Oxymercuration Research Articles

Protecting-Group-Directed Regio- and Stereoselective Oxymercuration–Demercuration: Synthesis of Piperidine Alkaloids Containing 1,2- and 1,3-Amino Alcohol Units

An efficient synthesis of naturally occurring 1,2- and 1,3-amino alcohol unit containing 2-substituted piperidine alkaloids and their analogues has been developed from l-pipecolinic acid. The protocol describes the regio- and stereoselective oxymercuration–demercuration of 2-alkenyl piperidines based on protecting groups to give piperidine alkaloids as a key step.

Regioselective reactions on a 1,3-disubstituted dihydroxymethyl or dicarboxyl hexahydropentalene skeleton

Iodo-, bromo-, chloro-etherification and oxymercuration–demercuration of hexahydropentalene 1,3-dimethanol were regioselectively realized with formation of pentalenofurane compounds in good yields. The corresponding hexahydropentaleno diacid and its monoester react regioselectively with MCPBA to give two γ-lactones. Haloetherification of the diacid also regioselectively gives halogenolactones in good yield. A new method for synthesis of a bislactone was developed in better yield (79%) than that presented in the literature (58%).

Convenient synthesis of Bioactive Pyranonaphthoquinones (±)9-Demethoxyeleutherin and (±)9-Demethoxyisoeleutherin

A convenient synthesis of (±)9-demethoxyeleutherin and (±)9-demethoxyisoeleutherin, the analogues of naturally occurring pyranonaphthoquinone antibiotics eleutherin and isoeleutherin, is described. The synthesis was achieved from 4-methoxy-1-napthol in four simple steps including Claisen rearrangement and oxymercuration–demercuration reactions.

Mercury(II) Acetate

Mercury(II) acetate is a commercially available reagent which can be prepared by the reaction of elemental mercury with peroxyacetic acid.[ 1 ] The standard use of this reagent is the textbook oxymercuration–demercuration reaction, an electrophilic addition in which mercury(II) acetate attacks a double bond forming a mercury–olefin complex, followed by nucleophilic ring opening with water and subsequent reductive demercuration with sodium borohydride.[ 2 ] The reaction proceeds in accordance with Markovnikov‘s rule, since the nucleophilic reagent attacks the higher substituted carbon atom to form the more stable carbocation intermediate. This reaction is also an anti-addition: the nucleophilic reagent attacks the double bond–mercury complex from the side opposite to the molecule.

Development and Applications of Fluorogenic Probes for Mercury(II) Based on Vinyl Ether Oxymercuration

Mercury is a major threat to the environment and to human health. It is highly desirable to develop a user-friendly kit for on-site mercury detection. Such a method must be able to detect mercury below the threshold levels for drinking water, 1-2 ppb. We developed a fluorescence method based on the oxymercuration of vinyl ethers to detect mercury in dental and environmental samples. Chloride ions interfered with the oxymercuration reaction, but the addition of AgNO(3) solved this problem. Fine electronic and structural tuning led to the development of a more responsive probe that was less sensitive to chloride ion interference. This second-generation probe could detect 1 ppb mercury ions in water.

Novel Glycosaminoglycan Glycotechnology: Method for Hybrid Synthesis of Glycosaminoglycan Chains Utilizing Chemo-enzymatic Procedures

A novel method for the synthesis of glycosaminoglycan chains is described. The 4,5-unsaturated hexuronic acid located at the nonreducing terminal, which derived from eliminase digestion of glycosaminoglycan, is chemically converted to glucuronic acid by employing the oxymercuration-demercuration reaction. Then, utilizing these oligosaccharides as acceptors for the transglycosylation reaction of bovine testicular hyaluronidase, glycosaminoglycan oligosaccharides were successfully constructed. It is thought that the present method will contribute to the development of glycosaminoglycan glycobiology and technology.

SYNTHESIS of 3.4-METHYLENEDIOXYPHENYL-2-PROPANONE from SAFROLE

The Synthesis of 3.4-methylenedioxyphenyl-2-propanone from safrole has been achieved through conversion of allyl group to secondary alcohol, followed by oxidation with pyridinium chlorochromate(PCC). The secondary alcohol has been achieved by two methods. The first method was formic acid adition reaction, followed by hydrolysis in aqueous ethanolic solution of potassium hydroxide. The second method was the oxymercuration-demercuration reaction of safrole. The addition reaction of safrole with formic acid yield safrylformate (34,70%). The hydrolysis of safrylformate with 3M KOH produced safrylalchohol (73,29%). The oxymercuration-demercuration reaction of safrole with Hg(OAc)2-NaBH4 gave (74,37%) of safrylalcohol. The oxidation of safryalcohol with PCC gave 3.4-methylenedioxyphenyl-2-propanone as a main target in 71,83%. The structure elucidations of these products were analyzed by FTIR , 1H-NMR, 13C-NMR and MS. Keyword: 3.4-methylenedioxyphenyl-2-propanone; safrole

Synthesis and application of organomercury haptens for enzyme-linked immunoassay of inorganic and organic mercury

Two organomercury haptens were synthesized via the classical oxymercuration reaction. An intramolecular oxymercuration reaction was the strategy employed to prepare a structurally simple, but chemically robust, organomercury hapten that was conjugated to chicken immunoglobulin G (IgG). The resulting immunogen afforded mouse anti-mercury antibodies that were evaluated in an enzyme-linked immunosorbent assay (ELISA). Antibodies demonstrating high titers were obtained, and various immunoassay parameters were investigated. The sensitivity and selectivity of the resulting antibodies were evaluated by exploring different cross-coupling chemistries and solid-phase synthetic variations. A second hapten was prepared with the intermolecular oxymercuration reaction, and the resulting compound, once coupled to carrier protein, afforded a solid-phase conjugate that revealed the versatility of the mouse anti-mercury antibody. The anti-mercury antibody developed in this study was capable of detecting both mercury(II) salts and organomercury compounds.

New enantioselective method for hydration of alkenes using cyclodextrins as phase transfer catalyst

A new enantioselective/inverse phase transfer catalysis (IPTC) reaction for the Markovnikov hydration of double bounds by an oxymercuration–demercuration reaction with cyclodextrins as catalysts was disclosed. Moderate ee (up to 32%) and yields (14–60%) were obtained for allylic amines and protected allylic alcohols as starting materials.

Highly Efficient and Diastereoselective Synthesis of (+)‐Lineatin.

[reaction: see text] A linear sequence was used to synthesize (+)-lineatin in 14 steps and 14% overall yield from a homochiral 2(5H)-furanone. Key steps of this synthetic approach feature the diastereoselective construction of a cyclobutene through a photochemical [2 + 2] cycloaddition and a regiocontrolled oxymercuration reaction.

Stable free radical polymerization––acrylate alkoxyamine synthesis

An efficient synthesis of the alkoxyamine containing a benzoyl peroxide fragment, one tert-butyl acrylate monomer unit and TEMPO via an oxymercuration reaction followed by an oxidative demercuration reaction is reported. The formation of significant amounts of an undesired reduced product with the latter reaction was overcome by using a milder reducing agent (NaBH 3CN) than those (NaBH 4, LiBH 4) reported to work well in other systems.

Highly efficient and diastereoselective synthesis of (+)-lineatin.

[reaction: see text] A linear sequence was used to synthesize (+)-lineatin in 14 steps and 14% overall yield from a homochiral 2(5H)-furanone. Key steps of this synthetic approach feature the diastereoselective construction of a cyclobutene through a photochemical [2 + 2] cycloaddition and a regiocontrolled oxymercuration reaction.

Synthesis of trichiliasterones A and B — 16-Ketosteroids isolated from Trichilia hirta and Trichilia americana

The syntheses of trichiliasterone A (3β-hydroxypregnan-2,16-dione) and trichiliasterone B (2-hydroxyandrost-1,4-diene-3,16-dione) have been carried out starting from isoandrosterone and testosterone acetate, respectively. In each synthesis the functionality in the D ring was installed prior to working on ring A. In the case of trichiliasterone A, the D ring chemistry involved a Wittig reaction to generate the 17-methylene group, followed by SeO2 oxidation to give an α,β-unsaturated ketone. Reaction with lithium dimethyl cuprate gave the required 17-ethyl-16-keto functionality. A 2,3-epoxy enol acetate served as the key intermediate for the generation of the 2-keto-3-hydroxy functions in ring A. The transposition of the keto function from C-16 to C-17 in the synthesis of trichiliasterone B was accomplished via oxymercuration–demercuration of the Δ16—17 double bond followed by oxidation. The hydroxyl group at C-2 and the additional ring A unsaturation were introduced by lead tetra-acetate treatment of the 3-keto-4-enone function and subsequent air oxidation.Key words: 16-ketosteroids, plant steroids, Trichilia hirta, trichiliasterones.

TLC-LSIMS of neoglycolipids of glycosaminoglycan disaccharides and of oxymercuration cleavage products of heparin fragments that contain unsaturated uronic acid

Heparin and chondroitin sulfate disaccharides have been investigated by high-performance (HP) TLC and liquid secondary-ion mass spectrometry (LSIMS) after conversion to neoglycolipid derivatives by reductive-amination with an aminolipid (dihexadecyl phosphatidylethanolamine, DHPE). Mobility on HPTLC was largely determined by the number of sulfate groups present, but was also influenced by the position of sulfate, monosaccharide composition and linkage. The mass spectra acquired directly from the TLC plate provided quasimolecular and fragment ions from which composition, including sulfate content, and sequence information was obtained at high sensitivity. Lipid DHPE conjugation and TLC-LSIMS were performed to analyse products of the oxymercuration reaction used to cleave unsaturated uronic acid (ΔUA) residues from glycosaminoglycan (GAG) fragments produced by enzymatic degradation with glycan lyases. Previously the identification of the product from ΔUA and the integrity of the remaining structures from oligosaccharides larger than disaccharide have not been made. Multiple and characteristic products of the cleaved ΔUA were detected and these can be used for identification of terminal ΔUA and its sulfate content. It was established with several disaccharides and a tetrasaccharide that glycosidic linkages and O- and N-sulfate groups are preserved in the remaining structures after removal ΔUA. These results indicate that the oxymercuration reaction will be applicable to generating series of GAG fragments containing unmodified sequences for biological activity studies.

Conformationally restricted hybrids of CP-55,940 and HHC: Stereoselective synthesis and activity

A stereoselective total synthesis of each of the two diastereomeric C6-hydroxyethyl analogs of (−)-9-nor-9β-hydroxyhexahydrocannabinol has been reported. Control of the stereochemistry at C6 during the key step is accomplished through an intramolecular oxymercuration reaction. The prediction that the analogs would exhibit different degrees of binding to the cannabinoid receptor was borne out. This observation sheds light on the stereochemical requirements of the receptor.

Synthetic modifications of ascomycin - I. A chemoselective removal of the cyclohexyl residue of ascomycin

An efficient semisynthetic preparation of des-28-(cyclohexyl)methylene-28-oxo-ascomycin derivatives starting from 24,33- O-bis( tert-butyldimethylsilyl)-ascomycin ( 1) is described. The strategy for preparing 28-oxo-ascomycin derivatives involves the reduction of C-22 carbonyl group, followed by 5-endo-cyclization of the resulting C-22 alcohol with the C-19/C-20 double bond using an oxymercuration reaction; ozonolysis of the C-28/C-29 double bond and regeneration of the C-19/C-20 double bond. Further, the 20-mercury-substituted ascomycin derivatives could be reduced to the corresponding metal free cyclic ethers using n-Bu 3SnH.

Analysis of Albumin Deposits on Hydroxylated Siloxane Films

The authors have developed methods to enhance albumin binding to modified silicone rubber (SR) films. An intermediate bifunctional coupling agent, polyvinylmethyl siloxane-comethyl-1-ethanol siloxane (PVMS-CO-MES), is prepared from a cyclic tetramer, vinyl-methyl siloxane, by an oxymercuration-demercuration reaction, and cross-linked to silicone rubber under mild peroxide catalytic conditions. Free mercury on the surface was obtained under many reaction conditions and is shown to materially enhance 125I-la-beled albumin binding. The mechanism most likely occurs via disulfide bond breakage, protein denaturation, and aggregation. The possible role of iodine-mercury bonds, an artefactual source, is ruled out with the aid of total internal reflectance-fluorescence measurements of the albumin adsorption rate constant. Although in situ albumin aggregation via disulfide bond breakage is a potentially attractive method for biocompatible protein gel formation, the toxic-ity of mercury makes the current method unfit for clinical practice.

The synthesis of norbornanes with functionalized carbon substituents at a bridgehead. 1-(3-Oxonorborn-1-yl)ethanone and 1-(3-oxonorborn-1-yl)-2-propanone

Treatment of 2-norobornene-1-carboxylic acid (7) with one equivalent of methyllithium in ether followed by a second molar equivalent after dilution with tetrahydrofuran gave 1-(norborn-2-en-lyl)ethanone (10) and only a trace of the tertiary alcohol 11. Reaction of 7 with formic acid followed by hydrolysis gave a 4:3 mixture of exo-3- and exo-2-hydroxynorbornane-1-carboxylic acid (16 and 17), whereas oxymercuration–demercuration gave only the exo-3-hydroxy isomer 16. Oxidation of 16 and 17 gave 3- and 2-oxonorbornane-1-carboxylic acid (27 and 29), respectively. Oxymercuration–demercuration of 10 gave exclusively 1-(exo-3-hydroxynorborn-1-yl)ethanone (30), which was also prepared by treatment of 16 with methyllithium in analogous fashion to that used for the conversion of 7 to 10. Oxidation of 30 gave 1-(3-oxonorborn-1-yl)ethanone (1). Dehydrobromination of exo-2-bromonorbornane-1-acetic acid and dehydration of 2-hydroxy-norbornane-2-acetic acid derivatives gave 1-(norborn-2-ylidene) acetic acid derivatives to the exclusion of norborn-2-ene-1 -acetic acid derivatives. Treatment of exo-5-acetyloxy-2-norobornanone (52) with ethyl bromoacetate and zinc gave ethyl exo-5-acetyloxy-2-hydroxynorbornane-(exo- and endo-2-acetate (53 and 54). Reaction of 53 with hydrogen bromide gave initially ethyl endo-3-acetyloxy-exo-6-bromonorbornane-1-acetate (59), which was subsequently converted to a mixture of 59 and its exo-3-acetyloxy epimer 61. Catalytic hydrogenation of this mixture gave a mixture of ethyl endo- and exo-3-acetyloxynorbornane-1 -acetate (62 and 63). Basic hydrolysis of this gave a mixture of the corresponding hydroxy acids, 70 and 71; the former was slowly converted to the latter at pH 5. Oxidation of the mixture of 70 and 71 gave 3-oxonorbornane-1-acetic acid (72). Treatment of the mixture with methyllithium as for 16 gave a mixture of 1-(endo- and exo-3-hydroxynorborn-1-yl)-2-propanone (73 and 74), which was oxidized to 1-(3-oxo-norborn-1-yl)-2-propanone (2). Reaction of exo-2-hydroxynorbornane-1-acetic acid lactone (75) with methyllithium in ether gave (1-(exo-2-hydroxynorborn-1-yl)-2-propanone (76), which on oxidation gave the 2-oxo isomer 78 of 2.

Intramolecular Addition of Hydroxy Group to a Diene System: Oxymercuration - Demercuration and Titanium Tetrachloride Catalyzed Synthesis of Manoyl Oxides

The stereochemistry of the formation of tetrahydropyran ring of ent-manoyl oxides from ent-8α-hydroxylabda-13(16), 4-dienes has been studied in one and two-step oxymercuration-demercuration (OM-DM) processes as well as by a new titanium tetrachloride catalyzed cyclization which allows the preparation of this tetrahydropyran moiety of C-13 epimer manoyl oxides in high yield

Oxidation products of 5-ethenyl-4-methyl-3-pyridinecarbonitrile and 2- and 4-methylpyridines

The anion of 5-ethenyl-4-methyl-3-pyridinecarbonitrile 1 undergoes oxidative coupling on treatment with dibenzoyl peroxide affording 1,2-bis-(5′-ethenyl-3′-cyano-4′-pyridyl)-ethane, 2. It is also shown that the anions of 2- and 4-methylpyridine undergo oxidative coupling. In the latter case, however, the coupling reaction is accompanied by addition to the carbonyl group of dibenzoyl peroxide. The addition products have been identified as phenacyl pyridines and dipicolyl phenyl carbinols. The ethenyl side chain of 1 has been hydrated by way of the oxymercuration–reduction process and the secondary alcohol oxidized to a ketone. Both the alcohol and ketone in protected form are potentially useful intermediates in alkaloid synthesis. Keywords: oxidative coupling, 2- and 4-methylpyridines, dibenzoyl peroxide, oxymercuration–reduction.