1
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Yang F, Wang XL, Zhao FK, Bin HY, Xie JH. Enantioselective Total Synthesis of (-)-Vallesamidine Enabled by Asymmetric Hydrogenation and Aza-Wacker Cyclization to Construct the Core Spirocyclopentane-1,2'-indoline Structure. Org Lett 2025. [PMID: 40400491 DOI: 10.1021/acs.orglett.5c01615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
An enantioselective total synthesis of (-)-vallesamidine is described, integrating asymmetric hydrogenation with aza-Wacker cyclization to form the chiral spirocyclopentane-1,2'-indoline. Intramolecular Stetter reaction and alkylation are employed to construct a tetracyclic framework featuring a chiral quaternary carbon center. Schmidt rearrangement and intramolecular aldol condensation facilitate the formation of the D and E rings. This synthesis achieves (-)-vallesamidine in 14 steps in an overall yield of 4.2% from an exocyclic enone ester.
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Affiliation(s)
- Fan Yang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Xia-Lin Wang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Feng-Kai Zhao
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Huai-Yu Bin
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Jian-Hua Xie
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
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2
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Yang F, Bin HY, Zhao FK, Cheng L, Wang H, Xie JH. Divergent Construction of Spirocyclopentene-3,2'-indolines with Vicinal Stereocenters via Palladium-Catalyzed Aza-Wacker Cyclization. Org Lett 2025; 27:4244-4250. [PMID: 40227830 DOI: 10.1021/acs.orglett.5c00931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Herein, we report an aerobic palladium-catalyzed aza-Wacker cyclization to produce spirocyclopentene-3,2'-indolines with vicinal stereocenters. Using 1,2-bis(diphenylphosphino)benzene (dppbz) and pyridine as ligands, we achieved a ligand-modulated diastereodivergent synthesis, producing cis- and trans-spirocyclopentene-3,2'-indolines with exceptional yields and diastereoselectivities. Density functional theory (DFT) calculations revealed that selective aza-Wacker cyclization proceeds through distinct trans- and cis-aminopalladation mechanisms.
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Affiliation(s)
- Fan Yang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Huai-Yu Bin
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Feng-Kai Zhao
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Li Cheng
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Hao Wang
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
| | - Jian-Hua Xie
- State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China
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3
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Li X, Chang Z, Duan S, Xie Z. Total Synthesis of Berkeleyone A and Preaustinoid A through Epoxypolyene Cyclization. Angew Chem Int Ed Engl 2025; 64:e202416211. [PMID: 39445483 DOI: 10.1002/anie.202416211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/03/2024] [Accepted: 10/23/2024] [Indexed: 10/25/2024]
Abstract
A bioinspired Lewis acid-catalyzed epoxypolyene cyclization was developed to construct the tetracyclic framework containing a bicyclo[3.3.1]nonane core and seven chiral centers. The usage of this approach for assembling these natural products of 6/6/6/6 tetracyclic skeleton with bicyclo[3.3.1]nonane core is demonstrated by the total synthesis of highly oxidized berkeleyone A and preaustinoid A.
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Affiliation(s)
- Xingyi Li
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, 730000, China
| | - Zhifang Chang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, 730000, China
| | | | - Zhixiang Xie
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou, 730000, China
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4
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Yang ZN, Rao H, Yin Y, Mu S, Jia Z, Ding H. Forging the Tetracyclic Core Framework of Rhodomolleins XIV and XLII: A Ring-Distortion Approach. Org Lett 2024; 26:3524-3529. [PMID: 38656200 DOI: 10.1021/acs.orglett.4c00885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
A ring distortion approach for the synthesis of an advanced intermediate en route to rhodomolleins XIV and XLII was described, which led to successful construction of the 5/8/5/5 tetracyclic core framework of the kalmane diterpenoids. Key steps of the strategy include an oxidative dearomatization-induced (ODI)-Diels-Alder cycloaddition, a Dowd-Beckwith rearrangement, and a bioinspired Wagner-Meerwein rearrangement.
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Affiliation(s)
- Zhen-Ning Yang
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Huijuanzi Rao
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Yuhao Yin
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Shan Mu
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Ziqi Jia
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
| | - Hanfeng Ding
- Department of Chemistry, Zhejiang University, Hangzhou 310058, China
- State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
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5
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Zhang Z, Qian X, Gu Y, Gui J. Controllable skeletal reorganizations in natural product synthesis. Nat Prod Rep 2024; 41:251-272. [PMID: 38291905 DOI: 10.1039/d3np00066d] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Covering: 2016 to 2023The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C-C and C-heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.
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Affiliation(s)
- Zeliang Zhang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
| | - Xiao Qian
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
| | - Yucheng Gu
- Syngenta, Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
| | - Jinghan Gui
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
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6
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Ebert KE, Belov VN, John M, Weiss T, Brüning T, Hayen H, Koch HM, Bury D. Identification, Organic Synthesis, and Sensitive Analysis of a cis-Homosalate-Specific Exposure Biomarker. Chem Res Toxicol 2024; 37:285-291. [PMID: 38227338 DOI: 10.1021/acs.chemrestox.3c00287] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Homosalate (HMS) is an organic UV filter used in sunscreens and personal care products. Despite its widespread use and detection in environmental matrices, little is known regarding its exposure in humans. HMS is used as a mixture of cis- and trans-isomers, and we recently revealed major differences in human toxicokinetics, indicating the need to consider these isomers separately in exposure and risk assessments. In the course of these previous investigations of human HMS toxicokinetics, we identified two trans-HMS-specific and one cis-HMS-specific biomarker candidates. However, the latter lacks sensitivity due to only low amounts excreted in urine, prompting the search for another cis-HMS-specific biomarker. Our toxicokinetic investigations revealed a total of five isomers of HMS carboxylic acid metabolites (HMS-CA). Of these, only one was specifically formed from cis-HMS (HMS-CA 5), but its full identity in terms of constitution and configuration had, so far, not been elucidated. Here, we describe the synthesis of three HMS-CA isomers, of which the isomer (1R,3S,5S)/(1S,3R,5R)-3-((2-hydroxybenzoyl)oxy)-1,5-dimethylcyclohexane-1-carboxylic acid turned out to be HMS-CA 5. Taken together with two previously synthesized HMS-CA isomers, we were able to identify the constitution and configuration of all five HMS-CA isomers observed in human metabolism. We integrated the newly identified cis-HMS-specific metabolite HMS-CA 5 into our previously published human biomonitoring LC-MS/MS method. Intra- and interday precisions had coefficients of variation below 2% and 5%, respectively, and the mean relative recovery was 96%. The limit of quantification in urine was 0.02 μg L-1, enabling the quantification of HMS-CA 5 in urine samples for at least 96 h after sunscreen application. The extended method thus enables the sensitive and separate monitoring of cis- and trans-HMS in future human biomonitoring studies for exposure and risk assessment.
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Affiliation(s)
- Katharina E Ebert
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - Vladimir N Belov
- Max Planck Institute for Multidisciplinary Sciences (MPI NAT), Facility for Synthetic Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
| | - Michael John
- Institute of Organic and Biomolecular Chemistry, Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
| | - Tobias Weiss
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - Heiko Hayen
- Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany
| | - Holger M Koch
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
| | - Daniel Bury
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
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7
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Lu F, Shao Y, Yan S, Yang D, Song H, Zhang D, Liu XY, Qin Y. Asymmetric Synthesis of the Functionalized A/E-Ring Fragment of C 18-Diterpenoid Alkaloids. J Org Chem 2024; 89:2807-2811. [PMID: 38324536 DOI: 10.1021/acs.joc.3c02745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.
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Affiliation(s)
- Fei Lu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yu Shao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Shulin Yan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Dingyi Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Hao Song
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Dan Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xiao-Yu Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yong Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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8
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Li C, Lu F, Cai Y, Zhang C, Shao Y, Zhang Y, Liu XY, Qin Y. Catalytic Asymmetric Total Synthesis of (-)-Garryine via an Enantioselective Heck Reaction. J Am Chem Soc 2024; 146:1081-1088. [PMID: 38113465 DOI: 10.1021/jacs.3c12171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
The first asymmetric total synthesis of the hexacyclic veatchine-type C20-diterpenoid alkaloid (-)-garryine is presented. Key steps include a Pd-catalyzed enantioselective Heck reaction, a radical cyclization, and a photoinduced C-H activation/oxazolidine formation sequence. Of note, a highly enantioselective Heck reaction developed in this work provides efficient access to 6/6/6 tricyclic compounds, in particular, containing a C19-functionalitiy, which is useful for diverse transformations.
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Affiliation(s)
- Chuang Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Fei Lu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yukun Cai
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Cheng Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yu Shao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuanyuan Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Xiao-Yu Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yong Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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9
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Xu Z, Li X, Rose JA, Herzon SB. Finding activity through rigidity: syntheses of natural products containing tricyclic bridgehead carbon centers. Nat Prod Rep 2023; 40:1393-1431. [PMID: 37140079 PMCID: PMC10472132 DOI: 10.1039/d3np00008g] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Covering: up to 2022Tricyclic bridgehead carbon centers (TBCCs) are a synthetically challenging substructure found in many complex natural products. Here we review the syntheses of ten representative families of TBCC-containing isolates, with the goal of outlining the strategies and tactics used to install these centers, including a discussion of the evolution of the successful synthetic design. We provide a summary of common strategies to inform future synthetic endeavors.
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Affiliation(s)
- Zhi Xu
- Department of Chemistry, Yale University, New Haven, Connecticut, 06520, USA.
| | - Xin Li
- Department of Chemistry, Yale University, New Haven, Connecticut, 06520, USA.
| | - John A Rose
- Department of Chemistry, Yale University, New Haven, Connecticut, 06520, USA.
| | - Seth B Herzon
- Department of Chemistry, Yale University, New Haven, Connecticut, 06520, USA.
- Departments of Pharmacology and Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, 06520, USA
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10
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Ji J, Chen J, Qin S, Li W, Zhao J, Li G, Song H, Liu XY, Qin Y. Total Synthesis of Vilmoraconitine. J Am Chem Soc 2023; 145:3903-3908. [PMID: 36779887 DOI: 10.1021/jacs.3c00318] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Vilmoraconitine belongs to one of the most complex skeleton types in the C19-diterpenoid alkaloids, which architecturally features an unprecedented heptacyclic core possessing a rigid cyclopropane unit. Here, we report the first total synthesis of vilmoraconitine relying on strategic use of efficient ring-forming reactions. Key steps include an oxidative dearomatization-induced Diels-Alder cycloaddition, a hydrodealkenylative fragmentation/Mannich sequence, and an intramolecular Diels-Alder cycloaddition.
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Affiliation(s)
- Jiujian Ji
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Jiajun Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Sixun Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Wanye Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Jun Zhao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Guozhao Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Hao Song
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Xiao-Yu Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yong Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
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11
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de la Torre A, Huang G, Kouklovsky C. Retro-[4+2]/Intramolecular Diels–Alder Cascade Allows a Concise Total Synthesis of Lucidumone. Synlett 2023. [DOI: 10.1055/s-0042-1751412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
AbstractLucidumone is a recently isolated meroterpenoid displaying interesting biological activity. This natural product possesses a complex structure, including a bicyclo[2.2.2]octane possessing 6 contiguous stereogenic centers. Herein, we discuss strategies to solve this synthetic challenge. In particular, we developed a new method for the inverse electron-demand Diels–Alder cycloaddition between 2-pyrones and acyclic enol ethers, as a mean to obtain a ‘masked’ cyclohexadiene. This method allowed an expeditious enantioselective synthesis of (+)-lucidumone through a retro-[4+2]/intramolecular Diels–Alder reaction cascade.1 Introduction2 Retrosynthetic Considerations on the Bicyclo[2.2.2]octane3 Development of a Methodology for Enantioselective IEDDA Cycloadditions4 Enantioselective Total Synthesis of (+)-Lucidumone5 Conclusion
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12
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Mo Y, Chen Q, Li J, Ye D, Zhou Y, Dong S, Liu X, Feng X. Asymmetric Catalytic Conjugate Addition of Cyanide to Chromones and β-Substituted Cyclohexenones. ACS Catal 2022. [DOI: 10.1021/acscatal.2c05509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Yuhao Mo
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Qiyou Chen
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Jinzhao Li
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Dong Ye
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Yuqiao Zhou
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Shunxi Dong
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Xiaohua Liu
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
| | - Xiaoming Feng
- Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
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13
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Huang G, Kouklovsky C, de la Torre A. Gram-Scale Enantioselective Synthesis of (+)-Lucidumone. J Am Chem Soc 2022; 144:17803-17807. [PMID: 36150082 DOI: 10.1021/jacs.2c08760] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The first enantioselective total synthesis of (+)-lucidumone is described through a 13-step synthetic pathway (longest linear sequence). The key steps involve the formation of a bridged bicyclic lactone by an enantioselective inverse-electron-demand Diels-Alder cycloaddition, C-O bond formation to assemble two fragments, and a one-pot retro-[4 + 2]/[4 + 2] cycloaddition cascade. The synthesis is scalable, and more than one gram of natural product was synthesized in one batch.
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Affiliation(s)
- Guanghao Huang
- Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Saclay, CNRS, 15 rue Georges Clémenceau, 91405 Orsay, Cedex, France
| | - Cyrille Kouklovsky
- Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Saclay, CNRS, 15 rue Georges Clémenceau, 91405 Orsay, Cedex, France
| | - Aurélien de la Torre
- Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Saclay, CNRS, 15 rue Georges Clémenceau, 91405 Orsay, Cedex, France
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14
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Jin S, Zhao X, Ma D. Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (-)-Napelline, (+)-Dehydronapelline, (-)-Songorine, (-)-Songoramine, (-)-Acoapetaldine D, and (-)-Liangshanone. J Am Chem Soc 2022; 144:15355-15362. [PMID: 35948501 DOI: 10.1021/jacs.2c06738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The napelline-type alkaloids possess an azabicyclo[3.2.1]octane moiety and an ent-kaurane-type tetracyclic skeleton (6/6/6/5) along with varied oxidation patterns embedded in the compact hexacyclic framework. Herein, we disclose a divergent entry to napelline-type alkaloids that hinges on convergent assembly of the ent-kaurane core using a diastereoselective intermolecular Cu-mediated conjugate addition and subsequent intramolecular Michael addition reaction as well as rapid construction of the azabicyclo[3.2.1]octane motif via an intramolecular Mannich cyclization. The power of this strategy has been demonstrated through efficient asymmetric total syntheses of eight napelline-type alkaloids, including (-)-napelline, (-)-12-epi-napelline, (+)-dehydronapelline, (+)-12-epi-dehydronapelline, (-)-songorine, (-)-songoramine, (-)-acoapetaldine D, and (-)-liangshanone.
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Affiliation(s)
- Shicheng Jin
- State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
| | - Xiangbo Zhao
- State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
| | - Dawei Ma
- State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
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15
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Chen C, Hsieh H. Recent advances in total synthesis of natural products by masked
ortho
‐benzoquinones. J CHIN CHEM SOC-TAIP 2022. [DOI: 10.1002/jccs.202200276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Chih‐Ming Chen
- Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Zhunan Taiwan
- Biomedical Translation Research Center Academia Sinica Taipei City Taiwan
| | - Hsing‐Pang Hsieh
- Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Zhunan Taiwan
- Biomedical Translation Research Center Academia Sinica Taipei City Taiwan
- Department of Chemistry National Tsing Hua University Hsinchu Taiwan
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16
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Shivam, Tiwari G, Kumar M, Chauhan ANS, Erande RD. Recent advances in cascade reactions and their mechanistic insights: a concise strategy to synthesize complex natural products and organic scaffolds. Org Biomol Chem 2022; 20:3653-3674. [PMID: 35416224 DOI: 10.1039/d2ob00452f] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The beauty of cascade reactions to bestow us with cumbersome organic scaffolds has made them a cutting-edge area of research. Although the planning of cascades may require intuition, their results can be highly impactful. The development of cascades to provide specific targeted molecules of an appropriate structural and stereochemical framework poses a significant challenge but can serve as one of the most impressive tools in organic synthesis. This review shares a broad interest in compiling cascade transformations towards the construction of polycyclic frameworks, induction of chirality/asymmetry in the protocol, etc. to solve diverse challenges in organic synthesis pursuits, as cascades enable the rapid and efficient construction of complex architectures from simple molecules. The studies highlighted herein manifest the utilization of a range of cascade reactions under various classifications for generating natural product skeletons such as palau'amine, benzosimuline, arcutinine, and others from simple building blocks, with emphasis on breakthroughs and potential for asymmetric synthesis. The exquisite synthetic designs of recently completed total synthesis of natural products with a focus on strategic concerns are also highlighted in this review.
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Affiliation(s)
- Shivam
- Department of Chemistry, Indian Institute of Technology Jodhpur, Jodhpur-342037, India.
| | - Geetika Tiwari
- Department of Chemistry, Indian Institute of Technology Jodhpur, Jodhpur-342037, India.
| | - Manish Kumar
- Department of Chemistry, Indian Institute of Technology Jodhpur, Jodhpur-342037, India.
| | | | - Rohan D Erande
- Department of Chemistry, Indian Institute of Technology Jodhpur, Jodhpur-342037, India.
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17
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He ZH, Wu BT, Xia Y, Yang SY, Wang ZY, Wang K, Wang W, Yang Y, Liu ZT. CO2 oxidative dehydrogenation of n-butane to butadiene over CrOx supported on CeZr solid solution. MOLECULAR CATALYSIS 2022. [DOI: 10.1016/j.mcat.2022.112262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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18
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Łowicki D, Przybylski P. Tandem construction of biological relevant aliphatic 5-membered N-heterocycles. Eur J Med Chem 2022; 235:114303. [PMID: 35344904 DOI: 10.1016/j.ejmech.2022.114303] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 12/20/2022]
Abstract
Nature often uses cascade reactions in a highly stereocontrolled manner for assembly structurally diverse nitrogen-containing heterocyclic scaffolds, i.e. secondary metabolites, important for medicinal chemistry and pharmacy. Five-membered nitrogen-containing heterocycles as standalone rings, as well as spiro and polycyclic systems are pharmacophores of drugs approved in various therapies, i.a. antibacterial or antiviral, antifungal, anticancer, antidiabetic, as they target many key enzymes. Furthermore, a large number of pyrrolidine derivatives are currently considered as drug candidates. Cascade transformations, also known as domino or tandem reactions, offer straightforward methods to build N-heterocyclic libraries of the great structural variety desired for drawing SAR conclusions. The tandem transformations are often atom economic and time-saving because they are performed as the one-pot, so no need for purification after each 'virtual' step and the limited necessity of protective groups are characteristic for these processes. Thus, the same results as in classical multistep synthesis can be achieved at markedly lower costs and shorter time, which is in line with modern green chemistry rules. Great advantage of cascade reactions is often reflected in their high regio- and stereoselectivities, enabling the preparing of the heterocyclic compound better fitted to the expected target in cells. This review reveals the biological relevance of N-heterocyclic scaffolds based on saturated 5-membered rings since we showed a number of examples of approved drugs together with the recent biologically attractive leading structures of drug candidates. Next, novel cascade synthetic procedures, taking into account the structure of the reactants and reaction mechanisms, enabling to obtain biological-relevant heterocyclic frameworks with good yields and relatively high stereoselectivity, were reviewed and compared. The review covers the advances of designing biological active N-heterocycles mainly from 2018 to 2021, whereas the synthetic part is focused on the last 7 years.
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Affiliation(s)
- Daniel Łowicki
- Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznan, Poland
| | - Piotr Przybylski
- Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznan, Poland.
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19
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Liu XY, Ke BW, Qin Y, Wang FP. The diterpenoid alkaloids. THE ALKALOIDS. CHEMISTRY AND BIOLOGY 2022; 87:1-360. [PMID: 35168778 DOI: 10.1016/bs.alkal.2021.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The diterpenoid alkaloids are a family of extremely important natural products that have long been a research hotspot due to their myriad of intricate structures and diverse biological properties. This chapter systematically summarizes the past 11 years (2009-2019) of studies on the diterpenoid alkaloids, including the "so-called" atypical ones, covering the classification and biogenetic relationships, phytochemistry together with 444 new alkaloids covering 32 novel skeletons and the corrected structures, chemical reactions including conversion toward toxoids, synthetic studies, as well as biological activities. It should be noted that the synthetic studies, especially the total syntheses of various diterpenoid alkaloids, are for the first time reviewed in this treatise. This chapter, in combination with our four previous reviews in volumes 42, 59, 67, and 69, will present to the readers a more completed and updated profile of the diterpenoid alkaloids.
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Affiliation(s)
- Xiao-Yu Liu
- Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu, China; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Bo-Wen Ke
- West China Hospital, Sichuan University, Chengdu, China
| | - Yong Qin
- Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu, China; Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China.
| | - Feng-Peng Wang
- Department of Chemistry of Medicinal Natural Products, West China School of Pharmacy, Sichuan University, Chengdu, China.
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20
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Hui C, Brieger L, Strohmann C, Antonchick AP. Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines. J Am Chem Soc 2021; 143:18864-18870. [PMID: 34748319 PMCID: PMC8603356 DOI: 10.1021/jacs.1c10175] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Here we report a contractive synthesis of multisubstituted cyclobutanes containing multiple stereocenters from readily accessible pyrrolidines using iodonitrene chemistry. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsymmetrical spirocyclobutanes were prepared successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported.
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Affiliation(s)
- Chunngai Hui
- Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.,Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
| | - Lukas Brieger
- Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
| | - Carsten Strohmann
- Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany
| | - Andrey P Antonchick
- Max Planck Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.,Technical University Dortmund, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44221 Dortmund, Germany.,Nottingham Trent University, School of Science and Technology, Department of Chemistry and Forensics, Clifton Lane, NG11 8NS Nottingham, United Kingdom
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21
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Shinde AH, Thomas AA, Mague JT, Sathyamoorthi S. Highly Regio- and Diastereoselective Tethered Aza-Wacker Cyclizations of Alkenyl Phosphoramidates. J Org Chem 2021; 86:14732-14758. [PMID: 34665630 PMCID: PMC10119688 DOI: 10.1021/acs.joc.1c01483] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We present highly diastereoselective tethered aza-Wacker cyclization reactions of alkenyl phosphoramidates. "Arming" the phosphoramidate tether with 5-chloro-8-quinolinol was essential to achieving >20:1 diastereoselectivity in these reactions. The substrate scope with respect to alkenyl alcohols and phosphoramidate tether was extensively explored. The scalability of the oxidative cyclization was demonstrated, and the product cyclophosphoramidates were shown to be valuable synthons, including for tether removal. With chiral alkenyl precursors, enantiopure cyclic phosphoramidates were formed.
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Affiliation(s)
- Anand H. Shinde
- Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA (66047)
| | - Annu Anna Thomas
- Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA (66047)
| | - Joel T. Mague
- Department of Chemistry, Tulane University, New Orleans, Louisiana, USA. (70118)
| | - Shyam Sathyamoorthi
- Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, USA (66047)
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22
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Qu P, Snyder SA. Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E. J Am Chem Soc 2021; 143:11951-11956. [PMID: 34338524 PMCID: PMC8397315 DOI: 10.1021/jacs.1c05942] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
![]()
The annotinolides are one of the
most recent additions to the Lycopodium family of
alkaloids, with its members possessing
challenging, caged structures that include a [3.2.1]-bicyclic core
bearing six contiguous stereocenters, including four that are fully
substituted. Herein, we document a concise and stereoselective route
that achieves the first total syntheses of three of its members: annotinolides
C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene
reaction that fashions much of the main core in a single operation,
as well as a number of other challenging and chemoselective transformations
to generate the remaining elements. Moreover, efforts utilizing the
natural products themselves, seeking adjustments in their oxidation
states and the rearrangement of individual ring systems, shed light
on their potential biogenesis with some outcomes counter to those
originally proposed. Finally, formal enantioenriched syntheses of
the target molecules are also presented.
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Affiliation(s)
- Pei Qu
- Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
| | - Scott A Snyder
- Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
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23
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Sharma D, Kumar M, Das P. Synthetic approaches for cyclohexane-1,3-diones: A versatile precursor for bioactive molecules. SYNTHETIC COMMUN 2021. [DOI: 10.1080/00397911.2021.1946824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Dharminder Sharma
- PG Department of Chemistry, JCDAV College Dasuya, Dasuya, Punjab, India
- Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
| | - Manish Kumar
- Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Department of Chemistry, Government College Seraj at Lambathach, Thunag, Himachal Pradesh, India
| | - Pralay Das
- Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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24
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Miki Y, Tomita N, Ban K, Sajiki H, Sawama Y. Synthesis of 1‐Pyrroline by Denitrogenative Ring Expansion of Cyclobutyl Azides under Thermal Conditions. Adv Synth Catal 2021. [DOI: 10.1002/adsc.202100329] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Yuya Miki
- Laboratory of Organic Chemistry Gifu Pharmaceutical University 1-25-4 Daigaku-nishi Gifu 501-1196, Japan
| | - Naohito Tomita
- Laboratory of Organic Chemistry Gifu Pharmaceutical University 1-25-4 Daigaku-nishi Gifu 501-1196, Japan
| | - Kazuho Ban
- Laboratory of Organic Chemistry Gifu Pharmaceutical University 1-25-4 Daigaku-nishi Gifu 501-1196, Japan
| | - Hironao Sajiki
- Laboratory of Organic Chemistry Gifu Pharmaceutical University 1-25-4 Daigaku-nishi Gifu 501-1196, Japan
| | - Yoshinari Sawama
- Laboratory of Organic Chemistry Gifu Pharmaceutical University 1-25-4 Daigaku-nishi Gifu 501-1196, Japan
- Graduate School of Pharmaceutical Sciences Osaka University 1-6 Yamada-oka, Suita Osaka 565-0871 Japan
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25
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Zhang Q, Yang Z, Wang Q, Liu S, Zhou T, Zhao Y, Zhang M. Asymmetric Total Synthesis of Hetidine-Type C 20-Diterpenoid Alkaloids: (+)-Talassimidine and (+)-Talassamine. J Am Chem Soc 2021; 143:7088-7095. [PMID: 33938219 DOI: 10.1021/jacs.1c01865] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Here, we report the first asymmetric total synthesis of (+)-talassimidine and (+)-talassamine, two hetidine-type C20-diterpenoid alkaloids. A highly regio- and diastereoselective 1,3-dipolar cycloaddition of an azomethine ylide yielded a chiral tetracyclic intermediate in high enantiopurity, thus providing the structural basis for asymmetric assembly of the hexacyclic hetidine skeleton. In this key step, the introduction of a single chiral center induces four new continuous chiral centers. Another key transformation is the dearomative cyclopropanation of the benzene ring and subsequent SN2-like ring opening of the resultant cyclopropane ring with water as a nucleophile, which not only establishes the B ring but also precisely installs the difficult-to-achieve equatorial C7-OH group.
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Affiliation(s)
- Quanzheng Zhang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Zhao Yang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Qi Wang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Shuangwei Liu
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Tao Zhou
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Yankun Zhao
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
| | - Min Zhang
- Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China
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26
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Delayre B, Wang Q, Zhu J. Natural Product Synthesis Enabled by Domino Processes Incorporating a 1,2-Rearrangement Step. ACS CENTRAL SCIENCE 2021; 7:559-569. [PMID: 34056086 PMCID: PMC8155462 DOI: 10.1021/acscentsci.1c00075] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Indexed: 05/07/2023]
Abstract
The art of natural product total synthesis is closely associated with two major determinants: the development/application of novel chemical reactions and the innovation in strategic use of classic organic reactions. While purposely seeking/applying a new synthetic methodology allowing nonconventional bond disconnections could shorten the synthetic route, the development of domino processes composed of a series of well-established reactions could also lead to a concise, practical, and aesthetically appealing synthesis. As an important class of textbook reactions, the 1,2-anionotropic rearrangements discovered at the dawn of modern organic chemistry have important bearings not only on chemical synthesis but also on the conceptual breakthroughs in the field. In its basic form, the 1,2-shift affords nothing but a constitutional isomer of the starting material and is therefore not a complexity-generating transformation. However, such a simple 1,2-shift could in fact change the molecular topology if the precursor is cleverly designed. More dramatically, it can metamorphosize the structure of the substrate when it is combined with other transformations in a domino sequence. In this Outlook, we highlight recent examples of natural product synthesis featuring a key domino process incorporating a 1,2-anionotropic rearrangement. Specifically, domino reactions integrating Wagner-Meerwein, pinacol, α-ketol, α-aminoketone, α-iminol, or benzilic acid rearrangements will be discussed.
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27
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Wu X, Nie W, Fu M, Liu XY, Xue F, Qin Y. Synthetic studies towards arcutinidine: An alternative strategy for construction of the complete carbon framework. Tetrahedron 2021. [DOI: 10.1016/j.tet.2021.132092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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28
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Yu SJ, Zhu YN, Ye JL, Huang PQ. A versatile approach to functionalized cyclic ketones bearing quaternary carbon stereocenters via organocatalytic asymmetric conjugate addition of nitroalkanes to cyclic β-substituted α,β-Enones. Tetrahedron 2021. [DOI: 10.1016/j.tet.2021.132005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Schuppe AW, Liu Y, Newhouse TR. An invocation for computational evaluation of isomerization transforms: cationic skeletal reorganizations as a case study. Nat Prod Rep 2021; 38:510-527. [PMID: 32931541 PMCID: PMC7956923 DOI: 10.1039/d0np00005a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Covering: 2010 to 2020This review article describes how cationic rearrangement reactions have been used in natural product total synthesis over the last decade as a case study for the many productive ways by which isomerization reactions are enabling for synthesis. This review argues that isomerization reactions in particular are well suited for computational evaluation, as relatively simple calculations can provide significant insight.
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Affiliation(s)
- Alexander W Schuppe
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511-8107, USA.
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30
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Liu XY, Wang FP, Qin Y. Synthesis of Three-Dimensionally Fascinating Diterpenoid Alkaloids and Related Diterpenes. Acc Chem Res 2021; 54:22-34. [PMID: 33351595 DOI: 10.1021/acs.accounts.0c00720] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the Aconitum and Delphinium species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies.Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C-H activation, aza-pinacol, and aza-Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an aza-Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the "Holy Grail" of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinating natural products.
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Affiliation(s)
- Xiao-Yu Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Feng-Peng Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yong Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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31
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Aconapelsulfonines A and B, seco C20-diterpenoid alkaloids deriving via Criegee rearrangements of napelline skeleton from Aconitum carmichaelii. CHINESE CHEM LETT 2021. [DOI: 10.1016/j.cclet.2020.09.062] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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32
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Abstract
The focus article discusses the innovation of hypervalent(iii) iodine regarding skeletal rearrangement, cycloaddition and cyclization, and sp3 C–H functionalization in natural product synthesis.
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Affiliation(s)
- Zhuo Wang
- Southern University of Science and Technology
- School of Medicine
- Shenzhen
- People's Republic of China
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33
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Gamidi RK, Dandawate M, Tothadi S, Choudhury R, Nangia AK, Reddy DS. Separation of a diastereomeric diol pair using the mechanical properties of crystals. CrystEngComm 2021. [DOI: 10.1039/d1ce01055g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The visually indistinguishable acicular crystals of a (2S,3R/S)-3-ethyl-1-phenylhex-5-ene-2,3-diol (ephd) diastereomeric pair are separated via the mechanical response based on elastic (2S,3R, right) and brittle (2S,3S, left) crystals.
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Affiliation(s)
- Rama Krishna Gamidi
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
| | - Monica Dandawate
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
| | - Srinu Tothadi
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
| | - Rahul Choudhury
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ashwini K. Nangia
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
- School of Chemistry, University of Hyderabad, Hyderabad 500046, India
| | - D. Srinivasa Reddy
- Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Sharma D, Kumar M, Das P. Application of cyclohexane-1,3-diones for six-membered oxygen-containing heterocycles synthesis. Bioorg Chem 2020; 107:104559. [PMID: 33418315 DOI: 10.1016/j.bioorg.2020.104559] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 11/23/2020] [Accepted: 12/10/2020] [Indexed: 12/17/2022]
Abstract
Cyclohexan-1,3-dione derivatives are versatile scaffolds for the synthesis of a variety of value-added organic molecules including heterocycles and natural products. Six-membered oxygen heterocycles prepared from cyclohexan-1,3-diones are of much importance as they are intermediate for the synthesis of a number of natural products and several other valuable bioactive molecules which shows anti-viral, anti-bacterial, analgesic, antimalarial, anti-inflammatory, anti-allergic, anti-tumor and anti-cancer activities. These advantages have inspired us to write a detailed survey on the newly developed methods which are very essential in the construction of six-membered oxygen heterocycles. Further, the versatility in the chemistry of cyclohexan-1,3-dione and its derivatives is due to the presence of highly active methylene moiety and its active di-carbonyl groups. Recently, reactions of cyclohexane-1,3-dione and its derivatives with other substrates for instance aldehydes, malononitriles, NMSM, chalcones, isatin etc. have been established for the construction of a variety of six-membered oxygen heterocycles. The studies reported in this review article involved the synthesis of six-membered oxygen-containing heterocycles which includes 4H-chromen-5(6H)-one, 2H-xanthen-1(9H)-one, 2H-xanthen-1,8(5H,9H)-dione, 6H-chromen-2,5-dione derivatives and natural products having six-membered oxygen heterocycles from cyclohexane-1,3-dione and its derivatives as one of the substrate.
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Affiliation(s)
- Dharminder Sharma
- PG Department of Chemistry, JCDAV College Dasuya, Punjab 144205, India; Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, HP, India.
| | - Manish Kumar
- Department of Chemistry, Govt. College Seraj at Lambathach, Distt. Mandi, 175048 HP, India; Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, HP, India
| | - Pralay Das
- Chemical Technology Department, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, HP, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Huang H, Mi F, Li C, He H, Wang F, Liu X, Qin Y. Total Synthesis of Liangshanone. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.202011923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Hong‐Xiu Huang
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Fen Mi
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Chunxin Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Huan He
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Feng‐Peng Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Xiao‐Yu Liu
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Yong Qin
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
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Huang H, Mi F, Li C, He H, Wang F, Liu X, Qin Y. Total Synthesis of Liangshanone. Angew Chem Int Ed Engl 2020; 59:23609-23614. [PMID: 32902096 DOI: 10.1002/anie.202011923] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Hong‐Xiu Huang
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Fen Mi
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Chunxin Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Huan He
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Feng‐Peng Wang
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Xiao‐Yu Liu
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
| | - Yong Qin
- Key Laboratory of Drug Targeting and Drug Delivery Systems of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drugs and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu 610041 China
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Guo Q, Xia H, Wu Y, Shao S, Xu C, Zhang T, Shi J. Structure, property, biogenesis, and activity of diterpenoid alkaloids containing a sulfonic acid group from Aconitum carmichaelii. Acta Pharm Sin B 2020; 10:1954-1965. [PMID: 33163346 PMCID: PMC7606178 DOI: 10.1016/j.apsb.2020.01.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/18/2019] [Accepted: 01/17/2020] [Indexed: 12/17/2022] Open
Abstract
Three new C20-diterpenoid alkaloids with a sulfonic acid unit, named aconicarmisulfonines B and C (1 and 2) and chuanfusulfonine A (3), respectively, were isolated from the Aconitum carmichaelii lateral roots ("fu zi" in Chinese). Structures of 1-3 were determined by spectroscopic data analysis. Intriguing chemical properties and reactions were observed for the C20-diterpenoid alkaloids: (a) specific selective nucleophilic addition of the carbonyl (C-12) in 1 with CD3OD; (b) interconversion between 1 and 2 in D2O; (c) stereo- and/or regioselective deuterations of H-11α in 1-3 and both H-11α and H-11β in aconicarmisulfonine A (4); (d) TMSP-2,2,3,3-d 4 promoted cleavage of the C-12-C-13 bond of 4 in D2O; (e) dehydrogenation of 4 in pyridine-d 5, and (f) Na2SO3-assisted dehydrogenation and N-deethylation of songorine (5, a putative precursor of 1-4). Biogenetically, 1 and 2 are correlated with 4, for which the same novel carbon skeleton is proposed to be derived from semipinacol rearrangements via migrations of C-13-C-16 and C-15-C-16 bonds of the napelline-type skeleton, respectively. Meanwhile, 3 is a highly possible precursor or a concurrent product in the biosynthetic pathways of 1, 2, and 4. In the acetic acid-induced mice writhing assay, at 1.0 mg/kg (i.p.), compounds 1, 2, 5, 5a, and 5b exhibited analgesic effects against mice writhing.
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Affiliation(s)
| | | | - Yuzhuo Wu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Shuai Shao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chengbo Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Tiantai Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jiangong Shi
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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38
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Xu Z, Zong Y, Qiao Y, Zhang J, Liu X, Zhu M, Xu Y, Zheng H, Fang L, Wang X, Lou H. Divergent Total Synthesis of Euphoranginol C, Euphoranginone D,
ent
‐Trachyloban‐3β‐ol,
ent
‐Trachyloban‐3‐one, Excoecarin E, and
ent
‐16α‐Hydroxy‐atisane‐3‐one. Angew Chem Int Ed Engl 2020. [DOI: 10.1002/ange.202009128] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ze‐Jun Xu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Yan Zong
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Ya‐Nan Qiao
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Jiao‐Zhen Zhang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Xuyuan Liu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Ming‐Zhu Zhu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Yuliang Xu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Hongbo Zheng
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Liyuan Fang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Xiao‐ning Wang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Hong‐Xiang Lou
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
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Xu Z, Zong Y, Qiao Y, Zhang J, Liu X, Zhu M, Xu Y, Zheng H, Fang L, Wang X, Lou H. Divergent Total Synthesis of Euphoranginol C, Euphoranginone D,
ent
‐Trachyloban‐3β‐ol,
ent
‐Trachyloban‐3‐one, Excoecarin E, and
ent
‐16α‐Hydroxy‐atisane‐3‐one. Angew Chem Int Ed Engl 2020; 59:19919-19923. [PMID: 32696611 DOI: 10.1002/anie.202009128] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Ze‐Jun Xu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Yan Zong
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Ya‐Nan Qiao
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Jiao‐Zhen Zhang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Xuyuan Liu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Ming‐Zhu Zhu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Yuliang Xu
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Hongbo Zheng
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Liyuan Fang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Xiao‐ning Wang
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
| | - Hong‐Xiang Lou
- Department of Natural Products Chemistry Key Lab of Chemical Biology (MOE) School of Pharmaceutical Sciences Shandong University No. 44 West Wenhua Road Jinan 250012 P. R. China
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Thomas AA, Nagamalla S, Sathyamoorthi S. Salient features of the aza-Wacker cyclization reaction. Chem Sci 2020; 11:8073-8088. [PMID: 34123081 PMCID: PMC8163389 DOI: 10.1039/d0sc02554b] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 07/20/2020] [Indexed: 11/23/2022] Open
Abstract
The intramolecular aza-Wacker reaction has unparalleled potential for the site-selective amination of olefins, but it is perhaps underappreciated relative to other alkene oxidations. The first part of this review makes the distinction between classical and tethered aza-Wacker cyclization reactions and summarizes examples of the latter. The second portion focuses on developments in asymmetric aza-Wacker cyclization technology. The final part of the review summarizes applications of all classes of aza-Wacker cyclization reactions to natural product assembly.
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Affiliation(s)
- Annu Anna Thomas
- Department of Medicinal Chemistry, University of Kansas Lawrence KS USA
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Suzuki T, Koyama T, Nakanishi K, Kobayashi S, Tanino K. Formal Total Synthesis of Atropurpuran. J Org Chem 2020; 85:10125-10135. [DOI: 10.1021/acs.joc.0c01462] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Takahiro Suzuki
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810 Hokkaido, Japan
| | - Takeshi Koyama
- Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, 060-0810 Hokkaido, Japan
| | - Kenta Nakanishi
- Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, 060-0810 Hokkaido, Japan
| | - Susumu Kobayashi
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
| | - Keiji Tanino
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, 060-0810 Hokkaido, Japan
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Vargová D, Némethová I, Šebesta R. Asymmetric copper-catalyzed conjugate additions of organometallic reagents in the syntheses of natural compounds and pharmaceuticals. Org Biomol Chem 2020; 18:3780-3796. [PMID: 32391843 DOI: 10.1039/d0ob00278j] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Access to enantiopure complex molecular structures is crucial for the development of new drugs as well as agents used in crop-protection. In this regard, numerous asymmetric methods have been established. Copper-catalyzed 1,4-additions of organometallic reagents are robust C-C bond formation strategies applicable in a wide range of circumstances. This review analyses the syntheses of natural products and pharmaceutical agents, which rely on the application of asymmetric Cu-catalyzed conjugate additions of various organometallic reagents. A wide range of available organometallics, e.g. dialkylzinc, trialkylaluminum, Grignard, and organozirconium, can now be used in conjugate additions to address various synthetic challenges present in targeted natural compounds. Furthermore, efficient catalysts allow high levels of stereofidelity over a diverse array of starting Michael acceptors.
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Affiliation(s)
- Denisa Vargová
- Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, Ilkovičova 6, SK-84215, Bratislava, Slovakia.
| | - Ivana Némethová
- Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, Ilkovičova 6, SK-84215, Bratislava, Slovakia.
| | - Radovan Šebesta
- Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, Ilkovičova 6, SK-84215, Bratislava, Slovakia.
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Heravi MM, Janati F, Zadsirjan V. Applications of Knoevenagel condensation reaction in the total synthesis of natural products. MONATSHEFTE FUR CHEMIE 2020. [DOI: 10.1007/s00706-020-02586-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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McCowen SV, Doering NA, Sarpong R. Retrosynthetic strategies and their impact on synthesis of arcutane natural products. Chem Sci 2020; 11:7538-7552. [PMID: 33552460 PMCID: PMC7860588 DOI: 10.1039/d0sc01441a] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 04/20/2020] [Indexed: 01/18/2023] Open
Abstract
Decisions, decisions, decisions: the interplay between different retrosynthetic strategies in the synthesis of the highly bridged, polycyclic arcutane natural products.
Retrosynthetic analysis is a cornerstone of modern natural product synthesis, providing an array of tools for disconnecting structures. However, discussion of retrosynthesis is often limited to the reactions used to form selected bonds in the forward synthesis. This review details three strategies for retrosynthesis, focusing on how they can be combined to plan the synthesis of polycyclic natural products, such as atropurpuran and the related arcutane alkaloids. Recent syntheses of natural products containing the arcutane framework showcase how these strategies for retrosynthesis can be combined to plan the total synthesis of highly caged scaffolds. Comparison of multiple syntheses of the same target provides a unique opportunity for detailed analysis of the impact of retrosynthetic disconnections on synthesis outcomes.
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Affiliation(s)
- Shelby V McCowen
- Department of Chemistry , University of California , Berkeley , California 94720 , USA .
| | - Nicolle A Doering
- Department of Chemistry , University of California , Berkeley , California 94720 , USA .
| | - Richmond Sarpong
- Department of Chemistry , University of California , Berkeley , California 94720 , USA .
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46
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Deng J, Ning Y, Tian H, Gui J. Divergent Synthesis of Antiviral Diterpenes Wickerols A and B. J Am Chem Soc 2020; 142:4690-4695. [PMID: 32073850 DOI: 10.1021/jacs.9b11838] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Wickerols A and B are diterpene natural products that have a novel fused 6-5-6-6 ring framework and exhibit potent antiviral activity against the H1N1 type A influenza virus. Herein, we report a divergent synthesis of wickerols A and B in 16 and 15 steps, respectively, from commercial sitolactone. The key reactions of the synthesis are a SmI2-mediated intramolecular ketone-allylic acetate reductive cyclization, a Claisen rearrangement, and an intramolecular alkylation/aldol reaction that rapidly assembled the compact tetracyclic core framework in a stereocontrolled manner. The work described herein allowed us to confirm the absolute configurations of wickerols A and B.
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Affiliation(s)
- Jiachen Deng
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Yuhan Ning
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Hailong Tian
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
| | - Jinghan Gui
- CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
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47
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Wang Z. Construction of all-carbon quaternary stereocenters by catalytic asymmetric conjugate addition to cyclic enones in natural product synthesis. Org Chem Front 2020. [DOI: 10.1039/d0qo00763c] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
This review discusses the construction of all-carbon quaternary stereocenters using catalytic asymmetric conjugate addition and its application in natural product synthesis.
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Affiliation(s)
- Zhuo Wang
- Southern University of Science and Technology
- School of Medicine
- Shenzhen
- People's Republic of China
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48
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Min XL, Xu XR, He Y. Axial-to-Central Chirality Transfer for Construction of Quaternary Stereocenters via Dearomatization of BINOLs. Org Lett 2019; 21:9188-9193. [PMID: 31664848 DOI: 10.1021/acs.orglett.9b03558] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
All-carbon quaternary stereocenters are versatile building blocks, and their asymmetric construction has attracted much attention. Herein, we disclose an axial-to-central chirality transfer strategy for the synthesis of chiral quaternary stereocenters via dearomatization of (S)-BINOLs. The reaction proceeded smoothly with a wide range of propargyl carbonates to afford chiral spiro-compounds in high yields with excellent enantioselectivities. In addition, the strategy was extended to kinetic resolution of rac-BINOLs albeit with moderate s value.
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Affiliation(s)
- Xiao-Long Min
- School of Chemical Engineering , Nanjing University of Science & Technology , Nanjing 210094 , China
| | - Xu-Ran Xu
- School of Chemical Engineering , Nanjing University of Science & Technology , Nanjing 210094 , China
| | - Ying He
- School of Chemical Engineering , Nanjing University of Science & Technology , Nanjing 210094 , China
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Wu Y, Shao S, Guo Q, Xu C, Xia H, Zhang T, Shi J. Aconicatisulfonines A and B, Analgesic Zwitterionic C20-Diterpenoid Alkaloids with a Rearranged Atisane Skeleton from Aconitum carmichaelii. Org Lett 2019; 21:6850-6854. [DOI: 10.1021/acs.orglett.9b02479] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Yuzhuo Wu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Shuai Shao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Qinglan Guo
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Chengbo Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Huan Xia
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Tiantai Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
| | - Jiangong Shi
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China
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Owens KR, McCowen SV, Blackford KA, Ueno S, Hirooka Y, Weber M, Sarpong R. Total Synthesis of the Diterpenoid Alkaloid Arcutinidine Using a Strategy Inspired by Chemical Network Analysis. J Am Chem Soc 2019; 141:13713-13717. [PMID: 31276621 DOI: 10.1021/jacs.9b05815] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Arcutinidine and other arcutinidine-type diterpenoid alkaloids feature an intricate polycyclic, bridged framework with unusual connectivity. A chemical network analysis approach to the arcutane skeleton enabled the identification of highly simplifying retrosynthetic disconnections, which indicated that the caged structure could arise from a simpler fused ring system. On this basis, a total synthesis of arcutinidine is reported herein, featuring an unprecedented oxopyrrolium Diels-Alder cycloaddition which furnishes a key tetracyclic intermediate. In addition, the synthesis utilizes a diastereoselective oxidative dearomatization/cycloaddition sequence and a SmI2-mediated C-C coupling to forge the bridged framework of the natural products. This synthetic plan may also enable future investigations into the biosynthetic relationships between the arcutanes, the related diterpenoid atropurpuran, and other diterpenoid alkaloids.
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Affiliation(s)
- Kyle R Owens
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Shelby V McCowen
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Katherine A Blackford
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Sohei Ueno
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Yasuo Hirooka
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Manuel Weber
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
| | - Richmond Sarpong
- Department of Chemistry , University of California , Berkeley , California 94720 , United States
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