Rationally designed Fe-cyclopentadienone with unique orientations for efficient asymmetric hydrogenation of acylsilanes

Domain: chemistry
Published: 2025-12-26
Editorial outcome: minor_revision

Abstract
Fe-cyclopentadienone complexes have been widely utilized in various hydrogenation and dehydrogenation catalytic processes, yet their applications have largely been restricted to non-asymmetric versions. This limitation is primarily due to the considerable challenge of constructing an efficient chiral environment around the active iron center. In this study, we present a structurally distinctive chiral Fe-cyclopentadienone complex with excellent enantiocontrol capabilities. This new iron complex features bulky side arms oriented downward toward the cyclopentadienone plane, which create an ideal chiral environment in front of the catalytically active iron center. It demonstrates excellent performance in the catalytic asymmetric hydrogenation of acylsilanes, exhibiting both high reactivity and selectivity. The broad substrate scope, encompassing aryl-, alkenyl-, and alkyl-acylsilanes, along with successful gram-scale synthesis, underscores its potential applications in pharmaceutical synthesis. Experimental and DFT studies reveal the structural stability and rigidity of the catalyst during catalytic intervals. Additionally, weak interactions between the catalyst and the silyl group in the substrate play a critical role in achieving efficient enantioselectivity. More importantly, this type of chiral iron complex also shows excellent catalytic reactivity and selectivity for asymmetric transfer hydrogenation, utilizing i-PrOH as the hydrogen source.

Introduction
Transition metal-catalyzed asymmetric hydrogenation (AH) has been widely explored due to its practicality in industrial production, particularly in pharmaceutical companies1. Since the first industrial application of Rh/DIPAMP by Knowles in 1974, and its subsequent recognition with the Nobel Prize in 2001, asymmetric hydrogenation has experienced a golden era of research centered around noble transition metals, such as ruthenium, rhodium, and iridium2–9. A significant shift occurred around 2010, when chemists began focusing on earth-abundant transition metals, such as manganese, iron, cobalt, nickel, and copper10–19. Among these, iron stands out as a promising candidate for replacing noble transition metals in industrial applications, owing to its status as the second most abundant metal in the Earth’s crust and negligible toxicity to humans20. Although several sophisticated iron complexes have been developed for asymmetric hydrogenation21–26, the quest for highly efficient and practical chiral Fe-catalysts, with the ultimate goal of industrial application, continues unabated.

Due to the smaller 3d orbitals and higher electronegativity of iron compared to its congener ruthenium, iron-based catalysts exhibit distinct catalytic behaviors. For instance, iron is more likely to undergo single-electron transfer processes and possesses complex valency and spin states27. Consequently, chemists have recognized that the classical catalytic modes of ruthenium cannot be directly and simply replicated with iron, which is often perceived as inferior in performance28. However, a notable exception is the Fe-cyclopentadienone (Fe-CPD) complex (Fig. 1a), which displays a similar concerted catalytic mode and comparable reactivity to its ruthenium analog, Shvo’s catalyst29. Although Fe-cyclopentadienone was initially synthesized in the 1950s30 and further explored by Pearson and Knölker in the 1990s31–33, its catalytic potential was largely overlooked until 2007, when Guan and co-workers demonstrated. It's high efficiency in the hydrogenation of ketones34,35. Fe-CPD offers several advantages, including being inexpensive, low in toxicity, easily accessible, phosphine-free, and air-stable. The catalytic mode of Fe-CPD can be attributed to a bifunctional active intermediate, consisting of a Lewis acidic iron center and a Lewis basic oxygen center (Fig. 1a). Based on this bifunctional catalytic model, a wide range of catalytic transformations involving hydrogenation and dehydrogenation have been developed36–43.

Despite the extensive application of Fe-CPD in various non-asymmetric transformations, the development of enantioselective reactions using chiral Fe-CPD has lagged far behind. The primary reason is the lack of an efficient chiral Fe-CPD catalyst, due to the difficulty in designing an effective chiral pocket around the iron active center. Addressing the challenge of designing an efficient enantioselective Fe-CPD, the Wills group noted that the limited enantioselectivity may result from the long distance between the side arms of the cyclopentadienone ring and the substituents of the substrate in the proposed reduction model (Fig. 1a)44.

Fe-CPD-catalyzed asymmetric transformations primarily rely on two strategies: 1) the introduction of a chiral cocatalyst and 2) the design of a chiral cyclopentadienone (CPD) backbone. The first strategy has been effective in limited instances, as it requires specific recognition between the substrate and the chiral cocatalyst, such as imines and chiral phosphoric acid catalysts45–47. The second strategy is more appealing due to the direct chiral recognition between the substrate and the chiral Fe-CPD, which is expected to have broader and more general applications. Significant efforts have been devoted to developing chiral CPD backbones, yet no substantial breakthroughs have been achieved, particularly at the practical application level44,48–51. To date, the highest enantiomeric excess (e.e.) value achieved is 77%, obtained through the asymmetric hydrogenation of a specific ketone, although this method lacks substrate generality49.

Given the bifunctional catalytic mode of Fe-CPD, a visionary enantiocontrol model for the asymmetric hydrogenation of polar double bonds, such as ketones and imines, can be established (Fig. 1b, left). The current challenge of designing an efficient enantioselective catalyst can be explained by model M1, which features open steric hindrance in front of the catalytically active iron center, making effective enantio-differentiation difficult (Fig. 1b). This conclusion is supported by the crystal structures of catalysts described in earlier reports44,48–51. Based on the concerted enantiocontrol model, we are able to figure out a desired and sterically feasible model M2 and an undesired, sterically crowded model M3 (Fig. 1b). In this work, we report a chiral Fe-CPD catalyst that simultaneously positions steric side arms downward to the CPD plane and creates two distinct steric environments in front of the catalytically active iron center (illustrated with Fe4, Fig. 1c). This type of catalyst demonstrates excellent performance in the asymmetric hydrogenation of acylsilanes, achieving up to a 96:4 enantiomeric ratio (e.r.) and a turnover number (TON) of 870. Moreover, a slight modification of the catalyst enables highly efficient asymmetric transfer hydrogenation, using i-PrOH as the hydrogen source.

Results
Catalyst design and test
At the outset of our study, we aimed to incorporate naturally abundant chiral scaffolds, such as amino acids, into the Fe-CPD framework (Fig. 2a). The chiral aldehyde precursor (P1), which can be readily synthesized from L-proline, was treated with the dimethyl(1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent) to produce the corresponding alkyne P2. Following -Boc removal and the installation of –SO2Ar, P3 was obtained, which then underwent a nucleophilic reaction with a diiodide to yield the dialkyne P4. The final Fe1–12 complexes were easily synthesized through the coordination of P4 with Fe2(CO)9. This synthetic route offers several advantages, including the easy availability of starting materials, high yields, friendly operation, and all products are air-stable. A notable feature is the production of a single diastereomer of the final Fe-complex, which significantly simplifies the isolation process. Starting from the common synthon P2, the final complexes Fe1–12 achieved a global yield ranging from 12% to 46% (see Supplementary Information). Consequently, this type of catalyst holds potential for large-scale production.

Compared to the extensively studied alkyl-aryl ketone substrates, acylsilanes have only been sporadically explored in asymmetric hydrogenation, despite the silyl group’s potential for diverse transformations and biological activities. The classical Ru-TsDPEN catalyst has been shown to be effective with aryl acylsilanes but less so with alkyl acylsilanes52. Ohkuma et al. successfully applied the Ru-diphosphine-diamine catalytic system for the asymmetric hydrogenation, but limited to the bulkier -TBS substituent, possibly due to the existence of a strong base, which may cause the Brook rearrangement53. We were also keen to apply our newly developed Fe-CPDs for the asymmetric hydrogenation of acylsilanes, addressing the existing unresolved challenges. Under H2 (30 atm) at 80°C, a preliminary screening of Fe1–12 revealed that Fe9 gave the best enantioselectivity (Fig. 2b, entries 1–12). These results indicate that a six-membered ring backbone is superior to a five-membered ring backbone (entry 4 vs. 10 and entry 9 vs. 12). Moreover, the different types of R substituents on the sulfonyl group do not significantly influence either catalytic reactivity or enantioselectivity. Further optimization, involving a solvent change to iPrOH/H2O and a temperature reduction to 60°C, resulted in the best enantiomeric ratio (e.r.) of 93:7 with high yield (entry 13).

Substrate scope exploration
With the optimized reaction conditions in hand, we primarily evaluated the substrate scope of Fe-catalyzed asymmetric hydrogenation of aryl acylsilanes (Fig. 3). First, changing the silyl groups from -TMS to -TES and -TBS resulted in a slight decrease in the er (2a–c). Second, while the electronic properties of different substituents did not affect substrate activity, they did have a slight influence on the er, with electron-rich groups generally exhibiting higher enantioselectivity (e.g., 2d–e vs. 2v–w). Third, substitutions at the ortho-position showed poorer enantiocontrol than those at the para- and meta-positions (2d–f vs. 2g and 2s–t vs. 2u). Additionally, heteroaromatic rings such as thiophenyl and furanyl were well tolerated (2z and 2aa). Notably, some bioactive drugs and natural product-derived acylsilanes were also successfully hydrogenated with high enantioselectivity and reactivity (2ab–ae). Overall, the aryl acylsilane substrates demonstrated high generality with respect to the catalytic system.

The robustness of this catalytic system was further demonstrated by its successful application to alkyl- and alkenyl-acylsilanes, which have been challenging for the classical Ru-TsDPEN catalyst52. With slight modification of the catalyst, specifically Fe5, a variety of alkyl- and alkenyl-acylsilanes were efficiently and selectively hydrogenated to the corresponding alcohols (Fig. 4). Notably, aryl- and oxygen-substituted acylsilanes (4a–i) exhibited higher enantioselectivity compared to bare or fluoro-substituted alkyl acylsilanes (4k–l). Of particular note, the alkenyl-acylsilanes achieved high enantiomeric ratios without affecting the alkenyl groups (4m–n).

Gram-scale synthesis and derivatizations
To further evaluate the robustness of this catalytic system, a turnover number (TON) test was conducted with gram-scales (Fig. 5a). Under a S/C ratio of 1000 at 80°C, we achieved full conversion with an isolated yield of 87% and a slightly reduced er of 91:9 (Fig. 5a). The low yield is due to the slow decomposition of 2a in water, which produces benzaldehyde54. Lowering the temperature to 70°C resulted in decreased catalytic reactivity, as an incomplete reaction was observed with S/C=500. However, a successful gram-scale synthesis was achieved with an S/C ratio of 300 at 70°C, yielding 86% with an er of 92:8, thereby demonstrating the potential practicality of this catalytic system. Furthermore, the chiral silyl alcohol 2a can be readily transformed into the corresponding amino product 5a via a Mitsunobu reaction (Fig. 5b). Another intriguing application is the use of the silyl alcohol as a chiral auxiliary, initially demonstrated by Linderman et al.55. The TMS-protected 5b was able to induce formylcyclohexane (CyCHO) to form an oxocarbenium ion intermediate, which can be enantioselectively attacked by allyl trimethylsilane (Allyl-TMS), yielding 5c with two chiral centers (Fig. 5b).

Mechanistic studies
Next, experimental and DFT studies were conducted using Fe4, which has been crystallographically characterized, as the standard model to elucidate the catalytic mechanism and enantiocontrol insight (Fig. 6). Initially, when D2 was used in place of H2 for the hydrogenation of 1a, 11% of H atoms were detected at the benzylic position, suggesting possible Fe-H formation, potentially arising from hydrogen transfer from i-PrOH (Fig. 6a, entry 1). The transfer hydrogenation process was conclusively confirmed by using i-PrOH as the sole hydrogen source, resulting in the successful isolation of the desired product with 10% yield (entry 3). Furthermore, entries 1–2 suggest that the reaction with D2 proceeds more slowly compared to H2. A more precise experiment employing H2/D2 (1:1) indicated a kinetic difference between H2 and D2, with an estimated kinetic isotope effect (KIE) of around 1.5 (entry 4). Combined with DFT calculations, it is proposed that H2 activation is the rate-determining step (see the Supplementary Information).

The crystal structure of Fe4 has satisfied all the requirements of the design principle (Fig. 1c, M2), with the two ArSO2− side arms oriented downward relative to the CPD plane, creating a steric difference in front of the catalytic center. However, concerns may arise regarding the potential flexibility of this configuration in solution, which could undermine the previous hypotheses. To investigate the rigidity of the structure, a 1H–1H NOESY test in CDCl3 was conducted (Fig. 6b). The 1H–1H NOESY signal intensities between Hc/Hd–Ha and He/Hf–Hb are positively correlated with the corresponding distances measured in the crystal structure (see the Supplementary Information for details), indicating that the structure in solution closely resembles of the crystal state. Actually, this structural arrangement can be rationalized by comparing the steric hindrance of the –CH2– and –NSO2Ar groups adjacent to C3 or C4. Although the physical volume of N–SO2Ar is larger than CH2, the –SO2Ar group can extend peripherally to the Fe center to avoid steric repulsion. In other words, the tetrahedral geometry of –CH2– is less effective at preventing proximity to the Fe center compared to the pyramidal geometry of –NSO2Ar. Furthermore, DFT optimized Fe4 (Fe4cal) reveals additional stabilization factors arising from C–H···O interactions (b1=2.969 Å, b2=3.399 Å, Fig. 6c) between CO ligands and hydrogens on side arms.

A detailed mechanistic understanding of the reaction was achieved through density functional theory (DFT) calculations (Fig. 6c, Supplementary Data 1). The Fe4 complex was confirmed to adopt singlet ground states (1Fe4cal), with other spin states exhibiting significantly higher Gibbs free energies (3Fe4cal 35.3 kcal·mol−1 and 5Fe4cal 66.2 kcal·mol−1). First, the pre-catalyst 1Fe4cal is activated with Me3NO by removal of one CO, followed by a spin crossover via the minimum energy crossing point (MECP) to afford the more stable triplet intermediate 3Int1. Then, H2 associates to Fe to form the triplet intermediate 3Int2, which then undergoes a spin inversion through MECP (−39.4 kcal mol−1) to produce the singlet intermediate 1Int2. Next, H2 is cleaved to form 1Int-H, which step experiences a free energy elevation of 27.0 kcal·mol−1, representing the rate-determining step. Examination of the critical intermediate 1Int-H reveals a strong hydrogen bond (b3=1.786 Å, Fig. 6c) between O–H···O=S, which helps preserve the chiral pocket. Finally, 1a is hydrogenated by 1Int-H via a concerted transition state (TSS=13.7 kcal·mol−1 and TSR=15.9 kcal·mol−1, Fig. 6c) to yield the desired product 2a.

To gain a deeper understanding of the enantiocontrol, non-covalent interaction (NCI) analysis of the enantiodetermining transition state TSS revealed critical stabilizing interactions, including C–H···π (b4=2.881 Å, b5=2.567 Å) and C–H···O (b6=2.354 Å) contacts (Fig. 6c). While both aryl- and alkyl-acylsilanes are attacked by Fe-H from the same face, we believe that the C–H···O contact is more significant in the enantiocontrol transition state56,57. In contrast, the disfavored transition state TSR lacked comparable interactions, providing a structural basis for the observed enantiocontrol in the Fe-CPD catalytic system. Interestingly, this weak interaction is not observed when the -TMS group in 1a is replaced with a -tBu group, aligning well with experimental observation (up to 75:25 er for tert-butyl phenyl ketone, see Supplementary Information). This difference may be attributed to the smaller atomic diameter of carbon compared to silicon (Supplementary Fig. 12).

Asymmetric transfer hydrogenation
Inspired by the deuterium experiments (Fig. 6a), we became interested in adapting this catalytic system for a more user-friendly transfer asymmetric hydrogenation process. Initially, the original Fe9 (2 mol%) exhibited low catalytic activity for the transfer hydrogenation of 1a using iPrOH as the hydrogen donor, achieving a yield of 30% of 2a in 12 h. Funk et al. demonstrated that replacing one of the three CO ligands with a weakly coordinating nitrile ligand could significantly enhance catalyst performance58. Consequently, we prepared the Fe5-PhCN and Fe9-PhCN complexes to test their efficacy in asymmetric transfer hydrogenation. To our delight, the PhCN-ligated complexes exhibited excellent catalytic activity at a slightly elevated temperature (70°C) in a mixed solvent of iPrOH/H2O (15:1) (Fig. 7). The enantiomeric ratios (e.r.) were very similar to those observed in H2-promoted hydrogenation, with only a slight decrease due to the higher temperature, indicating the formation of the same Fe–H intermediate and hydrogenation transition state. The successful implementation of the asymmetric transfer hydrogenation process further enhances the practicality of this catalytic system, particularly in laboratory settings.

In conclusion, we have successfully developed a new chiral Fe-cyclopentadienone catalyst. This new Fe-complex is characterized by two side arms oriented downward toward the cyclopentadienone plane, and these arms are able to create a steric difference in front of the catalytically active Fe-center. This structural feature was thoroughly explored and explained through experimental and DFT studies. This type of Fe-complex demonstrated excellent catalytic reactivity and selectivity in the asymmetric hydrogenation of acylsilanes, whether aryl- or alkyl-substituted. The broad substrate scope and successful gram-scale synthesis underscore the practicality of this catalytic system. Overall, this study represents a significant breakthrough in the development of chiral Fe-cyclopentadienone catalysts, which may be further applied in various bifunctional asymmetric catalytic transformations in the future.

Methods
General procedure for catalytic hydrogenation using H2
Under a nitrogen atmosphere, a 5-mL glass vial equipped with a magnetic stir bar was charged with Fe9 (9.7 mg, 2 mol %), solvent (1.2 mL iPrOH and 0.3 mL H2O), Me3NO (1.5 mg, 0.02 mmol, 4 mol%), and substrate 1 (0.5 mmol, 1.0 equiv.). The vial was then transferred to a 50-mL autoclave, which was purged with H2 twice (charging with 10 atm H2 and slowly releasing the H2 each time). The autoclave was subsequently charged with H2 to a pressure of 30 atm. The autoclave was stirred and heated in an oil bath at 60°C for 12 h. After cooling to ambient temperature, the H2 was carefully released. The solvent was then removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product 2.

General procedure for catalytic transfer hydrogenation using iPrOH
Under a nitrogen atmosphere, a 4-mL glass vial with a screw cap and a magnetic stir bar was charged with Fe9-PhCN (6.3 mg, 2 mol%), solvent (1.5 mL iPrOH and 0.1 mL H2O), and substrate 1 (0.3 mmol, 1.0 equiv.). The vial was tightly sealed with the screw cap. The mixture was stirred and heated in an oil bath at 70°C for 12 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired product 2.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Tan and co-workers developed a new chiral Fe-cyclopentadienone catalyst for asymmetric hydrogenation and hydrogen transfer of acylsilanes, achieving high yields and good enantioselectivity. The catalyst features easily accessible starting materials, facile synthesis, and air-stable products. Crucially, the Fe-complex forms as a single diastereomer, simplifying isolation. Its unique structure incorporates bulky downward-oriented side arms that create a confined chiral environment, enabling broad substrate scope (aryl-, alkenyl-, alkyl-acylsilanes) and gram-scale syntheses with low catalyst loading. It is noteworthy that both asymmetric hydrogenation and hydrogen transfer exhibit comparable enantioselectivity, suggesting the possible involvement of shared Fe-H intermediates. Mechanistic studies reveal the catalyst's structural stability and rigidity during catalysis through experimental and DFT analyses. DFT calculations further elucidate that weak substrate-catalyst interactions in key transition states govern enantiocontrol. The manuscript is well-structured with comprehensive Supporting Information. While this work represents a valuable contribution to asymmetric catalysis, minor concerns remain regarding condition optimization details and DFT methodology.\nComments:\n(1) In the substrate scope investigations, different iPrOH/H2O ratios were employed for the two reaction types (4:1 for asymmetric hydrogenation versus 15:1 for transfer hydrogenation). Why choose these ratios? What is the functional role of H2O in the reaction system?\n(2) The gram-scale reactions showed complete conversion at S/C=1000 and 300, yet afforded isolated yields of just 87% and 86%. Why? Were any byproducts detected?\n(3) In DFT calculations, the authors employed Fe2 as the catalyst model. Why was Fe7, which exhibits optimal catalytic performance, not adopted for these computations? The reasons should be mentioned.\n(4) In line 249, after ‘Funk et al. demonstrated that replacing one of the three CO ligands with a weakly coordinating nitrile ligand could significantly enhance catalyst performance’, the corresponding literature should be cited.\n(5) The authors mention that replacing one of the three CO ligands with a weakly coordinating nitrile ligand could significantly enhance catalyst performance in asymmetric transfer hydrogenation. Could higher turnover numbers be achieved by employing Fe7-PhCN as the catalyst in the asymmetric hydrogenation?\n(6) Relevant reviews and representative research papers on weak interactions in asymmetric hydrogenation should be cited.\n(7) Please check for minor issues in the article, such as the sentence in line 56 and the abbreviation \"TMAO.\"", "reviewer_2": "This contribution introduces a new chiral symmetric (C ) modification of a cyclopentadienone ligand for application in 2 Fe(cyclopentadienone)-catalysed hydrogenation and transfer hydrogenation of acylsilanes. The ligand can be rather easily assembled from commercially available L-proline and is obtained as a single enantiomer. A sufficiently wide scope is presented, with generally high enantiomeric ratios. The reason for the enantioselectivity has been traced to weak interactions established with the prochiral substrate, with support from DFT calculations.\nI think this paper is potentially impactful, but I would wish to have additional insight. The investigation is restricted to silyl-substituted ketones, a rather poorly investigated class of substrates in hydrogenation, relative to the more common diaryl-, alkyl-aryl-, and dialkyl ketones. In the abstract, the authors claim that a key factor is the weak interaction between the chiral catalyst and the silyl group, but this interaction involves in effect a C-H bond of one of the silyl methyl substituents. Thus, an analogous interaction could in principle be established with simpler aryl-alkyl ketones. I would with the authors to include in their paper at least one example of a hydrogenation of a representative aryl-alkyl ketone with analogous structure (for instance, phenyl-tert-butyl ketone, or perhaps propiophenone) from both the experimental and DFT point of view. If the key weak interaction is still present, the scope of the study would widen in a very interesting way. If, on the other hand, the weak interaction disappears and the results are poorer, the authors can gain additional insights on the key role of the silyl group.\nAdditional points:\n1. The authors quickly discard the possible intervention of other spin states on the basis of results obtained for the saturated tricarbonyl pre-catalyst. This is not representative. They should rather do the same test on the less saturated (16-electron) dicarbonyl analogues (Int1), or on the dihydrogen adduct of this (Int2). I believe that the system would still remain more stable in the singlet state, but the gap will certainly be must smaller.\n2. Line 95: who are catalysts A-D?\n3. Line 109: there should more details (or a literature reference) on the Bestmann-Ohira reagent.\n4. Line 113: the authors should add the global yield of the catalysts Fe1-10 from L-proline.", "reviewer_3": "The development of the efficient chiral Fe-cyclopentadienone catalyst for asymmetric catalysis represents a challenging task. In the manuscript, the authors developed a series of novel chiral Fe-cyclopentadienone catalysts through a rational design by simultaneously positioning steric side arms downward to the cyclopentadienone plane and creating two distinct steric environments in front of the catalytically active iron center. The resulting catalysts displayed excellent performance in the asymmetric hydrogenation or transfer hydrogenation of acylsilanes, achieving up to a 96:4 e.r. and a turnover number (TON) of 870. A detailed mechanistic understanding and enantiocontrol insight of the reaction were achieved through experimental and DFT studies. This study represents an efficient strategy for the construction of chiral Fe-cyclopentadienone catalyst and should be helpful to guide the new ligand design. The manuscript and the supporting information are well presented. The manuscript is therefore recommended for the publication in Nat. Commun. after the following points are addressed,\n1. As a key point in the design of new Fe-CPD catalysts, the introduction of the ArSO2 group should be crucial to the success of the present strategy as showed in Figure 1c. However, no data supported this assumption in the manuscript. Some comparative experiments should be provided to further elucidate the necessity of ArSO2 group in the ligand, including the use of parent chiral Fe-CPD catalyst without a ArSO2 group and the use of chiral Fe-CPD catalyst with acyl group such as Boc or acetyl instead of a ArSO2 group for the hydrogenation.\n2. The authors screened the substituent at the phenyl ring of ArSO2 group to establish the optimal catalyst in Figure 2. However, the result in Figure 2 did not display a clear relationship between the substituent at the phenyl ring and the catalytic performance. it seems that the substituent at the phenyl ring is not so critical to catalytic performance. Strangely, the authors did not investigate the Fe-CPD catalyst with the simplest PhSO2 group as a comparison. Thus, more extensive evaluation on representative sulfonyl groups such as PhSO2, tBuPhSO2, MeSO2 and tBuSO2 should be performed to clarify the importance of the substituent on the sulfonyl group.\n3. keep “Me3NO” and “TMAO” in Fig. 3 and 4 consistent with those in the footnote in Fig. 3 and 4."}, "author_response": "Response to the reviewers’ comments\nReviewer #1\nGeneral comments: Tan and co-workers developed a new chiral Fe-cyclopentadienone\ncatalyst for asymmetric hydrogenation and hydrogen transfer of acylsilanes, achieving high\nyields and good enantioselectivity. The catalyst features easily accessible starting materials,\nfacile synthesis, and air-stable products. Crucially, the Fe-complex forms as a single\ndiastereomer, simplifying isolation. Its unique structure incorporates bulky downward-oriented\nside arms that create a confined chiral environment, enabling broad substrate scope (aryl-,\nalkenyl-, alkyl-acylsilanes) and gram-scale syntheses with low catalyst loading. It is\nnoteworthy that both asymmetric hydrogenation and hydrogen transfer exhibit comparable\nenantioselectivity, suggesting the possible involvement of shared Fe-H intermediates.\nMechanistic studies reveal the catalyst's structural stability and rigidity during catalysis through\nexperimental and DFT analyses. DFT calculations further elucidate that weak substrate-\ncatalyst interactions in key transition states govern enantiocontrol. The manuscript is well-\nstructured with comprehensive Supplementary Information.\nOur response: We thank the referee for the positive comments.\nRemarks: While this work represents a valuable contribution to asymmetric catalysis, minor\nconcerns remain regarding condition optimization details and DFT methodology.\nRemark 1: In the substrate scope investigations, different iPrOH/H O ratios were employed\n2\nfor the two reaction types (4:1 for asymmetric hydrogenation versus 15:1 for transfer\nhydrogenation). Why choose these ratios? What is the functional role of H O in the reaction\n2\nsystem?\nOur response: Thank you for this insightful comment. Indeed, H O plays a crucial role in our\n2\ncatalytic system. We conducted the following three catalytic reactions under 60 °C, and the\nresults demonstrate that the inclusion of H O significantly enhances catalytic reactivity. This\n2\nenhancement may be attributed to H O acting as a proton shuttle, facilitating the formation of\n2\na bifunctional transition state. We have included experiments 1 and 2 in the Supplementary\nInformation, detailed in Table S3, entries 7-8.\nRegarding the different iPrOH/H O ratios used in hydrogenation (4:1) and transfer\n2\nhydrogenation (15:1), we performed several reactions for comparison. By keeping the total\nsolvent volume fixed at 2 mL, we found that a higher concentration of iPrOH improves\nreactivity. This result is imaginable as the transfer hydrogenation using iPrOH as the hydrogen\nsource. Although the results for the 9:1 ratio were comparable to those for the 15:1 ratio, we\nopted for the 15:1 ratio in subsequent studies to ensure broader substrate scope and generality.\nRemark 2: The gram-scale reactions showed complete conversion at S/C=1000 and 300, yet\nafforded isolated yields of just 87% and 86%. Why? Were any byproducts detected?\nOur response: Yes, in the high TON test experiment, we indeed observed a side product,\nbenzaldehyde, particularly in cases of low conversions. This side reaction has been documented\nin the literature (J. Chem. Res. 2000, 2000, 404-405. DOI: 10.3184/030823400103167868), as\nindicated by the following transition state. When the catalytic reaction is conducted at high\ncatalyst loading (2 mol%), the slow side reaction is not significant. However, at low catalyst\nloading (0.1 mol%), this side reaction becomes negligible. To clarify this issue, we have added\nthe following sentence to the gam-scale synthesis part: “The low yield is due to the slow\ndecomposition of 2a in water, which produces benzaldehyde.”\nRemark 3: In DFT calculations, the authors employed Fe4 as the catalyst model. Why was\nFe9, which exhibits optimal catalytic performance, not adopted for these computations? The\nreasons should be mentioned.\nOur response: We appreciate the referee's concern regarding the use of Fe9, the best-\nperforming catalyst, as a DFT model for a more accurate representation of the system. However,\nwe were unable to obtain a crystal structure for Fe9. As noted in the manuscript, the catalyst\nstructure is quite unique and unexpected, prompting us to focus on illustrating the catalyst\nstructure more clearly. Therefore, we chose to use a well-established crystal structure as the\nmodel for our calculations, allowing for a straightforward comparison between the calculated\nresults and the actual structure. To clarify this point, we have revised the first sentence in the\nDFT section to read: “Next, experimental and DFT studies were conducted using Fe4, which\nhas been crystallographically characterized, as the standard model to elucidate the catalytic\nmechanism and enantiocontrol insight (Fig. 6).”\nRemark 4: In line 249, after ‘Funk et al. demonstrated that replacing one of the three CO\nligands with a weakly coordinating nitrile ligand could significantly enhance catalyst\nperformance’, the corresponding literature should be cited.\nOur response: We appreciate the referee's suggestion. Due to an oversight on our part, this\nreference was cited as reference 55 in our original manuscript but was not annotated in the\nmain text. We have now added this citation as reference 58.\nRemark 5: The authors mention that replacing one of the three CO ligands with a weakly\ncoordinating nitrile ligand could significantly enhance catalyst performance in asymmetric\ntransfer hydrogenation. Could higher turnover numbers be achieved by employing Fe9-PhCN\nas the catalyst in the asymmetric hydrogenation?\nOur response: We appreciate the referee's constructive suggestion. By employing Fe9-PhCN\nas the catalyst, we conducted catalytic hydrogenation at S/C = 1000. However, analysis of the\nreaction revealed comparable TON values of Fe9-PhCN (810) and Fe9 (870).\nRemark 6: Relevant reviews and representative research papers on weak interactions in\nasymmetric hydrogenation should be cited.\nOur response: We appreciate the referee's friendly reminder. Due to the limitation on the\nnumber of references, we have added only two citations: references 56 and 57. Reference 56\ndescribes a very similar C–H···O interaction, while reference 57 provides an excellent review\nof weak interactions in asymmetric hydrogenation.\nRemark 7: Please check for minor issues in the article, such as the sentence in line 56 and the\nabbreviation \"TMAO.\"\nOur response: We appreciate the referee’s kind reminder. We have changed all TMAO to\nMe NO.\nGeneral comment: This contribution introduces a new chiral symmetric (C ) modification of\n2\na cyclopentadienone ligand for application in Fe(cyclopentadienone)-catalysed hydrogenation\nand transfer hydrogenation of acylsilanes. The ligand can be rather easily assembled from\ncommercially available L-proline and is obtained as a single enantiomer. A sufficiently wide\nscope is presented, with generally high enantiomeric ratios. The reason for the\nenantioselectivity has been traced to weak interactions established with the prochiral substrate,\nwith support from DFT calculations.\nOur response: We thank the referee for the positive comments.\nRemark 1: I think this paper is potentially impactful, but I would wish to have additional\ninsight. The investigation is restricted to silyl-substituted ketones, a rather poorly investigated\nclass of substrates in hydrogenation, relative to the more common diaryl-, alkyl-aryl-, and\ndialkyl ketones. In the abstract, the authors claim that a key factor is the weak interaction\nbetween the chiral catalyst and the silyl group, but this interaction involves in effect a C-H\nbond of one of the silyl methyl substituents. Thus, an analogous interaction could in principle\nbe established with simpler aryl-alkyl ketones. I would with the authors to include in their paper\nat least one example of a hydrogenation of a representative aryl-alkyl ketone with analogous\nstructure (for instance, phenyl-tert-butyl ketone, or perhaps propiophenone) from both the\nexperimental and DFT point of view. If the key weak interaction is still present, the scope of\nthe study would widen in a very interesting way. If, on the other hand, the weak interaction\ndisappears and the results are poorer, the authors can gain additional insights on the key role\nof the silyl group.\nOur response: We sincerely thank the reviewer for the valuable comment. In response, we\nhave performed additional experiments by replacing the silyl substituent with a tert-butyl group.\nThe silyl-substituted substrate exhibits a higher er than the tert-butyl–substituted one. Results\nare listed as follow:\nTheoretical calculations indicate that this phenomenon mainly arises from the larger atomic\nradius of silicon compared to carbon, which enables the silyl group to form a stronger C–H···O\nweak interaction with the catalyst (b₆ = 2.354 Å). Although the tert-butyl group can also\nparticipate in a similar interaction, the longer interaction distance (b₉ = 2.614 Å) leads to a\nweaker stabilizing effect relative to the silyl group. This comparison has been added in the\nSupplementary Information (Figure S5).\nFig. S5 | Non-covalent interaction analysis of transition state TS and TS .\nS-t-Bu R-t-Bu\nRemark 2: The authors quickly discard the possible intervention of other spin states on the\nbasis of results obtained for the saturated tricarbonyl pre-catalyst. This is not representative.\nThey should rather do the same test on the less saturated (16-electron) dicarbonyl analogues\n(Int1), or on the dihydrogen adduct of this (Int2). I believe that the system would still remain\nmore stable in the singlet state, but the gap will certainly be must smaller.\nOur response: We sincerely appreciate the reviewer’s insightful suggestion. Accordingly, we\nhave carried out theoretical calculations for all Fe-containing complexes involved in the\ncatalytic cycle, considering different spin states (see Figure S1). As correctly pointed out by\nthe reviewer, the Fe center indeed exhibits distinct spin multiplicities depending on its\nelectronic configuration. However, the calculated Gibbs free energy differences between the\nsinglet and triplet states of Int1, Int2, and Int-H are relatively small. Based on these results,\nwe have revised the proposed reaction pathway (see Figure S2). Specifically, ¹Fe4 initiates\ncal\nfrom the singlet state, followed by CO dissociation and a spin crossover via the minimum\nenergy crossing point (MECP1) to afford the more stable triplet intermediate ³Int1.\nSubsequent association with H₂ yields the triplet intermediate ³Int2, which then undergoes a\nspin inversion through MECP2 to produce the singlet intermediate ¹Int2. The reaction\nproceeds via ¹TS2 along the singlet potential energy surface to furnish the final product. We\nalso attempted to locate the triplet TS2, but unfortunately, this transition state has not yet been\nidentified. The corresponding description in the Supporting Information has been modified\naccordingly to read as: “As illustrated in Figure S2, the catalytic cycle starts from activation of\nthe pre-catalyst ¹Fe4 initiates with Me₃NO-assisted CO ligand dissociation, accompanied by\ncal\nthe release of CO₂ and Me₃N. This process yields intermediate ¹Int1 with a favorable free\nenergy of -51.3 kcal·mol⁻¹. The corresponding transition state ¹TS1 presents an activation\nbarrier of 12.2 kcal·mol⁻¹, indicating both kinetic accessibility and thermodynamic favorability.\nSubsequently, ¹Int1 undergoes a spin crossover via the minimum energy crossing point\n(MECP1), affording the more stable triplet intermediate ³Int1. Association of H₂ to ³Int1\ngenerates intermediate ³Int2, which similarly undergoes a spin crossover through MECP2,\nleading to the singlet intermediate ¹Int2. The latter proceeds via ¹TS2, involving H–H bond\ncleavage (ΔG‡ = 27.0 kcal·mol⁻¹), representing the rate-determining step. Int-H then reacts\nwith 1a to form 1Int3, followed by a concerted hydrogen transfer through 1TS (ΔG‡ = 13.7\nS\nkcal·mol⁻¹) to afford the desired product 2a. This final step is thermodynamically favorable,\nand ¹Int1 undergoes spin crossover via MECP3 to regenerate ³Int1, thereby completing the\ncatalytic cycle.”\nFig. S1 | The relative free energies of Fe complexes in different spin states.\nFig. S2 | DFT calculated free energies of the whole catalytic cycles.\nRemark 3: Line 95: who are catalysts A-D?\nOur response: We apologize for the confusion caused by our oversight. Catalysts A-D refer\nto the chiral Fe-cyclopentadienone complexes described in references 44 and 48-51. We\ninitially included these structures in Figure 1 but ultimately decided to remove them for clarity.\nTherefore, we have revised the sentence to read: “This conclusion is supported by the crystal\nstructures of the catalysts described in earlier reports (44, 48-51).”\nRemark 4: Line 109: there should more details (or a literature reference) on the Bestmann-\nOhira reagent.\nOur response: We appreciate the referee's kind reminder. We have now provided the full name\nof the Bestmann-Ohira reagent, \"dimethyl (1-diazo-2-oxopropyl)phosphonate,\" in both the text\nand the caption of Figure 2.\nRemark 5: Line 113: the authors should add the global yield of the catalysts Fe1-10 from L-\nproline.\nOur response: We appreciate this valuable suggestion, as providing global yields can offer\nreaders a clear perspective on the synthesis. Since all complexes share the common synthon\nP3, which is a known compound, we have detailed the yield of P3 from L-Proline as 63.5% in\nthe Supplementary Information. Additionally, the global yields of the Fe-complexes are\nindicated in the manuscript, stating: \"Starting from the common synthon P3, the final\ncomplexes Fe1-12 achieved a global yield ranging from 12% to 46% (see Supplementary\nInformation).\"\nReviewer #3\nGeneral comment: The development of the efficient chiral Fe-cyclopentadienone catalyst for\nasymmetric catalysis represents a challenging task. In the manuscript, the authors developed a\nseries of novel chiral Fe-cyclopentadienone catalysts through a rational design by\nsimultaneously positioning steric side arms downward to the cyclopentadienone plane and\ncreating two distinct steric environments in front of the catalytically active iron center. The\nresulting catalysts displayed excellent performance in the asymmetric hydrogenation or\ntransfer hydrogenation of acylsilanes, achieving up to a 96:4 e.r. and a turnover number (TON)\nof 870. A detailed mechanistic understanding and enantiocontrol insight of the reaction were\nachieved through experimental and DFT studies. This study represents an efficient strategy for\nthe construction of chiral Fe-cyclopentadienone catalyst and should be helpful to guide the new\nligand design. The manuscript and the Supplementary Information are well presented.\nOur response: We thank the referee for the positive comments.\nRemarks: The manuscript is therefore recommended for the publication in Nat. Commun. after\nthe following points are addressed.\nRemark 1: As a key point in the design of new Fe-CPD catalysts, the introduction of the ArSO\n2\ngroup should be crucial to the success of the present strategy as showed in Figure 1c. However,\nno data supported this assumption in the manuscript. Some comparative experiments should be\nprovided to further elucidate the necessity of ArSO group in the ligand, including the use of\n2\nparent chiral Fe-CPD catalyst without a ArSO group and the use of chiral Fe-CPD catalyst\n2\nwith acyl group such as Boc or acetyl instead of a ArSO group for the hydrogenation.\nsuggestion, we synthesized the Boc-substituted and bare H-substituted complexes, Fe13 and\nFe14. The results indicate that the Boc-substituted catalyst Fe13 is slightly inferior in enantio-\ninduction compared to the -SO Ar substituted catalyst, but it exhibits comparable catalytic\n2\nreactivity. However, Fe14 demonstrates significantly lower catalytic reactivity and\nenantiocontrol ability. We have included the synthesis of Fe13 and Fe14 in the Supplementary\nInformation, and the catalytic results are presented in Table S1.\nRemark 2: The authors screened the substituent at the phenyl ring of ArSO group to establish\n2\nthe optimal catalyst in Figure 2. However, the result in Figure 2 did not display a clear\nrelationship between the substituent at the phenyl ring and the catalytic performance. It seems\nthat the substituent at the phenyl ring is not so critical to catalytic performance. Strangely, the\nauthors did not investigate the Fe-CPD catalyst with the simplest PhSO2 group as a comparison.\nThus, more extensive evaluation on representative sulfonyl groups such as PhSO2, tBuPhSO2,\nMeSO2 and tBuSO2 should be performed to clarify the importance of the substituent on the\nsulfonyl group.\nOur response: Thank you for your constructive suggestions, which may help us gain a better\nunderstanding of the catalytic model. We synthesized two representative catalysts, Fe1 and\nFe2, with EtSO - and PhSO - substituents. When applied to the catalytic reaction, these two\n2 2\ncatalysts demonstrated comparable catalytic reactivity and enantiocontrol ability to other\nRSO - substituents. These comparisons suggest that a substituent (e.g., RSO -, Boc-) on the\n2 2\nnitrogen enhances both reactivity and enantioselectivity, with RSO - performing slightly better\n2\nthan the Boc substituent. However, the R group in RSO - shows only a slight difference in\n2\nenantioselectivity, which is not very significant. To reflect this information in the manuscript,\nwe have added Fe1 and Fe2 to Figure 2. And we also added a sentence in the manuscript:\n“Moreover, the different types of R substituents on the sulfonyl group does not significantly\ninfluence either catalytic reactivity or enantioselectivity.”\nRemark 3: keep “Me3NO” and “TMAO” in Fig. 3 and 4 consistent with those in the footnote\nin Fig. 3 and 4.\nOur response: We appreciate the referee’s kind reminder. We have changed all TMAO to\nMe NO.\n3"}, {"round": 2, "reviewer_comments": {"reviewer_1": "Having addressed all the issues raised during the review process, the manuscript in its current form satisfies the requirements for publication in this journal.", "reviewer_2": "The revision is satisfactory in terms of the additional work carried out to address my criticism, but I think that this additional work is not sufficiently well highlighted in the revised manuscript.\n1. I appreciate that the authors have carried out my suggested additional experiment with phenyl-tert-butyl ketone and related calculations. The results are very interesting and would highly deserve to be featured, or at least mentioned, in the main text, whereas currently that have only been added to the SI.\n2. In my opinion, the description of the catalytic mechanism (Figure S2 and the associated text) deserves to be featured in the main text, rather than relegated to the Supporting Information. At least the nature and spin state of the catalyst resting state (3Int2) should be highlighted in the main text.\n3. The revised description of the DFT gives the impression that the MECPs were located and optimized. However, the SI does not report the geometries and energies of these critical points. If they have not been located, they should not be explicitly shown in Figure S2. I would recommend, however, to also include the optimized MECPs, particularly MECP2, because this is placed between the rate-determining intermediate (3Int2) and the rate-determining transition state (1TS2). Thus, the energy span of the cycle may actually be greater than 27 kcal/mol, if the MECP2 is located at higher energy than TS2.\n4. There is no need for MECP3, because it is the same as MECP1.\n5. All species in Figure S2 should be redrawn to scale.", "reviewer_3": "The authors have well addressed the reviewers' concerns, this reviewer therefore recommend the manuscript for the publication as it is."}, "author_response": "Response to the reviewers’ comments (the 2nd round)\nReviewer #1\nGeneral comments: Having addressed all the issues raised during the review process, the\nmanuscript in its current form satisfies the requirements for publication in this journal.\nOur response: We appreciate the referee's efforts in reviewing our paper and are grateful for\nthe acceptance of our manuscript.\nReviewer #2\nGeneral comment: The revision is satisfactory in terms of the additional work carried out to\naddress my criticism, but I think that this additional work is not sufficiently well highlighted\nin the revised manuscript.\nOur response: We thank the referee’s suggestion and the following actions have been adopted.\nRemark 1: I appreciate that the authors have carried out my suggested additional experiment\nwith phenyl-tert-butyl ketone and related calculations. The results are very interesting and\nwould highly deserve to be featured, or at least mentioned, in the main text, whereas currently\nthat have only been added to the SI.\nOur response: This result has now been incorporated into the main text, following the non-\ncovalent interaction (NCI) analysis, as follows: \"Interestingly, this weak interaction is not\nobserved when the -TMS group in 1a is replaced with a -tBu group, which aligns well with\nexperimental observations (up to 75:25 er for tert-butyl phenyl ketone; see Supplementary\nInformation). This difference may be attributed to the smaller atomic diameter of carbon\ncompared to silicon (Supplementary Fig. 5).\"\nRemark 2: In my opinion, the description of the catalytic mechanism (Figure S2 and the\nassociated text) deserves to be featured in the main text, rather than relegated to the Supporting\nInformation. At least the nature and spin state of the catalyst resting state (3Int2) should be\nhighlighted in the main text.\nOur response: Thank you for your suggestion. We have now incorporated the calculated\nreaction pathway into Figure 6c, as well as the spin states are indicated and discussed in the\nmain text.\nRemark 3: The revised description of the DFT gives the impression that the MECPs were\nlocated and optimized. However, the SI does not report the geometries and energies of these\ncritical points. If they have not been located, they should not be explicitly shown in Figure S2.\nI would recommend, however, to also include the optimized MECPs, particularly MECP2,\nbecause this is placed between the rate-determining intermediate (3Int2) and the rate-\ndetermining transition state (1TS2). Thus, the energy span of the cycle may actually be greater\nthan 27 kcal/mol, if the MECP2 is located at higher energy than TS2.\nOur response: Thank you for your reminder, we have now added the coordinates of MECP2\nin the Supplementary Information. In the meanwhile, the energy level of MECP2 has been\nindicated as -39.4 kcal mol-1 in the corrected Figure S2 and Figure 6c.\nRemark 4: There is no need for MECP3, because it is the same as MECP1.\nOur response: We have deleted both MECP1 and MECP3 in the corrected Figure S2.\nRemark 5: All species in Figure S2 should be redrawn to scale.\nOur response: Thank you for your kind reminder. Figure S2 has been redrawn to scale.\nReviewer #3\nGeneral comment: The authors have well addressed the reviewers' concerns, this reviewer\ntherefore recommend the manuscript for the publication as it is.\nOur response: We appreciate the referee's efforts in reviewing our paper and are grateful for\nthe acceptance of our manuscript."}]

Decision letter