Organocatalyst Enabled Light Accelerated Amide and Peptide Synthesis

Organocatalyst Enabled Light Accelerated Amide and Peptide Synthesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Organocatalyst Enabled Light Accelerated Amide and Peptide Synthesis Wangsheng Sun, yiping li, Jingyue Li, Quan Zuo, Zhouming Shen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4938807/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Catalytic methods for amide and peptide synthesis have long been recognized as one of the most pressing challenges in industry and academia, requiring novel catalysts to meet this requirement. Herein, we report an organocatalyst, named Cat-Se , for direct amide and peptide synthesis. Cat-Se , which has a simple and exquisite chemical structure, can be conveniently synthesized and catalyzes the condensation of various carboxylic acids and amines to the corresponding amides in excellent yields within 30-40 minutes under very mild light irradiation conditions without any undesirable operations, such as heating, dehydration, or gas protection. The method exhibits high efficiency, selectivity, and functional group tolerance without loss of stereochemical integrity in peptide synthesis. Significantly, Cat-Se shows power in peptide fragment condensation and solid-phase peptide synthesis on resin, making it an attractive alternative for peptide drug synthesis. Physical sciences/Chemistry/Catalysis/Organocatalysis Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Amide bonds are widespread in natural products, drugs, fine chemicals and biomaterials, and are fundamental and essential functional groups of peptides and proteins, the importance of which cannot be overstated. 1 Amide synthesis from carboxylic acids and amines is the most executed transformation in organic and medicinal chemistry, 2-7 particularlywith the growing popularity of peptides as biological reagents and therapeutics. 8,9 However, the contemporary approach to amides and peptides usually relies on superstoichiometric coupling reagents, which generate significant waste, particularly in peptide synthesis. 10-12 As a consequence, ‘ General methods for catalytic/sustainable (direct) amide or peptide formation ’ has become one of the most pressing challenges in both academia and industry. 13,14 The urgency of addressing this challenge is also reflected in the succession of related perspectives and comment articles published in Nature Catalysis. 15,16 It leads to a multitude of efforts to develop catalysts that offer sustainable approaches to amide bond formation and peptide synthesis (Fig. 1a). 17,18 For instance, pioneeredby Yamamoto et al. in 1996, a series of boron-based catalysts have been developed by Yamamoto 19 , Shibasaki & Kumagai 20,21 , Shimada 22 , Takemoto 23 , Hall 24 , Sheppard 25 and others. 26 Adolfsson 27,28 , Williams 29 and Parac-Vogt 30 have investigated the group(IV) metal-based catalysts for amide synthesis. 31 Recently Arora et al. have designed a macrocyclic diselenide catalyst [Se]-1 on urea-based hydrogen-bonding scaffolds. 32,33 Yamamoto et al. have disclosed tantalum [Ta]-1 or aminosilane [Si]-1 catalyzed peptide condensation. 34-36 Zhao et al. have realized a radical strategy for the catalytic formation of acyloxyphosphoniumions that enables direct amidation under dual catalysis of photo-redox and cobaloxime. 37 Despite these elegant advances, there are still many problems that need to be solved during the application of these catalysts. For example, most catalysts usually functionunder heated conditions, and the reaction needs to be dehydrated using Dean-Stark or molecular sieves. Some catalysts need to be used under inert gas protection or are complex to be prepared. Additionally, excessively long reaction time, racemization, metal toxicity, and/or incompatibility with solid-phase peptide synthesis (SPPS) also limit their use in peptide manufacturing. 38,39 Obviously, catalysts that can simultaneously solve these problems have not been disclosed currently. 40,41 In this context, a novel readily available catalyst with a simple structure that can solve all the problems is still highly desired and its accomplishment is full of challenges. Inspired by the precedents and intrigued by the challenges, as a continuation of our interests in peptide synthesis 42 and modification 43-49 , herein we report our design and application of organocatalyst, Cat-Se , for direct amide and peptide synthesis(Fig. 1c). Cat-Se featuring a simple and exquisite chemical structure can be synthesized conveniently and cost-effectively and catalyzes the condensation of various carboxylic acids and amines to the corresponding amides in excellent yields within 30-40 minutes under very mild light irradiated conditions, without any undesired operations like heating, dehydration, or gas protection. The method exhibits high selectivity and functional group tolerance and no racemization was observed. It is noteworthy that Cat-Se exhibits remarkable efficacy in peptide fragment condensation and SPPS. In comparison to the prevailing HBTU approach, the method is capable of achieving comparable outcomes in terms of reaction time, side reaction control, and yield, rendering it a compelling alternative for peptide drug synthesis. Results Catalyst design and development The Corey-Nicolaou macrolactonization, in which the P-S ionium salt is formed from 2,2'-dithiodipyridine and triphenylphosphine, exhibits good reactivity in esterification. 50 This inspired the initial idea of combining the structural features of 4,6-dihydroxypyrimidine 51 into 4,6-dithiolpyrimidine dimer to regenerate the structure via tautomerization (Fig. 1b). Meanwhile, we envisioned accelerating the catalytic reaction using more mild light instead of heating by combining certain structural features of dyes and photosensitizers 52 into the catalyst. Consequently, the catalyst Cat-S (Fig. 1c) was designed, whose core structure was formed by the reaction of 4-nitrobenzaldehyde and 4,6-dihydroxypyrimidine in water, 53 with subsequent chlorination and thiolation with thiourea. The synthetic process for Cat-S is extremely convenient and easy to handle, without the need for column separation purification. To validate our design, we chose phenylacetic acid ( 1a ) and 2-phenylethylamine ( 2a ) as model substrates to test the catalytic ability of Cat-S in 10 mol% loads (Fig. 1c). The experiment showed that 1a and 2a were successfully converted to the amide in 73% isolated yield with the aid of 1 equiv. of PPh 3 after 3 hours under blue LEDs irradiation, without the need for heating, gas protection, or dehydration using Dean-Stark or molecular sieves. Encouraged by this result and to further improve the catalytic efficiency, the sulfur in Cat-S was replaced with selenium taking into account the notable difference between S and Se in the redox properties, 54 resulting in Cat-Se , which exhibited remarkably improved catalytic efficiency with 90% isolated yield amidation of 1a and 2a within 30 minutes under identical conditions. Reaction optimization With the optimal catalyst at hand, the reaction conditions were investigated. First, we continued to select phenylacetic acid ( 1a ) and 2-phenylethylamine ( 2a ) as model substrates and tested the catalytic ability of Cat-Se under ambient dark conditions. It was observed that Cat-Se could carry out the amidation process under dark conditions (Table 1, entries 1 vs. 2), albeit at a slow rate, resulting in a 31% yield after 12 hours. After heating the reaction to 60°C, the yield rose to 92% after 12 hours (entry 3). Nevertheless, when the reaction was conducted under irradiation by blue LEDs (440-445 nm) in transparent glass tubes, the reaction was significantly accelerated, resulting in an 81% yield after just 30 minutes at room temperature (entry 4). Furthermore, the yield could be increased to 90% by performing the same reaction within quartz tubes (entry 5), which was over 20 times faster than heating. The influence of distinct wavelengths of light was also investigated, the optimal yield was achieved under 440-445 nm blue LEDs light, although other wavelengths of light could also promote the reaction with reduced efficiency (entries 5-9). The results indicated that both light and heat could accelerate the catalytic reaction. The sun could provide both light and heat. When the light source was replaced by sunlight, a 95% yield was achieved after 30 minutes (entry 10). However, in the subsequent study, we still selected the 440 nm blue LEDs as the light source to maintain the stability of the light. Subsequently, the effect of catalyst dosage was investigated by reducing Cat-Se loading to 5 mol%. This resulted in the yield drop to 86% (entry 11). Therefore, it was concluded that a loading of 10 mol% was optimal. In addition, triphenylphosphine was one of the most commonly used phosphorus reagents. However, in liquid-phase reactions, the removal of the triphenylphosphane oxide was a significant challenge. 55 To address this issue, we proposed using diphenylphosphine oxide as an alternative reagent. This approach proved effective, and the byproduct diphenylphosphinic anhydride was more readily removable (entry 12). Nevertheless, triphenylphosphine was still chosen as the preferred phosphorus reagent in subsequent studies due to its lower cost and lack of influence on SPPS. In addition, the impact of the solvent was evaluated. Under identical conditions, the yields ranged from 13% to 81% in Tol, DMF, DCM, and THF after 30 minutes (entries 13-16), with a performance that was not as optimal as in MeCN. Finally, the effect of concentration on the reaction was investigated, and the optimal reaction conditions were determined based on these experiments (entry 17). Substrate scope With the optimal reaction conditions in hand, we investigated the reaction scope of the method in simple substrates (Fig. 2). We were pleased to observe that a series of primary amines ( 3a , 3b , 3e, and 3f ), secondary amine ( 3c ), substituted aniline ( 3d ), aliphatic acids ( 3g , 3h , 3j - 3r ), and aryl acid ( 3i , 3s ) could be amidated with excellent yields after about 30-40 minutes and without any racemization. Furthermore, even in the presence of competing groups on the substrates, such as -NH ( 3o ), and -OH ( 3p - 3s ), the catalyst demonstrated excellent selectivity. This highlights the impressive capabilities of Cat-Se in amidation. We next explored the reaction scope in peptide couplings. Amino acids protected with the typical amine-protecting groups Fmoc and Boc groups were tested in the reaction (Fig. 3). Cat-Se successfully catalyzed all twenty natural amino acids to the corresponding dipeptides with good yields after 30-40 minutes without any loss of stereochemical integrities ( 6a - 6r , ee or de >99%). The condensation of secondary amine substrates, such as N-Me-L-Leu-OMe⋅HCl and L-Pro-OMe⋅HCl, also yields the corresponding dipeptides in good yield and without any loss of stereochemical integrities ( 6w , 89% yield, de >99%; 6x , 88% yield, de >99%). Furthermore, Cat-Se exhibited excellent specific selectivity without any side reactions when the side chains of certain amino acids were unprotected, such as Tyr ( 6g - 6i ), Trp ( 6i - 6m , 6o - 6p ), Thr ( 6t ), Ser ( 6u ), and His ( 6v ). This suggests a new avenue for future research in the synthesis of unprotected peptides. Notably, the reactions of amino acids with sterically hindered side chains, such as Fmoc-L-Ile-OH and Fmoc-Aib-OH could be coupled with L-Ile-OMe⋅HCl or L-Ile-O t Bu⋅HCl to give 6y , 6y’ and 6z in 83-91% yields and without any loss of stereochemical integrities. Finally, the performance of Cat-Se in gram-scale dipeptide synthesis was also investigated. In the presence of 10 mol% Cat-Se , 2.0 mmol of Fmoc-L-Asp(OtBu)-OH and 2.0 mmol of L-Trp-OMe⋅HCl were successfully converted to 6o’ with 96% yield (1.18 g, de >99%). This demonstrated its effectiveness in amino acid substrates and established a strong foundation for its use in SPPS. Fragment condensation is one of the major methods of peptide drug synthesis. To further test the catalyst's performance, we investigated its reaction scope in peptide fragment condensation (Fig. 4). The reactions produced the corresponding peptides in 75-95% yields with dr >19:1. ( 9a - 9d ). This showed that it was suitable for peptide fragment condensation. Finally, we completed the fragment condensation of leuprorelin using this method. The protected substrates 7f and 8f were amidated in a 7+2 mode. After a series of deprotection, purification, and lyophilization, the target product, leuprorelin 9f , was obtained with a 36% yield and 99% purity. Mechanism study To further understand the reaction, phosphorus-31 nuclear magnetic resonance ( 31 P NMR) spectroscopy was conducted. After the reaction with Cat-Se participation was irradiated under blue light for a while, the 31 P NMR spectra displayed a new signal at 35.2 ppm, in addition to triphenylphosphine with triphenylphosphine oxide (Fig. 5a). It was identified as triphenylphosphine selenide by comparison with the relative sample. We corroborated the identification using LC-MS and found the catalyst intermediate III . Afterward, we analyzed the reaction involving Cat-S by the same method, and the 31 P NMR spectra also displayed a new signal at 43.0 ppm, which was identified as triphenylphosphine sulfide. The catalyst intermediate III’ also was identified using LC-MS. A plausible mechanism based on the above experimental results and previous reports 32,33,50 was shown in Fig. 5b. Cat-Se formed intermediate I with triphenylphosphine in the light, and it was attacked by carboxylic acid to form intermediate II and released triphenylphosphine selenide. The intermediate II was similar to the transition state of many coupling reagents and it easily reacted with amines to form amides. Finally, because the P-O bond was stronger than the P-Se bond, intermediate III would react with triphenylphosphine selenide to form triphenylphosphane oxide and release the Cat-Se . Catalytic solid-phase peptide synthesis Next, the feasibility of this new strategy for SPPS was evaluated (Fig. 6). The catalytic synthesis of peptide drugs tetragastrin and triptorelin was successfully achieved, and compared with the conventional method of using the coupling reagent HBTU. Tetragastrin was first synthesized on Rink MBHA resins using Cat-Se and HBTU, respectively (Fig. 6a, 6b). The purity of the crude peptides was analyzed using HPLC. The results were relatively similar, indicating that no significant additional side reactions occurred during the catalytic solid-phase peptide synthesis process using Cat-Se compared to the conventional method (Fig. 6b). The pure tetragastrin was obtained through further preparation and lyophilization. Both methods resulted in similar yields ( Cat-Se : 59% yield, 98% purity; HBTU: 66% yield, 97% purity). Our method was then extended to the solid-phase synthesis of the triptorelin (Fig. 6c). We also analyzed the purity of the crude peptides obtained by the two methods and found no significant additional side reactions. After purification and lyophilization, we obtained triptorelin using Cat-Se (34% yield, 99% purity) and HBTU (49% yield, 99% purity), respectively. We believed that the method would be attractive to the pharmaceutical industry. Conclusion In conclusion, we have developed a unique catalyst, Cat-Se , to solve the problems faced by previous catalysts in amide and peptide synthesis. This catalyst has a simple and exquisite structure and can condense various carboxylic acid and amine substrates to the corresponding amides with high yields in about 30 minutes. Cumbersome operations such as heating, dehydration, and gas protection, which were common in the past, are avoided with this method. The method also exhibited excellent chemoselectivity and chirality retention. The reasonable reaction time and good reaction effect made it well compatible with SPPS, which was demonstrated by the synthesis of tetragastrin and triptorelin using Cat-Se . It was already comparable to the conventional SPPS method in terms of reaction time, side reactions, and yield, which is attractive in the pharmaceutical industry. We believe that Cat-Se would have good application prospects in amide and peptide synthesis. Additionally, we think that combining Cat-Se with supported catalysis and continuous flow chemistry can enhance its value in the research of peptide drug synthesis, which is ongoing in our lab. Methods Classic Experimental Procedure Method A: Carboxylic acid (0.10 mmol), amine (0.10 mmol), triphenylphosphine (0.11 mmol or 0.15 mmol), and 10 mol% Cat-Se were added to a 10 mL quartz tube, followed by the solvent MeCN (2 mL). The tube was then placed in a photoreactor and subjected to irradiation using 440–445 nm blue LEDs (0.66 A, 25 V, with cooling water) while being stirred at room temperature. The reaction was monitored by TLC until complete consumption of triphenylphosphine. Subsequently, the reaction solution was concentrated, and the product was obtained through purification via silica gel column chromatography. Method B: Carboxylic acid (0.10 mmol), amino acid ester hydrochloride (0.10 mmol), DIEA (0.10 mmol), triphenylphosphine (0.11 mmol or 0.15 mmol), and 10 mol% Cat-Se were added to a 10 mL quartz tube, followed by the solvent MeCN (2 mL). The tube was then placed in a photoreactor and subjected to irradiation using 440–445 nm blue LEDs (0.66 A, 25 V, with cooling water) while being stirred at room temperature. The reaction was monitored by TLC until complete consumption of triphenylphosphine. Subsequently, the reaction solution was concentrated and the product was obtained through purification via silica gel column chromatography. Declarations Competing interests The authors declare no competing interests. Author contributions Y.L. designed and carried out most of the reactions and wrote the first draft of the paper. J.L., Q.Z., Z.S., H.K. and G.B. provided raw material support and performed some of the synthetic experiments. Y.L. and W.S. analyzed the data and edited the manuscript and supplementary materials. J.N., W.S. and R.W. designed and supervised the whole project. The paper was written through contributions from all authors. Acknowledgements We thank the financial support from the CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-074, 2021-I2M-3-001, 2021-I2M-1-026, and 2022-I2M-2-002), the Fundamental Research Funds for the Central Universities (lzujbky-2024-ey10), the Program for Chang-Jiang Scholars and Innovative Research Team in University (IRT_15R27), the National Natural Science Foundation of China (82173678). Data availability All information relating to experimental procedures, high-performance liquid chromatography, mechanistic studies, nuclear magnetic resonance spectra, and high-resolution mass spectrometry are available in Supplementary Information. 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Dev. 26 , 1845-1853, (2022). Table Table 1 is available in the Supplementary Files section Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.pdf Table1.docx Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4938807","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":353772893,"identity":"e8ade772-a9d7-45b0-be8f-574595858395","order_by":0,"name":"Wangsheng Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYNCCCgswJUGCljMSpGphbCNFi/yM3GOSP+dJ2BscYD54m4fBLo+gFoMbeWnSvNskmA0OsCVb8zAkFxPWIpFjdptxmwSbwQEeM2kehgOJDYQdlmN28+ccCR6DA/zfiNPCcCPH7AZvg4QE0BY24rQYnHlj/pvnmISB5GE2Y8s5BslEOKw9x9jwR42NPd/x5oc33lTYEeEwOGAGW0q8+lEwCkbBKBgFeAAAKb4y0lpwmHwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-5277-3329","institution":"Lanzhou University","correspondingAuthor":true,"prefix":"","firstName":"Wangsheng","middleName":"","lastName":"Sun","suffix":""},{"id":353772894,"identity":"fc0d0e38-99d7-4327-959f-6e443db99978","order_by":1,"name":"yiping li","email":"","orcid":"https://orcid.org/0009-0009-9665-858X","institution":"","correspondingAuthor":false,"prefix":"","firstName":"yiping","middleName":"","lastName":"li","suffix":""},{"id":353772895,"identity":"2964cf88-61a2-47f0-98f9-03ba0d404519","order_by":2,"name":"Jingyue Li","email":"","orcid":"","institution":"Lanzhou Univerisity","correspondingAuthor":false,"prefix":"","firstName":"Jingyue","middleName":"","lastName":"Li","suffix":""},{"id":353772896,"identity":"ecba6d23-448c-41e2-ab03-d6e93504c464","order_by":3,"name":"Quan Zuo","email":"","orcid":"","institution":"Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Zuo","suffix":""},{"id":353772897,"identity":"0abe266c-90dc-4362-b215-36730dada869","order_by":4,"name":"Zhouming Shen","email":"","orcid":"","institution":"Laznhou University","correspondingAuthor":false,"prefix":"","firstName":"Zhouming","middleName":"","lastName":"Shen","suffix":""},{"id":353772898,"identity":"533c3ebd-130b-4fc2-b94a-ecf2025b87ff","order_by":5,"name":"Haoyu Kuang","email":"","orcid":"","institution":"Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Haoyu","middleName":"","lastName":"Kuang","suffix":""},{"id":353772899,"identity":"5b8245f5-5d71-465f-8139-fc6145bebee2","order_by":6,"name":"Guangjun Bao","email":"","orcid":"","institution":"Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Guangjun","middleName":"","lastName":"Bao","suffix":""},{"id":353772900,"identity":"ca78d11f-f4c1-42d8-8822-1b9c60a162cc","order_by":7,"name":"Jingman Ni","email":"","orcid":"","institution":"Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Jingman","middleName":"","lastName":"Ni","suffix":""},{"id":353772901,"identity":"e3768a1e-40f9-4428-a3d0-4ce404a6f534","order_by":8,"name":"Rui Wang","email":"","orcid":"https://orcid.org/0000-0002-4719-9921","institution":"Lanzhou University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-08-19 13:05:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4938807/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4938807/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":65235020,"identity":"377fdbe4-746b-4be4-8fd9-4441e62608b5","added_by":"auto","created_at":"2024-09-25 05:25:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":87889,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReported catalysts for direct amidation, and the design and development of new catalyst. a\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003eSome catalysts reported that can be used for amidation between amino acids. \u003cstrong\u003eb\u003c/strong\u003e, Design Ideas for catalysts. \u003cstrong\u003ec\u003c/strong\u003e, Structure of catalysts \u003cstrong\u003eCat-S\u003c/strong\u003e and \u003cstrong\u003eCat-Se\u003c/strong\u003e, and verification of their catalytic ability in direct amidation. Reaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.10 mmol), \u003cstrong\u003e2a\u003c/strong\u003e (0.10 mmol), \u003cstrong\u003eCat\u003c/strong\u003e (10 mol%), PPh\u003csub\u003e3\u003c/sub\u003e (0.11 mmol), MeCN (1 mL), for reaction details, see Method A. Isolated yield was provided.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/c8679146b238b2d4b15ec92f.png"},{"id":65235023,"identity":"1d0af57e-ef84-4d5d-834c-99840f7c1436","added_by":"auto","created_at":"2024-09-25 05:25:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":119621,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of amide condensation. \u003c/strong\u003eRun with method A. \u003csup\u003ea\u003c/sup\u003ePPh\u003csub\u003e3\u003c/sub\u003e (0.15 mmol). Isolated yield was provided. The enantiomeric excess (\u003cem\u003eee\u003c/em\u003e) value was determined by chiral HPLC analysis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/f3dc8bc1af955ff41060d9b7.png"},{"id":65235024,"identity":"dc8e468f-139c-4931-9d80-eda225070a6c","added_by":"auto","created_at":"2024-09-25 05:25:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":108226,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of amino acid condensation.\u003c/strong\u003e \u003cstrong\u003e6a\u003c/strong\u003e-\u003cstrong\u003e6z\u003c/strong\u003e run with method B. Isolated yield was provided. The \u003cem\u003eee\u003c/em\u003e and diastereo excess (\u003cem\u003ede\u003c/em\u003e) value was determined by chiral HPLC analysis. \u003csup\u003ea\u003c/sup\u003eSee the Supplementary Information for reaction details. \u003csup\u003eb\u003c/sup\u003eThe \u003cem\u003ede\u003c/em\u003e value was determined by \u003csup\u003e1\u003c/sup\u003eH NMR analysis.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/db42abb232155de4fa6add90.png"},{"id":65235531,"identity":"795bb23a-e69b-4b2d-95fc-f9eb5acc3aaf","added_by":"auto","created_at":"2024-09-25 05:33:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62752,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of peptide condensation. 9a\u003c/strong\u003e-\u003cstrong\u003e9d \u003c/strong\u003erun with method A. The diastereo ratio (\u003cem\u003edr\u003c/em\u003e) value was determined by \u003csup\u003e1\u003c/sup\u003eH NMR analysis.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/fdb82b78ca99b9dadc3d7689.png"},{"id":65235025,"identity":"58149a5b-331a-4a04-a005-f1c39ea088e7","added_by":"auto","created_at":"2024-09-25 05:25:24","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":50562,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanism study. a\u003c/strong\u003e, \u003csup\u003e31\u003c/sup\u003eP NMR tracking and control experiment. \u003cstrong\u003eb\u003c/strong\u003e, Plausible mechanism.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/39250788e2e2e1be5d4c965a.png"},{"id":65235027,"identity":"906abeee-8473-403b-b0c3-7e2ffc93d44b","added_by":"auto","created_at":"2024-09-25 05:25:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":75146,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCatalytic solid-phase peptide drugs synthesis and comparison with conventional method. a\u003c/strong\u003e,\u003cstrong\u003e \u003c/strong\u003eSPPS process using \u003cstrong\u003eCat-Se\u003c/strong\u003e and HBTU, respectively. \u003csup\u003ea\u003c/sup\u003eDIEA was added to help amino acids dissolve better in the DCM.\u003cstrong\u003e b\u003c/strong\u003e, Synthesis and comparison of tetragastrin. \u003cstrong\u003ec\u003c/strong\u003e, Synthesis and comparison of triptorelin. The HPLC graph is the purity analysis of the crude peptide, and the comparison of the two methods is done by the percent area values. The yield and purity values are the result of pure peptide products after preparation.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/ff08ccda50f0d513e468ed11.png"},{"id":65236526,"identity":"c1ac44e4-f591-413a-b66d-3d7db3b6836f","added_by":"auto","created_at":"2024-09-25 05:41:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1070437,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/28a73e7f-5791-4c1a-a092-35be84f15624.pdf"},{"id":65235533,"identity":"5bb410ce-a436-4aa9-9292-c2865b9e668c","added_by":"auto","created_at":"2024-09-25 05:33:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6059538,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/42d900de9ee16d168b53a677.pdf"},{"id":65235022,"identity":"a0eda95e-1f4c-4286-a458-954b31244b54","added_by":"auto","created_at":"2024-09-25 05:25:24","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32281,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4938807/v1/8f86a7ef29e43b82e7c47075.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Organocatalyst Enabled Light Accelerated Amide and Peptide Synthesis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmide bonds are widespread in natural products, drugs, fine chemicals and biomaterials, and are fundamental and essential functional groups of peptides and proteins, the importance of which cannot be overstated.\u003csup\u003e\u0026nbsp;1\u003c/sup\u003e Amide synthesis from carboxylic acids and amines is the most executed transformation in organic and medicinal chemistry,\u003csup\u003e2-7\u0026nbsp;\u003c/sup\u003eparticularlywith the growing popularity of peptides as biological reagents and therapeutics.\u003csup\u003e8,9\u003c/sup\u003e However, the contemporary approach to amides and peptides usually relies on superstoichiometric coupling reagents, which generate significant waste, particularly in peptide synthesis.\u003csup\u003e10-12\u003c/sup\u003e As a consequence, ‘\u003cem\u003eGeneral methods for catalytic/sustainable (direct) amide or peptide formation\u003c/em\u003e’ has become one of the most pressing challenges in both academia and industry.\u003csup\u003e13,14\u003c/sup\u003e The urgency of addressing this challenge is also reflected in the succession of related perspectives and comment articles published in Nature Catalysis.\u003csup\u003e15,16\u003c/sup\u003e It leads to a multitude of efforts to develop catalysts that offer sustainable approaches to amide bond formation and peptide synthesis (Fig. 1a).\u003csup\u003e17,18\u0026nbsp;\u003c/sup\u003eFor instance, pioneeredby Yamamoto et al. in 1996, a series of boron-based catalysts have been developed by Yamamoto\u003csup\u003e19\u003c/sup\u003e, Shibasaki \u0026amp; Kumagai\u003csup\u003e20,21\u003c/sup\u003e, Shimada\u003csup\u003e22\u003c/sup\u003e, Takemoto\u003csup\u003e23\u003c/sup\u003e, Hall\u003csup\u003e24\u003c/sup\u003e, Sheppard\u003csup\u003e25\u003c/sup\u003e and others.\u003csup\u003e26\u003c/sup\u003e Adolfsson\u003csup\u003e27,28\u003c/sup\u003e, Williams\u003csup\u003e29\u003c/sup\u003e and Parac-Vogt\u003csup\u003e30\u003c/sup\u003e have investigated the group(IV) metal-based catalysts for amide synthesis.\u003csup\u003e31\u003c/sup\u003e Recently Arora et al. have designed a macrocyclic diselenide catalyst \u003cstrong\u003e[Se]-1\u003c/strong\u003e on urea-based hydrogen-bonding scaffolds.\u003csup\u003e32,33\u0026nbsp;\u003c/sup\u003eYamamoto et al. have disclosed tantalum \u003cstrong\u003e[Ta]-1\u003c/strong\u003e or aminosilane \u003cstrong\u003e[Si]-1\u0026nbsp;\u003c/strong\u003ecatalyzed peptide condensation.\u003csup\u003e34-36\u003c/sup\u003e Zhao et al. have realized a radical strategy for the catalytic formation of acyloxyphosphoniumions that enables direct amidation under dual catalysis of photo-redox and cobaloxime.\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eDespite these elegant advances, there are still many problems that need to be solved during the application of these catalysts. For example, most catalysts usually functionunder heated conditions, and the reaction needs to be dehydrated using Dean-Stark or molecular sieves. Some catalysts need to be used under inert gas protection or are complex to be prepared. Additionally, excessively long reaction time, racemization, metal toxicity, and/or incompatibility with solid-phase peptide synthesis (SPPS) also limit their use in peptide manufacturing.\u003csup\u003e38,39\u003c/sup\u003e Obviously, catalysts that can simultaneously solve these problems have not been disclosed currently.\u003csup\u003e40,41\u003c/sup\u003e In this context, a novel readily available catalyst with a simple structure that can solve all the problems is still highly desired and its accomplishment is full of challenges.\u003c/p\u003e\n\u003cp\u003eInspired by the precedents and intrigued by the challenges, as a continuation of our interests in peptide synthesis\u003csup\u003e42\u003c/sup\u003e and modification\u003csup\u003e43-49\u003c/sup\u003e, herein we report our design and application of organocatalyst, \u003cstrong\u003eCat-Se\u003c/strong\u003e, for direct amide and peptide synthesis(Fig. 1c). \u003cstrong\u003eCat-Se\u003c/strong\u003e featuring a simple and exquisite chemical structure can be synthesized conveniently and cost-effectively and catalyzes the condensation of various carboxylic acids and amines to the corresponding amides in excellent yields within 30-40 minutes under very mild light irradiated conditions, without any undesired operations like heating, dehydration, or gas protection. The method exhibits high selectivity and functional group tolerance and no racemization was observed. It is noteworthy that \u003cstrong\u003eCat-Se\u003c/strong\u003e exhibits remarkable efficacy in peptide fragment condensation and SPPS. In comparison to the prevailing HBTU approach, the method is capable of achieving comparable outcomes in terms of reaction time, side reaction control, and yield, rendering it a compelling alternative for peptide drug synthesis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCatalyst design and development\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Corey-Nicolaou macrolactonization, in which the P-S ionium salt is formed from 2,2\u0026apos;-dithiodipyridine and triphenylphosphine, exhibits good reactivity in esterification.\u003csup\u003e50\u0026nbsp;\u003c/sup\u003eThis inspired the initial idea of combining the structural features of 4,6-dihydroxypyrimidine\u003csup\u003e51\u003c/sup\u003e into 4,6-dithiolpyrimidine dimer to regenerate the structure via tautomerization (Fig. 1b). Meanwhile, we envisioned accelerating the catalytic reaction using more mild light instead of heating by combining certain structural features of dyes and photosensitizers\u003csup\u003e52\u003c/sup\u003e into the catalyst. Consequently, the catalyst \u003cstrong\u003eCat-S\u003c/strong\u003e (Fig. 1c) was designed, whose core structure was formed by the reaction of 4-nitrobenzaldehyde and 4,6-dihydroxypyrimidine in water,\u003csup\u003e53\u003c/sup\u003e with subsequent chlorination and thiolation with thiourea. The synthetic process for \u003cstrong\u003eCat-S\u0026nbsp;\u003c/strong\u003eis extremely convenient and easy to handle, without the need for column separation purification.\u003c/p\u003e\n\u003cp\u003eTo validate our design, we chose phenylacetic acid (\u003cstrong\u003e1a\u003c/strong\u003e) and 2-phenylethylamine (\u003cstrong\u003e2a\u003c/strong\u003e) as model substrates to test the catalytic ability of \u003cstrong\u003eCat-S\u0026nbsp;\u003c/strong\u003ein\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e10\u0026thinsp;mol% loads (Fig. 1c). The experiment showed that \u003cstrong\u003e1a\u003c/strong\u003e and \u003cstrong\u003e2a\u003c/strong\u003e were successfully converted to the amide in 73% isolated yield with the aid of 1 equiv. of PPh\u003csub\u003e3\u003c/sub\u003e after 3 hours under blue LEDs irradiation, without the need for heating, gas protection, or dehydration using Dean-Stark or molecular sieves. Encouraged by this result and to further improve the catalytic efficiency, the sulfur in \u003cstrong\u003eCat-S\u003c/strong\u003e was replaced with selenium\u0026nbsp;taking into account the notable difference between S and Se\u0026nbsp;in the redox properties,\u003csup\u003e54\u003c/sup\u003e resulting in \u003cstrong\u003eCat-Se\u003c/strong\u003e, which exhibited remarkably improved catalytic efficiency with 90% isolated yield amidation of \u003cstrong\u003e1a\u003c/strong\u003e and \u003cstrong\u003e2a\u003c/strong\u003e within 30 minutes under identical conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReaction optimization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith the optimal catalyst at hand, the reaction conditions were investigated. First, we continued to select phenylacetic acid (\u003cstrong\u003e1a\u003c/strong\u003e) and 2-phenylethylamine (\u003cstrong\u003e2a\u003c/strong\u003e) as model substrates and tested the catalytic ability of \u003cstrong\u003eCat-Se\u003c/strong\u003e under ambient dark conditions. It was observed that \u003cstrong\u003eCat-Se\u003c/strong\u003e could carry out the amidation process under dark conditions (Table 1, entries 1 vs. 2), albeit at a slow rate, resulting in a 31% yield after 12 hours. After heating the reaction to 60\u0026deg;C, the yield rose to 92% after 12 hours (entry 3). Nevertheless, when the reaction was conducted under irradiation by blue LEDs (440-445 nm) in transparent glass tubes, the reaction was significantly accelerated, resulting in an 81% yield after just 30 minutes at room temperature (entry 4). Furthermore, the yield could be increased to 90% by performing the same reaction within quartz tubes (entry 5), which was over 20 times faster than heating. The influence of distinct wavelengths of light was also investigated, the optimal yield was achieved under 440-445 nm blue LEDs light, although other wavelengths of light could also promote the reaction with reduced efficiency (entries 5-9). The results indicated that both light and heat could accelerate the catalytic reaction. The sun could provide both light and heat. When the light source was replaced by sunlight, a 95% yield was achieved after 30 minutes (entry 10). However, in the subsequent study, we still selected the 440 nm blue LEDs as the light source to maintain the stability of the light.\u003c/p\u003e\n\u003cp\u003eSubsequently, the effect of catalyst dosage was investigated by reducing Cat-Se loading to 5 mol%. This resulted in the yield drop to 86% (entry 11). Therefore, it was concluded that a loading of 10 mol% was optimal. In addition, triphenylphosphine was one of the most commonly used phosphorus reagents. However, in liquid-phase reactions, the removal of the triphenylphosphane oxide was a significant challenge.\u003csup\u003e55\u003c/sup\u003e To address this issue, we proposed using diphenylphosphine oxide as an alternative reagent. This approach proved effective, and the byproduct diphenylphosphinic anhydride was more readily removable (entry 12).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNevertheless, triphenylphosphine was still chosen as the preferred phosphorus reagent in subsequent studies due to its lower cost and lack of influence on SPPS. In addition, the impact of the solvent was evaluated. Under identical conditions, the yields ranged from 13% to 81% in Tol, DMF, DCM, and THF after 30 minutes (entries 13-16), with a performance that was not as optimal as in MeCN. Finally, the effect of concentration on the reaction was investigated, and the optimal reaction conditions were determined based on these experiments (entry 17).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith the optimal reaction conditions in hand, we investigated the reaction scope of the method in simple substrates\u0026nbsp;(Fig. 2). We were pleased to observe that a series of primary amines (\u003cstrong\u003e3a\u003c/strong\u003e, \u003cstrong\u003e3b\u003c/strong\u003e, \u003cstrong\u003e3e,\u003c/strong\u003e and \u003cstrong\u003e3f\u003c/strong\u003e), secondary amine (\u003cstrong\u003e3c\u003c/strong\u003e), substituted aniline (\u003cstrong\u003e3d\u003c/strong\u003e), aliphatic acids (\u003cstrong\u003e3g\u003c/strong\u003e, \u003cstrong\u003e3h\u003c/strong\u003e, \u003cstrong\u003e3j\u003c/strong\u003e-\u003cstrong\u003e3r\u003c/strong\u003e), and aryl acid (\u003cstrong\u003e3i\u003c/strong\u003e, \u003cstrong\u003e3s\u003c/strong\u003e) could be amidated with excellent yields after about 30-40 minutes and without any racemization. Furthermore, even in the presence of competing groups on the substrates, such as -NH (\u003cstrong\u003e3o\u003c/strong\u003e), and -OH (\u003cstrong\u003e3p\u003c/strong\u003e-\u003cstrong\u003e3s\u003c/strong\u003e), the catalyst demonstrated excellent selectivity. This highlights the impressive capabilities of \u003cstrong\u003eCat-Se\u003c/strong\u003e in amidation.\u003c/p\u003e\n\u003cp\u003eWe next explored the reaction scope in peptide couplings. Amino acids protected with the typical amine-protecting groups Fmoc and Boc groups were tested in the reaction (Fig. 3). \u003cstrong\u003eCat-Se\u003c/strong\u003e successfully catalyzed all twenty natural amino acids to the corresponding dipeptides with good yields after 30-40 minutes without any loss of stereochemical integrities (\u003cstrong\u003e6a\u003c/strong\u003e-\u003cstrong\u003e6r\u003c/strong\u003e, \u003cem\u003eee\u003c/em\u003e or \u003cem\u003ede\u003c/em\u003e \u0026gt;99%). The condensation of secondary amine substrates, such as N-Me-L-Leu-OMe\u0026sdot;HCl and L-Pro-OMe\u0026sdot;HCl, also yields the corresponding dipeptides in good yield and\u003c/p\u003e\n\u003cp\u003ewithout any loss of stereochemical integrities (\u003cstrong\u003e6w\u003c/strong\u003e, 89% yield, \u003cem\u003ede\u003c/em\u003e \u0026gt;99%; \u003cstrong\u003e6x\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e88% yield, \u003cem\u003ede\u003c/em\u003e \u0026gt;99%). Furthermore, \u003cstrong\u003eCat-Se\u003c/strong\u003e exhibited excellent specific selectivity without any side reactions when the side chains of certain amino acids were unprotected, such as Tyr (\u003cstrong\u003e6g\u003c/strong\u003e-\u003cstrong\u003e6i\u003c/strong\u003e), Trp (\u003cstrong\u003e6i\u003c/strong\u003e-\u003cstrong\u003e6m\u003c/strong\u003e, \u003cstrong\u003e6o\u003c/strong\u003e-\u003cstrong\u003e6p\u003c/strong\u003e), Thr (\u003cstrong\u003e6t\u003c/strong\u003e), Ser (\u003cstrong\u003e6u\u003c/strong\u003e), and His (\u003cstrong\u003e6v\u003c/strong\u003e). This suggests a new avenue for future research in the synthesis of unprotected peptides. Notably, the reactions of amino acids with sterically hindered side chains, such as Fmoc-L-Ile-OH and Fmoc-Aib-OH could be coupled with L-Ile-OMe\u0026sdot;HCl or L-Ile-O\u003cem\u003e\u003csup\u003et\u003c/sup\u003e\u003c/em\u003eBu\u0026sdot;HCl to give \u003cstrong\u003e6y\u003c/strong\u003e, \u003cstrong\u003e6y\u0026rsquo;\u003c/strong\u003e and \u003cstrong\u003e6z\u003c/strong\u003e in 83-91% yields and without any loss of stereochemical integrities. \u0026nbsp;Finally, the performance of \u003cstrong\u003eCat-Se\u003c/strong\u003e in gram-scale dipeptide synthesis was also investigated. In the presence of 10 mol% \u003cstrong\u003eCat-Se\u003c/strong\u003e, 2.0 mmol of Fmoc-L-Asp(OtBu)-OH and 2.0 mmol of L-Trp-OMe\u0026sdot;HCl were successfully converted to \u003cstrong\u003e6o\u0026rsquo;\u003c/strong\u003e with 96% yield (1.18 g, \u003cem\u003ede\u0026nbsp;\u003c/em\u003e\u0026gt;99%). This demonstrated its effectiveness in amino acid substrates and established a strong foundation for its use in SPPS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFragment condensation is one of the major methods of peptide drug synthesis. To further test the catalyst\u0026apos;s performance, we investigated its reaction scope in peptide fragment condensation (Fig. 4). The reactions produced the corresponding peptides in 75-95% yields with \u003cem\u003edr\u003c/em\u003e \u0026gt;19:1. (\u003cstrong\u003e9a\u003c/strong\u003e-\u003cstrong\u003e9d\u003c/strong\u003e). This showed that it was suitable for peptide fragment condensation. Finally, we completed the fragment condensation of leuprorelin using this method. The protected substrates \u003cstrong\u003e7f\u003c/strong\u003e and \u003cstrong\u003e8f\u003c/strong\u003e were amidated in a 7+2 mode. After a series of deprotection, purification, and lyophilization, the target product, leuprorelin \u003cstrong\u003e9f\u003c/strong\u003e, was obtained with a 36% yield and 99% purity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMechanism study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo further understand the reaction, phosphorus-31 nuclear magnetic resonance (\u003csup\u003e31\u003c/sup\u003eP NMR) spectroscopy was conducted. After the reaction with \u003cstrong\u003eCat-Se\u0026nbsp;\u003c/strong\u003eparticipation was irradiated under blue light for a while, the \u003csup\u003e31\u003c/sup\u003eP NMR spectra displayed a new signal at 35.2 ppm, in addition to triphenylphosphine with triphenylphosphine oxide (Fig. 5a). It was identified as triphenylphosphine selenide by comparison with the relative sample. We corroborated the identification using LC-MS and found the catalyst intermediate \u003cstrong\u003eIII\u003c/strong\u003e. Afterward, we analyzed the reaction involving \u003cstrong\u003eCat-S\u003c/strong\u003e by the same method, and the \u003csup\u003e31\u003c/sup\u003eP NMR spectra also displayed a new signal at 43.0 ppm, which was identified as triphenylphosphine sulfide. The catalyst intermediate \u003cstrong\u003eIII\u0026rsquo;\u003c/strong\u003e also was identified using LC-MS.\u003c/p\u003e\n\u003cp\u003eA plausible mechanism based on the above experimental results and previous reports\u003csup\u003e32,33,50\u003c/sup\u003e was shown in Fig. 5b. \u003cstrong\u003eCat-Se\u003c/strong\u003e formed intermediate \u003cstrong\u003eI\u003c/strong\u003e with triphenylphosphine in the light, and it was attacked by carboxylic acid to form intermediate \u003cstrong\u003eII\u003c/strong\u003e and released triphenylphosphine selenide. The intermediate \u003cstrong\u003eII\u003c/strong\u003e was similar to the transition state of many coupling reagents and it easily reacted with amines to form amides. Finally, because the P-O bond was stronger than the P-Se bond, intermediate \u003cstrong\u003eIII\u003c/strong\u003e would react with triphenylphosphine selenide to form triphenylphosphane oxide and release the \u003cstrong\u003eCat-Se\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCatalytic solid-phase peptide synthesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNext, the feasibility of this new strategy for SPPS was evaluated (Fig. 6). The catalytic synthesis of peptide drugs tetragastrin and triptorelin was successfully achieved, and compared with the conventional method of using the coupling reagent HBTU. Tetragastrin was first synthesized on Rink MBHA resins using \u003cstrong\u003eCat-Se\u003c/strong\u003e and HBTU, respectively (Fig. 6a, 6b). The purity of the crude peptides was analyzed using HPLC. The results were relatively similar, indicating that no significant additional side reactions occurred during the catalytic solid-phase peptide synthesis process using \u003cstrong\u003eCat-Se\u003c/strong\u003e compared to the conventional method (Fig. 6b). The pure tetragastrin was obtained through further preparation and lyophilization. Both methods resulted in similar yields (\u003cstrong\u003eCat-Se\u003c/strong\u003e: 59% yield, 98% purity; HBTU: 66% yield, 97% purity). Our method was then extended to the solid-phase synthesis of the triptorelin (Fig. 6c). We also analyzed the purity of the crude peptides obtained by the two methods and found no significant additional side reactions. After purification and lyophilization, we obtained triptorelin using \u003cstrong\u003eCat-Se\u0026nbsp;\u003c/strong\u003e(34% yield, 99% purity)\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand HBTU (49% yield, 99% purity), respectively. We believed that the method would be attractive to the pharmaceutical industry.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, we have developed a unique catalyst, \u003cb\u003eCat-Se\u003c/b\u003e, to solve the problems faced by previous catalysts in amide and peptide synthesis. This catalyst has a simple and exquisite structure and can condense various carboxylic acid and amine substrates to the corresponding amides with high yields in about 30 minutes. Cumbersome operations such as heating, dehydration, and gas protection, which were common in the past, are avoided with this method. The method also exhibited excellent chemoselectivity and chirality retention. The reasonable reaction time and good reaction effect made it well compatible with SPPS, which was demonstrated by the synthesis of tetragastrin and triptorelin using \u003cb\u003eCat-Se\u003c/b\u003e. It was already comparable to the conventional SPPS method in terms of reaction time, side reactions, and yield, which is attractive in the pharmaceutical industry. We believe that \u003cb\u003eCat-Se\u003c/b\u003e would have good application prospects in amide and peptide synthesis. Additionally, we think that combining \u003cb\u003eCat-Se\u003c/b\u003e with supported catalysis and continuous flow chemistry can enhance its value in the research of peptide drug synthesis, which is ongoing in our lab.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eClassic Experimental Procedure\u003c/h2\u003e \u003cp\u003eMethod A: Carboxylic acid (0.10 mmol), amine (0.10 mmol), triphenylphosphine (0.11 mmol or 0.15 mmol), and 10 mol% \u003cb\u003eCat-Se\u003c/b\u003e were added to a 10 mL quartz tube, followed by the solvent MeCN (2 mL). The tube was then placed in a photoreactor and subjected to irradiation using 440\u0026ndash;445 nm blue LEDs (0.66 A, 25 V, with cooling water) while being stirred at room temperature. The reaction was monitored by TLC until complete consumption of triphenylphosphine. Subsequently, the reaction solution was concentrated, and the product was obtained through purification via silica gel column chromatography.\u003c/p\u003e \u003cp\u003eMethod B: Carboxylic acid (0.10 mmol), amino acid ester hydrochloride (0.10 mmol), DIEA (0.10 mmol), triphenylphosphine (0.11 mmol or 0.15 mmol), and 10 mol% \u003cb\u003eCat-Se\u003c/b\u003e were added to a 10 mL quartz tube, followed by the solvent MeCN (2 mL). The tube was then placed in a photoreactor and subjected to irradiation using 440\u0026ndash;445 nm blue LEDs (0.66 A, 25 V, with cooling water) while being stirred at room temperature. The reaction was monitored by TLC until complete consumption of triphenylphosphine. Subsequently, the reaction solution was concentrated and the product was obtained through purification via silica gel column chromatography.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eY.L. designed and carried out most of the reactions and wrote the first draft of the paper. J.L., Q.Z., Z.S., H.K. and G.B. provided raw material support and performed some of the synthetic experiments. Y.L. and W.S. analyzed the data and edited the manuscript and supplementary materials. J.N., W.S. and R.W. designed and supervised the whole project. The paper was written through contributions from all authors.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe thank the financial support from the CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-074, 2021-I2M-3-001, 2021-I2M-1-026, and 2022-I2M-2-002), the Fundamental Research Funds for the Central Universities (lzujbky-2024-ey10), the Program for Chang-Jiang Scholars and Innovative Research Team in University (IRT_15R27), the National Natural Science Foundation of China (82173678).\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eAll information relating to experimental procedures, high-performance liquid chromatography, mechanistic studies, nuclear magnetic resonance spectra, and high-resolution mass spectrometry are available in Supplementary Information. All other data are available from the corresponding authors upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGreenberg, A. B., C. M.; Liebman, J. F. \u003cem\u003eThe Amide Linkage: Selected Structural Aspects in Chemistry, Biochemistry, and Materials Science\u003c/em\u003e. (John Wiley \u0026amp; Sons: New York, 2000.).\u003c/li\u003e\n \u003cli\u003eValeur Eric \u0026amp; Mark, B. Amide bond formation: beyond the myth of coupling reagents. \u003cem\u003eChem. Soc. Rev.\u003c/em\u003e\u003cstrong\u003e38\u003c/strong\u003e, 606-631, (2009).\u003c/li\u003e\n \u003cli\u003ePattabiraman, V. R. \u0026amp; Bode, J. W. Rethinking amide bond synthesis. \u003cem\u003eNature\u003c/em\u003e\u003cstrong\u003e480\u003c/strong\u003e, 471-479, (2011).\u003c/li\u003e\n \u003cli\u003ede Figueiredo, R. M., Suppo, J.-S. \u0026amp; Campagne, J.-M. Nonclassical Routes for Amide Bond Formation. \u003cem\u003eChem. 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Herein, we report an organocatalyst, named \u003cstrong\u003eCat-Se\u003c/strong\u003e, for direct amide and peptide synthesis. \u003cstrong\u003eCat-Se\u003c/strong\u003e, which has a simple and exquisite chemical structure, can be conveniently synthesized and catalyzes the condensation of various carboxylic acids and amines to the corresponding amides in excellent yields within 30-40 minutes under very mild light irradiation conditions without any undesirable operations, such as heating, dehydration, or gas protection. The method exhibits high efficiency, selectivity, and functional group tolerance without loss of stereochemical integrity in peptide synthesis. Significantly, \u003cstrong\u003eCat-Se\u003c/strong\u003e shows power in peptide fragment condensation and solid-phase peptide synthesis on resin, making it an attractive alternative for peptide drug synthesis.\u003c/p\u003e","manuscriptTitle":"Organocatalyst Enabled Light Accelerated Amide and Peptide Synthesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-25 05:25:19","doi":"10.21203/rs.3.rs-4938807/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"55b49c1e-1923-427f-9a21-230c71a43ffc","owner":[],"postedDate":"September 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":37598759,"name":"Physical sciences/Chemistry/Catalysis/Organocatalysis"},{"id":37598760,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2024-09-25T05:25:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-25 05:25:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4938807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4938807","identity":"rs-4938807","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}