- Chiral syntheses of methyl (R)-2-Sulfanylcarboxylic esters and acids with optical purity determination using HPLC
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Accessible chiral syntheses of 3 types of (R)-2-sulfanylcarboxylic esters and acids were performed: (R)-2-sulfanylpropanoic (thiolactic) ester (53%, 98%ee) and acid (39%, 96%ee), (R)-2-sulfanylsucciinic diester (59%, 96%ee), and (R)-2-mandelic ester (78%, 90%ee) and acid (59%, 96%ee). The present practical and robust method involves (i) clean SN2 displacement of methanesulfonates of (S)-2-hydroxyesters by using commercially available AcSK with tris(2-[2-methoxyethoxy])ethylamine and (ii) sufficiently mild deacetylation. The optical purity was determined by the corresponding (2R,5R)-trans-thiazolidin-4-one and (2S,5R)-cis-thiazolidin-4-one derivatives based on accurate high-performance liquid chromatography analysis with high-resolution efficiency. Compared with the reported method utilizing AcSCs (generated from AcSH and CsCO3), the present method has several advantages, that is, the use of odorless AcCOSK reagent, reasonable reaction velocity, isolation procedure, and accurate, reliable optical purity determination. The use of accessible AcSK has advantages because of easy-to-handle odorless and hygroscopic solid that can be used in a bench-top procedure. The Ti(OiPr)4 catalyst promoted smooth trans-cyclo-condensation to afford (2R,5R)-trans-thiazolidin-4-one formation of (R)-2-sulfanylcarboxylic esters with available N-(benzylidene)methylamine under neutral conditions without any racemization, whereas (2S,5R)-cis-thiazollidin-4-ones were obtained via cis-cyclo-condensation and no catalysts. Direct high-performance liquid chromatography analysis of methyl (R)-mandelate was also performed; however, the resolution efficiency was inferior to that of the thaizolidin-4-one derivatizations.
- Sasaki, Ryosuke,Tanabe, Yoo
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- New 4-aryl-1,3,2-oxathiazolylium-5-olates: Chemical synthesis and photochemical stability of a novel series of S-nitrosothiols
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S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide by-product. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the –SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound's overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if S-nitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts.
- Eilertsen, Monica,Allin, Steve M.,Pearson, Russell J.
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p. 1106 - 1110
(2018/02/28)
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- Combining a Clostridial Enzyme Exhibiting Unusual Active Site Plasticity with a Remarkably Facile Sigmatropic Rearrangement: Rapid, Stereocontrolled Entry into Densely Functionalized Fluorinated Phosphonates for Chemical Biology
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Described is an efficient stereocontrolled route into valuable, densely functionalized fluorinated phosphonates that takes advantage of (i) a Clostridial enzyme to set the absolute stereochemistry and (ii) a new [3,3]-sigmatropic rearrangement of the thiono-Claisen variety that is among the fastest sigmatropic rearrangements yet reported. Here, a pronounced rate enhancement is achieved by distal fluorination. This rearrangement is completely stereoretentive, parlaying the enzymatically established β-C-O stereochemistry in the substrate into the δ-C-S stereochemistry in the product. The final products are of interest to chemical biology, with a platform for Zn-aminopeptidase A inhibitors being constructed here. The enzyme, Clostridium acetobutylicum (CaADH), recently expressed by our group, reduces a spectrum of γ,δ-unsaturated β-keto-α,α-difluorophosphonate esters (93-99% ee; 10 examples). The resultant β-hydroxy-α,α-difluorophosphonates possess the L -stereochemistry, opposite to that previously observed for the CaADH-reduction of ω-keto carboxylate esters ( D ), indicating an unusual active site plasticity. For the thiono-Claisen rearrangement, a notable structure-reactivity relationship is observed. Measured rate constants vary by over 3 orders of magnitude, depending upon thiono-ester structure. Temperature-dependent kinetics reveal an unusually favorable entropy of activation (ΔS? = 14.5 ± 0.6 e.u.). Most notably, a 400-fold rate enhancement is seen upon fluorination of the distal arene ring, arising from favorable enthalpic (ΔΔH? = -2.3 kcal/mol) and entropic (ΔΔS? = 4 e.u., i.e. 1.2 kcal/mol at rt) contributions. The unusual active site plasticity seen here is expected to drive structural biology studies on CaADH, while the exceptionally facile sigmatropic rearrangement is expected to drive computational studies to elucidate its underlying entropic and enthalpic basis. (Chemical Presented).
- Panigrahi, Kaushik,Applegate, Gregory A.,Malik, Guillaume,Berkowitz, David B.
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supporting information
p. 3600 - 3609
(2015/03/30)
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- Highly enantioselective S-H bond insertion cooperatively catalyzed by dirhodium complexes and chiral spiro phosphoric acids
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The first highly enantioselective S-H bond insertion reaction was developed by cooperative catalysis of dirhodium(ii) carboxylates and chiral spiro phosphoric acids (SPAs) under mild and neutral reaction conditions with fast reaction rates, high yields (77-97% yields), and excellent enantioselectivities (up to 98% ee). The catalytic S-H bond insertion reaction provides a highly efficient method for the synthesis of chiral sulfur-containing compounds and advances the synthesis of a chiral sulfur-containing drug (S)-Eflucimibe. A systematic 31P NMR study revealed that no ligand exchange between dirhodium(ii) carboxylates and SPAs occurred in the reaction. The distinct behaviors of cooperative catalysts Rh2(TPA)4/(R)-1a and the prepared complex Rh2(R-1a)4 observed by in situ FT-IR spectroscopy excluded the feasibility of Rh2(R-SPA)4 being the real catalyst. DFT calculations showed that the activation barrier in the proton shift step became remarkably low as promoted by SPAs. Based on the experimental results and the calculations, the SPA was proposed as a chiral proton shuttle for the proton shift in reaction. Additionally, the single crystal structures of several SPAs were measured and used to rationalize the configurations of the S-H insertion products obtained in the reactions. The rigid and crowded environment around the SPAs ensures the high enantioselectivity in the S-H bond insertion reaction.
- Xu, Bin,Zhu, Shou-Fei,Zhang, Zhi-Chao,Yu, Zhi-Xiang,Ma, Yi,Zhou, Qi-Lin
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p. 1442 - 1448
(2014/03/21)
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- Synthesis and PGE2 production inhibition of s-triazine derivatives as a novel scaffold in RAW 264.7 macrophage cells
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We present the synthesis and biological evaluation of a collection of s-triazine derivatives as a novel scaffold of compounds with the capability to inhibit the PGE2 production in LPS-induced RAW 264.7 macrophage cells. A total of 12 derivatives were synthesized and assayed for PGE2 reduction at 10 μM concentration. Two compounds (7b and 7i) exhibiting >90% inhibition of PGE2 production were found to have IC50 values of 5.76 and 5.52 μM, respectively. They were counter screened for inhibition on COX-2 activity in a cell free assay. Specifically, compound 7i (R1 = 4-Bn-Ph, R2 = Cl, R3 = Ph, R5 = CO2Me) was highly active in cells while maintaining little COX-2 inhibition (~0% at 10 μM). Molecular docking study provides the possibility that compound 7i could inhibit PGE2 production by blocking the PGH2 binding site of mPGES-1 instead of COX-2 enzyme. Based on this result, our synthetic efforts will focus on intensive structure-activity relationship (SAR) study of s-triazine scaffold to discovery a potential PGE2 synthesis inhibitor.
- Kang, Seoung Mook,Lee, Jinsung,Jin, Jae Ho,Kim, Minju,Lee, Sunhoe,Lee, Hwi Ho,Shin, Ji-Sun,Lee, Kyung-Tae,Lee, Jae Yeol
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p. 5418 - 5422
(2015/01/08)
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- Reactions of α-mercaptocarboxylic acid hydrazides with triethyl orthoesters: Synthesis of 1,3,4-thiadiazin-5(6H)-ones and 1,3,4-oxadiazoles
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Reactions of α-mercapto-β-phenylpropionic and α-mercaptophenylacetic acid hydrazides with triethyl orthoesters were conducted under N2 in glacial acetic acid and resulted in the formation of two groups of products, derivatives of 1,3,4-thiadiazin-5(6H)-ones and 2-(1-mercaptomethyl)-1,3,4-oxadiazoles. When conducting the same transformations on α-mercaptophenylacetic acid hydrazide in the presence of air, two different products from the 1,3,4-oxadiazole family, the appropriate bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides and 2-benzyl-1,3,4- oxadiazoles, were formed with the liberation of free sulfur. The oxygenated bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides were reduced to the corresponding 2-(1-mercaptomethyl)-1,3,4-oxadiazoles with the use of zinc powder under mild conditions.
- Kudelko, Agnieszka
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p. 3616 - 3625
(2012/06/18)
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- Enantioselective Synthesis of α-Aryl Thioglycolic Acid Derivatives
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An enantioselective synthesis of α-aryl substituted thioglycolic acid from thioglycolic acid via a Pummerer reaction emploing (1R)-(+)-camphor as chiral auxiliary is described.
- Po, Shy-Yau,Liu, Hung-Hsin,Uang, Biing-Jiun
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p. 143 - 146
(2007/10/02)
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- Synthesis of (Racemization Prone) Optically Active Thiols by SN2 Substitution Using Cesium Thiocarboxylates
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The cesium salt of thioacetic acid is prepared by treatment with cesium carbonate.This salt has a solubility of about 0.7 M in DMF (even higher in Me2SO) at 50 deg C.The mesylates of (R)-2-octanol, the ethyl ester and N,N-dimethyl amide of (R)-mandelic acid, (S)-ethyl lactate, (S)-methyl 3-phenyllactate, and (S)-diethyl malate underwent clean SN2 substitution in DMF solution.Racemization occured only in the case of the mesylate of ethyl mandelate when allowed to react in DMF, but complete inversion was achieved on use of absolute ethanol as solvent.Hydrolysis or aminolysis is used to deacylate the thiols (except for aliphatic thioacetates, which are deprotected by treatment with lithium aluminum hydride) to afford 2-mercapto esters or amides.Owing to the sensitivity of mercapto-bearing carbon, some racemization (0-20percent depending on the system) occurs during deprotection.An alternate route to the same materials prepared by the cesium thiocarboxylate method involves treatment of the free alcohol with thioacetic acid in the presence of twofold amount of the preformed salt from diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.This method works well except for ethyl mandelate and N,N-dimethylmandelamide.Scale-up of the reaction is difficult, however, owing to the need for a chromatographic separation.Various NMR methods for determining the enantiomeric excesses of the various products are described.Particularly useful for determination of the high enantiomeric excesses is an internal calibration method based on the use of 13C satellite peaks in the presence of a chiral shift reagent.The enantiomeric excesses of the thiols were determined by conversion to the phosphonodithioates followed by measurement of the meso/d,l ratios obtained from 31P NMR spectra.Attempts to hydrolyze 2-acetylthio esters to the free 2-mercapto carboxylic acids lead to 10-40percent racemization depending on the compound.A partial solution to this problem was found by use of optically pure S bromides obtained from diazotation of (S)-alanine, (S)-phenylalanine, and (S)-valine in the presence of bromide.These bromides, on treatment with cesium thiobenzoate, underwent clean SN2 substitution, and debenzoylation could be brought about without significant racemization
- Strijtveen, Bert,Kellogg, Richard M.
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p. 3664 - 3671
(2007/10/02)
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