Stereodivergent synthesis of chiral amines bearing vicinal stereocenters via hydroamination of trisubstituted alkenes

Domain: chemistry
Published: 2026-03-04
Editorial outcome: minor_revision

Abstract
Chiral aliphatic amines bearing vicinal stereocenters are prevalent motifs in pharmaceuticals
and bioactive molecules, yet efficient and stereodivergent access to these structures remains a
longstanding challenge. Herein, we report a nickel-catalyzed enantioselective hydroamination of acyclic
trisubstituted alkenes that provides a unified platform for the stereodivergent construction of chiral amines
bearing β,γ-stereocenters. The reaction exhibits broad substrate scope, accommodating diverse amine
electrophiles and tri-substituted alkenes, including those derived from complex bioactive molecules, with
high levels of regio-, diastereo-, and enantioselectivity. By modulating the alkene geometry and the
configuration of a chiral biimidazoline ligand, all four stereoisomers can be accessed in a predictable
manner. The protocol proceeds under mild conditions, tolerates various functional groups, and enables
late-stage derivatization, demonstrating its utility for constructing densely functionalized, three-
dimensional amine scaffolds. This work provides a valuable platform for asymmetric synthesis and holds
strong potential for drug discovery and molecular design.

Introduction
Chiral aliphatic amines are recognized as one of the most significant classes of organic compounds
and serve as privileged scaffolds in pharmaceutical design1-4. Considerable efforts have been dedicated
to the preparation of enantioenriched aliphatic amines featuring a single C(sp3) stereocenter at various
positions (α, β, γ and beyond)5-14. Nevertheless, research has shown that incorporating a higher
proportion of sp³-hybridized carbons and more stereocenters into drug candidates can significantly boost
their clinical success15-16. Consequently, synthesizing valuable aliphatic amines with multiple stereogenic
centers, which are frequently found in various pharmaceuticals and biologically active natural products
(Fig. 1A), is highly desirable. Meanwhile, stereodivergent synthesis is increasingly recognized as
essential for advancing asymmetric synthesis and facilitating the discovery of pharmaceuticals and
agrochemicals17-18. This significance arises from the fact that different enantiomers exhibit distinct
physiological properties, which can markedly influence biological function and toxicity19-20. Therefore,
developing a modular and efficient platform for the stereodivergent synthesis of chiral amines bearing two
stereocenters would enhance drug discovery efforts and advance the field of organic synthesis, though it
remains exceptionally challenging and elusive.

Enantioselective hydrofunctionalization of alkenes has emerged as a state-of-the-art methodology in
asymmetic synthesis and greatly enlarged the library of three-dimensional chiral molecular
architechtures21-24. We envisioned that the stereoselective hydroamination25-28 of acyclic trisubstituted
alkenes would serve as an ideal and versatile approach for the stereodivergent synthesis of chiral amines
bearing vicinal stereocenters (Fig. 1B)29-45. Given that olefin migratory insertion occurs in a syn fashion,
this strategy can enable the access to all four stereoisomers by adjusting the geometry of the alkene and
the configuration of the chiral ligand, representing a distinct chiral induction model from stereodivergent
dual catalysis46-56. However, realizing this blueprint entails several formidable challenges. First, steric
congestion in trisubstituted olefins diminishes their binding affinity toward transition metal catalysts,
thereby reducing the efficiency of migratory insertion. Moreover, regioselectivity control is often difficult
due to the absence of stabilizing adjacent polar groups, which can lead to undesired migratory
hydrofunctionalization products57-61. Finally, achieving precise control over both the absolute
configurations of each stereocenter and their relative stereo-chemistry remains particularly challenging.

In light of these challenges, we envisioned that combining a strategically positioned monodentate
directing group with a judiciously selected chiral ligand within a single nickel catalytic system could offer a
viable solution62-65. In this study, we develop a practical and broadly applicable nickel-catalyzed protocol
for the enantioselective hydroamination of acyclic trisubstituted alkenes, enabling stereodivergent access
to enantioenriched three-dimensional amines bearing vicinal β,γ-stereocenters (Fig. 1C). To our
knowledge, examples of constructing contiguous stereocenters from acyclic trisubstituted alkenes via
NiH-catalyzed asymmetric hydrofunctionalization are limited, and this study establishes a general strategy
to address this challenge. Notably, by modulating both the geometry of the alkene (E or Z) and the
absolute configuration of the chiral biimidazoline ligand (R or S), all four stereoisomers can be selectively
accessed in a predictable manner. This approach not only addresses the longstanding challenges of
regio-, diastereo-, and enantioselective control in highly congested trisubstituted alkenes66-71, but also
provides a versatile strategy for the programmable construction of complex chiral amines, which would
accelerate the development of densely functionalized amine scaffolds for applications in medicinal
chemistry.

Results
Evaluation of reaction conditions. Our investigation toward this nickel-catalyzed enantioselective
hydroamination reaction commenced by selecting (E)-γ-methyl-γ-phenylethyl-substituted N-benzoyl allyl
amide (1a), and morpholino benzoate (2a) as model components to evaluate and optimize the reaction
parameters (Table 1). A series of chiral ligands were initially screened using NiBr2•DME as the nickel
source, LiOH as the base, and tBuOH as the solvent at 30 °C for 12 h. Common classes of privileged
chiral ligands, including, bioxazoline (L1-L3), pyridine-oxazoline (L4), quinoline-imidazoline (L5),
bis(oxazoline) (L6), phosphine-oxazoline (L7), diamine (L8), and various diphosphine ligands, all proved
ineffective in promoting the desired asymmetric transformation. To our delight, biimidazoline ligands (L9-
L11) exhibited promising performance, delivering high yield, excellent diastereoselectivity, and
outstanding enantioselectivity. In particular, L12 enabled the formation of hydroamination product 3a as a
single diastereomer in 90% isolated yield, with >99% ee and >20:1 dr (entry 1). Alternative nickel sources
such as Ni(OTf)₂ or NiBr₂ led to significantly diminished yields (entries 2-3). Among the silanes evaluated,
Me(EtO)2SiH was identified as the optimal hydrogen source (entries 4-5). Further screening of bases
revealed that LiOH provided the best yield and enantioselectivity (entries 6-8). The addition of KI was
found to enhance both yield and ee, probably by promoting the regeneration of the Ni–H species (entries
9-10)72. Notably, the choice of solvent proved critical, as tBuOH was essential for achieving high reactivity
and enantioselectivity (entries 11-12). When the reaction temperature was lowered to 10 °C, a reduced
yield was obtained while maintaining comparable enantioselectivity (entry 13), likely due to partial
solidification of the solvent at this temperature.

Substrate Scope. With the optimized conditions in hand, we next explored the scope of amine
electrophiles in the asymmetric hydroamination of trisubstituted alkenes (Fig. 2). In general, both cyclic
and acyclic O-benzoylhydroxylamine (N–O) reagents proved to be competent substrates, affording chiral
1,2-diamine products with excellent levels of enantio- and diastereoselectivity. Various tetrahydropyridine
and piperazine derivatives bearing functional groups such as esters, acetals, carbamates, and sulfones
were well tolerated (3b-3h). Notably, the synthesis of 3i with a pyrimidine motif underscores the method’s
tolerance of additional nitrogen donors without sacrificing reactivity or selectivity. Our protocol was further
expanded to acyclic secondary amine electrophiles (3j-3y). The steric bulk of the alkyl substituents on the
amine moiety had little effect on either reactivity or enantioselectivity (3j-3m). Moreover, alkyl chlorides
remained intact under the reaction conditions (3p and 3q), offering opportunities for downstream
diversification via cross-coupling73-74. A variety of dibenzyl-substituted hydroxylamine electrophiles bearing
versatile functional groups such as fluoride, chloride, thioether, trifluoromethoxy, and boronic ester were
well tolerated (3u-3y), delivering products with high reactivity and enantioselectivity. This result highlights
the potential of the method for drug-oriented synthesis and late-stage derivatization.

Subsequently, we evaluated the substrate scope of trisubstituted alkenes (Fig. 3). We first examined
various amide groups on γ,γ-disubstituted allyl amides and found that both electron-rich and electron-
deficient aromatic as well as aliphatic amides were well tolerated under the standard conditions, affording
products bearing vicinal stereocenters with high efficiency (4a-4i). Functionalized aryl and heteroaryl
groups, including cyano-, nitro-substituted phenyl and thiophene, were also compatible. The absolute
configuration was determined by X-ray crystallography of 4b (CCDC: 2403087) as (R, R). The nature of
the R2 substituent on the trisubstituted alkene had negligible impact on reaction efficiency or selectivity.
Substrates bearing benzyl groups (4j–4n), short-chain alkyls such as propyl (4o), and long-chain alkyls
(4p–4r) all underwent smooth hydroamination with excellent regio-, enantio-, and diastereoselectivity.
Alkenes derived from natural products such as phytol (4r) and citronellol (4s) also furnished the desired
products with high selectivity. Notably, alkyl chains containing silyl ethers (4j and 4u) or acetate (4v) groups
were also compatible, enabling further downstream derivatization. Furthermore, switching the R1
substituent from methyl to ethyl or isopropyl required ligand adjustment and still delivered the desired
product (4w, 4x) with high enantioselectivity, highlighting the catalyst’s ability to differentiate between
similar alkyl groups. In addition, exocyclic alkenes also participated in the hydroamination to deliver the
desired product (4y and 4z) in good yield with high enantioselectivity, while the unsymmetric counterpart
(4aa) reacted with diminished yield but retained high e.e. The N-methylated allylamide failed to react,
which may indicate that the N–H moiety contributes to facilitating olefin insertion, potentially through
noncovalent interactions as previously suggested71.

To assess the potential of this hydroamination strategy for stereodivergent synthesis, we examined
whether all four stereoisomers could be selectively accessed by systematically varying the olefin
geometry and ligand configuration (Fig. 4). Remarkably, the transformation of 3v proceeded smoothly
under each set of conditions, delivering all four stereoisomers in high yields with high levels of enantio-
and diastereocontrol. These results demonstrate that our protocol enables precise and programmable
access to any desired stereoisomer within a single catalytic platform. Such flexibility is particularly
valuable for applications in medicinal chemistry, where stereochemical diversity can play a crucial role in
modulating biological activity.

To further illustrate potential synthetic utility of our protocol in medicinal chemistry, the late-stage
derivatization of natural products and drug-like molecules was conducted (Fig. 5A). The alkenes derived
from Febuxostat and Isoxepac with 2a effectively underwent asymmetric hydroamination to afford
products (5a and 5b) in high yields with excellent ee and diastereoselectivity. Moreover, amino
electrophiles derivatized from Atomoxetine, Duloxetine, Maprotiline, and Nortriptyline, reacted smoothly to
deliver corresponding products (5c-5f) with moderate to good yields. We further demonstrated the
practicability and synthetic value of this enantioselective protocol through a gram-scale reaction and
product derivatizations (Fig. 5B). Delightfully, the catalytic system was successfully scaled up to a 5.0
mmol scale, leading to the formation of 3a in 78% yield with excellent enantio- and diastereoselectivity.
The amide group could be deprotected by NaOH at 120 °C, delivering the corresponding free primary
amine (6a) without loss of enantioselectivity. Reduction of the amide group with lithium aluminum hydride
provided the secondary amine (6b) with 98% e.e. Moreover, benzoyl amide could be smoothly converted
to N-Boc-amide (6c) and thioamide (6d), respectively. N-(2-ethylamino)amide scaffolds are structural
motifs frequently found in biologically active molecules, including the marketed drugs Moclobemide and
Procainamide (Fig. 5C). To further highlight the relevance and synthetic potential of our protocol, we
prepared two stereochemically enriched analogs of these drugs (7a and 7b), both containing two
additional stereocenters.

Mechanistic studies. To gain insight into the mechanism of this asymmetric hydroamination, we
conducted a series of preliminary mechanistic studies (Fig. 6). When terminal alkene 8a and 1,2-
disubstituted alkene 8b were subjected to the standard conditions (Fig. 6A), the corresponding β-selective
products 9a and 9b were obtained with slightly diminished enantio- and regioselectivity. These results
suggest that the γ-substituent plays a favorable steric role in controlling both regio- and enantioselectivity.
Deuterium-labeling experiments using a deuterated silane with terminal or trisubstituted alkenes revealed
exclusive deuterium incorporation at the γ-position (Fig. 6B), indicating that the hydride originates from
the silane and that the hydrometallation step is stereospecific and irreversible. Moreover, the use of
deuterium-labeled alkene 1a-d2 gave the product 3a-d2 without any H/D scrambling, supporting that the
alkyl–Ni intermediate couples directly with the N–O electrophiles without undergoing a isomerization
process. The addition of butylated hydroxytoluene (BHT) as a radical scavenger had minimal impact on
the reaction efficiency or selectivity, suggesting that a radical mechanism is unlikely to be operative (Fig.
6C). To gain some information on the active nickel catalyst, a positive linear correlation was observed
between the ee values of the chiral ligand and the corresponding hydroamination product (Fig. 6D),
implying that the catalytically active nickel species likely bears a single biimidazoline ligand. Furthermore,
a well-defined Ni(II) complex (L12•NiBr2) was synthesized and characterized by X-ray crystallography
(Fig. 6E), which confirmed the coordination geometry. Notably, this complex served as a competent
catalyst, delivering 3a in comparable yield and enantioselectivity. Finally, HRMS (ESI) analysis of the
reaction mixture revealed the presence of Ni(II)–H and Ni(I)–X species ligated with the chiral ligand (Fig.
6F), offering direct evidence for their existence and providing valuable mechanistic insight into the NiH
catalytic cycle. These findings represent a meaningful contribution to the broader understanding of nickel
hydride catalysis.

Based on the above experimental results and related literature precedents32,75, a plausible catalytic
cycle is proposed in Fig. 6G. The Ni(II) precatalyst (A), in the presence of a hydrosilane, a chiral ligand,
and a base, could be converted into a mixture of Ni(II)–H species (B) and a Ni(I)–X species (C)76-77. The
Ni(II)–H species undergoes migratory insertion with the trisubstituted alkene under the assistance of the
amide group, to form a Ni(II)–alkyl intermediate (D). This intermediate then undergoes transmetalation
with the Ni(I)–X species75,78, generating a Ni(I)–alkyl intermediate (E). Electrophilic interception of E by
the N–O electrophile, followed by reductive elimination, furnishes the hydroamination product 3 along with
regeneration of the Ni(I)–X species (X = OBz). The Ni(II)–H catalyst is then regenerated via the reaction
of the resulting Ni(II)–X species with silane, thus completing the catalytic cycle. Moreover, we cannot
rule out the possibility of transmetalation between Ni(II)–H and Ni(I)–H species. Although Ni(I)–H
intermediates were not detected by high-resolution mass spectrometry (HRMS), presumably due to their
inherent instability, they could plausibly arise from the reaction of Ni(I)–X with hydrosilane79-80.

In summary, we have developed a nickel-catalyzed enantioselective hydroamination of acyclic
trisubstituted alkenes that enables the stereodivergent synthesis of chiral aliphatic amines bearing vicinal
stereocenters. This strategy exhibits high levels of regio-, diastereo-, and enantioselectivity across a
broad array of amine electrophiles and alkene substrates, including those derived from complex bioactive
molecules. By tuning the alkene geometry and the configuration of the chiral ligand, all four stereoisomers
can be selectively accessed within a single catalytic platform. Mechanistic studies revealed the presence
of Ni(II) and Ni(I) species, and suggest that a transmetalation step between them plays a pivotal role in
the catalytic cycle. We anticipate that the developed protocol will greatly enrich the toolbox of asymmetric
catalysis for the synthesis of dual stereocenters, and accelerate the discovery and optimization of drug
candidates and complex functional molecules.

Methods
Procedure for the enantioselective hydroamination of trisubstituted alkenes.
In an argon-filled glovebox, NiBr2•DME (6.2 mg, 0.02 mmol, 10.0 mol%), Ligand (15.4 mg, 0.03 mmol, 15
mol%), relevant alkene substrate (0.2 mmol, 1.0 equiv), LiOH (9.6 mg, 0.4 mmol, 2.0 equiv), KI (33.2 mg
0.2 mmol, 1.0 equiv), tBuOH (1.0 mL) were added to a 4 mL reaction flask. Then relevant hydroxylamine
ester (0.3 mmol, 1.5 equiv), Me(EtO)2SiH (80 μL, 0.5 mmol, 2.5 equiv) were added to the mixture. The
reaction mixture was stirred at 30 oC for 12 h . After the reaction time, remove solvent under vacuum.
Remaining liquid was allowed to silica gel column chromatography. The crude product was purified by
column chromatography on silica gel with a mixture of ethyl acetate and petroleum ether as eluent. More
experimental details and characterization are available in Supplementary Information.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "In this manuscript, Wang and co-workers report a nickel-catalyzed enantioselective hydroamination of trisubstituted alkenes,\nenabling the construction of chiral amines bearing β,γ-stereocenters. The reaction displays a broad substrate scope across\nvarious amine electrophiles and trisubstituted alkenes, delivering products with high levels of regio-, diastereo-, and\nenantioselectivity. The synthetic value of this methodology is further highlighted by stereodivergent access to all four\npossible stereoisomers, achieved through modulation of alkene geometry and the chirality of the biimidazoline ligand. The\ntransformation proceeds under mild conditions, exhibits good functional group tolerance, and is applicable to late-stage\nfunctionalization.\nOverall, this work represents a synthetically valuable advance, particularly in light of the longstanding challenges associated\nwith the enantioselective construction of amine scaffolds bearing vicinal stereocenters. Accordingly, this reviewer\nrecommends publication in Nature Communications, provided that the following minor concerns are adequately addressed.\n- The Flack parameter of compound 4b is reported as −1.0 (Supplementary Information, Supplementary Figure 6, S91).\nWhile this reviewer is not an expert in X-ray crystallography, it is recognized that such a value may indicate that the assigned\nabsolute configuration should be inverted relative to that shown. The authors are encouraged to re-examine this issue. X-ray\ncrystallographic analysis of substrates bearing pre-existing chirality (e.g., compound 4r) might provide more reliable\nconfirmation of the absolute configuration.\n- Only β,γ-unsaturated substrates have been explored. Is it possible to extend the carbon chain between the amide and\nalkene functionalities, and if so, how does this affect reactivity and selectivity?\n- Is the amide functionality essential for controlling regio- and enantioselectivity? While directing groups are often crucial for\nregio-control, selectivity in the present system may instead be governed largely by steric effects, with nickel preferentially\ninserting into the monosubstituted alkene site. Although secondary amides were shown to be ineffective, investigation of\nother functional groups would be informative.\n- A notable limitation from a synthetic perspective is that a methyl group appears to be the only effective substituent on the\ndisubstituted carbon. If a small substituent is required for effective enantiodiscrimination, could other small substituents—\nsuch as heteroatoms (e.g., fluorine)—be tolerated?\n- The data provided in the Supplementary Information are generally of good quality; however, several 13C NMR spectra\nexhibit very weak signals, making it difficult to confidently assess the purity of the isolated compounds. Higher-quality NMR\nspectra should be provided.", "reviewer_2": "Wang and co-authors report an enantioselective nickel catalyzed hydroamination of acyclic trisubstituted alkenes to\ngenerate chiral amines bearing β,γ-stereocenters. The reaction demonstrates excellent regioselectivity, enantioselectivity,\ndiastereoselectivity and potential synthetic utility, delivering a diverse array of products in moderate to good yields. A series\nof mechanistic studies are conducted including the control experiments, deuterium-labeling experiments, radical trapping\nexperiment and NLE study, et. al, and the authors propose that the hydroamination reaction proceeds through synergistic\nNi(I)/Ni(II) cycles with a key transmetalation step between them. Overall, the paper is well written and portrayed nicely.\nHowever, with respect to the question of novelty and impact, there is a strong past precedent of asymmetric hydroamination\nof alkenes via Cu-H or Ni-H\ncatalysis as shown below:\nhttps://pubs.acs.org/doi/10.1021/ja4092819; https://pubs.acs.org/doi/10.1021/ja509786v;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.201410326;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.201803026;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.202109881;\nhttps://pubs.acs.org/doi/10.1021/acscatal.2c02892;\nhttps://pubs.acs.org/doi/full/10.1021/acscatal.3c01845;\nhttps://pubs.rsc.org/en/Content/ArticleLanding/2025/QO/D4QO02275K;\nhttps://pubs.acs.org/doi/pdf/10.1021/jacs.4c03854?ref=article_openPDF;\nhttps://pubs.acs.org/doi/full/10.1021/acs.orglett.3c02442.\nThere is also an analogous enantioselective example of this reaction via Ni-H catalysis (Ref. 26 cited in the manuscript)\nwhich is almost certainly mechanistically related.\nAs it stands, this manuscript is not suitable for publication in the Nature Communication.", "reviewer_3": "The manuscript entitled “Stereodivergent Synthesis of Chiral Amines bearing Vicinal Stereocenters via Hydroamination of\nTrisubstituted Alkenes” is authors' continuing research on NiH-catalyzed net hydrofunctionalization of alkenes with N-O\nelectrophiles. They systematically investigated the reaction parameters, including catalyst, ligand, base, and solvent, to\nidentify the effective system for the promotion of titled reaction. The observed yield, regioselectivity, diasteroselectivity, and\nenantioselectivity all are extremely high, thus delivering the enantioenriched chiral aliphatic amines with multiple\nstereocenters. In particular, the catalyst- and substrate geometory-controlled stereodivergent approach to all possible\nstereoisomers deserves significant attention.\nHowever, this reviewer has a critical concern on its novelty. In the literature, there are many successful examples of NiH-\ncatalyzed hydrofunctionalizations of alkenes with the assistance of native directing groups such as amine, amide, and\nalcohol. Of course, this reviewer agrees with the authors' claim that the\ntrisubstituted alkene still remains a challenging substrate, but the present optimal catalyst is the almost same as the authors'\nprevious work (ACS Catal. 2023, 13, 10041). The authors sate that the presently developed biimidazoline ligand\nshows uniquely high performance, but this is not new (e.g., JACS 2021, 143, 15873) and seems to be just minor modification of previous bioxazoline system. Such routine work\ncannot meet the criteria of novelty and urgency for publication in Nat. Commun.\nOn the basis of the above considerations, this reviewer recommends transfer to more specialized synthetic journals such as\nACIE and ChemistryEurope after the following revision.\n1) Seminal work and recent comprehensive review-type articles on metal-hydride-mediated net hydroamination of alkenes\nshould be mentioned and cited: ACIE 2013, 52, 10830; JACS 2013, 135, 15746; ACIE 2016, 55, 48; JACS 2022, 144, 648.\n2) Many biologically active amines contain the cyclic skeleton rather than the acyclic one. Thus, the authors should also try\nthe cyclic alkene substrate.\n3) The stereodivergent synthesis of all four possible stereoisomers within a single catalyst system deserves significant\nattention, but the precedent based on CuH should also be fairly mentioned and cited: Nature 2016, 532, 353.\n4) In Table 1, the authors observed significant impacts of base and solvent on the reaction efficiency, but their effects are not\ndiscussed at all in the part of mechanistic studies.\n5) In Table 3, various monodentate amide groups are compatible. This reviewer wonders if the bidentate amide such as\npicoline amide is also be tolerated.\n6) In the synthesis of 4r (Table 3), this reviewer wonders if the match-mismatch phenomenon is observed with ent-L12.\n7) Page 5, line 104; \"tertiary amines\" rather than \" secondary amines \"?\n8) In Figure 4G and related discussion parts, the authors use \"transmetalation\", but is it correct? \"electron transfer\" is better?\n9) minor errors:\npage 8, line 156; \"L\" of Lithium aluminum hydride should be lowercase.\npage 8, line 162; insert a space between additional and stereocenters.", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "First of all, we acknowledge the four reviewers for their valuable comments they\nmade to the title manuscript. The point-by-point responses to the reviewer’s\ncomments are listed in italic text in blue.\nReviewer 1\nIn this manuscript, Wang and co-workers report a nickel-catalyzed\nenantioselective hydroamination of trisubstituted alkenes, enabling the\nconstruction of chiral amines bearing β,γ-stereocenters. The reaction displays a\nbroad substrate scope across various amine electrophiles and trisubstituted\nalkenes, delivering products with high levels of regio-, diastereo-, and\nenantioselectivity. The synthetic value of this methodology is further highlighted\nby stereodivergent access to all four possible stereoisomers, achieved through\nmodulation of alkene geometry and the chirality of the biimidazoline ligand. The\ntransformation proceeds under mild conditions, exhibits good functional group\ntolerance, and is applicable to late-stage functionalization.\nOverall, this work represents a synthetically valuable advance, particularly in light\nof the longstanding challenges associated with the enantioselective construction\nof amine scaffolds bearing vicinal stereocenters. Accordingly, this reviewer\nrecommends publication in Nature Communications, provided that the following\nminor concerns are adequately addressed.\nResponse: We sincerely thank the reviewer for the positive and encouraging\nassessment of our work. We are delighted that the reviewer recognizes the\nsignificance of our nickel-catalyzed enantioselective hydroamination of\ntrisubstituted alkenes and its synthetic value in accessing amines bearing β,γ-\nstereocenters with high levels of stereocontrol. We are also grateful for the\nreviewer’s recommendation for publication in Nature Communications.\n1. The Flack parameter of compound 4b is reported as −1.0 (Supplementary\nInformation, Supplementary Figure 6, S91). While this reviewer is not an expert\nin X-ray crystallography, it is recognized that such a value may indicate that the\nassigned absolute configuration should be inverted relative to that shown. The\nauthors are encouraged to re-examine this issue. X-ray crystallographic analysis\nof substrates bearing pre-existing chirality (e.g., compound 4r) might provide\nmore reliable confirmation of the absolute configuration.\nResponse: We thank the reviewer for raising this important point regarding the\nFlack parameter of compound 4b. We have re-refined the crystallographic data,\nand the Flack parameter of 4b is now −0.1, which supports the originally\nassigned absolute configuration. The revised crystallographic data and updated\nparameters have been included in the Supplementary Information. Regarding the\nsuggestion to perform X-ray crystallographic analysis on substrates bearing pre-\nexisting chirality (e.g., compound 4r), we note that these compounds were\nobtained as an oil and did not yield suitable single crystals for X-ray diffraction\ndespite multiple attempts. Importantly, under the present reaction conditions, the\nstereocenter located on the substituent is not involved in bond formation or\ncleavage and is therefore generally expected to remain unchanged.\nSupplementary Table 6. Crystal data and structure refinement for 4b.\nIdentification code a250225a\nEmpirical formula C H N O\n29 34 2 2\nFormula weight 442.58\nTemperature/K 293(2)\nCrystal system monoclinic\nSpace group P2 (4)\n1\na/Å 8.7469(5)\nb/Å 5.5489(3)\nc/Å 25.1685(14)\nα/° 90\nβ/° 93.461(5)\nγ/° 90\nVolume/Å3 1219.35(11)\nZ 2\nρcalcg/cm3 1.205\nμ/mm 1 0.588\nF(000) 476\n‑\nCrystal size/mm3 0.12×0.13×0.25\nRadiation Cu K (λ=1.54184 Å)\nα\n2Θ range for data collection/ 7.04 to 134.14 (0.84 Å)\nIndex ranges −10 ≤ h ≤ 10, −6 ≤ k ≤ 6, −30 ≤ l ≤ 25\nReflections collected 8194\nIndependent reflections 4240 [R = 0.0442, R = 0.0433\nint sigma\nData/restraints/parameters 4240/1/294\nGoodness-of-fit on F2 1.030\nFinal R indexes [I>=2σ (I)] R = 0.0528, wR = 0.1416\n1 2\nFinal R indexes [all data] R = 0.0692, wR = 0.1564\n1 2\nLargest diff. peak/hole / e Å-3 0.15/-0.14\nFlack parameter -0.1(3)\n2. Only β,γ-unsaturated substrates have been explored. Is it possible to extend\nthe carbon chain between the amide and alkene functionalities, and if so, how\ndoes this affect reactivity and selectivity?\nResponse: We thank the reviewer for this insightful question. We did explore\nsuch substrates; however, no desired hydroamination products were observed.\nWe attribute this lack of reactivity to the increased distance between the amide\ndirecting group and the alkene, which likely weakens the effective coordination\nand directional control required for productive Ni–H insertion and subsequent\nfunctionalization. These results suggest that a suitably positioned directing group\nis crucial for achieving both reactivity and stereocontrol in the present catalytic\nsystem. We have clarified these unreactive substrates in the revised\nSupplementary Information.\n3. Is the amide functionality essential for controlling regio- and enantioselectivity?\nWhile directing groups are often crucial for regio-control, selectivity in the present\nsystem may instead be governed largely by steric effects, with nickel\npreferentially inserting into the monosubstituted alkene site. Although secondary\namides were shown to be ineffective, investigation of other functional groups\nwould be informative.\nResponse: We thank the reviewer for this insightful question. Control\nexperiments indicate that the amide functionality is essential for achieving both\nreactivity and selectivity in the present system. When alternative functional\ngroups, including carboxylic acid derivatives and ethers, were examined in place\nof the amide, no desired hydroamination products were observed. These results\nsuggest that regio- and enantioselectivity are not governed solely by steric\neffects. Instead, the amide directing group may participate in noncovalent\ninteractions with the nickel catalyst, which assist alkene migratory insertion and\nstereocontrol, as recently demonstrated in related systems (Ref. 61). We have\nincluded these unreactive examples in the revised Supplementary Information.\n4. A notable limitation from a synthetic perspective is that a methyl group\nappears to be the only effective substituent on the disubstituted carbon. If a small\nsubstituent is required for effective enantiodiscrimination, could other small\nsubstituents—such as heteroatoms (e.g., fluorine)—be tolerated?\nResponse: We thank the reviewer for this insightful comment. We have tested\nsubstrates with ethyl and propyl substituents at the disubstituted carbon, and\ngood results were obtained, although ligand adjustment was required to maintain\nhigh enantioselectivity. The relevant results and discussion have been included\nin the revised manuscript. Specifically, as described in the manuscript: switching\nthe R¹ substituent from methyl to ethyl or isopropyl required ligand adjustment\nand still delivered the desired products (4w, 4x) with high enantioselectivity,\nhighlighting the catalyst’s ability to differentiate between closely related alkyl\ngroups.\n5. The data provided in the Supplementary Information are generally of good\nquality; however, several 13C NMR spectra exhibit very weak signals, making it\ndifficult to confidently assess the purity of the isolated compounds. Higher-quality\nNMR spectra should be provided.\nResponse: We thank the reviewer for pointing this out. In response, we have re-\nrecorded the relevant 13C NMR spectra with longer acquisition times to enhance\nsignal quality, and the updated data have been included in the revised\nSupplementary Information.\n13C NMR (101 MHz, CDCl ) spectra of 3b\n3\n13C NMR (101 MHz, CDCl ) spectra of 3j\n3\n13C NMR (101 MHz, CDCl ) spectra of 3n\n3\n13C NMR (101 MHz, CDCl ) spectra of 3u\n3\n13C NMR (101 MHz, CDCl ) spectra of 3k\nWang and co-authors report an enantioselective nickel catalyzed hydroamination\nof acyclic trisubstituted alkenes to generate chiral amines bearing β,γ-\nstereocenters. The reaction demonstrates excellent regioselectivity,\nenantioselectivity, diastereoselectivity and potential synthetic utility, delivering a\ndiverse array of products in moderate to good yields. A series of mechanistic\nstudies are conducted including the control experiments, deuterium-labeling\nexperiments, radical trapping experiment and NLE study, et. al, and the authors\npropose that the hydroamination reaction proceeds through synergistic Ni(I)/Ni(II)\ncycles with a key transmetalation step between them. Overall, the paper is well\nwritten and portrayed nicely.\nHowever, with respect to the question of novelty and impact, there is a strong\npast precedent of asymmetric hydroamination of alkenes via Cu-H or Ni-H\ncatalysis as shown below:\nhttps://pubs.acs.org/doi/10.1021/ja4092819;\nhttps://pubs.acs.org/doi/10.1021/ja509786v;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.201410326;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.201803026;\nhttps://onlinelibrary.wiley.com/doi/full/10.1002/anie.202109881;\nhttps://pubs.acs.org/doi/10.1021/acscatal.2c02892;\nhttps://pubs.acs.org/doi/full/10.1021/acscatal.3c01845;\nhttps://pubs.rsc.org/en/Content/ArticleLanding/2025/QO/D4QO02275K;\nhttps://pubs.acs.org/doi/pdf/10.1021/jacs.4c03854?ref=article_openPDF;\nhttps://pubs.acs.org/doi/full/10.1021/acs.orglett.3c02442.\nThere is also an analogous enantioselective example of this reaction via Ni-H\ncatalysis (Ref. 26 cited in the manuscript) which is almost certainly\nmechanistically related.\nAs it stands, this manuscript is not suitable for publication in the Nature\nCommunication.\nResponse: We thank the reviewer for the careful reading and for their positive\ncomments on the clarity, writing, and mechanistic studies presented in our\nmanuscript. We also appreciate the thoughtful discussion regarding prior work on\nasymmetric hydroamination. We note that the cited examples primarily focus on\nthe formation of a single stereocenter from mono- or disubstituted alkenes. In\ncontrast, as discussed in the Introduction of our manuscript, our work addresses\nthe more challenging problem of constructing vicinal β,γ-stereocenters from\nacyclic trisubstituted alkenes, enabling stereodivergent access to all four\nstereoisomers of enantioenriched three-dimensional amines. This is achieved by\ncombining a strategically positioned monodentate directing group with a carefully\nchosen chiral biimidazoline ligand, and by modulating the geometry of the alkene\n(E or Z). To our knowledge, examples of NiH-catalyzed asymmetric\nhydrofunctionalization that construct contiguous stereocenters from acyclic\ntrisubstituted alkenes are exceedingly limited. We have therefore clarified in the\nmanuscript that our study establishes a general and broadly applicable strategy\nfor addressing this long-standing synthetic challenge.\nReviewer 3\nThe manuscript entitled “Stereodivergent Synthesis of Chiral Amines bearing\nVicinal Stereocenters via Hydroamination of Trisubstituted Alkenes” is authors'\ncontinuing research on NiH-catalyzed net hydrofunctionalization of alkenes with\nN-O electrophiles. They systematically investigated the reaction parameters,\nincluding catalyst, ligand, base, and solvent, to identify the effective system for\nthe promotion of titled reaction. The observed yield, regioselectivity,\ndiasteroselectivity, and enantioselectivity all are extremely high, thus delivering\nthe enantioenriched chiral aliphatic amines with multiple stereocenters. In\nparticular, the catalyst- and substrate geometory-controlled stereodivergent\napproach to all possible stereoisomers deserves significant attention.\nHowever, this reviewer has a critical concern on its novelty. In the literature, there\nare many successful examples of NiH-catalyzed hydrofunctionalizations of\nalkenes with the assistance of native directing groups such as amine, amide, and\nalcohol. Of course, this reviewer agrees with the authors' claim that the\ntrisubstituted alkene still remains a challenging substrate, but the present optimal\ncatalyst is the almost same as the authors' previous work (ACS Catal. 2023, 13,\n10041). The authors sate that the presently developed biimidazoline ligand\nshows uniquely high performance, but this is not new (e.g., JACS 2021, 143,\n15873) and seems to be just minor modification of previous bioxazoline system.\nSuch routine work cannot meet the criteria of novelty and urgency for publication\nin Nat. Commun.\nOn the basis of the above considerations, this reviewer recommends transfer to\nmore specialized synthetic journals such as ACIE and ChemistryEurope after the\nfollowing revision.\nResponse: We thank the reviewer for the careful reading of our manuscript and\nfor the positive comments regarding the high yield, regio-, diastereo-, and\nenantioselectivity, as well as the stereodivergent control achieved in this work.\nRegarding the novelty concern, while we agree that NiH-catalyzed\nhydrofunctionalizations of alkenes with native directing groups have been\nreported, these prior examples primarily focus on monosubstituted or\ndisubstituted alkenes and typically generate a single stereocenter. In contrast,\nour study addresses the challenging class of acyclic trisubstituted alkenes and\nenables the construction of vicinal β,γ-stereocenters, which has remained largely\nunexplored. The biimidazoline ligand, though structurally related to previously\nreported systems, exhibits uniquely high performance for these highly congested\ntrisubstituted alkenes, enabling stereodivergent access to all four stereoisomers\nby modulating both the alkene geometry (E/Z) and the ligand configuration. To\nour knowledge, this combination of substrate type, contiguous stereocenter\nconstruction, and predictable stereodivergence has not been demonstrated in\nprevious NiH-catalyzed hydrofunctionalization studies.\n1. Seminal work and recent comprehensive review-type articles on metal-\nhydride-mediated net hydroamination of alkenes should be mentioned and cited:\nACIE 2013, 52, 10830; JACS 2013, 135, 15746; ACIE 2016, 55, 48; JACS 2022,\n144, 648.\nResponse: We thank the reviewer for highlighting these important review\narticles, which have now been cited in the revised manuscript as Ref. 25–28.\n2. Many biologically active amines contain the cyclic skeleton rather than the\nacyclic one. Thus, the authors should also try the cyclic alkene substrate.\nResponse: We thank the reviewer for this helpful suggestion. Cyclic alkene\nsubstrates have been examined in this study, and they underwent the\nhydroamination smoothly to afford the corresponding cyclic amine products with\ngood yields and high levels of regio- and enantioselectivity (see products 4x, 4z,\nand 4aa). These results demonstrate that the present catalytic system is also\napplicable to cyclic alkene substrates.\nO\nO O O\nO\nPh N Ph N Ph N\nH H H\nN N N\nO O O\n4y,85%, 90% ee 4z,72%, 99% ee 4aa,26%, 93% ee, dr >20:1b\n3. The stereodivergent synthesis of all four possible stereoisomers within a single\ncatalyst system deserves significant attention, but the precedent based on CuH\nshould also be fairly mentioned and cited: Nature 2016, 532, 353.\nResponse: We thank the reviewer for this important suggestion. The seminal\nCuH-catalyzed stereodivergent approach reported in Nature (2016, 532, 353)\nhas now been cited in the revised manuscript as Ref. 66.\n4. In Table 1, the authors observed significant impacts of base and solvent on the\nreaction efficiency, but their effects are not discussed at all in the part of\nmechanistic studies.\nResponse: We thank the reviewer for this insightful comment. We agree that the\nbase and solvent have a pronounced influence on the reaction efficiency, as\nreflected in Table 1. At the present stage, we attribute these effects mainly to\ntheir roles in facilitating the generation and modulating the reactivity of the Ni–H\nspecies, as well as stabilizing key organonickel intermediates along the catalytic\ncycle. In particular, the base is likely involved in the formation of reactive\nNi(I)/Ni(II)–H species under the reaction conditions. As direct experimental\nevidence is currently unavailable, we refrain from overinterpreting these\nobservations. A discussion focusing on the role of the base has been added to\nthe revised manuscript to clarify this point.\n5. In Table 3, various monodentate amide groups are compatible. This reviewer\nwonders if the bidentate amide such as picoline amide is also be tolerated.\nResponse: We thank the reviewer for this insightful question. We examined\nbidentate directing groups, including picolinamide and 8-aminoquinoline amide;\nhowever, no desired hydroamination products were observed. We anticipate that\nthe strong bidentate coordination occupies the nickel coordination sphere and\nprevents effective binding of the chiral ligand, thereby reducing the reactivity of\nthe catalyst. These results further underscore the importance of a monodentate\namide directing group in enabling both reactivity and enantioselectivity in the\npresent system. Relevant results have been included in the revised\nSupplementary Information.\n6. In the synthesis of 4r (Table 3), this reviewer wonders if the match-mismatch\nphenomenon is observed with ent-L12.\nResponse: We thank the reviewer for this thoughtful question. When the (R,R)-\nL12 was employed in the synthesis of 4r, comparable yield and\ndiastereoselectivity were obtained relative to those observed with (S,S)-L12,\nindicating that no obvious match–mismatch effect is present in this case. These\nresults suggest that the pre-existing stereocenter in the substrate does not\nstrongly interfere with the catalyst-controlled stereochemical outcome. Relevant\ndata have been included in the revised Supplementary Information.\n7. Page 5, line 104; \"tertiary amines\" rather than \" secondary amines \"?\nResponse: We thank the reviewer for pointing this out. The phrase “secondary\namines” has been revised to “secondary amine electrophiles” in the revised\nmanuscript.\n8. In Figure 4G and related discussion parts, the authors use \"transmetalation\",\nbut is it correct? \"electron transfer\" is better?\nResponse: We thank the reviewer for this insightful comment. The use of the\nterm “transmetalation” is supported by well-established precedents in nickel\ncatalysis involving Ni(I)/Ni(II) species. In many NiH ‑ mediated\nhydrofunctionalization reactions, a transmetalation-type process is commonly\ninvoked to describe the net transfer of an organic fragment between Ni(I) and\nNi(II) intermediates, even if electron transfer may also occur. For example,\nligand-controlled NiH migratory hydrofunctionalization has been described using\nthis terminology (Chem 2021, 7, 3171–3188), and mechanistic studies of\nreductively induced aryl transmetalation in nickel-catalyzed cross-coupling\nexplicitly invoke Ni(I)-to-Ni(II) transmetalation pathways (Romero‑Arenas et al.,\nJ. Am. Chem. Soc. 2025, 147, 21697–21707). These examples illustrate that\n“transmetalation” is widely used to denote the net exchange of organic groups\nbetween nickel species of different oxidation states, and does not preclude\nconcomitant electron transfer. Relevant references have now been added in the\nrevised manuscript (Refs. 75 and 80).\n9. minor errors:\npage 8, line 156; \"L\" of Lithium aluminum hydride should be lowercase.\npage 8, line 162; insert a space between additional and stereocenters.\nResponse: We thank the reviewer for pointing these out. We have corrected\nthese errors.\nReviewer 4\nI co-reviewed this manuscript with one of the reviewers who provided the listed\nreports. This is part of the Nature Communications initiative to facilitate training in\npeer review and to provide appropriate recognition for Early Career Researchers\nwho co-review manuscripts.\nResponse: We thank Reviewer 4 for their participation in evaluating our\nmanuscript."}, {"round": 2, "reviewer_comments": {"reviewer_1": "While NiH-catalyzed hydrofunctionalization of alkenes has been broadly studied,\nthe concomitant installation of two stereocenters via trisubstituted alkenes\nremains underexplored, as it necessitates a distinct catalytic approach. In this\nrevised manuscript, the authors have successfully addressed the comments from\nthe previous round of reviews, further strengthening a manuscript that presents a\nnovel route to 1,2-stereocenters from trisubstituted alkenes. As such, this\nreviewer recommends this manuscript for publication in Nature Communications,\nprovided that the following minor corrections are further made.\n- The authors should correct '(4x and 4z)' to '(4y and 4z)' on page 6, line 131.\n- The authors noted in their response letter that several unsuccessful substrates (4ac, 4ad–4aj) were added to the SI. However, this reviewer was unable to locate these examples in the revised version. The authors should verify these results and include them in the final SI.", "reviewer_3": "I have reviewed the original submission of this manuscript. First, I do appreciate the authors' efforts to address my concerns.\nHowever, also as commented by the reviewer 2, I do not think that this work meets the criteria of novelty and urgency for\npublication in Nat. Commun. because there are many precedents of NiH- and related CuH-catalyzed stereoselective net\nhydroamination of alkenes.\nSubmission to more synthetic journals is recommended."}, "author_response": "First of all, we acknowledge the two reviewers for their valuable comments they\nmade to the title manuscript. The point-by-point responses to the reviewer’s\ncomments are listed in italic text in blue.\nReviewer 1\nWhile NiH-catalyzed hydrofunctionalization of alkenes has been broadly studied,\nthe concomitant installation of two stereocenters via trisubstituted alkenes\nremains underexplored, as it necessitates a distinct catalytic approach. In this\nrevised manuscript, the authors have successfully addressed the comments from\nthe previous round of reviews, further strengthening a manuscript that presents a\nnovel route to 1,2-stereocenters from trisubstituted alkenes. As such, this\nreviewer recommends this manuscript for publication in Nature Communications,\nprovided that the following minor corrections are further made.\nResponse: We sincerely thank the reviewer for the positive evaluation and\nconstructive comments. We are glad that our revisions have strengthened the\nmanuscript. All suggested minor corrections have been carefully implemented in\nthe revised version.\n1. The authors should correct '(4x and 4z)' to '(4y and 4z)' on page 6, line 131.\nResponse: We thank the reviewer for pointing this out. The text has been\ncorrected accordingly.\n2. The authors noted in their response letter that several unsuccessful substrates\n(4ac, 4ad–4aj) were added to the SI. However, this reviewer was unable to\nlocate these examples in the revised version. The authors should verify these\nresults and include them in the final SI.\nResponse: The examples of the unsuccessful substrates have been added to\nSection 5: “Unsuccessful substrates” of the Supplementary Information\nReviewer 2\nI have reviewed the original submission of this manuscript. First, I do appreciate\nthe authors' efforts to address my concerns. However, also as commented by the\nreviewer 2, I do not think that this work meets the criteria of novelty and urgency\nfor publication in Nat. Commun. because there are many precedents of NiH- and\nrelated CuH-catalyzed stereoselective net hydroamination of alkenes.\nSubmission to more synthetic journals is recommended.\nResponse: We thank Reviewer 2 again for their review."}]

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