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1.
Diversity‐Oriented Synthesis of Drug‐Like Macrocyclic Scaffolds Using an Orthogonal Organo‐ and Metal Catalysis Strategy
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Dr. André Grossmann Sean Bartlett Matej Janecek Dr. James T. Hodgkinson Prof. David R. Spring 《Angewandte Chemie (International ed. in English)》2014,53(48):13093-13097
Small‐molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity‐oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three‐dimensionality, to target a broad area of biological space. In this study, an organocatalysis‐derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity‐generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one‐pot protocol facilitated the synthesis of drug‐like macrocycles with natural‐product‐like levels of shape diversity in a single step. 相似文献
2.
Ramu Surakanti Sumalatha Sanivarapu Chiranjeevi Thulluri Pravin S. Iyer Raghuram S. Tangirala Rambabu Gundla Dr. Uma Addepally Y. L. N. Murthy Lakshmi Velide Dr. Subhabrata Sen 《化学:亚洲杂志》2013,8(6):1168-1176
An elegant reagent‐controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug‐like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14 . 相似文献
3.
Dr. Pilar Ventosa‐Andrés Dr. Agustina La‐Venia Dr. Carlos Alfonso Barea Ripoll Dr. Ludmila Hradilová Dr. Viktor Krchňák 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(37):13112-13119
Herein, we describe the synthesis of molecular scaffolds consisting of medium‐sized fused heterocycles using amino acids, which are some of the most useful building blocks used by nature as well as chemists to create structural diversity. The acyclic precursors were assembled by using traditional Merrifield solid‐phase peptide synthesis, and cyclization was carried out through acid‐mediated tandem endocyclic N‐acyliminium ion formation, followed by nucleophilic addition with internal nucleophiles. The synthesis of molecular scaffolds consisting of seven‐, eight‐, and nine‐membered rings proceeded with full stereocontrol of the newly generated stereogenic center in most cases. 相似文献
4.
Srikanth Annareddygari Venkateshwer Reddy Kasireddy Jayachandra Reddy 《Journal of heterocyclic chemistry》2019,56(12):3267-3276
A new and efficient method for the synthesis of various aza‐fused poly‐hetero aromatics has been described. This protocol includes an intermolecular condensation followed by metal‐free base‐promoted intramolecular C―N coupling reaction. The advantage of this one‐pot transformation lies in the use of simple cyclic amidines‐like compounds without prefunctionalization of the starting heterocycles. 相似文献
5.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(35):10661-10665
The ubiquitous use of π‐rich five‐membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis‐acid‐catalyzed oxetane rearrangement. Notably, this methodology employs a keto‐oxetane motif as a 1,4‐dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4‐dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo‐fused versions thereof. 相似文献
6.
PdII‐Catalyzed Oxidative Tandem aza‐Wacker/Heck Cyclization for the Construction of Fused 5,6‐Bicyclic N,O‐Heterocycles
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Chenghao Ye Xuezhen Kou Jingzhao Xia Dr. Guoqiang Yang Li Kong Quhao Wei Prof. Dr. Wanbin Zhang 《化学:亚洲杂志》2018,13(15):1897-1901
A PdII‐catalyzed oxidative tandem cyclization was developed for the construction of fused 5,6‐bicyclic N, O‐heterocycles. This reaction was enabled by the combined use of a 3‐methylpyridine ligand and pentafluorobenzoic acid additive. A range of heterocyclic products with different substituents could be prepared in moderate to good yields via this methodology. Several transformations, including a scaled‐up preparation of product 2 a , were also carried out showing the good applicability of our methodology. 相似文献
7.
The Synthesis and Biological Evaluation of N‐Substituted 1H‐Benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines
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The synthesis of 1H‐benzimidazol‐2‐yl‐1H‐pyrazole‐3,5‐diamines has been developed. Synthesized bisheteroaryls contain two privileged medicinal scaffolds, aminopyrazole and benzimidazole, with two diversity positions at N1 of benzimidazole and C3 of pyrazole, respectively. The three‐step synthesis includes the Mitsunobu N‐alkylation of benzimidazole and subsequent one‐pot formation of aminopyrazole involving substitution of methylthio groups with amine and hydrazine followed with final ring closure. Inhibitory activity toward cyclin‐dependent kinase 2/cyclin E and cytotoxicity against two cancer cell lines were evaluated for all novel pyrazoles. Two compounds showed modest cyclin‐dependent kinase inhibition activity and cytotoxicity against cancer cell lines K562 and MCF7. 相似文献
8.
Rapid Synthesis of Fused N‐Heterocycles by Transition‐Metal‐Free Electrophilic Amination of Arene CH Bonds
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Dr. Hongyin Gao Dr. Qing‐Long Xu Dr. Muhammed Yousufuddin Prof. Daniel H. Ess Prof. László Kürti 《Angewandte Chemie (International ed. in English)》2014,53(10):2701-2705
We disclose an efficient and operationally simple protocol for the preparation of fused N‐heterocycles starting from readily available 2‐nitrobiaryls and PhMgBr under mild conditions. More than two dozen N‐heterocycles, including two bioactive natural products, have been synthesized using this method. A stepwise electrophilic aromatic cyclization mechanism was proposed by DFT calculations. 相似文献
9.
Hongyin Gao Qing‐Long Xu Muhammed Yousufuddin Daniel H. Ess Lszl Kürti 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2014,126(10):2739-2743
We disclose an efficient and operationally simple protocol for the preparation of fused N‐heterocycles starting from readily available 2‐nitrobiaryls and PhMgBr under mild conditions. More than two dozen N‐heterocycles, including two bioactive natural products, have been synthesized using this method. A stepwise electrophilic aromatic cyclization mechanism was proposed by DFT calculations. 相似文献
10.
Stereodivergent Synthesis of N‐Heterocycles by Catalyst‐Controlled,Activity‐Directed Tandem Annulation of Diazo Compounds with Amino Alkynes
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Kai Liu Chenghao Zhu Junxiang Min Dr. Shiyong Peng Guangyang Xu Prof. Dr. Jiangtao Sun 《Angewandte Chemie (International ed. in English)》2015,54(44):12962-12967
A stereodivergent synthesis of five‐membered N‐heterocycles, such as 2,3‐dihydropyrroles, and 2‐methylene and 3‐methylene pyrrolidines, has been developed through a tandem annulation of amino alkynes with diazo compounds and involves the trapping of in situ formed intermediates. Mechanistic investigations indicate that the copper‐catalyzed tandem annulations proceed by allenoate formation and subsequent intramolecular hydroamination. In contrast, the rhodium‐catalyzed protocol features a carbenoid insertion into the N? H bond and subsequent Conia‐ene cyclization. 相似文献
11.
Regioselective Synthesis of N‐Heteroaromatic Trifluoromethoxy Compounds by Direct O−CF3 Bond Formation
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Apeng Liang Shuaijun Han Zhenwei Liu Liang Wang Dr. Jingya Li Prof.Dr. Dapeng Zou Prof. Dr. Yangjie Wu Prof. Dr. Yusheng Wu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(15):5102-5106
The first one‐step method for the synthesis of ortho‐N‐heteroaromatic trifluoromethoxy derivatives by site‐specific O?CF3 bond formation using hydroxylated N‐heterocycles and Togni's reagent is described. The approach enables the unprecedented syntheses of a wide range of six or five‐membered N‐heteroaromatic trifluoromethoxy compounds containing one or two heteroatoms from most commonly used hydroxylated N‐heterocycles. Notable advantages of this method include its simplicity and mild conditions, avoidance of the need for metals or toxic reagents, and compatibility with a variety of functional groups. Furthermore, this method is especially suitable for the larger scale application. 相似文献
12.
José Sebastián Barradas María Inés Errea Claudia Sepúlveda Elsa Beatriz Damonte Norma Beatriz D'Accorso 《Journal of heterocyclic chemistry》2014,51(1):96-100
Herein, we describe the synthesis of pyrrolo[2,1‐b]thiazoles substituted on C‐2 or C‐5 with a protected carbohydrate moiety. The new fused bicyclic heterocycles were obtained via thiazole intermediates, and the N‐alkylation step was assisted by microwave irradiation. The new products were completely characterized by physical and spectroscopic techniques. The cytotoxicity and antiviral activity against Junín virus of the methylated derivates was also evaluated. 相似文献
13.
Xi‐Jie Dai Oliver D. Engl Thierry Len Stephen L. Buchwald 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(11):3445-3449
Herein, we report a practical two‐step synthetic route to α‐arylpyrrolidines through Suzuki–Miyaura cross‐coupling and enantioselective copper‐catalyzed intramolecular hydroamination reactions. The excellent stereoselectivity and broad scope for the transformation of substrates with pharmaceutically relevant heteroarenes render this method a practical and versatile approach for pyrrolidine synthesis. Additionally, this intramolecular hydroamination strategy facilitates the asymmetric synthesis of tetrahydroisoquinolines and medium‐ring dibenzo‐fused nitrogen heterocycles. 相似文献
14.
Insertion of Isolated Alkynes into Carbon–Carbon σ‐Bonds of Unstrained Cyclic β‐Ketoesters via Transition‐Metal‐Free Tandem Reactions: Synthesis of Medium‐Sized Ring Compounds
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Yuanyuan Zhou Xianghua Tao Qiyi Yao Yulei Zhao Prof. Dr. Yanzhong Li 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(50):17936-17939
The transition‐metal‐free insertion of isolated alkynes into carbon–carbon σ‐bonds of unstrained cyclic β‐dicarbonyl compounds has been reported. These tandem reactions offer an efficient synthesis of medium‐sized ring or fused‐ring compounds through ring expansion. The methodology has the potential to be widely used throughout organic synthesis due to the easily accessible starting materials and mild reaction conditions. 相似文献
15.
Palladium‐Catalyzed Synthesis of Phenanthridine/Benzoxazine‐Fused Quinazolinones by Intramolecular CH Bond Activation
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Puneet K. Gupta Nisha Yadav Subodh Jaiswal Mohd. Asad Dr. Ruchir Kant Dr. Kanchan Hajela 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(38):13210-13215
A highly efficient synthesis of phenanthridine/benzoxazine‐fused quinazolinones by ligand‐free palladium‐catalyzed intramolecular C?H bond activation under mild conditions has been developed. The C?C coupling provides the corresponding N‐fused polycyclic heterocycles in good to excellent yields and with wide functional group tolerance. 相似文献
16.
Indrajeet J. Barve Chan‐Yu Chen Deepak B. Salunke Prof. Wen‐Sheng Chung Prof. Chung‐Ming Sun 《化学:亚洲杂志》2012,7(7):1684-1690
The present article describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4‐fluoro‐3‐nitrobenzoic acid, 2‐chloro‐3‐nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet–Spengler‐type condensation was used as a key step to construct tetracyclic indolo‐benzodiazepines and indolo‐quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three‐dimensional orientations. 相似文献
17.
Lei Peng Da Xu Xiaohong Yang Jiakun Tang Xuli Feng Shao‐Lin Zhang Hailong Yan 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(1):222-226
An organocatalytic one‐step desymmetrizing dearomatization reaction of indoles with in situ formed vinylidene ortho‐quinone methides is reported. A set of [6‐6‐5] and/or [5‐6‐5] fused indoline heterocycles were obtained in excellent yields with excellent diastereoselectivities (>20:1 d.r.) and enantioselectivities (up to 99 % ee). Moreover, some of the obtained products were screened against a panel of cancer cell lines, and one was identified to inhibit the proliferation of all the tested cancer cells, but showed marginal effects against non‐cancerous cells. The methodology provides a platform for the synthesis of new leading compounds with antitumor activity. 相似文献
18.
Avinash H. Bansode Aslam C. Shaikh Dr. Rahul D. Kavthe Shridhar Thorat Dr. Rajesh G. Gonnade Dr. Nitin T. Patil 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(6):2319-2323
The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical biology. One of the best ways to access collections of small molecules is to use various techniques in diversity‐oriented synthesis (DOS). Recently, a new form of DOS, namely “relay catalytic branching cascades” (RCBCs), has been introduced, wherein a common type of starting material reacts with several scaffold‐building agents (SBAs) to obtain structurally diverse molecular scaffolds under the influence of catalysts. Herein, the RCBC reaction of a common type of substrate with SBAs is reported to give two different types of molecular scaffolds and their formation is essentially dependent on the type of catalyst used. 相似文献
19.
Dalila Chouikhi Mihai Ciobanu Claudio Zambaldo Vincent Duplan Dr. Sofia Barluenga Prof. Nicolas Winssinger 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(40):12698-12704
Nucleic acid‐encoded libraries are emerging as an attractive and highly miniaturized format for the rapid identification of protein ligands. An important criterion in the synthesis of nucleic acid encoded libraries is the scope of reactions that can be used to introduce molecular diversity and devise divergent pathways for diversity‐oriented synthesis (DOS). To date, the protecting group strategies that have been used in peptide nucleic acid (PNA) encoded synthesis (PES) have limited the choice of reactions used in the library synthesis to just a few prototypes. Herein, we describe the preparation of PNA monomers with a protecting group combination (Mtt/Boc) that is orthogonal to Fmoc‐based synthesis and compatible with a large palette of reactions that have been productively used in DOS (palladium cross‐couplings, metathesis, reductive amination, amidation, heterocycle formation, nucleophilic addition, conjugate additions, Pictet–Spengler cyclization). We incorporate γ‐modifications in the PNA backbone that are known to enhance hybridization and solubility. We demonstrate the robustness of this strategy with a library synthesis that is characterized by MALDI MS analysis at every step. 相似文献
20.
Pd‐Catalyzed Carboamination of Alkylidenecyclopropanes: Synthesis of Congested Pyrrolidines and Piperidines
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Phillip R. Lazzara Keegan P. Fitzpatrick Dr. Chad C. Eichman 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(47):16779-16782
The synthesis of densely functionalized N‐heterocycles is an ongoing challenge in chemical synthesis. Herein, we report an efficient method for the construction of pyrrolidine and piperidine scaffolds using a palladium‐catalyzed carboamination of alkylidenecyclopropanes. 相似文献