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1.
《Journal of organometallic chemistry》2006,691(24-25):5163-5171
Peptidomimetic inhibitors of the hepatitis C NS3 protease often exhibit poor biopharmaceutical properties. Structure modification of a substrate-based tripeptide into a β-strand 15-membered ring scaffold provided a new class of peptidomimetics that are significantly superior as drug candidates to their acyclic precursors. Tripeptide dienes composed of three unnatural amino acid residues with numerous chiral centers were efficiently converted to macrocyclic peptides, in high diastereomeric purity, using ring-closing metathesis (RCM). The conformation of the acyclic diene and the protocol for the RCM reaction were investigated and optimized extensively in order to achieve an efficient synthesis of potential therapeutic agents for the treatment of hepatitis C infections. These studies provided the fist small molecule (BILN 2061) that was clinically validated for the treatment of hepatitis C infection in man and opened the door to a plethora of new pre-clinical pharmaceutical agents that can be made in multi kilogram quantities using RCM chemistry. 相似文献
2.
Synthesis of Cembranoid Analogues through Ring‐Closing Metathesis of Terpenoid Precursors: A Challenge Regarding Ring‐Size Selectivity 下载免费PDF全文
Tanja Heidt Dr. Angelika Baro Prof. Andreas Köhn Prof. Sabine Laschat 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(35):12396-12404
A systematic study on ring‐closing metathesis with Grubbs II catalyst to cembranoid macrocycles is described. Acyclic terpenoids with a functional group X in the homoallylic position relative to an RCM active terminus and substituents R, R1 directly attached to the other terminal double bond were prepared from geraniol derived trienes and fragments that are based on bromoalkenes and dimethyl malonate. Such terpenoids were suitable precursors, despite the presence of competing double bonds in their framework. The size of R and R1 is crucial for successful macrocyclization. Whereas small alkyl substituents at the double bond directed the RCM towards six‐membered ring formation, cross metathesis leading to dimers dominated for bulkier alkyl groups. A similar result was obtained for precursors without functional group X. In the case of unsymmetrically substituted terpenoid precursor (R=Et, R1=Me) with homoallylic OTBS or OMe group, the RCM could be controlled towards formation of macrocyclic cembranoids, which were isolated with excellent E‐selectivity. The role of the substituents was further studied by quantum chemical calculations of simplified model substrates. Based on these results a mechanistic rationale is proposed. 相似文献
3.
Ma C Schiltz S Le Goff XF Prunet J 《Chemistry (Weinheim an der Bergstrasse, Germany)》2008,14(24):7314-7323
BC ring-systems of taxol with different or no protecting group for the C1,C2-diol moiety have been efficiently synthesized. The eight-membered B ring is formed by a ring-closing metathesis reaction (RCM) between the C10 and C11 carbon atoms. The influence of the 1,2-diol protecting group on the RCM reaction has been studied in detail. 相似文献
4.
杯[4]芳烃的上端和下端通过金属复分解闭环反应以较高产率合成一系列新型杯[4]冠醚衍生物(8a-c),目标产物结构经元素分析、IR、MS、1H NMR及13C NMR证实。 相似文献
5.
The A ring of FR182877, exemplified by ent-4-b,c, has been synthesized, involving an enyne RCM as the key step. A systematic comparison of enyne vs diene RCM for the formation of cyclopentene derivatives showed that the latter metathesis proceeds much more easily even for this ring size. 相似文献
6.
F. Sbai M. Dakir A. Auhmani H. El Jamili M. Akssira A. Benharref A. Kenz M. Pierrot 《Acta Crystallographica. Section C, Structural Chemistry》2002,58(8):o518-o520
The stereochemistries of the title compounds, both C16H24Cl2O, have been established by X‐ray diffraction. In both structures, the seven‐membered ring adopts the same conformation, whereas the six‐membered ring shows an envelope conformation in the epoxydodecane structure and a boat conformation in the dodecan‐9‐one structure. 相似文献
7.
Jing Zhang Meng Liu Chuanhua Wu Gaoyuan Zhao Peiqi Chen Lin Zhou Prof. Dr. Xingang Xie Prof. Dr. Ran Fang Prof. Dr. Huilin Li Prof. Dr. Xuegong She 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(10):3994-3998
The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif. 相似文献
8.
Hillier IH Pandian S Percy JM Vincent MA 《Dalton transactions (Cambridge, England : 2003)》2011,40(5):1061-1072
The potential energy surfaces for ring-closing metathesis reactions of a series of simple α,ω-dienes which lead to 5-10 membered ring products, have been explored using density functional theory methods. We have investigated both the conformational aspects of the hydrocarbon chain during the course of the reactions, as well as the stationary structures on the corresponding potential energy surfaces. Extensive conformational searches reveal that the reaction proceeds via the conformation that would be expected for the cycloalkene product, though most unexpectedly, cyclohexene forms via complexes in boat-like conformations. The M06-L density functional has been used to map out the potential energy surfaces, and has identified metallocyclobutane fragmentation as being generally the highest barrier along the pathway. The structural variations along the pathway have been discussed for the reactant hydrocarbons of differing chain length to identify points at which cyclisation events may begin to affect reaction rates. Our study provides an excellent starting point from which to begin to learn about the way RCM reaction outcomes are controlled by diene structure. 相似文献
9.
Asx-Pro-turns have been identified with high frequency in protein structures nucleating type I β-turns. By bridging the amino acid side chain in position i with a nitrogen substituent in position i+2 by ring-closing olefin metathesis (RCM), peptide mimetics of type 1 could be developed. NMR based conformational investigations indicated a stable intramolecular H-bond constraining a U-turn conformation that was predicted to simulate a type I β-turn. 相似文献
10.
Jing Zhang Meng Liu Chuanhua Wu Gaoyuan Zhao Peiqi Chen Lin Zhou Xingang Xie Ran Fang Huilin Li Xuegong She 《Angewandte Chemie (International ed. in English)》2020,59(10):3966-3970
The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo‐epoxidation to control the eight‐membered‐ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight‐membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif. 相似文献
11.
T. N. Deshko A. V. Kamernitskii G. A. Kogan A. M. Turuta T. K. Ustynyuk T. M. Fadeeva 《Russian Chemical Bulletin》1976,25(12):2524-2528
1. | Study has been made of the circular dichroism spectra of 20-ketosteroids containing a three-membered ring (methylene, epoxide, episulfide, or aziridine) in the -position with respect to the keto group. |
2. | The observed n* and * transition Cotton effects have been correlated with the preferred conformation of the molecule. |
12.
Christian N. Kuzniewski Simon Glauser Fabienne Z. Gaugaz Raphael Schiess Javier Rodríguez‐Salarichs Stefan Vetterli Oliver P. Horlacher Jürg Gertsch Mariano Redondo‐Horcajo Angeles Canales Jesús Jimnez‐Barbero Jos Fernando Díaz Karl‐Heinz Altmann 《Helvetica chimica acta》2019,102(5)
A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones. 相似文献
13.
We present the synthesis of five- and six-membered cyclic phenylalanine mimics (1, 9, 16 and 17) that are constrained in a proline-like conformation. The five-membered mimetic 16 was prepared by Ring Closing Metathesis (RCM) of diene 15, itself prepared by alpha-benzylation of the L-methionine derived oxazolidinone 10, followed by oxidative elimination, ring hydrolysis and N-allylation. The six-membered mimetic 1 was prepared by allylating the L-phenylalanine-derived oxazolidinone 5, followed by hydrolysis, N-allylation and RCM. Olefins 1 and 16 were catalytically hydrogenated to give 9 and 17, respectively. The solid state structures of 9 and 16 were determined by X-ray crystallography and their conformations compared with that of 1. 相似文献
14.
Luis Amorim Dolores Díaz Jesús Jiménez-Barbero Yves Blériot 《Tetrahedron letters》2006,47(50):8887-8891
The synthesis of a β-d-mannopyranoside analog, fully identical to the naturally occurring d-mannopyranose in terms of hydroxyl pattern, and displaying a skew-boat conformation close to a B2,5 boat strongly believed to be adopted by the oxycarbenium transition state during glycosidic bond cleavage of β-mannane by family 26 β-mannanase, is described. The conformationally locked analog has been obtained by tethering the C-2 and C-5 carbon atoms of the sugar ring with a three carbon bridge using RCM methodology. Conformation of the mannose analog has been confirmed by NMR and molecular modelling. 相似文献
15.
Olefin metathesis catalyst: stabilization effect of backbone substitutions of N-heterocyclic carbene
Ruthenium olefin metathesis catalysts bearing an N-phenyl-substituted N-heterocyclic carbene (NHC) ligand that are resistant to decomposition through C-H activation have been prepared and tested in ring closing metathesis (RCM), cross metathesis (CM), and ROMP reactions. The N, N'-diphenyl-substituted NHC complex proved to be one of the most efficient catalysts in RCM to form tetrasubstituted olefins. 相似文献
16.
(5S,7S,8S)-(-)-N-Methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]benzeneacetamide (U69,593) is a potent agonist to opioid kappa-receptor. The crystal structure of U69,593 has been analyzed by the X-ray diffraction method. The molecule, as a whole, took an open conformation, and four cyclic rings composing the main skeleton were far apart from each other. The N and O atoms substituted for the cyclohexane ring were all in the equatorial position. The best planes of two 5-membered rings were almost perpendicular to that of the cyclohexane ring, and the N-methylamide linkage was also orthogonal to this ring plane. The conformation of the U69,593 molecule was compared with other kappa-agonists. 相似文献
17.
Ronald C. Crouch Ashok V. Bhatia O. William Lever 《Journal of heterocyclic chemistry》1990,27(2):385-389
High field 1H nmr studies have shown that the nature of the C -14 substituents has a remarkable influence on ring C conformation of epoxymorphinan opioids which have a 6α-hydroxyl group. In sharp contrast to the ring C twist-boat conformation observed in those 6α-hydroxy compounds which also have a 14-hydroxyl group (α-naltrexol; α-oxymorphol), ring C exists predominantly as a chair conformer in 6α-hydroxy compounds which have a proton bound to C -14 (dihydromorphine; dihydrocodeine). The 6β-hydroxy compounds (β-naltrexol; β-oxymorphol) have a ring C chair conformation in agreement with earlier studies. 相似文献
18.
New allocolchinoids having functionality in the C ring at position C10 or C11 have been synthesized using the enyne ring-closing metathesis (RCM) reaction for construction of the seven-membered ring and a Diels-Alder-aromatization sequence for the elaboration of the aromatic ring C. [reaction: see text]. 相似文献
19.
Blackwell HE Sadowsky JD Howard RJ Sampson JN Chao JA Steinmetz WE O'Leary DJ Grubbs RH 《The Journal of organic chemistry》2001,66(16):5291-5302
Heptapeptides containing residues with terminal olefin-derivatized side chains (3 and 4) have been treated with ruthenium alkylidene 1 and undergone facile ring-closing olefin metathesis (RCM) to give 21- and 23-membered macrocyclic peptides (5 and 6). The primary structures of peptides 3 and 4 were based upon a previously studied heptapeptide (2), which was shown to adopt a predominantly 3(10)-helical conformation in CDCl(3) solution and an alpha-helical conformation in the solid state. Circular dichroism, IR, and solution-phase (1)H NMR studies strongly suggested that acyclic precursors 3 and 4 and the fully saturated macrocyclic products 7 and 8 also adopted helical conformations in apolar organic solvents. Single-crystal X-ray diffraction of cyclic peptide 8 showed it to exist as a right-handed 3(10)-helix up to the fifth residue. Solution-phase NMR structures of both acyclic peptide 4 and cyclic peptide 8 in CD(2)Cl(2) indicated that the acyclic diene assumes a loosely 3(10)-helical conformation, which is considerably rigidified upon macrocyclization. The relative ease of introducing carbon-carbon bonds into peptide secondary structures by RCM and the predicted metabolic stability of these bonds renders olefin metathesis an exceptional methodology for the synthesis of rigidified peptide architectures. 相似文献
20.
Arindam Ghosh Dr. A. Srinivasan Dr. Cherumuttathu H. Suresh Prof. Dr. Tavarekere K. Chandrashekar 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(32):11152-11155
The synthesis of fused and nonfused core‐modified 40π nonaphyrins are reported. Spectroscopic and X‐ray structural studies reveal a twisted figure‐eight conformation in the freebase form that is nonaromatic. Structural changes occur, from figure‐eight to open extended conformation, upon protonation, thereby adopting 4nπ Hückel antiaromatic character, which is reflected in spectroscopic and theoretical studies. Such a structural change also induces ring inversions of specific heterocyclic rings by 180°. 相似文献