- Radical-Mediated Acyl Thiol-Ene Reaction for Rapid Synthesis of Biomolecular Thioester Derivatives
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The thiol-ene ‘click’ reaction has emerged as a versatile process for carbon–sulfur bond formation with widespread applications in chemical biology, medicinal chemistry and materials science. Thioesters are key intermediates in a wide range of synthetic and biological processes and efficient methods for their synthesis are of considerable interest. Herein, we report the first examples of acyl-thiol-ene (ATE) for the synthesis of biomolecular thioesters, including peptide, lipid and carbohydrate derivatives. A key finding is the profound effect of the amino acid side chain on the outcome of the ATE reaction. Furthermore, radical generated thioesters underwent efficient S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’ ligation products in an overall amidation process with diverse applications for chemical ligation and bioconjugation.
- Lynch, Dylan M.,McLean, Joshua T.,McSweeney, Lauren,Milbeo, Pierre,Scanlan, Eoin M.
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p. 4148 - 4160
(2021/08/24)
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- Chemoselective Arylation of Dialkyl Diselenides and Application to the Synthesis of a ε-N,N,N-Trimethyllysine Derivative
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Nucleophilic aromatic substitution of a dialkyl diselenide with 1-bromo-2,4-dinitrobenzene and sodium borohydride in EtOH/THF proceeded chemoselectively in the presence of a thiol, an amine, and a carboxylic acid. ε-N,N,N-Trimethyllysine derivative was synthesized from selenohomocysteine dimer by the present arylation, oxidation, cross-metathesis with 4-iodobutene, reduction, and substitution with trimethylamine.
- Takahashi, Ryuhei,Sakamoto, Kenta,Umezawa, Naoki,Umehara, Takashi,Matsuo, Jun-ichi
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supporting information
p. 6649 - 6652
(2020/10/19)
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- Macrocyclic cysteine protease inhibitors and compositions thereof
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The present invention provides a novel class of macrocyclic compounds, which are useful as cysteine protease inhibitors. Also provided are novel intermediates and methods of preparing the compounds. The invention also provides pharmaceutical compositions
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- Continuous-flow thermolysis for the preparation of vinylglycine derivatives
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Syn sulfoxide elimination was carried out under continuous-flow conditions in a mesofluidic thermolysis reactor. The design of the reactor enabled accurate control of reaction time and conditions, affording a convenient scale-independent procedure for the production of N,C-protected vinylglycine derivatives. Thermolysis at 270 °C under 1000 psi of pressure in superheated toluene enabled typical daily outputs ranging from 11 to 46 g per day with excellent selectivities and ee (>97%). The various competitive reaction pathways were studied and rationalized according to a computational study.
- Lamborelle, Nicolas,Simon, Justine F.,Luxen, André,Monbaliu, Jean-Christophe M.
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p. 11602 - 11606
(2015/12/08)
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- A convergent synthesis of carbocyclic sinefungin and its C-5 epimer
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A convergent synthesis of carbocyclic sinefungin (2), its C-5 epimer 3a, and adenine-modified derivative 3b is described. The key features of our approach include the use of commercially available L-methionine and readily available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate as starting materials, a cross-metathesis reaction, an enzymatic kinetic resolution, and a Staudinger reduction. The current synthesis is flexible and, therefore, provides convenient access to the synthesis of various carbocyclic sinefungin analogues for biological evaluation. A convergent synthesis of carbocyclic sinefungin (2), its C-5 epimer 3a, and adenine-modified derivative 3b is described. The key features of this approach include the use of commercially available L-methionine and readily available (1R,4S)-4-hydroxy-2-cyclopentenyl acetate, a cross-metathesis reaction, an enzymatic kinetic resolution, and a Staudinger reduction.
- Ghosh, Arun K.,Lv, Kai
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p. 6761 - 6768
(2016/02/18)
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- Macrocyclic Cysteine Protease Inhibitors and Compositions Thereof
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The present invention provides a novel class of macrocyclic compounds, which are useful as cysteine protease inhibitors. Also provided are novel intermediates and methods of preparing the compounds. The invention also provides pharmaceutical compositions
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- PREPARATION OF ALKENES BY MILD THERMOLYSIS OF SULFOXIDES
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Embodiments of this disclosure, among others, encompass methods for generating alkenes under mild thermolytic conditions that can provide almost total conversion of a precursor compound to an alkene without isomerization or the need to chromatographically purify the final product By selectively blocking the amino and carboxy groups of the depvatized amino acid, the methods of the disclosure provide for the synthesis of a peptide having the vinylglycine moiety at either the carboxy or the amino terminus of the peptide The mild conditions for the thermolytic removal of an o-NO2-phenyl substituted aryl group ensure that there is minimal if any damage to thermally sensitive conjugates such as a peptide bearing the vinylglycine The methods of the present disclosure have practical applications for the preparation of unsaturated compounds under mild, thermolytic conditions.
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Page/Page column 31-32
(2010/07/02)
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- An improved protocol for the preparation of (S)-vinylglycine from (S)-methionine
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We present an optimized procedure for the synthesis of (S)-vinylglycine from (S)-methionine. The key step is a solvent free pyrolysis of an intermediate sulfoxide at high temperature. Using our optimized reaction conditions, Cbz-protected vinylglycine was
- Kuechenthal,Migenda, Julia,Polednia, Magdalena,Maison, Wolfgang
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scheme or table
p. 443 - 448
(2010/11/17)
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- Preparation of vinylglycines by thermolysis of homocysteine sulfoxides
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The synthesis and efficacy of preparing Cbz-VG-OMe (1) by thermolysis of alkyl and aryl homocysteine sulfoxides were surveyed. This investigation determined that aryl sulfoxide analogs were more effective for the reaction and that the 2-nitrophenyl analog 10f possessed a unique ability to syn eliminate at temperatures as low as 100 °C. The thermolysis of sulfoxide 10f was additionally discovered to occur under toluene reflux and when sodium acetate was added, Cbz-VG-OMe (1) could be obtained in high purity by simple filtration of the precipitated sulfenic acid byproduct 12. This mild protocol which was also applied in the synthesis of VG dipeptide 13 would have utility in the general synthesis of olefins and alkenes from 2-nitrophenylsulfoxides.
- Patel, Sravan Kumar,Long, Timothy E.
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supporting information; experimental part
p. 5067 - 5070
(2009/12/01)
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- Enantiospecific synthesis of (+)-hyacinthacine A2
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We report an efficient synthesis of (+)-hyacinthacine A2 in six steps from (S)-N-Cbz-vinylgylcine. The key strategies were the olefin cross metathesis (CM), Sharpless asymmetric dihydroxylation, and a sequential double reductive cyclization. Wi
- Dewi-Wülfing, Purnama,Blechert, Siegfried
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p. 1852 - 1856
(2007/10/03)
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- A stereoselective synthesis of phosphinic acid phosphapeptides corresponding to glutamyl-γ-glutamate and incorporation into potent inhibitors of folylpoly-γ-glutamyl synthetase
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Radical addition of H3PO2 to N-/C-protected vinyl glycine led to the corresponding H-phosphinic acid in excellent yield. The non-nucleophilic H-phosphinic acid was converted to a nucleophilic P III species, RP(OTMS)2, which was used in two approaches to the target phosphinic acid containing pseudopeptide. New methodology was developed that led to excellent yields in the reaction of RP(OTMS)2 with unactivated electrophiles, including an acyclic homoallylic bromide. However, en route to the target pseudopeptide, Arbuzov reaction of RP(OTMS) 2 with a cyclic homoallylic bromide, (R)-3-(bromomethyl)-cyclopent-1- ene, led to a rearranged allylic phosphinic acid rather than the desired homoallylic derivative, a putative glutarate surrogate. Conjugate addition of RP(OTMS)2 to α-methylene glutarate containing a chiral auxiliary resulted in only modest diastereoselectivity. Purification by flash chromatography provided protected derivatives of both diastereomers of the pseudopeptide. Following global deprotection, coupling of (S)-H-Glu-γ- [Ψ(P(O)(OH)(CH2))]-(S)-Glu-OH and (S)-H-Glu-γ-[Ψ(P(O) (OH)(CH2))]-(R)-Glu-OH to (4-amino-4-deoxy-10-methyl)pteroyl azide led to the target compounds for biochemical study as inhibitors of the ATP-dependent ligase, folylpoly-γ-glutamate synthetase.
- Hartley, David M.,Coward, James K.
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p. 6757 - 6774
(2007/10/03)
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- Enantioselective Synthesis of Non-Natural Aromatic α-Amino Acids
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We present two complementary methods for the stereoselective synthesis of non-natural α-amino acids with aromatic or heteroaromatic side chains. One approach is based on the chemical transformation of methionine, whereas the other applies the stereoselective Myers alkylation of glycine. The resulting product types differ in the linker length between glycine and the aromatic substituent. Since methionine and pseudoephedrine are available in both absolute configurations, R- or S-configured enantiopure amino acids with either C2 or C3 linkers can be obtained on gram scales. In each case the key step of the synthesis is hydroboration of the unsaturated building blocks 9 and 17, followed by palladium-catalyzed Suzuki cross-coupling with aryl halides. Attention must in certain cases be paid to the stereochemical integrity when basic Suzuki conditions are applied. Our initial difficulties are reported as well as the final "racemization-proof" procedures. The protecting groups chosen for the α-amino acids should be compatible with solid-phase peptide synthesis. This was confirmed by the successful synthesis of a series of tripeptides.
- Krebs, Andreas,Ludwig, Verena,Pfizer, Jose,Duerner, Gerd,Goebel, Michael W.
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p. 544 - 553
(2007/10/03)
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- Synthesis of new 3- and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers
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The quorum sensing mechanism in Gram-negative bacteria uses small intercellular signal molecules, N-acyl-homoserine lactones (AHLs), to control transcription of specific genes in relation to population density. In this communication, we describe the parallel synthesis of new AHL analogues, in which substituents have been introduced into the 3- and 4-positions of the lactone ring. These analogues have been screened for their ability to activate and inhibit a Vibrio fischeri LuxI/LuxR-derived quorum sensing reporter system.
- Olsen,Severinsen,Rasmussen,Hentzer,Givskov,Nielsen
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p. 325 - 328
(2007/10/03)
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- Zirconocene-catalyzed epoxy ester - ortho ester rearrangement: A new method for the protection of polyfunctionalized carboxylic acids and the asymmetric synthesis of ortho esters
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In situ prepared Cp2(CI)Zr+ catalyzes the formation of ortho esters from epoxy esters. Acid-sensitive α-amino and α-hydroxy acid derivatives are converted in high yield to 2,7,8- trioxabicyclo[3.2.1]octanes (ABO-esters) using this protocol. This strategy is complementary to the OBO-ester technology, and orthogonal methods for the deprotection of ABO- and OBO-esters have been developed. The syntheses of the mushroom components (S)-γ- hydroxyleucine lactone and (S)-α-vinylglycine underline the value of ABO-ester protective group strategy. Using chiral epoxy alcohol derivatives, the first convenient and general asymmetric synthesis of bicyclic ortho esters has been achieved.
- Wipf, Peter,Wenjing, Xu,Hongyong, Kim,Takahashi, Hidenori
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p. 16575 - 16596
(2007/10/03)
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- The Heck reaction of N-protected vinylglycines with 4-iodoanisole
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Among N-protected and unprotected vinylglycines tested, N-(benzyloxycarbonyl)vinylglycine (1c) provided the highest yield of the coupling product 3c in the reaction with 1-iodo-4-methoxybenzene (2) in N,N-dimethylformamide in the presence of palladium acetate, sodium bicarbonate, and tetrabutylammonium chloride, whereas none of the desired product was obtained in the reaction with 4-methoxyphenyl trifluoromethanesulfonate (7). The stereo-selectivity of the reaction was reversed by employing triethylamine instead of sodium bicarbonate to furnish (Z)-3c predominantly. In the presence of sodium bicarbonate, replacement of the solvent by water improved not only the chemical yield and stereo-selectivity but also the optical purity: geometiically pure (E)-3c of 96% ee was formed in a good yield.
- Itaya,Shimizu
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p. 398 - 402
(2007/10/02)
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- Structure and Stereochemistry of Three Phytotoxins, Syringomycin, Syringotoxin and Syringostatin, Produced by Pseudomonas syringae pv. syringae
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The structures of two phytotoxins, syringomycin and syringotoxin, produced by Pseudomonas syringae pv. syringae, were determined.Several amino acid residues of syringomycin were different from those in the syringostatins.Syringotoxin B proved to be syringostatin A.The three kinds of phytotoxins showed close structural similarity, and the stereochemistry of their components was deduced and compared.
- Fukuchi, Naoyuka,Isogai, Akira,Nakayama, Jiro,Takayama, Seiji,Yamashita, Shuichi,et al.
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p. 1149 - 1158
(2007/10/02)
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- N-(BENZYLOXYCARBONYL)-L-VINYLGLYCINE METHYL ESTER FROM L-METHIONINE METHYL ESTER HYDROCHLORIDE
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A reproducible, large scale and practical synthesis of N-(benzyloxycarbonyl)-L-vinylglycine methyl ester starting from L-methionine methyl ester hydrochloride is described.
- Meffre, Patrick,Vo-Quang, Liliane,Vo-Quang, Yen,Goffic, Francois Le
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p. 3457 - 3468
(2007/10/02)
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- THE FREE RADICAL CHEMISTRY OF CARBOXYLIC ESTERS OF 2-SELENOPYRIDINE-N-OXIDE: A CONVENIENT SYNTHESIS OF (L)-VINYLGLYCINE
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Optically pure (L)-vinylglycine has been synthesised by two different methods.The first of these involves protected (L)-glutamate esters of N-hydroxy-2-seleno-pyridine.Such esters are shown to undergo the same decarboxylative rearrangement as their thio-a
- Barton, Derek H. R.,Crich, David,Herve, Yolande,Potier, Pierre,Thierry, Josiane
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p. 4347 - 4358
(2007/10/02)
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- A NOVEL AND EFFICIENT SYNTHESIS OF L-VINYLGLYCINE
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A simple and practical synthesis of the title compound starting with L-glutamic acid is described.
- Hanessian, Stephen,Sahoo, Soumya P.
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p. 1425 - 1428
(2007/10/02)
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- L-Vinylglycine
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Optically pure L-vinylglycine (1) has been synthesized from L-methionine in 54percent overall yield.The process consists in first preparing N-methionine methyl ester (9) which is then oxidized to methyl 2-amino>-
- Afzali-Ardakani, Ali,Rapoport, Henry
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p. 4817 - 4820
(2007/10/02)
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