Methylthio Methyl Research Articles

Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon–Phosphorus Bond Construction Methodology

Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a 7 g scale. This reimagined synthesis of TAF, inspired by a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 10 (as acceptor) with methylthiomethyl (MTM) ether derivative 11 (as donor) in the presence of NIS/TfOH combination as a promoter to construct the strategic carbon–phosphorus bond. This PMPA-free synthesis of TAF not only removes the intrinsic drawbacks encountered by the PMPA-dependent commercial process but also is beneficial to the diversification of the synthetic portfolio of TAF. Furthermore, this type of P-alkylation reaction with defined stereochemistry could be deployed for the late-stage modification of druglike molecules and natural products to access valuable phosphonate derivatives.

Chemoselective derivatisation and ultrahigh resolution mass spectrometry for the determination of hydroxyl functional groups within complex bio-oils.

Bio-oils are a renewable alternative resource for the production of fine chemicals and fuels. Bio-oils are characterised by a high content of oxygenated compounds with a diverse array of different chemical functionalities. Here, we performed a chemical reaction to transform the hydroxyl group of the various components in a bio-oil prior to characterisation with ultrahigh resolution mass spectrometry (UHRMS). The derivatisations were first evaluated using twenty lignin-representative standards with different structural features. Our results indicate a highly chemoselective transformation of the hydroxyl group despite the presence of other functional groups. Mono- and di-acetate products were observed in acetone-acetic anhydride (acetone-Ac2O) mixtures for non-sterically hindered phenols, catechols and benzene diols. Dimethyl sulfoxide-Ac2O (DMSO-Ac2O) reactions favoured the oxidation of primary and secondary alcohols and the formation of methylthiomethyl (MTM) products of phenols. The derivatisations were then performed in a complex bio-oil sample to gain insights into the hydroxyl group profile of the bio-oil. Our results indicate that the bio-oil before derivatisation is composed of 4500 elemental compositions containing 1-12 oxygen atoms. After the derivatisation in DMSO-Ac2O mixtures, the total number of compositions increased approximately five-fold. The reaction was indicative of the variety of hydroxyl group profiles within the sample in particular the presence of phenols that were ortho and para substituted, non-hindered phenols (about 34%), aromatic alcohols (including benzylic and other non-phenolic alcohols) (25%), and aliphatic alcohols (6.3%) could be inferred. Phenolic compositions are known as coke precursors in catalytic pyrolysis and upgrading processes. Thus, the combination of chemoselective derivatisations in conjunction with UHRMS can be a valuable resource to outline the hydroxyl group profile in elemental chemical compositions in complex mixtures.

Autocatalytic methylthiomethylation of carboxylic acid/phenol involving the formation of DMSO enolate: convenient synthesis of methylthiomethyl ester/ether.

This work reported a simple and practical protocol for the preparation of methylthiomethyl (MTM) esters/ethers directly from carboxylic acid/phenol and dimethylsulfoxide (DMSO) as solvent and methylthiomethyl source. With different types of carboxylic acids/phenols the reactions underwent smooth transformation to afford the corresponding MTM esters/ethers in moderate to excellent yields. This method features catalyst-free, easy to operate, broad substrate scope, good functional group tolerance and involvement of the formation of DMSO enolate.

Volatile compounds in two varieties of teff (Eragrostis tef (Zuccagni) Trotter) cultivated in Ethiopia by gas chromatography-mass spectrometry

ABSTRACT This study was aimed to investigate volatile compounds of white and brown teff grain samples using the hydro-distillation and its extract in dichloromethane and n-hexane by gas chromatography-mass spectrometry. The optimized time for the hydro-distillation of the white and brown teff grain samples was nine hours. The dominant volatile compounds identified in the white and brown teff grain samples of the dichloromethane extract corresponding to peak area proportion were furfural (29.9%, 38.1%) and 5-methyl-2-furancarboxaldehyde (15.1%, 23.8%), respectively. The relative amount of dominant volatile compounds determined in the white teff grain sample of the n-hexane extract were 10.2% and 7.27% for the 5-methyl-2-furancarboxaldehyde and 2-[(methylthio)methyl]furan, respectively, and 18.4%, 16.0%, 12.5% and 9.73%, for the furfural, 5-methyl-2-furancarboxaldehyde, 2-[(methylthio)methyl]furan and benzeneacetaldehyde, respectively, for the brown teff grain sample. This study revealed that dichloromethane was efficient to extract more volatile compounds in the white teff grain sample than in the brown teff grain sample, whereas n-hexane was efficient to extract almost equal number of volatiles in both white and brown teff samples. Besides, aldehydes were the major constituents of the white and brown teff grain samples in both dichloromethane and n-hexane extracts.

Capture and Reactivity of an Elusive Carbon-Sulfur Centered Biradical.

The initial oxidation product of dimethyl sulfide in the marine boundary layer, the methyl thiomethyl radical, has remained elusive. A structurally analogous biradical with one radical center in the α-position to a sulfur atom could now be obtained by UV irradiation of p-nitrobenzaldehyde dithiane isolated in solid dinitrogen (N2) or Ar at cryogenic temperatures. A spin-forbidden reaction with triplet dioxygen (3O2) does not occur. The dithiane of o-nitrobenzaldehyde rather undergoes a series of rearrangements under the same conditions, resulting in overall photodeprotection.

Unraveling the role of additional OH-radicals in the H–Abstraction from Dimethyl sulfide using quantum chemical computations

Dimethyl sulfide (DMS) is the main organosulfur compound in the atmosphere. Oxidation by OH radicals to form the methyl thiomethyl species (MTMr) has been studied under normal atmospheric conditions and in reaction chambers at different O2 partial pressure, including complete absence of oxygen. Scarce attention has been devoted however to the possibility of further reaction of OH with MTMr. We present here a computational study using DFT, CCSD(T) and composite methods, on the properties of two stable intermediates never fully investigated before, methanesulfenyl methanol (MSMOH) and S-methyl-methanesulfenic acid (SMMSA), arising from addition of a second OH radical to MTMr.

Phytochemical constituents and antimicrobial activity of Allium Eriophyllum Var. Eriophyllum from Iran

The aerial parts of Allium eriophyllum Var. eriophyllum (Syn. A. longisepalum Bertol.) were collected at full flowering stage.The essential oil was isolated by hydro distillation and analyzed by a combination of capillary GC and GC-MS. The main components were carvacrol (71.54%), Methyl (methylthio) methyl disulfide (9.51%), (E)-caryophyllene (8.37%) and β-bisabolene (4.38%). The in vitro antimicrobial activity of the essential oil of A. eriophyllum were studied against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Candida albicans. The results of the bioassays showed that the oil exhibited high antimicrobial activity against all the tested pathogens compared standard antibiotics.

3′-O-Substituted 5-(perylen-3-ylethynyl)-2′-deoxyuridines as tick-borne encephalitis virus reproduction inhibitors

A series of analogues of potent antiviral perylene nucleoside dUY11 with methylthiomethyl (MTM), azidomethyl (AZM) and HO-C1–4-alkyl-1,2,3-triazol-1,4-diyl groups at 3′-O-position as well as the two products of copper-free alkyne-azide cycloaddition of the AZM derivative were prepared and evaluated against tick-borne encephalitis virus (TBEV). Four compounds (4, 6, 8a, 8b) showed EC50 ≤ 10 nM, thus appearing the most potent TBEV inhibitors to date. Moreover, these nucleosides have higher lipophilicity (clogP) and increased solubility in aq. DMSO vs. parent compound dUY11.

Iridium/Bipyridine-Catalyzed ortho-Selective C-H Borylation of Phenol and Aniline Derivatives.

An iridium-catalyzed ortho-selective C-H borylation of phenol and aniline derivatives has been successfully developed. Iridium/bipyridine-catalyzed C-H borylation generally occurred at the meta- and para-positions of aromatic substrates. Introduction of an electron-withdrawing substituent on the bipyridine-type ligand and a methylthiomethyl group on the hydroxy and amino groups of the phenol and aniline substrates, however, dramatically altered the regioselectivity, affording exclusively ortho-borylated products. The reaction proceeded in good to excellent yields with good functional group tolerance. C-H borylation was applied to the synthesis of a calcium receptor modulator.

Oxidative cyclisation and methylene insertion in 1,3-indandione derivatives .The mechanistic studies

Dimethyl sulphoxide activated by acetic-anhydride introduces methylthiomethyl group into phenols,oxidises certain medicinally useful secondary alcohols to their corresponding ketones and brings about oxidative rearrangements in different substrates.It converts 4-hydroxy coumarins and dicoumarols,under varying conditions,to a variety of products of both pharmaceutical and mechanistic interest.
 When1,3-indandione (1) was interacted with this versatile reagent at water bath temperature,it afforded an ylide (2) and an oxidative cyclisation product (3).However,its interaction with Ar –CH = (CN)R,leads to the formation of a mechanistically interesting compound,indeno[1,2-b]-4H pyran(4). 
 DMSO alone has been used as a reagent and yields a number of products of mechanistic interest with different substrates.When 1,3-indandione (1) was refluxed with DMSO alone at elevated temperature,it results the formation of poly(methylene-bis) 1,3-indandione(5) involving methylene group insertion between different 1,3-indandione moieties.Methylene insertion has also been observed when 1,3-indandione (1) was condensed with formaldehyde in presence of alkali carbonates or primary amines to yield (6)and(7) respectively.

Fe 2 O 3 -catalyzed Pummerer rearrangement of acyl chlorides and sulfoxides: Facile synthesis of alkylthiomethyl ester

A simple, effective approach for the Pummerer rearrangement of acyl chlorides with sulfoxides by using a low-cost and more abundant Fe catalyst has been described. The alkylthiomethyl ester products were prepared in good to excellent yields for a range of different substrates including asymmetrical sulfoxides and acyl chlorides with a variety of functional groups under mild reaction conditions. The reaction features short reaction time, simple manipulation, cheap reagents and a broad substrate scope. Single crystal X-ray analysis of a representative methylthiomethyl (MTM) group containing product was also reported.

Dimethyl Sulphoxide a Useful Reagent for Organic Synthesis

Dimethyl sulphoxide as a reagent brings about N-methylthiomethylation and N,N/-methyl -thiomethylation in substituted barbituric acids. It converts 4-acetoxy coumarins to corresponding ylides and brings about methylene insertion in 1,6-naphtharidenes at reflux temperature.DMSO activated by trifluoro-aceticanhydride brings about formation of mono, bis and tris-sulphonic substituted derivatives when interacted with cyclo pentadiene and trimethylsilyl cyclopentadiene.This reagent converts 3-Nitro-4-hydroxy coumarins to salicylic acid in dichloromethane at low temperature.DMSO-acetic anhydride reagent converts enols to sulphur ylides, introduces methylthiomethyl group into phenols and oxidizes secondary alcohols to corresponding ketones. It brings about oxidative rearrangement in polyporic acid and converts 4-hydroxy coumarins and its 3-substituted derivatives into a wide range of products under different conditions.DMSO-SO3 pyridine complex in presence of triethyl amine oxidizes cis-diols to corresponding quinones.DMSO-activated by N-bromosuccinimide brings about methylation of alcohols and converts diols to their corresponding methylene-acetals.

α-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation.

Readily available α-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh-catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched α-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the α-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine.

Efficient Synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric Acid

3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric acid (9) was obtained from L-methionine in six steps with a total yield of 32%. The α-amino acid segment of L-methionine was transferred to chiral aziridine by amino protection, reduction, hydroxyl derivation, and cyclization. After ring opening of 2,4,5-trifluoro-phenyl magnesium bromide, the methylthiomethyl group was then hydrolyzed to β-amino alcohol and oxidized to the target β-amino acid.

A New Deprotection Procedure of MTM Ether

A new deprotection procedure of methylthiomethyl (MTM) ether, a protective group for the hydroxy group, was developed. MTM was oxidized with MCPBA or Oxone, and the resulting sulfoxide was treated under conditions of the Pummerer rearrangement, to give acetoxy sulfide and/or acetoxy acetal. Alkaline hydrolysis of the products provided the unprotected alcohols in good yields. Details of the reactions using several different substrates are described.

ChemInform Abstract: Total Synthesis of Chiriquitoxin, an Analogue of Tetrodotoxin Isolated from the Skin of a Dart Frog.

The first total synthesis of chiriquitoxin, the most structurally complex analogue of tetrodotoxin isolated from a Costa Rican dart frog, has been accomplished from a newly designed intermediate for a variety of tetrodotoxin derivatives. The synthesis includes the third total synthesis of tetrodotoxin in this laboratory, and its intermediate was transformed into chiriquitoxin by a stereocontrolled aldol reaction with a D-camphor-derived lactone for installation of the unique side chain, and a new deprotection of methylthiomethyl (MTM) ether by using a Pummerer rearrangement.

Total Synthesis of Chiriquitoxin, an Analogue of Tetrodotoxin Isolated from the Skin of a Dart Frog

The first total synthesis of chiriquitoxin, the most structurally complex analogue of tetrodotoxin isolated from a Costa Rican dart frog, has been accomplished from a newly designed intermediate for a variety of tetrodotoxin derivatives. The synthesis includes the third total synthesis of tetrodotoxin in this laboratory, and its intermediate was transformed into chiriquitoxin by a stereocontrolled aldol reaction with a D-camphor-derived lactone for installation of the unique side chain, and a new deprotection of methylthiomethyl (MTM) ether by using a Pummerer rearrangement.

Sulphur containing volatiles of Barbarea vulgaris W.T. Aiton from Kazakhstan

The most of samples were rich in sulfur containing compounds. Methyl (methylthio) methyl disulfide (14.5%), dimethyl trisulfide (11.2%), dimethyl sulfide (3.4%) were detected in the herb of B. vulgaris from Akmolinskaya province. Chemical composition of the flower and leaf volatiles was found to show some differences. Isopropyl isothiocyanate (36.7%) was the main constituent in flower, while phytol (25.7%), hexadecanoic acid (9.3%), hexahydrofarnesyl acetone (7.4%), dodecanoic acid (5.5%) and isopropyl isothiocyanate (5.3%) were detected in the leaf. It should be noted that another sample of B. vulgaris from Akmolinskaya province was found to be very different in volatile composition. Namely, borneol (20.3%), camphene (13.5%), bornyl acetate (8.0%) and germacrene D (5.4%) were the major constituents.

ChemInform Abstract: Synthesis of Manwuweizic Acid, an Anticancer Triterpenoid.

Abstract Manwuweizic acid ( 1 ), an anticancer triterpenoid isolated from Scisandra propinqua , was synthesized from lanosterol ( 2 ) by stereoselective introduction of the (Z) α,β-unsaturated carboxylic terminal of the side chain and by abnormal Beckmann rearrangement of ring A. A new reagent of DMSO-DCC-TFA for protection of a carboxyl group as a methylthiomethyl (MTM) ester is also described.

ChemInform Abstract: Mechanism of the Cleavage Reaction of (Methylthio)methyl Ether with Triphenylmethyl Cation.

ChemInform Abstract: Mechanism of the Cleavage Reaction of (Methylthio)methyl Ether with Triphenylmethyl Cation.