Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert
{"title":"Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides","authors":"Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert","doi":"10.1021/acs.oprd.4c00426","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00426","url":null,"abstract":"This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp, Limei Jin
{"title":"Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir","authors":"Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp, Limei Jin","doi":"10.1021/acs.oprd.4c00527","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00527","url":null,"abstract":"(1<i>R</i>,5<i>R</i>)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one is used in the asymmetric synthesis of lenacapavir. Herein, we report an enantioselective synthesis of this important chiral intermediate from the inexpensive commodity (<i>R</i>)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I<sub>2</sub>-promoted hydroxylation, and an Albright–Goldman oxidation. This sequence affords (1<i>R</i>,5<i>R</i>)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one in an overall 25% isolated yield as an enantiomerically pure compound. The entire process has been successfully demonstrated on a hundred-gram scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Subha Mukherjee*, David A. Thaisrivongs*, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai and Kevin D. Seibert,
{"title":"Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides","authors":"Subha Mukherjee*, David A. Thaisrivongs*, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai and Kevin D. Seibert, ","doi":"10.1021/acs.oprd.4c0042610.1021/acs.oprd.4c00426","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00426https://doi.org/10.1021/acs.oprd.4c00426","url":null,"abstract":"<p >This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"671–677 671–677"},"PeriodicalIF":3.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589)","authors":"Hirotsugu Usutani, Kiichi Kuroda, Kiyoto Sawamura, Jun Hirabayashi, Kenji Yamamoto, Masahiko Tanaka, Masayuki Ohira, Shigeaki Masuda, Takuya Nakagiri, Rui Ono, Tetsuji Kawamoto, Kazuki Hashimoto","doi":"10.1021/acs.oprd.4c00540","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00540","url":null,"abstract":"(<i>R</i>)-Troloxamide quinone (EPI-589) is a compound that is under development as a therapeutic agent for Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The compound is derived from Trolox, a vitamin E derivative, using optical resolution and subsequent chemical conversion processes to obtain the active pharmaceutical ingredient (API). However, in the initially developed manufacturing method, pseudoephedrine was used as the optical resolution reagent, although it is restricted for use as a stimulant drug raw material in several countries, and the reproducibility of the optical resolution was not high. Thus, it was necessary to find an alternative chiral amine, which would be more freely usable and give high reproducibility. Among several optical resolution conditions investigated, an unusual three-component complex between (<i>R</i>)-Trolox, (<i>R</i>)-phenylethylamine, and <i>N</i>-methyl-2-pyrrolidone (NMP) was identified as most effective. However, although the optical resolution process showed both high reproducibility and optical purity, the manufacturing method came with the risk of introducing nitrosamines into the active pharmaceutical ingredient, so further extensive investigations were conducted to address this issue. As a result, a flow chemistry process was developed, which could avoid the use of a nitrate reagent in the oxidation step, and thus eliminate the risk of nitrosamine generation. This paper discloses the process development studies and discusses the successful manufacturing of EPI-589 on a scale of several hundred kilograms, utilizing the novel optical resolution and flow chemistry process under GMP conditions.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeremy D. Mason, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia, Ganapati Reddy Pamulapati
{"title":"Development of a Scalable Manufacturing Process for AB-343 Drug Substance: A Potential Candidate for the Treatment of Coronavirus Infections","authors":"Jeremy D. Mason, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia, Ganapati Reddy Pamulapati","doi":"10.1021/acs.oprd.4c00528","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00528","url":null,"abstract":"A scalable process for manufacturing of the anticoronavirus clinical candidate AB-343 has been developed. The lactam-containing subunit of the molecule was prepared using a novel synthetic route involving a nitro-Michael reaction and a rhodium-catalyzed nitro group hydrogenation followed by <i>in situ</i> translactamization sequence as a key transformation. The drug substance was assembled via sequential amide coupling and deprotection reactions, followed by a final dehydration of a primary amide to the corresponding nitrile using T3P. AB-343 drug substance was successfully manufactured on a multikilogram scale using this route, which was suitable for supporting IND-enabling studies and Phase I clinical development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeremy D. Mason*, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia and Ganapati Reddy Pamulapati*,
{"title":"Development of a Scalable Manufacturing Process for AB-343 Drug Substance: A Potential Candidate for the Treatment of Coronavirus Infections","authors":"Jeremy D. Mason*, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia and Ganapati Reddy Pamulapati*, ","doi":"10.1021/acs.oprd.4c0052810.1021/acs.oprd.4c00528","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00528https://doi.org/10.1021/acs.oprd.4c00528","url":null,"abstract":"<p >A scalable process for manufacturing of the anticoronavirus clinical candidate AB-343 has been developed. The lactam-containing subunit of the molecule was prepared using a novel synthetic route involving a nitro-Michael reaction and a rhodium-catalyzed nitro group hydrogenation followed by <i>in situ</i> translactamization sequence as a key transformation. The drug substance was assembled via sequential amide coupling and deprotection reactions, followed by a final dehydration of a primary amide to the corresponding nitrile using T3P. AB-343 drug substance was successfully manufactured on a multikilogram scale using this route, which was suitable for supporting IND-enabling studies and Phase I clinical development.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"856–871 856–871"},"PeriodicalIF":3.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao, Oliver T. Ring
{"title":"Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle","authors":"Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao, Oliver T. Ring","doi":"10.1021/acs.oprd.4c00524","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00524","url":null,"abstract":"We describe our approach to the total synthesis of AZD5991 (<b>1</b>) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, <b>1</b>, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of <b>1</b> was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao and Oliver T. Ring*,
{"title":"Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle","authors":"Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao and Oliver T. Ring*, ","doi":"10.1021/acs.oprd.4c0052410.1021/acs.oprd.4c00524","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00524https://doi.org/10.1021/acs.oprd.4c00524","url":null,"abstract":"<p >We describe our approach to the total synthesis of AZD5991 (<b>1</b>) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, <b>1</b>, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of <b>1</b> was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"804–827 804–827"},"PeriodicalIF":3.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio, Beatriz G. de la Torre
{"title":"TFA Cleavage Strategy for Mitigation of S-tButylated Cys-Peptide Formation in Solid-Phase Peptide Synthesis","authors":"Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio, Beatriz G. de la Torre","doi":"10.1021/acs.oprd.4c00443","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00443","url":null,"abstract":"Cysteine (Cys) is the most versatile amino acid-forming part of a peptide chain but at the same time the most complex. Its presence is associated with a large number of side reactions. In particular, the formation of S-<i>tert-</i>butylated Cys residues results from the reaction of the liberated Cys thiol with the <i>t</i>Bu cations coming from the <i>t</i>Bu-based protecting groups. Here, we have studied this side reaction using different scavengers such as alkyl and aryl thiols (DTT, 1,4-BDMT), thioethers (DMS, thioanisole), and sulfur-free compounds such as <i>m</i>-cresol, anisole, PPh<sub>3</sub> and TCEP in addition to TIS and H<sub>2</sub>O. Three of these scavengers (DTT, 1,4-BDMT, PPh<sub>3</sub>) are disulfide-reducing agents. Furthermore, the study also considered the cleavage duration and the TFA content in the cleavage mixtures. In peptides containing Ser(<i>t</i>Bu) and/or Thr(<i>t</i>Bu), the reduction of the TFA content led to the incomplete removal of the <i>t</i>Bu protecting group. After this feasibility study, it can be concluded that the combined use of thioanisole and DMS in slightly higher quantity than TIS and H<sub>2</sub>O in the presence of 1% DTT is beneficial. Furthermore, optimal results are obtained if the cleavage is carried out in two steps: initial treatment of the peptide with TFA/TIS/H<sub>2</sub>O/thioanisole/DMS/1% DTT (70:5:5:10:10) for 30 min followed by TFA addition up to an 80% proportion and continued treatment for 150 min.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"40 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio* and Beatriz G. de la Torre*,
{"title":"TFA Cleavage Strategy for Mitigation of S-tButylated Cys-Peptide Formation in Solid-Phase Peptide Synthesis","authors":"Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio* and Beatriz G. de la Torre*, ","doi":"10.1021/acs.oprd.4c0044310.1021/acs.oprd.4c00443","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00443https://doi.org/10.1021/acs.oprd.4c00443","url":null,"abstract":"<p >Cysteine (Cys) is the most versatile amino acid-forming part of a peptide chain but at the same time the most complex. Its presence is associated with a large number of side reactions. In particular, the formation of S-<i>tert-</i>butylated Cys residues results from the reaction of the liberated Cys thiol with the <i>t</i>Bu cations coming from the <i>t</i>Bu-based protecting groups. Here, we have studied this side reaction using different scavengers such as alkyl and aryl thiols (DTT, 1,4-BDMT), thioethers (DMS, thioanisole), and sulfur-free compounds such as <i>m</i>-cresol, anisole, PPh<sub>3</sub> and TCEP in addition to TIS and H<sub>2</sub>O. Three of these scavengers (DTT, 1,4-BDMT, PPh<sub>3</sub>) are disulfide-reducing agents. Furthermore, the study also considered the cleavage duration and the TFA content in the cleavage mixtures. In peptides containing Ser(<i>t</i>Bu) and/or Thr(<i>t</i>Bu), the reduction of the TFA content led to the incomplete removal of the <i>t</i>Bu protecting group. After this feasibility study, it can be concluded that the combined use of thioanisole and DMS in slightly higher quantity than TIS and H<sub>2</sub>O in the presence of 1% DTT is beneficial. Furthermore, optimal results are obtained if the cleavage is carried out in two steps: initial treatment of the peptide with TFA/TIS/H<sub>2</sub>O/thioanisole/DMS/1% DTT (70:5:5:10:10) for 30 min followed by TFA addition up to an 80% proportion and continued treatment for 150 min.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 3","pages":"691–703 691–703"},"PeriodicalIF":3.1,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143667029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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