic insight into this transformation, a time-course study was performed using model substrates (Fig. 2b). Vinyl triflate 1a was rapidly consumed, accompanied by a steady increase in the intermediate vinyl boronate 4aa, which peaked and then gradually declined over nine hours. Concurrently, the desired product 4a accumulated continuously throughout the reaction. This result suggests that vinyl boronates likely serve as key reaction intermediates in the reaction pathway. To validate this hypothesis, vinyl boronate 4aa was subjected to the standard catalytic conditions, affording the desired product 4a in excellent yield, consistent with its role as a reaction intermediate. Based on these results, together with precedents in nickel catalysis34-39, we proposed a plausible catalytic cycle for this reaction (Fig. 2c). The cycle is initiated by transmetallation of B₂pin₂ with the nickel catalyst (I) to generate a [Ni]–Bpin species (II). Subsequent the vinyl boronate intermediate 4aa was formed through deoxygenative borylation. This intermediate then undergoes a second migratory insertion into [Ni]–Bpin to form species III, which reacts with 3a to deliver the target product 4a, while regenerating the active nickel catalyst (I).

Reaction scope
With optimal reaction conditions established, we first investigated the substrate scope of aryl bromides in this catalytic system, all of which exhibited excellent regio- and diastereoselectivity (>20:1 r.r. and d.r.). As shown in Fig 3, aryl bromides bearing various functional groups, including -Cl (4b), -NMe (4c), -CO Me (4d), and -Bpin (4e), were well-tolerated, affording the corresponding diboraryl products in good to high yields. Notably, unprotected aniline (4f) and alcohol (4g and 4h) groups also underwent efficient reactions. Furthermore, different heteroaromatic compounds reacted effectively in this system, including unprotected indole (4m), pyridine (4n), carbazole (4o), and thiazole (4p), with the target products obtained in moderate to excellent yields, demonstrating the broad functional group tolerance of this method. The relative configuration of product 4k was confirmed by X-ray crystallography. We next examined the scope of vinyl triflates, all of which smoothly underwent the reaction. Specifically, nitrogen-containing cyclohexenyl triflate and 5-membered fused-ring vinyl triflate were successfully transformed into target products (5b and 5c) with high efficiency. Addition-ally, sterically hindered bicyclic triflates and seven-membered ring substrates also showed good compatibility, affording the products (5e, 5f and 5i) in moderate yields, with the absolute configuration of product 5i confirmed by X-ray analysis. Notably, 3- and 4-substituted vinyl triflates (5g and 5h) successfully underwent the transformation, affording the target products with excellent diastereoselectivity. The absolute configurations of the products were unambiguously confirmed by single-crystal X-ray diffraction. Remarkably, a structurally complex fused-ring vinyl triflate derived from santonin was also well tolerated, delivering the desired product (5j) in moderate yield. Furthermore, linear polysubstituted vinyl triflates (5k and 5l) smoothly participated in the reaction, further demonstrating the broad substrate scope and robustness of the methodology.

Synthetic transformation and applications
The synthetic utility of this strategy was demonstrated as shown in Fig 4. First, a gram-scale experiment was conducted, in which the aryl-diboration product 4a was obtained in high yield (72%, 3.2 g) with excellent regio- and diastereoselectivity at a 10 mmol scale, highlighting the scalability and practicality of the reaction. Second, several downstream transformations were explored (Fig. 4). For instance, compound 7, featuring a [4.6]-spirocycle scaffold, was readily synthesized with excellent diastereoselectivity via a sequence of Zweifel olefination/oxidation/Heck reaction. Separately, cis-fused [6.5]- and [6.7]-bicyclic compounds 8 and 9 were synthesized in one pot through sequential boron oxidation and cyclization reactions, also with excellent diastereoselectivity.

Unsymmetrically ortho-aryl-substituted cyclohexanones are privileged motifs in numerous bioactive molecules, yet remain synthetically challenging to access40-43. Leveraging our strategy for molecular skeleton editing and late-stage functionalization, we conducted a series of arylative ketone displacement and migration reactions. As shown in Fig. 5, starting from simple ketones, the corresponding arylative ketone migration products 10, 11 and 13 were efficiently constructed in moderate yields via triflation, this nickel-catalyzed methodology, and subsequent oxidation/BF₃·Et₂O-mediated transformation. Notably, product 11 was obtained with excellent trans-selectivity, and its structure was confirmed by single-crystal X-ray diffraction. Moreover, late-stage modification of the A-ring in steroids is a pivotal transformation in medicinal chemistry. Applying our protocol, we achieved the trifunctionalization of drostanolone propionate in moderate yield. Following oxidation and BF₃·Et₂O treatment, we isolated the arylative ketone migration product 15 with exceptional diastereoselectivity (>20:1 d.r.). Similarly, arylative ketone migration products 17 and 19 were synthesized in moderate yields and high stereoselectivity from dihydrocholesterol and epiandrosterone derivatives, respectively, via a one-pot, three-step sequence. To further demonstrate the synthetic utility of our platform, we designed a programmable, stepwise arylative ketone displacement and migration sequence. Starting from a simple cyclohexanone substrate 20, the first arylation yielded 2-phenylcyclohexanone (21) in moderate yield. Subsequent iterative application of this reaction system successfully enabled the second, third, and fourth arylative ketone migration events, furnishing a series of highly functionalized cyclohexanone scaffolds bearing distinct aryl substituents (22-24), with excellent trans-diastereoselectivity observed at each step. Owing to pronounced steric hindrance, further installation of a fifth aryl group on the ring is not feasible under this protocol. Such structurally complex molecules are typically difficult to access using traditional synthetic methods, underscoring the broad applicability and strong synthetic potential of this strategy.

Methods
Representative procedure for trifunctionalization of vinyl triflates：
Under a nitrogen atmosphere, an oven-dried 10 mL reaction tube equipped with a magnetic stir bar and sealed with a rubber stopper was used. Sequentially, NiCl₂·DME (4.4 mg, 0.02 mmol, 5 mol%), MeOLi (68.3 mg, 1.0 mmol, 4.5 equiv.) and B₂pin₂ (406.2 mg, 1.6 mmol, 4.0 equiv.). Then anhydrous sBuOH (1.5 mL), 1a (0.4 mmol, 1.0 equiv.), 3a (0.8 mmol, 2.0 equiv.) and anhydrous sBuOH (1.0 mL) were added in this order, and the mixture was stirred at 60 °C for 10 - 24 h. Then the mixture was filtered through a silica plug with ethyl acetate and concentrated. The crude material was separated on a silica gel column affording the desired product. For further details, please refer to the Supplementary Information.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This manuscript describes a nickel-catalyzed deoxygenative trifunctionalization of vinyl triflates that enables the synthesis of\nboron-containing polysubstituted cyclohexanes featuring quaternary carbon centers under mild conditions. The methodology\nis robust, supported by extensive mechanistic studies, a broad substrate scope, and practical applications—including gram-\nscale synthesis and late-stage derivatization of complex bioactive molecules. Notably, formal arylative ketone migration is\nachieved via post-functionalization steps (oxidation/BF₃·Et₂O-mediated rearrangement), highlighting the method’s utility in\nmolecular skeleton editing. Particularly impressive is the demonstration of programmable arylative ketone migration (Fig.\n5b), which underscores the versatility and synthetic value of this approach. In summary, I find this work highly compelling\nand support its publication in Nature Communications after minor revisions. Below are several suggestions to enhance\nclarity and impact:\n1. The title and Introduction strongly emphasize functional group displacement and migration as the central theme. However,\nthe core of the manuscript focuses on the development and scope of nickel-catalyzed trifunctionalization (Fig. 2-4). The\nketone migration is a valuable yet secondary application that comes after further synthetic modification (Fig. 5). This\ndisconnect may confuse readers. Additionally, Fig. 1c aims to illustrate the concept of ketone migration but does not\nexplicitly show that the process requires additional 2 steps (oxidation and BF₃·Et₂O treatment) following the initial\ntrifunctionalization. Revising the title and Introduction to more accurately reflect the methodological advance, along with\nclarifying Fig. 1c to include the post-functionalization steps, would significantly improve conceptual clarity.\n2. The structure of compound 7 in Figure 4b appears to be incorrectly drawn. The connectivity shown seems inconsistent\nwith the described Heck reaction step. This should be carefully reviewed and corrected to avoid confusion.\n3. The programmable arylative ketone migration demonstrated for compounds 20 to 23 is very impressive. I am curious\nwhether any regioselectivity issues arise in the initial step of forming vinyl triflate from the alfa-arylated ketone.\nOther comments:\nThe supporting information is in good shape.", "reviewer_2": "The authors describe a Ni-catalyzed borylation strategy for cyclic vinyl triflates to achieve carbonyl walking. This\nprogrammed arylative ketone migration proceeds with excellent diastereoselectivity and provides an iterative protocol for\nediting peripheral substituents on cyclic ketones. The manuscript is well-written, and the supporting data are robust. Thus, I\nrecommend its publication in Nature Communications after minor revisions.\n1. The specific reaction conditions for the downstream transformations and migrations in Figures 4 and 5 should be provided\ndirectly in the figure legends.\n2. While the substrate scope for the initial borylation is abundant, the exploration of the ensuing arylative ketone migration is\nrelatively limited. To better demonstrate the generality and utility of this method, the authors should expand this section to\ninclude various cyclic ketones, such as strained rings, fused rings, bridged rings, and macrocyclic systems in the Fig.5.\n3. To further highlight the potential of this iterative method, is the synthesis of a sterically congested molecule like a hexa-\naryl substituted cyclohexane feasible?\n4. Please cite a relevant work on the programmed synthesis of tetra-aryl substituted alkenes via alkyne borylation strategy:\n“Nat. Commun. 2025, 16, 1025”.", "reviewer_3": "This manuscript presents a transformative nickel-catalyzed protocol for the deoxygenative trifunctionalization of vinyl\ntriflates, enabling efficient construction of boron-containing polysubstituted cyclohexanes featuring quaternary carbon\ncenters. The work represents a paradigm shift in migratory functionalization chemistry, offering an exceptionally\nprogrammable approach with profound implications for complex molecule synthesis and medicinal chemistry applications.\nKey Strengths and Innovations have been summarized here:\n1.Methodological Breakthrough: First report of nickel-catalyzed arylboration coupled with ketone migration in vinyl triflates,\nelegantly solving the longstanding challenge of regioselective α-arylation in unsymmetrical ketones.\n2.Unprecedented Stereocontrol: The \"programmable diastereoselectivity\" feature establishes new standards for\nstereochemical manipulation in polysubstituted cyclic systems.\n3.Molecular Complexity Generation: Simultaneous installation of aryl, boron, and quaternary carbon centers provides\nexceptional scaffold diversification potential, directly addressing critical needs in medicinal chemistry (\"scaffold hopping\").\n4.Technical Excellence: Comprehensive optimization studies and thorough characterization (including X-ray\ncrystallography) strongly support the mechanistic proposal.\nOverall, the manuscript is exceptionally well-prepared and merits publication in Nature Communications after addressing the\nfollowing points:\n1.The current focus on cyclohexanone derivatives is compelling, but demonstrating the protocol with other ring sizes\n(particularly cyclobutanone, cycloheptanone, and cyclooctanone derivatives) would significantly enhance the methodology's\ngenerality and impact.\n2.For potential medicinal chemistry applications, it would be valuable to examine: The reactivity and selectivity of the cyclic\nvinyl triflate with β-substitution in acyclic system. Whether steric hindrance from β-substituents affects Ni-Bpin insertion\nefficiency.\n3.Given the excellent diastereocontrol achieved, initial results with chiral ligands (even as proof-of-concept) would highlight\nthe potential for enantioselective synthesis. How about the reactivity in nickel-catalyzed trifuctionalization of vinyl triflate\nusing chiral ligand in this reaction?\n4.The programmable nature of this transformation raises the important question of whether it could be extended to construct\npentasubstituted cyclohexanones, which would represent a monumental advance in complex ring system synthesis."}, "author_response": "Response to Reviewers’ Comments\nReviewer #1:\nThis manuscript describes a nickel-catalyzed deoxygenative trifunctionalization of vinyl\ntriflates that enables the synthesis of boron-containing polysubstituted cyclohexanes featuring\nquaternary carbon centers under mild conditions. The methodology is robust, supported by\nextensive mechanistic studies, a broad substrate scope, and practical applications—including\ngram-scale synthesis and late-stage derivatization of complex bioactive molecules. Notably,\nformal arylative ketone migration is achieved via post-functionalization steps\n(oxidation/BF₃·Et₂O-mediated rearrangement), highlighting the method’s utility in molecular\nskeleton editing. Particularly impressive is the demonstration of programmable arylative ketone\nmigration (Fig. 5b), which underscores the versatility and synthetic value of this approach. In\nsummary, I find this work highly compelling and support its publication in Nature\nCommunications after minor revisions.\nOur response: We greatly appreciate the reviewer for these positive comments and their\nagreement to have it published in Nature Communications.\n1. The title and Introduction strongly emphasize functional group displacement and migration\nas the central theme. However, the core of the manuscript focuses on the development and\nscope of nickel-catalyzed trifunctionalization (Fig. 2-4). The ketone migration is a valuable yet\nsecondary application that comes after further synthetic modification (Fig. 5). This disconnect\nmay confuse readers. Additionally, Fig. 1c aims to illustrate the concept of ketone migration\nbut does not explicitly show that the process requires additional 2 steps (oxidation and BF₃·Et₂O\ntreatment) following the initial trifunctionalization. Revising the title and Introduction to more\naccurately reflect the methodological advance, along with clarifying Fig. 1c to include the post-\nfunctionalization steps, would significantly improve conceptual clarity.\nOur Response: We thank the reviewer for the valuable suggestions. In response, we have\nrevised Fig. 1c to include the two key steps that occur after the trifunctionalization (oxidation\nand BF₃·Et₂O treatment) and to more clearly illustrate how vinyl triflates, conveniently\nprepared from ketone substrates, evolve through subsequent functionalization. Regarding the\nreviewer’s concern about a potential disconnect between the nickel-catalyzed\ntrifunctionalization and the ensuing ketone migration, we would like to further clarify that the\ntrifunctionalized intermediates serve not only as important precursors for constructing highly\nsubstituted cyclic structures that are difficult to access by conventional methods, but also as key\nplatforms enabling the ketone displacement and migration sequence. Given the potential of this\nnew method to enhance molecular complexity, we chose to present the overall workflow. The\nketone-migration transformation is specifically highlighted because it represents a previously\nunreported synthetic strategy—one that fills a gap in existing methodology and enables\nasymmetric α-arylation of ketones with excellent regio- and stereocontrol. We further expanded\nthe substrate scope for the ketone-migration study to showcase the unique advantages of this\nnew transformation in constructing complex architectures, rather than repeating routine\nexamples already covered in the trifunctionalization scope. We believe that these clarifications\nmake the logical connection and complementarity between the two parts much clearer. We\nbelieve these modifications greatly enhance the conceptual coherence and readability of the\nmanuscript, and we thank the reviewer again for helping us improve the clarity of our work.\n2. The structure of compound 7 in Figure 4b appears to be incorrectly drawn. The connectivity\nshown seems inconsistent with the described Heck reaction step. This should be carefully\nreviewed and corrected to avoid confusion.\nOur Response: We sincerely thank the reviewer for this valuable suggestion. We have\ncorrected the structure of compound 7 in Fig. 4b accordingly and have carefully reviewed the\nentire manuscript.\n3. The programmable arylative ketone migration demonstrated for compounds 20 to 23 is very\nimpressive. I am curious whether any regioselectivity issues arise in the initial step of forming\nvinyl triflate from the alfa-arylated ketone.\nOur Response: In response to the reviewer’s question, we clarify that the α-arylated ketone\nwas alkylated using the bulky base LDA, resulting in a highly selective transformation. No\nregioisomeric products were observed experimentally.\nReviewer #2:\nThe authors describe a Ni-catalyzed borylation strategy for cyclic vinyl triflates to achieve\ncarbonyl walking. This programmed arylative ketone migration proceeds with excellent\ndiastereoselectivity and provides an iterative protocol for editing peripheral substituents on\ncyclic ketones. The manuscript is well-written, and the supporting data are robust. Thus, I\nrecommend its publication in Nature Communications after minor revisions.\nOur response: We greatly appreciate the reviewer for these positive comments and their\nagreement to have it published in Nature Communications.\n1. The specific reaction conditions for the downstream transformations and migrations in\nFigures 4 and 5 should be provided directly in the figure legends.\nOur Response: We thank the reviewer for this valuable suggestion. The captions of Figures 4\nand 5 have been updated to include the specific reaction conditions for the downstream\ntransformations and migrations.\n2. While the substrate scope for the initial borylation is abundant, the exploration of the ensuing\narylative ketone migration is relatively limited. To better demonstrate the generality and utility\nof this method, the authors should expand this section to include various cyclic ketones, such\nas strained rings, fused rings, bridged rings, and macrocyclic systems in the Fig.5.\nOur Response: We sincerely thank the reviewer for their valuable suggestion. Following the\nreviewer’s advice, we examined several representative cyclic ketone substrates, including\nstrained, fused, bridged, and medium-sized rings, to further evaluate the generality of the\narylative ketone migration reaction. However, the reactivity was found to be strongly dependent\non the ring structure. For strained-ring substrates, the yield of the corresponding\ntrifunctionalized intermediates was very low, and the arylative ketone migration products could\nnot be isolated. In the case of bridged-ring substrates, aromatization occurred during the\nrearrangement process, resulting in the loss of the desired migration products. For fused-ring\nsubstrates, ring-contraction products were observed instead of the expected migration products.\nIn contrast, the seven-membered ring substrate successfully afforded the desired migration\nproduct, while the eight-membered ring substrate did not undergo the reaction under the current\nconditions. These results have been added to the revised manuscript and Supplementary\nInformation (please see Fig. 5 & Supplementary Information).\n3. To further highlight the potential of this iterative method, is the synthesis of a sterically\ncongested molecule like a hexa-aryl substituted cyclohexane feasible?\nOur Response: We thank the reviewer for this insightful suggestion. We attempted to further\nextend the iterative method to the construction of more highly substituted cyclohexanes. Using\nthis strategy, we successfully synthesized tetra-aryl substituted cyclohexanes. However, when\nwe attempted to construct penta-aryl substituted cyclohexanes, the significantly increased steric\nhindrance prevented the formation of the trifunctionalized intermediate required for the key\nketone-migration step, and the reaction did not proceed. These results have been added to the\nrevised manuscript and Supplementary Information (please see Fig. 5 & Supplementary\nInformation).\n4. Please cite a relevant work on the programmed synthesis of tetra-aryl substituted alkenes via\nalkyne borylation strategy: “Nat. Commun. 2025, 16, 1025”.\nOur Response: We sincerely thank the reviewer for this suggestion. The manuscript has been\nupdated to include a citation of Nat. Commun. 2025, 16, 1025.\nReviewer #3:\nThis manuscript presents a transformative nickel-catalyzed protocol for the deoxygenative\ntrifunctionalization of vinyl triflates, enabling efficient construction of boron-containing\npolysubstituted cyclohexanes featuring quaternary carbon centers. The work represents a\nparadigm shift in migratory functionalization chemistry, offering an exceptionally\nprogrammable approach with profound implications for complex molecule synthesis and\nmedicinal chemistry applications. Key Strengths and Innovations have been summarized here:\n1.Methodological Breakthrough: First report of nickel-catalyzed arylboration coupled with\nketone migration in vinyl triflates, elegantly solving the longstanding challenge of\nregioselective α-arylation in unsymmetrical ketones.\n2.Unprecedented Stereocontrol: The \"programmable diastereoselectivity\" feature establishes\nnew standards for stereochemical manipulation in polysubstituted cyclic systems.\n3.Molecular Complexity Generation: Simultaneous installation of aryl, boron, and quaternary\ncarbon centers provides exceptional scaffold diversification potential, directly addressing\ncritical needs in medicinal chemistry (\"scaffold hopping\").\n4.Technical Excellence: Comprehensive optimization studies and thorough characterization\n(including X-ray crystallography) strongly support the mechanistic proposal.\nOverall, the manuscript is exceptionally well-prepared and merits publication in Nature\nCommunications after addressing the following points:\nOur response: We sincerely thank the reviewer for the positive evaluation of our work and for\nrecognizing the quality of our manuscript. We appreciate the reviewer’s thoughtful comments\nand constructive suggestions. We have carefully addressed all the points raised, as detailed\nbelow. We believe these revisions have further improved the clarity and scientific rigor of the\nmanuscript.\n1.The current focus on cyclohexanone derivatives is compelling, but demonstrating the protocol\nwith other ring sizes (particularly cyclobutanone, cycloheptanone, and cyclooctanone\nderivatives) would significantly enhance the methodology's generality and impact.\nOur Response: We sincerely thank the reviewer for this insightful suggestion. Following the\nreviewer’s advice, we further examined substrates derived from cyclobutanone,\ncycloheptanone, and cyclooctanone to evaluate the generality of this transformation. Due to the\nsteric hindrance from the substituents on cyclobutanone, the reaction proceeded with very low\nefficiency, and the desired product could not be obtained. The reaction with cycloheptanone\nderivatives proceeded smoothly, yielding the expected product. However, the cyclooctanone\nsubstrate did not undergo the transformation under the current conditions. These results have\nbeen added to the revised manuscript and Supplementary Information (please see Fig. 3 &\nSupplementary Information).\n2.For potential medicinal chemistry applications, it would be valuable to examine: The\nreactivity and selectivity of the cyclic vinyl triflate with β-substitution in acyclic system.\nWhether steric hindrance from β-substituents affects Ni-Bpin insertion efficiency.\nOur Response: We appreciate the reviewer’s valuable suggestion. In the revised manuscript,\nwe further expanded our investigation to the acyclic substrates 5k and 5l (Figure 3) to evaluate\nthe influence of β-substituents on the reaction activity and regioselectivity. The results indicate\nthat even with increasing steric hindrance at the β-position, the efficiency of the Ni-Bpin\ninsertion remains unaffected.\n3.Given the excellent diastereocontrol achieved, initial results with chiral ligands (even as\nproof-of-concept) would highlight the potential for enantioselective synthesis. How about the\nreactivity in nickel-catalyzed trifuctionalization of vinyl triflate using chiral ligand in this\nreaction?\nOur Response: We sincerely appreciate the reviewer’s valuable suggestion. Preliminary\nattempts using several commonly employed chiral ligands resulted in significant suppression\nof the reaction reactivity. Further investigation on the enantioselective version of this\ntransformation will be pursued in our future studies.\n4.The programmable nature of this transformation raises the important question of whether it\ncould be extended to construct pentasubstituted cyclohexanones, which would represent a\nmonumental advance in complex ring system synthesis.\nOur Response: We sincerely thank the reviewer for this insightful suggestion. We explored the\nextension of our iterative method toward the synthesis of more highly substituted cyclohexanes.\nUsing this approach, tetra-aryl substituted cyclohexanes were successfully constructed.\nHowever, attempts to synthesize penta-aryl substituted cyclohexanes were unsuccessful, as the\nsubstantially increased steric hindrance hindered the formation of the trifunctionalized\nintermediate necessary for the key ketone-migration step, preventing the reaction from\nproceeding. These findings have been incorporated into the revised manuscript and\nSupplementary Information (see Fig. 5 and Supplementary Information).\nwe wholeheartedly appreciate the reviewer's constructive comments on this work, and we\nwould like to express our sincere gratitude for providing us with the opportunity to enhance\nour paper.\nIn conclusion, we sincerely thank the reviewer for recognizing our work and for providing\nvaluable comments, which have greatly helped us further improve this research. We hope that\nour responses satisfactorily address all of your concerns.\nSincerely,\nGuoyin Yin"}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have addressed the reviewers' comments, and acceptance is recommended.", "reviewer_2": "Please add a note to the manuscript stating that the fifth aryl group cannot be installed on the ring via this protocol due to steric hindrance. This version is then approved for publication.", "reviewer_3": "The authors have solved the issues raised by reviewers. Therefore, I accept the current manuscript for publication in Nature Communications."}, "author_response": "Our Response: We sincerely thank you for your thorough review of our revised manuscript\nand for your positive feedback. Your valuable comments were crucial in helping us improve\nour work, and we greatly appreciate your recommendation to publish our research in Nature\nCommunications.\nOur Response: We thank the reviewer for the valuable suggestion. We have added a note in\nthe manuscript clarifying that, due to pronounced steric hindrance, the installation of a fifth\naryl group on the ring is not feasible under the present reaction conditions.\nOur Response: We deeply appreciate the reviewer for his/her constructive suggestions and\npositive comments to improved enhancement of our research. We are very pleased that our\nreply has satisfied the reviewers."}]

Decision letter