Pub Date : 2024-12-31DOI: 10.1021/acs.orglett.4c03893
Dae-Shik Kim, Hyeong-wook Choi, Francis G. Fang
An entirely chromium-free synthesis of eribulin, a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, was achieved through iterative sulfone fragment couplings followed by an intramolecular Prins reaction involving a C.26 homoallenyl alcohol and a C.27 aldehyde acetal. A notable feature of this new macrocyclization is the employment of a β-ketosulfone at C.15/14 as an acid-stable progenitor of the notoriously acid-sensitive polycyclic ketal moiety, characteristic of the halichondrins.
{"title":"Total Synthesis of Eribulin, a Macrocyclic Ketone Analogue of Halichondrin B, via Prins Macrocyclization","authors":"Dae-Shik Kim, Hyeong-wook Choi, Francis G. Fang","doi":"10.1021/acs.orglett.4c03893","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03893","url":null,"abstract":"An entirely chromium-free synthesis of eribulin, a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, was achieved through iterative sulfone fragment couplings followed by an intramolecular Prins reaction involving a C.26 homoallenyl alcohol and a C.27 aldehyde acetal. A notable feature of this new macrocyclization is the employment of a β-ketosulfone at C.15/14 as an acid-stable progenitor of the notoriously acid-sensitive polycyclic ketal moiety, characteristic of the halichondrins.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"33 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A novel palladium-catalyzed intramolecular C–H amination via oxidative coupling exploiting inactivated N-substituted aryl amines on indoles for the one-pot synthesis of novel 11H-benzo[4,5]imidazo[1,2-a]indole derivatives is reported. The optimized reaction conditions accommodated a wide range of electronic variations on both the indole and the pendant aryl amine ring, resulting in products with good to excellent yields.
{"title":"Palladium-Catalyzed Intramolecular C–H Amination via Oxidative Coupling on Indole Derivatives: Access to 11H-Benzo[4,5]imidazo[1,2-a]indoles","authors":"Yogesh Sharma, Simran Kaur, Hariprasath Kandhasamy, Subash Chandra Sahoo, Vinod D. Chaudhari","doi":"10.1021/acs.orglett.4c04563","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04563","url":null,"abstract":"A novel palladium-catalyzed intramolecular C–H amination via oxidative coupling exploiting inactivated N-substituted aryl amines on indoles for the one-pot synthesis of novel 11<i>H</i>-benzo[4,5]imidazo[1,2-<i>a</i>]indole derivatives is reported. The optimized reaction conditions accommodated a wide range of electronic variations on both the indole and the pendant aryl amine ring, resulting in products with good to excellent yields.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"13 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1021/acs.orglett.4c04412
Jia-Liang Zhou, Qiu-Yue Nie, Xian-Feng Hou, Kuan Zheng, Ran Hong, Gong-Li Tang
Rearrangement of the skeleton is crucial for improving the structural complexity and diversity of type II polyketide natural products. In this study, we investigated the rearrangement process from a planar aromatic tetracyclic intermediate to the caged lactones, which is managed by five oxidoreductases. We chemically synthesized the proposed linear tetracyclic substrate, validated the transformation process through in vivo and in vitro experiments, and elucidated the enzyme-catalyzed mechanism using isotope labeling. Significantly, a short-chain dehydrogenase TjhD5 was discovered to play a multifunctional role for multistep reactions.
{"title":"Multienzyme Cascade Catalyzed Skeleton Rearrangement in a Caged Polyketide Biosynthesis","authors":"Jia-Liang Zhou, Qiu-Yue Nie, Xian-Feng Hou, Kuan Zheng, Ran Hong, Gong-Li Tang","doi":"10.1021/acs.orglett.4c04412","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04412","url":null,"abstract":"Rearrangement of the skeleton is crucial for improving the structural complexity and diversity of type II polyketide natural products. In this study, we investigated the rearrangement process from a planar aromatic tetracyclic intermediate to the caged lactones, which is managed by five oxidoreductases. We chemically synthesized the proposed linear tetracyclic substrate, validated the transformation process through <i>in vivo</i> and <i>in vitro</i> experiments, and elucidated the enzyme-catalyzed mechanism using isotope labeling. Significantly, a short-chain dehydrogenase TjhD5 was discovered to play a multifunctional role for multistep reactions.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"6 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The C2- or C3-selective direct C–H arylation of nonsubstituted 1H-pyrrole with aryl chlorides/nonaflates was achieved using catalysts derived from palladium and appropriate phosphine ligands. The site selectivity of the arylation can be switched by changing the ligands, and the C3-selective arylation of nonsubstituted 1H-pyrrole was realized for the first time. tBuOLi played an important role in suppressing N-arylation and accelerating C2- or C3-arylation.
{"title":"Ligand-Controlled C2- or C3-Selectivity Switching in the Palladium-Catalyzed C–H Arylation of Nonsubstituted 1H-Pyrrole","authors":"Miyuki Yamaguchi, Kenichi Nakai, Kiho Morioka, Ayano Sato, Sakiko Fujiwara, Hideyuki Konishi, Kei Manabe","doi":"10.1021/acs.orglett.4c04085","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04085","url":null,"abstract":"The C2- or C3-selective direct C–H arylation of nonsubstituted 1<i>H</i>-pyrrole with aryl chlorides/nonaflates was achieved using catalysts derived from palladium and appropriate phosphine ligands. The site selectivity of the arylation can be switched by changing the ligands, and the C3-selective arylation of nonsubstituted 1<i>H</i>-pyrrole was realized for the first time. <i>t</i>BuOLi played an important role in suppressing N-arylation and accelerating C2- or C3-arylation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1021/acs.orglett.4c04304
Apisara Somteds, Thanapat Suebrasri, Sophon Boonlue, Brian O. Patrick, Somdej Kanokmedhakul, Raymond J. Andersen, Kwanjai Kanokmedhakul
The sesquiterpenoids nigrosporinol sulfoxides A (1) and B (2) have been isolated from cultures of the endophytic fungus Nigrospora lacticolonia harvested from the sunchoke Helianthus tuberosus L. collected in Thailand. Nigrosporinol sulfoxides A (1) and B (2) have 4/5/5/5/7 heterocyclic skeletons 3 featuring a sulfoxide bridge not previously found in a terpenoid natural product from any living source.
{"title":"Nigrosporinol Sulfoxides A and B, Sulfur-Bridged Heterocyclic Sesquiterpenoids Produced by Cultures of the Fungus Nigrospora lacticolonia","authors":"Apisara Somteds, Thanapat Suebrasri, Sophon Boonlue, Brian O. Patrick, Somdej Kanokmedhakul, Raymond J. Andersen, Kwanjai Kanokmedhakul","doi":"10.1021/acs.orglett.4c04304","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04304","url":null,"abstract":"The sesquiterpenoids nigrosporinol sulfoxides A (<b>1</b>) and B (<b>2</b>) have been isolated from cultures of the endophytic fungus <i>Nigrospora lacticolonia</i> harvested from the sunchoke <i>Helianthus tuberosus</i> L. collected in Thailand. Nigrosporinol sulfoxides A (<b>1</b>) and B (<b>2</b>) have 4/5/5/5/7 heterocyclic skeletons <b>3</b> featuring a sulfoxide bridge not previously found in a terpenoid natural product from any living source.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"25 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Capturing CO2 is highly valued in the field of organic synthesis, especially underdeveloped dual-CO2 conversion. In this study, we detail a novel reductive cyclization of 2-indolylanilines with dual CO2 as a difunctional reagent in the presence of PMHS [poly(methylhydrosiloxane)], delivering methyl-substituted quinoxalines. Furthermore, another chemoselective cyclization with 2-pyrrolylanilines is also realized by converting mono-CO2. Mechanistic investigations shed light upon the fact that this substrate-controlled divergence mainly depends on the formation of N-diacylative intermediates.
{"title":"Substrate-Controlled Divergent Reductive Cyclization of 2-Arylanilines Using CO2 as a Switching Reagent","authors":"Qiang Yan, Jiang Nan, Rui Cao, Lanxin Zhu, Shilei Liu, Chengyuan Liang, Chen Zhang","doi":"10.1021/acs.orglett.4c04538","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04538","url":null,"abstract":"Capturing CO<sub>2</sub> is highly valued in the field of organic synthesis, especially underdeveloped dual-CO<sub>2</sub> conversion. In this study, we detail a novel reductive cyclization of 2-indolylanilines with dual CO<sub>2</sub> as a difunctional reagent in the presence of PMHS [poly(methylhydrosiloxane)], delivering methyl-substituted quinoxalines. Furthermore, another chemoselective cyclization with 2-pyrrolylanilines is also realized by converting mono-CO<sub>2</sub>. Mechanistic investigations shed light upon the fact that this substrate-controlled divergence mainly depends on the formation of <i>N</i>-diacylative intermediates.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"48 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1021/acs.orglett.4c04391
Yan Xue, Da Song, Shi-Rong Liu, Chuan-Wen Lei, Hui Shi, Ying Zhou, Ting-Ting Feng, Xin Wei
In this work, coixalkyne A (1), a natural polynuclear calcium complex with a novel cross-shaped molecular architecture, was isolated from Coix lacryma-jobi L. along with the undescribed analogue coixalkyne B (2). Their structures were identified by means of NMR spectroscopy, ECD calculations, and single-crystal X-ray diffraction. It is noteworthy that the calcium ligands of 1 as well as compound 2 possess rare terminal alkynes and a nor-carbon sesquiterpene (C14) framework. The antihyperuricemic activity of C. lacryma-jobi and xanthine oxidase (XOD) inhibitory effects of 1–2 were elucidated by in vivo and in vitro assays, while the possible mechanism of action was suggested by molecular docking. Different from the reported chemical synthesis and protein calcium carriers, the discovery of compounds 1 and 2 provided new proof for the natural calcium metallophore in plants with xanthine oxidase inhibitory activity.
{"title":"Discovery, Characterization, and Anti-XOD Activity of Calcium Metallophore from Coix lacryma-jobi","authors":"Yan Xue, Da Song, Shi-Rong Liu, Chuan-Wen Lei, Hui Shi, Ying Zhou, Ting-Ting Feng, Xin Wei","doi":"10.1021/acs.orglett.4c04391","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04391","url":null,"abstract":"In this work, coixalkyne A (<b>1</b>), a natural polynuclear calcium complex with a novel cross-shaped molecular architecture, was isolated from <i>Coix lacryma-jobi</i> L. along with the undescribed analogue coixalkyne B (<b>2</b>). Their structures were identified by means of NMR spectroscopy, ECD calculations, and single-crystal X-ray diffraction. It is noteworthy that the calcium ligands of <b>1</b> as well as compound <b>2</b> possess rare terminal alkynes and a <i>nor</i>-carbon sesquiterpene (C14) framework. The antihyperuricemic activity of <i>C. lacryma-jobi</i> and xanthine oxidase (XOD) inhibitory effects of <b>1</b>–<b>2</b> were elucidated by <i>in vivo</i> and <i>in vitro</i> assays, while the possible mechanism of action was suggested by molecular docking. Different from the reported chemical synthesis and protein calcium carriers, the discovery of compounds <b>1</b> and <b>2</b> provided new proof for the natural calcium metallophore in plants with xanthine oxidase inhibitory activity.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"162 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This work describes a chiral bifunctional squaramide/DBU sequential catalytic strategy for the enantioselective synthesis of nonfused chiral eight-membered O-heterocycles through the asymmetric addition of ynones to β,γ-unsaturated α-ketoesters followed by the regio- and diastereoselective cyclization of the adduct intermediates. Mechanistic experiments revealed that an isomerization process should be involved in the ring formation step, and the origin of the high regioselectivity and diastereoselectivity has also been elucidated by the DFT calculations.
{"title":"Enantioselective Synthesis of Nonfused Eight-Membered O-Heterocycles by Sequential Catalysis","authors":"Suo-Suo Qi, Xiao-Ping Sun, Yan-Biao Sun, Jing-Jing Zhai, Yi-Feng Wang, Shao-Jie Lou, Dan-Qian Xu","doi":"10.1021/acs.orglett.4c04253","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04253","url":null,"abstract":"This work describes a chiral bifunctional squaramide/DBU sequential catalytic strategy for the enantioselective synthesis of nonfused chiral eight-membered O-heterocycles through the asymmetric addition of ynones to β,γ-unsaturated α-ketoesters followed by the regio- and diastereoselective cyclization of the adduct intermediates. Mechanistic experiments revealed that an isomerization process should be involved in the ring formation step, and the origin of the high regioselectivity and diastereoselectivity has also been elucidated by the DFT calculations.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"33 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report herein a robust enantioselective ring opening coupling of oxabenzonorbornadienes via Pd(II)-catalyzed domino cyclization of alkynylanilines, which features the formation of three covalent bonds and two contiguous stereocenters with excellent enantio- and diastereoselectivity and a broad substrate scope. The good functional group tolerance of this domino desymmetrization strategy enables efficient late-stage transformation of natural product-derived alkynylanilines. The resulting indolated dihydronaphthols could serve as a valuable platform to streamline the diversity-oriented synthesis of other valuable enantioenriched tetrahydronaphthalene derivatives.
{"title":"Palladium(II)-Catalyzed Enantioselective Ring Opening of Oxabenzonorbornadienes via Domino Aminopalladation of Alkynylanilines","authors":"Qianru Liu, Junjie Meng, Binhong Tan, Haoyuan Lin, Yue Zhang, Youzhi Tang, Zhaodong Li","doi":"10.1021/acs.orglett.4c04414","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04414","url":null,"abstract":"We report herein a robust enantioselective ring opening coupling of oxabenzonorbornadienes via Pd(II)-catalyzed domino cyclization of alkynylanilines, which features the formation of three covalent bonds and two contiguous stereocenters with excellent enantio- and diastereoselectivity and a broad substrate scope. The good functional group tolerance of this domino desymmetrization strategy enables efficient late-stage transformation of natural product-derived alkynylanilines. The resulting indolated dihydronaphthols could serve as a valuable platform to streamline the diversity-oriented synthesis of other valuable enantioenriched tetrahydronaphthalene derivatives.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"35 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1021/acs.orglett.4c04007
Qingyu Tian, Jin Ge, Yaopeng Liu, Xi Wu, Zhenghao Li, Guolin Cheng
The enantioselective synthesis of P(V)-stereogenic compounds has emerged as an interesting research topic primarily due to their significant biological activity and broad application prospects. Herein, we disclose a method for the construction of P(V)-stereogenic compounds from prochiral phosphinamides and aryl iodides via palladium- and chiral norbornene-catalyzed desymmetric annulation. The P(V)-stereogenic compounds were formed with a broad scope with excellent enantiomeric excesses. It is noteworthy that the synthetic value of this procedure was proven by a variety of transition metal-catalyzed cross-coupling reactions using the C–Br bond on the product as a versatile linchpin electrophile.
{"title":"Palladium-Catalyzed Enantioselective Synthesis of P(V)-Stereogenic Compounds via Desymmetric Annulation of Prochiral Phosphinamides and Aryl Iodides","authors":"Qingyu Tian, Jin Ge, Yaopeng Liu, Xi Wu, Zhenghao Li, Guolin Cheng","doi":"10.1021/acs.orglett.4c04007","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04007","url":null,"abstract":"The enantioselective synthesis of P(V)-stereogenic compounds has emerged as an interesting research topic primarily due to their significant biological activity and broad application prospects. Herein, we disclose a method for the construction of P(V)-stereogenic compounds from prochiral phosphinamides and aryl iodides via palladium- and chiral norbornene-catalyzed desymmetric annulation. The P(V)-stereogenic compounds were formed with a broad scope with excellent enantiomeric excesses. It is noteworthy that the synthetic value of this procedure was proven by a variety of transition metal-catalyzed cross-coupling reactions using the C–Br bond on the product as a versatile linchpin electrophile.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"103 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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