Harnessing P^V-oxirene for the modular synthesis of α-Oxy carbonyls

Domain: neuroscience
Published: 2026-01-22
Editorial outcome: minor_revision

Abstract
α-Oxycarbonyl compounds, characterized by their distinct electronic and topological properties, represent highly versatile building blocks and modifiers for functional molecules. Despite their potential, the synthetic challenges associated with these compounds have limited their exploration in chemical biology and drug discovery. In this study, we address this limitation by introducing a general Cu-catalyzed three-component carbonyl 1,2-transposition reaction, which proceeds via a PV-oxirene intermediate. Our method employs IIII/PV-hybrid ylides as carbene precursors to generate α-PV-Cu-carbenes, which subsequently facilitate the formation of PV-oxirene species. This intermediate undergoes regioselective ring-opening by carboxylate anions, followed by acylation of a third nucleophile, enabling the modular assembly of α-oxy carbonyl compounds. This strategy provides efficient access to α-oxy esters, amides, and thioesters, exhibiting broad tolerance to various functional groups. Furthermore, these compounds exhibit remarkable chemical versatility, as demonstrated in the synthesis of depsipeptides and late-stage drug modification, underscoring their applicability across diverse research areas. Our findings not only significantly expand the structural diversity of accessible α-oxy carbonyls but also introduce a versatile and biocompatible synthetic linkage for chemical synthesis.

Introduction
α-Oxycarbonyl compounds are privileged motifs in organic synthesis with essential roles in medicinal chemistry, food chemistry, and polymer science (Fig. 1A)1–3. For example, due to their structural similarity to α-amino acids, α-hydroxy acids (AHAs) are frequently incorporated into peptides and proteins by selectively replacing specific amino acid residues4,5. The introduction of an ester linkage into the peptide backbone offers a straightforward method to modulate intra- and intermolecular hydrogen bonding interactions, which, in turn, influences the conformation and bioactivity of the peptides6–9. Therefore, numerous studies in chemical biology, peptide chemistry, and drug discovery have employed α-oxy carbonyls as powerful molecular tools.

The traditional synthesis of α-oxy carbonyls mainly relies on four types of strategies: (1) Ready transformation of cyanohydrins originated via cyanation of aldehydes and ketones10,11; (2) Pre-functionalization on α-position of carbonyl derivatives followed by nucleophilic attack from O-nucleophiles12; (3) Selective oxidation of 1,2-diols13, enolates14 or selective reduction of α-keto carbonyls15; (4) Multi-component Passerini-type reactions which generally assemble α-acyloxy amides from highly reactive isocyanide reagents. Despite these advances, it is still highly desirable to develop modular synthetic strategies that could afford structurally diverse α-oxy carbonyl compounds to meet diversified demands from multiple disciplines16,17.

The progression of organic synthesis and the discovery of novel chemical transformations are often propelled by the rational design of bond-forming mechanisms that leverage highly reactive intermediates. Among these, oxirene—an anti-aromatic, strained ring system—has been identified as a pivotal, yet elusive, species that exists as multivalent isomers and mediates a range of intriguing processes18–21. Our investigation focused on three defining characteristics of oxirene intermediates: (i) their pronounced electrophilicity and strain-driven reactivity, (ii) their low selectivity between the two adjacent carbon centers, and (iii) their inherent propensity to undergo ring-opening to form carbonyl derivatives (Fig. 1B). However, exploiting oxirene intermediates in synthetic methodology has been impeded by challenges in controlling their extreme reactivity and a scarcity of efficient synthetic precursors22,23. Typically, nucleophilic attack on an oxirene intermediate occurs non-selectively at either carbon center, yielding a mixture of regioisomeric carbonyl products24. To modulate this high reactivity, we proposed the introduction of a substituent with tunable electronic and steric properties. This strategy aims to establish a synthetic paradigm for carbonyl generation via the catalytic formation of these underexplored oxirene species. Quaternary phosphonium salts, a significant class of organophosphorus compounds, are widely employed in synthetic chemistry due to their utility in diverse transformations25. We postulated that integrating these PV salts into the oxirene framework would leverage their combined electrophilicity and leaving group ability26. This approach is anticipated to significantly enhance regioselectivity during nucleophilic attack while facilitating a versatile three-component modular synthesis of α-functionalized carbonyl compounds.

Our research group maintains a longstanding interest in exploring the carbenic reactivity of hypervalent iodine reagents27,28. We initially hypothesized that IIII/PV hybrid ylides could serve as precursors to α-phosphonium-substituted carbenes (α-PV carbenes) via metallo- or photo-activation. Our recent investigations have demonstrated that these α-PV carbenes exhibit exclusive reactivity toward unsaturated functional groups, such as cyano29,30 or carbonyl moieties31,32, bypassing the typically favored X–H insertion pathways. Within this mechanistic paradigm, we determined that in the absence of external unsaturated acceptors, an intramolecular oxygen attack from an adjacent carbonyl group occurs, followed by demetalation, to furnish a key α-PV oxirene intermediate (Fig. 1C). Guided by this design principle, we have developed a copper-catalyzed, three-component reaction that couples IIII/PV hybrid ylides with carboxylic acids and N-, O-, S-, Se-nucleophiles. This strategy enables the modular synthesis of valuable α-oxy carbonyl compounds. This work significantly expands the accessible chemical space of both oxirene intermediates and α-oxy carbonyl products and is anticipated to find broad utility across diverse research fields (Fig. 1D).

Results
We commenced our exploration of the three-component reaction involving IIII/PV hybrid ylide (1a), p-methoxybenzoic acid (2), and ethanol (3) under Cu catalysis in basic dichloroethane (DCE) at room temperature (Table 1). We were pleased to find that the desired product 4 could be detected in good yield after 12 h, using Cu(MeCN)4PF6 catalysts and Cs2CO3 as base additive, accompanied by 3Å molecular sieves (entry 1). The counterion of mixed ylides (1b and 1c) moderately influenced the overall conversion (entries 2 and 3). No desired product was observed using the neutral cyclic reagent 1d, likely due to the lower tendency for I(III) to be activated under Cu catalysis (entry 4). Decreasing the loading of the catalyst caused a slight drop in the yield (entry 5). The reaction became sluggish under aerobic conditions, and less product was formed after removal of molecular sieves (entries 6 and 7). More expensive paddlewheel dirhodium complex L4Rh2 also catalyzed this transformation, albeit with much lower yields (entries 8 and 9). Another cheap FeCl2 worked poorly (entry 10). When CuCN was used as a catalyst, the reaction worked better, and the desired product could be isolated in 79% yield (entry 11). The control experiment showed no product was formed without the metal catalyst (entry 12). The reaction was sensitive to base additives: either organic Et3N or weak Na2CO3 hampered the yields (entries 13 and 14). Solvent screening quickly identified DCE as the best option (entries 15 and 16). Based on above results, we conclude the optimal conditions for the copper-catalyzed three-component synthesis of α-oxy carbonyl are: IIII/PV hybrid ylide 1 with BF4- as counterion (1.3 equiv.) as the carbene source, carboxylic acid as limiting reagent, nucleophile (1.2 equiv.) as reaction partner, CuCN (5 mol%) as the catalyst, Cs2CO3 as the base, 3Å molecular sieves (20 mg) as additive in N2-degassed DCE (0.1 M) at room temperature for 12 h (See the Section 3 of Supplementary Information file for more details of the condition screening).

With the optimal reaction conditions in hand, we explored the generality of this three-component reaction (Fig. 2). First, a series of IIII/PV mixed ylide reagents was evaluated. For reactions using ethanol as nucleophile, IIII/PV-hybrid ylide reagents with different lengths of linear alkyl ketyl and substituted aryl ketyl groups performed well, yielding α-oxy ester products (4-11) in moderate to high yields (53%–81%). When p-toluidine was used as a nucleophile, only alkyl ketyl IIII/PV mixed ylide reagents could work, affording desired α-oxy amide products (12-15) in good yields. It should be noted that for N-nucleophiles, Na2CO3 exhibits greater efficacy as a basic additive than Cs2CO3. This enhancement in reactivity can be attributed to the dual role of the base in the reaction mechanism: first, it deprotonates the carboxylic acid to form the nucleophilic carboxylate anion in situ, and second, it activates the heteroatom nucleophile during its addition to the acyl phosphonium intermediate. Consequently, differences in reactivity between nucleophile classes-such as N- versus O-nucleophiles-arise from their distinct sensitivities to such base-mediated activation. To illustrate the synthetic utility of the reaction, a 4.0 mmol scale reaction was implemented under the standard conditions, producing the product 12 in 81% yield (1.03 g). The steric bulky t-Bu substituted IIII/PV-hybrid ylide did not work to yield desired product, neither did the inaccessible aldehyde derived IIII/PV-hybrid ylide reagents. Next, a broad array of aliphatic carboxylic acids was subject to the reaction system and reacted with 1a and p-toluidine. Various primary carboxylic acids bearing linear substituents were suitable substrates, providing the corresponding α-oxy amide products in good yields (16-20). The successful transformation of substrates containing double bonds further demonstrated the chemoselectivity of this methodology (18 and 20); no [2+1] cyclopropanated product was observed in these cases. This reaction could also be applied to common steric bulky secondary (21-23) and even tertiary carboxylic acids (24 and 25), with no dramatic decrease in efficiency. Subsequently, we examined the scope of aromatic carboxylic acids in this reaction. Substituted benzoic acids bearing electron-deficient, electron-neutral, or electron-rich groups at the ortho-, meta-, or para-positions of the aromatic ring all underwent the reaction effectively, affording the corresponding products (26-35) in isolated yields ranging from 29% to 95%. Of note, this method exhibited high chemoselectivity even for substrates containing common carbenophiles—such as N-H (28), sulfide (29), and cyanide (30) moieties—in addition to double bonds (18 and 20), which are widely recognized as functionalities that can interfere with reactions involving carbene intermediates. Di-substituted (36) and heteroaromatic analogs (37-40) were also compatible, delivering the corresponding products in satisfactory yields. It is worth noting that the reaction using diphenylphosphinic acid as the starting material afforded the desired hybridized ester 41 in 48% yield. Carboxylic acids are recurrent functional groups in natural products and bioactive molecules33. By using the standard conditions, we tested the reactions of two amino acid derivatives (42 and 43) and three carboxylic acid-containing drug molecules (44-46). In all these cases, the α-oxy amide groups were smoothly installed, demonstrating the potential synthetic utility of the presented method.

We examined the applicability of our developed method to diverse nucleophiles under standardized conditions (Fig. 3). The protocol successfully accommodated various N-nucleophiles with selected IIII/PV mixed ylide 1a and p-methoxybenzoic acid (PMP-COOH). Various aromatic substituted anilines reacted smoothly to afford the corresponding α-oxy amide 47-54 in good to excellent yields. The low yield in the case of 55 is mainly attributed to the steric hindrance of the multi-substituted phenyl ring. 1-Naphthylamine and secondary N-methyl-p-toluidine could also work, providing desired products in 78% (56) and 70% (57) yields, respectively. We were glad to find that this method was able to convert aliphatic amines containing different straight-chain (58-60), branched (61 and 62) and even sterically bulky tertiary substrates (63 and 64) into amide products, with moderate to excellent yields. Several secondary amines with versatile functional groups worked smoothly to furnish the desired amide products (65-68). Gratifyingly, N-acyl sulfoximine 69 was obtained in 76% yield when dimethyl sulfoximine was subjected to the reaction conditions. This result has been unambiguously established by a single-crystal X-ray diffraction analysis (CCDC 2454723). Amine groups are ubiquitous in drug molecules34, such as alogliptin and fluvoxamine. By using the standard conditions, we successfully installed the α-oxy carbonyl group to these two primary amine-containing drug molecules in good yields (70 and 71). Moreover, our strategy permitted the use of a diverse range of oxygen nucleophiles, enabling rapid access to α-oxy esters. Substituted phenols with electron-donating (72-75) or withdrawing (76-78) groups worked smoothly to afford desired products in good yields. 3-Hydroxyquinoline (79) and 2-iodo-3-hydroxypyridine (80) reacted well, and the heteroaromatic rings were unaffected. Our protocol is suitable for aliphatic alcohol substrates that carry functionalities such as phenyl (81), bromide (82), alkene (83), alkyne (84), and heteroaromatic rings (85 and 86), some of which may interfere with the carbene formation process. Similarly to N-nucleophiles, more sterically bulky secondary alcohols (87 and 88) did not cause a significant reduction in the yields. We then tested our methodology in the derivatization of bioactive compounds and complex natural products that contained the -OH functional group. In this scenario, L-Menthol (89), 7-Hydroxycoumarin (90), estrone (91) and D-galactose (92) were all converted into targeted products in moderate to high yields. It was worth noting that our method provided a practical linchpin between N-Fmoc alanine and purine nucleoside, affording three-membered conjugates 93 in 75% yield and 1.7:1 d.r. When water was used as nucleophile, we can isolate the corresponding α-oxy acid product 94 in 53% yield. Thioesters are of vital importance not only in organic synthesis but also in materials, foods, cosmetics, antibiotics, and biology35–38. Due to their unique structural and chemical properties, the development of efficient methods for preparing thioester scaffolds has been a hot and challenging topic for organic synthetic chemists39,40. Traditional thioester synthesis is predominantly achieved through one of two approaches: (1) the condensation of carboxylic acids and thiols promoted by a dehydrating agent, or (2) the direct acylation of a thiol with a stoichiometric acylating reagent, commonly facilitated by metallic additives. Despite significant advances, reports on the direct approach to α-oxy thioesters are underexplored. We were delighted to find that using our methodology provided an efficient approach towards α-oxy thioesters (95-99) using different chalcogen nucleophiles as starting materials. Moreover, the reaction using phenyl selenol as starting material afforded the desired α-oxy selenol esters 100 in 27% yield. This preliminary result provided a practical synthetic route toward this previously inaccessible carboxylic acid derivative.

To further demonstrate the synthetic utility of the Cu-catalyzed three-component reaction, a series of experiments including depsipeptides synthesis, one-step construction of Lactofen library and homologation of carboxylic acids were conducted (Fig. 4). The incorporation of α-hydroxy acids into peptide backbones is commonly achieved through biotechnological methods, such as nonribosomal peptide synthetases and solid-phase peptide synthesis. Although the Passerini reaction can also yield products containing α-hydroxy acid fragments, the introduction of an ester linkage into the peptide backbone is challenging due to the limitations of isocyanide reagents41–43. Using amino- or carboxyl-protected amino acids/peptides as starting materials, we successfully synthesized seven peptides containing α-hydroxy acid fragments, including four tripeptides (101-104) and three tetrapeptides (105-107), demonstrating the scalability of this process in polypeptides and proteins (Fig. 4A). This method was also applied to the synthesis of the commercially available herbicide Lactofen (108), achieving a 77% yield in a one-step process using Acifluorfen as the starting material. Additionally, we obtained four previously unreported Lactofen analogs (109-111), which are difficult to synthesize by other existing methods (Fig. 4B). Furthermore, we could easily prepare two peptide-drug conjugates (113 and 114) based on Acifluorfen and amino acid esters. This provides an alternative pathway for Lactofen synthesis and offers more options for further optimization and structure-activity relationship studies of such herbicides.

Carboxylic acids are among the most widely available, broadly applicable building blocks in chemical synthesis, and are a standard functionality in biologically active drugs and natural products. Transformations of synthetically versatile carboxylic acids are invaluable in modern organic synthesis. Among them, lengthening the carboxylic acid chain via single-atom homologation remains a major synthetic challenge44. Although several seminal protocols to achieve carboxylic acid homologation have been developed, all of them delivered products with α-unsubstituted carboxylic acids45–51. A more general and direct synthetic method from carboxylic acid feed stocks to homologated α-hydroxyl carboxylic acid is highly appealing for the rigors of synthetic and medicinal chemistry. In this context, a three-step homologation sequence of four carboxylic acids to furnish α-hydroxyl carboxylic acids (115-118) has been established, involving the key Cu-catalyzed three-component modular pathways.

To investigate the reaction pathway, we conducted a series of mechanistic experiments (Fig. 5). First, deuterium-labeling studies were performed (Fig. 5A). When MeOD was employed as the nucleophile, product 119 was obtained in 68% yield with 11% deuteration. Additionally, using deuterated chloroform as the solvent under standard conditions resulted in 20% deuterium incorporation into 4. These results indicated a step-wise incorporation of nucleophiles during the reaction process. Next, to trace the origin of the oxygen atom in the α-hydroxy acid moiety, we carried out a coupling reaction between IIII/PV-hybrid ylide 18O-1k (31% 18O incorporation), p-methoxybenzoic acid 2, and ethanol. This yielded 18O-labeled product 7 in 68% yield with full retention of the 18O label (31% incorporation), detailed GC-MS analysis of the fragmentation pattern further confirmed that the carbonyl oxygen derives from the ylide reagent via a 1,2-carbonyl transposition pathway (Fig. 5B). Reaction with a 13C-labeled IIII/PV-hybrid ylide reagent 1k further confirmed a 1,2-carbonyl transposition occurred during the reaction (Fig. 5C). We initially hypothesized that a Wolff rearrangement of α-keto carbenes might generate a ketene intermediate24. To test this possibility, a control experiment was conducted by reacting P-ylide 120 with PMP-COOH, both in the presence and absence of the Cu catalyst. No desired product was observed under either condition, ruling out the involvement of a ketene intermediate in the current catalytic system (Fig. 5D). A step-wise study indicated that mixing α-oxy acyl chloride with PPh3 afforded the rapid formation of acyl phosphonium salt intermediate, which could be isolated and characterized by 31P-NMR (δ=33.97 ppm). This intermediate could be transformed into targeted product 121 during the subsequent reaction process in the presence of both p-toluidine and base (Fig. 5E). Finally, a Hammett analysis was performed using para-substituted benzoyl IIII/PV-hybrid ylides 1, yielding a small, positive reaction parameter (ρ=+1.03, Fig. 5F). The observed ρ value aligns with those typically associated with processes involving benzylic anion formation in the rate-limiting step, suggesting a partially charged transition state.

Based on the above mechanistic studies and literature report32, a plausible mechanism was proposed (Fig. 5G). The reaction begins with the formation of the electron-deficient α-keto-α’-PV Cu-carbenoid int-1 via copper-assisted decomposition of the IIII/PV-hybrid ylide reagents. Subsequently, the formed Fischer-type Cu-carbene species undergoes intramolecular O-attack from the adjacent ketyl moiety through C-O bond formation,52 resulting in the formation of the key α-PV substituted oxirene intermediate (int-2) and releases the Cu-catalyst. Next, with the aid of charge interaction between the in-situ generated carboxylate ion and phosphonium of int-2, a highly regio-selective nucleophilic attack occurred to form the enolonate int-3. Successive isomerization and protonation yielded acyl phosphonium intermediate (int-5) and trigger the acyl group transfer step to diversified nucleophiles, leading to the formation of desired α-oxy carbonyl products.

Methods
General procedure for the modular synthesis of α-oxy carbonyl compounds

IIII/PV-hybrid ylide reagents 1 (0.13 mmol, 1.3 equiv.), carboxylic acids 2 (0.1 mmol, 1.0 equiv.), CuCN (0.5 mg, 0.005 mmol, 5 mol%), base additives (0.22 mmol, 2.2 equiv.) and 3Å MS (20 mg) were added to a dry 10 mL reaction tube, successively. The vial was sealed, degassed, and filled with nitrogen. Then nucleophiles 3 (0.12 mmol, 1.2 equiv.) dissolved in dry 1,2-dichloroethane (1 mL) were added to the reaction tube. The resulting reaction mixture was stirred at 26 °C for 12 h. Solvent was removed under vacuum, and the crude mixture was purified by flash column chromatography on silica gel to afford α-oxy carbonyl products.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The present work describes a copper-catalyzed modular synthesis of α-oxy carbonyl compounds via a three-component reaction of I(III)/P(V)-hybrid ylides with carboxylic acids as oxygenating reagents and heteroatom nucleophiles. In this study, the I/P-hybrid ylides are activated by a copper catalyst to form a copper carbenoid, which undergoes intramolecular oxygen-atom attack to generate a P(V)-oxirene intermediate, proposed to be the key species in the reaction pathway. Site-selective attack of carboxylates on the oxirene intermediate induces ring opening to afford acyl phosphonium salts, which subsequently react with heteroatom nucleophiles to furnish various α-oxy carbonyl compounds. Two types of nucleophiles—carboxylates and other heteroatom nucleophiles—react in a site-selective and sequential manner, enabling controlled formation of the desired α-oxy carbonyl products.\n\nThe method exhibits a broad substrate scope and excellent functional group compatibility, and the three-component design allows for diverse product synthesis. A wide range of aliphatic and aromatic carboxylic acids can be employed as oxygenating reagents. Regarding heteroatom nucleophiles, alcohols, amines, and even thiols are compatible. The successful synthesis of polypeptides containing α-oxy carbonyl motifs further highlights the synthetic utility of the method. Mechanistic investigations suggest that the reaction proceeds through an oxygen-atom transfer process rather than a Wolff rearrangement. Overall, the method offers a new and practical approach for the diverse synthesis of an important class of α-oxy carbonyl compounds. The manuscript is well written and presents compelling results; however, I believe that revisions are necessary to address the following point before it can be considered for publication in Nature Communications.\n\nThe formation of the proposed P(V)-oxirene intermediate is somewhat questionable. An alternative pathway could involve nucleophilic attack by an external carboxylate at the carbonyl carbon of Int-1, followed by oxygen-atom attack on the copper carbenoid. A convincing explanation for why the intramolecular oxygen-atom attack would predominate to form such a highly strained oxirene intermediate should be provided. This issue is critical, as it directly impacts the mechanistic foundation of the present study.", "reviewer_2": "Wang and co-workers reported a novel copper-catalyzed three-component strategy for synthesizing α-oxy carbonyl compounds through the formation of oxirene intermediates. This method employed IIII/PV-hybrid ylide reagents, carboxylic acids, and a range of nucleophiles, offering a broad substrate scope and excellent functional-group tolerance. The authors also provided detailed mechanistic investigations that strongly support the proposed reaction pathway, along with valuable synthetic applications. The supporting information is clearly presented.\n\nOverall, the manuscript is of good quality and can be accepted after minor revision. Specific comments and queries are provided below.\n1. What is the reason behind chemo-selectivity of this reaction?\n2. The compound names in the Supporting Information should begin with a capital letter.\n3. Please provide clean spectra of the compounds: 109, 96, 104, 105.", "reviewer_3": "Review for Nature Communications manuscript NCOMMS-25-86531-T\nIn this manuscript, S. Huang, D. Duan, J. Luo, J. Chen, and Z. Wang disclose a protocol for the Cu-catalyzed multicomponent synthesis of α-oxy and α-amino carbonyls from IIII/PV-hybrid ylides, carboxylic acids, and O- or N-based nucleophiles. This work builds on the group’s previous research on phosphorous-containing ylides as reagents for accessing oxazoles (Chem. Sci. 2024, 15, 6515; Synlett 2024, 35, 1153). Significantly, this contribution leverages the unique reactivity of unprecedented PV-oxirene intermediates, generated via Cu-carbenes from thoughtfully designed IIII/PV-hybrid ylides. The synthetic utility of the method is illustrated through preparation of various biologically relevant molecules and highlighted as an efficient strategy for carboxylic acid homologation and 1,2-carbonyl transposition. Featuring good isolated yields, a robust substrate scope, and synthetically useful products, this method represents a promising modular approach for accessing α-oxy and α-amino carbonyls. Appropriate citations are included, spectral evidence of synthetic compounds is provided, and relevant experiments were conducted to support the proposed reaction mechanism. Overall, this is a well-written manuscript communicating an impactful synthetic transformation supported by solid experimental results. Further improvement can be achieved by addressing the following:\n\n1) What is the rationale for why Na2CO3 is the preferred base for N-nucleophiles while Cs2CO3 is optimal for O-nucleophiles (lines 88–89)?\n2) The reaction appears tolerant of sterics in the nucleophile and carboxylic acid substrates, but are bulky 3° R1 substituents (like t-Bu) on the IIII/PV-hybrid ylide tolerated? Conversely, does the reaction work if R1 = H?\n3) The authors prepare the acyl phosphonium salt from the corresponding acyl chloride and PPh3, and subsequently access product 121 (Figure 5E, bottom) as support for the formation of an intermediate like int-5 in the reaction mechanism (Figure 5G). Since this intermediate is isolable and observable by 1H and 31P NMR, can it also be observed under the standard reaction conditions? For instance, if the reaction in the top half of Figure 5E is monitored by NMR, can this intermediate be observed as it forms? Alternatively, if only 1 equiv of carboxylic acid and no additional nucleophile is used, can the initial product (i.e., the acyl phosphonium) be isolated?\n4) For the deuterium-labeling studies, what length of relaxation delay (d1) was used on the spectrometer to acquire the 1H NMR spectrum? Noting this in the SI would be helpful to confirm that a long enough relaxation delay was used to obtain an accurate value for % deuterium incorporation.\n5) Is MS fragmentation data or 13C NMR data available for product 18O-7? The GC-MS data confirms the label was transferred from the labeled ylide to the product but doesn’t necessarily prove the location of the label in the product. Considering the novelty of the proposed PV-oxirene intermediate, providing stronger evidence for its formation would be ideal and would enhance the usefulness of the 18O-labeling study.\n6) For the mechanistic studies in Figure 5, why was Cu(MeCN)4PF6 used as the catalyst when CuCN was found to be the optimal catalyst (Table 1) and used in the substrate scope experiments (Figures 2–3)?\n\nAdditionally, addressing the following writing and presentation issues is recommended:\n1) Line 27: “Readily transformation” should be “Ready transformation”.\n2) Figure 1B, top line of right side: “tradictional reactivity” should be “traditional reactivity”.\n3) Table 1: Consider moving Entry 17 elsewhere, such as Figure 2, since the reaction doesn’t fit the scheme shown in Table 1 (different nucleophile and different product).\n4) Line 103: “double bonds containing substrates” should be rephrased as “double bond-containing substrates” or “substrates containing double bonds”.\n5) Lines 109–111: Rephrase the sentence containing “…high chemoselectivity for substrates containing common carbenophiles rather than double bonds…” for clarity. It sounds like the authors mean to say the substrates reacted with carbenes instead of double bonds, but it’s somewhat ambiguous.\n6) Figure 2: Typo in product 19. “Pn” should be “Ph” based on the structure in the SI.\n7) Lines 142–143: Change the period at the end of Line 142 to a comma to avoid starting Line 143 with a sentence fragment.\n8) Figure 3: Headings are missing from the second two sections, depicting O-Nucleophiles and S/Se-Nucleophiles.\n9) Reference #19: publication year should be 1983, not 2002.\n10) SI p. S67: Figure S5. Caption compound “d-199” should be “d-119”.\n11) SI p. S72: The experimental procedure for preparing 121 from 123 should be written in passive voice, past tense, rather than imperative tense."}, "author_response": "Our responses: We thank reviewer 1 for devoting time to thoroughly read this manuscript andproviding an accurate summary ofour work.\n\nThe formation of the proposed P(V)-oxirene intermediate is somewhat questionable.\nAn alternative pathway could involve nucleophilic attack by an external carboxylate\nat the carbonyl carbon of Int-1, followed by oxygen-atom attack on the copper\ncarbenoid.\nOur responses: According to this reviewer’s description, we believe this reviewer\npoint out a plausible pathway (shown as follows) and we putatively rule out this\npathway mainlybased ontwo experimental results.\n1. We proposed if the reaction undergoes this pathway, the nucleophilic attack from\ncarboxylic anion to int-1 will be significantly effected by steric hindrance around\nC=Obonds. Shown as follows:\nWe set up reactions using CuCl and steric bulky ligand-coordinated\nCuCl as catalyst. According to the data, no kinetically difference was observed\nbetween these two reactions, thus indicating the nucleophilic attack of carboxylic\nanion may not involveCu-species.\n2. In the absence of nucleohphiles, we could only detect the formation of product A\n(via decomposition of IIII/PV -hybrid ylide) and B (via nucleophilic substitution from\ncarboxylate anion to IIII/PV -hybrid ylide). In both cases, the carbonyl group from\nIIII/PV-hybrid ylide remain untouched. This result indicated the nucleophilic attack\nfrom carboxylateanion toInt-1 was not favored inthis reaction pathway.\n\nA convincing explanation for why the intramolecular oxygen-atom attack would\npredominate to form such a highly strained oxirene intermediate should be provided.\nThis issue is critical, as it directly impacts the mechanistic foundation of the present\nstudy.\nOur responses: We agree with this reviewer that the catalytic formation of\nPV-substituted oxirene intermediate and subsequent highly selective transformation is\nthe key of our work. It has been well-established that -ketocarbenes can undergo\nWolff rearrangement via the formation of oxirene intermediates through an\nintramolecular oxygen-atom attack process (J. Am. Chem. Soc. 1968, 90, 7360-7361).\nThis highly reactive oxirene intermediate has been detected via IR spectroscopy on\nlow-temperature argon matrix (Ref. 22). We have incorporated the aforementioned\nreference about mechanistic investigation of Wolff rearrangement (updated Ref. 52)\nin the mechanism discussion section of our revised manuscript to substantiate the\nformation of a highly strained oxirene intermediate within our proposed reaction\npathways.\nOur group previously disclosed that IIII/PV hybrid ylides could serve as -PV carbenes\nprecursors upon activation of transition metals (Chem. Sci. 2024, 15, 6515-6521).\nThat study and follow-up research revealed that these electrophilic Fischer-type\ncarbenes react preferentially with unsaturated heteroatoms—such as the nitrogen of\ncyano groups or the carbonyl oxygen of aldehydes, ketones, and amides—to afford\nthe corresponding onium ylides, rather than engaging in X–H insertion processes.\nUnder conditions where no external unsaturated heteroatom sources are present, we\npropose that the in situ generated -PV-’-ketyl carbenes will instead undergo\nintramolecular nucleophilic attack by the ketyl oxygen at the carbene carbon center.\nThis process would yield oxirene intermediate Int-2, analogous to the initiating step\nina typical Wolffrearrangement.\nWhile the current mechanistic proposal is consistent with our observations, its exact\ndetails are stillunder investigation as we seek morerobust experimental verification.\n\nReviewer 2: Wang and co-workers reported a novel copper-catalyzed\nthree-component strategy for synthesizing -oxy carbonyl compounds through the\nformation of oxirene intermediates. This method employed IIII/PV-hybrid ylide\nreagents, carboxylic acids, and a range of nucleophiles, offering a broad substrate\nscope and excellent functional-group tolerance. The authors also provided detailed\nmechanistic investigations that strongly support the proposed reaction pathway, along\nwithvaluable syntheticapplications. The supporting information isclearly presented.\nOverall, the manuscript is of good quality and can be accepted after minor revision.\nSpecificcomments and queries are provided below.\nOur responses: We express our gratitude to reviewer 2 for dedicating valuable time to\nthoroughly review this manuscript and giving kind words for the overall novelty of\nthiswork.\n1. Whatis thereason behindchemo-selectivity ofthis reaction?\nOur responses: The stability and reactivity ofoxirene highly depends onits substitutes\n(Can. J. Chem. 2000, 78, 562-567). We propose the excellent chemo-selectivity of\nPV-oxirene was due to the PV substitutes, which rendering the oxirene to form two\nresonance structures:\nI\nAs shown in Int-2’, we believe the C1 is more electrophilic than C2, which making\nsuccessivenucleophilicattack form carboxylate anionhighly chemo-selective.\n2. The compound names in the Supporting Information should begin with a capital\nletter.\nOur responses: We have made corresponding modifications in our revised Supporting\nInformation.\n3.Pleaseprovide clean spectra ofthecompounds: 109,96,104,105.\nOur responses: We have purified these compounds and provided NMR spectra with\nbetter purity in the Supporting Information. However, despite repeated purification of\npeptide compounds 104 and 105 using various eluting systems (including PE/EA,\nPE/acetone, and DCM/MeOH), the NMR samples still contain solvent residuals as\nwell as trace amount ofunknown impurities.\n\nReviewer 3: In this manuscript, S. Huang, D. Duan, J. Luo, J. Chen, and Z. Wang\ndisclose a protocol for the Cu-catalyzed multicomponent synthesis of -oxy and\n-amino carbonyls from IIII/PV-hybrid ylides, carboxylic acids, and O- or N-based\nnucleophiles. This work builds on the group’s previous research on\nphosphorous-containing ylides as reagents for accessing oxazoles (Chem. Sci. 2024,\n15,6515; Synlett 2024, 35,1153). Significantly, this contribution leverages theunique\nreactivity of unprecedented PV-oxirene intermediates, generated via Cu-carbenes from\nthoughtfully designed IIII/PV-hybrid ylides. The synthetic utility of the method is\nillustrated through preparation of various biologically relevant molecules and\nhighlighted as an efficient strategy for carboxylic acid homologation and 1,2-carbonyl\ntransposition. Featuring good isolated yields, a robust substrate scope, and\nsynthetically useful products, this method represents a promising modular approach\nfor accessing -oxy and -amino carbonyls. Appropriate citations are included,\nspectral evidence of synthetic compounds is provided, and relevant experiments were\nconducted to support the proposed reaction mechanism. Overall, this is a well-written\nmanuscript communicating an impactful synthetic transformation supported by solid\nexperimental results.\nOur responses: We sincerely appreciate the positive feedback from Reviewer 3\nregarding thenovelty ofour work.\nFurtherimprovement can beachieved byaddressing thefollowing:\n1) What is the rationale for why Na CO is the preferred base for N-nucleophiles\n2 3\nwhileCs CO is optimalfor O-nucleophiles (lines 88–89)?\n2 3\nOur responses: We propose that the base serves a dual function: it not only\ndeprotonates the carboxylic acid to generate the nucleophilic carboxylate anion in situ,\nbut also activates the heteroatom nucleophile during its attack on the acyl\nphosphonium salt Int-5. The observed variations in reactivity among different\nnucleophiles (e.g., N- vs. O-nucleophiles) may be attributed to their differential\nresponses tobase activation.\n2) The reaction appears tolerant of sterics in the nucleophile and carboxylic acid\nsubstrates, but are bulky 3° R1 substituents (like t-Bu) on the IIII/PV-hybrid ylide\ntolerated? Conversely, does thereaction work if R1= H?\nOur responses: The bulky steric hindrance in IIII/PV-hybrid ylides significantly\nimpacts the reaction outcome. We tried model reaction using t-Bu substituted\nIIII/PV-hybrid ylide,but unfortunately, the desired product was not obtained.\nWhen R1= H, thecorresponding IIII/PV-hybrid ylide reagent could not beprepared.\n3) The authors prepare the acyl phosphonium salt from the corresponding acyl\nchloride and PPh , and subsequently access product 121 (Figure 5E, bottom) as\n3\nsupport for the formation of an intermediate like int-5 in the reaction mechanism\n(Figure 5G). Since this intermediate is isolable and observable by 1H and 31P NMR,\ncan it also be observed under the standard reaction conditions? For instance, if the\nreaction in the top half of Figure 5E is monitored by NMR, can this intermediate be\nobserved as it forms? Alternatively, if only 1 equiv of carboxylic acid and no\nadditional nucleophile is used, can the initial product (i.e., the acyl phosphonium)\nbe isolated?\nOur responses: As noted in the Supporting Information and previous literature, the\nacyl phosphonium salt is highly unstable and moisture-sensitive. After washing with\nhexane, it cannot be dried under vacuum and must be used immediately in the next\nstep. Although the intermediate is isolable and observable by 31P NMR ( =\n33.97ppm ), the spectrum was only acquired immediately after several hexane washes\non the crude product. Moreover, the compound decomposes rapidly over time, even\nduring short periods of standing.\nInt-5 121\nInt-5\nInt-5\n31P-NMR=33.97ppm\nThe31PNMRmonitoring(162MHz,CDCl3)ofInt-5formationandsubsequenttransformationinto121\nFollowing this reviewer’s suggestion, we performed real-time31P NMR monitoring of\nthe standard reaction using DCE and CDCl as solvents, respectively. After 20\n3\nminutes of reaction time, no formation of PPh was detected by 31P NMR, and only a\n3\nminimal amount of the target product was observed by TLC. After 1 hour, the\nappearance of PPh became clearly evident in the 31P NMR spectrum, and the target\n3\nproduct was also detected by TLC. Unfortunately, in both reactions using two\ndifferent solvents, no 31P signal corresponding to Int-5 ( = 33.97ppm) was observed.\nThis intermediate is likely highly unstable and may react immediately with the\nnucleophileuponformation, thusevading detection under theapplied conditions.\nThereal-time31PNMRmonitoring(162MHz,CDCl3)ofmodelreaction\nWhen the reaction is conducted under standard conditions without additional\nnucleophile, the only observable outcomes are the degradation of the IIII/PV-hybrid\nylide reagents. These results indicated the third nucleophiles may contribute to the\nformation of both oxirene and acyl phosphonium salt intermediates.\n4) For the deuterium-labeling studies, what length of relaxation delay (d ) was used\n1\non the spectrometer to acquire the 1H NMR spectrum? Noting this in the SI would be\nhelpful to confirm that a long enough relaxation delay was used to obtain an accurate\nvaluefor %deuterium incorporation.\nOur responses: The NMR spectra for the deuterium-labeling studies were acquired\nwith a relaxation delay (d1) of 1second. While a longer relaxation delay (d1 ≥ 5 T1)\nis technically required to ensure fully relaxed nuclear spins and thereby yield more\naccurate quantification of deuterium incorporation, we were not authorized to modify\nacquisition parameters on the NMR spectrometer. Consequently, data were not\ncollected under varied relaxation delays. Nevertheless, the experiments were repeated\nmultiple times, consistently yielding nearly identical results, which confirms the\nreproducibility of the deuterium-labeling data. Additionally, the relaxation delay used\nfor the 1H-NMR spectrum of compound d-119 has been provided in the revised\nSupportingInformation.\n5) Is MS fragmentation data or 13C NMR data available for product 18O-7? The\nGC-MS data confirms the label was transferred from the labeled ylide to the product\nbut doesn’t necessarily prove the location of the label in the product. Considering the\nnovelty of the proposed PV-oxirene intermediate, providing stronger evidence for its\nformation would beideal and would enhance theusefulness ofthe18O-labeling study.\nOur responses: The compound 18O-7 was re-synthesized, and its 13C NMR spectrum\nwas acquired. Comparison of the 13C-NMR spectra for 18O-7and 16O-7 revealed that\nthe only observable difference was the signal intensity of the oxygenated carbon,\nwhich was notably lower in the 18O-7 spectrum. The precise origin of this intensity\nreductionis not yet fully understood.\n13CNMR (101 MHz,CDCl ) of18O-7\nwhich provided clear evidence that a 1,2-carbonyl transposition had indeed occurred\nduring the reaction. We have added this data as updated Table S6 in our revised\nSupportingInformation.\nGC-MS dataof18O-7 and its fragments\nAbsolute Relative Proportionof\nfragmentation m/z\nIntensity Intensity 18O\n117.15 12400 0.15\n118.05 147119 1.78\n28%\n119.05 37902 0.46\n120.05 57713 0.70\n134.15 474099 5.74\n135.10 8261082 100.00\n2%\n136.05 2209514 26.75\n137.05 182081 2.20\n313.20 710 0.01\n314.20 20138 0.24\n31%\n315.20 4967 0.06\n316.20 9218 0.11\n6) For the mechanistic studies in Figure 5, why was Cu(MeCN) PF used as the\n4 6\ncatalyst when CuCN was found to be the optimal catalyst (Table 1) and used in the\nsubstratescope experiments (Figures 2–3)?\nOur responses: As the reviewer rightly surmised, our research group became keenly\ninterested in the underlying reaction mechanism immediately upon isolating the initial\nproducts. To evaluate our preliminary mechanistic hypotheses, we first conducted a\nseries of investigations using Cu(MeCN) PF in our laboratory, prior to embarking on\n4 4\nsystematic reaction optimization. Subsequent screening of catalytic conditions (Table\n1) revealed CuCN to be superior in terms of reaction yield. Consequently, CuCN was\nselected as the catalyst for exploring the substrate scope (Figures 2–3) and for\nsynthetic applications, ensuring the optimal practical utility of the methodology. For\nthe supplementary mechanistic studies conducted later, we returned to the original\ncatalyst, Cu(MeCN) PF , to maintain direct comparability with the data from our\n4 6\ninitialmechanistic experiments.\n\nAdditionally, addressing the following writing and presentation issues is\nrecommended:\n1)Line 27: “Readily transformation”should be “Ready transformation”.\n2) Figure 1B, top line of right side: “tradictional reactivity” should be “traditional\nreactivity”.\nOur responses: We thank this reviewer for his/her careful proofreading. We have\ncorrected thesetwo typos in ourrevised manuscript.\n3) Table 1: Consider moving Entry 17 elsewhere, such as Figure 2, since the reaction\ndoesn’t fit thescheme shown in Table 1(different nucleophile and different product).\nOur responses: The corresponding entry has been removed from Table 1, and the\nrationale for the choice of base additive for different nucleophile types has been\nclarified in thesubstrateevaluation section ofFigure 2.\n4) Line 103: “double bonds containing substrates” should be rephrased as “double\nbond-containing substrates”or“substrates containing doublebonds”.\nOur responses: We have made corresponding modifications in our revised manuscript\nbased onthis reviewer’s kind suggestions.\n5) Lines 109–111: Rephrase the sentence containing “…high chemoselectivity for substrates containing common carbenophiles rather than double bonds…” for clarity. It sounds like the authors mean to say the substrates reacted with carbenes instead of doublebonds, but it’s somewhat ambiguous.\nOurresponses: Following thisreviewer’s advice, we rewritethis sentence as follows:\n“Of note, this method exhibited high chemoselectivity even for substrates containing\ncommon carbenophiles—such as N-H (28), sulfide(29), and cyanide (30) moieties—\nin addition to double bonds (18 and 20), which are widely recognized as\nfunctionalities thatcan interferewithreactions involving carbene intermediates.”\n6)Figure 2: Typo in product 19.“Pn” shouldbe “Ph”based onthestructure in theSI.\n7) Lines 142–143: Change the period at the end of Line 142 to a comma to avoid\nstarting Line 143with asentence fragment.\n8) Figure 3: Headings are missing from the second two sections, depicting\nO-Nucleophiles and S/Se-Nucleophiles.\n9)Reference #19: publication year should be1983,not 2002.\nOur responses: we thank this reviewer for his/her careful proofreading. We have\ncorrected thesetypos in ourrevised manuscript.\n10)SIp.S67:Figure S5.Caption compound “d-199” shouldbe “d-119”.\n11) SI p. S72: The experimental procedure for preparing 121 from 123 should be\nwritten in passivevoice, past tense, rather than imperativetense.\nOur responses: We thank this reviewer for his/her careful proofreading. We have\nmadecorresponding modifications in our revised SupportingInformation."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The author has carefully considered the reviewers' comments and has made the necessary corrections. Extensive results from additional experiments have been added, which significantly improve the manuscript, particularly in terms of mechanistic parts. Therefore, I now think that the revised manuscript has reached a level of quality suitable for publication in Nature Communications.", "reviewer_2": "The reviewer is satisfied with the revised manuscript and recommend it to be published in the present form.", "reviewer_3": "The revised manuscript and rebuttal letter submitted by Chen, Wang, and co-workers adequately addresses the concerns raised in this reviewer’s previous report. The additional experiments and discussion provided by the authors in their rebuttal letter strengthen their case and add important context to the original submission. The revisions to the manuscript and SI are good. Further minor suggestions are as follows:\n\n1) In the manuscript, expand on the discussion of the role of the base. It may be helpful for readers to understand the rationale offered by the authors in their rebuttal letter addressing the different base preference (Cs2CO3 vs Na2CO3) when comparing N vs O nucleophiles.\n2) In the manuscript, mention the limitations of the ylide substrate scope (R1 = H or tBu), either in the main text or as a footnote, as that would be helpful for readers interested in using this method.\n3) In the SI, add the experiments conducted to address reviewer questions about the mechanism, since that is a key aspect of this work. Including the two experiments addressing Reviewer #1’s proposed alternative mechanism, along with the real-time 31P NMR monitoring studies and reaction performed with only carboxylate (no additional nucleophile) to address Reviewer #3’s questions, would provide helpful context for understanding the mechanism."}, "author_response": "Our responses: We greatly appreciate the reviewer’s recommendation of our work for publication in Nature Communications.\n\nOur responses: We greatly appreciate the reviewer’s recommendation of our work for publication in Nature Communications.\n\nOur responses: Following this reviewer’s advice, we expand on the discussion of the role of the base in the revised manuscript as follows:\n“It should be noted that for N-nucleophiles, Na2CO3 exhibits greater efficacy as a basic additive than Cs2CO3. This enhancement in reactivity can be attributed to the dual role of the base in the reaction mechanism: first, it deprotonates the carboxylic acid to form the nucleophilic carboxylate anion in situ, and second, it activates the heteroatom nucleophile during its addition to the acyl phosphonium intermediate. Consequently, differences in reactivity between nucleophile classes-such as N- versus O-nucleophiles-arise from their distinct sensitivities to such base-mediated activation. ”\n\nOur responses: We have added these two limited ylide substrates to Figure 2, as well as relevant discussions in the revised manuscript.\n\nOur responses:We have added all these experimental results mentioned by Reviewer #3 to our revised Supporting Information file."}]

Decision letter