- Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338
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We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.
- Wong, Nicholas,Petronijevi?, Filip,Hong, Allen Y.,Linghu, Xin,Kelly, Sean M.,Hou, Haiyun,Cravillion, Theresa,Lim, Ngiap-Kie,Robinson, Sarah J.,Han, Chong,Molinaro, Carmela,Sowell, C. Gregory,Gosselin, Francis
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p. 9099 - 9103
(2019/11/14)
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- Structure-Activity Relationships of cyclo(l -Tyrosyl- l -tyrosine) Derivatives Binding to Mycobacterium tuberculosis CYP121: Iodinated Analogues Promote Shift to High-Spin Adduct
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A series of analogues of cyclo(l-tyrosyl-l-tyrosine), the substrate of the Mycobacterium tuberculosis enzyme CYP121, have been synthesized and analyzed by UV-vis and electron paramagnetic resonance spectroscopy and by X-ray crystallography. The introduction of iodine substituents onto cyclo(l-tyrosyl-l-tyrosine) results in sub-μM binding affinity for the CYP121 enzyme and a complete shift to the high-spin state of the heme FeIII. The introduction of halogens that are able to interact with heme groups is thus a feasible approach to the development of next-generation, tight binding inhibitors of the CYP121 enzyme, in the search for novel antitubercular compounds.
- Rajput, Sunnia,McLean, Kirsty J.,Poddar, Harshwardhan,Selvam, Irwin R.,Nagalingam, Gayathri,Triccas, James A.,Levy, Colin W.,Munro, Andrew W.,Hutton, Craig A.
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supporting information
p. 9792 - 9805
(2019/11/13)
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- PROCESS FOR MAKING ARYLOMYIN RING ANALOGS
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Methods for making an arylomycin ring of formula t or salts or solvates thereof, wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R5, R10 and Pg1 are as defined herein.
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Page/Page column 32; 36-38
(2018/10/25)
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- Formal Total Synthesis of Diazonamide A by Indole Oxidative Rearrangement
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A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7-bromoindole by sequential palladium-catalysed couplings of an oxazole fragment at C-2, followed by a tyrosine fragment at C-3. With the key 2,3-disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3-disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.
- David, Nadège,Pasceri, Raffaele,Kitson, Russell R. A.,Pradal, Alexandre,Moody, Christopher J.
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supporting information
p. 10867 - 10876
(2016/07/27)
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- Total synthesis of mycocyclosin
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The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.
- Cochrane, James R.,White, Jonathan M.,Wille, Uta,Hutton, Craig A.
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p. 2402 - 2405
(2012/06/18)
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- Improved protocol for indoline synthesis via palladium-catalyzed intramolecular C(sp2)-H amination
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An efficient method has been developed for the synthesis of indoline compounds from picolinamide (PA)-protected β-arylethylamine substrates via palladium-catalyzed intramolecular amination of ortho-C(sp2)-H bonds. These reactions feature high efficiency, low catalyst loadings, mild operating conditions, and the use of inexpensive reagents.
- He, Gang,Lu, Chengxi,Zhao, Yingsheng,Nack, William A.,Chen, Gong
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supporting information; experimental part
p. 2944 - 2947
(2012/08/28)
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- Synthesis of antitumor marine alkaloid discorhabdin a oxa analogues
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Dlscorhabdin A (1) exhibits a strong cytotoxic activity in vitro, but it Is difficult to synthesize and handle due to the Instability of Its highly strained N.S-acetal structure. We then designed the analogues of discorhabdin A which also have strong cyto
- Wada, Yasufumi,Otani, Kouji,Endo, Noriko,Harayama, Yu,Kamimura, Daigo,Yoshida, Masako,Fujioka, Hiromichi,Kita, Yasuyuki
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supporting information; experimental part
p. 4048 - 4050
(2009/12/09)
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- A convenient catalyst for aqueous and protein Suzuki-Miyaura cross-coupling
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(Figure Presented) A phosphine-free palladium catalyst for aqueous Suzuki-Miyaura cross-coupling is presented. The catalyst is active enough to mediate hindered, ortho-substituted biaryl couplings but mild enough for use on peptides and proteins. The Suzuki-Miyaura couplings on protein substrates are the first to proceed in useful conversions. Notably, hydrophobic aryl and vinyl groups can be transferred to the protein surface without the aid of organic solvent since the aryl- and vinylboronic acids used in the coupling are water-soluble as borate salts. The convenience and activity of this catalyst prompts use in both general synthesis and bioconjugation.
- Chalker, Justin M.,Wood, Charlotte S. C.,Davis, Benjamin G.
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supporting information; experimental part
p. 16346 - 16347
(2010/01/29)
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- Use of a boroxazolidone complex of 3-iodo-l-tyrosine for palladium-catalyzed cross-coupling
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Complexation of 3-iodo-L-tyrosine with 9-borabicyclo[3.3.1]nonane (9-BBN) provides a convenient substrate for a palladium-catalyzed coupling reaction. The complex is stable to silica gel chromatography (hexanes/ethyl acetate), dilute triethylamine in THF, and potassium fluoride in DMF. The desired product, 3-ethynyl-L-tyrosine, was released from the complex by simply diluting its solution in methanol with chloroform. Interestingly, the complex remains stable in solutions of either methanol or chloroform individually.
- Walker IV, William H.,Rokita, Steven E.
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p. 1563 - 1566
(2007/10/03)
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- Preparation of selectively protected L-dopa derivatives: Oxidation of tyrosine-3-boronates
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Conversion of 3-iodo-L-tyrosine to protected tyrosine-3-boronate esters, followed by oxidation with hydrogen peroxide, provides a mild and efficient method for the preparation of selectively protected L-dopa derivatives.
- Hunter, Luke,Hutton, Craig A.
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p. 1095 - 1098
(2007/10/03)
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- A convenient preparation of selectively protected L-Dopa derivatives from 3-iodo-L-tyrosine
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Palladium-catalyzed hydroformylation of 3-iodo-L-tyrosine derivatives la,b followed by protection of the free phenol as its benzyl ether and Baeyer-Villiger oxidation of the 3-formyl group provided the desired L-Dopa derivatives 4b,c in 71 and 68% overall
- Morera,Ortar
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p. 2115 - 2122
(2007/10/03)
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- Chiral bipyridine and terpyridine ligands grafted with L-tyrosine fragments
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The synthesis of stable terpyridine and bipyridine frames substituted with L-tyrosine fragments is reported. These highly functionalized compounds have been prepared from the corresponding iodo, and ethynyl substituted analogs by a reaction catalyzed by l
- Khatyr,Ziessel
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p. 1665 - 1670
(2007/10/03)
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- ATTOGRAM-LEVEL DETECTION AND RELATIVE RESPONSE OF STRONG ELECTROPHORES BY GAS CHROMATOGRAPHY WITH ELECTRON CAPTURE DETECTION.
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The responses as peak areas of some divergent compounds, most of which are strong electron absorbers, are measured by gas chromatography with electron capture detection (GC-ECD). The most sensitive compounds are derivatized lodothyronines, which are essentially 20-fold more sensitive than lindane. N,N-Dipentafluorobenzoylpentafluoroaniline, a somewhat less sensitive but more volatile substance, was selected for determination of a detection limit. The value was 90 ag(1. 6 multiplied by 10** minus **1**9 mol), largely due to an anomalous increase in its response at the trace level. This increases the reported sensitivity of GC-ECD by 100-fold.
- Corkill,Joppich,Kuttab,Giese
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p. 481 - 485
(2007/10/02)
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