Introduction

The field of chemical science includes various areas of study, from the synthesis of new compounds to the investigation of their properties and applications. Among these areas, amides have become significant compounds, attracting the attention of scientists and researchers1,2,3. Amides, owing to their importance in natural products, pharmaceuticals, and materials, serve as essential building blocks in organic chemistry4,5,6,7. Amides stand out as one of the most common functional groups, constituting approximately 40% of a dataset with 420,000 bioactive molecules, as well as constituting two-thirds of the population of drug candidates. Additionally, surveys indicate that amides account for 25% of all pharmaceuticals currently accessible on the market3,8,9,10. Among these active molecules, chiral amides play a crucial role, demonstrating significant importance in the therapeutic intervention of specific diseases. Given the biological activities of stereoisomers may vary11,12, the development of methods for synthesizing amides with high stereochemical purity is particularly valuable.

The transition-metal-catalyzed hydroaminocarbonylation of readily available alkenes has emerged as an ideal approach to accessing amides13,14. Over the past few decades, significant advances have been made in ligand-controlled, metal-catalyzed hydroaminocarbonylation of alkenes15. A diverse array of valuable linear or branched amides has been selectively synthesized through Markovnikov or anti-Markovnikov hydroaminocarbonylation processes16,17,18,19,20. Notwithstanding the advancements made, achieving catalytic asymmetric hydroaminocarbonylation of alkenes to synthesize chiral amides with high enantioselectivity remains a major challenge. In 2020, the Guan group reported an effective Pd-catalyzed enantioselective Markovnikov hydroaminocarbonylation of alkenes with anilines by using a phosphoramidite ligand (Fig. 1a)21. A variety of amides bearing an α-stereocenter were obtained straightforwardly in high yields and enantioselectivities. In the same year, our group developed a copper-catalyzed enantioselective hydroaminocarbonylation of styrenes with electrophilic hydroxylamines22,23. The method exhibits broad functional group tolerance and operates under mild conditions, yielding α-chiral amides with high efficiency. Very recently, a general process for the anti-Markovnikov hydroaminocarbonylation of 1,1-disubstituted alkenes to β-chiral amides was realized by utilizing a bulky bidentate phosphine ligand (R)-DTBM-Segphos-based copper catalyst (Fig. 1a)24. While these strategies have been developed for the synthesis of chiral amides, they currently only provide control over the stereocenters at the α or β positions of the incorporated amide bonds. Despite the identification of γ-chiral amide moieties in numerous drugs and biologically active molecules (Fig. 1b), there is currently no documented direct asymmetric carbonylation for the synthesis of γ-chiral amide motifs. Moreover, simultaneously constructing well-defined stereocenters at sites distant from a newly introduced functional group continues to be a formidable challenge for synthetic organic chemists25,26,27,28.

Fig. 1: Catalytic asymmetric hydroamincarbonylation and alkenes to chiral amides.
figure 1

a State-of-the-art of asymmetric hydroaminocarbonylation of alkenes to α- and β-chiral amides. b Selected examples of biologically active molecules and pharmaceuticals featuring γ-chiral amide motifs. c This work: synthesis of γ-chiral amides via Cu-catalyzed reductive relay hydroaminocarbonylation.

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In light of the rapid rise of Cu-catalyzed enantioselective hydrofunctionalization and allylic substitution reactions in recent years29,30,31,32,33,34,35,36, we anticipate that a trisubstituted allylic substrate could potentially deliver the amide products with a stereocenter at the γ position. Under our previously reported hydroaminocarbonylation conditions, trisubstituted olefins exhibited general unreactivity due to the unfavorable nature of the insertion reaction involving highly substituted alkenes37,38. Herein, we report an efficient strategy to synthesize enantioenriched γ-chiral amides through the reductive relay process, in which a single cooper catalyst mediates sequential reduction and anti-Markovnikov hydroaminocarbonylation of trisubstituted allylic benzoates (Fig. 1c). This reaction is compatible with achiral allylic benzoates with both aliphatic and aromatic substituents, as well as cyclic and acyclic hydroxylamine electrophiles. The transformation offers a modular and versatile approach towards the synthesis of chiral amides containing minimally differentiated alkyl substituents at the γ-position with excellent enantioselectivity.

Results and discussion

Reaction development and optimization

Our investigation commenced with an exploration of the reaction between geraniol derived alkene 1a and hydroxylamine ester 2a (refer to Table 1 and Supplementary Tables S1 for additional details). After extensive experimentation, we identified that the best conditions were achieved using Cu(OAc)2 (5 mol%), (R)-DTBM-Segphos (7 mol%), PMHS (4 equiv.), and CsF (3 equiv.) in tetrahydrofuran (THF) at 60 °C under 10 bar CO atmosphere. Under these conditions, the reaction afforded γ-chiral amide 3a in 80% isolated yield with 98% enantiomeric excess (Table 1, entry 1). The yield slightly decreased with the use of 1,4-dioxane as solvent, and when 1,2-dichloroethane (DCE) was employed, only trace amounts of desired product 3a were generated (Table 1, entries 2 and 3). Using other copper sources, such as CuCl and CuOAc, did not lead to improved results (Table 1, entries 4 and 5). The use of LiOtBu instead of CsF resulted in trace amounts of 3a, with the majority of 1a being recovered (Table 1, entry 6). No or <10% yield of desired product was observed when replacing (R)-DTBM-Segphos (L1) with L2-L839,40 as ligands (Table 1, entries 7 and 8). The utilization of alternative electrophilic aminating reagents bearing a benzoyl group (2a-1) or a 4-(N,N-dimethylamino)benzoyl group (2a-2) resulted in moderate yields of 3a (Table 1, entries 9 and 10).

Table 1 Optimization of reaction conditionsaView full size image
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Substrate scope

A variety of leaving groups were examined, revealing that the reactivity is influenced by the nature of the leaving group but does not correlate with enantioselectivity. (Fig. 2). Reactions involving substrates 1 with alkoxy(1a-3) and silyloxy (1a-4) led to very low conversion, predominantly resulting in the recovery of 1a-3 and 1a-4. Improved yield of 3a with 96% ee was achieved when using carbonate 1a-6. Product yields ranging from 19% to 73% were obtained with a high level of enantioselectivity by employing carboxylates with different substituents (1a-5, 1a-7-11).

Fig. 2: Impact of leaving groups.
figure 2

Reactions were performed with 1a (0.18 mmol), 2a (0.1 mmol), Cu(OAc)2 (5 mol%), (R)-DTBM-Segphos (7 mol%), CsF (3 equiv.), PMHS (4 equiv.), CO (10 bar), 60 °C, and THF (0.5 mL). Yields are determined by GC-FID with n-hexadecane as the internal standard, ees were determined by chiral HPLC.

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As shown in Fig. 3, under our optimal conditions, we explored the scope of allylic benzoates that could undergo the transformation. Various 3,3-dialkyl substituted allylic benzoates were initially tested. The opposite enantiomer 3a’ can be obtained in 77% yield with −99% ee when using (S)-DTBM-Segphos instead of (R)-DTBM-Segphos as the ligand. Substrates derived from (E,E)-Farnesol, Solanesol, Phytol, and Monocyclofarnesol all furnished the corresponding γ-chiral amides in moderate to good yields and exceptionally high enantioselectivities (3b-3d, 3r). Diverse functional groups were readily accommodated, including aryl groups (3e,3f,3j), ethers (3k, 3m, 3n), an alkyl chloride (3l), esters (3p, 3q). The presence of bulky groups at the 3-position of the allylic substrates was well-tolerated, resulting in the formation of the desired γ-chiral amides 3h and 3i with yields of 68% with 99% ee and 53% with 99% ee, respectively. In the presence of a substrate containing an aldehyde, the reduction product 3o was obtained in 42% yield with 99% ee, as expected. The substrate containing an achiral epoxide functional group was also tolerated, affording a mixture of diastereomers (1:1) in 69% yield (3s), both diastereomers exhibited high enantioselectivities (99% ee). Furthermore, this reductive relay hydroaminocarbonylation was successfully extended to include allylic benzoates with 3-aryl substitution. Substrates with both electron-rich aryl substituent (3u) and electron-poor aryl substituents (3v-3w) were effectively tolerated under the catalytic system. Notably, the reaction conditions were also compatible with both a 2-naphthyl-substituted substrate (3x) and a 3-thienyl-substituted substrate (3y).

Fig. 3: Substrate scope of allylic benzoates.
figure 3

Reactions conditions: 1 (0.36 mmol), 2 (0.2 mmol), Cu(OAc)2 (5 mol%), (R)-DTBM-Segphos (7 mol%), CsF (3 equiv.), PMHS (4 equiv.), CO (10 bar), 60 °C and THF (1.0 mL). Isolated yields, ees were determined by chiral HPLC, and drs were determined by crude 1H NMR or chiral HPLC. aUse (S)-DTBM-Segphos (7 mol%) as the ligand. bFrom aldehyde 1o. cMorpholino 4-(diethylamino)benzoate as the substrate.

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The versatility of this catalytic system was further demonstrated by investigating various hydroxylamine electrophiles (Fig. 4). Cyclic hydroxylamine derivatives such as piperidine (4a), morpholine (4b), protected piperidone (4c), piperazine containing a carbamate protecting group (4d), and tetrahydroisoquinoline (4e) were introduced into the reaction, resulting in the desired γ-chiral amides in 51%-87% yields with 84%-99% ees. Additionally, acyclic dialkyl-substituted hydroxylamine electrophiles (4f–4i) proved to be suitable partners, providing the corresponding products in good yields and excellent enantioselectivities as well. Aniline-based hydroxylamine derivatives were also compatible substrates, generating products 4j and 4j–1 in 51%-61% yields with high enantioselectivities. Moreover, to showcase potential late-stage functionalization, hydroxylamines derived from drug fragments or natural products were introduced into this reductive relay hydroaminocarbonylation reaction, leading to their successful transformation into the corresponding drugs containing γ-chiral amide groups (4k–4o’). Employing 1aa and 1ab as the substrates also afforded liner amides 4q and 4r in 69%-78% yields.

Fig. 4: Substrate scope of hydroxylamine electrophiles.
figure 4

Reactions conditions: 1a (0.36 mmol), 2 (0.2 mmol), Cu(OAc)2 (5 mol%), (R)-DTBM-Segphos (7 mol%), CsF (3 equiv.), PMHS (4 equiv.), CO (10 bar), 60 °C and THF (1.0 mL). Isolated yields, ees were determined by chiral HPLC, and drs were determined by crude 1H NMR or chiral HPLC. aUse corresponding O-benzoylhydroxylamine as the electrophile. bUse corresponding O-pivaloylhydroxylamine as the electrophile. cUse (S)-DTBM-Segphos (7 mol%) as the ligand.

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Synthetic utility

To gain insight into the effects of substrate structure on reaction activity and enantioselectivity, we conducted reactions using substrates that vary in the geometry of the allylic benzoates. (Fig. 5a). When the isomeric nerol-derived benzoate (Z-1a), containing a (Z)-configured allylic double bond, was subjected to the standard conditions, the enantiomer with the opposite configuration 3a′ was obtained with a dramatically decreased yield and slightly lower enantioselectivity compared to 3a. Then, isomeric allylic benzoate 1z, with an E/Z ratio of 7/3, was exposed to the reaction under optimized conditions, the product 3z was obtained 41% yield with 95% ee, while 42% of the remaining starting material 1z was recovered with an E/Z ratio of 4.5/5.5. Gratifyingly, the reaction could be performed on 1 mmol scale with a 2.5 mol% catalyst loading, delivering the product 3a in good yield (72%, 191 mg) with almost complete enantioselectivity (Fig. 5b). Subsequently, the γ-chiral amides can undergo further reduction using Nickel catalysis41, resulting in δ-chiral amides with high yields (Fig. 5c). Unfortunately, the ee values for compounds 8 and 9 could not be determined under the current chiral HPLC conditions in our laboratory.

Fig. 5: Effect of olefin geometry and synthetic application.
figure 5

a Effect of allylic benzoates geometry. b 1 mmol scale reaction with reduced catalyst loading. c Ni-catalyzed reduction of γ-chiral amides to δ-chiral amines.

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Mechanistic investigations

To elucidate the mechanism underlying the reductive relay hydroaminocarbonylation, a reaction employing 1.5 equivalents of PMHS with 1i was conducted, yielding terminal alkene 7 in 81% yield with 98% ee (Fig. 6a). A deuterium-labelling experiment, utilizing Ph2SiD2 with 1i, resulted in the isolation of alkene 7-D with 74% yield and 70% deuterium incorporation at the α position of the C-C double bond. Subsequently, the terminal alkene 7 was reacted with 2a under hydroaminocarbonylation conditions using racemic DTBM-Segphos. The γ-chiral amide product 3i was obtained in a 59% yield with >99% ee (Fig. 6b). These results indicate that the terminal alkene 7 serves as a competent intermediate, and the enantioselectivity of the product (γ-chiral amide) is established in the initial reduction cycle, unrelated to the hydroaminocarbonylation cycle. In the non-linear effect experiments, a linear relationship was observed, suggesting that one ligand may coordinate with one copper atom to form the active catalyst (Fig. 6c).

Fig. 6: Mechanistic investigations and proposed mechanism.
figure 6

a Isolation of the plausible terminal alkene intermediate and deuterium-labelling experiment. b Using the racemic ligand to test the hydroaminocarbonylation cycle. c Non-linear effect study. d Proposed catalytic cycle of reductive relay hydroaminocarbonylation.

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Based on the experimental results and literature reports42,43,44,45,46, we tentatively propose a plausible reaction mechanism depicted in Fig. 6d. Initially, copper salts coordinate with the ligand, and subsequent interaction with the base and hydrosilane leads to the formation of the starting LCuH species. The following step involves LCuH species reacting with allylic benzoate to generate alkylcopper intermediate I. This intermediate I then undergoes β-OBz elimination, resulting in the transient formation of enantioenriched terminal alkene II and ligated LCuOBz species. The terminal alkene II enters the hydroaminocarbonylation cycle through an anti-Markovnikov hydrocupration, transforming into alkylcopper species III. The interception of alkylcopper species III by the hydroxylamine electrophile and CO leads to the formation of intermediate IV. Finally, reductive elimination occurs to deliver the desired γ-chiral amide and ligated LCuOR’. Both LCuOBz species and LCuOR’ could undergo transmetallation with hydrosilane to regenerate LCuH species for the next catalytic cycle.

Discussion

In summary, we have reported an enantioselective Cu-catalyzed reductive relay hydroaminocarbonylation for the synthesis of optically active γ-chiral amides from allylic benzoates, CO, and electrophilic aminating reagents. Employing the Cu/(R)-DTBM-Segphos catalytic system facilitates the challenging establishment of chiral centers at a remote distance from the amide bond, specifically at the γ position. Notably, this method also showcases a broad substrate scope with excellent enantioselectivity and regioselectivity, providing access to valuable enantioenriched γ-chiral amides that are often challenging to obtain using alternative approaches.

Methods

General procedure for the carbonylation-triggered migration

A vial (4 mL) was charged with (R)-DTBM-Segphos (7.0 mol%), Cu(OAc)2 (5.0 mol%), 2 (0.2 mmol, 1.0 equiv), CsF (91 mg, 3 equiv.), and a stirring bar. The vial was closed by PTFE/white rubber septum (Wheaton 13 mm Septa) and phenolic cap and connected with atmosphere with a needle. The vial was evacuated under vacuum and recharged with argon for three times. Then, THF (1.0 mL) was injected under argon by using a syringe. After that PMHS (0.8 mmol, 4 equiv.) and allylic benzoate 1 (0.36 mmol, 1.8 equiv.) were added, and the vial (or several vials) was placed in an alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments. After flushing the autoclave three times with CO, a pressure of 10 bar of CO was adjusted at ambient temperature. Then, the reaction was performed for 16 h at 60 oC. After the reaction was complete, the autoclave was cooled down with ice water to room temperature, and the pressure was released carefully. The reaction was diluted with EA (ethyl acetate) and filtered through a pad of silica gel (a pipette with about 3 cm silica gel). The filtrate was concentrated under reduced pressure and the residue was directly purified by column chromatography to afford the corresponding products. The enantiomeric excesses (% ee) were determined by HPLC analysis using chiral stationary phases. Note: Because of the high toxicity of carbon monoxide, all the reactions should be performed in an autoclave. The laboratory should be well-equipped with a CO detector and alarm system.