- Enantioselective Total Synthesis of Nigelladine A via Late-Stage C-H Oxidation Enabled by an Engineered P450 Enzyme
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An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A is described. Strategically, the synthesis relies on a late-stage C-H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C-H oxidation in the presence of four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening.
- Loskot, Steven A.,Romney, David K.,Arnold, Frances H.,Stoltz, Brian M.
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- Photoredox-Catalyzed Cascade Reactions Involving Aryl Radical: Total Synthesis of (±)-Norascyronone A and (±)-Eudesmol
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Herein, we have developed two types of photoredox-catalyzed cascade reactions using diaryliodonium salts for the concise synthesis of norascyronone A and β-eudesmol. A rationally designed photoredox-catalyzed arylation/cyclization/Friedel-Crafts cascade reaction of enone was exploited to generate the norascyronone polycyclic skeleton. A visible-light-induced radical cyclization/acyloxy-migration reaction was explored to forge the decalin skeleton of eudesmol, and mechanistic studies indicated the reaction was initiated by one-electron oxidation of the enol ester.
- Xu, Ze-Jun,Liu, Xu-Yuan,Zhu, Ming-Zhu,Xu, Yu-Liang,Yu, Yue,Xu, Hai-Ruo,Cheng, Ai-Xia,Lou, Hong-Xiang
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supporting information
p. 9073 - 9077
(2021/12/06)
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- Catalytic enantioselective total synthesis of (?)-ar-Tenuifolene
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First catalytic asymmetric total synthesis of aromatic sesquiterpene, (?)-ar-teunifolene (1) is featured (3 steps, 75% overall yields) from commercially available 3-methyl cyclohex-2-enone 16. The enantioenriched 3,3-disubstituted cyclohexanone 11 is obtained from Pd(II)-catalyzed enantioselective (p-tolyl)boronic acid addition to 3-methyl cyclohex-2-enone 16 in 90% ee, which is found to be the key intermediate. A diastereoselective methyllithium addition of this enantioenriched product followed by dehydration completes straightforward access to (?)-ar-teunifolene (1).
- Shaw, Kundan,Niyogi, Sovan,Bisai, Vishnumaya
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- Synthesis and evaluation of tetrahydroquinolin-2(1H)-one derivatives as novel anti-pancreatic cancer agents via targeting autophagy
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Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate of less than 6% owing to its remarkable tolerance to nutrient starvation, and new drugs and treatment strategies are urgently needed. During a project aiming at discovery of anticancer agents, we performed a structure modification on polycyclic polyprenylated acylphloroglucinols (PPAPs) skeleton, and discovered that PPAP rearranged to a tetrahydroquinolin-2(1H)-one feature. Here, series of tetrahydroquinolin-2(1H)-one derivatives were designed, synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (PANC-1), and the structure-activity relationship was also discussed. Among them, derivative 11k showed the most potent inhibitory activity with an IC50 value of 4.9 μM under nutrient-deprived condition. In contrast, all these derivatives exhibited low cytotoxicity against PANC-1 cells under normal nutrient condition, suggesting that the derivatives appeared to allow alternative tumor cell death mechanisms, and led to less toxicity. Further evaluations demonstrated that 11k decreased colony formation and induced the apoptosis of PANC-1 under nutrient-deprived condition in a concentration dependent manner. In in vivo study, 11k significantly suppressed the tumor development and weight in nude mice. Preliminary mechanism research revealed that 11k clearly downregulated LC3-II expression and increased the level of p62, two key autophagy markers and critical signals for pancreatic tumor growth and progression. Our current findings demonstrated that 11k might be a promising candidate for the new chemotherapeutic molecule of pancreatic cancer, and deserve further study.
- Shen, Qi,Wang, Jie,Liu, Chen-Xi,Cui, Wei,Zhang, Lei,Zhang, Yu-chao,Wang, Yue,Wu, Jing,Li, Jian-Xin
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- A Unique Skeletal Rearrangement of a Bicyclo[33.1]nonanetrione to a Tetrahydroquinolin-2(1 H)-one System
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The unexpected formation of a 4-hydroxytetrahydroquinolin-2(1 H)-one from a bicyclo[3.3.1]nonanetrione system and an amino alcohol in the presence of TsOH is reported. The mechanism of this transformation was studied by DFT calculations. The reaction provides an entry to the synthesis of highly functionalized 4-hydroxytetrahydroquinolin-2(1 H)-ones.
- Shen, Qi,Liu, Fang,Zhang, Yu-Chao,Wang, Jie,Zhang, Lei,Wang, Yue,Xu, Hong-Xi,Shao, Zhuzhou,Cao, Yang,Wu, Jing,Liang, Yong,Li, Jian-Xin
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supporting information
p. 1711 - 1716
(2018/07/06)
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- Pyridinone derivative as well as preparation method and application thereof
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The invention discloses a pyridinone derivative as well as a preparation method and application thereof. The pyridinone derivative is subjected to structural modification from the aspect of R1, R2 andR3 substituent groups, wherein modification of R1 is achieved mainly through allyl, isopentenyl, geranyl and fluorine benzyl and the like; modification of R2 is achieved mainly through ethoxyl, hydroxypropyl, amino ethyl and amino propyl and the like; and modification of R3 mainly concentrates on ethers with the certain structural features. The pyridinone derivative has the outstanding inhibitioneffect on pancreatic cancer cell PANC-1 at the state of lack of nutrition, while has no influence on the cell at the state of normal nutrition (indicating free of cytotoxicity). The preparation method of the pyridinone derivative comprises the steps that firstly basic nuclear parent bicyclo [3.3.1] nonanone is synthesized and subjected to a rearrangement reaction with a series of hydramine or diamine under catalysis of toluenesulfonic acid, and the pyridinone derivative having the remarkable inhibition effect on pancreatic cancer is prepared, and the pyridione derivative has the very good practicality.
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Paragraph 000; 0031; 0032; 0033
(2018/12/13)
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- Synthesis of Spirolactams and Fused Bicyclic Lactams via Acid-Promoted Cyclolactamization of (Ethynyl(tosyl)amino)methyl-Tethered Cyclohex-2-enols
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A simple synthetic method to construct the spirolactam framework from TfOH-catalyzed spirolactamization of cyclohex-2-enols bearing a tethered (arylethynyl(tosyl)amino)methyl moiety is described. The reaction proceeded through a keteniminium-allylic carbocation intermediate. Hydration of the keteniminium ion, followed by attack of the resulting enolate onto the tethered allylic carbocation, provided the spirolactam ring skeleton. This strategy could also be employed in the synthesis of fused bicyclic lactams from BF3·OEt2-assisted cyclolactamization of TBS-protected 2-(ethynyl(tosyl)amino)methylcyclohex-2-enols.
- Tung, Po-Ting,Zhong, Chang-Zhi,Chien, Tzu-Chiang,Yeh, Ming-Chang P.
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p. 11543 - 11557
(2017/11/10)
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- Systemic study on the biogenic pathways of Yezo'otogirins: Total synthesis and antitumor activities of (±)-Yezo'otogirin C and its structural analogues
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A systematic study of the biomimetic pathways to yezootogirin C under aerobic and anaerobic conditions has been investigated, and both are found to be feasible pathways to the natural product depending on the physiological conditions. Because of the lower activation energy, the aerobic process would be more favorable when the in vivo oxygen level is high. In the course of this study, a highly efficient synthetic route to (±)-yezootogirin C has been established in four steps (31% overall yield) from a readily available compound without using any protecting groups. The natural product and its structural analogues exhibited antitumor activities against several human cancer cell lines and appeared to arrest cell cycles in different phases.
- Yang, Wei,Cao, Jingming,Zhang, Mengxun,Lan, Rongfeng,Zhu, Lizhi,Du, Guangyan,He, Shuzhong,Lee, Chi-Sing
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p. 836 - 846
(2015/03/05)
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- Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation
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Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of "classic" natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.
- Liu, Yiyang,Liniger, Marc,McFadden, Ryan M.,Roizen, Jenny L.,Malette, Jacquie,Reeves, Corey M.,Behenna, Douglas C.,Seto, Masaki,Kim, Jimin,Mohr, Justin T.,Virgil, Scott C.,Stoltz, Brian M.
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p. 2501 - 2512
(2015/02/19)
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- Synthesis of 2-azaspiro[4.6]undec-7-enes from N -tosyl- N -(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ols
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The FeCl3-promoted synthesis of 2-azaspiro[4.6]undec-7-ene rings proceeds via ring expansion/cyclization/chlorination of N-tosyl-N-(3- arylpropargyl)-tethered 6-methylbicyclo[4.1.0]heptan-2-ols. This azaspirocyclic ring skeleton can also be obtained in one pot from the tert-butyldimethylsilyl- protected N-tosyl-N-(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ols and diethylzinc/diiodomethane.
- Yeh, Ming-Chang P.,Liang, Chia-Jung,Fan, Chern-Wei,Chiu, Wei-Hang,Lo, Jun-Yuan
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p. 9707 - 9717,11
(2012/12/12)
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- Methoxypyridines in the synthesis of lycopodium alkaloids: Total synthesis of (±)-lycoposerramine R
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A methoxypyridine serves as a masked pyridone in a concise synthesis of the Lycopodium alkaloid lycoposerramine R, which has been prepared for the first time. The key step of the synthesis is the use of an Eschenmoser Claisen rearrangement to forge a key quaternary carbon center.
- Bisai, Vishnumaya,Sarpong, Richmond
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supporting information; experimental part
p. 2551 - 2553
(2010/08/06)
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- Iron(III) tosylate in the preparation of dimethyl and diethyl acetals from ketones and β-keto enol ethers from cyclic β-diketones
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An efficient method for conversion of ketones to their corresponding dimethyl and diethyl acetals and of cyclic β-diketones into β-keto enol ethers using Fe(OTs)3 as a catalyst is described. Copyright Taylor & Francis Group, LLC.
- Mansilla, Horacio,Afonso, Maria M.
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p. 2607 - 2618
(2008/12/22)
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- Synthesis of fused oxabicyclic systems by metal-catalyzed intramolecular addition of 1,3-cycloalkyldiones to alkynes
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(Matrix presented) Readily available 4-propargyl-1,3-cyclohexanediones and cyclopentanediones can be chemo- and regioselectively cycloisomerized to synthetically appealing fused oxabicyclic systems by simply stirring at room temperature with catalytic amounts of an appropriate metal complex.
- Gulias, Moises,Rodriguez, J. Ramon,Castedo, Luis,Mascarenas, Jose L.
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p. 1975 - 1977
(2007/10/03)
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- Aldol condensation versus conjugate addition: Intramolecular cyclization using a combination of Lewis acid and 1,2-diol
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The reactivity of 3-substituted 4-methyl-4-(3-oxobutyl)-2-cyclohexen-1-ones (1) in the presence of a combination of a Lewis acid and a 1,2-diol was studied. The results suggest several factors that influence 6-membered ring formation, including two types of intramolecular aldol reaction and intramolecular 1,4-addition, due to the C3-substituent, Lewis acid, and the presence of diol. In this study, novel methodology to prepare two types of decalin skeleton could be developed.
- Yamada,Suemune
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p. 1171 - 1175
(2007/10/03)
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- Enantioselective total synthesis of (+)-taxusin
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For the total synthesis of (+)-taxusin, the AC-ring fragment 8 was prepared from an optically active 2-bromo-3-siloxycyclohexenecarbacetal 5 via 4 steps and was converted to the dienol silyl ether 13. The thus-obtained 13 underwent B-ring cyclization in the presence of Me2AlOTf to produce the ABC endo-tricarbocycle 14 having C9α, C10β-substituents, which was converted to the cyclopropyl ketone 21a. Introduction of C19 methyl via reductive cleavage of the cyclopropane ring under Birch conditions and successive in situ treatment of the resulting enol with methanol gave the C3α-protonated ketone 24. Next, 24 was converted to the allylsilane 29, which was then oxidized with m-CPBA to produce the fully functionalized taxusin carbon skeleton. Finally, removal of the silyl protecting groups followed by acetylation completed the total synthesis of (+)-taxusin.
- Hara, Ryoma,Furukawa, Takashi,Kashima, Hajime,Kusama, Hiroyuki,Horiguchi, Yoshiaki,Kuwajima, Isao
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p. 3072 - 3082
(2007/10/03)
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- A Formal Synthesis of Dihydrocompactin
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A formal synthesis of dihydrocompactin is reported.A key intermediate, tricyclic lactone (1b), was prepared by an efficient method of lactone synthesis, based on an intramolecular cycloaddition reaction of allenyl ether.
- Nagashima, Shigeru,Taishi, Teruhiko,Kanematsu, Ken
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