Introduction

In nature, 20 proteinogenic amino acids are chosen as the essential building blocks in almost all forms of life1. Whereas nature prefers amino acids of specific structures, chemists desire access to a wide array of analogues, referred to as unnatural amino acids, which exhibit various biological activities and are extensively employed as intermediates for pharmaceutical production. Among them, α- and γ- amino acids are present in numerous top-grossing FDA-approved drugs and are invaluable components of biologically active hybrid peptides2,3,4,5,6,7,8. The representative synthetic strategies for these amino acids typically involve semisynthetic methods from natural amino acids, multi-step procedures, or employment of pre-functionalized substrates9,10,11,12,13,14,15,16,17,18. In stark contrast, there is no report on the direct synthesis of α- and γ- amino acids from simple feedstocks, let alone the divergent synthesis of α- and γ- amino acids from a common intermediate. In this context, we sought to address this issue by designing a shared intermediate readily generated from bulk chemicals, which features multiple adjustable reaction sites, such as extended quinone methides. We reason that this strategy holds promise for enabling the switchable synthesis of α- and γ- amino acids from bulk feedstocks (Fig. 1a).

Fig. 1: Background and our working hypothesis.
figure 1

a Synthetic approaches to α- and γ-amino acids. b Background of para-quinone methide chemistry. c Our working hypothesis. p-QM para-quinone methide, p-BQM para-biphenyl quinone methide, Nap-QM naphthoquinone methide, Cat catalyst.

Full size image

Quinone methides (QMs), generally classified into o-QMs and p-QMs, have been widely recognized as versatile and practical intermediates in organic synthesis, biological processes and material sciences19,20,21. In the past few decades, various catalytic systems have found success in the assembly of diverse molecular architectures from o-QMs22,23,24. However, the chemistry of p-QM is relatively less developed, and their extended species, including alkynyl-p-quinone methide, p-biphenyl quinone methide, naphthoquinone methide, have only seen sporadic reports25,26,27,28. The reported extended p-QMs were all generated from pre-functionalized substrates, and only one reaction site was disclosed regardless of multiple potential reaction sites (Fig. 1b). To address this gap, an alkenyl-p-QM could be readily prepared from a simple alkyne, benzoquinone, and Wittig reagent, all of which are commercially available feedstocks, under very mild conditions. This extended p-QM contains multiple available reaction sites for amination process. To differentiate these similar reaction sites, we envision a tailored amination strategy that could achieve alternative reactivities. Specifically, this strategy is enabled by tailored amination reagents, and these amines could be selectively accommodated into different sites according to their similar yet inherently distinct properties, such as softness. Herein, we wish to report a four-component reaction for switchable synthesis of α- and γ-amino acids from simple bulk feedstocks, enabled by tailored amination under an identical catalytic system (Fig. 1c).

Results

Reaction design and development

Building on our tailored amination strategy, four primary amines with similar yet inherently different properties were carefully selected to participate in a four-component reaction with phenylacetylene (1a), benzoquinone (2a), and Wittig reagent (3a) under an identical set of catalytic protocols (for the detailed reaction optimization see Supplementary Table 1, and for preliminary results of asymmetric reactions see Supplementary Figs. 1, 2). To our expectation, the reactivities and regioselectivities of the resulting amino acid products varied significantly under the catalysis of Zn(OTf)2, with the only variable being the type of primary amines used. When p-toluidine 4a was subjected to the catalytic system, α-amino acid 5a was exclusively afforded in 81% yield with excellent E/Z selectivity (for the DFT-calculated transition states of E/Z selectivity, see Supplementary Figs. 15–17), while switching to hydroxylamine 4b reversed the regioselectivity to give γ-amino acid 6a with 9:1 regioselectivity and >20:1 E/Z selectivity. The employment of benzylamine 4c as the amination reagent resulted in a mixture of poor γ/α regioselectivity, and changing the amination reagent to benzenesulfonamide 4d completely suppressed the reaction (Fig. 2a). The proof-of-concept results demonstrated the feasibility of the designed tailored amination strategy, and we subsequently aimed to investigate the detailed mechanism underlying the switchable regioselectivity and reactivity. In our envisioned mechanistic pathways, the Paternò-Büchi [2 + 2] cycloaddition between an alkyne 1a and a quinone 2a was expected to generate a spirooxetene intermediate, which would open up to form a p-QM intermediate29,30,31,32,33,34. Subsequently, an incoming Wittig reagent 3a reacted with the aldehyde group to readily generate the extended alkenyl p-QM intermediate 9a, whose structure was fully characterized by NMR spectrum and HR-MS analysis. Finally, the isolated p-QM 9a was directly used for the amination process with the four aforementioned primary amines, and the similar regioselectivities and reactivities were observed, supporting the hypothesis that 9a was indeed the key reaction intermediate (Fig. 2b). With the plausible mechanistic pathway and confirmed reaction intermediate, we proceeded to examine the nature of intermediate 9a and these similar primary amines, and to investigate how the properties of amines resulted in different regioselectivities and reactivities. First, local electron attachment energy (LEAE) calculation35 (E(r)/eV) was performed to evaluate the potential reaction sites on the extended p-QM 9a for amination process (Fig. 2c). The conformation of Zn(OTf)2-associated-9a complex were optimized and analyzed at the molecular surfaces, i.e., ES(r), in which color-filled isodensity surface maps of LEAE and surface minima (ES,min) highlight the sites on the complex that were relatively more electrophilic. The calculations for this Zn(OTf)2-associated-9a complex revealed that the regions near α- and γ- positions exhibited lower electronic densities, and the values of surface minima (ES,min) were also lower compared to the overall values, which provided additional evidence that the α- and γ- positions on the Zn(OTf)2-associated-9a intermediate were more susceptible to nucleophilic addition. Further, local softness analysis was carried out on the Zn(OTf)2-associated-9a intermediate and amination reagents (Fig. 2d). The results indicate that α-position on the intermediate is “softer” than γ-position ((S+(α) > S+(γ))). The nitrogen atom of p-toluidine 4a exhibits the highest local softness (S-(nitrogen) = 0.434), while the nitrogen atom of hydroxylamine 4b displays the lowest local softness (S-(nitrogen) = 0.243). According to the local hard–soft acid–base principle36, the regioselectivity of amination process is potentially influenced by the compatibility between the local softness of the nitrogen atom (S-(nitrogen)) and the electrophilic site (S+ (electrophile))37,38, which aligns with the experimental regioselectivities of 4a and 4b. It is possible that the compatibility between the “softness” of amination reagents and the reaction sites on the Zn(OTf)2-associated-9a species is the key to achieving the switchable α- and γ-selectivities.

Fig. 2: Reaction design and development.
figure 2

a Reaction development. b Isolated vinyl p-QM intermediate and its reactivities. c Computed Es(r) of vinyl p-QM intermediate with Zn(OTf)2 at the 0.004 a.u. isodensity surface. d Local softness analysis.

Full size image

DFT calculations

Furthermore, density functional theory calculations were performed to gain more insight into the α- and γ-selectivity determined by tailored amination reagents. For the addition of p-toluidine 4a onto Zn(OTf)2-coordinated-9a intermediate, the difference between the free energy barriers (ΔΔG‡) for α- and γ-amination is computed to be −3.8 kcal/mol (ΔG‡(α)-ΔG‡(γ) = −3.8 kcal/mol), which agrees with the observed exclusive α-selectivity (Fig. 3a). As for the amination process applying hydroxylamine 4b, the difference between the free energy barriers for α- and γ-amination is +1.4 kcal/mol and the α/γ selectivity is computed to be 1:11, which also aligns with the experimental data (Fig. 3b). Benzylamine 4c exhibits medium softness compared to 4a and 4b, with a calculated ΔΔG‡ of only +0.4 kcal/mol, and the theoretical α/γ ratio (1:2) of its amino acid product is the same with observed value (1:2). However, the amination utilizing benzenesulfonamide 4d is energetically unfavorable (ΔG‡(α) = 45.3 kcal/mol, ΔG‡(γ) = 47.5 kcal/mol), which could be a possible explanation for its poor reactivity in the according amination process (see Supplementary Fig. 14 for more calculation details). These calculation results provide possible evidence on our proposed mechanistic pathways, and suggest a potential origin for the divergent synthesis of α- and γ-amino acids employing our designed tailored amination strategy.

Fig. 3: DFT calculation.
figure 3

Free energy barriers for different substrates computed at B3LYP-D3(BJ)/def2-TZVPP/SMD(CH2Cl2)//B3LYP-D3(BJ)/def2-SVP level of theory. a Free energy barrier for 4a. b Free energy barrier for 4b. c Free energy barrier for 4c. d Free energy barrier for 4d.

Full size image

Reaction scope

Subsequently, the generality of the four-component reaction was investigated under the standard catalytic system, and the substrate scope for the synthesis of α-amino acids was first evaluated (Fig. 4). The variation of the anilines and other amines was studied in detail, with the aim of facilitating the rapid construction of an α-amino acid molecular library (Fig. 4a). A wide range of aniline derivatives containing an aryl ring with a single substitution were proved to be compatible amination reagents, constantly furnishing the products in >65% yields with excellent E/Z ratio and exclusive α-selectivity, and this performance remained invariant to both the substitution pattern and the electronic characteristics of the substituent on the phenyl ring (5a-5s). The defined structures of α-amino acid products were assigned on the basis of the x-ray crystallographic analysis of 5a. In light of the crucial role fluorinated compounds play in pharmaceuticals, particular emphasis was placed on aniline derivatives bearing a fluoroaryl group. These compounds exhibited remarkable reactivity in the synthesis of α-amino acids (5d, 5h, 5q). Notably, many of the products containing halide or nitro groups (5e-5g, 5i, 5m-5o, 5r) were afforded in good to excellent yields and with good E/Z ratios, making them ideal candidates for further structural manipulations of the amino acid derivatives. Anilines bearing a di-substituted aryl group were also found to be good substrates for this reaction (5t, 5u), and the products were furnished in 69% and 63% yield, respectively. It is worth noting that aliphatic amines could also be well incorporated into the desired products in decent yields without any erosion of E/Z selectivity (5v-5y), and the successful employment of morpholine as a viable aminated product was delivered in 53% yield and with excellent E/Z selectivity (5w). The reaction was also applicable to several other modified benzoquinones and Wittig reagents (5z-5af). When (triphenylphosphoranylidene)acetonitrile is used as the Wittig reagent, an aldehyde product is formed as a result of the elimination/hydrolysis process (see the Supplementary Fig. 3). Given that alkynes are among the most accessible bulk feedstocks, we were aiming at developing a general methodology that was applicable to different alkynes (Fig. 4c). In all substrates examined, the desired α-amino acid products were selectively obtained in good yields, demonstrating consistency across various substitution patterns and irrespective of the electronic or steric properties of the substituent on the aryl group (5ag-5az). Importantly, 1,3-diethynylbenzene, possessing two triple bonds, selectively converted only one alkynyl moiety into the final product (5am), and the synthetically useful ester function was also well-preserved in the catalytic system (5ax). The E/Z selectivities of product 5af and 5ah-5aj were poor, suggesting that the E/Z selectivity of the amination process governed by the catalyst may be compromised by the relatively large steric hindrance present in these substrates. Additionally, heterocyclic 3-ethynylthiophene was well-tolerated in this system, giving the α-aminated product in 55% yield with an Z/E ratio of 12:1 (5ba). And the alkyl-substituted alkyne, 1-pentyne, could also be a compatible substrate to deliver the designed product in 46% yield with exclusive stereoselectivity (5bb). However, when 1-phenyl-1-propyne served as the alkyne substrate, the desired product 5bc cannot be generated because the Wittig reaction was unable to proceed (5bc’). The scope of α-amino acid derivatives demonstrates certain correlation between alkyne aryl substituents and the E/Z selectivity, and the DFT-calculated transition state geometries for para-substituted aryl groups have been included in Supplementary Information (see Supplementary Figs. 18-23).

Fig. 4: Synthesis of α-amino acids.
figure 4

a The scope of the amine substrates. b The scope of the benzoquinone and Wittig reagent substrates. c The scope of the alkyne substrates. aCH3CN as solvent. Ph phenyl, Et ethyl, p-Tolyl 4-methyl-phenyl, Bn benzyl, i-Pr isopropyl, t-Bu tert-butyl.

Full size image

At the inception, our objective was to devise a general methodology capable of facilitating the switchable synthesis of both α- and γ-amino acids in an efficient manner. We therefore carefully examined the generality of the reaction for the synthesis of γ-amino acids, including the variations of all four reaction components (Fig. 5). Hydroxylamines bearing different substituted aryl rings were evaluated first and all reactions proceeded with great yields (generally >70%) and good γ/α selectivities (up to 10:1) (Fig. 5a, 6a–6i). The silyl moiety in O-(tert-butyldiphenylsilyl)hydroxylamine remained intact during the reaction process and successfully delivered the resulting γ-amino acid in 56% yield (6j), which offered a synthetic handle for structural transformation. We then sought to explore the reaction scope using a variety of simple alkynes (Fig. 5b). Alkynes bearing an aryl group with an alkyl substituent of different chain length were well tolerated, and the γ-amino acids were formed with excellent regioselectivities (6k-6n). A diverse array of terminal alkynes bearing a mono-substituted and di-substituted aryl ring were subjected to the catalytic system, and in all these examples, the γ-amino acids were readily formed in generally good yields (6o-6z). For the scope of alkynes, some products were formed in relatively low yields. The main reason is low conversion in the photo-irradiated [2 + 2] cycloaddition step, and no 1,4-addition side products on the quinone moiety is detected. Lastly, the reaction scope regarding benzoquinones and Wittig reagents was summarized (Fig. 5c). Several benzoquinones with a methyl or a halide moiety were found compatible with this reaction, offering extra structural versatility on the phenolic ring (6aa-6ac). Wittig reagents represent a family of versatile building blocks, and their compatibility with the multicomponent reaction holds significant synthetic value. The electronic nature and spatial effects of the ester substituents in Wittig reagents had minimal influence on the reaction, furnished the corresponding products in >75% yields (6ad-6af). Notably, the branched Wittig reagent was found to be highly effective in ensuring exclusive γ-selectivity regardless of the structural modifications in other three reaction partners (6ag-6ao). When applying (triphenylphosphoranylidene)acetonitrile as the Wittig reagent, the desired γ-amination product is readily afforded in 63% yield with γ:α ratio of 8:1 (see the Supplementary Fig. 3). Additionally, N-(phenylmethoxy)benzenamine was also a viable substrate in this catalytic system, exclusively delivering the α-aminated product in 62% yield and with an E/Z ratio of 3.5:1 (see the Supplementary Fig. 4). It should be noted that during the investigation of the substrate scope of γ-amino acid derivatives, the undesired 1,4-addition process based on the α,β-unsaturated ester motif was not detected.

Fig. 5: Synthesis of γ-amino acids.
figure 5

a The scope of the hydroxylamine substrates. b The scope of the alkyne substrates. c The scope of the benzoquinone and Wittig reagent substrates. Ph phenyl, Et ethyl, Bn benzyl, i-Pr isopropyl, t-Bu tert-butyl.

Full size image

To further enhance the synthetic utility of the developed method, it is essential that it be applicable to a broader range of nucleophilic reagents. With this objective in mind, we performed a series of experiments to assess the suitability of various nucleophiles under the same catalytic system (Fig. 6). A number of thiophenols with mono- or di-substituted aryl moiety were subjected to the reaction, and all four-component reactions proceeded smoothly to give the desired products in great yields and with excellent E/Z selectivities (typically >10:1) (Fig. 6a, 11a-11k). Pyrrole and indole scaffolds are widely present in drugs and natural products, and accommodation of these nucleophiles into the resulting products are medicinally important. Pyrrole and indoles with various substituents were all found to be suitable, and the desired products were formed in good yields with excellent E/Z selectivities (Fig. 6b, 11l-11r). The scope of some electron-rich arenes was also investigated, and both phenolic and amino aromatics served as suitable nucleophiles, leading to the formation of desired products in up to 84% yield and E/Z selectivity of 13:1 (Fig. 6c, 11s-11u). It was worth noting that applying p-methoxyphenol and phenylethyl alcohol as nucleophiles would lead to the according products with opposite regioselectivities (11v, 11w). This result further demonstrates the feasibility of switchable synthesis of other α- and γ-products using the tailored reagent strategy.

Fig. 6: Evaluation of other nucleophiles.
figure 6

a The scope of the thiophenol substrates. b The scope of the pyrrole and indole substrates. c The scope of the electron-rich arenes substrates. d Reactivities of phenol versus alcohol. Ph phenyl, Bn benzyl.

Full size image

Synthetic application

The practicality of the method documented herein was illustrated by demonstrating its suitability for the late-stage functionalization of natural products and drugs (Fig. 7a). Importantly, a series of commercially available drugs and drug intermediates were directly utilized as the amination reagents in our reaction without any derivatization (12a-12f). Among them, Paroxetine is a well-known antidepressant drug that serves as a selective serotonin reuptake inhibitor39, Desloratadine is an antihistamine agent40 and Amoxapine is a tricyclic antidepressant drug41. It was noteworthy that the gastric cytoprotective agent Troxipide42 could selectively undergo nucleophilic addition at cyclohexylamine site instead of amide moiety. Further, this reaction was applied to the functionalization of other complex bioactive molecules, including menthol, borneol and Ibuprofen, and all the reactions proceeded in good yields with excellent stereoselectivities (12g-12l). The structure of 12j was especially sophisticated featuring a unique combination of menthol and desloratadine. These modified complex amino acid derivatives may have augmented the biological activities compared to the original molecules. The scale-up experiments at 5 mmol toward the synthesis of both α- and γ-amino acids were performed under the standard catalytic system (Fig. 7b). The α-amino acid 5c was exclusively obtained in 72% yield and with >20:1 E/Z selectivity, and the γ-amino acid 6a was also attainable in 62% yield. At last, concise syntheses of free α- and γ-amino acids were conducted (Fig. 7c). The hydrogenation of 6a would lead to γ-lactam 13, while the ester hydrolysis followed by hydrogenation process could readily deliver free γ-amino acid 15, which was also viable through one-step hydrogenation of product 6ae. The direct hydrogenation of 5y shifted the synthesis from a free γ-amino acid 15 to a free α-amino acid 16. Importantly, the hybrid tripeptide 21 was smoothly synthesized using peptide synthesis protocols, starting from glycine and the α- and γ-amino acid 15/16 prepared by our method. This synthetic efforts indicted that the amino acid products of our work held promises for preparing other peptide molecules and thus facilitating the peptide-based drug discovery.

Fig. 7: Synthetic applications.
figure 7

a Late-stage modification of complex natural products and drugs. b Scale-up experiments. c Synthetic transformations.

Full size image

Discussion

Whereas amino acids are fundamental building blocks in both biological systems and organic synthesis, their direct synthesis from readily available feedstocks has remained largely unexplored. In particular, the divergent synthesis of α- and γ-amino acids from a shared intermediate under the same catalytic conditions is an area that has not yet been addressed. Here, we have discovered a four-component reaction of alkynes, benzoquinones, Wittig reagents and amines, all of which are simple bulk chemicals, to achieve the switchable synthesis of α- and γ-amino acids enabled by the tailored amination strategy. The reporting method features excellent substrate generality ( > 120 examples) with regard to different amines and other types of nucleophilic reagents, as well as multiple complex drugs bearing amine moieties, and afford α- and γ-amino acids of sophisticated molecular structures in good yields and excellent E/Z selectivities. The extended alkenyl-p-QM species has been isolated and fully characterized. LEAE calculations indicate that the tailored amination process may originate from the compatibility between the “softness” of electrophilic sites on the alkenyl-p-QM species and nitrogen atoms on the amines. DFT calculations present the difference between the free energy barriers for α- and γ-amination, and provide additional evidence that α- and γ-selectivity are influenced by tailored amination reagents. In a broader sense, we anticipate that the methodology delineated herein will catalyze ensuing intensive endeavors toward the switchable synthesis of amino acids from readily accessible feedstocks, thereby facilitating the development of more practical synthetic methods for efficiently producing these biologically important molecules.

Methods

General procedure for the four-component reaction

To a 1.5 mL screw-cap vial equipped with a magnetic stir bar, alkynes 1 (2 eq, 0.2 mmol) and benzoquinones 2 (1 eq, 0.1 mmol) in CH2Cl2 (1.5 mL) were added. The mixture was then irradiated under two 440 nm Kessil LEDs for 55 min at room temperature. After turning off the light, Wittig reagent 3 (1.2 eq, 0.12 mmol) was added to the reaction mixture, which was stirred for 2 min at room temperature. Subsequently, Zn(OTf)2 (10 mol%) and nucleophiles (1.2 eq, 0.12 mmol) were added to the mixture. The reaction mixture was concentrated under reduced pressure after the reaction were finished, and the residue was purified by column chromatography on silica gel to yield the products.