- Simple and efficient N-acylation reactions of chiral oxazolidinone auxiliaries
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A simplified procedure for the N-acylation of oxazolidin-2-one chiral auxiliaries has been developed. The acylations occur at room temperature in the presence of triethylamine and catalytic quantities of 4-(N,N-dimethylamino)pyridine, thereby eliminating the necessity for a strong base such as butyllithium. Acylations with both symmetrical and mixed anhydrides, as well as acid chlorides, occur with a wide variety of oxazolidinone auxiliaries.
- Ager, David J.,Allen, David R.,Schaad, David R.
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- Substrate structure-activity relationships guide rational engineering of modular polyketide synthase ketoreductases
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Modular polyketide synthase ketoreductases can set two chiral centers through a single reduction. To probe the basis of stereocontrol, a structure-activity relationship study was performed with three α-methyl, β-ketothioester substrates and four ketoreductases. Since interactions with the β-ketoacyl moiety were found to be most critical, residues implicated in contacting this moiety were mutated. Two mutations were sufficient to completely reverse the stereoselectivity of the model ketoreductase EryKR1, converting it from an enzyme that generates (2S,3R)-products into one that yields (2S,3S)-products.
- Bailey, Constance B.,Pasman, Marjolein E.,Keatinge-Clay, Adrian T.
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- A Synthesis Strategy for the Production of a Macrolactone of Gulmirecin A via a Ni(0)-Mediated Reductive Cyclization Reaction
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A synthesis strategy for the production of a key synthetic intermediate of gulmirecin A was described. The key reaction in the preparation of the 12-membered macrolactone is the Ni(0)-mediated reductive cyclization reaction of ynal using an N-heterocyclic carbene ligand and silane reductant. In addition, the α-selective glycosylation reaction of the macrolactone was performed to demonstrate the synthesis of gulmirecin and disciformycin precursors.
- Ichikawa, Satoshi,Katsuyama, Akira,Kitahata, Shun
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- Modular Synthesis of Diverse Natural Product-Like Macrocycles: Discovery of Hits with Antimycobacterial Activity
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A modular synthetic approach was developed in which variation of the triplets of building blocks used enabled systematic variation of the macrocyclic scaffolds prepared. The approach was demonstrated in the synthesis of 17 diverse natural product-like macrocyclic scaffolds of varied (12–20-membered) ring size. The biological relevance of the chemical space explored was demonstrated through the discovery of a series of macrocycles with significant antimycobacterial activity.
- Dow, Mark,Marchetti, Francesco,Abrahams, Katherine A.,Vaz, Luis,Besra, Gurdyal S.,Warriner, Stuart,Nelson, Adam
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- DCC/DMAP-Mediated Coupling of Carboxylic Acids with Oxazolidinones and Thiazolidinethiones
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Dicyclohexylcarbodiimide and catalytic dimethylaminopyridine were successfully used in the coupling of carboxylic acids with oxazolidinones and thiazolidinethiones. The acylated products were obtained in good yields.
- Andrade, Carlos Kleber Z.,Rocha, Rafael O.,Vercillo, Otilie E.,Silva, Wender A.,Matos, Ricardo Alexandre F.
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- Novel chiral stationary phases based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin combining cinchona alkaloid moiety
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Novel chiral selectors based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5-dimethyl phenylcarbamoylated β-cyclodextrin (β-CD) chiral stationary phase (CSP) and 9-O-(tert-butylcarbamoyl)-QN-based CSP (QN-AX). Fmoc-protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD-based CSP and QN/QD-based CSPs have broader application range than β-CD-based CSP or QN/QD-based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc-amino acids accompanied by the synergistic effect of β-CD moiety, which lead to the different enantioseparation of β-CD-QN-based CSP and β-CD-QD-based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin-based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β-CD-based CSP for certain samples.
- Zhu, Lunan,Zhu, Junchen,Sun, Xiaotong,Wu, Yaling,Wang, Huiying,Cheng, Lingping,Shen, Jiawei,Ke, Yanxiong
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- The perils of rational design-unexpected irreversible elimination of fluoride from 3-fluoro-2-methylacyl-CoA esters catalysed by α-methylacyl-CoA racemase (AMACR; P504S)
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α-Methylacyl-CoA racemase (AMACR; P504S) catalyses 'racemization' of 2-methylacyl-CoAs, the activation of R-ibuprofen and is a promising cancer drug target. Human recombinant AMACR 1A catalyses elimination of 3-fluoro-2-methyldecanoyl-CoAs to give E-2-methyldec-2-enoyl-CoA and fluoride anion, a previously unknown reaction. 'Racemization' of 2-methyldec-3-enoyl-CoAs was also catalysed, without double bond migration. This journal is
- Yevglevskis, Maksims,Lee, Guat L.,Threadgill, Michael D.,Woodman, Timothy J.,Lloyd, Matthew D.
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- Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction
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"Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator2, which interacts with estrogen receptorα. The best peptide (IC50=89nm) replaces isoleucine689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes the syn-pentane interactions between the α- and γ-methyl groups.
- Speltz, Thomas E.,Fanning, Sean W.,Mayne, Christopher G.,Fowler, Colin,Tajkhorshid, Emad,Greene, Geoffrey L.,Moore, Terry W.
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- β N-O turns and helices induced by β2-aminoxy peptides: Synthesis and conformational studies
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Herein, we report an efficient route for the asymmetric synthesis of β2-aminoxy acids as well as experimental and theoretical studies of conformations of peptides composed of β2-aminoxy acids. The nine-membered-ring intramolecular hydrogen bonds, namely, β N-O turns, are generated between adjacent residues in those peptides, in accordance with our computational results. The presence of two consecutive homochiral β N-O turns leads to the formation of β N-O helical structures in solution, although both helical (composed of two β N-O turns of the same handedness) and reverse-turn (composed of two β N-O turns with opposite handedness) structures are of similar stability, as suggested by theoretical studies. Nevertheless, two slightly different conformations, with the same handedness, of β2-aminoxy monomers have been observed in the solid state and in solution according to our X-ray and 2D NOESY studies.
- Jiao, Zhi-Gang,Chang, Xiao-Wei,Ding, Wei,Liu, Guo-Jun,Song, Ke-Sheng,Zhu, Nian-Yong,Zhang, Dan-Wei,Yang, Dan
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- SUBSTITUTED TETRAHYDROFURANS AS MODULATORS OF SODIUM CHANNELS
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Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.
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Paragraph 00987-00988
(2021/06/11)
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- Thermal proteome profiling efficiently identifies ribosome destabilizing oxazolidinones
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Identifying the targets of bioactive small molecules is a challenging endeavor for which no general solution currently exists. Classical affinity purification experiments suffer from the need to functionalise a bioactive compound and link it to a solid support, which may interfere with target binding. A modern mass spectrometry-based proteomics technique that has partially circumvented this problem is thermal proteome profiling (TPP), which determines the effect of an unmodified small molecule on the thermal stability of the whole proteome simultaneously. Here, we use TPP to identify the mode-of-action of a newly-discovered autophagy inhibitor based on oxazolidinones often employed as chiral auxiliaries. Surprisingly, a significant portion of all ribosomal proteins were found to be destabilized by the inhibitor, highlighting the utility of this technology for determining a challenging mode-of-action.
- N?cker, Christina,Kaiser, Nadine,Foley, Daniel,Sievers, Sonja,Janning, Petra,Waldmann, Herbert,Laraia, Luca
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supporting information
(2021/04/22)
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- Synthesis and Bioactivity of a Macrocidin B Stereoisomer
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A stereoisomer of macrocidin B, a presumed metabolite of the fungus Phoma macrostoma, was synthesized in 18 steps and 2.7% yield from protected l-tyrosine that was N-β-ketoacylated with a fully functionalized octanoyl Meldrum's acid. Dieckmann condensation gave a 3-acyltetramic acid, which was macrocyclized via Williamson etherification between the phenol and epi-bromohydrin termini. This macrocidin B stereoisomer showed a weaker herbicidal effect than macrocidin A and no similar inhibitory effect on biofilms of Staphylococcus aureus.
- Weber, Stefanie E.,Ga?, Juliane,Zeng, Haoxuan,Erb-Brinkmann, Maike,Schobert, Rainer
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supporting information
p. 8273 - 8276
(2021/10/25)
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- Ring-closing metathesis approaches towards the total synthesis of rhizoxins
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Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ringclosure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.
- Altmann, Karl-Heinz,Liniger, Marc,Neuhaus, Christian M.
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supporting information
(2020/10/18)
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- Controllable Intramolecular Unactivated C(sp3)-H Amination and Oxygenation of Carbamates
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Dual catalyst-controlled intramolecular unactivated C(sp3)-H amination and oxygenation of carbamates merging visible-light photocatalysis and earth-abundant transition metal catalysis have been reported. Useful amino alcohol and diol derivatives could be selectively obtained from readily available tertiary alcohol derivatives. The possible mechanisms have been proposed via a 1,5-HAT process followed by Lewis acid-controlled cyclization. The nickel and zinc catalysts inhibit the formation of oxygenation and amination products, respectively. An interesting phenomenon of chirality transfer is also observed.
- Guo, Qihang,Ren, Xiang,Lu, Zhan
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supporting information
p. 880 - 884
(2019/05/16)
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- Total synthesis of natural (?)- and unnatural (+)-Melearoride A
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This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.
- Reed, Carson W.,Fulton, Mark G.,Nance, Kellie D.,Lindsley, Craig W.
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supporting information
p. 743 - 745
(2019/02/09)
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- Bombyx uterol ester (((R)-(-)-3-2- R) and its derivatives) and synthetic method thereof (by machine translation)
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The invention discloses a synthetic method of ((R)- (-) - 3 - rhodanshi ester (R)-2-methyl) propionate (methyl propionate) and a derivative thereof. To the synthetic method disclosed by the (S)- 4 - invention, as a raw material, a series of reactions such as acylation, substitution, hydrolysis, esterification, hydrogenation and ((R)- (-) - 3 - the like are synthesized to synthesize the Rogoligoligoligoligosl)-methyl propionate and derivatives thereof. The synthesis method is equally applicable to the synthesis of its enantiomers and derivatives thereof. The method has the advantages of short reaction time, high yield, good chiral selectivity, suitability for industrial production and the like. The invention relates to a roshi ester and a derivative structure thereof. . (by machine translation)
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Paragraph 0073-0077
(2019/11/29)
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- A method for synthesis of acylated oxazolidone
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The invention discloses a method for synthesis of acylated oxazolidone. Synthesis method of the invention, comprising the following steps: in the non-protic organic solvent, the compound III and under the action of an acid, the compound I with compound II carries out amidation reaction, to obtain compound IV. The method of the invention can be conducted under mild conditions, high yield, high purity, and is suitable for industrial production requirements.
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Paragraph 0025; 0026; 0027
(2019/01/08)
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- General and stereoselective aminoxylation of biradical titanium(iv) enolates with TEMPO: A detailed study on the effect of the chiral auxiliary
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A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.
- Kennington, Stuart C. D.,Gómez-Palomino, Alejandro,Salomó, Ernest,Romea, Pedro,Urpí, Fèlix,Font-Bardia, Mercè
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p. 4807 - 4815
(2018/07/13)
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- Multifunctional spiro lactone derivatives and synthetic method thereof
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The invention discloses a multifunctional spiro lactone derivative and a synthetic method thereof. According to the multifunctional spiro lactone derivative, reactions in a certain steps can be carried out to obtain different intermediates from the same raw material, and by utilizing differences of acyl chloride, products of different structures and derivatives thereof can be prepared. The synthetic method disclosed by the invention is reasonable in steps, the derivatives are prepared for the first time by utilizing a chemical method, the yield of the derivatives is improved, sufficient raw materials are provided for anti-disease researches, and the derivative has excellent scientific research values.
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Paragraph 0048; 0063; 0110; 0111
(2018/09/21)
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- Synthesis of new C3 symmetric amino acid- and aminoalcohol-containing chiral stationary phases and application to HPLC enantioseparations
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We recently reported a new C3-symmetric (R)-phenylglycinol N-1,3,5-benzenetricarboxylic acid-derived chiral high-performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N-3,5-dintrobenzoyl (DNB) (R)-phenylglycinol-derived CSP. Over a decade ago, (S)-leucinol, (R)-phenylglycine, and (S)-leucine derivatives were used as the starting materials of 3,5-DNB-based Pirkle-type CSPs for chiral separation. In this study, three new C3-symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3-symmetric CSPs (CSP 2–CSP 4).
- Yu, Jeongjae,Armstrong, Daniel W.,Ryoo, Jae Jeong
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- Nhatrangin A: Total Syntheses of the Proposed Structure and Six of Its Diastereoisomers
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A total synthesis of the proposed structure of nhatrangin A is described. This strategy relies on two aldol reactions to install the chiral centers at C3/C4 and C3′/C4′, a lithium-mediated coupling between an advanced intermediate alkyne and a Weinreb amide to complete the C1-C13 alkyl scaffold, and a Yamaguchi esterification to set the side chain. Discrepancies in the spectroscopic data between synthetic and natural nhatrangins led us to synthesize six more diastereoisomers of the proposed structure of nhatrangin A.
- Dias, Luiz C.,Polo, Ellen C.
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p. 4072 - 4112
(2017/04/28)
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- AHU - 377 preparation method of the midbody and intermediate and intermediate preparation method
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The invention relates to the field of chemical synthesis of medicines and in particular relates to a preparation method and intermediate of an AHU-377 intermediate and a preparation method of the intermediate. The preparation method of the AHU-377 intermediate shown in a formula (I) in the description comprises the following steps: performing a substitution reaction on a compound shown in a formula (II) in the description and a compound shown in a formula (III) in the description and then carrying out hydrolysis to prepare the AHU-377 intermediate shown in the formula (I), wherein the hydrolysis reaction is carried out in the presence of hydrogen peroxide and lithium hydroxide hydrate. The invention also aims to provide a new compound with a structure shown in the formula (II). In the new route, as a new compound shown in a formula (IV) in the description is prepared through reaction of the compound in the formula (II) and the compound in the formula (III), the selectivity is quite good, and a few diastereoisomers are generated in the reaction process and can be removed only through simple aftertreatment.
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Paragraph 0069; 0070; 0071; 0072
(2017/10/13)
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- A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
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Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d.
- Durham, Timothy B.,Marimuthu, Jothirajah,Toth, James L.,Liu, Chin,Adams, Lisa,Mudra, Daniel R.,Swearingen, Craig,Lin, Chaohua,Chambers, Mark G.,Thirunavukkarasu, Kannan,Wiley, Michael R.
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p. 5933 - 5939
(2017/07/22)
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- (HMe 2 SiCH 2) 2: A Useful Reagent for B(C 6 F 5) 3 -Catalyzed Reduction-Lactonization of Keto Acids: Concise Syntheses of (-)- cis -Whisky and (-)- cis -Cognac Lactones
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(HMe 2 SiCH 2) 2 has been utilized as a useful reagent for B(C 6 F 5) 3 -catalyzed reduction-lactonization of keto acids to synthesize γ- and δ-lactones. The process led concisely to (-)- cis -whisky and (-)- cis -cognac lactones in respective overall yields of 32% and 36%.
- Xie, Hengmu,Lu, Ji,Gui, Yingying,Gao, Lu,Song, Zhenlei
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supporting information
p. 2453 - 2459
(2017/10/06)
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- Preparation method of paricalcitol intermediate
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The invention relates to a preparation method of a paricalcitol intermediate, in particular to a preparation method for an intermediate (as shown in a formula (I)) for synthesizing paricalcitol (II). According to the method, a chiral intermediate as shown in a formula (V) through anti-and syn-aldol reaction of a chiral compound as shown in a formula (IV) and acetone, and the intermediate (as shown in a formula (I)) for synthesizing the paricalcitol is obtained through reduction, halogenations and reaction with triphenyl phosphine. The method has the advantages of mild reaction condition, simplicity and convenience in operation, high optical purity, low synthesis cost and the like, and is suitable for large-scale production. (The formulas are as shown in the description.).
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Paragraph 0057; 0058; 0059
(2017/09/26)
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- SYNTHETIC PRECURSOR OF EPOTHILONE FOR IMPROVING PRODUCTION OF EPOTHILONE AND METHOD FOR PREPARING EPOTHILONE USING THE SAME
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The present invention relates to a compound for increasing production of epothilone in actinomyces, and to a method for producing epothilone with increased yield. The method for producing epothilone of the present invention includes a step of culturing actinomyces in which epothilone-biosynthesizing genes in Sorangium cellulosum including epoD, epoE, epoF, orf6, orf3, and orf14 are introduced in a culture medium. According to the present invention, it is possible to increase the production yield of epothilone in actinomyces, even in actinomyces in which epoA, epoP, epoB, and epoC are not introduced therein.COPYRIGHT KIPO 2016
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Paragraph 0085; 0086; 0087
(2016/10/10)
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- Directed orthometalation and the asymmetric total synthesis of N -deoxymilitarinone A and torrubiellone B
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A diverted total synthesis (DTS) approach to the total synthesis of pyridone alkaloids N-deoxymilitarinone A (8) and torrubiellone B (10) has been developed. The common intermediate 14 was first assembled by a dual directed orthometalation process using a methoxymethyl group as directed metalation group. Other crucial steps include the assembly of polyenes under aldol condensation for DTS using general and concise strategy and diastereoselective synthesis of the syn-dimethyl array by an Evans aldol reaction.
- Ding, Feiqing,William, Ronny,Leow, Min Li,Chai, Hua,Fong, Jacqueline Zi Mei,Liu, Xue-Wei
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supporting information
p. 26 - 29
(2014/01/23)
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- Collective synthesis of 4-hydroxy-2-pyridone alkaloids and their antiproliferation activities
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A collective synthesis of 4-hydroxy-2-pyridone alkaloids - specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C - has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki-Miyaura cross-coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all-trans-polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC50 values of 7.05 μM. Hence, this approach could potentially contribute to the synthesis of bioactive small-molecule libraries as well as drug discovery.
- Ding, Feiqing,Leow, Min Li,Ma, Jimei,William, Ronny,Liao, Hongze,Liu, Xue-Wei
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supporting information
p. 2548 - 2554
(2014/10/15)
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- Asymmetric radical addition of TEMPO to titanium enolates
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A mild method for a-hydroxylation of N-acyl oxazolidinones by asymmetric radical addition of the 2,2,6,6-tetramethylpiperidine N-oxy (TEMPO) radical to titanium enolates was developed. The high diastereoselectivity and broad scope of the reaction show synthetic utility for the a-hydroxylation of substrates that are not tolerant to strongly basic conditions.
- Mabe, Phillip J.,Zakarian, Armen
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supporting information
p. 516 - 519
(2014/04/03)
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- Modular total synthesis of rhizopodin: A highly potent G-actin dimerizing macrolide
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A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29steps by employing a concise strategy that exploits the molecule′s C2 symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site-directed sequential cross-coupling strategy and the bidirectional attachment of the side chains by means of Horner-Wadsworth-Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.
- Kretschmer, Manuel,Dieckmann, Michael,Li, Pengfei,Rudolph, Sven,Herkommer, Daniel,Troendlin, Johannes,Menche, Dirk
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supporting information
p. 15993 - 16018
(2014/04/03)
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- Absolute configuration of lactams and oxazolidinones using kinetic resolution catalysts
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A simple method for determining the absolute configuration of oxazolidinones, lactams, and their derivatives using kinetic resolution catalysts is described. The optically pure substrates were acylated using the (S)-HBTM and the (R)-HBTM catalyst, and the faster reaction was determined. An empirical mnemonic was developed for the assignment of the absolute configuration based on the fast-reacting catalyst.
- Perry, Matthew A.,Trinidad, Jonathan V.,Rychnovsky, Scott D.
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supporting information
p. 472 - 475
(2013/04/11)
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- CHIRAL COMPOUNDS OF VARYING CONFORMATIONAL RIGIDITY AND METHODS OF SYNTHESIS
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Synthesis of compounds having varying degrees of conformational rigidity is obtained via a low cost, high yield and efficient synthetic reactions. The library of compounds is structurally diverse, having at least one or more chiral centers and providing large numbers of compounds having building block diversity and substantial scaffold diversity. The compounds further provide a novel method for obtaining candidate therapeutic agents for prevention, treatment or diagnosis of diseases.
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Paragraph 00177
(2013/03/26)
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- Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure
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The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to chemical and enzymatic hydrolysis of the strained β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its β-lactone carbonyl moiety and the conformational flexibility of the molecule.
- Kawamura, Shuhei,Unno, Yuka,Asai, Akira,Arisawa, Mitsuhiro,Shuto, Satoshi
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supporting information
p. 6615 - 6622
(2013/09/24)
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- Structure-activity relationship studies of S1P agonists with a dihydronaphthalene scaffold
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Structure-activity relationship (SAR) of sphingosine-1-phosphate receptor agonists with a dihydronaphthalene scaffold was investigated. Compound 1 was modified to improve S1P1 agonistic activity and in vivo peripheral lymphocyte lowering (PLL) activity without impairing selectivity over S1P 3 agonistic activity. A detailed SAR study of the terminal lipophilic part revealed that the introduction of substituents on the propylene linker and the terminal benzene ring influences in vitro and PLL activities. Compound 6n bearing a (S)-methyl group at the 2-position on the propylene linker and chlorine at the para-position on the terminal benzene ring showed potent hS1P1 agonistic activity with excellent selectivity over hS1P 3 and in vivo PLL activity in mice.
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Tokuda, Natsuko,Takada, Yuka,Shioya, Hiroki,Mizuno, Hirotaka,Komiya, Takaki,Ono, Takeji,Hagiya, Hiroshi,Minami, Masashi,Nakade, Shinji,Habashita, Hiromu
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scheme or table
p. 144 - 148
(2012/02/16)
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- A biomimetic polyketide-inspired approach to small-molecule ligand discovery
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The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on 'natural product-like' libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed 'chiral oligomers of pentenoic amides', COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.
- Aquino, Claudio,Sarkar, Mohosin,Chalmers, Michael J.,Mendes, Kimberly,Kodadek, Thomas,Micalizio, Glenn C.
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scheme or table
p. 99 - 104
(2012/04/10)
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- Chemoselective N-acylation of indoles and oxazolidinones with carbonylazoles
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Unique reactivity: In the presence of more reactive amine and alcohol functional groups and of carboxylic acids, the chemoselective N-acylation of indoles (see scheme) and oxazolidinones is achieved by taking advantage of the unique reactivity of carbonylazole acylating agents with catalytic amounts of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Copyright
- Heller, Stephen T.,Schultz, Erica E.,Sarpong, Richmond
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supporting information; experimental part
p. 8304 - 8308
(2012/09/08)
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- Synthesis and conformation of fluorinated β-peptidic compounds
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Experimental and theoretical data indicate that, for α-fluoroamides, the F-C-C(O)-N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C-F and C-N(CO) bonds in N-β-fluoroethylamides. This study details the synthesis of a series of fluorinated β-peptides (1-8) designed to use these stereoelectronic effects to control the conformation of β-peptide bonds. X-ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C=O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β-peptide bond, with the possibility of directing the secondary structures of β-peptides. Copyright
- Peddie, Victoria,Butcher, Raymond J.,Robinson, Ward T.,Wilce, Matthew C. J.,Traore, Daouda A. K.,Abell, Andrew D.
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supporting information; experimental part
p. 6655 - 6662
(2012/07/28)
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- Accessing the structural diversity of pyridone alkaloids: Concise total synthesis of rac-citridone A
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A unique route to the structural diversity of pyridone alkaloids is described based on the concept of a common synthetic strategy. Three different core structure analogues corresponding to akanthomycin, septoriamycin A, and citridone A have been prepared by using a highly selective and novel carbocyclization reaction.
- Fotiadou, Anna D.,Zografos, Alexandros L.
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supporting information; experimental part
p. 4592 - 4595
(2011/10/17)
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- Method for manufacturing stereoselective preparation of 4-BMA using a chiral auxiliary and chiral auxiliary
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The present invention relates to a process for preparing (3R,4S)-3-[[[R]-1′-t-butyldimethylsilyloxy]ethyl]-4-[(R)-1″-carboxyethyl]-2-azetidinone (beta-methylazetidin-2-one; 4-BMA), a key intermediate for the synthesis of carbapenem and penem antibiotics. Specifically, the present invention relates to a process comprising first, the preparation of a chiral auxiliary from cheap L-Phenylalaninol, and then the preparation of 4-BMA in high yield and high selectivity, under industrially mild condition.
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Page/Page column 2
(2011/06/26)
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- Method for manufacturing stereoselective preparation of 4-bma using a chiral auxiliary and chiral auxiliary
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The present invention relates to a process for preparing (3R,4S)-3-[[[R]-1 ' -t-butyldimethylsilyloxy ]ethyl]-4-[(R)-1 "-carboxyethyl]-2-azetidinone (beta- methylazetidin-2-one; 4-BMA), a key intermediate for the synthesis of carbapenem and penem antibiotics. Specifically, the present invention relates to a process comprising first, the preparation of a chiral auxiliary from cheap L-Phenylalaninol, and then the preparation of 4-BMA in high yield and high selectivity, under industrially mild condition.
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Page/Page column 4; 8
(2011/08/04)
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- Conformationally restricted analogs of the direct thrombin inhibitor FM 19
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The serine protease thrombin plays several key roles in the clotting cascade within the hemostatic system, such as in fibrin formation and platelet activation. Thus, development of an inhibitor that binds to the enzyme's active site (a direct thrombin inhibitor) offers an approach for the treatment of thrombus-associated diseases. Previous structure-activity relationship studies originally based on the bradykinin breakdown product Arg-Pro-Pro-Gly-Phe (RPPGF) led to the development of lead compound FM 19 (d-Arg-Oic-Pro-d-Ala-Phe(p-Me)- NH2). The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed sites of modification to potentially improve inhibition. In this study, we report the synthesis and biological characterization of nine peptides that replace only the d-Arg residue of the FM 19 sequence, investigating ways to add conformational restriction, modification of the basic moiety at the end of the side chain, and removal of the charge from the N-terminus. Two of these peptides, 6 and 7 (IC50 values of 0.51 and 0.45 μM, respectively), show similar potency to the best compounds in the FM 19 series reported thus far.
- Girnys, Elizabeth A.,Porter, Vanessa R.,Mosberg, Henry I.
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experimental part
p. 7425 - 7434
(2012/01/02)
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- Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks
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Chiral building blocks are valuable intermediates in the syntheses of natural products and pharmaceuticals. A scalable chemoenzymatic route to chiral diketides has been developed that includes the general synthesis of α-substituted, β-ketoacyl N-acetylcysteamine thioesters followed by a biocatalytic cycle in which a glucose-fueled NADPH-regeneration system drives reductions catalyzed by isolated modular polyketide synthase (PKS) ketoreductases (KRs). To identify KRs that operate as active, stereospecific biocatalysts, 11 isolated KRs were incubated with 5 diketides and their products were analyzed by chiral chromatography. KRs that naturally reduce small polyketide intermediates were the most active and stereospecific toward the panel of diketides. Several biocatalytic reactions were scaled up to yield more than 100 mg of product. These syntheses demonstrate the ability of PKS enzymes to economically and greenly generate diverse chiral building blocks on a preparative scale.
- Piasecki, Shawn K.,Taylor, Clint A.,Detelich, Joshua F.,Liu, June,Zheng, Jianting,Komsoukaniants, Arkady,Siegel, Dionicio R.,Keatinge-Clay, Adrian T.
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experimental part
p. 1331 - 1340
(2012/02/01)
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- Asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters
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A versatile methodology for the asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters has been developed that relies on a series of Evans' aldol, hydroxyl-directed cyclopropanation, methanolysis, and Hg(II) mediated cyclopropane ring-opening reactions for stereocontrol.
- Peed, Jennifer,Perinan Dominguez, Ignacio,Davies, Iwan R.,Cheeseman, Matt,Taylor, James E.,Kociok-Koehn, Gabriele,Bull, Steven D.
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supporting information; experimental part
p. 3592 - 3595
(2011/09/21)
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- Catalytic asymmetric synthesis of mycolipenic and mycolipanolic acid
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The first asymmetric synthesis of mycolipenic acid and mycolipanolic acid by using an improved iterative procedure involving catalytic asymmetric conjugate addition of MeMgBr as the key step is described. Mycolipenic and mycolipanolic acid are obtained in 11 steps with perfect stereocontrol, and both acids are identical to their counterparts from natural sources.
- Horst, Bjorn Ter,Van Wermeskerken, Jeroen,Feringa, Ben L.,Minnaard, Adriaan J.
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supporting information; experimental part
p. 38 - 41
(2010/03/24)
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- Valence tautomerism in titanium enolates: Catalytic radical haloalkylation and application in the total synthesis of neodysidenin
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(Chemical Equation Presented) A direct ruthenium-catalyzed radical chloroalkylation of N-acyl oxazolidinones capitalizing on valence tautomerism of titanium enolates has been developed. The chloroalkylation method served as the centerpiece in the enantioselective total synthesis of trichloroleucine-derived marine natural product neodysidenin.
- Beaumont, Stephane,Ilardi, Elizabeth A.,Monroe, Lucas R.,Zakarian, Armen
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supporting information; experimental part
p. 1482 - 1483
(2010/04/03)
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- Process for total synthesis of pladienolide B and pladienolide D
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[Problems to be Solved] To provide an effective process for total synthesis of pladienolide B and pladienolide D having excellent anti-tumor activity and to provide useful intermediates in the above-described process. [Measure for Solving the Problem] A process for producing a compound represented by Formula (11): wherein P1, P7, P8, P9 and R1 are the same as defined below, characterized by including reacting a compound represented by Formula (12): wherein P7 means a hydrogen atom or a protecting group for hydroxy group; R1 means a hydrogen atom or a hydroxy group, with a compound represented by Formula (13): wherein P1 means a hydrogen atom or a protecting group for hydroxy group; P8 means a hydrogen atom, an acetyl group or a protecting group for hydroxy group; P9 means a hydrogen atom or a protecting group for hydroxy group; or P8 and P9 may form together a group represented by a formula: wherein R5 means a phenyl group which may have a substituent, in the presence of a catalyst.
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Page/Page column 35-36
(2010/11/29)
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- Decarboxylative isomerization of N-Acyl-2-oxazolidinones to 2-oxazolines
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(Chemical Equation Presented) N-Acyl-2-oxazolidinones are ring-opened by lithium iodide and decarboxylated in the presence of a mild proton source. Further reaction with an amine base provides 2-oxazolines. The transformation is general for oxazolidinones unsubstituted in the 5 position and occurs under mild conditions (25-50°C). These results complement the existing methods for this transformation by allowing lower temperatures and/or avoiding metal catalysts.
- May, Aaron E.,Willoughby, Patrick H.,Hoye, Thomas R.
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p. 3292 - 3294
(2008/09/20)
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- SmI2-promoted intra- and intermolecular C-C bond formation with chiral N-acyl oxazolidinones
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The suitability of chiral oxazolidinones in the SmI2-mediated C-C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon-carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5-exo-trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.
- Taaning, Rolf H.,Thim, Laura,Karaffa, Jacob,Campa?a, Araceli G.,Hansen, Anna-Mette,Skrydstrup, Troels
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body text
p. 11884 - 11895
(2009/04/07)
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- Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof
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Palmerolide A is a recently disclosed marine natural product possessing striking biological properties, including potent and selective activity against the melanoma cancer cell line UACC-62. The total syntheses of five palmerolide A stereoisomers, including the originally proposed (1) and the revised [ent-(19-epi-20-epi-1)] structures, have been accomplished. The highly convergent and flexible strategy developed for these syntheses involved the construction of key building blocks 2, 19-epi-2, 20-epi-2, ent-2, 3, ent-3, 4, and enf-4, and their assembly and elaboration to the target compounds. For the union of the building blocks, the Stille coupling reaction, Yamaguchi esterification, Horner-Wadsworth-Emmons olefination, and ring-closing metathesis reaction were employed, the latter being crucial for the stereoselective formation of the macrocycle of the palmerolide structure. The Horner-Wadsworth-Emmons olefination and the Yamaguchi lactonization were also investigated and found successful as a means to construct the palmerolide macrocycle. The syntheses were completed by attachment of the enamide moiety through a copper-catalyzed coupling process.
- Nicolaou,Sun, Ya-Ping,Guduru, Ramakrishna,Banerji, Biswadip,Chen, David Y.-K.
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p. 3633 - 3644
(2008/09/20)
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- Synthesis and stereochemical assignment of FR252921, a promising immunosuppressant
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Synthetic detective work: FR252921, an unusual 19-membered lactone-dilactam, and three of its diastereomers were prepared by a versatile, convergent strategy from three key segments (see scheme). Comparison of the synthetic compounds with natural material established conclusively that FR252921 has the configuration 12S,13R,18R.
- Falck, J. Russell,He, Anyu,Fukui, Hiroki,Tsutsui, Hideyuki,Radha, Akella
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p. 4527 - 4529
(2008/09/17)
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- COMPOUND HAVING S1P RECEPTOR BINDING POTENCY AND USE THEREOF
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Provided are: a compound represented by formula (I): (wherein ring A and ring D each represent a cyclic group which may have a substituent(s); E and G each represent a bond or a spacer having 1 to 8 atoms in its main chain; L represents a hydrogen atom or a substituent; X represents amino which may have a substituent(s), or a heterocylcic group which contains at least one nitrogen atom and which may have a substituent(s); n represents 0 to 3, in which when n is 2 or more, a plurality of ring A's may be the same or different from one another); a salt thereof; an N-oxide form thereof; a solvate thereof; a prodrug thereof; and a medicament which includes those. The compound represented by formula (I) is capable of binding S1P receptors (in particular, EDG-1 and/or EDG-6), and useful for preventing and/or treating rejection in transplantation, autoimmune diseases, allergic diseases, etc.
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(2010/11/26)
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