Radical Debromination Research Articles

Synthesis of 22- and 23-dehydroxybrassinosteroids of the stigmastane series

The synthesis of previously undescribed 22- and 23-deoxyanalogues of homocastasterone has been carried out, which makes it possible to obtain target compounds without replacing the carbon skeleton of the side chain. The key reactions in their synthesis were epoxy ring opening and radical debromination.

Asymmetric Mannich/Radical Debromination Cascade of α‐Bromoketones by Dipeptide‐Phosphonium Salt Catalysis: Enantioselective Synthesis of β‐Amino Ketone‐Pyrazolinones

AbstractWe herein demonstrated an organocatalytic asymmetric Mannich/radical debromination cascade of α‐brominated ketones. With this protocol, a diversity of chiral β‐amino ketone‐pyrazolinone scaffolds, which have important versatilities in medicine and chemical synthesis, were constructed in high yields (up to 94%) with excellent enantioselectivities (up to 99% ee). This methodology features mild reaction conditions, broad substrate scope, and high functional group tolerance. Moreover, mechanistic investigations revealed that this cascade reaction proceeds through a bifunctional phosphonium salt‐catalyzed Mannich reaction of α‐brominated ketones with pyrazolinone ketimines, which is followed by an oxygen‐induced radical debromination. This protocol represents a novel activation mode for α‐brominated ketones and opens new avenues for catalytic enantioselective radical reactions under ion‐pair system.

Enantioselective Total Synthesis of (−)‐Hosieine A

AbstractThe first total synthesis of (−)‐hosieine A was accomplished and features an unprecedented nitroso–ene cyclization to construct the 2‐azabicyclo[3.2.1]octane ring system. Phosphine‐enabled stereoselective bromohydrination provided interesting mechanistic insights into the anti‐Markovnikov process. Also noteworthy is the retention of stereochemistry at C9 in the facile radical debromination initiated by Et3B/air.

Enantioselective Total Synthesis of (-)-Hosieine A.

The first total synthesis of (-)-hosieine A was accomplished and features an unprecedented nitroso-ene cyclization to construct the 2-azabicyclo[3.2.1]octane ring system. Phosphine-enabled stereoselective bromohydrination provided interesting mechanistic insights into the anti-Markovnikov process. Also noteworthy is the retention of stereochemistry at C9 in the facile radical debromination initiated by Et3 B/air.

Stereoselective synthesis of the C13-C22 fragment of callystatin A by a non-aldol approach.

An efficient synthetic route to the C13-C22 subunit of callystatin A is reported. The key features include diastereoselective alkylation, using Myers auxiliary, for the preparation of the three carbon synthon 7, stereo- and regioselective oxidative vicinal functionalization of an electron deficient trisubstituted (Z)-olefin using an intramolecular sulfinyl group as the nucleophile, diastereoselective radical debromination of a bromohydrin derivative using Guindon's protocol to prepare the C16-C18 anti-anti stereotriad, Lewis acid promoted crotylation following Keck's protocol to create C19, C20 stereocenters and the use of the Pummerer reaction to reveal an aldehyde for the extension of two carbons by Wittig olefination.

ChemInform Abstract: An Efficient Method for the Synthesis of Enantiopure 2,3-anti-Propionate Aldols Involving a 3,5-syn- or anti-Diol Subunit Through Chiral Borane-Mediated Enantioselective Aldol Reaction Coupled with Radical Reduction.

Abstract 2,3- anti -Propionate aldols involving a 3,5- syn- or anti -diol subunit, versatile enantiopure segments available for macrolide synthesis, were prepared by a chiral oxazaborolidinone-promoted asymmetric aldol reaction with 2-bromo-1-ethoxy-2-methyl-1-trimethylsiloxyethene and the following highly anti -preferential radical debromination.

Chemoenzymatic Synthesis and Biological Evaluation of (−)‐Conduramine C‐4

Previously unreported (−)‐conduramine C‐4 was synthesized in six steps from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic route involved toluene dioxygenase dihydroxylation, β‐epoxidation, epoxide ring‐opening, Staudinger reduction, radical debromination, and Amberlite‐ catalyzed hydrolysis. (−)‐Conduramine C‐4 and other related compounds synthesised were assayed for galactosidase‐activity inhibition against β‐D‐galactoside galactohidrolase isolated from Aspergillus oryzae.

A New Efficient Stereoselective Debromination Reaction with Trialkylgermanium Hydrides Useful in the Design of Short Synthetic Routes to β-Lactamase Inhibitor Prodrugs

Prodrugs derived from the β-lactamase inhibitor 6-β-hydroxymethylsulbactam can be synthesized efficiently in a three-step process by making use of the highly stereoselective radical debromination utilizing tri-n-butylgermanium hydride. This reagent is capable of abstracting bromine from the C-6 position of pairs of epimers 6-hydroxymethyl-6-bromo-penicillate-1,1-dioxide esters and functionalized esters suitable for prodrug use in high yields. The bromine abstraction usually results in favoured formation of the 6-β-hydroxymethyl epimer relative to the 6-α-hydroxymethyl epimer in ratios that exceed 97:3. Reaction of pure 6-α-hydroxymethyl-6-β-bromo-penicillate-1,1-dioxide ester results in almost exclusive formation of 6-β-hydroxymethylsulbactam ester. This methodology conserves the C−C bond formation at C-6 by making use of both epimers resulting from formylation, which is difficult and nonstereoselective in the β-hydroxymethylsulbactam prodrug synthesis.

Concise chemoenzymatic synthesis of epi-inositol

epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoenzymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical debromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol, and deoxy derivatives of epi-inositol.

An experimental investigation of tetrabromobisphenol A decomposition pathways

The primary thermal decomposition pathways of tetrabromobisphenol A (TBBA), a widely used brominated flame retardant, were investigated. TBBA decomposition was carried out in a laboratory-scale fixed bed reactor in both constant heating rate (10 °C/min, 30–600 °C) and isothermal (210–270 °C) modes. Quantitative data were obtained on the products formed in the thermal degradation process. TBBA decomposition resulted in a competitive process with evaporation, at least in the open system conditions used. Hydrogen bromide, brominated bisphenol A species, brominated phenols and char were the main products generated in the decomposition process. On the basis of the products formed, the decomposition pathways were analysed. Radical debromination reactions and scission reactions to phenols resulted the most important thermal degradation mechanisms of TBBA.

5-enolpyruvylshikimate 3-phosphate synthase: chemical synthesis of the tetrahedral intermediate and assignment of the stereochemical course of the enzymatic reaction.

A chemical synthesis of both diastereomers of the tetrahedral intermediate involved in 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) catalysis has been accomplished. Combination of methyl dibromopyruvate with a protected shikimic acid derivative, phosphorylation, and lactonization afforded the intermediates (S)-15 and (R)-15, whose configurations were assigned by NMR. After introduction of the 3-phosphate group and deprotection, photoinitiated radical debromination of the dibromo analogues (S)-5 and (R)-5 was accomplished with tributyltin hydride in mixed aqueous solvents in the presence of surfactant to give the pyruvate ketal phosphates (R)-TI and (S)-TI, respectively. These compounds are stable at high pH, but decompose at pH 7 with a half-life of ca. 10 min. (R)-TI proved to be inert to EPSPS, while (S)-TI was converted by the enzyme to a mixture of 5-enolpyruvylshikimate 3-phosphate, shikimate 3-phosphate, and phosphoenolpyruvate. The demonstration that the enzymatic intermediate possesses the S-configuration at the ketal center confirms the mechanism as an anti addition followed by a syn elimination. Furthermore, it appears that the syn stereochemistry of the second step requires the phosphate leaving group to serve as the base in catalyzing its own elimination.

Diastereoselective radical debromination approach toward divergent syntheses of syn- and anti-propionate units, coupled with enantioselective and/or diastereoselective Lewis acid-promoted aldol reactions

A practical methodology directed to the enantioselective synthesis of polypropionate backbones, available for the synthesis of polyketide natural products, has been developed by iterative enantio- and diastereoselective Lewis acid-promoted aldol reactions, followed by diastereoselective radical debromination reactions. A chiral oxazaborolidinone-promoted aldol reaction of a racemic aldehyde, derived from 2-methyl-1,3-propanediol, with a silylketene acetal from ethyl 2-bromopropionate, resulted in highly enantioselective formation of the corresponding bromo aldol adduct, followed by radical debromination with Bu 3SnH in the presence of Et 3B to divergently give syn- and anti-propionate aldols, which are versatile stereotriads. Furthermore, elongation of the propionate units has also been achieved: the BF 3·OEt 2-promoted aldol reaction of chiral syn- and anti-α-methyl-β-protected-oxy aldehydes with the silyl nucleophile proceeded with essentially complete syn-selectivity while the TiCl 4-promoted aldol reaction resulted in fairly good anti-selectivity. The resulting bromo aldol adducts were divergently debrominated by the radical reduction to give a complete set of stereotetrads.

Detoxification of brominated pyrolysis oils

The development of an innovative technology for the pyrolytic conversion of brominated phenols in a reductive medium aimed at product recovery for commercial use is discussed in this paper. Brominated phenols are toxic products, which contaminate pyrolysis oil of wastes from electronic and electrical equipment (WEEE). The pyrolysis experiments were carried out with 2,6-dibromophenol, tetrabromobisphenol A, WEEE pyrolysis oil and polypropylene or polyethylene in encapsulated ampoules under inert atmosphere in quasi-isothermal conditions (300–400 °C) with a different residence time (10–30 min). Optimal conditions were found to be the use of polypropylene at 350 °C with a residence time of 20 min. The main pyrolysis products were identified as HBr and phenol. A radical debromination mechanism for the pyrolytic destruction of brominated phenols is suggested.

The total synthesis of (−)-tetrahydrolipstatin

Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (−)-tetrahydrolipstatin.

The Total Synthesis of ( - )-Tetrahydrolipstatin

Careful control during the bromolactonization of β,γ;-unsaturated acid (4) was required to regioselectively afford the trans-β-lactone (3) as the major diastereomer. Radical debromination of (3) followed by a three-step sequence of reactions afforded the lipase inhibitor (–)-tetrahydrolipstatin (1).

A straightforward strategy toward the construction of polypropionate frameworks, based on a sequence of diastereoselective Lewis acid-mediated aldol reaction and diastereoselective radical debromination reaction

An approach joining highly diastereoselective Mukaiyama aldol reaction (process A ) to the following radical debromination reaction (process B ) provides a reliable way to the stereoselective divergent synthesis of polypropionate frameworks. A practical and reliable synthesis of the complete set of propionate stereotetrads from enantiopure syn- and anti-2-methyl-3-methoxy-3-phenylpropanals was achieved by using the straightforward strategy.

ChemInform Abstract: Versatile, High 2,4‐syn Dialkyl Diastereoselection in the Radical Debromination of α‐Bromo‐α‐methyl‐δ‐valerolactones with Tri‐n‐butyltin Hydride and a Catalytic Amount of Triethylborane.

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Versatile, high 2,4-syn dialkyl diastereoselection in the radical debromination of α-bromo-α-methyl-δ-valerolactones with tri-n-butyltin hydride and a catalytic amount of triethylborane

An interesting 2,4-syn dialkyl diastereoselection has been observed in the radical debromination of α-bromo-α-methyl-δ-valerolactones. The reaction of 4-alkyl-2-bromo-3-hydroxy-2-methyl-5-pentanolides with Bu3SnH and a catalytic amount of Et3B gave, essentially, a single diastereomer with a 2,4-syn dialkyl relationship, independent of the orientation of the hydroxy substituent at C-3.

A Divergent Synthesis of Essentially Enantiopure syn- and anti-Propionate Aldol Adducts Based on the Chiral 1,3,2-Oxazaborolidin-5-one-Promoted Asymmetric Aldol Reaction Followed by Diastereoselective Radical Reduction

Abstract Essentially, enantiopure syn- and anti-propionate aldol adducts were divergently synthesized using a novel strategy which utilizes both the highly enantioselective 1,3,2-oxazaborolidin-5-one-promoted aldol reaction with a ketene silyl acetal derived from ethyl 2-bromo propionate and a highly diastereoselective radical debromination reaction. These procedures provide yields that increase to a level available for practical synthesis.

An efficient method for the synthesis of enantiopure 2,3- anti-propionate aldols involving a 3,5- syn- or anti-diol subunit through chiral borane-mediated enantioselective aldol reaction coupled with radical reduction

2,3- anti-Propionate aldols involving a 3,5- syn- or anti-diol subunit, versatile enantiopure segments available for macrolide synthesis, were prepared by a chiral oxazaborolidinone-promoted asymmetric aldol reaction with 2-bromo-1-ethoxy-2-methyl-1-trimethylsiloxyethene and the following highly anti-preferential radical debromination.