Barton Deoxygenation Research Articles

Bioinspired synthesis of cucurbalsaminones B and C.

Cucurbalsaminones B (1) and C (2) are two abeo-cucurbitane triterpenoids with a unique 5/6/3/6/5-fused ring system and exhibited potent multidrug resistance (MDR)-reversing activity. Herein, we report the first synthesis of these two natural products, both of them were accomplished in 14 steps from commercially available inexpensive resource compound lanosterol. Key features of this synthesis include a biomimetic tandem Wagner-Meerwein type lanostane-to-cucurbitane rearrangement followed by a bioinspired photochemical oxa-di-π-methane (ODPM) rearrangement to complete the skeleton construction and an Eosin Y photoinduced Barton-McCombie deoxygenation to realize the challenging oxidation state adjustment of the sterically hindered C11 position.

Synthesis of Deoxy Pyranosides Via Fe(III) Catalyzed Regioselective Thiocarbonylation of Partially Protected Carbohydrates

AbstractRapid and efficient synthesis of targeted deoxygenated glycosides is highly desired. Herein, we disclose a two‐step procedure for the synthesis of deoxysugars from partially protected pyranosides via site‐selective thiocarbonylation followed by tin‐free Barton–McCombie deoxygenation. The selectivity can be smoothly achieved through anhydrous FeCl3 as the catalyst assisted by low‐priced benzoyltrifluoroacetonate (Hbtfa) ligand in the presence of K2CO3 as base. Further deoxygenation can be carried out using greener silicon reagent, avoiding highly toxic organotin reagents in traditional procedures. Conspicuous features of this method include mild conditions, easy operation, high selectivity and non or low toxic reagents, making it a more attractive strategy.

Redox-Active Thiocarbonyl Auxiliaries in Ni-Catalyzed Cross-Couplings of Aliphatic Alcohols.

ConspectusThe Barton-McCombie deoxygenation reaction first established the use of O-alkyl thiocarbonyl derivatives as powerful redox-active agents for C(sp3)-O reduction. In recent years, first-row transition metals capable of engaging with alkyl radical intermediates generated from O-alkyl thiocarbonyl derivatives using alternative stoichiometric radical precursors have been developed. Given the ability of select Ni catalysts to both participate in single-electron oxidative addition pathways and intercept alkyl radical intermediates, our group has investigated the use of O-alkyl thiocarbonyl derivatives as electrophiles in novel cross-coupling reactions. After describing related work in this area, this Account will first summarize our entry point into this field. Here, we used the cyclopropane ring as a reporter of leaving group reactivity to aid in the design and optimization of a novel redox-active O-thiocarbamate leaving group for C(sp3)-O arylation. Motivation for this pursuit was driven by the propensity of the cyclopropane ring to undergo ring opening under polar (2e) oxidative addition pathways or to be maintained under single-electron (1e) conditions. Using these guiding principles, we developed a method for the deoxygenative arylation of cyclopropanol derivatives using a Ni catalyst without the need for a stoichiometric external reductant or photocatalyst. We next summarize our evaluation of an alternative redox-active O-thiocarbonyl imidazole auxiliary in a related deoxygenative cross-coupling. This work demonstrated an extension of our initial approach to the deoxygenative arylation of primary and secondary aliphatic alcohol derivatives. A brief mechanistic investigation revealed that this reaction likely proceeds via a distinct mechanism involving direct homolytic C(sp3)-O bond cleavage. We conclude this Account with a summary of work aimed toward a unique approach for thiocarboxylic acid derivative synthesis. This project was inspired by the efficiency of thionoester generation under most of the reaction conditions evaluated in our prior investigations. Using alcohol, amine, or thiol starting materials, which were activated with convenient thiocarbonyl sources in a single step, we optimized for a Ni-catalyzed cross-coupling capable of providing access to a range of thionoester, thioamide, or dithioester products. In summary, our work has revealed the potential of redox-active thiocarbonyl auxiliaries in Ni-catalyzed cross-couplings with C(sp3)-O electrophiles. We anticipate that the continued investigation of aliphatic thiocarbonyl derivatives as radical precursors with alternative single-electron inputs will be an area of continued growth in the years to come.

Efficient Synthesis of the Key Intermediate of Scopolamine by [4+3] Cycloaddition Reaction

Abstract: Scopolamine, as an anticholinergic agent, plays a regulatory role in the peripheral nervous system. In this paper, 6,7-dehydrotropinone, which is the key intermediate of scopolamine, is synthesized in moderate yield through [4+3] cyclization reaction and Barton deoxygenation reaction. This route has good application prospects with mild reaction conditions, moderate yield, and simple operating procedures.

Study of the β-oxygen effect in the Barton–McCombie reaction for the total synthesis of (4R,5R)-4-hydroxy-γ-decalactone (Japanese orange fly lactone): a carbohydrate based approach

Efficient and facile synthesis of Japanese orange fly lactone (1) was achieved from a commercially available d-glucose by investigating the Barton–McCombie reaction with furanose anomeric isomers (12α, β) with an overall yield of 12.6%. During the course of this synthesis, the β-oxygen effect was discovered in the deoxygenation step at the C-3 position using the Barton–McCombie reaction, where the substrate allows the effect to operate in one of the isomers but not in the other. Under the same reaction conditions, xanthate derived from the β-furanose isomer affords a high yield of deoxygenated product, whereas the α-isomer produces a very low yield. The key transformations used were Wittig olefination, TEMPO mediated oxidation, and Barton–McCombie deoxygenation, resulting in a concise total synthesis of Japanese orange fly lactone (1). Our success will allow for further biological studies of this natural product, as well as opportunities for developing new potentially promising pheromones.

Synthesis of (+)-Davisinol

Key words (+)-davisinol - kinetic resolution - oxidative dearomatization - Diels–Alder cycloaddition - HAT cyclization - Barton–McCombie deoxygenation

Asymmetric Total Synthesis of Phomarol

Asymmetric Total Synthesis of Phomarol

Synthesis, antibacterial action, and ribosome inhibition of deoxyspectinomycins

Spectinomycin, an aminocyclitol antibiotic, is subject to inactivation by aminoglycoside modifying enzymes (AMEs) through adenylylation or phosphorylation of the 6-hydroxy group position. In this study, the effects of deoxygenation of the 2- and 6-hydroxy group positions on the spectinomycin actinamine ring are probed to evaluate their relationship to ribosomal binding and the antimicrobial activities of spectinomycin, semisynthetic aminomethyl spectinomycins (amSPCs), and spectinamides. To generate these analogs, an improved synthesis of 6-deoxyspectinomycin was developed using the Barton deoxygenation reaction. 6-Dehydrospectinamide was also synthesized from spectinamide 4 to evaluate the H-bond acceptor character on the C-6 position. All the synthesized analogs were tested for antibacterial activity against a panel of Gram (+) and Gram (−) pathogens, plus Mycobacterium tuberculosis. The molecular contribution of the 2- and 6-hydroxy group and the aryl functionalities of all analogs were examined by measuring inhibition of ribosomal translation and molecular dynamics experiments with MM/GBSA analysis. The results of this work indicate that the 6-hydroxy group, which is the primary target of AMEs, is a required motif for antimicrobial activity in current analogs. Removal of the 6-hydroxy group could be partially rescued by offsetting ribosomal binding contributions made by the aryl side chains found in the spectinamide and amSPCs. This study builds on the knowledge of the structure–activity relationships of spectinomycin analogs and is being used to aid the design of next-generation spectinomycins.

Interrupting the Barton-McCombie Reaction: Aqueous Deoxygenative Trifluoromethylation of O-Alkyl Thiocarbonates.

The site-selective trifluoromethylation of aliphatic systems remains an important challenge. This work describes a light-driven, copper-mediated trifluoromethylation of O-alkyl thiocarbonates. The reaction provides broad functional group tolerance (e.g., alkyne, alkene, phenol, free alcohol, electron-rich and -deficient arenes), thereby offering orthogonality and practicality for trifluoromethylation. A radical organometallic mechanism is proposed.

Light-Driven Metal-Free Direct Deoxygenation of Alcohols under Mild Conditions.

SummaryHydroxyl is widely found in organic molecules as functional group and its deprivation plays an inevitable role in organic synthesis. However, the direct cleavage of Csp3-O bond in alcohols with high selectivity and efficiency, especially without the assistance of metal catalyst, has been a formidable challenge because of its strong bond dissociation energy and unfavorable thermodynamics. Herein, an efficient metal-free strategy that enables direct deoxygenation of alcohols has been developed for the first time, with hydrazine as the reductant induced by light. This protocol features mild reaction conditions, excellent functional group tolerance, and abundant and easily available starting materials, rendering selective deoxygenation of a variety of 1° and 2° alcohols, vicinal diols, and β-1 and even β-O-4 models of natural wood lignin. This strategy is also highlighted by its “traceless” and non-toxic by-products N2 and H2, as readily escapable gases. Mechanistic studies demonstrated dimethyl sulfide being a key intermediate in this transformation.

Red-Light-Mediated Barton–McCombie Reaction

Abstract A red-light-mediated Barton–McCombie reaction is described, in which chlorophyll a is used as a photocatalyst and tris(trimethylsilyl)silane or Hantzsch ester is used as the hydrogen source. The reaction can be performed with a set of easily available equipment and reagents, and a variety of linear and cyclic xanthates could be applied. In contrast to the traditional conditions, the reaction does not involve toxic organotin or an explosive radical initiator. The reaction mechanism was analyzed both by experiments and computation, and it was suggested that the radical chain mechanism initiated by excitation of complex followed by charge transfer is likely to be operative.

Indirect synthetic route to α-l-fucosides via highly stereoselective construction of α-l-galactosides followed by C6-deoxygenation.

We developed an indirect synthetic method for α-l-fucosides. Based on the fact that l-fucose is 6-deoxy-l-galactose, our strategy consists of the stereoselective construction of α-l-galactoside and its conversion to α-l-fucoside via C6-deoxygenation. The formation of α-l-galactoside is strongly directed using 4,6-O-di-tert-butylsilylene(DTBS)-protected l-galactosyl donors. The DTBS-directed α-l-galactosylation showed broad substrate applicability along with excellent coupling yield and α-selectivity. In the C6-deoxygenation of α-l-galactosides, the Barton-McCombie reaction facilitated the conversion to l-fucosides with good yield. To demonstrate the applicability of our method, we synthesized naturally occurring α-l-fucosides.

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.

Metal‐Free Deoxygenation of α‐Hydroxy Carbonyl Compounds and Beyond

Efficient deoxygenation methods are needed now more than ever in the chemist's toolbox to convert biomass‐derived molecules such as carbohydrates into useful chemicals. Late‐stage deoxygenation of drug candidates constitutes also an interesting option to fine tune their drug‐like properties. Metal‐based processes, as exemplified by the Barton–McCombie reaction, have long dominated the field. The development of metal‐free alcohol deoxygenation reactions represents however a challenge that has to be tackled to circumvent drawbacks associated with metal‐based reagents including cost and toxicity. Deoxygenation of alcohols may be assisted by the presence in α‐position of an electron‐withdrawing group. This review provides an overview of metal‐free methods that have been developed in the past decades for the direct, one‐step deoxygenation of α‐hydroxyl carbonyl compounds.

A Facile Synthesis of 2‐Methyl‐3‐oxoindoline‐2‐carboxylates Utilizing Aza‐Brook Rearrangement as a Crucial Step

Synthesis of 2‐methyl‐3‐oxoindoline‐2‐carboxylates is developed using a bis(trimethylsilyl)aluminum chloride‐induced aza‐Brook rearrangement as a crucial step. Regarding the organoaluminum species, use of readily available tris(trimethylsilyl)aluminum·ether complex was not suitable for the present cyclization. After a series of examination of the reaction conditions, the aza‐Brook rearrangement and the subsequent cyclization with 2 equivalens of bis(trimethylsilyl)aluminum chloride were found to be the most effective. An application to the synthesis of a potential intermediate of duocarmycin A is also described, in which ozonolysis of the styrenyl moiety and the Barton–McCombie deoxygenation of the hydroxymethyl group were successfully carried out.

Radical-Driven Deoxygenation of Secondary Alcohols: The Barton–McCombie Reaction

Radical-Driven Deoxygenation of Secondary Alcohols: The Barton–McCombie Reaction

Blue light photoredox decarboxylation and tin-free Barton-McCombie reactions in the stereoselective synthesis of (+)-muscarine

Starting from a 1,2-O-isopropylidene-α-d-xylofuranose derivative, a non-toxic free-radical approach for the synthesis of (+)-muscarine is reported. To this end, a stereoselective allylation reaction at the anomeric position of a respective xylofuranose derivative was employed as a new synthetic strategy for the installation of the methyl group at the C-5 position of (+)-muscarine. Accordingly, the allyl group was transformed into the methyl group in three sequential steps highlighting a blue-light photoredox decarboxylation reaction. Additionally, a tin-free Barton-McCombie deoxygenation reaction of the respective C-methyl glycoside allowed the completion of this free-radical approach to (+)-muscarine.

Novel Position-Specific 18O/16O Measurement of Carbohydrates. I. O-3 of Glucose and Confirmation of 18O/16O Heterogeneity at Natural Abundance Levels in Glucose from Starch in a C4 Plant.

The 18O/16O ratio at both molecular and positional levels in the carbohydrates of higher plants is a reliable proxy for the plant growth environment, and a potential indicator of the plant photosynthetic carbon assimilation mode, and its physiological, biochemical and metabolic status. The lack of exploitable nuclear resonance in 18O and 16O and the extremely low 17O abundance make the NMR-based PSIA (position-specific isotopic analysis) a significant challenge. In this Article, an alternative three-step wet chemistry based method for accessing the 18O/16O of glucose O-3 is presented. The O atoms (OH groups) at positions 1, 2, 5, and 6 were first protected by acetonation (converting glucose to 1,2;5,6-di- O-isopropylidene-glucofuranose). The protected glucose was then esterified at O-3 by thionoformylation. Subsequent Barton-McCombie deoxygenation quantitatively removed the O-3 from the protected sugar. Mass balance was then applied to calculate the 18O/16O of O-3 using the isotopic values of the protected sugar before and after the deoxygenation step. The method is innovative in that (i) isolation and purification of individual compounds for 18O by EA/Pyrolysis/IRMS analysis is unnecessary as the reaction mixture can be analyzed on a GC/Pyrolysis/IRMS; (ii) sample quantity is dramatically reduced; and (iii) the approach to access the O-3 isotopic signal can be easily expanded to other positions within glucose and other sugars. It was shown that O-3 is enriched by 12 mUr relative to the molecular average (O-2-O-6) for a glucose of C4 photosynthetic origin. We highlighted the potential applications of the intramolecular O isotopic heterogeneity of glucose this method revealed.

Stereoselective synthesis of C12–C21 common fragment of thermolides 1–5

A highly stereoselective synthesis of C12–C21 common fragment of thermolides 1–5 has been described. The salient features of the synthesis are the utilization of desymmetrization protocol, Barton-McCombie reaction, Brown’s asymmetric allylation and Wacker oxidation.

Expanding the scope of methyl xanthate esters - From Barton-McCombie reaction auxiliary to versatile protective group

The methyl xanthate ester is presented as a versatile protective group for alcohols. Hydroxyl groups can easily be transformed into methyl xanthate esters by several methods and are commonly used as an auxiliary in the Barton-McCombie reaction. We show that these methyl xanthate esters can readily and chemoselectively be cleaved under mild conditions by the action of diethylenetriamine using microwave heating. This method is orthogonal to many common hydroxyl protective groups that can be introduced and cleaved in the presence of methyl xanthate ester.