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. 2023 Dec 20;9(51):eadk4950. doi: 10.1126/sciadv.adk4950

Expedient and divergent synthesis of unnatural peptides through cobalt-catalyzed diastereoselective umpolung hydrogenation

Xinjian Song 1, Shuangyi Bai 1, Yuan Li 1, Tong Yi 1, Xinyu Long 1, Qinghua Pu 1, Ting Dang 1, Mengjie Ma 1, Qiao Ren 1,*, Xurong Qin 1,2,*
PMCID: PMC10732522  PMID: 38117889

Abstract

The development of a reliable method for asymmetric synthesis of unnatural peptides is highly desirable and particularly challenging. In this study, we present a versatile and efficient approach that uses cobalt-catalyzed diastereoselective umpolung hydrogenation to access noncanonical aryl alanine peptides. This protocol demonstrates good tolerance toward various functional groups, amino acid sequences, and peptide lengths. Moreover, the versatility of this reaction is illustrated by its successful application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. This strategy eliminates the need for synthesizing chiral noncanonical aryl alanines before peptide formation, and the hydrogenation reaction does not result in racemization or epimerization. The underlying mechanism was extensively explored through deuterium labeling, control experiments, HRMS identification, and UV-Vis spectroscopy, which supported a reasonable CoI/CoIII catalytic cycle. Notably, acetic acid and methanol serve as safe and cost-effective hydrogen sources, while indium powder acts as the terminal electron source.

A cobalt-catalyzed asymmetric hydrogenation of dehydropeptides using acetic acid and methanol as the hydrogen sources is reported.

INTRODUCTION

Peptides are versatile scaffolds that have been applied in various research areas such as material science, chemical biology, and medicinal chemistry (1–6). In recent years, there has been a growing interest in the use of peptides as therapeutic agents for the treatment of various diseases. Now, there are over 80 commercially available peptide drugs globally, with approximately 170 in various stages of clinical trials and another 500 undergoing preclinical studies (7). Unnatural peptides that contain amino acid residues beyond the 20 canonical amino acids have demonstrated superior proteolytic stability, bioactivity, and pharmacokinetics compared with their natural counterparts (8–12). Among several classes of noncanonical amino acids, noncanonical aryl alanines are highly prevalent in pharmaceuticals due to their versatility (Fig. 1) (13–18). For instance, Cetrorelix, a synthetic decapeptide containing D-2-Nal, 4′-Cl-D-Phe, D-3-Pal residues, is a gonadotropin-releasing hormone antagonist used to prevent luteinizing hormone surges in women undergoing assisted reproduction therapy. Therefore, the continued exploration of methods to access unnatural peptides containing noncanonical aryl alanine residues and their potential therapeutic applications is highly desirable and promising.

Fig. 1. Selected peptide drugs containing unnatural aryl alanine residues.

Fig. 1.

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The coupling reagent–mediated condensation of unnatural aryl alanines through dehydration is a widely used and reliable approach for peptide formation (19–23). However, this approach has several limitations, including the tedious preparation of unnatural aryl alanines, poor atom economy, inevitable side reactions, and the potential risk for racemization/epimerization of the α-stereocenter caused by the overactivation of carboxyl groups by coupling reagents. An alternative approach is the transition metal-catalyzed cross-coupling reactions between an aryl halide and an AlaM reagent (Fig. 2A) (24–26). While this reaction offers reliable access to L-aryl alanine moieties, it still suffers from limitations such as the labile or difficult-to-synthesize nature of some AlaM reagents. Recently, several groups including Albericio, Ackermann, Yu, Wang, and Chen, and their respective colleagues (27–35) have pioneered Pd-catalyzed C-H arylation of L-alanine derivatives to unnatural aryl alanine peptides (Fig. 2B). However, this protocol typically requires an external directing group for excellent site selectivity, resulting in extra and cumbersome steps for installation and detachment (even irremovability). Another approach is Rh-catalyzed conjugate arylation of dehydroalanines, which can provide unnatural aryl alanine peptides in 4:1 diastereomeric ratio (dr) (Fig. 2C) (36, 37). Despite these considerable advances, efficient synthetic methods for constructing highly enantiopure unnatural D-aryl alanine peptides are still relatively limited (38–41), especially starting from other readily available sources.

Fig. 2. Transition metal-catalyzed methods of unnatural aryl alanine residues incorporation in peptides.

Fig. 2.

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Transition metal-catalyzed asymmetric hydrogenation has been certified as a powerful tool for the preparation of a wide range of pharmaceuticals, agrochemicals, bioactive compounds, and natural products (42–53). However, most of asymmetric hydrogenation catalysts today are based on scarce and costly heavy noble metals including Rh (54, 55), Ru (56), Ir (57–59), and Pd (60, 61), occurring at very low abundances in the earth’s crust (5 × 10−5 to 10−4 ppm). In addition, these heavy noble metals not only incur high costs in the production process but also require recovery and recycling due to environmental concerns (62, 63). Recently, there has been a renewed interest in using low-cost, earth-abundant, and biologically compatible 3d transition metal catalysts such as Mn, Fe, Co, Ni, and Cu for asymmetric hydrogenation (64–72). However, these strategies might use high-pressure hydrogen gas, a severe safety hazard during transport, storage, and use.

Despite the substantial advancements in transition metal-catalyzed asymmetric hydrogenation for various substrates, it is worth noting that the field of asymmetric hydrogenation of dehydropeptides has been largely overlooked. Although there has been some headway in rhodium-catalyzed hydrogenation of dehydrodipeptides (73–77) using H2 gas (30 to 70 atm under some conditions), considerable challenges persist (Fig. 2D). These challenges mainly encompass limited structural diversity, especially concerning peptide length, and the relatively modest level of diastereoselectivity achieved thus far. Here, we report the first diastereo- and regioselective cobalt-catalyzed umpolung hydrogenation for the divergent and expedient synthesis of unnatural aryl alanine peptides (Fig. 2E).To achieve these transformations, several formidable challenges need to be addressed, including the steric effect of peptides on reactivity and stereoselectivity, the compatibility of multiple reactive functional groups in different peptides, the availability of multiple coordination sites for binding to transition metals, and stereogenic centers that are prone to racemization/epimerization. Notably, commercially available acetic acid and methanol can serve as the safe and cheap hydrogen sources in our protocol, avoiding the safety hazards associated with the storage and usage of high-pressure hydrogen gas.

RESULTS AND DISCUSSION

Condition optimization

Initially, the readily synthetically available dehydro-Phe-Gly 1a was used as the model substrate to optimize various parameters including metal catalysts, ligands, reducing agents, and solvents. To our delight, the combination of CoI2 (10 mol %), Imamoto’s P-chiral bisphosphine (R,R)-QuinoxP* (12 mol %), indium powder (2 eq.) as the reducing agent, and acetic acid (3 eq.) in CH3OH provided the best result, giving rise to D-Phe-Gly 2a in 92% yield with 96:4 enantiomeric ratio (e.r.) (Table 1, entry 1). Control experiments confirmed the essential roles of cobalt salt, P-ligand, indium, and acetic acid in this asymmetric transformation (entries 2 to 5). Other solvents such as H2O, N,N′-dimethylformamide (DMF), and tetrahydrofuran (THF) typically led to lower yields of 2a (entries 6 to 8). It is noteworthy that Mark Burk’s ligand such as (R,R)-Ph-BPE was also catalytically active, but moderate e.r. was obtained (entry 9). Other chiral bisphosphines, including (R,R)-Me-Duphos and (1R,1′R,2S,2′S)-Duanphos, showed much lower catalytic activities (entries 10 to 11). Furthermore, the replacement of In with Fe, Mn, Zn, and Mg powder gave poor efficiencies and notable erosion of stereoselectivities, indicating some extents of background reactions (entries 12 to 15).

Table 1. Optimization of the reaction conditions for 1a.

Standard conditions: 1a (0.05 mmol), CoI2 (10 mol %), ligand (12 mol %), CH3CO2H (3.0 eq.), metal powder (2.0 eq.), solvent (0.3 ml), 90°C for 48 hours.

graphic file with name sciadv.adk4950-fx1.jpg

Entry Variation from the standard conditions Yield (%)* e.r.†
1 None 92 96:4
2 No CoI2 Trace –
3 No (R,R)-QuinoxP* Trace –
4 No CH3COOH Trace –
5 No indium Trace –
6 H2O instead of CH3OH Trace –
7 DMF instead of CH3OH 40 94:6
8 THF instead of CH3OH 9 47:53
9 (R,R)-Ph-BPE instead of (R,R)-QuinoxP* 86 13:87
10 (R,R)-Me-Duphos instead of (R,R)-QuinoxP* Trace –
11 (1R,1’R,2S,2’S)-Duanphos instead of (R,R)-QuinoxP* 10 83:17
12 Fe instead of In Trace –
13 Mn instead of In 30 91:9
14 Zn instead of In 75 71:29
15 Mg instead of In 9 56:44
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*The yield was determined by 1H NMR analysis with CH2Br2 as internal standard.

†e.r. values were determined by HPLC analysis.

Substrate scope

With the optimal conditions in hand, we turned our attention to establishing the scope for the peptide substrates (Figs. 3 to 5). It is noteworthy that various dehydropeptides could be smoothly hydrogenated to give the corresponding unnatural peptides in good to excellent yields with high enantioselectivities or diastereoselectivities. The absolute configuration of hydrogenated product 2ab was established to be R by single-crystal x-ray analysis, and other corresponding products were assigned in analogies to 2ab (see the Supplementary Materials for details).

Fig. 3. Scope of dipeptides.

Fig. 3.

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Standard conditions: 1a-1ae (0.10 mmol), CoI2 (10 mol %), (R,R)-QuinoxP* (12 mol %), CH3CO2H (3.0 eq.), In (2.0 eq.), CH3OH (0.5 ml), 90°C for 48 hours. The yield of isolated products. The e.r. and dr values were determined by HPLC analysis. aCoI2 (20 mol %), (R,R)-QuinoxP* (22 mol %), 80°C for 24 hours. b(S,S)-QuinoxP* instead of (R,R)-QuinoxP*.

Fig. 5. Scope of tetrapeptides and pentapeptides.

Fig. 5.

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Standard conditions: 5a-5j (0.10 mmol), CoI2 (10 mol %), (R,R)-QuinoxP* (12 mol %), CH3CO2H (3.0 eq.), In (2.0 eq.), CH3OH (0.5 ml), 90°C for 48 hours. The yield of isolated products. The dr values were determined by HPLC analysis. a(S,S)-QuinoxP* instead of (R,R)-QuinoxP*. bCoI2 (20 mol %), (S,S)-QuinoxP* (22 mol %). cCoI2 (20 mol %), (R,R)-QuinoxP* (22 mol %).

Scope of dipeptides

The substrate tolerance of this reaction toward dipeptides was evaluated (Fig. 3). Gratefully, various dehydrodipeptides were found to be suitable for this umpolung hydrogenation, resulting in the desired products 2 in good yields ranging from 61 to 94%. Substrates 1 embedded with both electron-rich and electron-poor substituents on the aryl ring of dehydro-aryl alanine moieties could be successfully hydrogenated with up to 97:3 enantioselectivity or 98:2 diastereoselectivity. The mild reaction conditions demonstrated good tolerance to various functional groups, including alkyl, aryl, ester, amide, methoxyl, trifluoromethyl, fluoro, thiomethyl, Boc, and Fmoc. We further explored the reactivity of dipeptides with diverse hydrophilic side chains. It is found that dehydrodipeptides containing free hydroxyl groups of Ser and Thr (2f, 2g, and 2s), as well as NH groups of Trp (2x), were compatible with the hydrogenation reaction. However, it is important to note that dehydrodipeptides with other hydrophilic side chains, such as Asp and Glu (-COOH), Cys (-SH), His (-NH), Lys (-NH2), and Tyr (-OH), require protective measures to ensure compatibility within the reaction system (2h, 2j-2n, 2p, and 2r). The incorporation of natural amino acids into dehydrodipeptides, including Gly, Ala, Val, Ile, Thr, Cys, Met, Asp, Glu, His, Phe, Tyr, Trp, and protected Lys residues, had little impact on the reaction efficiency and enantioselectivities or diastereoselectivities. In addition, dehydrodipeptides containing unnatural amino acid residues, such as D-Ala, D-Ser, Abu, t-Leu, D-Leu, and D-Phg at the C-terminal also reacted well, resulting in the corresponding unnatural dipeptides in 76 to 89% yields. However, the introduction of the sterically hindered Pro residue led to a substantial decrease in the reaction yield. Furthermore, our synthesis efforts have extended to dehydrodipeptides containing free His and Cys. Unfortunately, these attempts did not yield satisfactory results.

Scope of tripeptides

To further expand the scope of our methodology, the asymmetric umpolung hydrogenation of dehydrotripeptides was investigated as illustrated in Fig. 4. Under the optimized conditions, dehydro-Phe-Gly-Gly 3a was efficiently hydrogenated to give the desired product 4a in 69% isolated yield and with 93:7 e.r.. Next, the impact of the sequence of tripeptides on the reaction was evaluated. The results showed that incorporating different amino acids, such as Ala, Val, Ile, Asp, Met, Phe, Trp, Abu, D-Leu, and D-Phg, at the third residue of dehydro-Phe-Gly did not affect the hydrogenation, resulting in moderate to good yields and with high diastereoselectivities (4b-4l and 4t). It was noted that altering the second amino acid from Gly to Ala, D-Phe, D-Ala, and Ile also posed no problem (4m-4s and 4u-4w). In addition, the current hydrogenation procedure was successfully applied to dehydro-4′-i-Pr-Phe-Gly-Trp 4l, dehydro-1-Nal-Ala-Trp 4q, and dehydro-3′-Me-Phe-D-Phe-Leu 4r. Furthermore, this protocol was successfully used to synthesis of the nonribosomal antibacterial tripeptide Sevadicin derivative 4s and other diastereomers, such as D-Phe-Ala-Trp 4n, Phe-Ala-Trp 4u, and Phe-D-Ala-Trp 4v with excellent diastereoselectivities. Notably, the dehydro residue was successfully positioned in the middle of a peptide sequence rather than at the terminal position. Gly-dehydro-Phe-Gly (3x) and Gly-dehydro-Phe-Ala (3y) were synthesized and subjected to reactions under standard conditions. They were efficiently hydrogenated, yielding the desired products 4x and 4y in yields of 69 and 73%, respectively. However, the selectivity decreased to 76:24 e.r. and 82:18 dr, respectively.

Fig. 4. Scope of tripeptides.

Fig. 4.

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Standard conditions: 3a-3y (0.10 mmol), CoI2 (10 mol %), (R,R)-QuinoxP* (12 mol %), CH3CO2H (3.0 eq.), In (2.0 eq.), CH3OH (0.5 ml), 90°C for 48 hours. The yield of isolated products. The e.r. and dr values were determined by HPLC analysis. a(S,S)-QuinoxP* instead of (R,R)-QuinoxP*.

Scope of tetrapeptides and pentapeptides

Next, we further examined the effectiveness of the cobalt-catalyzed umpolung hydrogenation of oligopeptides with varying lengths and sequences (Fig. 5). Eight dehydrotetrapeptide derivatives, including dehydro-Phe-Gly-Ala-Pro 5a, dehydro-Phe-Gly-Ala-D-Leu 5b, dehydro-Phe-Gly-D-Ala-Trp 5c, dehydro-Phe-Gly-Abu-Trp 5d, dehydro-Phe-Gly-Trp-Leu 5e, dehydro-Phe-Ala-Trp-Leu 5f, dehydro-Phe-Gly-Ala-Phe 5g, and dehydro-Phe-D-Ala-Leu-Abu 5h, were efficiently hydrogenated to give the desired products in high yields with excellent diastereoselectivities. Notably, 5b, 5c, and 5h, which contain a D-Leu or D-Ala unnatural amino acid moiety, gave the similar outcomes to substrate 5a, indicating that the absolute configuration of amino acid residues in tetrapeptides has no impact on the reaction. Furthermore, dehydropentapeptide substrates 5i and 5j were carefully investigated. The hydrogenation reactions of dehydropentapeptides were found to be relatively slower than those of dehydrotetrapeptides, probably owing to multiple coordination sites available for binding to cobalt catalyst. Therefore, higher catalyst loading of CoI2 was beneficial for achieving good yields and high diastereoselectivities.

Late-stage diversification of natural products and pharmaceuticals

To showcase the potential of our strategy, we have successfully applied it in the late-stage diversification of natural products and pharmaceutical molecules (Fig. 6). Peptide-drug conjugates have become recognized as a modality for targeted drug delivery with improved efficacy, superior pharmacokinetics/pharmacodynamics, and reduced side effects during treatment (78). We obtained several peptide-drug conjugates embedded with representative clinical amine drugs, including pregabalin, 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and 1-amantadine, in useful yields with high diastereoselectivities (8a-8e). In addition, peptide-drug conjugates of dihydrocholesterol, and L-(−)-menthol were also amenable to hydrogenation smoothly under the reaction conditions at lower concentrations (8f-8g). Furthermore, given the risk of adverse side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we used our protocol to introduce unnatural peptides to carboxyl-containing NSAIDs, resulting in the asymmetric synthesis of 4′-t-Bu-Phe-D-Ser-(S)-(+)-Ibuprofen and 4′-SMe-Phe-D-Ser-Naproxen in acceptable yields and high diastereoselectivities at lower temperatures and concentrations (8h-8i). Valproic acid (8j), widely used for treating seizure disorders, was also tolerated under this hydrogenation conditions. These results showed that our late-stage strategy provided a straightforward and versatile method to access valuable peptide-drug conjugates with complex structures in medicinal chemistry.

Fig. 6. Scope of peptide-drug conjugates.

Fig. 6.

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Standard conditions: 7a-7j (0.10 mmol), CoI2 (20 mol %), (R,R)-QuinoxP* (22 mol %), CH3CO2H (3.0 eq.), In (2.0 eq.), CH3OH (0.5 ml), 90°C for 48 hours. The yield of isolated products. The e.r. and dr values were determined by HPLC analysis. aCoI2 (10 mol %), (R,R)-QuinoxP* (12 mol %). bCH3OH (1.5 ml). c(S,S)-QuinoxP* instead of (R,R)-QuinoxP*. d70°C. GABA, γ-aminobutyric acid.

Synthetic applications

To highlight the versatility of cobalt-catalyzed asymmetric umpolung hydrogenation, the formal synthesis of natural products and drugs was performed. First, this protocol enabled concise synthesis of dipeptide 10a, a key intermediate of artificial hormone Cetrorelix (79), with high yield and dr (Fig. 7A). Similarly, the critical synthon 10b for emerimicins V was obtained in 84% yield and with 10:90 e.r. value (Fig. 7B) (80). In addition, we accomplished a concise asymmetric synthesis of acidiphilamide A, an autophagy inhibitor found in acidophilic actinobacterium (81). Dehydro-Phe-Ile-Phe was efficiently hydrogenated to give the desired product 10c with 54% yield and 9:91 dr. Subsequent selective reduction with LiBH4 provided acidiphilamide A 10d in 94% yield (Fig. 7C). These results showcase the broad applicability of our cobalt-catalyzed asymmetric umpolung hydrogenation strategy for the synthesis of diverse chiral unnatural peptides.

Fig. 7. Practical synthetic applications of cobalt-catalyzed asymmetric hydrogenation.

Fig. 7.

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(A) Synthesis of cetrorelix intermediate. (B) Synthesis of emerimicins V intermediate. (C) Asymmetric synthesis of acidiphilamide A.

Biological testing

To assess the biological potential of these unnatural peptides, we evaluated their inhibitory activities against non–small cell lung cancer cell line PC-9OR2. Notably, the compound 4q exhibited notable antitumor effects against this human cancer cell line with median inhibitory concentration (IC50) value of 7.7 μM. The selected remaining compounds demonstrated moderate activities, with IC50 values ranging from 10.2 to 16.1 μM. These preliminary results indicate that these unnatural aryl alanine peptides have promising potential in the development of antitumor drug candidates (see table S1 in the Supplementary Materials for details).

Mechanism study

To investigate the effects of the catalyst and substrates on diastereomeric induction during hydrogenation, the dehydro-Phe-Ala 1b and dehydro-Phe-D-Ala 1c were synthesized and subject to reactions with (R,R)-QuinoxP* under standard conditions, respectively, resulting in a pair of diastereomers, (R,S)-2b and (R,R)-2c, in good yields (Fig. 8A). Similarly, dehydro-Phe-Asp (1j) was examined using (R,R)-QuinoxP* or (S,S)-QuinoxP* as the catalyst (Fig. 8B), yielding the corresponding peptides with R or S configuration of the newly generated chiral centers (2j and 2ad). Furthermore, tripeptides 3n and 3s were efficiently hydrogenated using (R,R)-QuinoxP* as the catalyst, resulting in the formation of a pair of diastereomers (R,S,S)-4n and (R,R,S)-4s with high enantiopurities. Using (S,S)-QuinoxP* as the catalyst, another two diastereomers (S,S,S)-4u and (S,R,S)-4v were obtained with excellent diastereoselectivities respectively (Fig. 8C). These results indicate that the chiral ligands, rather than the chiral conformation of the amino acid residues of the peptides, influence the stereoselective outcome, possibly because they are far away from the reaction centers, and the skeletons of the peptides are flexible.

Fig. 8. Investigation into factors influencing stereoselective outcome.

Fig. 8.

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(A) Hydrogenation of chiral dehydrodipeptides (1b and 1c) to explore the effect of substrates on diastereomeric induction. (B) Hydrogenation of enantiopure dehydro-Phe-Asp 1j to explore the effect of chiral ligands on diastereomeric induction. (C) Hydrogenation of chiral dehydrotripeptides (3n and 3s).

The reaction process of substrate 3s, meanwhile, was monitored to study the racemization/epimerization issue in this protocol. After 8 hours, the starting material 3s was converted to the corresponding product 4s in 60% yield and with 95:5 dr. Prolonging the reaction time resulted in the accumulation of the product 4s in 90% yield and no change in the dr value. Then, the hydrogenated pure product 4s further reacted under standard conditions for 8, 24, 32, and 48 hours. It was found that the newly developed chiral center did not suffer from epimerization as determined by high-performance liquid chromatography (HPLC) analysis (fig. S3, for more details, see the Supplementary Materials).

To gain insight into the reaction pathway, several control experiments investigating the importance of protected amino groups on double bonds were conducted under the standard conditions (Fig. 9A, for more details, see the Supplementary Materials). Initially, the NHPiv group was replaced by the NHAc group in dehydro-Phe-Gly 1a, resulting in 79% yield and 87:13 e.r. Subsequently, when the NHPiv group in 1a was substituted with NHBoc, the desired product was obtained, but only with 16% yield and poor enantioselectivity (84:16 e.r.). We also explored the substitution of the NHPiv group in 1a with NHCbz, NHFmoc, NHCOCF3, NHTs, NBn2, CN, and H. Unfortunately, unsatisfactory results were obtained with any of these substituents. In addition, NHNs resulted in a complex mixture, possibly due to the reduction of the nitro group by indium. These findings revealed that the carbonyl coordination of acylamino groups probably played a vital role in controlling reactivity and enantioselectivity by interacting with the cobalt center.

Fig. 9. Mechanistic investigation.

Fig. 9.

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(A) Control experiments investigating the tolerance of versatile nitrogen protecting groups. (B) Stoichiometric reaction of (R,R)-QuinoxP*Co0(COD) complex with 1a. (C) UV-Vis spectroscopy studies of different cobalt species in the reaction. (D) Proposed catalytic cycle.

Next, a series of deuterium-labeling experiments were performed. It was found that deuterium was not detected in product 2a when the hydrogenation was carried out in deuterated DMF, indicating that DMF was not the hydrogen source (see figs. S5 and S6 in the Supplementary Materials for details). In contrast, when the experiment was conducted with CD3CO2D or CH3CO2D, the product contained similar substantial amounts of deuterium at both the α- and β-positions. In addition, when the deuteration experiment was carried out in deuterated methanol, we observed that isolated product 2a-d2 was deuterated with 96% deuterium at α position and 96% deuterium at β position (syn/anti 91:5). Thus, these data suggested that acetic acid and methanol served as the hydrogen sources. Furthermore, careful nuclear magnetic resonance (NMR) spectrum analysis of 2a and D2-labeled product 2a-d2 indicated that the deuterium was predominantly added in a syn manner to the double bond, indicating that the resulting carbon-cobalt bond generated from the alkene insertion was predominantly protonated in situ at the front side of the carbon center.

According to literature precedents, both CoI and Co0 active species could be obtained by single-electron reduction of CoII complexes using the Zn protocol (82–85). To identify the active species involved in this catalytic cycle, several experiments were conducted. First, the (R,R)-QuinoxP*Co0(COD) complex was prepared by Zn reduction of preformed (R,R)-QuinoxP*CoIII2 in the presence of 1,5-COD (84). However, when a stoichiometric amount of the (R,R)-QuinoxP*Co0(COD) complex was used in this asymmetric hydrogenation, no product was detected at 24 hours, implying that Co(0) might not be the active catalytic species in this catalytic cycle (Fig. 9B). Second, we carried out the In reduction of in situ–formed complex (R,R)-QuinoxP*CoIII2 in DMF, monitored by ultraviolet-visible (UV-Vis) spectroscopy (86–88) (Fig. 9C, for more details, see the Supplementary Materials). (i) A light yellow solution of (R,R)-QuinoxP*CoIII2 showed three distinct peaks at wavelengths above 400 nm, including peaks at 480, 680, and 750 nm. (ii) The treatment of (R,R)-QuinoxP*CoIII2 solution with 10 equiv. of In and following removal of excess amount of indium powder afforded a dark brown solution of Co(I) complex. The disappearance of the distinct peaks of Co(II) complex and two broad absorption band at 480 to 660 nm were observed in UV-Vis spectra, indicating the formation of the Co(I) complex. (iii) The subsequent treatment of this dark brown solution of Co(I) complex with 10 equiv. of CH3CO2H slowly afforded a broad signal at 450 to 650 nm. No signals of Co(0) or Co(II) complexes were visible, which could rule out the Co(0)/Co(II) reactivity in our reaction system. Furthermore, when the stoichiometric reaction of 1a and (R,R)-QuinoxP*CoIII2 was conducted under the optimal reaction conditions, mass-to-charge ratio signals of putative complexes [(R,R)-QuinoxP*CoI]+ and [(R,R)-QuinoxP*CoIIIHOAc]+ were detected successfully by high resolution mass spectrometry (HRMS), further confirming the presence of CoI/CoIII redox mechanism (see table S3 in the Supplementary Materials for details).

On the basis of the above observations and literature studies (82, 83, 85, 89), a plausible CoI/CoIII redox mechanism has been proposed (Fig. 9D). The initial bis(phosphine)Co(II) diiodide complex A is reduced by indium powder to the cobalt(I) precursor B. Next, the cobalt(I) complex of a chiral bisphosphine C is reversibly protonated by acetic acid to generate cobalt(III) hydride complex D. Subsequently, the substrate 1a coordinates to the cobalt(III) hydride complex D to activate the double bond to form the intermediate E. Thereafter, cobalt(III) hydride inserts at the α-position of the olefin, leading to the formation of the C-Co intermediate G. Last, the product 2a is released through protonation by acetic acid and methanol, and the cobalt(III) catalyst H is reduced back to cobalt(I) C by indium powder as a terminal electron donor.

In conclusion, we have developed an efficient and versatile strategy to access unnatural peptides containing noncanonical aryl alanine residues through cobalt-catalyzed diastereoselective umpolung hydrogenation. A wide range of dehydropeptides with varying lengths, sequences, and steric/electronic properties were successfully hydrogenated into the corresponding unnatural aryl alanine–based peptides with moderate to excellent yields and high enantioselectivities or diastereoselectivities. Particularly noteworthy is that there is no racemization or epimerization in this hydrogenation reaction conditions, which is a common issue when activating serine, threonine, and methionine. In addition, this reaction does not require extra efforts to produce chiral unnatural aryl alanines before the amide bond formation. Furthermore, the versatility of this reaction is illustrated through its application in the late-stage functionalization and formal synthesis of various representative chiral natural products and pharmaceutical scaffolds. Mechanism investigations were conducted by combining deuterium-labeling experiments, control experiments, HRMS identification, and UV-Vis spectroscopy studies, supporting a reasonable CoI/CoIII catalytic cycle. It is noted that acetic acid and methanol were used as secure and economical hydrogen sources, while indium powder served as the electron source.

MATERIALS AND METHODS

All NMR spectra were acquired on Bruker 400 MHz NMR spectrometers. Glassware was dried at 120°C for at least 3 hours before use. Unless noted otherwise, commercially available chemicals were used as received without purification, and reactions occurred at a Heidolph MR Hei-Tec magnetic stirrer equipped with a metal bath of WATTCAS LAB-1000. Column chromatography was performed on silica gel (200 to 300 mesh). Chiral HPLC analysis was performed on a Shimadzu SPD-M20A instrument using Daicel Chiralcel columns at 30°C and a mixture of HPLC-grade hexanes and isopropanol as eluents. Electrospray ionization (ESI) mass spectrometry analysis was conducted on Shimadzu LCMS-8030 spectrometer. ESI/HRMS analysis was conducted on Bruker impact II. Optical rotation was measured using Rudolph Autopol I automatic polarimeter equipped with a sodium vapor lamp at 589 nm, and the concentration of samples was denoted as c. UV-Vis analysis was conducted on Shimadzu UV-2700.

General procedure for the asymmetric hydrogenation reaction

In an argon-filled glove box, CoI2 (3.1 mg, 0.01 mmol, 10 mol %), (R,R)-QuinoxP* (4.0 mg, 0.012 mmol, 12 mol %), and dry CH3OH (0.3 ml) were charged into a dry 10-ml Schlenk tube. After stirring for 10 min at room temperature, acetic acid (17 μl, 0.3 mmol, 3.0 equiv.), indium powder (23 mg, 0.2 mmol, 2.0 equiv.), dehydropeptides (0.1 mmol, 1.0 equiv.), and CH3OH (0.2 ml) were added in sequence. The reaction mixture was heated with vigorous stirring in a metal bath maintained at 90°C, until the dehydropeptides was mostly consumed by thin-layer chromatography monitoring. The reaction was maintained at 90°C for 48 hours. After the reaction mixture was cooled to room temperature, 2 ml of saturated NH4Cl solution was added to quench the mixture, followed by addition of 2 ml of EtOAc. The mixture was filtered with diatomite and extracted with EA (3 × 20 ml). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using ethyl acetate and petroleum ether or acetone and petroleum ether or acetone, ethyl acetate and petroleum ether as the eluents to give the product (in most cases, the polarity of the hydrogenated products was slightly less than that of the corresponding substrates), with addition of 1% Et3N or 1% ammonia if necessary. The e.r. or dr values of the purified products were determined by chiral HPLC analysis with Daicel Chiralcel columns.

Acknowledgments

We thank Y. He (Army Medical University, Chongqing, People’s Republic of China) for bioactivity study.

Funding: X.Q. thanks the National Natural Science Foundation of China (21502157), Innovation Research 2035 Pilot Plan of Southwest University (SWU-XDZD22011), Fundamental Research Funds for the Central Universities (SWU-XDJH202321 and SWU 019044), the Chongqing Science Technology Commission (cstc2020jcyj-msxmX1043), Venture and Innovation Support Program for Chongqing Overseas Returnees (cx2020086), and the State Key Laboratory of Medicinal Chemical Biology (2022004). Q.R. thanks the Chongqing Science Technology Commission (cstc2021jcyj-msxmX1131).

Author contributions: X.S. carried out most of the chemical reactions and analyzed most of the data. S.B., Y.L., T.Y., X.L., Q.P., T.D., and M.M. conducted part of the synthetic experiments and part of data analysis. X.S. and Q.R. wrote the original draft along with assisting with the “writing—review and editing”. X.Q. conceived the idea, guided the project, and wrote this paper. All authors contributed to discussions.

Competing interests: X.Q., X.S., S. B., Q.R., X.L., and T.Y. are authors on a patent application related to this work filed by SWU (application no. 202211067439.7, filed on 1 September 2022). The other authors declare that they have no competing interests.

Data and materials availability: All data needed to evaluate the conclusions are present in the paper and/or the Supplementary Materials. Crystallographic data for compound 2ab are available free of charge from the Cambridge Crystallographic Data Centre (https://ccdc.cam.ac.uk/) under reference number 2201820.

Supplementary Materials

This PDF file includes:

Supplementary Text

Figs. S1 to S9

Tables S1 to S4

References

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Supplementary Materials

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Figs. S1 to S9

Tables S1 to S4

References

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