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Search for "S-alkylation" in Full Text gives 13 result(s) in Beilstein Journal of Organic Chemistry.
Synthesis of ether lipids: natural compounds and analogues
- Marco Antônio G. B. Gomes,
- Alicia Bauduin,
- Chloé Le Roux,
- Romain Fouinneteau,
- Wilfried Berthe,
- Mathieu Berchel,
- Hélène Couthon and
- Paul-Alain Jaffrès
Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96
- precursor. The reaction started with the S-alkylation of thioglycerol by bromo- or iodoalkyl chains as previously reported [131]. Then, the primary alcohol was protected with a trityl group to form 26.1 (Figure 26A). The secondary alcohol was first deprotonated with sodium hydride and alkylated with
Graphical Abstract
Figure 1: Chemical structure of some natural ether lipids (ELs).
Figure 2: Synthesis of lyso-PAF and PAF from 1-O-alkylglycerol [64].
Figure 3: Synthesis of lyso-PAF from 1,3-benzylideneglycerol 3.1 [69].
Figure 4: A) Synthesis of the two enantiomers of octadecylglycerol (4.6 and 4.10) from ᴅ-mannitol (4.1); B) s...
Figure 5: Four-step synthesis of PAF 5.6 from (S)-glycidol [73].
Figure 6: Synthesis of 1-O-alkylglycerol A) from solketal, B) from ᴅ- or ʟ-tartaric acid and the intermediate ...
Figure 7: Synthesis of EL building blocks starting from substituted glycidol 7.1a–c [82].
Figure 8: Synthesis of PAF 8.5 by using phosphoramidite 8.2 [86].
Figure 9: Synthesis of oleyl-PAF 9.7 from ʟ-serine [88].
Figure 10: Synthesis of racemic analogues of lyso-PAF 10.8 and PAF 10.9 featuring a phenyl group between the g...
Figure 11: Synthesis of racemic deoxy-lyso-PAF 11.7 and deoxy-PAF 11.8 [91].
Figure 12: Synthesis of racemic thio-PAF 12.8 [93].
Figure 13: Racemic synthesis of 13.6 to illustrate the modification of the glycerol backbone by adding a methy...
Figure 14: Racemic synthesis of 14.5 as an illustration of the introduction of methyl substituents on the glyc...
Figure 15: Synthesis of functionalized sn-2-acyl chains of PC-EL; A) Steglich esterification or acylation reac...
Figure 16: Synthesis of racemic mc-PAF (16.3), a carbamate analogue of PAF [102].
Figure 17: A) Synthesis of (R)-17.2 and (S)-17.6 starting from (S)-solketal (17.1); B) synthesis of N3-PAF (17...
Figure 18: Modification of the phosphocholine polar head to produce PAF analogues [81].
Figure 19: Racemic PAF analogues 19.3 and 19.5 characterized by the absence of the phosphate group [107].
Figure 20: Synthesis of PIP3-PAF (20.7) [108].
Figure 21: Large-scale synthesis of C18-edelfosine (21.8) [116].
Figure 22: Synthesis of C16-edelfosine (22.10) starting from isopropylidene-ʟ-glyceric acid methyl ester (22.1...
Figure 23: Phosphocholine moiety installation by the use of chlorophosphite 23.2 as key reagent [119].
Figure 24: Synthesis of rac-1-alkyl-2-O-methylglycerol (AMG) [120].
Figure 25: Synthesis of stereocontrolled 1-alkyl-2-O-methyl glycerol 25.9 (AMG) from dimethyl ᴅ-tartrate [81].
Figure 26: A) Racemic synthesis of thioether 26.4 [129,130], B) structure of sulfone analogue 26.5 [129].
Figure 27: Stereocontrolled synthesis of C18-edelfosine thioether analogue 27.8 [118].
Figure 28: Synthesis of thioether 28.4 that include a thiophosphate function [134].
Figure 29: Synthesis of ammonium thioether 29.4 and 29.6 [135].
Figure 30: Synthesis of the N-methylamino analogue of edelfosine 30.6 (BN52211) [138].
Figure 31: Synthesis of 1-desoxy analogues of edelfosine; A) with a saturated alkyl chain; B) synthesis of the...
Figure 32: Stereocontrolled synthesis of edelfosine analogue (S)-32.8 featuring a C18:1 lipid chain [142].
Figure 33: Synthesis of edelfosine analogues with modulation of the lipid chain; A) illustration with the synt...
Figure 34: Synthesis of phospholipid featuring a carbamate function to link the lipid chain to the glycerol un...
Figure 35: Synthesis of sesquiterpene conjugates of phospho glycero ether lipids [148].
Figure 36: Racemic synthesis of methyl-substituted glycerol analogues 36.7 and 36.10: A) synthesis of diether ...
Figure 37: Racemic synthesis of ilmofosine (37.6) [155,156].
Figure 38: A) Stereoselective synthesis of 38.5 via a stereoselective hydroboration reaction; B) synthesis of ...
Figure 39: Racemic synthesis of SRI62-834 (39.6) featuring a spiro-tetrahydrofurane heterocycle in position 2 ...
Figure 40: Racemic synthesis of edelfosine analogue 40.5 featuring an imidazole moiety in sn-2 position [160].
Figure 41: Racemic synthesis of fluorine-functionalized EL: A) Synthesis of 41.6 and B) synthesis of 41.8 [161-163].
Figure 42: A) Synthesis of the β-keto-ester 42.6 that also features a decyl linker between the phosphate and t...
Figure 43: Synthesis of phosphonate-based ether lipids; A) edelfosine phosphonate analogue 43.7 and B) thioeth...
Figure 44: Enantioselective synthesis of phosphonates 44.3 and 44.4 [171].
Figure 45: Racemic synthesis of phosphinate-based ether lipid 45.10 [172].
Figure 46: Racemic synthesis of edelfosine arsonium analogue 46.5 [173].
Figure 47: Synthesis of edelfosine dimethylammonium analogue 47.2 [118].
Figure 48: Synthesis of rac-C18-edelfosine methylammonium analogue 48.4 [176].
Figure 49: A) Synthesis of edelfosine N-methylpyrrolidinium analogue 49.2 or N-methylmorpholinium analogue 49.3...
Figure 50: A) Synthesis of edelfosine’s analogue 50.4 with a PE polar group; B) illustration of a pyridinium d...
Figure 51: A) Synthesis of 51.4 featuring a thiazolium cationic moiety; B) synthesis of thiazolium-based EL 51...
Figure 52: Synthesis of cationic ether lipids 52.3, 52.4 and 52.6 [135,183].
Figure 53: Synthesis of cationic carbamate ether lipid 53.5 [184].
Figure 54: Synthesis of cationic sulfonamide 54.5 [185].
Figure 55: Chemical structure of ONO-6240 (55.1) and SRI-63-119 (55.2).
Figure 56: Synthesis of non-ionic ether lipids 56.2–56.9 [188].
Figure 57: Synthesis of ether lipid conjugated to foscarnet 57.6 [189].
Figure 58: A) Synthesis of ether lipid conjugated to arabinofuranosylcytosine; B) synthesis of AZT conjugated ...
Figure 59: Synthesis of quercetin conjugate to edelfosine [191].
Figure 60: Synthesis of 60.8 (Glc-PAF) [194].
Figure 61: A) Synthesis of amino ether lipid 61.7 functionalized with a rhamnose unit and its amide analogue 6...
Figure 62: A) Synthesis of glucose ether lipid 62.4; B) structure of ether lipid 62.5 possessing a maltose uni...
Figure 63: A) Synthesis of glucuronic methyl ester 63.8; B) structure of cellobiose 63.9 and maltose 63.10 ana...
Figure 64: A) Synthesis of maltosyl glycerolipid 64.7; B) structure of lactose analogue 64.8 prepared followin...
Figure 65: A) Asymmetric synthesis of the aglycone moiety starting from allyl 4-methoxyphenyl ether; B) glycos...
Figure 66: A) Synthesis of ohmline possessing a lactose moiety. B) Structure of other glyco glycero lipids pre...
Figure 67: A) Synthesis of lactose-glycerol ether lipid 67.5; B) analogues possessing a maltose (67.6) or meli...
Figure 68: Synthesis of digalactosyl EL 68.6, A) by using trityl, benzyl and acetyl protecting groups, B) by u...
Figure 69: A) Synthesis of α-ohmline; B) structure of disaccharide ether lipids prepared by using similar meth...
Figure 70: Synthesis of lactose ether lipid 70.3 and its analogue 70.6 featuring a carbamate function as linke...
Figure 71: Synthesis of rhamnopyranoside diether 71.4 [196].
Figure 72: Synthesis of 1-O-hexadecyl-2-O-methyl-3-S-(α-ᴅ-1'-thioglucopyranosyl)-sn-glycerol (72.5) [225].
Figure 73: A) Preparation of lipid intermediate 73.4; B) synthesis of 2-desoxy-C-glycoside 73.10 [226].
Figure 74: Synthesis of galactose-pyridinium salt 74.3 [228].
Figure 75: Synthesis of myo-inositol derivative Ino-C2-PAF (75.10) [230].
Figure 76: A) Synthesis of myo-inositol phosphate building block 76.7; B) synthesis of myo-inositolphosphate d...
Figure 77: A) Synthesis of phosphatidyl-3-desoxy-inositol 77.4; B) synthesis of phosphono-3-desoxyinositol 77.9...
Figure 78: A) Structure of diether phosphatidyl-myo-inositol-3,4-diphosphate 78.1; B) synthesis of phosphatidy...
Figure 79: A) Synthesis of diether-phosphatidyl derivative 79.4 featuring a hydroxymethyl group in place of a ...
Figure 80: Synthesis of Glc-amine-PAF [78].
Figure 81: Synthesis of glucosamine ether lipid 81.4 and its analogues functionalized in position 3 of the ami...
Figure 82: Synthesis of fully deprotected aminoglucoside ether lipid 82.5 [246].
Figure 83: Synthesis of C-aminoglycoside 83.12 using Ramberg–Bäcklund rearrangement as a key step [250].
Figure 84: A) List of the most important glyco lipids and amino glyco lipids included in the study of Arthur a...
Figure 85: Synthesis of mannosamine ether lipid 85.6 [254].
Figure 86: A) Synthesis of glucosamine ether lipids with a non-natural ʟ-glucosamine moiety; B) synthesis of e...
Figure 87: A) Structure of the most efficient anticancer agents 87.1–87.4 featuring a diamino glyco ether lipi...
Figure 88: A) Synthesis of diamino glyco ether lipid 87.4; B) synthesis of bis-glycosylated ether lipid 88.10 [256]....
Figure 89: Synthesis of triamino ether lipid 89.4 [260].
Figure 90: Synthesis of chlorambucil conjugate 90.7 [261].
Figure 91: Three main methods for the preparation of glycerol ether lipid 91.3; A) from solketal and via a tri...
Figure 92: Four different methods for the installation of the phosphocholine polar head group; A) method using...
Figure 93: Illustration of two methods for the installation of saccharides or aminosaccharides; A) O-glycosyla...
Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase
- Sanaz Ahmadipour,
- Alice J. C. Wahart,
- Jonathan P. Dolan,
- Laura Beswick,
- Chris S. Hawes,
- Robert A. Field and
- Gavin J. Miller
Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142
- accepted. Evaluation of GDP 6-chloro-6-deoxy-ᴅ-mannose suggests that the ligand can bind to GMD, but that targeting inhibitive S-alkylation of an sp3-hybridised C6 electrophilic probe is ineffective here. a) Proposed oxidative pathway for provision of GDP-ManA 5 from GDP-Man 1, C6 stereochemistry of 3 is
Graphical Abstract
Figure 1: a) Proposed oxidative pathway for provision of GDP-ManA 5 from GDP-Man 1, C6 stereochemistry of 3 i...
Scheme 1: Syntheses of C6-modified mannose 1-phosphates 13 and 17. Conditions a) PPh3, CBr4, DCM, rt, 75%; b)...
Figure 2: Structure of 16 with ADPs rendered at the 50% probability level. Acetyl group disorder is omitted f...
Scheme 2: Evaluation of enzymatic GDP-Man synthesis using C6-modified mannose 1-phosphates 13, 17, and 18; Y+...
Figure 3: GMD function with probe 19 over 120 min (GMD (100 µg/mL), GDP sugars (50 µM), NAD+ (200 µM)). Dotte...
One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates
- Jun Ki Kim,
- Hwan Jung Lim,
- Kyung Chae Jeong and
- Seong Jun Park
Beilstein J. Org. Chem. 2018, 14, 243–252, doi:10.3762/bjoc.14.16
- conditions – in the absence of an added base at room temperature. To obtain aminothioacetal 7a, we initially performed the S-alkylation of the intermediate thiolate salt with 2-(bromomethyl)pyridine at room temperature overnight. We interestingly found that the desired 5-(pyridin-2-yl)thiophenes 8a has
- intermediates 7, which are easily converted into the desired thiophenes 8, can be generated in situ by S-alkylation of the intermediate thiolate salts. By 1H NMR analysis of N,S-acetals 9 and methoxy group substitution of 9b, the formation of sulfur ylide-like intermediates was successfully demonstrated. The
Graphical Abstract
Figure 1: The selected examples of sulfur(IV) and sulfur(VI) ylides 1 [1], 2 [5-7], 3 [6,7,9], 4 [11,12], 5 [33,34], 6 [35-38].
Figure 2: Metal-free synthesis of thiophene-based heterocycles (A) [54,55], (B) [56].
Scheme 1: One-pot sequential synthesis of the trisubstituted 5-(pyridine-2-yl)thiophenes 8a. Substrate: amalo...
Figure 3: X-ray crystal structures of 8ad and 8an [68].
Figure 4: The proposed structure of sulfur ylide-like intermediates; resonance contributors (mesomeric struct...
Scheme 2: The substitution reaction with MeOH.
Selective synthesis of thioethers in the presence of a transition-metal-free solid Lewis acid
- Federica Santoro,
- Matteo Mariani,
- Federica Zaccheria,
- Rinaldo Psaro and
- Nicoletta Ravasio
Beilstein J. Org. Chem. 2016, 12, 2627–2635, doi:10.3762/bjoc.12.259
- substrates under mild reaction conditions. Keywords: no solvent; S-alkylation; solid acids; thioethers; transition-metal-free; Introduction The need for more sustainable processes in the fine chemical industry is growing continuously. An optimal use of resources, both energy and starting materials, and a
Graphical Abstract
Figure 1: Overview of the structures of the alcohols 1a–i used in the present work.
Figure 2: Structures of thiols 2a–f used in the present work.
Figure 3: Structures of thioethers 3a–p synthesized.
Figure 4: Product distribution during reaction of 5b and 2a over a solid acid catalyst.
Figure 5: Product distribution during reaction of 1c and 2e.
Scheme 1: Racemization of (R)-1-phenylethanol during the reaction with benzylmercaptan (2a) in the presence o...
Scheme 2: Reaction of cinnamyl alcohol 1i and benzylmercaptan (2a).
Figure 6: Recyclability test of SiAl 0.6 catalyst in the reaction of 1a and 2a.
A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis
- Mariano Goldberg,
- Denis Sartakov,
- Jan W. Bats,
- Michael Bolte and
- Michael W. Göbel
Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176
- reductive amination to form 18 (58%). After removal of the Boc protecting group (quant.), triamine 19 was reacted with dimethyl trithiocarbonate in refluxing nitromethane. The thiourea intermediate was activated in situ by S-alkylation with MeI. Upon further heating the final cyclization occured forming the
Graphical Abstract
Figure 1: Structure of guanidines 1–10.
Scheme 1: Synthesis of guanidine 10. Conditions: (a) 1 equiv HOOC-CH2-COOH, 2 equiv NH4OAc, EtOH, 78 °C, 5 h,...
Figure 2: Crystal structure of guanidine 10 as a benzoate salt. Only one of the ion pairs is shown for the sa...
Scheme 2: Reaction of anthrones and N-arylmaleimides catalyzed by guanidine 10. The guanidine deprotonates an...
Figure 3: A) Chromatogram of rac-25 after incubation with 0.1 equiv of 10 in THF at −15 °C for 64 h. The fast...
Scheme 3: Assignment of the absolute configurations by chemical correlation. The R configuration of compound ...
1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis
- Antonia Mielgo and
- Claudio Palomo
Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90
- analogous they do not show the Cα/Cγ selectivity problem [56][57][58]. 1.1 Synthesis of 1H-imidazol-4(5H)-ones 1 1H-Imidazol-4(5H)-ones 1 (R = SBn) are prepared by S-alkylation of the corresponding thiohydantoins [55][59] (Scheme 1a) prior trimethylsilyl enol ether formation which is necessary to avoid O
Graphical Abstract
Figure 1: Some α-substituted heterocycles for asymmetric catalysis, their reactivity patterns against enoliza...
Figure 2: 1H-Imidazol-4(5H)-ones 1 and thiazol-4(5H)-ones 2.
Scheme 1: a) Synthesis of 2-thio-1H-imidazol-4(5H)-ones [55] and b) preparation of the starting thiohydantoins [59].
Scheme 2: Selected examples of the Michael addition of 2-thio-1H-imidazol-4(5H)-ones to nitroalkenes [55]. aReact...
Scheme 3: Michael addition of thiohydantoins to nitrostyrene assisted by Et3N and catalysts C1 and C3. aAbsol...
Scheme 4: Elaboration of the Michael adducts coming from the Michael addition to nitroalkenes [55].
Figure 3: Proposed model for the Michael addition of 1H-imidazol4-(5H)-ones and selected 1H NMR data which su...
Scheme 5: Michael addition 2-thio-1H-imidazol-4(5H)-ones to the α-silyloxyenone 29 [55].
Scheme 6: Elaboration of the Michael adducts coming from the Michael addition to nitroolefins [55].
Scheme 7: Rhodanines in asymmetric catalytic reactions: a) Reaction with rhodanines of type 44 [78-80]; b) reactions...
Scheme 8: Michael addition of thiazol-4(5H)-ones to nitroolefins promoted by the ureidopeptide-like bifunctio...
Figure 4: Ureidopeptide-like Brønsted bases: catalyst design. a) Previous known design. b) Proposed new desig...
Scheme 9: Ureidopeptide-like Brønsted base bifunctional catalyst preparation. NMM = N-methylmorpholine, THF =...
Scheme 10: Selected examples of the Michael addition of thiazolones to different nitroolefins promoted by cata...
Scheme 11: Elaboration of the Michael adducts to α,α-disubstituted α-mercaptocarboxylic acid derivatives [85].
Scheme 12: Effect of the nitrogen atom at the aromatic substituent of the thiazolone on yield and stereoselect...
Scheme 13: Michael addition reaction of thiazol-4(5H)ones 74 to α’-silyloxyenone 29 [73].
Scheme 14: Elaboration of the thiazolone Michael adducts [73].
Scheme 15: Enantioselective γ-addition of oxazol-4(5H)-ones and thiazol-4(5H)-ones to allenoates promoted by C6...
Scheme 16: Enantioselective γ-addition of thiazol-4(5H)-ones and oxazol-4(5H)-ones to alkynoate 83 promoted by ...
Scheme 17: Proposed mechanism for the C6-catalyzed γ-addition of thiazol-4(5H)-one to allenoates. Adapted from ...
Scheme 18: Catalytic enantioselective α-amination of thiazolones promoted by ureidopeptide like catalysts C5 a...
Scheme 19: Iridium-catalized asymmetric allyllation of substituted oxazol-4(5H)-ones and thiazol-4(5H)-ones pr...
Amyloid-β probes: Review of structure–activity and brain-kinetics relationships
- Todd J. Eckroat,
- Abdelrahman S. Mayhoub and
- Sylvie Garneau-Tsodikova
Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116
- observed that bulky, hydrophobic thioether substituents (such as R4 = SCH2C6H4-p-OMe) were well tolerated at this position. This finding was of particular interest as it provided a possible means of generating new PET ligands via [11C]- or [18F]-labeling through S-alkylation. The [18F]-labeled
Graphical Abstract
Figure 1: Structures of A. dyes originally used to stain Aβ and B. newer scaffolds explored for the developme...
Scheme 1: General synthetic strategies (Gs) used to introduce A. 18F, B. 11C, C. 99mTc/Re, and D. 123I and 125...
Scheme 2: A. Structures of radiolabeled chalcone analogues discussed. B.–D. Synthetic schemes for the prepara...
Scheme 3: A. Structures of the radiolabeled flavone and aurone analogues discussed. B. Synthetic scheme for t...
Scheme 4: A. Structures of the radiolabeled stilbene analogues discussed. B. Synthetic scheme for the prepara...
Scheme 5: A. Structures of the diphenyl-1,3,4- and diphenyl-1,2,4-oxadiazoles discussed. B.,C. Synthetic sche...
Figure 2: Structures of the radiolabeled benzothiazole analogues discussed.
Scheme 6: A.–F. Synthetic schemes for the preparation of [11C]56b, [11C]56c, 57, 58a,b, 61, and [18F]65a–d.
Scheme 7: A. Structures of the [Re]- and [99mTc]-labeled benzothiazole analogues discussed. B.,C. Synthetic s...
Figure 3: Structures of the radiolabeled benzoxazole analogues discussed.
Scheme 8: A.–E. Synthetic schemes for the preparation of 94, [123I]95e, 96–98.
Figure 4: Structures of the radiolabeled benzofuran analogues discussed.
Scheme 9: A.–E. Synthetic schemes for the preparation of 121, [125I]122a, 123a,b, 125a,b, and 126.
Scheme 10: A. Structures of the radiolabeled imidazopyridine analogues discussed. B. Synthetic scheme for the ...
Scheme 11: Synthetic scheme for the preparation of the benzimidazole 146.
Figure 5: Structures of the quinolines discussed.
Scheme 12: Synthetic scheme for the preparation of the naphthalene analogues 152 and 160a,b.
Scheme 13: A. Structures of the radiolabeled analogues resulting from the combination of various scaffolds. B.,...
Scheme 14: A.–C. Synthetic schemes for the preparation of radiolabeled probes with unique scaffolds.
Scheme 15: A. Structures of the oxazine-derived fluorescence probes discussed. B. Synthetic scheme for the pre...
Figure 6: Structure of THK-265 (190).
Scheme 16: Synthetic scheme for the preparation of quinoxaline analogue 191.
A novel asymmetric synthesis of cinacalcet hydrochloride
- Veera R. Arava,
- Laxminarasimhulu Gorentla and
- Pramod K. Dubey
Beilstein J. Org. Chem. 2012, 8, 1366–1373, doi:10.3762/bjoc.8.158
- at room temperature for 2 h to give the product in 85% yield (Scheme 6). Regioselective N-alkylation of N-tert-butanesulfinamides was difficult to achieve as S-alkylation can also be possible [26]. To our knowledge, limited procedures were reported for the regioselective N-alkylation of N-tert
Graphical Abstract
Figure 1: Cinalcet hydrochloride (CNC·HCl, 1).
Scheme 1: Asymmetric synthesis of 1.
Scheme 2: Synthesis of the intermediates 5 and 6 from 8.
Scheme 3: Asymmetric synthesis of naphthylethylsulfinamide 4.
Scheme 4: Conversion of 8 to 10.
Scheme 5: Synthesis of alcohol intermediate 12 from 10.
Scheme 6: Synthesis of bromo 5 and iodo 6 derivatives.
Scheme 7: Regioselective N-alkylation of naphthyl ethyl sulfinamide 4a.
Scheme 8: Acid hydrolysis of N-tert-butanesulfinyl group in 7.
The Eschenmoser coupling reaction under continuous-flow conditions
- Sukhdeep Singh,
- J. Michael Köhler,
- Andreas Schober and
- G. Alexander Groß
Beilstein J. Org. Chem. 2011, 7, 1164–1172, doi:10.3762/bjoc.7.135
- desired Eschenmoser coupling products were obtained within 70 s residence time. The reaction kinetics was investigated and 15 examples of different building block combinations are given. Keywords: activation energy; episulfide; flow chemistry; keto imine; kinetics; S-alkylation; sulfide contraction
- is quite a valuable, metal free, carbon–carbon bond forming reaction. The necessary starting materials of type 3 can be prepared by S-alkylation of secondary thioamide or thiolactame building blocks of type 2 with α-bromoketones 1 (X = Br). The carbon–carbon coupling occurs between these building
- blocks as shown in Scheme 1. Due to the ease of accessibility of the building blocks and the usually high-yielding S-alkylation step, the Eschenmoser coupling is an interesting reaction for diversity-oriented combinatorial synthesis [15][16][17]. The new carbon–carbon bond formation occurs during the
Graphical Abstract
Scheme 1: Eschenmoser coupling reaction with secondary S-alkylated thioamide derivatives of type 3.
Scheme 2: Eschenmoser coupling sequence of S-alkylated ternary thioamides of type 7.
Figure 1: Conversion of 3aa to 4aa under different flow conditions.
Figure 2: Reaction kinetics analysis. Left: Rate constants with 0.1 M reaction solution. Right: Arrhenius-plo...
Scheme 3: Exclusive formation of thiazol 13 with dihydropyrimidine derivatives 11 take place in the case of a...
Figure 3: Flow chemistry setup scheme.
Figure 4: Capillary reactor with jacketed cover removed, and the process controller.
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
- Marcus Baumann,
- Ian R. Baxendale,
- Steven V. Ley and
- Nikzad Nikbin
Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57
- esomeprazole the subsequent steps involve an S-alkylation as well as an asymmetric oxidation of the newly formed thioether [59][60]. Additional structural diversity in the aniline component can be introduced by protection, nitration, deprotection and reduction of the starting amine compound 201. Scheme 40 for
Graphical Abstract
Figure 1: Structures of atorvastatin and other commercial statins.
Figure 2: Structure of compactin.
Scheme 1: Synthesis of pentasubstituted pyrroles.
Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
Scheme 6: Convergent synthesis towards atorvastatin.
Figure 3: Binding pocket of sunitinib in the TRK KIT.
Scheme 7: Synthesis of sunitinib.
Scheme 8: Alternative synthesis of sunitinib.
Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
Scheme 13: Alternative introduction of the sulfonamide.
Scheme 14: Negishi-type coupling to benzylic sulfonamides.
Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
Scheme 18: Improved synthesis of rizatriptan.
Scheme 19: Larock-type synthesis of rizatriptan.
Scheme 20: Synthesis of eletriptan.
Scheme 21: Heck coupling for the indole system in eletriptan.
Scheme 22: Attempted Fischer indole synthesis of elatriptan.
Scheme 23: Successful Fischer indole synthesis for eletriptan.
Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
Scheme 26: Palladium-mediated synthesis of ondansetron.
Scheme 27: Fischer indole synthesis of ondansetron.
Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
Figure 4: Structures of carvedilol 136 and propranolol 137.
Scheme 29: Synthesis of the carbazole core of carvedilol.
Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
Scheme 31: Convergent synthesis of etodolac.
Scheme 32: Alternative synthesis of etodolac.
Figure 5: Structures of imidazole-containing drugs.
Scheme 33: Synthesis of functionalised imidazoles towards losartan.
Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
Scheme 35: Synthesis of trisubstituted imidazoles.
Scheme 36: Preparation of the imidazole ring in olmesartan.
Scheme 37: Synthesis of ondansetron.
Scheme 38: Alternative route to ondansetron and its analogues.
Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
Scheme 40: Synthesis of benzimidazole core pantoprazole.
Figure 6: Structure of rabeprazole 194.
Scheme 41: Synthesis of candesartan.
Scheme 42: Alternative access to the candesartan key intermediate 216.
Scheme 43: .Medicinal chemistry route to telmisartan.
Scheme 44: Improved synthesis of telmisartan.
Scheme 45: Synthesis of zolpidem.
Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
Figure 7: Structure of celecoxib.
Scheme 47: Preparation of celecoxib.
Scheme 48: Alternative synthesis of celecoxib.
Scheme 49: Regioselective access to celecoxib.
Scheme 50: Synthesis of pazopanib.
Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
Scheme 52: Regioselective synthesis of anastrozole.
Scheme 53: Triazine-mediated triazole formation towards anastrozole.
Scheme 54: Alternative routes to 1,2,4-triazoles.
Scheme 55: Initial synthetic route to sitagliptin.
Figure 8: Binding of sitagliptin within DPP-IV.
Scheme 56: The process route to sitagliptin key intermediate 280.
Scheme 57: Synthesis of maraviroc.
Scheme 58: Synthesis of alprazolam.
Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
Scheme 60: Synthesis of itraconazole.
Scheme 61: Synthesis of rufinamide.
Scheme 62: Representative tetrazole formation in valsartan.
Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
Scheme 63: Early stage introduction of the tetrazole in losartan.
Scheme 64: Synthesis of cilostazol.
Figure 11: Structure of cefdinir.
Scheme 65: Semi-synthesis of cefdinir.
Scheme 66: Thiazole syntheses towards ritonavir.
Scheme 67: Synthesis towards pramipexole.
Scheme 68: Alternative route to pramipexole.
Scheme 69: Synthesis of famotidine.
Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
Scheme 71: Synthesis of ziprasidone.
Figure 12: Structure of mometasone.
Scheme 72: Industrial access to 2-furoic acid present in mometasone.
Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
Scheme 74: Synthesis of nitrofurantoin.
Scheme 75: Synthesis of benzofuran.
Scheme 76: Synthesis of amiodarone.
Scheme 77: Synthesis of raloxifene.
Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
Scheme 79: Gewald reaction in the synthesis of olanzapine.
Scheme 80: Alternative synthesis of olanzapine.
Figure 13: Access to simple thiophene-containing drugs.
Scheme 81: Synthesis of clopidogrel.
Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
Scheme 83: Alternative synthesis of key intermediate 422.
Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
Scheme 84: Synthesis of timolol.
Scheme 85: Synthesis of tizanidine 440.
Scheme 86: Synthesis of leflunomide.
Scheme 87: Synthesis of sulfamethoxazole.
Scheme 88: Synthesis of risperidone.
Figure 15: Relative abundance of selected transformations.
Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
Kinetic studies and predictions on the hydrolysis and aminolysis of esters of 2-S-phosphorylacetates
- Milena Trmčić and
- David R. W. Hodgson
Beilstein J. Org. Chem. 2010, 6, 732–741, doi:10.3762/bjoc.6.87
- ; heterobifunctional cross-linker; hydrolysis; kinetics; thiophosphate; Introduction Heterobifunctional cross-linking agents are used widely in protein science for forming covalently-bonded protein-protein complexes [1] and protein-small molecule systems [2]. S-Alkylation and N-acylation processes are used together
- extensively as orthogonal methods to effect hetero-cross-linking. S-Alkylation processes are not affected by competing hydrolysis, however, N-acylation using reactive esters is hampered by competing hydrolysis processes. The aminolysis and hydrolysis of activated esters has been well studied [3], however, the
Graphical Abstract
Scheme 1: Use of 2-bromoacetic acid esters as heterobifunctional cross-linking agents.
Scheme 2: Cross-linking between thiophosphate 4, D-glucosamine (GlcNH2) and bromoacetyl-N-hydroxybenzotriazol...
Scheme 3: Ligation of 2-bromoacetic acid esters 1 (R = pNP or mNP) to thiophosphate 4.
Scheme 4: Displacement of p- or m-nitrophenolate ions from nitrophenyl esters 7 (R = pNP) and 7 (R = mNP).
Figure 1: log khydrol vs pH for the hydrolysis p-nitrophenyl ester 7 (R = pNP) and m-nitrophenyl ester 7 (R = ...
Figure 2: log kaminol vs pH for the combined aminolysis and hydrolysis of p-nitrophenyl ester 7 (R = pNP) and ...
Scheme 5: Kinetic model for competing hydrolysis and aminolysis processes of nitrophenyl esters 7 (R = pNP) a...
Figure 3: Predicted concentration-time profile for the reaction between starting concentrations of 0.05 M p-n...
Figure 4: Predicted concentration-time profile for the reaction between starting concentrations of 0.05 M m-n...
Figure 5: Predicted leaving group pKaH values required for user-defined conversion levels of starting concent...
Scheme 6: (A) Direct aminolysis of the ester carbonyl group; (B) intramolecular nucleophilic catalysis of est...
Figure 6: 2-nitrophenyl 2-(ethylthio)acetate.
A superior P-H phosphonite: Asymmetric allylic substitutions with fenchol- based palladium catalysts
- Bernd Goldfuss,
- Thomas Löschmann,
- Tina Kop-Weiershausen,
- Jörg Neudörfl and
- Frank Rominger
Beilstein J. Org. Chem. 2006, 2, No. 7, doi:10.1186/1860-5397-2-7
- substitutions yields BIFOP-H-Re as the most stable transition structure. Its Re-addition of the NH3-nucleophile is slightly more favored than the Si-addition in the competing transition structure BIFOP-H-Si (Figure 5). This agrees with the experimentally observed formation of the S-alkylation product with BIFOP
- extrapolated energies: BIFOP-H-re: -1025.01553 H, BIFOP-H-si: -1025.01466 H. The by 0.5 kcal mol-1 slightly preferred re-addition of the NH3 model nucleophile corresponds to the experimental S-alkylation product. Pd-catalyzed allylic substitution with unsymmetrical substrates (Nu = dimethylmalonate, Nf = OAc
Graphical Abstract
Scheme 1: Pd-catalyzed allylic substitution with unsymmetrical substrates (Nu = dimethylmalonate, Nf = OAc).
Scheme 2: Bidentate P, N-ligands and a monodentate phosphoramidite for Pd-catalyzed allylic substitutions wit...
Scheme 3: Fenchole-based phosphorus ligands (i.e. FEENOPs and BIFOPs) for Pd-catalyzed allylic substitutions....
Scheme 4: Allylic alkylation of 1-phenyl-2-propenyl acetate by sodium dimethylmalonate (BSA-method) with Pd-F...
Figure 1: X-ray crystal structure of the cationic complex Pd-FENOP (CCDC 299944), the perchlorate counterion ...
Figure 2: X-ray crystal structure of the cationic complex Pd-FENOP-Me (CCDC 600369), the perchlorate counteri...
Figure 3: X-ray crystal structure of the cationic complex Pd-FENOP-NMe2 (CCDC 600370), the perchlorate counte...
Figure 4: The two most stable ONIOM(B3LYP/SDD(+ECP) (Pd) /6-31G* (C, H, O, N, P) : UFF) optimized transition ...
Figure 5: The two most stable ONIOM(B3LYP/SDD(+ECP) (Pd) /6-31G* (C, H, O, N, P) : UFF) optimized transition ...
Synthesis of phosphorothioates using thiophosphate salts
- Babak Kaboudin and
- Fatemeh Farjadian
Beilstein J. Org. Chem. 2006, 2, No. 4, doi:10.1186/1860-5397-2-4
- route to phosphorothioates via O,O'-dialkyl thiophosphate anion formation. Studies on the reaction of ambident nucleophile ammonium O,O'-diethyl thiophosphate with benzyl halides and tosylate in different solvents show that only S-alkylation is obtained. Reaction of this ambident nucleophile with
- microwave irradiation produces high yields of phosphothioates (S-alkylation, Scheme 1). [44] We decided to investigate the reaction of this ambident nuclophile under different conditions (different leaving groups and solvents). Firstly, we introduce a novel method for large-scale synthesis of ammonium O,O
- this reagent with benzyl bromide, chloride and tosylate in different aporotic and protic solvents show that S-benzyl O,O'-diethyl phosphorothioate (S-alkylation) was formed as sole product (Scheme 4). We conclude here that changing of leaving group and use of different media gives no O-alkylation
Graphical Abstract
Scheme 1: Synthesis of phosphorothioates using microwave irradiation
Scheme 2: Ambident nucleophile ammonium O,O'-diethylthiophosphate
Scheme 3: Synthesis of ammonium O,O'-diethyl thiophosphate
Scheme 4: Solvent and leaving group effects on the synthesis phosphorothioates
Scheme 5: Reaction of ammonium O,O'-diethyl thiophosphate with benzoyl chloride
Scheme 6: Reaction of triethylammonium O,O'-diethyl thiophosphate with benzoyl chloride
Scheme 7: Synthesis of phosphorothioates using triethylammonium O,O'-diethyl thiophosphate using microwave ir...
