Tamao Oxidation Research Articles

Enantioselective total synthesis of (‒)-lucidumone enabled by tandem prins cyclization/cycloetherification sequence

The Ganoderma meroterpenoids are a growing class of natural products with architectural complexity, and exhibit a wide range of biological activities. Here, we report an enantioselective total synthesis of the Ganoderma meroterpenoid (‒)-lucidumone. The synthetic route features several key transformations, including a) a Cu-catalyzed enantioselective silicon-tethered intramolecular Diels-Alder cycloaddition to construct the highly functionalized bicyclo[2.2.2]octane moiety; b) Brønsted acid promoted tandem O-deprotection/Prins cyclization/Cycloetherification sequence followed by oxidation to install concurrently the tetrahydrofuran and the fused indanone framework; c) Fleming-Tamao oxidation to generate the secondary hydroxyl; d) an iron-catalyzed Wacker-type oxidation of hindered vinyl group to methyl ketone.

Cobalt Catalyzed Enantio- and Regioselective Hydrosilation

Enantioselective and regioselective cobalt-catalyzed hydrosilation has been scarcely reported. Although this transformation catalyzed with other transition metals such as iron or copper is well known, cobalt being an abundant and cheap transition metal makes having its catalyst as an option to expand the "toolbox" highly desirable. In addition, enantioselective and regioselective silyl products can serve as important building blocks for creating chiral synthetic products. For example, chiral silanes can be converted into chiral alcohols via Fleming–Tamao oxidation. To conduct this experiment, 2-vinylnaphlene was chosen as the model substrate and various conditions for the hydrosilation of diphenylsilane were investigated. A variety of cobalt catalysts was screened and uniquely, cobalt chloride triphenylphosphine was used offering a cobalt(I) complex. Then the optimal solvent for this reaction was found to be dioxane. With this information, we screened various chiral ligands. The conversion and the regioselectivity of the reaction were determined with proton 1H-NMR. The enantioselectivity was determined through an HPLC assay.In the study, we were able to perform hydrosilation targeting the Markovnikov product. enantioselectivity was achieved with the optimal ligands, albeit with mild regioselectivity. The implications of this finding show promise for using cobalt for an enantioselective and regioselective hydrosilation reaction. Further steps could be taken toward modifying the ligand to enhance conversion, regioselectivity, and enantioselectivity. In addition, various other substrates and silanes could be explored to improve the scope of this study.

Ligand relay catalysis for cobalt-catalyzed sequential hydrosilylation and hydrohydrazidation of terminal alkynes

Sequential double hydrofunctionalizationalization of alkynes is a powerful method to construct useful vicinal compounds. Herein, we report a cobalt-catalyzed sequential hydrosilylation/hydrohydrazidation of alkynes to afford 1,2-N,Si compounds via ligand relay catalysis. A phenomenon of ligand relay is found that the tridentate anionic N-ligand (OPAQ) could capture the cobalt ion from bidentate neutral P-ligand (Xantphos) cobalt complex. This protocol uses three abundant chemical feedstocks, alkynes, silanes, and diazo compounds, and also features operationally simple, mild conditions, low catalyst loading (1 mol%), and excellent functional group tolerance. The 1,2-N,Si compounds can be easily further derivatized to afford various substituted silane derivatives via Si-H functionalization, alcohols via Fleming-Tamao oxidation, free amines and amides via N-N bond cleavage and protection. The asymmetric reaction could also be carried out to afford chiral products with up to 86% ee. The ligand relay has been supported by control experiments and absorption spectra.

Synthesis of Silicon-Stereogenic Silanols Involving Iridium-Catalyzed Enantioselective C–H Silylation Leading to a New Ligand Scaffold

Despite a growing focus on the construction of highly enantioenriched silicon-stereogenic organosilicon compounds, the enantioselective synthesis of silicon-stereogenic silanols through asymmetric catalysis remains a considerable challenge. Herein, we realized enantioselective construction of silicon-stereogenic diarylsilanols via an Ir-catalyzed C–H silylation of diarylsilanols along with stereospecific substitution or Tamao–Fleming oxidation. This strategy gives rise to a class of chiral diol catalyst cores (PSiOLs). Transformation of PSiOLs led to the ligand possessing both Si and P-stereocenters, which is capable of inducing excellent enantioselectivity in the rhodium(I)-catalyzed conjugate 1,4-addition of aryl boronic acids to cyclohexenone.

At Long Last: The Me3 Si Group as a Masked Alcohol.

For a long time, the Me3 Si group has been ostracized from the family of aryl- and heteroatom-substituted congeners for the difficulties associated with its further chemoselective manipulation into another synthetically useful functional group. A hypervalent iodine reagent has now been shown to do exactly that by electrophilic demethylation. Coupled with the Tamao-Fleming oxidation, the Me3 Si group becomes a placeholder for a hydroxy group.

Chemoselective Cleavage of Si-C(sp3) Bonds in Unactivated Tetraalkylsilanes Using Iodine Tris(trifluoroacetate).

Organosilanes are synthetically useful reagents and precursors in organic chemistry. However, the typical inertness of unactivated Si-C(sp3) bonds under conventional reaction conditions has hampered the application of simple tetraalkylsilanes in organic synthesis. Herein we report the chemoselective cleavage of Si-C(sp3) bonds of unactivated tetraalkylsilanes using iodine tris(trifluoroacetate). The reaction proceeds smoothly under mild conditions (-50 °C to room temperature) and tolerates various polar functional groups, thus enabling subsequent Tamao-Fleming oxidation to provide the corresponding alcohols. NMR experiments and density functional theory calculations on the reaction indicate that the transfer of alkyl groups from Si to the I(III) center and the formation of the Si-O bond proceed concertedly to afford an alkyl-λ3-iodane and silyl trifluoroacetate. The developed method enables the use of unactivated tetraalkylsilanes as highly stable synthetic precursors.

Enantioselective Synthesis of 4-Silyl-1,2,3,4-tetrahydroquinolines via Copper(I) Hydride Catalyzed Asymmetric Hydrosilylation of 1,2-Dihydroquinolines

C–Si bonds were constructed by utilizing copper hydride-catalyzed asymmetric hydrosilylation of 1,2-dihydroquinolines, affording various chiral 4-silyl-1,2,3,4-tetrahydroquinolines in good yields and enantioselectivity. In addition, the C–Si bonds were transformed into C–O bonds with retention of stereochemistry through the Tamao oxidation, giving a series of useful 4-hydroxy-1,2,3,4-tetrahydroquinolines. This method with the enantioselective introduction of silyl groups provides an option to adjust bioactive properties of tetrahydroquinolines.

Post-functionalization of dibenzothiophene to functionalized biphenyls via a photoinduced thia-Baeyer-Villiger oxidation

The Baeyer-Villiger reaction is used extensively in organic chemistry. Sila- and bora-variants have also been documented widely, with these processes underpinning, for example, the Fleming-Tamao oxidation and hydroborative alkene hydration, respectively. By contrast, the development of thia-Baeyer-Villiger reactions involving sulfoxides has long been considered unlikely because competitive oxidation to the sulfone occurs exclusively. Here, we disclose a photoinduced thia-Baeyer-Villiger-type oxidations; specifically, we find that exposure of dibenzothiophene (DBT) derivatives to an iron porphyrin catalyst under Ultraviolet irradiation in the presence of t-BuOOH generates sulfinic esters in up to 87% yield. The produced sulfinic esters are transformed to a variety of biphenyl substrates including biphenyl sulfoxides, sulfones and sulfonamides in 1-2 steps. These results provide a mild process for the selective functionalization of sulfur compounds, and offer a biomimetic approach to convert DBT into 2-hydroxybiphenyl under controllable stepwise pathway. Based upon experimental evidences and DFT calculation, a mechanism is proposed.

Catalytic Asymmetric Synthesis of Cyclopentene-spirooxindoles Bearing Vinylsilanes Capable of Further Transformations.

We report a scandium-catalyzed [3 + 2] annulation of alkylideneoxindoles with allenylsilanes for the enantioselective formation of cyclopentene-spirooxindoles containing vinylsilanes. Using a Sc(OTf)2/PyBOX/BArF complex, the spiroannulation of allenylsilanes affords products with >94:6 dr and >90:10 er. The effect of the counterion and ligand to control selectivity is discussed. The transformation of the vinylsilane is demonstrated using cross-coupling, epoxidation, and Tamao-Fleming oxidation reactions. A series of competition experiments provide a comparison of nucleophilicity between allyl- and allenylsilanes.

Diastereoselective Methylation at the Congested β-Position of a Butenolide Ring: Studies toward the Synthesis of seco-Prezizaane-Type Sesquiterpenes.

We established a method for installing a methyl group at the β-position of a butenolide ring. The methylated position is located at the congested ring juncture of a 5,6,5-tricyclic lactone, which is common to neurotrophic seco-prezizaane-type sesquiterpenes. The samarium(II)-mediated conjugate addition of the halomethylsilyl ethers tethered to the proximal hydroxy groups efficiently formed the desired C-C bond. Subsequent fluoride-free Tamao oxidation and Barton-McCombie deoxygenation converted the resultant cyclic silyl ether into the corresponding methyl group.

β-Ketoesters as Mono- or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (-)-Englerin A and B.

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring-group-participating [4+3] cycloaddition, a novel one-pot Heck coupling/regioselective 1,4-hydrosilylation/Tamao-Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (-)-englerin B.

Ag(I)-Fesulphos-Catalyzed Enantioselective Synthesis of 3-Silylproline Derivatives.

An efficient catalytic asymmetric 1,3-dipolar cycloaddition of N-benzylidineiminoglycinate-derived azomethine ylides to β-silylmethylene malonates catalyzed by a Ag(I)-Fesulphos complex has been developed, affording fully substituted 3-silylproline derivatives with an all carbon quaternary center. The silylproline derivatives were obtained in moderate-to-good yields (up to 81%) in high diastereoselectivities and enantioselectivities (dr up to 95:5; er up to 96:4). Tamao-Fleming oxidation of selected 3-silylproline derivatives provided not only an efficient route but also the shortest route to 3-hydroxyproline derivatives, which are not accessible by direct 1,3-dipolar cycloadditions of azomethine ylide with frequently used arylidene/alkylidene malonates.

Iridium-Catalyzed, β-Selective C(sp3)-H Silylation of Aliphatic Amines To Form Silapyrrolidines and 1,2-Amino Alcohols.

The functionalization of unactivated C(sp3)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp3)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.

Ti(III)-Mediated Radical-Induced Approach to a Bicyclic δ-Lactone with a Bridgehead β-Hydroxy Group

Herein, we portray a synthetic route to a bicyclic lactone containing a bridgehead hydroxy group, a structure that is present in many natural products of biological and medicinal relevance. Ethyl (E)-3-(dimethylphenylsilyl)-7,8-epoxyoct-2-enoate underwent radical-mediated­ reductive epoxide opening with concomitant intramolecular cyclization using Cp2Ti(III)Cl to give cis-6-(dimethylphenylsilyl)-3-oxabicyclo[4.3.0]nonan-4-one, a bicyclic lactone with a bridgehead silyl group serving as a masked hydroxy group. Furthermore, the bridgehead C–Si bond underwent stereoretentive oxidative cleavage to give cis-6-hydroxy-3-oxabicyclo[4.3.0]nonan-4-one in high yield under Tamao–Fleming oxidation conditions; this demonstrates the potential utility of this strategy in the synthesis of many natural products bearing similar hydroxylated bridgehead chiral center embedded in a bicyclic lactone framework.

Directed C–H Bond Oxidation of (+)-Pleuromutilin

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C-H silylation, followed by Tamao-Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure-activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C-H silylation reaction.

Traceless Silylation of β-C(sp3)-H Bonds of Alcohols via Perfluorinated Acetals.

We report the silylation of primary C-H bonds located β to secondary and tertiary alcohols by exploiting perfluorinated esters as traceless directing groups. The conversion of a secondary or tertiary alcohol to a perfluoroalkyl ester and conversion of the ester to the corresponding silyl acetals by hydrosilylation allows for selective β-C(sp3)-H silylation catalyzed by the combination of [Ir(cod)OMe]2 and Me4Phen (3,4,7,8-tetramethyl-1,10-phenanthroline) to form 6-membered dioxasilinane. Tamao-Fleming oxidation of these dioxasilinane leads to 1,2 diols. The developed sequence was applied to a series of natural products containing hydroxyl groups.

A Tamao–Fleming oxidation route to dipeptides bearing N,O-acetal functionality

Tamao–Fleming oxidation of the N-dimethylphenylsilylmethyl group linked to the nitrogen of a peptide bond enables access to dipeptide N,O-acetal functionality. The N-silylmethyl functionality serves as a latent form of the N,O-acetal which is revealed after peptide bond construction.

Synthesis of an advanced intermediate enroute to (−)-clavosolide A

Abstract A stereoselective route to an advanced intermediate toward the synthesis of clavosolide A is disclosed. The key steps include Wadsworth-Emmons cyclopropanation, utilization of a sulfinyl moiety as an internal nucleophile to open a cyclopropane ring activated by Hg(II)- to create the C3-C5 stereogenic centers, C C bond formation employing an α-chloro sulfide, asymmetric transfer hydrogenation, regioselective hydrosilylation and Tamao-Fleming oxidation.

Doubly N-Fused [24]Pentaphyrin Silicon Complex and Its Fluorosilicate: Enhanced Möbius Aromaticity in the Fluorosilicate.

Treatment of nonaromatic N-fused [24]pentaphyrin with trichloromethylsilane in the presence of a base afforded doubly N-fused [24]pentaphyrin and its silicon complex. Addition of fluoride ion to the silicon complex led to the formation of its fluorosilicate as an unprecedented monoanionic six-coordinated SiIV complex of porphyrinoid. Treatment of the fluorosilicate with acid led to the recovery of the silicon complex. The doubly N-fused pentaphyrin, the silicon complex, and the fluorosilicate were all characterized as distinct Möbius aromatic molecules by spectroscopic measurements and X-ray crystallographic analyses. Importantly, the second N-fusion reaction, Si-incorporation and fluoride addition to the Si-atom enhanced the aromaticity of doubly N-fused [24]pentaphyrins in this order. Tamao-Fleming oxidation of the silicon complex gave β-keto doubly N-fused pentaphyrin and triply fused [24]pentaphyrin, which were nonaromatic and Hückel anti-aromatic, respectively.

Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer.

Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao-Fleming oxidation of vinylsilanes and the Arndt-Eistert homologation.